A rapid, convenient, solventless green approach for the synthesis of oximes using grindstone chemistry.
Synthesis of oximes is an important reaction in organic chemistry, because these versatile oximes are used for protection, purification, and characterization of carbonyl compounds. Nitriles, amides via Beckmann rearrangement, nitro compounds, nitrones, amines, and azaheterocycles can be synthesised from oximes. They also find applications for selective α-activation. In inorganic chemistry, oximes act as a versatile ligand.Several procedures for the preparation of oximes exist, but, most of them have not addressed the green chemistry issue. They are associated with generation of pollutants, requirement of high reaction temperature, low yields, lack of a generalized procedure, etc. Hence, there is a demand for developing an efficient, convenient, and non-polluting or less polluting alternative method for the preparation of oximes. In this context, bismuth compounds are very useful as they are cheap in general, commercially available, air stable crystalline solids, safe, and non-toxic, hence easy to handle. Carbonyl compounds (aliphatic, heterocyclic, and aromatic) were converted into the corresponding oximes in excellent yields by simply grinding the reactants at room temperature without using any solvent in the presence of Bi2O3. Most importantly, this method minimizes waste disposal problems, provides a simple yet efficient example of unconventional methodology and requires short time. We have developed a novel, quick, environmentally safe, and clean synthesis of aldoximes and ketoximes under solvent-free grinding condition.


Functioning, problem behavior and health services use among nursing home residents with alcohol-use disorders: nationwide data from the VA minimum data set.
We examined (1) whether nursing home residents with alcohol-use disorders (AUDs) function more poorly, have more behavioral problems and use more health services than do demographically matched controls without such disorders, and (2) whether AUDs interact with alcohol consumption to predict poorer behavioral and health services outcomes among nursing home residents. We used Department of Veterans Affairs (VA) Patient Treatment File data to identify a nationwide sample of older VA nursing home residents with recent AUD diagnoses (n = 3,336) and a demographically matched sample without such diagnoses (n = 3,336). The groups were compared on the Resident Assessment Instrument Minimum Data Set indices of health-related functioning, substance use, problem behavior and health services use. We conducted two-way analyses of variance to determine interactions between presence of an AUD and alcohol consumption on problem behavior and health services use. Residents with AUD diagnoses functioned somewhat better than demographically matched controls. However, they were more likely to have falls and fractures, difficulties in social functioning and to use more health services. AUD diagnoses interacted with alcohol consumption to predict an elevated risk of falls and fractures and more mental health services use. Older residents with an AUD form a distinct nursing home population that functions somewhat better than residents without such disorders but they may pose more challenges to staff and use more health care services. Residents' drinking histories should be considered in formulating nursing home policies about alcohol consumption.


Identification and characterization of the defensin-like gene family of grapevine.
Defensins are a class of small and diverse cysteine-rich proteins found in plants, insects, and vertebrates, which share a common tertiary structure and usually exert broad-spectrum antimicrobial activities. We used a bioinformatic approach to scan the Vitis vinifera genome and identified 79 defensin-like sequences (DEFL) corresponding to 46 genes and allelic variants, plus 33 pseudogenes and gene fragments. Expansion and diversification of grapevine DEFL has occurred after the split from the last common ancestor with the genera Medicago and Arabidopsis. Grapevine DEFL localization on the 'Pinot Noir' genome revealed the presence of several clusters likely evolved through local duplications. By sequencing reverse-transcription polymerase chain reaction products, we could demonstrate the expression of grapevine DEFL with no previously reported record of expression. Many of these genes are predominantly or exclusively expressed in tissues linked to plant reproduction, consistent with findings in other plant species, and some of them accumulated at fruit ripening. The transcripts of five DEFL were also significantly upregulated in tissues infected with Botrytis cinerea, a necrotrophic mold, suggesting a role of these genes in defense against this pathogen. Finally, three novel defensins were discovered among the identified DEFL. They inhibit B. cinerea conidia germination when expressed as recombinant proteins.


Hospital admissions associated with medication non-adherence: a systematic review of prospective observational studies.
Medication non-adherence in ambulatory care has received substantial attention in the literature, but less so as it affects acute care. Accordingly, we aimed to estimate the frequency with which non-adherence to medication contributes to hospital admissions. We searched the Cochrane Library, EMBASE, Cumulative Index to Nursing and Allied Health Literature, International Pharmaceutical Abstracts and PubMed (until December 2017) to identify prospective observational studies that examined prevalence rates of hospital admissions associated with medication non-adherence. A quality assessment was performed using an expanded Crombie checklist. Data extraction covered patterns, circumstances, and patient and other key characteristics of non-adherence. Pooled estimates were obtained using a random-effect model. Of 24 included studies, 8 were undertaken in North America, 7 from Europe, 6 from Asia and 3 from Australia. Most studies (79%) were rated as low risk of bias. All but three studies used combination measures to detect non-adherence, but approaches to assess preventability varied considerably. Across the studies, there was high heterogeneity among prevalence estimates (χ2=548, df 23, p<0.001, I2=95.8%). The median prevalence rate of hospital admissions associated with non-adherence was 4.29% (IQR 3.22%-7.49%), with prevalence rates ranging from 0.72% to 10.79%. By definition, almost all of these admissions were considered preventable. The underlying causes contributing to these admissions included medication cost and side effects, and non-adherence most often involved cardiovascular medicines. Hospital admissions associated with non-adherence to medication are a common problem. This systematic review highlights important targets for intervention. Greater attention could be focused on adherence to medication during the hospital stay as part of an enhanced medication reconciliation process. Standardisation in study methods and definitions is needed to allow future comparisons among settings; future studies should also encompass emerging economies.


Association of HIV status with infection by multiple HPV types.
To identify the clinical and demographic characteristics of HIV-positive and HIV-negative women infected by multiple HPV types. 1399 women participated in the study (240 HIV-positive and 1159 HIV-negative women). Samples were provided for Pap tests and for HPV detection and typing by PCR. Data were collected on HPV infection, frequency of multiple infection, and HPV type distribution. Odds ratios were reported from logistic regression models. Compared with HIV-negative women, HIV-positive women had higher frequencies of cervical abnormality (30% vs. 20.8%), higher HPV prevalence (68.3% vs. 51.3%) and were more commonly infected with multiple HPV types (78.7% vs. 44.3%). HPV-16 was the most common type detected in the study population, with other types showing variable associations with HIV status. Positive associations were observed between infection by multiple HPV types and HIV status, cervical abnormality and having had more than three pregnancies. The odds of multiple infection by HPV types were higher in HIV-positive women who used an intrauterine device, who had a history of abortions and who had HIV viral loads >100 000 copies/ml, whilst the odds were lower in women with >500 CD4 cells/mm3 . HIV immunosuppression favours infection by multiple high-risk HPV types, mainly in women affected by low-grade squamous intraepithelial lesions. Antiretroviral therapy had no effect on infection by multiple HPV types. Risk factors related to progressive damage to the cervix were positively associated with infection by multiple HPV types in women living with HIV.


Apical Negative Pressure irrigation presents tissue compatibility in immature teeth.
To compare the apical negative pressure irrigation (ANP) with conventional irrigation in the teeth of immature dogs with apical periodontitis. Fifty-two immature pre-molar root canals were randomly assigned into 4 groups: ANP (n=15); conventional irrigation (n=17); healthy teeth (control) (n = 10); and teeth with untreated apical periodontitis (control) (n=10). After induction of apical periodontitis, teeth were instrumented using EndoVac® (apical negative pressure irrigation) or conventional irrigation. The animals were euthanized after 90 days. The sections were stained by HE and analyzed under conventional and fluorescence microscopy. TRAP histoenzymology was also performed. Statistical analyses were performed with the significance level set at 5%. There was difference in the histopathological parameters between ANP and conventional groups (p<0.05). The ANP group showed a predominance of low magnitude inflammatory infiltrate, a smaller periodontal ligament, and lower mineralized tissue resorption. There were no differences in the periapical lesion extensions between the ANP and conventional groups (p>0.05). However, a lower number of osteoclasts was observed in the ANP group (p<0.05). The EndoVac® irrigation system presented better biological results and more advanced repair process in immature teeth with apical periodontitis than the conventional irrigation system, confirming the hypothesis.


Antiproliferative effects of local anesthetics on mesenchymal stem cells: potential implications for tumor spreading and wound healing.
Mesenchymal stem cells (MSC) are self-renewing clonal progenitor cells of nonhematopoietic tissues that exhibit a marked tropism to wounds and tumors. The authors' studies aimed at exploring how local anesthetics would affect MSC biology. Proliferation, colony formation, in vitro wound healing, and bone differentiation assays of culture-expanded bone-marrow-derived murine MSC were performed in the presence of increasing concentrations of lidocaine, ropivacaine, and bupivacaine. Cytotoxicity was monitored by measuring lactate dehydrogenase activity and phosphatidylserine exposure/propidium iodide staining (early apoptotic cells/necrotic cells). Measurements of mitochondrial function in intact and permeabilized cells, transcriptional changes, and changes in nuclear factor κ-light-chain-enhancer of activated B cells signaling in MSC treated with ropivacaine were used to further characterize the biologic effects of local anesthetics on MSC. All local anesthetics reduced MSC proliferation at 100 μM, consistent with cell cycle delay or arrest at the G0/1-S phase transition. They increased lactate dehydrogenase release and the number of annexin V-positive MSC but not necrotic MSC. Colony formation was decreased, differentiation into osteoblasts impaired, and in vitro wound healing delayed. Mitochondrial respiration and adenosine 5'-triphosphate concentrations were reduced. Microarray analysis revealed significant expression changes in lysosomal genes and genes controlling sterol metabolism, indicating an impaired phospholipid metabolism in the lysosome. Multiple transcriptional programs related to cell differentiation, tumorigenesis, and metastasis were negatively affected by ropivacaine. The authors' studies demonstrate that local anesthetics significantly affect important aspects of MSC biology. These experiments provide novel rationales for the perioperative use of local anesthetics in patients with cancer but also highlight the potentially detrimental effects of local anesthetics on wound healing.


