The evaluation of methapyrilene for bacterial mutation with metabolic activation by Aroclor-induced, methapyrilene-induced and noninduced rat-liver S9.
The antihistamine methapyrilene (MP) has been shown to be a potent hepatocarcinogen in rats. However, it has demonstrated little genotoxic activity in a wide variety of short-term tests. In this study, Fischer 344 rats were fed a carcinogenic dose of 0.1% methapyrilene in the diet for 10 weeks prior to sacrifice. S9 was prepared from the livers of the control, MP-treated and Aroclor-induced Fischer 344 rats. Each type of S9 was analyzed for mixed function oxidase activity, cytochrome P-450, and protein content. MP was then evaluated for mutagenicity in 6 strains of S. typhimurium (TA1535, TA1537, TA98, TA100, TA2638 and TA104) and one strain of E. coli (WP2uvrA-) using the standard plate-incorporation assay. MP was not mutagenic in any of the 7 bacterial strains when tested at concentrations < or = 10 mg/ml in the presence of each type of S9. However, in the absence of metabolic activation, an approximate 2-fold increase in revertants was noted with strain TA1535. The data from this study show that MP was not converted to a mutagenic metabolite by any of the three S9 types examined. However, the "weak" positive response with strain 1535 in the absence of metabolic activation indicates that further research is needed to elucidate the mechanism of action of this rat carcinogen.


Editorial Commentary: Hip Arthroscopy Plays a Role in Painful Hip Resurfacing Arthroplasty but a Prearthroscopy Diagnosis Is Critical to Outcome.
Whereas hip arthroscopy plays a role in the investigation and treatment of the painful hip resurfacing arthroplasty, a diagnosis before arthroscopy is critical to improved outcome. The rate of conversion to total hip arthroplasty jumps from 7% to 37% when a pre-arthroscopy diagnosis is not known.


Mesenteric Castleman's disease: case report.
An asymptomatic case of hyaline vascular-type Castleman's disease localized to the mesentery and detected incidentally by ultrasound is presented. Computed tomographic, angiographic, and histologic findings are reported. This type of Castleman's disease predominates in the thorax and is very rare in the mesentery.


Influence of liver stiffness heterogeneity on staging fibrosis in patients with nonalcoholic fatty liver disease.
Despite that hepatic fibrosis often affects the liver globally, spatial distribution can be heterogeneous. This study aimed to investigate the effect of liver stiffness (LS) heterogeneity on concordance between MR elastography (MRE)-based fibrosis staging and biopsy staging in patients with NAFLD. We retrospectively evaluated data from 155 NAFLD patients who underwent liver biopsy and 3 Tesla MRE and undertook a retrospective validation study of 169 NAFLD patients at three hepatology centers. Heterogeneity of stiffness was assessed by measuring the range between minimum and maximum MRE-based LS measurement (LSM). Variability of LSM was defined as the stiffness range divided by the maximum stiffness value. The cohort was divided into two groups (homogenous or heterogeneous), according to whether variability was below or above the average for the training cohort. Based on histopathology and receiver operating characteristic (ROC) analysis, optimum LSM thresholds were determined for MRE-based fibrosis staging of stage 4 (4.43, kPa; AUROC, 0.89) and stage ≥3 (3.93, kPa; AUROC, 0.89). In total, 53 had LSM above the threshold for stage 4. Within this group, 30 had a biopsy stage of <4. In 86.7% of these discordant cases, variability of LSM was classified as heterogeneous. In MRE-based LSM stage ≥3, 88.9% of discordant cases were classified as heterogeneous. Results of the validation cohort were similar to those of the training cohort. Discordance between biopsy- and MRE-based fibrosis staging is associated with heterogeneity in LSM, as depicted with MRE.


Risk factors of acute and overuse musculoskeletal injuries among young conscripts: a population-based cohort study.
Military service in Finland is compulsory for all male citizens and annually about 80% of 19-year-old men enter into the service. The elevated risk for many chronic diseases and loss of function among those who are inactive and unfit can be often detected already in youth. On the other hand, activity-induced injuries among young are true public health issue. The purpose of the present prospective cohort follow-up study was to evaluate predictive associations between acute or overuse injuries and their various intrinsic risk factors. Four successive cohorts of conscripts who formed a representative sample of Finnish young men were followed for 6 months. At the beginning of the service, the risk factors of injuries were measured and recorded and then the acute and overuse injuries treated at the garrison clinic were identified. Predictive associations between injuries and their risk factors were examined by multivariate Cox's proportional hazard models. Of the 1411 participants, 27% sustained an acute injury and 51% suffered from overuse injury. Concerning acute injuries, highest risk for severe injuries were detected among conscripts with low fitness level in both the standing long-jump and push-up tests (hazard rate, HR=5.9; 95% CI: 1.6‒21.3). A history of good degree in school sports was not a protective factor against acute injuries. High waist circumference and, on the other hand, being underweight according to BMI increased the HR for overuse injuries. Brisk leisure time physical activity before military entry was a protective factor against overuse injuries. Poor result in Cooper's test was a warning signal of elevated risk of overuse injuries. We confirmed previous findings that low level of physical fitness is predictor for musculoskeletal injuries during intensive physical training. The U-shaped relationship between body composition and overuse injuries was noticed indicating that both obesity and underweight are risk factors for overuse injuries. Persons with excellent sports skills according to their earlier degrees in school sports had similar HR for acute injuries than those with poorer degrees. This indicates that school-age sports skills and fitness do not carry far and therefore preventive programmes are needed to prevent activity-induced injuries.


Results of computer tomography on chronic alcoholics.
Sixty adult patients with chronic alcoholism were examined by CT. Psychiatric and neurologic syndromes were given equal consideration. Pronounced brain atrophy was found in 75% of the cases. Cortical, as opposed to subcortical, atrophy was apparent in 64%; it was found especially in the frontotemporal region and cerebellum. Cases of Wernicke's encephalopathy as well as epileptic manifestations revealed global signs of atrophy, not restricted to the brain stem. Further correlations to problems of mental deficiency in alcoholism are discussed together with earlier results.


Retraction-related liver lobe necrosis after laparoscopic gastric surgery.
Liver retraction is necessary for optimal exposure during laparoscopic gastric surgery. Though transient venous congestion of the retracted lobe of the liver is invariably seen during operations, major parenchymal injury is rare. We describe a case of Nathanson liver retractor-induced left lobe liver necrosis and review the pertinent literature. A 78-year-old man underwent a laparoscopic-assisted total gastrectomy for gastric cancer. A Nathanson liver retractor was used to retract a large fatty left liver lobe. The operation was prolonged due to splenic bleeding requiring splenectomy. On the second postoperative day, the patient deteriorated rapidly and developed multi-organ failure. A computerized tomogram confirmed necrosis of the left lobe of the liver with gas in the liver parenchyma. The necrotic liver lobe was excised at reoperation. The patient died from a postoperative myocardial infarction. Though minor liver injuries, in the form of intraoperative trauma and congestion, are common with laparoscopic liver retraction, major lacerations and necrosis are rare. Prolonged surgery and enlarged fatty liver lobe increases the risks of major injury. In our report, we discuss various types of retractor-related liver injuries and their management and highlight the importance of intermittent release of retraction during prolonged surgery.


Comparison of the adherence to the american diabetes association guidelines of diabetes care in primary care and subspecialty clinics.
Diabetes mellitus is a major public health problem with significant morbidity and mortality. Evidence based guidelines have been proposed to reduce the micro and macrovascular complications, but studies have shown that these goals are not being met. We sought to compare the adherence to the American Diabetes Association guidelines for measurement and control of glycohemoglobin (A1c), blood pressure (BP), lipids (LDL) and microalbuminuria (MA) by subspecialty and primary care clinics in an academic medical center. 390 random charts of patients with diabetes from Family Practice (FP), Internal Medicine (IM) and Diabetes (DM) clinics at Michigan State University were reviewed. We reviewed 131, 134 and 125 charts from the FP, IM and DM clinics, respectively. DM clinic had a higher percentage of patients with type 1 diabetes 43/125 (34.4%) compared with 7/131 (5.3%) in FP and 7/134 (5.2%) in IM clinics. A1c was measured in 99%, 97.8% and 100% subjects in FP, IM and DM clinics respectively. B.P. was measured in all subjects in all three clinics. Lipids were checked in 97.7%, 95.5% and 92% patients in FP, IM and DM clinics respectively. MA was measured at least once during the year preceding the office visit in 85.5%, 82.8% and 76.8% patients in FP, IM and DM clinics respectively. A1C was controlled (<7%) in 38.9, 43.3, 28.8% of patients in the FP, IM and DM clinics, respectively (p = 0.034). LDL was controlled (<100 mg/dl or 2.586 mmol/l) in 71.8, 64.9, 64% of patients in the FP, IM and DM clinics, respectively. MA was controlled (<30 mg/gm creatinine) in 60.3%, 51.5% and 60% patients in FP, IM and DM clinics respectively (P = 0.032). BP was controlled (<130/80) in 59.5, 67.2 and 52.8% patients in the FP, IM and DM clinics, respectively. Testing rates for A1C, LDL, and MA were high, in both subspecialty and primary care clinics. However, the degree of control was not optimal. Significantly fewer patients in the DM clinic had A1c <7%, the cause of which may be multifactorial.


Effect of microserum environment stimulation on extraction and biological function of colorectal cancer stem cells.
3D cancer stem cell (CSC) cultures are widely used as in vitro tumor models. In this study, we determined the effects of enriching HCT116 tumor spheres initially cultured in serum-free medium with different concentrations of serum, focusing on the effect of microserum environment stimulation on extraction and biological function of colorectal cancer stem cells (CCSCs). CCSCs were enriched in standard serum-free medium and serum-free medium with different concentrations of serum for 1 week. The expression of CSC-associated markers in CCSCs, and the presence and relative proportion of CSCs (CD133/CD44 cell sorting) were then determined to elucidate the effect of the microserum environment on the preservation of CSC-related features. Further, the tumorigenic capacity of CCSCs was evaluated in an immunodeficiency mouse model. Our data indicated that a significantly greater number of spheres with a greater size range and high viability without drastic alteration in biological and structural features, which maintained self-renewal potential after sequential passages were formed after serum supplementation. Real-time analysis showed that both serum spheres and serum-free spheres displayed similar expression patterns for key stemness genes. Serum spheres showed higher expression of the CSC surface markers CD133 and CD44 than did CSCs spheres cultured in serum-free medium. Adherent cultures in complete medium could adapt to the serum-containing microenvironment faster and showed higher proliferation ability. The addition of serum induced EMT and promoted the migration and invasion of serum globular cells. Compared with serum-free cells and adherent cells, serum spheres showed higher tumor initiation ability. Microserum environment stimulation could be an effective strategy for reliable enrichment of intact CCSCs, and a more efficient CSC enrichment method.


