The role of social support and the built environment on diabetes management among structurally exposed populations in three regions in Ghana.
Sub-Saharan Africa is undergoing an epidemiological transition driven by rapid, unprecedented demographic, socio-cultural, and economic transitions. These transitions are driving increases in the risk and prevalence of diabetes and other non-communicable diseases (NCDs). As NCDs rise, several attempts have been made to understand the individual level factors that increase NCDs risks, knowledge, and attitudes around specific NCDs as well as how people live and manage NCDs. While these studies are important, and enhance knowledge on chronic diseases, little attention has been given to the role of social and cultural environment in managing chronic NCDs in underserved settings. Using purposive sampling among persons living with Diabetes Mellitus (PLWD) and participating in diabetes programs from regional and municipal hospitals in the three underserved regions in Ghana (n = 522), we assessed diabetes management and supportive care needs of PLWDs using linear latent and mixed models (gllamm) with binomial and a logit(log) link function. The result indicates that PLWDs with strong perceived social support (OR = 2.27, p ≤ 0.05) were more likely to report good diabetes management compared to PLWDs with weak perceived social support. The built environment, living with other health conditions, household wealth, ethnicity and age were associated with diabetes management. Overall, the study contributes to wider discussions on the role changing built and socio-cultural environments in the rise of diet-related diseases and their management as many Low- and Middle-Income Countries (LMICs) experience rapid epidemiological and nutrition transitions.


Roux-en-Y or Billroth II Reconstruction After Radical Distal Gastrectomy for Gastric Cancer: A Multicenter Randomized Controlled Trial.
The aim of the study was to compare the clinical symptoms between Billroth II (B-II) and Roux-en-Y (R-Y) reconstruction after distal subtotal gastrectomy (DG) for gastric cancer. Surgery is the mainstay of curative treatment for gastric cancer. The technique for reconstruction after DG remains controversial. Both B-II and R-Y are popular methods. This is a prospective multicenter randomized controlled trial. From October 2008 to October 2014, 162 patients who underwent DG were randomly allocated to B-II (n = 81) and R-Y (n = 81) groups. The primary endpoint is Gastrointestinal (GI) Symptoms Score 1 year after surgery. We also compared the nutritional status, extent of gastritis on endoscopy, and quality of life after surgery between the 2 procedures at 1 year. Operative time was significantly shorter for B-II than for R-Y [mean difference 21.5 minutes, 95% confidence interval (95% CI) 3.8-39.3, P = 0.019]. The B-II and R-Y groups had a peri-operative morbidity of 28.4% and 33.8%, respectively (P = 0.500) and a 30-day mortality of 2.5% and 1.2%, respectively (P = 0.500). GI symptoms score did not differ between R-Y versus B-II reconstruction (mean difference -0.45, 95% CI -1.21 to 0.31, P = 0.232). R-Y resulted in a lower median endoscopic grade for gastritis versus B-II (mean difference -1.32, 95% CI -1.67 to -0.98, P < 0.001). We noted no difference in nutritional status (R-Y versus B-II mean difference -0.31, 95% CI -3.27 to 2.65, P = 0.837) and quality of life at 1 year between the 2 groups too. Although BII is associated with a higher incidence of heartburn symptom and higher median endoscopic grade for gastritis, BII and RY are similar in terms of overall GI symptom score and nutritional status at 1 year after distal gastrectomy.


An Important Role of VEGF-C in Promoting Lymphedema Development.
Secondary lymphedema is a common complication after cancer treatment, but the pathomechanisms underlying the disease remain unclear. Using a mouse tail lymphedema model, we found an increase in local and systemic levels of the lymphangiogenic factor vascular endothelial growth factor (VEGF)-C and identified CD68+ macrophages as a cellular source. Surprisingly, overexpression of VEGF-C in a transgenic mouse model led to aggravation of lymphedema with increased immune cell infiltration and vascular leakage compared with wild-type littermates. Conversely, blockage of VEGF-C by overexpression of soluble VEGF receptor-3 reduced edema development, diminishing inflammation and blood vascular leakage. Similar findings were obtained in a hind limb lymph node excision lymphedema model. Flow cytometry analyses and immunofluorescence stainings in lymphedematic tissue showed that VEGF receptor-3 expression was restricted to lymphatic endothelial cells. Our data suggest that endogenous VEGF-C causes blood vascular leakage and fluid influx into the tissue, thus actively contributing to edema formation. These data may provide the basis for future clinical therapeutic approaches.


The use of molecular hybridization to evaluate the divergence of some altered Rickettsia prowazekii strains.
Molecular DNA/DNA hybridization was used to investigate the degree of divergence of different Rickettsia prowazekii strains, namely strain Breinl, the vaccine strain E, its spontaneous erythromycin-resistant mutant, nitrosoguanidine-induced rifampicin-resistant mutant and a variant of strain E with increased virulence upon mouse lung passaging. Hybridization of highly polymerised rickettsial DNAs was carried out on nitrocellulose filters with in vitro labelled fragments of reference DNA of the Breinl strain. Nucleotide composition of the strains was also studied. The results obtained suggest the high degree of homology of nucleotide sequences in DNAs of R. prowazekii strains under study; the existing differences found are within the intraspecies range.


Synthesis and antiviral bioactivities of alpha-aminophosphonates containing alkoxyethyl moieties.
A simple, efficient, and general method has been developed for the synthesis of various alpha-aminophosphonate derivatives 4a-4l by treatment of substituted benzaldehydes and aniline with bis(2-methoxyethyl)- or bis(2-ethoxyethyl) phosphite under microwave irradiation without solvents and catalysts. The products were characterized by elemental analysis, IR, 1H-NMR, 13C- and 31P-NMR spectra. The X-ray crystallographic data of the representative compound 4l was determined. The new alpha-aminophosphonate derivatives were found to possess moderate to good antiviral activity.


Effort-reward imbalance and depressive state in nurses.
The mental health of nurses is an important issue. To examine relationships between effort-reward imbalance (ERI) and depression and anxiety in nurses of a Japanese general hospital. A self-report survey was conducted among 406 nurses. Work stress was measured using a Japanese version of the ERI scale. Depression and anxiety were assessed by an item of the QOL-26. Logistic regression analysis was used to determine the independent contribution of the effort-reward ratios or overcommitment to the depressive state. Both higher effort-money ratio and higher overcommitment significantly correlated with the depressive state (OR: 2.75; 95% CI: 1.34-5.66 and OR: 1.27; 95% CI: 1.15-1.41, respectively). These findings suggest that in addition to effort-money ratio, overcommitment at work is an especially important issue that may be able to be managed in health promotion services for nurses in general hospitals.


Reactive oxygen species mediate oridonin-induced HepG2 apoptosis through p53, MAPK, and mitochondrial signaling pathways.
Oridonin, a diterpenoid isolated from Rabdosia rubescences, could induce apoptosis through the generation of reactive oxygen species (ROS) in human hepatoma HepG2 cells. p53, a specific inhibitor of pifithrin alpha (PFT alpha), markedly inhibited ROS generation and apoptosis, showing that p53 was responsible for the cytotoxity of oridonin through mediation by ROS. Moreover, the ROS activated the p38 kinase, which in turn promoted the activation of p53, as verified by evidence showing that the ROS scavenger N-acetyl-cysteine (NAC) not only blocked the phosphorylation of p38 but also partially inhibited the activation of p53, and the p38 inhibitor SB203580 reduced the activation of p53 as well. Mitochondria were either the sources or the targets of ROS. This study showed that oridonin stimulated mitochondrial transmembrane permeabilization in a ROS-dependent manner because NAC almost thoroughly reversed the drop of mitochondrial transmembrane potential (Deltapsim) and the release of cytochrome c from the mitochondrial inter-membrane space into cytosol. Furthermore, as a result of mitochondrial permeability transition, procaspases-9 and -3 were cleaved into 37- and 17-kDa proteolytic products, respectively, which acted as executors of oridonin-induced apoptosis.


Family history and the risk of prostate cancer.
A case-control study was performed to estimate the relative risk of developing prostate cancer for men with a positive family history. Extensive cancer pedigrees were obtained on 691 men with prostate cancer and 640 spouse controls. Fifteen percent of the cases but only 8% of the controls had a father or brother affected with prostate cancer (P less than .001). Men with a father or brother affected were twice as likely to develop prostate cancer as men with no relatives affected. In addition, there was a trend of increasing risk with increasing number of affected family members such that men with two or three first degree relatives affected had a five and 11-fold increased risk of developing prostate cancer. Recognizing that 9-10% of U.S. men will develop prostate cancer in their lifetime, men with a family history of prostate cancer should be advised of their significantly increased prostate cancer risk and should undergo appropriate screening measures for this disease.


Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis: effects on anxiety behavior in postpartum and virgin female rats.
Emotional hyperreactivity can inhibit maternal responsiveness in female rats and other animals. Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral bed nucleus of the stria terminalis (BSTv) with the α2-autoreceptor antagonist, yohimbine, or the more selective α2-autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine or idazoxan. It was further assessed if the α2-autoreceptor agonist clonidine (which decreases norepinephrine release) would, conversely, reduce dams' anxiety. Groups of diestrous virgins were also examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related behavior in postpartum females. However, BSTv infusion of idazoxan did not reproduce yohimbine's anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv clonidine. Because yohimbine is a weak 5HT1A receptor agonist, other groups of females received BSTv infusion of the 5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related behavior. Lastly, levels of norepinephrine and serotonin in tissue punches from the BSTv did not differ between postpartum and diestrous rats, but serotonin turnover was lower in mothers. These results suggest that the impaired maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both be readily explained by an increase in dams' anxiety, and that BSTv α2-autoreceptor modulation alone has little influence on anxiety-related behaviors in postpartum or diestrous rats.


