Protective effect of taurine against renal interstitial fibrosis of rats induced by cisplatin.
This study was undertaken to investigate the effect of taurine on the infiltration of macrophages and the progression of renal interstitial fibrosis in the kidneys of rats treated with cisplatin (CDDP). Male rats in different groups were treated as follows: (1) saline as control, (2) CDDP and (3) CDDP plus taurine in drinking water. At weeks 2, 4 and 6 after the fifth CDDP injection, we examined platinum content, the kinetics of macrophages and the areas of fibrosis. In the histologic analyses, fibrotic areas were found to have developed around dilated or atrophic tubules in the corticomedullary junction in the kidneys of CDDP-treated rats, while CDDP-plus-taurine-treated rats showed a reduction of the extent and magnitude of damage. These findings reflect the fact that the percentage of fibrotic areas in the kidney of CDDP-plus-taurine-treated rats was significantly lower than in that of CDDP-injected rats throughout the recovery period ( P<0.05). Compared with normal rats, the macrophages in CDDP-injected rats showed significant increases in number at weeks 2, 4 and 6 ( P<0.05). In contrast, the number of macrophages in CDDP-plus-taurine-treated rats was significantly smaller than that of CDDP-injected rats. These results suggested that taurine suppressed the increase of infiltrating macrophages, and led to the attenuation of renal interstitial fibrosis ( P<0.05).


Unusually high-pitched neonate distress calls of the open-habitat Mongolian gazelle (Procapra gutturosa) and their anatomical and hormonal predictors.
In neonate ruminants, the acoustic structure of vocalizations may depend on sex, vocal anatomy, hormonal profiles and body mass and on environmental factors. In neonate wild-living Mongolian gazelles Procapra gutturosa, hand-captured during biomedical monitoring in the Daurian steppes at the Russian-Mongolian border, we spectrographically analysed distress calls and measured body mass of 22 individuals (6 males, 16 females). For 20 (5 male, 15 female) of these individuals, serum testosterone levels were also analysed. In addition, we measured relevant dimensions of the vocal apparatus (larynx, vocal folds, vocal tract) in one stillborn male Mongolian gazelle specimen. Neonate distress calls of either sex were high in maximum fundamental frequency (800-900 Hz), but the beginning and minimum fundamental frequencies were significantly lower in males than in females. Body mass was larger in males than in females. The levels of serum testosterone were marginally higher in males. No correlations were found between either body mass or serum testosterone values and any acoustic variable for males and females analysed together or separately. We discuss that the high-frequency calls of neonate Mongolian gazelles are more typical for closed-habitat neonate ruminants, whereas other open-habitat neonate ruminants (goitred gazelle Gazella subgutturosa, saiga antelope Saiga tatarica and reindeer Rangifer tarandus) produce low-frequency (<200 Hz) distress calls. Proximate cause for the high fundamental frequency of distress calls of neonate Mongolian gazelles is their very short, atypical vocal folds (4 mm) compared to the 7-mm vocal folds of neonate goitred gazelles, producing distress calls as low as 120 Hz.


Spontaneous bladder perforation in a neonate.
Spontaneous bladder perforation in the newborn setting is a rare clinical phenomenon that can be life threatening if left untreated. Several risk factors have been identified in previously reported cases such as hypoxia and bladder diverticula. We present the first case of neonatal bladder rupture without any identifiable risk factors.


Profile of the use of dermoscopy among dermatologists in Brazil (2018).
Dermoscopy increases the diagnostic accuracy in dermatology. The aspects related to training, usage profile, or perceptions of usefulness of dermoscopy among dermatologists in Brazil have not been described. To evaluate the profile of the use of dermoscopy and the perception of the impact of the technique on clinical practice. The Brazilian Society of Dermatology invited all members to complete an online form with 20 items regarding demographic data, dermatological assistance, use of dermoscopy, and perceptions of the impact of the technique on clinical practice. The proportions between the categories were compared by analysis of residuals in contingency tables, and p-values < 0.01 were considered significant. The answers from 815 associates (9.1% of those invited to participate) were assessed, 84% of whom were female, and 71% of whom were younger than 50 years of age. The use of dermoscopy was reported in the daily practice of 98% of dermatologists: 88% reported using it more than once a day. Polarized light dermoscopy was the most used method (83%) and pattern analysis was the most used algorithm (63%). The diagnosis and follow-up of melanocytic lesions was identified as the main use of the technique, while the benefit for the diagnosis of inflammatory lesions was acknowledged by less than half of the sample (42%). This was a non-randomized study. Dermoscopy is incorporated into the clinical practice of almost all Brazilian dermatologists, and it is recognized for increasing diagnostic certainty in different contexts, especially for pigmented lesions.


Delayed peak response of cortisol to insulin tolerance test in patients with Prader-Willi syndrome.
Deaths among children with Prader-Willi syndrome (PWS) are often related to only mild or moderate upper respiratory tract infections, and many causes of death remain unexplained. Several reports have hypothesized that patients with PWS may experience latent central adrenal insufficiency. However, whether PWS subjects suffer from alteration of the hypothalamus-pituitary-adrenal (HPA) axis remains unclear. This study aimed to explore the HPA axis on PWS. We evaluated the HPA axis in 36 PWS patients (24 males, 12 females; age range, 7 months to 12 years; median age 2.0 years; interquartile range [IQR], 1.5-3.4 years) using an insulin tolerance test (ITT) in the morning between 08:00 and 11:00. For comparison, ITT results in 37 age-matched healthy children evaluated for short stature were used as controls. In PWS patients, basal levels of adrenocorticotropic hormone (ACTH) were 13.5 pg/ml (IQR, 8.3-27.5 pg/ml) and basal levels of cortisol were 18.0 μg/dl (IQR, 14.2-23.7 μg/dl). For all patients, cortisol levels at 60 min after stimulation were within the reference range (>18.1 μg/dl), with a median peak of 41.5 μg/dl (IQR, 32.3-48.6 μg/dl). Among control children, basal level of ACTH and basal and peak levels of cortisol were 10.9 (IQR, 8.5-22.0 pg/ml), 15.6 (IQR, 11.9-21.6 μg/dl), and 27.8 μg/dl (IQR, 23.7-30.5 μg/dl), respectively. Basal and peak levels of cortisol were all within normal ranges, but peak response of cortisol to ITT was delayed in the majority of PWS patients (64%). Although the mechanism remains unclear, this delay may signify the existence of central obstacle in adjustment of the HPA axis.


Evaluation of a quasi-passive biarticular prosthesis to replicate gastrocnemius function in transtibial amputee gait.
Lower limb amputees experience gait impairments, in part due to limitations of prosthetic limbs and the lack of a functioning biarticular gastrocnemius (GAS) muscle. Energy storing prosthetic feet restore the function of the soleus, but not GAS. We propose a transtibial prosthesis that implements a spring mechanism to replicate the GAS. A prototype Biarticular Prosthesis (BP) was tested on seven participants with unilateral transtibial amputation. Participants walked on an instrumented treadmill with motion capture, first using their prescribed prosthesis, then with the BP in four different spring stiffness conditions. A custom OpenSim musculoskeletal model, including the BP, was used to estimate kinematics, joint torques, and muscle forces. Kinematic symmetry was evaluated by comparing the amputated and intact angles of the ankle, knee, and hip. The BP knee and ankle torques were compared to the intact GAS. Finally, work done by the BP spring was calculated at the ankle and knee. There were no significant differences between conditions in kinematic symmetry, indicating that the BP performs similarly to prescribed prostheses. When comparing the BP torques to intact GAS, higher spring stiffness better approximated peak GAS torques, but those peaks occurred earlier in the gait cycle. The BP spring did positive work on the knee joint and negative work on the ankle joint, and this work increased as BP spring stiffness increased. The BP has the potential to improve amputee gait compensations associated with the lack of biarticular GAS function, which may reduce their walking effort and improve quality of life.


Reasonable expectations: how much aerobic capacity, muscle strength, and quality of life can improve with exercise training in heart failure.
In this article, the literature that describes the magnitude of functional and quality of life gains with a traditional moderate-intensity aerobic and resistance training programs is reviewed, and differences between the impact of exercise training in heart failure with preserved ejection fraction versus heart failure with reduced ejection fraction are discussed.


Mass and charge balance in self-assembled multilayer films on gold. Measurements with optical reflectometry and quartz crystal microbalance.
This work aimed to the determination of weight uptakes and charge balance in the course of successive deposition of polyelectrolytes, using the so-called self-assembled multilayer technique. Polyelectrolytes were the quaternized polydimethylaminoethyl methacrylate chloride, (MADQUAT) and poly(acrylic acid) (PAA). Experiments were made at pH 5.5 in NaCl solutions between 10(-3) and 10(-1) M. Deposits (5 bilayers) on a gold substrate were monitored using a quartz crystal microbalance (QCM) and optical fixed-angle reflectometry. Analysis of data lead to the determination of the sensitivity factor of the reflectometric output. QCM allowed the direct measurement of weight uptakes in 10(-3) and 10(-2) M solutions, while the viscoelastic properties of the film did not look appropriate for the measurement in 10(-1) M solutions. The layer-by-layer uptakes and charge balances in 10(-3) and 10(-2) M solutions revealed a large contribution of the counterions in the neutralization of the electrical charge in the film, more so for the highly charged MADQUAT polymer. The difference between two successive polymer charge densities increased significantly with the layer number and the electrolyte concentration. The increase of NaCl concentration induced an increase of MADQUAT but reversely a decrease of PAA deposits. The results were consistent with the determining influence of the salt in polyelectrolyte adsorption, both with regards to the concentration and the type of ions that has been well demonstrated in the literature. This work also draws attention to the role of small ions in the structural and application properties of self-assembled multilayer films.


Cardiac tamponade resulting from pericardial extramedullary hematopoiesis: a case report and review of the literature.
A patient with an unusual myeloproliferative disorder, characterized by hepatosplenomegaly, myelofibrosis, ringed sideroblasts, and conversion to acute myeloblastic leukemia developed cardiac tamponade secondary to pericardia extramedullary hematopoiesis. Diagnostic criteria are discussed. Irradiation and systemic chemotherapy were successful in controlling the effusion.


