Age-adjusted analysis of insulin responses during normal and abnormal glucose tolerance tests in children and adolescents.
This report analyzes age-specific glucose (PG) and immunoassayable insulin (IRI) responses during oral glucose tolerance testing (OGTT) and examines test results in children and adolescents with OGTT abnormality using the age-appropriate control data. Controls' (n = 93) and patients' (n = 63) results were compared on the basis of statural age (SA) at the time of testing. Control tests (n = 101) showed significant positive correlation of fasting and four-hour postingestion PG with SA (p less than 0.001), but mean area under the PG curves did not vary between the SA groups (I--18.69 months, II--70-131 months, III--132+ months). The absence of differences of other sampling times permits uniform diagnostic criteria for this age group. IRI was positively correlated with SA at all testing times, and mean levels differed significantly between each SA group at every sampling time; the mean areas under the IRI curve also differed significantly between SA groups as did the mean ratios of IRI area to PG area (group I--0.2639 +/- 0.0175 S.E.M., group II--0.3864 +/- 0.0235, group III--0.6262 +/-0.0491). Patient tests (n = 110) were separated into normal (N), borderline (B), and chemical-diabetic (C) for each SA group. IRI means were above control data for each test type in each SA group at all sampling times; one fourth of these differences were significant. IRI responses also increased within each SA group from N to B to C tests. Mean IRI areas and IRI area to PG are mean ratios were higher than in controls, and this difference was greatest with the most abnormal (C) test type in each SA group. A subgroup of three patients who had low IRI responses from the outset and developed overt diabetes in one to three years was excluded from the analysis. In contrast to apparent relative insulin inefficiency with normal maturation and with chemical diabetes, they had exceptional responsiveness to their low IRI levels. Variable involvement of alpha as well as beta cells in the pathophysiology of diabetes is suggested as one explanation for these paradoxic observations. Changing receptor affinity might also be implicated.


The role of hippocampal theta oscillations in working memory impairment in multiple sclerosis.
Working memory (WM) problems are frequently present in people with multiple sclerosis (MS). Even though hippocampal damage has been repeatedly shown to play an important role, the underlying neurophysiological mechanisms remain unclear. This study aimed to investigate the neurophysiological underpinnings of WM impairment in MS using magnetoencephalography (MEG) data from a visual-verbal 2-back task. We analysed MEG recordings of 79 MS patients and 38 healthy subjects through event-related fields and theta (4-8 Hz) and alpha (8-13 Hz) oscillatory processes. Data was source reconstructed and parcellated based on previous findings in the healthy subject sample. MS patients showed a smaller maximum theta power increase in the right hippocampus between 0 and 400 ms than healthy subjects (p = .014). This theta power increase value correlated negatively with reaction time on the task in MS (r = -.32, p = .029). Evidence was provided that this relationship could not be explained by a 'common cause' confounding relationship with MS-related neuronal damage. This study provides the first neurophysiological evidence of the influence of hippocampal dysfunction on WM performance in MS.


Three-dimensional organization of the glomeruli in the antennal lobe of the parasitoid wasps Cotesia glomerata and C. rubecula.
Two closely related parasitoid wasp species, Cotesia glomerata and C. rubecula, differ in their use of associative learning. To investigate the neural basis underlying these differences, it is necessary to describe the olfactory pathway of both wasp species. This paper focuses on the organization of the glomeruli in the antennal lobe. Glomeruli were stained by retrograde axon tracing of all axons in the antennal nerve and observed by confocal laser scanning microscopy. Stacks of optical sections were processed with AMIRA software, and 3D digital models of the glomeruli were produced. The combined use of 2D images and 3D surface models of the antennal lobes enabled the identification of a set of corresponding glomeruli in both wasp species. This offers unique opportunities for the study of subtle differences involved in synaptic plasticity that may occur at the glomerular level and factors regulating this plasticity.


Intra-pulmonary arteriovenous anastomoses and pulmonary gas exchange: evaluation by microspheres, contrast echocardiography and inert gas elimination.
Imaging techniques such as contrast echocardiography suggest that anatomical intra-pulmonary arteriovenous anastomoses (IPAVAs) are present at rest and are recruited to a greater extent in conditions such as exercise. IPAVAs have the potential to act as a shunt, although gas exchange methods have not demonstrated significant shunt in the normal lung. To evaluate this discrepancy, we compared anatomical shunt with 25-µm microspheres to contrast echocardiography, and gas exchange shunt measured by the multiple inert gas elimination technique (MIGET). Intra-pulmonary shunt measured by 25-µm microspheres was not significantly different from gas exchange shunt determined by MIGET, suggesting that MIGET does not underestimate the gas exchange consequences of anatomical shunt. A positive agitated saline contrast echocardiography score was associated with anatomical shunt measured by microspheres. Agitated saline contrast echocardiography had high sensitivity but low specificity to detect a ≥1% anatomical shunt, frequently detecting small shunts inconsequential for gas exchange. The echocardiographic visualization of transpulmonary agitated saline microbubbles suggests that anatomical intra-pulmonary arteriovenous anastomoses are recruited during exercise, in hypoxia, and when cardiac output is increased pharmacologically. However, the multiple inert gas elimination technique (MIGET) shows insignificant right-to-left gas exchange shunt in normal humans and canines. To evaluate this discrepancy, we measured anatomical shunt with 25-µm microspheres and compared the results to contrast echocardiography and MIGET-determined gas exchange shunt in nine anaesthetized, ventilated canines. Data were acquired under the following conditions: (1) at baseline, (2) 2 µg kg-1 min-1 i.v. dopamine, (3) 10 µg kg-1 min-1 i.v. dobutamine, and (4) following creation of an intra-atrial shunt (in four animals). Right to left anatomical shunt was quantified by the number of 25-µm microspheres recovered in systemic arterial blood. Ventilation-perfusion mismatch and gas exchange shunt were quantified by MIGET and cardiac output by direct Fick. Left ventricular contrast scores were assessed by agitated saline bubble counts, and separately by appearance of 25-µm microspheres. Across all conditions, anatomical shunt measured by 25-µm microspheres was not different from gas exchange shunt measured by MIGET (microspheres: 2.3 ± 7.4%; MIGET: 2.6 ± 6.1%, P = 0.64). Saline contrast bubble score was associated with microsphere shunt (ρ = 0.60, P < 0.001). Agitated saline contrast score had high sensitivity (100%) to detect a ≥1% shunt, but low specificity (22-48%). Gas exchange shunt by MIGET does not underestimate anatomical shunt measured using 25-µm microspheres. Contrast echocardiography is extremely sensitive, but not specific, often detecting small anatomical shunts which are inconsequential for gas exchange.


Conscientiousness and obsessive-compulsive personality disorder.
A dimensional perspective on personality disorder hypothesizes that the current diagnostic categories represent maladaptive variants of general personality traits. However, a fundamental foundation of this viewpoint is that dimensional models can adequately account for the pathology currently described by these categories. While most of the personality disorders have well established links to dimensional models that buttress this hypothesis, obsessive-compulsive personality disorder (OCPD) has obtained only inconsistent support. The current study administered multiple measures of 1) conscientiousness-related personality traits, 2) DSM-IV OCPD, and 3) specific components of OCPD (e.g., compulsivity and perfectionism) to a sample of 536 undergraduates who were oversampled for elevated OCPD scores. Six existing measures of conscientiousness-related personality traits converged strongly with each other supporting their assessment of a common trait. These measures of conscientiousness correlated highly with scales assessing specific components of OCPD, but obtained variable relationships with measures of DSM-IV OCPD. More specifically, there were differences within the conscientiousness instruments such that those designed to assess general personality functioning had small to medium relationships with OCPD, but those assessing more maladaptive variants obtained large effect sizes. These findings support the view that OCPD does represent a maladaptive variant of normal-range conscientiousness.


Mesenchymal stem cells inhibit thymic reconstitution after allogeneic cord blood transplantation.
Cord blood (CB) as a source of stem cells has been a successful addition to the field of allogeneic stem cell transplantation (ASCT). The increased human leukocyte antigen (HLA) permissiveness of CB grafts has made it possible for more patients to undergo treatment. The drawback is that patients suffer from a longer period of compromised immunity. We analyzed T-cell receptor excision circles (TRECs), immunoglobulin G (IgG), and immunoglobulin M (IgM) levels after cord blood transplantation (CBT) in 50 patients transplanted at our center. These immunological parameters were compared retrospectively with clinical factors and complications. We found that TREC levels after CBT were lower in adults, patients with myeloablative conditioning, and in patients with a lower nucleated cell dose in the graft. In addition mesenchymal stem cells (MSC) as co-infusion at the time of CBT had a negative effect on TREC reconstitution. This was found to be associated with decreased overall survival for this patient category. Reduced IgM and IgG levels post-CBT were associated with a major AB0 mismatch, and infusion of MSCs. Our results highlight the importance of close monitoring of the immune reconstitution after CBT. In addition it shows a potentially new suppressive effect of MSCs on the immune system.


Block excision of cystic and diffuse epithelial ingrowth of the anterior chamber. Report on 32 consecutive patients.
From 1980 to 1990, 32 consecutive patients with progressive cystic or diffuse epithelial ingrowth of the anterior chamber were treated successfully with block excision. This technique consists of simultaneous removal of adjacent iris, pars plicata of ciliary body, and all layers of sclera and cornea in contact with the lesion acting as a shell. The resulting defect is covered by a tectonic corneoscleral graft. Twelve patients had suffered from perforating ocular injury, 10 patients had previously undergone cataract extraction, and 10 patients had various causes of epithelial ingrowth. Cystic epithelial ingrowth occurred in 27 patients, diffuse sheetlike epithelial ingrowth occurred in four patients, and one lesion was identified as foreign body granuloma. On histopathologic examination, all but two patients revealed epithelial involvement of the surface of the ciliary body. All patients were followed up for an average of 60.1 months (range, 1 to 120 months). Long-term visual acuity was better than 20/60 in 37.5% of the patients. No recurrence of ingrowth was noted and enucleation was not necessary. Our results indicate that block excision currently may be the treatment of choice for cystic and diffuse sheetlike epithelial ingrowth of the anterior chamber.


Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected].
In the 1970s, survival rates after treatment for acute lymphoblastic leukaemia (ALL) in children and young adults (less than 25 years) in India were poor, even in specialised cancer centres. The introduction of a standard treatment protocol (MCP841) and improvements in supportive care in three major cancer centres in India led to an increase in the event-free survival rate (EFS) from less than 20% to 45-60% at 4 years. Results of treatment with protocol MCP841 between 1984 and 1990 have been published and are briefly reviewed here. In addition, previously unpublished data from 1048 patients treated between 1990 and 1997 are reported. Significant differences in both patient populations and treatment outcome were noted among the centres. In one centre, a sufficiently large number of patients were treated each year to perform an analysis of patient characteristics and outcome over time. Although steady improvement in outcome was observed, differences in the patient populations in the time periods examined were also noted. Remarkably, prognostic factors common to all three centres could not be defined. Total white blood cell count (WBC) was the only statistically significant risk factor identified in multivariate analyses in two of the centres. Age is strongly associated with outcome in Western series, but was not a risk factor for EFS in any of the centres. Comparison of patient characteristics with published series from Western nations indicated that patients from all three Indian centres had more extensive disease at presentation, as measured by WBC, lymphadenopathy and organomegaly. The proportions of ALLs with precursor T-cell immunophenotypes, particularly in Chennai, were also increased, even when differences in the age distribution were taken into consideration (in <18-year olds, the range was 21.1-42.7%), and in molecular analyses performed on leukaemic cells from over 250 patients less than 21-years-old with precursor B-cell ALL, a lower frequency of TEL-AML1-positive ALL cases than reported in Western series was observed. The worse outcome of treatment in Indian patients compared with recent Western series was probably due to the higher rate of toxic deaths in the Indian patients, and possibly also due to their more extensive disease - which is, at least partly, a consequence of delay in diagnosis. Differences in the spectrum of molecular subtypes may also have played a role. The higher toxic death rates observed are likely to have arisen from a combination of more extensive disease at diagnosis, co-morbidities (e.g., intercurrent infections), differences in the level of hygiene achievable in the average home, poor access to acute care, and more limited supportive care facilities in Indian hospitals. Toxic death was not associated with WBC at presentation, and hence would tend to obscure the importance of this, and, potentially, other risk factors, as prognostic indicators. Since the prevalence of individual risk factors varies in different populations and over time, their relative importance would also be expected to vary in different centres and in different time periods. This was, in fact, observed. These findings have important implications for the treatment of ALL in countries of low socioeconomic status; it cannot be assumed that risk factors defined in Western populations are equally appropriate for patient assignment to risk-adapted therapy groups in less affluent countries. They also demonstrate that heterogeneity in patient populations and resources can result in significant differences in outcome, even when the same treatment protocol is used. This is often overlooked when comparing published patient series.


Effect of dietary fats with odd or even numbers of carbon atoms on metabolic response and muscle damage with exercise in Quarter Horse-type horses with type 1 polysaccharide storage myopathy.
To evaluate effects of fats with odd and even numbers of carbon atoms on muscle metabolism in exercising horses with polysaccharide storage myopathy (PSSM). 8 horses with PSSM (6 females and 2 males; mean +/- SD age, 6.3 +/- 3.9 years). Isocaloric diets (grain, triheptanoin, corn oil, and high-fat, low-starch [HFLS] feed) were fed for 3 weeks each; horses performed daily treadmill exercise. Grain was fed to establish an exercise target, and HFLS feed was fed as a negative control diet. Daily plasma samples were obtained. For each diet, a 15-minute exercise test was performed, and gluteus medius muscle specimens and blood samples were obtained before and after exercise. Feeding triheptanoin, compared with the corn oil diet, resulted in exercise intolerance; higher plasma creatine kinase (CK) activity and concentrations of C3:0- and C7:0-acylcarnitine and insulin; and lower concentrations of nonesterified fatty acids (NEFA) and C16:0-, C18:1-, and C18:2-acylcarnitine, without changes in concentrations of plasma glucose or resting muscle substrates and metabolites. Feeding grain induced higher CK activity and insulin concentrations and lower NEFA concentrations than did corn oil or HFLS feed. Feeding grain induced higher glucose concentrations than did triheptanoin and corn oil. In muscle, feeding grain resulted in lower glucose-6-phosphate, higher citrate, and higher postexercise lactate concentrations than did the other diets. Triheptanoin had detrimental effects, reflecting decreased availability of NEFA, increased insulin stimulation of glycogen synthesis, and potential inhibition of lipid oxidation. Long-chain fats are the best dietetic for PSSM.


The negative regulation of red cell mass by neocytolysis: physiologic and pathophysiologic manifestations.
We have uncovered a physiologic process which negatively regulates the red cell mass by selectively hemolyzing young circulating red blood cells. This allows fine control of the number of circulating red blood cells under steady-state conditions and relatively rapid adaptation to new environments. Neocytolysis is initiated by a fall in erythropoietin levels, so this hormone remains the major regulator of red cell mass both with anemia and with red cell excess. Physiologic situations in which there is increased neocytolysis include the emergence of newborns from the hypoxic uterine environment and the descent of polycythemic high-altitude dwellers to sea level. The process first became apparent while investigating the mechanism of the anemia that invariably occurs after spaceflight. Astronauts experience acute central plethora on entering microgravity resulting in erythropoietin suppression and neocytolysis, but the reduced blood volume and red cell mass become suddenly maladaptive on re-entry to earth's gravity. The pathologic erythropoietin deficiency of renal disease precipitates neocytolysis, which explains the prolongation of red cell survival consistently resulting from erythropoietin therapy and points to optimally efficient erythropoietin dosing schedules. Implications should extend to a number of other physiologic and pathologic situations including polycythemias, hemolytic anemias, 'blood-doping' by elite athletes, and oxygen therapy. It is likely that erythropoietin influences endothelial cells which in turn signal reticuloendothelial phagocytes to destroy or permit the survival of young red cells marked by surface molecules. Ongoing studies to identify the molecular targets and cytokine intermediaries should facilitate detection, dissection and eventual therapeutic manipulation of the process.


25-gauge microincision vitrectomy to treat vitreoretinal disease in glaucomatous eyes after trabeculectomy.
Purpose. To determine the feasibility of using 25-gauge microincision vitrectomy surgery (25GMIVS) to treat vitreoretinal disease in glaucomatous eyes which have previously undergone trabeculectomy (TLE). Methods. A consecutive, interventional case series. We performed 25GMIVS in 15 glaucomatous eyes that had undergone TLE. Follow-up period was 11.5 months. Results. 25GMIVS was successfully used and led to improvement in visual acuity (P < 0.01). We performed 25GMIVS for proliferative diabetic retinopathy with neovascular glaucoma in 53% of eyes (8 of 15). Although 3 eyes needed further TLE following 25GMIVS, final IOP was below 21 mmHg in all eyes except one eye (93%) and was comparable to pre-25GMIVS IOP (P = 0.20) without an increase in the number of glaucoma medications (P = 0.14). Conclusions. 25GMIVS is a feasible treatment for vitreoretinal disease in eyes with preexisting TLE, effective in both significantly improving BCVA and preserving the filtering bleb, while not excluding further glaucoma surgery.


The arg2 gene of Trichoderma virens: cloning and development of a homologous transformation system.
The arg2 gene which encodes the small subunit of carbamoyl phosphate synthetase for Trichoderma virens has been cloned and used to develop a homologous transformation system. A genomic clone containing the arg2 gene was isolated from a cosmid library of T. virens based on complementation of an arginine auxotrophic mutant of this fungus. The predicted amino acid sequence of the arg2 gene shows 56-82% identity with homologous polypeptides from other fungi. It also contains an upstream open reading frame which encodes 24 amino acids. As is observed with other gene sequences encoding this polypeptide in filamentous fungi, the N-terminus of the predicted polypeptide showed characteristic features of a mitochondrial signal sequence. The arg2 gene was used for genetic transformation of T. virens in frequencies of up to 370 transformants/microgram of DNA. Heat-shock treatment of T. virens protoplasts increased the transformation frequency by fivefold, but more than 85% of the transformants were abortive. Both single-copy, homologous integration events and ectopic, non-homologous integration events were detected by Southern analyses of genomic DNA from transformed strains.


Diagnostic Performance of Carbon Monoxide Testing by Pulse Oximetry in the Emergency Department.
Carbon monoxide (CO) exposure causes roughly 40,000 emergency department (ED) visits annually and is commonly misdiagnosed. Whereas the standard method of carboxyhemoglobin (HbCO) measurement utilizes blood gas analysis, a noninvasive, FDA-cleared alternative exists. We evaluated the performance of pulse oximetry (SpCO) for identification of CO exposure in ED patients. We compared pulse oximetry to blood HbCO levels in a prospective observational study of adult and pediatric subjects recruited from the ED. Nurses screened a convenience sample of patients and referred those with SpCO ≥ 10% to research staff. Researchers also approached individuals who presented with signs and symptoms of CO toxicity. We determined diagnostic performance with a Bland-Altman analysis and calculated sensitivity and specificity for detection of elevated HbCO at thresholds of ≥ 10% and ≥ 15%. To optimize the potential sensitivity of SpCO for detection of CO toxicity, research technicians performed 3 SpCO readings within 5 min of the blood draw for laboratory measurement. A positive SpCO test was defined as any SpCO ≥ 10%. 42,000 patients were screened, 212 were evaluated, and 126 subjects were enrolled. Median HbCO level was 6% (range 1.6-21.9%). Limits of agreement were -10.3% and 8.1%. Of 23 individuals with elevated HbCO ≥ 10%, 13 were not suspected based on clinical assessment. Critically elevated HbCO was present in 6 individuals. Based on our a priori threshold of 10% for a positive test, pulse oximetry identified 14 of 23 subjects with HbCO ≥ 10%, with a sensitivity of 61% (95% CI 39-80%) and a specificity of 86% (95% CI 78-92%), and 5 of 6 subjects with HbCO ≥ 15%, with a sensitivity of 83% (95% CI 36-100%) and a specificity of 81% (95% CI 73-87%). Pulse oximetry underestimated HbCO and produced false negative results (ie, SpCO < 10% for all three measurements) in 17% of ED subjects with elevated HbCO ≥ 15%. Triage screening with pulse oximetry detected cases of elevated HbCO that were not suspected by the clinical provider.


