Selective sonographic screening for developmental dysplasia of the hip - increasing trends in late diagnosis.
There are concerns that selective sonographic screening for developmental dysplasia of the hip (DDH) may be suboptimal. Our aim was to test this hypothesis by identifying trends in presentation and surgical treatment in patients with DDH. This is a retrospective review of children born between 1997-2018 who were treated surgically for DDH at our sub- regional paediatric orthopaedic unit. Demographic data, risk factors, age of diagnosis and surgical treatments were analysed. Late diagnosis was defined as greater than 4 months. 103 children (14 male, 89 female) underwent surgery. 93 hips were operated for dislocation and 21 for dysplasia. 13 patients presented with bilateral hip dislocations. The median age at diagnosis was 10 months (95% CI: 4-15). 62/103 (60.2%) were diagnosed late (after 4 months) and the median age for diagnosis in this group was 18.5 months (95% CI: 16-20.5). Significantly more patients were referred late (p=0.0077). The presence of risk factors (breech presentation or family history) was associated with early diagnosis. Over the duration of our study the operation rate per 1000 live births gradually increased, and on Poisson regression analysis there was a statistically significant increasing trend towards late diagnosis in recent years (p=0.0237), which necessitated more aggressive surgical management. In the UK, the current selective sonographic screening programme for DDH has shown a deterioration over the years of this study and this questions its current effectiveness. It appears that the majority of irreducible hip dislocations are diagnosed late, with an increased need for surgical management.


Photocatalytic Generation of Trifluoromethyl Nitrene for Alkene Aziridination.
N-Trifluoromethylated organics may be applied in drug design, agrochemical synthesis, and materials science, among other areas. Yet, despite recent advances in the synthesis of aliphatic, cyclic and heterocyclic N-trifluoromethyl compounds, no strategy based on trifluoromethyl nitrene has hitherto been explored. Here we describe the formation of triplet trifluoromethyl nitrene from azidotrifluoromethane, a stable and safe-to-use precursor, by visible light photocatalysis. The addition of CF3 N to alkenes via biradical intermediates afforded previously unknown aziridines substituted with trifluoromethyl group on the nitrogen atom. The obtained aziridines were converted into either N-trifluoromethylimidazolines, via formal [3+2] cycloaddition with nitriles, mediated by a Lewis acid, or into N-trifluoromethylaldimines, via ring opening and aryl group migration mediated by a strong Brønsted acid. Our findings open new opportunities for the development of novel classes of N-CF3 compounds with possible applications in the life sciences.


Coronary revascularization--2009: state of the art.
Despite advances in percutaneous coronary intervention, coronary artery bypass grafting remains the most effective intervention for complex coronary artery disease in survival, freedom from reintervention, and cost-effectiveness. To ensure that patients have access to this "gold-standard" treatment, a multidisciplinary team approach, rather than an individual cardiologist acting as a "gatekeeper," should be the standard of care when intervention is necessary, to ensure transparency, real patient choice, and genuine informed consent.


Molecular and clinical analyses of two patients with UPD(16)mat detected by screening 94 patients with Silver-Russell syndrome phenotype of unknown aetiology.
Recently, a patient with maternal uniparental disomy of chromosome 16 (UPD(16)mat) presenting with Silver-Russell syndrome (SRS) phenotype was reported. SRS is characterised by growth failure and dysmorphic features. To clarify the prevalence of UPD(16)mat in aetiology-unknown patients with SRS phenotype and phenotypic differences between UPD(16)mat and SRS. We studied 94 patients with SRS phenotype of unknown aetiology. Sixty-three satisfied the Netchine-Harbison clinical scoring system (NH-CSS) criteria, and 25 out of 63 patients showed both protruding forehead and relative macrocephaly (clinical SRS). The remaining 31 patients met only three NH-CSS criteria, but were clinically suspected as having SRS. To detect UPD(16)mat, we performed methylation analysis for the ZNF597:TSS-differentially methylated region (DMR) on chromosome 16 and subsequently performed microsatellite, SNP array and exome analyses in the patients with hypomethylated ZNF597:TSS-DMR. We identified two patients (2.1%) with a mixture of maternal isodisomy and heterodisomy of chromosome 16 in 94 aetiology-unknown patients with SRS phenotype. Both patients exhibited preterm birth and prenatal and postnatal growth failure. The male patient had ventricular septal defect and hypospadias. Whole-exome sequencing detected no gene mutations related to their phenotypes. We suggest considering genetic testing for UPD(16)mat in SRS phenotypic patients without known aetiology.


Silencing mediator of retinoic acid and thyroid hormone receptors, as a novel transcriptional corepressor molecule of activating protein-1, nuclear factor-kappaB, and serum response factor.
Silencing mediator of retinoic acid and thyroid hormone receptors (SMRT) is known to interact with Sin3 and recruit the histone deacetylases (HDACs) that lead to hypoacetylation of histones and transrepression of target transcription factors. Herein, we found that coexpression of SMRT significantly repressed transactivations by activating protein-1 (AP-1), nuclear factor-kappaB (NFkappaB), and serum response factor (SRF) in a dose-dependent manner, but not in the presence of trichostatin A, a specific inhibitor of HDAC. Similarly, coexpression of HDAC1 and mSin3A also showed repressive effects. Consistent with these results, the C-terminal region of SMRT directly interacted with SRF, the AP-1 components c-Jun and c-Fos, and the NFkappaB components p50 and p65, as demonstrated by the yeast and mammalian two hybrid tests as well as the glutathione S-transferase pull down assays. Thus, we concluded that SMRT serves to recruit Sin3/HDACs to SRF, NFkappaB, and AP-1 in vivo and modulate their transactivation.


NP, PB1, and PB2 viral genes contribute to altered replication of H5N1 avian influenza viruses in chickens.
The virulence determinants for highly pathogenic avian influenza viruses (AIVs) are considered multigenic, although the best characterized virulence factor is the hemagglutinin (HA) cleavage site. The capability of influenza viruses to reassort gene segments is one potential way for new viruses to emerge with different virulence characteristics. To evaluate the role of other gene segments in virulence, we used reverse genetics to generate two H5N1 recombinant viruses with differing pathogenicity in chickens. Single-gene reassortants were used to determine which viral genes contribute to the altered virulence. Exchange of the PB1, PB2, and NP genes impacted replication of the reassortant viruses while also affecting the expression of specific host genes. Disruption of the parental virus' functional polymerase complexes by exchanging PB1 or PB2 genes decreased viral replication in tissues and consequently the pathogenicity of the viruses. In contrast, exchanging the NP gene greatly increased viral replication and expanded tissue tropism, thus resulting in decreased mean death times. Infection with the NP reassortant virus also resulted in the upregulation of gamma interferon and inducible nitric oxide synthase gene expression. In addition to the impact of PB1, PB2, and NP on viral replication, the HA, NS, and M genes also contributed to the pathogenesis of the reassortant viruses. While the pathogenesis of AIVs in chickens is clearly dependent on the interaction of multiple gene products, we have shown that single-gene reassortment events are sufficient to alter the virulence of AIVs in chickens.


Alveolar reconstruction in adolescent patients with cleft palates.
Treatment of patients with cleft palates requires optimal interdisciplinary care. The efforts of the entire team treating the patient with cleft palate must be closely coordinated, even when the deformity is confined to the alveolus. In a significant number of patients with cleft palate, surgical reconstruction of the alveolus and adjacent soft tissue is a necessary adjunct to orthodontic, prosthetic, and facial soft tissue management. Surgical treatment and its complications are discussed, with specific case examples.


Estimating antiretroviral treatment coverage rates and viral suppression rates for homosexual men in Australia.
Gay and other men who have sex with men (GMSM) are disproportionally affected by the HIV epidemic in Australia. The study objective is to combine a clinical-based cohort with a community-based surveillance system to present a broader representation of the GMSM community to determine estimates of proportions receiving antiretroviral therapy (ART) and/or with an undetectable viral load. Between 2010 and 2012, small increases were shown in ART uptake (to 70.2%) and proportions with undetectable viral load (to 62.4%). The study findings highlight the potential for significantly increasing ART uptake among HIV-positive GMSM to reduce the HIV epidemic in Australia.


Effect of refined cellulose on apparent energy, fat and nitrogen digestibilities.
Seven young women consumed a low cellulose diet for about 1 month and then the same diet for an additional month except that 16 g/day Solka Floc was added to the diet. Apparent digestibilities of energy, fat and nitrogen were measured for each subject during each diet. Digestibilities of fat and nitrogen were not affected by refined cellulose ingestion. Digestibility of nitrogen was 93.2% without and 92.9% with the Solka Floc, while fat digestibility was 96.3% during the control diet and 95.4% during the high cellulose diet. Mean digestibility of gross energy decreased significantly when cellulose was added to the diet, from 95.4% to 92.0% (P < 0.01). Undigested fecal fiber was the major source of the increased fecal energy. When fecal fiber energy was subtracted from total fecal energy and apparent energy digestibility recalculated, there was no difference in apparent energy digestibility during the 2 diets, 96.1% without and 95.6% with the Solka Floc supplement. Thus, ingestion of 16 g/day Solka Floc had no detrimental effect on the utilization of nitrogen and fat and increases in fecal energy could be explained by undigested refined cellulose.


The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis.
To investigate a possible association between the longitudinal changes in skin involvement and the fibroblast production of proteoglycans in vitro, among patients with early and untreated systemic sclerosis (SSc). In 11 patients, 6 with diffuse cutaneous systemic sclerosis (dSSc) and 5 with limited cutaneous systemic sclerosis (ISSc), and in 6 controls skin thickness and skin echogenicity of the forearm was measured by high frequency (20 MHz) ultrasound. A skin biopsy was taken from the area of the ultrasound measurements, and from cultivated fibroblasts the production of the proteoglycans versican, perlecan, biglycan and decorin were measured. To investigate longitudinal changes in skin involvement, the ultrasound examination was repeated after 1-3 years. Compared to controls, SSc patients had increased skin thickness at the first evaluation. Patients with dSSc had lower skin echogenicity than both patients with lSSc and the controls. Patients with greater changes in skin thickness and skin echogenicity produced more versican, whereas the production of biglycan and decorin was higher only in patients with greater changes in skin echogenicity. There was a negative correlation between fibroblast production of biglycan and disease duration. High fibroblast synthesis of the proteoglycans versican and biglycan is associated with changes in skin echogenicity and may predict more progressive skin sclerosis in SSc.