[The nutritional epidemic: How do we eat? How do we shop? What do we purchase?].
The aim of this article is to provide some simple, clear norms which can help us to adopt and to "help to adopt" some healthy feeding habits, habits which we should transmit to our future generations.


Satellite imaging data analysed to evaluate the effectiveness of land-use zoning for the protection of built heritage at Bagan, Myanmar.
This data in brief article describes the data collection and analysis process undertaken to assess the effectiveness of land-use zoning for heritage protection at the UNESCO World Heritage Site of Bagan Myanmar [1]. In order to measure the expansion of urban areas within the Archaeological Zone of Bagan from 1987 to 2018, and thus assess whether development controls functioned effectively, imaging data was acquired from the archives of the US Landsat 5, and the European Space Agency's Sentinel 2 platforms. Shapefiles were generated in QGIS for each settlement within the zone for each of the eight sample years. The changing area, in square kilometres, of these settlements was then analysed over time, with further reference to two 'control' settlements that exist outside of the Archaeological Zone.


Creutzfeldt-Jakob disease: a case with extensive white matter degeneration and optic atrophy.
A 52-year-old woman is described, whose clinical features were typical of Creutzfeldt-Jakob disease except for the presence of optic atrophy. Serial CT scans showed rapid development of brain atrophy early in the course. Postmortem examination revealed extensive degeneration of the cerebral and cerebellar white matter and of the optic nerves in addition to the classic findings of Creutzfeldt-Jakob disease. It is suggested that both the grey and white matter may undergo a severe destructive process early in the course of the disease, and the possibility is discussed that the white matter involvement is not a result of neuronal loss.


Antileishmanial activity in vitro and in vivo of constituents of sea cucumber Actinopyga lecanora.
In the search of new antileishmanial drugs from marine resources, we have investigated Actinopyga lecanora, a coral reef sea cucumber, for its in vitro and in vivo activities. Methanol extract and n-butanol fraction of A. lecanora exhibited excellent Leishmania donovani inhibition. Among the two glycosides isolated from n-butanol fraction, holothurin B (2) displayed excellent in vitro and moderate in vivo leishmanicidal activity, whereas holothurin A (1) revealed only moderate action. These findings provide an important marine lead toward the development of new antileishmanial drugs and necessitate the further exploration of rich and diverse marine resources for more potent bioactive molecules.


[Micro- and macroscale electrophoretic study of the constituent proteins of cerebral structures].
A comparative study of the protein composition of the brain structures of rats (premotor area of the cortex, the CA3 region of the hyppocampus, the caudate nucleus, the frontal area of the cerebellum) was carried out by the method of disc electrophoresis in the micro- and macroscale. Protein zones were identified by their relative electrophoretic mobility calculated according to the mobility of the "marker" protein (trypsin inhibitor from soya beans). Both methods revealed no significant differences in the composition of the electrophoretic separation of the brain proteins pointed to the greater resolving capacity of the micromethod.


Penetration of prulifloxacin into gynaecological tissues after single and repeated oral administrations.
This study aimed to evaluate the penetration into gynaecological tissues of ulifloxacin, the active metabolite of prulifloxacin, a once-daily fluoroquinolone administered once or in repeated doses. This was an open-label, randomised study that included 20 consenting female inpatients (age range 40-65 years) requiring total simple hysterectomy as a result of benign disease. Three groups of patients were enrolled: group A (four patients whose gynaecological tissue samples were used to set up the bioanalytical method); group B (eight patients treated 3 hours before surgery with one 600 mg tablet of prulifloxacin); group C (eight patients treated with prulifloxacin 600 mg once daily for 3 days and undergoing surgery 3 hours after the last dose). Patients to be treated with prulifloxacin were randomly allocated to group B or C. During surgery, samples of blood were collected jointly with healthy tissue removed from the endometrium, proximal fallopian tube, vaginal posterior fornix and portio vaginalis. Ulifloxacin concentrations in plasma and gynaecological tissues were determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) bioanalytical method. An intrastudy assessment of the bioanalytical method performance was also conducted for plasma and tissues using calibration and quality control data (spiked samples). Ulifloxacin mean concentrations were always higher in group C than in group B patients, both in plasma (0.76 vs 0.53 microg/mL) and in gynaecological tissues, namely fallopian tube (1.38 vs 0.81 microg/g), posterior fornix (1.48 vs 1.05 microg/g), portio vaginalis (1.46 vs 1.45 microg/g) and endometrium (2.20 vs 1.39 microg/g), as expected after repeated drug administrations. Tissue concentrations observed after repeated administrations were generally higher than the ulifloxacin minimum inhibitory concentrations for pathogens more frequently involved in gynaecological bacterial infections. The mean tissue/plasma ratios ranged between 1.5 and almost 3. The results of this study are promising but not fully predictive of clinical or microbiological efficacy for prulifloxacin. There is a need for appropriate clinical trials confirming that prulifloxacin is a useful therapeutic tool in patients with gynaecological bacterial infections.


Relativistic baryonic jets from an ultraluminous supersoft X-ray source.
The formation of relativistic jets by an accreting compact object is one of the fundamental mysteries of astrophysics. Although the theory is poorly understood, observations of relativistic jets from systems known as microquasars (compact binary stars) have led to a well established phenomenology. Relativistic jets are not expected to be produced by sources with soft or supersoft X-ray spectra, although two such systems are known to produce relatively low-velocity bipolar outflows. Here we report the optical spectra of an ultraluminous supersoft X-ray source (ULS) in the nearby galaxy M81 (M81 ULS-1; refs 9, 10). Unexpectedly, the spectra show blueshifted, broad Hα emission lines, characteristic of baryonic jets with relativistic speeds. These time-variable emission lines have projected velocities of about 17 per cent of the speed of light, and seem to be similar to those from the prototype microquasar SS 433 (refs 11, 12). Such relativistic jets are not expected to be launched from white dwarfs, and an origin from a black hole or a neutron star is hard to reconcile with the persistence of M81 ULS-1's soft X-rays. Thus the unexpected presence of relativistic jets in a ULS challenges canonical theories of jet formation, but might be explained by a long-speculated, supercritically accreting black hole with optically thick outflows.


In vitro effect of synthetic flavanoids on astrovirus infection.
In this study we investigated the activity of halogeno-, cyano- and amidino-isoflavenes, isoflavans and flavans on the multiplication of human astroviruses. These are naked small round viruses which have been recognized as causative agents of human gastroenteritis, and whose capsid proteins are similar to those of picornaviruses. Although all drugs tested caused a dose-dependent reduction of viral antigen synthesis as monitored by immunofluorescence, the chloro derivatives were the most effective.


Early identification of adverse drug reactions from search log data.
The timely and accurate identification of adverse drug reactions (ADRs) following drug approval is a persistent and serious public health challenge. Aggregated data drawn from anonymized logs of Web searchers has been shown to be a useful source of evidence for detecting ADRs. However, prior studies have been based on the analysis of established ADRs, the existence of which may already be known publically. Awareness of these ADRs can inject existing knowledge about the known ADRs into online content and online behavior, and thus raise questions about the ability of the behavioral log-based methods to detect new ADRs. In contrast to previous studies, we investigate the use of search logs for the early detection of known ADRs. We use a large set of recently labeled ADRs and negative controls to evaluate the ability of search logs to accurately detect ADRs in advance of their publication. We leverage the Internet Archive to estimate when evidence of an ADR first appeared in the public domain and adjust the index date in a backdated analysis. Our results demonstrate how search logs can be used to detect new ADRs, the central challenge in pharmacovigilance.


Synthesis, spectral studies and biological evaluation of 2-aminonicotinic acid metal complexes.
We synthesized 2-aminonicotinic acid (2-ANA) complexes with metals such as Co(II), Fe(III), Ni(II), Mn(II), Zn(II), Ag(I),Cr(III), Cd(II) and Cu(II) in aqueous media. The complexes were characterized and elucidated using FT-IR, UV-Vis, a fluorescence spectrophotometer and thermo gravimetric analysis (TGA). TGA data showed that the stoichiometry of complexes was 1:2 metal/ligand except for Ag(I) and Mn(II) where the ratio was 1:1. The metal complexes showed varied antibacterial, fungicidal and nematicidal activities. The silver and zinc complexes showed highest activity against Bacillus subtilis and Bacillus licheniformis respectively. Fusarium oxysporum was highly susceptible to nickel and copper complexes whereas Macrophomina phaseolina was completely inert to the complexes. The silver and cadmium complexes were effective against the root-knot nematode Meloidogyne javanica.


New trends in brain tumor immunity with the opportunities of lymph nodes targeted drug delivery.
Lymph nodes targeted drug delivery is an attractive approach to improve cancer immunotherapy outcomes. Currently, the depth of understanding of afferent and efferent arms in brain immunity reveals the potential clinical applications of lymph node targeted drug delivery in brain tumors, e.g., glioblastoma. In this work, we systematically reviewed the microenvironment of glioblastoma and its structure as a basis for potential immunotherapy, including the glial-lymphatic pathway for substance exchange, the lymphatic drainage pathway from meningeal lymphatic vessels to deep cervical lymph nodes that communicate intra- and extracranial immunity, and the interaction between the blood-brain barrier and effector T cells. Furthermore, the carriers designed for lymph nodes targeted drug delivery were comprehensively summarized. The challenges and opportunities in developing a lymph nodes targeted delivery strategy for glioblastoma using nanotechnology are included at the end.


Dementia in the oldest old: Beyond Alzheimer disease.
In a Perspective, Aimee Pierce and Claudia Kawas discuss risk factors and pathologies of dementia in the oldest-old.


