CYP24 promoter activity is affected by mechanical stress and mitogen-activated protein kinase in MG63 osteoblast-like cells.
For bone homeostasis, vitamin D plays an important role in the regulation of calcium. The enzyme CYP24 inactivates vitamin D and is involved in its regulation. However, the mechanism of expression of CYP24 in osteoblastic cells under mechanical stress is not clear. In this study we investigated CYP24 promoter activity in stretched osteoblastic cells and the participation of mitogen-activated protein kinase (MAPK) in expression of CYP24. MG63 osteoblastic cells were cultured on silicon-bottomed plates. Cells were transfected with a reporter gene that contained a CYP24 promoter. After activated vitamin D, 1,25(OH)2D3, was added or not added, cells were stretched. Stretched and non-stretched cells were investigated by luciferase dual assay. Cells were also investigated similarly using medium with an ERK1/2 inhibitor or p38 inhibitor. The CYP24 promoter was activated by 1,25(OH)2D3 and the promoter activity decreased in stretched cells. Inhibitor of MAPK decreased CYP24 promoter activity. However, CYP24 promoter activity decreased with mechanical stress after addition of p38 inhibitor, while it did not decrease with mechanical stress after addition of ERK1/2 inhibitor. The CYP24 promoter was not activated without 1,25(OH)2D3 in any case. Mechanical stress and MAPK control CYP24 promoter activity in the presence of Vitamin D in MG63 osteoblast-like cells.


Association of Circulating Wnt Antagonists With Severe Abdominal Aortic Calcification in Elderly Women.
There is great interest in the biology of vascular calcification. Wnt/β-catenin signaling is an important mediator of mineralization and may play a role in vascular calcification. We assessed the association between circulating Wnt antagonists and abdominal aortic calcification (AAC) severity in elderly women. This was a cross-sectional analysis of the Calcium Intake Fracture Outcome Study. The participants were recruited from the community-dwelling elderly population. We examined 768 women aged over 70 years. We collected blood samples, and lateral spine images captured during bone density assessment were used to score AAC with a validated 24-point scale. We tested the hypothesis that low Wnt antagonist levels of Dickkopf-1 (DKK1), secreted frizzled related protein 3 (sFRP3), and Wnt inhibitory factor 1 (WIF1) are associated with severe AAC (AAC24 score > 5). Severe AAC was present in 146 women (19%). Lower levels of DKK1, but not WIF1 and sFRP3, were associated with higher odds of severe AAC. Per standard deviation decrease in DKK1 was associated with increased multivariable-adjusted odds ratio (OR) of severe AAC [OR, 1.26; 95% confidence interval (CI), 1.04 to 1.52; P = 0.017]. In quartile analyses, the lowest and second-lowest quartiles of DKK1 had increased multivariable-adjusted odds of severe AAC vs the highest quartile (OR, 2.05; 95% CI, 1.18 to 3.56; P = 0.011 and OR, 1.83; 95% CI, 1.05 to 3.19; P = 0.035). In elderly women, DKK1, but not sFRP3 or WIF1, is associated with severe AAC. This study supports the concept that Wnt/β-catenin signaling is an important regulator of vascular mineral metabolism and is independent of other risk factors.


Tooth replacement related to number of natural teeth in a dentate adult population in Bulgaria: a cross-sectional study.
This study aimed to explore the relationships among tooth replacement, number of present natural teeth, and sociodemographic and behavioral factors in an adult population in Bulgaria. Quota sampling was used to recruit 2,531 dentate subjects aged 20 years and over from the capital city and four main urban centers, four towns, and seven small towns and villages of Bulgaria. Potential candidates for tooth replacement were classified as having functional dentitions (26 to 27 or 20 to 25 natural teeth present) or subfunctional dentitions (16 to 19 or 2 to 15 natural teeth present), not including third molars. Multiple logistic regression analyses were performed to determine the associations between tooth replacement and the factors of interest. Of the included subjects, 37% presented with tooth replacement, while 19% presented with fewer than 20 natural teeth. Molars were replaced significantly less often (P ≤ .017) than premolars and anterior teeth. The presence of tooth replacement was more likely in subjects with 2 to 15 teeth (odds ratio: 1.62) and less likely in subjects with 26 to 27 teeth (odds ratio: 0.29), but no significant difference was detected between subjects with 16 to 19 and 20 to 25 teeth. Tooth replacement was associated with age, occupational status, frequency of dental visits, and toothbrushing habits. In this Bulgarian population, the variables number of present teeth, age, dental visits, and toothbrushing were relevant factors with respect to tooth replacement. The cutoff value of 20 teeth did not discriminate high-risk from low-risk subjects.


[The placebo effect--a biochemical basis for a psychosomatic phenomenon].
We review the research over the past decade on the subject of the Placebo Neurochemical mechanism, and it's random presence in the clinic. Our goal is to present the scientific basis of the placebo, and to arouse the awareness of physicians and scientists to the crucial role of placebo in medicine and pharmacological research. The modeling of rationality in modern times displaced the placebo issue to the sidelines of consensus, and it was only around 1950 that scientific interest in the phenomenon reawakened. Today the existence of a Placebo Effect is not doubted--not in everyone, and not at all times, but it's existence is not doubted in relation to groups of people throughout their lives. The involvement of a neurochemical mechanism in the Placebo Effect is also supported by the literature presented, and chemicals such as CCK, Naloxone, Proglumide, and Endorphins seem to effect the neuronal webs mediating the Analgestic Placebo Effect.


Inward rectification and implications for cardiac excitability.
Since the cloning of the first inwardly rectifying K+ channel in 1993, a family of related clones has been isolated, with many members being expressed in the heart. Exogenous expression of different clones has demonstrated that between them they encode channels with the essential functional properties of classic inward rectifier channels, ATP-sensitive K+ channels, and muscarinic receptor-activated inward rectifier channels. High-level expression of cloned channels has led to the discovery that classic strong inward, or anomalous, rectification is caused by very steeply voltage-dependent block of the channel by polyamines, with an additional contribution by Mg2+ ions. Knowledge of the primary structures of inward rectifying channels and the ability to mutate them have led to the determination of many of the structural requirements of inward rectification. The implications of these advances for basic understanding and pharmacological manipulation of cardiac excitability may be significant. For example, cellular concentrations of polyamines are altered under different conditions and can be manipulated pharmacologically. Simulations predict that changes in polyamine concentrations or changes in the relative proportions of each polyamine species could have profound effects on cardiac excitability.


Repeatable glucocorticoid expression is associated with behavioural syndromes in males but not females in a wild primate.
Behavioural syndromes are a well-established phenomenon in human and non-human animal behavioural ecology. However, the mechanisms that lead to correlations among behaviours and individual consistency in their expression at the apparent expense of behavioural plasticity remain unclear. The 'state-dependent' hypothesis posits that inter-individual variation in behaviour arises from inter-individual variation in state and that the relative stability of these states within an individual leads to consistency of behaviour. The endocrine stress response, in part mediated by glucocorticoids (GCs), is a proposed behavioural syndrome-associated state as GC levels are linked to an individual's behavioural responses to stressors. In this study, in wild Barbary macaques (Macaca sylvanus), consistent inter-individual differences were observed in both sexes for GC activity (faecal glucocorticoid, fGC concentrations), but not GC variation (coefficient of variation in fGC concentrations). The expression of the behavioural syndrome 'Excitability' (characterized by the frequencies of brief affiliation or aggressive interactions) was related to GC activity in males but not in females; more 'excitable' males had lower GC activity. There was no relationship in females between any of the behavioural syndromes and GC activity, nor in either sex with GC variation. The negative relationship between GC activity and Excitability in males provides some support for GC expression as a behavioural syndrome-generating state under the state-dependent framework. The absence of this relationship in females highlights that state-behavioural syndrome associations may not be generalizable within a species and that broader sex differences in state need to be considered for understanding the emergence and maintenance of behavioural syndromes.


Recognition events in AM symbiosis: analysis of fungal gene expression at the early appressorium stage.
Arbuscular mycorrhizal symbiosis is induced upon a series of recognition events involving the reorganization of both plant and fungal cellular programs culminating in the formation of appressoria on the epidermal root cells. In this work we monitored for the first time the genetic changes occurring in the fungal partner during early appressorium development. We established an in vitro system of Glomus mosseae and Petroselinum crispum for studying appressorium formation and found that after 120 h first appressoria developed in the root epidermis. We have constructed a fungal subtractive suppressive library enriched in genes up-regulated at this stage. Our aim was to identify early signaling events during plant recognition leading to appressoria formation. The library contains 375 clones with an average size of 500 bp. From these, 200 clones were sequenced and most of them represent gene fragments with no known homologues (63%) and therefore putative new genes specific to the mycorrhiza symbiosis. Reverse-Northern blot and RT-PCR analyses confirmed that ca. 30% of the genes present in the library were up-regulated upon plant induction after 120 h. Among the genes with homologues in other organisms we found several genes common to other plant-microbe interactions including some genes related to Ca2+-dependent signaling. The up-regulation of these genes opens the possibility that Ca2+ plays a role in the early stages of mycorrhiza formation as it has been found in other plant-microbe interactions such as the Rhizobium symbiosis or the Magnaporthe grisea/rice pathogenic interaction.


[Chitinase from Serratia marcescens BKM B-851].
The chitinase biosynthesis was studied during the cultivation of the strain of Serratia marcescens BKM B-851 with a high chitinolytic activity. Under submerged cultivation of bacterial cells on the medium containing demineralized crab shell extracellular chitinase showed maximum activity on the 3rd day. Cells of S. marcescens BKM B-851 synthesized chitinase as an adaptive enzyme. Chitinase obtained from the culture liquid by ammonium sulphate precipitation was then dialyzed and liophylized. It displayed optimum hydrolysis of colloid chitin at pH 7-8 and 50 degrees C and of native chitin at 30 degrees C.


