Optical coherence tomography angiography (OCTA) findings in Serpiginous Choroiditis.
To describe changes in the retina/choroid in patients with Serpiginous Choroiditis (SC) by Optical Coherence Tomography Angiography (OCTA) in a multimodal imaging approach. Prospective, monocentric study of 24 eyes of 12 consenting patients diagnosed with SC, who underwent OCTA, which was analyzed and compared to other methods such as enhanced depth imaging-OCT, fluorescein angiography, indocyanine green angiography, and fundus autofluorescence. The study group consisted of 9 patients with peripapillary SC, 1 macular SC, and 2 atypical cases. All eyes presented an inactive SC confirmed by standard imaging. OCTA demonstrated the lesions tridimensionally in great detail. There was no difference in the angioarchitecture among the 3 forms of SC. A loss of the choriocapillaris/retinal pigment epithelium left a "window-defect", where the vessels of larger caliber of the choroid became recognizable and their appearance inverted ("white-on-black"). A relationship between the presence of segmentation errors (SE) in the slabs and low visual acuity was established with a one-way ANOVA. OCTA was able to non-invasively assess vascular lesions of the choroid/retina in patients with SC with a high degree of correlation to other diagnostic modalities. Consequent long-term assessments could lead to a better understanding of disease progression.


The Roles of Xenobiotic Receptors: Beyond Chemical Disposition.
Over the past 20 years, the ability of the xenobiotic receptors to coordinate an array of drug-metabolizing enzymes and transporters in response to endogenous and exogenous stimuli has been extensively characterized and well documented. The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are the xenobiotic receptors that have received the most attention since they regulate the expression of numerous proteins important to drug metabolism and clearance and formulate a central defensive mechanism to protect the body against xenobiotic challenges. However, accumulating evidence has shown that these xenobiotic sensors also control many cellular processes outside of their traditional realms of xenobiotic metabolism and disposition, including physiologic and/or pathophysiologic responses in energy homeostasis, cell proliferation, inflammation, tissue injury and repair, immune response, and cancer development. This review will highlight recent advances in studying the noncanonical functions of xenobiotic receptors with a particular focus placed on the roles of CAR and PXR in energy homeostasis and cancer development.


Interaction of the vitamin D receptor with a vitamin D response element in the Mullerian-inhibiting substance (MIS) promoter: regulation of MIS expression by calcitriol in prostate cancer cells.
Calcitriol (1,25-dihydroxyvitamin D(3)) inhibits the growth of a variety of cancer cells including human prostate cancer. Müllerian-inhibiting substance (MIS) also exhibits antiproliferative and proapoptotic actions on multiple cancer cells including human prostate cancer. In this study, we investigated whether calcitriol regulated MIS expression in prostate cancer, an action that might contribute to its antiproliferative activity. We identified a 15-bp sequence, GGGTGAgcaGGGACA, in the MIS promoter that was highly similar to direct repeat 3-type vitamin D response elements (VDREs). The human MIS promoter containing the putative VDRE was cloned into a luciferase reporter vector. In HeLa cells transfected with the vitamin D receptor (VDR), MIS promoter activity was stimulated by calcitriol. Coexpression of steroidogenic factor 1, a key regulator of MIS, increased basal MIS promoter activity that was further stimulated by calcitriol. Mutation or deletion of the VDRE reduced calcitriol-induced transactivation. In addition, the MIS VDRE conferred calcitriol responsiveness to a heterologous promoter. In gel shift assays, VDR and retinoid X receptor bound to the MIS VDRE and the binding was increased by calcitriol. Chromatin immunoprecipitation assays showed that VDR and retinoid X receptor were present on the MIS promoter in prostate cancer cells. In conclusion, we demonstrated that MIS is a target of calcitriol action. MIS is up-regulated by calcitriol via a functional VDRE that binds the VDR. Up-regulation of MIS by calcitriol may be an important component of the antiproliferative actions of calcitriol in some cancers.


High performance team interaction in an air medical program.
The purpose of this qualitative study was to identify and describe the elements of a high performance team interaction on an air medical transport mission. The phenomenologic method as described by Giorgi was used to guide data collection and analysis. Six flight nurses from around the United States were interviewed and audiotaped as they described their subjective perception of a high performance team experience. Four themes emerged from the data: collaboration, mutual respect and trust, fitness standards, and synergy. Implications for flight crews involved in this high performance environment may require attention to the identified themes to promote team performance.


Disparities in colostomy reversal after Hartmann's procedure for diverticulitis.
Hartmann's procedure for diverticulitis is a common procedure, with highly variable rates and timing of colostomy reversal. The aim of this study was to evaluate the impact of race and insurance coverage on reversal within 2 years of Hartmann's procedure for diverticulitis. The Healthcare Cost and Utilization Project (HCUP) State Inpatient Database of five states (2007-2010) was queried for patients who had Hartmann's procedure in the setting of diverticulitis. Patients were grouped by race and insurance status, and multivariable adjustment was performed to evaluate rate and timing of colostomy takedown at 2 years. Among 11,019 patients who had Hartmann's procedure for diverticulitis, 6900 (69%) patients had colostomy reversal by 2 years, with a median time to reversal of 19 weeks. Compared to white patients with private insurance, combinations of black race and non-private insurance significantly reduced likelihood of colostomy reversal at 2 years across all combinations. Black patients without insurance had the lowest likelihood of reversal at 2 years (OR 0.27, 95% CI 0.14-0.51, p < 0.001). For patients who had colostomy reversal within 2 years, black patients without insurance had a significant delay in time to reversal (11 weeks, 95% CI 6-16, p < 0.001) compared to white patients with private insurance, and delays persisted across all other groups. Black patients and those without private insurance experienced significantly lower rates of, and delayed time to, colostomy reversal compared to white patients with private insurance. These disparities must be considered for allocation of resources in marginalized communities.


Evolution study of the Baeyer-Villiger monooxygenases enzyme family: functional importance of the highly conserved residues.
Baeyer-Villiger monooxygenases (BVMOs) catalyze the transformation of linear and cyclic ketones into their corresponding esters and lactones by introducing an oxygen atom into a C-C bond. This bioreaction has numerous advantages compared to its chemical version; it does not induce the use of potentially harmful reagents (i.e., green chemistry) and displays significant better enantio- and regio-selectivity. New potential BVMOs were searched using sequence homology for type I BVMO proteins. 116 new sequences were identified as new putative BVMOs respecting the defined selection criteria. Multiple sequence alignments were carried out on the selected sequences to study the conservation of structurally and/or functionally important amino acids during evolution. Type I BVMO signature motif was found to be conserved in 94.8% of the sequences. We noticed also the highly conserved - but previously unnoticed - Threonine 167 (93.1%), located in the signature motif; this position could be added in the pattern used to characterize specific Type I enzymes. Amino acids at the vicinity of the FAD and NADPH cofactors were found also to be highly conserved and the details of the interactions were emphasized. Interestingly, residues at the enzyme binding site were found less conserved in terms of sequence evolution, leading sometimes to some important amino acid changes. These behaviors could explain the enzyme selectivity and specificity for different ligands.


Bandwidth optimization for filter-based fatigue index in different inter-electrode distances.
In this study, the bandwidth of the filter-based fatigue index was determined by the comparison of optimized cut-off frequencies in different inter-electrode distances. Sixty-one subjects participated in isometric knee extension, isotonic ankle dorsiflexion, and isotonic elbow extension exercises. Electromyography (EMG) signals were obtained from right rectus femoris, triceps brachii, and tibialis anterior muscles during exercises. The filter-based fatigue index was compared with mean root-mean-square values, median frequency, Dimitrov spectral index, and Gonzalez-Izal wavelet index. Optimized cut-off frequencies of the high-pass filter for three different exercises and three different inter-electrode distances were about 350 Hz. Results from this study support that around 350 Hz high-pass filter could be useful to determine cut-off frequency for fatigue prediction in general purposes.


Single-cell transcriptomics defines Dot1L interacting partners and downstream target genes in the mouse molar dental pulp.
Although histone methyltransferases are implicated in many key developmental processes, the contribution of individual chromatin modifiers in dental tissues is not well understood. Using single-cell RNA sequencing, we examined the expression profiles of the disruptor of telomeric silencing 1-like (Dot1L) gene in the postnatal day 5 mouse molar dental pulp. Dot1L is the only known enzyme that methylates histone 3 on lysine 79, a modification associated with gene expression. Our research revealed 15 distinct clusters representing different populations of mesenchymal stromal cells (MSCs), immune cells, pericytes, ameloblasts and endothelial cells. We documented heterogeneity in gene expression across different subpopulations of MSCs, a good indicator that these stromal progenitors undergo different phases of osteogenic differentiation. Interestingly, although Dot1L was broadly expressed across all cell clusters within the molar dental pulp, our analyses indicated specific enrichment of Dot1L within two clusters of MSCs, as well as cell clusters characterized as ameloblasts and endothelial cells. Moreover, we detected Dot1L co-expression with protein interactors involved in epigenetic activation such as Setd2, Sirt1, Brd4, Isw1, Bptf and Suv39h1. In addition, Dot1L was co-expressed with Eed2, Cbx3 and Dnmt1, which encode epigenetic factors associated with gene silencing and heterochromatin formation. Dot1l was co-expressed with downstream targets of the insulin growth factor and WNT signaling pathways, as well as genes involved in cell cycle progression. Collectively, our results suggest that Dot1L may play key roles in orchestrating lineage-specific gene expression during MSC differentiation.


Physical activity and congenital heart disease.
With advances in the diagnosis and management of congenital heart disease (CHD), the need has arisen for the assessment and counseling of patients as to appropriate physical activity levels through adulthood. Considerations to be evaluated before making exercise and athletic activity recommendations to the patient with CHD are outlined. Recommended guidelines of the American Heart Association are presented for recreational and occupational activities. Selected congenital heart defects are reviewed to address potential negative effects of incorrect recommendations.


The midwife and postnatal contraceptive advice.
Following childbirth, most hormonal methods are an effective way to prevent an unwanted pregnancy. There are a few medical conditions that may prevent a woman taking the COC; these need consultation with a family planning doctor. On the whole most oestrogen-free methods are suitable, particularly if a woman is breastfeeding. However, they may not be the method of choice if irregular bleeding is unacceptable for social or cultural reasons. The advantage of these methods is that they are not coitus-related and do not involve touching the genitalia. The mode of delivery also does not preclude the use of hormonal contraception.


