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At least 307 records · Page 17Linked to original sources

PubMed2001

Structural mechanisms of drug resistance for mutations at codons 181 and 188 in HIV-1 reverse transcriptase and the improved resilience of second generation non-nucleoside inhibitors.

Mutations at either Tyr181 or Tyr188 within HIV-1 reverse transcriptase (RT) give high level resistance to many first generation non-nucleoside inhibitors (NNRTIs) such as the anti-AIDS drug nevirapine. By comparison second generation inhibitors, for instance the drug efavirenz, show much greater resilience to these mutations. In order to understand the structural basis for these differences we have determined a series of seven crystal structures of mutant RTs in complexes with first and second generation NNRTIs as well as one example of an unliganded mutant RT. These are Tyr181Cys RT (TNK-651) to 2.4 A, Tyr181Cys RT (efavirenz) to 2.6 A, Tyr181Cys RT (nevirapine) to 3.0 A, Tyr181Cys RT (PETT-2) to 3.0 A, Tyr188Cys RT (nevirapine) to 2.6 A, Tyr188Cys RT (UC-781) to 2.6 A and Tyr188Cys RT (unliganded) to 2.8 A resolution. In the two previously published structures of HIV-1 reverse transcriptase with mutations at 181 or 188 no side-chain electron density was observed within the p66 subunit (which contains the inhibitor binding pocket) for the mutated residues. In contrast the mutated side-chains can be seen in the NNRTI pocket for all seven structures reported here, eliminating the possibility that disordering contributes to the mechanism of resistance. In the case of the second generation compounds efavirenz with Tyr181Cys RT and UC-781 with Tyr188Cys RT there are only small rearrangements of either inhibitor within the binding site compared to wild-type RT and also for the first generation compounds TNK-651, PETT-2 and nevirapine with Tyr181Cys RT. For nevirapine with the Tyr188Cys RT there is however a more substantial movement of the drug molecule. We conclude that protein conformational changes and rearrangements of drug molecules within the mutated sites are not general features of these particular inhibitor/mutant combinations. The main contribution to drug resistance for Tyr181Cys and Tyr188Cys RT mutations is the loss of aromatic ring stacking interactions for first generation compounds, providing a simple explanation for the resilience of second generation NNRTIs, as such interactions make much less significant contribution to their binding.

Binding Sites↗

PubMedDate not supplied

Using government schools to monitor iodine content of salt at household level in Delhi.

The Government had banned the sale of un-iodized salt in Delhi in 1989 as a step towards elimination of iodine deficiency disorders. The present study was done to detect the presence of iodine in salt samples every month from households of the students of government middle schools in Delhi using spot testing kits. One section each, from the classes six to eight of the thirty selected middle schools was chosen randomly. The children were asked to bring salt from their homes on a prefixed day. The salt samples were examined for the presence of iodine by a spot testing kit. This was repeated every month during the study (August '94 to February '95) among the same students in each school. A total of 16,596 salt samples were collected. Of this 12,736 (76.7%) tested positive for iodine and the rest (23.3%) of the salt samples did not contain iodine. The proportion of children who brought the salt samples varied between 53% to 72% in different months. As the study progressed, the trend showed more samples being tested positive for iodine. The differences in districts were not significant. Un-iodized salt thus still continues to be available in the households of the government school children of the National Capital Territory of Delhi. The use of rapid testing kits in schools is a practical and feasible way to enhance the monitoring activities of the government.

Community Medicine↗

PubMed1997

[Elastosis perforans serpiginosa in Down syndrome].

Elastosis perforans serpiginosa can arise as a rare complication in patients with Down syndrome. It is one of the primary perforating disorders characterized by transepithelial elimination of abnormal elastic fibers. This may reflect an immunological reaction aquist elastic fibers. We describe a 40-year-old woman with Down's syndrome whose skin lesions were histologically mistaken for lupus vulgaris for a long time.

Adult↗

PubMed1978

New concepts in dysmenorrhea.

