Reproductive factors and its association with peripheral arterial disease in women aged 52-81 years: the KORA F4 study.
Sex differences in the onset of cardiovascular disease disappear in the postmenopause, suggesting that reproductive factors could be influential. The aim of the present study was to examine the possible association between reproductive parameters and peripheral arterial disease (PAD) in a female population-based sample. In this cross-sectional study data of 887 women aged 52-81 years participating in the population-based KORA F4 study (conducted in 2006-2008) was analyzed. Reproductive parameters were obtained by standardized interviews. PAD was assessed by measuring noninvasively the ankle-brachial index and using a cut-off value of 0.9 and by assessing the presence of claudication by the Edinburgh questionnaire. In multivariable logistic regression analyses later age at menarche (>15 years) compared to age at menarche between 12 and 15 years was significantly associated with about half the probability for PAD (OR = 0.48; 95%CI 0.24-0.98). The presence of hot flashes was positively associated with PAD (OR = 2.09; 95%CI 1.11-3.92). Further reproductive parameters, such as parity, age at menopause, time since menopause, duration of fertility, ever use or current use of hormone replacement therapy, ever use of oral contraceptives, history of hysterectomy, bilateral oophorectomy and depressive mood in relation to menopausal transition showed no significant association with PAD. Later age at menarche was inversely related to PAD and the presence of hot flashes was associated with an increased presence of PAD. Prospective population-based studies in women are needed to assess the impact of reproductive parameters on the development of PAD and subsequently cardiovascular disease.


Genome-wide alignment-free phylogenetic distance estimation under a no strand-bias model.
While alignment has been the dominant approach for determining homology prior to phylogenetic inference, alignment-free methods can simplify the analysis, especially when analyzing genome-wide data. Furthermore, alignment-free methods present the only option for emerging forms of data, such as genome skims, which do not permit assembly. Despite the appeal, alignment-free methods have not been competitive with alignment-based methods in terms of accuracy. One limitation of alignment-free methods is their reliance on simplified models of sequence evolution such as Jukes-Cantor. If we can estimate frequencies of base substitutions in an alignment-free setting, we can compute pairwise distances under more complex models. However, since the strand of DNA sequences is unknown for many forms of genome-wide data, which arguably present the best use case for alignment-free methods, the most complex models that one can use are the so-called no strand-bias models. We show how to calculate distances under a four-parameter no strand-bias model called TK4 without relying on alignments or assemblies. The main idea is to replace letters in the input sequences and recompute Jaccard indices between k-mer sets. However, on larger genomes, we also need to compute the number of k-mer mismatches after replacement due to random chance as opposed to homology. We show in simulation that alignment-free distances can be highly accurate when genomes evolve under the assumed models and study the accuracy on assembled and unassembled biological data. Our software is available open source at https://github.com/nishatbristy007/NSB. Supplementary data are available at Bioinformatics Advances online.


Reimbursement decisions in health policy--extending our understanding of the elements of decision-making.
Previous theoretical and empirical work on health policy decisions about reimbursement focuses on specific rationales such as effectiveness, economic considerations and equal access for equal needs. As reimbursement decisions take place in a social and political context we propose that the analysis of decision-making should incorporate factors, which go beyond those commonly discussed. As an example we chose three health technologies (sildenafil, rivastigmine and statins) to investigate how decisions about reimbursement of medicines are made in the United Kingdom National Health Service and what factors influence these decisions. From face-to-face, in-depth interviews with a purposive sample of 20 regional and national policy makers and stakeholders we identified two dimensions of decision-making, which extend beyond the rationales conventionally cited. The first dimension relates to the role of 'subjectivity' or 'the personal' in the decisions, including personal experiences of the condition and excitement about the novelty or potential benefit of the technology-these factors affect what counts as evidence, or how evidence is interpreted, in practice. The second dimension relates to the social and political function of decision-making and broadens what counts as the relevant ends of decision-making to include such things as maintaining relationships, avoiding organisational burden, generating politically and legally defensible decisions and demonstrating the willingness to care. More importantly, we will argue that these factors should not be treated as contaminants of an otherwise rational decision-making. On the contrary we suggest that they seem relevant, reasonable and also of substantial importance in considering in decision-making. Complementing the analysis of decision-making about reimbursement by incorporating these factors could increase our understanding and potentially improve decision-making.


Effect of body posture on radionuclide measurements of gastric emptying.
The purpose of this investigation was to compare the effect of body posture on gastric emptying measurements of radiolabeled meals. Eight healthy male subjects were studied on four separate days. During each study subjects were fed a standardized meal of beef stew labeled with technetium-99m sulfur colloid, and orange juice. Measurements of solid-phase gastric emptying rates were obtained by a gamma camera. Subjects were studied in the lying, sitting, standing, or combined sitting-standing postures. The results demonstrated that the lying position significantly slowed gastric emptying compared to all other positions. Conversely, a decrease in emptying times of 51% and 35% occurred in the combined sitting-standing position compared to the lying and sitting position. These results support a marked effect of body posture on the radionuclide measurement of gastric emptying.


The impact of COVID-19 lockdown stringency on loneliness in five European countries.
The coronavirus pandemic has forced governments to implement a variety of different dynamic lockdown-stringency strategies in the last two years. Extensive lockdown periods could have potential unintended consequences on mental health, at least for at-risk groups. We present novel evidence on the heterogeneous direct and indirect effects of lockdown-stringency measures on individuals' perception of social isolation (i.e. loneliness) using panel data from five European countries (Germany, France, Spain, Italy and Sweden), which tracks changes in both in-person and remote social interactions between May 2020 and March 2021. We combine data from the COME-HERE panel survey (University of Luxembourg) and the Oxford COVID-19 Government Response Tracker (OxCGRT). We implement a dynamic mixture model in order to estimate the loneliness sub-population classes based on the severity of loneliness, as well as the evolution of social interactions. While loneliness is remarkably persistent over time, we find substantial heterogeneity across individuals, identifying four latent groups by loneliness severity. Group membership probability varies with age, gender, education and cohabitation status. Moreover, we note significant differences in the impact of social interactions on loneliness by degree of severity. Older people are less likely to feel lonely, but were more affected by lockdown measures, partly due to a reduction in face-to-face interactions. On the contrary, the younger, especially those living alone, report high levels of loneliness that are largely unaffected by changes in the pandemic after lockdown measures were initially implemented. Understanding the heterogeneity in loneliness is key for the identification of at-risk populations that can be severely affected by extended lockdown measures. As part of public-health crisis-response systems, it is critical to develop support measures for older individuals living alone, as well as promoting continuous remote communication for individuals more likely to experience high levels of loneliness.


Vocal cord dysfunction: the importance of psychologic factors and provocation challenge testing.
We present three case reports involving patients with vocal cord dysfunction. The onset of symptoms in one case was coincident with a generalized cutaneous reaction to penicillin with laryngeal involvement. The other cases had been misdiagnosed as food allergy and chemical sensitivity. We describe the psychologic factors in these cases in terms of the primary and secondary gain operative in the somatoform disorder of conversion reaction and emphasize the importance of belief and learned sensitivity in the induction of symptoms. The necessity of considering psychologic factors and the use of blinded, controlled, provocation challenges to evaluate subjective symptomatology is underscored. This study emphasizes the heterogenicity of clinical presentations involving vocal cord dysfunction and illustrates the value of fiberoptic-assisted examination of laryngeal function in conjunction with provocation challenge testing in establishing causal relationships for specific clinical symptoms.


Measuring the impact of an HIV rotation on trainees' knowledge and confidence level: The importance of inviting recent graduates.
The new Canadian Residency Accreditation Consortium (CanRAC) standards recommend surveying recently graduated trainees to target improvements in training programs. The goal of this study was to estimate the impact of a rotation in an HIV clinic on trainees' related knowledge, confidence, and practice profile at the Université de Montréal. An electronic survey was sent to practising physicians who completed the rotation between 2006 and 2016. Participants were asked to rate their agreement and level of confidence toward HIV- and HCV-related topics using 5-point Likert scales (0 to 4). Descriptive statistics and mean comparisons were calculated. Among invited participants, 27 of 45 (60%) completed the questionnaire. The majority of respondents were infectious diseases physicians (48%) or family physicians (37%) and had an outpatient caseload of <10 HIV patients/year (80%). For 37% of the respondents, the rotation had a large or very large impact on their career path. They considered that the rotation had increased their knowledge on the overall management of HIV (mean 3.2/4 [95% CI 2.9 to 3.4]), but less on pre-exposure prophylaxis (PrEP) (mean 1.5/4 [95% CI 1.1 to 2.0]) or HCV care (mean 1.9/4 [95% CI 1.4 to 2.3]). Participants felt less confident with genotyping interpretation (mean 2.6/4 [95% CI 2.2 to 2.9]) and PrEP (mean 2.4/4 [95% CI 2.0 to 2.8]). These results suggest that a rotation in an HIV clinic improves knowledge related to HIV care. Feedback from past graduates helped us identify gaps in knowledge or level of confidence in PrEP and HCV care, which will feed curriculum improvement.


Thai red rice extract provides liver protection in paracetamol-treated mice by restoring the glutathione system.
The incidence of drug-induced liver disease associated with oxidant-antioxidant imbalance is increasing. Colored rice can potentially improve these hepatic disorders through antioxidative and glutathione-restoring effects. The objective of this study is to determine the in vitro antioxidant properties of extracts from red (Hom-Dang and Hom-Kularb-Dang) and black (Hom-Dum-Sukhothai and Kum-Doi-Saket) Thai rice cultivars [Oryza sativa L. (Poaceae)] and to examine the in vivo hepatoprotective potential of Hom-Dang extract in paracetamol-treated mice. The in vitro antioxidant properties of the extracts were determined by ABTS, [Formula: see text], [Formula: see text], metal chelating capacity, and lipid peroxidation assays. To investigate hepatoprotective effects in vivo, mice administered 60 mg/kg/d paracetamol were given Hom-Dang extract (128, 256, and 512 mg/kg/d) and/or control antioxidant N-acetyl-cysteine (NAC, 150 mg/kg/d) for 7 and 30 d. Liver health was ascertained by measuring levels of hepatic transaminases (GPT/GOT), determining the glutathione profile (GSH/GSSG ratio), and histomorphological examination of liver tissue. Hom-Dang extract showed the highest in vitro antioxidant potency (an IC50 value of 36.50 ± 0.46, 12.98 ± 0.23, 21.83 ± 2.58, 15.87 ± 0.30, and 86.21 ± 2.45 mg/mL for ABTS, OH(•), [Formula: see text], metal chelating, and lipid peroxidation, respectively). Mice administered paracetamol exhibited increases in GPT/GOT with decreases in GSH and GSH/GSSG ratio followed by histomorphological signs of liver injury. In the presence of the Hom-Dang extract, the GPT/GOT values were normalized, GSH production was induced, and the GSH/GSSG ratio was increased. Thai colored rice cultivars, especially the Hom-Dang variety, are promising candidates for health supplements due to their antioxidative and hepatoprotective properties.