Influence of an ER-retention signal on the N-glycosylation of recombinant human α-L-iduronidase generated in seeds of Arabidopsis.
Processes associated with late events of N-glycosylation within the plant Golgi complex are a major limitation to the use of plant-based systems to produce recombinant pharmaceutical proteins for parenteral administration. Specifically, sugars added to the N-glycans of a recombinant protein during glycan maturation to complex forms (e.g. β1,2 xylose and α1,3 fucose) can render the product immunogenic. In order to avoid these sugars, the human enzyme α-L-iduronidase (IDUA, EC 18.104.22.168), with a C-terminal ER-retention sequence SEKDEL, was expressed in seeds of complex-glycan-deficient (cgl) mutant and wild-type (Col-0) Arabidopsis thaliana, under the control of regulatory (5'-, signal-peptide-encoding-, and 3'-) sequences from the arcelin 5-I gene of Phaseolus vulgaris (cgl-IDUA-SEKDEL and Col-IDUA-SEKDEL, respectively). The SEKDEL motif had no adverse effect on the specific activity of the purified enzyme. Surprisingly, the majority of the N-glycans of Col-IDUA-SEKDEL were complex N-glycans (i.e. contained xylose and/or fucose) (88 %), whereas complex N-glycans comprised a much lower proportion of the N-glycans of cgl-IDUA-SEKDEL (26 %), in which high-mannose forms were predominant. In contrast to the non-chimeric IDUA of cgl seeds, which is mainly secreted into the extracellular spaces, the addition of the SEKDEL sequence to human recombinant IDUA expressed in the same background led to retention of the protein in ER-derived vesicles/compartments and its partial localization in protein storage vacuoles. Our data support the contention that the use of a C-terminal ER retention motif as an effective strategy to prevent or reduce complex N-glycan formation, is protein specific.


Low frequency of mouse t haplotypes in wild populations is not explained by modifiers of meiotic drive.
t haplotypes are naturally occurring forms of mouse chromosome 17 that show non-mendelian transmission from heterozygous +/t males. In laboratory studies, transmission ratios of > or = 0.90 or higher are typically observed. With transmission ratios of this level, theoretical analyses predict high frequencies of t haplotypes (approximately 75%) in wild populations. In contrast, empirical frequencies of only 15-25% are typically found. This has led to the suggestion that modifiers of drive may play a role in reducing t frequencies. We have measured transmission ratio distortion (TRD) levels in wild +/t mice to examine this hypothesis. TRD was very high in both litters collected from wild-caught pregnant females, and in wild litters bred in the laboratory (mean = 0.9). Contrary to the results of other studies, we found no difference in TRD levels between semilethal and lethal t haplotypes nor between litters conceived from cycling or postpartum estrus. We found three litters with aberrantly low TRDs that were all multiply sired, although the role this might play in natural populations is unknown. These findings show a general absence of modifiers of drive in natural populations and suggest that other factors are responsible for the low observed frequencies of wild t haplotypes.


Radiographic determination of humeroradial, humeroulnar, and radioulnar subluxation indices to quantify elbow incongruence in dogs confirmed to have medial coronoid disease.
Medial coronoid disease and elbow incongruence are common orthopedic problems causing forelimb lameness in large breed dogs. Therefore, the objective of this retrospective clinical study is to radiographically quantify the incongruity of humeroradial, humeroulnar, and radioulnar joints in dogs with confirmed medial coronoid disease compared to controls. Sixty-six (93 elbows) control and 73 (113 elbows) diseased Labrador and Golden Retrievers were enrolled. Our objective was achieved by measuring the central humeroradial, humeroulnar, and radioulnar distances and calculating the corresponding subluxation index of each joint on the extended mediolateral elbow radiograph. The traditional radioulnar step was also measured on the same mediolateral projection. Variables were compared between control and diseased groups, and the significance level was P < .05. The central humeroradial, humeroulnar, and radioulnar distances and corresponding subluxation indices increased significantly (P ≤ .007) in elbows with confirmed medial coronoid disease compared to controls. Radioulnar step increased significantly (P < .0001) in diseased elbows. Elbow incongruence, manifested by increased humeroradial, humeroulnar, and radioulnar subluxation indices, appeared to be consistent with medial coronoid disease in Labrador and Golden Retrievers. An elbow with a humeroradial, humeroulnar, or radioulnar subluxation index >0.15, 0.10, or 0.14, respectively, or radioulnar step >1.4 mm, is more likely to be incongruent and may have a concomitant coronoid disease. However, future validation of the reported measurements is still warranted.


Comparison Between Viscous Teardrops and Saline Solution to Fill Orthokeratology Contact Lenses Before Overnight Wear.
To compare, in terms of efficacy, the differences between the use of saline solution and a viscous artificial tear to fill the lens during the first month of orthokeratology wear. A pilot, double-masked, crossed, randomized, and prospective study was conducted. In this study, 20 subjects (14 males and 6 females) with a mean age of 16.29±6.22 years (range, 10-26) were fitted with orthokeratology contact lenses. For the study, nonpreserved 0.9% NaCl commercial saline solution (Avizor, Madrid, Spain) and nonpreserved artificial teardrops with 0.3% of hyaluronic acid (Ocudry 0.3%; Avizor, Madrid, Spain) were used. Corneal staining, tear break up time (TBUT), topography, refraction, visual acuity, and subjective comfort and vision with the visual analog scale (score from 0 to 10, being 10 better comfort and vision) were evaluated at 1 day, 1 week, and 1 month of contact lens wear. The corneal staining was statistically greater in the saline group than in the Ocudry group for the first day and during 1 week of wear (P<0.05). Comfort was found to be statistically better, with Ocudry 0.3% than saline solution, being 7.17±1.94 and 6.37±1.63, for the first day, and 8.78±0.43 and 8.15±0.62 for the day 28, respectively (P<0.05). However, no differences were found for subjective vision scores, TBUT, spherical equivalent, best-corrected visual acuity and uncorrected visual acuity, and mean keratometry between groups for any visit (P>0.05). Viscous artificial tears improve the subjective comfort of patients and reduce the corneal staining, compared with saline solution during the orthokeratology lenses fitting process. However, no differences between solutions for the treatment efficacy, in vision and corneal topography, were found.


Humeral Fractures in South-Eastern Australia: Epidemiology and Risk Factors.
In this study, we report the epidemiology and risk factors for humeral fractures (proximal humerus and shaft) among men and women residing in south-eastern Australia. Incident fractures during 2006 and 2007 were identified using X-ray reports (Geelong Osteoporosis Study Fracture Grid). Risk factors were identified using data from case-control studies conducted as part of the Geelong Osteoporosis Study. Median age of fracture was lower in males than females for proximal humerus (33.0 vs 71.2 years), but not for humeral shaft (8.9 vs 8.5 years). For females, proximal humerus fractures occurred mainly in the 70-79 and 80+ years age groups, whereas humeral shaft fractures followed a U-shaped pattern. Males showed a U-shaped pattern for both proximal humerus and humeral shaft fractures. Overall age-standardised incidence rates for proximal humerus fractures in males and females were 40.6 (95% CI 32.7, 48.5) and 73.2 (95% CI 62.2, 84.1) per 100,000 person years, respectively. For humeral shaft fractures, the age-standardised rate was 69.3 (95% CI 59.0, 79.6) for males and 61.5 (95% CI 51.9, 71.0) for females. There was an increase in risk of proximal humerus fractures in men with a lower femoral neck BMD, younger age, prior fracture and higher milk consumption. In pre-menopausal women, increased height and falls were both risk factors for proximal humerus fractures. For post-menopausal women, risk factors associated with proximal humerus fractures included a lower non-milk dairy consumption and sustaining a prior fracture. Humeral shaft fractures in both sexes were sustained mainly in childhood, while proximal humerus fractures were sustained in older adulthood. The overall age-standardised rates of proximal humerus fractures were nearly twice as high in females compared to males, whereas the incidence rates of humeral shaft fractures were similar.


Bisphenol A Effects on Neurons' Neurochemical Character in the Urinary Bladder Intramural Ganglia of Domestic Pigs.
Bisphenol A (BPA), a substance globally used to produce plastics, is part of many everyday items, including bottles, food containers, electronic elements, and others. It may penetrate the environment and living organisms, negatively affecting, among others, the nervous, immune, endocrine, and cardiovascular systems. Knowledge of the impact of BPA on the urinary bladder is extremely scarce. This study investigated the influence of two doses of BPA (0.05 mg/kg body weight (b.w.)/day and 0.5 mg/kg b.w./day) given orally for 28 days on the neurons situated in the ganglia located in the urinary bladder trigone using the typical double immunofluorescence method. In the study, an increase in the percentage of neurons containing substance P (SP), galanin (GAL), a neuronal isoform of nitric oxide synthase (nNOS-used as the marker of nitrergic neurons), and/or cocaine- and amphetamine-regulated transcript (CART) peptide was noted after BPA administration. The severity of these changes depended on the dose of BPA and the type of neuronal factors studied. The most visible changes were noted in the cases of SP- and/or GAL-positive neurons after administering a higher dose of BPA. The results have shown that oral exposure to BPA, lasting even for a short time, affects the intramural neurons in the urinary bladder wall, and changes in the neurochemical characterisation of these neurons may be the first signs of BPA-induced pathological processes in this organ.


The effectiveness of varenicline versus nicotine replacement therapy on long-term smoking cessation in primary care: a prospective cohort study of electronic medical records.
There is limited evidence about the effectiveness of varenicline and nicotine replacement therapy (NRT) for long-term smoking cessation in primary care, or whether the treatment effectiveness differs by socioeconomic position (SEP). Therefore, we estimated the long-term effectiveness of varenicline versus NRT (> 2 years) on smoking cessation, and investigated whether effectiveness differs by SEP. This is a prospective cohort study of electronic medical records from 654 general practices in England, within the Clinical Practice Research Datalink, using three different analytical methods: multivariable logistic regression, propensity score matching and instrumental variable analyses. Exposure was prescription of varenicline versus NRT, and the primary outcome was smoking cessation at 2 years' follow-up; outcome was also assessed at 3, 6, and 9 months, and at 1 and 4 years after exposure. SEP was defined using the Index of Multiple Deprivation. At 2 years, 28.8% (N = 20 362/70 610) of participants prescribed varenicline and 24.3% (N = 36 268/149 526) of those prescribed NRT quit; adjusted odds ratio was 1.26 [95% confidence interval (CI): 1.23 to 1.29], P < 0.0001. The association persisted for up to 4 years and was consistent across all analyses. We found little evidence that the effectiveness of varenicline differed greatly by SEP. However, patients from areas of higher deprivation were less likely to be prescribed varenicline; adjusted odds ratio was 0.91 (95% CI: 0.90 to 0.92), P < 0.0001. Patients prescribed varenicline were more likely to be abstinent up to 4 years after first prescription than those prescribed NRT. In combination with other evidence, the results from this study may be used to update clinical guidelines on the use of varenicline for smoking cessation.


