Ex Vivo Confocal Spectroscopy of Autofluorescence in Age-Related Macular Degeneration.
We investigated the autofluorescence (AF) signature of the microscopic features of retina with age-related macular degeneration (AMD) using 488 nm excitation. The globes of four donors with AMD and four age-matched controls were embedded in paraffin and sectioned through the macula. Sections were excited using a 488 nm argon laser, and the AF emission was captured using a laser scanning confocal microscope (496-610 nm, 6 nm resolution). The data cubes were then analyzed to compare peak emission spectra between the AMD and the controls. Microscopic features, including individual lipofuscin and melanolipofuscin granules, Bruch's Membrane, as well macroscopic features, were considered. Overall, the AMD eyes showed a trend of blue-shifted emission peaks compared with the controls. These differences were statistically significant when considering the emission of the combined RPE/Bruch's Membrane across all the tissue cross-sections (p = 0.02). The AF signatures of ex vivo AMD RPE/BrM show blue-shifted emission spectra (488 nm excitation) compared with the control tissue. The magnitude of these differences is small (~4 nm) and highlights the potential challenges of detecting these subtle spectral differences in vivo.


The outcome for AHCPR. Interview by Laura Lynn Brown.
In late July, a House Appropriations Subcommittee voted to cut the Agency for Health Care Policy and Research (AHCPR) budget by 21 percent in fiscal year 1996. The six-year-old, $162 million agency has produced clinical practice guidelines for 10 of the 15 costliest conditions for which people are hospitalized. Their application has saved the health system far more than AHCPR costs, many experts believe. The agency's supporters say its work is a critical underpinning of the movement in value-based purchasing and quality assurance, while many Congressional Republicans believe the private sector could do AHCPR's work just as well. Health Systems REVIEW recently spoke with AHCPR administrator Clifton R. Gaus about the agency's mission and its strategy for survival.


Community-acquired methicillin-resistant Staphylococcus aureus endomyocardial abscesses in a heart transplant recipient.
Infective endocarditis is more common in heart transplant recipients than in the general population. We report a case of endomyocardial abscesses and sepsis syndrome due to community-acquired methicillin-resistant Staphylococcus aureus (MRSA) in a heart transplant recipient with a negative transesophageal echocardiogram. The suspected portal of entry for this MRSA infection was through infected herpes zoster lesions. This case demonstrates the difficulty of diagnosing endomyocardial abscesses in heart transplant patients.


Efficacy of hyperbaric oxygen after microtia reconstruction using costal cartilage: A retrospective case-control study.
Microtia reconstruction with autologous costal cartilage framework grafting is challenging because the three-dimensional structure of the ear is highly complex, and meeting the high aesthetic demands of patients can be difficult. If the skin flap overlying the framework is thinned to achieve a smooth and accentuated outline, a poor blood supply in the thin skin flap may lead to skin necrosis, exposure of the framework, and poor surgical results. Hyperbaric oxygen (HBO2) therapy can promote the healing of complex wounds and flaps. This study sought to determine the effectiveness of HBO2 therapy for the prevention of postoperative complications after framework grafting in microtia reconstruction. We retrospectively evaluated postoperative complications and compared outcomes in pediatric patients who underwent costal cartilage grafting for microtia reconstruction at our institution between 2011 and 2015, according to whether or not they received postoperative HBO2 therapy. HBO2 therapy was applied once daily for a total of 10 sessions starting on the first postoperative day. During the study period, eight patients received HBO2 therapy after costal cartilage grafting, and 12 did not. There was no significant difference in the incidence of postoperative ulcers. However, the incidence of framework exposure was lower, and the healing time was shorter in patients who received HBO2 therapy than in those who did not. HBO2 therapy can be used safely in pediatric patients to reduce postoperative complications and improve the aesthetic outcome of microtia reconstruction. After costal cartilage grafting, HBO2 therapy should be considered as adjuvant therapy.


[Effect of glutathione on choleragenic diarrhea and disorders of the antioxidant system of rat intestinal and liver cells].
The effects of reduced glutathione on the development of choleragenic diarrhea and the activity of glutathione transferase (GT), glutathione peroxidase (GP-GTB and GP-H2O2), superoxide dismutase (SOD), glutathione reductase (GR) in the small intestine and liver of rats with experimentally ligated jejunal loop have been studied. Diarrhea syndrome was found to decrease markedly after glutathione administration in a dose of 1 g/kg bw. GR activity in the jejunum and liver of rats treated with toxin and the following glutathione administration rose by 210 and 186%, respectively, and then reached the control level. Glutathione transferase activity in the jejunum increased by 150% (P less than 0.05), remaining, however, lower than the control values. The activity of other enzymes tested was unchanged. Polyfunctional cellular activity of glutathione suggests that antidiarrhea effect should be considered as an element of pathogenetic therapy.


Lactose intolerance and health.
We systematically reviewed evidence to determine lactose intolerance (LI) prevalence, bone health after dairy-exclusion diets, tolerable dose of lactose in subjects with diagnosed LI, and management. We searched multiple electronic databases for original studies published in English from 1967-November 2009. We extracted patient and study characteristics using author's definitions of LI and lactose malabsorption. We compared outcomes in relation to diagnostic tests, including lactose challenge, intestinal biopsies of lactase enzyme levels, genetic tests, and symptoms. Fractures, bone mineral content (BMC) and bone mineral density (BMD) were compared in categories of lactose intake. Reported symptoms, lactose dose and formulation, timing of lactose ingestion, and co-ingested food were analyzed in association with tolerability of lactose. Symptoms were compared after administration of probiotics, enzyme replacements, lactose-reduced milk and increasing lactose load. Prevalence was reported in 54 primarily nonpopulation based studies (15 from the United States). Studies did not directly assess LI and subjects were highly selected. LI magnitude was very low in children and remained low into adulthood among individuals of Northern European descent. For African American, Hispanic, Asian, and American Indian populations LI rates may be 50 percent higher in late childhood and adulthood. Small doses of lactose were well tolerated in most populations. Low level evidence from 55 observational studies of 223,336 subjects indicated that low milk consumers may have increased fracture risk. Strength and significance varied depended on exposure definitions. Low level evidence from randomized controlled trials (RCTs) of children (seven RCTs) and adult women (two RCTs) with low lactose intake indicated that dairy interventions may improve BMC in select populations. Most individuals with LI can tolerate up to 12 grams of lactose, though symptoms became more prominent at doses above 12 grams and appreciable after 24 grams of lactose; 50 grams induced symptoms in the vast majority. A daily divided dose of 24 grams was generally tolerated. We found insufficient evidence that use of lactose reduced solution/milk, with lactose content of 0-2 grams, compared to a lactose dose of greater than 12 grams, reduced symptoms of lactose intolerance. Evidence was insufficient for probiotics (eight RCTs), colonic adaptation (two RCTs) or varying lactose doses (three RCTs) or other agents (one RCT). Inclusion criteria, interventions, and outcomes were variable. Yogurt and probiotic types studied were variable and results either showed no difference in symptom scores or small differences in symptoms that may be of low clinical relevance. There are race and age differences in LI prevalence. Evidence is insufficient to accurately assess U.S. population prevalence of LI. Children with low lactose intake may have beneficial bone outcomes from dairy interventions. There was evidence that most individuals with presumed LI or LM can tolerate 12-15 grams of lactose (approximately 1 cup of milk). There was insufficient evidence regarding effectiveness for all evaluated agents. Additional research is needed to determine LI treatment effectiveness.


Prognostic value of serum hyponatremia for outcomes in patients with heart failure with preserved ejection fraction: An observational cohort study.
Hyponatremia is a risk factor associated with poor prognosis in patients with heart failure (HF) with reduced ejection fraction. However, whether hyponatremia has a similar role in patients with HF with preserved ejection fraction (HFpEF) has remained controversial. Therefore, the present study aimed to investigate the clinical characteristics and 24-month prognostic profile of a cohort of patients with HFpEF in China. From a registered observational cohort study on 1,027 subjects with HF, 496 patients with HFpEF were included. The association between baseline hyponatremia on admission and 24-month adverse outcomes (including all-cause mortality, re-hospitalization for HF and stroke) was analyzed using logistic regression with the Cox proportional hazards model. Of the 496 patients with HFpEF with a mean age of 72.8 years and proportion of males of 53.0%, 71 patients were diagnosed with hyponatremia. Furthermore, 29 patients (5.8%) were lost to follow-up. The hyponatremia group had lower blood pressure and serum hemoglobin, higher N-terminal pro B-type natriuretic peptide (NT-proBNP) and D-dimer, more patients with a history of atrial fibrillation and a higher proportion of spironolactone and loop diuretic use. According to a multivariate regression analysis, New York Heart Association functional classes III-IV and a serum NT-proBNP level above the median were risk factors for hyponatremia, while higher systolic blood pressure and β-blocker use were protective factors against hyponatremia. In the Kaplan-Meier analysis, hyponatremia was associated with all-causes of mortality, re-hospitalization for HF and a poor prognosis for patients suffering from strokes (log-rank P<0.05 for all 3 endpoints). On multivariate logistic regression analysis with the Cox proportional hazard model, hyponatremia was an independent predictor of three adverse outcomes [all-cause mortality: Hazard ratio (HR)=1.54, 95% CI=1.07-2.91, P=0.034; re-hospitalization for heart failure: HR=1.28, 95% CI=1.16-2.47, P=0.013; stroke: HR=1.78, 95% CI=1.04-2.89, P=0.016]. Collectively, the present results suggested that hyponatremia on admission was significantly associated with all-cause mortality, re-hospitalization and stroke within 24 months in a cohort of hospitalized patients with HFpEF in China. Thus, hyponatremia should be carefully monitored and frequently adjusted in patients with HFpEF (NCT04062500).