Enhancement pattern mapping technique for improving contrast-to-noise ratios and detectability of hepatobiliary tumors on multiphase computed tomography.
Currently, radiologists use tumor-to-normal tissue contrast across multiphase computed tomography (MPCT) for lesion detection. Here, we developed a novel voxel-based enhancement pattern mapping (EPM) technique and investigated its ability to improve contrast-to-noise ratios (CNRs) in a phantom study and in patients with hepatobiliary cancers. The EPM algorithm is based on the root mean square deviation between each voxel and a normal liver enhancement model using patient-specific (EPM-PA) or population data (EPM-PO). We created a phantom consisting of liver tissue and tumors with distinct enhancement signals under varying tumor sizes, motion, and noise. We also retrospectively evaluated 89 patients with hepatobiliary cancers who underwent active breath-hold MPCT between 2016 and 2017. MPCT phases were registered using a three-dimensional deformable image registration algorithm. For the patient study, CNRs of tumor to adjacent tissue across MPCT phases, EPM-PA and EPM-PO were measured and compared. EPM resulted in statistically significant CNR improvement (P < 0.05) for tumor sizes down to 3 mm, but the CNR improvement was significantly affected by tumor motion and image noise. Eighty-two of 89 hepatobiliary cases showed CNR improvement with EPM (PA or PO) over grayscale MPCT, by an average factor of 1.4, 1.6, and 1.5 for cholangiocarcinoma, hepatocellular carcinoma, and colorectal liver metastasis, respectively (P < 0.05 for all). EPM increases CNR compared with grayscale MPCT for primary and secondary hepatobiliary cancers. This new visualization method derived from MPCT datasets may have applications for early cancer detection, radiomic characterization, tumor treatment response, and segmentation. We developed a voxel-wise enhancement pattern mapping (EPM) technique to improve the contrast-to-noise ratio (CNR) of multiphase CT. The improvement in CNR was observed in datasets of patients with cholangiocarcinoma, hepatocellular carcinoma, and colorectal liver metastasis. EPM has the potential to be clinically useful for cancers with regard to early detection, radiomic characterization, response, and segmentation.


Use of digitonin extraction to distinguish between autophagic-lysosomal sequestration and mitochondrial uptake of [14C]sucrose in hepatocytes.
In isolated rat hepatocytes, electroinjected [14C]sucrose is sequestered both by mitochondria and by autophagosomes/lysosomes. Radioactivity can be selectively extracted from the latter organelles by low concentrations of digitonin, thereby providing a specific bioassay for autophagic sequestration. By including a digitonin extraction step in the assay procedure, autophagic [14C]sucrose sequestration could be shown to be virtually completely (greater than 90%) suppressed by the autophagy inhibitor 3-methyladenine (10 mM), whereas mitochondrial sugar uptake was unaffected. An amino acid mixture likewise suppressed autophagic sequestration very strongly, while having no detectable effect on the mitochondria.


Vibrational Coupling on Stepwise Hydrogen Bond Formation of Amide I.
Despite the key roles of proteins and nucleic acids in biology, understanding their labile structures and hydrogen bond interactions with guest molecules has posed a critical challenge to the scientific community. In this report, I have used dimethylformamide as a model amide to account for amide hydrogen bond interactions of protein. To quantify hydrogen bond conformation and the structural change, I have monitored the amide I infrared (IR) stretching frequencies while varying the pKa of phenol derivatives. For all phenol derivatives, amide I has formed one hydrogen bond and two hydrogen bond conformation. It has been observed that the formation constant for one hydrogen bond is higher than that of two hydrogen bonds for all phenol derivatives. During the formation of hydrogen bond with amide I, IR absorbance of C═C transition is enhanced for all phenol derivatives. Enhancement of the IR absorbance of the C═C transition indicates hydrogen bond-assisted vibrational coupling between the amide I and phenol ring transition. The relative coupling constant is estimated to be higher for single hydrogen-bonded conformer than the double hydrogen-bonded conformer. This is an intriguing result as the frequency difference between the two coupled transitions predicts otherwise. Using IR absorption spectroscopy, a delicate interplay between hydrogen bonding conformations and intermolecular vibrational coupling between amide I and H-bond donor phenol molecules has been shown. This study can be used as a point of reference for understanding the structural information of proteins, peptides, and nucleosides having hydrogen bond interaction with any drug or ligand molecules. My results as well provide an insight into the vibrational coupling of carbonyl and C═C transition of nucleobases.


Transgenic manipulation of beta-adrenergic receptor kinase modifies cardiac myocyte contraction to norepinephrine.
To determine the direct functional significance of the beta-adrenergic receptor (AR) kinase 1 (beta ARK1) on myocardial performance in the absence of tonic sympathoadrenal neural activation and mechanical loading, we measured the contractile responses to acute beta 1-AR stimulation in left ventricular myocytes isolated from nontransgenic control (NTG) and transgenic mice overexpressing either beta ARK1 (TG beta K12) or a beta ARK1 inhibitor (TGMini27). Contractile response to five concentrations (10(-8)-10(-7) M) of the beta 1-AR agonist norepinephrine (NE) plus prazosin (10(-6) M) was measured after a 60-s rest, i.e., rested-state contraction (RSC), and during steady-state contraction (SSC) stimulation at 0.5 Hz (23 degrees C). At baseline, resting cell length was significantly greater in TG beta K12 myocytes (P < 0.05); however, there were no significant differences in RSC or SSC among NTG, TG beta K12, or TG Mini27 mice. On the other hand, both the dose-response curve and kinetics for the NE-induced SSC response normalized to RSC (SSC/RSC) were significantly different among experimental groups (P < 0.001). Specifically, maximal SSC induced by NE in myocytes isolated from TG beta K12 was only 70% of the response observed in NTG cells and 50% of the response measured in TGMini27. These data suggest that 1) in the absence of circulating catecholamines or basal sympathetic tone, beta ARK1 actions in single myocytes are minimal, and 2) substantial functional beta ARK1 modulation of beta 1-AR signaling occurs in cardiac myocytes even during short-term beta 1-AR stimulation. These results are consistent with a role for agonist-induced phosphorylation and desensitization of cardiac beta 1-ARs by beta ARK1 in single myocytes and highlight the potential functional importance of beta ARK1 as a critical determinant of the cardiac beta 1-AR contractile response.


Aphrodisiac activity of 50% ethanolic extracts of Myristica fragrans Houtt. (nutmeg) and Syzygium aromaticum (L) Merr. & Perry. (clove) in male mice: a comparative study.
Spices are considered as sexual invigorators in the Unani System of Medicine. In order to explore the sexual function improving effect of Myristica fragrans Houtt. (nutmeg) and Syzygium aromaticum (L) Merr. & Perry. (clove) an experimental study was conducted in normal male mice. The extracts (50% ethanolic) of nutmeg and clove were administered (500 mg/kg; p.o.) to different groups of male Swiss mice. Mounting behaviour, mating performance, and general short term toxicity of the test drugs were determined and compared with the standard drug Penegra (Sildenafil citrate). The extracts of the nutmeg and clove were found to stimulate the mounting behaviour of male mice, and also to significantly increase their mating performance. The drugs were devoid of any conspicuous general short term toxicity. The extracts (50% ethanolic) of nutmeg and clove enhanced the sexual behaviour of male mice.


Transcription factor Runx3 regulates interleukin-15-dependent natural killer cell activation.
Natural killer cells belong to the family of innate lymphoid cells comprising the frontline defense against infected and transformed cells. Development and activation of natural killer cells is highly dependent on interleukin-15 signaling. However, very little is known about the transcription program driving this process. The transcription factor Runx3 is highly expressed in natural killer cells, but its function in these cells is largely unknown. We show that loss of Runx3 impaired interleukin-15-dependent accumulation of mature natural killer cells in vivo and under culture conditions and pregnant Runx3(-/-) mice completely lack the unique population of interleukin-15-dependent uterine natural killer cells. Combined chromatin immunoprecipitation sequencing and differential gene expression analysis of wild-type versus Runx3-deficient in vivo activated splenic natural killer cells revealed that Runx3 cooperates with ETS and T-box transcription factors to drive the interleukin-15-mediated transcription program during activation of these cells. Runx3 functions as a nuclear regulator during interleukin-15-dependent activation of natural killer cells by regulating the expression of genes involved in proliferation, maturation, and migration. Similar studies with additional transcription factors will allow the construction of a more detailed transcriptional network that controls natural killer cell development and function.


Essential requirement of antigen presentation by monocyte lineage cells for the activation of primary human gamma delta T cells by aminobisphosphonate antigen.
Human gammadelta T cells respond to nonpeptide Ags such as pyrophosphomonoesters and alkylamines in a gammadelta TCR-dependent manner in the absence of other APCS: Recently, aminobisphosphonates such as pamidronate have also been shown to activate human gammadelta T cells. In the present study, we indicate that activation of primary gammadelta T cells by pamidronate strictly depends on the presence of monocyte-lineage cells, unlike that by pyrophosphomonoesters. Thus, although pamidronate induced cell clustering, proliferation, and IFN-gamma production of gammadelta T cells in the culture of PBMC, it failed to induce any of these activities in the culture of purified primary gammadelta T cells. By adding back the purified monocytes, however, both cell clustering and IFN-gamma production of gammadelta T cells by pamidronate could be restored. The pamidronate-pulsed, but not untreated, myelomonocytic line, THP-1, was capable of activating the purified gammadelta T cells to produce IFN-gamma, which was associated with the down-regulation of gammadelta TCR. Furthermore, pamidronate-pulsed THP-1 cells were significantly more susceptible to gammadelta T cell-mediated cytotoxicity than untreated THP-1. Also, TCR-defective Jurkat T cells transfected with gammadelta TCR genes produced a significant level of IL-2 in response to the pamidronate-pulsed THP-1 cells. These results have suggested strongly that human gammadelta T cells are functionally activated via gammadelta TCR by aminobisphosphonate Ag presented on the surface of monocyte lineage cells rather than directly by its free form.


Metabolic syndrome and glucose tolerance status.
To determine justifiability of oral glucose tolerance test (OGTT) in non diabetic patients with metabolic syndrome (MetS). It was included 398 patients attended to Outpatient Clinics of Sisli Etfal Training and Research Hospital. Eligible patients were assigned as patients with MetS according to International Diabetes Federation (IDF) criteria. After OGTT, there were 7 (2%) diabetic patients, 119 (30%) patients had impaired glucose tolerance (IGT) and 272 (68%) were normal. Height, weight, waist circumference, fasting glycemia, high density cholesterol were not different between IGT and non IGT group. OGTT is necessary in MetS non diabetic situation for detection early prediabetic patients.