Plan-provider integration, premiums, and quality in the Medicare Advantage market.
To investigate how integration between Medicare Advantage plans and health care providers is related to plan premiums and quality ratings. We used public data from the Centers for Medicare and Medicaid Services (CMS) and the Area Resource File and private data from one large insurer. Premiums and quality ratings are from 2009 CMS administrative files and some control variables are historical. We estimated ordinary least-squares models for premiums and plan quality ratings, with state fixed effects and firm random effects. The key independent variable was an indicator of plan-provider integration. With the exception of Medigap premium data, all data were publicly available. We ascertained plan-provider integration through examination of plans' websites and governance documents. We found that integrated plan-providers charge higher premiums, controlling for quality. Such plans also have higher quality ratings. We found no evidence that integration is associated with more generous benefits. Current policy encourages plan-provider integration, although potential effects on health insurance products and markets are uncertain. Policy makers and regulators may want to closely monitor changes in premiums and quality after integration and consider whether quality improvement (if any) justifies premium increases (if they occur).


Transalveolar osmotic and diffusional water permeability in intact mouse lung measured by a novel surface fluorescence method.
A surface fluorescence method was developed to measure transalveolar transport of water, protons, and solutes in intact perfused lungs. Lungs from c57 mice were removed and perfused via the pulmonary artery (approximately 2 ml/min). The airspace was filled via the trachea with physiological saline containing a membrane-impermeant fluorescent indicator (FITC-dextran or aminonapthalene trisulfonic acid, ANTS). Because fluorescence is detected only near the lung surface due to light absorption by lung tissue, the surface fluorescence signal is directly proportional to indicator concentration. Confocal microscopy confirmed that the fluorescence signal arises from fluorophores in alveoli just beneath the pleural surface. Osmotic water permeability (Pf) was measured from the time course of intraalveolar FITC-dextran fluorescence in response to changes in perfusate osmolality. Transalveolar Pf was 0.017 +/- 0.001 cm/s at 23 degrees C, independent of the solute used to induce osmosis (sucrose, NaCl, urea), independent of osmotic gradient size and direction, weakly temperature dependent (Arrhenius activation energy 5.3 kcal/mol) and inhibited by HgCl2. Pf was not affected by cAMP activation but was decreased by 43% in lung exposed to hyperoxia for 5 d. Diffusional water permeability (Pd) and Pf were measured in the same lung from intraalveolar ANTS fluorescence, which increased by 1.8-fold upon addition of 50% D2O to the perfusate, Pd was 1.3 x 10(-5) cm/s at 23 degrees C. Transalveolar proton transport was measured from FITC-dextran fluorescence upon switching perfusate pH between 7.4 and 5.6; alveolar pH half-equilibrated in 1.9 and 1.0 min without and with HCO3-, respectively. These results indicate high transalveolar water permeability in mouse lung, implicating the involvement of molecular water channels, and establish a quantitative surface fluorescence method to measure water and solute permeabilities in intact lung.


Design and Properties of Ligand-Conjugated Guanine Oligonucleotides for Recovery of Mutated G-Quadruplexes.
The formation of a guanine quadruplex DNA structure (G4) is known to repress the expression of certain cancer-related genes. Consequently, a mutated G4 sequence can affect quadruplex formation and induce cancer progression. In this study, we developed an oligonucleotide derivative consisting of a ligand-containing guanine tract that replaces the mutated G4 guanine tract at the promoter of the vascular endothelial growth factor (VEGF) gene. A ligand moiety consisting of three types of polyaromatic hydrocarbons, pyrene, anthracene, and perylene, was attached to either the 3' or 5' end of the guanine tract. Each of the ligand-conjugated guanine tracts, with the exception of anthracene derivatives, combined with other intact guanine tracts to form an intermolecular G4 on the mutated VEGF promoter. This intermolecular G4, exhibiting parallel topology and high thermal stability, enabled VEGF G4 formation to be recovered from the mutated sequence. Stability of the intramolecular G4 increased with the size of the conjugated ligand. However, suppression of intermolecular G4 replication was uniquely dependent on whether the ligand was attached to the 3' or 5' end of the guanine tract. These results indicate that binding to either the top or bottom guanine quartet affects unfolding kinetics due to polarization in DNA polymerase processivity. Our findings provide a novel strategy for recovering G4 formation in case of damage, and fine-tuning processes such as replication and transcription.


Left ventricular hypertrophy is associated with an attenuated endothelium-dependent vasodilation in hypertensive men.
To investigate the relationship between left ventricular hypertrophy (LVH) and endothelium-dependent vasodilation (EDV), 30 untreated hypertensive patients, 18 treated hypertensives (53 +/- 7 years, all males) and 26 age-and sex-matched healthy normotensive controls, underwent evaluation of EDV and endothelium-independent vasodilation (EIDV) in the forearm, by means of local intra-arterial infusions of methacholine (MCh, evaluating EDV) and sodium nitroprusside (SNP, evaluating EIDV). Forearm blood flow was measured by venous occlusion plethysmography and LVH was measured by echocardiography. The reduction in forearm vascular resistance during MCh infusion (4 microg/min) was significantly smaller in the hypertensive patients with LVH when compared to those without LVH, both in the untreated (-61 +/- 12%, n = 19 vs -72 +/- 4%, n = 11, p < 0.01) and in the treated group (-60 +/- 15%, n = 11 vs -75 +/- 5%, n = 7, p < 0.01). Thereby, EDV was significantly impaired only in the hypertensive patients with LVH when compared to controls (-77 +/- 7% at MCh 4 microg/min, p < 0.001). EIDV was not significantly different between patients with and without LVH and controls. In conclusion, the presence of LVH was related to endothelial dysfunction, both in untreated and treated hypertensive patients, suggesting either a role for endothelial function in the development of LVH, or that a dysfunctional endothelium and LVH are coexisting markers of a more severe hypertensive disease.


Prescription writing trends of antihistamines at the university health centre.
The aim of the present study was to establish antihistamines drug prescribing pattern in order to improve the rational prescribing of antihistamines by physicians at Panjab University Health Centre. The study was performed in between the months of November 2005 to April 2006. Five hundred out patients were monitored and data was collected on WHO-based prescription-auditing performa. Demographic analysis of this prospective study revealed that out of the 500 patients, 293 (58.6 %) were male and 207 (41.4 %) were female and maximum patients were in the age group of 21-40 (34.8 %). Chlorpheniramine maleate (235 prescriptions) was the highest prescribed among antihistamine prescriptions (36.89 %) followed by diphenhydramine hydrochloride (186 prescriptions, 29.19%), cetirizine (175 prescriptions, 27.47 %) and promethazine (41 prescriptions, 6.4%). In comparison to generic drugs (169 prescriptions, 26.54%), branded were more prescribed at PUHC. Majority of antihistamines were in form of tablets (414 prescriptions, 64.99%) followed by liquid formulations (195 prescriptions, 30.61%) and injections (28 prescriptions, 4.40%). The average cost of different antihistamine drugs prescribed was as follows: diphenhydramine hydrochloride Rs. 34.74 followed by promethzine Rs. 22.46, chlorpheniramine maleate Rs. 15.30, and cetirizine Rs. 13.50. Average numbers of drugs prescribed per prescription were 1.27. The average consulting and dispensing time was 4.82 and 3.56 min, respectively. Out of the 500 university patients, 258 (51.6%) had the knowledge regarding the medication prescribed and 242 (48.4%) were unaware of the medication prescribed.


Context-dependent functions of avian duets revealed by microphone-array recordings and multispeaker playback.
In many tropical animals, male and female breeding partners combine their songs to produce vocal duets [1-5]. Duets are often so highly coordinated that human listeners mistake them for the songs of a single animal [6]. Behavioral ecologists rank duets among the most complex vocal performances in the animal kingdom [7, 8]. Despite much research, the evolutionary significance of duets remains elusive [9], in part because many duetting animals live in tropical habitats where dense vegetation makes behavioral observation difficult or impossible. Here, we evaluate the duetting behavior of rufous-and-white wrens (Thryothorus rufalbus) in the humid forests of Costa Rica. We employ two innovative technical approaches to study duetting behavior: an eight-microphone acoustic location system capable of triangulating animals' positions on the basis of recordings of their vocalizations [10] and dual-speaker playback capable of simulating duets in a spatially realistic manner [11]. Our analyses provide the first detailed spatial information on duetting in both a natural context and during confrontations with rivals. We demonstrate that birds perform duets across highly variable distances, that birds approach their partner after performing duets, and that duets of rivals induce aggressive, sex-specific responses. We conclude that duets serve distinct functions in aggressive and nonaggressive contexts.


Health Care Costs of Individuals With Chronic Psychotic Disorders Who Experience Incarceration in Ontario.
Little is known about the health care costs of individuals with chronic psychotic disorders who experience incarceration. This study sought to address this knowledge gap. The authors analyzed linked 2007-2010 correctional and administrative health care data on sex- and age-matched individuals with chronic psychotic disorders with and without known incarceration in prison for up to 2 years in the Ontario correctional system. Mean 1-year health care costs (overall and by sex) in the year before incarceration (when release occurred in 2010) were estimated from third-party payer data and compared between the two groups. Costs were calculated in 2018 Canadian dollars. Individuals who experienced incarceration (N=3,197) had mean 1-year costs of $15,728 in the year before incarceration, whereas those who did not (N=6,393) had 1-year costs of $11,588. This difference was mostly due to costs arising from psychiatric hospitalizations, emergency department visits, and physician services. The main factors associated with the difference were incarceration in the following year (increase of $4,827, p<0.001), being age 18-29 years compared with ages 30-39 or 40-49 (increase of $4,448 and $4,218, respectively, p<0.001), and chronic psychotic disorder duration of 1-2 years compared with ≤1 year duration (increase of $6,812, p=0.004). Women who experienced incarceration had higher costs than incarcerated men ($20,648 vs. $14,763). Individuals with chronic psychotic disorders who experienced incarceration had higher health care costs than comparable individuals who did not. These higher health care costs may signal the need for interventions and policies that help individuals with psychotic disorders avoid criminal justice system involvement.


