Selecting performance indicators for prison health care.
Improving prison health care requires a robust measurement dashboard that addresses multiple domains of care. We sought to identify tested indicators of clinical quality and access that prison health managers could use to ascertain gaps in performance and guide quality improvement. We used the RAND/UCLA modified Delphi method to select the best indicators for correctional health. An expert panel rated 111 indicators on validity and feasibility. They voted to retain 79 indicators in areas such as access, cardiac conditions, geriatrics, infectious diseases, medication monitoring, metabolic diseases, obstetrics/gynecology, screening/prevention, psychiatric disorders/substance abuse, pulmonary conditions, and urgent conditions. Prison health institutions, like all other large health institutions, need robust measurement systems. The indicators presented here provide a basic library for prison health managers developing such systems.


[Study of poly(C) and poly(I)-poly(C) complexes with model phospholipid membranes by infrared spectroscopy].
The temperature dependence of poly(C) is shown by the infrared spectroscopy to be different for the free polynucleotide and for the polynucleotide in complexes with membranes. The intensity of stretching vibrations of C = 0 bond of poly(C) in the complex appears to be sensitive to the temperature. The intensity of this band is sharply decreased by increasing the temperature. This effect depends upon concentration of Mg2+-cations. Adsorption of poly(I)-poly(C) on the surface of vesicles from phosphatidylcholine results in the increase of the double helix.


Purinergic signaling between neurons and satellite glial cells of mouse dorsal root ganglia modulates neuronal excitability in vivo.
Primary sensory neurons in dorsal root ganglia (DRG) are wrapped by satellite glial cells (SGCs), and neuron-SGC interaction may affect somatosensation, especially nociceptive transmission. P2-purinergic receptors (P2Rs) are key elements in the two-way interactions between DRG neurons and SGCs. However, because the cell types are in such close proximity, conventional approaches such as in vitro culture and electrophysiologic recordings are not adequate to investigate the physiologically relevant responses of these cells at a population level. Here, we performed in vivo calcium imaging to survey the activation of hundreds of DRG neurons in Pirt-GCaMP6s mice and to assess SGC activation in GFAP-GCaMP6s mice in situ. By combining pharmacologic and electrophysiologic techniques, we investigated how ganglionic purinergic signaling initiated by α,β-methyleneadenosine 5'-triphosphate (α,β-MeATP) modulates neuronal activity and excitability at a population level. We found that α,β-MeATP induced robust activation of small neurons-likely nociceptors-through activation of P2X3R. Large neurons, which are likely non-nociceptive, were also activated by α,β-MeATP, but with a delay. Blocking pannexin 1 channels attenuated the late phase response of DRG neurons, indicating that P2R stimulation may subsequently induce paracrine ATP release, which could further activate cells in the ganglion. Moreover, ganglionic α,β-MeATP treatment in vivo sensitized small neurons and enhanced responses of spinal wide-dynamic-range neurons to subsequent C-fiber inputs, suggesting that modulation via ganglionic P2R signaling could significantly affect nociceptive neuron excitability and pain transmission. Therefore, targeting functional P2Rs within ganglia may represent an important new strategy for pain modulation.


Detection of bacterial DNA in lymph nodes of Crohn's disease patients using high throughput sequencing.
Our aim was to determine whether or not specific microorganisms were transported selectively to lymph nodes in Crohn's disease (CD) by comparing node and mucosal microbial communities in patients and controls. We also sought evidence of dysbiosis and bacterial translocation. Lymph nodes, and involved and uninvolved mucosal samples were obtained from resections of 58 patients (29 CD, eight 'other inflammatory bowel disease' (IBD) and 21 non-IBD). Universal primers targeting V1-V3 regions of bacterial 16S rRNA genes were used to amplify bacterial DNA and amplicons sequenced using high throughput sequencing. 20 patients (eight CD (28%), two other IBD (25%) and 10 non-IBD (48%)) had PCR positive nodes. All samples from an individual were similar: there was no evidence of selective concentration of any microorganism in nodes. No specific microorganism was present in the nodes of all CD samples. Escherichia/Shigella were common in all patient groups but patients with ileal CD had a greater proportion of Escherichia coli reads in their nodes than other CD patients (p=0.0475). Campylobacter, Helicobacter and Yersinia were uncommon; Mycobacterium and Listeria were not detected. Dysbiosis was present in all groups but shifts were specific and no common pattern emerged. It is unlikely that a single bacterium perpetuates inflammation in late stage CD; dysbiosis was common and we found no evidence of increased bacterial translocation. We believe that future studies should focus on early disease and viable bacteria in nodes, aphthous ulcers and granulomas, as they may be more relevant in the initiation of inflammation in CD.


The lifetime medical cost savings from preventing HIV in the United States.
Enhanced HIV prevention interventions, such as preexposure prophylaxis for high-risk individuals, require substantial investments. We sought to estimate the medical cost saved by averting 1 HIV infection in the United States. We estimated lifetime medical costs in persons with and without HIV to determine the cost saved by preventing 1 HIV infection. We used a computer simulation model of HIV disease and treatment (CEPAC) to project CD4 cell count, antiretroviral treatment status, and mortality after HIV infection. Annual medical cost estimates for HIV-infected persons, adjusted for age, sex, race/ethnicity, and transmission risk group, were from the HIV Research Network (range, $1854-$4545/mo) and for HIV-uninfected persons were from the Medical Expenditure Panel Survey (range, $73-$628/mo). Results are reported as lifetime medical costs from the US health system perspective discounted at 3% (2012 USD). The estimated discounted lifetime cost for persons who become HIV infected at age 35 is $326,500 (60% for antiretroviral medications, 15% for other medications, 25% nondrug costs). For individuals who remain uninfected but at high risk for infection, the discounted lifetime cost estimate is $96,700. The medical cost saved by avoiding 1 HIV infection is $229,800. The cost saved would reach $338,400 if all HIV-infected individuals presented early and remained in care. Cost savings are higher taking into account secondary infections avoided and lower if HIV infections are temporarily delayed rather than permanently avoided. The economic value of HIV prevention in the United States is substantial given the high cost of HIV disease treatment.


Noninvasive Respiratory Metabolite Analysis Associated with Clinical Disease in Cetaceans: A Deepwater Horizon Oil Spill Study.
Health assessments of wild cetaceans can be challenging due to the difficulty of gaining access to conventional diagnostic matrices of blood, serum and others. While the noninvasive detection of metabolites in exhaled breath could potentially help to address this problem, there exists a knowledge gap regarding associations between known disease states and breath metabolite profiles in cetaceans. This technology was applied to the largest marine oil spill in U.S. history (The 2010 Deepwater Horizon oil spill in the Gulf of Mexico). An accurate analysis was performed to test for associations between the exhaled breath metabolome and sonographic lung abnormalities as well as hematological, serum biochemical, and endocrine hormone parameters. Importantly, metabolites consistent with chronic inflammation, such as products of lung epithelial cellular breakdown and arachidonic acid cascade metabolites were associated with sonographic evidence of lung consolidation. Exhaled breath condensate (EBC) metabolite profiles also correlated with serum hormone concentrations (cortisol and aldosterone), hepatobiliary enzyme levels, white blood cell counts, and iron homeostasis. The correlations among breath metabolites and conventional health measures suggest potential application of breath sampling for remotely assessing health of wild cetaceans. This methodology may hold promise for large cetaceans in the wild for which routine collection of blood and respiratory anomalies are not currently feasible.


Hyper-heuristics with low level parameter adaptation.
Recent years have witnessed the great success of hyper-heuristics applying to numerous real-world applications. Hyper-heuristics raise the generality of search methodologies by manipulating a set of low level heuristics (LLHs) to solve problems, and aim to automate the algorithm design process. However, those LLHs are usually parameterized, which may contradict the domain independent motivation of hyper-heuristics. In this paper, we show how to automatically maintain low level parameters (LLPs) using a hyper-heuristic with LLP adaptation (AD-HH), and exemplify the feasibility of AD-HH by adaptively maintaining the LLPs for two hyper-heuristic models. Furthermore, aiming at tackling the search space expansion due to the LLP adaptation, we apply a heuristic space reduction (SAR) mechanism to improve the AD-HH framework. The integration of the LLP adaptation and the SAR mechanism is able to explore the heuristic space more effectively and efficiently. To evaluate the performance of the proposed algorithms, we choose the p-median problem as a case study. The empirical results show that with the adaptation of the LLPs and the SAR mechanism, the proposed algorithms are able to achieve competitive results over the three heterogeneous classes of benchmark instances.


Post discharge clinically overt venous thromboembolism in orthopaedic surgery patients with negative venography--an overview analysis.
A high incidence of post-discharge venous thromboembolism in orthopaedic surgery patients has been recently reported drawing further attention to the unresolved issue of the optimal duration of the pharmacological prophylaxis. We performed an overview analysis in order to evaluate the incidence of late occurring clinically overt venous thromboembolism in major orthopaedic surgery patients discharged from the hospital with a negative venography and without further pharmacological prophylaxis. We selected the studies published from January 1974 to December 1995 on the prophylaxis of venous thromboembolism after major orthopaedic surgery fulfilling the following criteria: 1) adoption of pharmacological prophylaxis, 2) performing of a bilateral venography before discharge, 3) interruption of pharmacological prophylaxis at discharge in patients with negative venography, and 4) post-discharge follow-up of the patients for at least four weeks. Out of 31 identified studies, 13 fulfilled the overview criteria. The total number of evaluated patients was 4120. An adequate venography was obtained in 3469 patients (84.1%). In the 2361 patients with negative venography (68.1%), 30 episodes of symptomatic venous thromboembolism after hospital discharge were reported with a resulting cumulative incidence of 1.27% (95% C.I. 0.82-1.72) and a weighted mean incidence of 1.52% (95% C.I. 1.05-1.95). Six cases of pulmonary embolism were reported. Our overview showed a low incidence of clinically overt venous thromboembolism at follow-up in major orthopaedic surgery patients discharged with negative venography. Extending pharmacological prophylaxis in these patients does not appear to be justified. Venous thrombi leading to hospital re-admission are likely to be present but asymptomatic at the time of discharge. Future research should be directed toward improving the accuracy of non invasive diagnostic methods in order to replace venography in the screening of asymptomatic post-operative deep vein thrombosis.


