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by LymeScience Editor | posted in: Document repository, Science vs myths | 0
This 2007 article—originally published in the New England Journal of Medicine by 31 doctors and scientists—fully deconstructs the social phenomenon of chronic Lyme disease.
See also "The NEJM Takes On Lyme Quackery", by Dr. Steven Novella.
Because the authors include US federal employees, the content should be in the public domain.
The original PDF is also available. Due to space limitations, Tables 1 and 2 are not displayed below.
A Critical Appraisal of "Chronic Lyme Disease"
Categories of chronic Lyme disease
Treatment of post–Lyme disease symptoms
Persistent B. Burgdorferi infection and post–Lyme disease symptoms
Advice to clinicians
Chronic Lyme disease in the public domain
Advice to Clinicians Web Addendum
Henry M. Feder, Jr., M.D., Barbara J.B. Johnson, Ph.D., Susan O'Connell, M.D., Eugene D. Shapiro, M.D., Allen C. Steere, M.D., Gary P. Wormser, M.D., and the Ad Hoc International Lyme Disease Group
Lyme disease, the most common tick-borne infection in the northern hemisphere, is a serious public health problem. In North America, it is caused exclusively by Borrelia burgdorferi sensu stricto (hereafter referred to as B. burgdorferi), whereas in Europe it is caused by B. afzelii, B. garinii, B. burgdorferi, and occasionally by other species of borrelia.1
This complex infection has a number of objective manifestations, including a characteristic skin lesion called erythema migrans (the most common presentation of early Lyme disease), certain neurologic and cardiac manifestations, and pauciarticular arthritis (the most common presentation of late Lyme disease), all of which usually respond well to conventional antibiotic therapy.2 Despite resolution of the objective manifestations of infection after antibiotic treatment, a minority of patients have fatigue, musculoskeletal pain, difficulties with concentration or short-term memory, or all of these symptoms. In this article, we refer to these usually mild and self-limiting subjective symptoms as "post–Lyme disease symptoms," and if they last longer than 6 months, we call them "post–Lyme disease syndrome."
The word "chronic" has been applied to Lyme disease in a wide variety of contexts and is sometimes used interchangeably with the preferred term "late Lyme disease." For example, in Europe, certain late neurologic manifestations of previously untreated or inadequately treated infection, such as borrelial encephalomyelitis or long-standing meningitis, have been referred to as "chronic neuroborreliosis" (Table 1: Selected Late or Long-Term Manifestations of Borrelia burgdorferi Infection.).1-3 In the United States, reports have described untreated patients with recurrent or persistent arthritis that lasts for up to several years, presumably because of active infection.4 The focus of this review, however, is not the objective manifestations of late Lyme disease but rather the imprecisely defined condition referred to as "chronic Lyme disease." This term is used by a small number of practitioners (often self-designated as "Lyme-literate physicians") to describe patients whom they believe have persistent B. burgdorferi infection, a condition they suggest requires long-term antibiotic treatment and may even be incurable.5 Although chronic Lyme disease clearly encompasses post–Lyme disease syndrome, it also includes a broad array of illnesses or symptom complexes for which there is no reproducible or convincing scientific evidence of any relationship to B. burgdorferi infection. Chronic Lyme disease is used in North America and increasingly in Europe as a diagnosis for patients with persistent pain, neurocognitive symptoms, fatigue, or all of these symptoms, with or without clinical or serologic evidence of previous early or late Lyme disease.
The diagnosis of chronic Lyme disease and its treatment differ substantively from the diagnosis and treatment of recognized infectious diseases. The diagnosis is often based solely on clinical judgment rather than on well-defined clinical criteria and validated laboratory studies, and it is often made regardless of whether patients have been in areas where Lyme disease is endemic.6,7 Although proponents of the chronic Lyme disease diagnosis believe that patients are persistently infected with B. burgdorferi, they do not require objective clinical or laboratory evidence of infection as a diagnostic criterion.5,8-10
Several lines of reasoning are used to provide support for this diagnostic rationale. One is the unproven and very improbable assumption that chronic B. burgdorferi infection can occur in the absence of antibodies against B. burgdorferi in serum (Table 2: Laboratory Diagnosis of Lyme Disease and Chronic Lyme Disease in North America.). Negative results of serologic tests are often attributed to previous antibiotic therapy or to the theory that chronic infection with B. burgdorferi suppresses humoral immune responses; neither theory is well supported by scientific data.12-14 When physicians who diagnose chronic Lyme disease obtain laboratory tests to provide support for their diagnoses, they often rely heavily on "Lyme specialty laboratories." Such laboratories may perform unvalidated in-house tests that are not regulated by the Food and Drug Administration, or they may perform standard serologic tests interpreted with the use of criteria that are not evidence-based.11,12,15-17
Once the diagnosis of chronic Lyme disease is made, patients are commonly treated for months to years with multiple antimicrobial agents, some of which are inactive in vitro against B. burgdorferi.2,5,18-20 Antibiotics may be prescribed either simultaneously or sequentially, and they are often administered parenterally. Occasionally, these patients are treated with unconventional and highly dangerous methods such as bismuth injections or deliberate inoculation of plasmodia to cause malaria.2,21,22 No other spirochetal infection, including the neurologic complications of tertiary syphilis, is managed in an analogous fashion.2,23 The duration of treatment commonly prescribed for chronic Lyme disease often far surpasses even the conventional 6-month course of therapy successfully used for most cases of tuberculosis.
The Four Predominant Categories of Disease Associated with Chronic Lyme Disease.
Category 1: Symptoms of unknown cause, with no evidence of Borrelia burgdorferi infection
Category 2: A well-defined illness unrelated to B. burgdorferi infection
Category 3: Symptoms of unknown cause, with antibodies against B. burgdorferi but no history of objective clinical findings that are consistent with Lyme disease
Category 4: Post–Lyme disease syndrome
Only patients with category 4 disease have post–Lyme disease symptoms.
Diagnoses of chronic Lyme disease appear to fall predominantly into one of four categories (Figure 1).8-10 Patients with category 1 disease do not have objective clinical manifestations or laboratory evidence of B. burgdorferi infection, and they receive a diagnosis on the basis of the presence of nonspecific symptoms such as fatigue, night sweats, sore throat, swollen glands, stiff neck, arthralgia, myalgia, palpitations, abdominal pain, nausea, diarrhea, sleep disturbance, poor concentration, irritability, depression, back pain, headache, and dizziness.5 Nonspecific symptoms such as these are common, and some occur in more than 10% of the general population, regardless of whether Lyme disease is endemic in the area.24,25
Patients with category 2 disease have identifiable illnesses or syndromes other than Lyme disease. Such patients may or may not have a history of Lyme disease. They have received either a misdiagnosis or a diagnosis (e.g., multiple sclerosis) that they are reluctant to accept and have sought an alternative diagnosis from a physician willing to treat them for chronic Lyme disease.
Data from studies of patients who underwent reevaluation at academic medical centers suggest that the majority of patients presumed to have chronic Lyme disease have category 1 or 2 disease.8-10 Since patients in these two categories do not have evidence of active infection with B. burgdorferi, the potential benefit of treating them with antibiotics, beyond a placebo effect, would be attributable to the antiinflammatory or other nonantimicrobial effects of antibiotics.26 Antibiotic therapy in these patients is not warranted.
Patients with category 3 disease do not have a history of objective clinical findings that are consistent with Lyme disease, but their serum samples contain antibodies against B. burgdorferi, as determined by means of standardized assays that were ordered to investigate chronic, subjective symptoms of unknown cause.27 Patients with disease in this category have at most only equivocal evidence of B. burgdorferi infection, since the predictive value of positive serologic results in this setting is low.27,28 Although some clinicians would offer patients with category 3 disease an empirical trial of 2 to 4 weeks of an oral antibiotic, such patients should be told that the diagnosis is uncertain and that a benefit from treatment is unlikely.
Patients with category 4 disease have symptoms associated with post–Lyme disease syndrome.29-31 In prospective studies of patients with erythema migrans, subjective symptoms of unknown cause were present 1 year or more after treatment in 0.5 to 13.1% of patients.31 Whether this prevalence exceeds that of such symptoms in the general population is unknown, since none of these studies included a control group. A meta-analysis suggested that the prevalence of such symptoms exceeded that in control groups without Lyme disease, but this analysis relied on several retrospective studies in which the diagnosis and treatment of Lyme disease often did not meet current standards.30,31
Controlled treatment trials have been conducted only for patients with category 4 disease. Data from three double-blind, randomized, placebo-controlled trials have shown that there is substantial risk, with little or no benefit, associated with additional antibiotic treatment for patients who have long-standing subjective symptoms after appropriate initial treatment for an episode of Lyme disease.32-34
One of these trials enrolled 78 patients who were seropositive for antibodies against B. burgdorferi at trial entry; a second trial enrolled 51 patients who were seronegative.32 All patients had antecedent objective signs of Lyme disease, most often physician-diagnosed erythema migrans. Patients were treated either with a 1-month course of ceftriaxone administered intravenously, followed by 2 months of doxycycline given orally, or with identical-appearing intravenous and then oral placebos. Patients were assessed at enrollment and 3 months after completion of treatment with the use of the Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36). There were no significant differences in the scores between the patients in the antibiotic and placebo groups.
In a single-center trial conducted by Krupp et al., 55 patients with severe fatigue (as measured by an 11-item questionnaire) after treatment of well-documented Lyme disease underwent randomization to receive ceftriaxone or an identical-appearing placebo for 28 days.33 The investigators reported a reduction in scores for fatigue severity in the ceftriaxone group that exceeded the reduction in the placebo group by 13 percentage points (i.e., a reduction of 22% vs. 9%; P=0.01) but no significant improvement in cognitive function. There was no significant difference between the groups with regard to the degree of improvement in reported health status on the basis of the SF-36 score. Patients in the ceftriaxone group were significantly more likely than those in the placebo group to identify their treatment assignment correctly at the end of therapy, raising a concern that masking was compromised and that a placebo effect may explain the greater improvement in scores for fatigue severity in the treated group.33
Antibiotic therapy can cause considerable harm to patients treated for chronic Lyme disease or post–Lyme disease symptoms.2 Life-threatening anaphylaxis33 and biliary complications requiring cholecystectomy35 have occurred after ceftriaxone administration. Candidemia from infection of an intravenous catheter has resulted in death.36 In an unpublished study in which 37 patients underwent randomization to receive 10 weeks of treatment with either ceftriaxone or placebo, about one fifth of the patients had serious adverse events, the majority of which were related to intravenous catheters.37 In light of the risk of serious adverse events in their study, Krupp et al. concluded that "repeated courses of antibiotic treatment are not indicated for persistent symptoms following Lyme disease, including those related to fatigue and cognitive dysfunction."33
