The Effect of Mechanical Loading Upon Extracellular Matrix Bioscaffold-Mediated Skeletal Muscle Remodeling.
Mounting evidence suggests that site-appropriate loading of implanted extracellular matrix (ECM) bioscaffolds and the surrounding microenvironment is an important tissue remodeling determinant, although the role at the cellular level in ECM-mediated skeletal muscle remodeling remains unknown. This study evaluates crosstalk between progenitor cells and macrophages during mechanical loading in ECM-mediated skeletal muscle repair. Myoblasts were exposed to solubilized ECM bioscaffolds and were mechanically loaded at 10% strain, 1 Hz for 5 h. Conditioned media was collected and applied to bone marrow-derived macrophages followed by immunolabeling for proinflammatory M1-like markers and proremodeling M2-like markers. Macrophages were subjected to the same loading protocol and their secreted products were collected for myoblast migration, proliferation, and differentiation analysis. A mouse hind limb unloading volumetric muscle loss model was used to evaluate the effect of loading upon the skeletal muscle microenvironment after ECM implantation. Animals were sacrificed at 14 or 180 days. Isometric torque production was tested and tissue sections were immunolabeled for macrophage phenotype and muscle fiber content. Results show that loading augments the ability of myoblasts to promote an M2-like macrophage phenotype following exposure to ECM bioscaffolds. Mechanically loaded macrophages promote myoblast chemotaxis and differentiation. Lack of weight bearing impaired muscle remodeling as indicated by Masson's Trichrome stain. Isometric torque was significantly increased following ECM implantation when compared to controls, a response not present in the hind limb-unloaded group. This work provides an important mechanistic insight of the effects of rehabilitation upon ECM-mediated remodeling and could have broader implications in clinical practice, advocating multidisciplinary approaches to regenerative medicine, emphasizing rehabilitation.


Achieving optimal outcomes with all-zirconia crowns.
All-zirconia crowns are enjoying an unprecedented popularity. Dental laboratories are acquiring new equipment and adopting novel techniques, some of which require a learning curve. As a result, some crowns fabricated by computer-aided design/computer-aided manufacturing technology may come back to the dentist with unsatisfactory features. Dentists should carefully examine each crown under magnification prior to delivery to the patient. The dentist and dental laboratory should establish a close partnership with clear communication to yield the most favorable outcome for the patient.


Compound-heterozygous GRIN2A null variants associated with severe developmental and epileptic encephalopathy.
We report on an 8-year-old girl with severe developmental and epileptic encephalopathy due to the compound heterozygous null variants p.(Gln661*) and p.(Leu830Profs*2) in GRIN2A resulting in a knockout of the human GluN2A subunit of the N-methyl-D-aspartate receptor. Both parents had less severe GRIN2A-related phenotypes and were heterozygous carriers of the respective null variant. Functional investigations of both variants suggested a loss-of-function effect. This is the first description of an autosomal recessive, biallelic type of GRIN2A-related disorder. Nonetheless, there are marked parallels to two previously published families with severe epileptic encephalopathy due to homozygous null variants in GRIN1 as well as various knockout animal models. Compared to heterozygous null variants, biallelic knockout of either GluN1 or GluN2A is associated with markedly more severe phenotypes in both humans and mice. Furthermore, recent findings enable a potential precision medicine approach targeting GRIN-related disorders due to null variants.


Recurrent spontaneous early pregnancy loss and low dose aspirin.
Miscarriage is the most common complication of pregnancy, occurring in 10-15% of pregnant women. Accurate figures on prevalence are not available but it has been estimated that 2-5% of women have 3 or more miscarriages. The lack of methodological rigour in controlled trials of treatment efficacy in women with recurrent miscarriage makes it difficult to estimate the efficacy of treatment for this condition. To date, there is no evidence of improved outcome with aspirin compared to placebo or no treatment. Furthermore, animal data and limited human data suggest that prenatal use of aspirin may be associated with increased bleeding tendency, congenital malformations and cognitive and behavioural defects in the offspring. Seen and considered the lack of efficacy of low-dose aspirin and the potential for harm to the female and her offspring, the practice of recommending aspirin to women with recurrent miscarriage should be discontinued.


An integrated procedure for spine and full skeleton multi-sensor biomechanical analysis & averaging in posture gait and cyclic movement tasks.
Spine and posture disorders cover large interest in rehabilitation. Quantitative functional evaluation represents the main goal in Movement/Gait analysis. However very few studies outline the behaviour of spine during Posture and Movement/Gait analysis. To overcome such limits, several years ago our group started, a project to transfer into a complete fully 3D reliable and detailed representation, different segmental biomechanical models presented in literature. As result a complete 3D parametric biomechanical skeleton model has been developed to be used in quantitative analysis. Posture and Movement/Gait analysis are performed by 3D Opto-electronic stereophotogrammetric measurements of body landmarks labelled by passive markers. Depending on different analysis purposes, the model can work at different stages of complexity. Examples on the application of such model into biomechanical and clinical fields have been presented in literature. Our group is continuously working to add new features to such model, which is now able to fully integrate data deriving from force platforms, SEMG, foot pressure maps. By means of data fusion and optimisation procedures all these inputs are used in the model to assess lower limbs internal joint forces, torques and muscular efforts. The possibility to compute the average of cyclic or repetitive tasks has been included as well. Recently we added the possibility to assess internal joint forces and torques at each spine vertebral level and to correlate these latter with all the other model's features. The aim of this study is to present the methodological aspects of such new features and their potential applicability in clinical and biomechanical fields.


Clustering of Aromatic Residues in Prion-like Domains Can Tune the Formation, State, and Organization of Biomolecular Condensates.
In immature oocytes, Balbiani bodies are conserved membraneless condensates implicated in oocyte polarization, the organization of mitochondria, and long-term organelle and RNA storage. In Xenopus laevis, Balbiani body assembly is mediated by the protein Velo1. Velo1 contains an N-terminal prion-like domain (PLD) that is essential for Balbiani body formation. PLDs have emerged as a class of intrinsically disordered regions that can undergo various different types of intracellular phase transitions and are often associated with dynamic, liquid-like condensates. Intriguingly, the Velo1 PLD forms solid-like assemblies. Here we sought to understand why Velo1 phase behavior appears to be biophysically distinct from that of other PLD-containing proteins. Through bioinformatic analysis and coarse-grained simulations, we predict that the clustering of aromatic residues and the amino acid composition of residues between aromatics can influence condensate material properties, organization, and the driving forces for assembly. To test our predictions, we redesigned the Velo1 PLD to test the impact of targeted sequence changes in vivo. We found that the Velo1 design with evenly spaced aromatic residues shows rapid internal dynamics, as probed by fluorescent recovery after photobleaching, even when recruited into Balbiani bodies. Our results suggest that Velo1 might have been selected in evolution for distinctly clustered aromatic residues to maintain the structure of Balbiani bodies in long-lived oocytes. In general, our work identifies several tunable parameters that can be used to augment the condensate material state, offering a road map for the design of synthetic condensates.


Synergy of drug combinations in treating multidrug-resistant Pseudomonas aeruginosa.
With the emergence of metallo-betalactamases (MBL) in Pseudomonas aeruginosa (P. aeruginosa), the value of carbapenem, the drug of last resort, is being severely compromised. Curtailing the use of carbapenems becomes paramount if resistance is to be reined in. To study the role of synergy between combinations of drugs as an alternative treatment choice for P. aeruginosa. Synergy was studied between combinations of levofloxacin with piperacillin-tazobactam and levofloxacin with cefoperazone-sulbactam by time-kill and chequerboard techniques. P. aeruginosa were tested for antibiotic susceptibility by the disc diffusion assay (260 isolates) and E-test (60 isolates). Synergy testing by chequerboard and time-kill assays was performed with combinations of piperacillin-tazobactam with levofloxacin (11 isolates) and cefoperazone-sulbactam with levofloxacin (10 isolates). Nearly all isolates were susceptible to piperacillin-tazobactam (96.1 per cent), followed by piperacillin (78.5 per cent). Seventy-one isolates (27.3 per cent) were found to be multidrug resistant and 19.6 per cent were ESBL producers. MIC50 of amikacin was 32μg/ml and MIC90 was 64μg/ml. MIC50 and MIC90 of cefoperazone-sulbactam was 32μg/ml and 64μg/ml, and for levofloxacin it was 10μg/ml and 240μg/ml, respectively. Piperacillin-tazobactam had MIC50 and MIC90 of 5μg/ml and 10μg/ml, respectively. Synergy was noted in 72.7 per cent isolates for levofloxacin and piperacillin-tazobactam combination, the remaining 27.3 per cent isolates showed addition by both chequerboard and time-kill assay. For levofloxacin and cefoperazone-sulbactam, only 30 per cent isolates had synergy, 40 per cent showed addition, 20 per cent indifference, and 10 per cent were antagonistic by the chequerboard method. The combination of levofloxacin and piperacillin-tazobactam is a good choice for treatment of such strains.


Non-gluten sensitivity-related small bowel villous flattening with increased intraepithelial lymphocytes: not all that flattens is celiac sprue.
Seven patients (mean age, 37.6 years; 5 women) had several weeks of gluten sensitivity (GS)-like symptoms; 2 had flu-like symptom prodromes. The 7 cases had morphologically similar biopsy specimens; all tissue fragments had uniform injury--increased lymphoplasmacytic lamina propria inflammation, moderate to complete villous flattening, numerous crypt mitoses, and markedly increased villous intraepithelial lymphocytes (IELs). All patients were diagnosed with GS and prescribed a gluten-free diet; all returned 9 to 38 weeks later questioning their diagnosis because symptoms had resolved substantially or completely. Clinical improvement was unrelated to gluten abstinence or ingestion. Repeated endoscopy and colonoscopy performed 4.1 to 16 months later showed normal mucosa in all 7 patients. Diseases other than GS can cause marked villous flattening and increased villous IELs in adults. The cause of small bowel mucosal injury is unknown. A similar non-GS-associated clinicopathologic complex, assumed to be due to a protracted viral enteritis or slow regression of a virus-induced immune reaction, occurs in children. The temporal aspects of symptom improvement and mucosal restitution in these 7 patients are similar to "acute self-limited colitis." An overly exuberant immune response to an infectious agent is possible.