Downregulation of MDM2 expression by RNAi inhibits LoVo human colorectal adenocarcinoma cells growth and the treatment of LoVo cells with mdm2siRNA3 enhances the sensitivity to cisplatin.
To investigate the biological effect of mdm2 in human colorectal adenocarcinoma LoVo cells, three mdm2siRNA constructions were recombined and transient transfected into human colorectal adenocarcinoma LoVo cells with low differentiation character in vitro. The results showed that mdm2siRNA3 reduced mRNA level of mdm2 and protein level of mdm2, leading to proliferation inhibition on LoVo cells, and reduced tumor growth in nude mice. It was found that depletion of MDM2 in this pattern promoted apoptosis of LoVo cells and Cisplatin (DDP) treated in the mdm2siRNA3 transfected cell population would result in a substantial decrease by MTT colorimetry. Decreasing the MDM2 protein level in LoVo cells by RNAi could significantly inhibit tumor growth both in vitro and in vivo, which indicated that mdm2 gene played a definite role in the development and aggressiveness of human colon carcinoma. It also could be a therapeutic target in colorectal carcinoma. The synergistic activation of RNAi and cell toxicity agents indicated that the combination of chemotherapy and gene therapy will be a promising approach in the future.


Heterogeneous targets of dopamine synapses in monkey prefrontal cortex demonstrated by serial section electron microscopy: a laminar analysis using the silver-enhanced diaminobenzidine sulfide (SEDS) immunolabeling technique.
Dopamine projections to the cerebral cortex have been implicated in normal and pathological cognitive processes, notably, Parkinson's disease and schizophrenia. To help elucidate the function of these dopamine axons, they were characterized by serial section electron microscopy in individual layers of monkey prefrontal cortex. Dopamine immunoreactivity was visualized with a silver precipitation technique that allowed clear resolution of the internal structures and cell membranes of labeled axons. Apart from the occasional large microtubule-filled axon, dopamine axons were thin and varicose with many clear synaptic vesicles and fewer dense-core vesicles. With few exceptions, dopamine synapses were symmetric and quite small, seen in only one to three serial sections. A determination of the "synaptic incidence" showed that only 39% of labeled varicosities formed identifiable synapses. However, it is certain that some small synapses could not be visualized even in serial sections, and it is possible that the vast majority if not all varicosities form synapses. Except for one soma, dendritic spines and shafts were the recipients of dopamine synapses. Many postsynaptic shafts were small and spiny, indicating that they were distal pyramidal dendrites. However, some postsynaptic shafts especially in supragranular layers had distinctly nonpyramidal features. These lacked spines, had a high density of synaptic inputs, and often had a strikingly varicose morphology. The data suggest that the majority of dopamine synapses in all layers are on pyramidal cells, but that a significant fraction are on presumed GABAergic nonpyramidal cells.


Dietary S-methylmethionine, a component of foods, has choline-sparing activity in chickens.
Acid hydrolysis of dehulled soybean meal (SBM) and corn gluten meal (CGM) followed by chromatographic amino acid analysis (ninhydrin detection) revealed substantial quantities of S-methylmethionine (SMM) in both ingredients (1.65 g SMM/kg SBM; 0.5 g SMM/kg CGM). Young chicks were used to quantify the methionine- (Met) and choline-sparing bioactivity of crystalline L-SMM, relative to L-Met and choline chloride standards in 3 assays. A soy isolate basal diet was developed that could be made markedly deficient in Met, choline, or both. When singly deficient in choline or in both choline and Met, dietary SMM addition produced a significant (P < 0.01) growth response. In Assay 2, dietary SMM did not affect (P > 0.10) growth of chicks fed a Met-deficient, choline-adequate diet. A standard-curve growth assay revealed choline bioactivity values (wt:wt) of 14.2 +/- 0.8 and 25.9 +/- 5.1 g/100 g SMM based on weight gain and gain:food responses, respectively. A fourth assay, using standard-curve procedures, showed choline bioactivity values of 20.1 +/- 1.1 and 22.9 +/- 1.7 g/100 g SMM based on weight gain and gain:food responses, respectively. It is apparent that SMM in foods and feeds has methylation bioactivity, and this has implications for proper assessment of dietary Met and choline requirements as well as their bioavailability in foods and feeds.


Incarceration and mortality in the United States.
The ongoing COVID-19 pandemic has spotlighted the role of America's overcrowded prisons as vectors of ill health, but robust analyses of the degree to which high rates of incarceration impact population-level health outcomes remain scarce. In this paper, we use county-level panel data from 2927 counties across 43 states between 1983 and 2014 and a novel instrumental variable technique to study the causal effect of penal expansion on age-standardised cause-specific and all-cause mortality rates. We find that higher rates of incarceration have substantively large effects on deaths from communicable, maternal, neonatal, and nutritional diseases in the short and medium term, whilst deaths from non-communicable disease and from all causes combined are impacted in the short, medium, and long run. These findings are further corroborated by a between-unit analysis using coarsened exact matching and a simulation-based regression approach to predicting geographically anchored mortality differences.


Necrotizing Autoimmune Myopathy: Clinicopathologic Study from a Single Tertiary Care Centre.
Idiopathic inflammatory myopathies (IIMs) are a group of chronic, autoimmune disorders which include a new entity, necrotizing autoimmune myopathy (NAM). NAM lacks inflammation and presents with markedly elevated creatinine phosphokinase (CPK) levels. It is associated with connective tissue diseases (CTDs), statin use, malignancies, and most cases are idiopathic. The objectives of this study are to describe the clinicopathologic features in muscle biopsy-proven cases of NAM. To emphasize the role of laboratory parameters such as CPK levels and myositis profile in the diagnosis of NAM. This is a retrospective study including 15 patients of NAM diagnosed on muscle biopsy over a period of 2 years. The slides of the biopsies were reviewed, and clinical data, electromyography findings, and CPK levels were obtained. Myositis profile was done. Necrotizing myopathy accounted for 13.63% (15 cases) of total inflammatory myopathies (110 cases) in the study. These were grouped into CTD-associated NAM, statin-associated NAM, paraneoplastic NAM and idiopathic NAM which was the common type. All cases presented with progressive proximal muscle weakness and had markedly elevated CPK levels. Anti-3-hydroxy-3-methyl-glutaryl-coenzyme A reductase and antisignal recognition particle antibodies were seen to be positive in six patients. Muscle biopsies showed predominant fiber necrosis with significant fiber degeneration and regeneration in the absence of inflammation. All patients received immunotherapy with significant improvement was seen in six patients with two mortalities. Necrotizing myopathy is a new addition to the spectrum of IIM. Clinicopathologic correlation is important for appropriate diagnosis. It is found to be refractory to corticosteroids monotherapy. The course of illness is not uniform, and in some patients, there can be rapid worsening with mortality.


Machine learning in vascular surgery: a systematic review and critical appraisal.
Machine learning (ML) is a rapidly advancing field with increasing utility in health care. We conducted a systematic review and critical appraisal of ML applications in vascular surgery. MEDLINE, Embase, and Cochrane CENTRAL were searched from inception to March 1, 2021. Study screening, data extraction, and quality assessment were performed by two independent reviewers, with a third author resolving discrepancies. All original studies reporting ML applications in vascular surgery were included. Publication trends, disease conditions, methodologies, and outcomes were summarized. Critical appraisal was conducted using the PROBAST risk-of-bias and TRIPOD reporting adherence tools. We included 212 studies from a pool of 2235 unique articles. ML techniques were used for diagnosis, prognosis, and image segmentation in carotid stenosis, aortic aneurysm/dissection, peripheral artery disease, diabetic foot ulcer, venous disease, and renal artery stenosis. The number of publications on ML in vascular surgery increased from 1 (1991-1996) to 118 (2016-2021). Most studies were retrospective and single center, with no randomized controlled trials. The median area under the receiver operating characteristic curve (AUROC) was 0.88 (range 0.61-1.00), with 79.5% [62/78] studies reporting AUROC ≥ 0.80. Out of 22 studies comparing ML techniques to existing prediction tools, clinicians, or traditional regression models, 20 performed better and 2 performed similarly. Overall, 94.8% (201/212) studies had high risk-of-bias and adherence to reporting standards was poor with a rate of 41.4%. Despite improvements over time, study quality and reporting remain inadequate. Future studies should consider standardized tools such as PROBAST and TRIPOD to improve study quality and clinical applicability.


Fundamental Movement Skills among Iranian Primary School Children.
To determine the relationship between anthropometric indicators, physical activity (PA) and socioeconomic status (SES) with fundamental movement skills (FMS) among Iranian male students. In this descriptive study, based on SES scores, 241 students (7-10 years) were randomly selected and classified in high, medium and low groups. All children were measured by 8 morphology anthropometric measures. In order to examine a subset of manipulative skills and to measure physical activity and socioeconomic status, Test of Gross Motor Development (TGMD2) and, interviewer-administered questionnaires were used, respectively. The data were analyzed using Pearson correlation and multiple regression. There was a significant positive correlation between SES and body mass index (BMI), while a significant negative correlation existed between PA and BMI. Object control skills were significantly correlated with height, foot length, forearm length, hand length and physical activity. Students with low socioeconomic status were more qualified in movements than other students who were in medium and high socioeconomic status. Therefore, parents need to encourage students to be more active in order to prevent obesity and to facilitate development of object control skills in high socioeconomic status.


Root canal treatment of three-rooted maxillary second premolars: report of four cases.
The aim of this report is to contribute to a better understanding of the radiographic, clinical and anatomic findings in maxillary second premolars. This paper reports the endodontic treatment of two cases of three-rooted three-canal maxillary second premolars in different patients, and two sound maxillary second premolars also with three canals and three independent roots in a sibling of one of the patients. Although the presence of maxillary second premolars with one or two canals and one root is much more common, other anatomic conditions can be found. A correct clinical and radiographic diagnosis based on knowledge of root canal anatomy and critical interpretation of radiographs is necessary for a safer and successful endodontic treatment of these teeth.