The etiology of primary dysmenorrhea, which is the most common gynecologic complaint and cause of lost working hours, remains obscure but merits careful scientific investigation. Recent studies suggest that increased endometrial prostaglandin production and release may be responsible for dysmenorrhea. Prostaglandins cause myometrial contractility that, if excessive, leads to uterine ischemia and pain. This hypothesis has led to clinical trials of antiprostaglandin agents such as indomethacin and fenamates, which inhibit the synthesis of prostaglandin through the prostaglandin synthetase system as well as antagonize their action at the cell receptor level. The good response of dysmenorrhea to other conventional forms of therapy such as oral contraceptives and dilatation of the cervix can be partly explained on the basis of a reduced level of prostaglandins in the menstrual fluid with such therapy. There is a definite need for further evaluation of the antiprostaglandin compounds in the treatment of dysmenorrhea so that sound formulations can be evolved for the elimination of this incapacitating disorder.

Adrenergic beta-Agonists↗

PubMed2005

B-lymphocytes, innate immunity, and autoimmunity.

Having evolved to generate a huge Ag-specific repertoire and to mount T cell-dependent responses and long-term memory, the B lymphocyte is a central player in the adaptive branch of immune defense. However, accumulating evidence indicates that B-1 cells of the peritoneal cavity and marginal zone (MZ) B cells of the spleen also can play innate-like immune functions. Their anatomical locations allow frequent Ag encounter. Secreting essentially germline-encoded, polyreactive Abs, and responding rapidly and vigorously to stimulation, these two B cell subsets have evolved to impart potentially protective responses. With their additional capacities to secrete factors that can directly mediate microbial destruction and to express Toll-like receptors (TLR), B cells provide an important link between the innate and adaptive branches of the immune system. Currently, the relevance of these innate-like B cells to the pathogenesis of autoimmune disease is the focus of investigation. In experimental models of autoimmunity, the sequestration of autoreactive B cells in the MZ has been proposed to be essential for the maintenance of self-tolerance. The low activation threshold of MZ B cells makes them particularly reactive to high loads and/or altered self-Ags, potentially exacerbating autoimmune disease. Their expansion in autoimmune models and their association with autoantibody secretion indicate that they may participate in tissue damage. The demonstration that B cell depletion therapies may represent a highly beneficial therapeutic goal in autoimmune disorders suggests that specific elimination of B-1 and MZ B cells may represent a more efficient immunointervention strategy in systemic autoimmunity.

Animals↗

PubMed2004

Evolution of equine infection control programs.

The science of control of infectious diseases in hospitals was born in 1847 when Semmelweis, a physician, ordered his medical students to scrub their hands in chlorinated lime water between patients and demonstrated that this simple procedure resulted ina dramatic decline in patient morbidity and mortality. In the late nineteenth century came huge breakthroughs in the understanding that microorganisms cause many disorders, and methods to eliminate and control these microorganisms were attempted. By 1910, sterile instruments, gowns, masks, and gloves had become standard for surgical procedures in large university human hospitals, and isolation of human and veterinary patients with contagious diseases became standard. With the advent of vaccines, many epidemic viral diseases could be controlled, and antimicrobial drugs allowed many previously devastating bacterial diseases to be treated effectively. Before long, however, bacterial resistance became an important issue and remains so today, particularly for Salmonella and Staphylococcus aureus in horses. Vaccination has decreased the number of animals susceptible to equine influenza and equine herpesvirus 1, yet these contagious diseases still pose a serious issue in large equine veterinary hospitals. The development of equine isolation facilities and improved methods of barn cleaning; mandatory application of procedures, such as handwashing or use of disinfectant hand wipes, to prevent the spread of infectious diseases; and monitoring of antimicrobial resistance and use of restricted antimicrobial drugs were driven by recognition and necessity and have given rise to current equine infection control programs.

Animals↗

PubMed2004

Methodological and technical issues related to the diagnosis, screening, prevention, and treatment of pre-eclampsia and eclampsia.

In contrast with advances made in treating or eliminating many other serious disorders, severe morbidity and mortality associated with pre-eclampsia/eclampsia remain among the leading problems that threaten safe motherhood, particularly in developing countries. This article reviews technical issues related to diagnosis, screening, prevention, and treatment of pre-eclampsia and identifies corresponding needs. The authors stress the lack of standardized definitions of pre-eclampsia and eclampsia and discuss problems in blood-pressure measurements and assessment of urinary protein. They summarize the evidence for prevention strategies and screening tests for early detection. For treatment, magnesium sulfate has been proven effective, but not widely used. The authors outline priorities for narrowing the identified gaps and emphasize the need for coordinated efforts to reduce the morbidity and mortality due to pre-eclampsia/eclampsia. They conclude that the mystery of this disease must be resolved to achieve primary prevention of it.