High school football injuries: evaluation.
An epidemiologic survey of the literature on high school football injuries revealed methodologic problems. These numerator-denominator inconsistencies and other confounding factors are discussed. The authors suggest a more reliable system of reporting these parameters to further reduce the risk of high school football injuries.


Vesicoureteric reflux in children.
Vesicoureteric reflux is defined as the retrograde passage of urine from the bladder into one or both ureters and often up to the kidneys, and mainly affects babies and infants. In severe cases dilatation of the ureter, renal pelvis, and calyces might be seen. Traditionally it was thought that only a low percentage of children have vesicoureteric reflux, but studies have suggested as many as 25-40% are affected. Guidelines recommend that the number of investigations for vesicoureteric reflux in children who have had a febrile urinary tract infection be reduced, but this approach is controversial. The recommendations also suggest that prophylactic antibiotics and surgery should be avoided in children with non-severe vesicoureteric reflux. In this Seminar I present data on the management of children with vesicoureteric reflux and give suggestions on how to navigate this difficult area.


Roles and Educational Effects of Clinical Case Studies in Home Medical Care.
Due to the progression of aging in Japan, pharmacists need to participate in home medical care. To enable pharmacists with no previous experience to participate in home medical care of patients with various diseases in the home environment, it is necessary to adopt an approach of training them in advance. It is thought useful for such clinical training to include patient case studies, which may facilitate the training of pharmacists for home medical care through simulated experience. "The working group to create home clinical cases for education" was launched by a group of university faculty, who have educational knowledge, and trained pharmacists who work with the patients at home. The home care cases were compiled by the university faculty members and the home care practice pharmacists. Working pharmacists and students at pharmaceutical college studied the same case studies of home medical care, and their self-evaluations were compared. They showed that the students rated themselves higher than the pharmacists. One of the reasons was the systematic education of the case studies. The clinical case studies are a good educational tool to promote home care medicine in pharmacies and university pharmaceutical colleges.


The beta-ketoadipate pathway of Acinetobacter baylyi undergoes carbon catabolite repression, cross-regulation and vertical regulation, and is affected by Crc.
The degradation of many structurally diverse aromatic compounds in Acinetobacter baylyi is accomplished by the beta-ketoadipate pathway. In addition to specific induction of expression by certain aromatic compounds, this pathway is regulated by complex mechanisms at multiple levels, which are the topic of this study. Multiple operons feeding into the beta-ketoadipate pathway are controlled by carbon catabolite repression (CCR) caused by succinate plus acetate. The pathways under study enable the catabolism of benzoate (ben), catechol (catA), cis,cis-muconate (catB,C,I,J,F,D), vanillate (van), hydroxycinnamates (hca), dicarboxylates (dca), salicylate (sal), anthranilate (ant) and benzyl esters (are). For analysis of CCR at the transcriptional level a luciferase reporter gene cassette was introduced into the operons. The Crc (catabolite repression control) protein is involved in repression of all operons (except for catA), as demonstrated by the analysis of respective crc strains. In addition, cross-regulation was demonstrated for the vanA,B, hca and dca operons. The presence of protocatechuate caused transcriptional repression of the vanA,B- and hca-encoded funnelling pathways (vertical regulation). Thus the results presented extend the understanding both of CCR and of the effects of Crc for all aromatic degradative pathways of A. baylyi and increase the number of operons known to be controlled by two additional mechanisms, cross-regulation and vertical regulation.


Computer Aided Detection and measurement of peripheral artery disease.
Computer-Aided Tomography Angiography (CTA) images are the standard for assessing Peripheral artery disease (PAD). This paper presents a Computer Aided Detection (CAD) and Computer Aided Measurement (CAM) system for PAD. The CAD stage detects the arterial network using a 3D region growing method and a fast 3D morphology operation. The CAM stage aims to accurately measure the artery diameters from the detected vessel centerline, compensating for the partial volume effect using Expectation Maximization (EM) and a Markov Random field (MRF). The system has been evaluated on phantom data and also applied to fifteen (15) CTA datasets, where the detection accuracy of stenosis was 88% and the measurement accuracy was with an 8% error.


[Blood transfusion in oncologic surgery: the role of recombinant human erythropoietin (rHuEPO)].
Anemia is common in cancer patients. The pathophysiology is multifactorial, however the most common cause is the anemia of chronic diseases (ACD). In 20-50% of cancer patients, anemia restricts physical activity and quality of life and requires transfusion support. The percentage of patients necessitating transfusion dramatically increases when patients require surgery. The traditional belief that blood transfusion is an effective and safe therapy has been challenged by a heightened awareness of the infectious and immunologic risks associated with allogeneic blood administration. In cancer patients transfusion-induced immunomodulation may have the potential to significantly increase postoperative infections and cancer recurrence so that it seems reasonable to minimize allogeneic blood exposure. Several strategies have been adopted to reduce allogeneic transfusion in surgical patients, however to properly select the appropriate blood conservation strategies the blood transfusion requirements for each patient should be defined. Allogeneic blood transfusion in surgery can be reduced by the introduction of autologous blood (AB) programmes and by the use of rHuEPO, alone or in association with AB techniques. AB donation is currently a standard of care for elective surgical patients but its efficacy is limited by anemia that prevents the donation of the optimal number of AB units. rHuEPO has been shown to significantly increase the volume of AB that anemic patients can predeposit or, used perisurgically, to expand the circulating RBCs mass before surgery. Moreover clinical trials employed rHuEPO in anemic cancer patients with various solid tumors both on and off chemotherapy reporting a significantly increase in Hct in more than 50% of the treated patients. Recently different studies have shown the efficacy of rHuEPO in increasing the volume of AB also in patients with ACD and cancer, thus proving to be a useful addition to existing strategies of blood conservation to minimize exposure to allogeneic blood in surgical cancer patients.


Cardiovascular disease risk factors in Korean American elderly.
An in-depth cardiovascular risk factor assessment was carried out in a sample of 205 Korean American elderly in Maryland, consisting of 75 males and 130 females aged 60 to 89 years (mean age = 69.9 +/- 6.5 years). Six risk factors were assessed in each participant: high blood pressure, current smoking, high blood cholesterol, overweight, sedentary lifestyle, and diabetes. The findings of this cross-sectional study suggested that high blood pressure was the leading cardiovascular disease risk factor among Korean American elderly (71%), followed by high blood cholesterol (53%), overweight (43%), sedentary life style (24%), diabetes (18%), and smoking (7%). Two thirds of the sample had multiple cardiovascular disease risk factors. The pattern of prevalence and risk factors that was observed was consistent with the distribution of multiple risk factors in that the combination of high blood pressure, high blood cholesterol, and overweight was most common in Korean American elderly (62%). These findings indicate that culturally relevant and salient strategies are needed to reduce multiple risk factors in this population.


Bacterial adhesion: seen any good biofilms lately?
The process of surface adhesion and biofilm development is a survival strategy employed by virtually all bacteria and refined over millions of years. This process is designed to anchor microorganisms in a nutritionally advantageous environment and to permit their escape to greener pastures when essential growth factors have been exhausted. Bacterial attachment to a surface can be divided into several distinct phases, including primary and reversible adhesion, secondary and irreversible adhesion, and biofilm formation. Each of these phases is ultimately controlled by the expression of one or more gene products. Ultrastructurally, the mature bacterial biofilm resembles an underwater coral reef containing pyramidal or mushroom-shaped microcolonies of organisms embedded within an extracellular glycocalyx, with channels and cavities to allow the exchange of nutrients and waste. The biofilm protects its inhabitants from predators, dehydration, biocides, and other environmental extremes while regulating population growth and diversity through primitive cell signals. From a physiological standpoint, surface-bound bacteria behave quite differently from their planktonic counterparts. Recognizing that bacteria naturally occur as surface-bound and often polymicrobic communities, the practice of performing antimicrobial susceptibility tests using pure cultures and in a planktonic growth mode should be questioned. That this model does not reflect conditions found in nature might help explain the difficulties encountered in the management and treatment of biomedical implant infections.


Structured Emulgels by Interfacial Assembly of Terpenes and Nanochitin.
Interfacial assemblies formed by colloidal complexation are effective in multiphase stabilization, as shown in structured liquids and Pickering emulgels. Herein, we demonstrate a type of biobased colloidal system that spontaneously stabilizes an organic phase in a continuous hydrogel phase. Specifically, a triterpene extracted from bark (betulin, BE) is added to an organic phase containing a coniferous resin (rosin acid, a diterpene). BE is shown to take part in strong noncovalent interactions with the nanochitin dispersed in the aqueous (hydrogel) phase, leading to a complex of high interfacial activity. The viscoelastic response of the system is rationalized by the presence of a superstable structured dual network. When used as a templating material, the emulgel develops into structured liquids and cryogels. The herein introduced all-biobased type of nanoparticle surfactant system forms a gel ("emulsion-filled" with "aggregated droplets") that features the functional benefits of both betulin and nanochitin.


Estrogens and the circadian system.
Circadian rhythms are ~24 h cycles of behavior and physiology that are generated by a network of molecular clocks located in nearly every tissue in the body. In mammals, the circadian system is organized hierarchically such that the suprachiasmatic nucleus (SCN) is the main circadian clock that receives light information from the eye and entrains to the light-dark cycle. The SCN then coordinates the timing of tissue clocks so internal rhythms are aligned with environmental cycles. Estrogens interact with the circadian system to regulate biological processes. At the molecular level, estrogens and circadian genes interact to regulate gene expression and cell biology. Estrogens also regulate circadian behavior across the estrous cycle. The timing of ovulation during the estrous cycle requires coincident estrogen and SCN signals. Studies using circadian gene reporter mice have also elucidated estrogen regulation of peripheral tissue clocks and metabolic rhythms. This review synthesizes current understanding of the interplay between estrogens and the circadian system, with a focus on female rodents, in regulating molecular, physiological, and behavioral processes.


Cross-modal plasticity in cortical development: differentiation and specification of sensory neocortex.
Early developmental manipulations can induce sensory afferents of one modality to project to central targets of a different sensory modality. We and other investigators have used such cross-modal plasticity to examine the role of afferent inputs and their patterns of activity in the development of sensory neocortex. We suggest that the afferent rewiring can significantly influence the internal connectivity or microcircuitry of sensory cortex, aspects of which appear to be determined or specified relatively late in development, but that they cannot influence, or influence only to a minor extent, the laminar characteristics and external connectivity patterns of cortex, which appear to be specified earlier.