Decline in gastroenteritis-related triage calls after rotavirus vaccine licensure.
We sought to determine the impact of rotavirus vaccine implementation on gastroenteritis (GE)-related calls to a large telephone triage service in Tennessee. Total and GE-related calls received by the Vanderbilt Telephone Triage Program for children <5 years of age were examined from May 1, 2004 to April 30, 2010. Time series adapted Poisson regression models were used to compare weekly GE-related call proportions between the prevaccine (May 2004 to April 2007) and postlicensure (May 2007 to April 2010) periods. Separate models compared GE-related call proportions in the historical rotavirus (February to April) and nonrotavirus (May to January) seasons. Associations between call data and laboratory-confirmed rotavirus detections and regionally reported norovirus activity were also assessed. There were 156362 total calls and 19731 GE-related calls. Annual GE-related call proportions declined by 8% (95% confidence interval, 3%-12%) in the postlicensure period; declines ranging from 23% to 31% occurred during the historical rotavirus season in all 3 postlicensure years. No declines occurred in the nonrotavirus season. After vaccine licensure, reductions in laboratory-confirmed rotavirus activity were associated with declines in GE-related call proportions. Peak GE-related call proportions in the postlicensure period occurred earlier than in prevaccine years and were not strongly associated with laboratory-confirmed rotavirus but instead showed good correlation with norovirus outbreaks. A decline in GE-related call proportions among young children after rotavirus vaccine licensure was documented by using a novel surveillance platform that captures mild GE not detected in other surveillance systems. Since rotavirus vaccine licensure, peak call proportions correlate with regional norovirus activity, highlighting the role of that pathogen in community GE.


Self-Administered Lidocaine Gel for Intrauterine Device Insertion in Nulliparous Women: A Randomized Controlled Trial.
To evaluate self-administration of vaginal lidocaine gel to decrease pain with intrauterine device (IUD) insertion in nulliparous women. In this randomized, double-blind, placebo-controlled trial, women self-administered 2% lidocaine or placebo vaginal gel 5 minutes before IUD insertion. The primary outcome was change in pain from baseline to IUD insertion on a 100-mm visual analog scale. We also assessed pain after speculum insertion, tenaculum placement, uterine sounding, and 5 minutes after IUD insertion. Secondary outcomes included patient acceptability, ease of IUD insertion, and need for pain medication for up to 7 days. From July 2012 to May 2013, 59 women were randomized; 30 received lidocaine gel and 29 placebo. Baseline demographics, including age, race, and body mass index, were similar. There was no difference in median change in pain during IUD insertion in women receiving lidocaine (61 mm [interquartile range 53-71]) compared with placebo (69 mm [interquartile range 63-80], P=.06). Women receiving lidocaine experienced less pain with tenaculum placement (32 mm [interquartile range 18-54]) compared with placebo (56 mm [interquartile range 26-75], P=.02). Most (76%) women were satisfied with their IUD insertion experience and 86% would probably or definitely recommend an IUD to a friend. Thirty-four percent of women required pain medication for at least 3 days after IUD insertion. For nulliparous women, self-administered vaginal lidocaine gel does not reduce pain with IUD insertion, but does decrease pain with tenaculum placement. ClinicalTrials.gov, http://clinicaltrials.gov, NCT01534520.


Induction of serine hydroxymethyltransferase 2 promotes tumorigenesis and metastasis in neuroblastoma.
High-risk neuroblastoma (NB) remains an extremely difficult subgroup to cure and is associated with MYCN amplification. Serine hydroxymethyltransferase 2 (SHMT2) regulates serine metabolism in a myc-dependent manner; it is upregulated in several cancers and is associated with tumor aggressiveness. Akt-2, an important regulator of MYCN via the PI3K/Akt pathway, induces metastatic potential in NB. The association between SHMT2 and PI3K/Akt in hepatocyte regeneration has been well established but its mechanistic interaction in cancer has yet to be clearly elucidated. Herein, we evaluated the exact role of SHMT2 on the PI3K/Akt pathway, in addition to NB tumorigenesis and metastatic potential in vitro. SHMT2 gene expression and overall survival (OS) were assessed. Two human NB cell lines were examined. SHMT2 silencing and overexpression were performed. The downstream effects were analyzed with immunoblotting, RT-qPCR and functional assays were performed. We found SHMT2 gene expression is associated with decreased OS and MYCN amplification. SHMT2 protein and mRNA expression are increased in MYCN-amplified cells. SHMT2 expression has a direct interaction with Akt-2 and MYCN. Induction of SHMT2 increased cellular proliferation, colony formation and cellular migration and SHMT2 expression was increased in metastatic NB cells. We conclude that SHMT2 regulates N-Myc via phosphorylation of Akt-2 and plays an important role in NB tumorigenesis by contributing to cell growth, migration, colony formation and metastasis in vitro.


The impact of birth weight on blood pressure and arterial stiffness in later life: the Enigma Study.
Accumulating evidence suggests that low birth weight is associated with increased cardiovascular risk. However, the relationship between birth weight, blood pressure, arterial stiffness and wave reflections as putative mechanisms is controversial. Data from 882 participants (mean age 21 years) were analysed. Participants underwent a detailed physiological assessment, including anthropometric measurement, blood pressure, aortic pulse wave velocity, augmentation index (AIx) and cardiac output (CO). Analyses were conducted in men and women separately, according to birth weight quartiles and categories referenced to UK birth weight percentiles. In men, those in the lowest birth weight quartile had higher brachial SBP (P = 0.04), central pulse pressure (PP; P = 0.03) and AIx (P = 0.02). Further analysis of the low birth weight spectrum revealed that central PP (P = 0.03), AIx (P = 0.03) and peripheral vascular resistance index (P = 0.01) were higher in those in the lowest birth weight percentile, although the association with AIx disappeared after adjustment for adult height. In women, analysis by birth weight quartiles and categories referenced to UK birth weight percentiles revealed a significant positive association between birth weight and CO (P = 0.04, P = 0.02) and stroke volume (P = 0.03, P = 0.002); although these associations disappeared when body size was taken into account. There was no association between birth weight and aortic pulse wave velocity in either men or women. These data suggest that although lower birth weight is associated with altered haemodynamics in young adulthood, the associations are predominantly driven by other factors such as adult body size, rather than intrinsic structural changes within the large elastic arteries.


A Possible Link Between Pyriproxyfen and Microcephaly.
The Zika virus has been the primary suspect in the large increase in incidence of microcephaly in 2015-6 in Brazil. While evidence for Zika being the cause of some of the cases is strong, its role as the primary cause of the large number of cases in Brazil has not been confirmed. Recently, the disparity between the incidences in different geographic locations has led to questions about the virus's role. Here we consider the alternative possibility that the use of the insecticide pyriproxyfen for control of mosquito populations in Brazilian drinking water is the primary cause. Pyriproxifen is a juvenile hormone analog which has been shown to correspond in mammals to a number of fat soluble regulatory molecules including retinoic acid, a metabolite of vitamin A, with which it has cross-reactivity and whose application during development has been shown to cause microcephaly. Methoprene, another juvenile hormone analog that was approved as an insecticide based upon tests performed in the 1970s, has metabolites that bind to the mammalian retinoid X receptor, and has been shown to cause developmental disorders in mammals. Isotretinoin is another example of a retinoid causing microcephaly in human babies via maternal exposure and activation of the retinoid X receptor in developing fetuses. Moreover, tests of pyriproxyfen by the manufacturer, Sumitomo, widely quoted as giving no evidence for developmental toxicity, actually found some evidence for such an effect, including low brain mass and arhinencephaly-incomplete formation of the anterior cerebral hemispheres-in exposed rat pups. Finally, the pyriproxyfen use in Brazil is unprecedented-it has never before been applied to a water supply on such a scale. Claims that it is not being used in Recife, the epicenter of microcephaly cases, do not distinguish the metropolitan area of Recife, where it is widely used, and the municipality, and have not been adequately confirmed. Given this combination of information about molecular mechanisms and toxicological evidence, we strongly recommend that the use of pyriproxyfen in Brazil be suspended until the potential causal link to microcephaly is investigated further.


Percutaneous endoscopic gastrostomy for nutritional palliation of upper esophageal cancer unsuitable for esophageal stenting.
Esophageal cancer is often diagnosed at an advanced stage and has a poor prognosis. Most patients with advanced esophageal cancer have significant dysphagia that contributes to weight loss and malnutrition. Esophageal stenting is a widespread palliation approach, but unsuitable for cancers near the upper esophageal sphincter, were stents are poorly tolerated. Generally, guidelines do not support endoscopic gastrostomy in this clinical setting, but it may be the best option for nutritional support. Retrospective evaluation of patients with dysphagia caused advanced esophageal cancer, no expectation of resuming oral intake and with percutaneous endoscopic gastrostomy for comfort palliative nutrition. We selected adult patients with unresecable esophageal cancer histological confirmed, in whom stenting was impossible due to proximal location, and chemotherapy or radiotherapy were palliative, using gastrostomy for enteral nutrition. Clinical and nutritional data were evaluated, including success of gastrostomy, procedure complications and survival after percutaneous endoscopic gastrostomy, and evolution of body mass index, albumin, transferrin and cholesterol. Seventeen males with stage III or IV squamous cell carcinoma fulfilled the inclusion criteria. Mean age was 60.9 years. Most of the patients had toxic habits. All underwent palliative chemotherapy or radiotherapy. Gastrostomy was successfully performed in all, but nine required prior dilatation. Most had the gastrostomy within 2 months after diagnosis. There was a buried bumper syndrome treated with tube replacement and four minor complications. There were no cases of implantation metastases or procedure related mortality. Two patients were lost and 12 died. Mean survival of deceased patients was 5.9 months. Three patients are alive 6, 14 and 17 months after the gastrostomy procedure, still increasing the mean survival. Mean body mass index and laboratory parameters were roughly stable 1 and 3 months after the gastrostomy procedure. In patients with advanced upper esophageal cancer where only palliative treatment is possible, nutritional support is easily achieved with percutaneous endoscopic gastrostomy, allowing patients to be at homes, surviving a significant period of time. Percutaneous endoscopic gastrostomy feeding should be considered as standard definitive nutritional palliation in patients with upper esophageal cancer, unsuitable for esophageal stenting.


