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Internal Medicine/Pain

Pain-Sensory System
Pain refers to an uncomfortable sensation localized in a specific part of the body. It is frequently described in terms of a penetrating or tissue-damaging process (e.g., stabbing, burning, twisting, tearing, squeezing) and/or a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Additionally, pain of moderate or higher intensity is accompanied by anxiety and a desire to escape or terminate the sensation. These properties demonstrate that pain has a dual nature: it encompasses both sensation and emotion. In its acute form, pain is typically linked to increased alertness and a stress response, which includes elevated blood pressure, heart rate, pupil dilation, and plasma cortisol levels. Moreover, local muscle contractions (e.g., limb flexion, abdominal wall rigidity) are often observed.

Peripheral mechanism
A peripheral nerve consists of axons from three different types of neurons: primary sensory afferents, motor neurons, and sympathetic postganglionic neurons. Primary sensory afferents have their cell bodies located in the dorsal root ganglia within the vertebral foramina. These afferents have two branches, one projecting into the spinal cord and the other extending to innervate peripheral tissues. They are categorized based on their diameter, degree of myelination, and conduction speed. The largest-diameter afferent fibers, known as A-beta (Aβ), are most sensitive to light touch or moving stimuli and are primarily found in skin-innervating nerves. In normal circumstances, the activity of these fibers does not induce pain.

There are two other types of primary afferent nerve fibers: small-diameter myelinated A-delta (Aδ) and unmyelinated (C) axons. These fibers are present in nerves supplying the skin as well as deep somatic and visceral structures. Most Aδ and C fiber afferents respond intensely to noxious (painful) stimuli, causing the subjective experience of pain when activated. This identifies them as primary afferent nociceptors or pain receptors. Blocking conduction in Aδ and C fiber axons completely eliminates the ability to detect painful stimuli.

Individual primary afferent nociceptors can respond to various types of noxious stimuli, including heat, intense cold, intense mechanical distortion (e.g., pinching), changes in pH (especially acidity), and the application of chemical irritants like adenosine triphosphate (ATP), serotonin, bradykinin (BK), and histamine. The transient receptor potential cation channel subfamily V member 1 (TrpV1), also known as the vanilloid receptor, plays a role in detecting certain noxious stimuli, especially heat sensations, and is activated by heat, acidic pH, endogenous mediators, and capsaicin (a component of hot chili peppers).

When intense, repetitive, or prolonged stimuli are applied to damaged or inflamed tissues, the threshold for activating primary afferent nociceptors is lowered, and their firing frequency increases for all stimulus intensities. This process, called sensitization, involves inflammatory mediators such as BK, nerve-growth factor, some prostaglandins (PGs), and leukotrienes. Sensitization occurs both at the peripheral nerve terminal (peripheral sensitization) and at the dorsal horn of the spinal cord (central sensitization). Peripheral sensitization takes place in damaged or inflamed tissues, where inflammatory mediators trigger intracellular signal transduction in nociceptors, leading to increased production, transport, and membrane insertion of chemically gated and voltage-gated ion channels. These changes raise the excitability of nociceptor terminals and lower their activation threshold for mechanical, thermal, and chemical stimuli. Central sensitization happens when activity generated by nociceptors during inflammation heightens the excitability of nerve cells in the dorsal horn of the spinal cord. After injury and subsequent sensitization, stimuli that would normally be innocuous can trigger pain, a phenomenon known as allodynia. Sensitization is a significant process contributing to tenderness, soreness, and hyperalgesia (heightened pain intensity in response to the same noxious stimulus, such as a pinprick causing severe pain). An illustrative example of sensitization is sunburned skin, where gentle touch or a warm shower can produce severe pain.

Sensitization holds particular importance in deep tissues. Normally, viscera are relatively insensitive to noxious mechanical and thermal stimuli, although hollow viscera may cause significant discomfort when distended. However, when deep structures, such as joints or hollow viscera, are affected by a disease process with an inflammatory component, they typically become highly sensitive to mechanical stimulation.

In noninjured, noninflamed tissue, a substantial portion of Aδ and C fiber afferents innervating viscera are completely insensitive to known mechanical or thermal stimuli and remain inactive. Yet, in the presence of inflammatory mediators, these afferents become responsive to mechanical stimuli. Such afferents are termed silent nociceptors, and their distinct characteristics help explain how relatively insensitive deep structures can become sources of severe and debilitating pain and tenderness. Low pH, prostaglandins (PGs), leukotrienes, and other inflammatory mediators, such as BK, play a significant role in sensitization.

Primary afferent nociceptors do not merely convey information about tissue injury threats; they also play an active role in tissue protection by serving as neuroeffectors. Most nociceptors contain polypeptide mediators like substance P, calcitonin gene-related peptide (CGRP), and cholecystokinin. When activated, these mediators are released from the nociceptors' peripheral terminals. Substance P, for instance, is an 11-amino-acid peptide released in peripheral tissues by primary afferent nociceptors and possesses various biological functions. It acts as a potent vasodilator, triggers mast cell degranulation, attracts leukocytes, and enhances the production and release of inflammatory mediators. Interestingly, depleting substance P from joints has been shown to reduce the severity of experimental arthritis.

Central Mechanism
Primary afferent nociceptors' axons enter the spinal cord through the dorsal root, terminating in the dorsal horn of the spinal gray matter. These primary afferent axon terminals make contact with spinal neurons responsible for transmitting pain signals to areas in the brain associated with pain perception. When primary afferents are stimulated by noxious stimuli, they release neurotransmitters from their terminals, exciting spinal cord neurons. The primary neurotransmitter released is glutamate, which rapidly stimulates the second-order dorsal horn neurons. Additionally, primary afferent nociceptor terminals release substance P and CGRP, which result in a slower and longer-lasting excitation of the dorsal horn neurons. Each primary afferent's axon connects with numerous spinal neurons, and each spinal neuron receives input from multiple primary afferents. The convergence of sensory inputs onto a single spinal pain-transmission neuron is significant because it gives rise to referred pain. All spinal neurons receiving input from viscera and deep musculoskeletal structures also receive input from the skin.

The convergence patterns are determined by the spinal segment of the dorsal root ganglion that supplies afferent innervation to a structure. For instance, afferents supplying the central diaphragm originate from the third and fourth cervical dorsal root ganglia. These same ganglia's primary afferents supplying the skin of the shoulder and lower neck also come from there. As a result, sensory inputs from both the shoulder skin and the central diaphragm converge onto pain-transmission neurons in the third and fourth cervical spinal segments. Due to this convergence and the fact that spinal neurons are usually activated by skin inputs, the patient often mislocates the pain sensation produced by inputs from deep structures to a bodily area that roughly corresponds to the skin's innervated region from the same spinal segment. Consequently, inflammation near the central diaphragm is frequently reported as shoulder discomfort. This shift of pain sensation from the actual injury site is termed referred pain.

The majority of spinal neurons contacted by primary afferent nociceptors send their axons to the contralateral thalamus. These axons constitute the contralateral spinothalamic tract, which traverses the anterolateral white matter of the spinal cord, the lateral edge of the medulla, and the lateral pons and midbrain. The spinothalamic pathway is essential for pain perception in humans. Disruption of this pathway results in permanent deficits in pain and temperature discrimination.

Spinothalamic tract axons ascend to various thalamic regions. From these thalamic sites, the pain signal diverges significantly to several distinct regions of the cerebral cortex, each serving different aspects of the pain experience. One of these thalamic projections targets the somatosensory cortex, responsible for the sensory discriminative aspects of pain, such as its location, intensity, and quality. Other thalamic neurons project to cortical regions associated with emotional responses, like the cingulate and insular cortex. These pathways to the frontal cortex manage the affective or emotional dimension of pain, which leads to suffering and significantly influences behavior. The emotional dimension of pain induces fear as a constant companion of pain. Consequently, injuries or surgical lesions to frontal cortex areas activated by painful stimuli can reduce the emotional impact of pain while preserving the individual's ability to recognize noxious stimuli as painful.

Pain Modulation
The intensity of pain resulting from injuries of similar magnitude can vary widely across different situations and individuals. For instance, athletes have been known to sustain severe fractures with minimal pain, and Beecher's well-known World War II survey revealed that many soldiers in combat did not seem bothered by injuries that would have caused excruciating pain in civilian patients. Moreover, the mere suggestion that a treatment will alleviate pain can have a significant analgesic effect, known as the placebo effect. Conversely, many patients find even minor injuries like venipuncture terrifying and unbearable, and the expectation of pain can induce pain even without an actual noxious stimulus. The suggestion that pain will worsen after receiving an inactive substance can also amplify its perceived intensity, known as the nocebo effect.

Expectation and other psychological factors have a substantial impact on pain intensity, and this can be explained by brain circuits that modulate pain-transmission pathway activity. One of these circuits has connections to the hypothalamus, midbrain, and medulla, selectively regulating spinal pain-transmission neurons via a descending pathway.

Functional brain imaging studies in humans have implicated this pain-modulating circuit in the pain relief induced by attention, suggestion, and opioid analgesic medications. Additionally, all component structures of this pathway contain opioid receptors and respond to direct application of opioid drugs. In animals, lesions of this descending modulatory system reduce the analgesic effect of systemically administered opioids like morphine. The most consistent way to activate this endogenous opioid-mediated modulatory system is through suggestions of pain relief or strong emotions unrelated to the painful injury, such as during intense threat or athletic competition. Following surgical procedures and administration of a placebo for pain relief, endogenous opioid-mediated pain relief is observed.