Total parenteral nutrition with glutamine dipeptide after major abdominal surgery: a randomized, double-blind, controlled study.
To assess the efficacy of glutamine (Gln) dipeptide-enriched total parenteral nutrition (TPN) on selected metabolic, immunologic, and clinical variables in surgical patients. Depletion of Gln stores might lead to severe clinical complications. Recent studies indicate that the parenteral provision of Gln or Gln-containing dipeptides improves nitrogen balance, maintains the intracellular Gln pool, preserves intestinal permeability and absorption, and shortens hospital stay. Twenty-eight patients (age range, 42-86 years, mean 68 years) undergoing elective abdominal surgery were allocated, after randomization, to two groups to receive isonitrogenous (0.24 g nitrogen kg(-1) day(-1)) and isoenergetic (29 kcal/122 kJ kg(-1) day(-1)) TPN over 5 days. Controls received 1.5 g of amino acids kg(-1) day(-1), and the test group received 1.2 g of amino acids and 0.3 g of L-alanyl-L-glutamine (Ala-Gln) kg(-1) day(-1). Venous heparinized blood samples were obtained before surgery and on days 1, 3, and 6 after surgery for routine clinical chemistry and for the measurement of plasma free amino acids. Lymphocytes were counted and the generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes was analyzed before surgery and on days 1 and 6 after surgery. Nitrogen balances were calculated postoperatively on days 2, 3, 4, and 5. No side effects or complaints were noted. Patients receiving Gln dipeptide revealed improved nitrogen balances (cumulative balance over 5 days: -7.9 +/- 3.6 vs. -23.0 +/- 2.6 g nitrogen), improved lymphocyte recovery on day 6 (2.41 +/- 0.27 vs. 1.52 +/- 0.17 lymphocytes/nL) and improved generation of cysteinyl-leukotrienes from polymorphonuclear neutrophil granulocytes (25.7 +/- 4.89 vs. 5.03 +/- 3.11 ng/mL). Postoperative hospital stay was 6.2 days shorter in the dipeptide-supplemented group. We confirm the beneficial effects of Gln dipeptide-supplemented TPN on nitrogen economy, maintenance of plasma Gln concentration, lymphocyte recovery, cysteinyl-leukotriene generation, and shortened hospital stay in surgical patients.


Adaptation of the lapinized rinderpest virus to in vitro growth and attenuation of its virulence in rabbits.
A lapinized rinderpest virus, the L strain, which is virulent in rabbits and had been grown only in rabbits, was adapted to grow in Vero cells by the fusion of Vero cells with virus-infected rabbit spleen cells in the presence of polyethylene glycol, and subsequently passaged in Vero cells by co-culture technique. After several passages, free virus was produced at high titre. The Vero cell-adapted virus acquired the ability to infect several cell lines which were non-permissive to the unadapted virus. Analysis of virus proteins by immunofluorescence using monoclonal antibodies revealed that marked changes occurred in F, P, NP and M proteins by passage in Vero cells. In parallel to the adaptation to cell culture in vitro, the virulence of the virus measured in terms of clinical signs and histological lesions in the lymphoid tissues decreased in its severity whereas its immunosuppressive capacity was maintained unaltered. Thus, rinderpest virus with different degrees of virulence is now available for study in vitro.


Laminar Distribution of Cannabinoid Receptor 1 in the Prefrontal Cortex of Nonhuman Primates.
Cannabis is an annual herb of the genus Cannabis, with a history of medical use going back thousands of years. However, its abuse causes many side-effects, including confusion of consciousness, alienation, and mental disorders such as schizophrenia and depression. Research conducted on rodents suggests that there are two types of cannabinoid receptors-cannabinoid receptor 1 (CB1R) and cannabinoid receptor 2 (CB2R). CB1R is found mostly in the central nervous system, particularly in the prefrontal cortex (PFC), and alterations in its expression in the PFC have been strongly linked to mental disorders. Within the layers of the PFC, Brodmann area 46 is associated with the processing of complex cognitive information. However, it remains unclear whether CB1R is expressed in the PFC 46 area of non-human primate. In this work, we applied western blotting along with immunofluorescent histochemical staining to investigate the distribution pattern of CB1R in the PFC of nonhuman primate, Our findings reveal that CB1R is highly expressed in the monkey PFC, especially in area 46. Furthermore, CB1R exhibits a layered distribution pattern within area 46 of the PFC, with the inner granular layer displaying the highest expression levels. Additionally, CB1R+PV+ cells are widely distributed in lay II-VI of area 46, with layer IV showing notable prevalence. In conclusion, CB1R is distributed in the PV interneurons in area 46 of the prefrontal cortex, particularly in layer IV, suggesting that cannabis may modulate PFC activities via regulating interneuron in the PFC. And cannabis-induced side effects may be caused by abnormal expression of CB1R.


Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations.
Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes-imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis.


Segmental Series and Size: Clade-Wide Investigation of Molar Proportions Reveals a Major Evolutionary Allometry in the Dentition of Placental Mammals.
Iterative segments such as teeth or limbs are a widespread characteristic of living organisms. While their proportions may be governed by similar developmental rules in vertebrates, there is no emerging pattern as regards their relation to size. Placental mammals span eight orders of magnitude in body size and show a wide spectrum of dietary habits associated with size and reflected in their dentitions, especially molars. Although variation in size constitutes an important determinant for variation in biological traits, few major allometric trends have been documented on placental molars so far. Molar proportions have been intensively explored in placentals in relation to developmental models, but often at a small phylogenetic scale. Here, we analyzed the diversity of upper molar proportions in relation to absolute size in a large sample of placental species ($n = 299$) encompassing most of the group's dental diversity. Our phylogenetically informed analyses revealed a 2-fold pattern of evolutionary integration among upper molars: while molars covary in size with each other, their proportions covary with the absolute size of the entire molar field. With increasing absolute size, posterior molars increase in size relative to anterior ones, meaning that large-sized species have relatively large rear molars while the opposite is true for small-sized species. The directionality of proportional increase in the molar row exhibits a previously unsuspected allometric patterning among placentals, showing how large-scale variations in size may have influenced variation in dental morphology. This finding provides new evidence that processes regulating the size of individual molars are integrated with overall patterns of growth and calls for further testing of allometric variation in the dentition and in other segmental series of the vertebrate body. [Dentition; evolution; model; phylogeny; segmentation; size.].


M3G: maximum margin microarray gridding.
Complementary DNA (cDNA) microarrays are a well established technology for studying gene expression. A microarray image is obtained by laser scanning a hybridized cDNA microarray, which consists of thousands of spots representing chains of cDNA sequences, arranged in a two-dimensional array. The separation of the spots into distinct cells is widely known as microarray image gridding. In this paper we propose M3G, a novel method for automatic gridding of cDNA microarray images based on the maximization of the margin between the rows and the columns of the spots. Initially the microarray image rotation is estimated and then a pre-processing algorithm is applied for a rough spot detection. In order to diminish the effect of artefacts, only a subset of the detected spots is selected by matching the distribution of the spot sizes to the normal distribution. Then, a set of grid lines is placed on the image in order to separate each pair of consecutive rows and columns of the selected spots. The optimal positioning of the lines is determined by maximizing the margin between these rows and columns by using a maximum margin linear classifier, effectively facilitating the localization of the spots. The experimental evaluation was based on a reference set of microarray images containing more than two million spots in total. The results show that M3G outperforms state of the art methods, demonstrating robustness in the presence of noise and artefacts. More than 98% of the spots reside completely inside their respective grid cells, whereas the mean distance between the spot center and the grid cell center is 1.2 pixels. The proposed method performs highly accurate gridding in the presence of noise and artefacts, while taking into account the input image rotation. Thus, it provides the potential of achieving perfect gridding for the vast majority of the spots.


The pancreatohepatorenal cAMP-adenosine mechanism.
Stimulation of adenylyl cyclase causes cellular efflux of cAMP, and cAMP (unlike adenosine) is stable in blood. Therefore, it is conceivable that cAMP could function as a circulating adenosine prohormone by local target-organ conversion of distally released cAMP to adenosine via the sequential actions of ectophosphodiesterase and ecto-5'-nucleotidase (cAMP==> AMP==> adenosine; called the cAMP-adenosine pathway). A possible specific representation of this general concept is the pancreatohepatorenal cAMP-adenosine mechanism. The pancreas secretes glucagon into the portal circulation, and glucagon is a stimulant of hepatic adenylyl cyclase. Therefore, we hypothesize that the pancreas, via glucagon, stimulates hepatic cAMP production, which provides circulating cAMP for conversion to adenosine in the kidney via the cAMP-adenosine pathway. In normal rats, intravenous cAMP increased urinary and renal interstitial (assessed by renal microdialysis) cAMP and adenosine. Intraportal infusions of glucagon increased plasma cAMP 10-fold, it did not affect plasma adenosine, and it increased urinary and renal interstitial cAMP and adenosine. Local renal interstitial blockade (by adding inhibitors directly to the microdialysis perfusate) of ectophosphodiesterase (using 3-isobutyl-1-methylxanthine or 1,3-dipropyl-8-p-sulfophenylxanthine) or ecto-5'-nucleotidase (using alpha,beta-methyleneadenosine-5'-diphosphate) prevented the cAMP-induced and glucagon-induced increases in renal interstitial adenosine, but not cAMP. In ZSF1 rats with the metabolic syndrome, an oral glucose load increased plasma glucagon and urinary cAMP and adenosine excretion. We conclude that circulating cAMP is a substrate for local conversion to adenosine via the cAMP-adenosine pathway. A specific manifestation of this is the pancreatohepatorenal cAMP-adenosine mechanism (pancreas==> portal glucagon==> liver==> circulating cAMP==> kidney==> local cAMP-adenosine pathway).


