Stabilization of the E3 ubiquitin ligase Nrdp1 by the deubiquitinating enzyme USP8.
Nrdp1 is a RING finger-containing E3 ubiquitin ligase that physically interacts with and regulates steady-state cellular levels of the ErbB3 and ErbB4 receptor tyrosine kinases and has been implicated in the degradation of the inhibitor-of-apoptosis protein BRUCE. Here we demonstrate that the Nrdp1 protein undergoes efficient proteasome-dependent degradation and that mutations in its RING finger domain that disrupt ubiquitin ligase activity enhance stability. These observations suggest that Nrdp1 self-ubiquitination and stability could play an important role in regulating the activity of this protein. Using affinity chromatography, we identified the deubiquitinating enzyme USP8 (also called Ubpy) as a protein that physically interacts with Nrdp1. Nrdp1 and USP8 could be coimmunoprecipitated, and in transfected cells USP8 specifically bound to Nrdp1 but not cbl, a RING finger E3 ligase involved in ligand-stimulated epidermal growth factor receptor down-regulation. The USP8 rhodanese and catalytic domains mediated Nrdp1 binding. USP8 markedly enhanced the stability of Nrdp1, and a point mutant that disrupts USP8 catalytic activity destabilized endogenous Nrdp1. Our results indicate that Nrdp1 is a specific target for the USP8 deubiquitinating enzyme and are consistent with a model where USP8 augments Nrdp1 activity by mediating its stabilization.


The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia.
There is increasing evidence that cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer's disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier, and reduces the brain's repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In the absence of mechanism-based approaches to counteract cognitive dysfunction, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.


Efficacy and tolerability of sevelamer carbonate in hyperphosphatemic patients who have chronic kidney disease and are not on dialysis.
Sevelamer carbonate is an improved, buffered form of sevelamer hydrochloride developed for the treatment of hyperphosphatemia in patients with chronic kidney disease. This study investigated the ability of sevelamer carbonate to control serum phosphorous in hyperphosphatemic patients who had chronic kidney disease and were not on dialysis. This was an open-label, dosage-titration study. Patients with serum phosphorus > or =5.5 mg/dl were enrolled (n = 46). Sevelamer carbonate was administered for 8 wk. Patients were supplemented with native vitamin D (400 IU). The primary efficacy parameter was the change from baseline in serum phosphorous. Secondary measures included the percentage of serum phosphorus responders; changes in serum lipids, calcium-phosphorus product, and bicarbonate; and safety and tolerability. Sevelamer carbonate treatment resulted in a statistically significant decrease in mean serum phosphorous levels from baseline to end of treatment. A total of 75% of patients with stage 4 and 70% of patients with stage 5 chronic kidney disease achieved the target serum phosphorous at the end of treatment. There were statistically significant decreases in serum calcium-phosphorus product and total and low-density lipoprotein cholesterol at the end of treatment and a statistically significant increase in mean serum bicarbonate levels (from 16.6 to 18.2 mEq/L). Sevelamer carbonate was well tolerated. Sevelamer carbonate is an effective and well-tolerated therapy for the control of phosphorous levels in hyperphosphatemic patients who have chronic kidney disease and are not on dialysis.


High-affinity labeling and tracking of individual histidine-tagged proteins in live cells using Ni2+ tris-nitrilotriacetic acid quantum dot conjugates.
Investigation of many cellular processes using fluorescent quantum dots (QDs) is hindered by the nontrivial requirements for QD surface functionalization and targeting. To address these challenges, we designed, characterized and applied QD-trisNTA, which integrates tris-nitrilotriacetic acid, a small and high-affinity recognition unit for the ubiquitous polyhistidine protein tag. Using QD-trisNTA, we demonstrate two-color QD tracking of the type-1 interferon receptor subunits in live cells, potentially enabling direct visualization of protein-protein interactions at the single molecule level.


Neural tree density estimation for novelty detection.
In this paper, a neural competitive learning tree is introduced as a computationally attractive scheme for adaptive density estimation and novelty detection. The learning rule yields equiprobable quantization of the input space and provides an adaptive focusing mechanism capable of tracking time-varying distributions. It is shown by simulation that the neural tree performs reasonably well while being much faster than any of the other competitive learning algorithms.


Patient characteristics of smokers undergoing lumbar spine surgery: an analysis from the Quality Outcomes Database.
OBJECTIVE In this analysis the authors compare the characteristics of smokers to nonsmokers using demographic, socioeconomic, and comorbidity variables. They also investigate which of these characteristics are most strongly associated with smoking status. Finally, the authors investigate whether the association between known patient risk factors and disability outcome is differentially modified by patient smoking status for those who have undergone surgery for lumbar degeneration. METHODS A total of 7547 patients undergoing degenerative lumbar surgery were entered into a prospective multicenter registry (Quality Outcomes Database [QOD]). A retrospective analysis of the prospectively collected data was conducted. Patients were dichotomized as smokers (current smokers) and nonsmokers. Multivariable logistic regression analysis fitted for patient smoking status and subsequent measurement of variable importance was performed to identify the strongest patient characteristics associated with smoking status. Multivariable linear regression models fitted for 12-month Oswestry Disability Index (ODI) scores in subsets of smokers and nonsmokers was performed to investigate whether differential effects of risk factors by smoking status might be present. RESULTS In total, 18% (n = 1365) of patients were smokers and 82% (n = 6182) were nonsmokers. In a multivariable logistic regression analysis, the factors significantly associated with patients' smoking status were sex (p < 0.0001), age (p < 0.0001), body mass index (p < 0.0001), educational status (p < 0.0001), insurance status (p < 0.001), and employment/occupation (p = 0.0024). Patients with diabetes had lowers odds of being a smoker (p = 0.0008), while patients with coronary artery disease had greater odds of being a smoker (p = 0.044). Patients' propensity for smoking was also significantly associated with higher American Society of Anesthesiologists (ASA) class (p < 0.0001), anterior-alone surgical approach (p = 0.018), greater number of levels (p = 0.0246), decompression only (p = 0.0001), and higher baseline ODI score (p < 0.0001). In a multivariable proportional odds logistic regression model, the adjusted odds ratio of risk factors and direction of improvement in 12-month ODI scores remained similar between the subsets of smokers and nonsmokers. CONCLUSIONS Using a large, national, multiinstitutional registry, the authors described the profile of patients who undergo lumbar spine surgery and its association with their smoking status. Compared with nonsmokers, smokers were younger, male, nondiabetic, nonobese patients presenting with leg pain more so than back pain, with higher ASA classes, higher disability, less education, more likely to be unemployed, and with Medicaid/uninsured insurance status. Smoking status did not affect the association between these risk factors and 12-month ODI outcome, suggesting that interventions for modifiable risk factors are equally efficacious between smokers and nonsmokers.


A device for the detection of cognitive brain functions in completely paralyzed or unresponsive patients.
Unresponsive patients with remaining cognitive abilities may be able to communicate with a brain-computer interface (BCI) such as the Thought Translation Device (TTD). Before initiating TTD learning, which may imply considerable effort, it is important to classify the patients' state of awareness and their remaining cognitive abilities. A tool for detection of cognitive activity (DCA) in the completely paralyzed was developed and integrated into the TTD which is a psychophysiological system for direct brain communication. In the present version, DCA entails five event-related brain-potential (ERP) experiments and investigates the capability of a patient to discriminate, e.g., between semantically related and unrelated concepts and categories. ERPs serve as an indicator of the patients' cortical information processing. Data from five severely brain-injured patients in persistent vegetative state diagnosed as unresponsive and five healthy controls are presented to illustrate the methodology. Two patients showing the highest responsiveness were selected for TTD training. The DCA integrated in the TTD allows screening of cognitive abilities and direct brain communication in the patients' home.