Inter-alpha Inhibitor H4 as a Potential Biomarker Predicting the Treatment Outcomes in Patients with Hepatocellular Carcinoma.
Early prediction of treatment outcomes represents an essential step towards increased treatment efficacy and survival in patients with hepatocellular carcinoma (HCC). In this study, we performed two-dimensional electrophoresis (2-DE) followed by protein profiling to identify biomarkers predictive of therapeutic outcomes in patients with HCC who received liver-directed therapy (LDTx) involving local radiotherapy (RT), and studied the underlying mechanisms of the identified proteins. 2-DE analysis was conducted by pooling sera from patients with a good or poor prognosis; serum proteomic profiles of the two groups were compared and analyzed using matrixassisted laser desorption/ionization time-of-flight mass spectrometry. Identified proteins were confirmed via enzyme-linked immunosorbent assay. An invasion assay was performed after overexpression and knockdown of target protein in Huh7 cells. Levels of inter-alpha inhibitor H4 (ITIH4), fibrinogen gamma chain, keratin 9/1 complex, carbonic anhydrase I, and carbonmonoxyhemoglobin S were changed by more than 4-fold in response to LDTx. In particular, pre-LDTx ITIH4 expression was more than 5-fold higher in patients with a good prognosis, compared to patients with a poor prognosis. The migration ability of Huh7 cells was significantly suppressed and enhanced by ITIH4 overexpression and knockdown, respectively. The tumors of patients with HCC and a good prognosis expressed high levels of ITIH4, compared to those of patients with a poor prognosis. Taken together, ITIH4 may be a potential therapeutic target that could inhibit cancer metastasis, as well as a prognostic marker for patients with HCC who are receiving LDTx.


Naphthylphenstatins as tubulin ligands: synthesis and biological evaluation.
A new family of naphthalenic analogues of phenstatins with modifications on the ketone-bridge has been synthesised. The synthesised compounds have been assayed for tubulin polymerisation inhibitory activity as well as for cytotoxic activity against cancer cell lines. The naphthalene has been confirmed as a good surrogate for the isovanillin moiety (3-hydroxy-4-methoxyphenyl) of phenstatin, when combined with the 3,4,5-trimethoxyphenyl ring, but not when combines with the 2,3,4-trimethoxyphenyl ring. Binding models for the synthesised compounds have been generated and analysed in terms of a pharmacophore proposed for colchicine site ligands. The ketone is the optimal bridge substitution but E-acetyloximes or acetylhydrazones are also tolerated. Significant differences with indole substituted phenstatins are observed and discussed.


Maiden visit of visceral leishmaniasis to Malwa region.
Visceral leishmaniasis (VL) is a well known public health problem in eastern parts of India. So far the cases have not been reported from Malwa plateu of Madhya Pradesh, to the best of our knowledge and available literature. We report here two cases of Visceral Leishmaniasis first time from the Malwa region. Both the cases are from the migratory population of Bihar. The diseases like Leishmaniasis which were previously restricted to endemic areas of the country are spreading to non-endemic areas along with the large migratory population, which is seen with the development of the country. The cases are reported to inform the National health authorities to take proper steps to curb the spread of the disease to non-endemic areas and to emphasize the need of vector surveys in these areas.


Fluorescence multicolor hologram recorded by using a macrolens array.
We present a new efficient method for obtaining multicolor digital Fresnel holograms of three-dimensional (3-D) objects emitting incoherent fluorescent light. For each emitted fluorescent light wavelength, a single monochromatic digital modified Fresnel hologram of the 3-D scene is generated. Using a macrolens array, only nine projections of the 3-D scene are captured in a single camera shot and are then digitally processed to yield the hologram. The 3-D reconstructed images from all the monochromatic holograms are composed into a single multicolor image of the 3-D scene. The proposed holographic technique is demonstrated by experiments.


Antimicrobial, antiparasitic and anticancer properties of Hibiscus sabdariffa (L.) and its phytochemicals: in vitro and in vivo studies.
In the last few decades, Hibiscus sabdariffa L. (Malvaceae; H. sabdariffa) has gained much attention in research field because of its potentially useful bioactivity as well as a great safety and tolerability. For decades, microbial, parasitic and cancer diseases remain a serious threat to human health and animals as well. To treat such diseases, a search for new sources such as plants that provide various bioactive compounds useful in the treatment of several physiological conditions is urgently needed, since most of the drugs currently used in the therapy have several undesirable side effects, toxicity, and drug resistance. In this paper, we aim to present an updated overview of in vitro and in vivo studies that show the significant therapeutic properties of the crude extracts and phytochemicals derived from H. sabdariffa as antimicrobial, antiparasitic, and anticancer agents. The future directions of the use of H. sabdariffa in clinical trials will be discussed. Hibiscus sabdariffa L. antimicrobial agents cancer preventive agents antiparasitic drugs natural products.


Control of (multi)drug resistance and tuberculosis incidence over 23 years in the context of a well-supported tuberculosis programme in rural Malawi.
The rise in tuberculosis (TB) incidence following generalized HIV epidemics can overwhelm TB control programmes in resource-limited settings, sometimes accompanied by rising rates of drug resistance. This has led to claims that DOTS-based TB control has failed in such settings. However, few studies have described the effect of a sustained and well-supported DOTS programme on TB incidence and drug resistance over a long period. We present long-term trends in incidence and drug resistance in rural Malawi. Karonga District in northern Malawi has an adult HIV prevalence of ≈ 10%. A research group, the Karonga Prevention Study, collaborates with the National Tuberculosis Programme to support core TB control activities. Bacteriological, demographic and clinical (including HIV status) information from all patients starting TB treatment in the District have been recorded since 1988. During that period isolates from each culture-positive TB patient were exported for drug sensitivity testing. Antiretroviral therapy (ART) has been widely available since 2005. Incidence of new smear-positive adult TB peaked at 124/100,000/year in the mid-90 s, but has since fallen to 87/100,000/year. Drug sensitivity information was available for 95% (3132/3307) of all culture-positive cases. Initial resistance to isoniazid was around 6% with no evidence of an increase. Fewer than 1% of episodes involved a multi-drug resistant strain. In this setting with a generalised HIV epidemic and medium TB burden, a well-supported DOTS programme enhanced by routine culture and drug sensitivity testing may well have reduced TB incidence and maintained drug resistance at low levels.


[Changes in respiratory function, functional and true intrapulmonary shunts and acid-base state depending on the type of heart defect].
The respiratory disorders in various kinds of heart defects were studied in 226 patients with acquired heart defects. The following indices were determined: external respiration, alveolar ventilation, alveolar-capillary diffusion, functional and real intrapulmonary shunts and acid-base state. The complex studies via numerous indices, juxtaposed in the separate defects, revealed various stages of manifestation of the respiratory disorders according to the kind of defect, at identical degree of cardiac insufficiency. The lightest proved to be the respiratory disorders in combined aortic defects and most manifested--in biaxial defects (mitral and aortic). In mitral defects with predominant stenosis, the respiratory disorders are better manifested as compared with those with predominant insufficiency, and for some of the indices--they are considerable.


Interaction of opioid growth factor (OGF) and opioid antagonist and their significance in cancer therapy.
Endogenous opioids are neuro-peptides with multifunctional properties. Historically, opioids are used to mediate pain; however, excess opiate consumption can lead to addiction. One endogenous opioid, methionine enkephalin (MENK), was reported to modulate cell growth, MENK was identified as an opioid growth factor (OGF) that interacts with the OGF receptor (OGFr) and regulates cell proliferation. Further, opioid antagonists, including naltrexone and naloxone are widely used to reverse drug and alcohol overdoses. Naltrexone (NTX) acts on all opioid receptors, blocking the interaction between OGF and OGFr, and thus influencing cell growth. During the last decades, insights have been made concerning the interaction between OGF and OGFr, confirming that both opioids and opioid antagonists have an important role in balancing host homeostasis, host immunity and mediating cancer therapy. This review provides insight into the interactions between OGF and OGFr in the treatment of cancers.


Symptom control in stem cell transplantation: a multidisciplinary palliative care team approach. Part 1: Physical symptoms.
Stem cell transplantation (SCT) offers a potential cure for patients with otherwise incurable benign and malignant disorders, but the arduous SCT process may cause considerable physical, social, psychological, and spiritual suffering. Relief of suffering associated with SCT begins by understanding the patient experience and the SCT culture. Symptom burden is the combined impact of all disease- or therapy-related symptoms on the patient's ability to function. In approaching symptom management, the division between physical and psychological symptoms is blurred; physical symptoms are often interrelated with the patient's emotional status and social support. Physical symptoms that frequently occur in SCT include pain, nausea, mucositis, diarrhea, and delirium. At the same time, SCT is recognized as one of the most stressful treatments in modern cancer care, resulting in psychological distress, social isolation, and role changes. Psychological symptoms include depression/ anxiety, grief/loss, demoralization, and anger. Based on our experience on an academic SCT ward for adults, we review physical, psychological, social, and spiritual symptoms during the course of SCT in a two-part series and offer an approach to their management. This month, in part I, we focus on physical symptoms linked to SCT. In a future issue, part II will highlight psychosocial concerns in SCT.


Characteristics of ice hockey-related injuries treated in US emergency departments, 2001-2002.
Ice hockey, a popular sport in some regions, has potential for injury due to the velocities of players, pucks, and sticks. Previous studies conducted worldwide have shown that the rate of injury increases as the size and the speed of players increase, as well as when checking is allowed. However, national data about the annual number and types of injuries among ice hockey players are lacking. Data from previous studies were collected from regional tournaments, collegiate teams, local emergency departments (EDs), and different countries. The purpose of this article is to examine ice hockey injuries using a national US database to determine the age distribution of total injuries, injury types, and body regions injured, with a particular focus on ice hockey players <18 years old. Data regarding ice hockey-related injuries treated in US EDs between January 1, 2001, and December 31, 2002, were extracted from the National Electronic Injury Surveillance System (NEISS). Data considered included age, gender, race, injury diagnosis, and body region injured. Ice hockey-related injury cases were identified using the consumer product code for ice hockey and the narrative description of the incident in NEISS. An estimated 32,750 individuals with ice hockey-related injuries were treated in US EDs in 2001-2002, including >18,000 youths <18 years old. The number of injuries peak through adolescence (ages 12-17; 47% of all injuries). Males experienced 90% of all injuries. A very small percentage of individuals were hospitalized after injury (1.2% of individuals <18 years old; 0.5% of individuals > or =18 years old). The incidence of head injuries increased as age decreased, although the trend was not statistically significant. The upper extremity (44%) accounted for the highest total percentages of body regions injured for youths <18 years old, and trunk (14%) and facial injuries (10%) represented the smallest total percentages. Players > or =18 years old had significantly more lacerations than younger players (38% of injuries for 18- to 24-year-olds; 25% for 25- to 34-year-olds; 50% for 35- to 44-year-olds compared with 19% for 6- to 11-year-olds and 14% for 12- to 17-year-olds). Adolescents had the greatest number of ice hockey-related injuries treated in NEISS hospital EDs in 2001-2002; thus, ongoing efforts to develop injury prevention strategies should focus on this age group. Players < or =17 years old had a lower percentage of lacerations compared with all older players and a higher percentage of upper extremity injuries. The percentage of individuals hospitalized after injury was very low, yet youths <18 years old had twice the percentage of hospitalization after injury compared with individuals > or =18 years old. Males experienced the vast majority of all ice hockey-related injuries, with females representing a higher percentage of injuries among youths than among adults. Children and adults alike can reap the physical fitness and social benefits from ice hockey, when they are able to avoid predictable and preventable injuries.


