Physiology. Lactic acid--the latest performance-enhancing drug.
Explore the source record for details and available documents.
Action Potentials↗
Biomedical subjects
David Allen
Publications and source records attributed to David Allen.
Investigation into postoperative endophthalmitis and lessons learned.
PURPOSE: To describe an approach to the investigation of a series of endophthalmitis cases to determine whether there was a true outbreak. SETTING: Outpatient facility, Sunderland, England. METHODS: Different approaches to statistical analysis of the probability of infrequent events being due to chance occurrence are described. Potential factors leading to an outbreak were reviewed. RESULTS: Bayesian statistical analysis was shown to be appropriate in the determination of an endophthalmitis outbreak. The only factor found to account for the outbreak was the operating surgeon's recent abandonment of subconjunctival antibiotic prophylaxis. This decision was based on the absence of good evidence that subconjunctival antibiotic injection is effective in prophylaxis. These endophthalmitis cases demonstrate that the absence of evidence for effect is not the same as there being no effect. CONCLUSIONS: Bayesian statistical analysis has a place in determining whether an outbreak has occurred. Withdrawing treatment simply on the basis of a lack of good evidence can lead to undesirable outcomes.
Aged↗
Erythropoietin protects the kidney against the injury and dysfunction caused by ischemia-reperfusion.
Erythropoietin (EPO) is upregulated by hypoxia and causes proliferation and differentiation of erythroid progenitors in the bone marrow through inhibition of apoptosis. EPO receptors are expressed in many tissues, including the kidney. Here it is shown that a single systemic administration of EPO either preischemia or just before reperfusion prevents ischemia-reperfusion injury in the rat kidney. Specifically, EPO (300 U/kg) reduced glomerular dysfunction and tubular injury (biochemical and histologic assessment) and prevented caspase-3, -8, and -9 activation in vivo and reduced apoptotic cell death. In human (HK-2) proximal tubule epithelial cells, EPO attenuated cell death in response to oxidative stress and serum starvation. EPO reduced DNA fragmentation and prevented caspase-3 activation, with upregulation of Bcl-X(L) and XIAP. The antiapoptotic effects of EPO were dependent on JAK2 signaling and the phosphorylation of Akt by phosphatidylinositol 3-kinase. These findings may have major implications in the treatment of acute renal tubular damage.
Animals↗
Growth hormone improves body composition and motor development in infants with Prader-Willi syndrome after six months.
BACKGROUND: Infants with Prader-Willi syndrome (PWS) show abnormalities of body composition. Children with PWS treated with growth hormone (GH) demonstrate improved body composition and motor skills. OBJECTIVE: To assess body composition and motor changes in infants with PWS following 6 months GH therapy. METHODS: Twenty-five infants with PWS (mean age 15.5 mo) underwent dual energy X-ray absorptiometry (DEXA) assessment of body composition, and motor assessment with the Toddler Infant Motor Evaluation (TIME). Patients were then randomized to treatment (Genotropin, 1 mg/m2/day) or control, with reassessment at 6 months. RESULTS: GH treatment significantly increased lean body mass (6.4 +/- 2.4 kg to 8.9 +/- 2.7 kg) and decreased body fat (27.6 +/- 9.9% to 22.4 +/- 10.3%). Age equivalent motor scores improved 4 months in the treated group vs 2 months in controls (p < 0.01). CONCLUSIONS: Infants with PWS show significant body composition and motor development improvement following 6 months GH therapy. We are investigating whether this improvement leads to long-term reductions in obesity.
Anthropometry↗
Twelve-month safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years with recurrent wheezing.