Mouse cloning using a drop of peripheral blood.
Somatic cell nuclear transfer (SCNT) is a unique technology that produces cloned animals from single cells. It is desirable from a practical viewpoint that donor cells can be collected noninvasively and used readily for nuclear transfer. The present study was undertaken to determine whether peripheral blood cells freshly collected from living mice could be used for SCNT. We collected a drop of peripheral blood (15-45 μl) from the tail of a donor. A nucleated cell (leukocyte) suspension was prepared by lysing the red blood cells. Following SCNT using randomly selected leukocyte nuclei, cloned offspring were born at a 2.8% birth rate. Fluorescence-activated cell sorting revealed that granulocytes/monocytes and lymphocytes could be roughly distinguished by their sizes, the former being significantly larger. We then cloned putative granulocytes/monocytes and lymphocytes separately and obtained 2.1% and 1.7% birth rates, respectively (P > 0.05). Because the use of lymphocyte nuclei inevitably results in the birth of offspring with DNA rearrangements, we applied granulocyte/monocyte cloning to two genetically modified strains and two recombinant inbred strains. Normal-looking offspring were obtained from all four strains tested. The present study clearly indicated that genetic copies of mice could be produced using a drop of peripheral blood from living donors. This strategy will be applied to the rescue of infertile founder animals or a "last-of-line" animal possessing invaluable genetic resources.


Posttranscriptional gene silencing of gn1 in tobacco triggers accumulation of truncated gn1-derived RNA species.
Posttranscriptional silencing of basic beta-1,3-glucanase genes in the tobacco line T17 is manifested by reduced transcript levels of the gn1 transgene and homologous, endogenous basic beta-1,3-glucanase genes. An RNA ligation-mediated rapid amplification of cDNA ends (RLM-RACE) technique was used to compare the 3' termini of gn1 RNAs present in expressing (hemizygous and young homozygous) and silenced (mature homozygous) T17 plants. Full-length, polyadenylated gn1 transcripts primarily accumulated in expressing plants, whereas in silenced T17 plants, mainly 3'-truncated, nonpolyadenylated gn1 RNAs were detected. The relative abundance of these 3'-truncated gn1 RNA species gradually increased during the establishment of silencing in homozygous T17 plants. Similar 3'-truncated, nonpolyadenylated gn1 RNA products were observed in an independent case of beta-1,3-glucanase posttranscriptional gene silencing. This suggests that these 3'-truncated gn1 RNAs are a general feature of tobacco plants showing posttranscriptional silencing of the gn1 transgene.


Obturator nerve injury and repair during laparoscopic lymphadenectomy. Case report and review of the literature
To report a case of obturator nerve injury during laparoscopic lymphadenectomy and repair through the same approach during the same surgical procedure; and to present a review of the literature on this type of injury, techniques used, timing of the repair, and rehabilitation outcomes. Case presentation of a 29-year-old woman seen at the National Cancer Institute (Instituto Nacional de Cancerología) in Bogotá, Colombia. The patient had a clinical diagnosis of stage Ib1 squamous cell carcinoma of the cervix and was taken to radical trachelectomy plus bilateral pelvic lymphadenectomy because of her wish to preserve fertility. During the procedure, a complete dissection of the obturator nerve was recognized and repaired immediately through the laparoscopic approach. A literature search was conducted in the Medline database via PubMed. The terms used for the search were "Obturator Nerve," "Lymph Node Excision," "Trauma," "Nervous System". The search was limited to publications in Spanish and English and included case series and reports, cohorts and review articles published between 1968 and September 2018. Eight studies were included, all of them case reports. In six cases, complete sectioning of the nerve was recognized during surgery. In four cases, end-to-end anastomosis was used for repair; three cases were reconstructed using sural nerve grafting; and one case was managed with neurolysis and end-to-end anastomosis. All cases were approached laparoscopically. Over a nine-month follow-up period, three patients recovered full nerve function. The studies retrieved were all case reports, the most frequent injury being complete nerve sectioning. Several nerve repair techniques were used. Recovery after one year was not complete in a significant number of the cases reported.


Diabesity: an inflammatory metabolic condition.
Diabesity, that is to say, obesity-dependent diabetes, has emerged as a major public health problem. Though diabesity is basically explained by insulin resistance and pancreatic beta cell dysfunction, new paradigms have evolved to explain these alterations in the context of the modern epidemics of obesity and diabetes. Among these, the association of inflammation with obesity is an important component of the common soil from which diabetes and cardiovascular diseases (CVD) derive. This Review presents our epidemiological findings, based primarily on the ARIC Study, in the context of the other epidemiological studies supporting the inflammatory nature of diabetes, CVD and the metabolic syndrome. We also review the characteristics of the innate immune system, including the molecular interface of innate immunity with metabolism, components of which are responsible for the presence of a state of mild, chronic and systemic inflammation related to diabesity. Finally, we present obesity as an inflammatory condition, obesitis, and propose a conceptual framework that integrates the epidemiological findings with new provocative basic science results.


Ovarian cancer: an update for nursing practice.
A diagnosis of ovarian cancer is a crisis for any woman. Ovarian cancer has the highest mortality of all the gynaecological cancers. In addition to the very real threat of death, such a diagnosis raises critical issues concerning femininity, motherhood and sexuality. The high mortality associated with this disease is due (in part) to problems associated with early diagnosis. Women frequently experience non-specific symptoms, which may be attributed to other, less alarming causes. The lack of specific symptoms experienced by women, as well as the lack of effective mass screening strategies, make early detection difficult. This makes it crucial that nurses involved in the care of women be alert to the insidious and non-specific onset of this serious condition.


Spontaneous Coronary Artery Dissection Across the Health Care Pathway: A National, Multicenter, Patient-Informed Investigation.
Clinical practice guidelines for the management and convalescence of patients with spontaneous coronary artery dissection (SCAD) have yet to be developed. The targeted content, delivery, and outcomes of interventions that benefit this population remain unclear. Patient-informed data are required to substantiate observational research and provide evidence to inform and standardize clinical activities. Patients diagnosed with SCAD (N=89; 86.5% women; mean age, 53.2 years) were purposively selected from 5 large tertiary care hospitals. Patients completed sociodemographic and medical questionnaires and participated in an interview using a patient-piloted semistructured interview guide. Interviews were transcribed and subjected to framework analysis using inductive and then deductive coding techniques. Approximately 1500 standard transcribed pages of interview data were collected. Emotional distress was the most commonly cited precipitating factor (56%), with an emphasis on anxiety symptoms. The awareness and detection of SCAD as a cardiac event was low among patients (35%) and perceived to be moderate among health care providers (55%). Health care providers' communication of the prognosis and self-management of SCAD were perceived to be poor (79%). Postevent psychological disorders among patients were evident (30%), and 73% feared recurrence. Short- and longer-term follow-up that was tailored to patients' needs was desired (72%). Secondary prevention programming was recommended, but there were low completion rates of conventional cardiac rehabilitation (48%), and current programming was deemed inadequate. This early-stage, pretrial research has important implications for the acute and long-term management of patients with SCAD. Additional work is required to validate the hypotheses generated from this patient-oriented research.


Effect of N-1 arylation of monastrol on kinesin Eg5 inhibition in glioma cell lines.
An original and focused library of two sets of dihydropyrimidin-2-thiones (DHPMs) substituted with N-1 aryl groups derived from monastrol was designed and synthesized in order to discover a more effective Eg5 ligand than the template. Based on molecular docking studies, four ligands were selected to perform pharmacological investigations against two glioma cell lines. The results led to the discovery of two original compounds, called 20h and 20e, with an anti-proliferative effects, achieving IC50 values of about half that of the IC50 of monastrol in both cell lines. As with monastrol, flow cytometry analyses showed that the 20e and 20h compounds induced cell cycle arrest in the G2/M phase, and immunocytochemistry essays revealed the formation of monopolar spindles due to Eg5 inhibition without any toxicity to Caenorhabditis elegans.


Input prediction and autonomous movement analysis in recurrent circuits of spiking neurons.
Temporal integration of information and prediction of future sensory inputs are assumed to be important computational tasks of generic cortical microcircuits. It has remained open how cortical microcircuits could possibly achieve this, especially since they consist--in contrast to most neural network models--of neurons and synapses with heterogeneous dynamic responses. It turns out, however, that the diversity of computational units increases the capability of microcircuit models for temporal integration. Furthermore the prediction of future input may be rather easy for such circuits since it suffices to train the readouts from such microcircuits. In this article we show that very simple readouts from a generic recurrently connected circuit of integrate-and-fire neurons with diverse dynamic synapses can be trained in an unsupervised manner to predict movements of different objects, that move within an unlimited number of combinations of speed, angle, and offset over a simulated sensory field. The autonomously trained microcircuit model is also able to compute the direction of motion, which is a computationally difficult problem ('aperture problem') since it requires disambiguation of local sensory readings through the context of other sensory readings at the current and preceding moments. Furthermore the same circuit can be trained simultaneously in a supervised manner to also report the shape and velocity of the moving object. Finally it is shown that the trained neural circuit supports novelty detection and the generation of 'imagined movements'. Altogether the results of this article suggest that it is not necessary to construct specific and biologically unrealistic neural circuit models for specific sensory processing tasks, since 'found' generic cortical microcircuit models in combination with very simple perceptron-like readouts can easily be trained to solve such computational tasks.