Neandertal and Denisovan DNA from Pleistocene sediments.
Although a rich record of Pleistocene human-associated archaeological assemblages exists, the scarcity of hominin fossils often impedes the understanding of which hominins occupied a site. Using targeted enrichment of mitochondrial DNA, we show that cave sediments represent a rich source of ancient mammalian DNA that often includes traces of hominin DNA, even at sites and in layers where no hominin remains have been discovered. By automation-assisted screening of numerous sediment samples, we detected Neandertal DNA in eight archaeological layers from four caves in Eurasia. In Denisova Cave, we retrieved Denisovan DNA in a Middle Pleistocene layer near the bottom of the stratigraphy. Our work opens the possibility of detecting the presence of hominin groups at sites and in areas where no skeletal remains are found.


[Relation of echogenicity to the angle of incidence on musculature and tendon tissue].
Echogenic structures of the locomotor system are demonstrated with many or few echoes, depending on the angle at which ultrasound waves strike them. This causes a graduation in the demonstration of arcuate tendons in different planes, from dense to sparse echoes (the former in the case of portions perpendicular to the angle of incidence of the ultrasound waves, the latter in the case of portions which the waves strike at a slanting angle). This phenomenon occurs with arcuate tendons and is known as the "deflection phenomenon." It must be taken into account when assessing structural changes in tendons in order to avoid misinterpretations. Similar conditions are found in the muscles. They are important in those groups of muscles which pass over major joints with changed courses or manifest pronounced pinnation with different courses of their septa. In the musculature, failure to take this phenomenon into account causes changes in echogenicity to be misinterpreted as ruptures or partial ruptures.


Twelve 43-base-pair repeats map in a cis-acting region essential for partition of plasmid mini-F.
The nucleotide sequence of the DNA region involved in partitioning of plasmid mini-F has been determined. The sequence consists of 12 direct tandemly arranged repeats of 43 base pairs (the two flanking repeats, 43 plus 1 base pairs) with extensive homology to each other. Each repeat contains an additional inverted repeat of 7 base pairs.


Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor.
Transforming growth factor (TGF)-beta is produced in most human tumors and markedly inhibits tumor antigen-specific cellular immunity, representing a major obstacle to the success of tumor immunotherapy. TGF-beta is produced in Epstein-Barr virus (EBV)-positive Hodgkin disease and non-Hodgkin lymphoma both by the tumor cells and by infiltrating T-regulatory cells and may contribute the escape of these tumors from infused EBV-specific T cells. To determine whether tumor antigen-specific cytotoxic T lymphocytes (CTLs) can be shielded from the inhibitory effects of tumor-derived TGF-beta, we previously used a hemagglutinin-tagged dominant negative TGF-betaRII expressed from a retrovirus vector to provide CTLs with resistance to the inhibitory effects of TGF-beta in vitro. We now show that human tumor antigen-specific CTLs can be engineered to resist the inhibitory effects of tumor-derived TGF-beta both in vitro and in vivo using a clinical grade retrovirus vector in which the dominant negative TGF-beta type II receptor (DNRII) was modified to remove the immunogenic hemagglutinin tag. TGF-beta-resistant CTL had a functional advantage over unmodified CTL in the presence of TGF-beta-secreting EBV-positive lymphoma, and had enhanced antitumor activity, supporting the potential value of this countermeasure.


Nanodiamonds for field emission: state of the art.
The aim of this review is to highlight the recent advances and the main remaining challenges related to the issue of electron field emission (FE) from nanodiamonds. The roadmap for FE vacuum microelectronic devices envisages that nanodiamonds could become very important in a short time. The intrinsic properties of the nanodiamond materials indeed meet many of the requirements of cutting-edge technologies and further benefits can be obtained by tailored improvements of processing methodologies. The current strategies used to modulate the morphological and structural features of diamond to produce highly performing emitting systems are reported and discussed. The focus is on the current understanding of the FE process from nanodiamond-based materials and on the major concepts used to improve their performance. A short survey of non-conventional microsized cold cathodes based on nanodiamonds is also reported.


Robot-Assisted Surgery and Racial and Ethnic Disparities in Post-Prostatectomy Outcomes Among Prostate Cancer Patients.
We sought to determine whether the differences in short-term outcomes between patients undergoing robot-assisted radical prostatectomy (RARP) and those treated with open radical prostatectomy (ORP) differ by race and ethnicity. This observational study used New York State Cancer Registry data linked to discharge records and included patients undergoing radical prostatectomy for localized prostate cancer during 2008-2018. We used logistic regression to examine the association between race and ethnicity (non-Hispanic White [NHW], non-Hispanic Black [NHB], Hispanic), surgical approach (RARP, ORP), and postoperative outcomes (major events, prolonged length of stay [pLOS], 30-day re-admission). We tested interaction between race and ethnicity and surgical approach on multiplicative and additive scales. The analytical cohort included 18,926 patients (NHW 14,215 [75.1%], NHB 3195 [16.9%], Hispanic 1516 [8.0%]). The average age was 60.4 years (standard deviation 7.1). NHB and Hispanic patients had lower utilization of RARP and higher risks of postoperative adverse events than NHW patients. NHW, NHB, and Hispanic patients all had reduced risks of adverse events when undergoing RARP versus ORP. The absolute reductions in the risks of major events and pLOS following RARP versus ORP were larger among NHB {relative excess risk due to interaction (RERI): major events -0.32 [95% confidence interval (CI) -0.71 to -0.03]; pLOS -0.63 [95% CI -0.98 to -0.35]) and Hispanic (RERI major events -0.27 [95% CI -0.77 to 0.09]; pLOS -0.93 [95% CI -1.46 to -0.51]) patients than among NHW patients. The interaction was absent on the multiplicative scale. RARP use has not penetrated and benefited all racial and ethnic groups equally. Increasing utilization of RARP among NHB and Hispanic patients may help reduce disparities in patient outcomes after radical prostatectomy.


Reporting results from whole-genome and whole-exome sequencing in clinical practice: a proposal for Canada?
This article proposes recommendations for the use of whole-genome and whole-exome (WGS/WES) sequencing in clinical practice, endorsed by the board of directors of the Canadian College of Medical Geneticists. The publication of statements and recommendations by several international and national organisations on clinical WGS/WES has prompted a need for Canadian-specific guidance. A multi-disciplinary group consisting of lawyers, ethicists, genetic researchers, and clinical geneticists was assembled to review existing guidelines on WGS/WES and identify provisions relevant to the Canadian context. Definitions were provided to orient the recommendations and to minimize confusion with other recommendations. Recommendations include the following: WGS/WES should be used in a judicious and cost-efficient manner; WGS/WES should be used to answer a clinical question; and physicians need to explain to adult patients the nature of the results that could arise, so as to allow them to make informed choices over whether to take the test and which results they wish to receive. Recommendations are also provided for WGS/WES in the pediatric context, and for when results implicate patients' family members. These recommendations are only a proposal to be developed into comprehensive Canadian-based guidelines. They aim to promote discussion about the reporting of WGS/WES results, and to encourage the ethical implementation of these new technologies in the clinical setting.


Displacement of the Mandibular Condyles Immediately after Herbst Appliance Insertion - 3D Assessment.
To test the following two hypotheses regarding the consequences of Herbst appliance (HA) insertion: 1) a significant clockwise mandibular rotation will occur and 2) the displacement of the condyles will follow the same magnitude of the changes of overjet (OJ) and overbite (OB). Virtual 3D surface models of 25 patients were generated from cone-beam computed tomographs taken before treatment and immediately after HA insertion. Scans were registered on the cranial base and were analyzed using point-to-point measurements, color-coded maps, and semitransparent overlays. Statistical tests included correlation and simple regression analysis. Pitch rotation, ranging from -2.2° to 2.2° (mean, 0.2°), was observed in clockwise and counterclockwise directions. Condylar sagittal displacement presented a positive correlation with OJ changes. Each millimeter of OJ correction resulted in an anterior condylar displacement of approximately 0.95 mm. Vertical condylar displacement correlated with OB changes and varied mostly between 2 mm and 4.5 mm. Immediately after HA insertion, no significant clockwise mandibular rotation was observed. The condyles were displaced anteriorly and inferiorly. Condylar anterior displacement and OJ correction presented a ratio close to 1:1. The vertical displacement of the condyles did not follow the same magnitude of OB changes.


Epileptic qualia and self-awareness: a third dimension for consciousness.
Over the last few decades, there has been increasing awareness among epileptologists about the need to refine our understanding and assessment of ictal consciousness, focusing on both subjective and behavioral aspects of seizures. Specifically, there have been suggestions that both the internal and external milieux - the former related to the phenomenal qualia of experience, the latter related to behavior - must be taken into account for a better understanding of altered states of consciousness in epilepsy. It has been proposed that clinical and experimental data from patients experiencing alterations of consciousness during epileptic seizures could be better understood within a bidimensional model, in which any manifestation of conscious experience can be plotted according to the level and contents of consciousness. The 'level' axis measures the degree of alertness/arousal, whereas the 'contents' axis measures the vividness of specific experiential phenomena reported by the patient. We argue that certain seizure types might require more rigorous conceptual models for their characterization, and we highlight the potential usefulness of a more refined framework which includes a further dimension related to the 'self', in addition to those of 'level' and 'contents'. This model could be visualized in a three-dimensional space to allow fine-grained distinctions between epileptic seizures.


Regional Variation of Bitter Taste and Aftertaste in Humans.
Despite widespread and persistent myths of a tongue map, all 5 prototypical taste qualities are sensed over the entire tongue. However, modern psychophysical data also suggest there may be more nuanced differences in suprathreshold intensity across oral loci, especially for bitterness. Here, we test whether bitter stimuli matched for whole-mouth intensity differ in perceived intensity across regions of the oral cavity in 2 experiments. Experiment 1 consisted of a whole-mouth sip and spit approach and Experiment 2 consisted of a spatial taste test using cotton swabs. In Experiment 1, participants (n = 63) rated overall intensity of 3 bitter solutions at 5 different loci (front, middle, back of tongue; roof of mouth; and lip). Temporal effects were explored using in-mouth and aftertaste ratings. In Experiment 2, participants (n = 48) rated the intensity of quinine and Tetralone solutions after solutions were painted on fungiform, circumvallate, and foliate papillae with a swab. After the spatial taste test, participants completed a questionnaire on self-reported beer intake. Analysis of variance results of both experiments show a significant locus by stimulus interaction, suggesting different bitterants were perceived differently across the various loci. This result was apparently driven by low-intensity ratings for Tetralone on the anterior tongue. Aftertaste ratings in Experiment 1 also revealed significant temporal effects: ratings on the anterior tongue decreased for all bitterants and ratings for quinine decreased at all loci. Reasons for these effects are not known but may suggest differential expression of bitter taste receptors or differences in bitter agonist-receptor binding affinity across tongue regions.