Eligibility criteria for two controlled trials stipulated that symptoms must be severe enough to interfere with the patient's ability to function.32 Thus, the physical health status of the patients enrolled in these two studies was equivalent to that of patients with congestive heart failure or osteoarthritis.32 This finding was preordained by the study design, but it has been incorrectly interpreted by some to indicate that patients with post–Lyme disease symptoms typically are severely disabled.
The investigators who conducted the controlled treatment trials had great difficulty finding patients who met the criteria for entry, despite intensive efforts that included both the notification and involvement of Lyme disease support groups and associations.32,33 For two of the three studies, additional sites had to be engaged,32 and the enrollment period had to be extended for all three studies.32,33 To enroll 55 patients in one of the studies, investigators had to screen more than 500 people, most of whom were excluded because of the absence of a substantiated history of Lyme disease.33 This difficulty with enrollment appears to reflect the scarcity of persons with well-documented Lyme disease in whom clinically significant problems develop after conventional treatment.
Although anecdotal evidence and findings from uncontrolled studies have been used to provide support for long-term treatment of chronic Lyme disease,18-20 a response to treatment alone is neither a reliable indicator that the diagnosis is accurate nor proof of an antimicrobial effect of treatment. Many patients with intermittent or self-limited symptoms may feel better over time as a result of the natural course of their condition, and controlled trials indicate that nearly 40% of patients with post–Lyme disease symptoms have a positive response to placebo.32 In addition, the assessment of a change in symptoms may be confounded by antiinflammatory and other nonantimicrobial effects of antibiotics.26 Furthermore, the published reports of uncontrolled trials of antibiotic treatment for chronic Lyme disease used poorly standardized case definitions and either undefined criteria for interpreting immunoblots or criteria that have subsequently been found to have very low specificity (approximately 60%).38
A report by Phillips and colleagues39 is often cited to provide support for the hypothesis of persistent B. burgdorferi infection. They indicated that they detected B. burgdorferi in blood specimens from 43 of 47 patients who had received or were receiving prolonged antibiotic therapy for chronic Lyme disease (91%). Other investigators have been unable to reproduce these findings in patients with well-documented post–Lyme disease syndrome.32,40-42 Moreover, Phillips and colleagues used a new culture medium that specifically included Detroit tap water; this medium was subsequently shown to be bactericidal for B. burgdorferi.41 In contrast to the findings from their report,39 B. burgdorferi could not be detected in any of 843 specimens of blood or cerebrospinal fluid, tested by means of either culture or polymerase chain reaction (PCR), from the 129 patients enrolled in two of the controlled treatment trials.32,40 Moreover, there was no serologic evidence of tick-borne coinfections in the vast majority of patients.32
In another report, DNA of B. burgdorferi was detected by means of PCR in urine specimens from nearly three quarters of 97 patients who had received the diagnosis of chronic Lyme disease.43 However, the authors did not sequence the amplicons to confirm that the DNA was from B. burgdorferi. Such a high rate of positive results among patients who had been treated extensively with antibiotics is unlikely when one considers that only 1 of 12 urine samples (8%) from untreated patients with erythema migrans was found to be positive in a careful evaluation of this technique's value as a diagnostic test.44 Moreover, detection of bacterial DNA is not necessarily an indicator of either active infection or clinical disease.45 The central question is not whether a few spirochetes might persist after antibiotic treatment, but whether clinical disease can be attributed to their presence.
It is highly unlikely that post–Lyme disease syndrome is a consequence of occult infection of the central nervous system. This conclusion is based on evidence such as the absence of inflammation in the cerebrospinal fluid,32,33 negative results of both cultures and PCR assays for B. burgdorferi in the cerebrospinal fluid,32,40 the absence of structural abnormalities of the brain parenchyma,46 and normal neurologic function, with no effect of antibiotic therapy (as compared with placebo) on cognitive function.33,34
Additional evidence against the hypothesis that chronic symptoms are due to persistent infection is the fact that antibodies against B. burgdorferi in many of these patients are undetectable, which is inconsistent with the well-established immunogenicity of the spirochete's lipoproteins.13,14,20,29,32,47 Patients in whom treatment for most infectious diseases, including syphilis, has failed typically have persistent or rising titers of antibodies because of ongoing B-cell stimulation by microbial antigens.23
The lack of convincing evidence for the persistence of B. burgdorferi in treated patients (Table 3: Evidence against Active Infection in Patients with Subjective Symptoms Persisting for More Than 6 Months after Antibiotic Treatment for Lyme Disease.) is not surprising.2,20,23,24,29-33,40,47-49 The failure of treatment for bacterial infections typically occurs as a result of pathogens that either have or acquire resistance to antibiotics, difficulties in achieving sufficient concentrations of antibiotic at sites of infection, or impaired host-defense mechanisms.2 None of these factors are generally applicable to infection with B. burgdorferi. Although B. burgdorferi can develop into cystlike forms in vitro under certain conditions that can be created in the laboratory,50 there is no evidence that this phenomenon has any clinical relevance. B. burgdorferi may penetrate cells in vitro, but there is no evidence that the organism may be sheltered from antibiotics during an intracellular phase and then disseminate and cause clinical relapse.51,52 Indeed, the strategies used by B. burgdorferi to adapt to the vertebrate host and evade host defenses indicate an extracellular existence.53
Evidence against Active Infection in Patients with Subjective Symptoms Persisting for More Than 6 Months after Antibiotic Treatment for Lyme Disease.
Absence of concomitant objective clinical signs of either disease or inflammation and no progression to objective signs or development of inflammation29,32
Similar symptoms common in persons who have never had Lyme disease24,25,30,31,48
Persistence of symptoms independently of persistent seropositivity20,29,32,47
Absence of either positive cultures or positive polymerase-chain-reaction results from clinical specimens32,40
No substantive response to antibiotic therapy in controlled treatment
trials32-34
No documented resistance of Borrelia burgdorferi to recommended antibiotics2
Absence of recognized risks for failure of antibiotic therapy; these include host immunodeficiency or an infection in which there is local ischemia, a foreign body (biofilm), a sequestrum, or an abscess2
Other evidence
Certain studies in animals2
Lack of precedent for the use of long-term antibiotic treatment in other spirochetal infections23,49
How should clinicians handle the referral of symptomatic patients who are purported to have chronic Lyme disease? The scientific evidence against the concept of chronic Lyme disease should be discussed and the patient should be advised about the risks of unnecessary antibiotic therapy. The patient should be thoroughly evaluated for medical conditions that could explain the symptoms. If a diagnosis for which there is a specific treatment cannot be made, the goal should be to provide emotional support and management of pain, fatigue, or other symptoms as required.54-56 Explaining that there is no medication, such as an antibiotic, to cure the condition is one of the most difficult aspects of caring for such patients. Nevertheless, failure to do so in clear and empathetic language leaves the patient susceptible to those who would offer unproven and potentially dangerous therapies. Additional advice to clinicians is included in the Supplementary Appendix, available with the full text of this article at www.nejm.org.
Physicians and laypeople who believe in the existence of chronic Lyme disease have formed societies, created charitable foundations, started numerous support groups (even in locations in which B. burgdorferi infection is not endemic), and developed their own management guidelines.5 Scientists who challenge the notion of chronic Lyme disease have been criticized severely.
The attorney general of Connecticut has begun an unprecedented antitrust investigation of the Infectious Diseases Society of America, which issued treatment guidelines for Lyme disease that do not support open-ended antibiotic treatment regimens.2 In some states, legislation has been proposed to require insurance companies to pay for prolonged intravenous therapy to treat chronic Lyme disease. The media frequently disregard complex scientific data in favor of testimonials about patients suffering from purported chronic Lyme disease and may even question the competence of clinicians who are reluctant to diagnose chronic Lyme disease. All these factors have contributed to a great deal of public confusion with little appreciation of the serious harm caused to many patients who have received a misdiagnosis and have been inappropriately treated.
Chronic Lyme disease is the latest in a series of syndromes that have been postulated in an attempt to attribute medically unexplained symptoms to particular infections. Other examples that have now lost credibility are "chronic candida syndrome" and "chronic Epstein–Barr virus infection."57,58 The assumption that chronic, subjective symptoms are caused by persistent infection with B. burgdorferi is not supported by carefully conducted laboratory studies or by controlled treatment trials. Chronic Lyme disease, which is equated with chronic B. burgdorferi infection, is a misnomer, and the use of prolonged, dangerous, and expensive antibiotic treatments for it is not warranted.2
Clinicians who care for patients who have been diagnosed with chronic Lyme disease should carefully review the evidence on which the diagnosis was based, especially for patients who do not have post-Lyme disease syndrome but fall into categories 1-3 (as defined in the text). It is helpful to review symptoms, potential exposure to vector ticks and any laboratory evidence that may have been cited in support of the diagnosis. The nonspecific nature of the symptoms listed in reference 5 should be emphasized and their frequent occurrence in the general population discussed [27,28]. Potential exposure in an endemic area or a remote history of either a rash or an insect bite is not sufficient evidence to assume that a skin lesion was erythema migrans or that the "insect" bite was really the bite of an Ixodes tick, the vector of B. burgdorferi.
A sizeable proportion of patients with purported chronic Lyme disease will have received "positive" results from laboratories that utilized either unvalidated methods or unproven criteria to interpret the results; both lead to a high rate of false-positive results [15,38]. The poor reliability and the low positive predictive value of such findings should be indicated to patients who have been diagnosed in this fashion [15,28].
Many patients treated for chronic Lyme disease and the clinicians who prescribe their treatment regard an improvement in symptoms following antibiotic treatment as confirmation of the diagnosis. In addition to addressing possible placebo effects, it may be useful to explain that commonly used antibiotics, including tetracyclines, macrolides and certain beta lactams, have numerous non-antimicrobial properties, including anti inflammatory, immunomodulatory and neuroprotective effects [26; Ianaro A, Ialenti A, Maffia P, et al. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther 2000;292:156-163; Rothstein JD, Patel S, Regan MR et al. B lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005;433:73-77]. These agents may have temporary modifying effects on many disease processes, but all can cause potentially serious adverse effects as well. In addition, prolonged use of antibiotics will select for antibiotic-resistant bacteria in the patients being treated, which may also spread within the community.