Identifying the neural dynamics of category decisions with computational model-based functional magnetic resonance imaging.
Successful categorization requires a careful coordination of attention, representation, and decision making. Comprehensive theories that span levels of analysis are key to understanding the computational and neural dynamics of categorization. Here, we build on recent work linking neural representations of category learning to computational models to investigate how category decision making is driven by neural signals across the brain. We uniquely combine functional magnetic resonance imaging with drift diffusion and exemplar-based categorization models to show that trial-by-trial fluctuations in neural activation from regions of occipital, cingulate, and lateral prefrontal cortices are linked to category decisions. Notably, only lateral prefrontal cortex activation was associated with exemplar-based model predictions of trial-by-trial category evidence. We propose that these brain regions underlie distinct functions that contribute to successful category learning.


The blood supply of the lateral epiphyseal arteries in Perthes' disease.
We performed superselective angiography in 28 hips in 25 patients with Perthes' disease in order to study the blood supply of the lateral epiphyseal arteries (LEAs). Interruption of the LEAs at their origin was observed in 19 hips (68%). Revascularisation in the form of numerous small arteries was seen in ten out of 11 hips in the initial stage of Perthes' disease, in seven of eight in the fragmentation stage and in five of nine in the healing stage. Penetration of mature arteries into the depths of the epiphysis was seen in four of nine hips in the healing stage. Vascular penetration was absent in the weight-bearing portion of the femoral head below the acetabular roof. Interruption of the posterior column artery was seen where it passed through the capsule in seven hips when they lay either in internal rotation or in abduction with internal rotation. We suggest that in Perthes' disease the blood supply of the LEAs is impaired at their origin and that revascularisation occurs from this site by ingrowth of small vessels into the femoral epiphysis. This process may be the result of recurrent ischaemic episodes.


Robust, compact implementation of an off-axis digital holographic microscope.
Recent advances in digital technologies, such as high-speed computers and large-format digital imagers, have led to a burgeoning interest in the science and engineering of digital holographic microscopy (DHM). Here we report on a novel off-axis DHM, based on a twin-beam optical design, which avoids the limitations of prior systems, and provides many advantages, including compactness, intrinsic stability, robustness against misalignment, ease of use, and cost. These advantages are traded for a physically constrained sample volume, as well as a fixed fringe spacing. The first trade is not overly restrictive for most applications, and the latter provides for a pre-set assembly alignment that optimizes the spatial frequency sampling. Moreover, our new design supports use in both routine laboratory settings as well as extreme environments without any sacrifice in performance, enabling ready observation of microbial species in the field. The instrument design is presented in detail here, along with a demonstration of bacterial video imaging at sub-micrometer resolution at temperatures down to -15 °C.


DNase I hypersensitivity in the gamma globin gene locus of K562 cells.
We have probed the chromatin conformation of the G gamma-A gamma-delta-beta globin gene locus of K562 cells, a human hematopoietic cell line, with the enzyme pancreatic DNAse I. This enzyme preferentially digests genes in an active configuration. We have found that in K562 cells, which produce embryonic and fetal but not adult hemoglobins, both the active gamma and inactive beta genes are DNAse I sensitive. However, only the active gamma genes have DNAse I hypersensitive regions. The hypersensitive regions have been mapped to an area approximately 100 base pairs 5' to the G gamma and A gamma genes.


KCC2 activity is critical in limiting the onset and severity of status epilepticus.
The K(+)/Cl(-) cotransporter (KCC2) allows adult neurons to maintain low intracellular Cl(-) levels, which are a prerequisite for efficient synaptic inhibition upon activation of γ-aminobutyric acid receptors. Deficits in KCC2 activity are implicated in epileptogenesis, but how increased neuronal activity leads to transporter inactivation is ill defined. In vitro, the activity of KCC2 is potentiated via phosphorylation of serine 940 (S940). Here we have examined the role this putative regulatory process plays in determining KCC2 activity during status epilepticus (SE) using knockin mice in which S940 is mutated to an alanine (S940A). In wild-type mice, SE induced by kainate resulted in dephosphorylation of S940 and KCC2 internalization. S940A homozygotes were viable and exhibited comparable basal levels of KCC2 expression and activity relative to WT mice. However, exposure of S940A mice to kainate induced lethality within 30 min of kainate injection and subsequent entrance into SE. We assessed the effect of the S940A mutation in cultured hippocampal neurons to explore the mechanisms underlying this phenotype. Under basal conditions, the mutation had no effect on neuronal Cl(-) extrusion. However, a selective deficit in KCC2 activity was seen in S940A neurons upon transient exposure to glutamate. Significantly, whereas the effects of glutamate on KCC2 function could be ameliorated in WT neurons with agents that enhance S940 phosphorylation, this positive modulation was lost in S940A neurons. Collectively our results suggest that phosphorylation of S940 plays a critical role in potentiating KCC2 activity to limit the development of SE.


Executive function and employment status among veterans with bipolar disorder.
This study assessed the relationship between neurocognitive function (measured by the Executive Interview [EXIT]) and occupational role function (measured by employment status) in a large cohort of Veterans Affairs patients with bipolar disorder. A total of 213 patients in a national bipolar disorder intervention study (Department of Veterans Affairs Cooperative Study 430) were dichotomized into two groups--employed (N=91) and unemployed (N=122)--on the basis of responses to a semistructured interview regarding past-year work history. Bivariate analysis was used to assess whether any participant characteristics and course-of-illness variables were significantly different between the employed and unemployed groups and thus could confound results. A stepwise logistic regression was then performed to investigate the association between neurocognitive function and employment status by using the significant demographic and course-of-illness variables as covariates. There were significant differences in EXIT scores between the employed and unemployed groups, with the unemployed group showing greater executive impairment. Lifetime psychiatric hospitalizations and number of psychotropic medications prescribed had significant associations with employment status. When these variables were entered into a regression analysis, employment status could still be explained by executive functioning. This study found that poor executive function may be associated with poor work adjustment (unemployment) among patients with bipolar disorder. The etiology of this relationship and the contributory role of the prior number of hospitalizations and number of psychotropic medications to executive function remain to be further evaluated.


[Molecular and functional diversity of ATP-sensitive K+ channels: the pathophysiological roles and potential drug targets].
ATP-sensitive K(+) (K(ATP)) channels comprise the pore-forming subunit (Kir6.1 or Kir6.2) and the regulatory subunit sulfonylurea receptors (SUR1 or SUR2). K(ATP) channels with different combinations of these subunits are present in various tissues and regulate cellular functions. From the analysis of mouse models with targeted deletion of the gene encoding the pore-forming subunit Kir6.1 or Kir6.2, functional roles of K(ATP) channels in various organs have been clarified. Kir6.1(-/-) mice showed sudden death associated with ST elevation and atrioventricular block in ECG, a phenotype resembling Prinzmetal angina in humans. Kir6.2(-/-) mice were more susceptible to generalized seizure during hypoxia than wild-type (WT) mice, suggesting that neuronal K(ATP) channels, probably composed of Kir6.2 and SUR1, play a crucial role for the protection of the brain against lethal damage due to seizure. In Kir6.2(-/-) mice lacking the sarcolemmal K(ATP) channel activity in cardiac cells, ischemic preconditioning failed to reduce the infarct size, suggesting that sarcolemmal K(ATP) channels play an important role in cardioprotection against ischemia/reperfusion injuries in the heart. Mitochondrial K(ATP) channels have been also proposed to play a crucial role in cardioprotection, although the molecular identity of the channel has not been established. Nicorandil and minoxidil, K(+) channel openers activating mitochondrial K(ATP) channels, decreased the mitochondrial membrane potential, thereby preventing the Ca(2+) overload in the mitochondria of guinea-pig ventricular cells. SURs are the receptors for K(+) channel openers and the activating effects on sarcolemmal K(ATP) channels in cardiovascular tissues could be modulated by the interaction of nucleotides. Due to the molecular diversity of the accessory and pore subunits of K(ATP) channels, there would be considerable differences in the tissue selectivity of K(ATP) channel-acting drugs. Studies of Kir6.1 and Kir6.2 knockout mice indicate that K(ATP) channels are involved in the mechanisms of the protection against metabolic stress. Further clarification of physiological as well as pathophysiological roles of K(ATP) channels may lead to a new therapeutic strategy to improve the quality of life.


Left renal vein transposition for nutcracker syndrome.
Nutcracker syndrome, caused by compression of the left renal vein (LRV) between the superior mesenteric artery and the aorta, results in left renal and gonadal venous hypertension. Several treatment options have been described to relieve associated symptoms. The purpose of this study was to evaluate late results of LRV transposition and identify risk factors affecting outcomes. Clinical data from 23 consecutive patients diagnosed with nutcracker syndrome from January 1996 to October 2007 were retrospectively reviewed. There were 10 males and 13 females (median age 22 years; range, 14-67) with radiologic evidence of LRV compression. On ultrasound evaluation (15/23 patients), the mean ratio of LRV peak systolic velocity measured at the site of compression and the renal hilum was 7.3 (range, 2.5-12). On venography (14/23 patients), the mean renocaval pressure gradient was 4 mm Hg (range, 2-6 mm Hg). Twelve patients with atypical abdominal pain (n = 4), hematuria (n = 5), and varicocele (n = 6) were managed expectantly. Eleven patients underwent LRV transposition through a transperitoneal exposure. Symptoms in these patients included left flank pain (n = 10), hematuria (n = 7), and varicocele (n = 3). In 2/11 patients, the LRV was found to be occluded at operation. There were no early postoperative complications. Most conservatively managed patients remained stable or improved over a mean follow-up period of 26 months (range, 0.2-59 months). Two patients were lost to follow-up at our institution and ultimately underwent intervention with LRV stenting and autotransplantation elsewhere. One patient was diagnosed with thin basement membrane disease on renal biopsy. Five patients with varicocele remained asymptomatic; 1 underwent local repair. Over a mean follow-up of 39 months (range, 0.13-144 months) in surgically managed patients, symptoms of flank pain and hematuria resolved or improved in 8/10 and 7/7, respectively. Varicoceles recurred in 2/3 patients in spite of resolution of flank pain. Both preoperatively occluded LRVs rethrombosed; one underwent thrombolysis with stenting, the other reimplantation of the left gonadal vein into the IVC. Evaluation of the clinical significance of radiologic LRV compression remains challenging, as does selection of patients for intervention. LRV transposition is a safe, effective procedure in selected patients with persistent, severe symptoms. Patients with progression to occlusion of the LRV should be considered for alternative therapeutic procedures. Varicoceles, in the setting of nutcracker syndrome, may need independent repair.