TCRpMHCmodels: Structural modelling of TCR-pMHC class I complexes.
The interaction between the class I major histocompatibility complex (MHC), the peptide presented by the MHC and the T-cell receptor (TCR) is a key determinant of the cellular immune response. Here, we present TCRpMHCmodels, a method for accurate structural modelling of the TCR-peptide-MHC (TCR-pMHC) complex. This TCR-pMHC modelling pipeline takes as input the amino acid sequence and generates models of the TCR-pMHC complex, with a median Cα RMSD of 2.31 Å. TCRpMHCmodels significantly outperforms TCRFlexDock, a specialised method for docking pMHC and TCR structures. TCRpMHCmodels is simple to use and the modelling pipeline takes, on average, only two minutes. Thanks to its ease of use and high modelling accuracy, we expect TCRpMHCmodels to provide insights into the underlying mechanisms of TCR and pMHC interactions and aid in the development of advanced T-cell-based immunotherapies and rational design of vaccines. The TCRpMHCmodels tool is available at http://www.cbs.dtu.dk/services/TCRpMHCmodels/ .


An overview on 3D printing for abdominal surgery.
Three-dimensional (3D) printing is a disruptive technology that is quickly spreading to many fields, including healthcare. In this context, it allows the creation of graspable, patient-specific, anatomical models generated from medical images. The ability to hold and show a physical object speeds up and facilitates the understanding of anatomical details, eases patient counseling and contributes to the education and training of students and residents. Several medical specialties are currently exploring the potential of this technology, including general surgery. In this review, we provide an overview on the available 3D printing technologies, together with a systematic analysis of the medical literature dedicated to its application for abdominal surgery. Our experience with the first clinical laboratory for 3D printing in Italy is also reported. There was a tenfold increase in the number of publications per year over the last decade. About 70% of these papers focused on kidney and liver models, produced primarily for pre-interventional planning, as well as for educational and training purposes. The most used printing technologies are material jetting and material extrusion. Seventy-three percent of publications reported on fewer than ten clinical cases. The increasing application of 3D printing in abdominal surgery reflects the dawn of a new technology, although it is still in its infancy. The potential benefit of this technology is clear, however, and it may soon lead to the development of new hospital facilities to improve surgical training, research, and patient care.


Patients at high risk for a severe clinical course of COVID-19 - small-area data in support of vaccination and other population-based interventions in Germany.
Research has shown that the risk for a severe course of COVID-19 is increased in the elderly population and among patients with chronic conditions. The aim of this study was to provide estimates of the size of vulnerable populations at high risk for a severe COVID-19 course in Germany based on the currently available risk factor data. We used nationwide outpatient claims data from the years 2010 to 2019 collected according to § 295 of the Code of Social Law V, covering data for all statutory health insurees (SHI) which is nearly 87% of the entire German population. We considered 15 chronic disorders based on the current state of knowledge about clinically relevant risk factors. Three risk groups for a severe COVID-19 course were defined: 1. individuals in the age group 15 to 59 years with at least two comorbid disorders; 2. individuals aged 60 to 79 years with at least one disorder and 3. all individuals 80 years and older irrespective of the presence of chronic conditions. Regional analysis was conducted at the level of administrative districts (n = 401). Overall, 26% of individuals over 15 years were at high risk for a severe COVID-19 course in 2019 amounting to a total number of nearly 18.5 million individuals in Germany. This included 3.8 million individuals in risk group 1, 9.2 million in risk group 2, and 5.4 million in risk group 3, corresponding to 8, 50 and 100% of German inhabitants in the respective age groups. On the level of the 17 administrative regions formed by the Association of SHI Physicians (ASHIP regions), the proportion of individuals at high risk ranged between 21% in Hamburg and 35% in Saxony-Anhalt. Small-area estimates varied between 18% in Freiburg (Baden-Württemberg) and 39% in the district Elbe-Elster (Brandenburg). The present study provides small-area estimates of populations at high risk for a severe COVID-19 course. These data are of particular importance for planning of preventive measures such as vaccination. not applicable.


Cathelicidin-trypsin inhibitor loop conjugate represents a promising antibiotic candidate with protease stability.
Cathelicidins are regarded as promising antibiotics due to their capability against antibiotic-resistant bacteria without cytotoxicity. However, some concerns about the balance of cytotoxicity and antimicrobial activity, weak stability and enzymatic susceptibility sually restrict their therapeutic use. Here, we designed a series of shortened variants, Hc1~15, based on our previously characterized Hc-CATH. Hc3, the one with the best activity, after point mutation was engineered with a trypsin inhibitor loop, ORB-C, to obtain four hybrid peptides: H3TI, TIH3, H3TIF and TIH3F. All four except TIH3 were found possessing an appreciable profile of proteases inhibitory and antimicrobial characteristics without increase in cytotoxicity. Among them, TIH3F exhibited the most potent and broad-spectrum antimicrobial and anti-inflammatory activities. Fluorescence spectroscopy has demonstrated a quick induction of bacterial membrane permeability by TIH3F leading to the cell death, which also accounts for its fast anti-biofilm activity. Such mode of antimicrobial action was mainly attributed to peptides' amphiphilic and helical structures determined by CD and homology modeling. Besides, TIH3F exhibited good tolerance to salt, serum, pH, and temperature, indicating a much better physiological stability in vitro than Hc3, Most importantly, in the case of resistance against proteases hydrolysis, current hybrid peptides displayed a remarkable enhancement than their original templates.


Teaching-learning evaluation on the ICNP® using virtual learning environment.
Evaluating the teaching-learning process of undergraduates and nursing professionals on the International Classification for Nursing Practice (ICNP®) through a course on Moodle Platform. Mixed research conducted with 51 nursing students and nurses. Many technological and educational resources were used. To collect data, two semi-structured questionnaires were applied and focus groups were carried out. Statistical and thematic analysis of the data was performed. There was a correlation between the Wiki variable, the Animation Video (p = 0.002) and the Arch Method (p = 0.04), as well as a correlation between the Forum, the Virtual Book (P < 0.001) and time (p = 0.009). Three topics emerged: innovation in the application of technological resources, distance education in the professional education and permanent education and the teaching-learning process on the ICNP® in a collaborative way. Teaching-learning strategies and technological resources used were pointed out as innovative and helped students have a better performance.


Identification of multiple nonphotochemical quenching processes in the extremophilic red alga Cyanidioschyzon merolae.
Nonphotochemical quenching acts as a frontline response to prevent excitation energy from reaching the photochemical reaction center of photosystem II before photodamage occurs. Strong fluorescence quenching after merely one multi-turnover saturating light pulse characterizes a unique feature of nonphotochemical quenching in red algae. Several mechanisms underlying red algal nonphotochemical quenching have been proposed, yet which process(es) dominantly account for the strong fluorescence quenching is still under discussion. Here we assessed multiple nonphotochemical quenching processes in the extremophilic red alga Cyanidioschyzon merolae under light pulse and continuous illumination conditions. To assess the nonphotochemical quenching processes that might display different kinetics, fluorescence emission spectra at 77 K were measured after different periods of light treatments, and external fluorophores were added for normalization of the fluorescence level. The phycobilisome- and photosystem II-related nonphotochemical quenching processes were distinguished by light preferentially absorbed by phycobilisomes and photosystems, respectively. Multiple nonphotochemical quenching processes, including the energetic decoupling of phycobilisomes from photosystem II, the energy spillover from phycobilisomes to photosystem I and from photosystem II to photosystem I, were identified along with the previously identified intrinsic quenching within photosystem II. The ability to use multiple nonphotochemical quenching processes appears to maximize the light harvesting efficiency for photochemistry and to provide the flexibility of the energy redistribution between photosystem II and photosystem I. The effect of the various ionophores on the nonphotochemical quenching level suggests that nonphotochemical quenching is modulated by transmembrane gradients of protons and other cations.


Achievement of metabolic control among children and adolescents with type 1 diabetes in Spain.
To assess metabolic control in a paediatric T1D population in Spain and analyse the rate of severe acute decompensations and chronic complications. Data from patients treated at eight paediatric diabetes units with experienced diabetes teams between June and December 2014 were analysed in an observational prospective study. Variables included: age, sex, diabetes duration, number of follow-up visits/year, anthropometrical data, insulin treatment modalities, mean annual HbA1c and the prevalence of acute and chronic complications. SPSS statistics 21.0 was used. A total of 853 patients (49.7% female) with a mean age of 12.1 ± 3.7 years were included. Anthropometric data were normal. Mean diabetes duration was 8 ± 3.4 years. Mean outpatient follow-up was 4.7 ± 0.04 visits/year. Twenty-five per cent were on continuous subcutaneous insulin infusion (CSII). Mean HbA1c was 7.3 ± 1% (56 ± 8 mmol/mol) and 66.6% had HbA1c < 7.5% (58 mmol/mol). HbA1c value correlated negatively with age at onset and positively with years of diabetes, number of visits/year and current age (F = 7.06; p = 0.01). Patients on CSII (n = 213) were younger, attended the outpatient clinic more frequently, were diagnosed earlier, had better metabolic control and had presented more severe hypoglycaemic episodes the previous year. The rate of severe decompensation (episodes/100 patients/year) was ketoacidosis 1.5 and severe hypoglycaemia 4.5. The prevalence of chronic complications was very low. Our data describe the good compliance of paediatric T1D patients treated at eight paediatric units in Spain following international standards of metabolic control.


Environmental DNA of insects and springtails from caves reveals complex processes of eDNA transfer in soils.
Subterranean environments host a substantial amount of biodiversity, however assessing the distribution of species living underground is still extremely challenging. Environmental DNA (eDNA) metabarcoding is a powerful tool to estimate biodiversity in poorly known environments and has excellent performance for soil organisms. Here, we tested 1) whether eDNA metabarcoding from cave soils/sediments allows to successfully detect springtails (Hexapoda: Collembola) and insects (Hexapoda: Insecta); 2) whether eDNA mostly represents autochthonous (cave-dwelling) organisms or it also incorporates information from species living in surface environments; 3) whether eDNA detection probability changes across taxa with different ecology. Environmental DNA metabarcoding analyses detected a large number of Molecular Operational Taxonomic Units (MOTUs) for both insects and springtails. For springtails, detection probability was high, with a substantial proportion of hypogean species, suggesting that eDNA provides good information on the distribution of these organisms in caves. Conversely, for insects most of MOTUs represented taxa living outside caves, and the majority of them represented taxa/organisms living in freshwater environments (Ephemeroptera, Plecoptera and Trichoptera). The eDNA of freshwater insects was particularly abundant in deep sectors of caves, far from the entrance. Furthermore, average detection probability of insects was significantly lower than the one of springtails. This suggests that cave soils/sediments act as "conveyer belts of biodiversity information", possibly because percolating water lead to the accumulation of eDNA of organisms living in nearby areas. Cave soils hold a complex mix of autochthonous and allochthonous eDNA. eDNA provided unprecedented information on the understudied subterranean cave organisms; analyses of detection probability and occupancy can help teasing apart local eDNA from the eDNA representing spatially-integrated biodiversity for whole landscape.