[Pulmonary artery banding operation and results of terminal biventricular and univentricular repair].
In this study, we report the current indications, early-midterm results and the outcome of pulmonary artery banding (PAB) operation after definitive repair. Between 2000 and 2007, 28 infants underwent PAB operation. Ages were between 21 days and 6 months (mean 3.0+/-1.7 months). All patients had pulmonary hypertension at systemic level. Fourteen patients were candidates for terminal biventricular repair [atrioventricular septal defect (AVSD) (n=6), double outlet right ventricle (DORV) +ventricular septal defect (VSD) (n=4), Swiss cheese VSD (n=2), transposition of the great arteries (TGA) +Swiss cheese VSD (n=1), ASD+VSD+aortic coarctation (n=1)], and the remaining 14 were candidates for terminal univentricular repair [double inlet left ventricle (n=5), double inlet right ventricle (n=2), AVSD+left ventricular (LV) hypoplasia (n=2), DORV+LV hypoplasia (n=2); tricuspid atresia (n=1), left AV valve atresia (n=1), TGA+Swiss cheese VSD+LV hypoplasia (n=1). Three patients (1 in biventricular group; 2 in univentricular group) died in the early postoperative period (10.7%). Three patients needed long duration of mechanical ventilatory support. Twenty- three of the surviving patients (92%) were followed -up between 1 month to 7 years. Currently 7 patients underwent successful biventricular repair and five patients underwent univentricular repair (extracardiac Fontan 3; Glenn 2). Two patients died early and 1 patient died 1 year after extracardiac Fontan operation. Survival for biventricular group was 92.8% at 1 and 4 years and 85.7% and 58.4% respectively for univentricular group (p<0.05). Pulmonary artery banding operation has still a significant role in the palliation of certain congenital cardiac anomalies. Outcome of patients who are candidates for biventricular repair is better than the univentricular repairs.


Double Antithrombotic versus Triple Antithrombotic Therapy in Patients with Atrial Fibrillation and Acute Coronary Syndrome.
In atrial fibrillation (AF), oral anticoagulant (OAC) therapy with either vitamin K antagonist or non-vitamin K antagonist is used to prevent thromboembolic complications. In patients who presented with acute coronary syndrome (ACS) and were treated by percutaneous coronary intervention (PCI), dual antiplatelet therapy (DAPT) with aspirin and a P2Y 12 inhibitor reduces major adverse cardiac events (MACEs) and stent thrombosis. Consequently, in patients with AF who presented with ACS and were treated by PCI, the combination of OAC and DAPT, the so-called triple antithrombotic therapy (TAT) is needed to improve the outcome of the patients. However, the use of TAT increases the risk of bleeding. Several randomized clinical trials and a meta-analysis evaluated the use of TAT and double antithrombotic therapy (DAT) in this population, and DAT is defined as patients who receive combination of one antiplatelet and OAC. In general, the studies demonstrated a reduction in bleeding event in patients who received DAT as compared with TAT, with similar incidence of thromboembolic complications and MACE. To date, there is no established consensus or guideline for the most appropriate combination of antithrombotic agents in patients with AF and ACS who undergo PCI. Tailoring the treatment for each individual is likely the best approach to determine the balance of bleeding risk and ischemic events before starting antithrombotic therapy. Future trials with adequate sample size are needed to find the most appropriate combination of antiplatelet and OAC in patients with AF who presented with ACS and treated by PCI.


Onkopipe: A Snakemake Based DNA-Sequencing Pipeline for Clinical Variant Analysis in Precision Medicine.
NGS is increasingly used in precision medicine, but an automated sequencing pipeline that can detect different types of variants (single nucleotide - SNV, copy number - CNV, structural - SV) and does not rely on normal samples as germline comparison is needed. To address this, we developed Onkopipe, a Snakemake-based pipeline that integrates quality control, read alignments, BAM pre-processing, and variant calling tools to detect SNV, CNV, and SV in a unified VCF format without matched normal samples. Onkopipe is containerized and provides features such as reproducibility, parallelization, and easy customization, enabling the analysis of genomic data in precision medicine. Our validation and evaluation demonstrate high accuracy and concordance, making Onkopipe a valuable open-source resource for molecular tumor boards. Onkopipe is being shared as an open source project and is available at https://gitlab.gwdg.de/MedBioinf/mtb/onkopipe.


Neurotrophin receptor genes are expressed in distinct patterns in developing dorsal root ganglia.
All members of the neurotrophin family of neuronal growth factors promote survival and neurite outgrowth of dorsal root ganglion (DRG) neurons in vitro. The trk family of protooncogenes encodes receptors that are now thought to mediate the biological effects of neurotrophins. In order to learn more about the dependence of DRG neurons on neurotrophins in vivo, we have studied mRNA expression of members of the trk family in developing DRGs in embryonic and postnatal rats. We show here that neurotrophin receptors are expressed in thoracic and lumbar DRGs by embryonic day 13 (E13), which is only 24-48 hr after neurogenesis begins in these ganglia. Distinct patterns of expression of trkA, trkB, and trkC are readily apparent by E15. At this age, 40% of thoracic DRG neurons express trkA. In contrast, trkB and trkC are expressed by only 6% and 8%, respectively, of thoracic DRG neurons. These percentages change little between E15 and postnatal day 1. Although absolute numbers of DRG neurons expressing neurotrophin receptors are greater in lumbar than in thoracic ganglia, the ratios of DRG neurons expressing different members of the trk family are similar in the two regions. The different trks are expressed by distinct populations of DRG neurons from E15 onward. trkA is expressed predominantly by small neurons with darkly staining cytoplasm. trkB and trkC are expressed by large, lightly staining neurons. Size-frequency histograms show that trkA is expressed by neurons of variable sizes, but particularly by neurons at the smallest end of the spectrum. In contrast, trkC is expressed predominantly by large DRG neurons, including those with the largest soma areas. trkB is expressed by DRG neurons of intermediate size. Our results show that a majority of DRG neurons express mRNA for at least one member of the trk protooncogene family. Furthermore, trk expression occurs in a time frame consistent with the idea that trks mediate responses of DRG neurons to neurotrophins that are synthesized in both the periphery and spinal cord at early developmental stages. Finally, different populations of DRG neurons express different trks. We hypothesize that DRG neurons subserving different functions express different trks, and that trk expression of a particular class of DRG neurons determines its neurotrophin dependence during development.


Comparative study of pharmacokinetics and serum bactericidal activity of ceftizoxime and cefotaxime.
Single 2-g intravenous doses of ceftizoxime (CZX) and cefotaxime (CTX) were given over 30 min to 10 adult volunteers in a crossover manner on two separate occasions. Concentrations of CZX, CTX, and the primary metabolite of CTX, desacetylcefotaxime (dCTX), in serum, suction-induced-blister fluid, and urine were determined by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by using an extended least-squares modeling program (MKMODEL). CZX exhibited a half-life in serum (2.05 h) longer than that of CTX (1.43 h) but comparable to that of dCTX (2.02 h). The percentage of penetration in blister fluid, estimated by area under the curve ratios, was significantly higher for CZX (164.4%) than for CTX (60.8%). Serum bactericidal activity, determined for volunteer samples at 1, 6, 8, and 12 h after patients were dosed, against clinical isolates of the Bacteroides fragilis group, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and Morganella morganii were significantly higher for CZX than those for CTX against members of the family Enterobacteriaceae at all times. Serum bactericidal titers against B. fragilis were also higher for CZX than for CTX at 1 h postinfusion. Neither CZX nor CTX exhibited any bactericidal activity at any other time against the B. fragilis group. In conclusion, the serum bactericidal activity of CZX was greater and more-prolonged than that of CTX against tested strains in spite of the in vitro synergistic contribution of dCTX to CTX, equal serum elimination half-lives of dCTX and CZX, and similar antibacterial activity and similar instability under microbiological testing for CZX and CTX.


The role of cytocin imbalance in the development of man infertility.
The aim: Study of the clinical and pathogenetic role of IL-17, IL-35 and their correlation in the development of infertility in men with chronic ureoprostatitis. Materials and methods: 82 male aged 20 to 40 were examined. The patients were divided into three groups: the first - 10 practically healthy men, in which the levels of IL-17 and IL-35 in semen were taken as normal; second - 33 infertile men with chronic urethroprostatitis; third - 39 fertile men with chronic urethroprostatitis. In addition to conventional clinical and laboratory (clinical blood and urine tests) studies, all men in semen were tested for IL-17 and IL-35 cytokine levels. Results: The levels of the studied cytokines were found to have opposite tendencies to shifts in the semen of men with chronic urethroprostatitis. The level of IL-17 in sperm increases and the level of IL-35 decreases. The IL-17/IL-35 index increases more strongly in men with impaired fertility. Conclusions: Increas IL-17 concentrations, decreas IL-35 levels and increas their correlation may be an indicator of infertility in men with chronic ureoprostatitis. Determining the IL-17 / IL-35 correlation in general clinical practice will allow to single out a group of men with a high likelihood of developing infertility for follow-up and treatment by a doctor of family medicine.