An RNAi screen in human cell lines reveals conserved DNA damage repair pathways that mitigate formaldehyde sensitivity.
Formaldehyde is a ubiquitous DNA damaging agent, with human exposures occurring from both exogenous and endogenous sources. Formaldehyde exposure can result in multiple types of DNA damage, including DNA-protein crosslinks and thus, is representative of other exposures that induce DNA-protein crosslinks such as cigarette smoke, automobile exhaust, wood smoke, metals, ionizing radiation, and certain chemotherapeutics. Our objective in this study was to identify the genes necessary to mitigate formaldehyde toxicity following chronic exposure in human cells. We used siRNAs that targeted 320 genes representing all major human DNA repair and damage response pathways, in order to assess cell proliferation following siRNA depletion and subsequent formaldehyde treatment. Three unrelated human cell lines frequently used in genotoxicity studies (SW480, U-2 OS and GM00639) were used to identify common pathways involved in mitigating formaldehyde sensitivity. Although there were gene-specific differences among the cell lines, four inter-related cellular pathways were determined to mitigate formaldehyde toxicity: homologous recombination, DNA double-strand break repair, ionizing radiation response and DNA replication. Additional insight into cell line-specific response patterns was obtained by using a combination of exome sequencing and Cancer Cell Line Encyclopedia genomic data. The results of this DNA damage repair pathway-focused siRNA screen for formaldehyde toxicity in human cells provide a foundation for detailed mechanistic analyses of pathway-specific involvement in the response to environmentally-induced DNA-protein crosslinks and, more broadly, genotoxicity studies using human and other mammalian cell lines.


Synergistic computational and experimental proteomics approaches for more accurate detection of active serine hydrolases in yeast.
An analysis of the structurally and catalytically diverse serine hydrolase protein family in the Saccharomyces cerevisiae proteome was undertaken using two independent but complementary, large-scale approaches. The first approach is based on computational analysis of serine hydrolase active site structures; the second utilizes the chemical reactivity of the serine hydrolase active site in complex mixtures. These proteomics approaches share the ability to fractionate the complex proteome into functional subsets. Each method identified a significant number of sequences, but 15 proteins were identified by both methods. Eight of these were unannotated in the Saccharomyces Genome Database at the time of this study and are thus novel serine hydrolase identifications. Three of the previously uncharacterized proteins are members of a eukaryotic serine hydrolase family, designated as Fsh (family of serine hydrolase), identified here for the first time. OVCA2, a potential human tumor suppressor, and DYR-SCHPO, a dihydrofolate reductase from Schizosaccharomyces pombe, are members of this family. Comparing the combined results to results of other proteomic methods showed that only four of the 15 proteins were identified in a recent large-scale, "shotgun" proteomic analysis and eight were identified using a related, but similar, approach (neither identifies function). Only 10 of the 15 were annotated using alternate motif-based computational tools. The results demonstrate the precision derived from combining complementary, function-based approaches to extract biological information from complex proteomes. The chemical proteomics technology indicates that a functional protein is being expressed in the cell, while the computational proteomics technology adds details about the specific type of function and residue that is likely being labeled. The combination of synergistic methods facilitates analysis, enriches true positive results, and increases confidence in novel identifications. This work also highlights the risks inherent in annotation transfer and the use of scoring functions for determination of correct annotations.


Update on inpatient glycemic control in hospitals in the United States.
To provide data on glucose control in hospitals in the United States, analyzing measurements from the largest number of facilities to date. Point-of-care bedside glucose (POC-BG) test results were extracted from 575 hospitals from January 2009 to December 2009 by using a laboratory information management system. Glycemic control for patients in the intensive care unit (ICU) and non-ICU areas was assessed by calculating patient-day-weighted mean POC-BG values and rates of hypoglycemia and hyperglycemia. The relationship between POC-BG levels and hospital characteristics was determined. A total of 49,191,313 POC-BG measurements (12,176,299 ICU and 37,015,014 non-ICU values) were obtained from 3,484,795 inpatients (653,359 in the ICU and 2,831,436 in non-ICU areas). The mean POC-BG was 167 mg/dL for ICU patients and 166 mg/dL for non-ICU patients. The prevalence of hyperglycemia (>180 mg/dL) was 32.2% of patient-days for ICU patients and 32.0% of patient-days for non-ICU patients. The prevalence of hypoglycemia (<70 mg/dL) was 6.3% of patient-days for ICU patients and 5.7% of patient-days for non-ICU patients. Patient-day-weighted mean POC-BG levels varied on the basis of hospital size (P<.01), type (P<.01), and geographic location (P<.01) for ICU and non-ICU patients, with larger hospitals (≥400 beds), academic hospitals, and US hospitals in the West having the lowest mean POC-BG values. The percentage of patient-days in the ICU characterized by hypoglycemia was highest among larger and academic hospitals (P<.05) and least among hospitals in the Northeast (P<.001). Hyperglycemia is common in hospitals in the United States, and glycemic control may vary on the basis of hospital characteristics. Increased hospital participation in data collection may support a national benchmarking process for the development of optimal practices to manage inpatient hyperglycemia.


In vitro genetic recombination of bacteriophage lambda.
DNA of bacteriophage lambda recombines in a cell-free extract prepared from an induced Escherichia coli lysogen of bacteriophage lambda. The assay for recombination in vitro takes advantage of the ability of such an extract to package lambda DNA and to assemble complete phage particles. For example, when lambda DNA that has been extracted from phage with the immunity of 434 is added to an extract, infectious lambda imm 434 particles are produced. The precursor DNA molecule in this packaging reaction is a multichromosomal polymer; circular monomers, for example, are not packaged.Nevertheless, when 434 circular DNA monomers are added to an extract, some phage that contain the imm 434 marker are produced. In this case, the circular DNA had recombined with lambda DNA in the extract and thereby had become part of a polymeric structure, which by the normal packaging process could give rise to infectious particles with the imm 434 marker. Genetic recombination is demonstrated when imm 434 circular monomer DNA carries amber mutations in genes A and B; then most of the 434 plaque formers produced in vitro are A(+)B(+), the genotype of the endogenous lambda DNA. Genetic crossing-over occurs through a region that contains the prophage attachment site, suggesting that recombination is carried out by the lambda Int functions. The 434 recombinant plaque formers are particles physically identical to wild-type 434 particles, as judged by their buoyant density in a CsCl equilibrium gradient.


Reconstitution of brain mitochondria inner membrane into planar lipid bilayer.
Ion channels are present in the inner mitochondrial membrane. They play an important role in cellular processes. Potassium and chloride channels are involved in regulation of mitochondrial volume, membrane potential and acidification. The mitochondrial potassium channels have been suggested as triggers and end effectors in cytoprotection. In our study we measured single channel activities after reconstitution of submitochondrial particles from rat brain mitochondria into planar lipid membranes. After incorporation, two different potassium selective currents were recorded with single channel conductance from 260 to 320 pS and from 70 to 90 pS in gradient (cis/trans) 50/450 and 50/150 mM KCl solutions, respectively. We also observed activity of the chloride ion channel. The measured single channel conductance was from 80 to 90 pS in gradient (cis/trans) 50/450 mM KCl solution. Our results suggest that various ion channels are present in the inner mitochondrial membrane of brain mitochondria.


Clinical and epidemiological study on severe fever with thrombocytopenia syndrome in Yiyuan County, Shandong Province, China.
Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease in China. Polymerase chain reaction and enzyme-linked immunosorbent assay were used to detect SFTS virus (SFTSV) and Anaplasma phagocytophilum in previous clinically diagnosed human anaplasmosis patients and SFTS patients. A serosurvey for SFTSV infection was also conducted on healthy persons and animals in Yiyuan County in Shandong Province of China. Among 21 patients SFTSV was detected in 17 (81%) however A. phagocytophilum was not detected in any of the patients. The seroprevalence rate of IgG antibody to SFTSV antigens was 1.3% (1 of 78) in healthy persons, 95% (19 of 20) in goats, 50% (1 of 2) in dogs, 0% in cattle (0 of 21), and rats (Rattus norvegicus) (0 of 35). The conclusion of this study was that co-infection of SFTSV and A. phagocytophilum are rare in SFTS patients and goats might play an important role in transmission of SFTSV.


The presence of microplastics in commercial salts from different countries.
The occurrence of microplastics (MPs) in saltwater bodies is relatively well studied, but nothing is known about their presence in most of the commercial salts that are widely consumed by humans across the globe. Here, we extracted MP-like particles larger than 149 μm from 17 salt brands originating from 8 different countries followed by the identification of their polymer composition using micro-Raman spectroscopy. Microplastics were absent in one brand while others contained between 1 to 10 MPs/Kg of salt. Out of the 72 extracted particles, 41.6% were plastic polymers, 23.6% were pigments, 5.50% were amorphous carbon, and 29.1% remained unidentified. The particle size (mean ± SD) was 515 ± 171 μm. The most common plastic polymers were polypropylene (40.0%) and polyethylene (33.3%). Fragments were the primary form of MPs (63.8%) followed by filaments (25.6%) and films (10.6%). According to our results, the low level of anthropogenic particles intake from the salts (maximum 37 particles per individual per annum) warrants negligible health impacts. However, to better understand the health risks associated with salt consumption, further development in extraction protocols are needed to isolate anthropogenic particles smaller than 149 μm.


Hind leg heat balance in obese Zucker rats during exercise.
To analyse the effect of obesity on exercise-derived heat dissipation, lean and obese Zucker rats were exercised on an inclined treadmill until they would no longer run with gentle prodding. We measured their oxygen consumption, water vapour loss, the concentrations of adenosine tri- and diphosphate, creatine phosphate, and lactate in quick-frozen leg muscles, and the temperature of muscle, skin and blood in the aorta. We determined blood flow to leg muscle, fat and skin by measuring the entrapment of fluorescent microspheres. From the measurements we calculated heat flow rates between hind leg muscle, blood, fat and skin and the environment. The obese rats weighed twice as much as the lean (340-400 g and 175-200 g respectively) and ran half as fast (113 +/- 7 m versus 257 +/- 17 m). The differences between the two groups for basal oxygen consumption (lean: 6.7 +/- 0.9 micromol/min, obese: 5.0 +/- 1.9 micromol/min) and exercising oxygen consumption (lean: 37.8 +/- 5.6 micromol/min, obese: 22.2 +/- 3.8 micromol/min) were not significant. Both groups stopped running after the same time at their maximal speed (lean: 4.5 +/- 0.3 min, obese: 4.2 +/- 0.2 min). During exercise, lean rats had higher increases in core temperature (lean: 0.7 degrees C, obese: 0.4 degrees C) and muscle temperatures (lean: 1.3 degrees C, obese: 0.7 degrees C) than the obese rats. The calculated heat flows indicated a predominant conductive transfer of heat from muscle through the skin in lean rats but a higher proportion of heat transfer to the blood in obese rats. It is concluded that muscle heat accumulation did not cause fatigue in either case.