Induction of cholesterol biosynthesis by archazolid B in T24 bladder cancer cells.
Resistance of cancer cells towards chemotherapeutics represents a major cause of therapy failure. The objective of our study was to evaluate cellular defense strategies in response to the novel vacuolar H(+)-ATPase inhibitor, archazolid B. The effects of archazolid B on T24 bladder carcinoma cells were investigated by combining "omics" technologies (transcriptomics (mRNA and miRNA) and proteomics). Free cholesterol distribution was determined by filipin staining using flow cytometry and fluorescence microscopy. Flow cytometry was performed for LDLR surface expression studies. Uptake of LDL cholesterol was visualized by confocal microscopy. SREBP activation was determined performing Western Blotting. The efficiency of archazolid B/fluvastatin combination was tested by cytotoxicity assays. Archazolid B led to accumulation of free cholesterol within intracellular compartments and drastic disturbances in cholesterol homeostasis resulting in activation of SREBP-2 (sterol regulatory element-binding protein 2) and up-regulation of target genes including HMGCR (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis. LDLR surface expression was reduced and LDL uptake was completely inhibited after 24h, indicating newly synthesized cholesterol to be the main source of cholesterol in archazolid B treated cells. By combining archazolid B with the HMGCR inhibitor fluvastatin, cholesterol was reduced and cell viability decreased by about 20% compared to archazolid B treatment alone. Our study revealed cholesterol biosynthesis as an important resistance mechanism in T24 cells after archazolid B treatment. The combination of archazolid B with statins may be an attractive strategy to potentiate archazolid B induced cell killing by affecting cholesterol biosynthesis.


[Value of "medication screening" in therapy for chronic pain].
Drug therapy plays often an important role in the treatment of chronic pain. Former studies and also experiences of clinical practice have given evidence, that insufficient patient compliance is a widespread event. Therefore drug screening becomes a significant tool for quality assurance. In the following the methodical and practical aspects of drug screening are described and recommendations for its use in clinical practice are suggested. This tool can be used to check the intake of prescribed drugs, to detect hidden taken drugs, to decide whether side effects result of the prescribed medication or not and to support a withdrawal therapy. Drug screening presupposes an informed patient, who consents to the investigation. Otherwise confidence is risked and the handling with unexpected results is not possible any more. Testing of urine has the advantage of a non invasive procedure and makes use of the reservoir of the bladder. A close co-operation and good communication between therapist and laboratory prevents misinterpretations, which might result from inaccurate formulated questions or methodical limitations, for instance because of cross reacting substances or a too insensitive detection level for the respective drug. The finding must primary bee used to value the therapy and improve the compliance but can not prove the patient himself. Even if the value of drug screening is not prospectively investigated until now, clinical experiences reveals it is as powerful tool for monitoring effectiveness and side effects of pharmacotherapy of pain and also of patient compliance which the prescribed drug regimes.


Editorial Commentary: Should We Condemn the Shoulder Instability Severity Index Scoring System? Not at All!... Can We Improve Its Radiographic Component? Yes, We Can!
Is patient selection necessary in shoulder instability surgery? Absolutely. The risk-benefit discussion that the surgeon must have with the patient before proposing an arthroscopic Bankart repair remains crucial to provide informed consent. The most important preoperative risk factors are incorporated in the instability severity index (ISI) score to assist surgeons in the decision-making process. This 10-point score is based on factors derived from a preoperative questionnaire, physical examination, and simple plain radiographs. Using this score at the first visit, the surgeon can explain to the patient and family why a Bankart repair may be contraindicated and why other surgical options may be more suitable. A recent study found that the ISI score has no limited predictive value when applied in a preselected population of military patients without severe bone loss or hyperlaxity. This is not surprising because the authors analyzed a preselected patient population with lower risk than the general population. The value of the ISI scoring system relies on the fact that this tool has been developed after evaluation of arthroscopic Bankart repair in an unselected patient population and that there is no need for sophisticated imaging studies to make the decision. This scoring system should not be condemned but complemented with preoperative advanced imaging studies (computed tomography [CT] scanning or magnetic resonance imaging) to assess the severity of the bone lesions more accurately. Today, the choice of the surgical procedure depends not only on the clinical risk factors included in the ISI score (age, type of sports, level of practice, hyperlaxity) but also on the presence, location and size of bony lesions, as identified and measured on advanced CT scanning images.


Antibiotic dosing adjustments in hospitalized patients with chronic kidney disease: a retrospective chart review.
Infections in patients with chronic kidney disease (CKD) are a major cause of hospitalization. The pharmacokinetics of renally eliminated antibiotics may lead to drug accumulation, resulting in potential toxicity. The renal dosing adjustment of antibiotics is crucial to avoid toxicity and decrease mortality. In Lebanon, limited data are available on antibiotic dose adequacy in CKD. To estimate the prevalence of inappropriately dosed antibiotics in non-dialysis CKD patients and to identify possible risk factors that may be associated with unadjusted renal dosing. A retrospective chart review was conducted at two tertiary-care hospitals in Lebanon. International Statistical Classification of Diseases (ICD-10) code for CKD was used to search the databases. Demographic and clinical data were collected for patients who received antibiotics that requires renal dosing adjustment. Lexi-Comp online Drug Information database was the guideline used to evaluate the appropriateness of dosing. A total of 495 antibiotic orders were dispensed to 190 patients. 51.6% of patients received antibiotics without renal dose adjustments. The most inappropriately dosed class was penicillins (39.8%), while fluoroquinolones were the most adequately adjusted. Piperacillin/tazobactam was the most frequently prescribed drug (30.6%) without renal dose adjustment. Respiratory infections (OR 1.301, CI 95% 1.327-1.915) and multimorbidity (OR 1.183, CI 95% 1.358-2.081) were statistically highly significant associations for unadjusted antibiotic dosing from the fitted multivariable-adjusted logistic models. Our study revealed a high frequency of guideline-discordant antibiotic dosing in patients with CKD. This dosing error is preventable by increasing awareness of prescribing physicians and collaborating with clinical pharmacists.


Increased Circulating Autoantibodies Levels of IgG, IgA, IgM Against Cytokeratin 18 and Cytokeratin 19 in Chronic Obstructive Pulmonary Disease.
Autoimmune processes are involved in the progression of chronic obstructive pulmonary disease (COPD). Autoantibodies against cytokeratin 18 (CK18) and cytokeratin 19 (CK19) could be associated with lung injury. We undertook this study to investigate the role of these autoantibodies against CK18 and CK19 in the development of COPD. We used blood samples from 228 COPD patients or 136 healthy controls and male C57BL/6j mice as experimental subjects to analyze the serum autoantibody levels against CK18 or CK19 autoantigen by enzyme-linked immunosorbent assay (ELISA). We found that the circulating autoantibody levels of IgG, IgA, IgM against CK18 and CK19 were elevated in patients with COPD compared with healthy controls, which were increased gradually as the severity of the disease increases, especially in GOLD III and GOLD IV with the exception of anti-CK19 IgG and anti-CK18 IgA autoantibodies. Moreover, we observed that the serum levels of anti-CK18 and anti-CK19 IgG autoantibodies were higher in mice exposed to cigarette smoke compared with mice exposed to room air for 6 months and 9 months. Additionally, we identified the distribution of antibodies and the presence of autoantibodies (IgG) against CK18 and CK19 in the damaged lung tissues of mice. Increased circulating autoantibodies against CK18 and CK19 are closely related to the progression of COPD, which play an important role in the process of lung injury in COPD, suggesting that it is promising for anti-CK18 and anti-CK19 autoantibodies to serve as a tool to monitor lung damage and guide treatment.


Preclinical Toxicology of rQNestin34.5v.2: An Oncolytic Herpes Virus with Transcriptional Regulation of the ICP34.5 Neurovirulence Gene.
rQNestin34.5v.2 is an oncolytic herpes simplex virus 1 (oHSV) that retains expression of the neurovirulent ICP34.5 gene under glioma-selective transcriptional regulation. To prepare an investigational new drug (IND) application, we performed toxicology and efficacy studies of rQNestin34.5v.2 in mice in the presence or absence of the immunomodulating drug cyclophosphamide (CPA). ICP34.5 allows HSV1 to survive interferon and improves viral replication by dephosphorylation of the eIF-2α translation factor. rQNestin34.5v.2 dephosphorylated eIF-2α in human glioma cells, but not in human normal cells, resulting in significantly higher cytotoxicity and viral replication in the former compared to the latter. In vivo toxicity of rQNestin34.5v.2 was compared with that of wild-type F strain in immunocompetent BALB/c mice and athymic mice by multiple routes of administration in the presence or absence of CPA. A likely no observed adverse effect level (NOAEL) dose for intracranial rQNestin34.5v.2 was estimated, justifying a phase 1 clinical trial in recurrent glioma patients (ClinicalTrials.gov: NCT03152318), after successful submission of an IND.


Association between inflammation-associated cytokines, serum albumins, and mortality in the elderly.
To investigate the association between serum albumin, prealbumin, various serum inflammation associated-cytokines, and mortality in older geriatric recuperative care patients. A prospective cohort study. A geriatric rehabilitation unit of a university-affiliated Department of Veterans Affairs hospital. Participants were 53 geriatric patients (mean age 78 +/- 7.3, 96% male) admitted to a Geriatric Evaluation and Management (GEM) unit. Patients with documented near-terminal medical disorder, overt infections, and any systemic or localized inflammatory disorders were excluded. Inflammation-associated cytokines (IL-8, IL-1beta, IL-6, IL-10, TNF-alpha), albumin, prealbumin, and C-reactive protein were measured at hospital discharge and each subject was then tracked for 1 year. By Cox Proportional-Hazards Regression analysis, the strongest predictor of mortality within 6 months of study entry was the serum IL-6. For each log increase in IL-6, there was nearly a 9-fold greater 6-month mortality risk (RR 8.99, 95% CI 1.65 to 49.03). The association between albumin and mortality was no longer significant after controlling for IL-6. There was a strong inverse correlation between IL-6 and both albumin (R2 0.39, P < .001) and prealbumin (R2 0.41, P < .001). Subclinical inflammation appears to be an important factor contributing to low serum albumins in older recuperative care patients and may confound the association between albumin and mortality in this population. More in-depth studies of these associations are warranted.