Hundreds of conserved non-coding genomic regions are independently lost in mammals.
Conserved non-protein-coding DNA elements (CNEs) often encode cis-regulatory elements and are rarely lost during evolution. However, CNE losses that do occur can be associated with phenotypic changes, exemplified by pelvic spine loss in sticklebacks. Using a computational strategy to detect complete loss of CNEs in mammalian genomes while strictly controlling for artifacts, we find >600 CNEs that are independently lost in at least two mammalian lineages, including a spinal cord enhancer near GDF11. We observed several genomic regions where multiple independent CNE loss events happened; the most extreme is the DIAPH2 locus. We show that CNE losses often involve deletions and that CNE loss frequencies are non-uniform. Similar to less pleiotropic enhancers, we find that independently lost CNEs are shorter, slightly less constrained and evolutionarily younger than CNEs without detected losses. This suggests that independently lost CNEs are less pleiotropic and that pleiotropic constraints contribute to non-uniform CNE loss frequencies. We also detected 35 CNEs that are independently lost in the human lineage and in other mammals. Our study uncovers an interesting aspect of the evolution of functional DNA in mammalian genomes. Experiments are necessary to test if these independently lost CNEs are associated with parallel phenotype changes in mammals.


A comparison of the properties of Sox-3 with Sry and two related genes, Sox-1 and Sox-2.
The Sox gene family consists of a large number of embryonically expressed genes related via the possession of a 79-amino-acid DNA-binding domain known as the HMG box. Partial clones for the first three Sox genes (al-a3) were isolated by homology to the HMG box of the testis-determining gene Sry and are now termed Sox-1, Sox-2 and Sox-3, Sox-3 is highly conserved amongst mammalian species and is located on the X chromosome. This has led to the proposal that Sry evolved from Sox-3. We present the cloning and sequencing of Sox-1, Sox-2 and Sox-3 from the mouse and show that Sox-3 is most closely relate to Sry. We also confirm that mouse Sox-3 is located on the X chromosome between Hprt and Dmd. Analysis of the distribution of Sox-3 RNA shows that its main site of expression is in the developing central nervous system, suggesting a role for Sox-3 in neural development. Moreover, we demonstrate that Sox-3, as well as Sox-1 and Sox-2, are expressed in the urogenital ridge and that their protein products are able to bind the same DNA sequence motif as Sry in vitro, but with different affinities. These observations prompt discussion of an evolutionary link between the genes and support the model that Sry has evolved from Sox-3. However our findings imply that if this is true, then Sry has undergone concomitant changes resulting in loss of CNS expression and altered DNA-binding properties.


A Phenome-Wide Association Study of genes associated with COVID-19 severity reveals shared genetics with complex diseases in the Million Veteran Program.
The study aims to determine the shared genetic architecture between COVID-19 severity with existing medical conditions using electronic health record (EHR) data. We conducted a Phenome-Wide Association Study (PheWAS) of genetic variants associated with critical illness (n = 35) or hospitalization (n = 42) due to severe COVID-19 using genome-wide association summary data from the Host Genetics Initiative. PheWAS analysis was performed using genotype-phenotype data from the Veterans Affairs Million Veteran Program (MVP). Phenotypes were defined by International Classification of Diseases (ICD) codes mapped to clinically relevant groups using published PheWAS methods. Among 658,582 Veterans, variants associated with severe COVID-19 were tested for association across 1,559 phenotypes. Variants at the ABO locus (rs495828, rs505922) associated with the largest number of phenotypes (nrs495828 = 53 and nrs505922 = 59); strongest association with venous embolism, odds ratio (ORrs495828 1.33 (p = 1.32 x 10-199), and thrombosis ORrs505922 1.33, p = 2.2 x10-265. Among 67 respiratory conditions tested, 11 had significant associations including MUC5B locus (rs35705950) with increased risk of idiopathic fibrosing alveolitis OR 2.83, p = 4.12 × 10-191; CRHR1 (rs61667602) associated with reduced risk of pulmonary fibrosis, OR 0.84, p = 2.26× 10-12. The TYK2 locus (rs11085727) associated with reduced risk for autoimmune conditions, e.g., psoriasis OR 0.88, p = 6.48 x10-23, lupus OR 0.84, p = 3.97 x 10-06. PheWAS stratified by ancestry demonstrated differences in genotype-phenotype associations. LMNA (rs581342) associated with neutropenia OR 1.29 p = 4.1 x 10-13 among Veterans of African and Hispanic ancestry but not European. Overall, we observed a shared genetic architecture between COVID-19 severity and conditions related to underlying risk factors for severe and poor COVID-19 outcomes. Differing associations between genotype-phenotype across ancestries may inform heterogenous outcomes observed with COVID-19. Divergent associations between risk for severe COVID-19 with autoimmune inflammatory conditions both respiratory and non-respiratory highlights the shared pathways and fine balance of immune host response and autoimmunity and caution required when considering treatment targets.


Hemopoietic progenitor cells and bone marrow stromal cells in patients with autoimmune hepatitis type 1 and primary biliary cirrhosis.
Autologous hematopoietic stem cell transplantation has been used in severe cases of autoimmunity. We investigated whether hemopoietic progenitor cells and/or bone marrow (BM) microenvironment are affected in autoimmune hepatitis type-1 (AIH-1) and primary biliary cirrhosis (PBC). We studied 13 AIH-1 patients, 13 PBC patients, 12 cirrhotic controls (CC) and ten healthy controls (HC). Flow cytometry, expansion cultures, long-term BM cultures and clonogenic progenitor cell assays were used. Stromal cell function was assessed in long-term BM cultures recharged with normal CD34+ cells. AIH-1 had increased CD34+, CD34+/CD38+ and CD34+/CD38- cells compared to all groups (P<0.001). PBC had lower progenitor cells compared to controls (P<0.005). No differences were found between CC and HC. Committed progenitor cells in non-adherent cell fraction were increased in AIH-1 (P<0.05) but decreased in PBC compared to controls (P<0.05). Granulocyte-macrophage colony forming units (CFU) and erythroid-burst CFU were increased in AIH-1 compared to all groups (P<0.001). PBC had these CFUs decreased compared to controls (P<0.005). Stromal cells failed to support normal hemopoiesis in PBC. We demonstrated for the first time that AIH-1 had increased hemopoietic progenitor cells and normal stromal function. In PBC, progenitor cells and BM microenvironment were defective. Further studies will determine the significance of these novel findings.


v-src induction of the TIS10/PGS2 prostaglandin synthase gene is mediated by an ATF/CRE transcription response element.
We recently reported the cloning of a mitogen-inducible prostaglandin synthase gene, TIS10/PGS2. In addition to growth factors and tumor promoters, the v-src oncogene induces TIS10/PGS2 expression in 3T3 cells. Deletion analysis, using luciferase reporters, identifies a region between -80 and -40 nucleotides 5' of the TIS10/PGS2 transcription start site that mediates pp60v-src induction in 3T3 cells. This region contains the sequence CGTCACGTG, which includes overlapping ATF/CRE (CGTCA) and E-box (CACGTG) sequences. Gel shift-oligonucleotide competition experiments with nuclear extracts from cells stably transfected with a temperature-sensitive v-src gene demonstrate that the CGTCACGTG sequence can bind proteins at both the ATF/CRE and E-box sequences. Dominant-negative CREB and Myc proteins that bind DNA, but do not transactivate, block v-src induction of a luciferase reporter driven by the first 80 nucleotides of the TIS10/PGS2 promoter. Mutational analysis distinguishes which TIS10/PGS2 cis-acting element mediates pp60v-src induction. E-box mutation has no effect on the fold induction in response to pp60v-src. In contrast, ATF/CRE mutation attenuates the pp60v-src response. Antibody supershift and methylation interference experiments demonstrate that CREB and at least one other ATF transcription factor in these extracts bind to the TIS10/PGS2 ATF/CRE element. Expression of a dominant-negative ras gene also blocks TIS10/PGS2 induction by v-src. Our data suggest that Ras mediates pp60v-src activation of an ATF transcription factor, leading to induced TIS10/PGS2 expression via the ATF/CRE element of the TIS10/PGS2 promoter. This is the first description of v-src activation of gene expression via an ATF/CRE element.


Genome sequence of Babesia bovis and comparative analysis of apicomplexan hemoprotozoa.
Babesia bovis is an apicomplexan tick-transmitted pathogen of cattle imposing a global risk and severe constraints to livestock health and economic development. The complete genome sequence was undertaken to facilitate vaccine antigen discovery, and to allow for comparative analysis with the related apicomplexan hemoprotozoa Theileria parva and Plasmodium falciparum. At 8.2 Mbp, the B. bovis genome is similar in size to that of Theileria spp. Structural features of the B. bovis and T. parva genomes are remarkably similar, and extensive synteny is present despite several chromosomal rearrangements. In contrast, B. bovis and P. falciparum, which have similar clinical and pathological features, have major differences in genome size, chromosome number, and gene complement. Chromosomal synteny with P. falciparum is limited to microregions. The B. bovis genome sequence has allowed wide scale analyses of the polymorphic variant erythrocyte surface antigen protein (ves1 gene) family that, similar to the P. falciparum var genes, is postulated to play a role in cytoadhesion, sequestration, and immune evasion. The approximately 150 ves1 genes are found in clusters that are distributed throughout each chromosome, with an increased concentration adjacent to a physical gap on chromosome 1 that contains multiple ves1-like sequences. ves1 clusters are frequently linked to a novel family of variant genes termed smorfs that may themselves contribute to immune evasion, may play a role in variant erythrocyte surface antigen protein biology, or both. Initial expression analysis of ves1 and smorf genes indicates coincident transcription of multiple variants. B. bovis displays a limited metabolic potential, with numerous missing pathways, including two pathways previously described for the P. falciparum apicoplast. This reduced metabolic potential is reflected in the B. bovis apicoplast, which appears to have fewer nuclear genes targeted to it than other apicoplast containing organisms. Finally, comparative analyses have identified several novel vaccine candidates including a positional homolog of p67 and SPAG-1, Theileria sporozoite antigens targeted for vaccine development. The genome sequence provides a greater understanding of B. bovis metabolism and potential avenues for drug therapies and vaccine development.