Boron uptake measurements in a rat model for Boron Neutron Capture Therapy of lung tumours.
Lung carcinoma is the leading cause of cancer mortality in the Western countries. Despite the introduction over the last few years of new therapeutic agents, survival from lung cancer has shown no discernible improvement in the last 20 years. For these reasons any efforts to find and validate new effective therapeutic procedures for lung cancer are very timely. The selective boron uptake in the tumour with respect to healthy tissues makes Boron Neutron Capture Therapy a potentially advantageous option in the treatment of tumours that affect whole vital organs, and that are surgically inoperable. To study the possibility of applying BNCT to the treatment of diffuse pulmonary tumours, an animal model for boron uptake measurements in lung metastases was developed. Both healthy and tumour-bearing rats were infused with Boronophenylalanine (BPA) and sacrificed at different time intervals after drug administration. The lungs were extracted, and prepared for boron analysis by neutron autoradiography and α-spectroscopy. The boron concentrations in tumour and normal lung were plotted as a function of the time elapsed after BPA administration. The concentration in tumour is almost constant within the error bars for all the time intervals of the experiment (1-8 h), while the curve in normal lung decreases after 4 h from BPA infusion. At 4 h, the ratio of boron concentration in tumour to boron concentration in healthy lung is higher than 3, and it stays above this level up to 8 h. Also the images of boron distribution in the samples, obtained by neutron autoradiography, show a selective absorption in the metastases.


Determination of toxinotypes of environmental Clostridium perfringens by Polymerase Chain Reaction.
Toxinotype of Clostridium perfringens (CP) isolates collected from the Bernam River, Selangor River and Tengi Canal between April 2007 and January 2008 were determined by Polymerase Chain Reaction (PCR) using published primers. All the 147 isolates were toxinotype Type A, harbouring the alpha toxin gene. In addition, 5 of the isolates also had the enterotoxin (CPE) gene.


p300/Sp1-Mediated High Expression of p16 Promotes Endothelial Progenitor Cell Senescence Leading to the Occurrence of Chronic Obstructive Pulmonary Disease.
Chronic obstructive pulmonary disease (COPD) is a common chronic disease and develops rapidly into a grave public health problem worldwide. However, what exactly causes the occurrence of COPD remains largely unclear. Here, we are trying to explore whether the high expression of p16 mediated by p300/Sp1 can cause chronic obstructive pulmonary disease through promoting the senescence of endothelial progenitor cells (EPCs). Peripheral blood EPCs were isolated from nonsmoking non-COPD, smoking non-COPD, and smoking COPD patients. The expressions of p16, p300, and senescence-related genes were detected by RT-PCR and Western Blot. Then, we knocked down or overexpressed Sp1 and p300 and used the ChIP assay to detect the histone H4 acetylation level in the promoter region of p16, CCK8 to detect cell proliferation, flow cytometry to detect the cell cycle, and β-galactosidase staining to count the proportion of senescent cells. The high expression of p16 was found in peripheral blood EPCs of COPD patients; the cigarette smoke extract (CSE) led to the increase of p16. The high expression of p16 in EPCs promoted cell cycle arrest and apoptosis. The CSE-mediated high expression of p16 promoted cell senescence. The expression of p300 was increased in peripheral blood EPCs of COPD patients. Moreover, p300/Sp1 enhanced the histone H4 acetylation level in the promoter region of p16, thereby mediating the senescence of EPCs. And knockdown of p300/Sp1 could rescue CSE-mediated cell senescence. p300/Sp1 enhanced the histone H4 acetylation level in the p16 promoter region to mediate the senescence of EPCs.


Conditional expression of TGF-β1 in skeletal muscles causes endomysial fibrosis and myofibers atrophy.
To study the effects of transforming growth factor beta 1 (TGF-β1) on fibrosis and failure of regeneration of skeletal muscles, we generated a tet-repressible muscle-specific TGF-β1 transgenic mouse in which expression of TGF-β1 is controlled by oral doxycycline. The mice developed muscle weakness and atrophy after TGF-β1 over-expression. We defined the group of mice that showed phenotype within 2 weeks as early onset (EO) and the rest as late onset (LO), which allowed us to further examine phenotypic differences between the groups. While only mice in the EO group showed significant muscle weakness, pathological changes including endomysial fibrosis and smaller myofibers were observed in both groups at two weeks after the TGF-β1 was over-expressed. In addition, the size of the myofibers and collagen accumulation were significantly different between the two groups. The amount of latent and active TGF-β1 in the muscle and circulation were significantly higher in the EO group compared to the LO or control groups. The up-regulation of the latent TGF-β1 indicated that endogenous TGF-β1 was induced by the expression of the TGF-β1 transgene. Our studies showed that the primary effects of TGF-β1 over-expression in skeletal muscles are muscle wasting and endomysial fibrosis. In addition, the severity of the pathology is associated with the total amount of TGF-β1 and the expression of endogenous TGF-β1. The findings suggest that an auto-feedback loop of TGF-β1 may contribute to the severity of phenotypes.


Abnormal glucose metabolism and pancreatic cancer mortality.
Previous studies reported an increased risk of pancreatic cancer among persons with diabetes. Few data exist, however, on the association of postload plasma glucose concentration with pancreatic cancer, which could provide insight into the role of abnormal glucose metabolism in the etiology of pancreatic cancer. To determine the independent association between postload plasma glucose concentration and risk of pancreatic cancer mortality among persons without self-reported diabetes. Prospective cohort study. Employees of 84 Chicago-area organizations, with an average age of 40 years at baseline, were screened from 1963 to 1973 and followed up for an average of 25 years. A total of 96 men and 43 women died of pancreatic cancer among 20,475 men and 15,183 women, respectively. Relationship of pancreatic cancer mortality with postload plasma glucose levels. Compared with a postload plasma glucose level of 6.6 mmol/L (119 mg/dL) or less and after adjusting for age, race, cigarette smoking, and body mass index, the relative risks (95% confidence intervals) of pancreatic cancer mortality were 1.65 (1.05-2.60) for postload plasma glucose levels between 6.7 (120) and 8.8 (159) mmol/L (mg/dL); 1.60 (0.95-2.70) for levels between 8.9 (160) and 11.0 (199); and 2.15 (1.22-3.80) for levels of 11.1 (200) or more; P for trend=.01. An association appeared to be stronger for men than women. Estimates were only slightly lower after excluding 11 men and 2 women who died of pancreatic cancer during the first 5 years of follow-up. In men only, higher body mass index and serum uric acid concentration also were independently associated with an elevated risk of pancreatic cancer mortality. These results suggest that factors associated with abnormal glucose metabolism may play an important role in the etiology of pancreatic cancer. JAMA. 2000;283:2552-2558


Is It worth Considering Circulating microRNAs in Multiple Sclerosis?
New evidence has highlighted that miRNA production and trafficking can be dysregulated in both autoimmmune and neurological disorders. Multiple sclerosis (MS) in particular is an autoimmune pathology leading to neurodegeneration. Profiling studies performed on cells derived from MS patients have described a dysregulated network of miRNAs in both immune and neural cells. Interestingly, new evidence has emerged showing that circulating miRNAs are also dysregulated in MS body fluids, including plasma/serum and cerebrospinal fluid. This review summarizes the current scientific theories on the function of this altered circulating miRNA network. It builds up new insights about miRNA transfer mechanisms including extracellular vesicle trafficking involved in cell-to-cell communication and the possible physiopathological functions of these transfers in MS. Finally, this review proposes that monitoring altered miRNA expression levels could serve as a potential biomarker read-out of MS subtype and severity.


Cycloheximide and 4-OH-TEMPO suppress chloramphenicol-induced apoptosis in RL-34 cells via the suppression of the formation of megamitochondria.
Toxic effects of chloramphenicol, an antibiotic inhibitor of mitochondrial protein synthesis, on rat liver derived RL-34 cell line were completely blocked by a combined treatment with substances endowed with direct or indirect antioxidant properties. A stable, nitroxide free radical scavenger, 4-hydroxy-2,2,6, 6-tetramethylpiperidine-1-oxyl, and a protein synthesis inhibitor, cycloheximide, suppressed in a similar manner the following manifestations of the chloramphenicol cytotoxicity: (1) Oxidative stress state as evidenced by FACS analysis of cells loaded with carboxy-dichlorodihydrofluorescein diacetate and Mito Tracker CMTH2MRos; (2) megamitochondria formation detected by staining of mitochondria with MitoTracker CMXRos under a laser confocal microscopy and electron microscopy; (3) apoptotic changes of the cell detected by the phase contrast microscopy, DNA laddering analysis and cell cycle analysis. Since increases of ROS generation in chloramphenicol-treated cells were the first sign of the chloramphenicol toxicity, we assume that oxidative stress state is a mediator of above described alternations of RL-34 cells including MG formation. Pretreatment of cells with cycloheximide or 4-hydroxy-2,2, 6,6-tetramethylpiperidine-1-oxyl, which is known to be localized into mitochondria, inhibited the megamitochondria formation and succeeding apoptotic changes of the cell. Protective effects of cycloheximide, which enhances the expression of Bcl-2 protein, may further confirm our hypothesis that the megamitochondria formation is a cellular response to an increased ROS generation and raise a possibility that antiapoptotic action of the drug is exerted via the protection of the mitochondria functions.


The SH2 domains of Stat1 and Stat2 mediate multiple interactions in the transduction of IFN-alpha signals.
Analysis of the ability of IFN-alpha to rapidly stimulate genes has led to the identification of a new family of signal transducing factors (STFs). The STF activated by IFN-alpha consists of two members of the STAT (Signal Transducers and Activators of Transcription) family of signaling proteins, Stat1 and Stat2. Sequence comparison of these STATs has determined that they share several conserved domains, the most notable of which is an SH2 domain. Recently, studies have determined that these SH2 domains can mediate a specific association between a STAT and the cytoplasmic domain of the appropriate receptor. Once associated with the receptor, the STATs become activated by an associated tyrosine kinase, whereupon they dissociate from the receptor and dimerize to form active STFs. The SH2 domain has also been implicated in the formation of STAT dimers found in STFs, suggesting it may play multiple roles in signaling. We have carried out a detailed analysis on the role of the Stat1 and Stat2 SH2 domains in the mediation of IFN-alpha stimulated signals. These studies, which have determined that the SH2 domain of Stat1 and Stat2 can mediate homo- as well as heterodimerization, suggest that a single SH2 domain-phosphotyrosyl interaction is sufficient for dimerization. Moreover, they provide the first direct evidence that the target of the SH2 domain is the STAT tyrosine activation site. In addition, these studies implicate the SH2 domain in another step in the signaling cascade, namely mediation of the interaction between STATs and their activating kinases (i.e. the JAKs).


Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects.
P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein expression and oral bioavailability of digoxin. We wanted to establish easy-to-use and cost-effective genotyping assays for the major known MDR1 single nucleotide polymorphisms and study the allelic frequency distribution of the single nucleotide polymorphisms in a large sample of volunteers. In this study, the distribution of the major MDR1 alleles was determined in 461 white volunteers with the use of polymerase chain reaction and restriction fragment length polymorphism. Five amino acid exchanges were found with allelic frequencies of 11.2% for Asn21Asp and 5.5% for Ser400Asn. Strikingly, in exon 21 three variants were discovered at the same locus: 2677G (56.4%), 2677T (41.6%), and 2677A (1.9%), coding for 893Ala, Ser, or Thr. A novel missense Gln1107Pro mutation was found in two cases (0.2%). The highest frequencies were observed for intronic and silent polymorphisms; C3435T occurred in 53.9% of the subjects heterozygously, and 28.6% of individuals were homozygous carriers of 3435T/T with functionally restrained P-glycoprotein. This study provides the first analysis of MDR1 variant genotype distribution in a large sample of white subjects. It gives a basis for large-scale clinical investigations on the functional role of MDR1 allelic variants for bioavailability of a substantial number of drugs.


[Hypotension syndrome caused by shrinkage of the lens capsule].
Two cases of ocular hypotony in myopic eyes following extracapsular surgery are described. A trampoline-like shrinkage of the posterior capsule and severe hypotony developed four and eight weeks after cataract extraction without IOL implantation. After discussion of the capsule by YAG-laser an IOP overshoot to more than 50 mmHg occurred, but three weeks later the IOP had dropped to normal values without further medical treatment. All transition stages to hypotony seem to be possible, thus explaining the well-known pressure-lowering effect of extracapsular cataract surgery can be understood.


Hyperbolic metamaterial lens with hydrodynamic nonlocal response.
We investigate the effects of hydrodynamic nonlocal response in hyperbolic metamaterials (HMMs), focusing on the experimentally realizable parameter regime where unit cells are much smaller than an optical wavelength but much larger than the wavelengths of the longitudinal pressure waves of the free-electron plasma in the metal constituents. We derive the nonlocal corrections to the effective material parameters analytically, and illustrate the noticeable nonlocal effects on the dispersion curves numerically. As an application, we find that the focusing characteristics of a HMM lens in the local-response approximation and in the hydrodynamic Drude model can differ considerably. In particular, the optimal frequency for imaging in the nonlocal theory is blueshifted with respect to that in the local theory. Thus, to detect whether nonlocal response is at work in a hyperbolic metamaterial, we propose to measure the near-field distribution of a hyperbolic metamaterial lens.


A Leucine Aminopeptidase-Activated Theranostic Prodrug for Cancer Diagnosis and Chemotherapy.
Currently, chemotherapy is a widely used and important treatment for cancer. However, almost all of the treatments have shortcomings associated with poor specificity and high toxicity, which results in severe side effects to normal cells and tissue. This is a very important problem, and yet, it currently remains unanswered. Therefore, the development of the method for the more effective delivery of anticancer drugs to their targets and real-time monitoring of the localization of the drugs are very important. Herein, we designed a theranostic prodrug: CPT-p-Leu, which was constructed using fluorescent camptothecin (CPT), a self-immolative linker and leucine (Leu) residue. Upon exposure to LAP (leucine aminopeptidase: LAP), the amide bond in CPT-p-Leu will be cleaved, followed by an intramolecular 1,6-elimination, which triggers the active anticancer drug (CPT) release and recovers the fluorescence of CPT. With our design, the anticancer drug, CPT, can be used as both a drug and a fluorescence reporter, making our system suitable to accurately and effectively track the released CPT distribution. Based on this strategy, CPT-p-Leu could achieve the chemoselective detection of LAP and monitoring of the anticancer drug release. Furthermore, it also provides a very convenient way to accurately determine the location of the released drug in living samples. In addition, CPT-p-Leu shows a good cell membrane permeability and enhanced cytotoxicity toward LAP overexpressing cancer cells. We anticipate that our research will facilitate the development of improved theranostic systems for cancer therapy.


Clinical Reasoning as a Core Competency.
Diagnostic error is a challenging problem; addressing it effectively will require innovation across multiple domains of health care, including medical education. Diagnostic errors often relate to problems with clinical reasoning, which involves the cognitive and relational steps up to and including establishing a diagnostic and therapeutic plan with a patient. However, despite a call from the National Academies of Sciences for medical educators to improve the teaching and assessment of clinical reasoning, the creation of explicit, theory-informed clinical reasoning curricula, faculty development resources, and assessment tools has proceeded slowly in both undergraduate and graduate medical education. To accelerate the development of this critical element of health professions education and to promote needed research and innovation in clinical reasoning education, the Accreditation Council for Graduate Medical Education (ACGME) should revise its core competencies to include clinical reasoning. The core competencies have proven to be an effective means of expanding educational innovation across the United States and ensuring buy-in across a diverse array of institutions and disciplines. Reformulating the ACGME core competencies to include clinical reasoning would spark much-needed educational innovation and scholarship in graduate medical education, as well as collaboration across institutions in this vital aspect of physicianship, and ultimately, could contribute to a reduction of patient suffering by better preparing trainees to build individual, team-based, and system-based tools to monitor for and avoid diagnostic error.


Steroids in severe head injury: A prospective randomized clinical trial.
This is a prospective randomized study of the efficacy of steroid therapy in patients with severe head injury. One hundred patients were randomized into two equal groups: the steroid group received 5 mg/kg/day of methylprednisolone, and the nonsteroid group received no drug. The groups were similar in their clinical features. All patients received a standardized therapeutic regimen. The patients were also classified as early responders or nonresponders to the overall treatment protocol without regard to steroid administration, on the basis of change in Glasgow Coma Scale score during the first 3 days of admission. There was no statistically significant difference in the outcome of the steroid and nonsteroid group at 6 months. Of the responders who were on steroids, 74% had good outcomes or were disabled, compared with 56% of the responders who did not receive steroids. In the nonresponder group, the patients on steroids were actually associated with a worse outcome than those who did not receive steroids: 75% of the nonresponders who received steroids were dead or vegetative, compared to 56% of those who were not receiving steroids. The data suggest that: 1) the effect of steroids may be different for different patient groups; 2) in order to identify these patients, a sensitive coma scale is needed; and 3) a rational approach to steroid therapy in head-injured patients may be to start all patients on steroids, but to discontinue their use in patients identified as not benefiting from steroid therapy.


Behavioral health outcomes and social determinants of health in children with diabetes and juvenile arthritis.
Objective : Children with chronic illnesses, including arthritis, are at increased risk for adverse psychosocial outcomes influenced by social determinants of health (SDOH). Comparing psychosocial outcomes in families affected by juvenile arthritis compared to other chronic illnesses may help identify areas in need of special attention vs areas that may be addressed through adopting other disease examples' care models. We examined child and parent behavioral health outcomes for families with juvenile arthritis compared to diabetes, accounting for SDOH. Methods Secondary data analysis of the National Survey of Children's Health including 365 children (<18yrs) with arthritis and 571 children with diabetes. Psychosocial outcomes were depression, anxiety, ADHD, physical pain, behavioral problems, and treatment for mental health. School outcomes were school engagement, school absence, involvement in clubs/organization, and involvement in organized activities. Parent outcomes were family resilience, emotional support, coping with daily demands of raising a child, job change due to problems with childcare, and parent mental health. SDOH variables were food insecurity, food/cash assistance, unsafe neighborhood, detracting neighborhood elements, parent education, households earning <100% of the federal poverty line. Logistic regression analyses were utilized to examine variation in child and parent outcomes, variation in SDOH, and the role of SDOH. Results Children with arthritis experienced significantly more physical pain, anxiety, depression, ADHD, and behavior problems compared to children with diabetes. Children with arthritis were more likely to see a mental health professional and get treatment for problems with emotions/behaviors. When considering SDOH, children with arthritis were still more likely to experience adverse psychosocial outcomes but were no longer more likely to get treatment. Children with arthritis had increased likelihood of school absence and were less involved in organized activities than children with diabetes. Parents of children with arthritis had poorer mental health than parents of children with diabetes. SDOH were more prevalent in children with arthritis than children with diabetes. Conclusions Increased risk for adverse psychosocial outcomes in youth with arthritis compared to youth with diabetes indicates a need to mirror endocrinology models of care in rheumatology clinics. The role of SDOH highlights the need for regular SDOH screening in clinic.


Evaluation of body mass index, pre-vaccination serum progesterone levels and anti-anthrax protective antigen immunoglobulin G on injection site adverse events following anthrax vaccination in women.
In 2002, CDC initiated the Anthrax Vaccination Program (AVP) to provide voluntary pre-exposure anthrax vaccination for individuals at high risk for exposure to Bacillus anthracis spores. The AVP offered an opportunity to investigate hypothesized reasons for a reported gender difference in injection site adverse events (AEs) following anthrax vaccine adsorbed (AVA). To evaluate in women the impact of body mass index (BMI), pre-vaccination serum progesterone levels, and pre-vaccination anti-anthrax protective antigen immunoglobulin G concentrations (anti-PA IgG) on the occurrence of AEs following subcutaneous AVA vaccination. Participants' BMI was determined at enrollment. Also, pre-vaccination blood samples were assayed for serum progesterone and anti-PA IgG. Post-vaccination solicited AEs were recorded by participants using a 4-day diary card. Obese group had an elevated risk for arm soreness. Decreased pre-vaccination serum progesterone level was associated with arm swelling. Increased pre-vaccination anti-PA IgG was associated with itching on the arm; and within the obese group, was associated with arm swelling, lump or knot, redness, soreness, and warmth. In AVA vaccinated women, obesity was associated with arm soreness and decreased pre-vaccination serum progesterone levels were associated with increased rate of arm swelling. Increased pre-vaccination anti-PA IgG may be associated with an increased frequency of itching on the arm, and in obese women, may increase the occurrence of arm swelling, lump or knot, redness, and warmth. Administering AVA according to a woman's menstrual phase may reduce the occurrence of certain injection site reactions.