Lumbar extraforaminal entrapment: performance characteristics of detecting the foraminal spinal angle using oblique coronal MRI. A multicenter study.
Previous conventional magnetic resonance imaging reports on extraforaminal entrapment (e-FE) on L5-S1 have been problematic because of their complexity or lack of sensitivity and specificity. In this study, we propose a simple diagnostic method for e-FE. The purpose of this study was to determine the sensitivity and specificity of using the difference in the foraminal spinal nerve (FSN) angle of the L5 nerve, as determined by oblique coronal T2-weighted imaging (OC-T2WI), for diagnosing L5-S1 unilateral e-FE. The study design involves diagnostic accuracy with retrospective case-control study. Seventy consecutive patients with unilateral L5 radiculopathy who underwent unilateral L5-S1 extraspinal canal decompression for e-FE or 4/5 intraspinal canal decompression for lumbar spinal canal stenosis between 2009 and 2013 were included. The Japanese Orthopedic Association score, Visual Analog Scale score for leg pain, and OC-T2WI for the FSN angle of the L5 nerve were examined. The 70 patients were divided into two groups: Group A (n=21) with unilateral L5-S1 e-FE and Group B (n=49) with intraspinal canal L4-L5. Group C (n=44) comprised the control group, which included only patients with back pain without leg radiculopathy. All patients underwent OC-T2WI, and the differences in the FSN angle of the fifth lumbar spinal nerve between the symptomatic and asymptomatic sides (ΔFSN angle) were examined and compared among the groups. There were no significant differences in the patient characteristics among the three groups. The ΔFSN angle was 17° in Group A, 4.8° in Group B, and 6.4° in Group C, and the laterality was significantly larger in Group A than in the other two groups. A receiver-operating characteristic curve showed areas under the curve between groups A and B and between groups A and C of 0.93 and 0.97, respectively. In addition, the cutoff value of the ΔFSN angle (10°) indicated diagnostic accuracies of 94% and 91% (sensitivity and specificity) and of 93% and 95%, respectively. Determining differences in the FSN angle between the symptomatic and asymptomatic sides of greater than 10° via OC-T2WI represented a simple, readily available, and complementary diagnostic method for lumbar e-FE.


Problems in design of stroke treatment trials.
Critical evaluation of the literature was use to identify remediable flaws in the design of clinical trials of stroke treatment. Trials of dexamethasone, dextran, and glycerol were reviewed. Available studies have in common major weaknesses in case selection (failure to exclude arteriolar strokes due to hemorrhage or lacunar infarction), and failure to estimate required sample size. Problems of case selection can be avoided with computerized tomography; the sample size required to show superiority of active treatment over placebo can be estimated using standard formulas. Prognostic stratification is suggested as a method of overcoming problems of unbalanced allocation. Further studies with improved design are required to evaluate the prospects for medical limitation of cerebral infarct size.


Comparative cardiovascular safety of risperidone and olanzapine, based on electrocardiographic parameters and blood pressure: a prospective open label observational study.
To assess the cardiovascular safety of two commonly prescribed atypical antipsychotics risperidone (RSP) and olanzapine (OZP) in schizophrenic patients, using electrocardiography (ECG) and Blood Pressure (BP). This was a 10-week prospective open label, observational study, carried out in a newly diagnosed 64 schizophrenic patients receiving either RSP or OZP. RSP (n = 32) was started with dose of 2 mg/day and increased to 4 mg/day after 2 weeks, whereas OZP (n = 32) was started at a dose of 5 mg/day and was increased to 10 mg/day after 2 weeks. Heart rate (HR), ECG parameters (PR, RR, QRS, QT intervals and QTc and QTd) and BP (systolic and diastolic in supine and standing position) were recorded at baseline (before drug therapy)) and during follow-up visits at 2(I), 6(II) and 10(III) weeks. In the RSP group, at II and III follow-ups, a significant increase in the HR (P = 0.018, P = 0.011 respectively) as well as in QTc (P = 0.025, P = 0.015, respectively) was observed when compared to the basal values. In the OZP group, diastolic BP was significantly decreased in standing position at II and III follow-ups (P = 0.045 and P = 0.024, respectively) compared to the basal values. When the two groups were compared with each other, no significant differences were observed in the changes of HR, PR, QRS, QT, RR, QT, QTd and SBP (supine and standing position); and DBP (supine position). However, DBP in standing position showed a significant decrease in the OZP group at II and III follow-up (P = 0.036 and P = 0.016, respectively) compared to the RSP group. Patients treated with OZP are at higher risk to develop postural hypotension as compared with RSP; hence RSP could be better tolerated by patients taking antihypertensive drugs as compared with OZP whereas OZP would have a safer cardiac profile.


Congenital urethral anomalies in boys. Part I: posterior urethral valves.
The aims of this review are one, to consider that congenital urethral anomalies are not a simple disease entity in all patients. This is accomplished by reviewing the evidence for presence of posterior urethral valve subtypes and comorbidity of various unexplained clinical conditions in some children leading to chronic renal failure. The review's second aim is to describe the effects of fetal lower urinary tract obstruction on postnatal bladder function and the consequence of bladder dysfunction on the remaining postnatal renal function. The literature was extensively reviewed concerning the different types of congenital urethral outlet obstruction presentations, diagnosis, different types of treatment modalities, morbidity, mortality, and new concepts for this old problem. These findings were compared with conventional approaches to these anomalies. The 739 published papers on posterior urethral valves were evaluated, and a quarter of those are addressed. All radiologic presentations and figures in this review were selected from among the records of Iranian patients treated by the author during the last 25 years. A significant overlap of presentation before antenatally diagnosed era was observed. The natural history of these anomalies is becoming clear and the hypothesis of posterior urethral diaphragm is popular among several investigators in comparison to the original valves classification by Young in 1903. Further molecular investigation of the urinary tract is needed to better understand the pathophysiology of renal and bladder function in children who are born with antenatally diagnosed congenital urethral obstruction. These anomalies must be treated by urologists with a vast experience with valves and other rare congenital urethral anomalies.


Enhanced biogas production potential of microalgae and swine wastewater using co-digestion and alkaline pretreatment.
Biogas yield obtained from anaerobic digestion of swine wastewater (SWW) needs to be increased to produce electrical energy. To enhance biogas and prevent pollution, use of mixed culture microalgae grown in wastewater (MWW) with SWW has attracted a lot of interest. This research was focused on the possibility of utilizing MWW. Six experiments using raw SWW and MWW, and their co-digestion were conducted on a laboratory scale in one-litre reactors with the ratio of inoculum and substrate of 70:30 under without and with alkaline pretreatment (using 3% NaOH for pH adjustment every 15 min at pH 11 for 3 h). The results showed that co-digestion had the major effect on increasing biogas and methane yields (0.735 and 0.326 m3/kg of volatile solids (VS) removed), and the highest chemical oxygen demand and VS removal (60.29% and 63.17%). For pretreatment, the effect of ammonia inhibition at a high pH of 11 had more influence on biodegradation than the effect of destruction of MWW's cell walls, resulting in a low biogas production of pretreated MWW and pretreated co-digestion. These findings affirm the potential of co-digestion, and the possibility of using both single and co-substrate MWW. Pretreatment could be improved at a lower alkaline pH condition. A pilot scale of co-digestion should be performed.


[Early detection of prostate cancer--recommendations after 13 years of follow-up in the European randomised study].
The recent publication of updated results from the European randomised study of screening for prostate cancer (ERSPC) with a median 13-year follow-up confirms significant relative and absolute reductions in prostate cancer mortality. In spite of existing guidelines, Dutch men and professionals remain uncertain about the use of PSA testing. The data now available will be helpful in reaching informed decisions. In men aged 55-69 years, the relative mortality reduction remained similar at 21%; the absolute reduction increased from 0.9 to 1.28 fewer deaths/1000 men screened. This translates into much improved figures needing to be invited for screening and diagnosed, at 781 and 27 (1410 and 48 in 2009). As expected, overall mortality does not differ between the arms of the study. The main downside of PSA-driven screening remains the diagnosis of non-life-threatening cancers (overdiagnosis) by screening, at a frequency of about 40%, which can be reduced by use of the Prostate Cancer Risk Calculator. Current data support the present guideline which recommends informed decision-making, taking into account the advantages and potential damage caused by PSA testing.


The HeartQoL: Part I. Development of a new core health-related quality of life questionnaire for patients with ischemic heart disease.
Evaluation of health-related quality of life (HRQL) is important in improving the quality of patient care. The HeartQoL Project, with cross-sectional and longitudinal phases, was designed to develop a core ischemic heart disease (IHD) specific HRQL questionnaire, to be called the HeartQoL, for patients with angina, myocardial infarction (MI), or ischemic heart failure. Patients completed a battery of questionnaires and Mokken scaling analysis was used to identify items in the HeartQoL questionnaire. We enrolled 6384 patients (angina, n = 2111, 33.1%; MI, n = 2351, 36.8%; heart failure, n = 1922, 30.1%) across 22 countries and 15 languages. The HeartQoL questionnaire comprises 14-items with 10-item physical and 4-item emotional subscales which are scored from 0 (poor HRQL) to 3 (better HRQL) with a global score if needed. The mean baseline HeartQoL global score was 2.2 (±0.5) in the total group and was different (p < 0.001) by diagnosis (MI, 2.4 ± 0.5; angina, 2.2 ± 0.6; and heart failure, 2.1 ± 0.6). The HeartQoL questionnaire, with global and subscale scores, has the potential to allow clinicians and researchers to (a) assess baseline HRQL, (b) make between-diagnosis comparisons of HRQL, and (c) evaluate change in HRQL in patients with angina, MI, or heart failure with a single IHD-specific HRQL instrument.


Repeated clenching causes plasticity in corticomotor control of jaw muscles.
This study tested the effect of short-term tooth-clenching on corticomotor excitability of the masseter muscle using transcranial magnetic stimulation (TMS). Fifteen subjects with normal stomatognathic function participated. All subjects performed a tooth-clenching task (TCT) on five consecutive days. The TCT consisted of 10, 20, and 40% of maximum voluntary contraction in a randomized order within 1 h. All subjects underwent TMS in four sessions: pretask day 1 (baseline), post-task day 1, pretask day 5, and post-task day 5. Motor-evoked potentials (MEPs) from the masseter and the first dorsal interosseous (FDI) muscles were obtained using TMS in four sessions. Motor thresholds decreased, after the TCT, for the masseter muscle MEPs. Masseter muscle MEPs were dependent on stimulus intensity and on session, whereas FDI muscle MEPs were only dependent on stimulus intensity. Post-hoc Tukey tests demonstrated significantly higher masseter muscle MEPs post-task on day 5 with 80 and 90% stimulus intensity and above when compared with pre- and post-task day 1 values. Our results suggest that the performance of repeated TCTs can trigger neuroplastic changes in the corticomotor control of the jaw-closing muscles and that such neuroplastic changes may contribute to the mechanism underlying the clinical manifestations of tooth clenching.