Pain-modulating circuits can either amplify or suppress pain. Both pain-inhibiting and pain-facilitating neurons in the medulla project to and regulate spinal pain-transmission neurons. As a result, pain-transmission neurons can be activated by modulatory neurons, potentially generating a pain signal without a peripheral noxious stimulus. Human functional imaging studies have revealed increased activity in this circuit during migraine headaches, suggesting a central circuit that facilitates pain. This concept helps explain how psychological factors can contribute to chronic pain and how pain can be induced or intensified by suggestion or expectation.

Neuropathic pain
Lesions in peripheral or central nociceptive pathways typically result in a loss or impairment of pain sensation. Paradoxically, damage or dysfunction in these pathways can also lead to pain. For instance, damage to peripheral nerves, as seen in diabetic neuropathy, or primary afferents, as in herpes zoster infection, can lead to pain referred to the body region innervated by the affected nerves. Pain can also arise from damage to the central nervous system (CNS), such as after trauma or vascular injury affecting spinal cord, brainstem, or thalamic regions containing central nociceptive pathways. These pains are termed neuropathic and are often severe and resistant to standard pain treatments.

Neuropathic pain typically features a distinct burning, tingling, or electric shock-like quality and may occur spontaneously without any apparent stimulus or be triggered by very light touch. These characteristics are uncommon in other types of pain. On examination, a sensory deficit usually coincides with the area of the patient's pain. Hyperpathia, an exaggerated pain response to non-painful or mild noxious stimuli, especially with repetitive application, is another characteristic of neuropathic pain; patients often complain that even the slightest touch elicits severe pain (referred to as allodynia). Notably, a topical 5% lidocaine patch has proven effective for postherpetic neuralgia patients who experience prominent allodynia.

Various mechanisms contribute to neuropathic pain. Similar to sensitized primary afferent nociceptors, damaged primary afferents, including nociceptors, become highly responsive to mechanical stimulation and may generate impulses even in the absence of stimulation. Increased sensitivity and spontaneous activity are, in part, due to an elevated density of sodium channels in the damaged nerve fibers. Additionally, damaged primary afferents may become sensitive to norepinephrine. Intriguingly, spinal cord pain-transmission neurons disconnected from their normal input may also exhibit spontaneous activity. Therefore, both central and peripheral nervous system hyperactivity contribute to neuropathic pain.

Patients who have sustained peripheral nerve injuries sometimes develop spontaneous pain within or beyond the region innervated by the affected nerve. This pain often presents as a burning sensation. Typically, this pain begins after a delay of hours to weeks and is accompanied by swelling of the affected extremity, periarticular bone loss, and arthritis in the distal joints. Early in the course of this condition, the pain may be alleviated by a local anesthetic block of the sympathetic innervation to the affected extremity. Damaged primary afferent nociceptors acquire sensitivity to adrenergic stimulation and can be triggered by sympathetic outflow. This constellation of spontaneous pain and signs of sympathetic dysfunction following injury is referred to as complex regional pain syndrome (CRPS). When it occurs following a recognizable nerve injury, it is known as CRPS type II (also called posttraumatic neuralgia or causalgia if severe). If a similar clinical presentation occurs without an obvious nerve injury, it is termed CRPS type I (also known as reflex sympathetic dystrophy). CRPS can result from various injuries, including bone fractures, soft tissue trauma, myocardial infarction, and stroke. Typically, CRPS type I resolves with symptomatic treatment, but in cases of persistent pain, detailed examination often reveals evidence of peripheral nerve injury. Although the pathophysiology of CRPS is not well understood, acute pain and signs of inflammation are often rapidly relieved by blocking the sympathetic nervous system. This suggests that sympathetic activity can activate undamaged nociceptors in the presence of inflammation. Patients with posttraumatic pain and inflammation and no other apparent explanation should be evaluated for signs of sympathetic hyperactivity.

Treatment: Acute Pain
The primary goal in treating any pain is to identify and address the underlying cause. While immediate treatment can be initiated, efforts to diagnose and treat the root cause of the pain should always proceed alongside pain management. In some cases, treating the underlying condition may not provide immediate pain relief. Additionally, certain conditions are so painful that swift and effective pain relief is essential. Examples include the postoperative state, burns, trauma, cancer, or sickle cell crisis. In such cases, analgesic medications become the first line of treatment, and it's crucial for healthcare providers to be well-versed in their use.

Aspirin, Acetaminophen, and Nonsteroidal Anti-Inflammatory Agents (NSAIDs)
These drugs are grouped together because they are used to manage similar types of pain and may share a similar mechanism of action. All these medications inhibit an enzyme called cyclooxygenase (COX), with the exception of acetaminophen, and most of them have anti-inflammatory properties, particularly at higher doses. They are especially effective for treating mild to moderate headaches and pain originating from musculoskeletal conditions.

COX inhibitors, including aspirin and NSAIDs, are the most commonly used analgesics because they effectively alleviate common types of pain and are available without a prescription. They are absorbed efficiently in the gastrointestinal tract and, with occasional use, generally have minimal side effects. However, chronic use of aspirin and NSAIDs can lead to gastric irritation, which is the most common side effect. Aspirin, in particular, is associated with the risk of gastric mucosal erosion, ulcers, bleeding, or perforation due to its irreversible effect on platelet COX, affecting blood clotting.

Older individuals and those with a history of gastrointestinal problems are at an increased risk when using aspirin and NSAIDs. Besides the well-known gastrointestinal risks, NSAIDs can also have a negative impact on kidney function in individuals prone to renal insufficiency, especially when there is a significant decrease in intravascular volume, as seen with chronic diuretic use or acute hypovolemia. Additionally, NSAIDs may raise blood pressure in some individuals, necessitating regular blood pressure monitoring for those on long-term treatment. Unlike aspirin and NSAIDs, acetaminophen rarely causes gastric irritation and does not affect platelet function.

Ketorolac and diclofenac, two parenteral (administered through injection) forms of NSAIDs, have extended the utility of this class of drugs in managing severe acute pain. These agents are potent and fast-acting, often replacing opioids as the primary treatment for many patients with severe headaches and musculoskeletal pain.

It's worth noting that there are two major types of cyclooxygenase: COX-1, which is constitutively expressed, and COX-2, which is induced during inflammation.

Opioid Analgesics
Opioids are the most potent pain-relieving medications available. They have a broad spectrum of effectiveness and provide reliable and effective relief for severe pain. While opioids can cause side effects, most of these effects are reversible. Common opioid-related side effects include nausea, vomiting, itching, sedation, and constipation. Respiratory depression, although uncommon at standard analgesic doses, can be life-threatening and should be closely monitored. The opioid antagonist naloxone can rapidly reverse opioid-related side effects.

The fear of inducing addiction in patients is a concern for some healthcare providers and patients. However, the risk of patients becoming addicted to opioids when used for medical purposes is very low. For chronic pain, especially chronic noncancer pain, the risk of addiction in patients taking opioids on an ongoing basis remains small. The key principle in opioid use is to provide adequate pain relief, and healthcare providers should not hesitate to prescribe an adequate dose to ensure that patients are not suffering needlessly.

Patient-controlled analgesia (PCA) is a widely used approach for managing pain, especially postoperative pain. PCA devices allow patients to self-administer small, controlled doses of opioid medications. This approach is effective for achieving optimal pain relief and is often used in hospital settings. It can also be employed for short-term home care for patients with severe, uncontrolled pain.

Other Routes of Administration
In addition to traditional oral and intravenous administration, opioids can be delivered through various routes to improve patient comfort and adherence. These include intranasal (e.g., butorphanol), rectal, transdermal (e.g., fentanyl and buprenorphine), and oral mucosal (e.g., fentanyl) routes. These alternative routes help avoid frequent injections in patients who cannot take oral medication and can provide steady plasma levels, improving patient comfort.

Newer agents like alvimopan and methylnaltrexone have been developed to address opioid-related side effects. These peripherally acting opioid antagonists can help reverse the adverse effects of opioids in the gastrointestinal tract and alleviate constipation.

Combining Opioids with COX Inhibitors
When opioids are combined with COX inhibitors, their effects add up. This combination allows for the use of lower doses of each medication to achieve the same level of pain relief, reducing the severity of dose-related side effects. However, it's essential to be cautious when using fixed-ratio combinations of opioids with acetaminophen because of the risk of excessive acetaminophen exposure with escalating opioid doses. Excessive acetaminophen intake can lead to liver toxicity. Therefore, many practitioners avoid opioid-acetaminophen combination analgesics to mitigate this risk.

Chronic Pain
Managing patients with chronic pain presents both intellectual and emotional challenges. The nervous system can become sensitized without an apparent cause, such as in cases of fibromyalgia or chronic headaches. In many instances, chronic pain evolves into a distinct condition on its own. Determining the exact cause of the pain is often difficult or even impossible, and such patients can be demanding and emotionally distressed. The traditional medical approach of searching for an underlying organic issue is often unhelpful. Conversely, psychological assessment and treatments based on behavior can be beneficial, especially in multidisciplinary pain management centers. Unfortunately, this approach is underutilized in current medical practice.

Various factors can contribute to, perpetuate, or worsen chronic pain. First, patients may have an inherently painful condition without a known cure, like arthritis, cancer, chronic daily headaches, fibromyalgia, or diabetic neuropathy. Second, secondary factors can continue to cause pain even after the initial disease has resolved, such as damaged sensory nerves, sympathetic nerve activity, and painful muscle spasms. Finally, psychological conditions can exacerbate or even cause pain.

Several aspects of a patient's medical history warrant special attention. Given that depression is the most common emotional issue in chronic pain patients, it's important to inquire about mood, appetite, sleep patterns, and daily activity. A standardized questionnaire like the Beck Depression Inventory can be a useful screening tool. It's crucial to recognize that major depression is a common but treatable and potentially life-threatening condition.