Nonelectrocardiographic evidence that both ischemic preconditioning and adenosine preconditioning exist in humans.
The objective of this study was to use electrocardiogram (ECG)-independent parameters to determine whether preconditioning (PC) exists in humans during percutaneous transluminal coronary angioplasty (PTCA). Several studies suggest that both ischemia and adenosine induce PC in the human heart during PTCA. However, because almost all of these studies relied on ST-segment shifts as indicators of the severity of ischemia, their conclusions continue to be questioned, and the very existence of ischemic or adenosine PC in humans remains controversial. Eighteen patients received either intracoronary adenosine (n = 9) or normal saline (n = 9); 10 min later, they underwent PTCA (three 2-min balloon inflations 5 min apart). Compared with the first inflation, in untreated patients the second and third inflations were associated with less systolic dysfunction (two-dimensional echocardiography), less diastolic dysfunction (color M-mode echocardiography), less lactate production, and less H(+) release into the great cardiac venous blood. In adenosine-treated patients, the extent of all of these abnormalities during the first inflation was less than in untreated patients and did not change with subsequent inflations. Previous exposure to a brief episode of ischemia (first balloon inflation) or to adenosine produces concordant decreases in ECG, subjective, mechanical, and metabolic manifestations of ischemia during PTCA. These data support the concept that both ischemic PC and pharmacologic PC exist in humans and that PTCA is a useful clinical setting in which to discern their mechanism.


Ground-state phase diagram of the t-t'-J model.
We report results of large-scale ground-state density matrix renormalization group (DMRG) calculations on t-[Formula: see text]-J cylinders with circumferences 6 and 8. We determine a rough phase diagram that appears to approximate the two-dimensional (2D) system. While for many properties, positive and negative [Formula: see text] values ([Formula: see text]) appear to correspond to electron- and hole-doped cuprate systems, respectively, the behavior of superconductivity itself shows an inconsistency between the model and the materials. The [Formula: see text] (hole-doped) region shows antiferromagnetism limited to very low doping, stripes more generally, and the familiar Fermi surface of the hole-doped cuprates. However, we find [Formula: see text] strongly suppresses superconductivity. The [Formula: see text] (electron-doped) region shows the expected circular Fermi pocket of holes around the [Formula: see text] point and a broad low-doped region of coexisting antiferromagnetism and d-wave pairing with a triplet p component at wavevector [Formula: see text] induced by the antiferromagnetism and d-wave pairing. The pairing for the electron low-doped system with [Formula: see text] is strong and unambiguous in the DMRG simulations. At larger doping another broad region with stripes in addition to weaker d-wave pairing and striped p-wave pairing appears. In a small doping region near [Formula: see text] for [Formula: see text], we find an unconventional type of stripe involving unpaired holes located predominantly on chains spaced three lattice spacings apart. The undoped two-leg ladder regions in between mimic the short-ranged spin correlations seen in two-leg Heisenberg ladders.


Occurrence of different trichothecenes and deoxynivalenol-3-β-D-glucoside in naturally and artificially contaminated Danish cereal grains and whole maize plants.
Fusarium mycotoxins such as deoxynivalenol (DON) can occur in cereals conjugated to glucose and probably also to other sugars. These conjugates, which are often referred to as "masked mycotoxins", will not be detected with routine analytical techniques. Furthermore, it is suspected that the parent toxin may again be released after hydrolysis in the digestive tracts of animals and humans. Today, our knowledge of the occurrence of these compounds in cereal grains is limited. In this paper, a LC-MS/MS method for the simultaneous determination of DON, deoxynivalenol-3-β-D-glucoside (DON-3-glucoside), 3 acetyl-DON, nivalenol, fusarenon-X, diacetoxyscirpenol, HT-2 toxin, and T-2 toxin in naturally (n = 48) and artificially (n = 30) contaminated cereal grains (wheat, barley, oat, rye triticale) is reported. The method has also been applied to whole fresh maize plant intended for production of maize silage (n = 10). The samples were collected from the harvest years 2006-2010, The results show that DON-3-glucoside and DON co-occurred in cereal grains and, especially in several of the highly contaminated samples, the concentration of the glucoside can be relatively high, corresponding to over 37 % of the DON concentration. The DON-3-glucoside levels in both the naturally and in the artificially grain inoculated with Fusarium were second only to DON, and were generally higher than those of the other tested trichothecenes, which were found at low concentrations in most samples, in many cases even below the detection limit of the method. This argues for the importance of taking DON-3-glucoside into account in the ongoing discussion within the European Community concerning exposure re-evaluations for setting changed values for the tolerable intake for DON. Our results indicate that, in the naturally contaminated grains and in the Fusarium infested cereal grains (winter and spring wheat, oat, triticale), the concentration level of DON-3-glucoside is positively correlated to the DON content. When the DON concentration is high, then the content of DON-3-glucoside will most probably also be high and vice versa.


Cell junctions during the early development of the sea urchin embryo (Paracentrotus lividus).
Thin sections, lanthanum tracer and the freeze-fracture technique revealed the presence of different types of cell junctions in early sea urchin (Paracentrotus lividus) embryos. During the first four cleavage cycles, which are characterized by synchrony of cell division, sister blastomeres were connected only by intercellular bridges, formed as a result of incomplete cytokinesis; no trace of other junctions was found at these stages. From the 16-cell stage onwards, septate junctions and gap junctions began to appear between blastomeres. It is postulated that cell-cell interactions may provide a mechanism for the propagation of signals necessary for the coordination of cell proliferation and differentiation.


Impact of a required fourth-year medical student rotation in physical medicine and rehabilitation.
This study evaluated the impact of a 2-wk required rotation in Physical Medicine and Rehabilitation (PM&R) on fourth-year medical students' knowledge of PM&R and attitude toward teamwork in patient care. Survey results on attitudes toward a team approach to patient care and knowledge in PM&R were compared prerotation and postrotation. One hundred thirty-eight fourth-year medical students participated in this 2-yr study. The combined response rates for the attitude and knowledge surveys were 62% and 56%, respectively. As measured by a pretest and posttest self-reported knowledge assessment, the rotation increased knowledge of PM&R (P ≤ 0.05). Four aspects of the rotation that were rated higher by students from the second year of the rotation were role and responsibility definition, incorporation of current literature, enhancement of clinical skills, and general rotation satisfaction. The rotation provides an experience for medical students to increase their knowledge of PM&R.


Parotitis and acute pancreatitis in a patient with ulcerative colitis.
Ulcerative colitis (UC) has been associated with a number of extraintestinal manifestations, but an association with salivary gland involvement has never been reported. We describe a patient with UC who developed acute pancreatitis and parotitis. Some autoantibodies against common antigens presenting in both the parotid gland and the pancreas might have induced pancreatitis and parotitis in our patient with UC.


Maternal inheritance of mitochondrial genomes and complex inheritance of chloroplast genomes in Actinidia Lind.: evidences from interspecific crosses.
The inheritance pattern of chloroplast and mitochondria is a critical determinant in studying plant phylogenetics, biogeography and hybridization. To better understand chloroplast and mitochondrial inheritance patterns in Actinidia (traditionally called kiwifruit), we performed 11 artificial interspecific crosses and studied the ploidy levels, morphology, and sequence polymorphisms of chloroplast DNA (cpDNA) and mitochondrial DNA (mtDNA) of parents and progenies. Sequence analysis showed that the mtDNA haplotypes of F1 hybrids entirely matched those of the female parents, indicating strictly maternal inheritance of Actinidia mtDNA. However, the cpDNA haplotypes of F1 hybrids, which were predominantly derived from the male parent (9 crosses), could also originate from the mother (1 cross) or both parents (1 cross), demonstrating paternal, maternal, and biparental inheritance of Actinidia cpDNA. The inheritance patterns of the cpDNA in Actinidia hybrids differed according to the species and genotypes chosen to be the parents, rather than the ploidy levels of the parent selected. The multiple inheritance modes of Actinidia cpDNA contradicted the strictly paternal inheritance patterns observed in previous studies, and provided new insights into the use of cpDNA markers in studies of phylogenetics, biogeography and introgression in Actinidia and other angiosperms.


How homologous recombination generates a mutable genome.
Recombination and mutation have traditionally been regarded as independent evolutionary processes: the latter generates variation, which the former reshuffles. Recent studies, however, have suggested that allelic recombination influences the underlying mutation rate, as high mutation rates are inferred in regions of high recombination. Furthermore, recombination between duplicated sequences introduces structural variation into the human genome and facilitates the formation of clustered gene families. Comparisons of whole-genome sequences reveal the expansion of gene family clusters to be an important mode of genome evolution. The negative aspect of this genomic dynamism is the contribution of these rearrangements to genetic diseases.


[Value of enteroscopy in localization diagnosis of small intestinal hemorrhage].
To study the value of enteroscopy in determining bleeding lesion of small intestine. Clinical data of ten cases with small intestinal bleeding diagnosed by enteroscopy were analyzed retrospectively from June 2003 to June 2004. Bleeding sites disclosed by enteroscopy were consistent with those confirmed by operation in 10 patients,but qualitative diagnosis was not consistent in 2 patients. Enteroscopy is a safe,reliable and valuable modality for diagnosing bleeding lesion of small intestine.


Mosaic trisomy 16 in a thriving infant: maternal heterodisomy for chromosome 16.
Trisomy 16 is the most common trisomy in spontaneous abortions and is usually, if not always, lethal in the nonmosaic state. We report a liveborn infant with trisomy 16 mosaicism first diagnosed by amniocentesis at 20 weeks gestation. At birth, the infant was growth retarded and mildly dysmorphic. At age 14 months she was developmentally normal and had facial asymmetry. Her length, weight and head circumference were normal. Pure trisomy 16 was found in cells from the placenta. A normal female karyotype was found in lymphocytes from the infant. Skin fibroblasts revealed a trisomy 16 karyotype in 6 of 30 cells. Molecular analysis showed maternal uniparental heterodisomy, indicating that the trisomic conceptus arose from a nondisjunction of maternal meiosis. Fibroblasts may be the tissue of choice for detection of low-level trisomy 16 mosaicism.