Suspected giant cell arteritis: a study of referrals for temporal artery biopsy.
The purpose of this study is to describe the nature of cases undergoing temporal artery biopsy (TAB) for suspected giant cell arteritis (GCA). A retrospective review of case notes was undertaken for all patients on whom ophthalmologists had performed TAB in 2 teaching hospitals between 1995 and 2001. Presenting symptoms, referring specialty, TAB result, treatment, and discharge diagnosis were recorded. Ophthalmologists performed TAB on 110 patients for suspected GCA. A variety of specialties referred patients to ophthalmology for TAB; presenting symptoms varied with referral source. Of the 110 TABs, 21 (19%) were reported as positive for GCA, 84 (76%) were negative, and 5 (4.5%) were reported as inadequate. The symptoms most commonly associated with a positive TAB were visual disturbance (15/21) and headache (15/21). The odds ratios for having a positive TAB result rather than a negative result were 1.0 for the presence of headache, 4.1 for visual disturbance, and 6.7 for jaw claudication. Physicians were faced with a different population of GCA suspects than ophthalmologists. While physicians should be alert to the significance of visual symptoms or jaw claudication, ophthalmologists should be ready to facilitate prompt TABs when appropriate. TAB should be performed promptly and an adequate length of artery taken for biopsy. An argument can be made that TAB is not needed in cases of suspected GCA. However, a positive result provides firm justification for the use of steroids. We feel that TAB has a useful role and we make reference to methods to maximize its usefulness.


Depolarized cell growth precedes filamentation during the process of ethanol-induced pseudohyphal formation in the yeast Candida tropicalis.
Ethanol has been reported to cause mycelial growth in Candida tropicalis Pk233, and mycelial growth has also been shown to be abolished by concomitant addition of myo-inositol. In this study, the process of ethanol-induced mycelial growth in this organism was examined in combination with cytological characterization of actin localization. Cultivation with ethanol gave biphasic growth curves. During the first growth phase (doubling time 2.4 h), there was an accumulation of swollen spherical yeast cells, instead of the oblong ones observed in the control culture, followed by the appearance of spherical daughter cells in chains. Randomly-distributed actin patches were observed on these swollen yeast cells and the bud initiation sites of these cells appeared random. These observations suggested that ethanol caused depolarization of cell growth during the first phase. During the second growth phase (doubling time 7.4 h), pseudohyphal cells appeared, projecting from the swollen yeast cells. Activity of chitinase in the control culture rose during the exponential phase. In the ethanol culture the activity stayed at a low level throughout the growth phases. When pseudohyphal cells were transferred to fresh ethanol medium, yeast cells appeared from pseudohyphal filaments and changed their shape to spherical, and filamentation appeared to be inhibited during the first phase. From these observations, an initial effect of ethanol on C. tropicalis cells appeared to be depolarization of cell growth, and the resulting swollen cells grew as polar pseudohyphal cells. In the culture supplemented with both ethanol and inositol, or with both ethanol and sorbitol, the accumulation of swollen cells was not observed and single yeast cells with normal oblong shape were seen throughout the growth phases.


Is necropsy obsolete - an audit of the clinical autopsy over six decades: a study from Indian sub continent.
Several studies have documented a decrease in the autopsy rate. This study was taken up to analyse the cause of mortality, the discrepancies between the ante mortem and post mortem diagnosis and the discrepancies between diagnoses according to the type of the disease over a period of six decades. Autopsy reports and medical records were retrospectively analyzed over a 63 year period from 1947 to 2010. In our study, there was a steady increase in the percentage of neoplastic cases from 1947 to 1994 after which there has been a significant drop. The cases dying due to infection has also shown a steady decline over the years until 1994. After 1994, there has been a significant increase in the deaths until 2010 (p < 0.05). Death due to cardiac causes has shown an increase until 1962 which has been followed by a steady decline. There has been a sudden rise in the number of cases dying due to renal causes between 1994 and 2000 (p < 0.05). There has been a statistically significant decrease in the discrepancies between the ante mortem and the post mortem diagnosis over the years. This study shows that therapeutic and preventive measures correctly instituted have significantly reduce the mortality, particularly with reference to cardiac and infectious causes. The discrepancy between antemortem and post-mortem diagnosis in 2010 is still very high at 9.30 percent. The autopsy will continue to remain relevant especially in elucidating the molecular cause of disease.


Mice deficient for the synaptic vesicle protein Rab3a show impaired spatial reversal learning and increased explorative activity but none of the behavioral changes shown by mice deficient for the Rab3a regulator Gdi1.
Rab proteins are small GTPases involved in intracellular trafficking. Among the 60 different Rab proteins described in mammals, Rab3a is the most abundant in brain, where it is involved in synaptic vesicle fusion and neurotransmitter release. Rab3a constitutive knockout mice (Rab3a(-/-)) are characterized by deficient short- and long-term synaptic plasticity in the mossy fiber pathway and altered circadian motor activity, while no effects on spatial learning have been reported so far for these mice. The goals of this study were to analyse possible behavioral consequences of the lack of synaptic plasticity in the mossy fiber pathway using a broad battery of sensitive behavioral measures that has been used previously to analyse the behavior of Gdi1 mice lacking a protein thought to regulate Rab3a. Rab3a(-/-) mice showed normal acquisition but moderately impaired platform reversal learning in the water maze including reference memory and episodic-like memory tasks. A mild deficit in spatial working memory was also observed when tested in the radial maze. Analysis of explorative behavior revealed increased locomotor activity and enhanced exploratory activity in open field, O-maze, dark/light box and novel object tests. Spontaneous activity in normal home cage settings was unaffected but Rab3a(-/-) mice showed increased motor activity when the home cage was equipped with a wheel. No differences were found for delayed and trace fear conditioning or for conditioned taste aversion learning. Congruent with earlier data, these results suggest that Rab3a-dependent synaptic plasticity might play a specific role in the reactivity to novel stimuli and behavioral stability rather than being involved in memory processing. On the other hand, the phenotypic changes in the Rab3a(-/-) mice bore no relation to the behavioral changes as observed in the Gdi1 mice. Such divergence in phenotypes implies that the putative synaptic interaction between Gdi1 and Rab3a should be reconsidered and re-analysed.


Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study.
Chronic kidney disease (CKD) is common and disproportionally burdens United States ethnic minorities. Its genetic determinants may differ by disease severity and clinical stages. To uncover genetic factors associated CKD severity among high-risk ethnic groups, we performed genome-wide association studies (GWAS) in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study. We assembled multi-ethnic genome-wide imputed data on CKD non-overlapping cases [4,150 mild to moderate CKD, 1,105 end-stage kidney disease (ESKD)] and non-CKD controls for up to 41,041 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian, and American Indians). We implemented a generalized estimating equation approach for GWAS using ancestry combined data while adjusting for age, sex, principal components, study, and ethnicity. The GWAS identified a novel genome-wide associated locus for mild to moderate CKD nearby NMT2 (rs10906850, p = 3.7 × 10-8) that replicated in the United Kingdom Biobank white British (p = 0.008). Several variants at the APOL1 locus were associated with ESKD including the APOL1 G1 rs73885319 (p = 1.2 × 10-9). There was no overlap among associated loci for CKD and ESKD traits, even at the previously reported APOL1 locus (p = 0.76 for CKD). Several additional loci were associated with CKD or ESKD at p-values below the genome-wide threshold. These loci were often driven by variants more common in non-European ancestry. Our genetic study identified a novel association at NMT2 for CKD and showed for the first time strong associations of the APOL1 variants with ESKD across multi-ethnic populations. Our findings suggest differences in genetic effects across CKD severity and provide information for study design of genetic studies of CKD in diverse populations.


Pharmacokinetics and pharmacotherapy of thionamides in pregnancy.
Hyperthyroidism occurs in approximately 1 in every 1000 to 2000 pregnancies. Although the signs and symptoms of the disease are similar in the pregnant and nonpregnant patient, the complications of hyperthyroidism can have even more profound consequences for the mother and fetus during gestation. These include maternal heart failure, preeclampsia, miscarriage, and preterm labor; as well as fetal loss and low birth weight. Furthermore, thyroid function and laboratory testing for hyperthyroidism are altered in pregnancy. The gestational increase in thyroid size, increased thyroid-binding globulin levels, increased serum total T4 and total T3 levels, and decreased thyroid stimulating hormone levels often confuses the evaluation of the thyroid status in pregnancy. Worldwide, the thionamides-propylthiouracil, methimazole, and carbimazole-have been used in pregnancy for the treatment of hyperthyroidism. However, propylthiouracil has been the drug of choice in the United States because it is believed to have less potential to induce fetal/neonatal hypothyrodism, to cross the placenta and into breast milk to a lesser degree, and to be less teratogenic than methimazole or carbimazole. None of the above have been substantiated in more recent studies. The pharmacokinetics of the thionamides in the pregnant and nonpregnant states, as well as the pharmacotherapeutic recommendation for hyperthyroidism will be reviewed.


Successful treatment of disseminated interdigitating dendritic cell sarcoma with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy.
Interdigitating dendritic cell sarcoma (IDCS) is a very rare and aggressive neoplasm that arises from antigen presenting cells. IDCS usually involves lymph nodes; however, extra-nodal involvement has also been reported. Because a consistent standard therapy for IDCS has not been established to date, we report a case of the successful treatment of disseminated IDCS using ABVD chemotherapy (doxorubicin, bleomycin, vinblastine, and dacarbazine). A 64-year-old man was diagnosed with IDCS on the basis of immunohistochemical findings of a biopsy specimen of the inferior nasal concha. Immunohistochemical staining showed a positive reaction for CD68, leukocyte common antigen, and S-100 protein, but a negative reaction for CD34, CD1a, and CD21. Imaging studies showed cervical and axillary lymphadenopathies, subcutaneous nodules, and a soft tissue lesion in the nasal cavity. Treatment with the ABVD regimen resulted in complete remission after 8 cycles of chemotherapy.