Choline acts during preimplantation development of the bovine embryo to program postnatal growth and alter muscle DNA methylation.
The preimplantation period of embryonic development can be a key window for programming of postnatal development because extensive epigenetic remodeling occurs during this time. It was hypothesized that modification of one-carbon metabolism of the bovine embryo by addition of the methyl-donor choline to culture medium would change postnatal phenotype through epigenetic modification. Embryos produced in vitro were cultured with 1.8 mM choline chloride or control medium. Blastocysts were transferred into females and pregnancy outcomes and postnatal phenotype of the resultant calves determined. Exposure of embryos to choline increased gestation length and calf birth weight. Calves derived from choline-treated embryos were also heavier at weaning and had increased ratio of body weight to hip height than control calves. Choline altered muscle DNA methylation of calves 4 months after birth. A total of 670 of the 8149 CpG examined were differentially methylated, with the predominant effect of choline being hypomethylation. Among the genes associated with differentially methylated CpG were ribosomal RNAs and genes in AMPK, mTOR, integrin, and BEX2 canonical pathways and cellular functions involved in growth and proliferation. Results demonstrate that provision of the methyl-donor choline to the preimplantation embryo can alter its developmental program to increase gestation length, birth weight, and weaning weight and cause postnatal changes in muscle DNA methylation including those associated with genes related to anabolic processes and cellular growth. The importance of the nutritional status of the embryo with respect to one-carbon metabolism for ensuring health and well-being after birth is emphasized by these observations.


Impact of actin polymerization and filopodia formation on herpes simplex virus entry in epithelial, neuronal, and T lymphocyte cells.
Herpes simplex virus type 1 (HSV-1) has been known as a common viral pathogen that can infect several parts of the body, leading to various clinical manifestations. According to this diverse manifestation, HSV-1 infection in many cell types was demonstrated. Besides the HSV-1 cell tropism, e.g., fibroblast, epithelial, mucosal cells, and neurons, HSV-1 infections can occur in human T lymphocyte cells, especially in activated T cells. In addition, several studies found that actin polymerization and filopodia formation support HSV-1 infection in diverse cell types. Hence, the goal of this review is to explore the mechanism of HSV-1 infection in various types of cells involving filopodia formation and highlight potential future directions for HSV-1 entry-related research. Moreover, this review covers several strategies for possible anti-HSV drugs focused on the entry step, offering insights into potential therapeutic interventions.


MSH2 missense mutations and HNPCC syndrome: pathogenicity assessment in a human expression system.
Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is associated with germline mutations in one of several MisMatch Repair (MMR) genes. An increasing proportion (20-25%) of the reported MSH2 variants consists of single amino-acid substitution with uncertain disease-causing significance. The present study was undertaken to functionally characterize 3 MSH2 nontruncating variants: p.Gly162Arg (c.484G>C), p.Asp167His (c.499G>C) and p.Arg359Ser (c.1077A>T). Missense alterations, were assessed in a human system for expression/stability and for the ability to heterodimerize with MSH6 and correctly localize into the nucleus. Functional assays results were correlated with clinical and genetic features indicative of HNPCC as MicroSatellite-Instability (MSI), abnormalities of MMR gene expression in tumour tissue (IHC) and familial history. p.Gly162Arg and p.Arg359Ser variants showed a clearly decreased expression level of the MutSá complex and were associated with an abnormal subcellular localization pattern, which can be suggestive of an incorrect MSH2/MSH6 heterodimerization. Functional analysis results were supported by MSI and IHC data and by familial cancer history. The subcellular localization assay, performed in a human expression system, classifies as pathogenetic two MSH2 nontruncating alterations providing a useful tool in genetic testing programs.


Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis.
Several mutations involving the fibroblast growth factor receptor (FGFR) gene family have been identified in association with phenotypically distinct forms of craniosynostosis. One such point mutation, resulting in the substitution of proline by arginine in a critical region of the linker region between the first and second immunoglobulin-like domains, is associated with highly specific phenotypic consequences in that mutation at this point in FGFR1 results in Pfeiffer syndrome and analogous mutation in FGFR2 results in Apert syndrome. We now show that a much more variable clinical presentation accompanies analogous mutation in the FGFR3 gene. Specifically, mental retardation, apparently unrelated to the management of the craniosynostosis, appears to be a variable clinical consequence of this FGFR3 mutation.


Left Ventricular Non-compaction Cardiomyopathy: A Case Report and Literature Review.
Left Ventricular Non-Compaction Cardiomyopathy (LVNC) is a rare myocardial disorder characterized by abnormal myocardial tissue formation in which the left ventricular wall appears to be trabecular with prominent intertrabecular recesses. The diagnosis of LVNC is predominantly reliant on cardiac imaging, namely thoracic echocardiography, however, cardiac MRI is indicated in conditions in which echocardiography is inconclusive. Diagnostic criteria for both echocardiography and cardiac MRI differ, however, the general principle of diagnosis is a comparison of the thickness of non-compacted to compacted myocardial tissue. The management of LVNC is nearly identical to that of Heart Failure with reduced Ejection Fraction (HFrEF), however, anticoagulation is an additional measure of management to the thrombogenic nature of non-compacted myocardial tissue. Here, we discuss a case of LVNC and the current data on its management.


Solvatochromic and application in dye-sensitized solar cells of sandwich-like Cd(II) complexes: supramolecular architectures based on N(1),N(3)-bis[(6-methoxypyridin-2-yl)methylene]benzene-1,3-diamine.
A novel polydentate Schiff base ligand N(1),N(3)-bis[(6-methoxypyridin-2-yl)methylene]benzene-1,3-diamine (L) and its two dinuclear sandwich-like complexes {[CdL(NO3)(H2O)]·NO3}2 (1) and {[CdL(CH3CN)(H2O)]·(ClO4)2·(CH3CN)2}2 (2) were synthesized. Both C-H∙∙∙O, C-H∙∙∙N and π-π non-covalent interactions had essential roles in constructing the resulting three-dimensional supramolecular networks. L emits a more intense blue-green fluorescence emission around 493 nm than in dilute solution, exhibiting stacking-induced emission properties. Complexes 1 and 2 exhibited the dual properties of exceptional solvatochromism and fluorescence quenching towards CH3OH molecules. As these compounds could overcome the absent absorption of ruthenium complex N719 in the low wavelength region of the visible spectrum, offset the competitive visible light absorption of I3(-) and reduce the charge recombination of injected electrons, the Schiff base ligand l and complexes 1 and 2 were used as co-sensitizers in combination with N719 to investigate their effect on enhancing the performance of dye-sensitized solar cells. A short circuit current density of 14.37 mA cm(-2), an open-circuit voltage of 0.71 V and a fill factor of 0.61 corresponding to an overall conversion efficiency of 6.17% under AM 1.5 G solar irradiation were achieved when 1 was used as a co-sensitizer, which are much higher than the results obtained for dye-sensitized solar cells sensitized by N719 alone (5.06%).


The moral career of poor patients in free clinics.
This paper explores the lived experiences and the identity processes attached to attendance at free clinics. It draws on a qualitative study of 94 patients and 37 professionals who were interviewed at four free clinics in France. Since these facilities are for the poor and for people without health coverage, attendance reflects a medical experience as well as an experience of assistance, both of which have an impact on healthcare utilisation. Nevertheless, the meaning attached to the recourse to free clinics and the patients' lived experiences change over time and depend on interactions with clinic staff. This study proposes a typology of care recourse modes (occasional, regular and inconsistent attendance) crossed with different types of lived experiences. Occasional attendance and distant patient-professionals relationships, often due to the humiliation that some people feel when they have to ask for social assistance, characterise the first time people have recourse to care. Patients commit to regular follow-ups only when they have come to terms with their position in the medical and assistance system, doing so by rationalising and adjusting their identity. Our aim in discussing our findings is to gain greater insight into the utilisation of healthcare by different population groups and in different contexts.


Characterization of the sialate-7(9)-O-acetyltransferase from the microsomes of human colonic mucosa.
Sialic acids present on human colonic mucins are highly O-acetylated, however, little is known about the underlying enzymatic activity required for O-acetylation in this tissue. Here we report on the substrate specificity, subcellular localization and characterization of the sialate-7(9)-O-acetyltransferase in normal human colonic mucosa. Using CMP-Neu5Ac, the most efficient acceptor substrate of all those tested, the enzymatic activity was found to be optimal at 37 degrees C, with a pH optimum of 7.0. Activity was also found to be dependent on protein, CMP-Neu5Ac (Km: 59.2 microM) and AcCoA (Km: 6.1 microM) concentrations, as well as membrane integrity. The enzyme's activity could be inhibited by CoA with a Ki of 11.9 microM. In addition, enzymatic activity was found to be localized in the Golgi-enriched membrane fraction. The nature of the O-acetylated products formed were verified with the aid of chromatographic and enzymatic techniques. The main product was 9-O-acetylated Neu5Ac, with a significant amount of oligo-O-acetylated Neu5Ac also being detected. The utilization of CMP-Neu5Ac as the acceptor substrate was confirmed by the isolation and characterization of the putative product, CMP-Neu5,9Ac2, using ion-exchange chromatography. The ability of CMP-Neu5,9Ac2 to act as a sialic acid donor for sialyltransferases represents the conclusive demonstration for the formation of CMP-Neu5,9Ac2.


Differential induction of mitochondrial machinery by light intensity correlates with changes in respiratory metabolism and photorespiration in rice leaves.
The light responsiveness of mitochondrial function was investigated through changes in mitochondrial composition and metabolism in rice (Oryza sativa) shoots. The mitochondrial proteome and metabolite abundances under low light, (LL, 100 μmol m(-2) s(-1) ), and high light (HL, 700 μmol m(-2) s(-1) ) were measured along with information on shoot photosynthetic, respiratory and photorespiratory activity. Specific steps in mitochondrial tricarboxylic acid (TCA) cycle metabolism were decreased under HL, correlating with lower respiration rate under HL. The abundance of mitochondrial enzymes in branch chain metabolism was reduced under HL/LL, and correlated with a decrease in the abundance of a range of amino acids in the HL/LL. Mitochondrial nucleoside diphosphate kinase was increased under LL/HL treatments. Significant accumulation of glycine decarboxylase P, T subunits and serine hydroxymethyltransferase occurred in response to light. The abundance of the glycine decarboxylase (GDC) H subunit proteins was not changed by HL/LL treatments, and the abundance of GDC L subunit protein was halved under HL, indicating a change in the stoichiometry of GDC subunits, while photorespiration was fourfold higher in LL- than in HL-treated plants. Insights into these light-dependent phenomena and their importance for understanding the initiation of photorespiration in rice and adaptation of mitochondria to function in photosynthetic cells are discussed.


