[Dengue fever epidemic in Afghanistan: false alarm].
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Afghanistan↗
Biomedical subjects
P MacDonald
Publications and source records attributed to P MacDonald.
The reliability of lymph-node staging in rectal cancer after preoperative chemoradiotherapy.
AIMS: To determine the prognostic significance of the nodal stage and number of nodes recovered in the surgical specimen after preoperative synchronous chemoradiation (SCRT) and surgery for locally advanced or unresectable rectal cancer. MATERIALS AND METHODS: One hundred and eighty-two consecutive patients with locally advanced or unresectable (T3/T4) rectal carcinomas were entered on a prospective database and treated in this department with preoperative chemoradiation, followed 6-12 weeks later by surgical resection. Most patients received chemotherapy in the form of low-dose folinic acid and 5-fluorouracil (5-FU) 350 mg/m2 via a 60-min infusion on days 1-5 and 29-33 of a course of pelvic radiotherapy delivered at a dose of 45 Gy in 25 fractions over 33 days to a planned volume. After resection, patients with a positive circumferential margin (< or = 1 mm), extranodal deposits or Dukes' C histology received adjuvant 5-FU-based-chemotherapy (n = 40). RESULTS: After SCRT, 161 patients underwent resection. Twenty-one patients remained unresectable or refused an exenterative operation. Median follow-up is 36 months. Down-staging was achieved in most patients, with 19 having a complete pathological response (pT0). The median number of lymph nodes recovered for all patients was five (range 0-21). The 3-year survival rate for node-positive patients is 47%, for node-negative patients with less than three lymph nodes recovered is 62% and for node-negative patients with three or more lymph nodes recovered is 70%. Compared with node-positive patients, simple regression models revealed a reduced hazard ratio (HR) of 0.72 (0.36-1.43) for node-negative patients with less than three nodes recovered and 0.48 (0.26-0.89) for node-negative patients with three or more lymph nodes recovered. In a multivariate model, including nodal status, excision status, age and sex only positive excision margins significantly predicted a poor outcome: HR = 3.05 (1.55-5.97). CONCLUSIONS: The number of nodes found after preoperative chemoradiation is a significant prognostic factor by univariate analysis. In this study, patients with node-negative histology, and at least three nodes recovered, had better long-term survival than patients in whom two or less nodes were recovered or with positive nodes. This effect was attenuated by the inclusion of excision status in multivariate models.
Adenocarcinoma↗
Febuxostat (TMX-67), a novel, non-purine, selective inhibitor of xanthine oxidase, is safe and decreases serum urate in healthy volunteers.
In order to evaluate the safety, pharmacological properties, and urate-lowering efficacy of febuxostat, a non-purine, selective inhibitor of xanthine oxidase, a Phase 1, 2-week, multiple-dose, placebo-controlled, dose-escalation study was conducted in 154 healthy adults of both sexes. Daily febuxostat doses in the range 10 mg to 120 mg resulted in proportional mean serum urate reductions ranging from 25% to 70% and in proportional increases in maximum febuxostat plasma concentrations and area under plasma concentration versus time curves. Accompanying the hypouricemic effect were increases in serum xanthine concentrations, decreases in urinary uric acid excretion, and increases in urinary xanthine and hypoxanthine excretion, confirming inhibition of xanthine oxidase activity by febuxostat. Hepatic conjugation and oxidative metabolism were the major pathways of elimination of febuxostat from the body, and renal elimination did not appear to play a significant role. Although not uncommon, adverse events were mild and self-limited, and no deaths or serious adverse events were observed. Febuxostat is a safe and potent hypouricemic agent in healthy humans.
Adult↗
Tropical ulcers: a condition still hidden from the western world.
Tropical ulcers cause great pain and often lead to terrible deformities and amputations among very poor patients. Theories exist about their cause and treatments, but this literature review shows an urgent need for more research into this Cinderella area.
Acute Disease↗
Utility of inoculum counting (Walshe and English criteria) in clinical diagnosis of onychomycosis caused by nondermatophytic filamentous fungi.