Prevalence of Cutaneous Leishmaniasis in Iran (2000-2016): A Systematic Review and Meta-analysis Study.
Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis affecting humans. The purpose of this study was to determine the prevalence and epidemiological features of CL in Iran by a systematic review and meta-analysis. The literature search was performed in the SID, Magiran, IranDoc, PubMed, Scopus, Medlib, as well as the Google Scholar search engine databases to find studies on the prevalence of CL. The reference lists of the found articles were also reviewed to obtain additional relevant articles. Studies that were related to treatment and reservoirs of CL were excluded. Forty-four studies were selected for the final analysis. Meta-analysis with a random-effects model showed that the prevalence of leishmaniasis in Iran was 77 per 100,000 population. Overall, 60% of the patients were men. Most cases of CL occurred in autumn, and the majority of the patients had one lesion, mostly on hands. The most common age group was 20-30 years. In conclusion, CL is an endemic disease in Iran, and its prevalence is largely affected by geographical locations and regional customs. Appropriate preventing measures should be considered to decrease the incidence of CL in Iran.


Underrecording and underreporting of participant ethnicity in clinical trials is persistent and is a threat to inclusivity and generalizability.
People from ethnic minority groups are underserved by randomized trials, and poor representation of these groups reduces generalizability of results. There is no guidance on which ethnicity categories are appropriate for use in trials and thus inconsistency exists. The purpose of this study is to establish, in a large sample of trials, if participant ethnicity is recorded, how it is obtained (categories used), and if its reporting varies from its recording. We reviewed trial documentation for 407 randomized controlled trials published in the UK National Institute of Health Research library from 2016 to 2021. We extracted data on the recording (if it was recorded and the categories used) and reporting (if the categories remained the same as those obtained, or not) of ethnicity for each trial along with demographics. In the analysis we categorized the manner of recording and reporting of ethnicity in the trials according to UK Census ethnicity categories. Ethnicity was recorded in 67.3% (n = 274) of trials. The location in the trial report where ethnicity was recorded was available for 42% (n = 116) of trials. The details on how ethnicity was collected (predefined categories or self-defined) was available for 54/274 (20%) of trials and details on the specifics of the categories recorded was available for 44 (16%) trials. Of the 44, 6 of those did not go on to report on ethnicity in the trial report. Of the remaining 38, only 13 reported ethnicity exactly as it had been recorded. Taken as a whole from the 407 trial reports examined 9.3% (38/407) of trials demonstrated exactly how they both recorded, and reported, ethnicity. Authors made reference to whom results were relevant in terms of ethnicity in 80/407 (19.7%). Ethnicity is underrecorded and underreported in clinical trials. This is a threat to the generalizability of the findings and needs to be improved.


Causes of death in Canadian Forces members deployed to Afghanistan and implications on tactical combat casualty care provision.
As part of its contribution to the Global War on Terror and North Atlantic Treaty Organization's International Security Assistance Force, the Canadian Forces deployed to Kandahar, Afghanistan, in 2006. We have studied the causes of deaths sustained by the Canadian Forces during the first 28 months of this mission. The purpose of this study was to identify potential areas for improving battlefield trauma care. We analyzed autopsy reports of Canadian soldiers killed in Afghanistan between January 2006 and April 2008. Demographic characteristics, injury data, location of death within the chain of evacuation, and cause of death were determined. We also determined whether the death was potentially preventable using both explicit review and implicit review by a panel of trauma surgeons. During the study period, 73 Canadian Forces members died in Afghanistan. Their mean age was 29 (+/-7) years and 98% were male. The predominant mechanism of injury was explosive blast, resulting in 81% of overall deaths during the study period. Gunshot wounds and nonblast-related motor vehicle collisions were the second and third leading mechanisms of injury causing death. The mean Injury Severity Score was 57 (+/-24) for the 63 study patients analyzed. The most common cause of death was hemorrhage (38%), followed by neurologic injury (33%) and blast injuries (16%). Three deaths were deemed potentially preventable on explicit review, but implicit review only categorized two deaths as being potentially preventable. The majority of combat-related deaths occurred in the field (92%). Very few deaths were potentially preventable with current Tactical Combat Casualty interventions. Our panel review identified several interventions that are not currently part of Tactical Combat Casualty that may prevent future battlefield deaths.


Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts.
Adipose-derived stem cells (ADSCs) are a population of pluripotent cells, which have characteristics similar to bone marrow-derived mesenchymal stem cells. Whereas ADSCs have potential applications for the repair and regeneration of various damaged tissues, few studies have dealt with the effect of ADSCs on fibroblasts, which play a key role in skin biology. In this study, we investigated the possible roles of ADSCs in skin wound healing process, especially in the aspect of fibroblast activation-proliferation, collagen synthesis and migratory properties. ADSCs promoted human dermal fibroblast (HDF) proliferation, not only by cell-to-cell direct contact, which was confirmed by co-culture experiment, but also by paracrine activation through secretory factors, resolved by transwell co-culture and culturing with conditioned medium of ADSCs (ADSC-CM). ADSC-CM enhanced the secretion of type I collagen in HDFs by regulating the mRNA levels of extracellular matrix (ECM) proteins: up-regulation of collagen type I, III and fibronectin and down-regulation of MMP-1. Moreover, ADSC-CM showed stimulatory effect on migration of HDFs in in vitro wound healing models. Additional to those in vitro evidences, wound healing effect of ADSCs was also verified with in vivo animal study, resulted that ADSCs significantly reduced the wound size and accelerated the re-epithelialization from the edge. Collectively, these data suggest that ADSC is constitutionally well suited for dermal wound healing and secretory factors derived from ADSCs promote wound healing via HDFs and ADSCs can be used for the treatment of photoaging and wound healing.


Inducible and constitutive formation of fructanase in batch and continuous cultures of Streptococcus mutans.
The production of extracellular beta-D-fructanase by several strains of Streptococcus mutans was studied in continuous culture. When glucose was the limiting nutrient, S. mutans K1-R and OMZ176 accumulated fructanase to maximum levels at low growth rates (dilution rate 0.05-0.10 h-1), due to the longer residence times of the bacteria in the culture vessel under these conditions. Extracellular fructanase activity was greater than has been previously reported for batch cultures. The rate of fructanase production for both S. mutans strains K1-R and OMZ176 increased with increasing growth rate when glucose was limiting. Under conditions of glucose sufficiency, the rate of fructanase production was always lower than in cultures where glucose was limiting, irrespective of the growth rate. Cultures of S. mutans Ingbritt (serotype c) grown with sorbitol- or glucose-limitation synthesized fructanase at a very low basal rate. When fructose was the limiting carbohydrate the enzyme was induced with a maximum rate of production occurring at a dilution rate of 0.40 h-1. Strains of S. mutans from other serotypes (a, d, d/g) were either not affected by changing the limiting sugar from glucose to fructose or else fructanase activity was slightly decreased in the fructose-limited medium. Fructanases from various strains of S. mutans readily hydrolysed (2----6)-beta-D-fructans, but all possessed the ability to hydrolyse (2----1)-beta-D-fructans to varying degrees.


A randomized trial of chloramphenicol vs. trimethoprim-sulfamethoxazole for the treatment of malnourished children with community-acquired pneumonia.
Children in developing countries who present with malnutrition often have infections, particularly pneumonia, at the time of presentation. We evaluated the initial antibiotic management of 144 Gambian children who presented for the first time with malnutrition and who had clinical or radiologic evidence of pneumonia. They were enrolled in a double blind trial of trimethoprim-sulfamethoxazole vs. chloramphenicol. Most children in the study underwent detailed investigations of bacterial and viral etiology as part of another study. The study drug was administered for a week along with oral metronidazole, vitamins and standardized nutritional therapy. Treatment failure was defined as the need for change to parenteral antibiotics during treatment, failure to respond to a week of treatment with the study drug or relapse during the following 2 weeks. There were no differences between the treatment groups in the clinical indicators of severity, etiology or radiologic findings. Thirty-three children were excluded from the analysis because of tuberculosis, inappropriate enrollment or inadequate follow-up. Of the 111 children remaining, 32 (16 in each arm of the study) failed treatment. Clinical failure was not related to in vitro antimicrobial resistance in the 20 cases in which invasive bacterial isolates were obtained. Those who failed treatment were more likely to have had lower chest wall indrawing and positive bacterial cultures than those who were successfully treated. In an area with infrequent antimicrobial resistance of common respiratory pathogens, oral chloramphenicol and trimethoprim-sulfamethoxazole were equally effective in the initial management of malnourished children with community-acquired pneumonia.


Cooperation of oncogenes in cell transformation and sensitization to killing by the parvovirus minute virus of mice.
The established line of normal Fisher rat fibroblasts (FR3T3) is naturally resistant to the parvovirus minute virus of mice (MVM), and was used as a model system to study the influence of stepwise transformation on the susceptibility of cells to this virus. When transformed with genes encoding the class I nuclear oncoproteins large T antigen of polyomavirus (PyLT) or v-myc, cells retained a normal appearance, but acquired some ability to form colonies in soft agar. On the other hand, the class II transforming oncogenes encoding the middle T antigen of polyomavirus (PyMT) and c-Ha-ras-1 induced both morphological alterations and a high capacity for anchorage-independent growth in transfected cells. The concomitant expression of oncogenes from both classes (PyLT-(+)PyMT; v-myc+c-Ha-ras-1) induced a supertransformed phenotype characterized by the piling-up of cells into poorly adherent foci, even in low density cultures. The progressive transformation of this cellular system was found to coincide with a gradual increase in its susceptibility to MVMp (MVM prototype strain) infection. Compared to parental cells, class I, class II and double transformants proved to be sensitized to killing by MVMp to a low, moderate and large extent, respectively. Thus, oncogenes from different functional classes appeared to cooperate in the responsiveness of cells to parvovirus attack. Interestingly, this cooperation exacerbated both the killing of infected cells and their capacity to produce viral non-structural (NS) proteins, in agreement with the reported cytotoxic activity of NS polypeptides. Therefore, in this system, parameters of the parvovirus life cycle may serve as indications of the overall progression of the transformation process.