Who influences nutrition policy space using international trade and investment agreements? A global stakeholder analysis.
Regulation of food environments is needed to address the global challenge of poor nutrition, yet policy inertia has been a problem. A common argument against regulation is potential conflict with binding commitments under international trade and investment agreements (TIAs). This study aimed to identify which actors and institutions, in different contexts, influence how TIAs are used to constrain policy space for improving food environments, and to describe their core beliefs, interests, resources and strategies, with the objective of informing strategic global action to preserve nutrition policy space. We conducted a global stakeholder analysis applying the Advocacy Coalition Framework, based on existing academic literature and key informant interviews with international experts in trade and investment law and public health nutrition policy. We identified 12 types of actors who influence policy space in the food environment policy subsystem, relevant to TIAs. These actors hold various beliefs regarding the economic policy paradigm, the nature of obesity and dietary diseases as health problems, the role of government, and the role of industry in solving the health problem. We identified two primary competing coalitions: 1) a 'public health nutrition' coalition, which is overall supportive of and actively working to enact comprehensive food environment regulation; and 2) an 'industry and economic growth' focussed coalition, which places a higher priority on deregulation and is overall not supportive of comprehensive food environment regulation. The industry and economic growth coalition appears to be dominant, based on its relative power, resources and coordination. However, the public health nutrition coalition maintains influence through individual activism, collective lobbying and government pressure (e.g. by civil society), and expert knowledge generation. Our analysis suggests that industry and economic growth-focussed coalitions are highly capable of leveraging networks, institutional structures and ideologies to their advantage, and are a formidable source of opposition acting to constrain nutrition policy space globally, including through TIAs. Opportunities for global public health nutrition coalitions to strengthen their influence in the support of nutrition policy space include strategic evidence generation and coalition-building through broader engagement and capacity-building.


Menopausal experiences of South Asian immigrant women: a scoping review.
South Asians make up a significant portion of global immigration. Immigrants often face challenges when navigating the healthcare system, which can influence their experience during the menopausal transition. The purpose of this scoping review is to summarize the existing literature on South Asian immigrant women's menopausal experience. Various electronic databases were systematically searched to identify research articles. The menopausal experiences of South Asian immigrant women were examined. A total of 11 studies were included in this scoping review. A variety of physical symptoms were reported, including vasomotor symptoms, musculoskeletal symptoms, somatic symptoms, and early onset of menopause. Psychosocial symptoms included anxiety, depression, and decreased memory/concentration. Cultural experiences were both positive and negative, depending on the connotations surrounding menopause. Individual facilitators for a healthy transition included education and employment. Familial barriers included a lack of knowledge and support. Community and societal factors were both positive and negative, depending on the level of acculturation. Self-management was the most widely used intervention. Findings of this scoping review can help guide the development and evaluation of menopause interventions for South Asian immigrant women. Culturally sensitive care, increased discussion on sexual health, support networks, and reduction of socioeconomic barriers are needed to address the health needs of South Asian immigrant women. Further research is needed to better understand South Asian immigrant women's menopausal needs and help guide intervention design.


The impact of polyene, azole, and DNA analogue antimycotics on the cell surface hydrophobicity of Candida albicans and Candida tropicalis in HIV infection.
Oral candidiasis is the most common opportunistic infection in individuals infected with the human immunodeficiency virus. Though Candida albicans is the major aetiological agent, non-albicans species such Candida tropicalis are now emerging as important agents of such infection. The Candida cell surface hydrophobicity (CSH) is considered a critical factor contributing to its colonization potential and virulence. It is also known that brief exposure to sub-cidal concentrations of antifungal agents is a likely scenario in the oral environment where the administered drugs are diluted continuously due to the flushing action of saliva. Hence the objective of the present study was to compare the CSH of 10 isolates each of C. albicans and C. tropicalis from HIV-infected individuals following brief exposure (1 hour) of isolates to sub-therapeutic concentrations of nystatin, amphotericin B, ketoconazole, fluconazole and 5-flurocytosine. The CSH was assessed by a previously described biphasic aqueous-hydrocarbon assay. The mean percentage reduction of CSH of C. albicans following brief exposure to nystatin, amphotericin B, ketoconazole, fluconazole and 5-flurocytosine was 27.33 (p < 0.001), 21.34 (p < 0.05), 11.74 (p > 0.05), 18.4 (p > 0.05) and 14.64 (p > 0.05) respectively. The mean percentage reduction of CSH of C. tropicalis following brief exposure to nystatin, amphotericin B, ketoconazole, fluconazole and 5-flurocytosine was 33.81 (p < 0.01), 28.88 (p < 0.01), 12.6 (p > 0.05), 21.53 (p > 0.05) and 17.68 (p > 0.05) respectively. A significant interspecies variation in CSH was observed for nystatin and amphoterecin B. Overall the results reveal that the CSH of C. albicans is affected to a significantly lesser degree compared with C. tropicalis when exposed to the antifungals. These data further illustrate another mode of action of antifungals on Candida leading to a reduction in the CSH and thereby the yeast adherence to host tissues.


The surgical team as a source of postoperative wound infections caused by Streptococcus pyogenes.
Postoperative wound infection, caused by Streptococcus pyogenes transmitted during the operation from members of the surgical team, is a rare but serious complication of surgery. This study describes three cases, which could be traced to an orthopaedic surgeon, who carried the epidemic strain in this throat. Epidemiological characteristics of 14 other outbreaks, published in the English-language literature, are summarized. In total, these 15 outbreaks involved 136 patients. The overall case fatality rate was 12%. Anaesthesiologists and other assisting staff members were involved more often than surgeons and obstetricians. In outbreaks where an attack rate could be calculated, it was at least 7%. T-28 was the most commonly involved T-type, accounting for seven outbreaks. The anus and vagina were the most common carrier sites in staff members. A combination of penicillin and oral vancomycin seemed to be the most efficient treatment for anal and vaginal carriage. Relapse of carriage could occur several months after apparent eradication, and was often associated with a carrier in the family household.


CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis on Preventing Post-Thrombotic Syndrome) Trial: Long-Term Follow-Up Results.
Background The CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis Versus Anticoagulation for the Prevention of Post-Thrombotic Syndrome) trial did not show a reduction of post-thrombotic syndrome (PTS) after additional ultrasound-accelerated catheter-directed thrombolysis in patients with acute iliofemoral deep vein thrombosis at 1-year follow-up. This prespecified analysis of the CAVA trial aimed to determine the impact of additional thrombolysis on outcomes of PTS at long-term follow-up. Methods and Results Patients aged 18 to 85 years with a first-time acute iliofemoral deep vein thrombosis were included and randomly assigned (1:1) to either standard treatment plus ultrasound-accelerated catheter-directed thrombolysis or standard treatment alone. The primary outcome was the proportion of PTS (Villalta score ≥5 on 2 occasions ≥3 months apart or venous ulceration) at the final follow-up visit. Additionally, PTS according to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition was assessed to allow external comparability. Major bleedings were the main safety outcome. At a median follow-up of 39.0 months (interquartile range, 23.3-63.8), 120 patients (79.8%) participated in the final follow-up visit: 62 from the intervention group and 58 from the standard treatment group. PTS developed in 19 (30.6%) versus 26 (44.8%) patients, respectively (odds ratio [OR], 0.54; 95% CI, 0.26 to 1.15 [P=0.11]), with an absolute difference between groups of -14.2% (95% CI, -32.0% to 4.8%). Using the ISTH consensus definition, a significant reduction in PTS was observed (29 [46.8%] versus 40 [69.0%]) (OR, 0.40; 95% CI, 0.19-0.84 [P=0.01]) with an absolute difference between groups of -22.2% (95% CI, -39.8% to -2.8%). No new major bleedings occurred following the 12-month follow-up. Conclusions The impact of additional ultrasound-accelerated catheter-directed thrombolysis on the prevention of PTS was found to increase with time. Although this study was limited by its sample size, the overall findings indicate a reduction of mild PTS without impact on quality of life. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00970619.


The CamSol method of rational design of protein mutants with enhanced solubility.
Protein solubility is often an essential requirement in biotechnological and biomedical applications. Great advances in understanding the principles that determine this specific property of proteins have been made during the past decade, in particular concerning the physicochemical characteristics of their constituent amino acids. By exploiting these advances, we present the CamSol method for the rational design of protein variants with enhanced solubility. The method works by performing a rapid computational screening of tens of thousand of mutations to identify those with the greatest impact on the solubility of the target protein while maintaining its native state and biological activity. The application to a single-domain antibody that targets the Alzheimer's Aβ peptide demonstrates that the method predicts with great accuracy solubility changes upon mutation, thus offering a cost-effective strategy to help the production of soluble proteins for academic and industrial purposes.


[Clinical application and curative effect observation of follicular unit extraction and transplantation in the treatment of cicatricial alopecia].
Objective: To observe the clinical effect of treatment with follicular unit extraction (FUE) and transplantation in treating cicatricial alopecia. Methods: The retrospective cohort study was conducted. From January 2012 to January 2018, 56 patients (36 males and 20 females, aged (25±9) years, 1% to 30% alopecia area of the whole scalp area) who met the inclusion criteria visited the outpatient department of the First Affiliated Hospital of Xi'an Medical University. They were treated with FUE transplantation. The procedure of treatment was performed through the preoperative planning, follicular extraction, follicular preparation, punching recipient site and hair transplantation. The survival rate of hair and density of survived hair were calculated, hair growth and complication were observed. The evaluation was conducted through questionnaire survey by 4 levels: very satisfied, satisfied, not satisfied, and not at all satisfied with effects. Results: After a follow-up of 9 to 24 months, the survival rate of hair in 56 patients was (70±9)%, and the density of survived hair was (35±8) roots/cm2. In the evaluation of the curative effect after the first stage surgery, 34 cases (60.7%) were very satisfied, 16 cases (28.6%) were satisfied, and 6 cases (10.7%)thought the treatment was effective but not satisfied. Six unsatisfactory patients and 16 satisfactory patients underwent the second-stage transplantation, with 19 (86.4%) of them being very satisfied and 3 cases (13.6%) satisfied after the second-stage operation. None of the patients underwent the third-stage surgery. The transplanted hairs grew naturally, and there were no serious complications in all cases. Conclusions: FUE transplantation can effectively treat and improve cicatricial alopecia with less trauma, fewer complication, no scar in the donor site and rapid post-operative recovery, so it is worthy of clinical promotion.