Cooperativity between the preproinsulin mRNA untranslated regions is necessary for glucose-stimulated translation.
Glucose regulates proinsulin biosynthesis via stimulation of the translation of the preproinsulin mRNA in pancreatic beta-cells. However, the mechanism by which this occurs has remained unclear. Using recombinant adenoviruses that express the preproinsulin mRNA with defined alterations, the untranslated regions (UTRs) of the preproinsulin mRNA were examined for elements that specifically control translation of the mRNA in rat pancreatic islets. These studies revealed that the preproinsulin 5'-UTR was necessary for glucose stimulation of preproinsulin mRNA translation, whereas the 3'-UTR appeared to suppress translation. However, together the 5'- and 3'-UTRs acted cooperatively to markedly increase glucose-induced proinsulin biosynthesis. In primary hepatocytes the presence of the preproinsulin 3'-UTR led to reduced mRNA levels compared with the presence of the SV40 3'-UTR, consistent with the presence of mRNA stability determinants in the 3'-UTR that stabilize the preproinsulin mRNA in a pancreatic beta-cell-specific manner. Translation of these mRNAs in primary hepatocytes was not stimulated by glucose, indicating that regulated translation of the preproinsulin mRNA occurs in a pancreatic beta-cell-specific manner. Thus, the untranslated regions of the preproinsulin mRNA play crucial roles in regulating insulin production and therefore glucose homeostasis by regulating the translation and the stability of the preproinsulin mRNA.


Use of mobile phones as a tool for weight loss: a systematic review.
We conducted a systematic review of the literature on the use of mobile phones for weight loss. A total of 43 studies were identified on obese or overweight adults, aged 18 years or over. After review, ten articles met the inclusion criteria. There were 19-534 participants per study. Participants were from European, Asian and North American regions. The mean body mass index (BMI) of the subjects varied from 22 to 36 kg/m(2). Two studies used text messaging or multimedia messaging. All the other studies used mobile-phone apps or web-based programmes that could be accessed from mobile phones as a part of a weight-loss intervention or for evaluating their potential for use and their acceptance. Most studies lasted 2-4 months and the maximum duration was 1 year. All but two studies showed reductions in the participants' bodyweight, BMI, waist circumference and body fat in the various interventions. There appeared to be a proportional relationship between weight loss and programme use. The programmes most benefited those who took a pro-active approach to everyday problems. Frequent self-recording of weight seemed to be important, as was the personalisation of the intervention (counselling and individualized feedback). Finally, a social support system acted as a motivational tool.


Changes in renal phospholipid fatty acids in diabetes mellitus: correlation with changes in adenylate cyclase activity.
Male Sprague-Dawley rats made diabetic with alloxan (37.5 mg/kg) or streptozotocin (65 mg/kg) were killed after 3-6 weeks of disease; renal tissues were studied for phospholipid content and for fatty acid composition of the phospholipids. No consistent change was noted in total phospholipid content nor in the proportion of various phospholipids in diabetics. However, diabetic animals showed a consistent reduction of arachidonic acid content in phosphatidylcholine (PC) and phosphatidylethanolamine in whole renal cortex, plasma membranes purified from renal cortex, and in isolated glomeruli. Associated with the fall in arachidonic acid was a rise in linoleic acid in the samples studied. Insulin therapy returned the fatty acid profiles to normal. These results are similar to patterns observed in other diabetic tissues and suggest that diabetes is associated with generalized changes in cell membranes. That these structural changes may have functional significance is suggested by demonstrated alterations in the temperature-dependence of adenylate cyclase in renal plasma membranes of diabetic animals. Adenylate cyclase is thought to be intimately associated with PC in plasma membranes, a phospholipid showing significant changes in fatty acid content in diabetes (unsaturation index 165 +/- 2 for normals, 147 +/- 5 for diabetics). Na+,K+-ATPase which is thought to be primarily associated in vivo with phosphatidylinositol (PI), shows no change in apparent energy of activation in diabetes. The fatty acid content of PI is minimally altered in diabetes, and the unsaturation index is unchanged.


Metabolomics of a cell line-derived xenograft model reveals circulating metabolic signatures for malignant mesothelioma.
Malignant mesothelioma (MM) is a rare and highly aggressive cancer. Despite advances in multidisciplinary treatments for cancer, the prognosis for MM remains poor with no effective diagnostic biomarkers currently available. The aim of this study was to identify plasma metabolic biomarkers for better MM diagnosis and prognosis by use of a MM cell line-derived xenograft (CDX) model. The MM CDX model was confirmed by hematoxylin and eosin staining and immunohistochemistry. Twenty female nude mice were randomly divided into two groups, 10 for the MM CDX model and 10 controls. Plasma samples were collected two weeks after tumor cell implantation. Gas chromatography-mass spectrometry analysis was conducted. Both univariate and multivariate statistics were used to select potential metabolic biomarkers. Hierarchical clustering analysis, metabolic pathway analysis, and receiver operating characteristic (ROC) analysis were performed. Additionally, bioinformatics analysis was used to investigate differential genes between tumor and normal tissues, and survival-associated genes. The MM CDX model was successfully established. With VIP > 1.0 and P-value < 0.05, a total of 23 differential metabolites were annotated, in which isoleucine, 5-dihydrocortisol, and indole-3-acetamide had the highest diagnostic values based on ROC analysis. These were mainly enriched in pathways for starch and sucrose metabolism, pentose and glucuronate interconversions, galactose metabolism, steroid hormone biosynthesis, as well as phenylalanine, tyrosine and tryptophan biosynthesis. Further, down-regulation was observed for amino acids, especially isoleucine, which is consistent with up-regulation of amino acid transporter genes SLC7A5 and SLC1A3 in MM. Overall survival was also negatively associated with SLC1A5, SLC7A5, and SLC1A3. We found several altered plasma metabolites in the MM CDX model. The importance of specific metabolic pathways, for example amino acid metabolism, is herein highlighted, although further investigation is warranted.


[Expression of Bax and Caspase-3 and apoptosis in human lumbar intervertebral disc degeneration].
To detect the cell density, apoptotic incidence and the expressions of Bax and Caspase-3 in human lumbar intervertebral discs, so as to further understand the mechanism of human lumbar intervertebral disc degeneration and provide a new idea for biologic treatment of it in future. From May to December in 2006, 30 human lumbar intervertebral discs in experimental group (L2 to S1) were surgically collected from 27 patients undergoing posterior lumbar intervertebral discoidectomy and fusion. All the cases were affirmed by MRI and they never experienced discography, collagenolysis of nucleus pulposus and percutaneous laser disc decompression. The control group consisted of 20 human lumbar intervertebral discs (L2 to S1) harvested from 5 young men without spine-related condition immediately after their accidental death. Apoptotic disc cells were detected by TUNEL and histomorphology, and immunohistochemical staining with SP method was performed to examine the expressions of Bax and Caspase-3 in all specimens. HE staining disclosed that the average cell density in control group (17.16 +/- 1.22)/HP was higher than that in experimental group (12.41 +/- 0.95)/HP (P < 0.01). However, TUNEL staining observed that the average TUNEL positive incidence in control group (6.97% +/- 0.92%) was lower than that in experimental group (12.59% +/- 0.95%), (P < 0.01). Immunohistochemical staining with SP method showed that the Bax and Caspase-3 positive incidence of nucleus pulposus in control group (11.02% +/- 1.18%, 9.01% +/- 1.00%) were lower than those in experimental group (19.29% +/- 1.18%, 15.07% +/- 0.97%), (P < 0.01). The results of the average gray scale value of nucleus pulposus in control group were 187.33 +/- 7.88 and 185.68 +/- 3.26, respectively, with 124.98 +/- 6.69 and 160.13 +/- 4.37 in experimental group. There was significant difference between the two groups (P < 0.01). When the total 50 specimens in the two groups were analyzed, TUNEL positive incidence showed significant inverse correlations with their respectively corresponding cell densities (r = - 0.88, r = - 0.93, P < 0.01). The Bax and Caspase-3 positive incidence of nucleus pulposus showed significant positive correlation with the TUNEL positive incidence of nucleus pulposus (r = 0.83, r = 0.91, P < 0.01). The decrease of cell density is involved in the development of human lumbar intervertebral disc degeneration. Bax and Caspase-3 might play a role in disc cell apoptosis in nucleus pulposus of human lumbar intervertebral disc.


The impact of conventional morphologic analysis on response rates and survival in patients with advanced head and neck cancers treated initially with cisplatin-containing combination chemotherapy.
The response to initial treatment with cisplatin-containing combination chemotherapy as well as survival, were correlated with tumor differentiation (well, moderate or poorly differentiated) in 164 patients with advanced, untreated squamous cell carcinoma of the head and neck. Thirty-three percent of the tumors were graded as poorly differentiated, 59% moderately differentiated, and 8% were well differentiated. The overall clinical response rates were nearly equal for the three grades of differentiation: 79% for well differentiated, 86% for moderately differentiated, and 89% for poorly differentiated. The complete response rate was somewhat higher for poorly differentiated tumors: 46% as compared to 32% and 29% for moderately and well differentiated respectively, but the differences were not statistically significant. The median survival for each morphologic group was 22, 16, and 12 months for well differentiated, moderately differentiated and poorly differentiated tumor, respectively (P = 0.097). For patients achieving a complete clinical response to chemotherapy, there was a difference in survival when stratified according to degree of histologic differentiation. Patients who were complete responders and had well or moderately differentiated tumors attained 75% and 38% survival at 36 months, respectively, versus 19% for patients with complete response and poorly differentiated tumors (P = 0.064). The degree of differentiation of previously untreated squamous cell cancers of the head and neck does not conclusively predict tumor response to combination chemotherapy, but may reflect differences in natural history. Survival is improved in patients with differentiated tumors as compared to those with poorly differentiated tumors. Morphologic grading in patients achieving a complete response reveals a decrease in survival for patients with poorly differentiated tumors.


Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis.
Osteoarthritis (OA) is a degenerative joint disease for which there are no disease modifying therapies. Thus, strategies that offer chondroprotective or regenerative capability represent a critical unmet need. Recently, oral consumption of a hydrolyzed type 1 collagen (hCol1) preparation has been reported to reduce pain in human OA and support a positive influence on chondrocyte function. To evaluate the tissue and cellular basis for these effects, we examined the impact of orally administered hCol1 in a model of posttraumatic OA (PTOA). In addition to standard chow, male C57BL/6J mice were provided a daily oral dietary supplement of hCol1 and a meniscal-ligamentous injury was induced on the right knee. At various time points post-injury, hydroxyproline (hProline) assays were performed on blood samples to confirm hCol1 delivery, and joints were harvested for tissue and molecular analyses were performed, including histomorphometry, OARSI and synovial scoring, immunohistochemistry and mRNA expression studies. Confirming ingestion of the supplements, serum hProline levels were elevated in experimental mice administered hCol1. In the hCol1 supplemented mice, chondroprotective effects were observed in injured knee joints, with dose-dependent increases in cartilage area, chondrocyte number and proteoglycan matrix at 3 and 12 weeks post-injury. Preservation of cartilage and increased chondrocyte numbers correlated with reductions in MMP13 protein levels and apoptosis, respectively. Supplemented mice also displayed reduced synovial hyperplasia that paralleled a reduction in Tnf mRNA, suggesting an anti-inflammatory effect. These findings establish that in the context of murine knee PTOA, daily oral consumption of hCol1 is chondroprotective, anti-apoptotic in articular chondrocytes, and anti-inflammatory. While the underlying mechanism driving these effects is yet to be determined, these findings provide the first tissue and cellular level information explaining the already published evidence of symptom relief supported by hCol1 in human knee OA. These results suggest that oral consumption of hCol1 is disease modifying in the context of PTOA.