Measurement of the QT interval and the risk associated with QTc interval prolongation: a review.
The accurate measurement of the QT interval and its correction or adjustment for cycle length, age, and gender have been topics of increasing interest over the course of the past 70 years. The availability of digitized electrocardiographic recordings on large normal populations together with statistical adjustment for pertinent covariates has provided useful data for defining QT interval prolongation. Data from the International Long QT Syndrome Registry indicate that the probabilistic risk of developing malignant arrhythmias in patients with QT prolongation is exponentially related to the length of the QTc interval. The risk is further accentuated by the development of T-wave alternans, particularly at very prolonged QTc intervals.


Decreased sensitivity of isolated hepatocytes from baby rats, from regenerating and from poisoned livers to phalloidin.
Isolated hepatocytes, prepared from 5 day old rats, from regenerating livers of from livers after poisoning with carbon tetrachloride, are less sensitive to phalloidin in vitro than hepatocytes from untreated adult controls. The time course of the reduced susceptibility to phalloidin was compared with the ability of hepatocytes to take up bile acids under various conditions. SDS-electrophoresis of cell lysates gave no evidence for decreased levels of actin in cells with reduced sensitivity to phalloidin. In contrast, there was a good relationship between the active uptake of bile acids and the sensitivity of hepatocytes to phalloidin. The decreased response of hepatocytes from baby rats, from regenerating livers or from poisoned livers to phalloidin is more probably related to differences in phalloidin uptake than to a reduced endowment with microfilamentous structures.


Oncology outpatients with worse depression and sleep disturbance profiles are at increased risk for a higher symptom burden and poorer quality of life outcomes.
/Background - Depression and sleep disturbance are significant problems during chemotherapy. Study purposes were to identify subgroups of patients with distinct joint depression AND sleep disturbance profiles and evaluate for differences in demographic and clinical characteristics, severity of symptoms, and quality of life (QOL) outcomes among these subgroups. Oncology outpatients (n = 1331) completed measures of depression and sleep disturbance six times over two chemotherapy cycles. Latent profile analysis, that modeled the two symptoms together, was done to identify the distinct joint depression and sleep disturbance profiles. Five distinct profiles were identified (i.e., no depression or sleep disturbance (None, 21.4%); no depression and moderate sleep disturbance (32.3%); subsyndromal depression and very high sleep disturbance (20.4%); moderate depression and moderate sleep disturbance (17.7%); and high depression and very high sleep disturbance (8.2%)). Compared to the None class, the other four classes were more likely to be female; less likely to be employed; had a higher comorbidity burden; and had a lower functional status. Patients in the two very high sleep disturbance classes had problems with both sleep initiation and maintenance. These patients reported higher levels of depressive symptoms, trait and state anxiety, and fatigue as well as lower levels of energy, cognitive function, and poorer QOL. Over 45% of the patients had subsyndromal to high levels of depression AND moderate or very high levels of sleep disturbance. Characteristics associated with the higher risk profiles can be used to screen patients at increased risk for both symptoms.


The role of DNA-binding specificity in the evolution of bacterial regulatory networks.
Understanding the mechanisms by which transcriptional regulatory networks (TRNs) change through evolution is a fundamental problem.Here, we analyze this question using data from Escherichia coli and Bacillus subtilis, and find that paralogy relationships are insufficient to explain the global or local role observed for transcription factors (TFs) within regulatory networks. Our results provide a picture in which DNA-binding specificity, a molecular property that can be measured in different ways, is a predictor of the role of transcription factors. In particular, we observe that global regulators consistently display low levels of binding specificity, while displaying comparatively higher expression values in microarray experiments. In addition, we find a strong negative correlation between binding specificity and the number of co-regulators that help coordinate genetic expression on a genomic scale. A close look at several orthologous TFs,including FNR, a regulator found to be global in E. coli and local in B.subtilis, confirms the diagnostic value of specificity in order to understand their regulatory function, and highlights the importance of evaluating the metabolic and ecological relevance of effectors as another variable in the evolutionary equation of regulatory networks. Finally, a general model is presented that integrates some evolutionary forces and molecular properties,aiming to explain how regulons grow and shrink, as bacteria tune their regulation to increase adaptation.


Mechanistic evaluation of the initial burst release of leuprolide from spray-dried PLGA microspheres.
Spray-dried poly(lactic-co-glycolic acid) (PLGA) peptide-loaded microspheres have demonstrated similar long-term in vitro release kinetics compared to those produced by the solvent evaporation method and commercial products. However, the difficult-to-control initial burst release over the first 24 h after administration presents an obstacle to product development and establishing bioequivalence. Currently, detailed information about underlying mechanisms of the initial burst release from microspheres is limited. We investigated the mechanism and extent of initial burst release using 16 previously developed spray-dried microsphere formulations of the hormone drug, leuprolide acetate, with similar composition to the commercial 1-month Lupron Depot® (LD). The burst release kinetics was measured with a previously validated continuous monitoring system as well as traditional sample-and-separate methods. The changes in pore structure and polymer permeability were investigated by SEM imaging and the uptake of a bodipy-dextran probe. In vitro results were compared to pharmacokinetics in rats over the same interval. High-burst, spray-dried microspheres were differentiated in the well-mixed continuous monitoring system but reached an upper limit when measured by the sample-and-separate method. Pore-like occlusions observed by confocal microscopy in some formulations indicated that particle swelling may have contributed to probe diffusion through the polymer phase and showed the extensive internal pore structure of spray-dried particles. Continuous monitoring revealed a rapid primary (1°) phase followed by a constant-rate secondary (2°) release phase, which comprised ∼80% and 20% of the 24-hr release, respectively. The ratio of 1° phase duration (t1°) and the characteristic probe diffusion time (τ) was highly correlated to 1° phase release for spray dried particles. Of the four spray-dried formulations administered in vivo, three spray-dried microspheres with similar polymer density showed nearly ideal linear correlation between in vivo absorption and well-mixed in vitro release kinetics over the first 24 h. By contrast, the more structurally dense LD and a more-dense in-house formulation showed a slight lag phase in vivo relative to in vitro. Furthermore, in vitro dimensionless times (tburst/τ) were highly correlated with pharmacokinetic parameters for spray-dried microspheres but not for LD. While the correlation of increases in effective probe diffusion and 1° phase release strongly suggests diffusion through the polymer matrix as a major release mechanism both in vitro and in vivo, a fixed lower limit for this release fraction implies an alternative release mechanism. Overall, continuous monitoring release and probe diffusion appears to have potential in differentiating between leuprolide formulations and establishing relationships between in vitro release and in vivo absorption during the initial burst period.


Metabolic response to chronic bisphenol A exposure in C57bl/6n mice.
Fetal/neonatal exposure to the endocrine disruptor bisphenol A (BPA) has induced obesity and increased glucose intolerance. We hypothesized that chronic BPA exposure would worsen the obesity and glucose intolerance induced by a high fat diet (HFD). The drinking water of C57bl/6n dams was treated with vehicle (VEH) or BPA (25 ng/ml) from gestation day 11.5 to postnatal day 21. Another group was treated with oral diethylstilbestrol (DES, 1 μg/kg/day) during gestation. Progeny were treated with VEH (VEH and DES groups) or BPA (2.5 ng/ml) in the drinking water and fed either a control diet (CD) or HFD from weaning until euthanasia at 4 months of age. CD-fed mice were similar in size; however HFD-BPA males and HFD-DES mice were smaller than HFD-VEH mice. No CD-fed mice were glucose intolerant. All HFD-fed mice were glucose intolerant. Cholesterol and triglyceride were increased in HFD-VEH mice and HFD-BPA males. Total fat weight and adipocyte area were similar in HFD-VEH and HFD-BPA mice and reduced in HFD-DES mice. HFD-BPA females increased perirenal and reduced gonadal fat weights. Reduced leptin and increased IL-6 in CD-BPA and CD-DES mice were not found in their HFD-cohorts. Adiponectin levels were similar. Thus, although chronic BPA exposure did not increase body size or increase glucose intolerance, it induced an adipokine imbalance in CD-fed mice and sex-specifically altered the lipid response and adipose deposition when fed the HFD.


Redo ileal pouch-anal anastomosis for early versus late sepsis-related pouch failure.
Pouch failure after restorative proctocolectomy with ileal pouch-anal anastomosis occurs in 5% to 15% of cases, mostly due to septic complications. We aimed to determine if the timing of pouch failure impacted long-term outcomes for redo ileal pouch-anal anastomosis after sepsis-related complications. We retrospectively analyzed our prospectively collected institutional pouch database. Patients who underwent redo ileal pouch-anal anastomosis for septic complications between 1988 and 2020 were divided into an early (pouch failure within 6 months of stoma closure after index operation, or stoma never closed) and a late failure group (pouch failure after 6 months of stoma closure). The primary endpoint was pouch survival. In total, 335 patients were included: 241 (72%) in the early and 94 (28%) in the late failure group. The most common indication for failure was an anastomotic leak in the early failure group (163, 68%) and fistula in the late failure group (59, 63%), P < .001. Pouch survival at 3, 5, and 10 years was 77%, 75%, and 72% for the early and 79%, 75%, and 68% for the late failure group (P = .94). The most common reason for redo pouch failure was fistula in both groups. Quality of life was similar in both groups. In multivariate analysis, the only factor associated with pouch failure was the final diagnosis of Crohn's disease. Outcomes after redo ileal pouch-anal anastomosis were comparable between patients with early and late sepsis-related index pouch failure, with acceptable rates of long-term pouch survival and good quality of life.


Electrolytes and norepinephrine levels in blood of patients with cystic fibrosis.
Young adults with cystic fibrosis in good to excellent condition have reduced plasma sodium and chloride and elevated plasma potassium compared to a group of healthy young adult control subjects. Blood pressure was also lower in the patients with cystic fibrosis. However, plasma norepinephrine and dopamine-beta-hydroxylase and their response to standing and isometric hand grip were normal in the cystic fibrosis patients.


The history, evolution and basic science of osteotomy techniques.
Osteotomy techniques date back to Hippocrates circa 415 BC (Jones Hippocrates collected works I, Harvard University Press, Cambridge, 2006; Brorson in Clin Orthop Relat Res 467(7):1907-1914, 2009). There is debate about the best way to divide the bone surgically and which technique yields the best bone regenerate in lengthening; ensuring predictable new bone formation and healing of the osteotomy are the primary goals. We review the history and techniques of the osteotomy and consider the evidence for optimum bone formation. Methods discussed include variants of the 'drill and osteotome' technique, use of the Gigli saw and use of a power saw. Differences in bone formation through the different techniques are covered.