An analysis of the effects of HIV infection in a cohort of intravenous drug users.
Intravenous drug use has been a serious problem for Dublin's deprived inner city areas since the late 1970's. In 1985, a cohort of all known intravenous drug users (IVDUs) was identified in one inner city electoral cohort and has been followed since then. The cohort was identified before the introduction of HIV testing. The prevalence of HIV infection and its consequences have continued to rise. By 1994, 80% of the group were known to have had a HIV test: 53 (65%) are seropositive. Twenty-one (26%) have died, almost all from the seropositive group. Thirty-six (44%) continued to inject heroin during 1994. The implications of these grim statistics are discussed.


Influenza virus infection induces functional alterations in peripheral blood lymphocytes.
This report describes alterations in functional responses to lectin-induced stimulation of peripheral blood lymphocytes and in the natural killer cell (NKC) activity, of college students, obtained during an outbreak of influenza A/Philippines/2/82(H3N2) virus infection. These results are compared with similar observations in college students with an acute, febrile, noninfluenzal respiratory illness that occurred during the same outbreak. The lymphopenia typical of influenza during acute illness was shown to be due to a reduction in both T and B cells without alteration in the CD4:CD8 ratio. In addition, phytohemagglutinin and concanavalin A responses were reduced and NKC activity was increased, while pokeweed mitogen reactivity was unaltered at the time of admission to the study. Patients with noninfluenzal illness showed early polymorphonuclear leukocytosis and a similar lymphopenia. Lymphocyte functions were virtually unchanged during acute illness in noninfluenza patients. The relatively specific alterations in lymphocyte responses to lectin-induced stimulation in influenza patients may indicate that the peripheral T cells are incapable of activation via the CD3 or CD2 activation pathways. In addition, increased NKC activity in the periphery may be reflective of increased NKC activity in the lung. Influenza-infected individuals with higher NKC activity at the time of admission to the study also took longer to recover. Finally, the early lymphopenia and the later neutropenia in the influenza-infected patient may represent migration of these cells from the circulation to the infected respiratory tract as a consequence of infection.


Atomic resolution analysis of the catalytic site of an aspartic proteinase and an unexpected mode of binding by short peptides.
The X-ray structures of native endothiapepsin and a complex with a hydroxyethylene transition state analog inhibitor (H261) have been determined at atomic resolution. Unrestrained refinement of the carboxyl groups of the enzyme by using the atomic resolution data indicates that both catalytic aspartates in the native enzyme share a single negative charge equally; that is, in the crystal, one half of the active sites have Asp 32 ionized and the other half have Asp 215 ionized. The electron density map of the native enzyme refined at 0.9 A resolution demonstrates that there is a short peptide (probably Ser-Thr) bound noncovalently in the active site cleft. The N-terminal nitrogen of the dipeptide interacts with the aspartate diad of the enzyme by hydrogen bonds involving the carboxyl of Asp 215 and the catalytic water molecule. This is consistent with classical findings that the aspartic proteinases can be inhibited weakly by short peptides and that these enzymes can catalyze transpeptidation reactions. The dipeptide may originate from autolysis of the N-terminal Ser-Thr sequence of the enzyme during crystallization.


In vivo effects on the immune function of fathead minnow (Pimephales promelas) following ingestion and intraperitoneal injection of polystyrene nanoplastics.
Nanoplastics (1-100 nm) are potentially the most hazardous litter in the environment. Recent scientific studies have documented their toxic effects at the cellular and molecular levels, but knowledge underlying mechanisms of their toxicity is still scarce. Nanoplastics are known for their ability to induce immune and inflammatory responses as well as generating reactive oxygen species. While some studies have addressed the immunotoxicity of nanoplastics in vitro and on in vivo in fish after intraperitoneal injection, no information is available on adult fish after ingestion of a contaminated prey. The present study is the first to attempt to address the immunotoxicity of nanoplastics in adult fish after trophic transfer. Pimephales promelas is a well-established bioindicator species to study the immunotoxicity of nanoparticles and the innate immune responses of fish. This study aims to assess the in vivo innate immune response of adult P. promelas following exposure to polystyrene nanoplastics by measuring the gene expression of ncf, nox2, mst1 and c3; these genes are related with the immune function of neutrophils, macrophages and complement in fish. Two target organs (liver and head kidney) and two routes of exposure (IP- injection and ingestion) were analyzed. After 48 h of exposure, polystyrene nanoplastics were encountered in the liver and kidney of both IP-injection and ingestion exposed fish, and significantly affected the innate immune system of P. promelas by downregulating the gene expression ncf, mst1, and c3 in liver and kidney. Significant difference between treatments was only observed for the gene expression of nfc in liver. Results of this study indicate that polystyrene nanoplastics can exhibit immunotoxicity in fish through an environmentally relevant route of exposure, interfering with the synthesis and function of neutrophils, macrophages, and complement of P. promelas in their principal hematopoietic tissues, which may potentially compromise its ability to survive in nature.


Diagnosis of duck plague in waterfowl by polymerase chain reaction.
A recently developed polymerase chain reaction (PCR) assay was used for diagnosis of duck plague in waterfowl tissues from past and current cases of waterfowl mortality and to identify duck plague virus in combined cloacal/oral-pharyngeal swab samples from healthy mallards (Anas platyrhynchos) after a disease outbreak. The PCR was able to detect viral DNA from all the individual or pooled tissues assayed from 10 waterfowl, including liver and spleen samples from three Muscovy ducks (Cairina moschata domesticus) that did not yield virus isolates. The strong staining intensity of the PCR products from the waterfowl tissues indicated that large amounts of virus were present, even when virus was not isolated. Duck plague DNA was also detected in a cloacal swab sample from a wood duck (Aix sponsa) carcass submitted for diagnosis. The PCR assay identified duck plague DNA in 13 swab samples that produced virus isolates from carrier mallards sampled in 1981 after a duck plague die-off. The duck plague PCR clearly demonstrated the ability to quickly diagnose duck plague in suspect mortality cases and to detect virus shed by carrier waterfowl.


The effect of thawing protocols on follicle conservation in human ovarian tissue cryopreservation.
Ovarian tissue cryopreservation has the potential to improve fertility preservation for a growing number of patients undergoing sterilising therapy, particularly where oocyte or embryo cryopreservation is not suitable. However, its success is limited by significant follicular apoptosis upon thawing, and there is wide variation in thawing protocols used with little evidence of efficacy. To determine the best warming rates to maintain tissue viability. Ovarian tissue biopsies from 11 patients were taken with informed consent and divided into four pieces, which were allocated to either fresh assessment or to one of several freeze-thaw protocols. Cryopreservation was undertaken using a Stirling cycle cryo-cooler and cryopreserved samples were exposed to different warming protocols. Tissue conservation was then assessed using a marker, neutral red, to identify viable follicles. The results showed greatest follicle conservation rates in fresh samples, followed by those thawed using a rapid thawing protocol (Protocol 1). Tissue thawed using an ultra fast protocol (Protocol 2) and slow warming (Protocol 3) resulted in greater follicle loss. These preliminary results indicate thawing conditions significantly affect follicle conservation in cryopreserved human ovarian tissue.


Newly synthesized hepatic cholesterol as precursor for cholesterol and bile acids in rat bile.
Adult, male rats were given simultaneously 3H-mevalonate and 14C-cholesterol on autologous lipoproteins intravenously in barbital anaesthesia. The specific radioactivities of sterols in bile, liver and serum were determined. Newly synthesized hepatic cholesterol was a better substrate for cholic and chenodeoxycholic acid than was cholesterol reaching the liver via plasma lipoproteins. The cholesterol secreted into bile was derived from a pool of liver cholesterol which was in close contact with newly synthesized cholesterol. Specific radioactivity of chenodeoxycholate in bile was higher than that of cholate in bile, both when newly made radioactive cholesterol and when radioactive cholesterol on plasma lipoproteins was the precursor for the labelled bile acids.