One-lung ventilation induces hyperperfusion and alveolar damage in the ventilated lung: an experimental study.
One-lung ventilation (OLV) increases mechanical stress in the lung and affects ventilation and perfusion (V, Q). There are no data on the effects of OLV on postoperative V/Q matching. Thus, this controlled study evaluates the influence of OLV on V/Q distribution in a pig model using a gamma camera technique [single-photon emission computed tomography (SPECT)] and relates these findings to lung histopathology after OLV. Eleven anaesthetized and ventilated pigs (V(T)=10 ml kg(-1), Fio2=0.40, PEEP=5 cm H2O) were studied. After lung separation, OLV and thoracotomy were performed in seven pigs (OLV group). During OLV and in a two-lung ventilation (TLV), control group (n=4) ventilation settings remained unchanged. SPECT with (81m)Kr (ventilation) and (99m)Tc-labelled macro-aggregated albumin (perfusion) was performed before, during, and 90 min after OLV/TLV. Finally, lung tissue samples were harvested and examined for alveolar damage. OLV affected ventilation and haemodynamic variables, but there were no differences between the OLV group and the control group before and after OLV/TLV. SPECT revealed an increase of perfusion in the dependent lung compared with baseline (49-56%), and a corresponding reduction of perfusion (51-44%) in non-dependent lungs after OLV. No perfusion changes were observed in the control group. This resulted in increased low V/Q regions and a shift of V/Q areas to 0.3-0.5 (10(-0.5)-10(-0.3)) in dependent lungs of OLV pigs and was associated with an increased diffuse alveolar damage score. OLV in pigs results in a substantial V/Q mismatch, hyperperfusion, and alveolar damage in the dependent lung and may thus contribute to gas exchange impairment after thoracic surgery.


[State of supply services for industrial hygiene and safety in Colombia].
Institutions that supply occupational health services must offer services that are reliable and of high quality across the spectrum of industrial hygiene and safety needs. Services for occupational health were identified at several institutions, and the technical quality and reliability of these services were compared in different regions of Colombia. This descriptive study identified the services available for industrial hygiene and safety in 15 cities of Colombia. A survey was conducted in 192 institutions offering such services and a statistical analysis of these results was undertaken. This sample was taken from a nationwide list of institutions purportedly licensed for this activity. Thirty-two percent (61) of the evaluated institutions provided hygiene services, and 48% (93) provided safety services. The range of health services was provided on a subcontract basis both for professional personnel and the equipment. Six institutions in the area of industrial hygiene and 1 in the area of industrial security were supplying services with pending or suspended institutional licenses. Deficiencies in the quality, infrastructure and levels of automation were identified at institutions that supply services of hygiene and industrial security. The resulting recommendatios are that the Ministry of the Social Protection fortifies mechanisms for (1) the evaluation and control of the supplied services, and (2) verify that the institutional activity is in accordance with current and valid licensing.


A 100 kDa polypeptide associates with the V0 membrane sector but not with the active oat vacuolar H(+)-ATPase, suggesting a role in assembly.
The vacuolar H(+)-ATPase (V-ATPase) is responsible for acidifying endomembrane compartments in eukaryotic cells. Although a 100 kDa subunit is common to many V-ATPases, it is not detected in a purified and active pump from oat (Ward J.M. and Sze H. (1992) Plant Physiol. 99, 925-931). A 100 kDa subunit of the yeast V-ATPase is encoded by VPH1. Immunostaining revealed a Vph1p-related polypeptide in oat membranes, thus the role of this polypeptide was investigated. Membrane proteins were detergent-solubilized and size-fractionated, and V-ATPase subunits were identified by immunostaining. A 100 kDa polypeptide was not associated with the fully assembled ATPase; however, it was part of an approximately 250 kDa V0 complex including subunits of 36 and 16 kDa. Immunostaining with an affinity-purified antibody against the oat 100 kDa protein confirmed that the polypeptide was part of a 250 kDa complex and that it had not degraded in the approximately 670 kDa holoenzyme. Co-immunoprecipitation with a monoclonal antibody against A subunit indicated that peripheral subunits exist as assembled V1 subcomplexes in the cytosol. The free V1 subcomplex became attached to the detergent-solubilized V0 sector after mixing, as subunits of both sectors were co-precipitated by an antibody against subunit A. The absence of this polypeptide from the active enzyme suggests that, unlike the yeast Vph1p, the 100 kDa polypeptide in oat is not required for activity. Its association with the free Vo subcomplex would support a role of this protein in V-ATPase assembly and perhaps in sorting.


Plasma Surface Functionalization of Carbon Nanofibres with Silver, Palladium and Platinum Nanoparticles for Cost-Effective and High-Performance Supercapacitors.
Due to their relatively low cost, large surface area and good chemical and physical properties, carbon nanofibers (CNFs) are attractive for the fabrication of electrodes for supercapacitors (SCs). However, their relatively low electrical conductivity has impeded their practical application. To this end, a novel active-screen plasma activation and deposition technology has been developed to deposit silver, platinum and palladium nanoparticles on activated CNFs surfaces to increase their specific surface area and electrical conductivity, thus improving the specific capacitance. The functionalised CNFs were fully characterised using scanning electron microscope (SEM), energy dispersive X-ray analysis (EDX) and X-ray diffraction (XRD) and their electrochemical properties were evaluated using cyclic voltammetry and electrochemical impedance spectroscopy. The results showed a significant improvement in specific capacitance, as well as electrochemical impedance over the untreated CNFs. The functionalisation of CNFs via environmental-friendly active-screen plasma technology provides a promising future for cost-effective supercapacitors with high power and energy density.


Immune Responses and Anti-inflammatory Strategies in a Clinically Relevant Model of Thromboembolic Ischemic Stroke with Reperfusion.
The poor clinical relevance of experimental models of stroke contributes to the translational failure between preclinical and clinical studies testing anti-inflammatory molecules for ischemic stroke. Here, we (i) describe the time course of inflammatory responses triggered by a thromboembolic model of ischemic stroke and (ii) we examine the efficacy of two clinically tested anti-inflammatory drugs: Minocycline or anti-CD49d antibodies (tested in stroke patients as Natalizumab) administered early (1 h) or late (48 h) after stroke onset. Radiological (lesion volume) and neurological (grip test) outcomes were evaluated at 24 h and 5 days after stroke. Immune cell responses peaked 48 h after stroke onset. Myeloid cells (microglia/macrophages, dendritic cells, and neutrophils) were already increased 24 h after stroke onset, peaked at 48 h, and remained increased-although to a lesser extent-5 days after stroke onset. CD8+ and CD4+ T-lymphocytes infiltrated the ipsilateral hemisphere later on (only from 48 h). These responses occurred together with a progressive blood-brain barrier leakage at the lesion site, starting 24 h after stroke onset. Lesion volume was maximal 24-48 h after stroke onset. Minocycline reduced both lesion volume and neurological deficit only when administered early after stroke onset. The blockade of leukocyte infiltration by anti-CD49d had no impact on lesion volume or long-term neurological deficit, independently of the timing of treatment. Our data are in accordance with the results of previous clinical reports on the use of Minocycline and Natalizumab on ischemic stroke. We thus propose the use of this clinically relevant model of thromboembolic stroke with recanalization for future testing of anti-inflammatory strategies for stroke.


Analysis of volatile organic compounds released during food decaying processes.
A number of volatile organic compounds (VOCs) including acetone, methyl ethyl ketone, toluene, ethylbenzene, m,p-xylene, styrene, and o- xylene released during food decaying processes were measured from three types of decaying food samples (Kimchi (KC), fresh fish (FF), and salted fish (SF)). To begin with, all the food samples were contained in a 100-mL throwaway syringe. These samples were then analyzed sequentially for up to a 14-day period. The patterns of VOC release contrasted sharply between two types of fish (FF and SF) and KC samples. A comparison of data in terms of total VOC showed that the mean values for the two fish types were in the similar magnitude with 280 ± 579 (FF) and 504 ± 1,089 ppmC (SF), while that for KC was much lower with 16.4 ± 7.6 ppmC. There were strong variations in VOC emission patterns during the food decaying processes between fishes and KC that are characterized most sensitively by such component as styrene. The overall results of this study indicate that concentration levels of the VOCs differed significantly between the food types and with the extent of decaying levels through time.


Adaptive evolution to a high purine and fat diet of carnivorans revealed by gut microbiomes and host genomes.
Carnivorous members of the Carnivora reside at the apex of food chains and consume meat-only diets, rich in purine, fats and protein. Here, we aimed to identify potential adaptive evolutionary signatures compatible with high purine and fat metabolism based on analysis of host genomes and symbiotic gut microbial metagenomes. We found that the gut microbiomes of carnivorous Carnivora (e.g., Felidae, Canidae) clustered in the same clade, and other clades comprised omnivorous and herbivorous Carnivora (e.g., badgers, bears and pandas). The relative proportions of genes encoding enzymes involved in uric acid degradation were higher in the gut microbiomes of meat-eating carnivorans than plant-eating species. Adaptive amino acid substitutions in two enzymes, carnitine O-palmitoyltransferase 1 (CPT1A) and lipase F (LIPF), which play a role in fat digestion, were identified in Felidae-Candidae species. Carnivorous carnivorans appear to endure diets high in purines and fats via gut microbiomic and genomic adaptations.