CHL1 is a nuclear protein with an essential ATP binding site that exhibits a size-dependent effect on chromosome segregation.
Saccharomyces cerevisiae chl1 mutants have a significant increase in the rate of chromosome missegregation. CHL1 encodes a 99 kDa predicted protein with an ATP binding site consensus, a putative helix-turn-helix DNA binding motif, and homology to helicases. Using site-directed mutagenesis, I show that mutations that are predicted to abolish ATP binding in CHL1 inactivate its function in chromosome segregation. Furthermore, overexpression of these mutations interferes with chromosome transmission of a 125 kb chromosome fragment in a wild-type strain. Polyclonal antibodies against CHL1 show that CHL1 is predominantly in the nuclear fraction of S. CEREVISIAE: CHL1 function is more critical for the segregation of small chromosomes. In chl1Delta1/chl1Delta1 mutants, artificial circular or linear chromosomes <150 kb in size exhibit near random segregation (0.12 per cell division), whereas all chromosomes tested >225 kb were lost at rates (5 x 10(-)(3) per cell division) comparable to that observed for endogenous chromosome III. These results reveal an important role for ATPases/DNA helicases in chromosome segregation. Such enzymes may alter DNA topology to allow loading of proteins involved in maintaining sister chromatid cohesion.


Measurement: the key to success for providers, payors, and patients in long-term care.
The complex financing structure that supports home and community-based long-term care services has resulted in the application of different quality assurance requirements to similar services. Goals for home and community-based care are viewed differently by providers, payors, and customers. This raises the issue of how goals can be harmonized and what should be used to measure goals. Current quality assurance strategies are judge insufficient to assure the delivery of high-quality services; in part due to the state of health programs and lack of unified outcome measurement. The need for multidimensional assessment to adopt a baseline measure of health status to support allocation of services and enhance successful client outcomes has become the aim for health care providers.


Use of recombinant human bone morphogenetic protein (rhBMP2) in bilateral alveolar ridge augmentation: case report.
In recent years, the delivery of osteoinductive factors such as bone morphogenic proteins (BMPs) has become an alternative approach to traditional bone grafting due to their capacity to produce bone healing and new bone formation. BMP-2 has proved to possess the highest osteoinductive potential among BMPs. The case reported the clinical use of recombinant human BMP-2 for bilateral vertical alveolar ridge augmentation. In a case of 61 year-old patient with a significant bilateral vertical bony deficiency of the mandible, rhBMP-2 administered via an absorbable collagen sponge carrier (ACS) was used for bilateral alveolar ridge bone induction. Augmented sites were covered and fixed with titanium mesh. Augmented sites were reopened 6 months after surgery. Titanium membrane and retaining screws were removed and three dental implants were placed. The tissue samples for the histologic analysis were harvested. Following 3 months healing period, the submerged implants were uncovered and restored with zirconium-ceramic crowns. Cone beam computed tomography (CBCT), panoramix and 3D radiographic evaluation were obtained prior to and after the surgical procedure. Vertical gain of the bone was 5.5 mm on the left and 5 mm on the right side, with 6 mm width of the bone. Histologic analysis revealed formation of mature trabecular bone with signs of osteoblastic proliferation. Implant stability quotient (ISQ) values were in the range between 69 and 75 for all three implants. No suppuration, gingival recession or pain were present 24 months after surgery. Vertical bone augmentation using rhBMP-2 is optional treatment modality to consider when planning dental implant placement in sites where severe vertical insufficiency exists.


Role of keratinases in dermatophytosis. IV. Reactivities of sera from guinea pigs with heat-inactivated keratinase II.
Complement-fixing antibodies to the heat-inactivated keratinase II of Trichophyton mentagrophytes var. granulosum were detectable in sera from approximately 40% of the Hartley strain guinea pigs previously infected with this dermatophyte. However, no precipitating antibodies to the heat-inactivated keratinase II were detectable in these sera. Guinea pigs immunized with the heat-inactivated keratinase II had both complement-fixing and precipitating antibodies to the keratinase II. Circulating antibodies in sera from both the infected and the immunized guinea pigs also reacted with the active keratinase II but did not inhibit its proteolytic activity.


Amylin receptor signaling in the ventral tegmental area is physiologically relevant for the control of food intake.
The ability of amylin, a pancreatic β-cell-derived neuropeptide, to promote negative energy balance has been ascribed to neural activation at the area postrema. However, despite amylin binding throughout the brain, the possible role of amylin signaling at other nuclei in the control of food intake has been largely neglected. We show that mRNA for all components of the amylin receptor complex is expressed in the ventral tegmental area (VTA), a mesolimbic structure mediating food intake and reward. Direct activation of VTA amylin receptors reduces the intake of chow and palatable sucrose solution in rats. This effect is mediated by reductions in meal size and is not due to nausea/malaise or prolonged suppression of locomotor activity. VTA amylin receptor activation also reduces sucrose self-administration on a progressive ratio schedule. Finally, antagonist studies provide novel evidence that VTA amylin receptor blockade increases food intake and attenuates the intake-suppressive effects of a peripherally administered amylin analog, suggesting that amylin receptor signaling in the VTA is physiologically relevant for food intake control and potentially clinically relevant for the treatment of obesity.


Large BRCA1 and BRCA2 genomic rearrangements in Malaysian high risk breast-ovarian cancer families.
Early studies of genetic predisposition due to the BRCA1 and BRCA2 genes have focused largely on sequence alterations, but it has now emerged that 4-28% of inherited mutations in the BRCA genes may be due to large genomic rearrangements of these genes. However, to date, there have been relatively few studies of large genomic rearrangements in Asian populations. We have conducted a full sequencing and large genomic rearrangement analysis (using Multiplex Ligation-dependent Probe Amplification, MLPA) of 324 breast cancer patients who were selected from a multi-ethnic hospital-based cohort on the basis of age of onset of breast cancer and/or family history. Three unrelated individuals were found to have large genomic rearrangements: 2 in BRCA1 and 1 in BRCA2, which accounts for 2/24 (8%) of the total mutations detected in BRCA1 and 1/23 (4%) of the mutations in BRCA2 detected in this cohort. Notably, the family history of the individuals with these mutations is largely unremarkable suggesting that family history alone is a poor predictor of mutation status in Asian families. In conclusion, this study in a multi-ethnic (Malay, Chinese, Indian) cohort suggests that large genomic rearrangements are present at a low frequency but should nonetheless be included in the routine testing for BRCA1 and BRCA2.


Emetine Is Not Ipecac: Considerations for Its Use as Treatment for SARS-CoV2.
Emetine is a potent antiviral that acts on many viruses in the low-nM range, with several studies in animals and humans demonstrating antiviral activity. Historically, emetine was used to treat patients with Spanish influenza, in the last stages of the pandemic in the early 1900s. Some of these patients were "black" with cyanosis. Emetine rapidly reversed the cyanosis and other symptoms of this disease in 12-24 h. However, emetine also has been shown to have anti-inflammatory properties and it appears it is these anti-inflammatory properties that were responsible for the effects seen in patients with Spanish influenza. Emetine, in the past, has also been used in 10s to 100s of millions of people at a dose of ~60 mg daily to treat amoebiasis. Based on viral inhibition data we can calculate a likely SARS-CoV2 antiviral dose of ~1/10th the amoebiasis dose, which should dramatically reduce the risk of any side effects. While there are no anti-inflammatory dose response data available, based on the potential mode of action, the anti-inflammatory actions may also occur at low doses. This paper also examines the toxicity of emetine seen in clinical practice and that seen in the laboratory, and discusses the methods of administration aimed at reducing side effects if higher doses were found to be necessary. While emetine is a "pure drug" as it is extracted from ipecac, some of the differences between emetine and ipecac are also discussed.


Machine Learning-led Optimization of Combination Therapy: Confronting the Public Health Threat of Extensively Drug Resistant Gram Negative Bacteria.
Developing optimized regimens for combination antibiotic therapy is challenging and often performed empirically over many clinical studies. Novel implementation of a hybrid machine learning-pharmacokinetic/pharmacodynamic/toxicodynamic (ML-PK/PD/TD) approach optimizes combination therapy using human PK/TD data along with in vitro PD data. This study utilized human population PK (PopPK) of aztreonam, ceftazidime/avibactam, and polymyxin B along with in vitro pharmacodynamics from the Hollow Fiber Infection Model (HFIM) to derive optimal multi-drug regimens de novo through implementation of a genetic algorithm (GA). The mechanism-based PD model was constructed based on 7-day HFIM experiments across four clinical, extensively drug resistant K. pneumoniae isolates. GA-led optimization was performed using thirteen different fitness functions to compare the effects of different efficacy (60%, 70%, 80% or 90% of simulated subjects achieving bacterial counts of 102 CFU/mL) and toxicity (66% of simulated subjects having a target polymyxin B area under the concentration-time curve [AUC] of 100 mg•h/L and aztreonam AUC of 1332 mg•h/L) on the optimized regimen. All regimens, except those most heavily weighted for toxicity prevention, were able to achieve the target efficacy threshold (102 CFU/mL). Overall, GA-based regimen optimization using pre-clinical data from animal-sparing in vitro studies and human PopPK produced clinically relevant dosage regimens similar to those developed empirically over many years for all three antibiotics. Taken together, these data provide significant insight into new therapeutic approaches incorporating machine learning to regimen design and treatment of resistant bacterial infections.


Vermont: a multi-perspective visual interactive platform for mutational analysis.
A huge amount of data about genomes and sequence variation is available and continues to grow on a large scale, which makes experimentally characterizing these mutations infeasible regarding disease association and effects on protein structure and function. Therefore, reliable computational approaches are needed to support the understanding of mutations and their impacts. Here, we present VERMONT 2.0, a visual interactive platform that combines sequence and structural parameters with interactive visualizations to make the impact of protein point mutations more understandable. We aimed to contribute a novel visual analytics oriented method to analyze and gain insight on the impact of protein point mutations. To assess the ability of VERMONT to do this, we visually examined a set of mutations that were experimentally characterized to determine if VERMONT could identify damaging mutations and why they can be considered so. VERMONT allowed us to understand mutations by interpreting position-specific structural and physicochemical properties. Additionally, we note some specific positions we believe have an impact on protein function/structure in the case of mutation.