OBJECTIVE: Our aim was to compare the 12-month safety and efficacy of fluticasone propionate (FP) and sodium cromoglycate (SCG) in children aged 1 to 3 years with mild to moderate recurrent wheeze. METHODS: The study was a randomized, parallel-group, open-label multicenter study of 625 children, aged 1 to 3 years, with recurrent wheeze randomized in a 3:1 ratio to treatment for 52 weeks with FP (100 microg twice daily) via metered-dose inhaler and Babyhaler spacer device or SCG (5 mg 4 times daily) via metered-dose inhaler and Nebuhaler spacer device, respectively. RESULTS: There was no significant difference in mean adjusted growth rates between the 2 groups: 84.0 mm/year in the FP group versus 86.4 mm/year in the SCG group (difference FP-SCG: -2.4 mm/year; 95% confidence interval: -6.6 to 1.8). Growth comparisons were independent of age, gender, previous use of steroid, or whether measured as length and/or height. Serum and urinary cortisol concentrations showed a statistically significant suppression of 10% and 14%, respectively, but the number of patients with serum cortisol levels below the lower normal limit was reduced during the trial. Both treatments were well tolerated. The most common drug-related adverse events were cough (2% FP vs 1% SCG) and hoarseness (1% FP vs 0% SCG). One incident of cataract was observed at baseline and 1 after FP treatment; the latter had resolved after 12 months. The efficacy of FP was superior to SCG with fewer cases of symptom worsening, exacerbations, and requirements for oral steroid treatment and more symptom-free days and days without use of rescue treatment. CONCLUSIONS: Twelve months of treatment with inhaled FP (100 microg twice daily) in preschool children aged 1 to 3 years with recurrent wheeze has no effect on growth and no other clinically important side effects but is more efficacious than SCG.
Administration, Inhalation↗
Yes, steroids are safe in infants with asthma-like symptoms.
Explore the source record for details and available documents.
Administration, Inhalation↗
Skeletal and dental contributions to posterior crossbites.
The objective of this retrospective study was to compare skeletal and dental arch morphology of children with posterior crossbites with a control group of children without posterior crossbites. The study included 93 patients with a posterior crossbite (33 boys and 60 girls) and 97 patients without a posterior crossbite (50 boys and 47 girls). Skeletal and dental characteristics between the two groups were compared using measurements of dental casts, and lateral and posteroanterior cephalograms. Univariate analyses revealed that seven characteristics were significantly different between the crossbite and non-crossbite groups: mandibular plane angle, lower face height, skeletal maxillary to mandibular width ratio, maxillary intermolar width, mandibular intermolar width, maxillary to mandibular intermolar width ratio, and mandibular unit length. Using maxillary to madibular intermolar width ratio as the outcome measure, a stepwise variable selection technique, analyzed all 190 patients and found only two variables significantly associated with this measure: skeletal maxillary to mandibular width ratio and lower face height. The coefficient of multiple determination for this model was only 13%, indicating that these two variables accounted for only a small portion in the variation of the ratio between the maxillary and mandibular intermolar widths.
Adolescent↗
Pseudoepitheliomatous hyperplasia in lichen sclerosus of the vulva.