The central nucleus of the amygdala and corticotropin-releasing factor: insights into contextual fear memory.
The central nucleus of the amygdala (CeA) has been traditionally viewed in fear conditioning to serve as an output neural center that transfers conditioned information formed in the basolateral amygdala to brain structures that generate emotional responses. Recent studies suggest that the CeA may also be involved in fear memory consolidation. In addition, corticotropin-releasing factor systems were shown to facilitate memory consolidation in the amygdala, which contains a high density of CRF immunoreactive cell bodies and fibers in the lateral part of the CeA (CeAl). However, the involvement of CeA CRF in contextual fear conditioning remains poorly understood. Therefore, we first conducted a series of studies using fiber-sparing lesion and reversible inactivation methods to assess the general role of the CeA in contextual fear. We then used identical training and testing procedures to compare and evaluate the specific function of CeA CRF using CRF antisense oligonucleotides (CRF ASO). Rats microinjected with ibotenic acid, muscimol, or a CRF ASO into the CeA before contextual fear conditioning showed typical levels of freezing during acquisition training but exhibited significant reductions in contextual freezing in a retention test 48 h later. Furthermore, CeA inactivation induced by either muscimol or CRF ASO administration immediately before retention testing did not impair freezing, suggesting that the previously observed retention deficits were caused by inhibition of consolidation rather than fear expression. Collectively, our results suggest CeA involvement in the consolidation of contextual fear memory and specifically implicate CeA CRF as an important mediator.


[Cyclic adenosine monophosphate in the cerebrospinal fluid of patients with brain trauma and diseases].
The authors studied adenosine 3,5-cyclic monophosphate (cAMP) in the cerebrospinal fluid (csf) of patients with craniocerebral trauma (CCT), ischemic stroke, and brain tumors. A statistically significant increase of cAMP in csf of patients with moderate and severe CCT was revealed. In unfavourable outcomes of severe CCT the increase of cAMP continued to the time of death. The authors suggest using this index as a diagnostic criterion of the depth of the metabolic disorders in the brain tissue, as a prognostic criterion, and for purposes of differential diagnosis. The possible mechanism of lipid peroxidation activation in CCT is discussed.


Impact of TP53 Genomic Alterations in Large B-Cell Lymphoma Treated With CD19-Chimeric Antigen Receptor T-Cell Therapy.
Tumor-intrinsic features may render large B-cell lymphoma (LBCL) insensitive to CD19-directed chimeric antigen receptor T cells (CAR-T). We hypothesized that TP53 genomic alterations are detrimental to response outcomes in LBCL treated with CD19-CAR-T. Patients with LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing was performed on pre-CAR-T tumor samples in a subset of patients. Response and survival rates by histologic, cytogenetic, and molecular features were assessed. Within a cohort of newly diagnosed LBCL with genomic and transcriptomic profiling, we studied interactions between cellular pathways and TP53 status. We included 153 adults with relapsed or refractory LBCL treated with CD19-CAR-T (axicabtagene ciloleucel [50%], tisagenlecleucel [32%], and lisocabtagene maraleucel [18%]). Outcomes echoed pivotal trials: complete response (CR) rate 54%, median overall survival (OS) 21.1 months (95% CI, 14.8 to not reached), and progression-free survival 6 months (3.4 to 9.7). Histologic and cytogenetic LBCL features were not predictive of CR. In a subset of 82 patients with next-generation sequencing profiling, CR and OS rates were comparable with the unsequenced cohort. TP53 alterations (mutations and/or copy number alterations) were common (37%) and associated with inferior CR and OS rates in univariable and multivariable regression models; the 1-year OS in TP53-altered LBCL was 44% (95% CI, 29 to 67) versus 76% (65 to 89) in wild-type (P = .012). Transcriptomic profiling from a separate cohort of patients with newly diagnosed lymphoma (n = 562) demonstrated that TP53 alterations are associated with dysregulation of pathways related to CAR-T-cell cytotoxicity, including interferon and death receptor signaling pathway and reduced CD8 T-cell tumor infiltration. TP53 is a potent tumor-intrinsic biomarker that can inform risk stratification and clinical trial design in patients with LBCL treated with CD19-CAR-T. The role of TP53 should be further validated in independent cohorts.


Terrestrial microclimate: amelioration at high latitudes.
At latitudes north of the Arctic Circle the diel range of sun altitude declines progressively, reducing the frequency of temperature inversions over level, unshaded ground in summer and extending the frost-free season. North of about 70 degrees north, the potential number of inversion-free days increases rapidly with latitude; this ameliorates the microclimate close to the ground-the zone to which terrestrial organisms are increasingly restricted in higher latitudes. The relation between screen and ground-surface temperatures differs north and south of about 70 degrees north; north of that latitude there are progressively more frost-free days than would be inferred from screen temperatures, were no allowance made for this latitude-dependent change.


Nonsurgical delay of cutaneous flaps using the flashlamp pumped pulsed dye laser.
The surgical delay procedure is an effective method for improving skin flap survival. However, it has many disadvantages, such as bleeding, infection, and pain. It also requires an additional operation and a long time for wound management. Nonsurgical delay has a great importance, but pharmacological efforts for delay phenomena have never found clinical application. In this study, the authors attempted to reproduce the delay phenomena via the flashlamp pumped dye laser. Forty Sprague-Dawley rats were studied in four groups of 10 rats each. The experimental and control flaps were on the same rat. Flaps were planned on the ventral skin of the rats, and were symmetrical, three sided, based caudally, and were 2 cm in width, extended to the measured midpoint between the xiphoid and the sternal notch. The laser was applied to the different areas of the experimental flaps 15 days before flap elevation. A week later flap survival was determined by overlaying millimeter-grid acetate paper. Full-surface and perimeter "lased" experimental flaps showed a marked increase in surviving areas when compared with the control flaps. This kind of flap delay has a great potential in clinic application.


Mitotic Checkpoint Kinase Mps1 Has a Role in Normal Physiology which Impacts Clinical Utility.
Cell cycle checkpoint intervention is an effective therapeutic strategy for cancer when applied to patients predisposed to respond and the treatment is well-tolerated. A critical cell cycle process that could be targeted is the mitotic checkpoint (spindle assembly checkpoint) which governs the metaphase-to-anaphase transition and insures proper chromosomal segregation. The mitotic checkpoint kinase Mps1 was selected to explore whether enhancement in genomic instability is a viable therapeutic strategy. The basal-a subset of triple-negative breast cancer was chosen as a model system because it has a higher incidence of chromosomal instability and Mps1 expression is up-regulated. Depletion of Mps1 reduces tumor cell viability relative to normal cells. Highly selective, extremely potent Mps1 kinase inhibitors were created to investigate the roles of Mps1 catalytic activity in tumor cells and normal physiology (PF-7006, PF-3837; Ki<0.5 nM; cellular IC50 2-6 nM). Treatment of tumor cells in vitro with PF-7006 modulates expected Mps1-dependent biology as demonstrated by molecular and phenotypic measures (reduced pHH3-Ser10 levels, shorter duration of mitosis, micro-nucleation, and apoptosis). Tumor-bearing mice treated with PF-7006 exhibit tumor growth inhibition concomitant with pharmacodynamic modulation of a downstream biomarker (pHH3-Ser10). Unfortunately, efficacy only occurs at drug exposures that cause dose-limiting body weight loss, gastrointestinal toxicities, and neutropenia. Mps1 inhibitor toxicities may be mitigated by inducing G1 cell cycle arrest in Rb1-competent cells with the cyclin-dependent kinase-4/6 inhibitor palbociclib. Using an isogenic cellular model system, PF-7006 is shown to be selectively cytotoxic to Rb1-deficient cells relative to Rb1-competent cells (also a measure of kinase selectivity). Human bone marrow cells pretreated with palbociclib have decreased PF-7006-dependent apoptosis relative to cells without palbociclib pretreatment. Collectively, this study raises a concern that single agent therapies inhibiting Mps1 will not be well-tolerated clinically but may be when combined with a selective CDK4/6 drug.


Diisopropanolnitrosamine (DIPN) induced rat thyroid lesions. I. A histological classification.
DIPN induced localized lesions of the rat thyroid gland are described histologically and classified into three major types: type 1, foci of cellular alteration; type 2, proliferative nodules; and type 3, overt carcinomas. Follicular, papillary and mixed papillofollicular subtypes are recognized in the type 2 lesions, and follicular, papillary, anaplastic and mixed subtypes in the type 3 lesions. The nature of the individual lesions is discussed.


Radiological evaluation of malignant pleural mesothelioma - defining distant metastatic disease.
Malignant pleural mesothelioma (MPM) is traditionally characterized by local destructive spread of the pleura and surrounding tissues. Patient outcomes in MPM with distant metastatic dissemination are lacking. In this retrospective study, we reviewed a cohort of 164 MPM patients referred to a Phase I trials unit, aiming to describe identified metastatic sites, and correlate with clinical outcomes. 67% of patients were diagnosed with distant metastatic disease with a high incidence of bone (19%), visceral (14%), contralateral lung (35%) and peritoneal metastases (22%). Peritoneal metastases were more likely in epithelioid versus biphasic/ sarcomatoid MPM (p = 0.015). Overall survival was 23.8 months with no statistical difference in survival between those with distant metastases and those without. This report highlights the frequency of distant metastases and encourages further radiological investigations in the presence of symptoms. In particular, given the relatively high incidence of bone metastases, bone imaging should be considered in advanced MPM clinical workflow and trial protocols. The presence of distant metastases does not appear to have prognostic implications under existing treatment paradigms. This cohort of MPM patients gives an indication of patterns of metastatic spread that are likely to become prevalent as prognosis improves with emerging treatment paradigms.


Deletion of the GABA(A) receptor beta 3 subunit eliminates the hypnotic actions of oleamide in mice.
Oleamide (OA) is an endogenous unsaturated fatty acid amide with demonstrated sleep promoting effects in rodents. The sleep enhancing actions of OA may be mediated through interactions with the GABAergic, serotonergic or cannabinergic receptor systems. In this study, we investigated the possible interaction of OA with the GABA(A )receptor by administering OA to mice with a targeted mutation of the GABAA receptor beta 3 subunit (Gabarb3-/-). Peripherally administered OA significantly decreased sleep latency and wake time, while it increased non-rapid eye movement and total sleep times in wild-type (Gabarb3+/+) mice. OA failed to have any sleep-wake effect in Gabarb3-/- mice. On 24 h baseline recordings, no differences between Gabarb3-/- and Gabarb3+/+ mice were observed, indicating that the lack of a pharmacological response to OA in the Gabarb3-/- animals was not secondary to disruptions in physiological. sleep. Therefore, one mechanism by which OA exerts its sleep effects may be through interactions with GABA(A) receptors containing the beta 3 subunit.


The development and function of follicular helper T cells in immune responses.
Follicular helper T cells (Tfh) have been referred as a lineage that provides a help for B cells to proliferate and undergo antibody affinity maturation in the germinal center. Evidence has supported that Tfh subset development, like other lineages, is dependent on microenvironment where a particular transcriptional program is initiated. It has been shown that Bcl-6 and IL-21 act as master regulators for the development and function of Tfh cells. Tfh dysregulation is involved in the development of autoimmune pathologies, such as systemic lupus erythematosus, rheumatoid arthritis and other autoimmune diseases. The present review highlights the recent advances in the field of Tfh cells and focus on their development and function.