Sprouting interneurons in mushroom bodies of adult cricket brains.
In crickets, neurogenesis persists throughout adulthood for certain local brain interneurons, the Kenyon cells in the mushroom bodies, which represent a prominent compartment for sensory integration, learning, and memory. Several classes of these neurons originate from a perikaryal layer, which includes a cluster of neuroblasts, surrounded by somata that provide the mushroom body's columnar neuropil. We describe the form, distribution, and cytology of Kenyon cell groups in the process of generation and growth in comparison to developed parts of the mushroom bodies in adult crickets of the species Gryllus bimaculatus. A subset of growing Kenyon cells with sprouting processes has been distinguished from adjacent Kenyon cells by its prominent f-actin labelling. Growth cone-like elements are detected in the perikaryal layer and in their associated sprouting fiber bundles. Sprouting fibers distant from the perikarya contain ribosomes and rough endoplasmic reticulum not found in the dendritic processes of the calyx. A core of sprouting Kenyon cell processes is devoid of synapses and is not invaded by extrinsic neuronal elements. Measurements of fiber cross-sections and counts of synapses and organelles suggest a continuous gradient of growth and maturation leading from the core of added new processes out to the periphery of mature Kenyon cell fiber groups. Our results are discussed in the context of Kenyon cell classification, growth dynamics, axonal fiber maturation, and function.


Solitary Necrotic Nodule of Liver (SNNL): A Report of Two Cases.
SNNL is a rare, benign lesion which may arise from trauma, a sclerosing haemangioma or it may represent a burned out phase of various conditions like parasitic infections, or chronic infections like tuberculosis. Histopathology provides the definite diagnosis, which thus helps clinicians in allaying unnecessary anxiety of the patient and in planning proper management.We are reporting two cases here, which had solitary necrotic nodules of liver (SNNL), with emphasis on the aetiology and morphology of the lesions. SNNL was incidentally detected during cholecystectomy done in both young female patients. The lesion was solitary in one case and it was multiple in the other. The suspected aetiology in one of the cases was parasitic, whereas it was tuberculosis in the other. The clinical features in both cases were suggestive of neoplasms.


Association of improved air quality with lung development in children.
Air-pollution levels have been trending downward progressively over the past several decades in southern California, as a result of the implementation of air quality-control policies. We assessed whether long-term reductions in pollution were associated with improvements in respiratory health among children. As part of the Children's Health Study, we measured lung function annually in 2120 children from three separate cohorts corresponding to three separate calendar periods: 1994-1998, 1997-2001, and 2007-2011. Mean ages of the children within each cohort were 11 years at the beginning of the period and 15 years at the end. Linear-regression models were used to examine the relationship between declining pollution levels over time and lung-function development from 11 to 15 years of age, measured as the increases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) during that period (referred to as 4-year growth in FEV1 and FVC). Over the 13 years spanned by the three cohorts, improvements in 4-year growth of both FEV1 and FVC were associated with declining levels of nitrogen dioxide (P<0.001 for FEV1 and FVC) and of particulate matter with an aerodynamic diameter of less than 2.5 μm (P= 0.008 for FEV1 and P<0.001 for FVC) and less than 10 μm (P<0.001 for FEV1 and FVC). These associations persisted after adjustment for several potential confounders. Significant improvements in lung-function development were observed in both boys and girls and in children with asthma and children without asthma. The proportions of children with clinically low FEV1 (defined as <80% of the predicted value) at 15 years of age declined significantly, from 7.9% to 6.3% to 3.6% across the three periods, as the air quality improved (P = 0.001). We found that long-term improvements in air quality were associated with statistically and clinically significant positive effects on lung-function growth in children. (Funded by the Health Effects Institute and others.).


Immune function at diagnosis in relation to responses to therapy in acute lymphocytic leukemia of childhood.
Tests of immune capacity were performed on blood from 49 children with newly diagnosed, untreated acute lymphocytic leukemia, and relation to prognosis was determined. Patients were treated with multiple-drug therapy and prophylactic cranial irradiation. Median follow-up time was 16 mo (range 10--37 mo). Principal unfavorable findings at diagnosis were absolute numbers of T lymphoid cells outside the range 850--2500/mul blood, absence of whole blood responses to phytohemagglutinin in vitro, a low titer of complexed antibody, and the presence in serum of free leukemic blast cell membrane antigen. Fourteen patients showed two or more unfavorable findings at diagnosis. Eleven of these have died. Four of the remaining 35 patients have died. A shorter duration of first remission was found among patients with abnormal numbers of T cells at diagnosis. The findings suggest that the immunologic capacity of the patient at diagnosis is an important determinant in responses to therapy.


TAL effector specificity for base 0 of the DNA target is altered in a complex, effector- and assay-dependent manner by substitutions for the tryptophan in cryptic repeat -1.
TAL effectors are re-targetable transcription factors used for tailored gene regulation and, as TAL effector-nuclease fusions (TALENs), for genome engineering. Their hallmark feature is a customizable central string of polymorphic amino acid repeats that interact one-to-one with individual DNA bases to specify the target. Sequences targeted by TAL effector repeats in nature are nearly all directly preceded by a thymine (T) that is required for maximal activity, and target sites for custom TAL effector constructs have typically been selected with this constraint. Multiple crystal structures suggest that this requirement for T at base 0 is encoded by a tryptophan residue (W232) in a cryptic repeat N-terminal to the central repeats that exhibits energetically favorable van der Waals contacts with the T. We generated variants based on TAL effector PthXo1 with all single amino acid substitutions for W232. In a transcriptional activation assay, many substitutions altered or relaxed the specificity for T and a few were as active as wild type. Some showed higher activity. However, when replicated in a different TAL effector, the effects of the substitutions differed. Further, the effects differed when tested in the context of a TALEN in a DNA cleavage assay, and in a TAL effector-DNA binding assay. Substitution of the N-terminal region of the PthXo1 construct with that of one of the TAL effector-like proteins of Ralstonia solanacearum, which have arginine in place of the tryptophan, resulted in specificity for guanine as the 5' base but low activity, and several substitutions for the arginine, including tryptophan, destroyed activity altogether. Thus, the effects on specificity and activity generated by substitutions at the W232 (or equivalent) position are complex and context dependent. Generating TAL effector scaffolds with high activity that robustly accommodate sites without a T at position 0 may require larger scale re-engineering.


Selective loss of acetylcholine sensitivity in a nerve cell line cultured in hormone-supplemented serum-free medium.
When clonal rat pheochromocytoma PC12h cells were cultured in a hormone-supplemented serum-free medium, the carbamylcholine-elicited catecholamine release from cells cultured in serum-free medium was completely abolished. On the other hand, the high potassium-induced catecholamine release was not changed, even in PC12h cells cultured in serum-free medium. The lack of carbamylcholine sensitivity was confirmed directly by measuring carbamylcholine-induced 22Na influx, which was completely abolished in PC12h cells cultured in serum-free medium. The loss of carbamylcholine-induced 22Na influx seemed to obey nearly first-order kinetics and was fully restored upon a re-exposure to serum. The half-time for the loss was about 1 day, and the cultivation for 5 days in serum-free medium caused a 95% decrease of the nicotinic sensitivity in PC12h cells. The carbamylcholine-induced 45Ca influx into cells also was lost due to the serum-free cultivation. By contrast, the binding of alpha-bungarotoxin, which is an antagonist of nicotinic acetylcholine receptor in muscular cells, remained and did not change in PC12h cells cultured, even in the serum-free medium. In addition, veratridine-dependent 22Na influx and high potassium-induced 45Ca influx into cells, and high potassium-induced 86Rb efflux from cells cultured in the serum-free medium were also perfectly preserved. These results suggest that PC12h cells cultured in the serum-free medium seemed to be a useful model for comparing the differential mechanisms between acetylcholine sensitivity and other membranous functions on this cell.


A case of holocarboxylase synthetase deficiency with insufficient response to prenatal biotin therapy.
Holocarboxylase synthetase (HCS) deficiency is an inborn error of biotin metabolism, leading to a multiple carboxylases deficiency. As the affected fetus sometimes presents with enlargement of the cerebral ventricles and intrauterine growth retardation (IUGR), prenatal administration of biotin has been attempted in some pregnancies. We present herein the case of a Japanese neonate with HCS deficiency who received maternal administration of biotin (10mg/day) from 33 weeks' gestation. After biotin administration, the fetal body weight increased and gestation was continued to full term. However, lactic acidemia and metabolic acidosis were observed after birth. To evaluate the effects of prenatal therapy, we collected serum samples and measured the acylcarnitine profiles using high-performance liquid chromatography electrospray ionization tandem mass spectrometry. At birth, levels of propionylcarnitine and 3-hydroxyisovalerylcarnitine had already increased. At 2h after birth, these levels of acylcarnitines were further increased. At 3.5h after the start of biotin, these chemical findings were slightly improved. In conclusion, we considered that prenatal biotin therapy at 10mg/day may have been inadequate to avoid neonatal acidotic crisis in this case.


Acupuncture treatment of simple obesity.
In order to investigate the therapeutic effects of ear acupuncture, body acupuncture and the combined use of the two in the treatment of simple obesity, 195 cases of obesity were divided into three groups, in which different reinforcing and reducing methods were applied according to their symptoms and signs. The effects of body acupuncture and body plus ear acupuncture were obviously superior to that of ear acupuncture, and the combined use of ear acupuncture and body acupuncture was better than that of simple body acupuncture.


Terra incognita: The unknown risks to environmental quality posed by the spatial distribution and abundance of concentrated animal feeding operations.
Concentrated animal feeding operations (CAFOs) pose wide ranging environmental risks to many parts of the US and across the globe, but datasets for CAFO risk assessments are not readily available. Within the United States, some of the greatest concentrations of CAFOs occur in North Carolina. It is also one of the only states with publicly accessible location data for classes of CAFOs that are required to obtain water quality permits from the U.S. Environmental Protection Agency (EPA); however, there are no public data sources for the large number of CAFOs that do not require EPA water quality permits. We combined public records of CAFO locations with data collected in North Carolina by the Waterkeeper and Riverkeeper Alliances to examine the distribution of both permitted and non-permitted CAFOs across the state. Over half (55%) of the state's 6646 CAFOs are located in the Coastal Plain, a low-lying region vulnerable to flooding associated with regular cyclonic and convective storms. We identified 19% of CAFOs ≤ 100 m of the nearest stream, and some as close as 15 m to the nearest stream, a common riparian buffer width for water quality management. Future climate scenarios suggest large storm events are expected to become increasingly extreme, and dry interstorm periods could lengthen. Such extremes could exacerbate the environmental impacts of CAFOs. Understanding the potential impacts of CAFO agroecosystems will require remote sensing to identify CAFOs, fieldwork to determine the extent of environmental footprints, and modeling to identify thresholds that determine environmental risk under changing conditions.