Current Status of Angiotensin Receptor Blocker Recalls.
Losartan was the ninth most prescribed drug in the United States in 2016, and several other angiotensin-II receptor blockers (ARBs) are widely prescribed. Since July 2018, >2 dozen specific ARB products have been recalled owing to the presence of potentially carcinogenic nitrosamine impurities in selected lots. As is the case with all U.S. drug recalls, the ARB recalls have been voluntary on the part of the companies involved. In April 2019, the Food and Drug Administration categorized marketed ARB products with respect to nitrosamine impurities: (1) not present, (2) to be determined with no prior lots removed from the market (TBD), or (3) to be determined in the context of prior lots having been removed from the market (TBD*). The data were structured as hundreds of rows of products. Owing to the complexity of these data, more than a year into the recalls, it remains difficult for clinicians to understand which ARB products are free of impurities.


Confounding-adjustment methods for the causal difference in medians.
With continuous outcomes, the average causal effect is typically defined using a contrast of expected potential outcomes. However, in the presence of skewed outcome data, the expectation (population mean) may no longer be meaningful. In practice the typical approach is to continue defining the estimand this way or transform the outcome to obtain a more symmetric distribution, although neither approach may be entirely satisfactory. Alternatively the causal effect can be redefined as a contrast of median potential outcomes, yet discussion of confounding-adjustment methods to estimate the causal difference in medians is limited. In this study we described and compared confounding-adjustment methods to address this gap. The methods considered were multivariable quantile regression, an inverse probability weighted (IPW) estimator, weighted quantile regression (another form of IPW) and two little-known implementations of g-computation for this problem. Methods were evaluated within a simulation study under varying degrees of skewness in the outcome and applied to an empirical study using data from the Longitudinal Study of Australian Children. Simulation results indicated the IPW estimator, weighted quantile regression and g-computation implementations minimised bias across all settings when the relevant models were correctly specified, with g-computation additionally minimising the variance. Multivariable quantile regression, which relies on a constant-effect assumption, consistently yielded biased results. Application to the empirical study illustrated the practical value of these methods. The presented methods provide appealing avenues for estimating the causal difference in medians.


Reliability and variability of day-to-day vault training measures in artistic gymnastics.
Inter-day training reliability and variability in artistic gymnastics vaulting was determined using a customised infra-red timing gate and contact mat timing system. Thirteen Australian high performance gymnasts (eight males and five females) aged 11-23 years were assessed during two consecutive days of normal training. Each gymnast completed a number of vault repetitions per daily session. Inter-day variability of vault run-up velocities (at -18 to -12 m, -12 to -6 m, -6 to -2 m, and -2 to 0 m from the nearest edge of the beat board), and board contact, pre-flight, and table contact times were determined using mixed modelling statistics to account for random (within-subject variability) and fixed effects (gender, number of subjects, number of trials). The difference in the mean (Mdiff) and Cohen's effect sizes for reliability assessment and intra-class correlation coefficients, and the coefficient of variation percentage (CV%) were calculated for variability assessment. Approach velocity (-18 to -2m, CV = 2.4-7.8%) and board contact time (CV = 3.5%) were less variable measures when accounting for day-to-day performance differences, than pre-flight time (CV = 17.7%) and table contact time (CV = 20.5%). While pre-flight and table contact times are relevant training measures, approach velocity and board contact time are more reliable when quantifying vaulting performance.


Transfer of inner cell mass cells derived from bovine nuclear transfer embryos into the trophoblast of bovine in vitro-produced embryos.
Presence of placental tissues from more normal noncloned embryos could reduce the pregnancy failure of somatic cloning in cattle. In this study, inner cell mass (ICM) cells of in vitro-produced (IVP) embryos was replaced with those of nuclear transfer (NT) embryos to reconstruct bovine blastocysts with ICM and trophoblast cells from NT and IVP embryos, respectively. A total of 65 of these reconstructed embryos were nonsurgically transferred to 20 recipient beef females. Of those, two females were diagnosed pregnant by ultrasonography on day 30 of gestation. One pregnancy was lost at 60-90 days of gestation, and the other recipient cow remained pregnant at day 240 of gestation; however, this female died on day 252 of gestation. Gross pathology of the internal organs of the recipient female, a large fetus, and a large placental tissue mass suggested the massive size of the fetus and placental tissue were likely involved in terminating the life of the recipient female. Biopsy samples were harvested from the skin of the dead recipient cow, the fetus and from cotyledonary tissue. Microsatellite DNA analysis of these samples revealed that the genotype of the fetus was the same as that of the NT donor cells and different from that of the recipient cow. Correspondingly, neither the fetus nor recipient cow had the same genotype with that of the fetal cotyledonary tissue. These results present the first known documented case of a bovine somatic NT pregnancy with nonclone placental tissues after transfer of a blastocyst reconstructed by a microsurgical method to exchange of ICM cells and trophoblast tissue between NT and IVP blastocysts.


The assessment of oral health-related quality of life by factor analysis in patients with Behcet's disease and recurrent aphthous stomatitis.
The aim of the study was to test multidimensional properties of oral health impact profile-14 (OHIP-14) in Behcet's disease (BD) and recurrent aphthous stomatitis (RAS) patients with active oral ulcers. Ninety-six BD patients, 28 patients with RAS and 117 healthy controls (HC) were included in this study. In patients with active oral ulcers, the frequency and healing time of ulcers were recorded. Multidimensional properties of OHIP-14 were examined by factor analysis. Factor analysis revealed three subscales and explained 66.49% of overall variance in these patients with active oral ulcers. The score of Subscale 1 was positively correlated with the recurrence of oral ulcers per month (P = 0.037). Subscale 3 scores of the patients treated with colchicine were worse than those treated with immunosuppressives (P = 0.035). The factor structure of OHIP-14 was found to be reliable and sensitive to clinical parameters and treatment modalities in active patients.


Results of the post-U.S. Food and Drug Administration-approval study with a continuous flow left ventricular assist device as a bridge to heart transplantation: a prospective study using the INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support).
The aim of this study was to determine whether results with the HeartMate (HM) II left ventricular assist device (LVAD) (Thoratec Corporation, Pleasanton, California) in a commercial setting are comparable to other available devices for the same indication. After a multicenter pivotal clinical trial conducted from 2005 to 2008, the U.S. Food and Drug Administration approved the HM II LVAD for bridge to transplantation (BTT). A post-approval study was required by the U.S. Food and Drug Administration to determine whether results with the device in a commercial setting are comparable to other available devices for the same indication. The study was a prospective evaluation of the first 169 consecutive HM II patients enrolled in the national INTERMACS (Interagency Registry for Mechanically Assisted Circulatory Support) who were listed for transplant or likely to be listed. Patients were enrolled from April through August 2008 at 77 U.S. centers and followed for at least 1 year after implant. A comparison group (COMP) included all patients (n = 169 at 27 centers) enrolled in the INTERMACS registry with other types of LVADs (79% HeartMate XVE, 21% Implantable Ventricular Assist Device [Thoratec Corporation]) for the same BTT indication in the same time period. Survival rates, adverse events, and quality of life with the EuroQol EQ-5D visual analog scale were obtained in the INTERMACS registry. Baseline characteristics were similar, but creatinine and blood urea nitrogen were lower in the HM II versus COMP groups, and there were fewer patients in the highest-risk INTERMACS patient profile Number 1 (24% for HM II vs. 39% for COMP). Adverse event rates were similar or lower for HM II versus COMP for all events. Bleeding was the most frequent adverse event for both groups (1.44 vs. 1.79 events/patient-year). Operative 30-day mortality for HM II was 4% versus 11% for COMP. The percentage of patients reaching transplant, cardiac recovery, or ongoing LVAD support by 6 months was 91% for HM II and 80% for COMP, and the Kaplan-Meier survival for patients remaining on support at 1 year was 85% for HM II versus 70% for COMP. Quality of life was significantly improved at 3 months of support and sustained through 12 months in both groups compared with baseline. The results in a post-market approval, actual patient care setting BTT population support the original findings from the pivotal clinical trial regarding the efficacy and risk profile of the HM II LVAD. These data suggest that dissemination of this technology after approval has been associated with continued excellent results.


Atrophy, metaplasia and dysplasia: are they reversible?
The eradication of Helicobacter pylori results in the decrease and eventual disappearance of inflammation in the gastric mucosa. An important question with practical implications is whether treatment of H. pylori can promote the resolution of atrophy and intestinal metaplasia. If this happens, then one could infer that even in the presence of established multifocal atrophic gastritis the cure of Helicobacter pylori could reduce the risk of developing gastric cancer. Several investigators have addressed the issue, but the cumulative results remain inconclusive. The great latitude that there exists in the interpretation of the concept of atrophy and the patchy distribution of both atrophic changes and intestinal metaplasia (with resulting inevitable sampling error) are important reasons for the wide discrepancy in the conclusions reached by different authors. Controlled, long-term prospective studies conducted in different ethnic and geographic settings are needed to provide sound evidence-based answers to the question of reversibility of atrophy, intestinal metaplasia, and epithelial dysplasia.


[Change in the functional significance of structures of the cat brain as a result of reorganization of its activity].
A study was carried out on 8 adult cats of functional role of the frontal, parietal and occipital parts of the neocortex, and also of the dorsal hippocampus, mediodorsal thalamic nucleus and caudate nucleus head, in realization of a delayed spatial choice (DSCh) before and after compensatory reorganizations of the brain activity caused by multiple electrical stimulation of the frontal part of the cerebral cortex. Compensatory reorganization led to a change of functional significance of these structures. While before this change the frontal cortex, hippocampus and mediodorsal thalamic nucleus were critically necessary brain areas for the realization of the DSCh, after it parietal and occipital cortical areas acquired such significance. The obtained data are discussed proceeding from the principle of the integrity in the brain activity.


Complete structure of the human gene for the vitamin D 1alpha-hydroxylase, P450c1alpha.
The rate-limiting, hormonally regulated step in the biosynthesis of the biologically active form of vitamin D, 1,25(OH)2D, is its 1alpha-hydroxylation in the kidney by the mitochondrial P450 enzyme, P450c1alpha. We have recently cloned the human P450c1alpha cDNA and shown that this enzyme is the factor disrupted in vitamin D-dependent rickets, type 1 (VDDR-1). To facilitate the analysis of further patients with VDDR-1 and to permit studies of the regulation of the gene for P450c1alpha, we have used PCR-based tactics to clone the gene. Southern blotting studies indicate that there is only one copy of this gene in the human genome. The complete sequence of all exons and introns show that the gene consists of 9 exons spanning only 5 kb; the entire protein-coding region can be PCR-amplified as a single 4-kb fragment. The transcriptional start site, located by primer extension and S1 nuclease protection, lies 62-bp upstream from the ATG transitional start codon. Analysis of rodent/human somatic cell hybrid DNAs show that this gene lies on chromosome 12. Although the gene is substantially smaller than the human genes for other mitochondrial enzymes, its intron/exon organization is very similar, especially to that of P450scc. This indicates that although the mitochondrial P450 enzymes retain only 30%-40% amino acid sequence identity, they all belong to a single evolutionary lineage.