Pharmacokinetics and pharmacodynamics of enalapril in patients with congestive heart failure and patients with hypertension.
The clinical pharmacokinetics and pharmacodynamics of enalapril and its de-esterified active metabolite, MK 422, were determined in eight patients with congestive cardiomyopathy and five patients with hypertension. After administration of single doses of 2.5, 5, and 10 mg enalapril in the congestive heart failure patients and 20 or 40 mg in the hypertensive patients, serum levels and urine elimination of enalapril and MK 422 were determined. Standing and supine heart rate and blood pressure were measured as was ejection fraction in the congestive heart failure group and renin activity, aldosterone levels, and converting enzyme activity in the hypertensive group. Apparent oral clearance after administration of 5 and 10 mg enalapril was lower in the congestive heart failure patients (0.6 +/- 0.2 and 0.7 +/- 0.4 L/min) than after 20 and 40 mg given to hypertensive patients (2.5 +/- 1.3 and 2.7 +/- 2.7 L/min). The elimination of MK 422 was also slower in the congestive heart failure patients (7.8 +/- 5.0 and 6.8 +/- 2.5 h after 5 and 10 mg enalapril, respectively, vs. 4.6 +/- 2.0 and 5.3 +/- 1.1 h after 20 and 40 mg, respectively, in the hypertension group). The enalapril area under the concentration-time curve increased disproportionately to dose increments in both groups, but was more pronounced in congestive heart failure. Twenty and 40 mg enalapril lowered the blood pressure by 2 h after dosing in the hypertension group, and peak effects were seen 4-5 h after dosing. Peak effects correlated with peak serum MK 422 concentrations but not with enalapril (MK 421) levels. Supine heart rates were unchanged after 20 mg, but increased after 40 mg; standing heart rates were transiently increased after 20 and 40 mg enalapril. Blood pressure was not significantly changed in the congestive heart failure group, and cardiac ejection fraction was unchanged. In the hypertension group, renin stimulation and converting enzyme activity inhibition were seen at 4 h and persisted for at least 24 h after administration of 40 mg enalapril. In summary, the clearance of enalapril and elimination of MK 422 was slower in congestive heart failure patients versus hypertensive patients. Therefore, slower onset and longer duration of drug effect might be anticipated in patients with congestive heart failure versus patients with hypertension during enalapril administration.


Saline nasal irrigation and gargling in COVID-19: a multidisciplinary review of effects on viral load, mucosal dynamics, and patient outcomes.
With unrelenting SARS-CoV-2 variants, additional COVID-19 mitigation strategies are needed. Oral and nasal saline irrigation (SI) is a traditional approach for respiratory infections/diseases. As a multidisciplinary network with expertise/experience with saline, we conducted a narrative review to examine mechanisms of action and clinical outcomes associated with nasal SI, gargling, spray, or nebulization in COVID-19. SI was found to reduce SARS-CoV-2 nasopharyngeal loads and hasten viral clearance. Other mechanisms may involve inhibition of viral replication, bioaerosol reduction, improved mucociliary clearance, modulation of ENaC, and neutrophil responses. Prophylaxis was documented adjunctive to personal protective equipment. COVID-19 patients experienced significant symptom relief, while overall data suggest lower hospitalization risk. We found no harm and hence recommend SI use, as safe, inexpensive, and easy-to-use hygiene measure, complementary to hand washing or mask-wearing. In view of mainly small studies, large well-controlled or surveillance studies can help to further validate the outcomes and to implement its use.


The mannose receptor binds Trichuris muris excretory/secretory proteins but is not essential for protective immunity.
Trichuris muris is a natural mouse model of the human gastrointestinal nematode parasite Trichuris trichiura and it is well established that a T helper type 2-dominated immune response is required for worm expulsion. Macrophages accumulate in the large intestine of mice during infection and these cells are known to express the mannose receptor (MR), which may act as a pattern recognition receptor. The data presented here show for the first time that T. muris excretory/secretory products (E/S) induce bone-marrow-derived macrophages (BMDM) to produce several cytokines and have MR-binding activity. Using alternatively activated BMDM from MR knockout mice it is shown that the production of interleukin-6 partially depends on the MR. Infection of MR knockout mice with T. muris reveals that this receptor is not necessary for the expulsion of the parasite because MR knockout mice expel parasites with the same kinetics as wild-type animals and have similar cytokine responses in the mesenteric lymph nodes. Furthermore, despite acting to reduce serum levels of proinflammatory mediators, absence of the MR does not lead to increased gut inflammation after T. muris infection when assessed by macrophage influx, goblet cell hyperplasia and crypt depth. This work suggests that, despite binding components of T. muris E/S, the MR is not critically involved in the generation of the immune response to this parasite.


Assessing the quality of health care in the management of bronchiolitis in Australian children: a population-based sample survey.
Bronchiolitis is the most common cause of respiratory hospitalisation in children aged <2 years. Clinical practice guidelines (CPGs) suggest only supportive management of bronchiolitis. However, the availability of CPGs do not guarantee that they are used appropriately and marked variation in the clinical management exists. We conducted an assessment of guideline adherence in the management of bronchiolitis in children at a subnationally representative level including inpatient and ambulatory services in Australia. We searched for national and international CPGs relating to management of bronchiolitis in children and identified 16 recommendations which were formatted into 40 medical record audit indicator questions. A retrospective medical record review assessing compliance with the CPGs was conducted across three types of healthcare setting: hospital inpatient admissions, emergency department (ED) presentations and general practice (GP) consultations in three Australian states for children aged <2 years receiving care in 2012 and 2013. Purpose-trained surveyors conducted 13 979 eligible indicator assessments across 796 visits for bronchiolitis at 119 sites. Guideline adherence for management of bronchiolitis was 77.3% (95% CI 72.6 to 81.5) for children attending EDs, 81.6% (95% CI 78.0 to 84.9) for inpatients and 52.3% (95% CI 44.8 to 59.7) for children attending GP consultations. While adherence to some individual indicators was high, overall adherence to documentation of 10 indicators relating to history taking and examination was poorest and estimated at 2.7% (95% CI 1.5 to 4.4). The study is the first to assess guideline-adherence in both hospital (ED and inpatient) and GP settings. Our study demonstrated that while the quality of care for bronchiolitis was generally adherent to CPG indicators, specific aspects of management were deficient, especially documentation of history taking.


[Farmer's lung disease caused by straw or hay? Case report].
A young woman was admitted to Akranes Regional Hospital because of dyspnea, fatigue and fever. She was found to have bilateral pneumonia but etiology was not found. She was treated with antibiotics with good resolution and was discharged after eight days from the hospital. Four weeks later she noticed rapidly progressive dyspnea and was found to be hypoxemic, and to have restrictive spirometry and diffuse interstitial changes on chest radiography. Computerized tomography of the lungs showed diffuse ground glass changes. Transbronchial biopsies from the lungs showed numerous small granulomas. She was treated with prednisolone for a short time with excellent recovery. She stall-fed horses and underneath them was straw containing organic dust. This is important to keep in mind as a differential diagnosis to farmers lung disease that is caused by hay.


Small intestinal angiosarcoma leading to perforation and acute abdomen: a case report and review of the literature.
A 76-year-old man presented to the emergency room with abdominal pain and fatigue. The patient had a history of gastrointestinal bleeding. An abdominal computed tomographic scan showed collections of free air in the abdomen with obstruction of the distal small intestine and multiple masses in the liver. Laparotomy revealed a widespread malignant neoplasm in the abdomen, with multiple tumor nodules in the ileal wall, mesentery, and liver. The ileal wall was perforated within the area of one of the tumors. Pathologic examination of the lesion showed a neoplasm composed of solid sheets of spindle and undifferentiated cells, forming interlacing delicate vascular channels with atypical endothelial cells. The tumor cells were positive for the endothelial marker CD31, whereas reactivity for a broad panel of epithelial and other endothelial markers was negative. This case demonstrates that although angiosarcomas of the gastrointestinal tract are rare, they should be considered in cases of intestinal perforation or severe bleeding, especially in the elderly. A broad panel of immunochemical markers might be necessary to establish the pathologic diagnosis.


Effect of vitamin E supplementation on carbogen-induced amelioration of noise induced hearing loss in man.
The study explores the effect of occupational noise on oxidative stress status and prophylactic effect of Vitamin E and carbogen (5% CO 2 +95%O 2 ) breathing in alleviating the oxidative damage and conserving the hearing in human volunteers exposed to intense occupational noise. Plasma total antioxidant status, blood glutathione (GSH), malondialdehyde (MDA), antioxidant enzyme activities of GSH peroxidase (EC 184.108.40.206, GPx), superoxide dismutase (EC 22.214.171.124; SOD) in erythrocytes, nitric oxide and nitric oxide synthase in plasma were assessed before and after 6 days of administration of Vitamin E and Carbogen. Results of the study indicate that the exposure to noise for 6 days increased blood concentration of MDA, decreased concentrations of reduced GSH, antioxidant enzyme activity of SOD and plasma total antioxidant status in control (noise) group. Vitamin E- supplemented group showed decline in oxidative stress reflected by significant decrease in blood concentration of MDA and increase in antioxidant enzyme activity of erythrocyte SOD. Results of audiometric studies revealed that breathing of carbogen prevented the development of temporary threshold shift; thereby reducing the risk of noise induced hearing loss.


Preliminary assessment of differential expression of candidate genes associated with atherosclerosis.
Identifying susceptible genes associated with the pathogenesis of atherosclerosis (ATH) may contribute toward better management of this condition. This preliminary study was aimed at assessing the expression levels of 11 candidate genes, namely tumor protein (TP53), transforming growth factor, beta receptor II (TGFBR2), cysthathionenine-beta-synthase (CBS), insulin receptor substrate 1 (IRS1), lipoprotein lipase (LPL), methylenetetrahydrofolate reductase (MTHFR), thrombomodulin (THBD), lecithin-cholesterol acyltransferase (LCAT), matrix metallopeptidase 9 (MMP9), low density lipoprotein receptor (LDLR), and arachidonate 5-lipoxygenase-activating protein (ALOX5AP) genes associated with ATH. Twelve human coronary artery tissues (HCATs) were obtained from deceased subjects who underwent post-mortem procedures. Six atherosclerotic coronary artery tissue (ACAT) samples representing the cases and non-atherosclerotic coronary artery tissue (NCAT) samples as controls were gathered based on predetermined inclusion and exclusion criteria. Gene expression levels were assessed using the GenomeLab Genetic Analysis System (GeXP). The results showed that LDLR, TP53, and MMP9 expression levels were significantly increased in ACAT compared to NCAT samples (p < 0.05). Thus, LDLR, TP53, and MMP9 genes may play important roles in the development of ATH in a Malaysian study population.