Multi-spectroscopic and molecular modeling studies of bovine serum albumin interaction with sodium acetate food additive.
Sodium acetate (SA) has been used as a highly effective protectant in food industry and the possible effect of this additive on the binding to albumin should be taken into consideration. Therefore, for the first time, the mechanism of SA interaction with bovine serum albumin (BSA) has been investigated by multi-spectroscopic and molecular modeling methods under physiological conditions. Stern-Volmer fluorescence quenching analysis showed an increase in the fluorescence intensity of BSA upon increasing the amounts of SA. The high affinity of SA to BSA was demonstrated by a binding constant value (1.09×103 at 310°K). The thermodynamic parameters indicated that hydrophobic binding plays a main role in the binding of SA to Albumin. Furthermore, the results of UV-vis spectra confirmed the interaction of this additive to BSA. In addition, molecular modeling study demonstrated that A binding sites of BSA play the main role in the interaction with acetate.


PP/Jute Fiber Composites: Effect of Biological Route of Surface Treatment and Content of Jute on Composites.
Jute as a fiber has many applications. It is also used in polymers as reinforcement due to its good tensile properties. However, when it is used in polymer matrices, there is a lack of adhesion between the polymer and jute fiber. Surface treatment of fiber using chemicals has been found to improve the properties. However, the use of chemicals causes environmental pollution, when these chemicals are discharged into the environment. In this paper, an attempt has been made to study the effect of the biological route to surface treat the jute fiber. The effect of surface treatment on the morphology of jute was examined. A comparative study was on the crystalline, thermal, and tensile fracture morphology of the composites to understand the effect of the incorporation of untreated and treated jute fibers in polypropylene (PP).


Tumor-derived EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates collagenase transcription through MAPK p38.
EMMPRIN (extracellular matrix metalloproteinase inducer) stimulates fibroblast metalloproteinases (MMP) 1, 2 and 3 (Kataoka et al. (1993) Cancer Res. 53, 3154-3158). Here we focus on MMP-1, showing that in lung tumors, MMP-1's cognate mRNA is strongly expressed in stromal fibroblasts adjacent to EMMPRIN-expressing tumor cells. In vitro, EMMPRIN upregulates MMP-1 mRNA expression in a concentration-dependent manner, with a peak accumulation at 24 h. The response is genistein-sensitive, suggesting it is dependent on tyrosine kinase activity. Analysis of tyrosine phosphorylation-dependent MAP kinases ERK 1/2, SAPK/JNK, and p38 showed that the activity of p38 but not that of the other 2 kinases was elevated in response to EMMPRIN. That p38 activity was required for EMMPRIN stimulation of MMP-1 was evident from results showing that the p38 inhibitor SB203580 blocked this response. This is the first available information regarding the mechanism by which tumor-associated molecules upregulate MMP synthesis in stromal fibroblasts.


Maternal heat stress reduces body and organ growth in calves: Relationship to immune status.
Late-gestation heat stress of dairy cows reduces fetal growth and influences postnatal performance and immune status of the offspring. Our first objective was to evaluate the effect of in utero heat stress on overall fetal and organ growth, particularly organs associated with immune function. The second objective was to examine the cellular mechanism of altered passive immunity in neonatal bull calves after in utero heat stress. Specifically, we examined the rate of apoptosis of intestinal cells early in life, as it is associated with gut closure. Dams were dried off approximately 45 d before expected calving and randomly assigned to 1 of 2 treatments: heat stress (HT) or cooling (CL). During the dry period all cows were housed under shade in a freestall barn, where the pen for CL cows was equipped with active cooling, including water soakers and fans, whereas the pen for HT cows had no soakers or fans. Using rectal temperature and respiration rate as indicators, heat stress was severe. Average rectal temperature in HT cows was 39.3°C compared with 39.0°C in CL cows, and HT cows had a respiration rate of 66.7 breaths/min compared with 43.2 breaths/min for CL cows. Bull calves (n = 30) were immediately separated from their dams at birth, weighed, and then killed before colostrum feeding (n = 5/treatment; d 0) or at 1 or 2 d of age following colostrum feeding (n = 5/treatment per day). After slaughter, the small intestine was removed and weighed, and samples from the jejunum were fixed for immunohistochemistry. Birth weight of bulls from HT dams was 1.1 kg lower than that of bulls from CL dams. Thymus, spleen, and heart weights of HT bulls were lower relative to those of CL bulls, whereas liver weight of HT bulls tended to be lower relative to that of CL bulls. Jejunal cell apoptosis decreased with age in both HT and CL calves after birth, mirroring gut closure. However, in utero heat stress increased the apoptotic rate in the jejunum, particularly at birth. We conclude that the chronic exposure to heat strain of HT compared with CL dams in late gestation significantly affected fetal growth and immune tissue development, which may be associated with reduced immune function in early life. Also, late-gestation heat stress increased calves' intestinal apoptosis in the first 2 d of life, which might explain the decreased IgG uptake and limited passive immune competence observed in previous studies.


Trends, patterns and psychological influences on COVID-19 vaccination intention: Findings from a large prospective community cohort study in England and Wales (Virus Watch).
Vaccination intention is key to the success of any vaccination programme, alongside vaccine availability and access. Public intention to take a COVID-19 vaccine is high in England and Wales compared to other countries, but vaccination rate disparities between ethnic, social and age groups has led to concern. Online survey of prospective household community cohort study participants across England and Wales (Virus Watch). Vaccination intention was measured by individual participant responses to 'Would you accept a COVID-19 vaccine if offered?', collected in December 2020 and February 2021. Responses to a 13-item questionnaire collected in January 2021 were analysed using factor analysis to investigate psychological influences on vaccination intention. Survey response rate was 56% (20,785/36,998) in December 2020 and 53% (20,590/38,727) in February 2021, with 14,880 adults reporting across both time points. In December 2020, 1,469 (10%) participants responded 'No' or 'Unsure'. Of these people, 1,266 (86%) changed their mind and responded 'Yes' or 'Already had a COVID-19 vaccine' by February 2021. Vaccination intention increased across all ethnic groups and levels of social deprivation. Age was most strongly associated with vaccination intention, with 16-24-year-olds more likely to respond "Unsure" or "No" versus "Yes" than 65-74-year-olds in December 2020 (OR: 4.63, 95 %CI: 3.42, 6.27 & OR 7.17 95 %CI: 4.26, 12.07 respectively) and February 2021 (OR: 27.92 95 %CI: 13.79, 56.51 & OR 17.16 95 %CI: 4.12, 71.55). The association between ethnicity and vaccination intention weakened, but did not disappear, over time. Both vaccine- and illness-related psychological factors were shown to influence vaccination intention. Four in five adults (86%) who were reluctant or intending to refuse a COVID-19 vaccine in December 2020 had changed their mind in February 2021 and planned to accept, or had already accepted, a vaccine.


Anti-MHC immunity detected prior to intentional alloimmunization. III. Natural autoreactive H-2-specific antibodies.
Cell fusion was performed between spleen cells from young BALB/cBy (H-2d) mice which have never been immunized and SP2/0 mouse plasmacytoma cells. A monoclonal H-2 specific cytotoxic IgM antibody was obtained (By-1) which detected a new public biregional H-2 specificity, H-2.m210. The mcAb By-1 reacted strongly with H-2Kd, Dd, and H-2s antigens, gave weak cross-reactions with H-2Kk, Dq, H-2r, and H-2v antigens and was negative with H-2b, H-2f, H-2p, and H-2Ld antigens. A polymorphic reaction pattern was also observed on a panel of lymphocytes from B10.W strains. The intriguing finding on this reaction pattern was the reactivity on H-2d cells, including the syngeneic BALB/cBy and truly autologous cells. As shown by capping and immunoprecipitation experiments on H-2d cells and by studies on H-2d-transfected mouse L cells, the target molecules for McAb By-1 were H-2Kd and H-2Dd molecules. The BALB/cBy mouse, from whose spleen cells the McAb By-1 was obtained, survived after the fusion experiment, and serum was examined for the presence of cytotoxic H-2-specific antibodies during the rest of its life. At the time of the fusion, no autoreactive serum antibodies were found, but about 4 months later, we found in the serum of this mouse autoreactive H-2-specific cytotoxic IgM antibodies. The serum antibodies followed the same reaction pattern as that of the McAb By-1. As far as we know, this is the first report of autoreactive H-2-specific antibodies in serum of a mouse which has never been immunized and of the first natural autoreactive H-2-specific monoclonal antibody.


The development and impact of tuberculosis vaccines.
Vaccination is expected to make a major contribution to the goal of eliminating tuberculosis worldwide by 2050. But developing a new effective vaccine will require innovation in scientific research, a proactive approach to clinical trials of new vaccine candidates, and application of vaccines as part of an integrated approach to disease control.


Acuity card testing of retarded children.
Evaluating the vision of retarded children is important, but it is often very difficult because the children cannot cooperate with the usual symbol recognition acuity tests. A total of 33 unselected children with Down's syndrome were tested with a standard symbol recognition test (Osterberg) and with a new test using acuity cards, which contain black and white square-wave gratings. The acuity cards were found to be useful for testing this group, both in terms of the children's ability to cooperate with the test and the test-retest variability of the results. Although eyes with strabismic amblyopia showed better acuity for gratings than for symbols, there was general agreement with symbol recognition acuities of the same patients. Acuity cards were also used to test 19 severely retarded young children with cerebral palsy, who were unable to be tested with symbols. Acuity card tests were almost always possible with this group, too, though test-retest variability was greater for these children. Acuity card testing can provide useful information about the visual acuity of many retarded children in less than 10 minutes.


Production of mRNA in Chinese hamster cells: relationship of the rate of synthesis to the cytoplasmic concentration of nine specific mRNA sequences.
We constructed cloned DNA sequences complementary to unselected mRNAs [poly(A)+ cytoplasmic RNA] from Chinese hamster ovary cells and used them in RNA:DNA hybridization experiments. Each cloned DNA hybridized a single mRNA from 1.3-3.5 kb in length. The relative rates of labeling (transcription rates) of nuclear RNA complementary to each individual DNA segment varied approximately 10 fold. The relative cytoplasmic concentration of the same specific RNA sequences in the mRNA after an equilibrium labeling of the cells varied approximately 100 fold. In addition, we estimated the sizes of the nuclear RNA precursor molecules to these cytoplasmic mRNAs. Four main conclusions arise from these studies. First, the primary RNA transcripts, which range in size from 2.4-13.5 kb, are 2-6 times larger than the mRNAs; second, each cloned DNA segment is complementary to only one species of mRNA; third, for the RNA complementary to at least three of the nine cloned DNA segments, the relative cytoplasmic content is considerably different from the relative rate of nuclear RNA synthesis, suggesting the post-transcriptional events are involved in the determination of the cytoplasmic concentrations of some mammalian mRNAs; and fourth, the fraction of total nonribosomal nuclear RNA complementary to the nine cloned DNA segments is in most cases 10 fold less than the fraction of cytoplasmic mRNA complementary to the same cloned DNA segments, suggesting the synthesis of many hnRNA molecules that are qualitatively different from those which eventually contribute mRNA to the cytoplasm.