Leukonychia due to cytostatic agents.
Chromonychia induced by antineoplastic agents has been known for several years. The most frequent of these is melanonychia, either diffuse or in tranverse or longitudinal bands, that may co-exist with diffuse pigmentation of the skin. Although any cytostatic agent may be involved in melanonychia, this condition appears most commonly after treatment with adriamycin and cyclophosphamide or in polychemotherapy. Leukonychia, either true or apparent, seems to be less frequent and is the reason for our reporting two patients with this colour change.


Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis.
The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages. A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta-analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data. Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mg·h/L (SEM 2.60) and 38.73 mg·h/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies. Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field.


Disposition of azole antifungal agents. I. Nonlinearities in ketoconazole clearance and binding in rat liver.
The disposition of ketoconazole was characterized in the rat over a wide dose/concentration range. Bolus dose (0.03-10 mg/kg) studies indicate that plasma concentration-time profiles for ketoconazole are not superimposable when dose normalized because of nonlinearities occurring in both volume of distribution and clearance. The volume of distribution decreases from 3 to less than 1 L/kg, while the plasma clearance decreases 10-fold from 25 mL/min/kg as the dose is escalated. From these results, infusion rates were calculated to maintain the plasma concentrations achieved with particular bolus doses. The curvilinear relationship between steady-state plasma concentration (0.015-8.3 mg/L) and ketoconazole infusion rate (0.021-2.45 mg/hr/kg) was analyzed in terms of Michaelis-Menten kinetics. A Vmax of 3.2 mg/hr/kg and Km of 2.1 mg/L were obtained by nonlinear regression analysis. At the end of the ketoconazole infusion, liver, adrenals and kidneys were removed and assayed for ketoconazole. Tissue-to-plasma partition coefficients for the liver and adrenals showed a marked dependence upon steady-state plasma concentration. Both parameters (liver, 22; and adrenals, 53) showed a decrease of approximately 10-fold as the plasma concentrations were increased. In contrast, the kidney:plasma partition coefficient (1.8), blood:plasma concentration ratio (0.6), and plasma binding (96%) of ketoconazole did not show a concentration dependence over the range studied. It is concluded that the liver is an important determinant of ketoconazole's volume of distribution and that saturation of this process accounts largely for the reduction in volume of distribution with increasing dose.(ABSTRACT TRUNCATED AT 250 WORDS)


Eukaryotic DNA damage tolerance and translesion synthesis through covalent modifications of PCNA.
In addition to well-defined DNA repair pathways, all living organisms have evolved mechanisms to avoid cell death caused by replication fork collapse at a site where replication is blocked due to disruptive covalent modifications of DNA. The term DNA damage tolerance (DDT) has been employed loosely to include a collection of mechanisms by which cells survive replication-blocking lesions with or without associated genomic instability. Recent genetic analyses indicate that DDT in eukaryotes, from yeast to human, consists of two parallel pathways with one being error-free and another highly mutagenic. Interestingly, in budding yeast, these two pathways are mediated by sequential modifications of the proliferating cell nuclear antigen (PCNA) by two ubiquitination complexes Rad6-Rad18 and Mms2-Ubc13-Rad5. Damage-induced monoubiquitination of PCNA by Rad6-Rad18 promotes translesion synthesis (TLS) with increased mutagenesis, while subsequent polyubiquitination of PCNA at the same K164 residue by Mms2-Ubc13-Rad5 promotes error-free lesion bypass. Data obtained from recent studies suggest that the above mechanisms are conserved in higher eukaryotes. In particular, mammals contain multiple specialized TLS polymerases. Defects in one of the TLS polymerases have been linked to genomic instability and cancer.


Abnormalities of the Vertebrobasilar Arterial System Leading to Sleep Disorders.
The abnormalities in the vertebrobasilar arterial system such as enlarged, tortuous or dilated arteries and aneurysms can generate pressure and distortion of brain structures especially in the medulla and pons. This brainstem compression by abnormal arteries can lead to various sleep disorders such as sleep related hypoventilation, central sleep apnea, obstructive sleep apnea, and positional sleep apnea. To highlight brainstem compression due to vascular abnormalities as a cause of sleep disordered breathing. Manuscripts were identified using the National Institutes of Health PubMed literature search system. Search terms included sleep disorders, vertebrobasilar dolichoectasia, tortuous vertebral arteries, vertebrobasilar aneurysms, vascular compression and brainstem compression. Inclusion criteria required that the articles were written in English, highlighted both a sleep disorder and a vascular abnormality. The literature search resulted in 10 case reports where vascular abnormalities were leading to sleep disorders. Out of these: four patients had central sleep apnea; three had sleep related hypoventilation; one had positional central sleep apnea; one had positional central apnea along with obstructive sleep apnea; and one had obstructive sleep apnea. The various vascular lesions identified were: megadolichobasilar artery; dolichoectatic vertebral artery; fusiform vertebrobasilar aneurysm; tortuous and elongated vertebral arteries; calcified vertebral artery and medullary telangiectasia. Arterial compression of the respiratory centers in the pons and medulla can lead to central sleep apnea. Obstructive sleep apnea can also result from vascular compression of the medulla. The proposed mechanism is compression of nucleus ambiguus which controls pharyngeal tone. Pressure on cranial nerves IX and X can lead to pharyngeal dysfunction leading to occlusive apnea.


Sensitive phosphorimetric determination of bumetanide in human urine with its inhibition effect on the formation of [Fe-morin]3+ complex.
A novel solid substrate-room temperature phosphorimetry (SS-RTP) was developed for determination of bumetanide (BMTN). It was validated by determining selectivity, linearity, accuracy, precision, and signal to noise ratio (S/N) for analysis. And all the experiments presented in this work were based on that BMTN inhibited the formation of [Fe-morin](3+) ([FeR](3+)) complex by the reaction between Fe(3+) and R, which led to severe quenching of room temperature phosphorescence (RTP) signal. The rate constant of the reaction (k) was 2.44 x 10(-4) s(-1), the activation energy (E) was 21.39 kJ mol(-1). Detection limit of this method (LD, 5.0 ag spot(-1), corresponding concentration was 1.2 x 10(-14) g mL(-1)) was evaluated and compared with other methods, indicating better sensitivity for BMTN determination using this technique. And due to the high sensitivity of the method, it has been successfully applied to determine BMTN in human urine samples. The linear range was from 0.040 pg mL(-1) to 4.0 pg mL(-1), allowing wide determined range of BMTN. Meanwhile, the mechanism of this method was also discussed.


Calix[4]arene C-90 selectively inhibits Ca2+,Mg2+-ATPase of myometrium cell plasma membrane.
The supramolecular compound calix[4]arene C-90 (5,11,17,23-tetra(trifluoro)methyl(phenylsulfonylimino)-methylamino-25,26,27,28-tetrapropoxycalix[4]arene) is shown to efficiently inhibit the ATP hydrolase activity of Ca2+,Mg2+-ATPase in the myometrium cell plasma membrane fraction and also in a preparation of the purified enzyme solubilized from this subcellular fraction. The inhibition coefficient I0.5 values were 20.2 ± 0.5 and 58.5 ± 6.4 µM for the membrane fraction and the solubilized enzyme, respectively. The inhibitory effect of calix[4]arene C-90 was selective comparatively to other ATPases localized in the plasma membrane: calix[4]arene C-90 did not influence the activities of Na+,K+-ATPase and "basal" Mg2+-ATPase. The inhibitory effect of calix[4]arene C-90 on the Ca2+,Mg2+-ATPase activity was associated with the cooperative action of four trifluoromethylphenylsulfonylimine (sulfonylamidine) groups oriented similarly on the upper rim of the calix[4]arene macrocycle (the calix[4]arene "bowl"). The experimental findings seem to be of importance for studies, using calix[4]arene C-90, of membrane mechanisms of regulation of calcium homeostasis in smooth muscle cells and also for investigation of the participation of the plasma membrane Ca2+-pump in control of electro- and pharmacomechanical coupling in myocytes.


Magnetic properties of a Kramers doublet. An univocal bridge between experimental results and theoretical predictions.
The magnetic response of a Kramers doublet is analyzed in a general case taking into account only the formal properties derived from time reversal operation. It leads to a definition of a matrix G (gyromagnetic matrix) whose expression depends on the chosen reference frame and on the Kramers conjugate basis used to describe the physical system. It is shown that there exists a reference frame and a suitable Kramers conjugate basis that gives a diagonal form for the G-matrix with all non-null elements having the same sign. A detailed procedure for obtaining this canonical expression of G is presented when the electronic structure of the KD is known regardless the level of the used theory. This procedure provides a univocal way to compare the theoretical predictions with the experimental results obtained from a complete set of magnetic experiments. In this way the problems arising from ambiguities in the g-tensor definition are overcome. This procedure is extended to find a spin-Hamiltonian suitable for describing the magnetic behavior of a pair of weakly coupled Kramers systems in the multispin scheme when the interaction between the two moieties as well as the individual Zeeman interaction are small enough as compared with ligand field splitting. Explicit relations between the physical interaction and the parameters of such a spin-Hamiltonian are also obtained.