Code of ethics for the American Association of Physicists in Medicine (Revised): Report of Task Group 109.
The American Association of Physicists in Medicine (AAPM) has established a comprehensive Code of Ethics for its members. The Code is a formal part of AAPM governance, maintained as Professional Policy 24, and includes both principles of ethical practice and the rules by which a complaint will be adjudicated. The structure and content of the Code have been crafted to also serve the much broader purpose of giving practical ethical guidance to AAPM members for making sound decisions in their professional lives. The Code is structured in four major parts: a Preamble, a set of ten guiding Principles, Guidelines that elucidate the application of the Principles in various practice settings, and the formal Complaint process. Guidelines have been included to address evolving social and cultural norms, such as the use of social media and the broadening scope of considerations important in an evolving workplace. The document presented here is the first major revision of the AAPM Code of Ethics since 2008. This revision was approved by the Board of Directors to become effective 1 January 2019.


Prospective Relationships Between Ethnic Discrimination and Substance Use by Mexican-American Adolescents.
Guided by the integrative model (García Coll et al., 1996), this study examines prospective associations between perceived ethnic discrimination by peers, parental support, and substance use from 7th to 11th grades (Mage = 12.3-16.3 years) in a community sample of 674 Mexican-American adolescents. Results from a cross-lagged panel model indicate that discrimination predicts relative increases in adolescent substance use. Results also revealed a transactional relation between substance use and supportive parenting over time. Supportive parenting was associated with reductions in substance use, but adolescent substance use also predicted lower levels of later parental support. The findings suggest reducing discrimination by peers and supportive parenting as potential targets for intervention in the prevention of substance use.


Different antidiabetic regimens and the development of renal dysfunction in US Veterans with type 2 diabetes mellitus.
The aim of this study was to evaluate the development of renal dysfunction in veterans with type 2 diabetes mellitus (T2DM) treated with different antidiabetic regimens. A retrospective cohort study involving 1715 patients with T2DM and baseline serum creatinine (SCr) of 1.5 mg/dL or lesser. The development of renal dysfunction, defined as 0.5 mg/dL or greater increase from baseline SCr during 4.8 years of follow-up with monotherapy metformin (M), 2 combination therapy groups: metformin + insulin (MI) and metformin + sulfonylurea (MS) users were compared with changes observed in sulfonylurea monotherapy users (S). Both MI and MS groups had higher mean baseline hemoglobin A1C (HbA1C) (9.0 and 8.6%, respectively) and higher rates of baseline macroalbuminuria (17.3 and 12.1%, respectively) as compared with M and S groups (mean HbA1C7.7% in both groups, and proteinuria M-5.1% and S-7.4%). In unadjusted analysis, the development of renal dysfunction was more frequent in MI and MS but not in M group as compared with sulfonylurea monotherapy (unadjusted HRs and [95% confidence interval (CI), 2.1[1.4-3.0], 1.4[1.1-1.9], and 1.0[0.6-1.7], respectively). However, differences in the development of renal dysfunction were not significant between the 4 groups after adjusting for baseline variables. Baseline macroalbuminuria was a strong predictor of Scr elevation of 0.5 mg/dL or greater during follow-up (adjusted HR, 3.1[1.9-4.7]). Unexpectedly, baseline use of renin-angiotensin-aldosterone system blockers was also associated with the development of renal dysfunction (adjusted HR, 1.9[1.3-2.8]). In this retrospective cohort study involving US predominantly male veterans with T2DM, baseline macroalbuminuria and use of RAAS blockers were associated with increased risk of development of renal dysfunction, whereas different antidiabetic regimens were not.


HIV infection in vitro enhances the activity of src-family protein tyrosine kinases.
We examined the effect of HIV infection on src-family protein tyrosine kinase (PTK) activity to determine if alterations in src-family PTK activity could contribute to the HIV-related chronic immune system activation observed in patients infected with HIV. Jurkat, a CD4+ human T lymphocyte cell line was infected with HIV IIIB. Kinase activity was determined by in vitro immune complex kinase assays using antibodies specific for the src-family PTKs, p56lck, p59fyn and p60c-src expressed in T lymphocytes. PTK protein and total phosphotyrosine levels were assessed by Western blotting. The role of the gp120-CD4-Lck interaction in HIV-related PTK activation was determined using gp 120-treated Jurkat cells and HIV-infection of JCaM 1.6 cells, a Jurkat-derived cell line that lacks p56lck. Cells infected with HIV for 24 h exhibited increased levels of total tyrosine phosphorylation and enhanced src-family PTK activity without altered levels of expression of src-family kinases. The activity of Lck and Fyn was enhanced within 30 min of infection. HIV-related src-family PTK activation was not a function of the gp120-CD4-Lck interaction and occurred in the presence of 10 mmol/l zidovudine indicating that reverse transcriptase and activation of the HIV genome is not required. HIV-related activation of src-family PTK is a response of the cell to early stages of the virus life cycle, possibly either membrane fusion or viral uncoating. These results indicate that endogenous src-family PTKs may play a role in HIV-related immune activation and dysfunction. Moreover, activation of src-family PTK may be a mechanism used by the virus to facilitate some aspect of its own life cycle.


Histamine receptors and antihistamines: from discovery to clinical applications.
The synthesis and the identification of histamine marked a milestone in both pharmacological and immunological research. Since Sir Henry Dale and Patrick Laidlaw described some of its physiological effects in vivo in 1910, histamine has been shown to play a key role in the control of gastric acid secretion and in allergic disorders. Using selective agonists and antagonists, as well as molecular biology tools, four histamine receptors (H1R, H2R, H3R and H4R) have been identified. The Nobel Prize in Physiology and Medicine was awarded to Daniel Bovet in 1957 for the discovery of antihistamines (anti-H1R) and to Sir James Black in 1988 for the identification of anti-H2R antagonists. Anti-H1R and anti-H2R histamine receptor antagonists have revolutionized the treatment of certain allergic disorders and gastric acid-related conditions, respectively. More recently, anti-H3R antagonists have entered early-phase clinical trials for possible application in obesity and a variety of neurologic disorders. The preferential expression of H4R by several immune cells and its involvement in the development of allergic inflammation provide the rationale for the use of anti-H4R antagonists in allergic and in other immune-related disorders.


Bioactive glass BAG-S53P4 for the adjunctive treatment of chronic osteomyelitis of the long bones: an in vitro and prospective clinical study.
This study aimed to explore the in vitro antibacterial activity of the bioglass BAG S53P4 against multi-resistant microorganisms commonly involved in osteomyelitis and to evaluate its use in surgical adjunctive treatment of osteomyelitis. In vitro antibacterial activity of BAG-S53P4 against methicillin resistant Staphylococcus aureus and Staphylococcus epidermidis, Pseudomonas aeruginosa and Acinetobacter baumannii isolates was evaluated by means of time kill curves, with colony counts performed after 24, 48 and 72 hours of incubation. In vivo evaluation was performed by prospectively studying a cohort of 27 patients with a clinically and radiologically diagnosed osteomyelitis of the long bones in an observational study. Endpoints were the absence of infection recurrence/persistence at follow-up, no need for further surgery whenever during follow-up and absence of local or systemic side effects connected with the BAG use. In vitro tests regarding the antibacterial activity of BAG S53P4 showed a marked bactericidal activity after 24 hrs against all the tested species. This activity continued in the subsequent 24 hrs and no growth was observed for all strains after 72 hrs. Results of the clinical study evidenced no signs of infection in 24 patients (88.9%) at the follow-up, while 2 subjects showed infection recurrence at 6 months from index operation and one more needed further surgical procedures. BAG-S53P4 was generally well tolerated. The in vitro and in vivo findings reinforce previous observations on the efficacy of BAG-S53P4 for the treatment of chronic osteomyelitis of the long bones, also in the presence of multi-resistant strains and in immunocompromised hosts, without relevant side effects and without the need for locally adding antibiotics. Deutschen Register Klinischer Studien (DRKS) unique identifier: DRKS00005332.


Providing alternative health care: an ancient system for a modern age.
Ayurveda, the oldest health care system in the world, has unique potential waiting to be exploited by the advanced practice nurse (APN) practicing in family health and primary care settings. The background, paradigm, interventions, scientific research, and strategies to implement Ayurveda in APN practice are explored. Although little is known about Ayurveda in Western cultures, it offers many health promotive interventions that can help the APN fulfill the needs of families who seek a level of wellness not offered by conventional medicine.


Cloning and identification of mouse steroid receptor coactivator-1 (mSRC-1), as a coactivator of peroxisome proliferator-activated receptor gamma.
Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor superfamily, is expressed predominantly in adipose tissue. Forced expression of the two isoforms of this receptor, PPARgamma1 and PPARgamma2, in fibroblasts initiates a transcriptional cascade that leads to the development of adipocyte phenotype. Using the yeast two-hybrid system and GAL4-PPARgamma as bait to screen mouse liver cDNA library, we isolated a mouse steroid receptor coactivator (mSRC-1) involved in nuclear hormone receptor transcriptional activity as a mPPARgamma interactive protein. mSRC-1 cDNA we isolated contains an open reading frame of 1447 amino acids and encodes a new member of the basic helix-loop-helix-PAS domain family. We show that the binding of mSRC-1 to mPPARgamma is ligand independent and coexpression of mSRC-1 with mPPARgamma increases the transcriptional activity of mPPARgamma in the presence of mPPARgamma ligand. We have identified the presence of two putative mPPARgamma binding sites in the mSRC-1, one between residues 620 and 789, and the second between residues 1231 and 1447. These two regions exhibit different degrees of binding affinity for mPPARgamma. We also show that mSRC-1 exhibits its own constitutive transcriptional activity in the yeast as well as in mammalian cells. These results suggest that mSRC-1 interacts with PPARgamma and plays a role in the PPARgamma-mediated signaling pathway.