RBV: Read balance validator, a tool for prioritising copy number variations in germline conditions.
The popularisation and decreased cost of genome resequencing has resulted in an increased use in molecular diagnostics. While there are a number of established and high quality bioinfomatic tools for identifying small genetic variants including single nucleotide variants and indels, currently there is no established standard for the detection of copy number variants (CNVs) from sequence data. The requirement for CNV detection from high throughput sequencing has resulted in the development of a large number of software packages. These tools typically utilise the sequence data characteristics: read depth, split reads, read pairs, and assembly-based techniques. However, the additional source of information from read balance (defined as relative proportion of reads of each allele at each position) has been underutilised in the existing applications. Here we present Read Balance Validator (RBV), a bioinformatic tool that uses read balance for prioritisation and validation of putative CNVs. The software simultaneously interrogates nominated regions for the presence of deletions or multiplications, and can differentiate larger CNVs from diploid regions. Additionally, the utility of RBV to test for inheritance of CNVs is demonstrated in this report. RBV is a CNV validation and prioritisation bioinformatic tool for both genome and exome sequencing available as a python package from https://github.com/whitneywhitford/RBV.


Glial AP1 is activated with aging and accelerated by traumatic brain injury.
The emergence of degenerative disease after traumatic brain injury is often described as an acceleration of normal age-related processes. Whether similar molecular processes occur after injury and in age is unclear. Here we identify a functionally dynamic and lasting transcriptional response in glia, mediated by the conserved transcription factor AP1. In the early post-TBI period, glial AP1 is essential for recovery, ensuring brain integrity and animal survival. In sharp contrast, chronic AP1 activation promotes human tau pathology, tissue loss, and mortality. We show a similar process activates in healthy fly brains with age. In humans, AP1 activity is detected after moderate TBI and correlates with microglial activation and tau pathology. Our data provide key molecular insight into glia, highlighting that the same molecular process drives dynamic and contradictory glia behavior in TBI, and possibly age, first acting to protect but chronically promoting disease.


Congenital unilateral adduction deficit with simultaneous abduction. A variant of Duane's retraction syndrome.
Congenital adduction deficit not associated with other signs of oculomotor nerve weakness occurs infrequently. Type 2 Duane's retraction syndrome accounts for some of these cases. The authors identified three children with unilateral adduction deficits and simultaneous abduction of the eyes on attempted lateral gaze into the field of action of the apparently paretic medial rectus muscle. This is the first report of a series of patients with this condition previously termed simultaneous or synergistic divergence. All patients had a large exotropia, and two had a horizontal face turn away from the involved eye. A large (14 mm) lateral rectus muscle recession done on one of these children reduced the face turn but did not eliminate the simultaneous abduction. Clinical, intraoperative, and electromyographic data suggest that this condition is an unusual variant of type 2 Duane's syndrome.


Enhanced nose-to-brain delivery of siRNA using hyaluronan-enveloped nanomicelles for glioma therapy.
Gliomas are the most malignant brain tumors, and their treatment is very challenging because of the presence of the blood-brain barrier (BBB). Intranasal administration has been considered a noninvasive strategy for glioma therapy in recent years, but our explorations of the intranasal delivery of siRNA-based therapies are still clearly inadequate. In this study, the cell-penetrating peptide DP7-C was enveloped with hyaluronic acid (HA) to develop the multifunctional core-shell structure nanomicelle HA/DP7-C. In vitro studies of HA/DP7-C revealed low cytotoxicity and a higher cell uptake efficiency, which was associated with the interaction between HA and CD44. In vivo experiments indicated that HA/DP7-C delivered the siRNA to the central nervous system through the trigeminal nerve pathway within hours after intranasal administration and that the interaction between HA and CD44 also increased its accumulation at the tumor site. Successful intracellular delivery of an antiglioma siRNA inhibited tumor growth and ultimately prolonged the survival time and decreased the tumor volume in GL261 tumor-bearing mice. In addition, toxicity tests on rats showed no adverse effects on the nasal mucosa and trigeminal nerves. In conclusion, HA/DP7-C is a potential intranasal delivery system for siRNAs in glioma therapy.


A de novo heterozygous variant in the SON gene is associated with Zhu-Tokita-Takenouchi-Kim syndrome.
Zhu-Tokita-Takenouchi-Kim (ZTTK, OMIM# 617140) syndrome is a rare, autosomal dominant genetic disorder caused by heterozygous variants in the SON gene (OMIM#182465, GenBank#NC_000021.9). There are only 33 cases and 26 causative SON variants reported to date since the first report in 2015. Here, we report a new case of ZTTK syndrome and a de novo disease-causing SON variant. We conducted whole-exome sequencing (WES) to obtain genetic data of the patient. The clinical and genetic data of the patient were analyzed. The clinical features of our patient were strikingly similar to previously reported cases. Notably, our patient had unique presentations, including a bridged palmar crease in the left hand and growth hormone deficiency. The c.5297del de novo variant in SON causes an amino change (p.Ser1766Leufs*7). Our report expands the mutant spectrum of the SON gene and refines the genotype-phenotype map of ZTTK syndrome. Our findings also highlighted the importance of WES for early diagnosis of ZTTK syndrome, which may improve diagnostic procedures for affected individuals.


Nuclear PARP1 expression and its prognostic significance in breast cancer patients.
Poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) plays important roles in DNA damage response pathways and is often overexpressed in various human tumors. Currently, the use of PARP inhibitors for breast cancer (BC) therapy is the subject of debate, and there is an urgent need to understand much the expression and prognostic role of the PARP1 protein. The aim was to investigate the clinicopathological and prognostic significance of PARP1 in BC patients. The PARP1 and breast cancer susceptibility gene 1 (BRCA1) protein expressions were evaluated in 114 BCs by immunohistochemistry. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Our results showed that nuclear PARP1 expression was significantly associated with peritumoral vascular invasion (P = 0.046), chemotherapeutic treatment (P = 0.026), oestrogen receptor (ER; P = 0.013), human epidermal growth factor receptor 2 (HER2; P = 0.003) and BRCA1 (P < 0.001) expression. Survival analyses showed a significant association with clinical outcome in the subgroup of ER-negative patients (P = 0.017 for DFS and P = 0.048 for OS) and in the subgroup of patients treated with chemotherapeutic agents (P = 0.042 for DFS and P = 0.046 for OS). A significant correlation was also found for DFS in patients characterized by tumors without peritumoral vascular invasion (P = 0.022). More importantly, multivariate analyses revealed that high nuclear PARP1 expression was associated with decreased DFS (P = 0.012) and OS (P = 0.026). In conclusion, PARP1 expression may be used as an independent prognostic factor in BC patients. In addition, this study demonstrated that high PARP1 expression may represent a marker of poorer prognosis both for patients with worse clinical outcome and in less aggressive clinical conditions.


Phosphorylation at Connexin43 Serine-368 Is Necessary for Myocardial Conduction During Metabolic Stress.
Connexin43 (Cx43) phosphorylation alters gap junction localization and function. In particular, phosphorylation at serine-368 (S368) has been suggested to alter gap junctional conductance, but previous reports have shown inconsistent results for both timing and functional effects of S368 phosphorylation. The objective of this study was to determine the functional effects of isolated S368 phosphorylation. We evaluated wild-type Cx43 (AdCx43) and mutations simulating permanent phosphorylation (Ad368E) or preventing phosphorylation (Ad368A) at S368. Function was assessed by optical mapping of electrical conduction in patterned cultures of neonatal rat ventricular myocytes, under baseline and metabolic stress (MS) conditions. Baseline conduction velocity (CV) was similar for all groups. In the AdCx43 and Ad368E groups, MS moderately decreased CV. Ad368A caused complete conduction block during MS. Triton-X solubility assessment showed no change in Cx43 location during conduction impairment. Western blot analysis showed that Cx43-S368 phosphorylation was present at baseline, and that it decreased during MS. Our data indicate that phosphorylation at S368 does not affect CV under baseline conditions, and that preventing S368 phosphorylation makes Cx43 hypersensitive to MS. These results show the critical role of S368 phosphorylation during stress conditions.


Variations in aganglionic segment length of the enteric neural plexus in Mowat-Wilson syndrome.
Patients with zinc finger homeo box 1B (ZFHX1B) mutations or deletions develop multiple congenital anomalies including Hirschsprung disease, known as Mowat-Wilson syndrome (MWS). In this study, we investigated variations in the enteric neural plexus abnormalities in MWS using morphometry-based histopathologic analysis. Seven patients with MWS (3 with mutations in exon 8 of ZFHX1B and 4 with deletions) who had undergone modified Duhamel's operations for Hirschsprung disease were examined. Surgically resected rectosigmoid specimens were analyzed morphometrically. The length of the aganglionic segment was longer than 3 cm in all the patients with deletions. In 3 patients with mutations, the aganglionic region was not detected in the surgically resected specimens; however, the parameters of the ganglions and plexus were significantly smaller than those of controls (cloaca and aproctia), indicative of a transitional zone. Variation in the severity of pathological changes among the 3 patients with mutations was also noted. The variations in myenteric plexus pathologies in MWS appear to be caused by both variations in ZFHX1B abnormalities and epigenetic factors.


Role and Image of Nursing in Children's Literature: A Qualitative Media Analysis.
Nurses' role and image as portrayed in young children's literature were described and analyzed. A total of 30 children's books (pre-kindergarten through grade two audience) written in English were chosen using progressive theoretical sampling. Included were books, both fiction and non-fiction and with varying years of publication, that mentioned nurses and/or were about general healthcare topics. The books were analyzed using the method of qualitative media analysis which is derived from the theoretical framework of symbolic interactionism. Nurses were generally portrayed positively but simply and inaccurately in this sample of children's literature. The seven themes discovered were labeled as nurse characters using traits evident in the sample: nurse unlikely, nurse minimal, nurse caring, nurse subordination, nurse skillful, nurse diversity, and nurse obvious. The image of nursing is socially and culturally constructed, and accurate portrayals of nurses and their roles are necessary in all media. Thus, better representation of nurses in children's books is needed as young children's literature is an important first exposure to the art and science of nursing. Future children's books authored by nurses may more closely reflect accurate contemporary nursing practice and contribute to an improved image of the nursing profession.