Species-specific elimination of polychlorinated biphenyls in estuarine animals and its impact on residue patterns.
Elimination kinetics of tetra-, penta- and hexachlorobiphenyls (IUPAC Nos. 44, 52, 87, 95, 101, 153) were investigated by laboratory experiments in three species of different phyla: Nereis diversicolor (Polychaeta), Palaemon longirostris (Crustacea) and Platichthys flesus (Pisces). Half-lives were species-specific and structure-dependent. Palaemon longirostris eliminated all components fastest. N. diversicolor was faster than Platichthys flesus except for components 95 and 153. Contrary to the fish species, the two invertebrates contained significant amounts of polar transformation products of No. 52, which had been applied as 14C labelled. Therefore, the faster elimination by Palaemon longirostris and N. diversicolor was assumed to be generally due to increased biotransformation. Elimination was in accordance with polychlorinated biphenyl (PCB) residue patterns obtained from field samples of the species. Congeners with vicinal H atoms in m,p positions were under-represented in Palaemon longirostris and so were congeners with > or = 7 Cl in N. diversicolor, while the PCB residue pattern in Platichthys flesus was similar to that of Clophen A60. By comparing percentages of the experimental congeners in sigma PCB and their elimination half-lives in the three species, it was revealed that residue patterns were also influenced by species-dependent uptake, e.g. feeding habits. Extractable organic matter-based sigma PCB levels increased with trophic levels of the three species.


Molecular Footprints of the Immune Assault on Pancreatic Beta Cells in Type 1 Diabetes.
Type 1 diabetes (T1D) is a chronic disease caused by the selective destruction of the insulin-producing pancreatic beta cells by infiltrating immune cells. We presently evaluated the transcriptomic signature observed in beta cells in early T1D and compared it with the signatures observed following in vitro exposure of human islets to inflammatory or metabolic stresses, with the aim of identifying "footprints" of the immune assault in the target beta cells. We detected similarities between the beta cell signatures induced by cytokines present at different moments of the disease, i.e., interferon-α (early disease) and interleukin-1β plus interferon-γ (later stages) and the beta cells from T1D patients, identifying biological process and signaling pathways activated during early and late stages of the disease. Among the first responses triggered on beta cells was an enrichment in antiviral responses, pattern recognition receptors activation, protein modification and MHC class I antigen presentation. During putative later stages of insulitis the processes were dominated by T-cell recruitment and activation and attempts of beta cells to defend themselves through the activation of anti-inflammatory pathways (i.e., IL10, IL4/13) and immune check-point proteins (i.e., PDL1 and HLA-E). Finally, we mined the beta cell signature in islets from T1D patients using the Connectivity Map, a large database of chemical compounds/drugs, and identified interesting candidates to potentially revert the effects of insulitis on beta cells.


Gly972Arg variant of insulin receptor substrate 1 gene and colorectal cancer risk in overweight/obese subjects.
Given the major role of obesity and insulin resistance (IR) in colorectal cancer (CRC), we investigated whether genetic variants in ghrelin (GHRL), resistin (RETN) and insulin receptor substrate 1 (IRS1) were associated with CRC risk. This study was conducted as a case-control study, and 750 subjects, including 438 controls and 312 patients with CRC, were enrolled and genotyped using the PCR-RFLP method. No significant differences were observed for GHRL (rs696217), RETN (rs3745367) and IRS1 (rs1801278, Gly972Arg or G972R) gene variants between the cases and controls. However, the IRS1 G972R R allele compared with the G allele and the G972R RR+GR genotype compared with the GG genotype appeared to be markers of decreased CRC susceptibility in the overweight/obese subjects (p = 0.024; odds ratio [OR] = 0.42, 95% confidence interval [95% CI], 0.20-0.91; and p = 0.048; OR = 0.42, 95% CI, 0.17-0.99, respectively). Furthermore, the R allele and RR+GR genotype were also associated with decreased risks for obesity in the patients with CRC (p = 0.007; OR = 0.35, 95% CI, 0.15-0.77; and p = 0.015; OR = 0.35, 95% CI, 0.15-0.72, respectively). In accordance with previous studies, our findings suggest that the IRS1 G972R R allele and RR+GR genotype have protective effects for CRC in overweight/obese patients and for obesity in patients with CRC. Nevertheless, further studies are required to confirm these findings.


High Mobility Group Box Chromosomal Protein-1 Induces Myofibroblast Differentiation and Extracellular Matrix Production via RAGE, p38, JNK and AP-1 Signaling Pathways in Nasal Fibroblasts.
Chronic rhinosinusitis is involved in myofibroblast differentiation and extracellular matrix (ECM) accumulation. High mobility group box chromosomal protein 1 (HMGB-1) is known to stimulate lung fibroblast to produce ECM in lung fibrosis. The aim of this study was to investigate whether HMGB-1 induces myofibroblast differentiation and ECM production in nasal fibroblasts and to identify the signal pathway. Human nasal fibroblasts were cultured. After stimulation with HMGB-1, expressions of α-smooth muscle actin (α-SMA) and fibronectin were determined by real-time PCR and western blot. Total collagen was measured by Sircol assay. To investigate signal pathway, various signal inhibitors and RAGE siRNA were used. HMGB-1 increased α-SMA and fibronectin in mRNA and protein levels. It also increased collagen production. RAGE siRNA inhibited HMGB-1-induced α-SMA and fibronectin, and production of collagen. Furthermore, the inhibitors of RAGE downstream molecules such as p38, JNK and AP-1 also blocked the HMGB-1-induced effects. HMGB-1 induces myofibroblast differentiation and ECM production in nasal fibroblast, which is mediated by RAGE, p38, JNK and AP-1 signal pathway. These results suggest that HMGB-1 may play an important role in tissue remodeling during chronic rhinosinusitis progression.


Clonal mutations in the cancer-associated fibroblasts: the case against genetic coevolution.
It is well established that carcinoma-associated fibroblasts (CAFs) differ phenotypically from fibroblasts associated with normal tissue, but the mechanisms underlying these differences remain controversial. Because CAFs can be propagated in vitro for extended periods and still maintain their cancer promoting phenotype, it has been proposed that they might have acquired somatic genetic alterations analogous to those observed in malignant epithelium. Whereas some investigators have reported frequent and profound genomic alterations in CAFs, other groups have found no such evidence. One striking common trait of those studies reporting frequent clonal somatic alterations in CAFs is the use of tissues and techniques which are well known to be highly prone to generating artefacts, such as limiting and poor quality DNA followed by highly multiplexed PCR-based analysis. We conclude that reported frequent clonal somatic mutations in CAFs are likely to be artefacts and are not the biological basis of the cancer promoting attributes of CAFs. [corrected]


Gastrointestinal symptoms associated with orthostatic intolerance.
The term orthostatic intolerance is used to describe symptoms of hemodynamic instability such as lightheadedness, fatigue, impaired cognition and syncope that develop on assuming an upright posture. Common forms of orthostatic intolerance in childhood include postural tachycardia syndrome and neurally mediated hypotension. A descriptive report of the clinical characteristics of patients presenting with gastrointestinal symptoms who are ultimately found to have orthostatic intolerance. A medical record review of all patients referred to the pediatric gastroenterology service at the Johns Hopkins Children's Center who had an abnormal tilt table test between June 1996 and December 2000. Of 24 eligible subjects aged 9-17 years (mean, 14.3 years), four had postural tachycardia syndrome, eight had both postural tachycardia and neurally mediated hypotension, and 12 had neurally mediated hypotension alone. The most common presenting gastrointestinal symptoms were abdominal pain, nausea and vomiting. Median number of gastrointestinal symptoms per patient was 3 (range, 1-7), and 87% of the patients experienced gastrointestinal symptoms for more than 1 year and 48% experienced gastrointestinal symptoms for more than 3 years. Follow-up information was available on 18 patients. Seventy-eight percent of patients (14 of 18) had complete resolution of symptoms with treatment of orthostatic intolerance. Pediatric patients with chronic upper gastrointestinal symptoms may have underlying orthostatic intolerance. In patients with upper gastrointestinal symptoms and orthostatic intolerance, treatment of orthostatic intolerance may result in resolution of gastrointestinal symptoms.


Mapping of murine Th1 helper T-Cell epitopes of mycolyl transferases Ag85A, Ag85B, and Ag85C from Mycobacterium tuberculosis.
BALB/c (H-2(d)) and C57BL/6 (H-2(b)) mice were infected intravenously with Mycobacterium tuberculosis H37Rv or vaccinated intramuscularly with plasmid DNA encoding each of the three mycolyl transferases Ag85A, Ag85B, and Ag85C from M. tuberculosis. Th1-type spleen cell cytokine secretion of interleukin-2 (IL-2) and gamma interferon (IFN-gamma) was analyzed in response to purified Ag85 components and synthetic overlapping peptides covering the three mature sequences. Tuberculosis-infected C57BL/6 mice reacted strongly to some peptides from Ag85A and Ag85B but not from Ag85C, whereas tuberculosis-infected BALB/c mice reacted only to peptides from Ag85A. In contrast, spleen cells from both mouse strains produced elevated levels of IL-2 and IFN-gamma following vaccination with Ag85A, Ag85B, and Ag85C DNA in response to peptides of the three Ag85 proteins, and the epitope repertoire was broader than in infected mice. Despite pronounced sequence homology, a number of immunodominant regions contained component specific epitopes. Thus, BALB/c mice vaccinated with all three Ag85 genes reacted against the same amino acid region, 101 to 120, that was also immunodominant for Ag85A in M. bovis BCG-vaccinated and tuberculosis-infected H-2(d) haplotype mice, but responses were completely component specific. In C57BL/6 mice, a cross-reactive T-cell response was detected against two carboxy-terminal peptides spanning amino acids 241 to 260 and 261 to 280 of Ag85A and Ag85B. These regions were not recognized at all in C57BL/6 mice vaccinated with Ag85C DNA. Our results underline the need for comparative analysis of all three Ag85 components in future vaccination studies.