Red blood cell and tissue water content in experimental thermal injury.
Oedema formation and changes in local blood flow are known phenomena in burns. The relationship between these two is not clearly described. The aim of this study was firstly to examine both the contents of red blood cells and tissue water in skin and subcutaneous fat after experimental burns of different depths in pigs, and secondly, to confirm our recent findings of the increased dielectric constant of skin and subcutaneous fat reflecting considerable oedema formation, especially in fat after thermal injury. Superficial, partial and full thickness contact burns were created to pigs and followed for 24h. Radioactive Cr-51 labelling of red cells was used to estimate the number of red cells in tissue, and the absolute amount of water was determined by lyophilization. A decreased number of labelled red cells in skin and an increase in tissue water in subcutaneous fat were found regardless of burn depth. The highest water amount in fat was found in the partial thickness burns. All burn depths resulted in a diminished number of labelled red blood cells in skin and a significant increase in the absolute water amount in subcutaneous fat at 24h post injury. The findings in fat support our recent findings of highly elevated dielectric constants measured by the new in vivo method of dielectric measurements.


Community-led delivery of HIV self-testing to improve HIV testing, ART initiation and broader social outcomes in rural Malawi: study protocol for a cluster-randomised trial.
Prevention of new HIV infections is a critical public health issue. The highest HIV testing gaps are in men, adolescents 15-19 years old, and adults 40 years and older. Community-based HIV testing services (HTS) can contribute to increased testing coverage and early HIV diagnosis, with HIV self-testing (HIVST) strategies showing promise. Community-based strategies, however, are resource intensive, costly and not widely implemented. A community-led approach to health interventions involves supporting communities to plan and implement solutions to improve their health. This trial aims to determine if community-led delivery of HIVST can improve HIV testing uptake, ART initiation, and broader social outcomes in rural Malawi. The trial uses a parallel arm, cluster-randomised design with group village heads (GVH) and their defined catchment areas randomised (1:1) to community-led HIVST or continue with the standard of the care (SOC). As part of the intervention, informal community health cadres are supported to plan and implement a seven-day HIVST campaign linked to HIV treatment and prevention. Approximately 12 months after the initial campaign, intervention GVHs are randomised to lead a repeat HIVST campaign. The primary outcome includes the proportion of adolescents 15-19 years old who have tested for HIV in their lifetime. Secondary outcomes include recent testing in adults 40 years and older and men; ART initiation; knowledge of HIV prevention; and HIV testing stigma. Outcomes will be measured through cross-sectional surveys and clinic registers. Economic evaluation will determine the cost per person tested, cost per person diagnosed, and incremental cost effectiveness ratio. To the best of our knowledge, this is the first trial to assess the effectiveness of community-led HTS, which has only recently been enabled by the introduction of HIVST. Community-led delivery of HIVST is a promising new strategy for providing periodic HIV testing to support HIV prevention in rural communities. Further, introduction of HIVST through a community-led framework seems particularly apt, with control over healthcare concurrently devolved to individuals and communities. Clinicaltrials.gov registry ( NCT03541382 ) registered 30 May 2018.


Outcomes of fixation of Vancouver B periprosthetic fractures around cemented versus uncemented stems.
The incidence of periprosthetic femur fracture (PPFF) in the setting of total hip arthroplasty (THA) is steadily increasing. We seek to address whether there is a difference in outcomes between Vancouver B fracture types managed with ORIF when the original stem was a press-fit stem versus a cemented stem. In this retrospective cohort study at a level 1 trauma center, we identified 136 patients over 65 years-of-age with Vancouver B-type fractures sustained between 2005 and 2019. Patients were treated by ORIF and had either cemented or press-fit stems prior to their injury. Outcomes were subsidence of the femoral implant, time to full weight bearing, rate of the hip implant revision, estimated blood loss (EBL), postoperative complications, and the one-year mortality rate. A total of 103 (75.7%) press-fit and 33 (24.3%) cemented patients were reviewed. Patient baseline characteristics, Vancouver fracture sub-types, and implant characteristics were not found to be significantly different between groups. The difference in subsidence rates, postoperative complications, and time to weight bearing were not significantly different between groups. EBL and one-year mortality rate were significantly higher in the cemented group. In geriatric patients with Vancouver B type periprosthetic fractures managed with ORIF, patients with an originally press fit stem may have lower mortality, lower estimated blood loss, and similar subsidence and hospital length of stays when compared to those with a cemented stem.


Three-dimensional printing facilitates surgical planning for resection of an atypical cardiac myxoma.
Cardiac myxomas are common and account for 50% of primary intracardiac tumors. Atypical locations of cardiac myxoma increase the risk of intraoperative iatrogenic injuries. Herein, we report a case of using three-dimensional printing (3D) to facilitate the removal of an atypical cardiac myxoma in a 63-year-old woman. Mass in the high posterior atrial septum was confirmed through imaging. Due to the potential involvement of the mass to surrounding vital structures, 3D printing of the cardiac mass was performed. The tumor was completely resected via median sternotomy and the resulting defect was repaired with the bovine pericardium. The patient had an uncomplicated postoperative course except for the development of sick sinus syndrome. One-year follow-up showed no tumor recurrent. 3D printing technology in patients with atypical cardiac tumors enhances our understanding of the extent of the tumor invasion and facilitates planning the operation to avoid intraoperative complications.


Successful utilization of aliskiren, a direct renin inhibitor in Bartter syndrome.
Bartter syndrome is traditionally treated with large doses of oral potassium with or without suppression of the renin-angiotensin system. Since plasma renin activity is invariably elevated in Bartter syndrome, the availability of the direct renin inhibitor aliskiren should lead to the ability to maintain potassium levels without utilizing large doses of oral potassium. This case report is, to my knowledge, the first to show the efficacy of a renin receptor blocker in Bartter syndrome.


The TRH stimulation test in endemic goitre in Greece.
The serum T4=T4(D), T3 in vitro uptake=RT3U and TSH were measured before and 30 min after the injection of 200 mug of TRH in 30 subjects from an iodine deficient area of Central Greece. These persons were divided in two groups of 16 goitrous and 14 nongoitrous patients and the results from each group compared to each other and also with the same parameters obtained from 14 controls subjects, all nongoitrous and from a nonendemic area. It has been found that in this area with a mild iodine deficiency serum T4 is the only hormone decreased whereas RT3U and TSH both before and 30 min after TRH injection are normal. There existed however a negative correlation between serum T4 and TSH in the goitrous group. Why the nongoitrous iodine deficient persons achieve the same compensation without thyroid gland enlargement remains unsolved but it may be stated from the present results that goitre development should be regarded as a maladaptation rather than a compensatory process.


Synthesis and Molecular Docking of Some Novel Thiazoles and Thiadiazoles Incorporating Pyranochromene Moiety as Potent Anticancer Agents.
Chemotherapy has become one of the methods that are being adopted to treat cancer. Coumarins, thiazoles and thiadiazoles are versatile synthetic scaffolds possessing wide spectrum of biological effects including potential anticancer activity. In the efforts to develop suitable anticancer drugs, medicinal chemists have focused on coumarin derivatives. A series of novel thiazole-pyranochromene and thiadiazole-pyranochromene derivatives were synthesized via heterocyclization of varies hydrazonoyl halides with methyl pyrano[3,2- g]chromen-3-yl)ethylidene)hydrazine-1-carbodithioate and pyrano[3,2-g]chromen-3-yl)ethylidene)- hydrazine-1-carbothioamide, respectively. All the newly synthesized compounds have been characterized on the basis of elemental analysis and spectral data (IR, 1H and 13C NMR, Mass). Moreover, all the products were evaluated for their anticancer activity against HEPG2-1. The results revealed that six new compounds showed promising anticancer activity. In the present paper, 3-acetyl-5-methoxy-8-methyl-2H,6H-pyrano[3,2-g]chromene-2,6- dione proved to be a useful precursor for synthesis of various 1,3-thiazoles and 1,2,4-thiadiazoles incorporating pyrano[3,2-g]chromene moiety as anticancer agents. The computational studies using MOE 2014.09 software are confirming the results in biological activity.


Characterizing blood cells by biophysical measurements in flow.
One effect of automation in the hematology laboratory has been to introduce new characterizations of blood cells. Resistive pulse sensing (Coulter) and light scatter measurements in flow provide rapid and reproducible cell counts. They also provide information about red cell size, shape, and deformability. Thus, they have provided new characterization of these cells in terms of their biophysical properties. Leukocytes have been classified by optical scatter and absorption measurements in flow after being stained cytochemically. This provides rapid and precise WBC differential counts. However, here again, additional information about relative cell-enzyme content or activity is also accessible to provide a new characterization of the leukocytes. The ultimate range of utility of this expanding technology in the automated hematology laboratory of the future will, of course, depend upon establishing relations between the biophysical parameters and the functions of the cells. This, in turn, must depend upon the use of the technology by researchers and clinicians in studying cell function and the aberrations of these functions which define disease.


Assessment of reproductive disorders and birth defects in communities near hazardous chemical sites. III. Guidelines for field studies of male reproductive disorders.
Exposures to environmental toxicants can have detrimental effects on several aspects of human male reproduction: fertility, sexual function, hormone status, and pregnancy/birth outcomes. However, no simple prescreening methods are available for reliably identifying potential hazards; questionnaires alone are relatively imprecise and inefficient in the absence of field data. Multidisciplinary field studies are required that include detailed exposure information, health and reproductive histories, physical examinations, semen analyses, and possibly, hormone analyses. Semen analysis is a critical component of field studies for evaluating two aspects of male reproduction: 1) changes in sperm or seminal content, which may be indicative of adverse effects on the male reproductive system with possible implications for fertility potential; and 2) defects in sperm DNA or chromosomes, which may be associated with subsequent changes in viability during embryonic development and health risks to the offspring. Semen analyses may be tiered: 1) initially, each semen study may include conventional semen assays (concentration, motility, and morphology) as well as specific biomarkers indicated by the health effect of concern in the study cohort: and 2) archived samples (i.e., frozen, videotaped, or smeared) may be utilized in later second-tier analyses to further characterize specific findings. Before initiating any field study, it is cost effective to critically evaluate the suitability of the cohort by confirming exposure and determining that there are adequate numbers of male participants in each exposure category. Such evaluations must be based on the statistical sensitivities of the specific tissue biomarkers and health endpoints for detecting changes. This article summarizes the components of the ideal field study and identifies research needs for improving field studies of male effects and for understanding the mechanisms of male reproductive toxicity. Several promising semen methods currently under development are also discussed.