Other signs that a significant emotional issue may be contributing to a patient's chronic pain include pain occurring in unrelated areas, a history of recurrent but separate pain issues starting in childhood or adolescence, pain associated with emotional trauma, such as the loss of a loved one, a history of physical or sexual abuse, and current or past substance abuse.

During the physical examination, it's important to note whether the patient protects the painful area and avoids specific movements or postures due to pain. Identifying a mechanical aspect of the pain can be both diagnostic and therapeutic. Painful areas should be examined for deep tenderness, focusing on whether it's localized to muscle, ligaments, or joints. Chronic myofascial pain is common, and deep palpation may reveal localized trigger points, which are firm knots or bands in muscles. Pain relief following the injection of a local anesthetic into these trigger points supports the diagnosis. Evidence of nerve damage, such as sensory loss, heightened skin sensitivity (allodynia), weakness, muscle atrophy, or diminished deep tendon reflexes, suggests a neuropathic component to the pain. Symptoms indicative of sympathetic nervous system involvement include generalized swelling, changes in skin color and temperature, and hypersensitive skin and joint tenderness compared to the unaffected side. Pain relief following a sympathetic block supports this diagnosis, although its effectiveness can vary for chronic conditions, and the role of repeated sympathetic blocks remains unclear in the overall management of complex regional pain syndrome (CRPS).

An important principle when evaluating patients with chronic pain is to consider both emotional and somatic causes and perpetuating factors before initiating treatment. Addressing these aspects together, instead of postponing emotional evaluations until somatic causes are ruled out, can improve patient compliance by showing that the physician values their complaint's validity. Even when a somatic cause is identified, it's still prudent to explore other contributing factors. For instance, a cancer patient with painful bone metastases may also experience pain from nerve damage or depression. Optimal treatment necessitates assessing and managing each of these factors.

Treatment: Chronic Pain
Once the evaluation is complete and the likely causes and factors that worsen the pain are identified, a specific and realistic treatment plan should be established. Part of this process involves identifying functional goals for therapy, such as achieving better sleep, resuming daily activities like shopping, or returning to work. A multidisciplinary approach, involving medications, counseling, physical therapy, nerve blocks, and possibly surgery, may be needed to improve the patient's quality of life. There are also minimally invasive procedures, like epidural injections of glucocorticoids for acute radicular pain or radiofrequency treatment of facet joints for chronic facet-related back and neck pain, which can be helpful for some patients with intractable pain. These interventions are guided by evolving criteria and are generally reserved for patients who have not responded to standard pharmacological treatments. Before invasive procedures, patients should typically be referred to a multidisciplinary pain clinic for a comprehensive evaluation. Such referrals aren't necessary for all chronic pain patients, as pharmacological management alone may suffice for some.

Antidepressants
Tricyclic antidepressants (TCAs), particularly nortriptyline and desipramine, are useful in managing chronic pain. Despite being developed for depression treatment, TCAs have various biological activities at different doses, including analgesic effects in numerous chronic conditions. Their analgesic effect often occurs at lower doses and more rapidly than required for treating depression. Notably, even non-depressed chronic pain patients can experience pain relief from TCAs. TCAs have been shown to enhance the analgesic effect of opioids, making them valuable in severe persistent pain, such as that associated with cancer. However, TCAs have significant side effects, including orthostatic hypotension, drowsiness, cardiac conduction abnormalities, memory problems, constipation, and urinary retention, which can be particularly troublesome for elderly patients and additive to the side effects of opioid pain relievers. Selective serotonin reuptake inhibitors (SSRIs), like fluoxetine, have milder side effects than TCAs but are less effective in pain relief. However, newer non-tricyclic antidepressants like venlafaxine and duloxetine, which inhibit both serotonin and norepinephrine reuptake, appear to maintain most of the pain-relieving effects of TCAs while having side effects more similar to SSRIs. These drugs may be preferable for patients unable to tolerate TCAs.

Anticonvulsants and Antiarrhythmics
These medications are primarily useful for neuropathic pain. Drugs like phenytoin and carbamazepine were initially shown to relieve the pain of trigeminal neuralgia, characterized by brief, shooting, electric shock-like pain. More recently, newer anticonvulsants such as gabapentin and pregabalin have proven effective for a wide range of neuropathic pains, with favorable side effect profiles, often making them the first-line treatment choice.

Cannabinoids
Cannabinoids are commonly used for their analgesic properties, though evidence suggests their effects on pain are usually modest, causing slight increases in pain threshold and variable reductions in clinical pain intensity. However, they tend to consistently reduce the unpleasantness of the pain experience and, in cancer-related pain, can alleviate the nausea and vomiting caused by chemotherapy. Cannabis and related compounds are further discussed in another chapter.

Chronic Opioid Medication
Long-term opioid use is accepted for patients with pain resulting from malignant diseases. However, using opioids for chronic nonmalignant pain is controversial. Still, for many patients, opioids are the only option that provides meaningful pain relief. Opioids are potent and effective for a wide range of painful conditions but can lead to tolerance, physical dependence, and, in some cases, worsened pain (opioid-induced hyperalgesia) during long-term use. Thus, before starting opioid therapy, alternative options should be explored, and patients should be educated about the limitations and risks associated with opioids. Some opioid analgesics have mixed agonist-antagonist properties and can induce an abstinence syndrome when used concurrently with other opioids, creating practical challenges for patients on multiple opioid therapies. For long-term outpatient use of orally administered opioids, extended-release compounds such as methadone, levorphanol, extended-release morphine, oxycodone, or transdermal fentanyl can help maintain stable analgesic blood levels, potentially minimizing side effects. Extended-release opioids are generally approved for patients already using other opioids and should not be the first choice for pain management. While long-acting opioids may provide superior pain relief for patients with constant pain, those with intermittent severe episodic pain might benefit more from periodic use of short-acting opioids. Opioid use frequently leads to constipation, which should be managed. Peripherally acting opioid antagonists that reverse opioid-induced constipation without affecting pain relief are a recent development and are beneficial for patients. It's important to mention that the introduction of extended-release oxycodone (OxyContin) led to a significant increase in emergency room visits and deaths, primarily due to nonmedical use of prescription opioids. These issues led to increased scrutiny of opioid prescribing practices and the development of guidelines and monitoring programs to address prescription drug abuse and reduce the improper prescription of opioids.

Treatment of Neuropathic Pain
Treatment for neuropathic pain should be individualized. Two key principles should guide therapy: providing quick relief and minimizing side effects. For example, patients with postherpetic neuralgia and heightened cutaneous sensitivity can benefit from topical lidocaine (Lidoderm patches) for immediate relief without significant side effects. Anticonvulsants like gabapentin or pregabalin, as well as antidepressants such as nortriptyline, desipramine, duloxetine, or venlafaxine, are first-line treatments for neuropathic pain. Systemic administration of antiarrhythmic drugs like lidocaine and mexiletine is less effective. While intravenous lidocaine infusion can provide temporary pain relief for various neuropathic pain types, it's often short-lived. Mexiletine, an oral lidocaine derivative, is associated with frequent gastrointestinal side effects and is poorly tolerated. The choice of the initial drug class isn't standardized, but due to the relatively high doses of anticonvulsants required for pain relief, sedation can be problematic. Sedation is less common with TCAs but more so with serotonin/norepinephrine reuptake inhibitors (SNRIs) like venlafaxine and duloxetine. Therefore, SNRIs are recommended as the first-line option for elderly patients or those requiring high-level mental activity. In contrast, opioids should be considered second- or third-line treatments. Opioids, while highly effective for many types of pain, can cause sedation, and their effectiveness may decrease over time, leading to dose escalation and occasional worsening of pain. Tramadol and tapentadol, two drugs with mixed opioid and norepinephrine reuptake inhibition actions, offer alternatives to pure opioids. Tramadol is relatively weak, sometimes effective when other non-opioid analgesics fail. Tapentadol is a stronger opioid, but its analgesic action is potentially enhanced by norepinephrine reuptake inhibition. Combining medications from different classes can optimize pain control. Repeated botulinum toxin injections are a promising approach for treating focal neuropathic pain, especially post-herpetic, trigeminal, and post-traumatic neuralgias.

It's essential to understand that many patients with chronic pain seek medical care primarily for relief because physicians can provide the necessary medications. One of a physician's main responsibilities is to minimize the physical and emotional discomfort of their patients. Familiarity with pain mechanisms and analgesic medications is a crucial step in achieving this goal.

title: Internal Medicine/Pain


text:
Sylheti/Links

 * SYLHETI (Basic Conversation) by Asif Adnan.
 * https://community-courses.memrise.com/community/course/731571/sylheti-basic-conversation/

 * Sylheti class by Kate Pline.
 * https://www.brainscape.com/packs/sylheti-2419893

 * Words with ɛ from Sylheti word initial vowels, by Nidaba lexicon analysis and comparison.
 * http://nidaba.co.uk/Contents/RetranscribedWords?sequenceSetId=&sequenceId=16589&parameterValueId=&listId=

 * Brief history of language trends from Syheti’s numbers by Sylheti Project SOAS (University of London) in Camden.
 * https://sylhetiproject.wordpress.com/2021/12/22/brief-history-of-language-trends-from-syhetis-numbers/

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Sylheti/Links


text:
Sylheti/Glossary

1. 2. 3.

title: Sylheti/Glossary


text:
Internal Medicine/Fever

The body's temperature is regulated by the hypothalamus, which acts as a thermostat. Neurons in both the preoptic anterior hypothalamus and the posterior hypothalamus receive two types of signals. One type comes from peripheral nerves that transmit information from skin receptors sensitive to warmth or cold. The other type of signal comes from the temperature of the blood flowing through these regions. The hypothalamus integrates these signals to maintain the body's temperature within a normal range of 36.5–37.5°C (97.7–99.5°F) when in a neutral environmental temperature.