Metabolic effect of alpha-and the beta-adrenergic stimulation of rat submaxillary gland in vitro.
1. Incubation of submaxillary-gland slices with isoproterenol, a beta-adrenergic agonist, stimulated glucose removal by 41% and decreased tissue [glucose 6-phosphate] by 50%. Propranolol blocked these effects of isoproterenol. 2. Phenylephrine, an alpha-adrenergic agonist, stimulated glucose removal by 35% and decreased tissue [glucose 6-phosphate] by 75%. In addition, phenylephrine also completely overcame the inhibition of pyruvate removal caused by acetoacetate metabolism and decreased tissue [atp] by 45%. Phentolamine blocked the effects of phenylephrine. 3. In contrast with beta-adrenergic stimulation, alpha-adrenergic stimulation required exogenous Ca2+. 4. These results explain the different metabolic responses of the submaxillary gland to adrenaline in the presence and absence of exogenous Ca2+.


[Outlook of surgical treatment of servicemen with pathology of knee joint in the specialized orthopedo-traumatology department].
Analyzed data from annual reports of major trauma districts, chiefs of departments of hospitals and centers and reviewed the frequency and structure of surgical interventions on the knee, made in the last 5 years (2005-2010) in health care facilities the Defense Ministry. The frequency of the most typical injuries and diseases of the knee joint in different categories of servicemen. An integrated laboratory and endoscopic examination of patients with reactive arthritis, associated with latent urogenital infection and how the underlying disease and disease associated surgical pathology knee. Formulated evidence-based recommendations for improving the organization of surgical treatment of soldiers with the pathology of the knee.


Vascularization in Ornamented Osteoderms: Physiological Implications in Ectothermy and Amphibious Lifestyle in the Crocodylomorphs?
Vascularization in the core of crocodylian osteoderms, and in their superficial pits has been hypothesized to be a key feature involved in physiological thermoregulation and/or acidosis buffering during anoxia (apnea). However, up to now, there have been no quantitative data showing that the inner, or superficial, blood supply of the osteoderms is greater than that occurring in neighboring dermal tissues. We provide such data: our results clearly indicate that the vascular networks in both the osteoderms and the pits forming their superficial ornamentation are denser than in the overlying dermis. These results support previous physiological assumptions and indicate that vascularization in pseudosuchian (crocodylians and close relatives) ornamented osteoderms could be part of a broad eco-physiological adaptation towards ectothermy and aquatic ambush predation acquired by the crocodylomorphs during their post-Triassic evolution. Moreover, regressions demonstrate that the number of enclosed vessels is correlated with the sectional area of the cavities housing them (superficial pits and inner cavities). These regressions can be used to infer the degree of vascularization on dry and fossilized osteoderms and thus document the evolution of the putative function of the osteoderms in the Pseudosuchia. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 301:175-183, 2018. © 2017 Wiley Periodicals, Inc.


Expression of p53 protein product in triple negative breast cancers and relation with clinical and histopathological parameters.
"Triple" negative breast cancer is a subgroup of so-called basal-like breast cancer. They are represented with 15% of all breast cancers, characterized with lack of hormone receptor as well as with negative expression of HER2 test. These tumors are more frequent in Afro-Americans and Latin-Americans, in patients with BRCA1 mutations and in patients with recent delivery. The aim of this study is to present the immunohistochemical and clinico-pathological characteristics of the triple negative breast cancer and their correlation with expression of the protein product of the tumor suppressor gene p53. A retrospective analyses of 24 patients with triple negative breast cancer was performed. All of the patients were evaluated in the Histopathological Laboratory of the Clinical Hospital Sistina, during the period from June 2009, until June 2011. The standard immunohistochemical procedures, including the hormone receptor status, HER2 status, proliferative index - Ki67 and p53 gene protein product were performed, as well as additional immunohistochemical staining for so-called basal keratins (Cytokeratin 5/6 and high molecular weight cytokeratin 34BE12). The age of the patients ranged from 29-77 years. Positive lymph nodes were found in 14 (59%) patients. The tumor was poorly differentiated in 19 patients (79%). Overexpression of the p53 protein product was evaluated in 19 (79%) of the cases. All p53 negative patients (5/5) had poorly differentiated tumors (G3), associated with positive regional lymph nodes. The p53 positive group expressed quite opposite correlation, only 9/19 (47%) were with positive lymph nodes (p = 0.03). The expression of p53 protein product was also associated with the nuclear grade (p = 0.005), the mitotic index (p = 0.001), lymph-vascular invasion (p = 0.005) and with the proliferation index Ki67 (p = 0.003). There was a trend for association with the tumor size - pT (p = 0.05). According to the results, the triple negative breast cancers are subgroup of the poorly differentiated neoplasms frequently associated in the younger age groups. The majority of these have overexpression of the p53 protein product, which in other hand, are inversely correlated with lymph nodes metastases. Hence, the necessity of enriching the immunohistochemical protocol of these patients with new antibodies, in order to evaluate their expression, which would be helpful for prediction the outcome of different therapeutical modalities.


The metabolic syndrome induces early changes in the swine renal medullary mitochondria.
The metabolic syndrome (MetS) is associated with nutrient surplus and kidney hyperfiltration, accelerating chronic renal failure. Mitochondria can be overwhelmed by substrate excess, leading to inefficient energy production and thereby tissue hypoxia. Mitochondrial dysfunction is emerging as an important determinant of renal damage, but whether it contributes to MetS-induced renal injury remains unknown. We hypothesized that early MetS induces kidney mitochondrial abnormalities and dysfunction, which would be notable in the vulnerable renal medulla. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with the mitochondria-targeted peptide elamipretide (0.1 mg/kg SC q.d), and Lean controls (n = 7 each). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were measured in-vivo, whereas cortical and medullary mitochondrial structure and function and renal injurious pathways were studied ex-vivo. Blood pressure was slightly elevated in MetS pigs, and their renal blood flow and glomerular filtration rate were elevated. Blood oxygen level-dependent magnetic resonance imaging demonstrated that this was associated with medullary hypoxia, whereas cortical oxygenation remained intact. MetS decreased renal content of the inner mitochondrial membrane cardiolipin, particularly the tetra-linoleoyl (C18:2) cardiolipin species, and altered mitochondrial morphology and function, particularly in the medullary thick ascending limb. MetS also increased renal cytochrome-c-induced apoptosis, oxidative stress, and tubular injury. Chronic mitoprotection restored mitochondrial structure, ATP synthesis, and antioxidant defenses and decreased mitochondrial oxidative stress, medullary hypoxia, and renal injury. These findings implicate medullary mitochondrial damage in renal injury in experimental MetS, and position the mitochondria as a therapeutic target.


Exposure to phthalates and their alternatives in relation to biomarkers of inflammation and oxidative stress in adults: evidence from NHANES 2017-2018.
Phthalates and their alternatives are considered significant environmental risk factors that potentially influence inflammation and oxidative stress. However, their impact on biomarkers of inflammation and oxidative stress was inconsistent. This study aimed to explore the associations between phthalates and high-sensitivity C-reactive protein (hsCRP), gamma-glutamyl transferase (GGT), and white blood cell (WBC) counts, employing both univariate exposure and multivariate co-exposure models. For this analysis, a total of 1619 individuals aged 18 years and above, sourced from the National Health and Nutrition Examination Survey (NHANES) conducted between 2017 and 2018, were selected as subjects. We explored the associations between hsCRP, GGT, and WBC counts and eighteen different phthalate metabolites. Multiple linear regression analysis revealed significant associations between both MCNP and MEHP and hsCRP. We observed negative correlations of MCOP, MCPP, MHBP, and MONP with GGT. Conversely, MEHHP and MEHHTP exhibited positive correlations with GGT. Furthermore, MECPTP and MEHHTP showed positive correlations with WBC. Notably, we identified a non-linear relationship between phthalates and inflammation and oxidative stress markers. The Bayesian kernel machine regression (BKMR) analysis demonstrated a negative joint effect of the phthalates mixture on GGT, particularly at lower concentrations. The BKMR model also found that MEOHP and MHiBP were negatively associated with GGT. In contrast, MEHHP showed a significant positive association with GGT. Moderating effect analysis suggested that dietary inflammatory index (DII), income-to-poverty ratio (PIR), age, BMI, and physical activity influenced the association between phthalates and inflammation and oxidative stress. These findings contribute to a deeper understanding of the relationships between phthalates and inflammation and oxidative stress.


Diel, daily, and spatial variation of coral reef seawater microbial communities.
Reef organisms influence microorganisms within the surrounding seawater, yet the spatial and temporal dynamics of seawater microbial communities located in proximity to corals are rarely investigated. To better understand reef seawater microbial community dynamics over time and space, we collected small-volume seawater samples during the day and night over a 72 hour period from three locations that differed in spatial distance from 5 Porites astreoides coral colonies on a shallow reef in St. John, U.S. Virgin Islands: near-coral (sampled 5 cm horizontally from each colony), reef-depth (sampled 2 m above each colony) and surface seawater (sampled 1 m from the seawater surface). At all time points and locations, we quantified abundances of microbial cells, sequenced small subunit rRNA genes of bacterial and archaeal communities, and measured inorganic nutrient concentrations. Prochlorococcus and Synechococcus cells were consistently elevated at night compared to day and these abundances changed over time, corresponding with temperature, nitrite, and silicate concentrations. During the day, bacterial and archaeal alpha diversity was significantly higher in reef-depth and near-coral seawater compared to the surface seawater, signifying that the reef influences the diversity of the seawater microorganisms. At night, alpha diversity decreased across all samples, suggesting that photosynthesis may favor a more taxonomically diverse community. While Prochlorococcus exhibited consistent temporal rhythmicity, additional taxa were enriched in reef seawater at night compared to day or in reef-depth compared to surface seawater based on their normalized sequence counts. There were some significant differences in nutrient concentrations and cell abundances between reef-depth and near-coral seawater but no clear trends. This study demonstrates that temporal variation supersedes small-scale spatial variation in proximity to corals in reef seawater microbial communities. As coral reefs continue to change in benthic composition worldwide, monitoring microbial composition in response to temporal changes and environmental fluctuations will help discern normal variability from longer lasting changes attributed to anthropogenic stressors and global climate change.