Cluster coarsening on drops exhibits strong and sudden size-selectivity.
Autophagy, an important process for degradation of cellular components, requires the targeting of autophagy receptor proteins to potential substrates. Receptor proteins have been observed to form clusters on membranes. To understand how receptor clusters might affect autophagy selectivity, we model cluster coarsening on a polydisperse collection of spherical drop-like substrates. Our model receptor corresponds to NBR1, which supports peroxisome autophagy. We recover dynamical scaling of cluster sizes, but find that changing the drop size distribution changes the cluster-size scaling distribution. The magnitude of this effect is similar to how changing the spatial-dimension affects scaling in bulk systems. We also observe a sudden onset of size-selection of the remaining drops with clusters, due to clusters evaporating from smaller drops and growing on larger drops. This coarsening-driven size selection provides a physical mechanism for autophagy selectivity, and may explain reports of size selection during peroxisome degradation.


Alcohol, nutrition and malabsorption.
Malabsorption occurs frequently in chronic alcoholics. Alcoholics may malabsorb fat, nitrogen, sodium, water, thiamine, folic acid, vitamin B12 and D-xylose. Malabsorption is due to an abnormal luminal phase of digestion as well as a diffuse functional mucosal abnormality. Malabsorption may, therefore, contribute to clinically significant malnutrition, diarrhoea, folate-deficiency and to abnormalities in tests of xylose and vitamin B12 absorption. Factors producing malabsorption in alcoholics include dietary folic acid and protein deficiency, pancreatic insufficiency, abnormalities of biliary secretions and direct effects of alcohol on the gastrointestinal tract. Many of the absorptive abnormalities are reversed when alcoholics are given a nutritious diet, even with continued intake of alcohol. This highlights the causal role of nutritional deficiencies in the malabsorption of chronic alcoholics.


Sleep during basic combat training: a qualitative study.
Anecdotal accounts indicate that Basic Combat Training (BCT) is associated with significant sleep impairment, which conceivably could impact health, attrition, and training. However, there has been little empirical investigation of sleep during BCT. The aim of this study was to obtain a qualitative assessment of soldiers' perceptions about their sleep and consequences of sleep disruption during BCT. During November/December of 2010, focus group discussions were conducted with soldiers, ages > or = 18 years, who had completed at least 4 weeks of BCT at Fort Jackson, SC. The soldiers were assessed in 45 to 60 min sessions involving three groups of female soldiers (total n = 28) and three groups of male soldiers (total n = 38). Soldiers reported reductions in their sleep duration and quality, which were attributed to many factors, particularly noise, nighttime work detail, stress, and hunger. These sleep changes had many perceived negative effects on performance, mood, and other components of BCT. These effects were more evident in soldiers of lower physical fitness. This study suggests associations between sleep and BCT outcomes. Whether these associations warrant changes in the sleep environment of BCT will require much further investigation.


Global gene expression profiling of endothelium exposed to heme reveals an organ-specific induction of cytoprotective enzymes in sickle cell disease.
Sickle cell disease (SCD) is characterized by hemolysis, vaso-occlusion and ischemia reperfusion injury. These events cause endothelial dysfunction and vasculopathies in multiple systems. However, the lack of atherosclerotic lesions has led to the idea that there are adaptive mechanisms that protect the endothelium from major vascular insults in SCD patients. The molecular bases for this phenomenon are poorly defined. This study was designed to identify the global profile of genes induced by heme in the endothelium, and assess expression of the heme-inducible cytoprotective enzymes in major organs impacted by SCD. Total RNA isolated from heme-treated endothelial monolayers was screened with the Affymetrix U133 Plus 2.0 chip, and the microarray data analyzed using multiple bioinformatics software. Hierarchical cluster analysis of significantly differentially expressed genes successfully segregated heme and vehicle-treated endothelium. Validation studies showed that the induction of cytoprotective enzymes by heme was influenced by the origin of endothelial cells, the duration of treatment, as well as the magnitude of induction of individual enzymes. In agreement with these heterogeneities, we found that induction of two major Nrf2-regulated cytoprotective enzymes, heme oxygenase-1 and NAD(P)H:quinone oxidoreductase-1 is organ-specific in two transgenic mouse models of SCD. This data was confirmed in the endothelium of post-mortem lung tissues of SCD patients. Individual organ systems induce unique profiles of cytoprotective enzymes to neutralize heme in SCD. Understanding this heterogeneity may help to develop effective therapies to manage vasculopathies of individual systems.


Muc1, a mucin-like protein that is regulated by Mss10, is critical for pseudohyphal differentiation in yeast.
Pseudohyphal differentiation in Saccharomyces cerevisiae was first described as a response of diploid cells to nitrogen limitation. Here we report that haploid and diploid starch-degrading S. cerevisiae strains were able to switch from a yeast form to a filamentous pseudohyphal form in response to carbon limitation in the presence of an ample supply of nitrogen. Two genes, MSS10 and MUC1, were cloned and shown to be involved in pseudohyphal differentiation and invasive growth. The deletion of MSS10 resulted in extremely reduced amounts of pseudohyphal differentiation and invasive growth, whereas the deletion of MUC1 abolished pseudohyphal differentiation and invasive growth completely. Mss10 appears to be a transcriptional activator that responds to nutrient limitation and coregulates the expression of MUC1 and the STA1-3 glucoamylase genes, which are involved in starch degradation. MUC1 encodes a 1367-amino acid protein, containing several serine/threonine-rich repeats. Muc1 is a putative integral membrane-bound protein, similar to mammalian mucin-like membrane proteins that have been implicated to play a role in the ability of cancer cells to invade other tissues.


Ureaplasma Species Multiple Banded Antigen (MBA) Variation Is Associated with the Severity of Inflammation In vivo and In vitro in Human Placentae.
Background: The multiple banded antigen (MBA), a surface-exposed lipoprotein, is a proposed virulence factor of Ureaplasma spp. We previously demonstrated that the number of Ureaplasma parvum MBA size variants in amniotic fluid was inversely proportional to the severity of chorioamnionitis in experimentally infected pregnant sheep. However, the effect of ureaplasma MBA size variation on inflammation in human pregnancies has not been reported. Methods: Ureaplasmas isolated from the chorioamnion of pregnant women from a previous study (n = 42) were speciated/serotyped and MBA size variation was demonstrated by PCR and western blot. Results were correlated with the severity of chorioamnionitis and cord blood cytokines. In vitro, THP-1-derived macrophages were exposed to recombinant-MBA proteins of differing sizes and NF-κB activation and cytokine responses were determined. Results: MBA size variation was identified in 21/32 (65.6%) clinical isolates (in 10 clinical isolates MBA size variation was unable to be determined). Any size variation (increase/decrease) of the MBA (regardless of Ureaplasma species or serovar) was associated with mild or absent chorioamnionitis (P = 0.023) and lower concentrations of cord blood cytokines IL-8 (P = 0.04) and G-CSF (P = 0.008). In vitro, recombinant-MBA variants elicited different cytokine responses and altered expression of NF-κB p65. Conclusion: This study demonstrates that size variation of the ureaplasma MBA protein modulates the host immune response in vivo and in vitro.


Institutional outbreaks of rotavirus diarrhoea: potential role of fomites and environmental surfaces as vehicles for virus transmission.
To assess the potential of fomites and environmental surfaces as vehicles in the transmission of rotaviral diarrhoea, disks (1 cm diameter) of various porous and non-porous materials were contaminated with about 10(5) plaque-forming units of the Wa strain of human rotavirus (HRV) suspended in faecal matter. The contaminated disks were then held for 10 days at either room temperature (22 +/- 2 degrees C) or 4 degrees C with the relative humidity (RH) at the high (85 +/- 5%), medium (50 +/- 5%) or low (25 +/- 5%) level. Survival was longer on non-porous surfaces at the lower temperature and at lower humidity. In contrast, survival on porous surfaces was very variable; better on cotton-polyester than on poster card or paper currency on which HRV survived very poorly. These results suggest that under the right environmental conditions, HRV-contaminated objects could play a role in the transmission of rotavirus infections in hospitals, nursing homes and day-care centres.


Theoretical studies on the metathesis processes, (Tp(PH3)MR(eta 2-H[bond]CH3)]-->[Tp(PH3)M(CH3)(eta 2-H[bond]R)] (M=Fe, Ru, and Os; R=H and CH3).
Theoretical calculations on the metathesis process, [Tp(PH3)MR(eta 2-H[bond]CH3)] --> [Tp(PH3)M(CH3)(eta 2-H[bond]R)] (M=Fe, Ru, and Os; R=H and CH3), have been systematically carried out to study their detailed reaction mechanisms. Other than the one-step mechanism via a four-center transition state and the two-step mechanism through an oxidative addition/reductive elimination pathway, a new one-step mechanism, with a transition state formed under oxidative addition, has been found. Based on the intrinsic reaction coordinate calculations, we found that the trajectories of the transferring hydrogen atom in the metathesis processes studied are similar to each other regardless of the nature of reaction mechanisms.