Three-state kinetic mechanism for scaffold-mediated signal transduction.
Signaling events in eukaryotic cells are often guided by a scaffolding protein. Scaffold proteins assemble multiple proteins into a spatially localized signaling complex and exert numerous physical effects on signaling pathways. To study these effects, we consider a minimal, three-state kinetic model of scaffold-mediated kinase activation. We first introduce and apply a path summation technique to obtain approximate solutions to a single molecule master equation that governs protein kinase activation. We then consider exact numerical solutions. We comment on when this approximation is appropriate and then use this analysis to illustrate the competition of processes occurring at many time scales that are involved in signal transduction in the presence of a scaffold protein. We find that our minimal model captures how scaffold concentration can influence the times over which signaling is distributed in kinase cascades. For a range of scaffold concentrations, scaffolds allow for signaling to be distributed over multiple decades. The findings are consistent with recent experiments and simulation data. These results provide a framework and offer a mechanism for understanding how scaffold proteins can influence the shape of the waiting time distribution of kinase activation and effectively broaden the times over which protein kinases are activated in the course of cell signaling.


Identification of cichlid fishes from Lake Malawi using computer vision.
The explosively radiating evolution of cichlid fishes of Lake Malawi has yielded an amazing number of haplochromine species estimated as many as 500 to 800 with a surprising degree of diversity not only in color and stripe pattern but also in the shape of jaw and body among them. As these morphological diversities have been a central subject of adaptive speciation and taxonomic classification, such high diversity could serve as a foundation for automation of species identification of cichlids. Here we demonstrate a method for automatic classification of the Lake Malawi cichlids based on computer vision and geometric morphometrics. For this end we developed a pipeline that integrates multiple image processing tools to automatically extract informative features of color and stripe patterns from a large set of photographic images of wild cichlids. The extracted information was evaluated by statistical classifiers Support Vector Machine and Random Forests. Both classifiers performed better when body shape information was added to the feature of color and stripe. Besides the coloration and stripe pattern, body shape variables boosted the accuracy of classification by about 10%. The programs were able to classify 594 live cichlid individuals belonging to 12 different classes (species and sexes) with an average accuracy of 78%, contrasting to a mere 42% success rate by human eyes. The variables that contributed most to the accuracy were body height and the hue of the most frequent color. Computer vision showed a notable performance in extracting information from the color and stripe patterns of Lake Malawi cichlids although the information was not enough for errorless species identification. Our results indicate that there appears an unavoidable difficulty in automatic species identification of cichlid fishes, which may arise from short divergence times and gene flow between closely related species.


Differences in pregnancy and perinatal outcomes among symptomatic versus asymptomatic COVID-19-infected pregnant women: a systematic review and meta-analysis.
There is dearth of information on COVID-19's impact on pregnant women. However, literature reported trends of COVID-19 differ, depending on the presence of clinical features upon presentation. This systematic review aimed to assess differences in risk factors, management, complications, and pregnancy and perinatal outcomes in symptomatic vs. asymptomatic pregnant women with confirmed SARS-CoV-2 infection. A search was run on electronic databases to identify studies reporting COVID-19 in pregnancy. Meta-analysis was performed and odds ratios and mean difference with 95% confidence intervals were calculated using Review Manager 5.4. Review Prospero registration number CRD42020204662. We included ten articles reporting data from 3158 pregnancies; with 1900 symptomatic and 1258 asymptomatic pregnant women. There was no significant difference in the mean age, gestational age, and body mass index between the two groups. The meta-analysis suggested that pregnant women who were obese (OR:1.37;95%CI:1.15 to 1.62), hypertensive (OR:2.07;95%CI:1.38 to 3.10) or had a respiratory disorder (OR:1.64;95%CI:1.25 to 2.16), were more likely to be symptomatic when infected with SARS-CoV-2. Pregnant women with Black (OR:1.48;95%CI:1.19 to 1.85) or Asian (OR:1.64;95%CI:1.23 to 2.18) ethnicity were more likely to be symptomatic while those with White ethnicity (OR:0.63;95%CI:0.52 to 0.76) were more likely to be asymptomatic. Cesarean-section delivery (OR:1.40;95%CI:1.17 to 1.67) was more likely amongst symptomatic pregnant women. The mean birthweight(g) (MD:240.51;95%CI:188.42 to 293.51), was significantly lower, while the odds of low birthweight (OR:1.85;95%CI:1.06 to 3.24) and preterm birth (< 37 weeks) (OR:2.10;95%CI:1.04 to 4.23) was higher amongst symptomatic pregnant women. Symptomatic pregnant women had a greater requirement for maternal ICU admission (OR:13.25;95%CI:5.60 to 31.34) and mechanical ventilation (OR:15.56;95%CI:2.96 to 81.70) while their neonates had a higher likelihood for Neonatal Intensive Care Unit admission (OR:1.96;95%CI:1.59 to 2.43). The management strategies in the included studies were poorly discussed, hence could not be analyzed. The evidence suggests that the presence of risk factors (co-morbidities and ethnicity) increased the likelihood of pregnant women being symptomatic. Higher odds of complications were also observed amongst symptomatic pregnant women. However, more adequately conducted studies with adjusted analysis and parallel comparison groups are required to reach conclusive findings.


Facial Anatomical Landmark Detection Using Regularized Transfer Learning With Application to Fetal Alcohol Syndrome Recognition.
Fetal alcohol syndrome (FAS) caused by prenatal alcohol exposure can result in a series of cranio-facial anomalies, and behavioral and neurocognitive problems. Current diagnosis of FAS is typically done by identifying a set of facial characteristics, which are often obtained by manual examination. Anatomical landmark detection, which provides rich geometric information, is important to detect the presence of FAS associated facial anomalies. This imaging application is characterized by large variations in data appearance and limited availability of labeled data. Current deep learning-based heatmap regression methods designed for facial landmark detection in natural images assume availability of large datasets and are therefore not well-suited for this application. To address this restriction, we develop a new regularized transfer learning approach that exploits the knowledge of a network learned on large facial recognition datasets. In contrast to standard transfer learning which focuses on adjusting the pre-trained weights, the proposed learning approach regularizes the model behavior. It explicitly reuses the rich visual semantics of a domain-similar source model on the target task data as an additional supervisory signal for regularizing landmark detection optimization. Specifically, we develop four regularization constraints for the proposed transfer learning, including constraining the feature outputs from classification and intermediate layers, as well as matching activation attention maps in both spatial and channel levels. Experimental evaluation on a collected clinical imaging dataset demonstrate that the proposed approach can effectively improve model generalizability under limited training samples, and is advantageous to other approaches in the literature.


Not All Injuries Are the Same: Different Patterns in Sports Injuries and Their Psychosocial Correlates.
Sports injuries are ubiquitous and can have far-reaching consequences for athletes (e.g., health, performance). Previous studies have examined various psychosocial influencing factors (e.g., stress), but have mostly focused on only one or two injury characteristics (e.g., frequency), neglecting the broader injury pattern. Thus, the present study aimed to obtain a more differentiated picture of potentially different injury patterns and related profiles of psychosocial factors. We investigated a sample of 213 athletes from a cross-sectional online study. Current injury status, frequency, severity, chronicity, medical treatment, and rehabilitation measures were subjected to cluster analysis indicating a 3-cluster solution with predominantly chronically injured athletes (n = 54), athletes not seeking treatment (n = 62), and athletes utilizing medical treatment and rehabilitation (n = 97). Building on the Model of Stress and Athletic Injury, we subsequently conducted three multivariate analyses of variance (MANOVAs) to examine whether the obtained clusters differed in terms of personality factors (e.g., athletic identity), history of stressors (e.g., life events), and coping resources (e.g., self-compassion). We observed significant differences in all three categories of psychosocial variables implying different intervention possibilities for different injury patterns in the future.


Thermographic assessment of perforating arteries. A preoperative screening method for fasciocutaneous and musculocutaneous flaps.
Pre-operative localization of the involved perforating arteries in the planning of musculocutaneous or fasciocutaneous flaps may lead to a higher survival rate of the whole skin island. This in particular will be of importance in donor areas with changed haemodynamics. A noninvasive method is described for the accurate preoperative localization of the perforating arteries of the trunk and extremities; a method which causes minimal discomfort to the patient, but which will help in preparing for a successful operation. We have used this method since 1983 for all high-risk patients, and it has proved to be very useful in our hands.


Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell?
BACKGROUND AND PURPOSE: Posttranslational modifications of cysteine residues represent a major aspect of redox biology, and their reliable detection is key in providing mechanistic insights. The metastable character of these modifications and cell lysis-induced artifactual oxidation render current state-of-the-art protocols to rely on alkylation-based stabilization of labile cysteine derivatives before cell/tissue rupture. An untested assumption in these procedures is that for all cysteine derivatives, alkylation rates are faster than their dynamic interchange. However, when the interconversion of cysteine derivatives is not rate limiting, electrophilic labelling is under Curtin-Hammett control; hence, the final alkylated mixture may not represent the speciation that prevailed before alkylation. Buffered aqueous solutions of inorganic, organic, cysteine, GSH and GAPDH polysulfide species were used. Additional experiments in human plasma and serum revealed that monobromobimane can extract sulfide from the endogenous sulfur pool by shifting speciation equilibria, suggesting caution should be exercised when interpreting experimental results using this tool. In the majority of cases, the speciation of alkylated polysulfide/thiol derivatives depended on the experimental conditions. Alkylation perturbed sulfur speciation in both a concentration- and time-dependent manner and strong alkylating agents cleaved polysulfur chains. Moreover, the labelling of sulfenic acids with dimedone also affected cysteine speciation, suggesting that part of the endogenous pool of products previously believed to represent sulfenic acid species may represent polysulfides. We highlight methodological caveats potentially arising from these pitfalls and conclude that current derivatization strategies often fail to adequately capture physiological speciation of sulfur species. This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.