Prevalence of Antiphospholipid Antibodies Negativisation in Patients with Antiphospholipid Syndrome: A Long-Term Follow-Up Multicentre Study.
This article aims to analyse the rate of antiphospholipid antibodies (aPL) negativisation in patients with antiphospholipid syndrome (APS), and to evaluate potential new clinical manifestations after negativisation and/or aPL fluctuations in a long-term follow-up. Inclusion criteria are (1) any patients with an APS diagnosis according to the current Sydney criteria and (2) patients in whom aPL negativisation occurred. aPL negativisation was defined as repeated aPL measurements on at least two consecutive occasions at least 12 weeks apart, with a follow-up of at least 1 year since aPL first turned negative. Out of 259 APS patients, a total of 23 patients (8.9%) met the inclusion criteria for persistent aPL negativisation. Patients were followed-up for 14.4 ± 8.1 years, experienced aPL negativisation after a mean of 5.3 ± 3.5 years and were followed-up after experiencing the aPL negativisation for a mean of 7.6 ± 5.8 years. Seventeen patients (73.9%) presented with thrombotic APS, 2 with pregnancy morbidity (8.7%) and 4 (17.4%) with both. Most of the patients (18; 78.3%) had a single aPL positivity, 5 (21.7%) double, while no triple aPL positivity was observed. At the time of data collection, after aPL negativisation, anticoagulation was stopped in 8 patients with previous thrombotic venous event (8/21, 38%) according to the treating physicians' judgements. None of the patients experienced any recurrent thrombotic event during the follow-up period after their aPL negativisation. In our patient cohort consisting of 259 patients with definitive APS, we observed over a mean observation period of > 5 years, that aPL negativisation occurred in approximately 9% of patients. Negativisation occurred most often in patients who were previously found to be positive for only one aPL.


Cost-effectiveness of HPV vaccination in 195 countries: A meta-regression analysis.
Cost-effectiveness analysis (CEA) is a well-known, but resource intensive, method for comparing the costs and health outcomes of health interventions. To build on available evidence, researchers are developing methods to transfer CEA across settings; previous methods do not use all available results nor quantify differences across settings. We conducted a meta-regression analysis of published CEAs of human papillomavirus (HPV) vaccination to quantify the effects of factors at the country, intervention, and method-level, and predict incremental cost-effectiveness ratios (ICERs) for HPV vaccination in 195 countries. We used 613 ICERs reported in 75 studies from the Tufts University's Cost-Effectiveness Analysis (CEA) Registry and the Global Health CEA Registry, and extracted an additional 1,215 one-way sensitivity analyses. A five-stage, mixed-effects meta-regression framework was used to predict country-specific ICERs. The probability that HPV vaccination is cost-saving in each country was predicted using a logistic regression model. Covariates for both models included methods and intervention characteristics, and each country's cervical cancer burden and gross domestic product per capita. ICERs are positively related to vaccine cost, and negatively related to cervical cancer burden. The mean predicted ICER for HPV vaccination is 2017 US$4,217 per DALY averted (95% uncertainty interval (UI): US$773-13,448) globally, and below US$800 per DALY averted in 64 countries. Predicted ICERs are lowest in Sub-Saharan Africa and South Asia, with a population-weighted mean ICER across 46 countries of US$706 per DALY averted (95% UI: $130-2,245), and across five countries of US$489 per DALY averted (95% UI: $90-1,557), respectively. Meta-regression analyses can be conducted on CEA, where one-way sensitivity analyses are used to quantify the effects of factors at the intervention and method-level. Building on all published results, our predictions support introducing and expanding HPV vaccination, especially in countries that are eligible for subsidized vaccines from GAVI, the Vaccine Alliance, and Pan American Health Organization.


Knowledge of dental faculty in gulf cooperation council states of multiple-choice questions' item writing flaws.
Multiple-Choice Questions provide an objective cost/time effective assessment. Deviation from appropriate question writing structural guidelines will most probably result in commonly ignored multiple-choice questions writing flaws, influencing the ability of the assessment to measure students' cognitive levels thereby seriously affecting students' academic performance outcome measures. To gauge the knowledge of multiple-choice question items writing flaws in dental faculty working at colleges in Gulf Cooperation Council (GCC) countries. A cross-sectional short online Survey MonkeyTM multiple-choice questions-based questionnaire was disseminated to dental faculty working in GCC countries during the academic year 2018/2019. The questionnaire included five test incorrect (flawed) multiple-choice questions and one correct control question. The participants were asked to identify flawed multiple-choice question items from the known 14 items writing flaws. Out of a total of 460 faculty, 216 respondents completed the questionnaires, 132 (61.1%) were from Saudi Arabia, while numbers of participants from United Arab Emirates, Kuwait and Oman were 59 (27.3), 14 (6.5%) and 11 (5.1%) respectively. Majority of participants were male (n = 141, 65.9%) compared to 73 females (34.1%). Eighty percent of the participants possessed more than five years of teaching experience. Assistant professors constituted the majority (43.3%) of the academic positions participating in this study. The overall fail rate ranged from 76.3% to 98.1% and almost 2/3rds of the participants were unable to identify one or more of the flawed item(s). No significant association was observed between the demographics (age, region, academic position and specialty) and knowledge except that of participant's gender (p < 0.009). GCC dental faculty demonstrated below average knowledge of multiple-choice question items writing flaws. Training and workshops are needed to ensure substantial exposure to proper multiple-choice question items construction standards.


The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration.
HOTTIP is a long non-coding RNA (lncRNA) transcribed from the 5' tip of the HOXA locus and is associated with the polycomb repressor complex 2 (PRC2) and WD repeat containing protein 5 (WDR5)/mixed lineage leukemia 1 (MLL1) chromatin modifying complexes. HOTTIP is expressed in pancreatic cancer cell lines and knockdown of HOTTIP by RNA interference (siHOTTIP) in Panc1 pancreatic cancer cells decreased proliferation, induced apoptosis and decreased migration. In Panc1 cells transfected with siHOTTIP, there was a decrease in expression of 757 genes and increased expression of 514 genes, and a limited gene analysis indicated that HOTTIP regulation of genes is complex. For example, Aurora kinase A, an important regulator of cell growth, is coregulated by MLL and not WDR5 and, in contrast to previous studies in liver cancer cells, HOTTIP does not regulate HOXA13 but plays a role in regulation of several other HOX genes including HOXA10, HOXB2, HOXA11, HOXA9 and HOXA1. Although HOTTIP and the HOX-associated lncRNA HOTAIR have similar pro-oncogenic functions, they regulate strikingly different sets of genes in Panc1 cells and in pancreatic tumors.


High-resolution microcontact printing and transfer of massive arrays of microorganisms on planar and compartmentalized nanoporous aluminium oxide.
Handling microorganisms in high throughput and their deployment into miniaturized platforms presents significant challenges. Contact printing can be used to create dense arrays of viable microorganisms. Such "living arrays", potentially with multiple identical replicates, are useful in the selection of improved industrial microorganisms, screening antimicrobials, clinical diagnostics, strain storage, and for research into microbial genetics. A high throughput method to print microorganisms at high density was devised, employing a microscope and a stamp with a massive array of PDMS pins. Viable bacteria (Lactobacillus plantarum, Esherichia coli), yeast (Candida albicans) and fungal spores (Aspergillus fumigatus) were deposited onto porous aluminium oxide (PAO) using arrays of pins with areas from 5 x 5 to 20 x 20 microm. Printing onto PAO with up to 8100 pins of 20 x 20 microm area with 3 replicates was achieved. Printing with up to 200 pins onto PAO culture chips (divided into 40 x 40 microm culture areas) allowed inoculation followed by effective segregation of microcolonies during outgrowth. Additionally, it was possible to print mixtures of C. albicans and spores of A. fumigatus with a degree of selectivity by capture onto a chemically modified PAO surface. High resolution printing of microorganisms within segregated compartments and on functionalized PAO surfaces has significant advantages over what is possible on semi-solid surfaces such as agar.


Haemophilia A presenting as spontaneous spinal epidural haematoma in a 3-month-old infant.
Spinal epidural haematoma (SEH) is a rare complication of haemophilia. A 3-month-old boy presenting with non-traumatic acute onset quadriparesis was found to have SEH on MRI scan. On further investigations, diagnosis of severe haemophilia A was confirmed. He responded well to conservative treatment with replacement of factor VIII without any need for surgical decompression. Neurological recovery was complete. We believe this is the youngest reported case of haemophilia presenting with spontaneous SEH. Another peculiarity of this case is absence of excessive bleeding due to forceps and vacuum application, circumcision and intramuscular injection, even in the presence of severe haemophilia. This case calls attention to the clinical features, radiological appearances and management options of this rare complication of SEH in people with haemophilia.


JC virus T protein expression in owl monkey tumor cell lines.
Four owl monkey tumor cell lines were tested for the presence of JCV early gene products. Owl 26 was the only cell line in which large T protein could be immunoprecipitated using cross-reactive anti-SV40 hamster tumor sera. Small t protein could not be detected in any of the four cell lines. The monoclonal antibody Cl 122, directed against the host-cell 53K protein, could bind the SV40-T-53K host protein complex in human embryonic kidney cells transformed by SV40. However, the Cl 122 antibody only reacted with a 53K protein in Owl 26 not complexed with the JCV T protein.


[Nursing history research groups: a Brazilian reality].
The objective of this study is to examine the activities of Nursing History research groups in Brazil and their relationships with the nursing undergraduate and graduate courses. This exploratory, descriptive, qualitative documental study was performed from July 2008 to March 2010. We identified 34 research groups that had Nursing History as the focus of at least one of the lines of research. Results showed that the groups have produced a great amount of bibliographical material, research lines and broad participation of undergraduate and graduate students. It was also found that there is a communication network among groups working within the same line of research. In conclusion, there is a need to increase interdisciplinarity and also strengthen some lines of research in order to support knowledge of the history of Brazilian nursing.


Purification of Protease from Pseudomonas thermaerum GW1 Isolated from Poultry Waste Site.
An extracellular protease was purified from Pseudomonas thermaerum GW1 a new strain identified by morphological, biochemical and 16S rDNA sequencing. It was isolated from soil of Poultry waste site at Ghazipur near Ghaziabad, Delhi. The strain produces extra cellular protease in the culture media that was maintained at 37°C, 140 rpm. The media was harvested for protease after 48 hrs of incubation at 37°C in basal media supplemented with 1% casein. We report 6.08 fold purification of enzyme following ammonium sulphate precipitation and DEAE-cellulose chromatography. The molecular weight of the enzyme was estimated to be approximately 43,000 daltons as shown by casein zymography studies. The optimum pH for the proteolytic activity was pH 8.0 and enzyme remained stable between pH 5 -11 at 60°C. Interestingly Mn(2+) (5mM) activated enzyme activity by 5 fold, while Cu(2+), Mg(2+)and Ca(2+) moderately activated enzyme activity, where as Zn(2+), Fe(2+) and Hg(2+) inhibited enzyme activity. The protease produced was stable in presence of 50 % (v/v) ethylacetate and acetone. Isopropanol, methanol and benzene increased protease activity by 2.7, 1.3 and 1.1 fold respectively but was inhibited in presence of glycerol and DMSO. This organic solvent-stable protease could be used as a biocatalyst for enzymatic peptide synthesis.