Les liaisons dangereuses: immunological synapse formation in animals and plants.
The immunological synapse in vertebrates describes a specialized junction between a T cell and a target cell, enabling execution of immune responses through focal secretion. Recent insights in the plant immune system suggest that plant cells assemble a pathogen-inducible machinery at the cell surface that shares several features with the immunological synapse. Apparent mechanistic commonalities include co-stimulatory non-self alarm signals as triggers, cell polarization driven by actin cytoskeleton remodeling, protein concentration into ring-shaped assemblies at the cell periphery and focal exocytosis mediated by soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) proteins that are core factors for vesicle fusion. Although in plants, execution of immune responses by polar secretion seems to be a cell type-independent property, its confinement to T cells in the vertebrate immune system might reflect a greater division of labor.


Decrease of serum chemerin concentration in patients with end stage renal disease after successful kidney transplantation.
Chemerin is an adipokine associated with metabolic syndrome, systemic inflammation and innate immune system. It has been suggested recently that the decrease in renal function may cause an increase in serum chemerin concentration. In this paper we investigated the effect of kidney transplantation on elevated serum chemerin concentration in dialyzed patients with end stage renal disease (ESRD). Twenty five ESRD patients were tested before and 3months after the kidney transplantation. The control group was comprised of twenty one healthy subjects. Serum chemerin concentrations were measured using commercial ELISA kit, and were related to clinical status, and biomarkers of renal function. We have shown that the kidney transplantation resulted in the decrease of the serum chemerin concentration. Concomitantly, serum creatinine, blood urea nitrogen, phosphate and C-reactive protein concentrations were significantly reduced, while estimated glomerular filtration rate (eGFR), calcium and hemoglobin substantially increased. Univariate regression analysis showed that serum chemerin concentration was positively correlated with serum creatinine and phosphate concentrations and negatively correlated with eGFR. The results presented here indicate that the serum chemerin concentration in patients with ESRD normalizes after the kidney transplantation, and provide additional evidence that serum chemerin concentration is related to renal function.


Neuronal Network Oscillations in Neurodegenerative Diseases.
Cognitive and behavioral acts go along with highly coordinated spatiotemporal activity patterns in neuronal networks. Most of these patterns are synchronized by coherent membrane potential oscillations within and between local networks. By entraining multiple neurons into a common time regime, such network oscillations form a critical interface between cellular activity and large-scale systemic functions. Synaptic integrity is altered in neurodegenerative diseases, and it is likely that this goes along with characteristic changes of coordinated network activity. This notion is supported by EEG recordings from human patients and from different animal models of such disorders. However, our knowledge about the pathophysiology of network oscillations in neurodegenerative diseases is surprisingly incomplete, and increased research efforts are urgently needed. One complicating factor is the pronounced diversity of network oscillations between different brain regions and functional states. Pathological changes must, therefore, be analyzed separately in each condition and affected area. However, cumulative evidence from different diseases may result, in the future, in more unifying "oscillopathy" concepts of neurodegenerative diseases. In this review, we report present evidence for pathological changes of network oscillations in Alzheimer's disease (AD), one of the most prominent and challenging neurodegenerative disorders. The heterogeneous findings from AD are contrasted to Parkinson's disease, where motor-related changes in specific frequency bands do already fulfill criteria of a valid biomarker.


Prevention of human granulocyte colony-stimulating factor protein aggregation in recombinant Pichia pastoris fed-batch fermentation using additives.
rhG-CSF (recombinant human granulocyte colony-stimulating factor) was expressed in the yeast Pichia pastoris under the control of the AOX1 (alcohol oxidase 1) promoter. The production of rhG-CSF was induced by switching from growth on glycerol to growth on methanol. In the induction phase, the methanol feed rate had a significant effect on the specific expression rate of rhG-CSF. A constant feed rate of 16 ml.h(-1).l(-1) was found to be optimal for a high specific expression rate of rhG-CSF (0.058 mg(-1).h(-1).g DCW(-1); DCW is dry cell weight). Under this condition, a maximum concentration of 300 mg/l of rhG-CSF and the expression yield of 0.6 mg of rhG-CSF/g of methanol were attained. However, the secreted rhG-CSF was shown to exist as aggregates in the culture broth, owing to hydrophobic interactions. To prevent undesirable protein aggregation, the presence of additional additives in the P. pastoris culture medium was investigated. Among seven additives tested, Tween 20, Tween 80 and betaine exhibited the best results in respect of preventing the formation of rhG-CSF protein aggregates.


Serum creatinine to cystatin C ratio predicts skeletal muscle mass and strength in patients with non-dialysis chronic kidney disease.
Muscle wasting is highly prevalent in patients with chronic kidney disease (CKD). However, the assessment of skeletal muscle mass and strength in clinical settings is not commonly available. We aimed to evaluate the feasibility of serum creatinine/cystatin C (Cr/CysC) ratio in the assessment of muscle wasting. In 272 patients with CKD aged 66.5 ± 15.1 years, skeletal muscle mass and handgrip strength (HGS) were assessed. Skeletal muscle index (SMI) was calculated as skeletal muscle mass/height2. Low muscle mass was defined as SMI below the sex-specific 10th percentile of study population and low handgrip strength as less than 26 Kg for men and 18 Kg for women. The Cr/CysC ratio was significantly lower in both the low SMI and low HGS groups. Moreover, the Cr/CysC ratio correlated with SMI (r = .306, p < .001) and HGS (r = .341, p < .001). After adjusting for confounding factors, age, sex, waist circumference, body fat mass, and Cr/CysC ratio were independently associated with SMI, whereas age, sex, diabetes, hemoglobin, estimated glomerular filtration rate, urine protein/creatinine ratio, SMI, and Cr/CysC ratio were independently associated with HGS. Cr/CysC ratio appears to be a promising surrogate marker for detecting muscle wasting in patients with CKD. Further studies are needed to extend our findings.


An approach to remove alpha amylase for proteomic analysis of low abundance biomarkers in human saliva.
Proteomic characterization of human whole saliva for the identification of disease-specific biomarkers is guaranteed to be an easy-to-use and powerful diagnostic tool for defining the onset, progression and prognosis of human systemic diseases and, in particular, oral diseases. The high abundance of proteins, mainly alpha amylase, hampers the detection of low abundant proteins appearing in the disease state and therefore should be removed. In the present study a 2-DE was used to analyze human whole saliva following the removal of alpha amylase by affinity adsorption to potato starch. After alpha amylase removal whole saliva was analyzed by SDS-PAGE showing at least sixfold removal efficiency and by an alpha amylase activity assay showing 97% reduced activity. MS identification of the captured alpha amylase after elution demonstrated specific removal; 2-DE analysis showed the selective removal of alpha amylase and consequently increased gel resolution. MS identification of protein spots in the 60 kDa area revealed 15 proteins, which were masked before alpha amylase removal. In conclusion, treatment of human whole saliva with an alpha amylase removal device increases gel resolution and enables a higher protein sample for analysis.


Molecular biology studies of the uptake hydrogenase of Rhodobacter capsulatus and Rhodocyclus gelatinosus.
In the photosynthetic bacteria, as in other N2-fixing bacteria, two main enzymes are involved in H2 metabolism: nitrogenase, which catalyses the photoproduction of H2, and a membrane-bound (NiFe) hydrogenase, which functions as an H2-uptake enzyme. The structural genes for Rhodobacter capsulatus and Rhodocyclus gelatinosus uptake hydrogenases were isolated and sequenced. They present the same organization, with the gene encoding the small subunit (hupS) (molecular masses 34.2 and 34.6 kDa, respectively) preceding the gene encoding the large one (hupL) (molecular masses 65.8 and 68.5 kDa, respectively). The two hupSL genes apparently belong to the same operon. The deduced protein sequences of the small and of the large subunits share nearly 80% and maximally 70% identity, respectively, with their counterparts in uptake hydrogenases found in N2-fixing bacteria. However, unlike in Bradyrhizobium japonicum, R. gelatinosus or Azotobacter chroococcum, another open reading frame (ORFX) was found downstream and contiguous to the R. capsulatus hupSL whose transcription seemed to depend on the same hup promoter as hupSL. ORFX contained 786 nucleotides capable of encoding a hydrophobic polypeptide of 262 amino acids (30.2 kDa).


Proteomics and constraint-based modelling reveal enzyme kinetic properties of Chlamydomonas reinhardtii on a genome scale.
Metabolic engineering of microalgae offers a promising solution for sustainable biofuel production, and rational design of engineering strategies can be improved by employing metabolic models that integrate enzyme turnover numbers. However, the coverage of turnover numbers for Chlamydomonas reinhardtii, a model eukaryotic microalga accessible to metabolic engineering, is 17-fold smaller compared to the heterotrophic cell factory Saccharomyces cerevisiae. Here we generate quantitative protein abundance data of Chlamydomonas covering 2337 to 3708 proteins in various growth conditions to estimate in vivo maximum apparent turnover numbers. Using constrained-based modeling we provide proxies for in vivo turnover numbers of 568 reactions, representing a 10-fold increase over the in vitro data for Chlamydomonas. Integration of the in vivo estimates instead of in vitro values in a metabolic model of Chlamydomonas improved the accuracy of enzyme usage predictions. Our results help in extending the knowledge on uncharacterized enzymes and improve biotechnological applications of Chlamydomonas.


Feasibility of the extracardiac conduit Fontan procedure in patients weighing less than 10 kilograms.
The extracardiac conduit Fontan procedure has led to improved outcomes. We performed the procedure in patients weighing less than 10 kg and evaluated its feasibility. Since January 1999, 72 patients weighing less than 20 kg underwent extracardiac conduit Fontan procedure with polytetrafluoroethylene conduits. The patients were divided into 2 groups: 36 patients weighing less than 10 kg in group S and 36 weighing more than 10 kg in group L. Mean weight, median age, and median follow-up period in groups S and L were 8.5 +/- 1.1 and 14.0 +/- 3.0 kg, 18.9 and 42.0 months, and 29.2 (1.7-79.7) and 42.1 (2.8-94.2) months, respectively. Postoperatively, most patients received peritoneal drainage catheters. We reviewed data precatheterization and postcatheterization and postoperative course. Conduit sizes in groups S and L were 17.0 +/- 1.3 and 17.9 +/- 1.9 mm, respectively (P = .03). Five patients required fenestrations. There were 2 hospital deaths, 1 in each group, and 2 late deaths in group S. The postoperative course was identical in both groups, except for median length of stay in the intensive care unit and peritoneal drainage volume. Group S versus L: ventilator support, 11 versus 7 hours; pleural drainage, 9 days each; pleural drainage greater than 14 days, 6 versus 5 cases; peritoneal drainage, 8 versus 7 days; intensive care unit stay, 7 versus 4 days (P = .01), peritoneal drainage volume, 26.1 versus 14.1 mL x kg x d(-1) (P = .0007). The early outcome of the extracardiac conduit Fontan procedure was satisfactory in patients weighing less than 10 kg. However, the required size of the conduit remains debatable.