Essential key indicators for disaster medical response suggested to be included in a national uniform protocol for documentation of major incidents: a Delphi study.
Registration of data from a major incident or disaster serves several purposes such as to record data for evaluation of response as well as for research. Data needed can often be retrieved after an incident while other must be recorded during the incident. There is a need for a consensus on what is essential to record from a disaster response. The aim of this study was to identify key indicators essential for initial disaster medical response registration. By this is meant nationally accepted processes involved, from the time of the emergency call to the emergency medical communication centre until medical care is provided at the emergency department. A three round Delphi study was conducted. Thirty experts with a broad knowledge in disaster and emergency response and medical management were invited. In this study we estimated 30 experts to be approximately one third of the number in Sweden eligible for recruitment. Process, structure and outcome indicators for the initial disaster medical response were identified. These were based on previous research and expressed as statements and were grouped into eight categories, and presented to the panel of experts. The experts were instructed to score each statement, using a five point Likert scale, and were also invited to include additional statements. Statements reaching a predefined consensus level of 80% were considered as essential to register. In total 97 statements were generated, 77 statements reached consensus. The 77 statements covered parts of all relevant aspects involved in the initial disaster medical response. The 20 indicators that did not reach consensus mostly concerned patient related times in hospital, types of support systems and security for health care staff. The Delphi technique can be used for reaching consensus of data, comprising process, structure and outcome indicators, identified as essential for recording from major incidents and disasters.


Current use of the automatic retinal oximetry. Review.
To inform about possible use of the automatic retinal oximetry for the retinal oxygen saturation measurement in the eye and systemic diseases. We performed a literature review dealing with issues of retinal oxygen saturation monitoring by dual non-invasive retinal oximetry Oxymap T1 (Oxymap ehf. Reykjavík, Iceland). We have found two main strains writing our paper on retinal oxygen saturation eye diseases. The first section concerns diseases created by having hypoxia as its main pathological factor - for example diabetes mellitus and retinal vein occlusion. The second group deals with atrophy as the main pathological mechanism which is typical for decreasing retinal oxygen consumption - for example glaucoma or retinitis pigmentosa (the second one named is not included in our work). Oximetry in systemic diseases creates a relatively new chapter of this branch with a very big potential of interdisciplinary cooperation for the future. It is possible the cooperation will not only include diabetologists but also neurologists (for example, in diseases like sclerosis multiplex or Devics, Alzheimers and Parkinsons disease) and haematologists (retinal oxygen saturation changes in patients with different rheological attributes of blood). Retinal oxygen saturation measuring by automatic retinal oximetry is a relatively new method with scientifically confirmed high reproducibility of results. Currently it is the only experimental method with vast potentials not only in the realm of the possibility of observing eye diseases (diabetic retinopathy, retinal vein occlusion or glaucoma) but also in developing interdisciplinary cooperation with diabetologists, neurologists and haematologists.


Rho activation drives luminal collapse and eversion in epithelial acini.
Epithelial cells lining a gland and cells grown in a soft extracellular matrix polarize with apical proteins exposed to the lumen and basal proteins in contact with the extracellular matrix. Alterations to polarity, including an apical-out polarity, occur in human cancers. Although some aberrant polarity states may result from altered protein trafficking, recent observations of an extraordinary tissue-level inside-out unfolding suggest an alternative pathway for altered polarity. Because mechanical alterations are common in human cancer, including an upregulation of RhoA-mediated actomyosin tension in acinar epithelia, we explored whether perturbing mechanical homeostasis could cause apical-out eversion. Acinar eversion was robustly induced by direct activation of RhoA in normal and tumor epithelial acini, or indirect activation of RhoA through blockage of β1-integrins, disruption of the LINC complex, oncogenic Ras activation, or Rac1 inhibition. Furthermore, laser ablation of a portion of the untreated acinus was sufficient to induce eversion. Analyses of acini revealed high curvature and low phosphorylated myosin in the apical cell surfaces relative to the basal surfaces. A vertex-based mathematical model that balances tension at cell-cell interfaces revealed a fivefold greater basal cell surface tension relative to the apical cell surface tension. The model suggests that the difference in surface energy between the apical and basal surfaces is the driving force for acinar eversion. Our findings raise the possibility that a loss of mechanical homeostasis may cause apical-out polarity states in human cancers.


Identification of Quinolinones as Antivirals against Venezuelan Equine Encephalitis Virus.
Venezuelan equine encephalitis virus (VEEV) is a reemerging alphavirus that can cause encephalitis resulting in severe human morbidity and mortality. Using a high-throughput cell-based screen, we identified a quinolinone compound that protected against VEEV-induced cytopathic effects. Analysis of viral replication in cells identified several quinolinone compounds with potent inhibitory activity against vaccine and virulent strains of VEEV. These quinolinones also displayed inhibitory activity against additional alphaviruses, such as Mayaro virus and Ross River virus, although the potency was greatly reduced. Time-of-addition studies indicated that these compounds inhibit the early-to-mid stage of viral replication. Deep sequencing and reverse genetics studies identified two unique resistance mutations in the nsP2 gene (Y102S/C; stalk domain) that conferred VEEV resistance on this chemical series. Moreover, introduction of a K102Y mutation into the nsP2 gene enhanced the sensitivity of chikungunya virus (CHIKV) to this chemical series. Computational modeling of CHIKV and VEEV nsP2 identified a highly probable docking alignment for the quinolinone compounds that require a tyrosine residue at position 102 within the helicase stalk domain. These studies identified a class of compounds with antiviral activity against VEEV and other alphaviruses and provide further evidence that therapeutics targeting nsP2 may be useful against alphavirus infection.


[Hypothalamic-pituitary-adrenal function in primary hypothyroidism].
Hypothyroidism is known to lead to a certain degree of functional insufficiency of the adrenal gland by affecting both the hypophyseal axis and peripheral metabolism of cortisol. This study was conducted to evaluate hypothalamic, pituitary, and adrenal function in a homogeneous group of patients with long-standing major hypothyroidism. Forty-five patients (32 females, 13 males; mean age 42.9 +/- 9.6 years; range 20-59) with major primary hypothyroidism known to be long-standing (> 1 year in 1 and for an undetermined duration of several years in all the others) were included. Twenty-nine age-matched subjects served as controls. Insulin-induced hypoglycaemia and oral metyrapone tests were performed before and after treatment had induced euthyroidism. Plasma ACTH and cortisol were measured every 20 min for 2 hours during the hypoglycaemia test and ACTH before and after the last dose of metyrapone. Plasma cortisol levels were determined before and 30 min after injection of tetracosactide. Baseline ACTH and cortisol were not different in patients and controls and were unchanged by treatment. ACTH and cortisol response to hypoglycaemia were weaker in patients with ongoing hypothyroidism (p < 0.05 vs controls) and improved significantly (p < 0.05 vs baseline) after treatment. Adreno-cortical response to exogenous ACTH stimulation was weaker in patients with hypothyroidism (p < 0.05 vs controls) and returned to normal after treatment. Modifications of the hypothalamic-pituitary-adrenal system resulting from hypothyroidism were minimal and evidenced only by dynamic exploration. Levels returned to normal after adequate treatment and the deficit restricted to the hypothalamus and pituitary might also involve the adrenal gland.


Using family life drawings in medical student education.
A life drawing technique was used to educate third-year medical students in a diagnostic and therapeutic approach to young children. Students were asked to produce their own early family life drawings. A sample of 48 drawings were collected. A major goal was to sensitize students as to how their early family experiences likely shaped their current perceptions regarding children and families in the practice of medicine. Six of these student drawings were chosen to illustrate this goal. A few students even found that their drawings helped them resolve personal early life stresses.


The acute effect of IABP-induced pulsatility on coronary vascular resistance and graft flow in critical ill patients during ECMO.
The combination of the two cardiac support mechanisms of intra-aortic balloon pumping (IABP) and non-pulsatile circulatory extracorporeal membrane oxygenation (ECMO) has been confirmed to improve efficacy of the cardiac support as a whole. However, reports on benefits of diastolic augmentation on coronary vascular bed and graft flowmetry during concomitant use of IABP and ECMO are lacking. The aim of this study was to evaluate the acute impact of IABP support on coronary vascular resistance (CVR) and coronary bypass flows (CBF) in high-risk patients with peripheral ECMO following coronary artery bypass grafting (CABG). In eight emergency CABG patients (mean age=67.8±1.9 years; gender: six male and two female; EF=25.5±2.4%) requiring mechanical circulatory support with ECMO hemodynamic parameters, CVR, CBF, diastolic filling index (DFI), graft flow reserve (GFR), and pulsatility index (PI) were analyzed with and without diastolic augmentation using a transit time flowmeter. The addition of IABP to ECMO decreased CVR significantly by 6.5%±1.9% compared to baseline with ECMO alone (1.62±0.2 versus 1.78±0.2; P<0.0045). Accordingly, significant higher mean CBF were found during IABP assist, resulting in a 21.6%±2.6% increase (60.7±8.7 mL/min with versus 51.3±7.4 mL/min without IABP; P<0.0001). IABP also significantly increased DFI by 9.8±0.9% (73.2%±1.4% with versus 66.7%±1.3% without IABP; P<0.0001). GFR was recruited during IABP in all grafts (GFR>1). There were no statistically significant differences in PI with and without IABP assistance (2.6±0.1 versus 2.5±0.2). IABP-induced pulsatility significantly improves diastolic filling index and mean coronary bypass graft flows by lowering coronary vascular resistance during non-pulsatile peripheral ECMO. The combination of ECMO with IABP may provide more optimal myocardial oxygen conditions resulting in an improved efficacy of the cardiac support as a whole in critical ill patients with postcardiotomy myocardial dysfunction following CABG.


Adaptations of diaphragm neuromuscular junction following inactivity.
We hypothesized that differences exist in the morphological adaptations of neuromuscular junctions (NMJs) on different fiber types in response to prolonged inactivation. Two weeks of inactivity of both phrenic motoneurons and diaphragm muscle was induced by spinal cord hemitransection at C2 (spinal isolation; SI). A three-color fluorescent immunocytochemical technique, combined with laser-scanning confocal microscopy, was used to create two- (2D) and three-dimensional (3D) images of NMJs and obtain morphological information concerning: (1) innervating axons and presynaptic nerve terminals; (2) motor endplates (postsynaptic apparatus consisting of acetylcholine receptors), and (3) myosin heavy chain (MHC) phenotype of muscle fibers. In both sham controls (CTL) and SI animals, planar (2D) and surface (3D) areas of motor endplates and nerve terminals on type II muscle fibers (anti-fast MHC immunoreactive) were smaller than on type I (nonimmunoreactive to anti-fast MHC) fibers, when normalized for fiber diameter. The number of branches, total branch length and perimeter of both motor endplates and nerve terminals were greater for NMJs on type II fibers than on type I fibers. The extent of overlap between nerve terminal and endplate was greater on type I fibers than on type II fibers. After SI, there was a significant expansion of NMJs on type II fibers. Planar and surface areas of motor endplates and nerve terminals, number of endplate and nerve terminal branches, total branch length, and perimeter were all increased on type II fibers following SI. The extent of overlap of nerve terminal and endplate increased on type II fibers, approaching that observed in type I fiber NMJs. These results indicate that neuromuscular inactivation leads to a selective expansion of type II fiber NMJs through addition of new terminal area, and elongation of existing terminal branches. These changes may represent a compensatory effort to improve neuromuscular transmission.