Altered peripheral helper T cells in peripheral blood and muscle tissue of the patients with dermatomyositis.
Peripheral helper T (Tph) cells, phenotypically PD-1hiCXCR5-CD4+, are a recently identified Th cell subset that relates to several autoimmune diseases. Contrary to PD-1hiCXCR5+CD4+ follicular helper T (Tfh) cells, Tph cells are not located in lymphoid organs but accumulate in inflamed tissues. This study investigated Tph cells to determine their involvement in dermatomyositis (DM). The frequency of circulating Tph and Tfh cells was evaluated by flow cytometry at baseline and after glucocorticoid treatment. The expression of Tph and B cells was determined in muscle tissue by immunohistochemistry (IHC). Further, the correlations between circulating Tph cells and clinical characteristics were investigated. Flow cytometry revealed that circulating Tph and Tfh cells were decreased in peripheral blood of DM patients compared with healthy controls (HCs). However, the muscular expression of Tph and B cells was upregulated in patients with DM compared to that in the controls by IHC. Interestingly, the increased B cells accumulated around Tph cells in infiltrated lesions. The frequency of circulating Tph cells was positively correlated with Tfh cells, CD3+ T cells, CD4+ T cells, and CD8+ T cells, whereas negatively correlated with erythrocyte sedimentation rate (ESR), interleukin (IL)-6, and IL-10 levels. Furthermore, the abnormal circulating Tph cells in peripheral blood were recovered after glucocorticoid treatment. These results indicate that Tph cells might be involved in the immunopathogenesis of DM and therefore might provide novel insight for the development of DM therapies.


Phorbol esters down-regulate protein kinase C in rat brain cerebral cortical slices.
The effect of phorbol esters on cyclic AMP production in rat cerebral cortical slices was studied using a prelabelling technique to measure cyclic nucleotide accumulation. Cholera toxin-stimulated cyclic AMP accumulation was enhanced approximately 2-fold by phorbol 12-myristate, 13-acetate (PMA) which alone had no effect on cyclic AMP production. The augmentation by PMA was maximal within the first hour of incubation, decreasing progressively thereafter. Protein kinase C activity was decreased 80-90% during a 3 hr exposure to PMA, as was 3H-phorbol 12,13-dibutyrate binding. Both phosphatidyl serine and arachidonic acid were found to enhance protein kinase C activity in a concentration-dependent manner, an effect that was attenuated by prolonged incubation of the brain tissue with PMA. The results indicate that exposure of brain slices to phorbol esters causes a down-regulation of rat brain protein kinase C, and that this modification corresponds with a decrease in the ability of PMA to augment cyclic AMP production, suggesting a functional relationship between the two systems in rat brain.


Comparison of psychological symptoms in post-cryptogenic cerebral-vascular accident (CVA) and/or transient ischemic attack (TIA) patients who have undergone foramen ovale closure, and in post-CVA patients.
The patent foramen ovale (PFO) is a controversial risk factor for CVA or TIA. In our center, adult PFO patients diagnosed with post cryptogenic CVA/TIA undergo trans-catheter closure of the PFO to decrease the risk of recurrent stroke. The aim of the study was to compare levels of functioning, depression and anxiety in post PFO closure patients following cryptogenic CVA/TIA and in other patients post CVA/TIA without PFO. Eighty-nine patients who had undergone trans-catheter PFO closure and 56 non-PFO post-CVA patients completed demographic, functioning, anxiety and depression questionnaires. Additional medical data were recorded from the medical files. Patients who had undergone trans-catheter PFO closure post CVA or TIA reported better level of functioning and substantially lower levels of depression and anxiety. The 70% of depression and 55% of anxiety variances were explained by female gender, older age, lower education, lower functioning level and additional health problems. Functioning level was the strongest contributor to the explained variance of psychological symptoms. We conclude that patients who have undergone trans-catheter PFO closure following cryptogenic CVA/TIA, which may prevent stroke recurrence, show good functioning and low levels of psychological symptoms. The procedure helps to keep these patients in a good physical and psychological health.


Bone age estimation by cervical vertebral dimensions in lateral cephalometry.
A critical issue in contemporary orthodontics is bone age estimation. The most reliable method for skeletal age evaluation is hand-wrist radiography; but it requires further radiation. There is an increasing attention for evaluating cervical vertebrae to reduce the radiation to the patients. The aim of this study was to estimate bone age by measuring 3rd and 4th cervical vertebrae (C3, C4) dimensions. We conducted a correlational study on 91 Iranian individuals aged 8-18 years. After taking lateral cephalometry and hand-wrist radiographs, C3 and C4 were measured using Vixwin 2000 software. Hand-wrist bone age, determined on Greulich Atlas, was the reference test. Stepwise multiple linear regression model demonstrated the correlation between the two measurements. Anterior height of the fourth cervical vertebrae (AH4) had the strongest simple correlation with hand-wrist bone age (r=0.831, P<0.001) and was the only variable that remained in stepwise multivariate regression model. The regression model was: Bone age=0.989×AH4+3.308. Adjusted R2 was 0.686 (p<0.001). Lateral cephalometric radiographs are useful for bone age estimation, and might be an alternative for hand-wrist radiography, with the advantage of radiation reduction.


[Problems in technical development of laparoscopy and thoracoscopy in infancy].
In neonates a new fixation of the trocars must be found since the umbilical ring is large and distensible and the abdominal wall is very thin. The pressure-controlled pneumoperitoneum is maintained by using a special "surgiflator" system which prevents high pressure peaks in the small abdominal cavity of neonates. By using a Nd:YAG laser for transection during coagulation an additional trocar can be dispensed with.


Sorting single-cell microcarriers using commercial flow cytometers.
The scale of biological discovery is driven by the vessels in which we can perform assays and analyze results, from multi-well plates to microfluidic compartments. We report on the compatibility of sub-nanoliter single-cell containers or "nanovials" with commercial fluorescence activated cell sorters (FACS). This recent lab on a particle approach utilizes 3D structured microparticles to isolate cells and perform single-cell assays at scale with existing lab equipment. Use of flow cytometry led to detection of fluorescently labeled protein with dynamic ranges spanning 2-3 log and detection limits down to ∼10,000 molecules per nanovial, which was the lowest amount tested. Detection limits were improved compared to fluorescence microscopy measurements using a 20X objective and a cooled CMOS camera. Nanovials with diameters between 35-85 µm could also be sorted with purity from 99-93% on different commercial instruments at throughputs up to 800 events/second. Cell-loaded nanovials were found to have unique forward and side (or back) scatter signatures that enabled gating of cell-containing nanovials using scatter metrics alone. The compatibility of nanovials with widely-available commercial FACS instruments promises to democratize single-cell assays used in discovery of antibodies and cell therapies, by enabling analysis of single cells based on secreted products and leveraging the unmatched analytical capabilities of flow cytometers to sort important clones.


Human Gut Microbiota and Its Metabolites Impact Immune Responses in COVID-19 and Its Complications.
We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and we validate the results with follow-up, the Japanese 4D (Disease, Drug, Diet, Daily Life) microbiome cohort, and non-Japanese data sets. We performed shotgun metagenomic sequencing and metabolomics on stools and cytokine measurements on plasma from 112 hospitalized patients with SARS-CoV-2 infection and 112 non-COVID-19 control individuals matched by important confounders. Multiple correlations were found between COVID-19-related microbes (eg, oral microbes and short-chain fatty acid producers) and gut metabolites (eg, branched-chain and aromatic amino acids, short-chain fatty acids, carbohydrates, neurotransmitters, and vitamin B6). Both were also linked to inflammatory cytokine dynamics (eg, interferon γ, interferon λ3, interleukin 6, CXCL-9, and CXCL-10). Such interrelationships were detected highly in severe disease and pneumonia; moderately in the high D-dimer level, kidney dysfunction, and liver dysfunction groups; but rarely in the diarrhea group. We confirmed concordances of altered metabolites (eg, branched-chain amino acids, spermidine, putrescine, and vitamin B6) in COVID-19 with their corresponding microbial functional genes. Results in microbial and metabolomic alterations with severe disease from the cross-sectional data set were partly concordant with those from the follow-up data set. Microbial signatures for COVID-19 were distinct from diabetes, inflammatory bowel disease, and proton-pump inhibitors but overlapping for rheumatoid arthritis. Random forest classifier models using microbiomes can highly predict COVID-19 and severe disease. The microbial signatures for COVID-19 showed moderate concordance between Hong Kong and Japan. Multiomics analysis revealed multiple gut microbe-metabolite-cytokine interrelationships in COVID-19 and COVID-19related complications but few in gastrointestinal complications, suggesting microbiota-mediated immune responses distinct between the organ sites. Our results underscore the existence of a gut-lung axis in COVID-19.


Injury of the dentato-rubro-thalamic tract in a patient with intentional tremor after mild traumatic brain injury: a case report.
We imaged the dentato-rubro-thalamic tract (DRTT) and cortico-ponto-cerebellar tract (CPCT) using diffusion tensor tractography (DTT) to evaluate the cortico-cerebellar-cortical circuit in a patient with tremor in both hands after mild TBI. We found bilateral DRTT injury in the DTT. A 50-year-old male presented with action tremor in both hands 1 week after mild TBI. One month before the visit, the patient had a head injury from a fall on a bus. The patient lost consciousness for 1 min and experienced post-traumatic amnesia for approximately 5 min after the accident. His Glasgow Coma Scale score was 15. The action tremor presented with a frequency of 3 Hz in both hands. No specific lesion was observed with a conventional brain MRI. DTT, performed 1.5 months after TBI, showed that the right DRTT was not reconstructed and the left DRTT had thinned. However, CPCT integrity was well-preserved in both hemispheres. The tremor disappeared after oral treatment with 30 mg/day indenol. The patient's tremor would have been caused by disruption of the bilateral DRTT following mild TBI. DRTT and CPCT analysis using DTT would be useful for diagnosing abnormal movement problems, including tremor and ataxia, in patients following mild TBI.