Ablation of neuropsin-neuregulin 1 signaling imbalances ErbB4 inhibitory networks and disrupts hippocampal gamma oscillation.
Parvalbumin-expressing interneurons are pivotal for the processing of information in healthy brain, whereas the coordination of these functions is seriously disrupted in diseased brain. How these interneurons in the hippocampus participate in pathological functions remains unclear. We previously reported that neuregulin 1 (NRG1)-ErbB4 signaling, which is actuated by neuropsin, is important for coordinating brain plasticity. Neuropsin cleaves mature NRG1 (bound to extracellular glycosaminoglycans) in response to long-term potentiation or depression, liberating a soluble ligand that activates its receptor, ErbB4. Here, we show in mice that kainate-induced status epilepticus transiently elevates the proteolytic activity of neuropsin and stimulates cFos expression with a time course suggesting that activation of ErbB4- and parvalbumin-expressing interneurons follows the excitation and subsequent silencing of pyramidal neurons. In neuropsin-deficient mice, kainate administration impaired signaling and disrupted the neuronal excitation-inhibition balance (E/I balance) in hippocampal networks, by decreasing the activity of parvalbumin-positive interneurons while increasing that of pyramidal neurons, resulting in the progression of status epilepticus. Slow, but not fast, gamma oscillations in neuropsin-deficient mice showed reduced power. Intracerebroventricular infusion of the soluble NRG1 ligand moiety restored the E/I balance, status epilepticus and gamma oscillations to normal levels. These results suggest that the neuropsin-NRG1 signaling system has a role in pathological processes underlying temporal lobe epilepsy by regulating the activity of parvalbumin-expressing interneurons, and that neuropsin regulates E/I balance and gamma oscillations through NRG1-ErbB4 signaling toward parvalbumin-expressing interneurons. This neuronal system may be a useful target of pharmacological therapies against cognitive disorders.


Training recurrent networks by Evolino.
In recent years, gradient-based LSTM recurrent neural networks (RNNs) solved many previously RNN-unlearnable tasks. Sometimes, however, gradient information is of little use for training RNNs, due to numerous local minima. For such cases, we present a novel method: EVOlution of systems with LINear Outputs (Evolino). Evolino evolves weights to the nonlinear, hidden nodes of RNNs while computing optimal linear mappings from hidden state to output, using methods such as pseudo-inverse-based linear regression. If we instead use quadratic programming to maximize the margin, we obtain the first evolutionary recurrent support vector machines. We show that Evolino-based LSTM can solve tasks that Echo State nets (Jaeger, 2004a) cannot and achieves higher accuracy in certain continuous function generation tasks than conventional gradient descent RNNs, including gradient-based LSTM.


Imaging findings in a distinct lethal inherited arteriopathy syndrome associated with a novel mutation in the FBLN4 gene.
We present the imaging findings of a newly identified lethal arteriopathy associated with a novel mutation in the gene encoding fibulin-4, occurring in a distinct community from southern India. A total of 31 children from a distinct population subgroup who presented with characteristic arterial dilatation and tortuosity were studied. All children except one belonged to unrelated families from an ethno-religious group (Muslim) from the northern coastal belt of southern India. CT angiography was performed in 30 children and contrast MRA in one. Impressive dilatation and elongation of ascending aorta, arch, descending aorta and main pulmonary arteries with characteristic narrowing of aortic isthmus were seen in all patients. Stenosis of arch branches, abdominal visceral branches and pulmonary artery branches was observed in 21 (68%), 23 (62.5%) and 20 (65%) patients respectively. Genetic studies revealed an identical mutation in exon 7 of the FBLN4 gene. On follow-up, 27 of them had died before the age of 3 years and only two children were alive after the age of 4 years. FBLN4-associated vasculopathy is a highly lethal disease characterized by severe aneurysmal dilatation of thoracic aorta, its branches and pulmonary arteries with stenoses at typical locations. • Homozygous mutations in exon 7 of the FBLN4 gene can produce lethal vasculopathy. • Fibulin-4 is a critical determinant in human elastogenesis. • Imaging findings can give a clue to underlying connective tissue disorders.


Structural Integrity of Steel Pipeline with Clusters of Corrosion Defects.
The main goal of this paper is to evaluate the burst pressure and structural integrity of a steel pipeline based on in-line inspection results, in respect to the grouping criteria of closely spaced volumetric surface features. In the study, special attention is paid to evaluation of data provided from the diagnostics using an axial excitation magnetic flux leakage technology in respect to multiple defects grouping. Standardized clustering rules were applied to the corrosion pits taken from an in-line inspection of the gas transmission pipeline. Basic rules of interaction of pipe wall metal losses are expressed in terms of longitudinal and circumferential spacing of the features in the colony. The effect of interactions of the detected anomalies on the tube residual strength evaluated according to the Det Norske Veritas Recommended practice was investigated in the current study. In the presented case, groups of closely-spaced defects behaved similarly as individual flaws with regard to their influence on burst pressure and pipeline failure probability.


Are Melamine and Its Derivatives the Alternatives for Per- and Polyfluoroalkyl Substance (PFAS) Fabric Treatments in Infant Clothes?
Per- and polyfluoroalkyl substances (PFAS) and melamine (MEL)-based compounds are used in textile finishing as grease, stain, and water repellents. Here, we investigated the occurrence of a large suite of PFAS and MEL compounds in 86 infant clothing items. The ∑MEL concentrations ranged from below the method detection limit to 250,000 ng/g with a median concentration of 78.2 ng/g, significantly higher (p < 0.05) than the ∑PFAS levels (1.22-203 ng/g; median 3.62 ng/g). MEL and its derivatives were most abundant in nylon clothes (median 32,800 ng/g), followed by organic cotton (median 6120 ng/g). In a simulated laundering experiment, the ∑MEL concentrations in clothing decreased on an average by ∼60 and 90% when washed in cool (20 °C) and warm (50 °C) water, respectively. This removal rate increased to 97% when the samples were washed with a detergent. The estimated daily intakes of MEL and PFAS through dermal absorption from nylon clothes were three orders of magnitude higher than those from the non-nylon clothes and decreased by more than half for washed clothes. Our findings demonstrate that MEL-based compounds are abundant in infant clothing and suggest that this group of compounds could be used as potential PFAS replacements in textile finishing.


One-Year Outcome After Percutaneous Coronary Intervention for Acute Coronary Syndrome - An Analysis of 20,042 Patients From a Japanese Nationwide Registry.
Acute coronary syndrome (ACS) hospital survivors experience a wide array of late adverse cardiac events, despite considerable advances in the quality of care. We investigated 30-day and 1-year outcomes of ACS hospital survivors using a Japanese nationwide cohort.Methods and Results:We studied 20,042 ACS patients who underwent percutaneous coronary intervention (PCI) in 2017: 10,242 (51%) with ST-elevation myocardial infarction (STEMI), 3,027 (15%) with non-ST-elevation myocardial infarction (NSTEMI), and 6,773 (34%) with unstable angina (UA). The mean (±SD) age was 69.6±12.4 years, 77% of the patients were men, and 20% had a previous history of PCI. The overall 30-day all-cause, cardiac, and non-cardiac mortality rates were 3.0%, 2.4%, and 0.6%, respectively. The overall 1-year incidence of all-cause, cardiac, and non-cardiac death was 7.1%, 4.2%, and 2.8%, respectively. Compared with UA patients, STEMI patients had a higher risk of all fatal events, non-fatal ischemic stroke, and acute heart failure, and NSTEMI patients had a higher risk of heart failure. The results from our ACS hospital survivor PCI database suggest the need to improve care for the acute myocardial infarction population to lessen the burden of 30-day mortality due to ACS, heart failure, and sudden cardiac death, as well as 1-year ischemic stroke and heart failure events.


Otolaryngology Providers Must Be Alert for Patients with Mild and Asymptomatic COVID-19.
More than half of COVID-19 patients are afebrile early in the disease course, yet mildly ill or asymptomatic patients can still spread SARS-CoV-2 with high efficiency. Atypically presenting patients may be seen in noninfectious disease settings such as otolaryngology, which is a specialty prone to occupational exposure. Otolaryngologists have been infected with COVID-19 at higher rates than other specialties in China and other countries. Otolaryngology providers should maintain high clinical suspicion for mild and asymptomatic COVID-19 patients. Protective strategies should be implemented including preappointment screening, triaging, restriction of nonurgent visits and surgeries, telemedicine, and appropriate personal protective equipment use.


Von Hippel Lindau disease with metastatic pancreatic neuroendocrine tumor causing ectopic Cushing's syndrome.
We present a 39-year-old woman who was previously diagnosed with Von Hippel Lindau Disease (VHLD). She had surgery and radiotherapy for cranial hemangioblastoma (HA) 11 years ago and had unilateral adrenalectomy for pheochromocytoma in another hospital 6 month prior to her admission to our center. Moon face, buffalo hump, central obesity, progressive weight gain and menstrual irregularities persisted after adrenalectomy. Her laboratory results were consistent with ectopic Cushing's syndrome (ECS). A pancreatic solid mass with a nodule on the left lung were revealed upon computed tomography. In addition, Gallium-68 Somatostatin Receptor PET confirmed the pancreatic involvement and demonstrated additional lesions on the left lung and in the aortocaval lymphatic system on the right side, suggesting metastatic pancreatic neuroendocrine tumor (PNET). Peptide receptor radionuclide therapy (PRRT) with [177Lutetium-DOTA0,Tyr3] octreotate was performed on the patient, with no side effects observed. She was discharged from the hospital 10 days after the first cycle.


Health status after traumatic injury.
This study explored the relationships between health-related quality of life and postacute factors such as patients' perceived access to information and support, perceptions of illness and ability to provide self-care after traumatic injury. Adults (18 years or older) admitted to hospital for ≥ 24 hours for the acute treatment of trauma in two hospitals in Queensland, Australia, were enrolled in a prospective cohort study. Questionnaires completed at hospital discharge and 3 months and 6 months incorporated the following: demographic data; psychological factors (Revised Illness Perception Questionnaire, Information, Autonomy and Support Scale, and Therapeutic Self-Care Scale); and outcome data (medical short form-36). Data on injury and hospital stay were obtained from health care records and the Queensland Trauma Registry. One hundred ninety-four patients with a median Injury Severity Score 9 (interquartile range, 5-14) were enrolled, with 125 (64%) completing questionnaires at 6 months. More than half the cohort reported symptoms of pain, fatigue, stiff joints, sleep difficulties, and loss of strength. All subscale scores on the short form-36 were below Australian norms 6 months after injury. Predictors of poor physical health included older age, lower extremity injury, and increased perceived consequences of their injuries, whereas predictors of poor mental health included younger age, female gender, and lower perceived control over their environment. Patients with minor to moderate injury based on anatomic injury scoring systems have ongoing challenges with recovery including problematic symptoms and low quality of life. Interventions aimed toward assisting recovery should not be limited to trauma patients with major injury. Prognostic study, level III.