Transcriptional regulation of drug-resistance genes in Candida albicans biofilms in response to antifungals.
Biofilm formation is a major virulence attribute of Candida albicans and is directly associated with therapeutic failure. One method by which Candida acquires antifungal resistance is the expression of drug-resistance genes. This study aimed to evaluate the transcriptional regulation of several genes associated with antifungal resistance of C. albicans under planktonic, recently adhered and biofilm growth modes and in C. albicans biofilms in response to antifungal agents. Initially, the antifungal susceptibility of C. albicans cultures in different growth modes was evaluated by standard antifungal susceptibility testing. Next, to assess CDR1, CDR2, MDR1, ERG11, FKS1 and PIL1 expression, RNA was harvested from cells in each growth mode, and from biofilms after drug treatment, and subjected to quantitative real-time RT-PCR (qRT-PCR). Biofilm C. albicans was more resistant to antifungals than recently adhered cells and stationary-phase planktonic cultures. Transcriptional expression of CDR1, CDR2, MDR1, ERG11 and FKS1 was lower in recently adhered C. albicans than in the stationary-phase planktonic cultures. In contrast, PIL1 levels were significantly increased in recently adhered and biofilm modes of growth. The expression of MDR1 in biofilms greatly increased on challenge with amphotericin B but not with the other drugs tested (P<0.01). ERG11 was significantly upregulated by ketoconazole (P<0.01). Caspofungin and amphotericin B significantly upregulated FKS1 expression, whereas they significantly downregulated PIL1 expression (P<0.01). These results indicate that the expression of drug-resistance genes is associated with higher drug resistance of Candida biofilms, and lay a foundation for future large-scale genome-wide expression analysis.


Tests for candidate-gene association using case-parents design.
In the case-parents design for testing candidate-gene association, the conditional likelihood method based on genotype relative risks has been developed recently. A specific relation of the genotype relative risks is referred to as a genetic model. The efficient score tests have been used when the genetic model is correctly specified under the alternative hypothesis. In practice, however, it is usually not able to specify the genetic model correctly. In the latter situation, tests such as the likelihood ratio test (LRT) and the MAX3 (the maximum of the three score statistics for dominant, additive, and recessive models) have been used. In this paper, we consider the restricted likelihood ratio test (RLRT). For a specific genetic model, simulation results demonstrate that RLRT is asymptotically equivalent to the score test, and both are more powerful than the LRT. When the genetic model cannot be correctly specified, the simulation results show that RLRT is most robust and powerful in the situations we studied. MAX3 is the next most robust and powerful test. The TDT is the easiest statistic to compute, compared to MAX3 and RLRT. When the recessive model can be eliminated, it is also as robust and powerful as RLRT for other genetic models.


Risk and protective factors for postpartum depression among Polish women - a prospective study.
This prospective study conducted at a single center in 2022 aims to identify risk and protective factors for postpartum depression (PPD) in Polish women and to assess the impact of pregnancy, delivery, the postpartum period, and psychosocial factors on PPD. After delivery and 4 weeks later, 311 women filled out two questionnaires of our design related to risk factors for PPD. Immune Power Personality Questionnaire, Walsh Family Resilience Questionnaire, and Edinburg Postnatal Depression Scale were also applied. The predictors of PPD identified at two time points included: use of antidepressants, previous depressive episodes, family history of depression, risk of preterm delivery, anxiety about child's health, and breastfeeding and sleep problems. Risk factors for PPD found only after delivery were: suicidal ideation before pregnancy, stressful life events, premature rupture of the membranes, and cesarean section. Inhalation analgesia during labor reduced the PPD frequency. At 4 weeks' postpartum, regular physical activity was also predictive of PPD, while breastfeeding, financial satisfaction, and sufficient sleep duration were protective factors. PPD after delivery was negatively correlated with capacity to confide, hardiness, assertiveness, self-complexity, and communication. PPD at 4 weeks postpartum decreased belief systems, organization patterns, and communication. Two proposed self-designed questionnaires can be useful for effectively screening PPD in the Polish population.


Dermatology on Tumblr.
Tumblr broke into the social media scene in 2007 as a micro-blogging platform that hosts 169 million blogs, 75 billion total posts, and 111 million posts daily to date. This study aimed to determine the presence of dermatology-focused journals, organizations, and groups on Tumblr. These were entered into the Tumblr search query to identify affiliated Tumblr blogs and 'dermatology Tumblr' was searched on Google to determine the first four distinct results that were active within the last six months. None of the dermatology-focused journals, organizations, or groups maintained a Tumblr blog and three of the first four blogs on Google were maintained by private practices. In conclusion, Tumblr remains a social media domain that lacks a strong presence from dermatology journals and organizations, remaining an untapped resource for information dissemination and interaction with the public.


Architecture and prototypical implementation of a semantic querying system for big Earth observation image bases.
Spatiotemporal analytics of multi-source Earth observation (EO) big data is a pre-condition for semantic content-based image retrieval (SCBIR). As a proof of concept, an innovative EO semantic querying (EO-SQ) subsystem was designed and prototypically implemented in series with an EO image understanding (EO-IU) subsystem. The EO-IU subsystem is automatically generating ESA Level 2 products (scene classification map, up to basic land cover units) from optical satellite data. The EO-SQ subsystem comprises a graphical user interface (GUI) and an array database embedded in a client server model. In the array database, all EO images are stored as a space-time data cube together with their Level 2 products generated by the EO-IU subsystem. The GUI allows users to (a) develop a conceptual world model based on a graphically supported query pipeline as a combination of spatial and temporal operators and/or standard algorithms and (b) create, save and share within the client-server architecture complex semantic queries/decision rules, suitable for SCBIR and/or spatiotemporal EO image analytics, consistent with the conceptual world model.


Multiple bilateral lower limb fractures in a 2-year-old child: previously unreported injury with a unique mechanism.
Fall from height is a common cause of unintentional injuries in children and accounts for 6% of all trauma-related childhood deaths, usually from head injury. We report a case of a 2-year-old child with multiple fractures of the bilateral lower limbs due to this reason. A child fell from a height of around 15 feet after toppling from a balcony. He developed multiple fractures involving the right femoral shaft, right distal femoral epiphysis (Salter Harris type 2), right distal metaphysis of the tibia and fibula, and undisplaced Salter Harris type 2 epiphyseal injury of the left distal tibia. There were no head, abdominal or spinal injuries. The patient was taken into emergency operation theatre after initial management which consisted of intravenous fluids, blood transfusion, and splintage of both lower limbs. Fracture of the femoral shaft was treated by closed reduction and fixation using two titanium elastic nails. Distal femoral physeal injury required open reduction and fixation with K wires. Distal tibia fractures were closely reduced and managed nonoperatively in both the lower limbs. All the fractures united in four weeks. At the last follow-up, the child had no disability and was able to perform daily activities comfortably. We also proposed the unique mechanism of injury in this report.


Low Serum Carotenoids Are Associated with Self-Reported Cognitive Dysfunction and Inflammatory Markers in Breast Cancer Survivors.
Background: Dietary carotenoids may exert anti-inflammatory activities to reduce inflammation-driven cognitive impairments during cancer and cancer treatment. Our objective was to explore if cognitive function in breast cancer survivors (BCS) differs by serum carotenoid concentrations, and if blood carotenoids concentrations are associated with reduced systemic inflammation. Methods: Objective cognitive function and perceived cognitive impairment of 29 BCS and 38 controls were assessed cross-sectionally with the National Institutes of Health Toolbox Cognition Battery and The Functional Assessment of Cancer Therapy-Cognitive Function Questionnaire, respectively. Serum carotenoid and inflammatory marker (sTNF-RII, IL-6, IL-1ra, CRP) concentrations were measured. Results: Low-carotenoid BCS had more cognitive complaints compared to the low-carotenoid controls (Mdiff = -43.0, p < 0.001) and high-carotenoid controls (Mdiff = -44.5, p < 0.001). However, the cognitive complaints of high-carotenoid BCS were intermediate to and not different than the low-carotenoid BCS, or low- or high-carotenoid controls. BCS performed similarly to controls on all objective cognitive measures. Multiple linear regression, controlling for age and body mass index (BMI), demonstrated an inverse association between serum carotenoid concentrations and pro-inflammatory sTNFR-II (β = 0.404, p = 0.005) and IL-6 concentrations (β = -0.35, p = 0.001), but not IL-1ra or CRP. Conclusions: Higher serum carotenoid concentrations may convey cognitive and anti-inflammatory benefits in BCS. Future research should identify dietary components and patterns that support cognitive health in cancer survivors.


Autophagy negatively regulates keratinocyte inflammatory responses via scaffolding protein p62/SQSTM1.
The scaffolding adaptor protein p62/SQSTM1 (p62) has been shown to be an autophagy receptor that acts as a link between the ubiquitination and autophagy machineries. However, the roles of autophagy and p62 in human keratinocytes are not well understood. In this study, we show that keratinocyte autophagy negatively regulates p62 expression, which is essential for the prevention of excessive inflammation and the induction of cathelicidin in human keratinocytes. Stimulation of TLR2/6 or TLR4 in primary human keratinocytes robustly activated autophagy pathways and up-regulated p62 expression through induction of NADPH oxidases 2 and 4 and the generation of reactive oxygen species. MyD88 and TNFR-associated factor 6, key signaling molecules that mediate TLR activation, played an essential role in the induction of autophagy and p62 expression. Additionally, blockade of autophagy significantly increased the generation of inflammatory cytokines and expression of p62 in primary human keratinocytes. Notably, silencing hp62 through RNA interference resulted in a significant decrease in NF-κB activation, inflammatory cytokine production, cathelicidin expression, and cell proliferation (as well as cyclin D1 expression) in keratinocytes. Epidermal expression of p62 was further found to be significantly higher in psoriatic skin than in skin affected by atopic dermatitis or from healthy controls. Collectively, our data provide new insights into the roles of autophagy and p62 in controlling cutaneous inflammation.