Classification and definition of premature ejaculation.
Premature ejaculation (PE) is a poorly understood condition and is considered as the most common sexual disorder in men. The ambiguity surrounding PE is in part due to the difficulty in conducting and interpreting research in the absence of a standardised definition that adequately encompasses the characteristics of these patients. An enhanced awareness of sexual dysfunctions in the recent decades has lead to an increase in scientific research that has challenged the traditional paradigm regarding PE. This has also enabled to establish a universal definition and classification of the disease. A move to a more evidence based approach has improved the clinicians' ability to define those who need medical treatment, as well as perform further research in this complex condition.


[Long-term results of dyslipoproteinemia surgical correction in patients with obliterating atherosclerosis of the lower extremity].
An analysis of long-term (up to 20 years) results of performing operations of partial ileoshunting as a method of surgical correction of dislipoproteidemia in 49 patients with obliterating atherosclerosis of the lower extremity vessels has shown that operations of partial ileoshunting have a pronounced and stable lipid correcting effect. Decreased level of atherogenic lipids in blood improved the course of obliterating atherosclerosis of the lower extremity vessels. Worse long-term clinical results after partial ileoshunting were in a considerable degree due to the presence of residual dislipoproteidemia that resulted in additional medicamentous hypolipidemic therapy.


Monolithic Two-Dimensional Photonic Crystal Reflectors for the Fabrication of Highly Efficient and Highly Transparent Dye-Sensitized Solar Cells.
The transparent characteristic of dye-sensitized solar cells (DSCs) makes them suitable for building integrated photovoltaic (BIPV) devices. However, the diffusive scattering layer, which is usually used to increase the efficiency of these devices, greatly lowers the transparency of the DSC. This paper described a two-dimensional (2D) photonic crystal (PC) reflector with a sub-micrometer characteristic length that can improve the efficiency of these devices while maintaining transparency. This 2D PCs were fabricated directly onto TiO2 photoelectrodes using colloidal lithography and have the structure of a nanopillar array. A nanopillar with a height of 430 nm was observed to selectively reflect up to 40% of the light of 400-500 nm wavelength. The perceived transparency of the 2D PC electrode was 52%, which is much higher than 0.3% of the conventional scattering layer. The DSC fabricated using the 2D PC electrode demonstrated a maximum photon-to-electric conversion efficiency of 8.23%, which is 18% higher than the pristine electrode. The 2D PC is a highly efficient and wavelength-selective reflector that can be applied to various photoelectric conversion devices.


Rationale and design of South Asian Birth Cohort (START): a Canada-India collaborative study.
People who originate from the Indian subcontinent (South Asians) suffer among the highest rates of type 2 diabetes in the world. Prior evidence suggests that metabolic risk factors develop early in life and are influenced by maternal and paternal behaviors, the intrauterine environment, and genetic factors. The South Asian Birth Cohort Study (START) will investigate the environmental and genetic basis of adiposity among 750 South Asian offspring recruited from highly divergent environments, namely, rural and urban India and urban Canada. Detailed information on health behaviors including diet and physical activity, and blood samples for metabolic parameters and DNA are collected from pregnant women of South Asian ancestry who are free of significant chronic disease. They also undergo a provocative test to diagnose impaired glucose tolerance and gestational diabetes. At delivery, cord blood and newborn anthropometric indices (i.e. birth weight, length, head circumference and skin fold thickness) are collected. The mother and growing offspring are followed prospectively and information on the growth trajectory, adiposity and health behaviors will be collected annually up to age 3 years. Our aim is to recruit a minimum of 750 mother-infant pairs equally divided between three divergent environments: rural India, urban India, and Canada. The START cohort will increase our understanding of the environmental and genetic determinants of adiposity and related metabolic abnormalities among South Asians living in India and Canada.


Chemotherapy for malignant pleural mesothelioma.
Malignant pleural mesothelioma is an aggressive malignancy with no known single curative modality. Most patients are candidates for chemotherapy at some point in their treatment, but no standard regimen has been established. Several phase II single-agent and combination chemotherapy studies have been performed over the past 2 decades. Although the true impact of chemotherapy in mesothelioma remains to be determined, agents with consistent antitumor activity include doxorubicin, platinum agents, and antimetabolites. Combination chemotherapy is associated with higher response rates, but not necessarily longer median survivals. Large randomized trials, which are currently ongoing or have been performed in the past few years, will yield important answers in regard to the role of chemotherapy and the efficacy of various single and combination chemotherapy agents. Furthermore, the biologic and genetic studies of mesothelioma have identified several receptor tyrosine kinases that are aberrantly expressed in these tumors. Orally available small molecule inhibitors of several receptor tyrosine kinases have been developed and are now being evaluated in clinical trials.


In utero and lactational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces genital dysmorphogenesis in the female rat.
Recently, Gray and Ostby (Toxicol. Appl. Pharmacol. 133, 285-294, 1995) reported that in utero and lactational TCDD exposure causes striking abnormalities in the rat female reproductive system, including reduced fecundity and vaginal threads. The mechanism by which TCDD induces such abnormalities is unknown. Thus, we sought to determine: (1) whether TCDD reduced fecundity by destroying ovarian follicles and (2) whether the vaginal threads resulted from a TCDD-induced developmental defect during embryogenesis or abnormal vaginal opening at puberty. Pregnant Holtzman rats were treated with 1.0 microgram TCDD/kg or vehicle by a single oral dose on gestation day (GD) 11, 15, or 18. Female offspring were monitored for vaginal opening and terminated on postnatal days 2, 21, and 42. The reproductive tract was removed and evaluated for structural abnormalities. The number of primordial follicles also was determined for each ovary. TCDD exposure on GD 11, 15, or 18 did not change the day of vaginal opening, affect ovarian morphology, or reduce the number of primordial follicles. However, this exposure induced the cleft clitoris and vaginal thread originally described by Gray and Ostby (1995) in approximately 55-96% and 36-44% of the litters in our study, respectively. Histologically the thread presented as a thick cord of mesenchyme surrounded by epithelial cells. This defect was clearly visible in histological sections at birth and was noted in the closed vaginas of prepubertal animals. These data suggest that in utero and lactational exposure to TCDD does not reduce the size of the primordial follicle pool; however, it induces developmental abnormalities in the vaginal canal.


A prodrug approach to improve the physico-chemical properties and decrease the genotoxicity of nitro compounds.
In therapeutics research, the nitro compounds are part of an important group of drugs with multiple pharmacological activities. However, in drug design, the inclusion of a nitro group in a molecule changes the physico-chemical and electronic properties and is associated with increased mutagenicity and carcinogenicity. In addition, several studies have related the relationship between the antimicrobial and/or anti-protozoal activity and the mutagenic effect to reduction of the nitro group. This work reviews the toxicity of nitro compounds and shows how the use of prodrugs can increase the biological activity and decrease the genotoxicity of nitro compounds, without any modification in nitro reduction behavior, but rather by physico-chemical improvement. Examples are given of metronidazole and nitrofurazone prodrugs.


[Mediterranean Diet and the sea: fishes].
The excellent quality of the Mediterranean Diet, apart from other products, is associated to a high consumption of fish. Epidemiological studies have shown over time certain beneficial effects of fish consumption in the prevention of chronic diseases. The specific components found in fish, the long chain omega 3 eicosapentanoic and docosahexanoic fatty acids, have been identified as the principle elements responsible for this protective effect in Mediterranean populations. There is also evidence for a relationship between elevated fish consumption and reduced cardiovascular mortality, especially in populations at greater risk for this disease or those with high fatty fish intakes. Moreover, fish consumption of > or = 3.5 servings/week appears to have a protective effect against certain site specific cancers, and is also associated with a number of lifestyle factors. It's been shown that this protective effect is reduced in those who smoke, consume alcohol, are less physically active and who consume fish preserved in salt. However, these preventive effects are seen fundamentally when lipid profiles approximate those typical of the Mediterranean Diet, which is also rich in monounsaturated fatty acids. In light of new evidence, current nutritional objectives for the Spanish population recommend that polyunsaturated fatty acids account for 5% of total calories, with an omega6:omega3 ratio ranging from 6/1 to 10/1.