Assessing telomeric DNA content in pediatric cancers using whole-genome sequencing data.
Telomeres are the protective arrays of tandem TTAGGG sequence and associated proteins at the termini of chromosomes. Telomeres shorten at each cell division due to the end-replication problem and are maintained above a critical threshold in malignant cancer cells to prevent cellular senescence or apoptosis. With the recent advances in massive parallel sequencing, assessing telomere content in the context of other cancer genomic aberrations becomes an attractive possibility. We present the first comprehensive analysis of telomeric DNA content change in tumors using whole-genome sequencing data from 235 pediatric cancers. To measure telomeric DNA content, we counted telomeric reads containing TTAGGGx4 or CCCTAAx4 and normalized to the average genomic coverage. Changes in telomeric DNA content in tumor genomes were clustered using a Bayesian Information Criterion to determine loss, no change, or gain. Using this approach, we found that the pattern of telomeric DNA alteration varies dramatically across the landscape of pediatric malignancies: telomere gain was found in 32% of solid tumors, 4% of brain tumors and 0% of hematopoietic malignancies. The results were validated by three independent experimental approaches and reveal significant association of telomere gain with the frequency of somatic sequence mutations and structural variations. Telomere DNA content measurement using whole-genome sequencing data is a reliable approach that can generate useful insights into the landscape of the cancer genome. Measuring the change in telomeric DNA during malignant progression is likely to be a useful metric when considering telomeres in the context of the whole genome.


Prospective cohort study comparing intravenous busulfan to total body irradiation in hematopoietic cell transplantation.
We conducted a prospective cohort study testing the noninferiority of survival of ablative intravenous busulfan (IV-BU) vs ablative total body irradiation (TBI)-based regimens in myeloid malignancies. A total of 1483 patients undergoing transplantation for myeloid malignancies (IV-BU, N = 1025; TBI, N = 458) were enrolled. Cohorts were similar with respect to age, gender, race, performance score, disease, and disease stage at transplantation. Most patients had acute myeloid leukemia (68% IV-BU, 78% TBI). Grafts were primarily peripheral blood (77%) from HLA-matched siblings (40%) or well-matched unrelated donors (48%). Two-year probabilities of survival (95% confidence interval [CI]), were 56% (95% CI, 53%-60%) and 48% (95% CI, 43%-54%, P = .019) for IV-BU (relative risk, 0.82; 95% CI, 0.68-0.98, P = .03) and TBI, respectively. Corresponding incidences of transplant-related mortality (TRM) were 18% (95% CI, 16%-21%) and 19% (95% CI, 15%-23%, P = .75) and disease progression were 34% (95% CI, 31%-37%) and 39% (95% CI, 34%-44%, P = .08). The incidence of hepatic veno-occlusive disease (VOD) was 5% for IV-BU and 1% with TBI (P < .001). There were no differences in progression-free survival and graft-versus-host disease. Compared with TBI, IV-BU resulted in superior survival with no increased risk for relapse or TRM. These results support the use of myeloablative IV-BU vs TBI-based conditioning regimens for treatment of myeloid malignancies.


Sexual trauma and the female brain.
Sexual aggression and violence against women (VAM) are not only social problems; they are mental health problems. Women who experience sexual trauma often express disruptions in emotional and cognitive processes, some of which lead to depression and post-traumatic stress disorder (PTSD). Animal models of neurogenesis and learning suggest that social yet aggressive interactions between a pubescent female and an adult male can disrupt processes of learning related to maternal care, which in turn reduce survival of new neurons in the female hippocampus. Mental and Physical (MAP) Training is a novel clinical intervention that was translated from neurogenesis research. The intervention, which combines meditation and aerobic exercise, is currently being used to help women learn to recover from traumatic life experiences, especially those related to sexual violence and abuse.


Phlebotomy skills expected of career entry CLS/CLT graduates: a Missouri hospital perspective.
To determine how much, what type, and what proficiency of phlebotomy experience CLS/CLT students should have during the training program to be prepared to meet the needs of the majority of Missouri hospital employers. Survey to determine the role healthcare professionals, inside and outside the laboratory, play in today's blood collection patterns and phlebotomy management. The Missouri Organization of Clinical Laboratory Science mailed 204 surveys to the Missouri Hospital Association member laboratories. MAIN OUTCOMES/CONCLUSIONS: This research examined the need for modifying phlebotomy skills of clinical laboratory science students. Data gathered from employers support the premise that entry-level competencies of CLS/CLT graduates will vary according to clinical facility size. CLS/CLT programs may use data from this study to plan phlebotomy practicums. It can be extrapolated that Missouri employers who are most likely to employ career entry graduates expect them to draw blood from 9.3 patients within one hour. Fifty-three percent of 40 to 400 bed hospitals expect graduates to perform difficult draws in at least eight types of hospital units. Laboratories are the major managers of hospital wide phlebotomy services; thus, CLS/CLT curricula should include phlebotomy management methods.


In Vitro Fractional Inhibitory Concentration (FIC) Study of Cefixime and Azithromycin Fixed Dose Combination (FDC) Against Respiratory Clinical Isolates.
Acute respiratory infections (ARI) contribute to more than 75% of health care seeking in primary health care facilities in India. Respiratory tract infections (RTIs) are managed frequently by β-lactam, macrolide and fluroquinolone class of antibiotics. However, these recommended classes of antibiotic have shown resistance in community settings. Antibiotic combinations may provide broader spectrum not only in terms of coverage but also to overcome multiple resistance mechanisms overcoming individual class limitations. The study aimed to determine In vitro interactions interpreted according to calculated fractional inhibitory concentration (FIC) index between cefixime and azithromycin against common respiratory clinical isolates. Forty four bacterial respiratory clinical isolates from microbiology department of tertiary care hospital from Mumbai were used to determine the minimum inhibitory concentration (MIC) values of cefixime and azithromycin. Synergy testing of cefixime combination with azithromycin was performed by checkerboard method. Interaction was determined according to calculated FIC index. MIC values were ranging from 2-128 μg/ml and 0.24-128 μg/ml for cefixime and azithromycin respectively against K.pneumoniae, M.catarrhalis, S.pneumoniae and H.influenzae isolates. All the tested isolates were resistant to cefixime. Azithromycin resistance was noted in all the isolates except six M. catarrhalis isolates. FIC index showed synergy and additive effect in 66% (29/44) and 34% (15/44) all bacterial clinical isolates. Maximum synergy between cefixime and azithromycin was observed against K. pneumoniae in 91% isolates. This is one of the first attempts to check the rationality of fixed dose antibiotic combination of cefixime and azithromycin in India market. Though results of this study cannot be generalized considering the limitations of low sample size and in vitro model, our data provides stepping stone for further validation of cefixime and azithromycin fixed dose combinations (FDCs) in clinical setting by conducting randomized controlled trials. We think that judicious and rational use of FDCs may help to reduce the risk of selection of further drug resistance along with better clinical outcome.


[Palliative care for the patients and their families].
This article discusses palliative care for the patients and their families and the role of nurses for a smooth change from inpatient services to home care. Home is where a patient feels most comfortable. To provide the best possible care it is important to respect the decision of the patient and his family maximally and QOL takes top priority. Through the participation of home care doctors, home health nurses, pharmacists, etc., a 24-hour system can be established to improve home care. Simultaneously, the up of a patient self-care agency regards it as an importance. However, it is very difficulty for the patients and their families demonstrate the identity in the complicated medical situation, and thus providing support to them is a function of the nurses. It has been required that nurses in hospitals and home health nurses function to raise patients' self care.


High prevalence of gouty arthritis among the Hmong population in Minnesota.
The prevalence of gout is on the rise worldwide, especially among newly industrialized populations. We evaluated the prevalence of gout in the recently established Hmong of Minneapolis/St. Paul (MSP) compared with that in non-Hmong populations. The prevalence of self-reported gout in the Hmong population was estimated from 2 cross-sectional community surveys and compared with national data extrapolated from the Third National Health and Nutrition Examination Survey. The prevalence of physician-diagnosed gout in Hmong and non-Hmong MSP residents was separately estimated from the diagnosis codes of 11 MSP primary care clinics. The prevalence of self-reported gout among MSP Hmong was 2-fold higher than in the general US population (6.5% versus 2.9%; P < 0.001). Although women of both groups reported gout at a rate of 1.9%, Hmong men were significantly more likely than their non-Hmong counterparts to report gout (11.5% versus 4.1%; P < 0.001). Similar results were observed when investigating physician-diagnosed gout in MSP (2.8% Hmong versus 1.5% non-Hmong; P < 0.001). No difference was observed between the women of the 2 groups (0.8% versus 0.7%; P = 0.833), whereas Hmong men were more than twice as likely to be diagnosed with gout compared with their non-Hmong counterparts (6.1% versus 2.5%; P < 0.001). Among Hmong men, advancing age was associated with a considerably higher likelihood of being diagnosed with gout. A significant association is observed between Hmong ethnicity and gout, both self-reported and physician diagnosed. This unique population may provide an opportunity to further our understanding of the pathophysiology of gout.


Impaired immunity in harbour seals (Phoca vitulina) exposed to bioaccumulated environmental contaminants: review of a long-term feeding study.
Mass mortalities among seals and dolphins inhabiting contaminated marine regions have led to speculation about a possible involvement of immunosuppression associated with environmental pollution. To evaluate whether contaminants at ambient environmental levels can affect immune function of seals, we carried out an immunotoxicological study under semifield conditions. Two groups of 11 harbour seals (Phoca vitulina) originating from a relatively uncontaminated area were fed herring from either the highly polluted Baltic Sea or the relatively uncontaminated Atlantic Ocean. Changes in immune function were monitored over a 2 1/2-year period. The seals that were fed contaminated Baltic herring developed significantly higher body burdens of potentially immunotoxic organochlorines and displayed impaired immune responses as demonstrated by suppression of natural killer cell activity and specific T-cell responses. During a 2-week fasting experiment performed at the end of the feeding study, mobilization of organochlorines from the blubber did not lead to a strong increase of contaminant levels in the blood, and no enhancement of the existing immunosuppression was observed. These results demonstrate that chronic exposure to environmental contaminants accumulated through the food chain affects immune function in harbour seals, whereas short-term fasting periods, which are normal for seals, do not seem to pose an additional risk. The seals of this study were not exposed perinatally to high levels of environmental chemicals, and body burdens of organochlorines measured near the end of the study were lower than those generally observed in free-ranging seals inhabiting many contaminated regions. Therefore, it may be expected that environmental contaminants adversely affect immune function of free-ranging seals inhabiting contaminated regions at least as seriously as observed in these studies.