Comparison of Laser Doppler and Laser-Assisted Indocyanine Green Angiography Prediction of Flap Survival in a Novel Modification of the McFarlane Flap.
The McFarlane rat ischemic dorsal skin flap model has been commonly used for clinical vector studies, as well as the testing of noninvasive diagnostics. However, variability of this model secondary to flap contact with the wound bed has led many to question its validity. Here we present a novel modification to the McFarlane skin flap using sterile silicone. We also use this model to test the prognostic efficacy of laser-assisted indocyanine green (ICG) angiography and laser Doppler imaging (LDI). A 3 × 9-cm dorsal skin flap with a cranially based pedicle was created, centered 1 cm distal to the scapulae. The flap was undermined, and in one of the 2 groups, a sterile silicone sheet was placed onto the wound bed. All flaps were then reapproximated with sutures 1-cm intervals. Clinical assessment and perfusion imaging was performed immediately postoperative, and at 24, 48, and 72 hours postsurgery. Postoperative day 7 clinical assessment was obtained before euthanasia. A comparative study using silicone blocked versus unblocked models (n = 6 per group) showed that, clinically, both models had equivalent flap survival [8.5 (0.913) vs 9.5 (1.01) cm]. However, a statistically significant increase in perfusion in the mid-third of unblocked models was observed on POD3 [20.28% (2.7%) vs blocked 13.45% (2.5%), P < 0.05], with a similar increase in the distal third on POD7 [18.73% (2.064%) vs 10.91% (4.19%), P < 0.05]. A prognostic study comparing LDI and ICG angiography prediction of POD7 survival at early time points (n = 10) found that LDI underpredicted flap survival at early time points [84.2% (12.03%) on POD0, 87.35% (16.11%) on POD1]. In contrast, ICG was more proficient [100.1% (10.1%) on POD0]. We present a modification of the McFarlane skin flap model that results in similar clinical results, but with a noted reduction in perfusion inconsistencies noted in unblocked models. The ICG angiography is superior to LDI in predicting POD7 flap necrosis within the first 48 hours postinjury. Future work will focus on histologic validation of our model, and vector efficacy testing.


Comparison of Age of Onset and Frequency of Diabetic Complications in the Very Elderly Patients with Type 2 Diabetes.
The prevalence of type 2 diabetes in elderly people has increased dramatically in the last few decades. This study was designed to clarify the clinical characteristics of type 2 diabetes in patients aged ≥80 years according to age of onset. We reviewed the medical records of 289 patients aged ≥80 years with type 2 diabetes at the outpatient diabetes clinics of Kangwon National University Hospital from September 2010 to June 2014. We divided the patients into middle-age-onset diabetes (onset before 65 years of age) and elderly-onset diabetes (onset at 65+ years of age). There were 141 male and 148 female patients. The patients had a mean age of 83.2±2.9 years and the mean duration of diabetes was 14.3±10.4 years. One hundred and ninety-nine patients had elderly-onset diabetes. The patients with elderly-onset diabetes had a significantly lower frequency of diabetic retinopathy and nephropathy, lower serum creatinine levels, lower glycated hemoglobin (HbA1c) levels, and similar coronary revascularization and cerebral infarction rates compared to those with middle-age-onset diabetes. There was no frequency difference in coronary revascularization and cerebral infarction and HbA1c levels between three subgroups (<5, 5 to 15, and ≥15 years) of diabetes duration in elderly onset diabetes. However, both in the elderly onset diabetes and middle-age-onset diabetes, the cumulative incidence of retinopathy was increasing rapidly according to the duration of diabetes. We report that individuals with elderly-onset diabetes have a lower frequency of diabetic retinopathy and nephropathy and similar cardiovascular complications compared to those with middle-age-onset diabetes.


Phylogenetic analysis of the species Theilovirus: emerging murine and human pathogens.
The Cardiovirus genus of the family Picornaviridae includes two distinct species, Encephalomyocarditis virus and Theilovirus. We now report the complete nucleotide sequences of three Theiler's murine encephalomyelitis virus (TMEV) strains (TO Yale, TOB15, and Vie 415HTR) and of Vilyuisk human encephalomyelitis virus (VHEV). This information, together with the recently reported sequences of divergent theiloviruses (Theiler's-like rat virus [TRV] and Saffold viruses 1 and 2 [SAFV-1 and SAFV-2]), enables an updated phylogenetic analysis as well as a reexamination of several gene products important in the pathogenesis of this emerging group of viruses. In the light of the known neurotropism of TMEV and the new human SAFV-1 and SAFV-2, the resulting data suggest the existence of theiloviruses that cause human central nervous system infections. Our phylogenetic analyses point to the classification of presently known theiloviruses into five types: TMEV, VHEV, TRV, SAFV-1, and SAFV-2.


Comparison of serologic assays for measurement of antibody response to coronavirus in cats.
Serologic virus neutralization tests, indirect immunofluorescence tests, and ELISA, using tissue culture-adapted feline infectious peritonitis virus (FIPV) or feline enteric coronavirus (FECV) were compared for their ability to distinguish specific virus exposure in cats. Sera of specific-pathogen-free cats inoculated with virulent or modified FIPV or FECV were used to compare the sensitivity and specificity of the homologous assays to a heterologous assay that measures antibody reactivity with transmissible gastroenteritis virus of swine. The geometric means of the serologic titers in FIPV and FECV assays were higher for FIPV- or FECV-infected specific-pathogen-free cats than the geometric means of the transmissible gastroenteritis virus assays for most groups. None of the assays was specific enough to discern the virus to which a cat had been exposed. However, the FIPV virus neutralization test appeared to be more sensitive for detection of an early response to FIPV infection than did the FIPV immunofluorescence test or FIPV-ELISA.


Behaviors and strategies of bacterial navigation in chemical and nonchemical gradients.
Navigation of cells to the optimal environmental condition is critical for their survival and growth. Escherichia coli cells, for example, can detect various chemicals and move up or down those chemical gradients (i.e., chemotaxis). Using the same signaling machinery, they can also sense other external factors such as pH and temperature and navigate from both sides toward some intermediate levels of those stimuli. This mode of precision sensing is more sophisticated than the (unidirectional) chemotaxis strategy and requires distinctive molecular mechanisms to encode and track the preferred external conditions. To systematically study these different bacterial taxis behaviors, we develop a continuum model that incorporates microscopic signaling events in single cells into macroscopic population dynamics. A simple theoretical result is obtained for the steady state cell distribution in general. In particular, we find the cell distribution is controlled by the intracellular sensory dynamics as well as the dependence of the cells' speed on external factors. The model is verified by available experimental data in various taxis behaviors (including bacterial chemotaxis, pH taxis, and thermotaxis), and it also leads to predictions that can be tested by future experiments. Our analysis help reveal the key conditions/mechanisms for bacterial precision-sensing behaviors and directly connects the cellular taxis performances with the underlying molecular parameters. It provides a unified framework to study bacterial navigation in complex environments with chemical and non-chemical stimuli.


In vivo regulation of syndecan-3 expression in the rat uterus by 17 beta-estradiol.
The immature rat uterus has been extensively used as an in vivo model system to study the molecular mechanisms of steroid hormone actions. In this study, we demonstrated the regulated expression of syndecan-3 in the rat uterus by the steroid hormone 17 beta-estradiol. Administration of a single physiological dose of 17 beta-estradiol (40 microg/kg) to ovariectomized immature animals induced a rapid and transient increase in uterine syndecan-3 mRNA. Transcript levels reached a peak elevation of 3-fold above saline control tissues 4 h after hormone administration. Inhibition of message up-regulation by actinomycin D but not cycloheximide indicated a hormone response dependent on RNA transcription but not new protein synthesis. The estrogenic ligands estriol and tamoxifen were also effective at raising syndecan-3 mRNA levels; however, nonestrogenic ligands, including progesterone, 5 alpha-dihydrotestosterone, and dexamethasone, failed to stimulate a change in mRNA levels. Hormone-induced changes in mRNA led to transient changes in syndecan-3 protein content and significant alteration in the temporal and spatial expression in endometrial epithelial cells. Collectively, these data show that the steroid hormone 17 beta-estradiol, regulates transcription of the syndecan-3 gene in the uterus via an estrogen receptor-dependent mechanism. This estrogen-regulated expression of syndecan-3 may play an important role in changes in tissue ultrastructure crucial for proper uterine growth.


Pelagicoccus mobilis gen. nov., sp. nov., Pelagicoccus albus sp. nov. and Pelagicoccus litoralis sp. nov., three novel members of subdivision 4 within the phylum 'Verrucomicrobia', isolated from seawater by in situ cultivation.
Five Gram-negative, white-pigmented, spherical, chemoheterotrophic bacteria were isolated from seawater from Japan and the Republic of Palau by use of an in situ cultivation technique. Phylogenetic analyses based on 16S rRNA gene sequences indicated that the five novel isolates, 02PA-Ca-133(T), YM14-201(T), H-MN57(T), H-MN48 and MN1-156, were closely affiliated to members of subdivision 4 within the phylum 'Verrucomicrobia'. The novel isolates shared 96-100 % sequence similarity with each other and showed less than 90 % similarity with the cultivated strains of subdivision 4. DNA-DNA relatedness values between strains 02PA-Ca-133(T), YM14-201(T) and H-MN57(T) were less than 70 %; the value commonly accepted as the threshold for the phylogenetic definition of a species. Antibiotic susceptibility tests and amino acid analysis of cell-wall hydrolysates indicated that the novel isolates did not contain muramic acid or diaminopimelic acid in their cell walls, suggesting that these strains lack peptidoglycan. The DNA G+C contents of the five strains were 51-57 mol%. The major menaquinone was MK-7 and C(16 : 0), C(16 : 1)omega 7c and anteiso-C(15 : 0) were the major fatty acids. On the basis of polyphasic taxonomic evidence, it is concluded that these strains should be classified as representing a new genus and three novel species in subdivision 4 of the phylum 'Verrucomicrobia', for which the names Pelagicoccus mobilis gen. nov., sp. nov. [type strain 02PA-Ca-133(T) (=MBIC08004(T)=IAM 15422(T)=KCTC 13126(T))], Pelagicoccus albus sp. nov. [type strain YM14-201(T) (=MBIC08272(T)=IAM 15421(T)=KCTC 13124(T))] and Pelagicoccus litoralis sp. nov. [type strain H-MN57(T) (=MBIC08273(T)=IAM 15423(T)=KCTC 13125(T))] are proposed.


Biomimetic spiral grating for stable and highly efficient absorption in crystalline silicon thin-film solar cells.
By emulating the phyllotaxis structure of natural plants, which has an efficient and stable light capture capability, a two-dimensional spiral grating is introduced on the surface of crystalline silicon solar cells to obtain both efficient and stable light absorption. Using the rigorous coupled wave analysis method, the absorption performance on structural parameter variations of spiral gratings is investigated firstly. Owing to diffraction resonance and excellent superficies antireflection, the integrated absorption of the optimal spiral grating cell is raised by about 77 percent compared with the conventional slab cell. Moreover, though a 15 percent deviation of structural parameters from the optimal spiral grating is applied, only a 5 percent decrease of the absorption is observed. This reveals that the performance of the proposed grating would tolerate large structural variations. Furthermore, the angular and polarization dependence on the absorption of the optimized cell is studied. For average polarizations, a small decrease of only 11 percent from the maximum absorption is observed within an incident angle ranging from -70 to 70 degrees. The results show promising application potentials of the biomimetic spiral grating in the solar cell.