Cytogenetic and molecular characterization of the Abies alba genome and its relationship with other members of the Pinaceae.
Genome size, karyotype structure, heterochromatin distribution, position and number of ribosomal genes, as well as the ITS2 sequence of the internal transcribed spacer (ITS) were analysed in silver fir (Abies alba Mill.). The analysis also included characterization of the Arabidopsis-type of telomeric repeats in silver fir and in related species. The results were compared with results from other species of the Pinaceae, to evaluate phylogeny and chromosomal and molecular evolution in the Pinaceae. Integrated chromosomal data provided insights into chromosome and karyotype evolution in the Pinaceae. The evolutionary trend for GC-rich heterochromatic blocks seems to involve loss of blocks that are not associated with rDNA. Similarly, numerous large blocks of interstitial plant telomeric repeats that are typical for all analysed species of the genus Pinus were not observed in the evolutionarily younger genera, such as Abies, Picea and Larix. On the contrary, the majority of telomeric sequences in these three genera appeared confined to the chromosome ends. We confirmed the current position of Abies and Tsuga in subfamily Abietoideae and the position of Pinus in the subfamily Pinoideae based on ITS2 sequences. Pseudotsuga is placed together with Larix into the subfamily Laricoideae. We conclude that the current position of the genus Picea in the subfamily Abietoideae should be reconsidered and, possibly, the genus Picea should be reclassified as a separate subfamily, Piceoideae, as recently proposed.


B-1 cell (CD5+B220+) outgrowth in murine schistosomiasis is genetically restricted and is largely due to activation by polylactosamine sugars.
Previously, we demonstrated that lacto-N-fucopentaose III, a sugar found on egg Ags of Schistosoma mansoni, stimulated splenic B cells from parasite-infected mice to proliferate and produce IL-10 and PGE2. The major source of B cell IL-10 is the B-1 subset (CD5+B220+). Thus we examined whether levels of peritoneal exudate B-1 cells changed as a consequence of infection. In CBA/J, BALB/c, and C3H/HeJ mice, we observed significant increases in B-1 cells at 2 to 4 wk postinfection, declining to baseline by 6 to 8 wk. In contrast, the percentage of B-1 cells remained unchanged in C57BL/6 and BALB/c X.id mice after infection. B-1 cells were not observed in the spleens of infected mice; however, coincident with peritoneal B-1 cell decline, splenic CD23+B220+ cells increased from 11% to 30%. Peritoneal B-1 cells could also be expanded by injection of soluble egg Ag, but not by its deglycosylated form, suggesting a role for carbohydrates in B-1 recruitment. In addition, these cells secreted in vitro large amounts of IL-10 in response to lacto-N-fucopentaose III. Further, this sugar induced B-1 cell outgrowth in CBA/J and C3H/HeJ mice, but not in C57BL/6 mice. Thus, early activation of polylactosamine-reactive, IL-10-producing peritoneal B-1 and splenic B cells may be related to early dominance of the Th2-type CD4+ T cell subset. The degree to which this occurs may in part explain differences in the degree of granulomatous pathology reported among various strains of mouse.


The effect of critical process parameters of the high pressure homogenization technique on the critical quality attributes of flurbiprofen nanosuspensions.
Flurbiprofen (FB) is an effective nonsteroidal anti-inflammatory and BCS class II drug and its poor solubility plays a critical role in limiting its bioavailability. Nanosuspensions can be defined as nanosized colloidal dispersions of drug particles stabilized with stabilizers. The solubility of poor soluble drugs can be increased thanks to their small size and large surface area. The aim of this study is to optimize FB nanosuspensions. The formulations were stabilized with Plantacare 2000® as a surfactant using a combination of High Speed Homogenization (HSH) and High Pressure Homogenization techniques (HPH). We also investigated the effects of the critical process parameters (CPPs) of these techniques (homogenization speed & time for HSH and homogenization pressure & cycle for HPH) on three critical quality attributes of nanosuspensions, being the particle size (PS), polydispersity index (PDI) and zeta potential (ZP). After the optimization of HSH, the macrosuspension was transferred to a high pressure homogenizer. After producing FB nanosuspensions by the HPH technique, seven processes which comprise different homogenization pressures, or combinations and different cycles, were applied. Due to the combination of HSH and HPH techniques and the optimization of CPPs, an optimum formulation for a dermal application was found using a 33 full factorial design with these process parameters, and characterization studies were also performed.


"BLACK LIGHT" INACTIVATION OF TRANSFORMING DEOXYRIBONUCLEIC ACID FROM HAEMOPHILUS INFLUENZAE.
Cabrera-Juárez, Emiliano (Instituto Politecnico Nacional, Mexico, D.F., Mexico). "Black light" inactivation of transforming deoxyribonucleic acid from Haemophilus influenzae. J. Bacteriol. 87:771-778. 1964.-The biological activity (intrinsic genetic markers or nitrous acid mutable regions) of transforming deoxyribonucleic acid (DNA) from Haemophilus influenzae has been inactivated by "black light" (BL) by two mechanisms: (i) photodynamic action (oxygen-dependent) and (ii) "BL inactivation" (oxygen-independent). The BL inactivation is greater in denatured than in native DNA, and it is dependent on the pH. It does not depend on the temperature, and the damage produced is stable. The effective wavelength of inactivation is between 330 and 360 mmu. The BL inactivation is not reactivated by photoreactivating enzyme or nitrous acid. The BL and ultraviolet inactivations are additive, suggesting that the changes produced by BL and ultraviolet irradiation on transforming DNA are different. T(2) phage was also inactivated by BL. The nature of the photochemical changes produced in DNA by BL is not known.


Kinetic and structural insights into the mechanism of AMPylation by VopS Fic domain.
The bacterial pathogen Vibrio parahemeolyticus manipulates host signaling pathways during infections by injecting type III effectors into the cytoplasm of the target cell. One of these effectors, VopS, blocks actin assembly by AMPylation of a conserved threonine residue in the switch 1 region of Rho GTPases. The modified GTPases are no longer able to interact with downstream effectors due to steric hindrance by the covalently linked AMP moiety. Herein we analyze the structure of VopS and its evolutionarily conserved catalytic residues. Steady-state analysis of VopS mutants provides kinetic understanding on the functional role of each residue for AMPylation activity by the Fic domain. Further mechanistic analysis of VopS with its two substrates, ATP and Cdc42, demonstrates that VopS utilizes a sequential mechanism to AMPylate Rho GTPases. Discovery of a ternary reaction mechanism along with structural insight provides critical groundwork for future studies for the family of AMPylators that modify hydroxyl-containing residues with AMP.


Atg7 senses ATP levels and regulates AKT1-PDCD4 phosphorylation-ubiquitination axis to promote survival during metabolic stress.
We report that autophagy-related gene 7 (ATG7) modulates p53 activity to regulate cell cycle and survival during metabolic stress, and that indicates Atg7 is functionally involved in cellular homeostasis in autophagy independent fashion. As a protein translation inhibitor, Programmed cell death 4 (PDCD4) expression is regulated by AKT1 phosphorylation. Here, we find that Atg7 interacts with PDCD4 and AKT1 to regulate AKT1-PDCD4 phosphorylation-ubiquitination axis during metabolic stress. We demonstrate that Atg7 senses decrease of ATP levels to suppress AKT-mediated PDCD4 phosphorylation at Ser67, which inhibits PDCD4 ubiquitinating during metabolic stress. Finally, PDCD4 accumulates and functions as a protein translation inhibitor to conserve energy, thus reducing apoptosis and allowing cells to survive stress periods. These results suggest that the ATP-Atg7-PDCD4 axis acts as a metabolic adaptation pathway which dictates cells to overcome metabolic stress.


Trans-activation of an artificial dTam3 transposable element in transgenic tobacco plants.
In Antirrhinum majus only autonomous Tam3 transposons have been characterized. We investigated whether an artificial dTam3 element, with a deletion in the presumptive transposase coding region, can be trans-activated in tobacco by an activator Tam3 element, which was immobilized by the deletion of one inverted repeat. A phenotypic assay based on restored hygromycin resistance demonstrates that a dTam3 element harbouring a bacterial plasmid can be trans-activated with a low frequency. Molecular analysis confirms that the dTam3 element has been excised from the HPTII marker gene. Reintegration of the dTam3 element into the tobacco genome is detected only in one out of six hygromycin-resistant plants analysed. PCR analysis of empty donor sites shows that excision of the dTam3 element in tobacco results in rearrangements (deletions and additions), that have been shown to be characteristic of Tam3 excision in the original host Antirrhinum majus. This trans-activation assay allowed us to establish that, in contrast to what has been detected in Antirrhinum majus, a periodical temperature shift down to 15 degrees C does not enhance dTam3 transposition in regenerating tobacco calli.