Factors affecting implementation of accreditation programmes and the impact of the accreditation process on quality improvement in hospitals: a SWOT analysis.
The objectives of this review were to identify factors that influence implementation of hospital accreditation programmes and to assess the impact of the accreditation process on quality improvement in public hospitals. Two electronic databases, Medline (OvidSP) and PubMed, were systematically searched. "Public hospital", "hospital accreditation", and "quality improvement" were used as the search terms. A total of 348 citations were initially identified. After critical appraisal and study selection, 26 articles were included in the review. The data were extracted and analysed using a SWOT (strengths, weaknesses, opportunities, threats) analysis. Increased staff engagement and communication, multidisciplinary team building, positive changes in organisational culture, and enhanced leadership and staff awareness of continuous quality improvement were identified as strengths. Weaknesses included organisational resistance to change, increased staff workload, lack of awareness about continuous quality improvement, insufficient staff training and support for continuous quality improvement, lack of applicable accreditation standards for local use, and lack of performance outcome measures. Opportunities included identification of improvement areas, enhanced patient safety, additional funding, public recognition, and market advantage. Threats included opportunistic behaviours, funding cuts, lack of incentives for participation, and a regulatory approach to mandatory participation. By relating the findings to the operational issues of accreditation, this review discussed the implications for successful implementation and how accreditation may drive quality improvement. These findings have implications for various stakeholders (government, the public, patients and health care providers), when it comes to embarking on accreditation exercises.


Zebrafish for the study of the biological effects of nicotine.
Zebrafish are emerging as a powerful animal model for studying the molecular and physiological effects of nicotine exposure. The zebrafish have many advantageous physical characteristics, including small size, high fecundity rates, and externally developing transparent embryos. When combined with a battery of molecular-genetic tools and behavioral assays, these attributes enable studies to be conducted that are not practical using traditional animal models. We reviewed the literature on the application of the zebrafish model as a preclinical model to study the biological effects of nicotine exposure. The identified studies used zebrafish to examine the effects of nicotine exposure on early development, addiction, anxiety, and learning. The methods used included green fluorescent protein-labeled proteins to track in vivo nicotine-altered neuron development, nicotine-conditioned place preference, and locomotive sensitization linked with high-throughput molecular and genetic screens and behavioral models of learning and stress response to nicotine. Data are presented on the complete homology of all known human neural nicotinic acetylcholine receptors in zebrafish and on the biological similarity of human and zebrafish dopaminergic signaling. Tobacco dependence remains a major health problem worldwide. Further understanding of the molecular effects of nicotine exposure and genetic contributions to dependence may lead to improvement in patient treatment strategies. While there are limitations to the use of zebrafish as a preclinical model, it should provide a valuable tool to complement existing model systems. The reviewed studies demonstrate the enormous opportunity zebrafish have to advance the science of nicotine and tobacco research.


The relationship between level of knowledge and vaginal discharge prevention behavior for nursing student.
Reproductive health in adolescent girls is very important. To determine the relationship between the level of knowledge and the behavior of preventing vaginal discharge among nursing students. a quantitative, cross-sectional study, with 155 first-year female students at a private faculty of nursing. Data were collected from February to March 2022, using an electronic questionnaire. 98.1% of participants have a good level of knowledge and 92.3% of participants practice good vaginal discharge prevention behavior. good knowledge produces appropriate prevention behavior. The result of this study can be used as a contribution of thoughts and references as a more in-depth study of the factors that influence the level of knowledge and behavior about the disease of the genitalia and the dangers of pathological vaginal discharge.


Potential benefits of pH 8.8 alkaline drinking water as an adjunct in the treatment of reflux disease.
At the cellular level, tissue-bound pepsin is fundamental to the pathophysiologic mechanism of reflux disease, and although the thresholds for laryngeal damage in laryngopharyngeal reflux and for esophageal damage in gastroesophageal reflux disease differ, both forms of damage are due to pepsin, which requires acid for its activation. In addition, human pepsin remains stable at pH 7.4 and may be reactivated by hydrogen ions from any source. Thus, most tap and bottled waters (typically pH 6.7 to 7.4) would not be expected to affect pepsin stability. The purposes of these in vitro studies were to investigate whether artesian well water containing natural bicarbonate (pH 8.8) might irreversibly denature (inactivate) human pepsin, and to establish its potential acid-buffering capacity. Laboratory studies were performed to determine whether human pepsin was inactivated by pH 8.8 alkaline water. In addition, the buffering capacity of the alkaline water was measured and compared to that of the two most popular commercially available bottled waters. The pH 8.8 alkaline water irreversibly inactivated human pepsin (in vitro), and its hydrochloric acid-buffering capacity far exceeded that of the conventional-pH waters. Unlike conventional drinking water, pH 8.8 alkaline water instantly denatures pepsin, rendering it permanently inactive. In addition, it has good acid-buffering capacity. Thus, the consumption of alkaline water may have therapeutic benefits for patients with reflux disease.


Summary of ICD-9-CM Coordination and Maintenance Committee meeting.
The ICD-9-CM Coordination and Maintenance Committee, cosponsored by the National Center for Health Statistics (NCHS) and the Health Care Financing Administration (HCFA), recently met in Baltimore, MD. Donna Pickett, RRA (NCHS), and Patricia Brooks, RRA (HCFA), cochaired the meeting. Proposed modifications to ICD-9-CM were presented and are summarized below. Unless otherwise indicated, the audience generally supported the proposed changes.


Age-Dependent Decline in Common Femoral Artery Flow-Mediated Dilation and Wall Shear Stress in Healthy Subjects.
Femoral artery (FA) endothelial function is a promising biomarker of lower extremity vascular health for peripheral artery disease (PAD) prevention and treatment; however, the impact of age on FA endothelial function has not been reported in healthy adults. Therefore, we evaluated the reproducibility and acceptability of flow-mediated dilation (FMD) in the FA and brachial artery (BA) (n = 20) and performed cross-sectional FA- and BA-FMD measurements in healthy non-smokers aged 22−76 years (n = 50). FMD protocols demonstrated similar good reproducibility. Leg occlusion was deemed more uncomfortable than arm occlusion; thigh occlusion was less tolerated than forearm and calf occlusion. FA-FMD with calf occlusion was lower than BA-FMD (6.0 ± 1.1% vs 6.4 ± 1.3%, p = 0.030). Multivariate linear regression analysis indicated that age (−0.4%/decade) was a significant independent predictor of FA-FMD (R2 = 0.35, p = 0.002). The age-dependent decline in FMD did not significantly differ between FA and BA (pinteraction agexlocation = 0.388). In older participants, 40% of baseline FA wall shear stress (WSS) values were <5 dyne/cm2, which is regarded as pro-atherogenic. In conclusion, endothelial function declines similarly with age in the FA and the BA in healthy adults. The age-dependent FA enlargement results in a critical decrease in WSS that may explain part of the age-dependent predisposition for PAD.


Bis(4,4'-sulfanediyldipyridinium) tetra-chloridonickelate(II) dichloride.
In the title compound, (C10H10N2S)2[NiCl4]Cl2, the Ni(2+) cation is tetra-hedrally coordinated by four chloride anions. Two 4,4'-sulfanediyldipyridinium cations and two non-coordinating chloride anions are connected via N-H⋯Cl hydrogen-bonding inter-actions into 20-membered rings, in the middle of which are situated the [NiCl4](2-) complex anions. These rings are stacked in the b-axis direction. The Ni(2+) cation is located on a twofold rotation axis, whereas the chloride anions and the 4,4'-sulfanediyldipyridinium cations occupy general positions.


Effects of nerve growth factor on differentiation of muscle spindles following nerve lesion in neonatal rats.
Central synaptic function of Group Ia sensory fibers has been shown to be enhanced by daily applications of NGF in neonatal rats. In the periphery, Group Ia sensory fibers are known to trigger the differentiation of muscle spindles. In the present study we examined, in neonatal rats, whether daily NGF treatment affects the number or structure of spindles formed in muscle whose nerve has been crushed. The results show that 25-35 d after nerve crush, de novo supernumerary spindles were formed by treatment with NGF in the temporarily denervated muscle. The number of spindles in the corresponding muscle on the contralateral, intact side was not affected by NGF treatment. Following nerve crush alone, the mean number of spindles in the muscle was not significantly different from the normal value. It is suggested that treatment of neonatal rats with NGF may facilitate the outgrowth of excessive peripheral collaterals of regenerating Group Ia sensory fibers, which, in turn, contributes to the formation of de novo spindles as a result of interaction with myotubes.


Longitudinal Associations between Prenatal Exposure to Phthalates and Steroid Hormones in Maternal Hair Samples from the SEPAGES Cohort.
We assessed phthalate-hormone associations in 382 pregnant women of the new-generation SEPAGES cohort (2014-2017, France) using improved exposure and outcome assessments. Metabolites from seven phthalate compounds and the replacement di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (≈21 samples/trimester). Metabolites from five steroid hormones were measured in maternal hair samples collected at delivery, reflecting cumulative levels over the previous weeks to months. Adjusted linear regression and Bayesian weighted quantile sum (BWQS) mixture models were performed. Each doubling in third-trimester urinary mono-benzyl phthalate (MBzP) concentrations was associated with an average increase of 13.3% (95% CI: 2.65, 24.9) for ∑cortisol, 10.0% (95% CI: 0.26, 20.7) for ∑cortisone, 17.3% (95% CI: 1.67, 35.4) for 11-dehydrocorticosterone, and 16.2% (95% CI: 2.20, 32.1) for testosterone, together with a suggestive 10.5% (95% CI: -1.57, 24.1) increase in progesterone levels. Each doubling in second-trimester urinary di-isononyl phthalate (DiNP) concentrations was inversely associated with testosterone levels (-11.6%; 95% CI: -21.6, -0.31). For most hormones, a nonsignificant trend toward a positive phthalate mixture effect was observed in the third but not in the second trimester. Our study showed that exposure to some phthalate metabolites, especially MBzP, may affect adrenal and reproductive hormone levels during pregnancy.