HIV prevalence, risk behaviour, and treatment and prevention cascade outcomes among cisgender men, transgender women, and transgender men who sell sex in Zimbabwe: a cross-sectional analysis of programme data.
There is a paucity of evidence on HIV vulnerabilities and service engagements among people who sell sex in sub-Saharan Africa and identify as cisgender men, transgender women, or transgender men. We aimed to describe sexual risk behaviours, HIV prevalence, and access to HIV services among cisgender men, transgender women, and transgender men who sell sex in Zimbabwe. We did a cross-sectional analysis of routine programme data that were collected between July 1, 2018, and June 30, 2020, from cisgender men who sell sex, transgender women who sell sex, and transgender men who sell sex, as part of accessing sexual and reproductive health and HIV services provided through the Sisters with a Voice programme, at 31 sites across Zimbabwe. All people who sell sex reached by the programme had routine data collected, including routine HIV testing, and were referred using a network of peer educators. Sexual risk behaviours, HIV prevalence, and HIV services uptake during the period from July, 2018, to June, 2020, were analysed through descriptive statistics by gender group. A total of 1003 people who sell sex were included in our analysis: 423 (42·2%) cisgender men, 343 (34·2%) transgender women, and 237 (23·6%) transgender men. Age-standardised HIV prevalence estimates were 26·2% (95% CI 22·0-30·7) among cisgender men, 39·4% (34·1-44·9) among transgender women, and 38·4% (32·1-45·0) among transgender men. Among people living with HIV, 66·0% (95% CI 55·7-75·3) of cisgender men, 74·8% (65·8-82·4) of transgender women, and 70·2% (59·3-79·7) of transgender men knew their HIV status, and 15·5% (8·9-24·2), 15·7% (9·5-23·6), and 11·9% (5·9-20·8) were on antiretroviral therapy, respectively. Self-reported condom use was consistently low across gender groups, ranging from 26% (95% CI 22-32) for anal sex among transgender women to 32% (27-37) for vaginal sex among cisgender men. These unique data show that people who sell sex and identify as cisgender men, transgender women, or transgender men in sub-Saharan Africa have high HIV prevalences and risk of infection, with alarmingly low access to HIV prevention, testing, and treatment services. There is an urgent need for people-centred HIV interventions for these high-risk groups and for more inclusive HIV policies and research to ensure we truly attain universal access for all. Aidsfonds Netherlands.


The pathology of thyroiditis.
Although the term "thyroiditis" suggests inflammation, many disorders of the thyroid that are of unknown etiology are also currently included under this heading. Thus, only infective thyroiditis and subacute thyroiditis are clearly inflammatory; autoimmune thyroiditis is a result of lymphocytic and fibroblastic infiltration secondary to immune processes, and Riedel's struma (a rare disorder) results from a curious form of fibroblastic proliferation of unknown nature. The pathology of infective thyroiditis is that of the particular infective organism. The picture of subacute thyroiditis is that of a unique type of follicular disruption with histiocytes surrounding extravasated colloid masses, producing the appearance of giant cells. Autoimmune thyroiditis is characterized by lymphocytic infiltration, lymphoid follicles. Askanazy cells, and fibrosis, each to a variable degree, with atrophy of follicles. The fibroblastic proliferation in Riedel's struma transcends the thyroid capsule and involves adjacent tissues. The electron microscopic appearance of each form of thyroiditis is also briefly described.


Expressive and perceptual asymmetries of the resting face.
Lateral facial composites reveal the asymmetry of the resting face. In the current research, we created lateral composites of 30 resting faces, then had subjects compare the two composites of a face with a depiction of the whole face in either normal- or mirror-image. Results indicate that the side of the face in a subject's left visual hemi-space dominates facial recognition. The magnitude of this bias can be altered by priming tasks. It is a bias in facial perception, not memory.


Hypoxia-inducible factor 1 (HIF-1) is a new therapeutic target in JAK2V617F-positive myeloproliferative neoplasms.
Classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic malignancies including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The JAK2V617F mutation plays a central role in these disorders and can be found in 90% of PV and ~50-60% of ET and PMF. Hypoxia-inducible factor 1 (HIF-1) is a master transcriptional regulator of the response to decreased oxygen levels. We demonstrate the impact of pharmacological inhibition and shRNA-mediated knockdown (KD) of HIF-1α in JAK2V617F-positive cells. Inhibition of HIF-1 binding to hypoxia response elements (HREs) with echinomycin, verified by ChIP, impaired growth and survival by inducing apoptosis and cell cycle arrest in Jak2V617F-positive 32D cells, but not Jak2WT controls. Echinomycin selectively abrogated clonogenic growth of JAK2V617F cells and decreased growth, survival, and colony formation of bone marrow and peripheral blood mononuclear cells and iPS cell-derived progenitor cells from JAK2V617F-positive patients, while cells from healthy donors were unaffected. We identified HIF-1 target genes involved in the Warburg effect as a possible underlying mechanism, with increased expression of Pdk1, Glut1, and others. That was underlined by transcriptome analysis of primary patient samples. Collectively, our data show that HIF-1 is a new potential therapeutic target in JAK2V617F-positive MPN.


Fatal HHV-6 associated encephalitis in an HIV-1 infected patient treated with cidofovir.
We describe the case of a patient infected with HIV and a concomitant HHV-6 encephalitis. The patient experienced virological failure following cidofovir treatment. RT-PCR was used both for early diagnosis and follow-up.


Complete duplication of the bladder, urethra and external genitalia in a neonate--a case report.
We report a rare case of complete duplication of the bladder, urethra and external genitalia associated with other multiple congenital anomalies, such as ventriculoseptal defect, malrotation of the gut, ectopic anal opening, malascended left kidney, rachischisis of the lumbar spine and sacrum, and an umbilical hernia. To our knowledge the occurrence of these associated anomalies in a single case of complete duplication of the bladder, urethra and external genitalia has not been reported previously.


Cytocompatibility and mechanical properties of novel porous 316 L stainless steel.
Novel 316 L stainless steel (SS) foam with 85% porosity and an open pore diameter of 70-440 μm was developed for hard tissue application. The foam sheet with a 200-μm diameter had superior cell proliferation and penetration as identified through in vitro experiments. Calcification of human osteosarcoma cells in the SS foam was observed. Multi-layered foam preparation is a potential alternative technique that satisfies multi-functional requirements such as cell penetration and binding strength to the solid metal. In tensile tests, Young's modulus and the strength of the SS foam were 4.0 GPa and 11.2 MPa respectively, which is comparable with human cancellous bone.


A comprehensive comparison and evaluation of surgical techniques for anterior shoulder instability: a Bayesian network meta-analysis.
Anterior shoulder instability is a common clinical problem; however, conflicting evidence exists regarding optimal treatment algorithms. We perform a comparative analysis of stabilization techniques used for recurrent anterior shoulder instability to identify the one associated with the lowest rate of recurrent instability. We additionally explore how glenoid bone loss and osseus lesions affect recurrence rates. PubMed, MEDLINE, Embase, and Cochrane databases were searched for clinical studies comparing surgical techniques for anterior shoulder instability. Two team members independently assessed all potential studies for eligibility and extracted data. Each included study underwent a risk of bias assessment using the Cochrane risk of bias summary tool. The primary outcome of interest was the rate of recurrent instability, which underwent a Bayesian network meta-analysis. Additional analyses were performed relating to the degree of glenoid bone loss and the presence of osseous lesions. Of 2699 studies screened, 52 studies with 4209 patients were included. Patients who underwent open Latarjet demonstrated the overall lowest rate of recurrent instability [log odds ratio (LOR) 1.93], whereas patients who underwent arthroscopic Bankart repair demonstrated the highest (LOR 2.87). When glenoid bone loss was 10% to 20%, open Latarjet had significantly lower recurrent instability (P = .0016) compared to arthroscopic Bankart repair. When glenoid bone loss increased from 0%-10% to 10%-20%, arthroscopic Bankart repair had a significantly increased rate of recurrence (P = .021). In the presence of an engaging Hill-Sachs lesion, both open Latarjet (P = .01) and arthroscopic Bankart with remplissage (P = .029) had significantly reduced recurrence rates compared to arthroscopic Bankart repair. Finally, regardless of procedure, the presence of a Hill-Sachs or bony Bankart lesion was associated with an increased risk of recurrent instability (r = 0.44, P = .0003, and r = 0.40, P = .006, respectively). The open Latarjet has the overall lowest recurrent instability and significantly lower compared to arthroscopic Bankart repair in the setting of increasing glenoid bone loss. Bone loss between 0% and 10% results in similar outcomes across all procedures.


First UTI episode in life in infants <1 year of age: Epidemiologic, clinical, microbiologic and disease recurrence characteristics.
To examine the epidemiologic and microbiologic characteristics of first and recurrent UTI in young infants. A retrospective study of all infants <1 year hospitalized during 2014-2017 with their first UTI and followed during their first year of life. 191 infants were enrolled; 69 (36.12%) patients were <2 months and 32 (16.8%) developed R-UTI during the follow-up. The five most common uropathogens were Escherichia coli, Klebsiella spp., Enterococcus spp., Proteus mirabilis and Staphylococcus aureus. High resistance rates were recorded for ampicillin, amoxicillin/clavulanic acid, TMP/SMX, cefuroxime, ceftriaxone, piperacillin/tazobactam and gentamicin among E. coli and Klebsiella spp.; 29.15% E. coli and 42.9% Klebsiella spp. were ESBL-positive. 53.2% of recurrent UTI (R-UTI) episodes were diagnosed within 2 months after the initial UTI episode. E. coli (40.6%) and Klebsiella spp. (37.55) were the most frequent R-UTI pathogens. Twenty-five (78.1%) R-UTIs were caused by recurrent uropathogens representing new infections. Antibiotic resistance rates at recurrence were similar to those at initial UTI, except for a significant increase in E. coli and Klebsiella spp. resistance to piperacillin/tazobactam. We reported high antibiotic resistance rates to major antibiotic classes used in UTI treatment. Most R-UTI episodes were caused by uropathogens different than those isolated at the initial UTI episode and were caused by highly-resistant organisms. Our findings require frequent monitoring and possible modification of the empiric and prophylactic antibiotic therapy protocols in use. As a result of our findings, the protocol for initial empiric treatment of infants with suspicion of UTI was modified by changing gentamicin to amikacin in the treatment of infants <2 months of life and amikacin monotherapy (intravenous or intramuscular) was introduced as first-line therapy for infants >2 months of life.