Determination of chloroacetanilides, triazines and phenylureas and some of their metabolites in soils by pressurised liquid extraction, GC-MS/MS, LC-MS and LC-MS/MS.
Pressurised liquid extraction (PLE) technique was used for the simultaneous extraction of phenylureas, triazines and chloroacetanilides and some of their metabolites from soils. Extractions were performed by mixing 15 g of dried soil with 30 mL of acetone under 100 atm at 50 degrees C, during 3 min and with three PLE cycles. Prior to the analysis of naturally contaminated soils, each of the five representative soil matrices used as blanks (of different depths) was spiked in triplicate with standards of each parent and degradation compound at about 10, 30 and 120 microg/kg. For each experiment, isoproturon-D6 and atrazine-D5 were used as surrogates. Analysis of phenylureas and metabolites of triazines and phenylureas was carried out by reversed phase liquid chromatography/mass spectrometry (LC-MS) and LC-MS/MS in the positive mode. Gas chromatography (GC)/ion trap mass spectrometry was used in the MS/MS mode for the parent triazines and chloroacetanilides. The average extraction recoveries were above 85%, except for didesmethyl-isoproturon, and quantification limits were between 0.5 and 5 microg/kg. The optimised multi-residue method was applied to soils and solids below the root zone, sampled from agricultural plots of a small French hydrogeological basin.


Normative models and healthcare planning: network-based simulations within a geographic information system environment.
Network analysis to integrate patient, transportation and hospital characteristics for healthcare planning in order to assess the role of geographic information systems (GIS). A normative model of base-level responses of patient flows to hospitals, based on estimated travel times, was developed for this purpose. A GIS database developed to include patient discharge data, locations of hospitals, US TIGER/Line files of the transportation network, enhanced address-range data, and U.S. Census variables. The study area included a 16-county region centered on the city of Charlotte and Mecklenburg County, North Carolina, and contained 25 hospitals serving nearly 2 million people over a geographic area of nearly 9,000 square miles. Normative models as a tool for healthcare planning were derived through a spatial Network analysis and a distance optimization model that was implemented within a GIS. Scenarios were developed and tested that involved patient discharge data geocoded to the five-digit zip code, hospital locations geocoded to their individual addresses, and a transportation network of varying road types and corresponding estimated travel speeds to examine both patient discharge levels and a doubling of discharge levels associated with total discharges and DRG 391 (Normal Newborns). The Network analysis used location/allocation modeling to optimize for travel time and integrated measures of supply, demand, and impedance. Patient discharge data from the North Carolina Medical Database Commission, address-ranges from the North Carolina Institute for Transportation Research and Education, and U.S. Census TIGER/Line files were entered-into the ARC/INFO GIS software system for analysis. A relational database structure was used to organize the information and to link spatial features to their attributes. Advances in healthcare planning can be achieved by examining baseline responses of patient flows to distance optimization simulations and healthcare scenarios conducted within a spatial context that uses a normative model to integrate characteristics of population, patients, hospitals, and transportation networks. Model runs for the defined scenarios indicated that a doubling of the 1991 patient discharge levels resulted in an areal constriction of the service areas to those zip codes immediately adjacent to the hospitals, thereby leaving substantial areas unassigned to hospitals during the allocation process, but that doubling the demand for obstetrics care (DRG 391) resulted in little change in the pattern of accessibility to care as indicated by the size, orientation, and pattern of the service areas. The GIS-Network system supported "what if" simulations, portrayed service areas within a spatial context, integrated disparate data in the execution of the location/allocation model, and used estimated travel time along a transportation network instead of Euclidean distance for calculating accessibility. The results of the simulations suggest that the GIS-Network system is an effective approach for exploring a variety of healthcare scenarios where changes in the supply, demand, and impedance variables can be examined within a spatial context and where variations in system trajectories can be simulated and observed.


Managing uncertainty in couples living with atrial fibrillation.
Living with a chronic disease such as atrial fibrillation (AF) not only affects the patient but also has implications for the partner. There is a lack of research on couples living with AF and, in particular, how they experience and deal with the disease. The aim of this study was to explore couples' main concerns when one of the spouses is afflicted with AF and how they continually handle it within their partner relationship. Classical grounded theory was used throughout the study for data collection and analysis. Interviews were conducted with 12 couples (patient and partner together). There were follow-up interviews with 2 patients and 2 partners separately. Couples living with AF experience uncertainty as a common main concern. This uncertainty was fundamentally rooted in not knowing the cause of AF and apprehension about AF episodes. Couples managed this uncertainty by either explicitly sharing concerns related to AF or through implicitly sharing their concerns. Explicit sharing incorporated strategies of mutual collaboration and finding resemblance, whereas implicit sharing incorporated strategies of keeping distance and tacit understanding. Time since diagnosis and time being symptom-free were factors influencing afflicted couples' shifting between implicit and explicit sharing. Atrial fibrillation affects the partner relationship by bringing uncertainty into couples' daily lives. Even though this study shares similarities with previous studies on couples living with chronic disease, it contributes to the existing knowledge by presenting a set of strategies used by couples in managing uncertainty when living with AF.


Screening Mammography: A Pilot Study on Its Pertinence in Indian Population by Means of a Camp.
Breast cancer incidence and related mortality is increasing in Indian women. Indian ladies hesitate to seek medical care for breast related issues. Screening mammography, proved to effectively reduce mortality, has been deemed not feasible in Indian context due to cost considerations. The suggested alternatives have not been proven to improve mortality rates. To find the relevance of screening mammography camp among Indian women. A week long screening mammography camp was organized in a tertiary care hospital. Clinical examination was done followed by bilateral mammography. Mammograms were reported as per American College of Radiology-Breast Imaging Reporting and Data Systems (ACR-BIRADS) 5th edition specifications. Lesions deemed BIRADS 4 and 5 were biopsied. BIRADS 3 category findings were suggested short interval follow up. A total of 118 women, ranging from 35 to 64 years of age with mean age of 49.6 years underwent mammography. Thirty ladies with dense breast compositions further underwent sono-mammography. Six (5.1%) new cases of breast carcinomas were detected during this study and 28 (23.7%) cases with probably benign findings were advised short interval follow up. Mammography, being a proven screening modality effective in reducing mortality, needs incorporation into the nationwide program for breast cancer detection, inspite of financial considerations. Organizing mammography camps will help create awareness and encourage public to utilize services.


De novo balanced translocation (6;18)(q21;q21.3 or q22) [corrected] in a patient with heterotaxia.
We report on a sporadic case of heterotaxia with a de novo chromosome structural abnormality. The patient had inversely located heart (dextrocardia), stomach, duodenum, and cecum. In addition, she had cerebral atrophy, hypertelorism with telecanthus, infraorbital skin furrows, ear-lobe grooves, prominent maxilla and teeth, large carp mouth, short fifth fingers with limited flexion, generalized hypotonicity, and severe psychomotor retardation. High-resolution chromosome banding analysis demonstrated an apparently balanced translocation: 46,XX,t(6;18)(q21;q21.3). It is hypothesized that both heterotaxia and the chromosomal abnormality in the patient are causally related and a putative situs determining gene has been disrupted by the chromosome break, i.e., a position effect or a cryptic deletion at around the breakpoints. The translocation in our patient may be a good source for positional cloning of the gene.


Exploring causal associations between alcohol and coronary heart disease risk factors: findings from a Mendelian randomization study in the Copenhagen General Population Study.
To explore the causal effect of long-term alcohol consumption on coronary heart disease risk factors. We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on body mass index (BMI), blood pressure (BP), lipids, fibrinogen, and glucose. Analyses were undertaken in 54 604 Danes (mean age 56 years). Both confounder-adjusted multivariable and IV analyses suggested that a greater alcohol consumption among those who drank any alcohol resulted in a higher BP [mean difference in SBP per doubling of alcohol consumption among drinkers: 0.76 mmHg (95% CI: 0.63, 0.90) from multivariable analyses and 0.94 mmHg (-3.03, 4.69) from IV analyses; P-value for difference in these results = 0.95]. The positive association of alcohol with HDLc in the multivariable analyses [4.9% (4.7, 5.1)] appeared stronger than in the IV analyses [1.5% (-4.5, 7.4)], and the weak inverse association with fibrinogen in the multivariable analysis [-2.0% (-2.1, -1.8)] was not present in the IV analyses [0.6% (-3.8, 5.0)], but statistically the results for both of these could not be reliably distinguished from each other (P-values 0.21 and 0.32, respectively). The weak inverse association of alcohol with BMI [-0.13 kg/m(2) (-0.16, -0.10)] and with triglycerides [-0.4% (-0.7, 0.4)] in multivariable analyses were in contrast to the strong positive association of alcohol with BMI [1.37 kg/m(2) (0.59, 2.15)] and the strong inverse association with triglycerides [-14.9% (-25.6, -4.3)] in IV analyses; P = 0.006 and 0.01, respectively, for difference between the two. Alcohol was not associated with non-HDLc or glucose. Our results show adverse effects of long-term alcohol consumption on BP and BMI. We also found novel evidence for a potentially beneficial effect on triglyceride levels, which needs further replication.


Hematopoietic stem cell transplantation with umbilical cord multipotent stromal cell infusion for the treatment of aplastic anemia--a single-center experience.
The purpose of this study was to observe the outcome of co-transfusion of umbilical cord multipotent stromal cells (UC-MSC) and allogeneic hematopoietic stem cells in the treatment of heavily-transfused patients with severe aplastic anemia. Of the 22 patients, eight cases received haploidentical hematopoietic stem cells from granulocyte colony-stimulating factor-primed bone marrow and peripheral blood grafts; the other patients received granulocyte colony-stimulating factor-mobilized peripheral blood grafts from human leukocyte antigen-matched related (six cases) and unrelated donors (eight cases). MSCs were intravenously infused at a mean dose of 1.2 × 10(6)/ kg (range, 0.27-2.5 × 10(6)/kg). Fludarabine-based conditioning was conducted, and graft-versus-host disease prophylaxis containing cyclosporine A, methotrexate and mycophenolate mofetil with or without addition of anti-CD25 monoclonal antibody was performed. Hematopoietic engraftment, the occurrence of graft-versus-host disease (GVHD) and infections and overall survival were documented. All patients had rapid engraftment; mean time for neutrophil and platelet recovery was 13.95 d and 20.27 d, respectively. No acute toxicity associated with UC-MSC transfusion was observed. Acute GVHD developed in seven cases (grade I-II), and none had development of chronic GVHD. Cytomegalovirus reactivation was observed in 11 cases. One patient died of pulmonary complication 6 months after transplantation. Twenty-one patients are currently alive, at a median follow-up of 15 months; they are transfusion-independent and reached full donor chimerism at the time of reporting. UC-MSC infusion might be an alternative option to promote hematopoietic engraftment and reduce the occurrence of GHVD in hematopoietic stem cell transplantation in the treatment of heavily transfused patients with severe aplastic anemia.