In normal conditions, the human body produces more heat than is required to maintain its core temperature. This excess heat is generated through metabolic activity in muscles and the liver. Despite variations in the environment, the hypothalamus ensures that the core body temperature remains stable. A study involving over 35,000 individuals found that the average oral temperature is 36.6°C (95% confidence interval, 35.7–37.3°C). A temperature above 37.7°C (99.9°F), which represents the 99th percentile for healthy individuals, is considered a fever. It's important to note that higher ambient temperatures are associated with higher baseline body temperatures. Additionally, body temperatures vary throughout the day and across seasons, with lower levels in the morning and during the summer and higher levels in the afternoon and during the winter. Various factors such as age, demographics, and certain medical conditions can influence baseline temperatures. Interestingly, a slight increase in baseline temperature is associated with a higher risk of mortality, even after adjusting for other factors.

Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. This difference may be attributed to mouth breathing, especially in patients with respiratory infections and rapid breathing. Lower-esophageal temperatures closely reflect core temperature. Tympanic membrane thermometers measure radiant heat from the tympanic membrane and nearby ear canal. These measurements can vary and may not be as accurate as directly determined oral or rectal values. In women who menstruate, body temperature typically decreases during the two weeks before ovulation and then rises by about 0.6°C (1°F) during ovulation, remaining at that level until menstruation. The circadian rhythm of body temperature remains relatively constant during the luteal phase of the menstrual cycle.

Fever vs. Hyperthermia
Fever is an elevation of body temperature beyond the normal daily variation and is accompanied by an increase in the hypothalamic set point. This shift in the set point is similar to raising the thermostat setting in a room. Fever involves processes like vasoconstriction, shivering, and nonshivering heat production to raise body temperature, and it is generally characterized by an increase of 1–2°C. Fever management includes behaviors like adding clothing or bedding to raise body temperature.

Hyperpyrexia is an extremely high fever, with temperatures exceeding 41.5°C (106.7°F). This level of fever is rare but can occur in severe infections or central nervous system hemorrhages. Unlike fever, which involves raising the set point, hyperthermia is characterized by uncontrolled overheating of the body, exceeding its ability to dissipate heat. Hyperthermia can result from excessive heat production, such as intense physical exertion in a hot environment, and does not involve pyrogenic molecules. It is essential to distinguish between fever and hyperthermia because hyperthermia can be life-threatening and does not respond to antipyretic drugs like aspirin or acetaminophen.

Pathogenesis of Fever
Pyrogens are substances that cause fever, and they can be exogenous (derived from outside the body) or endogenous (produced within the body). Exogenous pyrogens include microbial products, toxins, and whole microorganisms. Examples include the endotoxin produced by gram-negative bacteria and toxins from gram-positive bacteria like Staphylococcus aureus. Pyrogenic cytokines, which include interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor (TNF), and others, are endogenous pyrogens that regulate immune and inflammatory processes. These cytokines can trigger fever when injected into humans at specific doses.

The elevation of the hypothalamic set point and the initiation of fever involve prostaglandin E2 (PGE2) levels increasing in hypothalamic tissue. Pyrogenic cytokines stimulate the production of PGE2. PGE2 in the brain side of the hypothalamic endothelium triggers the release of cyclic adenosine 5'-monophosphate (cAMP), a neurotransmitter. This process leads to changes in the hypothalamic set point, raising the core body temperature. Microbial products and pyrogenic cytokines can activate receptors on the hypothalamic endothelium, known as Toll-like receptors and IL-1 receptors, to induce PGE2 production and fever.

Cytokines produced within the brain may also contribute to hyperpyrexia in conditions like central nervous system infections, trauma, or hemorrhage. Viral infections of the brain can induce the production of cytokines in microglial and neuronal cells. These cytokines may lead to hyperpyrexia when injected directly into the brain or brain ventricles, bypassing the circumventricular organs. These hyperpyrexic states are not caused by pyrogenic molecules but result from abnormal cytokine production within the central nervous system.

In summary, fever is a regulated response to pyrogens, both exogenous and endogenous, involving changes in hypothalamic temperature set points and subsequent alterations in heat production and conservation to maintain the elevated body temperature. Hyperthermia, on the other hand, is uncontrolled overheating, typically due to excessive heat production or inability to dissipate heat effectively, and it does not involve pyrogenic molecules or changes in the hypothalamic set point.

Patient Evaluation for Fever
When assessing a patient with fever, it is essential to consider various disease processes that can manifest with fever as a primary symptom. A detailed patient history can help distinguish between these categories. The timing of events leading to fever, such as exposure to infected individuals or disease vectors, should be investigated. Electronic devices for temperature measurement, including oral, tympanic membrane, or rectal thermometers, are reliable, but it's crucial to consistently use the same site for monitoring fever. It's worth noting that certain populations, like newborns, the elderly, individuals with chronic liver or kidney issues, or those taking glucocorticoids or undergoing anticytokine therapy, might not exhibit fever despite having an underlying infection due to a blunted febrile response.

Laboratory Tests
In the evaluation of fever, conducting a complete blood count is typically necessary. A differential count should be performed to identify specific features in the blood that may suggest a bacterial infection, such as the presence of juvenile or band forms, toxic granulations, or Döhle bodies. Neutropenia, a low neutrophil count, can also be present in some viral infections.

Measuring circulating cytokine levels may not be useful in patients with fever because these levels often fall below the detection limit of assays or may not correlate with fever. Instead, when evaluating patients with low-grade fever or suspected underlying disease, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are valuable markers of inflammation. Circulating interleukin-6 (IL-6) levels, which induce CRP production, can also be informative. While IL-6 levels may fluctuate during a feverish disease, CRP levels typically remain elevated. These markers are part of the acute-phase reactants used in diagnosing and monitoring inflammatory processes.

Fever in Patients Receiving Anticytokine Therapy
Patients undergoing long-term anticytokine therapy may experience increased susceptibility to infections due to compromised host defenses. For instance, anti-TNF therapy can lead to the dissemination of latent Mycobacterium tuberculosis infection. As anticytokines are increasingly used in conditions like Crohn's disease, rheumatoid arthritis, or psoriasis to reduce the activity of IL-1, IL-6, IL-12, IL-17, or TNF, it's crucial to consider that these therapies may reduce the febrile response. Blunting the fever response can be a concern, especially when evaluating patients with low-grade fever or suspected underlying diseases in the context of anticytokine therapy.

Treatment of Fever
When deciding whether to treat fever, it's important to recognize that fever itself is not an illness but rather a normal response to various physiological disturbances. Most fevers are associated with self-limited infections, like common viral diseases. Antipyretics are not contraindicated in such infections and do not delay recovery or affect the resolution of infections significantly. However, in bacterial infections, withholding antipyretic therapy can be useful in assessing the effectiveness of a particular antibiotic, as it can unmask an inadequately treated bacterial infection.

Some infections follow specific fever patterns, with episodes of fever separated by intervals of normal temperature. Recognizing these patterns can help tailor diagnostic testing and treatment. While recurrent fevers can be seen in autoimmune diseases, autoinflammatory diseases, and periodic fever syndromes, they are especially characteristic of autoinflammatory conditions, which include rare diseases like familial Mediterranean fever and more common conditions like idiopathic pericarditis and gout. Many of these conditions respond well to anticytokine therapies like IL-1 blockers.

Mechanisms of Antipyretic Agents
Antipyretics aim to reduce fever by lowering the elevated hypothalamic set point and enhancing heat loss. Drugs like aspirin and NSAIDs work by inhibiting the enzyme cyclooxygenase, which is involved in prostaglandin synthesis. Prostaglandins, particularly PGE2, play a crucial role in raising the hypothalamic set point during fever. Acetaminophen, while not a strong cyclooxygenase inhibitor in peripheral tissues, acts as a more effective antipyretic in the brain. Glucocorticoids reduce fever by both inhibiting cyclooxygenase and blocking the transcription of mRNA for pyrogenic cytokines. The use of antipyretic agents does not affect normal core body temperature regulation.

Regimens for Fever Treatment
Oral acetaminophen is the preferred antipyretic due to its efficacy and safety profile. In children, oral ibuprofen is also a suitable option, while aspirin should be avoided due to the risk of Reye's syndrome. In cases where oral antipyretics cannot be taken, parenteral NSAIDs and rectal suppositories can be used. It's essential to treat fever in patients with preexisting cardiac, pulmonary, or CNS conditions, as fever increases oxygen demand. Additionally, children with a history of febrile or nonfebrile seizures should receive prompt treatment to reduce fever. In hyperpyrexia, cooling blankets can be used to lower temperature, but they should be combined with oral antipyretics. Cooling is particularly important in hyperpyretic patients with CNS conditions or trauma, as it helps mitigate the harmful effects of high temperature on the brain.

title: Internal Medicine/Fever


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Internal Medicine/Photosensitivity and Other Reactions to Sunlight

Sunlight's Impact on Health
Sunlight, or solar radiation, is a readily noticeable and important element of our environment. It offers us warmth and helps our bodies synthesize vitamin D, but excessive exposure to the sun can also have negative health consequences. Prolonged exposure to sunlight is a leading cause of skin cancer in humans and can weaken our immune systems.