Cellular Senescence, Represented by Expression of Caveolin-1, in Cancer-Associated Fibroblasts Promotes Tumor Invasion in Pancreatic Cancer.
The role of senescence of cancer-associated fibroblasts (CAFs) in the development of cancer is controversial. In this study, we investigated whether cellular senescence of CAFs, represented by CAV1 expression, affects tumor progression in pancreatic cancers (PC). Because CAV1 plays a major role in cellular senescence, we used CAV1 expression to monitor cellular senescence. A total of 157 consecutive patients with PC who underwent curative resection were enrolled in the study. Patients were divided into two groups according to CAV1 expression in CAFs by immunohistochemistry. We investigated the relationship between the CAV1 expression in CAFs and the patients' clinicopathological characteristics, including survival. We also established ten CAFs cell lines using PC clinical samples and chose one of them to knock down CAV1 expression. Finally, we cultured a PC cell line (MIAPaCa-2) in CAF-conditioned medium (CM). Regarding patients' clinicopathological characteristics, the serum levels of carbohydrate antigen 19-9 and the rate of advanced tumor stage (pT2, 3, and 4) were significantly higher in the high-CAV1 group. The high-CAV1 group had significantly worse outcomes in both overall and disease-free survival (p < 0.01). Additionally, in co-culture assays using CAFs-CM and MIAPaCa-2 cells, we found that knockdown of CAV1 in CAFs negatively affected the invasion of PC cells. In PC, CAV1 expression in CAFs is associated with patients' poor prognosis and the downregulation of CAV1 in CAFs reduces the invasiveness of PC cells. Therefore, CAV1 of CAFs might be a new target for the treatment of PC.


Methyl-CpG targeted transcriptional activation allows re-expression of tumor suppressor genes in human cancer cells.
DNA methylation and histone modifications are both major features of the epigenetic silencing seen at tumor suppressor genes (TSGs) in cancer. DNA methylation inhibitors, but not, in general, histone deacetylase, can reactivate TSGs. However, DNA methylation inhibitors frequently upregulate genes whose promoters remain unmethylated. Herein we demonstrated that the methyl-CpG targeted transcriptional activation (MeTA), which allows re-expression of TSGs without DNA demethylation, is widely seen in human cancer. We further analyzed MeTA and found that transcriptional coactivators are recruited at hypermethylated promoter regions of TSGs using the methyl-CpG binding domain (MBD). Reactivation of MLH1 by MeTA accompanied acetylation of histone H3 lysine 9/14 at the promoter region. Furthermore, all ten genes analyzed in three cell lines were reactivated by the effect of MeTA. Our present results lead to an efficient way to search for transcriptionally silenced genes with highly methylated CpG islands, particularly TSGs in cancer and developmentally important genes in embryonic stem cells.


Evaluation of artificial neural networks in the classification of primary oesophageal dysmotility.
Artificial neural networks (ANNs) can rapidly analyse large data sets and exploit complex mathematical relationships between variables. We investigated the feasibility of utilizing ANNs in the recognition and objective classification of primary oesophageal motor disorders, based on stationary oesophageal manometry recordings. One hundred swallow sequences, including 80 that were representative of various oesophageal motor disorders and 20 of normal motility, were identified from 54 patients (34 F; median age 59 years). Two different ANN techniques were trained to recognize normal and abnormal swallow sequences using mathematical features of pressure wave patterns both with (ANN(+)) and without (ANN(-)) the inclusion of standard manometric criteria. The ANNs were cross-validated and their performances were compared to the diagnoses obtained by standard visual evaluation of the manometric data. Interestingly, ANN(-), rather than ANN(+), programs gave the best overall performance, correctly classifying >80% of swallow sequences (achalasia 100%, nutcracker oesophagus 100%, ineffective oesophageal motility 80%, diffuse oesophageal spasm 60%, normal motility 80%). The standard deviation of the distal oesophageal pressure and propagated pressure wave activity were the most influential variables in the ANN(-) and ANN(+) programs, respectively. ANNs represent a potentially important tool that can be used to improve the classification and diagnosis of primary oesophageal motility disorders.


N,N-dicarboxymethyl Perylene-diimide-modified CdV2O6 Nanorods for Colorimetric Sensing of H2O2 and Pyrogallol.
The peroxidase-like activity of CdV2O6 nanorods has been considerably improved by modification with N, N-dicarboxymethyl perylene-diimide (PDI) as a photosensitizer. The peroxidase-like behaviors are evaluated by virtue of the colorless chromogenic substrate 3,3',5,5'-tetramethylbenzidine (TMB), which is fast changed into blue oxTMB in the presence of H2O2 in only 90 s. PDI-CdV2O6 exhibits high stability at elevated temperatures and PDI-CdV2O6 retains more than 70% of its catalytic activity over a wide range of 15 to 60 °C. The catalytic mechanism of PDI-CdV2O6 is ascribed to the synergistic interaction between PDI and CdV2O6 and the generation of •O2- radicals. Based on the enhanced peroxidase-like activity of PDI-CdV2O6, a selective colorimetric sensor has been constructed for H2O2 and pyrogallol (PG) with detection limits of 36.5 μM and 0.179 μM, respectively. The feasibility of the proposed sensing platform has been validated by detecting H2O2 in milk and pyrogallol in tap water.


Erratum: A case report of two Kala-azar cases in China diagnosed by metagenomic next-generation sequencing.
[This corrects the article DOI: 10.3389/fmicb.2022.922894.].


Detrimental impact of temporomandibular disorders (mis)beliefs and possible strategies to overcome.
This topical review presents common patients' misbeliefs about temporomandibular disorders (TMD) and discusses their possible impact on the diagnosis, treatment and prognosis. We also discussed the possible influence of the beliefs and behaviours of healthcare providers on the beliefs of patients with TMD and suggested possible strategies to overcome the negative impacts of such misbeliefs. This topical review was based on a non-systematic search for studies about the beliefs of patients and healthcare professionals about TMD in PubMed and Embase. Patients' beliefs can negatively impact the diagnosis, treatment and prognosis of TMD. These beliefs can be modulated by several factors such as culture, psychosocial aspects, gender, level of knowledge and previous experiences. Moreover, primary healthcare professionals, including dentists, may lack sufficient experience and skills regarding TMD diagnosis and treatment. Misbeliefs of the healthcare professionals can be based on outdated evidence that is not supported by rigorous methodological investigations. Education and dissemination of knowledge to patients and the general population are effective for prevention, promotion of health and disruption of the cycle of misinformation and dissemination of misbeliefs. The lack of basic information about TMD and the dissemination of mistaken and outdated concepts may delay the diagnosis, hinder the treatment, and consequently increase the risk of worsening the condition. Education is key to overcome TMD misbeliefs.


Is there a role for perioperative adjuvant therapy in the treatment of early breast cancer?
Despite having been investigated for many years, the role of adjuvant perioperative chemotherapy in the treatment of early breast cancer has still to be fully defined. This paper reviews the early trials of perioperative cytotoxic therapy and overviews the two largest trials; the Scandinavian Adjuvant Chemotherapy Study Group (SACSG) Trial, which began in 1965 and recruited 1026 patients, and the Cancer Research Campaign (CRC) Adjuvant Trial with 2230 patients entered between 1981 and 1985. Overview analysis of these two trials clearly shows a small but highly significant increase in time to first event (P less than 0.001). Increased survival, although significant in the SACSG trial, has not yet been demonstrated in the CRC study, but at this stage of follow-up (median 2.5 years) this is not surprising.


WT1-AS promotes cell apoptosis in hepatocellular carcinoma through down-regulating of WT1.
The antisense of the tumor suppressor gene WT1 (WT1-AS) is a long non-coding RNA. The role of WT1-AS in the development of hepatocellular carcinoma (HCC) has not yet been elucidated. Quantitative real-time PCR and western blot analyses were used to measure levels of WT1-AS and its related genes in tumor and corresponding adjacent tumor tissues of HCC patients. The effect on HCC cell proliferation and apoptosis was assessed by EdU incorporation assays and PI-Annexin-V staining, respectively. ShRNA and dual-luciferase assays were used to investigate the regulatory relationship between WT1-AS and WT1 in cell lines. WT1-AS expression correlated negatively with WT1 expression in HCC tumor tissue. Kaplan-Meier curve analysis revealed that WT1-AS expression is a reliable indicator of HCC prognosis. The downregulation of WT1 expression by WT1-AS promoted cell apoptosis by suppressing the JAK/STAT3 signaling pathway. Bioinformatics analysis showed that WT1-AS downregulates WT1 by binding to the TATA region of the WT1 promotor. WT1-AS was also able to reverse WT1-mediated resistance to Dox based chemotherapy in HCC cells. WT1-AS downregulates WT1 expression in HCC tumors and promotes apoptosis by binding to the promoter region of WT1. Our findings suggest that WT1-AS may function as a tumor suppressor in HCC by reversing the oncogenic effects of WT1.


The interaction between CO2 and plant nutrition: comments on a paper by Coleman, McConnaughay and Bazzaz.
Effects of CO2 on plants are often confounded with effects of nutrition. Coleman et al. (1993) showed that nitrogen concentrations in plants grown under different CO2 levels did not differ if plants of equal sizes were compared but varied at equal times and equal sizes for different levels of nitrogen additions. I will suggest why this must occur under the conditions of the experiment. I will also suggest why nitrogen productivity should be used to interpret experimental results rather than the dubious nitrogen use efficiency.


The Childhood Asthma Management Program (CAMP): Contributions to the Understanding of Therapy and the Natural History of Childhood Asthma.
The Childhood Asthma Management Program (CAMP) has been in continuous existence for almost two decades, which makes it the largest randomized, placebo-controlled clinical trial with extended follow-up for children with mild to moderate asthma. As such, its cumulative data from baseline, active treatment, and post-treatment have proved to be an invaluable resource for not only assessing the efficacy and safety of long-term inhaled corticosteroid therapy in childhood, but for discovery of many other aspects of childhood asthma, including genetics and biomarkers.


Correction: Glioma IL13Rα2 Is Associated with Mesenchymal Signature Gene Expression and Poor Patient Prognosis.
[This corrects the article DOI: 10.1371/journal.pone.0077769.].


Hand fractures: a review of current treatment strategies.
Fractures of the tubular bones of the hand are common and potentially debilitating. The majority of these injuries may be treated without an operation. Surgery, however, offers distinct advantages in properly selected cases. We present a review of hand fracture management, with special attention paid to advances since 2008. The history and mechanisms of these fractures are discussed, as are treatment options and common complications. Early mobilization of the fractured hand is emphasized because soft tissue recovery may be more problematic than that of bone.