Dominantly inherited retinitis pigmentosa. Ultrastructure and biochemical analysis.
A 66-year-old white man had dominant retinitis pigmentosa. He developed progressive restriction of his visual field, night blindness, pallor of the optic discs, pigmentary retinopathy and posterior subcapsular cataracts. Postmortem examination of the eyes included electron microscopy and biochemical analysis of cyclic nucleotides and interphotoreceptor retinoid-binding protein (IRBP). Except for the fovea and periphery, the retina showed extensive gliosis and neuronal loss with loss of photoreceptor cells. The choriocapillaris was variably occluded in the regions of absent retinal pigment epithelium (RPE). In places, the pigment epithelium invaded the retina to the level of the internal limiting membrane. Biochemical analysis revealed that the interphotoreceptor retinoid-binding protein (IRBP), an important glycoprotein of the interphotoreceptor space, was virtually absent even in retinal areas where photoreceptor cells were still present. Cyclic nucleotide determinations indicated a decrease in the cyclic GMP concentration that reflected the general loss of photoreceptor elements. On the other hand the cyclic AMP levels in all retinal areas tested were abnormally elevated, indicating the possible involvement of this nucleotide in the pathogenesis of the disease.


Single-particle tracking of oriC-GFP fluorescent spots during chromosome segregation in Escherichia coli.
DNA regions close to the origin of replication were visualized by the green fluorescent protein (GFP)-Lac repressor/lac operator system. The number of oriC-GFP fluorescent spots per cell and per nucleoid in batch-cultured cells corresponded to the theoretical DNA replication pattern. A similar pattern was observed in cells growing on microscope slides used for time-lapse experiments. The trajectories of 124 oriC-GFP spots were monitored by time-lapse microscopy of 31 cells at time intervals of 1, 2, and 3 min. Spot positions were determined along the short and long axis of cells. The lengthwise movement of spots was corrected for cell elongation. The step sizes of the spots showed a Gaussian distribution with a standard deviation of approximately 110 nm. Plots of the mean square displacement versus time indicated a free diffusion regime for spot movement along the long axis of the cell, with a diffusion coefficient of 4.3+/-2.6x10(-5) microm2/s. Spot movement along the short axis showed confinement in a region of the diameter of the nucleoid ( approximately 800 nm) with an effective diffusion coefficient of 2.9+/-1.7x10(-5) microm2/s. Confidence levels for the mean square displacement analysis were obtained from numerical simulations. We conclude from the analysis that within the experimental accuracy--the limits of which are indicated and discussed--there is no evidence that spot segregation requires any other mechanism than that of cell (length) growth.


Dynamic postnatal development of the cellular and circuit properties of striatal D1 and D2 spiny projection neurons.
Imbalances in the activity of the D1-expressing direct pathway and D2-expressing indirect pathway striatal projection neurons (SPNs) are thought to contribute to many basal ganglia disorders, including early-onset neurodevelopmental disorders such as obsessive-compulsive disorder, attention deficit hyperactivity disorder and Tourette's syndrome. This study provides the first detailed quantitative investigation of development of D1 and D2 SPNs, including their cellular properties and connectivity within neural circuits, during the first postnatal weeks. This period is highly dynamic with many properties changing, but it is possible to make three main observations: many aspects of D1 and D2 SPNs progressively mature in parallel; there are notable exceptions when they diverge; and many of the defining properties of mature striatal SPNs and circuits are already established by the first and second postnatal weeks, suggesting guidance through intrinsic developmental programmes. These findings provide an experimental framework for future studies of striatal development in both health and disease. Many basal ganglia neurodevelopmental disorders are thought to result from imbalances in the activity of the D1-expressing direct pathway and D2-expressing indirect pathway striatal projection neurons (SPNs). Insight into these disorders is reliant on our understanding of normal D1 and D2 SPN development. Here we provide the first detailed study and quantification of the striatal cellular and circuit changes occurring for both D1 and D2 SPNs in the first postnatal weeks using in vitro whole-cell patch-clamp electrophysiology. Characterization of their intrinsic electrophysiological and morphological properties, the excitatory long-range inputs coming from cortex and thalamus, as well their local gap junction and inhibitory synaptic connections reveals this period to be highly dynamic with numerous properties changing. However it is possible to make three main observations. Firstly, many aspects of SPNs mature in parallel, including intrinsic membrane properties, increases in dendritic arbours and spine densities, general synaptic inputs and expression of specific glutamate receptors. Secondly, there are notable exceptions, including a transient stronger thalamic innervation of D2 SPNs and stronger cortical NMDA receptor-mediated inputs to D1 SPNs, both in the second postnatal week. Thirdly, many of the defining properties of mature D1 and D2 SPNs and striatal circuits are already established by the first and second postnatal weeks, including different electrophysiological properties as well as biased local inhibitory connections between SPNs, suggesting this is guided through intrinsic developmental programmes. Together these findings provide an experimental framework for future studies of D1 and D2 SPN development in health and disease.


Fat-Soluble Vitamins in Standard vs. Liposomal Form Enriched with Vitamin K2 in Cystic Fibrosis: A Randomized Multi-Center Trial.
We aimed to assess a liposomal fat-soluble vitamin formulation containing vitamin K2 with standard treatment in cystic fibrosis (CF). A multi-center randomized controlled trial was carried out in 100 pancreatic-insufficient patients with CF. The liposomal formulation contained vitamin A as retinyl palmitate (2667 IU daily) and beta-carotene (1333 IU), D3 (4000 IU), E (150 IU), K1 (2 mg), and K2 as menaquinone-7 (400 µg). It was compared with the standard vitamin preparations in the closest possible doses (2500 IU, 1428 IU, 4000 IU, 150 IU, 2.14 mg, respectively; no vitamin K2) over 3 months. Forty-two patients finished the trial in the liposomal and 49 in the control group (overall 91 pts: 22.6 ± 7.6 years, 62.6% female, BMI 19.9 ± 2.8 kg/m2, FEV1% 70% ± 30%). The main outcome was the change of vitamin status in the serum during the study (liposomal vs. standard): all-trans-retinol (+1.48 ± 95.9 vs. -43.1 ± 121.4 ng/mL, p = 0.054), 25-hydroxyvitamin D3 (+9.7 ± 13.4 vs. +2.0 ± 9.8 ng/mL, p = 0.004), α-tocopherol (+1.5 ± 2.5 vs. -0.2 ± 1.6 µg/mL, p < 0.001), %undercarboxylated osteocalcin (-17.2 ± 24.8% vs. -8.3 ± 18.5%, p = 0.061). The secondary outcome was the vitamin status at the trial end: all-trans-retinol (370.0 ± 116.5 vs. 323.1 ± 100.6 ng/mL, p = 0.045), 25-hydroxyvitamin D3 (43.2 ± 16.6 vs. 32.7 ± 11.5 ng/mL, p < 0.001), α-tocopherol (9.0 ± 3.1 vs. 7.7 ± 3.0 µg/mL, p = 0.037), %undercarboxylated osteocalcin (13.0 ± 11.2% vs. 22.7 ± 22.0%, p = 0.008). The liposomal fat-soluble vitamin supplement containing vitamin K2 was superior to the standard form in delivering vitamin D3 and E in pancreatic-insufficient patients with CF. The supplement was also more effective in strengthening vitamin K-dependent carboxylation, and could improve vitamin A status.


Placenta previa increta/percreta in Japan: a retrospective study of ultrasound findings, management and clinical course.
Placenta accreta is an abnormally firm attachment of placental villi to the uterine wall, which may cause postpartum hemorrhage resulting in maternal morbidity and mortality. The purpose of the present study was to clarify the incidence, clinical background and prognosis of placenta previa increta/percreta treated with different modalities in Japan. Medical records of cases with placenta previa increta/percreta in eight tertiary centers between January 1994 and December 2004 were reviewed. Placenta accreta without actual invasion into the myometrium confirmed by pathology was not included in placenta increta/percreta. Details of obstetric history, maternal background, ultrasonographical findings, the course of delivery, subsequent complications and management were noted. Among the total of 59,008 deliveries, 45,261 were by the vaginal route (76.7%) and 13 747 by cesarean section (23.3%). In this study, 408 cases were diagnosed as placenta previa (0.69%), 18 of these being placenta increta and 5 placenta percreta. Only 1.1% of cases of placenta previa without prior cesarean section were increta/percreta, in contrast to 37% of placenta previa after prior cesarean sections. Mean intraoperation blood loss was 3630 +/- 2216 g (increta) and 12,140 +/- 8343 g (percreta). One patient with placenta previa percreta died of hemorrhage. Stepwise treatment (cesarean section without separation of the placenta, arterial embolization and hysterectomy) was applied for 4 cases, which had the least blood loss. Placenta previa increta/percreta is a life-threatening disease. Patients who undergo hysterectomy after uterine arterial embolization demonstrate reduced intraoperation blood loss, and this treatment should be incorporated to reduce maternal morbidity.


Poor Antibody Response After Two Doses of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccine in Transplant Recipients.
A low anti-spike antibody response of 28.6% was observed 28 days after BNT162b2 vaccine second dose among 133 solid organ transplant recipients without previous coronavirus disease 2019 (COVID-19). No serious adverse events were recorded. Four severe COVID-19 cases were reported between or after the 2 doses. Our data suggest to change the vaccine strategy.


Hepatotoxic Effects of Atrazine on Clarias gariepinus (Burchell, 1822): Biochemical and Histopathological Studies.
The hepatotoxic effects of sub-lethal concentrations of atrazine (2.5, 25, 250, and 500 μg L-1) on Clarias gariepinus juveniles were assessed for 28 days in a quality-controlled laboratory procedure. The study was designed to determine the effects of atrazine on selected liver function biomarkers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), albumin (ALB) and total protein (TP), and to analyze the liver tissues of the fish using a quantitative and qualitative histology-based health assessment protocol. The levels of ALB and TP in exposed specimens were observed to decrease with increasing concentrations of atrazine. However, the activities of ALT, AST, and ALP showed significant (p < 0.05) increase with increasing concentrations of atrazine. Hepatic assessment of the liver tissues revealed marked histopathological alterations, including structural changes (necrotic/apoptotic liver tissue, poor hepatic cord structure, and loss of normal architecture) in 52.2% of the liver tissues in the treatment groups; plasma alterations (vacuolation or fat inclusions, 22.9%) of hepatocytes; hypertrophied hepatocyte (55.2%); nuclear alterations (52.1%); focal necrosis (16.7%); complete degeneration of hepatocytes (60.45%); sinusoids congested with red blood cells or vascular congestion (70.8%); and karyolysis of the nucleus (18.8%). Findings from this study suggest that atrazine interferes with liver function markers and disrupts the normal architectural and structural components of the liver resulting in noninfectious liver injury. This condition resulted in repeated cycles, cell deaths, and inflammation, which could result in the eventual death of the exposed fish if exposure duration was prolonged.