Small tentacles or separated nests of squamous cells in the dermis are not uncommonly seen in long-standing vulvar lichen sclerosus (LS) associated with epidermal thickening. We recently encountered a case where separated nests of well-differentiated squamous cells in the dermis were difficult to distinguish from squamous cell carcinoma (SCC). Further biopsies showed similar nests originating from every hair follicle. We postulated a diagnosis of multifocal pseudoepitheliomatous hyperplasia (PEH) to explain this phenomenon. Because we could find no reference to PEH in the setting of LS, we reviewed the biopsies of 92 women with extragenital and vulvar LS with and without carcinoma to determine its frequency and histological appearance. The study population, which excluded the index case, comprised 10 women with extra-anogenital LS, 58 with vulvar LS without carcinoma, and 24 with vulvar LS with carcinoma. The presence of PEH, epidermal thickness, predominant dermal collagen change, degree of inflammation, and presence of fibrin and red blood cells were recorded. The presence or absence of lichen simplex chronicus (LSC), squamous cell hyperplasia (SCH), and differentiated vulvar intraepithelial neoplasia (VIN) were recorded. PEH was identified only in vulvar LS, where it was seen in 7/58 (12.1%) women without carcinoma, 1/24 (8.3%) with carcinoma, and 0/10 (0%) with extra-anogenital LS. Two forms of PEH were seen: predominantly epidermal 7/8 (87.5%) and predominantly follicular 1/8 (12.5%). PEH was associated with increased epidermal thickness, less dermal edema, more dermal inflammation, fresh fibrin, and red blood cell extravasation. In all cases, there was associated LSC, but there was no SCH or differentiated VIN. In conclusion, PEH may explain many of the cases of dermal tentacles and separated squamous nests in vulvar LS with LSC. The association with fresh fibrin and red blood cells suggests that PEH might be a reaction to tissue damage. PEH is distinguished from SCC by its lack of atypia, confinement to the abnormal collagen, and limited growth. The pathologist must be careful about making a diagnosis of PEH in LS with epidermal thickening, looking carefully for basal atypia and other features of differentiated VIN in the overlying epidermis or dermal proliferation. We do not know whether PEH occurs in differentiated VIN and, if it does, how it could be distinguished from SCC.
Aged↗
Rapid and sensitive determination of nalmefene in human plasma by gas chromatography-mass spectrometry.
A rapid gas chromatography-mass spectrometric method for the determination of nalmefene in human plasma is described. The procedure involves protein precipitation, extraction with ethanol-chloroform mixture and derivatization with pentafluropropionic anhydride. The deuterated analog of nalmefene, 6beta-naltrexol-d(7), was used as the internal standard. Quantitation was achieved on a HP-1 column (12 mx0.2 mm I.D.) with negative chemical ionization (NCI) using methane:ammonia (95:5) as the reagent gas. The standard curves were fitted using a quadratic equation with the curve encompassing a range of 0.5 to 200 ng/ml, and the intra- and inter-assay variations for three different nalmefene levels were less than 10% throughout. The limit of quantitation was found to be 0.5 ng/ml. The method described is highly specific and reproducible, and could also be applied for the determination of naltrexone and 6beta-naltrexol. Application of the method to actual human plasma samples is demonstrated.
Gas Chromatography-Mass Spectrometry↗
Minimizing risk to the capsule during surgery for posterior polar cataract.
Posterior polar cataract is associated with a deficiency of the posterior capsule in a high percentage of cases, leading to a high incidence of capsule rupture and potential vitreous loss. We describe an approach that minimizes the risk of vitreous loss. The key is viscodissection, a technique that can be applicable in other situations.
Cataract↗
Platelet alphaIIbbeta3 recombinant autoantibodies from the B-cell repertoire of a post-transfusion purpura patient.
The biallelic human platelet alloantigen (HPA) 1 system encodes a leucine to proline substitution at position 33 in the beta3 integrin. Homozygous individuals can be immunized by the non-self allele-encoded protein following transfusion or during pregnancy. In post-transfusion purpura (PTP), a subsequent recall alloantibody response against the non-self form of beta3 is paralleled by the destruction of autologous platelets, leading to profound thrombocytopenia. Although serological evidence suggests platelet autoantibodies are responsible, such autoantibodies are poorly defined. We used variable gene phage display to isolate alphaIIbbeta3 autoantibodies formed in the acute phase of PTP and determined the epitopes recognized. An immunoglobulin G (IgG)-encoded variable heavy-chain domain (VH) gene repertoire containing 4.7 x 10(7) single-chain Fv fragments was cloned and three alphaIIbbeta3 antibodies were isolated (clones 2F2, E3 and B12). All three used different VH genes with a low level of somatic mutation for genes derived from gamma-encoding mRNA. Two (2F2 and E3) recognized an overlapping epitope and their binding was inhibited by sera from patients with PTP; all three recognized Ca2+-dependent compound epitopes on alphaIIbbeta3. Our results support the theory that a transient loss of tolerance for alphaIIbbeta3 with autoantibody formation occurs in PTP.