Developing Countries↗

PubMed2004

Congenital diseases of feline muscle and neuromuscular junction.

Although muscle diseases occur relatively rarely in cats, a number of congenital feline myopathies have been described over the last 20 years and are reviewed in this paper. Some of them have been reported exclusively in specific breeds, including the hypokalaemic myopathy of Burmese cats, type IV glycogen storage disease in Norwegian Forest cats, or the myopathy of Devon Rex. Other congenital disorders of muscle and neuromuscular junction such as myotonia congenita, dystrophin-deficient hypertrophic feline muscular dystrophy, laminin alpha2 deficiency, or congenital myasthenia gravis may occur in any cat. A systematic approach is essential in order to efficiently obtain a timely diagnosis in cats showing signs of muscle disease. After a thorough clinical examination, this approach includes blood analyses (eg, serum concentration of muscle enzymes), electrophysiology where available (electromyography, nerve conduction studies), and sampling of muscle biopsies for histological, histochemical and immunohistochemical evaluation. When available, detection of healthy carriers of these genetic disorders is important to eliminate the gene mutations from breeding families. Clinicians regularly receiving feline patients must have a good knowledge of congenital feline myopathies and the features which enable a diagnosis to be made and prognosis given. Besides preserving or restoring the well-being of the myopathic patient, rapid and efficient information and counselling of the breeders are of central importance in order to prevent the recurrence of the problem in specific breeding lines.

Animals↗

PubMed1996

Gender, quality of life, and mental disorders in primary care: results from the PRIME-MD 1000 study.

BACKGROUND: Recently there has been increased interest in the special mental health needs of women. We used data from the PRIME-MD 1000 study to assess gender differences in the frequency of mental disorders in primary care settings, and to explore the potential impact of these differences on health-related quality of life (HRQL). SUBJECTS AND METHODS: One thousand primary care patients (559 women) were interviewed during the PRIME-MD study, which was conducted at four primary care clinics affiliated with university hospitals throughout the eastern United States. Patients completed a one-page questionnaire in the waiting room prior to being seen by the physician; patients and physicians then completed together a clinician evaluation guide that used DSM-III-R algorithms to diagnose mood, anxiety, somatoform, eating, and alcohol related disorders. Health-related quality of life was assessed with the Medical Outcomes Study SF-20 General Health Survey. RESULTS: Women were more likely than men to have at least one mental disorder (43% versus 33%, P < 0.05). Higher rates were particularly prominent for mood disorders (31% of women versus 19% of men, odds ratio [OR] = 1.9, 95% confidence interval [CI] 1.4 to 2.6), anxiety disorders (22% versus 13%, OR = 1.9, CI = 1.3 to 2.8), and somatoform disorders (18% versus 9%, OR = 2.2, CI = 1.5 to 3.4). Psychiatric comorbidity was also more common in women (26% of women had two or more mental disorders versus 15% of men, P < 0.05). Unadjusted HRQL scores, ranging from 0 to 100, with 100 = best health, were all significantly lower in women than in men (eg, physical function = 67 in women versus 76 in men, P < 0.0001; mental health = 69 in women versus 76 in men, P < 0.0001). Many HRQL differences persisted after controlling for age, education, ethnicity, marital status, and number of physical disorders; however, differences in HRQL were eliminated in 5 of 6 domains after controlling for number of mental disorders. When compared with female patients of male physicians, female patients of female physicians demonstrated similar satisfaction with care, health care utilization, HRQL, and recognition rate of mental disorders. CONCLUSIONS: In the 1,000 patients of the PRIME-MD study, mood, anxiety, and somatoform disorders and psychiatric comorbidity were all significantly more common in women than men. The HRQL scores were poorer in women than men, although most of this difference was accounted for by the difference in prevalence of mental disorders. These data suggest that one of the most important aspects of a primary care physician's care of female patients is to screen for and treat common mental disorders.

Adult↗

PubMed1997

Accumulation of ubiquitinated proteins in mouse neuronal cells induced by oxidative stress.