The Social Life of Health Insurance in Low- to Middle-income Countries: An Anthropological Research Agenda.
The following article identifies new areas for engaged medical anthropological research on health insurance in low- and middle-income countries (LMICs). Based on a review of the literature and pilot research, we identify gaps in how insurance is understood, administered, used, and abused. We provide a historical overview of insurance as an emerging global health panacea and then offer brief assessments of three high-profile attempts to provide universal health coverage. Considerable research on health insurance in LMICs has been quantitative and focused on a limited set of outcomes. To advance the field, we identify eight productive areas for future ethnographic research that will add depth to our understanding of the social life and impact of health insurance in LMICs. Anthropologists can provide unique insights into shifting health and financial practices that accompany insurance coverage, while documenting insurance programs as they evolve and respond to contingencies.


Doxycycline-mediated quantitative and tissue-specific control of gene expression in transgenic mice.
The tet regulatory system in which doxycycline (dox) acts as an inducer of specifically engineered RNA polymerase II promoters was transferred into transgenic mice. Tight control and a broad range of regulation spanning up to five orders of magnitude were monitored dependent on the dox concentration in the water supply of the animals. Administration of dox rapidly induces the synthesis of the indicator enzyme luciferase whose activity rises over several orders of magnitude within the first 4 h in some organs. Induction is complete after 24 h in most organs analyzed. A comparable regulatory potential was revealed with the tet regulatory system where dox prevents transcription activation. Directing the synthesis of the tetracycline-controlled transactivator (tTA) to the liver led to highly specific regulation in hepatocytes where, in presence of dox, less than one molecule of luciferase was detected per cell. By contrast, a more than 10(5)-fold activation of the luciferase gene was observed in the absence of the antibiotic. This regulation was homogeneous throughout but stringently restricted to hepatocytes. These results demonstrate that both tetracycline-controlled transcriptional activation systems provide genetic switches that permit the quantitative control of gene activities in transgenic mice in a tissue-specific manner and, thus, suggest possibilities for the generation of a novel type of conditional mutants.


Pivotal role of cerebral interleukin-17-producing gammadeltaT cells in the delayed phase of ischemic brain injury.
Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that gammadeltaT lymphocytes, but not CD4(+) helper T cells, were a major source of IL-17. Moreover, depletion of gammadeltaT lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including gammadeltaT lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia.


Morphological and biochemical studies on the development of cholinergic properties in cultured sympathetic neurons. II. Dependence on postnatal age.
Superior cervical ganglion (SCG) neurons taken from perinatal rats and dissociated in culture develop cholinergic properties. This report examines this "plasticity" of neurotransmitter function with regard to its dependence on the stage of neuronal development. Explants of SCG from rats ranging in age from 2 d to adult were cultured, and the number of neurons surviving after 6 wk in culture was evaluated. The activities of choline acetyltransferase (ChAc) and DOPA decarboxylase (DDC) were assayed for each age group over time in culture, and the cytochemistry of the synaptic vesicle population was studied after norepinephrine loading and KMnO4 fixation. The specific activity of ChAc in all explants fell during the first 3--4 d in culture (secondary to degeneration of presynaptic terminals), with an increase during the next 30 d in explants from all age groups except in those from the 22-d-old and adult rats. The highest activity found after 1 mo in culture was in explants from 2-d-old rats (62.5 mmol per kg dry wt per h); the lowest was in explants from adults (1.3 nmol per kg dry wt per h). After 1 mo in vitro, there were no significant differences in DDC activity among explants from animals of any age (similar to approximately 220 mmol per kg dry wt per h). Co-culture of the SCG explants with heart muscle increased even further the ChAc activity in explants from 2-d-old rats but not in explants from 16-d-old and 6.5-wk-old animals. The cytochemistry of the synaptic vesicle population in 1-mo-old cultures correlated well with the ChAc activity; when the ChAc activity was high, the proportion of synaptic vesicles with clear centers was 71--88%. In explants from adult animals, only 12% of the vesicles contained clear centers. From these data we conclude that the maturity of the SCG neuron influences the degree to which it is able to adjust its neurotransmitter mechanisms. That the axons of this neuron are interacting with target tissues during the time that neurotransmitter plasticity is retained suggests that interaction with the target may play a role in the determination of transmitter type.


The changing epidemiology of prevalent diagnosed HIV infections in England, Wales, and Northern Ireland, 1997 to 2003.
To present the current epidemiology of prevalent diagnosed HIV infections in England, Wales, and Northern Ireland (E, W, & NI) and describe trends over time. Descriptive analyses of the annual national Survey of Prevalent HIV Infections Diagnosed (SOPHID) for the period 1997 to 2003. In 2003, 34 251 adults (15 years of age or over) were seen for HIV related care in E, W, & NI, representing a 17% increase in the prevalence of diagnosed HIV infections compared with 2002 and a 132% increase compared with 1997. Between 1997 and 2003, as a proportion of total prevalent cases, adults who acquired their infection through heterosexual sex increased from 26% to 49%; black African adults increased from 15% to 35% and diagnosed adults resident in London fell from 62% to 55% of the total. The male to female ratio declined from 5:1 to 2:1. The proportion of adults receiving combination antiretroviral therapy increased from 53% in 1998 to 64% in 2003. There has been a large increase in the number of adults with diagnosed HIV infection seen for care in E, W, & NI since 1997. Changes in the epidemiology of prevalent diagnosed HIV were seen by sex, route of infection, ethnicity, level of antiretroviral therapy, and areas of residence and treatment. In 2003, for the first time, prevalent diagnosed infections acquired through heterosexual sex over-took those acquired through sex between men. These increases have serious implications for the planning and financing of HIV services in the United Kingdom.


Prevention of peripherally inserted central line-associated blood stream infections in very low-birth-weight infants by using a central line bundle guideline with a standard checklist: a case control study.
Catheter-related infections (CRIs) are one of the severe complications of PICC placement. If treatment is not timely or correct, the incidence of infection and mortality rate can be high. A central line bundle (CLB) guideline was first proposed by the Institute for Healthcare Improvement, and included five key measures. Very low-birth-weight infants (VLBWIs) have a low immune response and indistinct symptoms after infection compared with other populations (Costa P, Kimura AF, de Vizzotto MP, de Castro TE, West A, Dorea E. Prevalence and reasons for non-elective removal of peripherally inserted central catheter in neonates. Rev Gaucha Enferm. 2012;33:126-33). Some reviews have focused on the effect and safety of a CLB in VLBWIs and its preventive effect on bacterial colonization and infection. Fifty-seven VLBWIs who underwent PICC insertion at a hospital in Qingdao, China, between November 2012 and June 2013, and for whom a CLB guideline and a standard checklist were adopted, were included in the CLB group. In contrast, 53 VLBWIs who underwent PICC insertion, but for whom a CLB guideline and a standard checklist were not adopted, were included in the control group. The incidence of CRIs was compared between before and after the treatment. The incidence of infection showed a statistically significant reduction from 10.0 to 2.20 per 1000 catheter days in the control group (P < 0.05). The incidence of catheter-related bloodstream infections decreased from 3.1 to 0 per 1000 catheter days, and that of colonization infections decreased from 6.9 to 2.2 per 1000 catheter days (P < 0.05), both of which indicated a statistically significant difference. The indwelling catheter time was 24.8 ± 7.4 days in the control group and 31.9 ± 15.0 days in the study group (P < 0.05), and these values were significantly different. The use of a CLB guideline with a standard checklist could be effective and feasible for preventing CRIs in VLBWIs and prolonging indwelling catheter time.


The therapy of myelofibrosis: targeting pathogenesis.
Myelofibrosis with myeloid metaplasia (MMM) encompasses the diagnoses of agnogenic myeloid metaplasia (idiopathic myelofibrosis), as well as the advanced phases of polycythemia vera and essential thrombocythemia (post polycythemic and post thrombocythemia myeloid metaplasia, respectively). MMM is a clonal, hematopoietic stem cell disorder in which neither the pathogenesis, nor a broadly applicable effective therapy have been described. Clinically, these patients experience progressive marrow replacement by fibrotic tissue, ineffective hematopoiesis, problematic cytopenia's, significant hepato-splenomegaly, extramedullary hematopoiesis, profound constitutional symptoms, and a risk of blastic transformation. Historically, therapies have been targeted at palliating symptoms (i.e. splenectomy, transfusions, hydroxyurea, erythropoietin, androgens, localized radiotherapy). Stem cell transplantation appears promising, but is often toxic and not broadly applicable due to co-morbidities and age of MMM patients. Non-myeloablative approaches to conditioning may broaden the applicability of stem cell transplantation in MMM, yet results to date are preliminary. Although a definitive molecular abnormality responsible for the pathogenesis of MMM has not been described, much has been learned about the aberrant expression of pro-fibrotic cytokines and the presence of increased angiogenesis in MMM. These pathogenetic insights have led to a series of pilot clinical trials with therapeutic agents targeting aberrantly expressed cytokines (and possibly angiogenesis) including Thalidomide (alone or in combination), Etanercept, and STI-571. Amongst these later agents Thalidomide has demonstrated the most promise (palliating disease associated cytopenia's), whereas the TNF-alpha inhibitor Etanercept has aided with MMM associated constitutional symptoms. Although these later trials have been helpful in a subset of patients, no agent to date has led to solid complete responses in MMM across the spectrum of disease manifestations. Further insights into the pathogenetic mechanisms responsible for myeloproliferation (aberrant cell signaling pathways, apoptotic resistance, other) are necessary to guide selection and testing of the expanding number of novel anti-neoplastic agents in chronic myeloid disorders and MMM.