The relationship between digital media use during pregnancy, maternal psychological wellbeing, and maternal-fetal attachment.
The widespread accessibility and use of the internet provides numerous opportunities for women to independently seek out pregnancy-related information and social and emotional support during the antenatal period. Given the heightened psychological vulnerability of the pregnancy period there is a critical need to examine digital media use within the context of the feelings that women have about themselves and towards their fetus. The current study examined the relationship between digital media use during pregnancy, psychological wellbeing and their maternal-fetal attachment using an online survey. Forty-eight pregnant women completed a self-report questionnaire on their reasons for using digital media, and standardised measures of self-criticism, negative affect, social quality of life (QOL), and maternal-fetal attachment. The mean age of participants was 29.4 years (SD = 5.26), with a mean of 24.3 weeks gestation (SD = 9.95). Information seeking, emotional support and social support were highly endorsed reasons for digital media use (85.42%, 66.67%, 62.5% respectively). However, digital media use was positively correlated with negative affect (p = .003) and self-criticism (p < .001). Digital media use was also negatively correlated with QOL (p = .007). There was no evidence of a relationship between digital media use and maternal-fetal attachment (p = .330). Digital environments may be an important social context within which a pregnant woman develops her own maternal identity and knowledge. There are a number of benefits and limitations of this medium for providing information and support for women during pregnancy. Enhancing the opportunities to promote pregnant women's wellbeing in this context is an important avenue for further research and practice.


Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress.
The ability to respond to perturbations in endoplasmic reticulum (ER) function is a fundamentally important property of all cells, but ER stress can also lead to apoptosis. In settings of chronic ER stress, the associated apoptosis may contribute to pathophysiological processes involved in a number of prevalent diseases, including neurodegenerative diseases, diabetes, atherosclerosis and renal disease. The molecular mechanisms linking ER stress to apoptosis are the topic of this review, with emphases on relevance to pathophysiology and integration and complementation among the various apoptotic pathways induced by ER stress.


Bosentan does not affect renal resistive index in scleroderma/systemic sclerosis patients.
If properly evaluated, chronic kidney disease can be found in up to 50% of patients with systemic sclerosis (SSc). The renal resistive index (RRI) is a marker of intrarenal vascular resistance and can predict SSc-associated vasculopathy. This study aimed to determine the impact of bosentan, a nonselective endothelin-1 receptor antagonist, on RRI and kidney function in SSc patients with recurrent digital ulcers. Twenty-one patients (age 57±9 years, 19 females) were recruited in a 16-week prospective open-label uncontrolled study. Standardized procedures were used to measure general clinical and laboratory characteristics, systolic, diastolic, and mean blood pressure (MAP), pulse pressure (PP), diastolic to systolic blood pressure (D/S) ratio, and urinary endothelin-1 levels. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was used to calculate kidney function as an estimated glomerular filtration rate (eGFR). RRI was measured by Doppler ultrasound as the average of three samplings of intrarenal blood flow in different kidney regions of both kidneys. Patients with secondary causes of kidney disease or kidney diseases associated with albuminuria were excluded. Bosentan treatment for 16 weeks did not change RRI (0.731±0.049 to 0.730±0.054, p=0.925), but increased urine endothelin-1 to creatinine ratio (0.27±0.15 to 0.49±0.57 pg/mg, p=0.032) and reduced MAP (123±10 to 101±11 mm Hg, p<0.001), PP (76±11 to 68±10 mm Hg, p=0.003), D/S ratio (0.563±0.044 to 0.538±0.031, p=0.006), and eGFR (92±20 to 84±24 ml/min/1.73 m2, p=0.003). In conclusion, in patients with systemic sclerosis complicated by digital ulcers and normal to mildly diminished kidney function, bosentan had no effect on intrarenal hemodynamics, but reduced blood pressure levels and kidney function.


Classification of Corynebacterium species from axillary skin by numerical analysis of electrophoretic protein patterns.
The genus Corynebacterium, defined by the presence of mesodiaminopimelic acid, arabinose and corynomycolic acids in the cell wall, contains a very diverse group of organisms according to the results of numerical analysis of protein patterns; 13 groups were distinguished in this study. Strains isolated from axillary skin and hair included representatives of several groups but many strains were placed in groups 1 and 6A. Neither of these groups contained any reference strains and may constitute hitherto undescribed species. The reference strains of C. diphtheriae formed a coherent group not closely related to any non-pathogenic Corynebacterium species.


Interactions of platinum clusters with a graphite substrate.
Density functional theory calculations are used to elucidate the interactions of platinum clusters with graphite; the results are analyzed in terms of geometry, and energetic and electronic properties. Adsorption of platinum clusters from 1 to 38 atoms is evaluated on a 3-layer graphite model structure. The approach includes van der Waals interactions, which have proved to be essential to describe relatively weak interactions. The results show that when interacting with graphite, the clusters tend to slightly wetting the surface. Although the effect is more pronounced in the larger clusters investigated, the energy difference among total, partial, and non-wetting structures in small clusters is very low and may be easily overcome by thermal effects. The van der Waals energy contributes to enhance the graphite-cluster strength and is proportional to the number of interacting atoms at the interface. Small charge transfer takes place from the metallic cluster to the graphite surface and the cluster becomes polarized, with positive values at the interface, and negative values in the top. The interaction with graphite enhances the metallic character of the cluster as shown by density of states analyses. New states resulting from the interaction between graphite and the metal cluster may modify its catalytic behavior.


The Fluid Mechanics of Transcatheter Heart Valve Leaflet Thrombosis in the Neosinus.
Transcatheter heart valve (THV) thrombosis has been increasingly reported. In these studies, thrombus quantification has been based on a 2-dimensional assessment of a 3-dimensional phenomenon. Postprocedural, 4-dimensional, volume-rendered CT data of patients with CoreValve, Evolut R, and SAPIEN 3 transcatheter aortic valve replacement enrolled in the RESOLVE study (Assessment of Transcatheter and Surgical Aortic Bioprosthetic Valve Dysfunction With Multimodality Imaging and Its Treatment with Anticoagulation) were included in this analysis. Patients on anticoagulation were excluded. SAPIEN 3 and CoreValve/Evolut R patients with and without hypoattenuated leaflet thickening were included to study differences between groups. Patients were classified as having THV thrombosis if there was any evidence of hypoattenuated leaflet thickening. Anatomic and THV deployment geometries were analyzed, and thrombus volumes were computed through manual 3-dimensional reconstruction. We aimed to identify and evaluate risk factors that contribute to THV thrombosis through the combination of retrospective clinical data analysis and in vitro imaging in the space between the native and THV leaflets (neosinus). SAPIEN 3 valves with leaflet thrombosis were on average 10% further expanded (by diameter) than those without (95.5±5.2% versus 85.4±3.9%; P<0.001). However, this relationship was not evident with the CoreValve/Evolut R. In CoreValve/Evolut Rs with thrombosis, the thrombus volume increased linearly with implant depth (R2=0.7, P<0.001). This finding was not seen in the SAPIEN 3. The in vitro analysis showed that a supraannular THV deployment resulted in a nearly 7-fold decrease in stagnation zone size (velocities <0.1 m/s) when compared with an intraannular deployment. In addition, the in vitro model indicated that the size of the stagnation zone increased as cardiac output decreased. Although transcatheter aortic valve replacement thrombosis is a multifactorial process involving foreign materials, patient-specific blood chemistry, and complex flow patterns, our study indicates that deployed THV geometry may have implications on the occurrence of thrombosis. In addition, a supraannular neosinus may reduce thrombosis risk because of reduced flow stasis. Although additional prospective studies are needed to further develop strategies for minimizing thrombus burden, these results may help identify patients at higher thrombosis risk and aid in the development of next-generation devices with reduced thrombosis risk.


Randomised double blind trial of somatostatin in the treatment of massive upper gastrointestinal haemorrhage.
In order to evaluate the effect of somatostatin in the treatment of massive upper gastrointestinal bleeding a randomised double blind trial of 95 patients has been undertaken during a 28 months period. Patients with oesophageal varices have been excluded as well as patients with diabetes. All patients were endoscoped within eight hours of admission to the hospital, whereupon the source of bleeding and types of stigmata were assessed. Forty six patients, chosen at random, were given a 72 hour infusion of somatostatin, while the remaining 49 patients received infusion of placebo. The two groups were well matched for sex, age, and source of bleeding. On the day after admission, an additional endoscopy was performed at which eight patients in the somatostatin group and 16 in the placebo group were found to have a persistent bleeding. A total of five patients in the somatostatin group and 14 in the placebo group underwent surgery (Fisher's exact test, 2-tail, p = 0.04). Rebleeding occurred in six patients in the somatostatin group, of whom five experienced rebleeding after completion of the somatostatin treatment. In the placebo group, rebleeding occurred in five patients, of whom four rebled on the day after admission. The need for blood transfusions and the mortality rate did not differ significantly between the two groups. No toxic side effects were found as a result of the infusion of somatostatin. In this study, somatostatin reduced the number of patients needing surgery with massive upper gastrointestinal bleeding.


Genetic and environmental influences on cortical surface area and cortical thickness in bipolar disorder.
The risk of developing bipolar disorder (BD) has been linked to structural brain abnormalities. The degree to which genes and environment influence the association of BD with cortical surface area remains to be elucidated. In this twin study, genetic and environmental contributions to the association between liability to develop BD and surface area, thickness and volume of the cortex were examined. The study cohort included 44 affected monozygotic (nine concordant, 12 discordant) and dizygotic (four concordant, 19 discordant) twin pairs, and seven twins from incomplete discordant monozygotic and dizygotic discordant twin pairs. In addition, 37 monozygotic and 24 dizygotic healthy control twin pairs, and six twins from incomplete monozygotic and dizygotic control pairs were included. Genetic liability to develop BD was associated with a larger cortical surface in limbic and parietal regions, and a thicker cortex in central and parietal regions. Environmental factors related to BD were associated with larger medial frontal, parietal and limbic, and smaller orbitofrontal surfaces. Furthermore, thinner frontal, limbic and occipital cortex, and larger frontal and parietal, and smaller orbitofrontal volumes were also associated with environmental factors related to BD. Our results suggest that unique environmental factors play a prominent role in driving the associations between liability to develop BD and cortical measures, particularly those involving cortical thickness. Further evaluation of their influence on the surface and thickness of the cortical mantle is recommended. In addition, cortical volume appeared to be primarily dependent on surface and not thickness.