Effects of Acetylcholinesterase Inhibitors on Nutritional Status in Elderly Patients with Dementia: A 6-month Follow-up Study.
Nutritional status is one of the factors that affects disease progression, morbidity and mortality in elderly patients with dementia. The present study aimed to evaluate the effect of acetylcholinesterase inhibitor (AchEI) therapy on nutritional status and food intake in the elderly. Newly diagnosed patients with dementia, who underwent comprehensive geriatric assessment (CGA) and were followed at regular intervals, were retrospectively evaluated. A total of 116 patients, who began to receive AchEI therapy and completed 6-month follow-up period under this treatment, were enrolled in the study. Socio-demographic characteristics and data on comorbidity, polypharmacy, cognitive function, depression, activities of daily living and nutritional status (weight, Body Mass Index (BMI), Mini Nutritional Assessment (MNA)-Short Form) were recorded. The mean age of the patients was 78.0±8.9 years. There was no significant difference between baseline and 6-month BMI, weight and MNA scores of dementia patients who received AchEI therapy (p>0.05). With regard to the relation between changes in BMI, weight and MNA on the 6th month versus baseline, and donepezil, rivastigmine and galantamine therapies, no difference was determined (p>0.05). However, no worsening in food intake was observed (kappa: 0.377). When the effects of each AchEI on food intake were compared, food intake in rivastigmine treated patients was not decreased as much as it was in galantamine or donepezil treated patients (p<0.05). AchEI therapy has no unfavorable effect on nutritional status or weight in elderly patients with different types of dementia, but it seems that food intake is better in those treated by rivastigmine patch.


[Cytologic and histochemical study of cell cultures chronically infected with fixed rabies virus].
Cytoplasmic inclusion bodies corresponding in their tinctorial properties to Negri bodies were detected in TEp-2/2 and BHK-21/13S cell cultures chronically infected with fixed rabies virus. The number of cells containing the inclusions was always than that of the cells producing virus-specific antigen. Histological examinations of chronically infected cultures revealed considerable inhibition of the acid phosphatase activity, some weakening of the reaction to alkaline phosphatase, and a marked decline in the activity of succinate dehydrogenase. The intensity of reaction to RNA in chronically infected cultures was increased, particularly in those zones of the cells where RNA-containing inclusions were detected. The activity of the respiratory enzyme HAD-H2 tetrasolium reductase in HEp-2/2 cells was reduced and in BHK-21/13S cells increased as compared to the control.


Editorial.
Since early spring, the COVID-19 pandemic has catapulted the healthcare community from a largely comprehensible world of work to unfamiliar territory, where the ground is ever shifting. What does it take to serve the public in this environment? Constant recalibration, endless reserves of energy, quick wits and a wide-open mind willing to look for solutions in new places working with new people.


Domain-specific effector interactions within the central cavity of human adult hemoglobin in solution and in porous sol-gel matrices: evidence for long-range communication pathways.
The water-filled central cavity of human adult hemoglobin (Hb A) is the binding or interaction site for many different allosteric effectors. Oxygen binding titrations reveal that pyrenetetrasulfonate (PyTS), a fluorescent analogue of 2,3-diphosphoglycerate, behaves like an allosteric effector. The ligation state, pH, and concentrations of other effectors (IHP, L35, and chloride) alter PyTS fluorescence for both solution-phase and sol-gel-encapsulated Hb samples. These conditions also alter the resonance Raman spectra and rates of geminate recombination of CO-ligated Hb. Together, these results demonstrate that there are conformational and functional consequences resulting from interactions between specific domains of the central cavity and individual effectors as well as from long-range synergistic effects that are mediated through the central cavity.


Immunofluorescence approach to the study of the ecology of Thermoplasma acidophilum in coal refuse material.
Specific immunofluorescence staining was applied to the study of the localization, distribution, and growth of Thermoplasma acidophilum in its natural habitat, the coal refuse pile. Different antigenic groups of T. acidophilum could be isolated from the same refuse pile, and the same antigenic groups were isolated from piles from different geographical areas. No correlation could be established between the antigenic groups and the pH or temperature of the habitats. Brightly fluorescing cells of T. acidophilum were detected on microscope slides buried in contact with the coal refuse material or immersed in the water in the stream draining a refuse pile. T. acidophilum grew when inoculated into either coal refuse material and/or an aqueous extract of coal refuse when incubated at its optimal temperature of 55 C, but not when incubated at room temperature or 37 C. The coal refuse pile appears to be a primary habitat for T. acidophilum.


Quantum plasmon resonances of individual metallic nanoparticles.
The plasmon resonances of metallic nanoparticles have received considerable attention for their applications in nanophotonics, biology, sensing, spectroscopy and solar energy harvesting. Although thoroughly characterized for spheres larger than ten nanometres in diameter, the plasmonic properties of particles in the quantum size regime have been historically difficult to describe owing to weak optical scattering, metal-ligand interactions, and inhomogeneity in ensemble measurements. Such difficulties have precluded probing and controlling the plasmonic properties of quantum-sized particles in many natural and engineered processes, notably catalysis. Here we investigate the plasmon resonances of individual ligand-free silver nanoparticles using aberration-corrected transmission electron microscope (TEM) imaging and monochromated scanning TEM electron energy-loss spectroscopy (EELS). This technique allows direct correlation between a particle's geometry and its plasmon resonance. As the nanoparticle diameter decreases from 20 nanometres to less than two nanometres, the plasmon resonance shifts to higher energy by 0.5 electronvolts, a substantial deviation from classical predictions. We present an analytical quantum mechanical model that describes this shift due to a change in particle permittivity. Our results highlight the quantum plasmonic properties of small metallic nanospheres, with direct application to understanding and exploiting catalytically active and biologically relevant nanoparticles.


Ascorbate-dependent protection of human erythrocytes against oxidant stress generated by extracellular diazobenzene sulfonate.
Diazobenzene sulfonic acid (DABS) has been used to label thiols and amino groups on cell-surface proteins. However, we found that in addition to inhibiting an ascorbate-dependent trans-plasma membrane oxidoreductase in human erythrocytes, it also depleted alpha-tocopherol severely in the cell membrane. When erythrocytes were loaded with ascorbate, DABS-dependent loss of alpha-tocopherol was decreased, despite little change in intracellular ascorbate content. Sparing of alpha-tocopherol also was seen in erythrocyte ghosts resealed to contain ascorbate, although this was accompanied by loss of intravesicular ascorbate, probably due to the inability of ghosts to recycle ascorbate. A transmembrane transfer of electrons from ascorbate was confirmed by electron paramagnetic resonance spectroscopy, in which extracellular DABS was found to generate the ascorbate free radical within cells. When the membrane content of alpha-tocopherol was decreased to 20% of the initial value by DABS treatment, lipid peroxidation ensued, manifest by generation of F(2)-isoprostanes in the cell membranes. Intracellular ascorbate also strongly protected against F(2)-isoprostane formation. These results show that DABS causes an oxidant stress at the membrane surface that is transmitted within the cell, in part by an alpha-tocopherol-dependent mechanism, and that ascorbate recycling of alpha-tocopherol can protect against loss of alpha-tocopherol and the ensuing lipid peroxidation.


WRN or telomerase constructs reverse 4-nitroquinoline 1-oxide sensitivity in transformed Werner syndrome fibroblasts.
WRN encodes a RecQ helicase, which is mutated in Werner syndrome. Werner syndrome is a genetic condition of young adults characterized by premature aging, limited replicative capacity of cells in vitro, and increased cancer risk. Telomerase is a reverse transcriptase that extends the G-rich strand of telomeric DNA. Primary cells in vitro typically lack telomerase activity and undergo senescence, whereas telomerase is reactivated in many, but not all, tumors. The roles of the two genes are not known to be related. Here we report the development of an effective colony-forming assay in which a SV40-transformed Werner fibroblast cell line is 6-18-fold more sensitive to 4-nitroquinoline 1-oxide than SV40-transformed normal cell lines. The sensitivity can be partially reversed by transfecting a normal WRN gene but not a mutated WRN gene into the cells. Curiously, the sensitivity can be reversed equally well by transfecting a telomerase gene (TERT) into the cells. These data indicate the possibility of an interdependent function of these two genes.


Missed lumbar transverse process fractures in a high school football player.
To discuss the case of a football player who had suffered a transverse process fracture of the lumbar spine that was overlooked on initial chiropractic and medical examination. A 17-year-old male football player had been speared in the back by another player. He reported severe initial pain that caused him to fall to the ground, and there was a moderate degree of pain at the time of his chiropractic examination 1 week after injury. Initial chiropractic treatment consisted of spinal manipulation to the lumbar spine. Follow-up care consisted of lumbar spine radiographs that showed evidence of a lumbar transverse process fracture at 2 levels. The boy was referred to his medical doctor, who was not convinced of the presence of a fracture and returned him to play. A computed tomography scan was subsequently performed; this confirmed fractures of the transverse processes of L2 and L3. The patient was precluded from contact sports for 4 weeks. Chiropractic care 3 weeks after injury included physiotherapy and drop table mobilization to the sacroiliac joints. The patient returned to play 4 weeks after the injury. Transverse process fractures commonly occur secondary to blunt trauma in contact sports such as football. With high-force direct trauma, radiographs should be performed to rule out fracture before returning the athlete to play or commencing spinal manipulation.


Androgen levels and female social dominance in Lemur catta.
Morphological and behavioural traits which improve agonistic power are subject to intrasexual selection and, at the proximate level, are influenced by circulating androgens. Because intrasexual selection in mammals is more intense among males, they typically dominate females. Female social dominance is therefore unexpected and, indeed, rare. Ring-tailed lemurs (Lemur catta) are sexually monomorphic primates in which all adult females dominate all males. The goal of our study was to test the prediction that female dominance in this species is associated with high androgen levels. Using two captive groups, we collected data on agonistic behaviour and non-invasively assessed their androgen concentrations in faeces and saliva by enzyme immunoassay. We found that adult female L. catta do not have higher androgen levels than males. However, during the mating season there was a twofold increase in both the androgen levels and conflict rates among females. This seasonal increase in their androgen levels was probably not due to a general increase in ovarian hormone production because those females showing the strongest signs of follicular development tended to have low androgen concentrations. At the individual level neither the individual aggression rates nor the proportion of same-sexed individuals dominated were correlated with their androgen levels. We conclude that female dominance in ring-tailed lemurs is neither based on physical superiority nor on high androgen levels and that it is equally important to study male subordination and prenatal brain priming effects for a complete understanding of this phenomenon.