Opportunistic onychomycosis caused by nondermatophytic molds may differ in treatment from tinea unguium. Confirmed diagnosis of opportunistic onychomycosis classically requires more than one laboratory analysis to show consistency of fungal outgrowth. Walshe and English in 1966 proposed to extract sufficient diagnostic information from a single patient consultation by counting the number of nail fragments positive for inoculum of the suspected fungus. Twenty fragments were plated per patient, and each case in which five or more fragments grew the same mold was considered an infection by that mold, provided that compatible filaments were also seen invading the nail tissue by direct microscopy. This widely used and often recommended method has never been validated. Therefore, the validity of substituting any technique based on inoculum counting for conventional follow-up study in the diagnosis of opportunistic onychomycosis was investigated. Sampling of 473 patients was performed repeatedly. Nail specimens were examined by direct microscopy, and 15 pieces were plated on standard growth media. After 3 weeks, outgrowing dermatophytes were recorded, and pieces growing any nondermatophyte mold were counted. Patients returned on two to eight additional occasions over a 1- to 3-year period for similar examinations. Onychomycosis was etiologically classified based on long-term study. Opportunistic onychomycosis was definitively established for 86 patients. Counts of nondermatophyte molds in initial examinations were analyzed to determine if they successfully predicted both true cases of opportunistic onychomycosis and cases of insignificant mold contamination. There was a strong positive statistical association between mold colony counts and true opportunistic onychomycosis. Logistic regression analysis, however, determined that even the highest counts predicted true cases of opportunistic onychomycosis only 89.7% of the time. The counting criterion suggested by Walshe and English was correct only 23.2% of the time. Acremonium infections were especially likely to be correctly predicted by inoculum counting. Inoculum counting could be used to indicate a need for repeat studies in cases of false-negative results from laboratory direct microscopy. Inoculum counting cannot serve as a valid substitute for follow-up study in the diagnosis of opportunistic onychomycosis. It may, nonetheless, provide useful information both to the physician and to the laboratory, and it may be especially valuable when the patient does not present for follow-up sampling.
Aged↗
Medicines for children and gentamicin toxicity.
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Anti-Bacterial Agents↗
Protective effect of short-tem calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation.
Bone loss is most rapid in the immediate period after cardiac or lung transplantation. This randomized study compared the efficacy of 6 months of treatment with either calcitriol (1,25-dihydroxyvitamin D3; 0.5 microg/day) or two cycles of etidronate plus calcium in preventing bone loss in 41 patients undergoing cardiac or lung transplantation. Patients were followed for 18 months after cessation of treatment. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). There were no significant differences between groups with respect to age or cumulative dose of prednis(ol)one or cyclosporin over the 2 years. Bone loss did not differ between groups after 6 months and, despite 6 months prophylaxis with either agent, bone loss was significant in both groups at 6 months and 12 months. However, compared with an untreated reference group, both therapies offered significant protection at 6 months and etidronate provided significant protective carryover after therapy had been discontinued. These data suggest short-term prophylaxis with calcitriol or cyclical etidronate is partially effective in reducing bone loss after cardiac or lung transplantation but treatment needs to be continued for a longer term.
Adrenal Cortex Hormones↗
Coronary artery bypass surgery for elderly patients: is our practice based on evidence or faith?
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Age Factors↗
Epidemiology and prevalence of onychomycosis in HIV-positive individuals.