Defective HIV-1 Proviruses Are Expressed and Can Be Recognized by Cytotoxic T Lymphocytes, which Shape the Proviral Landscape.
Despite antiretroviral therapy, HIV-1 persists in memory CD4+ T cells, creating a barrier to cure. The majority of HIV-1 proviruses are defective and considered clinically irrelevant. Using cells from HIV-1-infected individuals and reconstructed patient-derived defective proviruses, we show that defective proviruses can be transcribed into RNAs that are spliced and translated. Proviruses with defective major splice donors (MSDs) can activate novel splice sites to produce HIV-1 transcripts, and cells with these proviruses can be recognized by HIV-1-specific cytotoxic T lymphocytes (CTLs). Further, cells with proviruses containing lethal mutations upstream of CTL epitopes can also be recognized by CTLs, potentially through aberrant translation. Thus, CTLs may change the landscape of HIV-1 proviruses by preferentially targeting cells with specific types of defective proviruses. Additionally, the expression of defective proviruses will need to be considered in the measurement of HIV-1 latency reversal.


Climate change-derived environmental and physical factors influencing the socioeconomic development in the Himalayan region.
Spatio-temporal fluctuation of climatic variables with the terrain characteristics and their inter-relationship is a priority for predicting flash-flood-induced landslide hazards over the fragile Himalayas. The present study addressed this anxiety by assimilating satellite data products and auxiliary datasets in the Bhagirathi River basin of the Indian Himalayas. Snow Covered Area (SCA) is a critical indicator of the ecosystem that influenced the flash flood along different terrain features such as Altitude, Hill-Gradient, and Aspect. GIS-based multi-criteria decision analysis (GIS-MCDA) technique is used to analyze the possible landslide zones and flood extent along the river basin, and MODIS Terra (MOD10A2) data products derived annual SCA is 4278 km2 for the year 2021, the analysis of geospatial maps at 25° intervals of Altitude, hill-gradient, and Aspect. The SCA distribution reveals that apart from the Altitude, the Aspect of the hill gradient significantly impacts snow accumulation. Hill-Gradient, ranging from 13.06 to 19.52, occupies 24.7% of the total area, and 45.3 to 51.83 are found without snow. The highest variation of SCA is along the Western direction (9.19%), followed by North-East (8.79%), while the least (3.78%) variance is in the Southwest direction. Additionally, it was found that many bridges, roads, and other properties are under threat in this study area, even with a moderate flash flood. Findings from this study provide the spatiotemporal status of SCA in various geological stress conditions during the last decades and probable landslide zones. This will be a preliminary pathway to policymakers in rehabilitation and early evacuation of human lives due to flash flood occurrence.


Risk factors for treatment failure in patients with severe acute cardiogenic pulmonary oedema.
Intubation is necessary in 7 to 20% of patients with severe acute cardiogenic pulmonary oedema despite optimal treatment. This study evaluated the usefulness of parameters largely available in clinical practice to predict the need for intubation in a population of acute cardiogenic pulmonary oedema patients treated with medical therapy and continuous positive airway pressure. The present retrospective cohort study involved 142 patients with severe acute cardiogenic pulmonary oedema who were admitted to coronary care or the intensive care unit of a university hospital and were treated by an in-hospital protocol. Physiological measurements and blood gas samples were evaluated at 'baseline' (just after admission), 'early' (one to three hours after beginning treatment) and 'late' (eight to 10 hours after beginning treatment). Twenty-two patients (15.5%) required intubation. A systolic blood pressure at admission lower than 140 mmHg was significantly associated with a higher risk for intubation, while hypercapnic patients or those with a reduced left ventricular ejection fraction at admission did not show a worse prognosis. A simple score based on largely available parameters (1 point for each: age >78 years, systolic blood pressure <140 mmHg at admission, arterial blood gas acidosis and heart rate >95 bpm at early time) is proposed. The rate of intubation according to this score ranged from 0% (score of 0) to 90% (score of 3). Our study found that simple parameters available in clinical practice are significantly associated with the need for intubation in acute cardiogenic pulmonary oedema patients treated with continuous positive airway pressure and medical therapy. A simple score to evaluate the need for endotracheal intubation is proposed.


Role of Clofazimine in Treatment of Mycobacterium avium Complex.
Background: Non-tuberculous mycobacteria (NTM), specifically Mycobacterium avium complex (MAC), is an increasingly prevalent cause of pulmonary dysfunction. Clofazimine has been shown to be effective for the treatment of M. avium complex, but there were no published large-scale analyses comparing clofazimine to non-clofazimine regimens in MAC treatment. The objective of this large-scale meta-analysis was to evaluate patient characteristics and treatment outcomes of individuals diagnosed with MAC and treated with a clofazimine-based regimen. Methods: We used Pubmed/Medline, Embase, Web of Science, and the Cochrane Library to search for studies published from January 1, 1990 to February 9, 2020. Two reviewers (SSH and NY) extracted the data from all eligible studies and differences were resolved by consensus. Statistical analyses were performed with STATA (version 14, IC; Stata Corporation, College Station, TX, USA). Results: The pooled success treatment rate with 95% confidence intervals (CI) was assessed using random effect model. The estimated pooled treatment success rates were 56.8% in clofazimine and 67.9% in non-clofazimine groups. Notably, success rates were higher (58.7%) in treatment of HIV patients with disseminated infection. Conclusions: Treatment was more successful in the non-clofazimine group overall. However, HIV patients with disseminated infection had higher treatment response rates than non-HIV patients within the clofazimine group.


Temporal Filtering to Improve Single Molecule Identification in High Background Samples.
Single molecule localization microscopy is currently revolutionizing the life sciences as it offers, for the first time, insights into the organization of biological samples below the classical diffraction limit of light microscopy. While there have been numerous examples of new biological findings reported in the last decade, the technique could not reach its full potential due to a set of limitations immanent to the samples themselves. Particularly, high background signals impede the proper performance of most single-molecule identification and localization algorithms. One option is to exploit the characteristic blinking of single molecule signals, which differs substantially from the residual brightness fluctuations of the fluorescence background. To pronounce single molecule signals, we used a temporal high-pass filtering in Fourier space on a pixel-by-pixel basis. We evaluated the performance of temporal filtering by assessing statistical parameters such as true positive rate and false discovery rate. For this, ground truth signals were generated by simulations and overlaid onto experimentally derived movies of samples with high background signals. Compared to the nonfiltered case, we found an improvement of the sensitivity by up to a factor 3.5 while no significant change in the localization accuracy was observable.


The Bitter Taste Receptor TAS2R14 as a Drug Target.
G protein-coupled receptors (GPCRs) mediate most of our physiological responses to hormones, neurotransmitters and environmental stimulants. Besides human senses like vision and olfaction, taste perception is mostly mediated by GPCRs. Hence, the bitter taste receptor family TAS2R comprises 25 distinct receptors and plays a key role in food acceptance and drug compliance. The TAS2R14 subtype is the most broadly tuned bitter taste receptor, recognizing a range of chemically highly diverse agonists. Besides other tissues, it is expressed in human airway smooth muscle and may represent a novel drug target for airway diseases. Several natural products as well as marketed drugs including flufenamic acid have been identified to activate TAS2R14, but higher potency ligands are needed to investigate the ligand-controlled physiological function and to facilitate the targeted modulate for potential future clinical applications. A combination of structure-based molecular modeling with chemical synthesis and in vitro profiling recently resulted in new flufenamic acid agonists with improved TAS2R14 potency and provided a validated and refined structural model of ligand-TAS2R14 interactions, which can be applied for future drug design projects.