Optimised mounting conditions for poly (ether sulfone) in radiation detection.
Poly (ether sulfone) (PES) is a candidate for use as a scintillation material in radiation detection. Its characteristics, such as its emission spectrum and its effective refractive index (based on the emission spectrum), directly affect the propagation of light generated to external photodetectors. It is also important to examine the presence of background radiation sources in manufactured PES. Here, we optimise the optical coupling and surface treatment of the PES, and characterise its background. Optical grease was used to enhance the optical coupling between the PES and the photodetector; absorption by the grease of short-wavelength light emitted from PES was negligible. Diffuse reflection induced by surface roughening increased the light yield for PES, despite the high effective refractive index. Background radiation derived from the PES sample and its impurities was negligible above the ambient, natural level. Overall, these results serve to optimise the mounting conditions for PES in radiation detection.


Imaging of the cerebrum.
The history of the development of cerebral imaging is a complex combination of the forces of innovation at both the individual and industrial levels. Principal paradigms of neuroimaging shifted as a result of technological breakthroughs, beginning with the discovery of x-rays and continuing with the development of computerized imaging to the latest imaging paradigm, nuclear magnetic resonance imaging. We discuss these landmarks in neuroimaging in historical context, with emphasis on the particularly rapid development of imaging technology during the past 30 to 40 years, including the most recent emerging technologies.


Growth factors and female reproduction in vertebrates.
Female reproductive efficiency is influenced by the outcomes of various processes, including folliculogenesis, apoptosis, response to gonadotropin signaling, oocyte maturation, and ovulation. The role of hormones in regulating these processes and other reproductive activities has been well established. It is becoming increasingly evident that in addition to well-characterized hormones, growth factors play vital roles in regulating some of these reproductive activities. Growth factors and their receptors are widely distributed in vertebrate ovaries at different stages of ovarian development, indicating their involvement in intraovarian reproductive functions. In the ovary, cell surface receptors allow growth factors to regulate intraovarian reproductive activities. Understanding these actions in the reproductive axis would provide a tool to target growth factors and/or their receptors to yield desirable reproductive outcomes. These include enrichment of in vitro maturation and fertilization culture media, and management of infertility. This review discusses some widely characterized growth factors belonging to the TGF, EGF, IGF, FGF, and BDNF family of peptides and their role in female reproduction in vertebrates, with a focus on mammals.


Genome evolution of dengue virus serotype 1 under selection by Wolbachia pipientis in Aedes aegypti mosquitoes.
The introgression of antiviral strains of Wolbachia into Aedes aegypti mosquito populations is a public health intervention for the control of dengue. Plausibly, dengue virus (DENV) could evolve to bypass the antiviral effects of Wolbachia and undermine this approach. Here, we established a serial-passage system to investigate the evolution of DENV in Ae. aegypti mosquitoes infected with the wMel strain of Wolbachia. Using this system, we report on virus genetic outcomes after twenty passages of serotype 1 of DENV (DENV-1). An amino acid substitution, E203K, in the DENV-1 envelope protein was more frequently detected in the consensus sequence of virus populations passaged in wMel-infected Ae. aegypti than wild-type counterparts. Positive selection at residue 203 was reproducible; it occurred in passaged virus populations from independent DENV-1-infected patients and also in a second, independent experimental system. In wild-type mosquitoes and human cells, the 203K variant was rapidly replaced by the progenitor sequence. These findings provide proof of concept that wMel-associated selection of virus populations can occur in experimental conditions. Field-based studies are needed to explore whether wMel imparts selective pressure on DENV evolution in locations where wMel is established.


Bone induction effect of fine bone shavings in polyester fibre. An experimental study.
Autogenous marrow-free bone shavings of dense lamellar bone spread over polyester mesh were transplanted into muscle, the palate and the tibia. A thin sheet of silastic was used to eliminate the induction effect of the adjacent bone, and the results were evaluated histologically. It was found that finely divided autogenous bone shavings actively induce new bone formation, and that the rate of bone production depends on the proximity of bone-competent tissue, such as a muscle tendon or a muscle attachment. Osteogenesis is also stimulated by a direct blood supply from the adjacent bone. Polyester mesh (Mersilene) is a relatively inert material, which could be used to great advantage in the transplantation of bone. Preliminary results of this research indicate that it may be of great value in bone reconstruction. These experiments support the idea of a non-cellular and diffusible bone stimulatory substance which influences the inducible osteogenic precursor cells to produce bone.


Benign myoepithelial tumors of the breast have immunophenotypic characteristics similar to metaplastic matrix-producing and spindle cell carcinomas.
We immunohistochemically compared benign myoepithelial tumors (adenomyoepitheliomas [AMEs]) and metaplastic matrix-producing (MMP-CA) and spindle cell (MSC-CA) carcinomas of the breast to identify helpful diagnostic markers. Normal myoepithelial cells (MECs) consistently expressed cytokeratin, alpha-smooth muscle actin (SMA), myosin, S-100, CD10, and maspin. They were variably positive for vimentin and negative for epithelial membrane antigen (EMA), steroid receptors, p53, and HER-2/neu. MECs in AMEs less frequently expressed CD10 (4/8 [50%]) and myosin (6/8 [75%]) but frequently acquired characteristics of luminal cells, such as expression of EMA (5/8 [63%]) and steroid receptors (5/8 [63%]). No abnormal p53 or HER-2/neu expression was seen in AMEs. MMP-CA and MSC-CA were similar to AMEs in cytokeratin, vimentin, S-100, maspin, and HER-2/neu expression. MMP-CAs expressed less alpha-SMA (2/8 [25%]) and myosin (2/7 [29%]) and lacked estrogen receptor (0/9 [0%]). MSC-CAs were consistently CD10+ (4/4 [100%]) yet failed to express myosin (0/3 [0%]). p53 overexpression was seen frequently in MMP-CAs (4/8 [50%]) and MSC-CAs (1/3 [33%]). Benign myoepithelial mammary tumors differ immunophenotypically from normal MECs; a panel of immunohistochemical markers may be required to establish their myoepithelial origin. A similarly altered myoepithelial phenotype also is characteristic of metaplastic mammary carcinomas. The abnormal expression of oncogenes or antioncogenes, such as p53, may be more useful for distinguishing between those entities than the expression of the classic myoepithelial markers.


[Two rare complications in patients with bone-anchored hearing aids].
In our program of bone-anchored hearing aids we experienced two rare complications: a child with a hearing aid fell on her head and got an intrusion of the bone-screw into the intracranial space with a fracture of tabula externa and interna. There were no further intracranial complications, no hematoma or infection. The screw was explanted immediately with oto-microsurgical instruments and diamond burrs. The site of the screw was covered with a local skin flap. There were no complications in wound healing and the child got a second implant on the other side. A patient got an infection of his bone fixation screw and we took out the external fixation but left in place the bone screw, which was obviously still well fixed and the adjacent bone was without signs of infection. There was good secondary wound healing with local and systemic antibiotics. With almost completely healed external wound the patient got an intracranial abscess, that needed neurosurgical drainage. After long-time antibiotic treatment the patient is well again.


Review article. Magnesium deficiency provoked by diuretics.
Many diuretics cause hypermagnesiuria which may lead to magnesium deficiency, presenting as hypomagnesaemia, cardiac arrhythmias and tetany. Loop diuretics cause hypermagnesiuria mainly through direct blockade of magnesium reabsorption at the loop of Henle. Distal tubular diuretics block magnesium reabsorption at the distal convoluted tubule and also reduce magnesium reabsorption at the loop of Henle by an indirect mechanism.


Age- and gender-related distribution of bone tissue of osteoporotic humeral head using computed tomography.
Treatment of proximal humeral fractures is very challenging in elderly patients with osteoporosis. Difficulty in obtaining a stable osteosynthesis remains the main problem for the surgeon. Knowing more details about the bone quality of the humeral head can be helpful for treatment. The purpose of this study was to evaluate the bone quality of the humeral head based on age, sex, and location. Three groups of patients were identified according to age: group A (aged <30 years), group B (aged >40 years but <60 years), and group C (aged >60 years). Computed tomography (CT) was performed on each patient to evaluate the humeral head bone quality. The distribution of bone density was assessed by the CT value expressed in Hounsfield units. The maximum, minimum, and mean CT values were calculated in the cancellous bone of the humeral head for each image. The humeral head was then divided into 3 equal zones, and a map of the 3 zones was made. The results showed that there was a significant difference between men and women in our series with regard to the percentage of bone tissue. There was also a significant difference among the 3 groups (age-related), as well as between the medial and lateral sides, with regard to the percentage of bone tissue. Osteopenic change in the humeral head has a negative correlation with aging. The medial side, especially the articular side, has more bone tissue than other areas. These results suggest that, when we treat humeral head fractures of elderly patients, we need to define bone quality for each case. We should then take care when establishing the site and angle of insertion for fixation to obtain optimal fixation on the lateral side.


Maillard-conjugate based core-shell co-assemblies for nanoencapsulation of hydrophobic nutraceuticals in clear beverages.
Maillard reaction based protein-polysaccharide conjugates (PPC) are typically better emulsifiers than the proteins used to form them. Such conjugates have been proposed as encapsulation agents, but their potential as nanoencapsulation agents in clear beverages has not yet been proposed. In this research we formed casein-maltodextrin (CN-MD) conjugates and co-assembled them with hydrophobic nutraceuticals to create nanovehicles for the enrichment of clear beverages. Conjugation was validated using gel electrophoresis and by ortho-phthaldialdehyde (OPA) assay. Vitamin D (VD) was nano-entrapped by the conjugates, and compared to controls based on an unconjugated CN-MD mixture and unencapsulated VD. The following advantages of the conjugates were shown: the diameters of conjugate-VD nanoparticles was smaller and their solution was more transparent than that of the vitamin dispersion or the protein-polysaccharide mixture with VD. Conjugates conferred better protection against oxidation to both VD and epigallocatechin gallate (EGCG) than the CN-MD mixture. Conjugates were more colloidally stable at the CN original pI, allowing the formation of nanoparticles with mean diameter below 30 nm when mixed with VD, even at the original pI of CN. Conjugates provided protection against degradation at low pH and during shelf life. Entrapment efficiency was measured using Nile red (NR), a fluorescent model for a hydrophobic nutraceutical. Protein affinity to the hydrophobic compound was not diminished due to conjugation, and 90% entrapment efficiency was obtained under the conditions tested. During simulated gastric digestion, Nile red was not released from the conjugates, suggesting potential application in enteric delivery.