Meditative Movement Therapies and Health-Related Quality-of-Life in Adults: A Systematic Review of Meta-Analyses.
Poor health-related quality-of-life (HRQOL) is a significant public health issue while the use of meditative movement therapies has been increasing. The purpose of this investigation was to carry out a systematic review of previous meta-analyses that examined the effects of meditative movement therapies (yoga, tai chi and qigong) on HRQOL in adults. Previous meta-analyses of randomized controlled trials published up through February, 2014 were included by searching nine electronic databases and cross-referencing. Dual-selection and data abstraction occurred. The Assessment of Multiple Systematic Reviews Instrument (AMSTAR) was used to assess methodological quality. Standardized mean differences that were pooled using random-effects models were included. In addition, 95% prediction intervals were calculated as well as the number needed-to-treat and percentile improvements. Of the 510 citations screened, 10 meta-analyses representing a median of 3 standardized mean differences in 82 to 528 participants (median = 270) with breast cancer, schizophrenia, low back pain, heart failure and diabetes, were included. Median methodological quality was 70%. Median length, frequency and duration of the meditative movement therapies were 12 weeks, 3 times per week, for 71 minutes per session. The majority of results (78.9%) favored statistically significant improvements (non-overlapping 95% confidence intervals) in HRQOL, with standardized mean differences ranging from 0.18 to 2.28. More than half of the results yielded statistically significant heterogeneity (Q ≤ 0.10) and large or very large inconsistency (I2 ≥ 50%). All 95% prediction intervals included zero. The number-needed-to-treat ranged from 2 to 10 while percentile improvements ranged from 9.9 to 48.9. The results of this study suggest that meditative movement therapies may improve HRQOL in adults with selected conditions. However, a need exists for a large, more inclusive meta-analysis (PROSPERO Registration #CRD42014014576).


Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC).
Upper-tract urothelial carcinoma (UTUC) is a relatively uncommon disease with limited available evidence on specific topics. The purpose of this article was to review the previous literature to summarize the current knowledge about UTUC epidemiology, diagnosis, preoperative evaluation and prognostic assessment. Using MEDLINE, a non-systematic review was performed including articles between January 2000 and February 2016. English language original articles, reviews and editorials were selected based on their clinical relevance. UTUC accounts for 5-10 % of all urothelial cancers, with an increasing incidence. UTUC and bladder cancer share some common risk factors, even if they are two different entities regarding practical, biological and clinical characteristics. Aristolochic acid plays an important role in UTUC pathogenesis in certain regions. It is further estimated that approximately 10 % of UTUC are part of the hereditary non-polyposis colorectal cancer spectrum disease. UTUC diagnosis remains mainly based on imaging and endoscopy, but development of new technologies is rapidly changing the diagnosis algorithm. To help the decision-making process regarding surgical treatment, extent of lymphadenectomy and selection of neoadjuvant systemic therapies, predictive tools based on preoperative patient and tumor characteristics have been developed. Awareness regarding epidemiology, diagnosis, preoperative evaluation and prognostic assessment changes is essential to correctly diagnose and manage UTUC patients, thereby potentially improving their outcomes.


Changes in platelet alpha 2-adrenoceptor binding post partum: possible relation to maternity blues.
Platelet alpha 2-adrenoceptor binding characteristics were investigated in 28 healthy women during the peripartum period. The number of platelet alpha 2-adrenoceptors fell after childbirth, corresponding to a fall in the circulating levels of oestrogen and progesterone. Two-thirds of the women had an episode of maternity blues. At 7-10 days post partum the platelet alpha 2-adrenoceptor capacity in these subjects was significantly higher than in those women who did not show signs of maternity blues and significantly higher than a control group of normally menstruating women. We conclude that platelet alpha 2-adrenoceptors may be affected by the circulating levels of endogenous oestrogen and progesterone and that a delayed or diminished fall in platelet alpha 2-adrenoceptor capacity after childbirth may be associated with the development of maternity blues.


Systematic affinities of the lyrebirds (Passeriformes: Menura), with a novel classification of the major groups of passerine birds.
Phylogenetic relationships of the lyrebirds are investigated using DNA sequence data. The aligned data matrix consists of 4027 bp obtained from three nuclear genes (c-myc, RAG-1 and myoglobin intron II) and two mitochondrial genes (cytochrome b and ND2). Both maximum-likelihood and parsimony analyses show that the lyrebirds unambiguously belong to the oscine radiation, and that they are the sister taxon to all other oscines. The results do not support the suggestion based on DNA-DNA hybridization data (Sibley and Ahlquist, 1990) that the treecreepers and bowerbirds are part of the lyrebird clade. Nevertheless, treecreepers and bowerbirds are sister taxa to all other oscines (except the lyrebirds) and may constitute a monophyletic group, although bootstrap support values for this clade are low. A major disagreement between the present analysis and that based on DNA-DNA hybridization data is that the Corvida (sensu Sibley and Ahlquist, 1990) and Passerida are not reciprocally monophyletic, as we find the latter group be nested within the Corvida. Also, the superfamilies Meliphagoidea and Corvoidea sensu, are not recovered as monophyletic in the present study. Within the oscine radiation, all taxa belonging to the earliest splits are confined to the Australo-Papuan region. This suggests strongly that the origins and early radiation of the oscines occurred in the southern supercontinent Gondwana. A new classification of the major groups of passerines is presented following from the results presented in the present study, as well as those published recently on analyses of sequence data from the nuclear c-myc and RAG-1 genes (Ericson et al., 2002; Irestedt et al., 2001).


Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid.
Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore pharmacological interventions should aim to improve insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, thioctic acid, ALA), a natural occurring compound frequently used for treatment of diabetic polyneuropathy, enhances glucose utilization in various experimental models. To see whether this compound also augments insulin mediated glucose disposal in NIDDM, 13 patients received either ALA (1000 mg/Thioctacid/500 ml NaCl, n = 7) or vehicle only (500 ml NaCl, n = 6) during a glucose-clamp study. Both groups were comparable in age, body-mass index and duration of diabetes and had a similar degree of insulin resistance at baseline. Acute parenteral administration of ALA resulted in a significant increase of insulin-stimulated glucose disposal; metabolic clearance rate (MCR) for glucose rose by about 50% (3.76 ml/kg/min = pre vs. 5.82 ml/kg/min = post, p < 0.05), whereas the control group did not show any significant change (3.57 ml/kg/min = pre vs. 3.91 ml/kg/min = post). This is the first clinical study to show that alpha-lipoic acid increases insulin stimulated glucose disposal in NIDDM. The mode of action of ALA and its potential use as an antihyperglycemic agent require further investigation.


Impaired cognitive functioning during spontaneous dieting.
In one of a continuing series of studies, the cognitive performance of normal weight female dieters was compared on two sessions, 3 weeks apart. Those who reported themselves as being on a weight-reducing diet on only one of the two sessions displayed poorer vigilance performance, slower reaction times and poorer immediate recall of words when they were dieting. In contrast, performance on a low processing load tapping task was unaffected. Self-report measures showed that dietary restraint, but not state anxiety or depression was increased during dieting. These results are interpreted in terms of an association between dieting behaviour and high levels of distractibility, and extend earlier findings by demonstrating that these deficits in cognitive performance are closely related to dieting or the perceived need to diet per se.


Moving interdisciplinary science forward: integrating participatory modelling with mathematical modelling of zoonotic disease in Africa.
This review outlines the benefits of using multiple approaches to improve model design and facilitate multidisciplinary research into infectious diseases, as well as showing and proposing practical examples of effective integration. It looks particularly at the benefits of using participatory research in conjunction with traditional modelling methods to potentially improve disease research, control and management. Integrated approaches can lead to more realistic mathematical models which in turn can assist with making policy decisions that reduce disease and benefit local people. The emergence, risk, spread and control of diseases are affected by many complex bio-physical, environmental and socio-economic factors. These include climate and environmental change, land-use variation, changes in population and people's behaviour. The evidence base for this scoping review comes from the work of a consortium, with the aim of integrating modelling approaches traditionally used in epidemiological, ecological and development research. A total of five examples of the impacts of participatory research on the choice of model structure are presented. Example 1 focused on using participatory research as a tool to structure a model. Example 2 looks at identifying the most relevant parameters of the system. Example 3 concentrates on identifying the most relevant regime of the system (e.g., temporal stability or otherwise), Example 4 examines the feedbacks from mathematical models to guide participatory research and Example 5 goes beyond the so-far described two-way interplay between participatory and mathematical approaches to look at the integration of multiple methods and frameworks. This scoping review describes examples of best practice in the use of participatory methods, illustrating their potential to overcome disciplinary hurdles and promote multidisciplinary collaboration, with the aim of making models and their predictions more useful for decision-making and policy formulation.


Sequence and structural organization of murine cytomegalovirus immediate-early gene 1.
In murine cytomegalovirus, abundant immediate-early transcription originates from 0.769 to 0.815 map units of the genome. This region contains the immediate-early gene (gene ieI) which encodes pp89, a phosphoprotein active in transcriptional regulation. In this paper we report on the precise location, structural organization, and sequence of gene ieI. The predominant ieI transcript, a 2.75-kilobase mRNA, is generated by splicing and composed of four exons. The precise termini of the 2.75-kilobase mRNA and the positions of the exons were determined by nuclease digestion experiments with either 5' or 3' end-labeled DNA fragments or in vitro transcribed cRNA probes. Exons of 300, 111, 191, and 1,703 nucleotides are separated by introns of 825, 95, and 122 nucleotides. The first AUG is located in the second exon of 111 nucleotides, and a single open reading frame of 1,785 nucleotides predicts a protein of 595 amino acids with a calculated molecular weight of 66,713. The N-terminal region of the protein contains sequences similar to a consensus sequence of histone 2B proteins. The regulatory function of pp89 and the role of this protein as an immunodominant antigen are discussed in relation to the amino acid sequence.