BACKGROUND: Patients who are human immunodeficiency virus (HIV) positive are predisposed to the development of infections including tinea pedis and onychomycosis. While smaller studies have been reported, there has been no large study evaluating the prevalence of onychomycosis in HIV-positive individuals, or comparing the development of onychomycosis in a typical temperate area with that in a typical tropical area. METHODS: HIV-positive individuals were evaluated at five clinics: four in Ontario, Canada and one in Sao Paulo, Brazil. The subjects were asked questions to determine the epidemiology of onychomycosis in HIV-positive individuals. The feet were examined and nail material was obtained for mycologic examination to determine the causative organism of onychomycosis. RESULTS: A total of 500 subjects were examined (415 men and 85 women; age (mean +/- SE), 39 +/- 0.4 years; 400 Canadian, 100 Brazilian). The racial origins of the Canadian patients were: Caucasian, 83.8%; Asian, 4.3%; African-American, 8.1%; Hispanic, 3.3%; American Indian, 0.3%. The Brazilian origins were: Caucasian, 68.7%; African, 18.1%; mixed race, 13.3%. Abnormal appearing nails and mycologic evidence of onychomycosis were present in 200 (40.0%) and 116 (23.2%), respectively, of 500 subjects. The prevalence of onychomycosis in the Canadian and Brazilian samples was 24.0% (96 of 400) and 20.0% (20 of 100), respectively. The projected prevalence of onychomycosis in HIV-positive individuals in Canada was 19.9% (95% CI: 16.0-23.9%) after taking into account the age and sex distribution of HIV-positive individuals in the population. When nails appeared clinically abnormal, the prevalence of onychomycosis was 50.5% (Canada, 51.3%; Brazil, 45.5%). For comparison, published data indicate that the prevalence of onychomycosis in immunocompetent individuals living in Canada is 6.9%. The clinical presentation of onychomycosis for the whole sample (n=500) was: distal and lateral subungual onychomycosis (DLSO), 20.0%; white superficial onychomycosis (WSO), 3.6%; proximal subungual onychomycosis (PSO), 1.8% (Canadian and Brazilian samples: DLSO 21.2% vs. 15.0%, WSO 3.3% vs. 5.0%, and PSO 1.5% vs. 3.0%). The distribution of the causative fungal organisms was: dermatophytes: Candida species: nondermatophyte molds, 73:2:2 (Canadian and Brazilian samples: dermatophytes 95.5% vs. 90.9%, Candida species 3.0% vs. 0%, and nondermatophyte molds 1.5% vs. 9.0%). The use of protease inhibitors, reverse transcriptase inhibitors, or oral antifungal agents did not make a significant difference in the prevalence of onychomycosis for both the Canadian and Brazilian groups. Patients with onychomycosis were aware of their abnormal appearing nails (chi2(1)=69.7, P<0.001), embarrassed by the appearance of their nails (chi2(1)=29.7, P<0.001), and took measures to hide their nails from other individuals. A higher proportion of individuals with onychomycosis experienced discomfort compared with those without the disease (chi2(1)=9.0, P=0.003). Also, individuals who experienced pain in the nail unit were more likely to have onychomycosis (risk odds ratio (ROR), 2.2; 95% CI: 1.0-4.7, P=0.05). CONCLUSIONS: The prevalence of onychomycosis in HIV-positive individuals in the sample of 500 patients was 23.2%. In the Canadian (n=400) and Brazilian (n=100) samples, the corresponding figures were 24% and 20%, respectively, with the predominant causative organisms being dermatophytes. The projected prevalence of onychomycosis in HIV-positive Canadians is 19.9%. Predisposing factors include a CD4 count of approximately 370, a positive family history of onychomycosis, a history of tinea pedis, and walking barefoot around pools. Onychomycosis can be symptomatic, a source of embarrassment, and a potential cause of morbidity.
Adolescent↗
The epidemiology of onychomycosis: possible role of smoking and peripheral arterial disease.
BACKGROUND: Onychomycosis is a relatively common condition the aetiology of which appears to be multifactorial, with both genetic and acquired factors being responsible. In our clinical practice we have observed that smokers and individuals with peripheral arterial disease may have an increased prevalence of onychomycosis compared to normal individuals. PATIENTS AND METHODS: Patients attending a vascular clinic in a hospital were asked about a history of smoking and peripheral arterial disease. The lower extremity was assessed for peripheral arterial disease. Material was obtained from toenails for mycological evaluation. RESULTS: Two hundred and fifty-four patients (male 146, female 108; age, mean +/- standard error, 66.6 +/- 0.8 years) were enrolled. Abnormal-appearing nails and onychomycosis were present in 49.2% and 22.4% of patients, respectively. Factors associated with onychomycosis included, increasing age (risk odds ratio [ROR] 1.05, P = 0.002), male gender (ROR 1.7, P = 0.09), smoking (packs per day) (ROR 1.9, P = 0.02) and peripheral arterial disease (ROR 4.8, P = 0.02). CONCLUSIONS: The factors predisposing to the development of onychomycosis are multifactorial. Both smoking (number of packs of cigarettes consumed per day) and peripheral arterial disease are independent predictors of onychomycosis. Awareness of these factors may help in the prevention of onychomycosis and the optimal management of this disease.