[Hepatitis E infections in rheumatology. A previously underestimated infectious disease?].
The detection and estimation of hepatitis E have greatly changed in recent years. An increasing number of hepatitis E virus (HEV) infections, which were acquired in Europe and knowledge on chronic hepatitis E in immunosuppressed patients, give this infectious disease a new significance in industrial nations in contrast to the previous assumption of merely being a tropical disease with an acute course. Rheumatology patients under immunosuppressive therapy generally have an increased risk of infections. An HEV infection should always be taken into consideration for the differential diagnostics, particularly in cases of increased transaminase levels and/or diarrhea. In contrast to healthy individuals where the course of HEV infections is mostly innocuous, in immunocompromised patients isolated severe and also chronic courses have been described. Testing of these patients should initially also include PCR of HEV-RNA because serological markers are not always reliable. Therapy with ribavirin (cave: off-label) is a possible therapeutic option and should be considered in individual cases in cooperation with a hepatologist and/or specialist for infections. Whether a general screening for HEV before therapy with biologics is recommendable, cannot yet be conclusively assessed. Additionally, an HEV infection should be included in the differential diagnostics of unclear systemic diseases because the disease can have diverse extrahepatic manifestations. There are serological indications that hepatitis E can act as a trigger for autoimmune diseases, such as autoimmune hepatitis and cryoglobulinemia but this phenomenon and the underlying pathological mechanisms need further clarification.


Wintertime pharmacokinetics of intravenously and orally administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus).
To investigate the pharmacokinetics of orally and intravenously (IV) administered meloxicam in semi-domesticated reindeer (Rangifer tarandus tarandus). A crossover design with an 11 day washout period. A total of eight young male reindeer, aged 1.5-2.5 years and weighing 74.3 ± 6.3 kg, mean ± standard deviation. The reindeer were administered meloxicam (0.5 mg kg-1 IV or orally). Blood samples were repeatedly collected from the jugular vein for up to 72 hours post administration. Plasma samples were analysed for meloxicam concentrations with ultraperformance liquid chromatography combined with triple quadrupole mass spectrometry. Noncompartmental analysis for determination of pharmacokinetic variables was performed. The pharmacokinetic values, median (range), were determined. Elimination half-life (t½) with the IV route (n = 4) was 15.2 (13.2-16.8) hours, the volume of distribution at steady state was 133 (113-151) mL kg-1 and clearance was 3.98 (2.63-5.29) mL hour-1 kg-1. After oral administration (n = 7), the peak plasma concentration (Cmax) was detected at 6 hours, t½ was 19.3 (16.7-20.5) hours, Cmax 1.82 (1.17-2.78) μg mL-1 and bioavailability (n = 3) 49 (46-73)%. No evident adverse effects were detected after either administration route. A single dose of meloxicam (0.5 mg kg-1 IV or orally) has the potential to maintain the therapeutic concentration determined in other species for up to 3 days in reindeer plasma.


The impact of compensated and decompensated cirrhosis on the postoperative outcomes of patients undergoing hernia repair: a propensity score-matched analysis of 2011-2017 US hospital database.
Since there is clinical overlap between populations with cirrhosis and those who require hernia repair (i.e. due to stretching of abdominal walls), we systematically evaluate the effects of cirrhosis on post-hernia repair outcomes. 2011-2017 National Inpatient Sample was used to identify patients who underwent hernia repair (included: inguinal, umbilical, and other abdominal hernia repairs). The population was stratified into those with compensated cirrhosis (CC), decompensated cirrhosis (DC), and no cirrhosis; hepatic decompensation was defined as those with portal hypertension, ascites, and varices. The propensity score was used to match the no-cirrhosis controls to CC and DC using the 1:1 nearest neighbor mechanism. Endpoints included mortality, length of stay, costs, and complications. Postmatch, there were 392/446 CC/DC with equal number controls in those undergoing inguinal hernia repair, 714/1652 CC/DC with equal number controls in those undergoing umbilical hernia repair, and 784/702 CC/DC. In multivariate, for inguinal repair, there was no difference in mortality [CC vs. no-cirrhosis aOR 2.61, 95% confidence interval (CI) 0.50-13.52; DC vs. no-cirrhosis: aOR 1.75, 95% CI 0.84-3.63]. For umbilical repair, there was no difference in mortality for CC vs. no-cirrhosis: aOR 0.94, 95% CI 0.36-2.42); however, DC had higher mortality (aOR 2.86, 95% CI 1.76-4.63) when comparing DC vs. no-cirrhosis. For other abdominal repairs, there was no difference in mortality for CC vs. no-cirrhosis (aOR 1.10, 95% CI 0.54-2.23); however, DC had higher mortality (P < 0.001, aOR 2.58, 95% CI 1.49-4.46) when comparing DC vs. no-cirrhosis. This study demonstrates that the presence of DC affects postoperative survival in patients undergoing umbilical or other abdominal hernia repair surgery.


Residual pattern based test for interactions in two-way ANOVA.
This article proposes a new test to detect interactions in replicated two-way ANOVA models, more powerful than the classical F -test and more general than the test of Terbeck and Davies (1998, Annals of Statistics 26, 1279-1305) developed for the case with unconditionally identifiable interaction pattern. We use the parameterization without the conventional restrictions on the interaction terms and base our test on the maximum of the standardized disturbance estimates. We show that our test is unbiased and consistent, and discuss how to estimate the p -value of the test. In a 3 x 3 case, which is our main focus in this article, the exact p -value can be computed by using four-dimensional integrations. For a general I x J case which requires an (I - 1) x (J - 1) dimensional integration for a numerical evaluation of the exact p -value, we propose to use an improved Bonferroni inequality to estimate an upperbound of the p -value and simulations indicate a reasonable accuracy of the upperbound. Via simulations, we show that our test is more powerful than the classical F -test and also that it can deal with both situations: unconditionally identifiable and non-unconditionally identifiable cases. An application to genetic data is presented in which the new test is significant, while the classical F -test failed to detect interactions.


Traditional Chinese medicine combined with radiofrequency ablation improves primary liver cancer outcomes: A systematic review with meta-analysis.
Traditional Chinese medicine and radiofrequency ablation are becoming increasingly important in the treatment of primary liver cancer. However, the clinical outcome of traditional Chinese medicine plus radiofrequency ablation is contentious. This study aimed to conduct a meta-analysis of randomized controlled clinical trials to address this gap. Short-term efficacy, alpha-fetoprotein level, immune function, liver function, and quality of life outcomes in patients with primary liver cancer treated with Chinese herbal medicine adjuvant radiofrequency ablation were systematically reviewed. Eighteen randomized controlled clinical trials with 1488 patients with primary liver cancer were included. The combination treatment significantly increased the objective remission rate and quality of patient survival compared to the control group. Combination treatment significantly improved immunity and liver function factors, including CD3, CD4, CD4/CD8, alanine aminotransferase, aspartate aminotransferase, total bilirubin, and albumin levels. However, there were no statistical differences in CD8 levels across treatments. Trial sequential analysis showed that the cumulative Z-curve of the Objective response rate crossed the conventional and test sequence monitoring boundaries; however, it did not cross the required information size line. Traditional Chinese medicine combined with radiofrequency ablation for primary liver cancer can effectively reduce alpha-fetoprotein and improve clinical efficacy, immune function, liver function, as well as the quality of life.


Application of heparin-conjugated Sepharose for the measurement of cobalamin-saturated and unsaturated transcobalamin II.
The cobalamin-binding plasma protein transcobalamin II has a high affinity for the anticoagulant heparin. This phenomenon has been exploited in a new method for the quantification of cobalamin-saturated (holo-) and unsaturated (apo-) transcobalamin II in human plasma. Transcobalamin II is adsorbed from human plasma to heparin-conjugated Sepharose under suitable conditions and either cobalamin from adsorbed holo-transcobalamin II is measured by a radioisotope dilution assay or apo-transcobalamin II is determined by measuring the adsorbed unsaturated cobalamin-binding capacity with radioactive cobalamin. The assay results for apo- and holo-transcobalamin II are similar (r = 0.99 and 1.0, respectively) to those obtained with the established radioimmunosorbent assay using specific rabbit anti-human transcobalamin II-conjugated Sepharose. The assay cannot be carried out in heparin-anticoagulated plasma, because the free heparin competes with the immobilized heparin for the binding of transcobalamin II. The amount of heparin in plasma from patients being treated with subcutaneous or intravenous heparin is too low to interfere significantly with the measurement of transcobalamin II. Also the presence of circulating anti-transcobalamin II antibodies, as occur in some rare patients after frequent intramuscular injections of cobalamin, does not influence the assay.


Myocardial perfusion of infarcted and normal myocardium in propofol-anesthetized minipigs using (82)Rubidium PET.
Cardiac Rubidium-82 ((82)Rb) positron-emission-tomography (PET) is a good method for quantification of myocardial blood flow in man. Quantification of myocardial blood flow in animals to evaluate new treatment strategies or to understand underlying disease is also of great interest but raises some challenges. Animals, which have been anesthetized during PET acquisition, might react differently to used stress medications, and therefore difficulties might exist while evaluating the resulting PET images using standard software packages from commercial vendors optimized for human hearts. Furthermore propofol, used for anesthesia, can influence myocardial perfusion and coronary flow reserve due to its vasorelaxant effect, and interactions might exist between propofol and used stress agents, potentially affecting the result of the examination. We present cardiac (82)Rb-PET studies performed in propofol-anesthetized minipigs with normal and infarcted myocardium stressed with both adenosine and dipyridamole. Despite the mentioned challenges, we were able to trace the small minipig heart with software designed for human cardiac PET and to achieve blood flow measurements comparable with results in humans with both adenosine and dipyridamole. We found dipyridamole to be a superior stress agent for this experimental setup. Finally, we were able to clearly identify the myocardial perfusion defect after an induced myocardial infarction.