Medical Cannabis: A Review from the American Society of Pain and Neuroscience.
Cannabinoids have recently gained a renewed interest due to their potential applicability to various medical conditions, specifically the management of chronic pain conditions. Unlike many other medications, medical cannabis is not associated with serious adverse events, and no overdose deaths have been reported. However, both safety and efficacy data for medical cannabis treatment of chronic, nonmalignant pain conditions are lacking. Therefore, representatives from the American Society of Pain and Neuroscience summarize the evidence, according to level and grade, for medical cannabis treatment of several different pain conditions. Treatment of cancer-related pain has prospective evidentiary support for the use of medical cannabis. Although 3 large and well-designed randomized controlled trials investigated cannabis treatment of cancer-related pain, the evidence yielded only a grade D recommendation. Neuropathic pain has been investigated in prospective studies, but a lack of high-quality evidence renders cannabis treatment for this indication a grade C recommendation. Both safety and efficacy data are lacking for use of medical cannabis to treat chronic nonmalignant pain conditions.


Investigating Narrative Performance in Children With Developmental Language Disorder: A Systematic Review and Meta-Analysis.
Narrative assessment is one potentially underutilized and inconsistent method speech-language pathologists may use when considering a diagnosis of developmental language disorder (DLD). However, narration research encompasses many varied methodologies. This systematic review and meta-analysis aimed to (a) investigate how various narrative assessment types (e.g., macrostructure, microstructure, and internal state language) differentiate children with typical development (TD) from children with DLD, (b) identify specific narrative assessment measures that result in greater group differences, and (c) evaluate participant and sample characteristics that may influence performance differences. Electronic databases (PsycINFO, ERIC, and PubMed) and ASHAWire were searched on July 30, 2019, to locate studies that reported oral narrative language measures for both DLD and TD groups between ages 4 and 12 years; studies focusing on written narration or other developmental disorders only were excluded. We extracted data related to sample participants, narrative task(s) and assessment measures, and research design. Group differences were quantified using standardized mean differences. Analyses used mixed-effects meta-regression with robust variance estimation to account for effect size dependencies. Searches identified 37 eligible studies published between 1987 and 2019, including 382 effect sizes. Overall meta-analysis showed that children with DLD had decreased narrative performance relative to TD peers, with an overall average effect of -0.82 SD, 95% confidence interval [-0.99, -0.66]. Effect sizes showed significant heterogeneity both between and within studies, even after accounting for effect size-, sample-, and study-level predictors. Across model specifications, grammatical accuracy (microstructure) and story grammar (macrostructure) yielded the most consistent evidence of TD-DLD group differences. Present findings suggest some narrative assessment measures yield significantly different performance between children with and without DLD. However, researchers need to improve consistency of inclusionary criteria, descriptions of sample characteristics, and reporting of correlations between measures to determine which assessment measures reliably distinguish between groups. https://doi.org/10.23641/asha.21200380.


Fast-Acting Insulin Aspart Improves Glycemic Control in Basal-Bolus Treatment for Type 1 Diabetes: Results of a 26-Week Multicenter, Active-Controlled, Treat-to-Target, Randomized, Parallel-Group Trial (onset 1).
This multicenter, treat-to-target, phase 3 trial evaluated the efficacy and safety of fast-acting insulin aspart (faster aspart) versus conventional insulin aspart (IAsp) in adults with type 1 diabetes. The primary end point was change from baseline in HbA1c after 26 weeks. After an 8-week run-in, subjects were randomized (1:1:1) to double-blind mealtime faster aspart (n = 381), IAsp (n = 380), or open-label postmeal faster aspart (n = 382)-each with insulin detemir. HbA1c was reduced in both treatment groups, and noninferiority to IAsp was confirmed for both mealtime and postmeal faster aspart (estimated treatment difference [ETD] faster aspart-IAsp, mealtime, -0.15% [95% CI -0.23; -0.07], and postmeal, 0.04% [-0.04; 0.12]); mealtime faster aspart statistically significantly reduced HbA1c versus IAsp (P = 0.0003). Postprandial plasma glucose (PPG) increments were statistically significantly lower with mealtime faster aspart at 1 h (ETD -1.18 mmol/L [95% CI -1.65; -0.71], -21.21 mg/dL [-29.65; -12.77]; P < 0.0001) and 2 h (-0.67 mmol/L [-1.29; -0.04], -12.01 mg/dL [-23.33; -0.70]; P = 0.0375) after the meal test; superiority to IAsp for the 2-h PPG increment was confirmed. The overall rate of severe or blood glucose-confirmed (plasma glucose <3.1 mmol/L [56 mg/dL]) hypoglycemic episodes and safety profiles were similar between treatments. Faster aspart effectively improved HbA1c, and noninferiority to IAsp was confirmed, with superior PPG control for mealtime faster aspart versus IAsp. Subjects randomized to postmeal faster aspart for all meals maintained HbA1c noninferior to that obtained with mealtime IAsp.


Brain graph super-resolution using adversarial graph neural network with application to functional brain connectivity.
Brain image analysis has advanced substantially in recent years with the proliferation of neuroimaging datasets acquired at different resolutions. While research on brain image super-resolution has undergone a rapid development in the recent years, brain graph super-resolution is still poorly investigated because of the complex nature of non-Euclidean graph data. In this paper, we propose the first-ever deep graph super-resolution (GSR) framework that attempts to automatically generate high-resolution (HR) brain graphs with N' nodes (i.e., anatomical regions of interest (ROIs)) from low-resolution (LR) graphs with N nodes where N<N'. First, we formalize our GSR problem as a node feature embedding learning task. Once the HR nodes' embeddings are learned, the pairwise connectivity strength between brain ROIs can be derived through an aggregation rule based on a novel Graph U-Net architecture. While typically the Graph U-Net is a node-focused architecture where graph embedding depends mainly on node attributes, we propose a graph-focused architecture where the node feature embedding is based on the graph topology. Second, inspired by graph spectral theory, we break the symmetry of the U-Net architecture by super-resolving the low-resolution brain graph structure and node content with a GSR layer and two graph convolutional network layers to further learn the node embeddings in the HR graph. Third, to handle the domain shift between the ground-truth and the predicted HR brain graphs, we incorporate adversarial regularization to align their respective distributions. Our proposed AGSR-Net framework outperformed its variants for predicting high-resolution functional brain graphs from low-resolution ones. Our AGSR-Net code is available on GitHub at https://github.com/basiralab/AGSR-Net.


Regulation of constitutive gene expression through interactions of Sp1 protein with the nuclear aryl hydrocarbon receptor complex.
The region of residues -145 to -119 (CD/L) of the cathepsin D gene promoter contains a GC-rich motif that binds Sp1 protein and an adjacent pentanucleotide (CACGC) that corresponds to the core sequence of a dioxin responsive element (DRE) and binds the aryl hydrocarbon receptor (AhR)-AhR nuclear translocator (Arnt) complex. This Sp1(N)(4)DRE(core) motif has been identified in promoters of several genes in which Sp1 plays an important role in basal gene expression. In transient transfection assays with MCF-7 human breast cancer cells using wild-type pCD/L and constructs mutated in the core DRE (pCD/L(m1)) and Sp1 (pCD/L(m2)) sites, it was shown that both motifs were required for maximal basal activity. The requirements for AhR-Arnt interactions with Sp1 protein for maximal activity of pCD/L were confirmed in wild-type MCF-7 and Hepa 1c1c7 cells and Arnt-deficient Hepa 1c1c7 cells using antisense Arnt and Arnt expression plasmids. The functional interactions of Sp1 with AhR-Arnt were paralleled by physical interactions showing that AhR-Arnt and Sp1 proteins were co-immunoprecipitated and AhR-Arnt enhanced Sp1-[(32)P]CD/L binding in electrophoretic mobility shift assays. The physical and functional interactions of Sp1 with AhR-Arnt proteins bound to the Sp1(N)(4)DRE(core) motif were also dependent on the proximity of these sites, and both the activity and the extent of Sp1-DNA binding decreased as the number of intervening nucleotides increased from 4 to 20. These studies show that regulation of basal expression of some genes by Sp1 may also require interactions with AhR-Arnt.


Distinct roles of two binding sites for the bovine papillomavirus (BPV) E2 transactivator on BPV DNA replication.
The modulation of DNA replication by transcription factors was examined by using bovine papillomavirus type 1 (BPV). BPV replication in vivo requires two viral proteins: E1, an origin-binding protein, and E2, a transcriptional transactivator. In the origin, E1 interacts with a central region flanked by two binding sites for E2 (BS11 and BS12), of which only BS12 has been reported to be essential for replication in vivo. Using chemical interference and electrophoretic mobility shift assays, we found that the binding of E2 to each site stimulates the formation of distinct E1-origin complexes. A high-mobility C1 complex is formed by using critical E2 contacts to BS12 and E1 contacts to the dyad symmetry element. In contrast, interaction of E2 with the BS11 element on the other origin flank promotes the formation of the lower-mobility C3 complex. C3 is a novel species that resembles C2, a previously identified complex that is replication active and formed by E1 alone. The binding of E1 greatly differs in the C1 and C3 complexes, with E1 in the C1 complex limited to the origin dyad symmetry region and E1 in the C3 complex encompassing the region from the proximal edge of BS11 through the distal edge of BS12. We found that the presence of both E2-binding sites is necessary for wild-type replication activity in vivo, as well as for maximal production of the C3 complex. These results show that in the normal viral context, BS11 and BS12 play separate but synergetic roles in the initiation of viral DNA replication that are dependent on their location within the origin. Our data suggest a model in which the binding of E2 to each site sequentially stimulates the formation of distinct E1-origin complexes, leading to the replication-competent complex.