Captopril attenuates diuretic and natriuretic actions of furosemide but not atrial natriuretic peptide.
Atrial Natriuretic Peptide (ANP) exerts a potent diuretic and natriuretic action in rat, dog and man. To test whether these actions of ANP are due to antagonism of the antinatriuretic actions of endogenous angiotensin II, an examination was made of the renal actions of ANP in anesthetized rats with and without captopril pretreatment. Captopril treatment did not alter the diuretic and natriuretic action of a single, intravenous bolus injection of ANP (1000 ng of the 8-33 ANP). Captopril treatment did significantly attenuate the diuretic and natriuretic actions of Furosemide (20 mg/kg ip). This attenuation was not reversed by concomitant, exogenous angiotensin II infusion. These results suggest that while ANP exerts its renal actions independently of the circulating renin-angiotensin system the diuretic and natriuretic action of Furosemide is modulated by a substrate of angiotensin converting enzyme.


Examining the robustness and concentration dependency of PFAS air-water and NAPL-water interfacial adsorption coefficients.
Determining robust values for the air-water or NAPL-water interfacial adsorption coefficient, KIA, is key to characterizing and modeling PFAS transport and fate in several environmental systems. Direct, high-resolution measurements of surfactant adsorption at the fluid-fluid interface were aggregated from the literature. This data set was used to examine the accuracy and applicability of Γ and KIA measurements determined for three PFAS from transport experiments and surface-tension data. The transport-measured Γ and KIA data were observed to be fully consistent with the directly-measured data. Specifically, Γ values for the two methods were entirely coincident in the region of overlapping concentrations, which spanned ~4 orders-of-magnitude. Furthermore, the two data sets adhered to an identical Γ-C profile. These results conclusively demonstrate the accuracy of the transport-measured values. Γ and KIA values determined from the application of the Gibbs adsorption equation to measured surface-tension data were fully consistent with the directly-measured and transport-measured data sets, demonstrating their applicability for representing PFAS transport in environmental systems. The directly-measured data were used to examine the concentration dependency of KIA values, absent the potential confounding effects associated with the use of surface-tension or transport-measured data. The directly-measured data clearly demonstrate that KIA attains a constant, maximum limit at lower concentrations. Two separate analyses of the transport-measured data both produced observations of constant KIA values at lower concentrations, consistent with the directly-measured data. These outcomes are discussed in terms of surface activities, relative surface coverages, and critical concentrations.


Maternal and obstetric risk factors for sudden infant death syndrome in the United States.
The objectives of this study were to 1). study the incidence of sudden infant death syndrome (SIDS) among singleton births in the United States and 2). identify maternal and obstetric risk factors for SIDS. A cohort of all live births in the United States from 1995 to 1998, formed the source population (n = 15627404). The data were obtained from the National Centers for Health Statistics Linked Births and Infant Deaths File. A nested case-control study was used to examine risk factors for SIDS. From this birth cohort, all SIDS deaths (n = 12404) were first identified (case group). From the remaining non-SIDS births, a 4-fold larger sample (n = 49616) was randomly selected as a control group. The overall incidence of SIDS was 81.7 per 100000 live births. More mothers in the case group than in the control group were reported to have placenta previa (odds ratio [OR]: 1.70; 95% confidence interval [CI] 1.24, 2.33), abruptio placentae (OR 1.57; 95% CI 1.24, 1.98), premature rupture of membranes (OR 1.48; 95% CI 1.33, 1.66), or small for gestational age (OR 1.40; 95% CI 1.30, 1.50 for the 10th percentile). SIDS cases were also more likely to be male. Mothers of cases were more likely to be younger, less educated, and nonwhite, and more of them smoked during pregnancy and did not attend prenatal care. This analysis confirms the importance of several well known demographic and lifestyle risk factors for SIDS. In addition, placental abnormalities were risk factors for SIDS. II-2


Template free synthesis of hollow ball-like nano-Fe2O3 and its application to the detection of dimethyl methylphosphonate at room temperature.
This paper is focused on the template-free synthesis of nanosized ferric oxide (nano-Fe(2)O(3)) and its application in quartz crystal microbalance (QCM) resonators to detect dimethyl methylphosphonate (DMMP), a simulant of Sarin. The X-ray diffraction (XRD) patterns confirm that the synthesized samples are made of Fe(2)O(3) and the scanning electron microscopy (SEM) pictures show that the samples have ball-like shapes. The DMMP sensors with a sensing film of hollow ball-like and solid ball-like Fe(2)O(3) are fabricated and their sensing characteristics are compared. The sensitivity of the hollow ball-like Fe(2)O(3) sensor is more than 500% higher than the one of the solid ball-like Fe(2)O(3) sensor. The hollow ball-like nano-Fe(2)O(3) can be synthesized by a novel low temperature hydrothermal method. The sensors with the hollow ball-like Fe(2)O(3) film perform well in a range of 1 to 6 ppm, with a sensitivity of 29 Hz/ppm at room temperature, while the appropriate recoverability and selectivity are maintained. In addition, the performance of different thicknesses of the sensing film of the hollow ball-like nano-Fe(2)O(3) is investigated and the optimized relative film thickness of the hollow ball-like nano-Fe(2)O(3) is found to be 20 μg/mm(2).


Disease-specific and patient-reported outcomes under active surveillance.
To give insight into literature from the past 12-18 months, reporting on disease-specific and patient-reported outcomes of men under active surveillance for prostate cancer. From recently published established active surveillance cohorts, we learnt that medium and long-term follow-up outcome data provide favorable evidence for the feasibility and safety of active surveillance. The mortality rates reported are consistent with expected mortality in favorable-risk patients who were managed with initial radical therapy. More definite conclusions on the safety of active surveillance can only be drawn on the basis of randomized controlled trial data. With respect to quality of life, men on active surveillance seem to do well, also with respect to urinary and erectile function. Further research on this subject is, however, warranted. Prostate cancer-specific mortality under active surveillance is very low. The combination of disease-specific and patient-reported outcomes indicates that active surveillance is feasible. This is also reflected in smaller, population-based studies which confirm the acceptance of active surveillance in clinical practice.


Effect of albumin mediated clustering on the magnetic behavior of MnFe2O4 nanoparticles: experimental and theoretical modeling study.
Over the last two decades, iron oxide based nanoparticles ferrofluids have attracted significant attention for a wide range of applications. For the successful use of these materials in biotechnology and energy, surface coating and specific functionalization is critical to achieve high dispersibility and colloidal stability of the nanoparticles in the ferrofluids. In view of this, the magnetic behavior of clusters of ultra-small MnFe2O4 nanoparticles covered by bovine serum albumin, which is known as a highly biocompatible and environmentally friendly surfactant, is investigated by magnetization measurements, and numerical simulations at an atomic and mesoscopic scale. The coating process with albumin produces a change in the structure, actual size and shape distribution of clusters of exchange coupled particles, giving rise to a distribution of blocking temperatures. The coated system exhibits a superspin glass (SSG) behavior with the SSG freezing temperatures similar to the uncoated ones, providing evidence that the strength of the dipolar interactions is not affected by the presence of the albumin. The DFT calculations show that the albumin coating reduces the surface anisotropy and the saturation magnetization in the nanoparticles leading to lower values of the coercive field in agreement with the experimental findings. Our results clearly demonstrate that the albumin coated clusters of MnFe2O4 particles are ideal systems for energy and biomedical applications since colloidal and thermal stability as well as biosafety is obtained through the albumin coating.


Microscopic studies of human press fit titanium hip prostheses.
Seven cementless, press fit, rectangular cross section, titanium alloy femoral prostheses were implanted for the treatment of displaced subcapital hip fractures in elderly patients and retrieved postmortem for microscopic evaluation. The mean patient age was 88 years (range, 66-103 years), and prostheses were in situ an average of 29 months (range, 6-45 months). Microscopic examination of the specimens revealed regions of bone to prosthesis contact without interposed connective tissue, and all were considered stably osseointegrated. The mean microscopic bone to prosthesis contact for five cross sections was 28%. Implantation of this prosthesis achieved satisfactory primary stability in endosteal cortical bone in these elderly patients. Secondary stabilization was apparent, as evidenced by new, viable bone formation and remodeling in apposition to the prosthesis.


[Angiographic evaluation and embolization of cervico-cranial tumors -- juvenile paraganglioma and angiofibroma of the nasopharynx].
The goal of pre-operative embolization is tumoral desvascularization, with decrease of intraoperative hemorrhage and shortening of operation time and, consequently, decrease operative morbility. The authors review their experience in angiographic evaluation and preoperative embolization of paragangliomas and juvenile nasopharyngeal angiofibroma (JNA). There were reviewed the angiographic characteristics of 22 patients with paragangliomas, most of them jugular and/or tympanic, 10 of them embolized with PVA. There were angiographically evaluated 6 JNA, 5 of which were embolized with PVA. There weren't any neurological complications during the procedures, diagnostic angiography and embolization. In the cases submitted to endovascular treatment, there was a significative preoperative desvascularization rate, with subjective improving of intraoperative conditions in terms of blood loss. A detailed angiographic characterization of the tumor allows the evaluation of embolization risks, due to the presence of anastomoses or arterial feeding of important structures. Tumor preoperative embolization must be done in a restricted group of hypervascular tumors, in a multidisciplinary approach with the surgical team and must be a safe procedure, without carrying additional morbility to the surgery.


Recruitment in a sea anemone population: juvenile substrate becomes adult prey.
Populations of the sea anemone Anthopleura xanthogrammica (Brandt) occur in tide pools and surge channels below intertidal mussel beds where they capture mussels dislodged by wave action and by sea star foraging. Dense concentrations of small juvenile anemones occur only within mussel beds and are probably the result of larval settlement or differential survival in that habitat. Areas experimentally cleared of anemones showed that recruitment was primarily by migrating juveniles and that the rate of immigration over a 2-year period was much higher in experimental removal areas near mussel beds than in those further away. Mussel beds thus function as an important juvenile habitat (refuge and nursery); juveniles later migrate downward and are then in a position to capture dislodged mussels and grow to adult size.