Age Distribution↗
Baseline predictors of tolerability to carvedilol in patients with chronic heart failure.
OBJECTIVE: To determine baseline predictors of tolerance to the alpha/beta blocker carvedilol in everyday clinical practice. DESIGN: Retrospective analysis of tolerance to carvedilol in patients with chronic heart failure. Tolerance was defined as currently on carvedilol or on it at the time of death or heart transplantation. To meet the criteria for tolerance, carvedilol had to be prescribed at a stable dose for >/= 3 months. SETTING: Everyday clinical practice, comprising both hospital specialist practice and private practice. Tolerance was assessed in all patients prescribed carvedilol for chronic heart failure in those practices. PATIENTS: 808 consecutive patients in both hospital specialist (611 patients) and private practice (197 patients). MAIN OUTCOME MEASURES: Baseline predictors of tolerance assessed by proportional hazards analysis. Both univariate and multivariate analyses were performed. RESULTS: Within the entire cohort of 808 patients, 95 had stopped carvedilol, 606 were currently receiving the drug, 50 had died, and 44 had received a heart transplant. Overall, 88% of patients tolerated carvedilol (87% in the hospital specialist group, 92% in the private practitioner group). Factors that indicated impaired tolerance by univariate analysis were increased age in years (hazard ratio 1.01, 95% confidence interval (CI) 1.0 to 1.3), low diastolic blood pressure (hazard ratio 1.04, 95% CI 1.02 to 1.08), and raised plasma urea concentration (hazard ratio 1.04, 95% CI 1.02 to 1.05). New York Heart Association (NYHA) class was also a marker of tolerance (proportion not tolerated: 3% class I; 9% class II; 13% class III, 22% class IV). By multivariate analysis, no single baseline variable was an independent marker of inability to tolerate carvedilol. Tolerance was also assessed in relation to traditional precautions or relative contraindications to beta blockade. Tolerance in these subgroups was: chronic obstructive airways disease/asthma 85% (89 patients), diabetes 86% (127 patients), peripheral vascular disease 84% (58 patients), concomitant amiodarone treatment 83% (230 patients), and heart rate < 70 beats/min 84% (184 patients). CONCLUSIONS: beta Blocker treatment was well tolerated in everyday clinical practice, including non-hospital-based private practice. There was no single predictor of poor tolerance on multivariate analysis, although there was a clear association with NYHA class as well as age, diastolic blood pressure, and plasma urea on univariate analysis. Carvedilol was tolerated well among selected patients with traditional contraindications to beta blockade in this situation.
Adolescent↗
Effect of calcitriol on bone loss after cardiac or lung transplantation.
Rapid bone loss after cardiac and lung transplantation results in an increased risk of osteoporotic fracture. This study examined the efficacy of treatment with calcitriol (1,25-dihydroxyvitamin D3) in preventing bone loss in patients undergoing cardiac or lung transplantation. In this 2-year double-blind, stratified study, 65 patients undergoing cardiac or single lung transplantation were randomly allocated to receive either placebo or calcitriol (0.5-0.75 microg/day), the latter for either 12 months or 24 months. All patients received 600 mg calcium/day. Bone mineral density (BMD) was measured every 6 months for 2 years by dual-energy X-ray absorptiometry. There was no significant difference between groups with respect to age or cumulative dose of prednis(ol)one or cyclosporine over the 2 years. Bone loss at the proximal femur was significantly reduced or prevented at all three sites by treatment with calcitriol for 2 years compared with treatment with calcium alone. Treatment with calcitriol for 12 months followed by calcium for 12 months resulted in similar proximal femoral bone loss to that seen in those patients treated with calcium for 24 months, suggesting calcitriol prophylaxis needs to be continued beyond 12 months. At the lumbar spine, there were no significant differences in BMD between groups. Over a period of 2 years, 22 new vertebral fractures/deformities occurred in 4 patients treated with calcium alone compared with one new vertebral fracture in 1 patient treated with calcitriol. Because the sample size was too low to provide reliable interpretation of vertebral fracture rates, this difference is likely a chance result. Mild hypercalcemia was common with calcitriol therapy, as was mild hypercalciuria (59% of patients vs. 10% controls), but there were no significant differences between groups in serum creatinine after 2 years. These data suggest calcitriol has a role in reducing proximal femur bone loss after cardiac or lung transplantation but treatment needs to be continued beyond 1 year.