[The effect of reduced drinking water supply on feed absorption, apparent digestibility of crude nutrients and rumen fermentation of sheep].
Based on the fact that the insufficient supply of agricultural domestic animals with drinking water in tropical and subtropical regions is often the factor limiting their performance, the effect of different drinking water supply of sheep (ad libitum, 54% of ad libitum and 27% of ad libitum) on various parameters was studied. A water supply reduced to 54 and 27% resp. diminished dry matter intake to 84% and 45% resp. A water supply reduced to 54% improved the digestibility of organic matter, crude fibre, crude cellulose and N-free extractives, it was, however, not significant. A reduction to 27% of the ad libitum water supply improved the digestibility of all crude nutrients, significantly, however, only that of organic matter, crude fibre, crude cellulose and N-free extractives. In comparison with a supply of water reduced to 54%, a water supply reduced to 27% also resulted in an improvement of the digestibility of all crude nutrients. Both the reduction of the ad libitum water supply and the increasing time interval for the sampling of rumen fluid resulted in an increased concentration of volatile fatty acids in the rumen fluid, which was sampled 15 min, 1 hour and 2 hours after feeding.


Genetic reinforcement learning through symbiotic evolution for fuzzy controller design.
An efficient genetic reinforcement learning algorithm for designing fuzzy controllers is proposed in this paper. The genetic algorithm (GA) adopted in this paper is based upon symbiotic evolution which, when applied to fuzzy controller design, complements the local mapping property of a fuzzy rule. Using this Symbiotic-Evolution-based Fuzzy Controller (SEFC) design method, the number of control trials, as well as consumed CPU time, are considerably reduced when compared to traditional GA-based fuzzy controller design methods and other types of genetic reinforcement learning schemes. Moreover, unlike traditional fuzzy controllers, which partition the input space into a grid, SEFC partitions the input space in a flexible way, thus creating fewer fuzzy rules. In SEFC, different types of fuzzy rules whose consequent parts are singletons, fuzzy sets, or linear equations (TSK-type fuzzy rules) are allowed. Further, the free parameters (e.g., centers and widths of membership functions) and fuzzy rules are all tuned automatically. For the TSK-type fuzzy rule especially, which put the proposed learning algorithm in use, only the significant input variables are selected to participate in the consequent of a rule. The proposed SEFC design method has been applied to different simulated control problems, including the cart-pole balancing system, a magnetic levitation system, and a water bath temperature control system. The proposed SEFC has been verified to be efficient and superior from these control problems, and from comparisons with some traditional GA-based fuzzy systems.


Indirect and verbal victimization by peers among at-risk youth in residential care.
Verbal and indirect violence among peers in residential care settings (RCSs) are understudied social problems. This study, based on a sample of 1,324 Jewish and Arab adolescents aged 11-19 in 32 RCSs, examines the prevalence and multilevel correlates of verbal (such as cursing) and indirect (such as social exclusion) forms of victimization by peers in RCSs. Adolescents completed a self-report anonymous questionnaire in their facility. Hierarchical Linear Modeling (HLM) is used to examine the links between adolescents' victimization, individual-level characteristics (gender, age, adjustment difficulties, self-efficacy, staff maltreatment experiences and perceived institutional social climate), and RCS-level characteristics (setting type of care, size, structure, and ethnic affiliation). Most adolescents reported having been verbally (73%) and indirectly (62%) victimized by their peers at least once in the month prior to filling out the questionnaire. Vulnerability to indirect violence is higher among girls and those with low perception of their social self-efficacy. Younger adolescents, adolescents with higher levels of overall adjustment difficulties, those experiencing high levels of physical maltreatment by RCS staff and those perceiving levels of child friendliness in their RCS as poor, were all more vulnerable to verbal and indirect victimization by peers. Verbal victimization is positively associated with residence in Jewish RCSs and indirect victimization is positively associated with residence in therapeutic settings which contain higher concentrations of vulnerable youth compared with rehabilitative settings. The findings can assist in designing anti-bullying intervention and prevention programs tailored for the at-risk children and institutions identified in the study.


Disruption of PML-associated nuclear bodies by IE1 correlates with efficient early stages of viral gene expression and DNA replication in human cytomegalovirus infection.
In human cytomegalovirus (HCMV) infection, both of the major immediate-early proteins IE1(IE68, UL123) and IE2(IE86, UL122) target to PML protein-associated nuclear bodies known as PODs or ND10 at very early times after infection. IE1 causes a redistribution of both PML and IE1 from the PODs into a nuclear diffuse form, whereas IE2 initially localizes adjacent to PODs but later associates with viral DNA replication compartments. The peripheries of PODs are also believed to be sites for initiation of both viral IE transcription and DNA replication. However, because IE1 is nonessential at high multiplicity of infection (m.o.i.) in HF cells, the exact role of these processes in viral infection has been enigmatic. Therefore, we investigated the effects of overexpression of PML in the presence or absence of IE1 on the intranuclear distribution of IE2 and formation of viral DNA replication compartments, as well as on the levels of delayed-early and late viral transcription and protein accumulation. Infection with wild-type HCMV(Towne) and the IE1-deleted derivative HCMV(CR208), which fails to disrupt PODs, was compared in a pair of related astrocytoma/glioblastoma cell lines, the U373-Neo control and a variant U373-PML that constitutively overexpresses PML(560) in much larger than normal PODs. IFA studies on the localization patterns for IE1, IE2, and PML showed that, although the numbers of IE2-positive cells were not significantly reduced in either the wild-type virus-infected U373-PML cell line or in DeltaIE1-infected control cells, POD disruption by IE1 in wild-type virus infection was delayed by up to 6 h in U373-PML cells compared to control cells. Furthermore, there was considerable enhancement of IE2 colocalization with PODs in Delta IE1-infected U373-PML cells. Formation of viral DNA replication compartments in the U373-PML cell line was also greatly delayed, measured at fivefold lower after wild-type virus infection and 12-fold lower after infection with Delta IE1 than in the control cell line at 48 h at an m.o.i. of 1.0. The levels of representative early and late viral proteins detected by Western blotting were suppressed by fivefold and 22-fold at 24 and 72 h, respectively, in the U373-PML cell line, even with high m. o.i. wild-type HCMV infection. Decreased viral protein levels also occurred when control cells were infected with the Delta IE1 virus and these two effects were additive in the U373-PML cell line. Similarly, when U373-PML cells were infected with recombinant HCMV expressing an extragenic luciferase reporter gene under the control of viral early (Pol) or late (pp28) promoters, their transcriptional activation was reduced up to fivefold at both high and low m.o.i. compared to that of the control cells. Overall, these results suggest that POD disruption by IE1 and subsequent redistribution of both PML and IE1 at very early times after infection may play an important role in the efficient utilization of cellular transcription and replication machinery by HCMV and contribute to rapid progression of the HCMV lytic cycle.


Molecular phylogeny of Burkholderia pseudomallei from a remote region of Papua New Guinea.
The island of New Guinea is located midway between the world's two major melioidosis endemic regions of Australia and Southeast Asia. Previous studies in Papua New Guinea have demonstrated autochthonous melioidosis in Balimo, Western province. In contrast to other regions of endemicity, isolates recovered from both environmental and clinical sources demonstrate narrow genetic diversity over large spatial and temporal scales. We employed molecular typing techniques to determine the phylogenetic relationships of these isolates to each other and to others worldwide to aid in understanding the origins of the Papua New Guinean isolates. Multi-locus sequence typing of the 39 isolates resolved three unique sequence types. Phylogenetic reconstruction and Structure analysis determined that all isolates were genetically closer to those from Australia than those from Southeast Asia. Gene cluster analysis however, identified a Yersinia-like fimbrial gene cluster predominantly found among Burkholderia pseudomallei derived from Southeast Asia. Higher resolution VNTR typing and phylogenetic reconstruction of the Balimo isolates resolved 24 genotypes with long branch lengths. These findings are congruent with long term persistence in the region and a high level of environmental stability. Given that anthropogenic influence has been hypothesized as a mechanism for the dispersal of B. pseudomallei, these findings correlate with limited movement of the indigenous people in the region. The palaeogeographical and anthropogenic history of Australasia and the results from this study indicate that New Guinea is an important region for the further study of B. pseudomallei origins and dissemination.


Pertussis toxin triggers rapid second messenger production in human T lymphocytes.
Pertussis toxin (PT) is a known mitogen for T lymphocytes. The mechanism by which the toxin stimulates proliferation has remained obscure and paradoxical because, in some types of cells, the toxin also inhibits growth factor-mediated signal transduction. It has previously been shown that the adenosine-diphosphate ribosyltransferase activity of the toxin is not required to produce the mitogenic effect. A biochemical explanation for the mitogenic activity has therefore remained obscure. We investigated the biochemical basis for the mitogenic activity of PT by using the transformed human T cell line, Jurkat. PT stimulated a rapid rise in cytosolic-free [Ca2+] from both intra- and extracellular sources. This was associated with an increase in the cellular diacylglycerol and inositol triphosphate levels with a concomitant decrease in the levels of phosphatidylinositol-4-phosphate and phosphatidylinositol-4,5-bisphosphate. The half-maximal effective dose of PT was 1.7 nM. PT also stimulated the production of interleukin 2. Only the holotoxin or B-oligomer (the presumptive membrane-binding subunit) was capable of stimulating an increase in [Ca2+] in these cells. This activity of PT mimicked that of some anti-T3-T cell antigen receptor complex monoclonal antibodies that also stimulate increases in the second messengers, diacylglycerol and Ca2+. The effects of PT and anti-T3 complex antibody were identical and not additive in Jurkat cells, suggesting that both agents were activating the same signal transduction pathway. These data provide a mechanistic explanation for the mitogenic effects of PT and suggest that the toxin may be interacting with a specific receptor in the T lymphocyte plasma membrane.