Paradoxically, many patients treated for chronic Lyme disease and the clinicians who prescribe their treatment also interpret worsening of symptoms while being treated with antibiotics as confirmation of the diagnosis, since they believe this to be related to spirochetal killing, i.e., a Jarisch-Herxheimer reaction (or as "herxing" in the jargon frequently used). Some practitioners treating chronic Lyme disease assert that these reactions may occur at any time during the treatment course, despite evidence that these reactions are only seen in early disease and then are usually confined to the first 24 hours of treatment [2]. Making matters worse, reluctance to consider that the patient's deteriorating state may instead be due to the natural history of the underlying condition that was not diagnosed or to a drug-related adverse event places the patient in jeopardy. Most patients with medically unexplained symptoms who received a diagnosis of chronic Lyme disease will require emotional and psychological support in addition to symptomatic management. For example, many patients with post-Lyme disease syndrome fear that their symptoms are indicative of a chronic infection that may cause neurologic damage. These concerns should be openly addressed and the patients reassured [32-34]. There is no substitute for sympathetic listening and explanation [Steere AC. A 58-year-old man with a diagnosis of chronic Lyme disease. JAMA 2002;288:1002-10].
Chronic Lyme disease shares many of the clinical features of functional somatic syndromes, especially the presence of diffuse nonspecific symptoms such as fatigue, muscle and joint pains and problems with memory and concentration, in the absence of objective evidence of tissue inflammation or damage. A collaborative approach between physician and patient is crucial to the goals of palliation of symptoms and rehabilitation, and the patient should be encouraged to take an active role in the treatment process [54-56; Barsky AJ, Borus JF. Functional somatic syndromes. Ann Intern Med 1999;130:910- 921.].
Physicians in endemic areas have an opportunity and a responsibility to provide anticipatory counseling to every patient with Lyme disease whom they treat. It is to be expected that the patient will soon encounter inaccurate information about the prognosis from some members of their community or from the internet [Cooper JD, Feder HM Jr. Inaccurate information about Lyme disease on the internet. Pediatr Infect Dis J 2004;23:1105-08]. The physician should "arm" them with an explanation of: the antibiotic-responsive nature of this infection and its lack of persistence; the limited number of manifestations that do occur in Lyme disease; reliable sources of information [Sood SK Effective retrieval of Lyme disease information on the Web. Clin Infect Dis 2002;35:451-64]; and the high likelihood that they will hear otherwise when they share their diagnosis with friends. They should be informed that it is not rare for mild symptoms such as fatigue, musculoskeletal pain and/or perceived difficulties with memory to continue beyond the usual treatment duration of 14 days (range 10-28 days) [2]. Retreatment with antibiotics does not accelerate the rate of resolution of these symptoms, which typically diminish and resolve over several weeks to several months [Oksi J, Nikoskelainen J, Hiekanen H, et al. Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind, randomized, placebo-controlled, multicenter clinical study. Eur J Clin Microbiol Infect Dis 2007;June 22; Wormser GP, Ramanathan R, Nowakowski J, et al. Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003;138:697-704; Dattwyler RJ, Wormser GP, Rush TJ, et al. A comparison of two treatment regimens of ceftriaxone in late Lyme disease. Wien Klin Wochenschr 2005;117:393-7; Wormser GP. Clinical practice. Early Lyme disease. N Engl J Med 2006;354:2794-801.] Patients should be instructed to return to the physician promptly if objective signs develop, such as joint swelling, recurrent skin rash, weakness of facial or other muscles, or severe headache. Such an anticipatory approach provides a positive therapeutic boost to the patient who is often anxious about receiving the diagnosis of Lyme disease, and may help to prevent the spurious diagnosis of chronic Lyme disease.
The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
Dr. Feder reports receiving lecture fees from Merck and serving as an expert witness in medical-malpractice cases related to Lyme disease. Dr. Johnson reports holding patents on diagnostic antigens for Lyme disease. Dr. O'Connell reports serving as an expert witness related to Lyme disease issues in civil and criminal cases in England. Dr. Shapiro reports serving as an expert witness in medical-malpractice cases related to Lyme disease, reviewing claims of disability related to Lyme disease for Metropolitan Life Insurance Company, and receiving speaker's fees from Merck and Sanofi-Aventis. Dr. Steere reports receiving a research grant from Viramed and fees from Novartis. Dr. Wormser reports receiving research grants related to Lyme disease from Immunetics, Bio-Rad, and Biopeptides and education grants from Merck and AstraZeneca to New York Medical College for visiting lecturers for infectious-disease grand rounds, being part owner of Diaspex (a company that is now inactive with no products or services), owning equity in Abbott, serving as an expert witness in a medical-malpractice case, and being retained in other medical-malpractice cases involving Lyme disease. He may become a consultant to Biopeptides. No other potential conflict of interest relevant to this article was reported.
We thank Alex P. Butensky, Julie Chacko, Rachel Hart, and Lisa Giarratano for assistance.
From the Departments of Family Medicine and Pediatrics, Connecticut Children's Medical Center, Hartford, and University of Connecticut Health Center, Farmington (H.M.F.); Microbiology Laboratory, Division of Vector-Borne Infectious Diseases, Centers for Diseases Control and Prevention, Fort Collins, CO (B.J.B.J.); Lyme Borreliosis Unit, Health Protection Agency Microbiology Laboratory, Southampton General Hospital, Southampton, United Kingdom (S.O.); Departments of Pediatrics and Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT (E.D.S.); Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston (A.C.S.); and the Division of Infectious Diseases, Department of Medicine, New York Medical College, Valhalla (G.P.W.)
Other members of the Ad Hoc International Lyme Disease Group who were authors are listed in the Appendix.
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Sexually transmitted diseases treatment guidelines, 2006. MMWR Recomm Rep 2006;55:1-94
Wessely S. Chronic fatigue: symptoms and syndrome. Ann Intern Med 2001;134:838-843
Luo N, Johnson JA, Shaw JW, Feeny D, Coons SJ. Self-reported health status of the general adult U.S. population as assessed by the EQ-5D and Health Utilities Index. Med Care 2005;43:1078-1086
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Lightfoot RW Jr, Luft BJ, Rahn DW, et al. Empiric parenteral antibiotic treatment of patients with fibromyalgia and fatigue and a positive serologic test for Lyme disease: a cost-effectiveness analysis. Ann Intern Med 1993;119:503-509
Tugwell P, Dennis DT, Weinstein A, et al. Laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med 1997;127:1109-1123
Nowakowski J, Nadelman RB, Sell R, et al. Long-term follow-up of patients with culture-confirmed Lyme disease. Am J Med 2003;115:91-96
Cairns V, Godwin J. Post-Lyme borreliosis syndrome: a meta-analysis of reported symptoms. Int J Epidemiol 2005;34:1340-1345
Shapiro ED, Dattwyler R, Nadelman RB, Wormser GP. Response to meta-analysis of Lyme borreliosis symptoms. Int J Epidemiol 2005;34:1437-1439
Klempner MS, Hu LT, Evans J, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001;345:85-92
Krupp LB, Hyman LG, Grimson R, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003;60:1923-1930
Kaplan RF, Trevino RP, Johnson GP, et al. Cognitive function in post-treatment Lyme disease: do additional antibiotics help? Neurology 2003;60:1916-1922
Ettestad PJ, Campbell GL, Welbel SF, et al. Biliary complications in the treatment of unsubstantiated Lyme disease. J Infect Dis 1995;171:356-361
Patel R, Grogg KL, Edwards WD, Wright AJ, Schwenk NM. Death from inappropriate therapy for Lyme disease. Clin Infect Dis 2000;31:1107-1109
Fallon BA, Sackheim HA, Keilp J, et al. Double-blind placebo-controlled retreatment with IV ceftriaxone for Lyme encephalopathy: clinical outcome. Presented at the 10th International Conference on Lyme Borreliosis and Other Tick-Borne Diseases, Vienna, Austria, September 11–15, 2005.
Wormser GP, Dattwyler RJ, Shapiro E, et al. Reply to Pollack, Donta, Wilson and Arnez. Clin Infect Dis 2007;44:1137-1139
Phillips SE, Mattman LH, Hulinska D, Moayad H. A proposal for the reliable culture of Borrelia burgdorferi from patients with chronic Lyme disease, even from those previously aggressively treated. Infection 1998;26:364-367
Klempner MS. Controlled trials of antibiotic treatment in patients with post-treatment chronic Lyme disease. Vector Borne Zoonotic Dis 2002;2:255-263
Marques AR, Stock F, Gill V. Evaluation of a new culture medium for Borrelia burgdorferi. J Clin Microbiol 2000;38:4239-4241
Tilton RC, Barden D, Sand M. Culture of Borrelia burgdorferi. J Clin Microbiol 2001;39:2747-2747
Bayer ME, Zhang L, Bayer MH. Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme disease symptoms: a PCR study of 97 cases. Infection 1996;24:347-353
Rauter C, Mueller M, Diterich I, et al. Critical evaluation of urine-based PCR assay for diagnosis of Lyme borreliosis. Clin Diagn Lab Immunol 2005;12:910-917
Hellyer TJ, Fletcher TW, Bates JH, et al. Strand displacement amplification and the polymerase chain reaction for monitoring response to treatment in patients with pulmonary tuberculosis. J Infect Dis 1996;173:934-941
Morgen K, Martin R, Stone RD, et al. FLAIR and magnetization transfer imaging of patients with post-treatment Lyme disease syndrome. Neurology 2001;57:1980-1985
Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A. Lyme disease: an infectious and postinfectious syndrome. J Rheumatol 1994;21:454-461
Sigal LH, Patella SJ. Lyme arthritis as the incorrect diagnosis in pediatric and adolescent fibromyalgia. Pediatrics 1992;90:523-528
Wormser GP. Lyme disease: insights into the use of antimicrobials for prevention and treatment in the context of experience with other spirochetal infections. Mt Sinai J Med 1995;62:188-195
Alban PS, Johnson PW, Nelson DR. Serum-starvation-induced changes in protein synthesis and morphology of Borrelia burgdorferi. Microbiology 2000;146:119-127
Livengood JA, Gilmore RD Jr. Invasion of human neuronal and glial cells by an infectious strain of Borrelia burgdorferi. Microbes Infect 2006;8:2832-2840
Pachner AR, Gelderblom H, Cadavid D. The rhesus model of Lyme neuroborreliosis. Immunol Rev 2001;183:186-204[Erratum, Immunol Rev 2002;187:139.]
Pal U, Fikrig E. Adaptation of Borrelia burgdorferi in the vector and vertebrate host. Microbes Infect 2003;5:659-666
Goldenberg DL, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA 2004;292:2388-2395
Prins JB, van der Meer JW, Bleijenberg G. Chronic fatigue syndrome. Lancet 2006;367:346-355
Richardson RD, Engel CC Jr. Evaluation and management of medically unexplained physical symptoms. Neurologist 2004;10:18-30
Sigal LH, Hassett AL. Contributions of societal and geographical environments to "chronic Lyme disease": the psychopathogenesis and aporology of a new "medically unexplained symptoms" syndrome. Environ Health Perspect 2002;110:607-611
Renfro L, Feder HM Jr, Lane TJ, Manu P, Matthews DA. Yeast connection among 100 patients with chronic fatigue. Am J Med 1989;86:165-168
The following members of the Ad Hoc International Lyme Disease Group were also authors:
Gundersen Lutheran Medical Foundation, La Crosse, WI — W.A. Agger
National Microbiology Laboratory, Health Canada, Winnipeg, MB, Canada — H. Artsob
Johns Hopkins Medical Institutions, Baltimore — P. Auwaerter, J.S. Dumler
St. Luke's Hospital, Duluth, MN — J.S. Bakken
Yale University School of Medicine, New Haven, CT — L.K. Bockenstedt, J. Green
New York Medical College, Valhalla — R.J. Dattwyler, J. Munoz, R.B. Nadelman, I. Schwartz
Danbury Hospital, Danbury, CT — T. Draper
Johns Hopkins Medical Institutions, Crofton, MD — E. McSweegan
Atlantic Neuroscience Institute, Summit, NJ, and the New York University School of Medicine, New York — J.J. Halperin
Boston University School of Medicine and Boston Medical Center, Boston — M.S. Klempner
University of Connecticut School of Medicine and Connecticut Children's Medical Center, Farmington — P.J. Krause
Centers for Disease Control and Prevention, Fort Collins, CO — P. Mead
University of British Columbia, Vancouver, Canada — M. Morshed
University of Medicine and Dentistry of New Jersey– Robert Wood Johnson Medical School, Piscataway — R. Porwancher
University of Connecticut Health Center, Farmington — J.D. Radolf
Maine Medical Center, Portland, ME — R.P. Smith, Jr.
Schneider Children's Hospital at North Shore, Manhasset, NY — S. Sood
Washington Hospital Center and Georgetown University Medical Center, Washington, DC — A. Weinstein
Wadsworth Center, New York State Department of Health, Albany — S.J. Wong
Connecticut Children's Medical Center, University of Connecticut, Hartford — L. Zemel.
CDC, Doctor and scientist commentaries