The sun's energy that reaches Earth's surface is composed of various components within the ultraviolet (UV), visible, and infrared spectra. The shorter UV wavelengths below approximately 290 nm are mostly filtered out by the Earth's stratospheric ozone layer, protecting us from the more harmful solar radiation. Concerns about ozone layer depletion due to substances like chlorofluorocarbons have led to international agreements to limit their production.

Measurements of solar energy show significant regional variations due to factors like seasons, the path of sunlight through the atmosphere, altitude, latitude, and the presence of clouds, fog, and pollution.

The key wavelengths of solar radiation that affect human skin are in the UV and visible spectra, ranging from 290 to 700 nm. Additionally, wavelengths beyond 700 nm primarily generate heat and, under certain conditions, can exacerbate the negative effects of UV and visible radiation.

UV Radiation and Skin Structure
Solar UV radiation is divided into UV-B and UV-A segments, ranging from 290 to 400 nm. UV-B, which covers wavelengths between 290 and 320 nm, is the most effective at causing skin redness, commonly known as sunburn. UV-A, spanning from 320 to 400 nm, is about a thousand times less efficient in causing skin redness compared to UV-B.

Visible light, within the 400 to 700 nm range, cannot harm human skin in the absence of photosensitizing chemicals. These chemicals absorb specific wavelengths and initiate photosensitivity reactions. The absorption spectrum of a molecule indicates the wavelengths it absorbs, while the action spectrum shows the wavelengths that produce a response in the presence of incident radiation.

Photosensitivity occurs when a molecule in the skin absorbs energy from photons, becomes excited, and transfers this energy to various structures or to molecular oxygen.

Effects of UVR on Skin Structure and Function

Human skin comprises two main layers: the outer epidermis and the underlying dermis, both vulnerable to sun damage. Various molecules in these layers, such as nucleic acids, proteins, and lipids, can absorb solar energy. The outermost epidermal layer, the stratum corneum, primarily absorbs UV-B, with only a fraction of UV-B wavelengths reaching the dermis. UV-A, however, penetrates more deeply into the skin and can modify structural and matrix proteins, contributing to premature aging, especially in individuals with light skin.

Molecular Targets and Skin Effects from UVR

UV radiation can cause structural changes in epidermal DNA, primarily in keratinocytes and Langerhans cells, forming DNA lesions like cyclobutane dimers and 6,4-photoproducts. Effective repair mechanisms are crucial for preventing skin cancer development. Individuals with defective DNA repair mechanisms, like those with xeroderma pigmentosum, are at a higher risk of skin cancer.

Solar UVR also targets molecular oxygen, producing reactive oxygen species (ROS). ROS can damage skin components through oxidative processes, affecting DNA, lipids, proteins, and enzymes. UVR can also lead to increased cross-linking and degradation of dermal matrix proteins, contributing to photoaging or solar elastosis.

Chromophores and Cutaneous Optics

Chromophores are chemicals that can absorb physical energy and can be endogenous (naturally occurring in the skin) or exogenous (introduced from external sources). Skin's endogenous chromophores include nucleic acids, proteins, lipids, and 7-dehydrocholesterol, a precursor of vitamin D. Exogenous chromophores can include porphyrins, which are normally present in trace amounts but can accumulate in certain diseases, leading to skin damage upon exposure to solar energy.

Porphyrins can generate ROS upon absorbing sunlight, causing skin damage such as erythema, edema, urticaria, or blister formation. Photodynamic therapy (PDT) uses photoexcited porphyrins for targeted destruction of tumor cells in conditions like basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).

Acute Effects of Sun Exposure

Immediate effects of sun exposure include sunburn and vitamin D synthesis. Sunburn, characterized by skin redness, is primarily caused by UV-B and, to a lesser extent, UV-A radiation. It results from an inflammatory response in the skin, involving the release of various cytokines and growth factors, along with the accumulation of ROS. UV-B is particularly efficient at inducing sunburn, but UV-A can contribute to it, especially during midday when UV-A levels are higher.

Sunburn also triggers the formation of "sunburn cells," which are apoptotic keratinocytes attempting to repair DNA damage.

Vitamin D Synthesis and Photocchemistry

UV-B exposure can stimulate the synthesis of vitamin D in the skin. It begins with the photolysis of 7-dehydrocholesterol, converting it into pre-vitamin D3, which then undergoes temperature-dependent transformation into stable vitamin D3. This vitamin is transported through the bloodstream to the liver and kidneys, where it becomes the biologically active hormone, 1,25-dihydroxyvitamin D3.

Vitamin D has various physiological effects, including aiding in calcium metabolism, regulating bone health, and potentially reducing the risk of certain internal malignancies. The debate continues about the risk-to-benefit ratio of sun exposure for vitamin D production. However, the potential risks of skin cancer and photodamage outweigh the benefits, and supplementation is recommended for individuals with vitamin D deficiency, especially as skin's ability to produce vitamin D decreases with age.

Chronic Effects of Sun Exposure: Nonmalignant The visible signs of photoaging, often referred to as dermatoheliosis, encompass characteristics such as wrinkles, uneven pigmentation, visible blood vessels (telangiectasia), and a rough, uneven, and weathered appearance of the skin.

Sunlight plays a significant role in causing photoaging in human skin, and it is likely that reactive oxygen species (ROS) are involved in this process. Sun-associated chronic damage primarily targets the dermis and its connective tissue matrix, leading to a condition known as solar elastosis. This involves a significant increase in the thickened, irregular masses of abnormal elastic fibers. Collagen fibers in the deeper layers of sun-damaged skin also appear clumped together. While the exact mechanisms behind these changes are not fully understood, it is believed that UV-A radiation, which penetrates deeper into the skin, plays a major role. Interestingly, both chronologically aged skin protected from the sun and photoaged skin share molecular features, including damage to connective tissues and elevated levels of matrix metalloproteinases (MMPs), enzymes that break down the extracellular matrix. UV-A radiation induces the expression of certain MMPs, like MMP-1 and MMP-3, which increase collagen degradation and also reduce the expression of type I procollagen mRNA, affecting collagen synthesis. As a result, chronic sun exposure leads to structural and functional alterations in dermal collagen, inhibiting its production and promoting its breakdown. This knowledge has led to the use of high-dose UV-A phototherapy in the treatment of specific skin conditions characterized by localized fibrosis, such as localized scleroderma.

Chronic Effects of Sun Exposure: Malignant Excessive and prolonged exposure of the skin to sunlight is a well-known cause of non-melanoma skin cancers (NMSCs), including squamous cell carcinomas (SCCs), basal cell carcinomas (BCCs), and Merkel cell carcinomas (MCCs). The development of skin cancer follows a multi-step process that involves initiation, promotion, and progression.

Initiation occurs when the DNA of skin cells is structurally altered by factors like UV-B radiation, making them prone to malignant transformation. However, exposure to a tumor initiator, such as UV-B, is necessary but not sufficient for cancer development; other factors are required. Promotion is the next stage, driven by chronic sun exposure, leading to further changes in the initiated cells, clonal expansion, and the development of premalignant growths known as actinic keratoses, which can progress to SCCs. UV-B radiation is considered a complete carcinogen as it can act both as a tumor initiator and promoter. Finally, malignant conversion marks the transition of benign precursors into cancers, involving genetic instability.

On a molecular level, skin cancer is driven by accumulated gene mutations, causing inactivation of tumor suppressors, activation of oncogenes, or reactivation of cellular signaling pathways that are normally active during embryonic skin development, leading to uncontrolled cell proliferation. Studies have shown that UV-induced mutations that drive oncogenesis in SCCs are already present in sun-exposed normal skin, providing a growth advantage to precancerous clones carrying these mutations. These mutations are particularly common in genes influencing the proliferation of epidermal stem cells. The pattern of oncogenic mutations in sun-exposed skin overlaps with those in SCCs but differs from those in BCCs and melanomas. For example, mutations in NOTCH1 are found in approximately 20% of normal sun-exposed skin cells and around 60% of SCCs. Furthermore, mutations in the tumor suppressor gene p53, primarily caused by UVR, can promote skin carcinogenesis.

In contrast to SCCs, BCCs have distinct mutations, primarily involving the tumor-suppressor gene patched or the oncogene smoothened, leading to the activation of the sonic hedgehog signaling pathway. The Wnt/β-catenin signaling pathway is also implicated in skin cancer development. Clonal analysis in mouse models has shown that BCCs originate from stem cells in the interfollicular epidermis and upper hair follicle infundibulum. SCCs can initiate from both interfollicular epidermis and hair follicle bulge stem cells. The transcription factor Myc is associated with both BCCs and SCCs.

Merkel cell carcinoma (MCC), another form of NMSC, is linked to Merkel cell polyoma virus (MCPyV). MCCs can be MCPyV-positive or MCPyV-negative. MCPyV-negative MCCs display high levels of UV-induced signature mutations and tumor suppressor inactivation. MCPyV-positive MCCs result from viral integration into the host genome and mutations in the large T antigen. Both forms of MCC are immunogenic, and some patients with metastatic MCC have shown positive responses to PD-1/PD-L1 immune checkpoint inhibitors.

Global Considerations The incidence of skin cancer varies globally, influenced by geographic location and the predominant skin phototype of the population in each region. For example, Australia experiences high rates of both melanoma and NMSCs due to its sunny climate.