Public perceptions of changing the terminology for low-risk thyroid cancer: a qualitative focus group study.
To investigate public perceptions of overdiagnosis and overtreatment in low-risk thyroid cancer and explore opinions regarding the proposed strategy to change the terminology of low-risk cancers. Qualitative study using focus groups that included a guided group discussion and presentation explaining thyroid cancer, overdiagnosis and overtreatment, and proposed communication strategies. Transcripts were analysed thematically. Sydney, Australia. Forty-seven men and women of various ages from a range of socioeconomic backgrounds with no personal history of thyroid cancer. Participants had low pre-existing general awareness of concepts of overdiagnosis and overtreatment and expressed concern regarding this new information in relation to thyroid cancer. Overall, participants understood why the strategy to change the terminology was being proposed and could see potential benefits including reducing the negative psychological impact and stigma associated with the term 'cancer'; however, many still had reservations about the strategy. The majority of the concerns were around their worry about the risk of further disease progression and that changing the terminology may create confusion and cause patients not to take the diagnosis and its associated managements seriously. Despite varied views towards the proposed strategy, there was a strong overarching desire for greater patient and public education around overdiagnosis and overtreatment in both thyroid cancer and cancer generally in order to complement any revised terminology and/or other mitigation strategies. We found a strong and apparently widely held desire for more information surrounding the topic of overdiagnosis and overtreatment. Careful consideration of how to inform both the public and current patients about the implications of a change in terminology, including changes to patients' follow-up or treatments, would be needed if such a change were to go ahead.


An assessment of cumulative external doses from Chernobyl fallout for a forested area in Russia using the optically stimulated luminescence from quartz inclusions in bricks.
Optically stimulated luminescence (OSL) has been used for estimation of the accumulated doses in quartz inclusions obtained from two fired bricks, extracted in July 2004 from a building located in the forested surroundings of the recreational area Novie Bobovichi, the Bryansk Region, Russia. The area was significantly contaminated by Chernobyl fallout with initial (137)Cs ground deposition level of approximately 1.1 MBq m(-2). The accumulated OSL doses in sections of the bricks varied from 141 to 207 mGy, of which between 76 and 146 mGy are attributable to Chernobyl fallout. Using the OSL depth-dose profiles obtained from the exposed bricks and the results from a gamma-ray-survey of the area, the Chernobyl-related cumulative gamma-ray dose for a point detector located in free air at a height of 1m above the ground in the study area was estimated to be ca. 240 mGy for the time period starting on 27 April 1986 and ending on 31 July 2004. This result is in good agreement with the result of deterministic modelling of the cumulative gamma-ray dose in free air above undisturbed ground from the Chernobyl source in the Bryansk Region. Over the same time period, the external Chernobyl-related dose via forest pathway for the most exposed individuals (e.g., forest workers) is estimated to be approximately 39 mSv. Prognosis for the external exposure from 1986 to 2056 is presented and compared with the predictions given by other investigators of the region.


Rocket-shape crossing technique: A combination of lead extraction and modified venoplasty for device upgrade with venous occlusion.
This case discusses an upgrade method to cardiac resynchronization therapy defibrillator for a 54 year old man with superior vena cava occlusion. Right ventricular lead extraction with modified venoplasty, Rocket shape Crossing Technique (RCT), was performed. In RCT the integration of the inflated balloon, halfway inside the laser sheath, and the laser sheath are advanced through the occlusion like a rocket shape crossing.


A conflicted tribe under pressure: A qualitative study of negative workplace behaviour in nursing.
This study explored workplace interactions of Australian nurses in regional acute care hospitals through an examination of nurses' experiences and perceptions of workplace behaviour. This research is informed by Social Worlds Theory and is the qualitative component of an overarching mixed methods sequential explanatory study. Between January and March 2019, data were collected from 13 nursing informants from different occupational levels and roles, who engaged in semi-structured, in-depth, face-to-face interviews. Data analysis was guided by Straussian grounded theory to identify the core category and subcategories. Theoretical saturation occurred after 13 interviews. The core category identified is A conflicted tribe under pressure, which is comprised of five interrelated subcategories: Belonging to the tribe; 'It's a living hell'; Zero tolerance-'it's a joke'; Conflicted priorities; Shifting the cultural norm. This study provides valuable insight into the nursing social world and the organizational constraints in which nurses work. Although the inclination for an individual to exhibit negative behaviours cannot be dismissed, this behaviour can either be facilitated or impeded by organizational influences. By considering the nurses' experiences of negative workplace behaviour and identifying the symptoms of a struggling system, nurse leaders can work to find and implement strategies to mitigate negative behaviour and create respectful workplace behaviours. This study involved registered nurse participants and there was no patient or public contribution. Study registration Australian New Zealand Clinical Trials Registry (Registration No. ACTRN12618002007213; December 14, 2018).


"I stand alone." An ethnodrama about the (dis)connections between a client and professionals in a residential care home.
Client participation in elderly care organizations requires shifting traditional power relations and establishing communicative action that involves the lifeworlds of clients and professionals alike. This article describes a particular form of client participation in which one client was part of a team of professionals in a residential care home. Their joint remit was to plan the implementation of a new personal care file for residents. We describe the interactions within this team through an ethnodrama, based on participant observations and the embodied presence of the researcher (first author). The narratives and voices of all team members are dramatized in this ethnodrama. Throughout the project the team members experienced confusion relating to the confrontation between lifeworld and system, as experienced by the client and professionals in the team. We analyze these tensions by making use of a Habermasian theoretical framework. We conclude that forms for collective client participation in residential care homes should be developed based on communicative action between clients and professionals, with room for emotional engagement.


Stimulated microglia supernatants induced overexpression of neuronal nitric oxide gene in astrocytes.
The glia-glia, glia-neuron interactions are very complex and have not yet been clearly understood. Microglia gain reactivity in almost every type of brain insult and by affecting astrocytes and neurons, they determine the fate of damaged brain. In the present study we aimed to see the effect of stimulated microglia on nNOS and iNOS expression of astrocytes. The microglia cultures were stimulated with zymosanA and astrocytes were treated with the medium of microglia for 48 h. The results revealed that the astrocytes treated with microglia medium expressed more nNOS and iNOS than the ones treated with normal medium.


The inferior olive of a prosimian primate, Galago senegalensis. II. Olivocerebellar projections to the vestibulocerebellum.
Olivocerebellar projections to the vestibulocerebellum of Galago senegalensis, a prosimian primate, were studied by using a horseradish peroxidase (HRP) method. Following implants of HRP into the flocculus, labeled cells are found in subgroup d of contralateral medial accessory olive (MAO), while labeled somata are present throughout subgroups c and d after injections of HRP into the nodulus and adjacent parts of the uvula. Labeled cells are also located throughout the dorsomedial cell column (DMCC) and a small contingent of HRP-filled cells are seen in dorsomedial areas of the ventral lamellae of the principal olivary nucleus (PO) after HRP placements in nodulus and uvula. Subsequent to injections of paraflocculus, labeled cells are found in subgroup a of MAO, in the lateral bend of PO, and in its ventral lamella (VLPO). Collectively these data indicate a topographically organized projection of olivocerebellar fibers to the flocculonodular lobe and adjacent areas of paraflocculus and uvula. The paraflocculus receives input from subgroup a of MAO, the lateral bend of PO, and VLPO. Subgroup d of MAO projects to the flocculus and nodulus with a relatively minor contribution to uvula. Neurons in subgroups c and DMCC of MAO project to specific portions of nodulus and adjacent uvula. These data are in general agreement with those from other species. In contrast to earlier reports, however, this study describes a projection from VLPO to lateral areas of the contralateral nodulus and uvula. A zonal organization of olivocerebellar terminations in the nodulus and ventral portions of uvula is suggested. A medial zone is subdivided into medial and lateral parts which receive projections from subgroups c and d of MAO, and from cells in DMCC, respectively. A more lateral area receives axons from cells in VLPO.


Effects of cyclic enteral nutrition on the immunological status of malnourished patients.
The effects of 2 weeks of refeeding by cyclic enteral nutrition on chronically malnourished (mean global nutritional deficiency 19.9 +/- 1.1%) hospitalized patients were assessed in a prospective study with special attention paid to immunological status. All patients were immunodeficient, with cell-mediated immunity being more affected than humoral immunity. After 2 weeks of refeeding, nutritional status had improved by 29.8%. Initially abnormal parameters of humoral immunity (IgM, C3 and C4) improved significantly (P < 0.05) between day 0 and day 15. The following cell-mediated immunity parameters also improved significantly (P < 0.05): CD8, monocyte count, natural killer cell activity and skin tests. Short-term refeeding by cyclic enteral nutrition appears to be a safe and effective way of improving immunodeficiency in chronically malnourished patients, with predictable consequences on infection.


Race and surgical outcomes: it is not all black and white.
Studies using Medicare data have suggested that African American race is an independent predictor of death after major surgery. We hypothesized that the apparent adverse effect of race on surgical outcomes is due to confounding by comorbidity, not race itself. We identified all non-Hispanic white and African American general surgery, private sector patients included in the National Surgery Quality Improvement Program (NSQIP) Patient Safety in Surgery Study (2001-2004). Patient characteristics, comorbidities, and postoperative outcomes were collected/analyzed using NSQIP methodology. Characteristics between races were compared using Student t and chi(2) tests. Odds ratios (OR) for 30-day morbidity and mortality were calculated using multivariable logistic regression. We identified 34,141 white and 5068 African American patients. African Americans were younger but more likely to undergo emergency surgery and present with hypertension, dyspnea, diabetes, renal failure, open wounds/infection, or advanced American Society of Anesthesiology class (all P < 0.001). African Americans underwent less complex procedures but had higher unadjusted 30-day morbidity (14.33% vs. 12.35%; P < 0.001) and mortality (2.09% vs. 1.65%; P = 0.02). After controlling for comorbidity, African American race had no independent effect on mortality (OR 0.95, (0.74-1.23)) but was associated with a higher risk of postoperative cardiac arrest (OR 2.49, (1.80-3.45)) and renal insufficiency/failure (OR 1.70 (1.32-2.18)). African American race is associated with greater comorbidity and cardiac/renal complications but is not an independent predictor of perioperative mortality after general surgery. Efforts to improve postoperative outcomes in African Americans should focus on reducing the need for emergency surgery and improving perioperative management of comorbid conditions.