More Made In England New Balance goodness right here, with this double offering of the legendary 577 in two reserved make-ups.
The New Balance Flimby factory here in England has strong credentials and is renowned for its heritage. This Made In England M577 is fine example as to why.
To celebrate the launch of their three-way collaboration, SneakersNStuff, Milkcrate Athletics, and New Balance get together with London boutique Foot Patrol to launch their two limited 577 models this Thursday.
An international effort has led to two New Balance 577 gems, the result of a collaborative effort involving Sweden, England and the United States.
Celebrating Schuh's 30th anniversary, New Balance team up with the long serving UK footwear outlet for a double release of some solid Made In England 577's.
SoleHeaven and New Balance have got a little creative with a couple of pairs of 577's, making this very special and extremely collectable ceramic rendition that is up for grabs to win in a competition.
Next to step up for a collaboration with Size? is New Balance.
We do love a good New Balance collab here at TDS, and when I say good I mean really good. This new 577 pack from 24 Kilates is exactly that.
Here's a peek at the New Balance 577's coming out of the Flimby factory this March.


GEOLOGY MODELLING Full 3D geology model-building including all input/output, editing, visualisation, advanced drill hole management, interpolation of drill hole attributes, 2D/3D grid/mesh visualisation & computation, geology & resource volumetrics, property optimisation. Forward Grav-Mag geophysics modelling in 2.5D & 3D. And forward prediction of synthetic 2D seismographs.