Low-dose corticosteroid treatment in septic shock: a propensity-matching study.
Given conflicting data and current guidelines, low-dose corticosteroids are often used in the treatment of septic shock. To evaluate the therapeutic benefit of early low-dose corticosteroid in patients with septic shock. Retrospective, multicenter, propensity-matched cohort study. ICUs of 28 academic and community hospitals in three countries between 1996 and 2007. Six thousand six hundred sixty-three eligible patients with septic shock of whom 1,838 received IV low-dose corticosteroid treatment within 48 hours of the diagnosis of septic shock and were matched to a comparable group who did not receive low-dose corticosteroid. The primary outcome was 30-day mortality. Mortality analyses were stratified by severity of illness (Acute Physiology and Chronic Health Evaluation II quartile). Using a Cox proportional hazards model, corticosteroid therapy was associated with similar 30-day mortality when compared with the matched control cohort (652/1,838 [35.5%] vs 641/1,838 [34.9%]; hazard ratio, 0.98; 95% CI, 0.88-1.10; p = 0.77). In the subgroup of patients with the Acute Physiology and Chronic Health Evaluation II score quartile more than or equal to 30, low-dose corticosteroid was associated with lower mortality (232/461 [50.6%] vs 251/450 [55.8%]; hazard ratio, 0.81; 95% CI, 0.68-0.97; p = 0.02). In logistic regression models, corticosteroid therapy was not associated with reductions in ICU (556/1,838 [30.3%] vs 558/1,838 [30.4%]; odds ratio, 0.99; 95% CI, 0.86-1.15; p = 0.94) or hospital mortality (797/1,838 [43.4%] vs 773/1,838 [42.1%]; odds ratio, 1.05; 95% CI, 0.93-1.20; p = 0.42). Similarly, there were no significant differences in ventilator- (median and interquartile range, 13 [0-25] vs 15 [0-25]; p = 0.8) and pressor/inotrope-free days (median and interquartile range, 25 [3-27] vs 24 [2-28]; p = 0.63) up to 30 days between groups. Early administration of low-dose corticosteroid is not associated with decreased mortality when it is administered to unselected patients with septic shock. A beneficial effect of low-dose corticosteroid on mortality may exist in patients with the highest severity of illness. Future trials of low-dose corticosteroid in septic shock should consider restricting the study population to this cohort.


Histone Deacetylase 8: Characterization of Physiological Divalent Metal Catalysis.
Histone deacetylases (HDACs) are responsible for the removal of acetyl groups from histones, resulting in gene silencing. Overexpression of HDACs is associated with cancer, and their inhibitors are of particular interest as chemotherapeutics. However, HDACs remain a target of mechanistic debate. HDAC class 8 is the most studied HDAC, and of particular importance due to its human oncological relevance. HDAC8 has traditionally been considered to be a Zn-dependent enzyme. However, recent experimental assays have challenged this assumption and shown that HDAC8 is catalytically active with a variety of different metals, and that it may be a Fe-dependent enzyme in vivo. We studied two opposing mechanisms utilizing a series of divalent metal ions in physiological abundance (Zn(2+), Fe(2+), Co(2+), Mn(2+), Ni(2+), and Mg(2+)). Extensive sampling of the entire protein with different bound metals was done with the mixed quantum-classical QM/DMD method. Density functional theory (DFT) on an unusually large cluster model was used to describe the active site and reaction mechanism. We have found that the reaction profile of HDAC8 is similar among all metals tested, and follows one of the previously published mechanisms, but the rate-determining step is different from the one previously claimed. We further provide a scheme for estimating the metal binding affinities to the protein. We use the quantum theory of atoms in molecules (QTAIM) to understand the different binding affinities for each metal in HDAC8 as well as the ability of each metal to bind and properly orient the substrate for deacetylation. The combination of this data with the catalytic rate constants is required to reproduce the experimentally observed trend in metal-depending performance. We predict Co(2+) and Zn(2+) to be the most active metals in HDAC8, followed by Fe(2+), and Mn(2+) and Mg(2+) to be the least active.


Assessment of occupational health and safety hazard exposures among working college students.
Adolescents and young adults have higher injury rates than their adult counterparts in similar jobs. This study used the working college student population to assess health and safety hazards in the workplace, characterize related occupational diseases and injuries, and describe worker health/safety activities provided by employers. College students (≥17 years old) were assessed via online surveys about work history, workplace exposure to hazards, occupational diseases/injuries, and workplace health/safety activities. Approximately half (51%) of participants (n = 1,147) were currently employed at the time of the survey or had been employed while enrolled in college. Restaurants (other than fast food) were the most frequently reported work setting. The most reported workplace hazards included noise exposure and contact with hot liquids/surfaces. Twenty percent of working students experienced injury at work; some injuries were severe enough to limit students' normal activities for >3 days (30%) or require medical attention (44%). Men had significantly higher prevalence of injuries (P = 0.05) and near-misses (P < 0.01) at work than women. Injury occurrence was associated with near-misses (AOR = 5.08, P < 0.01) and co-worker injuries (AOR = 3.19, P < 0.01) after gender and age adjustments. Most (77%) received worker safety training and half were given personal protective equipment (PPE) by their employers. Risk reduction from workplace injuries and illnesses among working college students may be achieved by implementing occupational health and safety (OHS) strategies including incorporation of OHS in the college curriculum, promotion of OHS by university/college student health services, and improving awareness of OHS online resources among college students, employers, and educators.


Dietary (n-3) polyunsaturated fatty acids suppress murine lymphoproliferation, interleukin-2 secretion, and the formation of diacylglycerol and ceramide.
Elucidation of the mechanism(s) by which dietary fish oil, enriched in eicosapentaenoic acid (EPA, 20:5(n-3)] and docosahexaenoic acid [DHA, 22:6(n-3)], suppresses the inflammatory process is essential in maximizing this potentially therapeutic effect. Murine T-lymphocyte function and signal transduction were examined in response to a low fat, short term diet enriched in highly purified EPA or DHA ethyl esters. For 10 d, mice were fed comparable diets containing either 3% safflower oil ethyl esters (SAF), 2% SAF + 1% arachidonic acid triglyceride (AA), 2% SAF + 1% EPA, or 2% SAF + 1% DHA. Concanavalin A-induced T-lymphocyte proliferation in splenocyte cultures was significantly suppressed by dietary EPA and DHA while AA had no effect relative to the SAF control. The suppressed proliferative response in EPA- and DHA-fed mice was preceded temporally by a significant reduction in IL-2 secretion. Kinetics of mitogen-induced diacyl-sn-glycerol (DAG) and ceramide production did not differ significantly between SAF and AA diet groups. In contrast, DAG production was significantly suppressed in EP- and DHA-fed mice relative to the SAF and AA groups. The reduced DAG mass was paralleled by reduced ceramide mass following EPA and DHA feeding compared to the SAF and AA groups. Thus, low dose, short term dietary exposure to highly purified EPA or DHA appears to suppress mitogen-induced T-lymphocyte proliferation by inhibiting IL-2 secretion, and these events are accompanied by reductions in the production of essential lipid second messengers, DAG and ceramide.


Phase retrieval based on the vectorial model of point spread function.
We present an efficient phase retrieval approach for imaging systems with high numerical aperture based on the vectorial model of the point spread function. The algorithm is in the class of alternating minimization methods and can be adjusted for applications with either known or unknown amplitude of the field in the pupil. The algorithm outperforms existing solutions for high-numerical-aperture phase retrieval: (1) the generalization of the method of Hanser et al., based on extension of the scalar diffraction theory by representing the out-of-focus diversity applied to the image by a spherical cap, and (2) the method of Braat et al., which assumes through the use of extended Nijboer-Zernike expansion the phase to be smooth. The former is limited in terms of accuracy due to model deviations, while the latter is of high computational complexity and excludes phase retrieval problems where the phase is discontinuous or sparse. Extensive numerical results demonstrate the efficiency, robustness, and practicability of the proposed algorithm in various practically relevant simulations.


Identification of differentially expressed genes in prostatic epithelium in relation to androgen receptor CAG repeat length.
The CAG repeat within exon 1 of the androgen receptor (AR) has been associated with the development of prostate cancer. The shorter number of glutamine residues in the protein has been associated with a higher transcriptional activity of the AR and increased relative risk for prostate cancer. In an attempt to identify differentially expressed genes in prostate cancer in relation to AR CAG repeat length variation, in this study we used total mRNA from normal and tumor tissues from 2 prostate cancer patients with AR alleles containing 19 and 26 CAG repeats to perform differential-display RT-PCR analysis. We were able to identify 48 different transcripts that showed homology to several known genes associated with different biological pathways. Among the differentially expressed genes, ATRX and SFRP1 were further validated by quantitative RT-PCR. The transcripts of both ATRX and SFRP1 genes proved to be down-regulated in most of the prostate tumors analyzed by quantitative RT-PCR. Hypermethylation of the promoter region of the SFRP1 gene was found in 17.5% (7/40) of the cases analyzed and was associated with the loss of SFRP1 expression (p=0.014). The differentially expressed genes identified in this study are implicated in several cellular pathways that, when up- or down-regulated, might play a role in the tumorigenic process of the prostate.