ZFHX3 knockdown increases arrhythmogenesis and dysregulates calcium homeostasis in HL-1 atrial myocytes.
ZFHX3 plays an important role in the genesis of atrial fibrillation. However, the atrial electrophysiological effects of ZFHX3 are not clear. This study sought to investigate roles of ZFHX3 in atrial electrophysiology and calcium homeostasis by using HL-1 atrial myocytes knocked-down with ZFHX3. Patch clamp, confocal fluorescence microscopy and Western blot were used to study electrical activity, ionic currents, calcium homeostasis and protein expressions in stable ZFHX3 shRNA cells. As compared to control, ZFHX3 shRNA cells with 28% decline of ZFHX3 protein had a larger sarcoplasmic reticulum Ca(2+) content by 62%, Ca(2+) transient by 20%, and calcium leak by 75%. ZFHX3 shRNA cells (n=35) had shorter action potential duration (APD) at 50% (14.7 ± 0.9 versus 20.3 ± 1.4 ms, P<0.005), and 20% (6.1 ± 0.3 versus 8.3 ± 0.8 ms, P<0.005) repolarization than control cells (n=30). ZFHX3 shRNA cells (n=10) had larger amplitudes of isoproterenol (1 μM)-induced delayed after depolarization (14.1 ± 0.9 versus 7.2 ± 0.2 mV, P<0.05) than control cells (n=10). Besides, acetylcholine (3 μM) shortened APD at 90% repolarization to a greater extent (19 ± 4% versus 7 ± 2%, P<0.01) in ZFHX3 shRNA cells (n=11) than in control cells (n=12). In addition, ZFHX3 shRNA cells had increased expressions of SERCA2a, ryanodine receptor, Kv1.4, Kv1.5 and Kir3.4. Moreover, ZFHX3 shRNA cells had a larger SERCA2a activity, ultra-rapid delayed rectifier potassium currents, transient outward currents and acetylcholine-sensitive potassium currents. ZFHX3 knock-down in atrial myocytes dysregulated calcium homeostasis and increased atrial arrhythmogenesis, which may contribute to the occurrence of AF.


Plasma for direct therapeutic use, for today and tomorrow: A short critical overview.
Plasma for direct therapeutic use is a fast-evolving blood component in terms of its production and presentation. More than a dozen forms are available worldwide, which is often overlooked since most countries apply policies making only one or very few forms available for treating patients in need. It is most often reserved for the same three clinical indications, i.e. overall clotting-factor deficiency, reversal of vitamin K antagonists in the context of active bleeding or prior to urgent surgery, and therapeutic plasma exchange. The level of evidence is often less robust than generally acknowledged for such major indications while novel indications are tending to emerge in medical and trauma settings. This short review explores classical views and new prospects opened up by novel presentations and statuses for therapeutic plasma.


Use of the afterloading technique for intraoral radiation carriers.
A method for fabrication of a radiation carrier with an adaptation of the afterloading technique has been described. The use of the afterloading technique allows for quick and easy placement of multiple radioactive sources; thus time and exposure to the radiotherapist and the patient are minimized during the period of placement and activation of the prosthesis at the time of therapy.


Ameliorative effect of the oil components derived from sweet potato shochu on impaired short-term memory in mice after amyloid β25-35 injection.
Sweet potato shochu oil is a by-product of shochu production and usually discarded although some physiological functions are considered. In this study, we investigated the effects of shochu oil on short-term memory using a murine model of spontaneous alternating behavior induced by the intracerebroventricular (ICV) administration of amyloid β25-35 (Aβ25-35). Mice were orally administered shochu oil for 15 days. Experiments with a Y-maze model revealed that the Aβ25-35 caused a significant decrease in spontaneous alternation behavior, and supplementation with shochu oil significantly improved this behavior. DNA microarray analysis revealed that the administration of shochu oil downregulated the expression of S100a9 and Ptgs2, which reportedly exacerbate amyloid β deposition in Alzheimer's disease. The administration of shochu oil upregulated the expression of Dnaja1 and PP2A, which is typically downregulated in Alzheimer's disease. These data suggest that shochu oil possible ameliorates on impaired short-term memory in mice after amyloid β25-35 injection, as indicated by its effects on improving spontaneous alternation behavior and modulating the expressions of related genes.


Identity of mitochondrial and cytosolic glycerate kinases in rat liver and regulation of their intracellular localization by dietary protein.
Glycerate kinase (ATP: D-glycerate 2-phosphotransferase EC 126.96.36.199) is a key enzyme of glyconeogenesis from serine via hydroxypyruvate. A differential centrifugation of rat liver homogenate and an analysis of the particle fraction by sucrose density gradient centrifugation indicated that 72% and 26% of glycerate kinase are present in mitochondria and cytosol, respectively. A study on the intramitochondrial localization of the enzyme suggested that the mitochondrial glycerate kinase was present in inner membrane and/or matrix. It was found that dietary protein selectively induced mitochondrial glycerate kinase. This result suggested that mitochondrial glycerate kinase had a physiological function for gluconeogenesis from serin. However, the metabolic significance of the cytoplasmic enzyme was still unclear. The properties of solubilized-mitochondrial and cytosolic glycerate kinases were compared. However, no difference between the two enzymes could be found in the kinetic properties, thermal stability, molecular size or electrochemical properties. These results suggested that both enzymes originate from common genetic information. In order to elucidate the regulatory mechanism of the intracellular distribution of glycerate kinase in rat liver, the responses of mitochondrial and cytosolic glycerate kinases to an alteration of dietary protein were studied. The result suggested that an alteration of dietary protein content may regulate the distribution and the translocation of glycerate kinase to mitochondria and cytosol as well as the total amount of glycerate kinase.


Observational evidence on the effects of mega-fires on the frequency of hydrogeomorphic hazards. The case of the Peloponnese fires of 2007 in Greece.
Even though rare, mega-fires raging during very dry and windy conditions, record catastrophic impacts on infrastructure, the environment and human life, as well as extremely high suppression and rehabilitation costs. Apart from the direct consequences, mega-fires induce long-term effects in the geomorphological and hydrological processes, influencing environmental factors that in turn can affect the occurrence of other natural hazards, such as floods and mass movement phenomena. This work focuses on the forest fire of 2007 in Peloponnese, Greece that to date corresponds to the largest fire in the country's record that burnt 1773km2, causing 78 fatalities and very significant damages in property and infrastructure. Specifically, this work examines the occurrence of flood and mass movement phenomena, before and after this mega-fire and analyses different influencing factors to investigate the degree to which the 2007 fire and/or other parameters have affected their frequency. Observational evidence based on several data sources collected during the period 1989-2016 show that the 2007 fire has contributed to an increase of average flood and mass movement events frequency by approximately 3.3 and 5.6 times respectively. Fire affected areas record a substantial increase in the occurrence of both phenomena, presenting a noticeably stronger increase compared to neighbouring areas that have not been affected. Examination of the monthly occurrence of events showed an increase even in months of the year were rainfall intensity presented decreasing trends. Although no major land use changes has been identified and chlorophyll is shown to recover 2years after the fire incident, differences on the type of vegetation as tall forest has been substituted with lower vegetation are considered significant drivers for the observed increase in flood and mass movement frequency in the fire affected areas.


Modeling the Filler Phase Interaction with Solidification Front in Al(TiC) Composite Produced by the In Situ Method.
This paper presents simulation results of the interaction of TiC nanoparticle in liquid aluminum. The behavior of the TiC particle in the frontal interaction region stems from the operation of a system of such forces as gravity, viscous flow drag force, and Saffman force. The difference in density between the TiC and the aluminum matrix makes the particle fall, regardless of the radius dimension; while the Saffman force-which accounts for the local velocity gradient of the liquid aluminum-causes that particles with the smallest radii considered in the calculations 6.4 × 10-8 m; 7 × 10-8 m; 7.75 × 10-8 m; 9.85 × 10-8 m are repelled from the solidification front and the particles with 15.03 × 10-8 m are attracted to it. The viscosity growth in the course of casting caused by the lowering temperature reduces this effect, though the trend is maintained. The degree to which the particle is attracted to the front clearly depends on the velocity gradient of the liquid phase. For a very small gradient of 0.00001 m/s, the particle is at its closest position relative to the front.


More efficient barley malting under catalyst: Thermostability improvement of a β-1,3-1,4-glucanase through surface charge engineering with higher activity.
β-1,3-1,4-Glucanase is an indispensable biocatalyst in barley brewing industry for its crucial effect in reducing the viscosity of mash. However, the unsatisfactory thermostability greatly limited its application performance. In this study, structure-based surface charge engineering was conducted aiming at thermostability improvement of BisGlu16B, a highly active β-1,3-1,4-glucanase from Bispora sp. MEY-1. By applying the enzyme thermal stability system (ETSS), residues D47, D213, and D253 were inferred to be critical sites for thermal properties. Single (D47A, D213A, and D253A) and combination (D47A/D213A/D253A) mutants were generated and compared with BisGlu16B. Among all improved mutants, D47A/D213A/D253A outstanded in thermostability. In comparison with BisGlu16B, its T50 and Tm were respectively increased by 7.0 °C and 4.3 °C, while the t1/2 at 70 °C was 8.1 times that of the wild type. Furthermore, the catalytic activity of D47A/D213A/D253A also increased by 42.5%, compared with BisGlu16B (42,900 ± 300 U/mg vs. 30,100 ± 800 U/mg). Comparing with BisGlu16B and commercial enzyme treatment groups, under simulated malting conditions, efficiency improvement was observed in decreasement of viscosity (35.5% and 90.7%) and filtration time (30.9% and 34.6%) for D47A/D213A/D253A treatment group. Molecular dynamics simulation showed that mutation sites A47, A213, and A253 increased the protein rigidity by lowering the overall root mean square deviation (RMSD). This study may bring optimization of technology and improvement of producing efficiency to the present brewing industry.


[Cellular and humoral immunity of volunteers consuming diets with various protein levels].
Eight male volunteers were examined for the functions of T and B lymphocytes (blast transformation reaction, leukocyte migration inhibition test, lymphocyte cytotoxicity, suppressor activity, measurement of IgG, IgM, IgA, IgD and IgE in blood serum, and concentration of natural staphylococcal antibodies) in the background of varying protein supply of the body. Reduction of the protein quota (5 to 9 g/day according to nitrogen) in the diet led to inhibition of the activity of immunocompetent cells.