text:
//
//  ParserConfig.h
//  SMIParser
//
//  Created by Kang Jinyeoung on 2016. 12. 31..
//  Copyright © 2016년 SuperbDerrick. All rights reserved.
//

#ifndef ParserConfig_h
#define ParserConfig_h

#define STEPSIZE 100 //Basic Maxsimum size.
#define LINEBYBUFFERMAXIMUMSIZE 1000 //Basic Maxsimum size.

#define CARRAGE_RETURN  "\r\n"
#define NULL_CHAR       '\0'
#endif /* ParserConfig_h */

redpajama_set_name: RedPajamaGithub


This video is a visual interpretation of China's irresistible process of growth through urban development. Series of photographs, computer-generated graphics and sounds are amalgamated together in a 3D virtual environment. Here a process of metamorphosis transforms the existing architectural matter into a fleeting two-dimensional skin, revealing its precariousness. The fragmented reality achieved in the video is a metaphor for the collision of two opposing worlds: one related to contemporary urban development and the other representing China's traditions and spirituality.


text:
United States of Indonesia
Republik Indonesia Serikat
Last modified: 2019-02-18 by zachary harden
Keywords: indonesia | east sumatra | south sumatra |
East Sumatra
Indonesia Timur (East Indonesia)
Indonesia - Index of all pages
South Moluccas
After the WWII the Republic of Indonesia, based in Java, proclaimed its independence from Netherlands (17 August 1945). Its claim to represent the entiere Indonesian archipelago was challenged by the Dutch, who assisted local regimes opposed to Javanese rule to create their own states.
In [e.g.] Sumatra were proclaimed the states of East Sumatra and South Sumatra.
In 1949 the states became part of the United States of Indonesia (27 December 1949) but in 1950 the federal system was supressed and the flags were abolished, after a small resistence in South Moluccas. The flags of the short-lived states are interesting. Jan M. Pluvier in "Historical Atlas of South East Asia" give the list of states (flag colours are reported by Jaume Ollé - all are horizontally striped):
East Sumatra (capital Medam)
South Sumatra (Negara Sumatera Selantan, capital Palembang; the great part of the island is under the rule of the Republic of Indonesia), yellow-green
Billiton
West Borneo (capital Pontianak)
Kotawaringin (in the South West of Borneo, I don't know the capital)
Greater Dajak (central South Borneo, I don't know the capital)
Bandar (capital Bandjarmasin)
South East Borneo
East Borneo (capital Samarinda)
Pasundan (capital Bandung), green-white-green or green-white
East Java (capital Surabaja)
Madura (center and west of the island of Java was under the rule of the republic Indonesia in two parts separated for the state of Pasundan)
East Indonesia (including Bali, Sumbawa, Flores, Sumba, [West] Timor, Molucas and Celebes), yellow-red-white-green
Jaume Ollé, 15 September 1996
image by Jaume Ollé, 15 September 1996
image by Antonio Martins, 19 May 1998
In Flag Master *079*:8 there is a report about the flags of the native states of the Indonesian Federation (1945-1949) which bear no relation (except for Aceh and Riau) to the current provinces. A four stripped flag of yellow-red-white-green (horizontally) is given for a state called Indonesia Timur (meaning East Indonesia), a "Federation of East Indonesian States", according to D. Rühl: "Flag and Arms of the Indonesian Republic" Indonesië *4-2*:104-105.
It should be noted that in Indonesia Timur federal state was included only West Timor, the formerly Dutch half. (Note that "timur" is Malay for "east"; the toponym "Timor" comes from it. Radical and poetically inclined resistants, fighting also the Indonesian language and culture oppression, react prefering the autonym "Mauberia"). West Timor (capital Kupang) was largely under the "empire" (or rather "tribe" federation) of Surviam, while the Portuguese part (East Timor, capital Dili) was mostly the Belos "empire".
Antonio Martins, 19 May 1998
Also the daerah South Moluccas was part of the Federation of East Indonesian States (Negara Indonesia Timur [NIT], established in December 1946).
On 27 December 1949 the Republik Indonesia Serikat (United States of Indonesia) was established. On 4 April 1950 of the 16 original states and territories only four remained: the Republik Indonesia, the NIT and the states East Sumatra and West Borneo. On 15 August 1950 the unitary Republik Indonesia was proclaimed.
During the Linggadjati conference in August 1946 the idea of a United States of Indonesia was accepted by both the Republik Indonesia [based at Yogjakarta, MS] and the Netherlands. Three states were recognised in the treaty: the Republik Indonesia, Borneo and the "Grote Oost" (Great East). Other states were soon established by Lt. Governor-General Van Mook. During the conference in Den Pasar (Bali) on 23 December 1946 the Negara Indonesia Timur (NIT, state East Indonesia) was established.
The national anhtem of the NIT was the "Wilhelmus" (the Dutch anthem) and the flag of the new state was the red-white-blue.
Source: http://dlm.org/ned/Geschiedenis/RMS.Geschiedenis/ (Dutch only; link no longer active)
Mark Sensen, 21 May 1998

redpajama_set_name: RedPajamaCommonCrawl


My latest experience with LaGrange Toyota was I think the best car buying experience I've had. Wayne Pittman was my salesman. He and The LaGrange Toyota Team from the first contact on the lot through the financial department proved the most professional Team Work experience I've ever seen. They worked hard to insure my dream came through and at affordable budget. I can't express my appreciation for the quick action to cut to the best deal and save time. LaGrange Toyota should be your next stop for your next car purchase!!!! Thanks, Wayne, Jason, Bentley, Shane and Mavorick!
My latest experience with LaGrange Toyota was I think the best car buying experience I've had. Wayne Pittman was my salesman. He and The LaGrange Toyota Team from the first contact on the lot through the financial department proved the most professional Team Work experience I've ever seen. They worked hard to insure my dream came through and at affordable budget. I can't express my appreciation for the quick action to cut to the best deal and save time. LaGrange Toyota should be your next stop for your next car purchase!!!! Thanks, Wayne, Jason, Bentley, Shane and Mavorick.
Great customer service. This was my third 4Runner from this dealership. Had great service from my salesman Jim Hunt and Charlie Shirey. I have been satisfied every time. I even drive the 65 miles back to the dealership to have my car serviced.
My latest experience with LaGrange Toyota was I think the best car buying experience I've had. Wayne Pittman was my salesman. He and The LaGrange Toyota Team from the first contact on the lot through the financial department proved the most professional Team Work experience I've ever seen. They worked hard to insure my dream came through and at affordable budget. I can't express my appreciation for the quick action to cut to the best deal and save time. LaGrange Toyota should be your next stop for your next car purchase!!!! Thanks, Wayne, Jason, Bentley, Shane and Mavorick.
My latest experience with LaGrange Toyota was I think the best car buying experience I've had. Wayne Pittman was my salesman. He and The LaGrange Toyota Team from the first contact on the lot through the financial department proved the most professional Team Work experience I've ever seen. They worked hard to insure my dream came through and at affordable budget. I can't express my appreciation for the quick action to cut to the best deal and save time. LaGrange Toyota should be your next stop for your next car purchase!!!!Thanks, Wayne, Jason, Bentley, Shane and Mavorick.
Heather Brown is absolutely the BEST! She put us in a 2015 Kia Sorento, and I'm in love! She made us feel so welcomed at Lagrange Toyota. That's my sis from another Miss! Thank you Heather Brown ❤❤❤❤❤ I would recommend her in a heart beat. If you think it can't be done, leave it in her hands and a dream will come true!
These guys were very respectful and nice. Help me pick what truck I wanted to buy. And a big thanks to Steven Adamson. Great sale sales guy!
My Review of LaGrange Toyota Amulkey34 4/09/2019 Reason For Visit Sales (Used) "Best dealership around!!" Wanda Norris was a fantastic salesman(lady). She made sure I had the car and the price I wanted! She took the time to understand all our needs and made us feel like family. If you want a great salesman for your next purchase, choose Wanda Norris!


Small manufacturing businesses are a diverse and evolving driver of the U.S. economy. In fact, according to the National Association of Manufacturers, for every $1.00 spent in manufacturing, another $1.89 is added to the economy, proving that this sector continues to thrive.
While the opportunities are tremendous, most entrepreneurs face a primary challenge in funding their manufacturing companies, as they tend to be more expensive to get off the ground than many other types of small businesses.
Essentially all manufacturing-based small businesses will need financing to start up and grow. Without it they risk being underfunded, which means they don't have the money needed for day-to-day operations, to invest in new opportunities or to increase market competitiveness.
Working capital: Loans for working capital are used to finance everyday operations of a company. Working capital can be calculated by subtracting a business's current short-term liabilities from its current assets. Current assets include on-hand cash and things that are easily converted into cash, like inventory and accounts receivable. Current liabilities are primarily loans due within a year and accounts payable.
Many small manufacturing businesses turn to EGF when they are in need of a working capital boost. For instance,Maria Boustead owner of Po Campo, a bike bag manufacturing business, used her EGF loan to make the switch to a more sustainable factory. Through her working capital loan, Maria was able to get the financing she needed to secure a business relationship with a sustainable partner to produce her products.
Equipment: Manufacturing equipment eventually needs to be replaced. New or used equipment may be purchased to replace an older model or upgrade with more efficient equipment. For example, after being awarded a large and lucrative government contract, Advanced Automation Corporation, a systems-engineering and manufacturing business, received an EGF loan to purchase the equipment they needed to fulfill their contract.
Expansion and growth: As your business grows, you may need money for additional inventory, staff, marketing and more, as well as to scale up your company's capacity to bid on larger projects and contracts.
When Anita Shepard, owner of vegan yogurt manufacturer Anita's Yogurt, needed a loan to expand her business, she turned to EGF. Anita used her loan funds to redevelop products that are now scalable for large-batch production.
Once you have determined that you're ready to seek financing, it's important to explore and research the different financing options available. To help you get started we've outlined some key small business lending sources for manufacturing businesses.
Banks: Banks are the first place to turn for financing as they can usually offer lower interest rates than many other sources. Talk to your commercial-banking representative, ask for advice and be responsive to questions or concerns. This will help you be better prepared when the time comes to apply.
U.S. Small Business Administration (SBA): While the SBA doesn't make loans directly, it does support small businesses by making it easier for banks and other lending institutions to make loans to new and expanding businesses.
With loans that go as high as $5 million for qualified borrowers and eligible businesses, SBA-backed programs are often exactly what small business borrowers need, including manufacturing operations that have much higher startup and early-stage costs. EGF offers SBA loans up to $50,000 through the SBA Microloan program. For loans over $50,000, EGF's affiliate The 504 Company offers SBA loans for manufacturers looking to purchase machinery, equipment, or commercial real estate.
Community Development Financial Institutions (CDFIs): CDFIs, like EGF, are mission-driven, non-profit lenders that often have more flexible requirements to offer financing and other small business support. EGF's SmartLoan® is one of our most popular products, offering borrowers up to $100,000 with quick, online applications, decisions in 48 hours and access to funds in about five business days.
EGF and our affiliates have funded several manufacturing businesses in a broad diversity of industries. In addition, we have experience with programs that support manufacturing-based entrepreneurship in the New York City metro area and those that aim to export their products.
EGF's Business Advisors have the experience, relationships and knowledge needed to help you succeed, and we offer access to numerous loan programs. We also offer a broad range of support services to help small business owners achieve success, like assistance with business plans, financials and marketing. When you're ready, contact us to learn how we can help.