Photoimmunology Exposure to solar radiation leads to immunosuppression, affecting both local and systemic immune responses. Local immunosuppression reduces the immune response to antigens applied at the irradiated site, while systemic immunosuppression affects responses to antigens applied at distant, unirradiated sites. UV radiation targets chromophores in the upper epidermis, including DNA, urocanic acid, and membrane components, initiating immunosuppression. DNA damage induced by UV radiation can inhibit antigen presentation by Langerhans cells. Urocanic acid, which accumulates in the upper epidermis due to the breakdown of the protein filaggrin, undergoes trans-cis isomerization upon UV exposure, contributing to immunosuppression.

Various immunomodulatory factors and cytokines are implicated in UV-induced systemic immunosuppression, including tumor necrosis factor-α, interleukin 4 (IL-4), interleukin 10 (IL-10), and eicosanoids. Additionally, UV radiation can activate Toll-like receptor signaling via damage-associated molecular patterns (DAMPs) released from necrotic keratinocytes.

Chronic sun exposure and the resulting immunosuppression increase the risk of skin cancer, especially in organ transplant recipients who require lifelong immunosuppressive drug regimens. These individuals are at a significantly higher risk of developing skin cancers, emphasizing the importance of photoprotection measures.

Sun exposure can exacerbate autoimmune and inflammatory skin conditions, such as systemic lupus erythematosus (SLE), by promoting DNA damage that may trigger autoantibody production.

In conclusion, skin cancer and various immune-related skin responses are influenced by chronic exposure to UV radiation, affecting both local and systemic immunity. This underscores the importance of sun protection and early detection to mitigate these risks.

Photosensitivity Diseases
To diagnose photosensitivity conditions, it's essential to gather a detailed medical history to understand the duration of symptoms, the time between sunlight exposure and the onset of symptoms, and the age when symptoms began. Certain diseases, like erythropoietic protoporphyria (EPP), often start in infancy or early childhood, while others, such as porphyria cutanea tarda (PCT), tend to appear in one's forties or fifties. A patient's exposure to drugs and chemicals, both topical and systemic, can provide diagnostic clues, as many of these substances can induce photosensitivity through either phototoxic or photoallergic reactions.

Skin examination plays a vital role in diagnosis. Areas naturally shielded from direct sunlight, like the scalp, upper eyelids, and other covered regions, may remain unaffected, while exposed areas exhibit characteristic signs of photosensitivity. These patterns can be helpful in diagnosis, but they are not foolproof. For instance, airborne allergens that settle on the skin can lead to dermatitis in both sun-exposed and shielded areas, complicating diagnosis.

Various dermatological conditions can be triggered or worsened by sunlight exposure, influenced by genetic factors such as DNA repair defects in xeroderma pigmentosum and abnormalities in heme synthesis seen in porphyrias.

Polymorphous Light Eruption (PMLE)

Polymorphous light eruption (PMLE) is the most common type of photosensitivity disorder. Many individuals with PMLE may not seek medical attention as the condition is often temporary, with symptoms arising in the spring upon initial sun exposure but subsiding with continued exposure (a phenomenon known as "hardening"). PMLE is characterized by pruritic (itchy), erythematous (red), and papular (raised) skin lesions that can merge into plaques, typically appearing on sun-exposed areas of the trunk and forearms, with the face being less affected. While the skin findings remain consistent in each recurrence for an individual, there can be significant variations in symptoms among different individuals.

Diagnosis can be confirmed through a skin biopsy and phototesting, where the skin is exposed to UV-A and UV-B radiation to reproduce symptoms. The action spectrum for PMLE usually falls within these portions of the solar spectrum.

Preventing PMLE is essential, and measures include using high-SPF broad-spectrum sunscreens and inducing "hardening" through cautious exposure to artificial UV-B or UV-A radiation or using psoralen plus UV-A (PUVA) photochemotherapy for several weeks before the initial sun exposure in the spring to prevent subsequent PMLE outbreaks during the summer.

Actinic Prurigo

Actinic prurigo is another photosensitivity condition with similarities to PMLE. It typically occurs in the spring, can persist throughout the summer, and extend into the winter months.

Phototoxicity and Photoallergy

Phototoxic and photoallergic reactions result from exposure to drugs and chemicals, which act as chromophores. In both reactions, the substance absorbs energy, becomes photoexcited, and generates tissue-damaging chemical species, including reactive oxygen species (ROS). Phototoxicity is a non-immunologic reaction caused by various drugs and chemicals, while photoallergy involves an immunopathologic process. Phototoxicity and photoallergy reactions can be confirmed through phototest procedures.

Porphyria

Porphyrias are a group of disorders related to heme synthesis abnormalities. Some porphyrins in the body act as potent photosensitizers, absorbing light in the visible spectrum and leading to photosensitivity. The two major categories of cutaneous porphyrias are chronic blistering photosensitivity and acute non-blistering photosensitivity. The latter category includes diseases like erythropoietic protoporphyria (EPP), which causes painful skin burning and stinging upon sun exposure.

The management of these photosensitivity disorders involves various strategies, including eliminating exposure to triggering substances, protecting the skin from sunlight, and, in some cases, using medications to alleviate symptoms or suppress the immune response. For instance, afamelanotide, a synthetic peptide analogue of α-MSH, has been approved by the FDA for treating EPP and can increase skin pigmentation to improve sunlight tolerance. Additionally, β-carotene supplements have shown moderate benefits in increasing sunlight tolerance for some patients with EPP.

Treatment approaches may vary depending on the specific condition and its severity.

Photoprotection
As photosensitivity disorders stem from sunlight exposure, complete avoidance of sunlight could theoretically prevent these conditions. However, this approach is often unfeasible in today's modern lifestyles. Therefore, alternative methods of photoprotection have been explored. The skin naturally provides some photoprotection through structural proteins in the epidermis, especially keratins and melanin. The amount and distribution of melanin in cells are genetically controlled, and individuals with darker skin types (IV-VI) are less prone to acute sunburn and skin cancers. Other forms of photoprotection encompass clothing and sunscreen use. Clothes made of densely woven sun-protective fabrics, regardless of color, offer substantial protection. Covering up with wide-brimmed hats, long sleeves, and trousers can also reduce direct sun exposure.

Sunscreens are now considered over-the-counter drugs, and the FDA has identified category I ingredients as both safe and effective. Sunscreens are rated for their photoprotective capacity based on their Sun Protection Factor (SPF). SPF represents the ratio of time required to produce sunburn erythema with and without sunscreen application. Most sunscreens primarily protect against UV-B but not UV-A. According to the FDA, sunscreens must be categorized as minimal (SPF ≥2 and <12), moderate (SPF ≥12 and <30), or high (SPF ≥30, labeled as 30+).

Broad-spectrum sunscreens contain chemicals that absorb both UV-B and UV-A rays (organic filters). These chemicals soak up UV radiation and transmit the absorbed energy to surrounding cells. For instance, cinnamates, PABA derivatives, and salicylates primarily absorb UV-B, while benzophenones and ecamsule (terephthalylidene dicamphor sulfonic acid) offer protection against both UV-B and UV-A2, and avobenzone primarily guards against UV-A1. In contrast, physical UV blockers such as zinc oxide and titanium dioxide either absorb or reflect UV radiation, providing broad-spectrum protection against both UV-B and UV-A. In addition to light absorption, water resistance significantly affects the sustained photoprotective ability of sunscreens. Sunscreen products with SPF 30 or higher, broad-spectrum coverage, and resistance to water or sweat are recommended for adequate sun protection.

Limiting sun exposure during the day can also provide some photoprotection. Since a significant portion of a person's lifetime sun exposure occurs by age 18, educating parents and young children about the risks of sunlight is important. Reducing exposure at midday can substantially reduce a person's overall UV radiation exposure throughout their life.

Phototherapy and Photochemotherapy
Ultraviolet radiation (UVR) can be used therapeutically. UV-B exposure alone or in combination with topically applied agents can induce remission in various dermatological conditions like psoriasis, atopic dermatitis, and vitiligo. Narrow-band UV-B treatments, utilizing fluorescent bulbs emitting radiation at around 311 nm, have shown enhanced efficacy compared to broad-band UV-B in psoriasis treatment.

Photochemotherapy, where psoralens are topically applied or systemically administered and combined with UV-A (PUVA), is effective in treating psoriasis, early-stage cutaneous T-cell lymphoma, and vitiligo. Psoralens, tricyclic furocoumarins, intercalate into DNA and form adducts with pyrimidine bases when exposed to UV-A, leading to DNA cross-linking. This process is believed to reduce DNA synthesis, contributing to psoriasis improvement. The effectiveness of PUVA in cutaneous T-cell lymphoma treatment is not fully understood but is thought to induce apoptosis in atypical T lymphocyte populations in the skin. Photopheresis, which directly treats atypical lymphocytes in circulation, has been used in severe systemic conditions with circulating atypical lymphocytes, like Sézary syndrome and graft-versus-host disease.

Apart from DNA effects, PUVA therapy stimulates epidermal thickening and melanin synthesis, making it suitable for treating depigmenting diseases like vitiligo. The oral form of 8-methoxypsoralen with UV-A appears most effective, but extensive treatment over 12-18 months may be necessary for satisfactory repigmentation.

The major side effects of long-term UV-B phototherapy and PUVA photochemotherapy resemble those resulting from chronic sun exposure. Nonetheless, these treatment modalities continue to provide excellent therapeutic results. Selecting the most suitable phototherapeutic approach for a specific dermatological condition is crucial. For instance, narrow-band UV-B has been reported to be as effective as PUVA photochemotherapy in treating psoriasis while posing a lower risk of skin cancer development than PUVA.