Jointly Predicting Postprandial Hypoglycemia and Hyperglycemia Using Continuous Glucose Monitoring Data in Type 1 Diabetes.
The development of continuous glucose monitoring (CGM) systems has enabled people with type 1 diabetes mellitus (T1DM) to track their glucose trajectory in real-time and inspired research in personalised glucose prediction. In this paper, our aim is to predict postprandial abnormal-glycemia events. Different from prior research which focuses on hypoglycemia only, we make the first attempt to establish our problem as the joint prediction of hyperglycemia and hypoglycemia. On this basis, we propose a machine learning model that learns from the pattern of 1 hour past glucose and makes predictions for the two tasks simultaneously using a unified backbone. Key benefits of our methodology include 1) requiring only the CGM sequence as the input, thus making it more widely applicable than other counterparts using extra inputs such as the nutrition details, and 2) minimising the computational cost as the two tasks are unified into a single model. Our experiments on the openly available OhioT1DM dataset achieve state-of-the-art performance (Matthew's correlation coefficient of 0.61 for hyperglycemia and 0.48 for hypoglycemia). To encourage further study, we release our codes at https://github.com/r-cui/PostprandialHyperHypoPrediction under the MIT license.


FK506-associated thrombotic microangiopathy: report of two cases and review of the literature.
FK506 is a recently developed immunosuppressant that has been useful in improving the survival of transplanted organs. Among the numerous adverse side effects of FK506, thrombotic microangiopathy (TMA) stands out as an infrequent but severe complication. We report two cases of FK506-associated TMA and review the 19 previous reported cases. From these 21 cases, the reported incidence of FK506-associated TMA is between 1% and 4.7%. It is more frequent in females, and the mean age at presentation is 47 years. Eighty-one percent of the cases occurred in patients with kidney allografts, and the remaining patients had liver, heart, or bone marrow transplants. Clinically, TMA was diagnosed at an average interval of 9.3 months from the time of transplantation. Patients may be asymptomatic or may present with the full-blown picture of hemolytic uremic syndrome. All patients had an elevated serum creatinine level but did not always show signs of hemolysis. Trough levels of FK506 were not predictive for the development of TMA, but generally a reduction of drug dose correlated with kidney function improvement and disappearance of the hemolytic picture. The renal allograft biopsy provided a conclusive diagnosis in all 17 cases in which this procedure was performed. Treatment, which mainly consisted of reduction or discontinuation of FK506, anticoagulation, and/or plasmapheresis with fresh-frozen plasma exchange, resolved TMA in most patients (57%). However, in one of these patients (5%), the graft was subsequently lost due to causes unrelated to TMA, such as acute or chronic rejection. Despite treatment, one patient (5%) lost the graft due to acute rejection and persistent TMA, and three other patients (14%) who had bone marrow, heart, and liver transplants, died of multiple organ failure, probably unrelated to TMA. In the remaining four patients (19%), response to treatment was not reported. TMA must be considered in organ transplant patients treated with FK506 whenever kidney function deteriorates, even in the absence of microangiopathic hemolytic anemia. Although TMA usually responds to treatment, it may, in rare cases, lead to loss of kidney function or even the patient's death.


Mid-foot retinaculum: an unrecognized entity.
Retinacula are thickenings of deep fascia in the region of joints that hold down the tendons preventing them from bowing out of position. In the region of ankle, number of such retinacula have been described. Retinacula like superior and inferior extensor retinacula have been described which hold down the tendons of leg muscles passing to the foot beneath them. As the extensor tendons of the leg have more distal attachment to the toes, the present study was conducted to ascertain the presence of any additional retinaculum in the mid-foot region, which would tie down the tendons for their effective action at the distal joints. The aim was also to determine the attachments of the retinaculum, if present as well as the structures passing beneath them. Fifty cadaveric feet were dissected carefully for this purpose. Presence of an additional extensor retinaculum distal to the inferior band of inferior extensor retinaculum in the mid-foot region was found in 22 feet. Besides the extensor tendons, medial terminal branch of deep peroneal nerve and dorsalis pedis artery was found to pass beneath the retinaculum. A partial or complete mid-foot retinaculum existed in the mid-foot region covering the tarsometatarsal joints in about half of study population. Functionally, this retinaculum may prevent bowstringing of the extensor tendons, clinically it may predispose to entrapment of deep peroneal nerve mimicking anterior tarsal tunnel syndrome.


Multiple Olefin Metathesis Polymerization That Combines All Three Olefin Metathesis Transformations: Ring-Opening, Ring-Closing, and Cross Metathesis.
We demonstrated tandem ring-opening/ring-closing metathesis (RO/RCM) polymerization of monomers containing two cyclopentene moieties and postmodification via insertion polymerization. In this system, well-defined polymers were efficiently formed by tandem cascade RO/RCM reaction pathway. Furthermore, these polymers could be transformed to new A,B-alternating copolymers via a sequential cross metathesis reaction with a diacrylate. Additionally, we demonstrated the concept of multiple olefin metathesis polymerization in which the dicyclopentene and diacrylate monomers underwent all three olefin metathesis transformations (ring-opening, ring-closing, and cross metathesis) in one shot to produce A,B-alternating copolymer.


Adult surgical experience with Loeys-Dietz syndrome.
Loeys-Dietz syndrome (LDS) results from mutations in receptors for the cytokine transforming growth factor-β leading to aggressive aortic pathology sometimes accompanied by specific phenotypic features including bifid uvula, hypertelorism, cleft palate, and generalized arterial tortuosity. We reviewed our adult surgical experience with LDS in order to validate current recommendations regarding management of this newly described disease. All adult (≥ 18 years old) patients with LDS undergoing surgical treatment at a single referral institution from September 1999 to May 2013 were retrospectively reviewed. Eleven adult LDS patients were identified by clinical criteria and genotyping. Seven (64%) experienced acute type A dissection at some point in their lives. All eventually required aortic root replacement, and 73% required multiple vascular surgical interventions. Over a mean follow-up of 65 ± 49 months, 2.8 cardiovascular procedures per patient were performed. In patients with type A dissection, a mean of 3.4 operations were performed versus 1.8 operations for patients without dissection. Total aortic replacement was required in 5 patients (45%) and 2 (18%) required neurosurgical intervention for cerebrovascular pathology. There was 1 late death from infectious complications, and no deaths from vascular catastrophe. These results confirm the aggressive nature of LDS aortic pathology. However, the improved survival compared with earlier LDS reports suggest that aggressive treatment strategies may alter outcomes and improve the natural history of this syndrome.


Biomechanical factors in coronary vulnerable plaque risk of rupture: intravascular ultrasound-based patient-specific fluid-structure interaction studies.
The aim of this study was to elucidate the mechanisms and underlying biomechanical factors that may play a role in the risk of rupture of vulnerable plaques (VPs) by studying patient-based geometries of coronary arteries reconstructed from intravascular ultrasound (IVUS) imaging utilizing fluid-structure interaction (FSI) numerical simulations. According to recent estimates, coronary artery disease is responsible for one in six deaths in the USA, and causes about one million heart attacks each year. Among these, the rupture of coronary VPs followed by luminal blockage is widely recognized as a major cause of sudden heart attacks; most importantly, the patients may appear as asymptomatic under routine screening before the occurrence of the index event. FSI simulations of patient-based geometries of coronary arteries reconstructed from IVUS imaging were performed to establish the dependence of the risk of rupture of coronary VP on biomechanical factors, such as the fibrous cap thickness, presence of microcalcification in the fibrous cap, arterial anisotropy, and hypertension. Parametric FSI simulations indicated that mechanical stresses (von Mises stresses) increase exponentially with the thinning of the fibrous cap as well as with increasing levels of hypertension. The inclusion of a microcalcification in the fibrous cap considerably increases the risk of rupture of VP , with an ∼two-fold stress increase in the VP stress burden. Furthermore, the stress-driven reorientation and biochemical degradation of the collagen fibers in the vessel wall because of atherosclerosis (studied with an anisotropic fibrous cap 65° fiber reorientation angle) results in a 30% increase in the stress levels as compared with simulations with isotropic material models, clearly indicating that the latter, which are commonly used in such studies, underestimate the risk of rupture of VP. The results indicate that IVUS-based patient-specific FSI simulations for mapping the wall stresses, followed by analysis of the biomechanical risk factors, may be used as an additional diagnostic tool for clinicians to estimate the plaque burden and determine the proper treatment and intervention.