Teaching and learning resilience: building adaptive capacity for rural practice. A report and subsequent analysis of a workshop conducted at the Rural Medical Educators Conference, Savannah, Georgia, May 18, 2010.
Resilience, the capacity to endure and overcome hardship, has been suggested as a basic competency for rural medical practice. Unfortunately for physician educators, the medical education literature offers only limited guidance for nurturing this adaptive capacity. We describe the process and subsequent analysis of a daylong curriculum development workshop conducted at the annual meeting of Rural Medical Educators in 2010. Fifty administrator, faculty and student attendees reflected individually and worked in groups to construct key curricular components and modalities for teaching this competency. Prior to the meeting, participants were asked to submit a personal story about resilience. The 22 narratives received were distributed across 8 groups and provided the grist for the small group discussions, in which each group identified key concepts for teaching and learning about resilience, constructed a concept map, and developed a curriculum that was presented to all session participants. Concept maps, curriculum outlines and notes taken during the presentations were analyzed using content analysis techniques. Data highlight the importance of (1) embracing hardship as an opportunity for growth, (2) viewing resilience as both an individual and community property, (3) pursuing adaptability more than hardiness, and (4) setting a lifelong pattern of learning this competency in practice. Specific teaching modalities are suggested including individual reflective time and group activities. To our knowledge this represents a first effort to define and develop a medical curriculum for teaching resiliency in rural predoctoral and residency education.


Relapse after severe acute malnutrition: A systematic literature review and secondary data analysis.
The objectives of most treatment programs for severe acute malnutrition (SAM) in children focus on initial recovery only, leaving post-discharge outcomes, such as relapse, poorly understood and undefined. This study aimed to systematically review current literature and conduct secondary data analyses of studies that captured relapse rates, up to 18-month post-discharge, in children following recovery from SAM treatment. The literature search (including PubMed and Google Scholar) built upon two recent reviews to identify a variety of up-to-date published studies and grey literature. This search yielded 26 articles and programme reports that provided information on relapse. The proportion of children who relapsed after SAM treatment varied greatly from 0% to 37% across varying lengths of time following discharge. The lack of a standard definition of relapse limited comparability even among the few studies that have quantified post-discharge relapse. Inconsistent treatment protocols and poor adherence to protocols likely add to the wide range of relapse reported. Secondary analysis of a database from Malawi found no significant association between potential individual risk factors at admission and discharge, except being an orphan, which resulted in five times greater odds of relapse at 6 months post-discharge (95% CI [1.7, 12.4], P = 0.003). The development of a standard definition of relapse is needed for programme implementers and researchers. This will allow for assessment of programme quality regarding sustained recovery and better understanding of the contribution of relapse to local and global burden of SAM.


Estimation of 6-Degree-of-Freedom (6-DOF) Rigid-Body Patient Motion From Projection Data by the Principal-Axes Method in Iterative Reconstruction.
We developed a unique method for estimating and compensating rigid-body translations and rotations from scatter and-attenuation-compensated projection data in iterative reconstruction when multiple projection angles are acquired at the same time. During reconstruction, both the non-attenuated and attenuated line-integrals are calculated. Their ratios are then multiplied to the scatter-corrected projection data to estimate scatter-and-attenuation- compensated projection data. At the end of each iteration, the sets of compensated projection data for the angles acquired at the same time are employed to calculate the center-of mass and the inertia tensor, which are used to estimate the location and orientation of the imaging object by the principle-axes method. The estimated motion is applied in the next iteration to reposition the estimated slices and attenuation map in the projector and back-projector to match the pose of the patient at time the projections were acquired. To evaluate our method, we simulated an acquisition of the MCAT phantom with a 3-head SPECT system and imaged the Data Spectrum anthropomorphic phantom on a 3-head IRIX SPECT system. In simulations the phantom translated and rotated by the same amount 9 times. A numerical projector modeling the motion, attenuation, and distance-dependent blurring was used to generate the projection data. Poisson noise was added and 30 noise-realizations were generated. In the experiment with the anthropomorphic phantom, four 360-degree acquisitions were performed with the phantom translated or rotated beforehand. A motion-present dataset was made by mixing the 4 acquisitions. For both the MCAT phantom simulations and anthropomorphic phantom experiment, the motion-present data were reconstructed with 10 iterations of the OSEM which estimates and corrects the motion as described above. Our method obtained visually artifact-free reconstructions, while the reconstruction with no motion correction showed severe artifacts. The motion estimated from our method was in good agreement with the motion simulated. We determined in MCAT simulated and actual phantom acquisitions that our data-driven approach was effective reducing motion artifacts.


Suppressed Spontaneous Emission for Coherent Momentum Transfer.
Strong optical forces with minimal spontaneous emission are desired for molecular deceleration and atom interferometry applications. We report experimental benchmarking of such a stimulated optical force driven by ultrafast laser pulses. We apply this technique to accelerate atoms, demonstrating up to an average of 19ℏk momentum transfers per spontaneous emission event. This represents more than an order of magnitude improvement in suppression of spontaneous emission compared to radiative scattering forces. For molecular beam slowing, this technique is capable of delivering a many-fold increase in the achievable time-averaged force to significantly reduce both the slowing distance and detrimental losses to dark vibrational states.


Analysis of the resistance-breaking ability of different beet necrotic yellow vein virus isolates loaded into a single Polymyxa betae population in soil.
The genome of most Beet necrotic yellow vein virus (BNYVV) isolates is comprised of four RNAs. The ability of certain isolates to overcome Rz1-mediated resistance in sugar beet grown in the United States and Europe is associated with point mutations in the pathogenicity factor P25. When the virus is inoculated mechanically into sugar beet roots at high density, the ability depends on an alanine to valine substitution at P25 position 67. Increased aggressiveness is shown by BNYVV P type isolates, which carry an additional RNA species that encodes a second pathogenicity factor, P26. Direct comparison of aggressive isolates transmitted by the vector, Polymyxa betae, has been impossible due to varying population densities of the vector and other soilborne pathogens that interfere with BNYVV infection. Mechanical root inoculation and subsequent cultivation in soil that carried a virus-free P. betae population was used to load P. betae with three BNYVV isolates: a European A type isolate, an American A type isolate, and a P type isolate. Resistance tests demonstrated that changes in viral aggressiveness towards Rz1 cultivars were independent of the vector population. This method can be applied to the study of the synergism of BNYVV with other P. betae-transmitted viruses.


Dendritic polyglycerol and N-isopropylacrylamide based thermoresponsive nanogels as smart carriers for controlled delivery of drugs through the hair follicle.
Nanoparticles with a size of several hundred nanometers can effectively penetrate into the hair follicles and may serve as depots for controlled drug delivery. However, they can neither overcome the hair follicle barrier to reach the viable cells nor release the loaded drug adequately. On the other hand, small drug molecules cannot penetrate deep into the hair follicles. Thus, the most efficient way for drug delivery through the follicular route is to employ nanoparticles that can release the drug close to the target structure upon exposure to some external or internal stimuli. Accordingly, 100-700 nm sized thermoresponsive nanogels with a phase transition temperature of 32-37 °C were synthesized by the precipitation polymerization technique using N-isopropylacrylamide as a monomer, acrylated dendritic polyglycerol as a crosslinker, VA-044 as an initiator, and sodium dodecyl sulphate as a stabilizer. The follicular penetration of the indodicarbocyanine (IDCC) labeled nanogels into the hair follicles and the release of coumarin 6, which was loaded as a model drug, in the hair follicles were assessed ex vivo using porcine ear skin. Confocal laser scanning microscopy (CLSM) enabled independent tracking of the nanogels and the loaded dye, although it is not as precise and accurate as standard analytical methods. The results showed that, unlike smaller nanogels (<100 nm), medium and larger sized nanogels (300-500 nm) penetrated effectively into the hair follicles with penetration depths proportional to the nanogel size. The release of the loaded dye in the hair follicles increased significantly when the investigation on penetration was carried out above the cloud point temperature of the nanogels. The follicular penetration of the nanogels from the colloidal dispersion and a 2.5% hydroxyethyl cellulose gel was not significantly different.


Identification and genetic comparison of leishmanial parasites causing viscerotropic and cutaneous disease in soldiers returning from Operation Desert Storm.
Six Leishmania major and seven L. tropica parasites were isolated and identified from participants in Operation Desert Shield/Storm. A complete enzyme analysis (21 enzymes) revealed that there was enzyme polymorphism among the isolates of each species group. Any one Desert Storm L. major isolate could differ from any other for 1-3 enzymes, and any L. tropica isolate could differ from any one other for up to eight enzymes. Enzyme polymorphism data from other L. major and L. tropica isolates from Africa and the Middle East region were obtained and combined with the Desert Storm data to produce population enzyme polymorphism estimates. Results from these population data indicated that L. major parasites could be expected to differ from each other for as many as eight enzymes and still be L. major, and similarly, L. tropica isolates could differ for as many as 14 enzymes. These expected isolate variation extremes have not been observed among the isolates studied. All L. major and most L. tropica isolates were from patients who, as expected, presented with cutaneous disease, but the Desert Storm and two Kenyan patients infected with L. tropica presented with a viscerotropic disease, the symptoms of which are unlike those of classic visceral leishmaniasis. Such unrecognized presentation for these L. tropica-infected patients indicates that both parasite and patient can play critical roles in disease manifestations. The Desert Storm isolates are, as indicated, either L. major or L. tropica.


Perception of hearing loss: use of the subjective faces scale to screen hearing among the elderly.
Presbycusis is a disorder present among the elderly. However, it is under-diagnosed, making it important to develop and enhance simple screening tools. The subjective faces scale has been proposed as a method to assess auditory self-perception among the elderly, and its correlation with audiological tests. We looked at elderly patients referred to the audiology service of a reference center for the care of the elderly in a public university hospital between February and November 2013. Patients were submitted to meatoscopy, tonal and vocal audiometry and the whisper test. They also answered the subjective faces scale. A total of 164 elderly individuals participated, and the average age was 77. We found a good correlation between the subjective faces scale and audiometry thresholds (r = 0.66). Our results show that the faces and hearing loss correlate, with face 1 corresponding to normal hearing, face 2 to mild hearing loss, and face 3 to Grade I moderate hearing loss. When evaluating the psychometric qualities of the subjective faces scale, we found that faces 2 or 3 have good sensitivity and specificity, with the area under the ROC curve being 0.81. The subjective faces scale seems to be a good, low-cost and easy to use supplementary tool for auditory screening in geriatric services.