SUMOylation in control of accurate chromosome segregation during mitosis.
Posttranslational protein modification by small ubiquitin-related modifier (SUMO) has emerged as an important regulatory mechanism for chromosome segregation during mitosis. This review focuses on how SUMOylation regulates the centromere and kinetochore activities to achieve accurate chromosome segregation during mitosis. Kinetochores are assembled on the specialized chromatin domains called centromeres and serve as the sites for attaching spindle microtubule to segregate sister chromatids to daughter cells. Many proteins associated with mitotic centromeres and kinetochores have been recently found to be modified by SUMO. Although we are still at the early stage of elucidating how SUMOylation controls chromosome segregation during mitosis, a substantial progress has been achieved over the past decade. Furthermore, a major theme that has emerged from the recent studies of SUMOylation in mitosis is that both SUMO conjugation and deconjugation are critical for kinetochore assembly and disassembly. Lastly, we propose a model that SUMOylation coordinates multiple centromere and kinetochore activities to ensure accurate chromosome segregation.


Wide Awake Local Anesthesia No Tourniquet Forearm Triple Tendon Transfer in Radial Nerve Palsy.
Tendon transfer for radial nerve palsy is a common procedure done under general anesthesia. We describe a surgical technique of triple tendon transfer with wide awake local anesthesia no tourniquet (WALANT). We transfer flexor carpi radialis to extensor digitorum communis, palmaris longus to extensor pollicis longus, and pronator teres to extensor carpi radialis brevis. This is commonly known as the Brand transfer. Our anesthetic or WALANT solution consists of up to 200 mL of 1:400,000 epinephrine, 0.25% lidocaine buffered with sodium bicarbonate. This technique overcomes the problem of judging the appropriate amount of transfer tension by observing awake patients actively extend their fingers, thumb, and wrist during the surgery and making adjustments before we close the wound. In our experience, there is no need of brain retraining because a patient is able to immediately use the flexor muscles to perform extension movements. WALANT is a safe and viable option for radial nerve tendon transfers.


Recent advances in surgery of ongenital heart disease.
In the cyanotic group palliative procedures for transposition of the great arteries are frequently life-saving in infancy, and the definitive operations such as the atrial baffle, and the Rastelli procedure for those with ventricular septal defect and pulmonic stenosis, are now firmly established. In tetralogy of Fallot shunting procedures continue to be employed in infancy and early childhood, and the complete repair is usually done after the age of five. Corrective operations for total anomalous venous return may have to be staged, and the results are more satisfactory in older children. The various forms of endocardial cushion defects can usually be recognized accurately preoperatively, and where the normal anatomical relationships can be restored, excellent results obtained. Brilliant operative success can now be had in some forms of truncus arteriosus and double outlet right ventricle. It is quite common to find congenital heart disease in adults, frequently after many years of having been treated as rheumatic heart disease. The operative risk in this group is less than 10 percent, and in most instances such patients are restored to their normal physiological age after operation.


The involvement of central alpha adrenoceptors in the antihypertensive actions of methyldopa and clonidine in the rat.
The antihypertensive effects of methyldopa and clonidine result from agonist activity at alpha adrenoceptor sites within the brain. Methyldopa is converted enzymatically to alpha-methylnoradrenaline in noradrenergic neurones in rat brain and replaces the natural transmitter, noradrenaline. Radioligand receptor studies show that alpha-methylnoradrenaline differs from noradrenaline in being much more selective (70 times) for the alpha 2 subclass of adrenoceptors than noradrenaline and it is likely that the antihypertensive action of methyldopa results from selective activation of alpha 2 adrenoceptors by alpha-methylnoradrenaline in the nucleus tractus solitarius and the anterior hypothalamus. Radioligand studies also show that clonidine is a selective alpha 2 adrenoceptor agonist although it probably interacts with alpha 1 adrenoceptors at higher concentrations. With regard to a withdrawal syndrome after cessation of clonidine treatment, the cardiovascular and behavioural components can now be characterised in a rat model. The components include increases in basal blood pressure and heart rate, as well as increases in cardiovascular reactivity and also increases in rapid eye movement (REM) sleep, body shakes and tremor which is reminiscent of an opiate withdrawal syndrome. Increased central noradrenergic activity is involved in this syndrome and alpha 1 and alpha 2 adrenoceptors mediate opposing effects on the REM sleep rebound component.


Guidance for reporting intervention development studies in health research (GUIDED): an evidence-based consensus study.
To improve the quality and consistency of intervention development reporting in health research. This was a consensus exercise consisting of two simultaneous and identical three-round e-Delphi studies (one with experts in intervention development and one with wider stakeholders including funders, journal editors and public involvement members), followed by a consensus workshop. Delphi items were systematically derived from two preceding systematic reviews and a qualitative interview study. Intervention developers (n=26) and wider stakeholders (n=18) from the UK, North America and Europe participated in separate e-Delphi studies. Intervention developers (n=13) and wider stakeholders (n=13) participated in a 1-day consensus workshop. e-Delphi participants achieved consensus on 15 reporting items. Following feedback from the consensus meeting, the final inclusion and wording of 14 items with description and explanations for each item were agreed. Items focus on context, purpose, target population, approaches, evidence, theory, guiding principles, stakeholder contribution, changes in content or format during the development process, required changes for subgroups, continuing uncertainties, and open access publication. They form the GUIDED (GUIDance for the rEporting of intervention Development) checklist, which contains a description and explanation of each item, alongside examples of good reporting. Consensus-based reporting guidance for intervention development in health research is now available for publishers and researchers to use. GUIDED has the potential to lead to greater transparency, and enhance quality and improve learning about intervention development research and practice.


Sleep disorders and sleep problems in childhood.
Sleep problems are common in childhood. A distinction is made between problems in which polysomnography is abnormal (i.e., the parasomnias, sleep apnea and narcolepsy) and problems that are behavioral in origin and have normal polysomnography. The parasomnias--sleep terrors, somnambulism and enuresis--appear to be related to central nervous system immaturity and are often outgrown. Obstructive sleep apnea syndrome (OSAS) is frequently missed in children and can often be cured through surgery. Behavioral sleep problems may be overcome after parents make interventions. Physicians can be of great assistance to these families by recommending techniques to parents that have been shown to be effective.


Comparison of palatability characteristics of beef gluteus medius and triceps brachii muscles.
The objective of this experiment was to evaluate triceps brachii steaks as a substitute for gluteus medius steaks in foodservice and retail applications, including the effect of aging time and USDA quality grade on the palatability of both muscles. Top sirloin butts (n = 600) and shoulder clod arm roasts (n = 600) representing US Choice and US Select quality grades were selected at 48 h postmortem and aged for 7, 14, 21, 28, 35, or 42 d. Steaks were evaluated using a trained sensory panel, slice shear force, sarcomere length, and Western blotting of desmin measurements. Sarcomere length was measured only on steaks at 14 and 42 d. Triceps brachii and gluteus medius steaks were similar in tenderness rating at 7 and 14 d, but triceps brachii steaks aged longer were more tender (P < 0.05) than were gluteus medius steaks. Triceps brachii steaks reached ultimate tenderness values by 21 d. Gluteus medius steak tenderness ratings improved through 35 d, and at 42 d were similar to those given to triceps brachii steaks at 21 d. Sarcomere lengths were longer (P < 0.05) in triceps brachii than in gluteus medius (2.09 and 1.58 mum, respectively). Significant increases in desmin degradation were detected through 42 d in both muscles (30.9, 46.3, 50.6, 51.0, 57.6, and 64.1% at d 7, 14, 21, 28, 35, and 42 for gluteus medius and 28.9, 40.8, 49.3, 59.2, 61.8, and 71.9% at d 7, 14, 21, 28, 35, and 42 for triceps brachii). At 14 d, gluteus medius had more (P < 0.05) desmin degraded than triceps brachii, but by 28 d, desmin degradation was greater (P < 0.05) in triceps brachii. Quality grade had minimal effects on palatability traits. Desmin degradation contributed to gluteus medius tenderness variation (r = 0.36) across all aging times, but not at individual aging times. Sarcomere length contributed to variation in slice shear force values of gluteus medius at 14 and 42 d (r = -0.59 and -0.48, respectively). Sarcomere length contributed to triceps brachii tenderness variation at 14 d, but not 42 d (r = 0.44 and -0.12, respectively). Desmin degradation was strongly correlated (r = 0.55) to triceps brachii tenderness ratings pooled across aging times but not at individual aging times. These data indicate that triceps brachii steaks could provide the same or improved palatability as gluteus medius steaks at the same or slightly shorter aging times.


Trying to Raise (Low) Math Achievement and to Promote (Rigorous) Policy Evaluation in Italy: Evidence From a Large-Scale Randomized Trial.
Italy is a country showing low math achievement, especially in the Southern regions. Moreover, national student assessments are recent and rigorous policy evaluation is lacking. This study presents the results of one of the first randomized controlled trials implemented in Italian schools in order to measure the effects of a professional development (PD) program for teachers on student math achievement. The program was already at scale when it was being evaluated. Assessing the effects of a PD program for math teachers on their students' achievement and making suggestions for future policy evaluations. A large-scale clustered randomized control trial has been conducted. It involves 175 lower secondary schools (sixth - eighth grade) in four among the Italian lowest performing regions. Alongside national standard math assessments, the project collected a wide amount of information. Math in lower secondary schools. Math achievement as measured by standardized tests provided by the National Education Assessment Institute (Istituto Nazionale per la Valutazione del Sistema di Istruzione e Formazione); teacher and student practices and attitudes collected through questionnaires. Findings suggest that the program had no significant impact on math scores during the first year (when the program was held). Nonetheless some heterogeneity was detected, as the treatment does seem "to work" with middle-aged teachers. Moreover, effects on teaching practice and student attitudes appear. Some effects attributable to the intervention have been detected. Moreover, this project shows that a rigorous approach to evaluation is feasible also in a context lacking attention towards evidence-based policies, such the Italian school system.