Ubiquitin protein conjugates are commonly detected in neuronal brain inclusions of patients with neurodegenerative disorders. The failure to eliminate the ubiquitin-protein deposits in the degenerating neurons may result from changes in the activity of the ubiquitin/ATP-dependent proteolytic pathway. This proteolytic pathway plays a major role in the degradation of short lived, abnormal and denatured proteins. Cadmium is a potent cell poison and is known to affect the ubiquitin pathway and to cause oxidative stress. Increases in protein mixed-disulfides (Pr-SSG) and decreases in glutathione (GSH) are often used as markers of oxidative stress. To investigate the relationship between the ubiquitin pathway and cellular glutathione (GSH), we treated HT4 cells (a mouse neuronal cell line) and rat mesencephalic primary cultures with different concentrations of the heavy metal. We observed marked increases in Pr-SSG as well as decreases in GSH, after exposure of HT4 cells or primary mesencephalic cultures to Cd2+. Furthermore, our results show that Cd2+ induced the accumulation of ubiquitinated proteins. Detection was by Western blotting of total cell extracts probed with antibodies that recognize ubiquitin-protein conjugates. These results suggest that the ubiquitin-pathway is closely involved in the cell response to cadmium-mediated oxidative stress.

Animals↗

PubMed1994

Membrane lipids of adult human brain: lipid composition of frontal and temporal lobe in subjects of age 20 to 100 years.

The membrane lipid composition of human frontal and temporal cortices and white matter has been studied in 118 subjects, age 20-100 years. The brain specimens were selected from subjects who lived a normal social life and died suddenly and unexpectedly with no history of neurologic or psychiatric disease. Macroscopic and microscopic examinations ruled out any signs of organic brain disorder. The sudden death eliminated all risk of changes over a long agonal stage. The data for total solids and major lipids are summarized in graphic form. Total solids, phospholipids, and cholesterol diminished linearly from 20 years of age in frontal and temporal cortices, whereas total solids phospholipids, cholesterol, cerebroside, and sulfatide showed a curvilinear diminution in frontal and temporal white matter. Gangliosides differed from the other lipids, showing an almost constant concentration between 20 and 70 years of age with a slight peak around 50 years of age. The ganglioside pattern showed continuous change with aging, with decreasing proportions of GM1 and GD1a and increasing proportions of GD1b, GM3, and GD3. Equations are given that can be used to calculate the lipid composition of normal human frontal and temporal cortices and white matter at any age between 20 and 100 years of age. These data can be used where data by direct analysis are not available for comparison with values for various pathological states.

Adult↗

PubMed1993

Preparation of a dietary fiber mixture derived from different sources and its metabolic effects in rats.

In this study we analyzed a commercial dietary fiber blend known as Fiber-Plus and a dietary fiber mixture (DFM) prepared in our lab (10% apple pectin, 10% orange pectin, 36% locust bean gum and 44% corncob composed of 56% fiber). DFM provided greater inhibition of starch digestion and glucose absorption (p < 0.05) than did Fiber-Plus. DFM was also found to be significantly more efficient (p < 0.05) than Fiber-Plus at reducing the glycemic response following starch loading. Rats fed DFM or corncob demonstrated a much lower glycemic response following a test meal as compared to those fed a fiber-free diet. Both fiber sources decreased fasting cholesterol and triglyceride concentrations; transit time was shortened and fecal values were higher than those of controls. beta-glucuronidase activity in intestinal segment contents and feces was lower in rats fed fiber. We conclude that DFM is effective in controlling plasma glucose and lipid levels. Corncob, a novel fiber source, could be beneficial in the treatment of gastrointestinal tract disorders and in the elimination of carcinogenic elements.

Animals↗

PubMed1989

Effect of elimination of occlusal interferences on signs and symptoms of craniomandibular disorder in young adults.

Sixty-two dental students judged not to be in need of treatment for craniomandibular disorder (CMD) were randomly divided into two groups, one receiving occlusal adjustment and the other mock adjustment. A double-blind study design was applied. After 2 years of education in dentistry, including courses in stomatognathic physiology, the increase in the subjective symptoms of CMD was significantly greater in the placebo control group than in the treatment group. The difference between the groups in the increase of sites tender to palpation was less clear, showing only a trend. However, the increase was statistically significant within the placebo group but not within the treatment group. Prophylactic occlusal adjustment thus appears to be effective in reducing the occurrence of symptoms of CMD, and possibly also the occurrence of clinical signs.

Adult↗

PubMed1980

Chondrodermatitis nodularis helicis: a transepidermal perforating disorder.

Chondrodermatitis nodularis helicis is a chronic disorder occurring exclusively on the ear. It is most common in the sixth decade, and two thirds of the patients are men. Although it has no single characteristic histologic feature, a diagnosis can be made with certainty with a clinical history and a combination of morphologic changes seen in the cartilage and overlying skin. The natural history and histology are similar to a group of disorders characterized by transepithelial elimination known as the perforating dermatoses.