Chemical formation of soft metal electrodes for flexible and wearable electronics.
Flexible and wearable electronics is one major technology after smartphones. It shows remarkable application potential in displays and informatics, robotics, sports, energy harvesting and storage, and medicine. As an indispensable part and the cornerstone of these devices, soft metal electrodes (SMEs) are of great significance. Compared with conventional physical processes such as vacuum thermal deposition and sputtering, chemical approaches for preparing SMEs show significant advantages in terms of scalability, low-cost, and compatibility with the soft materials and substrates used for the devices. This review article provides a detailed overview on how to chemically fabricate SMEs, including the material preparation, fabrication technologies, methods to characterize their key properties, and representative studies on different wearable applications.


Elevated Fab glycosylation of anti-hinge antibodies.
Rheumatoid arthritis (RA) is characterized by systemic inflammation and the presence of anti-citrullinated protein antibodies (ACPAs), which contain remarkably high levels of Fab glycosylation. Anti-hinge antibodies (AHAs) recognize immunoglobulin G (IgG) hinge neoepitopes exposed following cleavage by inflammation-associated proteases, and are also frequently observed in RA, and at higher levels compared to healthy controls (HCs). Here, we investigated AHA specificity and levels of Fab glycosylation as potential immunological markers for RA. AHA serum levels, specificity, and Fab glycosylation were determined for the IgG1/4-hinge cleaved by matrix metalloproteinase-3, cathepsin G, pepsin, or IdeS, using enzyme-linked immunosorbent assay and lectin affinity chromatography, in patients with early active RA (n = 69) and HCs (n = 97). AHA reactivity was detected for all hinge neoepitopes in both RA patients and HCs. Reactivity against CatG-IgG1-F(ab´)2s and pepsin-IgG4-F(ab´)2s was more prevalent in RA. Moreover, all AHA responses showed increased Fab glycosylation levels in both RA patients and HCs. AHA responses are characterized by elevated levels of Fab glycosylation and highly specific neoepitope recognition, not just in RA patients but also in HCs. These results suggest that extensive Fab glycosylation may develop in response to an inflammatory proteolytic microenvironment, but is not restricted to RA.


SelexGLM differentiates androgen and glucocorticoid receptor DNA-binding preference over an extended binding site.
The DNA-binding interfaces of the androgen (AR) and glucocorticoid (GR) receptors are virtually identical, yet these transcription factors share only about a third of their genomic binding sites and regulate similarly distinct sets of target genes. To address this paradox, we determined the intrinsic specificities of the AR and GR DNA-binding domains using a refined version of SELEX-seq. We developed an algorithm, SelexGLM, that quantifies binding specificity over a large (31-bp) binding site by iteratively fitting a feature-based generalized linear model to SELEX probe counts. This analysis revealed that the DNA-binding preferences of AR and GR homodimers differ significantly, both within and outside the 15-bp core binding site. The relative preference between the two factors can be tuned over a wide range by changing the DNA sequence, with AR more sensitive to sequence changes than GR. The specificity of AR extends to the regions flanking the core 15-bp site, where isothermal calorimetry measurements reveal that affinity is augmented by enthalpy-driven readout of poly(A) sequences associated with narrowed minor groove width. We conclude that the increased specificity of AR is correlated with more enthalpy-driven binding than GR. The binding models help explain differences in AR and GR genomic binding and provide a biophysical rationale for how promiscuous binding by GR allows functional substitution for AR in some castration-resistant prostate cancers.


Movement and mood disorder in two brothers with Gaucher disease.
Gaucher disease (GD) is a lysosomal storage disorder with a wide spectrum of phenotypic presentations. We report the case histories of two adult brothers with GD who developed both parkinsonism and psychiatric symptoms. Direct sequencing and real-time polymerase chain reaction were used to establish that the patients were homozygous for mutation L444P. While parkinsonism has been described previously in GD, these patients had atypical features, including a complicated mood disorder. The comorbidity of GD and a mood disorder is a new finding, as psychiatric manifestations of GD have been described rarely. The etiology of the mental illness could be related to the processes contributing to the development of parkinsonism.


Memory bias for emotional facial expressions in major depression.
Sixteen clinically depressed patients and sixteen healthy controls were presented with a set of emotional facial expressions and were asked to identify the emotion portrayed by each face. They, were subsequently given a recognition memory test for these faces. There was no difference between the groups in terms of their ability to identify emotion between from faces. All participants identified emotional expressions more accurately than neutral expressions, with happy expressions being identified most accurately. During the recognition memory phase the depressed patients demonstrated superior memory for sad expressions, and inferior memory for happy expressions, relative to neutral expressions. Conversely, the controls demonstrated superior memory for happy expressions, and inferior memory for sad expressions, relative to neutral expressions. These results are discussed in terms of the cognitive model of depression proposed by Williams, Watts, MacLeod, and Mathews (1997).


High-resolution prediction of organic matter concentration with hyperspectral imaging on a sediment core.
In the case of environmental samples, the use of a chemometrics-based prediction model is highly challenging because of the difficulty in experimentally creating a well-ranged reference sample set. In this study, we present a methodology using short wave infrared hyperspectral imaging to create a partial least squares regression model on a cored sediment sample. It was applied to a sediment core of the well-known Lake Bourget (Western Alps, France) to develop and validate a model for downcore high resolution LOI550 measurements used as a proxy of the organic matter. In lake and marine sediment, the organic matter content is widely used, for example, to reconstruct carbon flux variations through time. Organic matter analysis through routine analysis methods is time- and material-consuming, as well as not spatially resolved. A new instrument based on hyperspectral imaging allows high spatial and spectral resolutions to be acquired all along a sediment core. In this study, we obtain a model characterized by a 0.95 r prediction, with 0.77 wt% of model uncertainty based on 27 relevant wavelengths. The concentration map shows the variation inside each laminae and flood deposit. LOI550 reference values obtained with the loss on ignition are highly correlated to the inc/coh ratio used as a proxy of the organic matter in X-ray fluorescence with a correlation coefficient of 0.81. This ratio is also correlated with the averaged subsampled hyperspectral prediction with a r of 0.65.


Stat3 and c-Myc genome-wide promoter occupancy in embryonic stem cells.
Embryonic stem (ES) cell pluripotency is regulated in part by transcription factor (TF) pathways that maintain self-renewal and inhibit differentiation. Stat3 and c-Myc TFs are essential for maintaining mouse ES cell self-renewal. c-Myc, together with Oct4, Sox2, and Klf4, is a reprogramming factor. While previous studies have investigated core transcriptional circuitry in ES cells, other TF pathways that promote ES cell pluripotency have yet to be investigated. Therefore, to further understand ES cell transcriptional networks, we used genome-wide chromatin immunoprecipitation and microarray analysis (ChIP-chip) to map Stat3 and c-Myc binding targets in ES cells. Our results show that Stat3 and c-Myc occupy a significant number of genes whose expression is highly enriched in ES cells. By comparing Stat3 and c-Myc target genes with gene expression data from undifferentiated ES cells and embryoid bodies (EBs), we found that Stat3 binds active and inactive genes in ES cells, while c-Myc binds predominantly active genes. Moreover, the transcriptional states of Stat3 and c-Myc targets are correlated with co-occupancy of pluripotency-related TFs, polycomb group proteins, and active and repressive histone modifications. We also provide evidence that Stat3 targets are differentially expressed in ES cells following removal of LIF, where culture of ES cells in the absence of LIF resulted in downregulation of Stat3 target genes enriched in ES cells, and upregulation of lineage specific Stat3 target genes. Altogether, we reveal transcriptional targets of two key pluripotency-related genes in ES cells--Stat3 and c-Myc, thus providing further insight into the ES cell transcriptional network.


Towards a FHIR-Based Data Model for Coronary Angiography Observations.
Coronary heart disease is among the most frequent causes of death globally. Thus, our research project aims to develop prognostic models, to predict the risk of spontaneous myocardial infarctions based on a combination of clinical parameters and image data sets (invasive coronary angiograms). To train such models we use data from more than 30,000 coronary angiograms acquired at the cardiology department of Erlangen University Hospital. To linking such proprietary data with additional clinical parameters and to harmonize it for future cross-hospital federated machine learning approaches we defined a mapping for coronary angiography based on the symptom/ clinical phenotype HL7® FHIR® module of the German medical informatics initiative. In this paper we describe the final design of the coronary angiography information model and our mapping approach to ICD-10 and SNOMED CT. From the database we use a subset of 15 required values patient characteristics to create the HL7® FHIR® resource.


Conservatism of Late Pennsylvanian vegetational patterns during short-term cyclic and long-term directional environmental change, western equatorial Pangea.
Patterns of plant distribution by palaeoenvironment were examined across the Pennsylvanian-Permian transition in North-Central Texas. Stratigraphically recurrent packages of distinct lithofacies, representing different habitats, contain qualitatively and quantitatively different macrofloras and microfloras. The species pools demonstrate niche conservatism, remaining closely tied to specific habitats, during both short-term cyclic environmental change and a long-term trend of increasing aridity. The deposits examined principally comprise the terrestrial Markley and its approximate marine equivalent, the Harpersville Formation and parts of lower Archer City Formation. Fossiliferous deposits are lens-like, likely representing fill sequences of channels formed during abandonment phases. Palaeosols, represented by blocky mudstones, comprise a large fraction of the deposits. They suggest progressive climate change from minimally seasonal humid to seasonal subhumid to seasonal dry subhumid. Five lithofacies yielded plants: kaolinite-dominated siltstone, organic shale, mudstone beds within organic shale, coarsening upward mudstone-sandstone interbeds and channel sandstone. Both macro- and microflora were examined. Lithofacies proved compositionally distinct, with different patterns of dominance diversity. Organic shales (swamp deposits), mudstone partings (swamp drainages) and coarsening upward mudstone-sandstone interbeds (floodplains) typically contain Pennsylvanian wetland vegetation. Kaolinite-dominated siltstones and (to the extent known) sandstones contain taxa indicative of seasonally dry substrates. Some kaolinite-dominated siltstones and organic shales/coals yielded palynomorphs. Microfloras are more diverse, with greater wetland-dryland overlap than macrofloras. It appears that these two floras were coexistent at times on the regional landscape.