Primary synovial osteochondromatosis of the first metatarsophalangeal joint.
Synovial osteochondromatosis is an uncommon disorder, generally seen in large joints such as the knee, elbow, shoulder, hip and ankle. We report a 35-year-old man with synovial osteochondromatosis of the metatarsophalangeal joint of the great toe. Despite the rarity of the location, the radiographic appearance ought to suggest the diagnosis. Histological confirmation is required, since malignancy cannot be totally ruled out clinically and radiographically.


Gametogony of Eimeria cameli in the small intestine of one-humped camel (Camelus dromedarius).
Domesticated Old World camels (Camelus dromedarius and Camelus bactrianus) are important for the economy of several countries in Asia, Africa, and the Arabian Peninsula, and coccidiosis is an important disease in camels. There is confusion concerning the species of coccidian parasites in camels and their life cycles. Although five species of Eimeria (E. cameli, E. rajasthani, E. dromedarii, E. bactriani, and E. pellerdyi) were named from camels, E. cameli is considered the most pathogenic. Here, development of gametogonic stages and oocysts of E. cameli are described in the lamina propria of the small intestines of naturally infected camels. Only sexual stages have been confirmed.


Cannabinoid and opioid interactions: implications for opiate dependence and withdrawal.
Withdrawal from opiates, such as heroin or oral narcotics, is characterized by a host of aversive physical and emotional symptoms. High rates of relapse and limited treatment success rates for opiate addiction have prompted a search for new approaches. For many opiate addicts, achieving abstinence may be further complicated by poly-drug use and co-morbid mental disorders. Research over the past decade has shed light on the influence of endocannabinoids (ECs) on the opioid system. Evidence from both animal and clinical studies point toward an interaction between these two systems, and suggest that targeting the EC system may provide novel interventions for managing opiate dependence and withdrawal. This review will summarize the literature surrounding the molecular effects of cannabinoids and opioids on the locus coeruleus-norepinephrine system, a key circuit implicated in the negative sequelae of opiate addiction. A consideration of the trends and effects of marijuana use in those seeking treatment to abstain from opiates in the clinical setting will also be presented. In summary, the present review details how cannabinoid-opioid interactions may inform novel interventions in the management of opiate dependence and withdrawal.


Unsupervised machine learning with independent component analysis to identify areas of progression in glaucomatous visual fields.
To determine whether a variational Bayesian independent component analysis mixture model (vB-ICA-mm), a form of unsupervised machine learning, can be used to identify and quantify areas of progression in standard automated perimetry fields. In an earlier study, it was shown that a model using vB-ICA-mm can separate normal fields from fields with six different patterns of visual field loss related to glaucomatous optic neuropathy (GON) along maximally independent axes. In the present study, an independent group of 191 patient eyes (66 with ocular hypertension (OHT), 12 with suspected glaucoma by field, 61 with suspected glaucoma by disc, and 52 with glaucoma) with five or more standard visual fields under observation for a mean of 6.24 +/- 2.65 years and 8.11 +/- 2.42 visual fields were evaluated with the vB-ICA-mm. In addition, eyes with progressive GON (PGON) were identified (n = 39). Each participant had a series of fields tested, with each field entered independently and placed along the axes of the previously developed model. This allowed change in one pattern of visual field defect (along one axis) to be assessed relative to results other areas of that same field (no change along other axes). Progression was based on a slope falling outside the 5th and the 95th percentile limits of all slopes, with at least two axes not showing such a deviation in a given individual's series of fields. Fields were also scored using Advanced Glaucoma Intervention Study (AGIS) and the Early Manifest Glaucoma Treatment Trial (EMGT) criteria. Thirty-two of 191 eyes progressed on vB-ICA-mm by this definition. Of the 32, 22 had field loss at baseline, 7 had only GON, 3 were OHTs and 12 were from the 39 eyes (31%) with PGON. The vB-ICA-mm identified a higher percentage of progressing eyes in each diagnostic category than did AGIS or and the EMGT. The vB-ICA-mm can quantitatively identify progression in eyes with glaucoma by evaluating change in one or more patterns of the visual field loss while other areas or patterns remain stable. This may enable each eye to contribute to the determination of whether change is caused by true progression or by variability.


Facilitated diffusion of p-nitrophenyl-alpha-D-maltohexaoside through the outer membrane of Escherichia coli. Characterization of LamB as a specific and saturable channel for maltooligosaccharides.
LamB, an outer membrane protein of Escherichia coli, is a component of the maltose-maltooligosaccharide transport system. We used p-nitrophenyl-alpha-D-maltohexaoside, a chromogenic analog of maltohexaose, and a periplasmic amylase that hydrolyzes this compound to study the LamB-mediated diffusion of p-nitrophenyl-alpha-D-maltohexaoside into the periplasm. Using this approach, we were able to characterize LamB in vivo as a saturable channel for maltooligosaccharides. Permeation through LamB follows Michaelis-Menten kinetics, with a Km of 0.13 mM and a Vmax of 3.3 nmol/min/10(9) cells. Previous studies suggested that maltose-binding protein increases the rate of maltooligosaccharide diffusion through LamB. We show here that, at least in strains that are unable to transport maltooligosaccharides into the cytoplasm, maltose-binding protein does not influence the rate of substrate diffusion. The periplasmic amylase had been previously described as being of the alpha-type. We have now purified this protein and analyzed its mode of action using chromogenic maltooligosaccharides of varying length. Analysis of the hydrolytic products revealed that the enzyme recognizes its substrate from the nonreducing end and preferentially liberates maltohexaose, in contrast to the behavior of classical alpha-amylases that are endohydrolases. Using p-nitrophenyl-alpha-D-maltohexaoside as a substrate, we determined a Km of 3 microM and a Vmax of 0.14 mumol/min/mg of protein.


A combined intravesical therapy with hyaluronic acid and chondroitin for refractory painful bladder syndrome/interstitial cystitis.
The aims of this study were to evaluate the efficacy and tolerability of intravesical instillations of high-molecular-weight hyaluronic acid (HA) 1.6% and chondroitin sulfate (CS) 2.0% in patients with refractory painful bladder syndrome/interstitial cystitis (PBS/IC) and to observe their impact on Quality of Life. Twenty-three women were enrolled. They received bladder instillations with HA and CS weekly for 20 weeks and then monthly for 3 months. Mean follow-up after completion of therapy was 5 months. We observed a significant improvement in urinary symptoms on voiding diaries and Visual Analogue Scale for frequency (p = 0.045), urgency (p = 0.005), and pain (p = 0.001). The O'Leary-Sant Interstitial Cystitis Symptom Index and Interstitial Cystitis Problem Index resulted in a significant improvement in both scores (p = 0.004 and 0.01, respectively). The Pelvic Pain and Urgency/Frequency Symptom Scale only showed significant improvement in the symptom score (p = 0.001). This promising experience seems to offer an additional therapeutic option in patients with refractory PBS/IC.


Radiologically occult hepatocellular carcinoma in a cirrhotic liver presenting with bilateral adrenal metastases.
Although it is common to have extra-hepatic metastasis of hepatocellular carcinoma (HCC) at the time of presentation, it is extremely rare to have extra-hepatic metastatic HCC without a detectable primary in the liver. We report a unique case in which a patient presented with bilateral large adrenal masses which were subsequently proven to be metastases from HCC. However, there was no tumour seen in the liver on imaging.


Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor.
Consistent with their function in immune surveillance, natural killer (NK) cells are distributed throughout lymphoid and nonlymphoid tissues. However, the mechanisms governing the steady-state trafficking of NK cells remain unknown. The lysophospholipid sphingosine 1-phosphate (S1P), by binding to its receptor S1P1, regulates the recirculation of T and B lymphocytes. In contrast, S1P5 is detected in the brain and regulates oligodendrocyte migration and survival in vitro. Here we show that S1P5 was also expressed in NK cells in mice and humans and that S1P5-deficient mice had aberrant NK cell homing during steady-state conditions. In addition, we found that S1P5 was required for the mobilization of NK cells to inflamed organs. Our data emphasize distinct mechanisms regulating the circulation of various lymphocyte subsets and raise the possibility that NK cell trafficking may be manipulated by therapies specifically targeting S1P5.


Vagal sensory evoked potentials disappear under the neuromuscular block - an experimental study.
Transcutaneous vagal nerve stimulation is a promising treatment modality in patients suffering mood disorders and chronic pain, however, the mechanisms are still to be elucidated. A recently developed technique of EEG responses to electrical stimulation of the inner side of the tragus suggests that these responses are far field potentials, generated in the vagal system - Vagal Sensory Evoked Potentials (VSEP). To reproduce the VSEP technique free from myogenic artifacts. Fourteen ASA I-II patients scheduled for elective surgery in standardized Total Intravenous Anesthesia (TIVA) were enrolled. Transcutaneous electrical stimulation was applied to the inner side of the right tragus. Averaged EEG responses were recorded from the electrode positions C4-F4 and T4-O2 before and after induction of TIVA, during the maximal effect of the non-depolarizing muscle relaxing agent, cis-atracurium (C-AR) and after recovery from C-AR under TIVA. Typical response curves with P1, N1 and P2 peaks could be reproduced in all patients before and after anesthesia induction. The response curves disappeared during the C-AR action and re-appeared after recovery from C-AR under TIVA. The disappearance of the scalp responses to electrical tragus stimulation under the neuromuscular block suggests a muscular origin of these potentials.


Mortality, length of stay, and cost associated with hospitalized adult cancer patients with febrile neutropenia.
Febrile neutropenia (FN) is a serious complication following chemotherapy and is associated with significant mortality and financial expenditure. The aim of this study was to evaluate risk factors for longer length of stay (LOS) and mortality and cost of treatment among hospitalized adults with cancer who developed febrile neutropenia in Thailand. Information on illness of inpatients and casualties came from hospitals nationwide and from hospital withdrawals from the 3 health insurance schemes in fiscal 2010. The data covered 96% of the population and were analyzed by age groups, hospital level, and insurance year schemes in patients with febrile neutropenia. A total of 5,809 patients were identified in the study. The mortality rate was 14%. The median LOS was 8.67 days and 69% of patients stayed for longer than 5 days. On bivariate analysis, age, cancer type, and infectious complications (bacteremia/sepsis, hypotension, fungal infections, and pneumonia) were significantly associated with longer LOS and death. On multivariate analysis, acute leukemia and infectious complications were linked with longer LOS and death significantly. The median cost of hospitalized FN was THB 33,686 (USD 1,122) with the highest cost observed in acute leukemia patients. FN in adult patients results in significant mortality in hospitalized Thai patients. Factors associated with increased mortality include older age (>70), acute leukemia, comorbidity, and infectious complications.