[Stress reactions--stress fracture of the upper femoral neck in endurance sports].
Stress reactions of the musculoskeletal system may be interpreted as possible precursors of stress fractures. Biological material, in contrast to artificial products, can react in numerous and complex ways. This can not only lead to a continual weakening of the tissue, but also to adaptation phenomena in response to overuse. The causes of such stress reactions are still unclear in many respects. For example, it is unknown to what extent a predisposition to these stress symptoms is created by mechanical stress alone or whether other factors such as physical condition, nutrition or even hormone balance come into play. Early diagnosis considerably reduces the healing process and, the later the diagnosis of the stress reaction, the more drawn out is the healing process and the extent of the athlete's absence from training. In this connection may be discussed whether the stress reaction can be the represent as the precursor of the stress fracture. In light of the need for taking special care in obtaining anamnestic data and determining the predisposition of an athlete, it appears to be justified to perform whole body bone scanning in the initial stages and particularly after an innocuous radiological finding. To what extent more current methods (e. g. MRI) can be applied without exposing the athlete to undue radiation cannot be conclusively judged at present. The treatment of a stress reaction should, at least at the beginning, be the same as for a diagnosed stress fracture.


Dynamics of NAD in cortical nephron segments: effect of nicotinamide and of dietary phosphate intake.
NAD content and the rate of NAD hydrolysis were determined in proximal convoluted tubules (PCT), proximal straight tubules (PST), and adjacent cortical nephron segments microdissected from kidneys of thyroparathyroidectomized (TPTX) rats. In the basal state, rats fed a normal phosphate diet had an NAD content higher in PCT, PST, and in cortical ascending limb (CAL) than in glomeruli. After intraperitoneal injection of nicotinamide, the NAD content increased significantly in all nephron segments except CAL; the greatest (delta + 277%) increase was found in PCT, with less (delta + 82%) in PST. In experiments conducted on TPTX rats stabilized on a low-phosphorus diet, NAD content increased in response to a nicotinamide injection in PCT (delta + 197%), but did not change significantly in PST. The catabolism of NAD was determined by generation of [3H]adenosine, a major metabolite of [adenine-2,8-3H]NAD. The rate of [3H]adenosine generation from [3H]NAD was significantly (P less than 0.001) higher in PST than in PCT. We conclude that, in response to nicotinamide administration in vivo, the NAD content increases more in PCT than in PST and that this difference may be, at least partly, due to a lower rate of NAD breakdown in PCT. In a state of dietary phosphate deprivation, NAD also increases significantly in response to intraperitoneal nicotinamide in PCT, but it does not increase significantly in PST. The nicotinamide-elicited increase of NAD content in proximal tubules, mainly in PCT, may be related to inhibition of Na+-gradient-dependent inorganic phosphate (Pi) reabsorption across the brush-border membrane of proximal tubules and to the phosphaturic effect of nicotinamide in rats fed normal-Pi diet.


Molecular Classification Improves Therapeutic Options for Infants and Young Children With Medulloblastoma.
Medulloblastoma in infants and young children is a major challenge to treat because craniospinal irradiation (CSI), a cornerstone of therapy for older children, is disproportionately damaging to very young children. As a result, trials have attempted to delay, omit, and replace this therapy. Although success has been limited, the approach has not been a complete failure. In fact, this approach has cured a significant number of children with medulloblastoma. However, many children have endured intensive regimens of chemotherapy only to experience relapse and undergo salvage treatment with CSI, often at higher doses and with worse morbidity than they would have initially experienced. Recent advancements in molecular diagnostics have proven that response to therapy is biologically driven. Medulloblastoma in infants and young children is divided into 2 molecular groups: Sonic Hedgehog (SHH) and group 3 (G3). Both are chemotherapy-sensitive, but only the SHH medulloblastomas are reliably cured with chemotherapy alone. Moreover, SHH can be molecularly parsed into 2 groups: SHH-1 and SHH-2, with SHH-2 showing higher cure rates with less intensive chemotherapy and SHH-1 requiring more intensive regimens. G3 medulloblastoma, on the other hand, has a near universal relapse rate after chemotherapy-only regimens. This predictability represents a significant breakthrough and affords oncologists the ability to properly risk-stratify therapy in such a way that the most curative and least toxic therapy is selected. This review examines the treatment of medulloblastoma in infants and young children, discusses the molecular advancements, and proposes how to use this information to structure the future management of this disease.


Working in a pandemic: Exploring the impact of COVID-19 health anxiety on work, family, and health outcomes.
The COVID-19 pandemic has unhinged the lives of employees across the globe, yet there is little understanding of how COVID-19 health anxiety (CovH anxiety)-that is, feelings of fear and apprehension about having or contracting COVID-19-impacts critical work, home, and health outcomes. In the current study, we integrate transactional stress theory (Lazarus & Folkman, 1984) with self-determination theory (Deci & Ryan, 2000) to advance and test a model predicting that CovH anxiety prompts individuals to suppress emotions, which has detrimental implications for their psychological need fulfillment. In turn, lack of psychological need fulfillment hinders employees' abilities to work effectively, engage with their family, and experience heightened well-being. Our model further predicts that handwashing frequency-a form of problem-focused coping-will mitigate the effects of CovH anxiety. We test our propositions using a longitudinal design that followed 503 employees across the first four weeks that stay-at-home and social distancing orders were enacted. Consistent with predictions, CovH anxiety was found to impair critical work (goal progress), home (family engagement) and health (somatic complaints) outcomes due to increased emotion suppression and lack of psychological need fulfillment. Further, individuals who frequently engage in handwashing behavior were buffered from the negative impact of CovH anxiety. Combined, our work integrates and extends existing theory and has a number of important practical implications. Our research represents a first step to understanding the work-, home-, and health-related implications of this unprecedented situation, highlighting the detrimental impact of the anxiety stemming from the COVID-19 pandemic. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Reagents for reversible coupling of proteins to the active centres of trypsin-like serine proteinases.
In order to extend the scope for the application of acyl-enzymes as fibrinolytic agents, p-amidinophenyl ester enzyme substrates were prepared that gave stabilized acyl-enzymes capable of being coupled to other proteins. Coupling was achieved by reaction of protein thiol functions with a 2-pyridyldithio moiety within the acyl group. Acyl-enzymes derived from such substrates were stable enough to permit isolation of reversible conjugates between proteins and the active centres of plasminogen activators. Hydrolytic release of active enzyme from a conjugate of human immunoglobulin G and urokinase could be demonstrated.


Myelin abnormalities in merosin-deficient congenital muscular dystrophy.
Merosin is a protein complex located in the basement membrane of skeletal muscles and laminin α2-containing regions of the central and peripheral nervous systems. However, because of the prominence of muscle-related symptoms, peripheral neuropathy associated with merosin-deficient congenital muscular dystrophy type 1A (MDC1A) has received little clinical attention. This study aimed to present pathological changes in intramuscular nerves of three patients with MDC1A and discuss their relationship with electrophysiological findings to provide new evidence of peripheral nerve involvement in MDC1A. MDC1A was confirmed by clinical features, muscle biopsy, and genetic testing for variants in LAMA2. To clarify peripheral nerve involvement, we statistically evaluated electrophysiological and muscle pathology findings of intramuscular nerves. These findings were compared with those of age-matched boys with Duchenne muscular dystrophy (DMD) as controls with normal nerves. Nerve conduction studies (NCS) were performed before biopsy. Biopsied intramuscular nerves were examined with electron microscopy using g-ratio, which is the ratio of axon diameter to myelinated fiber diameter. The myelin sheaths were significantly thinner in MDC1A patients than in age-matched DMD patients, with a mean g-ratio of 0.76 ± 0.07 in MDC1A patients and 0.65 ± 0.14 in DMD patients (p < .0001). No neuropathic changes were identified in muscle pathology. Low compound muscle action potential amplitudes, positive sharp waves and fibrillation potentials, and low-amplitude motor unit potentials with increased polyphasia indicated myopathic changes; no neurogenic changes were seen. We postulate that the thin myelin associated with MDC1A reflects the role of merosin in myelin maturation.


Autonomic Cardioregulatory Function Does Not Correlate With Symptom Improvement After Concussion in Children and Adolescents.
Although there is significant variability in the manifestations of persisting post-concussive symptoms (PPCS), autonomic dysfunction has been reported to contribute to PPCS and could serve as a biomarker of recovery. The objective of this study was to evaluate cardiac autonomic reflexes and autonomic function after concussion injury comparing those with prolonged concussion symptoms to those without. This is a case-control study where a non-referred population of concussed children or adolescent participants were enrolled from the Emergency Department (ED) of the Stollery Children's Hospital, a tertiary pediatric hospital in Edmonton, Alberta, Canada. Children and adolescents 8 through <18 years of age who presented with mild traumatic brain injury were diagnosed with concussion. Our study reported concussion symptoms and standardized clinical cardiac autonomic reflex testing at 4 and 12 weeks after injury. Our findings showed that 28 participants with concussion completed the 4-week follow-up questionnaires, and that 17 (61%) were diagnosed with PPCS. Difficulty concentrating, fatigue, noise sensitivity, light sensitivity, and headache were most commonly reported at baseline among those who were later diagnosed with PPCS. The mean change in heart rate (HR) with head-up tilt was 44.2 bpm (standard deviation [SD] 9.1) in the non-PPCS group and 46.6 bpm (SD 14.1) in the PPCS group at 4 weeks and was not significant in the unadjusted (p = 0.2) or adjusted analysis for age and female sex (p = 0.2). Overall, 70% (19/27) had significant orthostatic tachycardia >40 bpm, but PPCS and non-PPCS groups were similar. Similar results were observed among 23 participants at 12-week follow-up. The median maximum decrease in systolic blood pressure (SBP) with head-up tilt was -26.9 mm Hg (interquartile range [IQR] -32.6, -22.3) in the non-PPCS group and -25.1 mm Hg (IQR -32.2, -18.2) in the PPCS group, and was not significantly different in the unadjusted (p = 0.8) or adjusted (p = 0.8) analysis. Overall, 19 of 26 participants (73%) demonstrated orthostatic hypotension (SBP change >20 mm Hg) with no significant difference between the PPCS and non-PPCS groups. Similar results were observed at 12-week follow-up. In conclusion, cardiac autonomic reflex responses are abnormal in most children and adolescents with a concussion injury at 4- and 12-week follow-up and may reflect ongoing autonomic dysfunction. However, autonomic function did not differentiate PPCS, indicating that reported symptoms are not sensitive to autonomic abnormalities.