A creative, quality-minded Software Engineer/Computer Programmer with over thirty years experience programming web based, mobile/tablet, client-server, and mainframe applications covering a broad range of functional areas. Knowledgeable in a multitude of computer languages and software packages on multiple hardware/OS platforms. Ability to manage multiple tasks; efficient in organizing and prioritizing assigned duties; experienced in managing personnel and leading large group projects. Dependable, reliable worker; intend to contribute to future company's success through hard work and the contribution of innovative ideas.
Lead application developer in applications group responsible for SharePoint intranet site, external facing customer website (nmgco.com, continentalllc.com, asp.net based), and Oracle enterprise applications (PeopleSoft, PowerPlant, Service Suite, and custom in-house Oracle based applications).
Notable projects: installation and upgrade of SharePoint intranet, development and maintenance of external facing asp.net website, installation and porting of Unix (Solaris) based Service Suite application, installation of OSSEC/Splunk IDS (Intrusion Detection System).
Supervise small to mid-sized working group of Web Application Developers. Act as technical lead on complex projects, assist application developers with technical questions, work with business owners on project specifications and development.
Act as project/technical lead on complex projects – develop and present solutions that promote efficiencies and accelerate market acquisitions, assist application owners in development of business requirements, develop application technical requirements, perform system analysis and design, develop unit and system test plans, schedule programmer tasks, and assist with debugging and problem resolution.
Lead "mass market enrollment" project that resulted in dramatic reduction in costs associated with the acquisition of new customers and a significant reduction in turn-around time. Application was written using ASP.Net, VB.Net, Oracle PL/SQL, XML, and gateways to third parties (real time credit card processing, credit checks).
Promoted and lead "contact system" project that resulted in significant reduction in call turn-around time and reduced costs. Reverse engineering existing systems (Oracle Forms/Reports based) and introduced new automated functionalities that produced further cost reductions. Application was written using ASP.Net, ASP, VB.Net, Oracle PL/SQL.
Acted as technical project lead on installation/upgrade of Oracle financial systems (AP, AR, PA, GL, HR/Payroll, Project Management) to Oracle 11i. Lead Installation, debugged/resolved problems, assisted programmers with coding/development questions.
Act as project lead on new application systems development. Gather and document project requirements, budget and assign resources, assign work tasks to analysts and programmers, oversee program development activities, monitor project status, report results to management.
Responsible for new internet based application development (examples include online auction application, web based call support system, customer information systems, business partner portals). Responsible for advanced application development projects using C/C++ (Windows and Unix), Unix shell scripting, Visual Basic, Java, SQL/PL SQL, Pro*C, Developer 2000, and Microsoft Access.
Responsible for new, emerging technology development, implementations, and recommendations. Duties primarily encompass the learning of new technologies and demonstration of their abilities and applicability within our existing environment. Examples include the introduction of the first client/server application in our company, introduction of our first web site (1996), introduction of our first wireless/mobile based application, and introduction of our first .NET application, introduction of our first XML based application.
Maintain Oracle Applications security and Windows 2000/Unix application environments (General Ledger, Accounts Payable, Accounts Receivable, Project Accounting, Human Resources, Payroll, and Oracle Training) on Windows NT and UNIX platforms. Oracle Applications environments include character mode (Unix based), Smart Client (client/server), and NCA (java/web).
Maintain security and applications environment on a SCT Banner Customer Information system. System is Oracle Forms 4.5 system running over Citrix. Provide support to developers/programmers when problems that cross application boundaries arise or when complexity falls outside the programmers area of expertise.
Provide assistance/guidance with proper design and development strategies. Provide user support when problems with the Oracle or SCT Banner applications arise. This includes acting as the mediator between users, developers, and Oracle Technical Support. Assist DBA(s) on Oracle Application installations and upgrades as needed. Have acted as technical support lead for 10.6, 10.7 NCA, and 11i Oracle Financials upgrades.
Develop and maintain Client/Server based application systems using Microsoft Access, Visual Basic, and C++. Develop, maintain, and manage the corporate Web sites.
Develop and maintain Client/Server based application systems. Develop and maintain Mainframe Customer Information System application, engineering systems.
Develop and maintain Mainframe Customer Information System application, 401K system, Financials systems, Payroll system, Inventory system.
Develop and maintain mainframe Financials applications (Accounts Payable, Accounts Receivable, General Ledger, Payroll).
Turbomeca USA (contract) – converted web site to ASP and fixed several irregularities and design problems.
Casting Source (contract) – retrofit and conversion of existing web "magazine" and online catalog to ASP technology.
AEC Nelmor (contract) – conversion of existing site to MS Sql Server.
Develop various application software packages using Visual Basic, Visual C/C++, and Microsoft Access. Applications were distributed as shareware via the Internet and on retail CD. Applications have been featured on America Online, CompuServe, Prodigy, and Ziff-Davis (one was awarded 4-stars in a Ziff-Davis product review). Applications have been distributed on CDs in retail stores (one featured on the cover), carried on several major Internet sites, and written/reviewed in magazines in the US and overseas. One application was featured as CNET's Shareware of the Week (1997).
Experience developing TCP/IP based applications using C/C++. Applications including Email reader/utility, Usenet reader/utility, Web "spider", Web harvester, web up-time monitor, and a security monitor.
Develop and maintain several Web sites for fun and profit. Some sites have been written about in national level magazines, referenced in retail IT books, and featured on video. One site has been distributed on several educational CDs. One site was spotlighted in the American Library Journal twice (October 1998 and 1999 issues), reviewed in the Washington Times (November 1999) and mentioned in the New York Times (January 2010).
Develop and maintain several Google Android based applications which are distributed on Google's Android Market. One has over 25,000 installs and is rated 4.7 stars (out of 5 stars possible).
Perform miscellaneous contract programming duties. Applications include Visual Basic Development, C++ development, MS Access Development, IIS Active Server Pages development (database integration).


text:
StedmanFamiliesResearchCenter
One Name Study of the Stedman/Steadman/Steedman Families
You are currently anonymous
Wilhelmina Phillips
Personal Information | Event Map | All | PDF
Name Wilhelmina Phillips
Born Limerick, Limerick, Munster, Ireland
Alt. Birth 16 May 1840 Limerick, Limerick, Munster, Ireland
1861 England Census 1861
not located
Death Registration Between 1 Jan 1927 and 31 Mar 1927 Guildford RD, Surrey, England, UK
Vol. 2a, p. 195
Wilhelmina Stedman, age 86, died.
Died 8 Jan 1927 Guildford, Surrey, England, UK
Probate 21 Feb 1927 Norwich RD, Norfolk, England, UK
England & Wales, National Probate Calendar (Index of Wills and Administrations),1861-1941
STEDMAN, Wilhelmina of Thorpe House Epsom-road Guildford died 8 January 1927.
Probate Norwich 21 February to Alice Maud Mary Bavin widow. Effects £4148 9s. 5d.
Person ID I1795 Stedman Families of the United Kingdom
Last Modified 6 Mar 2013
Father William Phillips, b. Abt 1814, ____, ____, Ireland, UK , d. Unknown
Mother Anne Peyton, d. Unknown
Family 1 John George McWalter, d. Unknown
Married 12 Jan 1850 Dublin, Dublin, Leinster, Ireland
At Church of Sts. Michael & John
1. John George Patrick MacWalter, b. 15 Mar 1853, Dublin, Dublin, Leinster, Ireland , d. Unknown
Family 2 Dr. James Henry Stedman, b. 11 Apr 1832, East Rudham, Norfolk, England, UK , d. 6 Apr 1918, Great Plumstead, Norfolk, England, UK (Age 85 years)
Marriage Registration Between 1 Jul 1860 and 30 Sep 1860 Islington RD, Middlesex, England, UK
Vol. 1b, p. 382
James Henry Stedman and Wilhelmina MacWalter were married.
Married 25 Aug 1860 Islington, Middlesex, England, UK
James Henry Stedman, son of Charles Stedman and Harriet Rouse Buck, and Wilhelmina MacWalter, daughter of William Phillips, were married at Islington, London, according to an IGI submission.
1. Alice Maud Mary Stedman, b. 17 Sep 1861, Kennington, Surrey, England, UK , d. 27 Feb 1932, Guildford, Surrey, England, UK (Age 70 years)
Born - - Limerick, Limerick, Munster, Ireland
Alt. Birth - 16 May 1840 - Limerick, Limerick, Munster, Ireland
Married - 12 Jan 1850 - Dublin, Dublin, Leinster, Ireland
Marriage Registration - Vol. 1b, p. 382 - Between 1 Jul 1860 and 30 Sep 1860 - Islington RD, Middlesex, England, UK
Married - 25 Aug 1860 - Islington, Middlesex, England, UK
Death Registration - Vol. 2a, p. 195 - Between 1 Jan 1927 and 31 Mar 1927 - Guildford RD, Surrey, England, UK
Died - 8 Jan 1927 - Guildford, Surrey, England, UK
Probate - 21 Feb 1927 - Norwich RD, Norfolk, England, UK


text:
OCA shifts 6th Asian Beach Games in Sanya to next April
The decision taken jointly in collaboration with the Chinese Olympic Committee (COC) and the Sanya Asian Beach Games Organizing Committee (SABGOC)
KUWAIT CITY, August 10, 2020: The Olympic Council of Asia announced that the 6th Asian Beach Games to be held in the City of Sanya, China, will now commence on April 2, 2021, and culminate on April 10, 2021. The nomenclature of the Games, the Sixth Asian Beach Games Sanya 2020, and the logo of the Games shall remain unchanged.
The decision taken jointly in collaboration with the Chinese Olympic Committee (COC) and the Sanya Asian Beach Games Organizing Committee (SABGOC) will ensure the safety of the athletes and officials as well as the spectators in these unprecedented times of COVID 19 pandemic.
The Sports Entry as well as other technical details will be readjusted in collaboration with SABGOC and announced shortly.
The OCA is extremely positive that the games with the joint efforts of all the involved parties will be a great success.