Diagnostic and prognostic value of synovial biopsy in adult undifferentiated peripheral inflammatory arthritis: a systematic review.
Our aim was to systematically review the literature on the diagnostic and prognostic value of synovial biopsy in undifferentiated peripheral inflammatory arthritis (UPIA) as an evidence base for generating clinical practice recommendations. The results lead to multinational recommendations in the 3e Initiative in Rheumatology. We performed a systematic literature review according to the PICO strategy (Patients, Intervention, Comparator, and Outcome). Using a designed search strategy we ran literature searches using Medline, Embase, the Cochrane Library, and abstracts presented at the 2007 and 2008 meetings of the American College of Rheumatology and European League Against Rheumatism. Articles fulfilling predefined inclusion criteria were reviewed, and quality appraisal was performed. Six publications from a total of 3265 diagnostic and 3271 prognostic studies were included, of which 2 were review articles. Data pooling was impossible because of significant clinical and statistical heterogeneity. Three themes of outcome were identified: anti-citrullinated peptide antibody (ACPA) staining in synovium, immunohistochemistry (CD22, CD38, CD68), and vascular patterns. Prognostic and diagnostic value was poor for these themes, although diagnostic trends favoring a particular diagnosis were identified. In contrast to serological ACPA testing, ACPA staining was shown not to be specific for diagnosis of rheumatoid arthritis (RA). Synovial CD22 and CD38 positivity seem to differentiate between RA and non-RA, while synovial CD38 and CD68 positivity can differentiate among RA, spondyloarthritis (SpA), and other diagnoses. Vascular patterns in undifferentiated arthritis are insufficiently specific to differentiate between SpA and RA. There is sparse evidence that synovial biopsy has diagnostic or prognostic value in patients with UPIA in clinical care. We urgently need systematic studies investigating the diagnostic and prognostic potential of synovial markers. A clear, broadly accepted, and unequivocal definition of undifferentiated arthritis is required as a starting point.


Kinetics and mechanism of the NCN + NO2 reaction studied by experiment and theory.
The rate constant for the NCN + NO 2 reaction has been measured by a laser photolysis/laser-induced fluorescence technique in the temperature range of 260-296 K at pressures between 100 and 500 Torr with He and N 2 as buffer gases. The NCN radical was produced from the photolysis of NCN 3 at 193 nm and monitored by laser-induced fluorescence with a dye laser at 329.01 nm. The rate constant was found to increase with pressure but decrease with temperature, indicating that the reaction occurs via a long-lived intermediate stabilized by collisions with buffer gas. The reaction mechanism and rate constant are also theoretically predicted for the temperature range of 200-2000 K and the He and N 2 pressure range of 10 (-4) Torr to 1000 atm based on dual-channel Rice-Ramsperger-Kassel-Marcus (RRKM) theory with the potential energy surface evaluated at the G2M//B3LYP/6-311+G(d) level. In the low-temperature range (<700 K), the most favorable reaction is the barrierless association channel that leads to the intermediate complex (NCN-NO 2). At high temperature, the direct O-abstraction reaction with a barrier of 9.8 kcal/mol becomes the dominant channel. The rate constant calculated by RRKM theory agrees reasonably well with experimental data.


In vivo targeting of de novo DNA methylation by histone modifications in yeast and mouse.
Methylation of cytosines (5(me)C) is a widespread heritable DNA modification. During mammalian development, two global demethylation events are followed by waves of de novo DNA methylation. In vivo mechanisms of DNA methylation establishment are largely uncharacterized. Here, we use Saccharomyces cerevisiae as a system lacking DNA methylation to define the chromatin features influencing the activity of the murine DNMT3B. Our data demonstrate that DNMT3B and H3K4 methylation are mutually exclusive and that DNMT3B is co-localized with H3K36 methylated regions. In support of this observation, DNA methylation analysis in yeast strains without Set1 and Set2 shows an increase of relative 5(me)C levels at the transcription start site and a decrease in the gene-body, respectively. We extend our observation to the murine male germline, where H3K4me3 is strongly anti-correlated while H3K36me3 correlates with accelerated DNA methylation. These results show the importance of H3K36 methylation for gene-body DNA methylation in vivo.


"The pitfalls and merits of using commonly accepted orthodontic cephalometric analyses".
With these thoughts in mind, a realistic, systematic approach can be designed to better develop and interpret cephalometric tracings. After all landmarks are traced and located, connect Sella to Nasion to D point. The triangle formed by connecting these landmarks without other planar values interfering will facilitate evaluation of these three landmarks to each other. With the apex of the triangle formed at D point, the angle formed by Sella-D point and D Axis should be anterior to an iscosoles triangle position. If not, the patient is likely to evidence a vertical growth and mandibular retrognathism, or the Sella-Nasion pattern plane has a severely flat cant. In cases where this same apex (SDN) is severely anterior to an "iscosoles angle," this patient is likely to have either mandibular prognathism or a steep cant of the Sella-Nasion Plane (see Figs. 11 and 12). To determine the relative cant of Sella-Nasion, locate and trace the desired planar position of Frankfurt Horizontal using one of the three choices listed previously. If the Sella-Nasion Plane is 10 degrees or more greater than the cant of Frankfurt Horizontal, the Sella-Nasion plane will be inaccurate as a reference plane for A point, B point and D point gnathic relations, as well as Occlusal Plane to Sella-Nasion. Once it has been established which horizontal reference plan is to be used, the relative positions of the remaining planar values can be traced and compared. In so doing, more accurate interpretation of cephalometric data can be achieved without the puzzling conflicts with other analysis values that might otherwise occur.


Characterizing recurrent positive selection at fast-evolving genes in Drosophila miranda and Drosophila pseudoobscura.
Characterizing the distribution of selection coefficients in natural populations remains a central challenge in evolutionary biology. We resequenced a subset of 19 fast-evolving protein-coding genes in the sister species Drosophila miranda and D. pseudoobscura and their flanking regions to characterize the spatial footprint left by recurrent and recent selection. Consistent with previous findings, fast-evolving genes and their flanking regions show reduced levels of neutral diversity compared with randomly chosen genes, as expected under recurrent selection models. Applying a variety of statistical tests designed for the detection of selection at different evolutionary timescales, we attempt to characterize parameters of adaptive evolution. In D. miranda, fast-evolving genes generally show evidence of increased rates of adaptive evolution relative to random genes, whereas this pattern is somewhat less pronounced in D. pseudoobscura. Our results suggest that fast-evolving genes are not characterized by significantly different selection coefficients but rather a shift in the distribution of the rate of fixation.


On the asymptotic evolution of finite energy Airy wave functions.
In general, there is an inverse relation between the degree of localization of a wave function of a certain class and its transform representation dictated by the scaling property of the Fourier transform. We report that in the case of finite energy Airy wave packets a simultaneous increase in their localization in the direct and transform domains can be obtained as the apodization parameter is varied. One consequence of this is that the far-field diffraction rate of a finite energy Airy beam decreases as the beam localization at the launch plane increases. We analyze the asymptotic properties of finite energy Airy wave functions using the stationary phase method. We obtain one dominant contribution to the long-term evolution that admits a Gaussian-like approximation, which displays the expected reduction of its broadening rate as the input localization is increased.


Transfer of Synthetic Human Chromosome into Human Induced Pluripotent Stem Cells for Biomedical Applications.
AlphoidtetO-type human artificial chromosome (HAC) has been recently synthetized as a novel class of gene delivery vectors for induced pluripotent stem cell (iPSC)-based tissue replacement therapeutic approach. This HAC vector was designed to deliver copies of genes into patients with genetic diseases caused by the loss of a particular gene function. The alphoidtetO-HAC vector has been successfully transferred into murine embryonic stem cells (ESCs) and maintained stably as an independent chromosome during the proliferation and differentiation of these cells. Human ESCs and iPSCs have significant differences in culturing conditions and pluripotency state in comparison with the murine naïve-type ESCs and iPSCs. To date, transferring alphoidtetO-HAC vector into human iPSCs (hiPSCs) remains a challenging task. In this study, we performed the microcell-mediated chromosome transfer (MMCT) of alphoidtetO-HAC expressing the green fluorescent protein into newly generated hiPSCs. We used a recently modified MMCT method that employs an envelope protein of amphotropic murine leukemia virus as a targeting cell fusion agent. Our data provide evidence that a totally artificial vector, alphoidtetO-HAC, can be transferred and maintained in human iPSCs as an independent autonomous chromosome without affecting pluripotent properties of the cells. These data also open new perspectives for implementing alphoidtetO-HAC as a gene therapy tool in future biomedical applications.


The da Vinci robotic system in head and neck surgery.
Intuitive Surgical Inc. (Sunnyvale, Ca, USA) extended the use of the da Vinci robot to head and neck surgery in 2005 following the previous use in urological, gynecological and cardiothoracic surgery. It then gained wide popularity throughout the globe. Our aim is to describe the da Vinci Robot System and discuss its applications in head and neck surgery. Continued refinements and applications in robotic surgery for otolaryngology will in time be possible as new robotic procedures are developed for endolaryngeal work.


Identification of potent, selective P2Y-purinoceptor agonists: structure-activity relationships for 2-thioether derivatives of adenosine 5'-triphosphate.
Study of P2-purinoceptor subtypes has been difficult due to the lack of potent and selective ligands. With the goal of developing high affinity P2-purinoceptor-selective agonist, we have synthesized a series of analogues of adenine nucleotides modified on the purine ring as chain-extended 2-thioethers or as N6-methyl-substituted compounds. Chemical functionality incorporated in the thioether moiety included cyanoalkyl, nitroaromatic, amino, thiol, cycloalkyl, n-alkyl, and olefinic groups. Apparent affinity of the compounds for P2Y-purinoceptors was established by measurement of P2Y-purinoceptor-promoted phospholipase C activity in turkey erythrocyte membranes and relaxation of carbachol-contracted smooth muscle in three different preparations (guinea pig taenia coli, rabbit aorta, and rabbit mesenteric artery). Activity at P2X-purinoceptors was established by measurement of contraction of rabbit saphenous artery and of the guinea pig vas deferens and urinary bladder. All 11 of the 2-thioethers of ATP stimulated the production of inositol phosphates with K0.5 values of 1.5-770 nM, with an (aminophenyl)ethyl derivative being most potent. Two adenosine diphosphate analogues were equipotent to the corresponding ATP analogues. Adenosine monophosphate analogues were full agonists, although generally 4 orders of magnitude less potent. ATP 2-thioethers displayed pD2 values in the range of 6-8 in smooth muscle assay systems for activity at P2Y-receptors. There was a significant correlation for the 2-thioether compounds between the pK0.5 values for inositol phosphate production and the pD2 values for relaxation mediated via the P2Y-purinoceptors in the guinea pig taenia coli, but not for the vascular P2Y-receptors or for the P2X-receptors. At P2X-receptors, no activity was observed in the rabbit saphenous artery, but variable degrees of activity were observed in the guinea pig vas deferens and bladder depending on distal substituents of the thioether moiety. N6-Methyl-ATP was inactive at P2X-receptors, and approximately equipotent to ATP at taenia coil P2Y-receptors. This suggested that hybrid N6-methyl and 2-thioether ATP derivatives might be potent and selective for certain P2Y-receptors, as was shown for one such derivative, N6-methyl-2-(5-hexenylthio)-ATP.