Methyl mercury, but not inorganic mercury, associated with higher blood pressure during pregnancy.
Prior studies addressing associations between mercury and blood pressure have produced inconsistent findings; some of this may result from measuring total instead of speciated mercury. This cross-sectional study of 263 pregnant women assessed total mercury, speciated mercury, selenium, and n-3 polyunsaturated fatty acids in umbilical cord blood and blood pressure during labor and delivery. Models with a) total mercury or b) methyl and inorganic mercury were evaluated. Regression models adjusted for maternal age, race/ethnicity, prepregnancy body mass index, neighborhood income, parity, smoking, n-3 fatty acids and selenium. Geometric mean total, methyl, and inorganic mercury concentrations were 1.40µg/L (95% confidence interval: 1.29, 1.52); 0.95µg/L (0.84, 1.07); and 0.13µg/L (0.10, 0.17), respectively. Elevated systolic BP, diastolic BP, and pulse pressure were found, respectively, in 11.4%, 6.8%, and 19.8% of mothers. In adjusted multivariable models, a one-tertile increase of methyl mercury was associated with 2.83mmHg (0.17, 5.50) higher systolic blood pressure and 2.99mmHg (0.91, 5.08) higher pulse pressure. In the same models, an increase of one tertile of inorganic mercury was associated with -1.18mmHg (-3.72, 1.35) lower systolic blood pressure and -2.51mmHg (-4.49, -0.53) lower pulse pressure. No associations were observed with diastolic pressure. There was a non-significant trend of higher total mercury with higher systolic blood pressure. We observed a significant association of higher methyl mercury with higher systolic and pulse pressure, yet higher inorganic mercury was significantly associated with lower pulse pressure. These results should be confirmed with larger, longitudinal studies.


Bridging innate and adaptive antitumor immunity targeting glycans.
Effective immunotherapy for cancer depends on cellular responses to tumor antigens. The role of major histocompatibility complex (MHC) in T-cell recognition and T-cell receptor repertoire selection has become a central tenet in immunology. Structurally, this does not contradict earlier findings that T-cells can differentiate between small hapten structures like simple glycans. Understanding T-cell recognition of antigens as defined genetically by MHC and combinatorially by T cell receptors led to the "altered self" hypothesis. This notion reflects a more fundamental principle underlying immune surveillance and integrating evolutionarily and mechanistically diverse elements of the immune system. Danger associated molecular patterns, including those generated by glycan remodeling, represent an instance of altered self. A prominent example is the modification of the tumor-associated antigen MUC1. Similar examples emphasize glycan reactivity patterns of antigen receptors as a phenomenon bridging innate and adaptive but also humoral and cellular immunity and providing templates for immunotherapies.


Plasma Membrane Channel TRPM4 Mediates Immunogenic Therapy-Induced Necrosis.
Several emerging therapies kill cancer cells primarily by inducing necrosis. As necrosis activates immune cells, potentially, uncovering the molecular drivers of anticancer therapy-induced necrosis could reveal approaches for enhancing immunotherapy efficacy. To identify necrosis-associated genes, we performed a genome-wide CRISPR-Cas9 screen with negative selection against necrosis-inducing preclinical agents BHPI and conducted follow-on experiments with ErSO. The screen identified transient receptor potential melastatin member 4 (TRPM4), a calcium-activated, ATP-inhibited, sodium-selective plasma membrane channel. Cancer cells selected for resistance to BHPI and ErSO exhibited robust TRPM4 downregulation, and TRPM4 reexpression restored sensitivity to ErSO. Notably, TRPM4 knockout (TKO) abolished ErSO-induced regression of breast tumors in mice. Supporting a broad role for TRPM4 in necrosis, knockout of TRPM4 reversed cell death induced by four additional diverse necrosis-inducing cancer therapies. ErSO induced anticipatory unfolded protein response (a-UPR) hyperactivation, long-term necrotic cell death, and release of damage-associated molecular patterns that activated macrophages and increased monocyte migration, all of which was abolished by TKO. Furthermore, loss of TRPM4 suppressed the ErSO-induced increase in cell volume and depletion of ATP. These data suggest that ErSO triggers initial activation of the a-UPR but that it is TRPM4-mediated sodium influx and cell swelling, resulting in osmotic stress, which sustains and propagates lethal a-UPR hyperactivation. Thus, TRPM4 plays a pivotal role in sustaining lethal a-UPR hyperactivation that mediates the anticancer activity of diverse necrosis-inducing therapies. A genome-wide CRISPR screen reveals a pivotal role for TRPM4 in cell death and immune activation following treatment with diverse necrosis-inducing anticancer therapies, which could facilitate development of necrosis-based cancer immunotherapies.


Perceptions of HIV/AIDS leaders about faith-based organisations' influence on HIV/AIDS stigma in South Africa.
The extent of the HIV pandemic-particularly in the hardest-hit countries, including South Africa-has prompted a call for greater engagement of all groups, including faith-based organisations (FBOs). Although FBOs are known to play a substantial role in providing care and support to those affected by HIV and AIDS, empirical evidence in regard to their actions in the broader context of stigma is limited. A qualitative, key-informant survey was conducted in South Africa as part of a six-country international study to examine perceptions of how FBOs have contributed to reduction in HIV risk, vulnerability and related impacts. The special emphasis of this paper is the influence of FBOs on stigma and discrimination. In-depth interviews were held with 34 senior-level key informants who act as key decision-makers in the response to HIV and AIDS in South Africa. Secular and faith-based respondents shared their perceptions of the faith-based response, including FBOs' actions in relation to HIV/AIDS stigma and discrimination. Our study revealed that while FBOs were perceived as taking some action to address stigma in South Africa, FBOs were also thought to contribute to HIV/AIDS- discrimination through conflating issues of sexuality and morality, and through associating HIV and AIDS with sin. The interviewees indicated a number of internal and external challenges faced by FBOs to deal effectively with stigma, including lack of information and skills, the difficulty of maintaining confidentiality in health services, and self-stigmatisation which prevents HIV-infected persons from revealing their status. Findings from this study may help both faith-based and secular groups capitalise on the perceived strengths of FBOs as well as to elucidate their perceived weaknesses so that these areas of concern can be further explored and addressed.


Regioselective Thiol-yne Reaction of Thiol with ((Methyl-d3)sulfonyl)ethyne: Synthesis of (2-((Methyl-d3)sulfonyl)vinyl)sulfides.
Herein, we have developed a new method for the synthesis of ((methyl-d3)sulfonyl)ethyne, which is cost-effective and environmentally friendly and can be synthesized at the gram level. As an ideal thiol-yne reagent, it can be reacted with various types of thiols to afford (Z)- and (E)-type vinyl sulfides under different conditions with high selectivity. In addition, it can complete the conformational transition from Z- to E-type products under suitable conditions, and can also carry out further derivatization smoothly. The deuterium content of all products was greater than 99%. The preliminary mechanistic studies support the visible light-mediated radical course, and herein provide a novel and efficient synthetic strategy for the direct introduction of deuterated methyl groups, enriching the methods for the construction of C-S bond-containing compounds.


Multiorgan Involvement Confounding the Diagnosis of Bartonella henselae Infective Endocarditis in Children With Congenital Heart Disease.
Two children with congenital heart disease status post surgical correction presented with prolonged constitutional symptoms, hepatosplenomegaly and pancytopenia. Concern for malignancy prompted bone marrow biopsies that were without evidence thereof. In case 1, echocardiography identified a multilobulated vegetation on the conduit valve. In case 2, transthoracic, transesophageal and intracardiac echocardiography were performed and were without evidence of cardiac vegetations; however, pulmonic emboli raised concern for infective endocarditis. Both patients underwent surgical resection of the infected material and had histopathologic evidence of infective endocarditis. Further diagnostics identified elevated cytoplasmic antineutrophil cytoplasmic antibodies and antiproteinase 3 antibodies in addition to acute kidney injury with crescentic glomerulonephritis on renal biopsy. Serologic evidence of infection with Bartonella henselae was observed in both patients. These 2 cases highlight the potential multiorgan involvement that may confound the diagnosis of culture-negative infective endocarditis caused by B. henselae.


Plasma-modified Ti3C2Tx/CdS hybrids with oxygen-containing groups for high-efficiency photocatalytic hydrogen production.
Noble-metal-free Ti3C2Tx/CdS hybrids with oxygen-containing groups were successfully prepared through a mild solvothermal method of in situ heterogeneous nucleation. The abundant oxygen-containing groups and the increased surface roughness of plasma-treated Ti3C2Tx sheets provided active sites for the heterogeneous nucleation of CdS nanoparticles and strengthened the physical bond between CdS NPs and layered Ti3C2Tx. The optimized Ti3C2Tx/CdS hybrid without noble-metal co-catalyst achieved a high hydrogen-production rate of 825 μmol h-1 g-1 with an apparent quantum efficiency of 10.2% at 450 nm. The prepared Ti3C2Tx/CdS hybrid with 1.0 wt% Ti3C2Tx had a photocatalytic hydrogen-production rate higher than those of pure CdS nanoparticles and the Ti3C2/CdS hybrid obtained using non-plasma-treated Ti3C2 as the support matrix under visible-light irradiation. The photocatalytic-activity improvement of CdS nanoparticles was due to the increased hydrophilicity after plasma treatment with the abundant oxygen-containing groups on the Ti3C2Tx surface and the intimate contact between CdS nanoparticles and layered Ti3C2Tx. The former enabled the effective capture of water molecules and hydrogen ions by oxygen-containing groups on the surface of plasma-treated Ti3C2Tx. The latter provided a stable transfer channel for electrons to suppress the recombination of photogenerated electron-hole pairs. The proposed schematic for the improved photocatalytic activity of CdS nanoparticles decorated with plasma treated Ti3C2Tx was further confirmed by transient photocurrent response and time-resolved photoluminescence analyses.