Garnet, a dazzling red hued gemstone looks opulent when engraved in jewelry pieces. But only the jewelry items will not make your look complete. So, today we have come up with some gorgeous Garnet looks that you will love to try.
These looks include a lovely team of fabulous Garnet dress, matching pair of heels and toning clutch.
Check out this opulent Garnet look that you are going to love a lot. Spot out this strapless red fish cut dress which is looking amazing. This floor touching dress is appended with frill at its base. You may wear it with this riveting piece of a pendant on which silver shapes are crafted. It will look nice when you don it with this impressive pair of heels with peel toes. This fascinating flower clutch will make this look complete.
Spot out this great look of Garnet, which will get you look distinctive in the crowd. Look at this lovely floor kissing dress which is given a transparent touch. Various flowers are too stamped on it that are enhancing its beauty. It will look marvelous when you team it up with an impressive neck piece embellished with Garnet gemstone, a pair of peeping toes heels with reddish gawk and a striking sequined clutch.
Witness this lovely Garnet look which is looking glamorous and will attract various compliments. You may try it with a shiny and stylish neck dress. It is given a fresh touch. It will look nice when you wear it with this stunning neck piece decorated with red Garnet gemstone. A sleek pair of heels and an engrossing bow attached clutch will make this look complete.
Last but not the least; you are going to love this sequined touch Garnet look. It includes a glittering, sweet-heart shape gown with a golden belt attached. A lovely piece of pendant engraved with double moon shaped red Garnet charm. The silver carving that is handcrafted on the boundary is enhancing its beauty. You will look gorgeous when you wear it along with this bright lips shaped clutch and a pair of glistening heels.
All these Garnet looks will make you stand out in the crowd, and you will get flooded with several fantastic compliments and praises. So, get ready and achieve your hot damn look today!


If you look at the chapters in FREEFALL, you'll see they're not numbered. Instead, each chapter is identified by location: "Upperworld," "Lowerworld," or "Otherworld." The first two locations are based on Earth during the years 2150-2151. The third location is an exoplanet (a planet outside the solar system), with the action taking place in the year 3151. The novel moves back and forth among these three places, showing the events that led to the colonization of outer space and what happens after the colonists arrive at the end of their journey.
The two Earth-worlds, the Upperworld and the Lowerworld, exist on the same planet, but they might as well not. That's because, in the twenty-second century Earth of FREEFALL, the wealthiest 1% of humanity (the Upperworld) has cut itself off from the remaining 99% (the Lowerworld). When my narrator, Cam Newell, the son of Upperworld executives, embarks for the Lowerworld in the company of Sofie, the girl who leads a Lowerworld crusade for equality, it's as if he's traveled to an entirely new planet. The things he learns in the Lowerworld—about how its people live and think and struggle and dream—change him forever.
And then he travels to a planet that's literally new to him (and to everyone): the Otherworld, so named because it's not the planet the colonists were aiming for. Instead of touching down on a pristine pleasure-spot just waiting to be terraformed, they find themselves trapped by a malfunctioning starship on a desolate world with a toxic atmosphere, deadly radiation, and no life except for fearsome nighttime predators. If the first two worlds were modeled after our own, with its international hostilities and deepening divide between rich and poor, the Otherworld represents, perhaps, the nightmare dead-end for humanity if we don't learn to coexist.
The challenge for any science fiction writer is to build an alternate world that's original, interesting, and (maybe most important) internally coherent. The challenge in FREEFALL was to make sure that all three worlds not only met these criteria but worked together in logical and dramatic ways. I like to think I succeeded, but in the end, it's up to my readers to judge.
FREEFALL is my third science fiction novel, and maybe that's why I decided to give it three worlds. But I've got to tell you, building worlds is hard work. Next time around, I think I'll stick with one!
Joshua David Bellin is the sci-fi author of SURVIVAL COLONY, SCAVENGER OF SOULS, and FREEFALL. Josh taught college for 20 years and lives in one world, Pittsburg.


1 Eddie Cheng Holiday Hours ~ Open or Closed Today?
2 Eddie Cheng Holiday Hours and General Hours of Operation.
Eddie Cheng Holiday Hours ~ Open or Closed Today?
Eddie Cheng Holiday Hours and General Hours of Operation.
Some locations are closed on Monday. Restaurants may operate on holiday schedules with reduced hours during "open" holidays. In addition, several fast food outlets are franchise stores, so hours will vary. Eddie Cheng holiday hours of operation. Also, please note that some locations are closed on Sundays..
Eddie Cheng Holiday Hours ~ Closed/Open – 2018/2019.


text:
Biografia

Era il figlio ultimogenito di Gianfrancesco Gonzaga, capostipite del ramo dei "Gonzaga di Luzzara".

Nel 1539 acquistò da Ferrante I Gonzaga il castello di Poviglio, divenendo conte di quel luogo. Ma nel 1553 lo rivendette ai Farnese.

Sposò Isabella Gonzaga, figlia di Pirro Gonzaga, signore di Gazzuolo e San Martino dell'Argine e di Emilia Camilla Bentivoglio figlia di Annibale II Bentivoglio signore sovrano di Bologna e di Lucrezia d'Este.

Dopo la morte della prima moglie sposò Caterina Pico, figlia di Galeotto II Pico, signore di Mirandola e conte di Concordia e di Ippolita Gonzaga figlia di Ludovico Gonzaga conte di Rodigo con Rivalta e di Francesca Fieschi.

Discendenza

Rodolfo e Isabella ebbero numerosi figli, tra cui:
 Luigi (1538-1570), suo successore, visse a lungo alla corte di Alfonso II d'Este. Morì assassinato a Ferrara;
 Fabrizio;
 Orazio;
 Settimio;
 Antonia (?-1572), sposò Roberto Sanvitali;
 Ginevra.

Ebbe anche alcuni figli naturali.

Note

Bibliografia
  .

Voci correlate
Gonzaga di Luzzara

Altri progetti

Rodolfo Gonzaga
Gonzaga Rodolfo
Gonzaga Rodolfo

redpajama_set_name: RedPajamaWikipedia


No ripe fruit goes un-enjoyed this season! The fruit picker harvesting basket, attached to a telescoping pole, is perfect for pulling down highest avocados, mangoes, or peaches from the safety of the ground.
Rust resistant Fruit Picker with 5 1/2" wide clawed opening, basket padding to collect fruit bruise-free, and built in fastener for attaching to handle of choice.


Washington D.C./Baltimore has more than 3,200 University of Dayton alumni in the area. Be sure to register for our online alumni community so you can keep in touch with them, as well as update your contact information to receive news and event invitations.
You can also get involved with the Washington D.C./Baltimore Alumni Community by completing a volunteer form or sending an email to our community leader.


MARINE CORPS BASE CAMP COURTNEY, OKINAWA, Japan - Joint Task Force 505 completed its 25th and final scheduled flight March 28 for Operation Pacific Passage, relocating on a volunteer basis Defense Department families stationed in designated areas of Japan affected by the tragic March 11 earthquake and tsunami.
The 111 family members and 15 pets departed Naval Air Facitiy Atsugi were the last to be voluntarily moved on military contracted flights. While the number of families volunteering has shrunk to a trickle, the Operation continues and future authorized departures will be arranged through commercial travel offices.
On March 17, the office of the under secretary of defense authorized DoD eligible family members located in selected prefectures on the island of Honshu, Japan, to voluntarily depart for designated locations of the United States and other designated safe haven locations.
To date, more than 7,400 eligible family members have temporarily relocated, along with 409 family pets.
Joint Task Force 505 is headquartered on Okinawa with a forward operating element at Yokota Air Base near Tokyo.