Autoantibodies↗
September 11th and the eminent practicality of poststructuralism.
Explore the source record for details and available documents.
Cultural Diversity↗
Sepsis- and endotoxemia-generated cytokines do not trigger activation of human platelets.
OBJECTIVE: To analyze the effect of cytokines generated in sepsis and endotoxemia (tumor necrosis factor [TNF]-alpha and interleukins [IL]-1beta, -6, and -8) on activation of human platelets and to study the effect of cytokines on platelet activation in the presence of alpha-thrombin, a potent inducer of coagulation and platelet activation generated in sepsis and endotoxemia. DESIGN: flow cytometric study of platelet activation induced by cytokines and/or thrombin in the whole blood and platelet-rich plasma (PRP) of healthy volunteers. SETTING: Research laboratory in a Canadian hospital. SUBJECTS: Nine healthy volunteers recruited from laboratory staff. MEASUREMENTS AND MAIN RESULTS: Venous blood samples were obtained into acid-citrate-dextrose anticoagulant. Whole blood and PRP were diluted with appropriate buffer optimized for analyzing platelet activation by flow cytometry. TNF-alpha, IL-1beta, IL-6, and IL-8 were added to blood or PRP in concentrations ranging from 1 to 100 ng/mL and incubated for 15 mins at 37 degrees C in the presence or absence of a submaximal concentration of human alpha-thrombin (0.025 units/mL). Samples were stained with fluorescent antibodies against markers of platelet activation (P-selectin [CD62], lysosomal protein [CD63], and fibrinogen and von Willebrand factor receptors [CD41 and CD42b, respectively]) and analyzed by flow cytometry. The data obtained show that none of these cytokines trigger activation of resting platelets in whole blood or PRP and do not modulate the effect of thrombin on platelet activation as measured by quantitation of CD62, CD63, and CD42b markers on the platelet surface. CONCLUSIONS: Cytokines TNF-alpha, IL-1beta, IL-6, and IL-8, which are extensively produced in sepsis and endotoxemia, do not trigger activation of resting human platelets directly or indirectly by mediating processes in white or red blood cells. The cytokines did not affect thrombin-induced platelet activation.
Cytokines↗
The behavioral impact of growth hormone treatment for children and adolescents with Prader-Willi syndrome: a 2-year, controlled study.
INTRODUCTION: Prader-Willi syndrome (PWS) is characterized by obesity, hypotonia, hypogonadism, hyperphagia, short stature, and a neurobehavioral profile that includes cognitive deficits, learning problems, and behavioral difficulties that increase in both quantity and severity over time. PWS results from an alteration in the molecular composition of a critical region of C#15q. Morbid obesity resulting from hyperphagia is amplified by decreased energy expenditure and reduced physical activity. The hyperphagia has proven refractory to all psychopharmocologic intervention; the behavioral components are equally resistant to psychotropic intervention. PWS patients' body composition resembles that of individuals with growth hormone (GH) deficiency, including short stature and reduced lean body mass with concomitant increased fat mass. We hypothesized that GH administration to children with PWS, in addition to stimulating linear growth, would improve body composition, increase energy expenditure and fat utilization, and improve muscle strength, physical agility, and pulmonary function. Two recent reports from this study document significant positive effects of GH treatment on these children's physical parameters measured in a 2-year, controlled study. However, the behavioral impact of GH treatment in this population remains incompletely described. A psychosocial burden, including emotional, behavioral, and cognitive disturbances associated with short stature, has been previously described in a non-PWS population with GH deficiency and idiopathic short stature. An impaired quality of life and psychosocial status is also documented in otherwise normal adults with GH deficiency. In both populations, growth hormone replacement therapy (GHRT) is reported to improve alertness, activity level, endurance, irritability, tendency to worry, and extroversion resulting in better personal relationships with fewer conflicts. This report focuses on that portion of the study investigating the behavioral and psychosocial outcomes accompanying increased stature and improved physical status for persons with PWS treated with GHRT. We hypothesized