Prefrontal norepinephrine determines attribution of "high" motivational salience.
Intense motivational salience attribution is considered to have a major role in the development of different psychopathologies. Numerous brain areas are involved in "normal" motivational salience attribution processes; however, it is not clear whether common or different neural mechanisms also underlie intense motivational salience attribution. To elucidate this a brain area and a neural system had to be envisaged that were involved only in motivational salience attribution to highly salient stimuli. Using intracerebral microdialysis, we found that natural stimuli induced an increase in norepinephrine release in the medial prefrontal cortex of mice proportional to their salience, and that selective prefrontal norepinephrine depletion abolished the increase of norepinephrine release in the medial prefrontal cortex induced by exposure to appetitive (palatable food) or aversive (light) stimuli independently of salience. However, selective norepinephrine depletion in the medial prefrontal cortex impaired the place conditioning induced exclusively by highly salient stimuli, thus indicating that prefrontal noradrenergic transmission determines approach or avoidance responses to both reward- and aversion-related natural stimuli only when the salience of the unconditioned natural stimulus is high enough to induce sustained norepinephrine outflow. This affirms that prefrontal noradrenergic transmission determines motivational salience attribution selectively when intense motivational salience is processed, as in conditions that characterize psychopathological outcomes.


Evaluation of surface roughness as a function of multiple blasting processing variables.
This study evaluated the effect of implant surface blasting variables, such as blasting media size, velocity, and surface coverage and their two- and three-way interaction in surface roughness parameters. Machined, grade IV titanium-alloy implants (n = 180) had their surfaces treated by a combination of 36 different blasting protocols according to the following variables: aluminum oxide blasting media particle size (50, 100, and 150 μm); velocity (75, 100, 125, and 150 m/s), and surface coverage (5, 15, 25 g/in.(2) ) (n = 5 per blasting protocol). A single 0.46 inch nozzle of the blaster was pointed at the threaded area and spaced 0.050 inches away. Surface topography (n = 5 measurements per implant) was assessed by scanning electron microscopy. Roughness parameters Sa, Sq, Sdr, and Sds were evaluated by optical interferometry. A GLM statistical model evaluated the effects of blasting variables on the surface parameters, and their two- and three-way interaction (P < 0.05). Statistical inferences for Sa and Sq were performed after a log(10) transformation to correct for data skewness. Prior to the log(10) transformation, Sa and Sq values for all processing groups ranged from ~0.5 to ~2.6 μm and from ~0.75 to 4 μm, respectively. Statistical inferences showed that Sa, Sq, and Sdr values were significantly dependent on blasting media, velocity, and surface coverage (all P < 0.001). Media × velocity, media × coverage, and media × velocity × coverage also significantly affected Sa, Sq, and Sdr values (P < 0.002). The highest levels were obtained with 100 μm blasting media, coverage for 5 g/in.(2) , and velocity of 100 m/s. No significant differences were observed for Sds (P > 0.15). The blasting variables produced different surface topography features and knowledge of their interaction could be used to tailor a desired implant surface configuration.


Molecular response of 4T1-induced mouse mammary tumours and healthy tissues to zinc treatment.
Breast cancer patients negative for the nuclear oestrogen receptor α have a particularly poor prognosis. Therefore, the 4T1 cell line (considered as a triple-negative model) was chosen to induce malignancy in mice. The aim of the present study was to assess if zinc ions, provided in excess, may significantly modify the process of mammary oncogenesis. Zn(II) ions were chosen because of their documented antitumour effects. Zn(II) is also known to induce the expression of metallothioneins (MT) and glutathion (GSH). A total dose of zinc sulphate per one gram of mouse weight used in the experiment was 0.15 mg. We studied the expression of MT1, MT2, TP53 and MTF-1 genes and also examined the effect of the tumour on antioxidant capacity. Tumour-free mice had significantly higher expression levels of the studied genes (p<0.003). Significant differences were also revealed in the gene expression between the tissues (p<0.001). The highest expression levels were observed in the liver. As compared to brain, lung and liver, significantly lower concentrations of MT protein were found in the primary tumour; an inverse trend was observed in the concentration of Zinc(II). In non-tumour mice, the amount of hepatic hydrosulphuryl groups significantly increased by the exposure to Zn(II), but the animals with tumour induction showed no similar trend. The primary tumour size of zinc-treated animals was 20% smaller (p=0.002); however, no significant effect on metastasis progression due to the zinc treatment was discovered. In conclusion, Zn(II) itself may mute the growth of primary breast tumours especially at their early stages.


The Error-Prone DNA Polymerase κ Promotes Temozolomide Resistance in Glioblastoma through Rad17-Dependent Activation of ATR-Chk1 Signaling.
The acquisition of drug resistance is a persistent clinical problem limiting the successful treatment of human cancers, including glioblastoma (GBM). However, the molecular mechanisms by which initially chemoresponsive tumors develop therapeutic resistance remain poorly understood. In this study, we report that Pol κ, an error-prone polymerase that participates in translesion DNA synthesis, was significantly upregulated in GBM cell lines and tumor tissues following temozolomide treatment. Overexpression of Pol κ in temozolomide-sensitive GBM cells conferred resistance to temozolomide, whereas its inhibition markedly sensitized resistant cells to temozolomide in vitro and in orthotopic xenograft mouse models. Mechanistically, depletion of Pol κ disrupted homologous recombination (HR)-mediated repair and restart of stalled replication forks, impaired the activation of ATR-Chk1 signaling, and delayed cell-cycle re-entry and progression. Further investigation of the relationship between Pol κ and temozolomide revealed that Pol κ inactivation facilitated temozolomide-induced Rad17 ubiquitination and proteasomal degradation, subsequently silencing ATR-Chk1 signaling and leading to defective HR repair and the reversal of temozolomide resistance. Moreover, overexpression of Rad17 in Pol κ-depleted GBM cells restored HR efficiency, promoted the clearance of temozolomide-induced DNA breaks, and desensitized cells to the cytotoxic effects of temozolomide observed in the absence of Pol κ. Finally, we found that Pol κ overexpression correlated with poor prognosis in GBM patients undergoing temozolomide therapy. Collectively, our findings identify a potential mechanism by which GBM cells develop resistance to temozolomide and suggest that targeting the DNA damage tolerance pathway may be beneficial for overcoming resistance. Cancer Res; 76(8); 2340-53. ©2016 AACR.


Comparison of Lidocaine Gel-Assisted Transconjunctival and Transcutaneous Local Anesthesia for Outpatient Eyelid Surgery.
Determine whether transconjunctival local anesthesia using 2% lidocaine gel decreases pain perception in comparison with transcutaneous anesthesia in patients undergoing outpatient eyelid surgery. This is a randomized controlled clinical trial. This study approved by an institutional review board and adhered to the Declaration of Helsinki and the Health Insurance Portability and Accountability Act. A total of 120 patients undergoing bilateral upper or lower eyelid surgery were enlisted. Topical 2% lidocaine gel was administered to the palpebral conjunctiva for 1 minute, followed by a local transconjunctival injection. Local anesthetic was administered to the contralateral eyelid by a transcutaneous approach without use of topical anesthetic. Both injections were 1 ml of 1% lidocaine with epinephrine 1:100,000 on a 30-gauge needle. After each injection, patients rated the pain on a 0-to-10 visual analog scale. Patients were also asked for preference between the 2 sides. The mean pain scores were 2.33 (standard deviation 0.98) for the transconjunctival side and 3.42 (standard deviation 0.88) for the transcutaneous side. The reduction in pain scores for lidocaine gel-treated sides was statistically significant (p < 0.001) when controlling for side of intervention, upper versus lower eyelid procedures, sex of participants, and type of procedure. In addition, 85% of participants found the transconjunctival injection to be less painful than the transcutaneous (p < 0.001). Transconjunctival local anesthesia in conjunction with topical anesthesia with 2% lidocaine gel provides a clinically and statistically significant decrease in perceived pain when compared with transcutaneous anesthesia in patients undergoing outpatient eyelid surgery.


Climate mitigation by dairy intensification depends on intensive use of spared grassland.
Milk and beef production cause 9% of global greenhouse gas (GHG) emissions. Previous life cycle assessment (LCA) studies have shown that dairy intensification reduces the carbon footprint of milk by increasing animal productivity and feed conversion efficiency. None of these studies simultaneously evaluated indirect GHG effects incurred via teleconnections with expansion of feed crop production and replacement suckler-beef production. We applied consequential LCA to incorporate these effects into GHG mitigation calculations for intensification scenarios among grazing-based dairy farms in an industrialized country (UK), in which milk production shifts from average to intensive farm typologies, involving higher milk yields per cow and more maize and concentrate feed in cattle diets. Attributional LCA indicated a reduction of up to 0.10 kg CO2 e kg-1 milk following intensification, reflecting improved feed conversion efficiency. However, consequential LCA indicated that land use change associated with increased demand for maize and concentrate feed, plus additional suckler-beef production to replace reduced dairy-beef output, significantly increased GHG emissions following intensification. International displacement of replacement suckler-beef production to the "global beef frontier" in Brazil resulted in small GHG savings for the UK GHG inventory, but contributed to a net increase in international GHG emissions equivalent to 0.63 kg CO2 e kg-1 milk. Use of spared dairy grassland for intensive beef production can lead to net GHG mitigation by replacing extensive beef production, enabling afforestation on larger areas of lower quality grassland, or by avoiding expansion of international (Brazilian) beef production. We recommend that LCA boundaries are expanded when evaluating livestock intensification pathways, to avoid potentially misleading conclusions being drawn from "snapshot" carbon footprints. We conclude that dairy intensification in industrialized countries can lead to significant international carbon leakage, and only achieves GHG mitigation when spared dairy grassland is used to intensify beef production, freeing up larger areas for afforestation.