Businessmen and entrepreneurs in Harris County and the surrounding area have consulted with Slate & Associates, Attorneys at Law for years regarding structuring, financing, growing, and developing their business interests.
This representation includes assistance from starting a new business and operating it properly, to negotiating and selling the business. The firm advises business clients in virtually every aspect of their business ventures.
Subchapter S electionWhat to do if you are involved in an accident.
Unpaid debts create cash flow and growth problems for business. Although the debt can take many forms, unpaid receivables, notes, accounts, and contracts cannot be ignored in a successful business organization.
Slate & Associates, Attorneys at Law has extensive experience representing clients in collection of debts. The firm has represented clients in every stage of the collection process from the initial demands through post-judgment enforcement and appeals.
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Since the formation of Slate & Associates, Attorneys at Law, our attorneys have drafted, negotiated, mediated, and litigated claims relating to contracts. Whether the contract concerns real or personal property or is an agreement between individuals or companies, the transaction attorneys at the law firm can assist you in preparing documents to meet your individual requirements, and the litigation attorneys can assist you in enforcing the contract terms.
Committed to helping clients meet the challenges in the ever-changing workplace, Slate & Associates, Attorneys at Law provides representation for employers and employees in various employment matters.
For employers, the firm provides assistance in drafting employee handbooks, policies and procedures, and implementing strategies to avoid litigation. Additionally, the firm provides defense against employee lawsuits and other affairs.
Real estate transactions and land use have been a part of the legal services performed by Slate & Associates, Attorneys at Law since its formation.
This representation includes every aspect of real estate use. The attorneys' experience provides the firm's clients with well-balanced problem-solving techniques to efficiently guide its clients through the very simple to the most complex real property transactions.


text:
Letter: Reade allegations deserve an airing, just like those of Blasey Ford
May 6 -- To the Editor:
I have been following the letters related to the Tara Reade allegations closely, especially those submitted by Mr. McCord, Mr. Cooper and Ms. Greenslit. The latter two writers appear to have been quite upset by Mr. McCord's writings and responded with lengthy challenges. To me, they simply advance their personal opinions then ground arguments in them as though they are facts.
As I read it, Mr. McCord's first letter made a simple and incontrovertible claim, that there is a double standard in the way the media and Democrat leaders have (not) handled the Reade allegations, compared to the Christine Blasey Ford allegations against Judge Brett Kavanaugh. They have moved from giving all such allegations a complete airing to the claim that the Republicans have drummed this up and their man Mr. Biden is morally superior to President Trump in any case.
The claim that the two issues are essentially the same is incorrect and no real facts have surfaced to substantiate it, just opinions. In the Kavanaugh case, Ms. Ford did not even advance her allegations to the public herself. Instead she worked through her local Democrat Congressperson who forwarded the matter to California Democrat Senator Feinstein. The honorable Senator then tossed this into the Senate confirmation hearings very late in the game. The firestorm that followed in the media is a matter of fact, it cannot be credibly denied. Mr. Cooper calls the ensuing FBI investigation a sham, without advancing any facts in support.
By comparison, Ms. Reade went public herself more than a year ago, along with two other women claiming that Mr. Biden had touched them inappropriately. In April of this year, for reasons best known to her, Reade elected to make her assault claims public. The silence that followed from the media and leading Democrats over the ensuing weeks is undeniably a matter of fact. Interestingly, even after Mr. Biden's belated denial, there is meaningful support among many Democrats to pursue the claims further or even replace their candidate. Readers can substantiate this with some Google searching.
None of this carries any weight with Mr. Cooper and Ms. Greenslit. Instead they essentially pivot to their negative feelings about their Republican political opponents and President Trump. Mr. Cooper sees a "coordinated attack" by the "Publicans" and, in support of that contention, points out that two other Seacoastonline LTE writers shared opinions similar to Mr. McCord's. Seems like a very thin reed indeed. Mr. Cooper also essentially says that compared to President Trump Mr. Biden is a worthy chap. But the Reade allegations should be fully aired no matter how many other people are deemed to be morally inferior. Two wrongs do not make a right.
The original correspondence I have seen was narrowly focused on the Tara Reade claims and called out hypocrisy mainly in the media and also by leading Democrats. It was not about President Trump but these critics seem drawn to him like moths to a flame. And the opinion that President Trump is a low form of human life is also irrelevant. These arguments simply obscure the underlying concerns in this matter enabling the writers to segue to their anti-Trump, anti-Republican feelings.


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text:
Q: Is Reading Windows Reserved Filenames Through a URL Valid for OS Enumeration? I'm aware that writing a file with a reserved name such as CON.txt or CON.mp3, aux.txt, lpt1.html, etc. is not allowed by Windows and can be leveraged for enumeration.
However, what about reading a file with a reserved name?
For example, in my current web application, most invalid file requests return a proper 404 from the application. However, /con, /aux, etc. return a 500 runtime error message like this (which looks a lot like the IIS format, and that server instance may be likely to run on Windows but that's not enough to say definitively that it is Windows):
The 500 error from the app
I realize this may be more appropriate on Security Stack Exchange so I've moved it there.

redpajama_set_name: RedPajamaStackExchange


Abt 1914 - 1944 (~ 30 years) Has 6 ancestors but no descendants in this family tree.
2. Fred George Linstedt, Jr.
Family Fred George Linstedt, Sr.
Name: Fred G. Linstedt Jr.
Ancestry.com. WWI, WWII, and Korean War Casualty Listings [database on-line]. Provo, UT, USA: The Generations Network, Inc., 2005. Original data: American Battle Monuments Commission. World War I Listing; World War II Listing; Korean War Listing. American Battle Monuments Commission.
Father Fred George Linstedt, Sr.
Reference Fred Feldman. "Fred George Linstedt, Jr.". Feldman Family Trees. https://www.feldmanfamilytree.com/getperson.php?personID=I289&tree=Feldman (accessed April 19, 2019).


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So the ring has been purchased, the question popped and the craziness of wedding planning is underway. With your remaining single days counting down, there is the promise of one final night with the guys. The bachelor party is a rite of passage that every soon-to-be groom revels in.
Whether you want to keep it classy is entirely up to you.
Instead of the typical clichés of Vegas (cue The Hangover) or less than classy strip clubs, why not think outside the box and celebrate on one of our craft beer or cocktail focused tours? Night out on the town with the guys? Check. Beer and liquor? Check. Fiance approved? Definitely! Just tell her you're going on a Vancouver Food Tour and she'll be put at ease.
On a Vancouver Food Tour, there's no need for bill-splitting, waiting to get into a crowded bar, or even your wallet. We pride ourselves on taking care of every detail so our guests can simply kick back, relax and enjoy the experience. No planning or stress is required! Our industry professional guides know the ins and outs of our favourite Vancouver neighbourhoods and food landmarks. We are even there to offer our best suggestions to continue on with your epic night.
Sick of restaurants waits, bar lines and less than stellar service? On a Vancouver Food Tour you're treated like a VIP at some of the best, independent restaurants in Vancouver. (We don't do cheesy chain restaurants). We're all about creating an exclusive experience for our guests and can even work with you to incorporate extra accommodations. Bottle service anyone?
Once you've completed one of our food and drink driven tours, the night is still young. Schedule a Craft Beer 'n Bites Tour or Gastown Tasting Tour to kick off your night, fill your stomach, and get your buzz going. Our tours begin and end in the heart of Gastown, which means you're surrounded with countless options to keep the party going. We'd be happy to recommend some of our favourites to you.
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When I use Google voice input, after complete, the text will have an underline for me to select the best word. In using with the evernote black theme, the selection box is in white color with light grey text, it's nearly non-readable. Does anybody setting could help?


F. Gerald Burnett will speak on Drafting Operating Agreements Under Alabama's New LLC Act on December 16, 2015. He will speak at the National Business Institute's seminar, Limited Liability Companies – Planning Under Alabama's New LLC Act, at the SprinhHill Suites by Marriott in Downtown Birmingham.
Nancy W. Ball spoke at the 38th Annual Estate Planning Seminar, hosted by the University of Alabama, on Friday, December 4th at the Embassy Suites Hoover Hotel in Birmingham, Alabama. Mrs. Ball spoke on Ethics Issues: Letters to Clients.
F. Gerald Burnett spoke on November 6, 2015 on "Commercial Lease Provisions and Issues" sponsored by M. Lee Smith Publishers in Birmingham, Alabama.
Cabaniss Johnston would like to welcome our new associates to the Firm. Steven W. Strother, Jr. is an associate whose practice encompasses Corporate and Tax Law, Real Estate Law, and Trust and Estate Administration. Laura E. Collins is an associate practicing in the area of Commercial and Business Litigation.
We are also pleased to announce the following lawyers have been recognized in the 2016 edition of The Best Lawyers in America. The Best Lawyers in America list is based on a rigorous national survey involving more than 4 million detailed evaluations of lawyers by other lawyers.
BP recently settled with several municipalities over the 2010 oil spill. Donald J. Stewart, City Attorney for the City of Gulf Shores, assisted with the successful negotiation on that city's behalf in the settlement with BP. For the complete article, please click here.
Congratulations to Patrick H. Sims for being published in the May 2015 edition of the Alabama Lawyer. To read his article, Removing Diversity Cases: The Thrill Is Gone, please click here.
Congratulations to Crawford S. McGivaren, Jr.
Congratulations to Crawford S. McGivaren, Jr. who has been named to the 2015 Who's Who In Law list by the Birmingham Business Journal.
Melanie Merkle Atha is co-chairing the Global Collaborative Law Council's 11th Annual Collaborative Law Conference, September 15-18, 2015 at the Belo Mansion in Dallas, Texas. This year, the conference will focus on use of Collaborative Practice in medical error cases. Ms. Atha serves as the Secretary for the GCLC Board.
Congratulations to Melanie Atha, Diane Maughan, and Annette Kinderman who have been selected to B-Metro's Top Women Lawyers 2015 and will be listed in the August 2015 issue of B-Metro Magazine. Congratulations to all three!