The evolution of diverse antimicrobial responses in vancomycin-intermediate Staphylococcus aureus and its therapeutic implications.
Staphylococcus aureus causes serious clinical infections, including bacteremia and endocarditis. When clinicians suspect these diseases, they prescribe broad-spectrum antibiotics like vancomycin and then adjust treatment based on antimicrobial susceptibility test results. However, these results reflect the infection's state before treatment and do not account for any potential changes in its antibiotic response arising from intervening evolution. Thus, an initial test may indicate that the infection is susceptible to a particular drug, but this recommendation may be tentative. In this study, we aimed to understand how treatment effectiveness changes over time by accounting for evolution. First, we evolved 18 methicillin-susceptible S. aureus (MSSA) populations under increasing vancomycin concentrations until they reached intermediate resistance levels. We then sequenced their complete genomes to characterize the mutational paths to their evolved vancomycin-intermediate states. Lastly, we subjected these evolved populations to seven antibiotics used to treat MSSA infections and compared drug susceptibilities between the evolved lines and their common ancestor. Mutations in several genes responsible for regulating the cell membrane stress response and cell-wall biosynthesis appeared in parallel among the evolved vancomycin-intermediate S. aureus (VISA) populations, and these lines were repeatedly cross-resistant to daptomycin. These observations align with previous clinical findings, reinforcing the role of these genes in mediating resistance. In contrast, the populations exhibited diverse responses to other antibiotics. Most lines were susceptible to meropenem, gentamicin, and nafcillin, but several replicates were also resistant. We accounted for this diversity by deriving likelihood estimates that express a population's probability of exhibiting a drug response following vancomycin treatment. Our findings support using antistaphylococcal penicillins (e.g., nafcillin) as a first-line treatment for MSSA, even in light of intermediate vancomycin resistance. They also emphasize the inherent uncertainty and risk that evolution poses to effective therapies, attributes one cannot account for by susceptibility tests alone. Instead, clinicians must consider infections as evolving systems that may take several different paths, with implications on their potential sensitivities to other drugs.


Untargeted metabolomics as an unbiased approach to the diagnosis of inborn errors of metabolism of the non-oxidative branch of the pentose phosphate pathway.
Inborn errors of metabolism (IEM) involving the non-oxidative pentose phosphate pathway (PPP) include the two relatively rare conditions, transketolase deficiency and transaldolase deficiency, both of which can be difficult to diagnosis given their non-specific clinical presentations. Current biochemical testing approaches require an index of suspicion to consider targeted urine polyol testing. To determine whether a broad-spectrum biochemical test could accurately identify a specific metabolic pattern defining IEMs of the non-oxidative PPP, we employed the use of clinical metabolomic profiling as an unbiased novel approach to diagnosis. Subjects with molecularly confirmed IEMs of the PPP were included in this study. Targeted quantitative analysis of polyols in urine and plasma samples was accomplished with chromatography and mass spectrometry. Semi-quantitative unbiased metabolomic analysis of urine and plasma samples was achieved by assessing small molecules via liquid chromatography and high-resolution mass spectrometry. Results from untargeted and targeted analyses were then compared and analyzed for diagnostic acuity. Two siblings with transketolase (TKT) deficiency and three unrelated individuals with transaldolase (TALDO) deficiency were identified for inclusion in the study. For both IEMs, targeted polyol testing and untargeted metabolomic testing on urine and/or plasma samples identified typical perturbations of the respective disorder. Additionally, untargeted metabolomic testing revealed elevations in other PPP metabolites not typically measured with targeted polyol testing, including ribonate, ribose, and erythronate for TKT deficiency and ribonate, erythronate, and sedoheptulose 7-phosphate in TALDO deficiency. Non-PPP alternations were also noted involving tryptophan, purine, and pyrimidine metabolism for both TKT and TALDO deficient patients. Targeted polyol testing and untargeted metabolomic testing methods were both able to identify specific biochemical patterns indicative of TKT and TALDO deficiency in both plasma and urine samples. In addition, untargeted metabolomics was able to identify novel biomarkers, thereby expanding the current knowledge of both conditions and providing further insight into potential underlying pathophysiological mechanisms. Furthermore, untargeted metabolomic testing offers the advantage of having a single effective biochemical screening test for identification of rare IEMs, like TKT and TALDO deficiencies, that may otherwise go undiagnosed due to their generally non-specific clinical presentations.


Oral conditions and quality of life.
Oral conditions can have serious, disabling effects. The purposes of this study are 2-fold: first to estimate the prevalence and severity of self-reported oral problems in male veterans who use Department of Veterans Affairs (VA) outpatient medical (but not dental) care and, second, we examine to what extent the impact of oral conditions is associated with measures of general health and well-being. Male veteran users of outpatient VA medical care from the Veterans Health Study (N = 2425) were surveyed using questionnaires, which included sociodemographic information, the SF-36, the Geriatric Oral Health Assessment Index (GOHAI), and the Oral Health and Quality of Life (OHQOL) measure. Only 28% of these users of VA outpatient care rated their oral health as excellent or very good, 32% as good, and nearly 40% as fair or poor. Furthermore, only one half of respondents could always eat without discomfort, were pleased with the looks of their teeth, and had no worries about their teeth. Factor analysis of the SF-36, GOHAI, and OHQOL items confirmed that both the GOHAI and the OHQOL are separate and independent of the 8 scales of the SF-36. Regression analyses showed that the GOHAI but not the OHQOL is significantly associated with the mental and physical component summary scales of the SF-36 when both sociodemographics and disease burden are controlled for in the models. Oral problems, as measured by the GOHAI and the OHQOL, are significant burdens on the health and function of veterans who use VA outpatient care. Oral health, as measured by the GOHAI, contributes in an important way to the functional well-being of users of VA healthcare.


Mycophenolate Mofetil and Mood Changes in Children with Skin Disorders.
The Risk Evaluation and Mitigation Strategy program that the U.S. Food and Drug Administration has mandated has intensified the counseling associated with prescribing mycophenolate mofetil (MMF), because of its teratogenicity. In this brief report, two children are described who were prescribed MMF and within weeks developed psychiatric symptoms, with rapid resolution after discontinuation of the medication and no recurrence over 4 years of follow-up. Mood disorders are a rare but possible side effect that should be mentioned when discussing MMF with patients and families. Prompt discontinuation of the drug should lead to reversal of symptoms when the drug is implicated.


An embryonic story: analysis of the gene regulative network controlling Xist expression in mouse embryonic stem cells.
In mice, dosage compensation of X-linked gene expression is achieved through the inactivation of one of the two X-chromosomes in XX female cells. The complex epigenetic process leading to X-inactivation is largely controlled by Xist and Tsix, two non-coding genes of opposing function. Xist RNA triggers X-inactivation by coating the inactive X, while Tsix is critical for the designation of the active X-chromosome through cis-repression of Xist RNA accumulation. Recently, a plethora of trans-acting factors and cis-regulating elements have been suggested to act as key regulators of either Xist, Tsix or both; these include ubiquitous factors such as Yy1 and Ctcf, developmental proteins such as Nanog, Oct4 and Sox2, and X-linked regulators such as Rnf12. In this paper we summarise recent advances in our knowledge of the regulation of Xist and Tsix in embryonic stem (ES) and differentiating ES cells.


Estimation of tissue blood perfusion rate from diffusible indicator measurements: a sensitivity analysis.
Recording the washout of indicator (for example, heat, radio-labeled dissolved gas, etc.) transiently introduced into tissue allows the estimation of tissue blood perfusion rate. Analysis of the washout data requires a material balance which appropriately accounts for all transport mechanisms and sources and sinks of the given indicator. From that balance one may perform a sensitivity analysis which specifies the susceptibility of the perfusion estimate to experimental errors in any of the pertinent parameters and variables. The sensitivity analysis is based on the normalized partial derivatives of tissue indicator concentration with respect to the experimental variables. The results indicate that the estimation of the tissue blood perfusion rate is highly sensitive to errors in the concentration of the diffusible indicator which dominate, by two orders of magnitude or more, the errors attributed to other parameters. For typical experimental conditions, the errors in the perfusion estimate due to the various parameters are shown to vary considerably, according to the sensor position and time of measurement. Based on this type of analysis, one may specify optimal temporal and spatial domains for the parameter estimation in order to minimize error propagation. The optimal time domains are shown to differ from those used in typical indicator washout analyses for estimating tissue perfusion rate.


Efficacy of the ADEC in Identifying Autism Spectrum Disorder in Clinically Referred Toddlers in the US.
The Autism Detection in Early Childhood (ADEC) is a brief, play-based screening tool for the assessment of autism spectrum disorder (ASD) in children aged 12-36 months. We examined the psychometric properties of the ADEC in a clinical sample of toddlers (n = 114) referred to a US pediatric hospital for assessment due to concerns of developmental delay or ASD. The ADEC (cutoff = 11) returned good sensitivity (.93-.94) but poorer specificity (.62-.64) for best estimate clinical diagnosis of ASD, and compared favorably with the ADOS-2. Internal consistency was acceptable, α = .80, and inter-rater reliability was high, ICC = .95. Results support the use of the ADEC as a clinical screen for ASD.


Alkaline phosphatase activities in intestinal mucosa from calves infected with Cooperia punctata and Eimeria bovis.
Thirty calves 12 weeks of age raised under essentially parasite-free conditions were used to determine the effects of Cooperia punctata and Eimeria bovis (in single and combination infections) on mucosal alkaline phosphatase activities at 8 locations in the small intestine. In experiment 1, 5 calves infected with C punctata 3 weeks previously had highly significant (P less than 0.01) reductions in mucosal alkaline phosphatase activities compared with those in 5 noninfected control calves. These reductions were greatest in the 2 locations of the intestine closest to the pylorus. Infected calves had a mean of 44,356 C punctata adults present. In experiment 2, 5 calves infected with E bovis 2 weeks previously had significant (P less than 0.05) reductions in mucosal alkaline phosphatase activities compared with those in 5 noninfected control calves. These reductions were present in the caudal half of the intestine. Numerous 1st-generation E bovis schizonts were present in the caudal third of the intestine. In experiment 3, 5 calves infected with C punctata and E bovis of the same durations as in experiments 1 and 2 had highly significant (P less than 0.01) reductions in mucosal alkaline phosphatase activities in the cranial half of the intestine compared with those in the controls. These reductions were much larger than in either of the monospecific infections (experiments 1 and 2). A mean of 31,968 adult C punctata were recovered from the infected calves, and numerous E bovis schizonts were observed in the caudal third of the intestine.