Clinical use of endovenous indocyanine green during rectosigmoid segmental resection for endometriosis.
To describe a new use of endovenous indocyanine green (ICG) to allow real-time visualization of bowel perfusion in women with recto-sigmoid endometriosis who may be candidates for segmental resection. Step-by-step explanation of this method using descriptive text and educational video. Tertiary level referral academic center. A nulliparous 36-year-old woman affected by a large rectal endometriotic nodule was referred for severe dysmenorrhea, dyspareunia, hematochezia, and dyschezia, despite progestinic therapy. An intravenous injection of 1.5 mL solution containing 3.75 mg dose of ICG for intraoperative fluorescence imaging. Evaluation of blood perfusion of bowel and rectal endometriosis nodule. Evaluation of neoanastomosis vascularization after bowel resection. The procedure of endometriosis removal was performed using the daVinciXi surgical platform (Intuitive Surgical, Sunnyvale, CA). After ovarian endometriosis removal and adhesiolysis, we identified the endometriosis nodule on the anterior surface of the rectum. Pararectal, rectovaginal, and retrorectal spaces were dissected with a nerve-sparing technique. Indocyanine green was administered through a peripheral line. A near-infrared camera head enabled vision of the colorant after latency of a few seconds. We observed the ischemic area around the rectal nodule and perfusion areas upstream and downstream from the lesion. We selected the transecting line for rectal resection, taking account of this objective evaluation, beyond the limits of macroscopic disease. After direct mechanical anastomosis, we checked the rectal vascularization with ICG. To the best of our knowledge, this is the first reported use of endovenous ICG during a bowel resection for deep endometriosis. Endovenous ICG is proposed during surgery for rectosigmoid endometriosis to assess the perfusion of the bowel and select the transecting line. With ICG fluorescence imaging, we can objectively evaluate whether blood supply to the anastomosis is adequate. Endovenous ICG for objective vascular assessment is simple and rapid to use, and no complications related to ICG use were recorded.


Loss of NR5A1 in mouse Sertoli cells after sex determination changes cellular identity and induces cell-death by anoikis.
To investigate the role of the nuclear receptor NR5A1 in testis after sex determination, we have analyzed mice lacking NR5A1 in Sertoli cells (SC) from embryonic day (E) 13.5 onwards. Ablation of Nr5a1 impairs the expression of genes characteristic of the SC identity (e.g., Sox9, Amh), causes SC death from E14.5 through a Trp53-independent mechanism related to anoikis, and induces disorganization of the testis cords. Together, these effects cause germ cells to enter meiosis and die. Single-cell RNA-sequencing experiments revealed that NR5A1-deficient SC change their molecular identity: some acquire a "pre-granulosa-like" identity, while other revert to a "supporting progenitor-like" cell identity, most of them being "intersex" because they express both testicular and ovarian genes. Fetal Leydig cells (LC) do not display significant changes, indicating that SC are not required beyond E14.5 for their emergence or maintenance. In contrast, adult LC were absent from the postnatal testes. In addition, adult mutant males display persistence of Müllerian duct derivatives, decreased anogenital distance and reduced penis length, which can be explained by the loss of AMH and testosterone synthesis due to SC failure.


Hydrostatic pressure effects on deswelling of de-epithelialized and de-endothelialized corneas.
The effects of varying hydrostatic pressure on the thinning rate of preswollen de-epithelialized or de-endothelialized corneas has been determined in the specular microscope. The appropriate membrane was removed, the cornea given access to Ringer to swell, and then fluid exchange at that surface blocked with oil. De-epithelialized corneas thin more slowly as hydrostatic pressure on the posterior surface is increased, until fluid movement ceases at 60 to 70 mm. Hg. Fluid movement can occur, therefore, against a considerable hydrostatic pressure. De-endothelialized corneas thin at a higher rate as hydrostatic pressure is increased; this effect is probably a mechanical one with increasing pressure forcing fluid out across the epithelium.


[Transcription start site determination in Stylonychia lemnae tubulin genes].
Contemporary experimental literature concerning transcription regulation study contains a lot of inconsistencies between data on precise transcription start site position in tubulin genes of hypotrychious ciliates. We have revealed that the reason of these inconsistencies lies in the methods applied by scientists. In present study, the basic methods of transcription start site identification were analyzed. The modification of transcription start site identification method based on the analysis of sequencing and primer extension reactions products on the same PAA gel was elaborated using Stylonychia lemnae tubulin genes as a model object. The use ofnon-phosphorylated primers in sequencing reaction (in accordance with standard procedure) leads to the appearance of band shifting which causes mistakes in results evaluation. This band shifting can be eliminated by the use of primers phosphorylated by non-radioactive phosphorus. In present study we applied this method to redetermine transcription start sites in alpha1-, alpha2-, beta1- and beta2-tubulin genes of S. lemnae.


Mapping multiscale breeding bird species distributions across the United States and evaluating their conservation applications.
Species distribution models are vital to management decisions that require understanding habitat use patterns, particularly for species of conservation concern. However, the production of distribution maps for individual species is often hampered by data scarcity, and existing species maps are rarely spatially validated due to limited occurrence data. Furthermore, community-level maps based on stacked species distribution models lack important community assemblage information (e.g., competitive exclusion) relevant to conservation. Thus, multispecies, guild, or community models are often used in conservation practice instead. To address these limitations, we aimed to generate fine-scale, spatially-continuous, nationwide maps for species represented in the North American Breeding Bird Survey (BBS) between 1992-2019. We developed ensemble models for each species at three spatial resolutions - 0.5, 2.5, and 5 km - across the conterminous United States. We also compared species richness patterns from stacked single-species models with those of 19 functional guilds developed using the same data to assess the similarity between predictions. We successfully modeled 192 bird species at 5-km resolution, 160 species at 2.5-km resolution, and 80 species at 0.5-km resolution. However, the species we could model represent only 28-56% of species found in the conterminous US BBS surveys across resolutions owing to data limitations. We found stacked maps and guild maps generally had high correlations across resolutions (median = 84%), but spatial agreement varied regionally by resolution and was most pronounced between the East and West at the 5-km resolution. The spatial differences between our stacked maps and guild maps illustrate the importance of spatial validation in conservation planning. Overall, our species maps are useful for single-species conservation and can support fine-scale decision-making across the United States, and can also support community-level conservation when used in tandem with guild maps. However, there are still data scarcity issues for many species of conservation concern when using the BBS for single-species models. This article is protected by copyright. All rights reserved.


A study of the readiness of Jewish/Israeli students in the health professions to authorize and execute involuntary mass euthanasia of "severely handicapped" patients.
The responses of 92 Jewish/Israeli students in the health professions in Israel were studied in the context of a projected future situation where the subjects would be working as physicians/psychologists/social workers, first in a developing country somewhere in Africa, and then, in the second experimental scenario, at a well-known treatment institution in the center of Israel. A successive series of contraints were described that led to a scarcity of resources, in which context the health authorities considered it advisable first to limit and then to curtail the treatment of the severebly handicapped who could benefit least from treatment, and as the situation became more severe to implement a program of involuntary mass euthanasia. Although an eithical point of view would call for zero participation in the policies which would bring about dealths of patients, it had been predicted that as many as 15% of the subjects would agree to curtailing treatment, 5% to participate in planning involunary mass euthanasia, and 2% to execute the euthanasia themselves. However, the results were that in African 39% agreed to curtail treatment, 17% to plan euthanasia, and 11% them selves to terminate the patients' lives; in Israel the corresponding figures were 38%, 12%, and 9% - the differences between Africa and Israel were not significant. The study is seen as contributing to emerging knowledge (in the Milgram tradition) of the widespread availability of human beings to undertake policies which harm, hurt and kill other human beings when instructed to do so by a policy directive.


Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention.
Women and their clinicians are increasingly encouraged to use risk estimates derived from statistical models, primarily that of Gail et al., to aid decision making regarding potential prevention options for breast cancer, including chemoprevention with tamoxifen. We evaluated both the goodness of fit of the Gail et al. model 2 that predicts the risk of developing invasive breast cancer specifically and its discriminatory accuracy at the individual level in the Nurses' Health Study. We began with a cohort of 82 109 white women aged 45-71 years in 1992 and applied the model of Gail et al. to these women over a 5-year follow-up period to estimate a 5-year risk of invasive breast cancer. All statistical tests were two-sided. The model fit well in the total sample (ratio of expected [E] to observed [O] numbers of cases = 0.94; 95% confidence interval [CI] = 0.89 to 0.99). Underprediction was slightly greater for younger women (<60 years), but in most age and risk factor strata, E/O ratios were close to 1.0. The model fit equally well (E/O ratio = 0.93; 95% CI = 0.87 to 0.99) in a subset of women reporting recent screening (i.e., within 1 year before the baseline); among women with an estimated 5-year risk of developing invasive breast cancer of 1.67% or greater, the E/O ratio was 1.04 (95% CI = 0.96 to 1.12). The concordance statistic, which indicates discriminatory accuracy, for the Gail et al. model 2 when used to estimate 5-year risk was 0.58 (95% CI = 0.56 to 0.60). Only 3.3% of the 1354 cases of breast cancer observed in the cohort arose among women who fell into age-risk strata expected to have statistically significant net health benefits from prophylactic tamoxifen use. The Gail et al. model 2 fit well in this sample in terms of predicting numbers of breast cancer cases in specific risk factor strata but had modest discriminatory accuracy at the individual level. This finding has implications for use of the model in clinical counseling of individual women.


Bacterium Lacking a Known Gene for Retinal Biosynthesis Constructs Functional Rhodopsins.
Microbial rhodopsins, comprising a protein moiety (rhodopsin apoprotein) bound to the light-absorbing chromophore retinal, function as ion pumps, ion channels, or light sensors. However, recent genomic and metagenomic surveys showed that some rhodopsin-possessing prokaryotes lack the known genes for retinal biosynthesis. Since rhodopsin apoproteins cannot absorb light energy, rhodopsins produced by prokaryotic strains lacking genes for retinal biosynthesis are hypothesized to be non-functional in cells. In the present study, we investigated whether Aurantimicrobium minutum KNCT, which is widely distributed in terrestrial environments and lacks any previously identified retinal biosynthesis genes, possesses functional rhodopsin. We initially measured ion transport activity in cultured cells. A light-induced pH change in a cell suspension of rhodopsin-possessing bacteria was detected in the absence of exogenous retinal. Furthermore, spectroscopic analyses of the cell lysate and HPLC-MS/MS analyses revealed that this strain contained an endogenous retinal. These results confirmed that A. minutum KNCT possesses functional rhodopsin and, hence, produces retinal via an unknown biosynthetic pathway. These results suggest that rhodopsin-possessing prokaryotes lacking known retinal biosynthesis genes also have functional rhodopsins.