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Pokémon Diamond and Pearl Surf glitch/Seabreak Path

The Pokémon games by Game Freak have been known for their solid gameplay as well as a healthy dosage of secrets. Aside from the standard batch of creatures that roam the regions that you travel in, there are always a special few Pokémon that you have the one rare opportunity to challenge and either defeat or attempt to capture. In Pokémon Diamond and Pearl, not only is this still the case, but to an even greater degree. You have a lot more of the rare kind this time around, and you're still given that one measly Master Ball. It's simply something all players of Pokémon games will have to deal with once again.

Getting to Flower Paradise
Sheimi/Shaymin is also acquired in the exact same way, but it's in a different location. It is easier, when you start all over again, to reset your Poketch's steps counter, as you can very easily get lost. You shouldn't have to needlessly lose time, because again, this is a very easy glitch. After you wind up once more in the void outside the door of that same room, walk 200 steps east. Afterwards, walk 363 steps south, totaling 563 steps taken. After that, walk 722 steps east, totaling 1285 steps. From where you stand, walk 19 steps west, for a total of 1304 steps.

Don't think you can shorten the 722 steps east by 19 to reach the same place -- trust me, it won't work. Make sure you go 722 steps east, and only then take 19 steps west. It is important that you follow directions for your safety. Again, go underground with your Explorer Kit, and without moving, immediately resurface. Look at your Map Key Item to help take care of the visual glitchiness you are probably experiencing. You're now below the "Flower Paradise" with Sheimi/Shaymin straight ahead of you.

Shaymin isn't that difficult to catch. It has a catch rate of 45/255, making it relatively easy to capture, much like Dialga and Palkia. You don't want to risk more than you need to by saving at the "Flower Paradise" unless you've checked beforehand that you have that option. Once you're done with either capturing or killing it (if you have beaten the game, Sheimi/Shaymin won't give you any problems), you can fly away at your earliest convenience. If you can't, know that that sometimes can happen in some Japanese games, so turn off your game and try it again.


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Pokémon Diamond and Pearl Surf glitch/Darkrai Path

The Pokémon games by Game Freak have been known for their solid gameplay as well as a healthy dosage of secrets. Aside from the standard batch of creatures that roam the regions that you travel in, there are always a special few Pokémon that you have the one rare opportunity to challenge and either defeat or attempt to capture. In Pokémon Diamond and Pearl, not only is this still the case, but to an even greater degree. You have a lot more of the rare kind this time around, and you're still given that one measly Master Ball. It's simply something all players of Pokémon games will have to deal with once again.

Newmoon Island
To access Darkrai, from where you should now be standing, and using the Poketch's built-in Step Counter, walk 146 steps to the east. After that, walk 254 steps south, for a total of 400 steps.

If you feel you've messed up, you can either attempt to fly from where you are to the game's other areas or retrace your steps if that does not work. The next part is what can mess some people up very easily, as you will have to be unusually still for a certain amount of time.

Now, use the Explorer Kit to go underground. This will cause you to save. When you go underground, DON'T MOVE! Simply resurface. Guess where you are? You're at Newmoon Island! The place looks a little messed up, but don't worry about that. Maneuver yourself west around the glitchy visuals for a short distance, or look at your Map Key Item to help clear it up, then afterwards travel north into the woods. Floating right before you is the rare Pokémon Darkrai!


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Exercise Physiology

Exercise Physiology is the study of how the body responds and adapts to physical activity and exercise. It delves into the physiological processes that occur within our bodies when we engage in various forms of exercise, from a leisurely walk to ultramarathoner training, and everything in between. This WikiBook aims to give you a deeper scientific understanding of how the body reacts to exercise and functions in general. By understanding these mechanisms, we can optimize training programs, improve athletic performance, and enhance the overall health and well-being of individuals.

Table of contents
Here's the planned outline, which is unfinal:

 * 1) Introduction to Exercise Physiology
 * 2) * 1.1 Fundamentals of Exercise Physiology
 * 3) * 1.2 History and Milestones
 * 4) * 1.3 Physiological Systems in Action
 * 5) Cardiovascular Physiology
 * 6) * 2.1 Cardiovascular Adaptations to Exercise
 * 7) * 2.2 Heart Function and Exercise
 * 8) * 2.3 Blood Pressure Regulation
 * 9) * 2.4 Oxygen Transport and Utilization
 * 10) Muscle Physiology
 * 11) * 3.1 Skeletal Muscle Structure and Function
 * 12) * 3.2 Muscle Contraction and Energy Metabolism
 * 13) * 3.3 Muscular Adaptations to Training
 * 14) Respiratory Physiology
 * 15) * 4.1 The Respiratory System and Exercise
 * 16) * 4.2 Ventilation and Gas Exchange
 * 17) * 4.3 Oxygen Transport in the Blood
 * 18) Nutrition and Exercise
 * 19) * 5.1 Macronutrients and Micronutrients
 * 20) * 5.2 Dietary Strategies for Performance
 * 21) * 5.3 Hydration and Exercise
 * 22) Training Principles and Program Design
 * 23) * 6.1 Principles of Training
 * 24) * 6.2 Program Design and Periodization
 * 25) * 6.3 Monitoring and Assessment
 * 26) Special Topics
 * 27) * 7.1 Endurance Training
 * 28) * 7.2 Strength and Power Training
 * 29) * 7.3 Aging and Exercise
 * 30) * 7.4 Environmental Factors in Exercise
 * 31) Applied Exercise Physiology
 * 32) * 8.1 Exercise for Health and Disease Prevention
 * 33) * 8.2 Sports Performance Enhancement
 * 34) * 8.3 Rehabilitation and Injury Prevention
 * 35) Current Research and Trends
 * 36) * 9.1 Emerging Concepts and Technologies
 * 37) * 9.2 Recent Studies and Breakthroughs
 * 38) * 9.3 Future Directions in Exercise Physiology
 * 39) References and Further Reading
 * 40) * 10.1 Books and Textbooks
 * 41) * 10.2 Scientific Journals and Articles
 * 42) * 10.3 Online Resources and Organizations

title: Exercise Physiology


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Cookbook:Plain Kefir

Ingredients

 * 50 grams (1¾ oz) of kefir grains (see note)
 * 500 ml (1 pint) fresh milk (see note)

Preparation

 * 1) Remove kefir grains from previous batch of starter, using a sieve or colander.
 * 2) Shake kefir grains to remove excess kefir. Rinsing is not necessary (but optionally, rinse in fresh milk).
 * 3) Place kefir grains in glass jar or jug with fresh milk. Generally, keep a ratio of kefir grains to milk of about 1:10 or 5% w/w.
 * 4) Set aside to ferment at room temperature (18–22°C) for 12–24 hours (see notes) until a smooth yoghurt-like consistency develops.

Ingredients

 * Kefir grains are gelatinous lumps. You can often get them for free, or for the cost of postage. Once you've got some, they grow in the milk until you have enough to give to someone else.
 * As an alternative to kefir grains, some health food shops carry a powdered kefir starter containing selected bacteria and yeasts isolated from kefir grains. This will never make kefir grains, but the powdered starter will make good, consistent kefir and is easier for some people to manage.
 * The milk can be almost any milk from a mammal. Full cream cow's milk is best, but kefir can be made from low-fat milk, goat's milk, or sheep's milk.
 * Non-milk kefir can be made from sugary water, fruit juice, coconut juice, rice milk, or soy milk. However, the kefir grains will stop growing in these liquids, so it is best to only use excess kefir grains or powdered kefir starter for this.

Technique

 * In cold weather, kefir will ferment very slowly. Put the jar or jug in a warm place, but not where it will get too warm—the top of a warm refrigerator or a cupboard above the stove are suitable places. In warm weather, kefir will ferment very quickly and can become separated into curds and whey, so kefir may be produced in warm to hot climates by placing the fermentation vessel into the refrigerator during the day and on the counter top at night. Kefir should be kept out of direct sunlight.
 * If you have left your kefir to ferment for too long the curds and whey will start to separate. Adding some additional milk, with a vigorous stirring, to dilute it can remedy this. It may be that rinsing the kefir grains with some additional milk after the kefir has been left for too long can also help to get the kefir back on track
 * Carbonated kefir may be produced by sealing the fermented product into beer bottles for ripening (1–3 days at 10°C).

title: Cookbook:Plain Kefir


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Cookbook:Brown Sugar Mulling Spice Mix

Ingredients

 * 1 cup (180 g) brown sugar
 * 2 teaspoons ground cinnamon
 * 1 teaspoon ground cloves
 * 1 teaspoon dried ground orange peel
 * 1 teaspoon ground allspice
 * ½ teaspoons ground nutmeg

Procedure

 * 1) Combine all ingredients in a medium bowl.
 * 2) Stir with wire whisk until well blended.
 * 3) Store in an airtight container in a cool place.

title: Cookbook:Brown Sugar Mulling Spice Mix


text:
Cookbook:Mulling Spice with Anise

Ingredients

 * 2 cups (320 g) dried orange peel
 * 2 cups (250 g) broken cinnamon sticks
 * 1 cup (125 g) whole allspice berries
 * 1 cup (125 g) whole cloves
 * 4 broken star anise

Procedure

 * 1) Mix ingredients together well.
 * 2) Store in closed jar.

Use

 * Mix ¼ cup (150 g) of spice mixture per 16 cups (4 L) of wine, cider, or apple juice.
 * Simmer for 30 minutes.
 * Serve hot in mugs with cinnamon stick stirrers or fill a punch bowl and garnish with orange slices.

title: Cookbook:Mulling Spice with Anise


text:
Cookbook:Sweetened Mulling Spice Mix

Ingredients

 * 2 cups (450 g) sugar
 * 2 teaspoons ground cinnamon
 * 1 teaspoon ground cloves
 * 1½ teaspoons ground allspice
 * ½ teaspoons ground mace
 * ¼ teaspoons ground nutmeg

Procedure

 * 1) Combine all ingredients together.
 * 2) Store in an airtight container.

title: Cookbook:Sweetened Mulling Spice Mix


text: Category:Mulling spice recipes

title: Category:Mulling spice recipes


text:
Cookbook:Pizza Sauce From Scratch

This recipe is for those who have the time (preparation only - no cooking required!) to mix the ingredients for a purer and more customized taste.