Two-photon imaging and the activation of cortical neurons.
Based on two-photon calcium imaging, Histed et al. (2009) concluded that electrical microstimulation of cortical tissue in mammals activates a sparse and distributed population of neurons. This work has been cited by many as proof that electrical microstimulation is nonfocal, which means it may lack the precision needed for applications in neuroprosthetics. We affirm that the generation of stimulation-evoked behaviour is based primarily on the orthodromic conduction of signals originating mainly from the deepest layers of cortex, while the work of Histed et al. is effectively limited to investigating the antidromic activation of lateral projection neurons of the superficial cortex. The apparent sparse activation is a consequence of the pattern of axonal projections based on activating a volume of axons while imaging cell bodies transecting a single plane through the cortex. This creates the false impression that the distribution of activated neurons is sparse and nonfocal. We recommend how two-photon calcium imaging, which is superb for the study of individual and groups of neurons, might be more effectively used to ascertain how electrical stimulation affects the brains of mammals. This is a timely topic since investigators are using electrical microstimulation in animals to develop prosthetic devices to restore sensory and motor functions in disabled patients.


Systematic microcarrier screening and agitated culture conditions improves human mesenchymal stem cell yield in bioreactors.
Production of human mesenchymal stem cells for allogeneic cell therapies requires scalable, cost-effective manufacturing processes. Microcarriers enable the culture of anchorage-dependent cells in stirred-tank bioreactors. However, no robust, transferable methodology for microcarrier selection exists, with studies providing little or no reason explaining why a microcarrier was employed. We systematically evaluated 13 microcarriers for human bone marrow-derived MSC (hBM-MSCs) expansion from three donors to establish a reproducible and transferable methodology for microcarrier selection. Monolayer studies demonstrated input cell line variability with respect to growth kinetics and metabolite flux. HBM-MSC1 underwent more cumulative population doublings over three passages in comparison to hBM-MSC2 and hBM-MSC3. In 100 mL spinner flasks, agitated conditions were significantly better than static conditions, irrespective of donor, and relative microcarrier performance was identical where the same microcarriers outperformed others with respect to growth kinetics and metabolite flux. Relative growth kinetics between donor cells on the microcarriers were the same as the monolayer study. Plastic microcarriers were selected as the optimal microcarrier for hBM-MSC expansion. HBM-MSCs were successfully harvested and characterised, demonstrating hBM-MSC immunophenotype and differentiation capacity. This approach provides a systematic method for microcarrier selection, and the findings identify potentially significant bioprocessing implications for microcarrier-based allogeneic cell therapy manufacture.


Antimicrobial activity of gatifloxacin tested against 1676 strains of ciprofloxacin-resistant gram-positive cocci isolated from patient infections in North and South America.
Gatifloxacin (formerly AM-115) is a new 8-methoxy fluoroquinolone with an expanded spectrum against Gram-positive cocci and some anaerobes. To assess this new agent's activity, a collection of 1,676 Gram-positive cocci were selected for resistance to ciprofloxacin (> or = 4 micrograms/mL) and tested against gatifloxacin and 18 other compounds by reference broth microdilution methods. The strains (approximately 23,000 total isolates from the SENTRY Antimicrobial Surveillance Program) were from significant blood stream, respiratory tract, wound, and urinary tract infections in patients in North (38 hospitals) and South (10 hospitals) America. Against Enterococcus faecalis and E. faecium, gatifloxacin inhibited only 16% and 10% of strains compared with 12% and 5% for recently released trovafloxacin, respectively. Among Staphylococcus aureus (90% oxacillin-resistant) strains, gatifloxacin was more active (67% susceptible at < or = 4 micrograms/mL) than trovafloxacin (59%) or sparfloxacin (4%). Gatifloxacin had a wider spectrum than trovafloxacin against coagulase-negative staphylococci especially S. epidermidis, 2% versus 58% resistance. The glycopeptides, chloramphenicol and rifampin were most active. Against all genus/species groups with more than 100 sample strains (1,566), high-level resistance to gatifloxacin and trovafloxacin (> 4 micrograms/mL) was not significantly different (41.7% versus 39.1%; p > 0.05). Emerging resistance to the fluoroquinolones remains a clinical problem among Gram-positive species, and gatifloxacin seems to be active in vitro against many of these contemporary strains isolated in the Americas.


Intraspecific competition among first instars of the parasitic wasp Biosteres longicaudatus.
Females of the solitary endoparasitic wasp Biosteres longicaudatus sometimes deposit >1 egg (superparasitism) in each larva of the Caribbean fruit fly host, Anastrepha suspensa. As host density increases, there is an inverse relationship between the level of superparasitism and the number of progeny produced/female. Larval parasitoid competition in superparasitized hosts causes an abrupt decline from >1 to 1 or <1 parasitoid/host 24-36 h before the surviving parasitoid larva molts to the 2nd instar. The mechanism by which supernumaries are eliminated was investigated by indirect, in vivo and direct, in vitro methods. There is no apparent competition between parasitoid eggs of the same age. Parasitoid first instars utilize their heavily sclerotized mandibles to eliminate competitors, some of which are subsequently encapsulated by the host. First instars in vitro produce a substance that kills conspecifics. Presumably, this substance is secreted into the surrounding medium. One of each pair of parasitoid first instars, evenly matched for age and size, may live up to 6.4 days longer and grow to 0.13 mm larger than the other. Thus, B. longicaudatus, like other solitary endoparasitoids eliminates competitors by both combat and interference competitions. The latter case, presumably involves allelochemical toxins against conspecifics in the absence of physical encounter.


Physiological adjustments to hypohydration: Impact on thermoregulation.
Sufficient body water is required to sustain thermoregulatory function, thus losses in total body water (TBW) can challenge the thermoregulatory system. A TBW deficit ≥2% body mass (hypohydration) is recognized as the threshold when thermoregulatory function becomes measurably altered. Hypohydration may occur from voluntary fluid restriction, insufficient fluid availability, or thermoregulatory sweating. The secretion and evaporation of sweat important avenues of body heat loss, and if the water lost is not replaced, hypohydration will decrease plasma volume and increase plasma osmotic pressure (hyperosmotic hypovolemia). Both osmotic and/or volume stressors delay the onset and/or reduce the sensitivity of sweating and blood flow responses. The magnitude of hypohydration, environmental heat stress, the population and circumstances of interest will determine the degree, significance and outcome of these thermoregulatory alterations and their contribution to physiological stress.


[Why nurses fly and surgeons rotate. The surgical study network CHIR-Net].
The German National Surgical Trial Network (CHIR-Net) which has been funded since 2006 by the Federal Ministry of Education and Research (BMBF, funding code 01GH1001A-01GH1001F, 01GH0702) is made up of eight regional surgical centers. The aim of the CHIR-Net is the design, implementation and publication of prospective, randomized, multicenter trials to support evidence-based medicine in surgery. Two main pillars of the CHIR-Net are the surgeon on rotation program and the flying study nurse program. With these two programs the surgical hospitals are supported in their trial working by educating competent investigators and the infrastructural support of flexible and mobile study nurses. The surgeon on rotation program and the concept of the flying study nurse are presented descriptively. Furthermore, this paper provides reports of experiences of a surgeon on rotation and a flying study nurse of the CHIR-Net. Additionally, the results of an on-line evaluation of the regional surgical hospitals (belonging to the regional surgical center of the universities Witten/Herdecke and Cologne) regarding the needs and requirements of the regional surgical hospitals are presented. The surgeon on rotation program of the CHIR-Net offers investigators the possibility to acquire the basics of designing, developing and implementation of high quality clinical trials. In addition, their own study projects could be intensively driven forward. The flying study nurse program enables in particular non-university surgical hospitals to be supported competitively in performing their own study projects and participating in muliticenter clinical trials. The success of these two programs has been confirmed by the conducted evaluations and the presented field reports. The CHIR-Net is able to develop a high quality study culture in Germany with its surgeon on rotation and flying study nurse program. In addition to the funding period by the BMBF, the continuance of the CHIR-Net should be a primary aim of further measures.


Pharmacology of the nitric oxide receptor, soluble guanylyl cyclase, in cerebellar cells.
The nitric oxide (NO) receptor, soluble guanylyl cyclase (sGC), is commonly manipulated pharmacologically in two ways. Inhibition of activity is achieved using 1-H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-l-one (ODQ) which oxidizes the haem prosthetic group to which NO binds, while the compound 3-(5-hydroxymethyl-2-furyl)-1-benzylindazole (YC-1) is considered an 'allosteric' activator. Knowledge of how these agents function and interact in a normal cellular environment is limited. These issues were addressed using rat cerebellar cells. Inhibition by ODQ was not simply competitive with NO. The rate of onset was ODQ concentration-dependent and developed in two kinetic phases. Recovery from inhibition occurred with a half-time of approximately 5 min. YC-1 slowed the rate at which sGC deactivated on removal of NO by 45 fold, consistent with YC-1 increasing the potency of NO for sGC. YC-1 also enhanced the maximal response to NO by 2 fold. Furthermore, when added to cells in which sGC was 90% desensitized, YC-1 abruptly enhanced sGC activity to a degree that indicated partial reversal of desensitization. After pre-exposure to YC-1, sGC became resistant to inhibition by ODQ. In addition, YC-1 rapidly reversed inhibition by ODQ in cells and for purified sGC, suggesting that YC-1 either increases the NO affinity of the oxidized sGC haem or reverses haem oxidation. It is concluded that the actions of ODQ and YC-1 on sGC are broadly similar in cells and purified preparations. Additionally, YC-1 transiently reverses sGC desensitization in cells. It is hypothesized that YC-1 has multiple actions on sGC, and thereby both modifies the NO binding site and enhances agonist efficacy.