The association of smoking and socioeconomic status on cutaneous melanoma: a population-based, data-linkage, case-control study.
Previous studies have identified an inverse association between melanoma and smoking; however, data from population-based studies are scarce. To determine the association between smoking and socioeconomic (SES) on the risk of development of melanoma. Furthermore, we sought to determine the implications of smoking and SES on survival. We conducted a population-based case-control study. Cases were identified from the Welsh Cancer Intelligence and Surveillance Unit (WCISU) during 2000-2015 and controls from the general population. Smoking and SES were obtained from data linkage with other national databases. The association of smoking status and SES on the incidence of melanoma were assessed using binary logistic regression. Multivariate survival analysis was performed on a melanoma cohort using a Cox proportional hazard model using survival as the outcome. During 2000-2015, 9636 patients developed melanoma. Smoking data were obtained for 7124 (73·9%) of these patients. There were 26 408 controls identified from the general population. Smoking was inversely associated with melanoma incidence [odds ratio (OR) 0·70, 95% confidence interval (CI) 0·65-0·76]. Smoking was associated with an increased overall mortality [hazard ratio (HR) 1·30, 95% CI 1·09-1·55], but not associated with melanoma-specific mortality. Patients with higher SES had an increased association with melanoma incidence (OR 1·58, 95% CI 1·44-1·73). Higher SES was associated with an increased chance of both overall (HR 0·67, 95% CI 0·56-0·81) and disease-specific survival (HR 0·69, 95% CI 0·53-0·90). Our study has demonstrated that smoking appeared to be associated with reduced incidence of melanoma. Although smoking increases overall mortality, no association was observed with melanoma-specific mortality. Further work is required to determine if there is a biological mechanism underlying this relationship or an alternative explanation, such as survival bias. What's already known about this topic? Previous studies have been contradictory with both negative and positive associations between smoking and the incidence of melanoma reported. Previous studies have either been limited by publication bias because of selective reporting or underpowered. What does this study add? Our large study identified an inverse association between smoking status and melanoma incidence. Although smoking status was negatively associated with overall disease survival, no significant association was noted in melanoma-specific survival. Socioeconomic status remains closely associated with melanoma. Although higher socioeconomic populations are more likely to develop the disease, patients with lower socioeconomic status continue to have a worse prognosis.


Childhood Undernutrition and Its Predictors in a Rural Health and Demographic Surveillance System Site in South Africa.
Overweight and obesity are increasing at an alarming rate in South Africa, while childhood undernutrition remains persistently high. This study determined the magnitude and predictors of stunting and underweight among schoolchildren in the Dikgale and Health Demographic Surveillance System Site, a rural site in South Africa. A cross sectional study using multistage sampling was conducted among 508 schoolchildren and their mothers. Anthropometric measurements were taken from children and their mothers, while sociodemographic information was obtained from mothers using a questionnaire. The World Health Organization Anthro Plus was used to generate height-for-age and weight-for-age z-scores to indicate stunting and underweight, respectively, among the children. Maternal overweight and obesity were assessed using body mass index. Bivariate and multivariate logistic regression analyses were used to evaluate the predictors of stunting and underweight among schoolchildren. Twenty-two percent (22%) of children were stunted and 27% were underweight, while 27.4% of the mothers were overweight and 42.3% were obese. The odds of being stunted were lower in younger children, whereas having a mother who was overweight/obese and had a short stature increased the odds of stunting. Access to water, having a refrigerator, and having a young mother were protective against being underweight. Having a mother who was overweight/obese increased the odds of being underweight. The study showed a high prevalence of stunting and underweight among children, and overweight and obesity among mothers, indicating a household double burden of malnutrition. The age of the child and maternal overweight/obesity and short stature were predictors of stunting and underweight, while having a younger mother and access to water and a refrigerator were protective against being underweight. The need for an evidence-based and feasible nutrition program for schoolchildren, especially those in rural schools, cannot be over-emphasized.


Co-treatment of gonadotropin and letrozole in infertile women with endometriosis: A double-blind randomized clinical trial.
The common causes of infertility in women with endometriosis are folliculogenesis alternation, steroidogenesis and fertilization impairment, oocyte and embryo quality reduction, and implantation defect. To compare in vitro fertilization (IVF) cycle success rates of women with endometriosis who were treated with letrozole + gonadotropin (LA) vs. placebo + gonadotropin (PA). This double-blind, randomized clinical trial study was conducted with 94 infertile women with endometriosis (47 in the LA group and 47 in the PA group) who were candidates for IVF, from April-June 2021. For all participants, the long agonist protocol was applied. In both groups, gonadotropin-releasing hormone agonist was prescribed in the mid-luteal stage and from the third day of the cycle, and gonadotropin was started and its doses were regulated based on the patient's age, serum anti-Mullerian hormone and follicle-stimulating hormone. From the third day of the menstrual cycle, 5 mg of letrozole daily for 5 days was prescribed for the LA group, while the placebo was prescribed for the PA group on the identical days and duration. After embryo transfer, biochemical and clinical pregnancy were measured in the 2 groups. The gonadotropin dosage (p < 0.01) and estradiol level (p = 0.02) on the human chorionic gonadotropin administration day were significantly lower in the LA group compared with in the PA group. Fetus transfer was done for 32 women. No significant differences were detected between the study groups regarding biochemical or clinical pregnancy (p = 0.72 for both). Letrozole as a co-treatment drug in the IVF cycle of women with endometriosis can significantly reduce the gonadotropin dosage and estradiol level with the same pregnancy rates.


Hypertrophic cardiomyopathy: prognostic factors and survival analysis in 128 Egyptian patients.
Hypertrophic cardiomyopathy is an important cause of disability and death in patients of all ages. Egyptian children may differ from Western and Asian patients in the pattern of hypertrophy distribution, clinical manifestations, and risk factors. The aim of our study was to report the clinical characteristics and outcomes of Egyptian children with hypertrophic cardiomyopathy studied over a 7-year duration and to determine whether the reported adult risk factors for sudden cardiac death are predictive of the outcome in these affected children. This retrospective study included 128 hypertrophic cardiomyopathy children. The data included personal history, family history, physical examination, baseline laboratory measurements, electrocardiogram, and Holter and echocardiographic results. Logistic regression analysis was used for the detection of risk factors of death. Fifty-one out of 128 patients died during the period of the study. Of the 51 deaths, 36 (70.5%) occurred in patients presenting before 1 year of age. Only eight patients had surgical intervention. Extreme left ventricular hypertrophy, that is, interventricular septal wall thickness or posterior wall thickness Z-score >6, sinus tachycardia, and supraventricular tachycardia were found to be independent risk factors for prediction of death in patients with hypertrophic cardiomyopathy. At our Egyptian tertiary care centre, hypertrophic cardiomyopathy has a relatively worse prognosis when compared with reports from Western and Asian series. Infants have a worse outcome than children presenting after the age of 1 year. A poorer prognosis in childhood hypertrophic cardiomyopathy is predicted by an extreme left ventricular hypertrophy, the presence of sinus tachycardia, and supraventricular tachycardia.


Cognitive Engineering to Improve Patient Safety and Outcomes in Cardiothoracic Surgery.
Cognitive engineering is focused on how humans can cope and master the complexity of processes and technological environments. In cardiothoracic surgery, the goal is to support safe and effective human performance by preventing medical errors. Strategies derived from cognitive engineering research could be introduced in cardiothoracic surgery practice in the near future to enhance patient safety and outcomes.


How the methyl group position influences the ultrafast deactivation in aromatic radicals.
Excited xylyl (methyl-benzyl) radical isomers have been studied by femtosecond time-resolved photoelectron spectroscopy and mass spectrometry. Depending on the substitution we find different deactivation channels after excitation into the D3(2A'') state (310 nm, 4 eV). While the ortho and para isomer exhibit deactivation rates similar to the benzyl radical, meta-xylyl sticks out and depletes twice as fast into the vibrationally hot ground state. We found that a ring deformation mode rather than the methyl pseudorotation enables access to a conical intersection, which is responsible for the faster deactivation. Transitions in the photoelectron spectrum can be assigned to several Rydberg series with mostly d angular momentum components. Absorption of two 4 eV photons triggers hydrogen loss reactions on a femtosecond timescale.


Accuracy of cytology vs. microbiopsy for the diagnosis of well-differentiated hepatocellular carcinoma and macroregenerative nodule. Definition of standardized criteria from a study of 100 cases.
To determine the accuracy of ultrasound (US)-guided fine needle aspiration (FNA) for the diagnosis of well-differentiated hepatocellular carcinoma (wd HCC) and macroregenerative nodule (MRN) and to identify the most useful cytologic and histologic criteria to distinguish between those two diagnoses. Cytologic and histologic specimens of 50 wd HCC and 50 MRN were reviewed blindly and the diagnosis compared to the final clinical diagnosis. Twenty-eight cytologic and 25 histologic criteria were examined and subjected to statistical analysis. Among 100 cases studied, the final diagnosis was available for 43. In those 43 cases, combining analysis of cytologic and histologic specimens, the sensitivity of US-guided FNA was of 75% and the specificity 100%. Cytologic analysis was better than isolated histologic analysis, with a sensitivity of 75% vs. 68%, respectively. Sensitivity of cytologic diagnosis was lower for smaller nodules and for those located in poorly accessible hepatic segments. With the use of stepwise logistic regression analysis, four cytologic features (increased nuclear/cytoplasmic ratio, cellular monomorphism, nuclear crowding, loss of bile duct cells) and four histologic features (increased nuclear/cytoplasmic ratio, decreased Kupffer cells, cellular monomorphism, increased trabeculae thickness) were identified as predictive of HCC.