Non-detection of human herpesvirus 8 (HHV-8) DNA in HHV-8-seropositive blood donors from three Brazilian regions.
Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the etiologic agent of all forms of Kaposi's sarcoma, primary effusion lymphoma and the plasmablastic cell variant of multicentric Castleman disease. In endemic areas of sub-Saharan Africa, blood transfusions have been associated with a substantial risk of HHV-8 transmission. By contrast, several studies among healthy blood donors from North America have failed to detect HHV-8 DNA in samples of seropositive individuals. In this study, using a real-time PCR assay, we investigated the presence of HHV-8 DNA in whole-blood samples of 803 HHV-8 blood donors from three Brazilian states (São Paulo, Amazon, Bahia) who tested positive for HHV-8 antibodies, in a previous multicenter study. HHV-8 DNA was not detected in any sample. Our findings do not support the introduction of routine HHV-8 screening among healthy blood donors in Brazil. (WC = 140).


Sono-bromination of aromatic compounds based on the ultrasonic advanced oxidation processes.
A novel, mild "sono-halogenation" of various aromatic compounds with potassium halide was investigated under ultrasound in a biphasic carbon tetrachloride/water medium. The feasibility study was first undertaken with the potassium bromide and then extended to chloride and iodide analogues. This methodology could be considered as a new expansion of the ultrasonic advanced oxidation processes (UAOPs) into a synthetic aspect as the developed methodology is linked to the sonolytic disappearance of carbon tetrachloride. Advantages of the present method are not only that the manipulation of the bromination is simple and green, but also that the halogenating agents used are readily available, inexpensive, and easy-handling.


Novel genome polymorphisms in BCG vaccine strains and impact on efficacy.
Bacille Calmette-Guérin (BCG) is an attenuated strain of Mycobacterium bovis currently used as a vaccine against tuberculosis. Global distribution and propagation of BCG has contributed to the in vitro evolution of the vaccine strain and is thought to partially account for the different outcomes of BCG vaccine trials. Previous efforts by several molecular techniques effectively identified large sequence polymorphisms among BCG daughter strains, but lacked the resolution to identify smaller changes. In this study, we have used a NimbleGen tiling array for whole genome comparison of 13 BCG strains. Using this approach, in tandem with DNA resequencing, we have identified six novel large sequence polymorphisms including four deletions and two duplications in specific BCG strains. Moreover, we have uncovered various polymorphisms in the phoP-phoR locus. Importantly, these polymorphisms affect genes encoding established virulence factors including cell wall complex lipids, ESX secretion systems, and the PhoP-PhoR two-component system. Our study demonstrates that major virulence factors are different among BCG strains, which provide molecular mechanisms for important vaccine phenotypes including adverse effect profile, tuberculin reactivity and protective efficacy. These findings have important implications for the development of a new generation of vaccines.


ALG9 Mutation Carriers Develop Kidney and Liver Cysts.
Mutations in PKD1 or PKD2 cause typical autosomal dominant polycystic kidney disease (ADPKD), the most common monogenic kidney disease. Dominantly inherited polycystic kidney and liver diseases on the ADPKD spectrum are also caused by mutations in at least six other genes required for protein biogenesis in the endoplasmic reticulum, the loss of which results in defective production of the PKD1 gene product, the membrane protein polycystin-1 (PC1). We used whole-exome sequencing in a cohort of 122 patients with genetically unresolved clinical diagnosis of ADPKD or polycystic liver disease to identify a candidate gene, ALG9, and in vitro cell-based assays of PC1 protein maturation to functionally validate it. For further validation, we identified carriers of ALG9 loss-of-function mutations and noncarrier matched controls in a large exome-sequenced population-based cohort and evaluated the occurrence of polycystic phenotypes in both groups. Two patients in the clinically defined cohort had rare loss-of-function variants in ALG9, which encodes a protein required for addition of specific mannose molecules to the assembling N-glycan precursors in the endoplasmic reticulum lumen. In vitro assays showed that inactivation of Alg9 results in impaired maturation and defective glycosylation of PC1. Seven of the eight (88%) cases selected from the population-based cohort based on ALG9 mutation carrier state who had abdominal imaging after age 50; seven (88%) had at least four kidney cysts, compared with none in matched controls without ALG9 mutations. ALG9 is a novel disease gene in the genetically heterogeneous ADPKD spectrum. This study supports the utility of phenotype characterization in genetically-defined cohorts to validate novel disease genes, and provide much-needed genotype-phenotype correlations.


Serum oxytetracycline concentrations in African elephant (Loxodonta africana) calves after long-acting formulation injection.
Serum oxytetracycline pharmacokinetics were studied in 18 African elephant (Loxodonta africana) calves. Each elephant received separate injections of oxytetracycline at approximately 18 mg/kg i.m. and 8 mg/kg i.v. in a cross-over study. Blood samples were drawn at 0, 24, 48, 72, and 96 hr postinjection. An additional sample was drawn 110 hr before the animals were reinjected in the cross-over study and a final blood sample was drawn 48 hr after the second dose. No lameness or stiffness was observed following i.m. injections. Serum oxytetracycline concentrations >0.5 microg/ml were present 48 hr after initial dosing for all elephants (i.m., i.v., high or low dosage). Only elephants given the high i.m. dosage (18 mg/kg) maintained levels >0.5 microg/ml 72 hr postinjection. No significant difference in serum oxytetracycline concentration with time was observed between the groups given different i.v. dosages. These studies demonstrated that quantifiable serum oxytetracycline concentrations can be maintained in young African elephants with a low-dosage multidose i.m. regimen.


Tenofovir alafenamide revisited.
Two Tenofovir pro-drugs are available for the treatment of HIV and HBV infection. Tenofovir Alafenamide (TAF) was clinically developed as a safer alternative to the older Tenofovir Disoproxil Fumarate (TDF) as the latter was consistently found to be associated to proximal renal tubule dysfunction and decrease in bone mineral density (BMD). As compared to TDF, the pharmacological properties of TAF are such that a more active drug is delivered into target cells while much less is measurable in general circulation. This translates into an antiretroviral action comparable to TDF with a significantly lower impact on proximal renal tubular function and bone structural integrity. The lipid-lowering effects of TDF as well as its lesser tendency to be associated to undesired body weight increase have raised some doubts about the substitution of TDF with TAF. Both issues, whose genesis is multifactorial, are strictly linked to the hypothesis of increased cardiovascular risk that might follow the switch from TDF to TAF. However, the long-term impact of decreasing renal function on cardiovascular risk must also be considered, especially in aging patients. It is thus a matter of balance: while the action on modifiable behavioural variables may well reduce lipid levels and body weight, the permanent dysfunctional pressure exerted by TDF on the proximal renal tubule could cause irreversible damage to both kidneys and bones. Therefore, all things considered, avoidance of TDF, particularly when aging patients are concerned, appears the preferable approach.


Prognostic factors and clinical outcome of patients with Ewing's sarcoma family of tumors in adults: multicentric study of the Anatolian Society of Medical Oncology.
The aim of this study was to evaluate prognostic factors, survival rate and the efficacy of the treatment modalities used in patients with Ewing sarcoma family of tumors (ESFT). Data of patients with ESFTs followed up at different cancer centers in Turkey between 2001 and 2010 were retrospectively analyzed. The median age of 114 patients was 26 years (range 14-66). The median follow-up was 20 months (range 1-118 months). Tumor size was between 1.5 and 14 cm (median 8 cm). Eighty-six percent of patients had localized disease at presentation, and 14 % had metastatic disease. Local therapy was surgery alone in 31 % of patients, surgery combined with radiotherapy in 41 % and radiotherapy alone in 18 %. Approximately 70 % of patients were treated with vincristine, doxorubicin, cyclophosphamide and actinomycin-D, alternating with ifosfamide and etoposide every 3 weeks. In patients with localized disease at presentation, the 5-year disease-free survival and overall survival were 60 and 65 %, respectively. At univariate analysis, patients with tumor size ≥ 8 cm, high serum lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy and positive surgical margin had significantly worse event-free survival. The significant predictors of worse overall survival at univariate analysis were tumor size ≤ 8 cm, high lactate dehydrogenase, metastasis at presentation, poor histological response to chemotherapy, radiotherapy only as local treatment and positive surgical margin. ESFTs are aggressive tumors with a high incidence of local recurrence and distant metastasis. Multimodality treatment consisting of adequate surgical resection, aggressive chemotherapy (VAC alternating with IE) and radiotherapy is recommended for patients with ESFTs.


Mössbauer studies of solid thionin-oxidized MoFe protein of nitrogenase.
Recently Hagen et al. (Hagen, W. R., Wassink, H., Eady, R. R., Smith, B. E., and Haaker, H. (1987) Eur. J. Biochem. 169, 457-465) reported the observation of S = 7/2 EPR signals for thionin-oxidized nitrogenase MoFe protein. Here we have studied the protein from Azotobacter vinelandii and Klebsiella pneumoniae with Mössbauer and EPR spectroscopies, with the following results: when the MoFe protein is oxidized by addition of stoichiometric amounts (6-8 equivalents) of dissolved thionin, the well characterized P-cluster state Pox results. Pox has an as yet undetermined, but half-integer electronic spin; however, the state is EPR-silent. In contrast, oxidation by addition of a large excess of solid thionin powder, the method used by Hagen et al., yields mixtures with variable proportions of two oxidized P-cluster forms, namely the familiar Pox and the new state Pox(S = 7/2) observed by Hagen et al. The Mössbauer data suggest that Pox and Pox(S = 7/2) are isoelectronic. The two states, however, have distinct electronic structures; the Mössbauer spectra of Pox exhibit the characteristic trapped-valence Fe2+ site, whereas the spectra of Pox(S = 7/2) lack this feature. Hagen et al. have proposed two new P-cluster models. We conclude that one of the models is incompatible with the Mössbauer data and that the basic assumptions of the other model are not supported by the available data. Finally, the Mössbauer data show that either oxidation method puts the cofactor centers into the diamagnetic state Mox.


Non-operating room anaesthesia for embolisation of ductus closure device to the pulmonary artery in a child with patent ductus arteriosus.
ABSTRACTPatent ductus arteriosus is among the most common congenital heart diseases. With the increasing use of transcatheter closure procedures, the incidence of complications related to the procedure has increased. Embolization of the ductus closure device to the pulmonary artery is a very rare complication. Since those procedures are often performed under non-operating room anesthesia, anesthetic management of such patients is of great importance. Herein, anesthetic management of embolization of the ductus closure device to the pulmonary artery in a little girl was presented. This is the first case regarding the anesthetic management of such complication.