Evaluating the Effectiveness of an E-Mental Health Intervention for People Living in Lebanon: Protocol for Two Randomized Controlled Trials.
The lack of availability of evidence-based services for people exposed to adversity globally has led to the development of psychological interventions with features that will likely make them more scalable. The evidence for the efficacy of e-mental health from high-income countries is compelling, and the use of these interventions could be a way to increase the coverage of evidence-based psychological interventions in low- and middle-income countries. Step-by-Step is a brief (5-session) intervention proposed by the World Health Organization as an innovative approach to reducing the suffering and disability associated with depression. This study aims to evaluate the effectiveness and cost-effectiveness of a locally adapted version of Step-by-Step with Syrian nationals (trial 1) and Lebanese nationals and other populations residing in Lebanon (trial 2). This Step-by-Step trial involves 2 parallel, two-armed, randomized controlled trials comparing the e-intervention Step-by-Step to enhanced care as usual in participants with depressive symptoms and impaired functioning. The randomized controlled trials are designed and powered to detect effectiveness in 2 populations: Syrians in Lebanon (n=568) and other people residing in Lebanon (n=568; Lebanese nationals and other populations resident in Lebanon). The primary outcomes are depressive symptomatology (measured with the Patient Health Questionnaire-9) and functioning (measured with the World Health Organization Disability Assessment Scale 2.0). Secondary outcomes include anxiety symptoms, posttraumatic stress disorder symptoms, personalized measures of psychosocial problems, subjective well-being, and economic effectiveness. Participants are mainly recruited through online advertising. Additional outreach methods will be used if required, for example through dissemination of information through partner agencies and organizations. They can access the intervention on a computer, tablet, and mobile phone through a hybrid app. Step-by-Step has 5 sessions, and users are guided by trained nonspecialist "e-helpers" providing phone-based or message-based support for around 15 minutes a week. The trials were funded in 2018. The study protocol was last verified June 20, 2019 (WHO ERC.0002797) and registered with ClinicalTrials.gov (NCT03720769). The trials started recruitment as of December 9, 2019, and all data collection was completed in December 2020. The Step-by-Step trials will provide evidence about the effectiveness of an e-mental health intervention in Lebanon. If the intervention proves to be effective, this will inform future scale-up of this and similar interventions in Lebanon and in other settings across the world. ClinicalTrials.gov NCT03720769; https://clinicaltrials.gov/ct2/show/NCT03720769. DERR1-10.2196/21585.


From disaster to development: a systematic review of community-driven humanitarian logistics.
A plethora of untapped resources exist within disaster-affected communities that can be used to address relief and development concerns. A systematic review of the literature relating to community participation in humanitarian logistics activities revealed that communities are able to form ad hoc networks that have the ability to meet a wide range of disaster management needs. These structures, characterised as Collaborative Aid Networks (CANs), have demonstrated efficient logistical capabilities exclusive of humanitarian organisations. This study proposes that CANs, as a result of their unique characteristics, present alternatives to established humanitarian approaches to logistics, while also mitigating the challenges commonly faced by traditional humanitarian organisations. Furthermore, CANs offer a more holistic, long-term approach to disaster management, owing to their impact on development through their involvement in humanitarian logistics. This research provides the foundation for further theoretical analysis of effective and efficient disaster management, and details opportunities for policy and practice.


Multiphoton fluorescence microscopy of the live kidney in health and disease.
The structural and functional heterogeneity of the kidney ensures a diversity of response in health and disease. Multiphoton microscopy has improved our understanding of kidney physiology and pathophysiology by enabling the visualization of the living kidney in comparison with the static view of previous technologies. The use of multiphoton microscopy with rodent models in conjunction with endogenous fluorescence and exogenous infused dyes permits the measurement of renal processes, such as glomerular permeability, juxtaglomerular apparatus function, tubulointerstitial function, tubulovascular interactions, vascular flow rate, and the intrarenal renin-angiotensin-aldosterone system. Subcellular processes, including mitochondrial dynamics, reactive oxygen species production, cytosolic ion concentrations, and death processes apoptosis and necrosis, can also be measured by multiphoton microscopy. This has allowed valuable insight into the pathophysiology of diabetic nephropathy, renal ischemia-reperfusion injury, hypertensive nephropathy, as well as inflammatory responses of the kidney. The current review presents an overview of multiphoton microscopy with a focus on techniques for imaging the kidney and gives examples of instances where multiphoton microscopy has been utilized to study renal pathophysiology in the living kidney. With continued advancements in the field of biological optics and increased adoption in experimental nephrology, multiphoton microscopy will undoubtedly continue to create new paradigms in kidney disease.


An Interpretable Framework for Identifying Cerebral Microbleeds and Alzheimer's Disease Severity using Multimodal Data.
Cerebral microbleeds (CMBs) are tiny chronic brain haemorrhages that have been recognised as prognostic indicators for a number of acute cerebrovascular disorders, such as stroke, traumatic disorder, and Alzheimer's disease. For early-stage chronic disease diagnosis, it is challenging to automate the detection of CMBs and increase the reliability of prediction outputs. This study developed a system for identifying microbleeds in MRI images and gene expression data and determining the severity of Alzheimer's disease (AD). Initially, a spike neural network (SNN) and decision tree were utilised to identify microbleeds in AD from MRI images and gene expression respectively. However, the conclusions of these two methods cannot be interpreted due to the complexity of their internal processing steps. This study proposed two explainable artificial intelligence (XAI) methods for interpreting prediction outputs in an effort to boost reliability. Pixel density analysis (PDA) and probabilistic graphical model (PGM) explain the decision-making processes for MRI images and gene expression data for the diagnosis of microbleeds and the severity analysis of AD.


PI-PLCβ1 gene copy number alterations in breast cancer.
Deregulation of signal transduction pathways frequently confers selective biological advantages to tumors. Phosphoinositides play an essential role in numerous cellular functions and, among the enzymes implicated in these processes, phosphoinositide-specific phospholipase C β1 (PI-PLCβ1) is one of the key regulators. In the present study, a fluorescence in situ hybridization (FISH) approach was used to investigate PI-PLCβ1 gene copy number alterations in various types of breast cancer differing in their invasiveness and proliferative activity, according to their mitotic index. At the molecular level, we also performed both real-time PCR and immunohistochemical analyses on PI-PLCβ1 to further investigate its expression in primary breast cancers. Finally, we analyzed the correlation between PI-PLCβ1 gene copy number and clinicopathological parameters. Our results show that most of our cases had aneusomies on the PI-PLCβ1 locus (20p12) and amplification of this specific region was the most frequent alteration observed. Our findings also indicate that the amplification of the region containing the PI-PLCβ1 gene was mostly related to the mitotic index, rather than to the invasion status. Finally, even though our case series is limited, PI-PLCβ1 gene amplification seems to be correlated to clinicopathological parameters.


Prehospital intraosseus access with the bone injection gun by a helicopter-transported emergency medical team.
To evaluate the use of the bone injection gun to obtain vascular access in the prehospital setting by an Helicopter-Transported Emergency Medical Team. Prospective descriptive study to assess the frequency and success rate of the use of the bone injection gun in prehospital care by a Helicopter-Transported Emergency Medical Team. In 40 of 780 (5.1%) patients, an attempt was made to obtain intraosseous access with the bone injection gun. Intraosseous access was attempted more often in children than in adults (p < 0.01). The success rate was 71% (10 out of 14) in children <16 years and 73% (19 out of 26) in adults (p = 1.0). There were no complications to the health care providers involved and no unwanted sequels to the patients involved. The bone injection gun is an effective and safe device for the resuscitation of patients in a prehospital setting. It seems to be equivalent in success rate as intraosseous needles in children, but it seems to be more successful in adults.


Treatment initiation among persons diagnosed with drug resistant tuberculosis in Johannesburg, South Africa.
In South Africa, roughly half of the drug-resistant TB cases diagnosed are reported to have been started on treatment. We determined the proportion of persons diagnosed with rifampicin resistant (RR-) TB who initiated treatment in Johannesburg after the introduction of decentralized RR-TB care in 2011. We retrospectively matched adult patients diagnosed with laboratory-confirmed RR-TB in Johannesburg from 07/2011-06/2012 with records of patients initiating RR-TB treatment at one of the city's four public sector treatment sites (one centralized, three decentralized). Patients were followed from date of diagnosis until the earliest of RR-TB treatment initiation, death, or 6 months' follow-up. We report diagnostic methods and outcomes, proportions initiating treatment, and median time from diagnosis to treatment initiation. 594 patients were enrolled (median age 34 (IQR 29-42), 287 (48.3%) female). Diagnosis was by GenoType MTBDRplus (Hain-Life-Science) line probe assay (LPA) (281, 47.3%), Xpert MTB/RIF (Cepheid) (258, 43.4%), or phenotypic drug susceptibility testing (DST) (30, 5.1%) with 25 (4.2%) missing a diagnosis method. 320 patients (53.8%) had multi-drug resistant TB, 158 (26.6%) rifampicin resistant TB by Xpert MTB/RIF, 102 (17.2%) rifampicin mono-resistance, and 14 (2.4%) extensively drug-resistant TB. 256/594 (43.0%) patients initiated treatment, representing 70.7% of those who were referred for treatment (362/594). 338/594 patients (57.0%) did not initiate treatment, including 104 (17.5%) who died before treatment was started. The median time from sputum collection to treatment initiation was 33 days (IQR 12-52). Despite decentralized RR-TB treatment, fewer than half the patients diagnosed in Johannesburg initiated appropriate treatment. Offering treatment at decentralized sites alone is not sufficient; improvements in linking patients diagnosed with RR-TB to effective treatment is essential.


Frontal activity during a verbal emotional working memory task in patients with Alzheimer's disease: A functional near-infrared spectroscopy study.
Emotional working memory (EWM) is suggested as a working memory (WM) type, distinguished to process emotional stimuli, and may or may not be spared in Alzheimer's disease (AD). The aim was to compare patients with AD and healthy older adults (HC) on verbal EWM performance and accompanying prefrontal cortex activity. Twenty AD patients along with 20 HC individuals are required to complete an emotional one-back task in three conditions (neutral, positive and negative word lists). Prefrontal oxyhemoglobin (oxyHb) concentrations were measured simultaneously by a 24- channel functional near infrared spectroscopy device. Correct response rates were similar in two groups in all conditions. Reaction times were comparable in the EWM positive condition but longer in the AD group in EWMneutral and negative conditions. In the HC group, emotional words had no significant effect on WM. On the other hand, positive compared to neutral words led to greater activation in the left ventral prefrontal cortex (VPFC) in AD group. When compared to HCs, activity in the VPFC was significantly higher in AD patients during the positive condition. Positive words facilitated WM performance in participants with AD. Activity in VPFC may be the functional correlate of this phenomenon.


Interdisciplinary thinking in agricultural and life sciences higher education.
Interdisciplinary thinking as a skill appears to be of value to higher education students and those in employment. This idea is explored with reference to the agricultural and life sciences. The need for further understanding of the development of interdisciplinary thinking is acknowledged. This is closely related to the requirement for well-founded curriculum and course design. This publication presents a brief introduction to a systematic review of scientific research into teaching and learning in interdisciplinary higher education. While tentative, the understanding arising from the review findings is considered to be of potential value to educational practice. A selection of the review findings is presented by way of illustration. The selection is believed to be of relevance to the agricultural and life sciences. The review findings presented here take the form of interdisciplinary thinking sub skills and enabling conditions.