Computing multiscale curve and surface skeletons of genus 0 shapes using a global importance measure.
We present a practical algorithm for computing robust, multiscale curve and surface skeletons of 3D objects. Based on a model which follows an advection principle, we assign to each point on the skeleton a part of the object surface, called the collapse. The size of the collapse is used as a uniform importance measure for the curve and surface skeleton, so that both can be simplified by imposing a single threshold on this intuitive measure. The simplified skeletons are connected by default, without special precautions, due to the monotonicity of the importance measure. The skeletons possess additional desirable properties: They are centered, robust to noise, hierarchical, and provide a natural skeleton-to-boundary mapping. We present a voxel-based algorithm that is straightforward to implement and simple to use. We illustrate our method on several realistic 3D objects.


Light-adaptive role of nitric oxide in the outer retina of lower vertebrates: a brief review.
The role of nitric oxide (NO) as a novel neurochemical mechanism controlling light adaptation of the outer retina is discussed by considering mainly published results. The emphasis is on the retinae of fishes and amphibia, but some data from the mammalian (rabbit) retinae have also been included for completeness. In the fish retina, application of NO donors in the dark caused light-adaptive photomechanical movements of cones. The normal effect of light adaptation in inducing cone contractions was suppressed by pretreatment of retinae with an NO scavenger. NO donors modulated horizontal cell activity by uncoupling the cells' lateral gap junctional interconnections and enhancing negative feedback to cones, again consistent with a light-adaptive role of NO. Direct evidence for light adaptation-induced release of NO has been obtained in fish (carp) and rabbit retinae. The results strongly suggest that control of retinal light adaptation is, under multiple neurochemical control, with NO and dopamine having an interactive role.


Liver injury in acute fatty liver of pregnancy: possible link to placental mitochondrial dysfunction and oxidative stress.
Acute fatty liver of pregnancy (AFLP) is a rare disorder which is fatal if not recognized and treated early. Delivery of the feto-placental unit results in dramatic improvement in maternal liver function, suggesting a role for the placenta. However, the mechanisms by which defects in the fetus or placenta lead to maternal liver damage are not well understood and form the focus of this study. Placenta and serum were obtained at delivery from patients with AFLP, and placental mitochondria and peroxisomes were isolated. Placental mitochondrial function, oxidative stress, and fatty acid composition as well as serum antioxidants, oxidative and nitrosative stress markers, and fatty acid analysis were carried out. Hepatocytes in culture were used to evaluate cell death, mitochondrial function, and lipid accumulation on exposure to fatty acids. Oxidative stress was evident in placental mitochondria and peroxisomes of patients with AFLP, accompanied by compromised mitochondrial function. Increased levels of arachidonic acid were also seen in AFLP placenta when compared to control. Patients with AFLP also had a significant increase in oxidative and nitrosative stress markers in serum, along with decreased antioxidant levels and elevated levels of arachidonic acid. These levels of arachidonic acid were capable of inducing oxidative stress in hepatocyte mitochondria accompanied by induction of apoptosis. Exposure to arachidonic acid also resulted in increased lipid deposition in hepatocytes. Oxidative stress in placental mitochondria and peroxisomes is accompanied by accumulation of toxic mediators such as arachidonic acid, which may play a causative role in maternal liver damage seen in AFLP.


Contrasting effects of electroconvulsive shock on mRNAs encoding the high affinity kainate receptor subunits (KA1 and KA2) and cyclophilin in the rat.
Kainate-preferring glutamate receptors may contribute to the glutamatergic responses to seizures. The cloning of their encoding genes overcomes limitations of the receptor ligands available for their investigation. We have examined the expression of the high affinity kainate receptor subunits KA1 and KA2 mRNAs in the rat hippocampus, using electroconvulsive shock (ECS) as a seizure paradigm not confounded by neurotoxicity. A single shock reduced the levels of KA1 mRNA in the CA3c region, while increasing the expression of KA2 mRNA in the dentate gyrus. Following repeated ECS (5 shocks over 10 days), KA1 mRNA was reduced in CA3c and in CA3a-b but was unchanged in dentate gyrus. KA2 mRNA, on the other hand, significantly increased in dentate gyrus, and to a lesser extent in CA3c and CA1. All changes in KA1 and KA2 mRNAs had returned to baseline 3 weeks after the last shock. We also measured the expression of cyclophilin mRNA, and found it to be reduced in all hippocampal subfields, and in the parietal cortex, after a single ECS. It returned to control levels after repeated ECS but was again reduced following 3 weeks recovery from repeated ECS. These results indicate that the expression of KA1 and KA2 not only change in opposite directions in the rat hippocampus after ECS, but that the alterations are anatomically and temporally regulated. In the respect that cyclophilin is regarded as a housekeeping gene, the reduction in its mRNA suggests that ECS may have more persistent and widespread effects on brain gene expression than previously suspected.


Review of attacks on health care facilities in six conflicts of the past three decades.
In the ongoing conflicts of Syria and Yemen, there have been widespread reports of attacks on health care facilities and personnel. Tabulated evidence does suggest hospital bombings in Syria and Yemen are far higher than reported in other conflicts but it is unclear if this is a reporting artefact. This article examines attacks on health care facilities in conflicts in six middle- to high- income countries that have occurred over the past three decades to try and determine if attacks have become more common, and to assess the different methods used to collect data on attacks. The six conflicts reviewed are Yemen (2015-Present), Syria (2011- Present), Iraq (2003-2011), Chechnya (1999-2000), Kosovo (1998-1999), and Bosnia and Herzegovina (1992-1995). We attempted to get the highest quality source(s) with summary data of the number of facilities attacked for each of the conflicts. The only conflict that did not have summary data was the conflict in Iraq. In this case, we tallied individual reported events of attacks on health care. Physicians for Human Rights (PHR) reported attacks on 315 facilities (4.38 per month) in Syria over a 7-year period, while the Monitoring Violence against Health Care (MVH) tool launched later by the World Health Organization (WHO) Turkey Health Cluster reported attacks on 135 facilities (9.64 per month) over a 14-month period. Yemen had a reported 93 attacks (4.65 per month), Iraq 12 (0.12 per month), Chechnya > 24 (2.4 per month), Kosovo > 100 (6.67 per month), and Bosnia 21 (0.41 per month). Methodologies to collect data, and definitions of both facilities and attacks varied widely across sources. The number of reported facilities attacked is by far the greatest in Syria, suggesting that this phenomenon has increased compared to earlier conflicts. However, data on attacks of facilities was incomplete for all of the conflicts examined, methodologies varied widely, and in some cases, attacks were not defined at all. A global, standardized system that allows multiple reporting routes with different levels of confirmation, as seen in Syria, would likely allow for a more reliable and reproducible documentation system, and potentially, an increase in accountability.


Bimetallic effects in homopolymerization of styrene and copolymerization of ethylene and styrenic comonomers: scope, kinetics, and mechanism.
This contribution describes the homopolymerization of styrene and the copolymerization of ethylene and styrenic comonomers mediated by the single-site bimetallic "constrained geometry catalysts" (CGCs), (mu-CH2CH2-3,3'){(eta(5)-indenyl)[1-Me2Si(tBuN)](TiMe2)}2 [EBICGC(TiMe2)2; Ti2], (mu-CH2CH2-3,3'){(eta(5)-indenyl)[1-Me2Si(tBuN)](ZrMe2)}2 [EBICGC(ZrMe2)2; Zr2], (mu-CH2-3,3'){(eta(5)-indenyl)[1-Me2Si(tBuN)](TiMe2)}2 [MBICGC(TiMe2)2; C1-Ti2], and (mu-CH2-3,3'){(eta(5)-indenyl)[1-Me2Si(tBuN)](ZrMe2)}2 [MBICGC(ZrMe2)2; C1-Zr2], in combination with the borate activator/cocatalyst Ph3C+ B(C6F5)4- (B1). Under identical styrene homopolymerization conditions, C1-Ti2 + B1 and Ti2 + B1 exhibit approximately 65 and approximately 35 times greater polymerization activities, respectively, than does monometallic [1-Me2Si(3-ethylindenyl)(tBuN)]TiMe2 (Ti1) + B1. C1-Zr2 + B1 and Zr2 + B1 exhibit approximately 8 and approximately 4 times greater polymerization activities, respectively, than does the monometallic control [1-Me2Si(3-ethylindenyl)(tBuN)]ZrMe2 (Zr1) + B1. NMR analyses show that the bimetallic catalysts suppress the regiochemical insertion selectivity exhibited by the monometallic analogues. In ethylene copolymerization, Ti2 + B1 enchains 15.4% more styrene (B), 28.9% more 4-methylstyrene (C), 45.4% more 4-fluorostyrene (D), 41.2% more 4-chlorostyrene (E), and 31.0% more 4-bromostyrene (F) than does Ti1 + B1. This observed bimetallic chemoselectivity effect follows the same general trend as the pi-electron density on the styrenic ipso carbon (D > E > F > C > B). Kinetic studies reveal that both Ti2 + B1 and Ti1 + B1-mediated ethylene-styrene copolymerizations follow second-order Markovian statistics and tend to be alternating. Moreover, calculated reactivity ratios indicate that Ti2 + B1 favors styrene insertion more than does Ti1 + B1. All the organozirconium complexes (C1-Zr2, Zr2, and Zr1) are found to be incompetent for ethylene-styrene copolymerization, yielding only mixtures of polyethylene and polystyrene. Model compound (mu-CH2CH2-3,3'){(eta(5)-indenyl)[1-Me2Si(tBuN)][Ti(CH2Ph)2]}2 {EBICGC[Ti(CH2Ph)2]2; Ti2(CH2Ph)4} was designed, synthesized, and structurally characterized. In situ activation studies with cocatalyst B(C6F5)3 suggest an eta(1)-coordination mode for the benzyl groups, thus supporting the proposed polymerization mechanism. For ethylene-styrene copolymerization, polar solvents are found to increase copolymerization activities and coproduce atactic polystyrene impurities in addition to ethylene-co-styrene, without diminishing the comonomer incorporation selectivity. Both homopolymerization and copolymerization results argue that substantial cooperative effects between catalytic sites are operative.