Evaluation of tolmetin in the treatment of arthritis: open and controlled double-blind studies.
In a 6-week open study in 24 patients with rheumatoid arthritis, tolmetin was shown to have analgesic and anti-inflammatory activity at daily doses in excess of 1200 mg per day and produced statistically significant reductions in overall joint pain, walking time and articular index. The drug was well tolerated, but 2 patients were withdrawn because of persistent indigestion and 1 because of an urticarial type rash. In a double-blind crossover comparison against indomethacin and placebo in 22 patients, 1400 mg tolmetin daily showed efficacy comparable with that of 150 mg indomethacin daily. Few side-effects were reported and did not necessitate any patients being withdrawn.


[Prevalence of lower urinary tract symptoms in men and its influence on their quality of life: Boxmeer Study].
To assess the prevalence of lower urinary tract symptoms (LUTS) in men and its influence on quality of life. Questionnaire investigation. Recruitment of subjects was conducted in 1998 in the municipality of Boxmeer. Men in the age range between 40-79 years were sampled from the Municipality Basic Administration System. Data on LUTS, quality of life, and health care seeking behaviour were collected with a postal questionnaire. Severity of LUTS was evaluated with the Dutch translation of the seven items of the International Prostate Symptom Score (IPSS), to which 6 questions were added regarding micturition frequency, dribbling, difficulty to start micturition, painful micturition, decreased force of stream since the age of twenty, and how long one could wait before micturition from the moment urge was noticed. The female partners of the respondents were asked to answer the questions as well. 1233 men completed the questionnaire, a response of 70%. One-fifth of all participants reported moderate to severe symptoms. Dribbling, reduced force of stream and urgency appeared to be the three most prevalent symptoms. The prevalence of LUTS increased with age: 10% of men aged 40-49 reported moderate to severe symptoms (IPSS > 7) compared with 44% of men over 70. Twenty-nine per cent of the men with severe LUTS reported poor disease specific quality of life, while another 28% of these men reported excellent disease specific quality of life. All men with mild symptoms reported excellent quality of life. Nine percent of all men consulted a doctor because of LUTS, with a mean delay of 10 months. The LUTS frequencies among the female partners equalled those among the responding men. LUTS were common among men over forty and among their female partners. The prevalence increases with age. Ageing of the population may lead to increased numbers of men experiencing LUTS and to concomittant medicalization costs. It is therefore of great importance to realise that the impact of symptoms on the reported quality of life was not pronounced.


Life history trade-offs and behavioral sensitivity to testosterone: an experimental test when female aggression and maternal care co-occur.
Research on male animals suggests that the hormone testosterone plays a central role in mediating the trade-off between mating effort and parental effort. However, the direct links between testosterone, intrasexual aggression and parental care are remarkably mixed across species. Previous attempts to reconcile these patterns suggest that selection favors behavioral insensitivity to testosterone when paternal care is essential to reproductive success and when breeding seasons are especially short. Females also secrete testosterone, though the degree to which similar testosterone-mediated trade-offs occur in females is much less clear. Here, I ask whether testosterone mediates trade-offs between aggression and incubation in females, and whether patterns of female sensitivity to testosterone relate to female life history, as is often the case in males. I experimentally elevated testosterone in free-living, incubating female tree swallows (Tachycineta bicolor), a songbird with a short breeding season during which female incubation and intrasexual aggression are both essential to female reproductive success. Testosterone-treated females showed significantly elevated aggression, reduced incubation temperatures, and reduced hatching success, relative to controls. Thus, prolonged testosterone elevation during incubation was detrimental to reproductive success, but females nonetheless showed behavioral sensitivity to testosterone. These findings suggest that the relative importance of both mating effort and parental effort may be central to understanding patterns of behavioral sensitivity in both sexes.


Refractory residues classification strategy using emission spectroscopy of laser-induced plasmas in tandem with a decision tree-based algorithm.
The recycling of refractory scraps began to be forged just over a decade ago. Until then, virtually all refractory scraps were disposed off in landfill sites without any application. Over these past few years, a growing interest and a gain steady momentum of the circular economy, the emergent framing around waste and resource management that promotes the notions of their productive cycling, has been the driving force towards the "zero waste" culture across the spectrum of refractory users and producers. In this way, the circular economy, operated following strategies such as, but not limited to, reusing, recycling, and remanufacturing, has played the pillar role in the different essential value chains of the refractory industry to the entering the new era of secondary raw material supply. In any case, prior to starting any sustainable process, it is really necessary to know the wastes and to classify them. In this context, the present research focused on a refractory residue-classification strategy based on combined laser-induced breakdown spectroscopy (LIBS) and a decision tree algorithm for a qualitative analytical performance. This tandem approach allowed the categorization of a rich set of residues in up to 10 different refractory groups. By choosing original LIBS emission intensities and intensity ratios involving the most relevant constituent elements (Al, Mg, C ‒through its related-species CN‒, Si and Zr) of various refractory wastes, a decision tree with multiple nodes that decided how to classify inputs was designed and trained. Categorization performed from LIBS emission spectra of "blind" refractory residues showed that LIBS data combined with this supervised machine learning algorithm provided good refractory scraps-classification performance, with a classification accuracy of up to 75%. However, some more than justified decisions of the algorithm on allegedly misclassified residues showed that scores for the decision tree could found to be far superior to those obtained. The results achieved support the strategy designed for its industrial implementation, either directly in the iron and steel industry, as the major end-user of refractories, in the refractory waste management industry, or in both.


Use of a Remote Inhaler Monitoring Device to Measure Change in Inhaler Use with Chronic Obstructive Pulmonary Disease Exacerbations.
Remote inhaler monitoring is an emerging technology that enables the healthcare team to monitor the time and location of a patient's inhaler use. We assessed the feasibility of remote inhaler monitoring for chronic obstructive pulmonary disease (COPD) patients and the pattern of albuterol inhaler use associated with COPD exacerbations. Thirty-five participants with COPD used an electronic inhaler sensor for 12 weeks which recorded the date and time of each albuterol actuation. Self-reported COPD exacerbations and healthcare utilization were assessed monthly. We used generalized estimating equations with a logit link to compare the odds of an exacerbation day to a nonexacerbation day by the frequency of daily albuterol use. Average daily albuterol use on nonexacerbation days varied greatly between patients, ranging from 1.5 to 17.5 puffs. There were 48 exacerbation events observed in 29 participants during the study period, of which 16 were moderate-to-severe exacerbations. During the moderate-to-severe exacerbation days, the median value in average daily albuterol use increased by 14.1% (interquartile range: 2.7%-56.9%) compared to average nonexacerbation days. A 100% increase in inhaler use was associated with increased odds of a moderate-to severe exacerbation (odds ratio 1.54; 95% CI: 1.21-1.97). Approximately 74% of participants reported satisfaction with the sensor. The electronic inhaler sensor was well received in older patients with COPD over a 12-week period. Increased albuterol use captured by the device was associated with self-reported episodes of moderate-to-severe exacerbations.


Naturalistic inquiry: an appropriate model for family medicine.
Family medicine's stated philosophy is consistent with the philosophical basis of naturalistic inquiry, a research paradigm from the social sciences. However, the majority of published family medicine research more nearly resembles traditional biomedical research, here termed rationalistic inquiry. Adding naturalistic inquiry to family medicine's research armamentarium would be consistent with the specialty's stated philosophy and would foster investigation in areas not well addressed by the traditional biomedical approach.


Pharmacodynamic considerations in the selection of dosage of tinzaparin for various indications: experimental studies in primates.
Like unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs) are polypharmacologic agents that can modulate the hemostatic system at multiple points. Thus, to select an optimal dose of LMWH for a given indication, it is necessary to consider multiple actions of the drug. In this study, nonhuman primates were treated with intravenous or subcutaneous boluses of the LMWH tinzaparin or UFH. Doses were selected on the basis of the expected prophylactic (75 U/kg) and therapeutic (175 U/kg) dosing of tinzaparin. Blood samples were drawn periodically up to 24 hours after administration. Circulating anti-Xa and anti-thrombin (anti-IIa) activities determined using amidolytic assays were used to estimate plasma tinzaparin (heparin) concentrations. In addition, total tissue factor pathway inhibitor (TFPI) levels were measured in these primates. Subcutaneous administration of 75 U/kg tinzaparin resulted in plasma levels of approximately 0.2 to 0.3 U/mL, concentrations sufficient for DVT prophylaxis. Such drug levels were not associated with a significant release of TFPI. Intravenous administration of the same dose resulted in a peak drug level of approximately 1.5 anti-Xa U/mL. The elimination half-life was approximately 1 hour. Thus, intravenously administered tinzaparin may be useful for providing anticoagulation during coronary interventions. Subcutaneous administration of 175 U/kg resulted in tinzaparin levels of approximately 0.7 anti-Xa U/mL and a significant increase in TFPI levels. Interestingly, the increase in TFPI levels occurred over a different time frame than anticoagulant activity. Intravenous administration of 175 U/kg resulted in peak drug concentrations of almost 5 anti-Xa U/mL. The pharmacokinetic behavior of intravenously administered tinzaparin was comparable to that of UFH. The data show that the pharmacokinetic and pharmacodynamic effects measured using different assays widely differ. For a proper pharmacodynamic analysis, multiple assays should be considered, given that both UFH and LMWHs are polycomponent in nature.


Future developments with 'Tomudex' (raltitrexed).
The efficacy and tolerability of raltitrexed ('Tomudex', formerly ZD1694) as a single agent for the treatment of advanced colorectal cancer has been established in a large clinical trial programme. It is now possible to move the drug forward into the treatment of earlier stages of colorectal cancer. In addition, its mode of action lends itself to combination with other agents, not only 5-fluorouracil, but also oxaliplatin and irinotecan for the treatment of advanced disease. Preclinical and early clinical data also suggest that raltitrexed may show activity in a range of other tumour types. Studies evaluating these potential clinical applications of raltitrexed are either planned or already under way.