Crucial role of the cryptic epitope SLAYGLR within osteopontin in renal crystal formation of mice.
Osteopontin plays a crucial role in the formation of renal calcium crystals, which are primarily induced by renal tubular cell injury, especially mitochondrial damage. We have previously shown that the impaired Arg-Gly-Asp (RGD) sequence of osteopontin inhibits renal crystal formation by using OPN-transgenic mice and OPN-knockout (OPN-KO) mice. Here, we investigated the effects of an antimurine osteopontin antibody (35B6-Ab) that specifically reacts with the (162) SLAYGLR(168) sequence, which is exposed by thrombin cleavage and is located adjacent to the RGD sequence, on renal crystal formation. Renal crystals induced by daily administration of glyoxylate over 9 days (from days 1 to 9) in a murine model were sporadically detected in the renal tubular cells at the corticomedullary junction, where thrombin-cleaved osteopontin expression was also coincidentally detected. On days 0, 3, 6, and 9, 35B6-Ab administration inhibited renal crystal formation and induced significant morphological changes in a dose-dependent manner (250, 500, and 1000 µg per mouse). Scanning electron microscopy showed that the crystals in 35B6-Ab-treated mice were aberrantly formed and their density was low; in contrast, the crystals in untreated mice that were not administered 35B6-Ab had a radial pattern of growth (rosette petal-like crystals), and their density was high. Microstructure analysis of renal tubular cells by transmission electron microscopy revealed that untreated mice showed collapsed mitochondria in the flattened cytoplasm of renal tubular cells, unlike the corresponding structures in 35B6-Ab-treated mice, in which renal tubular cell injury was inhibited. In vitro, 35B6-Ab was found to inhibit the attachment of (14) C-labeled crystals to renal tubular culture cells and reduce morphological damage to these cells. We conclude that thrombin-cleaved osteopontin plays an important role in formation of renal calcium crystals and that 35B6-Ab contributes to the remarkable inhibition of early-stage renal crystal formation by preventing renal tubular cell injury and crystal-cell attachment.


Aluminum inhibits calpain-mediated proteolysis and induces human neurofilament proteins to form protease-resistant high molecular weight complexes.
We studied the effects of aluminum salts on the degradation of human neurofilament subunits (NF-H, NF-M, and NF-L, the high, middle, and low molecular weight subunits, respectively) and other cytoskeletal proteins using calcium-activated neutral proteinase (calpain) purified from human brain. Calpain-mediated proteolysis of NF-L, tubulin, and glial fibrillary acidic protein (GFAP), three substrates that displayed constant digestion rates in vitro, was inhibited by AlCl3 (IC50 = 200 microM) and by aluminum lactate (IC50 = 400 microM). Aluminum salts inhibited proteolysis principally by affecting the substrates directly. After exposure to 400 microM aluminum lactate and removal of unbound aluminum, human cytoskeletal proteins were degraded two- to threefold more slowly by calpain. When cytoskeleton preparations were exposed to aluminum salt concentrations of 100 microM or higher, proportions of NF-M and NF-H formed urea-insoluble complexes of high apparent molecular mass, which were also resistant to proteolysis by calpain. Complexes of tubulin and of GFAP were not observed under the same conditions. Aluminum salts irreversibly inactivated calpain but only at high aluminum concentrations (IC50 = 1.2 and 2.1 mM for aluminum lactate and AlCl3, respectively), although longer exposure to the ion reduced by twofold the levels required for protease inhibition. These interactions of aluminum with neurofilament proteins and the effects on proteolysis suggest possible mechanisms for the impaired axoplasmic transport of neurofilaments and their accumulation in neuronal perikarya after aluminum administration in vivo.


BCAT1 controls embryonic neural stem cells proliferation and differentiation in the upper layer neurons.
The regulation of neural stem cell (NSC) proliferation and differentiation during brain development is a precisely controlled process, with the production of different neuronal subtypes governed by strict timelines. Glutamate is predominantly used as a neurotransmitter by the subtypes of neurons in the various layers of the cerebral cortex. The expression pattern of BCAT1, a gene involved in glutamate metabolism, in the different layers of neurons has yet to be fully understood. Using single-cell data, we have identified seven different states of NSCs and found that state 4 is closely associated with the development of projection neurons. By inferring the developmental trajectory of different neuronal subtypes from NSC subsets of this state, we discovered that BCAT1 is involved in the regulation of NSC proliferation and differentiation and is specifically highly expressed in layer II/III and IV neurons. Suppression of BCAT1 through shRNA resulted in a reduction in NSC proliferation and an abnormal development of layer II/III and IV neurons. These findings provide new insights into the role of BCAT1 in the regulation of NSC behavior and neuronal development.


Neuroimaging characteristics of pseudosubcortical laminar heterotopia.
Subcortical laminar heterotopia (SLH) is a subtype of malformation of cortical development characterized by laminar gray matter between the cortex and ventricles, which can vary in thickness and may be continuous or discontinuous. The objective of this study is to describe a normal finding of high-resolution magnetic resonance imaging that may simulate an SLH. SLH is isointense to cortex on both T1- and T2-weighted/FLAIR images, usually both anteriorly and posteriorly in location. Conversely, pseudo-SLH is a normal variant present only at the posterior aspect of the brain, and with dark signal on both T1- and T2-weighted/FLAIR images.


Is Slovakia Almost a Hepatitis D Free Country?
It is assumed that the prevalence of hepatitis D in HBsAg-positive individuals reaches 4.5-13% in the world and on average about 3% in Europe. Data from several European countries, including Slovakia, are missing or are from an older period. We analyzed all available data on hepatitis D from Slovakia, including reports from the Slovak Public Health Authority and the results of one prospective study, and three smaller surveys. The determination of anti-HDV IgG and IgM antibodies and/or HDV RNA was used to detect hepatitis D. In the years 2005-2022, no confirmed case of acute or chronic HDV infection was reported in Slovakia. The presented survey includes a total of 343 patients, of which 126 were asymptomatic HBsAg carriers, 33 acute hepatitis B, and 184 chronic hepatitis B cases. In a recent prospective study of 206 HBsAg-positive patients who were completely serologically and virologically examined for hepatitis B and D, only 1 anti-HDV IgG-positive and no anti-HDV IgM or HDV RNA-positive cases were detected. In other smaller surveys, two anti-HDV IgG-positive patients were found without the possibility of HDV RNA confirmation. In total, only 3 of 329 HBsAg-positive patients (0.91%) tested positive for anti-HDV IgG antibodies, and none of 220 tested positive for HDV RNA. The available data show that Slovakia is one of the countries with a very low prevalence of HDV infection, reaching less than 1% in HBsAg-positive patients. Routine testing for hepatitis D is lacking in Slovakia, and therefore it is necessary to implement testing of all HBsAg-positive individuals according to international recommendations.


SPC-180002, a SIRT1/3 dual inhibitor, impairs mitochondrial function and redox homeostasis and represents an antitumor activity.
Since sirtuins (SIRTs) are closely associated with reactive oxygen species (ROS) and antioxidant system, the development of their selective inhibitors is drawing attention for understanding of cellular redox homeostasis. Here, we describe the pharmacological properties of SPC-180002, which incorporates a methyl methacrylate group as a key pharmacophore, along with its comprehensive molecular mechanism as a novel dual inhibitor of SIRT1/3. The dual inhibition of SIRT1/3 by SPC-180002 disturbs redox homeostasis via ROS generation, which leads to an increase in both p21 protein stability and mitochondrial dysfunction. Increased p21 interacts with and inhibits CDK, thereby interfering with cell cycle progression. SPC-180002 leads to mitochondrial dysfunction by inhibiting mitophagy, which is accompanied by a reduction in oxygen consumption rate. Consequently, SPC-180002 strongly suppresses the proliferation of cancer cells and exerts anticancer effect in vivo. Taken together, the novel SIRT1/3 dual inhibitor, SPC-180002, impairs mitochondrial function and redox homeostasis, thereby strongly inhibiting cell cycle progression and cancer cell growth.


An age-related loss of the isogeneic barrier to the successful passive cell transfer of antimicrobial immunity in mice.
The results of this study show that an isogeneic barrier to the successful adoptive immunotherapy of Mycobacterium tuberculosis infected mice is progressively lost as these animals age. This was shown in this study by the demonstration that increasing levels of transferred acquired specific resistance could be conferred on normal old recipients of greater than 22 months of age, whereas in young recipients such transfers were unsuccessful without the prior exposure of recipients to sublethal levels of whole-body ionizing gamma irradiation. These data indicate that strategies of adoptive immunotherapy in the elderly may not have to overcome the age-related isogeneic physiological barrier to this procedure.


Optical Coherence Tomography in Neuromyelitis Optica spectrum disorder and Multiple Sclerosis: A population-based study.
The aim of this study was to identify and compare the characteristics of retinal nerve layers using spectral domain-optical coherence tomography (SD-OCT) in neuromyelitis optica spectrum disorder (NMOSD), relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs). It is a cross-sectional population-based study in Isfahan, Iran. We enrolled 98 participants including 45 NMOSD patients (90 eyes), 35 RRMS patients (70 eyes) and 18 HCs (36 eyes). Evaluation criteria were thickness of different sectors in peripapillary retinal nerve fiber layer (pRNFL) and intra-retinal layers around the macula. History of previous optic neuritis (ON) was obtained through chart review and medical record. Without considering ON, total macular, ganglion cell layer (GCL) and pRNFL were significantly thinner in both groups of patients compared to HCs. On macular examination, GCL and total macular thickness were significantly thinner than HCs in all NMOSD and RRMS eyes with and without history of ON. While there was no significant difference between MS-ON and MS without a history of ON in the macular measures, the reduction in total macular and GCL thickness was significantly greater in NMOSD-ON compared to NMOSD without a history of ON. Also in NMOSD-ON eyes, the RNFL, GCL, IPL and GCIPL layers were significantly thinner than that of MS-ON. On the other hand, the pRNFL study showed significant thinning of all quadrants in the RRMS and NMOSD groups relative to HCs. While the decrease of pRNFL thickness in the eyes of NMOSD-ON and MS with and without a previous history of ON was significantly greater than that of HCs, no difference was observed between NMOSD without ON and HCs. In addition, in NMOSD patients, pRNFL was significantly thinner in eyes with history of ON compared to non ON-eyes. Furthermore, in patients with a history of ON, reduction in all sectors of pRNFl (except in T) was significantly greater in NMOSD compared to MS patients. Our findings showed that although macular and retinal damage occurred in both NMOSD and RRMS patients without significant differences, the severity of injury in eyes with history of ON was significantly higher in NMOSD compared to MS patients, that could be considered as a marker to distinguish them. In addition, our results confirmed the absence of subclinical optic nerve involvement in NMOSD unlike MS patients.