Adrenal Cortex Hormones↗
Corticosteroid regulation of amiloride-sensitive sodium-channel subunit mRNA expression in mouse kidney.
Corticosteroid control of distal nephron sodium handling, particularly through the amiloride-sensitive sodium channel (ENaC), has a key role in blood pressure regulation. The mechanisms regulating ENaC activity remain unclear. Despite the generation of useful mouse models of disorders of electrolyte balance and blood pressure, there has been little study of distal nephron sodium handling in this species. To investigate how corticosteroids regulate ENaC activity we isolated cDNA for the three mouse ENaC subunits (alpha, beta and gamma), enabling their quantitation by competitive PCR and in situ hybridisation. Kidneys were analysed from mice 6 days after adrenalectomy or placement of osmotic mini-pumps delivering aldosterone (50 microg/kg per day), dexamethasone (100 microg/kg per day), spironolactone (20 mg/kg per day) or vehicle alone (controls). In controls, renal ENaCalpha mRNA exceeded beta or gamma by approximately 1.75- to 2.8-fold. All subunit mRNAs were expressed in renal cortex and outer medulla, where the pattern of expression was fully consistent with localisation in collecting duct, whereas the distribution in cortex suggested expression extended beyond the collecting duct into adjacent distal tubule. Subunit mRNA expression decreased from cortex to outer medulla, with a gradual reduction in beta and gamma, and ENaCalpha decreased sharply ( approximately 50%) across the outer medulla. Expression of ENaCbeta and gamma (but not alpha) extended into inner medulla, suggesting the potential for inner medulla collecting duct cation channels in which at least ENaCbetagamma participate. Aldosterone significantly increased ENaC subunit expression; the other treatments had little effect. Aldosterone caused a 1.9- to 3.5-fold increase in ENaCalpha (particularly marked in outer medullary collecting duct), but changes for beta and gamma were minor and limited to the cortex. The results raise the possibility that medullary ENaCalpha upregulation by aldosterone will create more favourable subunit stoichiometry leading to a more substantial increase in ENaC activity. In cortex, such a mechanism is unlikely to have a major role.
Adrenal Cortex Hormones↗
Measuring patient satisfaction--be prepared.
This article describes the approach used by the Queen Elizabeth II Health Sciences Centre to measure inpatient satisfaction at the recently merged institution. It presents some of the issues that arose in the planning stages, including use of prior consent. It is important to plan the methodology, the execution, the communication strategy and the follow-up before the process begins to ensure the results are credible, communicated and translated into quality improvement actions.
Humans↗
The relationship of magnetic source imaging to ictal electrocorticography in a neuronavigational workspace.
Magnetic source imaging (MSI) registers magnetoencephalographic (MEG) activity to a three-dimensional MRI volume. State-of-the-art MSI allows concurrent whole head coverage, but is practically restricted to interictal recording. However, the purpose of the presurgical evaluation of epileptic patients, in which MSI is playing an increasing role, is the elucidation of the ictal epileptogenic focus. The manner in which interictal MSI activity relates to the ictal focus has not yet been adequately examined. To facilitate this analysis, we are developing techniques to precisely coregister MSI to the ictal onset zone as defined by extraoperative intracranial grid/strip monitoring. The neuronavigational workspace is a convenient area in which to precisely coregister these (and other) imaging and physiological data sets.