Ingredients

 * 6 ounce (170 g) can of tomato paste (with no additives is best)
 * 1–1½ cups (250–375 ml) of water (depending on desired consistency)
 * About ⅓ cup (80 ml) extra virgin olive oil (more or less depending on taste)
 * 1–3 cloves garlic, minced
 * 1 pinch of anise (or substitute fennel)
 * About ½ tablespoon dried oregano (according to preference)
 * About ½ tablespoon dried basil (according to preference)
 * Kosher salt to taste
 * Ground black pepper to taste

Procedure

 * 1) Combine tomato paste, water, and oil.
 * 2) Add garlic, basil, and oregano, mixing thoroughly.
 * 3) Add salt and pepper to taste.
 * 4) For best results place in refrigerator overnight or allow the mixture to rest before using.

Notes, tips, and variations

 * A quart mason jar works perfectly; ingredients can be added and shaken to mix.

title: Cookbook:Pizza Sauce From Scratch


text: Subject:Sylheti language

title: Subject:Sylheti language


text:
Talk:Contemporary Educational Psychology/Chapter 10: Teacher-Made Assessment Strategies/Selecting Appropriate Assessments, Part 1

How to reduce the number of High Population in a particular country as Geography Learners
Topic: Development Orefemetswe (discuss • contribs) 13:21, 20 September 2023 (UTC)


text:
User:Tony Rose Orge-Monzales/sandbox

= Educational Developments in the Philippines =

Brief History
Pre-colonial Education: Before the arrival of the Spanish colonizers in the 16th century, education in the Philippines was informal and based on oral traditions. Indigenous Filipinos had their own systems of transmitting knowledge, which included apprenticeship, storytelling, and community-based learning. (Constantino, 1975)

Spanish Colonial Period (1565-1898): With the arrival of the Spanish, formal education was introduced as a tool for spreading Christianity and Spanish influence. The first schools were established by religious orders, such as the Dominicans and the Jesuits. Education was primarily accessible to the elite and focused on religious instruction, Latin, and Spanish language and culture. (Santiago, 1995)

American Colonial Period (1898-1946): The United States took control of the Philippines after the Spanish-American War. Under American rule, significant educational reforms were implemented. English replaced Spanish as the medium of instruction, and a public school system was established. The Thomasites, a group of American teachers, played a vital role in expanding public education across the archipelago. (Lasco, 2018)

Japanese Occupation (1942-1945): During World War II, the Japanese occupied the Philippines, and education was severely disrupted. Schools were closed, and teachers and students were subjected to harsh conditions and restrictions. Education during this period was often limited to clandestine or underground classes. (Maca, 2014)

Post-World War II Period: After the war, efforts were made to rebuild the education system. The government focused on expanding access to education, particularly at the elementary level. The Education Act of 1949 aimed to provide free and compulsory education for all Filipino children. (Benavot, 1988)

Contemporary Era: In recent years, the Philippine education system has undergone various changes and reforms. Efforts have been made to enhance the quality of education, improve teacher training, and address issues of accessibility and equity. The K-12 Basic Education Program, implemented in 2012, extended the basic education cycle from ten to twelve years to align with international standards. (Barrot, 2021)

Philippine Curriculum (1987-2023)
The Philippines' educational system has undergone significant changes over the years, transitioning from the 6-4 system to the Basic Education Curriculum (BEC), and finally to the K-12 program. Each system has its unique features, advantages, and disadvantages.

The 6-4 education system, in place before BEC, was academically focused. It consisted of six years of elementary education and four years of high school. The curriculum was heavily centered on traditional academic subjects such as Mathematics, Science, English, and Social Studies. The advantage of this system was its simplicity and focus on academic knowledge. However, it lacked in providing holistic development for students as it did not include subjects that would prepare students for real-world scenarios and life beyond school. (Durban, 2012)

In 2002, the BEC was introduced as a reform to the 6-4 system. It aimed at providing a more comprehensive and well-rounded education. The inclusion of new subjects such as Technology and Livelihood Education (TLE), Edukasyon sa Pagpapakatao (Values Education), and Music, Arts, Physical Education, and Health (MAPEH) was seen as a significant improvement. This curriculum emphasized the development of critical thinking and problem-solving skills. However, one of its disadvantages was that it required more resources, such as teachers who are trained to deliver these new subjects, which may not have been readily available in all schools. (Bernardo, 2009)

The K-12 program, introduced in 2013, added two more years to the basic education system. It includes Kindergarten, six years of elementary education, four years of Junior High School, and two years of Senior High School. The K-12 program aims to provide sufficient time for mastery of concepts and skills, develop lifelong learners, and prepare graduates for tertiary education, middle-level skills development, employment, and entrepreneurship. The major advantage of this system is that it aligns the Philippines' educational system with international standards. However, its implementation has faced challenges such as budget constraints, lack of facilities, and the need for teacher training. (DepEd, 2013)

In conclusion, as a researcher and a teacher each educational system has its strengths and weaknesses. The 6-4 system provided a solid academic foundation but lacked holistic education. The BEC improved on this by including more subjects for well-rounded development but faced resource challenges. The K-12 system aligns with international standards and prepares students better for their future but requires significant investment in resources. It is essential to continually assess and improve these systems to provide the best education for future generations.

The Philippine education system has several positive aspects:
1. Strong Emphasis on English Proficiency: English is widely used as a medium of instruction in Philippine schools. This emphasis on English proficiency has led to a high level of English language skills among Filipinos, which is advantageous in global communication and job opportunities.

2. High Literacy Rate: The Philippines has made significant progress in achieving a high literacy rate. Basic education is free and accessible to most Filipino children, resulting in improved literacy levels across the country.

3. Strong Higher Education System: The Philippines has a robust higher education system with many reputable universities and colleges. These institutions offer a wide range of degree programs and produce graduates who are sought-after in various fields.

4. Skilled Workforce: The country produces many skilled professionals in fields such as nursing, engineering, information technology, and business administration. Many Filipinos excel in technical and vocational fields, making them valuable contributors to the local and global workforce.

5. Cultural Diversity and Multilingualism: The Philippines is a culturally diverse country with multiple languages and dialects. This diversity promotes cultural appreciation and tolerance among students, fostering a rich multicultural environment in schools.

6. Strong Global Presence: Filipino professionals, particularly in fields like nursing, teaching, and the IT sector, are highly regarded internationally. Many Filipino workers globally contribute to the development of other countries and remit significant amounts of money back to the Philippines, boosting the economy.

7. Resilience and Adaptability: Filipino students often display resilience and adaptability, which are valuable qualities in a rapidly changing world. Despite challenges, many Filipino students demonstrate a strong work ethic and dedication to their studies. (DepEd, n.d.)

It is important to note that while there are positive aspects, there are also areas in the education system that need improvement, such as infrastructure, access to quality education in remote areas, and addressing socio-economic disparities.

References:
Barrot, J. S. (2021). K to 12 curriculum reform in the Philippines: Towards making students future ready. Asia Pacific Journal of Education, 1-15.

Benavot, A., & Riddle, P. (1988). The expansion of primary education, 1870-1940: Trends and Issues. Sociology of education, 191-210.

Bernardo, A. B., & Mendoza, R. J. (2009). Makabayan in the Philippine basic education curriculum: Problems and prospect for reforming student learning in the Philippines. In Reforming learning: Concepts, issues, and practice in the Asia-Pacific Region (pp. 181-197). Dordrecht: Springer Netherlands.

Constantino, R., & Constantino, L. R. (1975). The Philippines: A past revisited (Vol. 1). Quezon City: Renato Constantino.

Department of Education. (2013). Enhanced Basic Education Act of 2013. Retrieved from https://www.officialgazette.gov.ph/2013/05/15/republic-act-no-10533/

Department of Education. (n.d.). https://www.deped.gov.ph/

Durban, J. M., & Catalan, R. D. (2012). Issues and concerns of Philippine education through the years. Asian Journal of Social Sciences & Humanities, 1(2), 61-69.

Lasco, G. (2018). " Little brown brothers": Height and the Philippine–American colonial encounter (1898–1946). Philippine Studies: Historical & Ethnographic Viewpoints, 375-406.

Maca, M., & Morris, P. (2014). 12 National identity formation and the portrayal of the Japanese occupation in Filipino textbooks1. Imagining Japan in Post-war East Asia: Identity Politics, Schooling and Popular Culture, 229.

Santiago, L. P. (1995). " To love and to suffer": the development of the religious congregations for women in the Philippines during the Spanish era (1565-1898). Philippine quarterly of culture and society, 23(2), 151-195.

Waters, A., & Vilches, M. L. C. (2008). Factors affecting ELT reforms: The case of the Philippines basic education curriculum. RELC Journal, 39(1), 5-24.'

title: User:Tony Rose Orge-Monzales/sandbox


text:
User talk:Tony Rose Orge-Monzales

Your edit filter report
You had too many URLs in your edit. I have made the edit for you in your sandbox here User:Tony Rose Orge-Monzales/sandbox MarcGarver (discuss • contribs) 13:54, 20 September 2023 (UTC)

title: User talk:Tony Rose Orge-Monzales