Adult↗

PubMed1994

CPAP therapy via oronasal mask for obstructive sleep apnea.

STUDY OBJECTIVE: To determine the effectiveness of oronasal masks for positive pressure therapy in alleviating obstructive sleep apnea (OSA). METHODS AND PROCEDURES: Polysomnographic records of all 245 patients with OSA who underwent therapeutic trials of either continuous positive airway pressure (CPAP) or bilevel positive airway pressure between January 1991 and December 1992 were reviewed. Thirty patients who had been prescribed positive pressure therapy employing an oronasal mask were identified. Two patients known to be successfully treated with CPAP via oronasal mask underwent repeat polysomnography. The initial portion of the study was a diagnostic evaluation during which the patients were untreated. During the second portion of the study, both patients used CPAP via an oronasal mask while wearing a mouthpiece designed to maintain oral patency. RESULTS: The 30 patients with OSA who were identified in this study had significant amelioration of OSA while receiving positive pressure therapy via oronasal mask compared with the baseline, diagnostic polysomnogram (apnea index: 55.3 +/- 36.9-->1.6 +/- 3.7, p < 0.001; hypopnea index: 21.2 +/- 20-->2.7 +/- 4.9, p < 0.001; nadir of SaO2: 72.5 +/- 13.9-->87.1 +/- 4.3, p < 0.001, mean +/- SD). Improvement of OSA did not depend on maintenance of a closed mouth, as evidenced by elimination of sleep-disordered breathing in the two patients receiving positive pressure via oronasal mask while wearing a mouthpiece to keep the mouth open. CONCLUSION: Oronasal masks are a viable alternative interface for alleviating OSA with positive pressure therapy in those patients who are unwilling or unable to tolerate conventional nasal interfaces. Although there were no adverse consequences associated with the use of oronasal masks in our patients, appropriate safety precautions should be taken to minimize the possibility of aspiration of gastric contents and avoid untoward sequelae due to positive pressure device failure.

Adult↗

PubMed2000

Endemic goiter associated with high iodine intake.

OBJECTIVES: This study assessed the relation of iodine content of household water to thyroid size and urinary iodine excretion in an area with high iodine concentration in the water. METHODS: The iodine content of household water and indicators of iodine status (thyroid size and urinary iodine level) were assessed in selected villages in Jiangsu Province, China. RESULTS: Water iodine levels were positively correlated with urinary iodine levels and indicators of thyroid size at the township level. CONCLUSIONS: Excess iodine in household water was the likely cause of endemic goiter and elevated urinary iodine levels in the study area. This finding affects public health policy on the institution of universal salt iodization for the elimination of iodine deficiency disorders.

China↗

PubMed1997

Morbidity and mortality associated with intracranial aneurysms.

Subarachnoid hemorrhage (SAH) is bleeding into the subarachnoid space. It may result from a rupture of an intracranial aneurysm, bleeding from an arteriovenous malformation, hypertensive intracerebral hemorrhage with extension into the subarachnoid space, hemorrhage from an intracranial tumor, trauma, and hematologic disorders. If trauma is eliminated as a cause of SAH, more than 80% of SAHs are due to rupture of an intracranial aneurysm. This paper will focus on morbidity and mortality associated with ruptured and unruptured intracranial aneurysms.

Adult↗

PubMed1999

Anti-inflammatory therapy.

The inflammatory response involves a complex set of stereotyped biochemical and cellular reactions that aim to eliminate pathogens. Systemic inflammatory disorders, such as rheumatoid arthritis and systemic lupus erythematosus, feature a persistent, uncontrolled inflammatory response that typically culminates in tissue damage. The control of this inflammatory response is of paramount importance in preventing irreversible tissue damage, as well as in controlling symptoms. NSAIDs and corticosteroids are the most effective agents currently available to control the clinical manifestations of inflammation, although they usually need to be used in conjunction with other "disease modifying" strategies in order to achieve optimum control of chronic inflammatory disorders. As with all pharmacologic therapy, the risk to benefit ratio of each agent needs to be considered carefully before embarking on extended courses of therapy. Strategies to minimize the long-term risks of NSAIDs and corticosteroids are continuing to evolve and hold the promise of greater safety without loss of efficacy.

Anti-Inflammatory Agents↗