Cerebral Cortex↗
The Nuclear Receptor Resource: a growing family.
Last year, the original Glucocorticoid Receptor Resource was expanded into a comprehensive project: the Nuclear Receptor Resource (NRR, http:// nrr.georgetown.edu/nrr/nrr.html ). The NRR has since been offering comprehensive information on nuclear receptor structure and function, as well as general facts of interest to the scientific community on meetings, funding and employment opportunities. The project now includes individual resources as part of a network which integrates information on glucocorticoid, androgen, mineralocorticoid, thyroid hormone, Vitamin D and peroxisome-proliferator activated receptors. Many investigators have joined the NRR network by filling the Who is who? form available in the NRR home page. This has facilitated communication among scientists in the field and dissemination of data nor otherwise published. Because several investigators have contacted NRR authors over the past few months asking for advice and materials for educational purposes, we have recently decided to include in our project an educational resource on nuclear receptors termed the 'Graphics Library'. The input and suggestions of NRR users do shape the future direction of the project, so we encourage user to give us feedback.
Computer Communication Networks↗
Tacrolimus (FK506) increases neuronal expression of GAP-43 and improves functional recovery after spinal cord injury in rats.
Tacrolimus (FK506), a widely used immunosuppressant drug, has neurite-promoting activity in cultured PC12 cells and peripheral neurons. The present study investigated whether tacrolimus affects the expression of the neuronal growth-associated protein, GAP-43, as well as functional recovery after photothrombotic spinal cord injury in the rat. In injured animals receiving tacrolimus, the number of neurons expressing GAP-43 mRNA and protein approximately doubled compared to that in injured animals receiving vehicle alone. This increase in GAP-43-positive cells was paralleled by a significant improvement in neurological function evaluated by open-field and inclined plane tests. Another FKBP-12 ligand (V-10,367) had similar effects on GAP-43 expression and functional outcome, indicating that the observed effects of tacrolimus do not involve inhibition of the phosphatase calcineurin. Thus, tacrolimus, a drug which is already approved for use in humans, as well as other FKBP-12 ligands which do not inhibit calcineurin, could potentially enhance functional outcome after CNS injury in humans.
Animals↗
Prevalence and epidemiology of toenail onychomycosis in diabetic subjects: a multicentre survey.
The number of individuals diagnosed with diabetes mellitus is increasing. The diabetic may present with complications involving all systems of the body. While onychomycosis is often observed in diabetics, there have been no large studies on the prevalence of the condition in this patient group. We examined the prevalence of onychomycosis in diabetics attending diabetes and dermatology clinics in London, Ontario, Canada and Boston, MA, U.S.A. Diabetic subjects seen in dermatology offices were for unrelated dermatoses; those referred specifically for the management of onychomycosis were excluded from the sample. A total of 550 diabetic subjects was evaluated (283 males and 267 females), age 56.1 +/- 0.7 years (mean +/- SEM). Patients with type I diabetes constituted 34% of the sample. The racial origin was: 531 Caucasians, 17 Asians, one African-American and one American-Indian. Abnormal-appearing nails and mycological evidence of onychomycosis (mostly due to dermatophytes) were present in 253 (46%) and 144 (26%), respectively, of 550 subjects. The development of onychomycosis was significantly correlated with age (P < 0.0001) and male gender (P < 0.0001). Males were 2.99 times more likely to have onychomycosis compared with females (95% confidence interval, CI 1.94-4 61). After controlling for age and sex, the risk odds ratio for diabetic subjects to have toenail onychomycosis was 2.77 times compared with normal individuals (95% CI 2.15-3.57). After controlling for age and sex, a stepwise logistic regression demonstrated that significant predictors for onychomycosis included a family history of onychomycosis (P = 0.0001), concurrent intake of immunosuppressive therapy (P = 0.035) and peripheral vascular disease (P = 0.023). Toenail onychomycosis was present in 26% of the sample and is projected to affect approximately one-third of subjects with diabetes. Predisposing factors include increasing age, male gender, family history of onychomycosis, concurrent intake of immunosuppressive agents and peripheral vascular disease.
Adolescent↗