that, as in other populations, GHRT for persons with PWS would have a significant positive effect on their psychosocial status as well as an improvement in their growth parameters. METHODS: A 2-year, controlled study with control group crossover in the second year was used. Fifty-four consecutive children with genetically confirmed PWS were enrolled. Patients were 4 to 16 years of age at time of enrollment, had skeletal maturation <13 for girls and <15 for boys; all but 3 participants remained prepubertal (Tanner stage 1) throughout the study. Children who had previous therapy with GH were excluded, as were children with a scoliosis >20 degrees. After a 6-month growth assessment were randomized into a 60:40 treatment:control ratio. Treatment consisted of Nutropin (Genentech), 1 mg/m2/day. A modified Offord Survey Diagnostic Instrument (SDI) was used to monitor behavior at 6-month intervals. The SDI is a 165-item behavioral checklist with items rated on a scale of 0 = Never or Not True, 1 = Sometimes or Somewhat True, and 2 = Often or Very True. The items are balanced between positively and negatively scored items. The present instrument was designed to derive diagnoses for the following Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition categories: Depression, Obsessive-Compulsive Disorder, Anxiety Disorder, Somatization Disorder, Conduct Disorder, and Attention-Deficit/Hyperactivity Disorder. The SDI was modified to include 10 items specifically inquiring about PWS (eg, denies having PWS, picks excessively at skin, nose, or other body parts). Because diagnoses are not mutually exclusive, an individual can meet criteria for 1 or more diagnostic categories. The SDI contains a second section measuring behavior functioning in the school environment, in the family, and in personal and social relationships. A wider scoring range is used and is question-specific. Parallel forms of this measure are available for parents, teachers, and the child him/herself. We gathered data from both parents and teachers at 6-month intervals. No questionnaire was scored until the completion of the entire study to avoid any possibility of an inadvertent "feedback" or "self-fulfilling prophecy" effect. All questionnaires were scored by a Bachelor's level research assistant blind to study assignment. Family stress was monitored with the Family Inventory of Life Events. At study completion, the impact of GH was measured with a 13-item summary interview adapted from Wiren et al. After completion of all final study visits, a single research assistant blind to treatment assignment interviewed all families by phone. This method was chosen to minimize any positively biased demand characteristics. RESULTS: Both between-group and within-group contrasts were computed for baseline, 12 (time 1) and 24 month (time 2) measures. Because behavioral deterioration, as well as improvement, was a possibility, a 2-tailed hypothesis test was used for all comparisons. No differences were found between treatment and control groups, nor within groups across measurement points for attentional symptoms, anxiety, obsessive-compulsive complex, violence, or psychotic symptoms. Similarly, no differences were noted between groups on depressive symptoms; however, a significant positive effect (reduction of depressive symptoms) was noted for the treatment group from baseline to time 1, and was retained at time 2. The group was divided by age, with those 11.0 years and younger comprising one group and those older the second group. This analysis indicated that the major reduction in depressive symptoms occurred in those over 11 years old. When divided by age, a second unexpected finding emerged. There was a significant increase in attention-deficit/hyperactivity disorder symptoms from baseline to 24 months in those children 11 and under, independent of treatment status. The groups were subsequently further broken down by sex and by genetic status (deletion versus disomy) with no significant findings. At no time was the expected behavioral deterioration reported. We conclude that in addition to the previously detailed improvements in physical parameters for these children, behavioral improvement, including a lack of predictable behavioral deterioration during the treatment period, is a strong argument for the use of GHRT for this difficult syndrome.
Adolescent↗
Harm from unadjusted data?
Explore the source record for details and available documents.
Centers for Medicare and Medicaid Services, U.S.↗