Pancreatic Hepatoid Carcinoma Mimicking a Solid Pseudopapillary Neoplasm: A Challenging Case on Endoscopic Ultrasound-guided Fine-needle Aspiration.
A 59-year-old man was admitted to our hospital for treatment of a 45 mm pancreatic mass found during a medical examination. Endoscopic ultrasound-guided fine-needle aspiration cytology showed polygonal cells with pseudopapillary structures. The tumor cells were positive for nuclear/cytoplasmic β-catenin and CD10, and negative for chromogranin A. After a tentative diagnosis of a solid pseudopapillary neoplasm, middle pancreatectomy was performed. Histologically, polygonal cells with abundant eosinophilic cytoplasm formed in the trabeculae and were immunohistochemically positive for HepPar1 and protein induced by vitamin K absence or antagonist-II. The tumor was finally diagnosed to be pancreatic hepatoid carcinoma. No recurrence occurred for 12 months, even without adjuvant chemotherapy.


Ventricular filling pressure as a determinant of coronary blood flow during ischemia.
The role of ventricular filling pressure (VFP) as a determinant of coronary blood flow (CBF) in the acutely ischemic ventricle was examined in the open-chest dog under conditions of a reduced, constant coronary artery pressure and an unstable VFP. Blood delivery to different layers of the ventricle and ischemic metabolic changes occurring in these layers were also determined and compared with appropriate control data. A close, inverse, linear relationship between VFP and CBF was found in animals exhibiting a progressive rise in VFP from 6 +/- 0 to 25 +/- 1 mmHg (r = 0.99). A lower endocardial-to-epicardial ratio of delivered blood and a steeper transmural gradient in ischemic metabolic changes were noted in these animals compared with similarly prepared animals exhibiting a stable VFP. The findings demonstrate the importance of VFP as a determinant of CBF during ischemia, and they lend support to the concept that blood flow in the ischemic ventricle is regulated by a preload-dependent transmural gradient in coronary driving pressure.


Enhanced light extraction efficiency and viewing angle characteristics of microcavity OLEDs by using a diffusion layer.
The viewing angle characteristics and light extraction efficiency of organic light-emitting diodes (OLEDs) with a micro-cavity structure were enhanced. This was accomplished by inserting a diffusion layer composed of nano-sized structures of a transparent polymer poly(methyl methacrylate) (PMMA) combined with a zinc oxide (ZnO) semi-planarization layer with a high refractive index (n = 2.1) into the devices. The PMMA nanostructures were fabricated by employing a reactive ion etching (RIE) process. The height and density of the PMMA nanostructures were controlled by varying the speed at which the PMMA was spin-coated onto the substrate. The insertion of the diffusion layer into the micro-cavity OLEDs (MC-OLEDs) improved the external quantum efficiency (EQE) by as much as 17% when compared to that of a MC-OLED without a diffusion layer. Furthermore, adjustment of the viewing angle from 0° to 60° halved the peak shift distance of the electroluminescence (EL) spectra from 42 to 20 nm. Additionally, changing the viewing angle from 0° to 60° changed the color coordinate movement distance of the MC-OLED with the diffusion layer to 0.078, less than half of the distance of the MC-OLED without the diffusion layer (0.165).


Experience with nerve allograft transplantation.
Nerve allograft transplantation should be used for the repair of devastating peripheral nerve injuries that cannot be reconstructed through traditional means such as autologous nerve grafting or nerve transfer procedures. The risks of required systemic immunosuppression, although only temporary for nerve allograft recipients, preclude widespread use of this treatment modality. Translational research has led to several advancements in this field including the use of preoperative allograft cold preservation in University of Wisconsin organ preservation solution and inclusion of tacrolimus as part of the immunosuppressive regimen. Investigation of how to further diminish nerve allograft immunogenicity, speed neuroregeneration by use of agents such as tacrolimus, and promote preferential motor regeneration will further advance this field with the goal of restoring optimal function while minimizing patient morbidity.


Synthesis, Biological Evaluation, and Molecular Modeling Studies of Chiral Chloroquine Analogues as Antimalarial Agents.
In a focused exploration, we designed, synthesized, and biologically evaluated chiral conjugated new chloroquine (CQ) analogues with substituted piperazines as antimalarial agents. In vitro as well as in vivo studies revealed that compound 7c showed potent activity (in vitro 50% inhibitory concentration, 56.98 nM for strain 3D7 and 97.76 nM for strain K1; selectivity index in vivo [up to at a dose of 12.5 mg/kg of body weight], 3,510) as a new lead antimalarial agent. Other compounds (compounds 6b, 6d, 7d, 7h, 8c, 8d, 9a, and 9c) also showed moderate activity against a CQ-sensitive strain (3D7) and superior activity against a CQ-resistant strain (K1) of Plasmodium falciparum Furthermore, we carried out docking and three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of all in-house data sets (168 molecules) of chiral CQ analogues to explain the structure-activity relationships (SAR). Our new findings specify the significance of the H-bond interaction with the side chain of heme for biological activity. In addition, the 3D-QSAR study against the 3D7 strain indicated the favorable and unfavorable sites of CQ analogues for incorporating steric, hydrophobic, and electropositive groups to improve the antimalarial activity.


Efficient implementation of accurate geometric transformations for 2-D and 3-D image processing.
This paper proposes the use of a polynomial interpolator structure (based on Horner's scheme) which is efficiently realizable in hardware, for high-quality geometric transformation of two- and three-dimensional images. Polynomial-based interpolators such as cubic B-splines and optimal interpolators of shortest support are shown to be exactly implementable in the Horner structure framework. This structure suggests a hardware/software partition which can lead to efficient implementations for multidimensional interpolation.


Effects of daily consumption of honey solution on hematological indices and blood levels of minerals and enzymes in normal individuals.
Seven men and three women (mean age, 31.2 years; range, 20-45 years) received a strictly controlled regular diet during a 2-week control period, followed by the regular diet supplemented with daily consumption of 1.2 g/kg body weight honey dissolved in 250 ml of water during a 2-week test period. At the end of each period, overnight fasting blood samples were withdrawn for assays of blood glucose, blood minerals, vitamin C, beta-carotene, uric acid, glutathione reductase, immunoglobulin E, hemoglobin, blood indices and cells, serum ferritin, serum iron, and iron-binding capacity. Results showed that honey increased antioxidant agents. It increased blood vitamin C concentration by 47%, beta-carotene by 3%, uric acid by 12%, and glutathione reductase by 7%. Honey increased serum iron by 20% and decreased plasma ferritin by 11%. It increased the percentage of monocytes by 50%, and increased lymphocyte and eosinophil percentages slightly. Honey reduced serum immunoglobulin E by 34% and increased serum copper by 33%. It decreased aspartate transaminase by 22% and alanine transaminase by 18%. Honey markedly reduced lactic acid dehydrogenase by 41%, decreased creatinine kinase by 33%, and reduced fasting blood sugar by 5%. It caused slight elevations in blood zinc and magnesium, hemoglobin, and packed cell volume. It may be concluded that honey increased antioxidant agents, serum iron and blood indices, and trace elements and decreased immunoglobulin E, liver and muscle enzymes, and fasting blood sugar in healthy subjects.


Development of an energy spread analyzer for secondary ion mass spectrometry ion source.
The energy spread (ΔE) of an ion source is an important parameter in the production of a finely focused primary ion beam applied in secondary ion mass spectrometry (SIMS). A variable-focusing retarding field energy analyzer (RFEA) has been developed and tested with an Ar+ beam and an oxygen ion beam extracted from a 2.45 GHz microwave ion source, which is developed as a candidate ion source for SIMS applications. The simulation results show that the relative resolution ΔE/E of the designed RFEA reaches 7 × 10-5. The experimental results indicate that a focusing electrode can improve the ΔE measurement results, which is consistent with the simulation results. The ion energy distributions of the Ar+ beam and oxygen ion beam are of Gaussian distribution with the value of ΔE of 3.3 and 2.9 eV, respectively. These results indicate that the designed RFEA is reliable for measuring the ion beam energy spread. The developed RFEA is also used to study the plasma behavior in different settings, which reveals that plasma stability is critical to making a low energy spread ion beam. This paper will present the simulation, design, and test of the variable-focusing RFEA. Preliminary ion beam quality studies with this instrument will also be discussed.


The effect of calcium channel blocker diltiazem on photoreceptor degeneration in the rhodopsin Pro213His rat.
To determine whether the calcium channel blocker D-cis-diltiazem promotes photoreceptor survival in rats with the Pro23His rhodopsin mutation. Heterozygous Pro23His rhodopsin line 1 rats (n = 11) were treated daily, according to a protocol applied successfully in rd mice, with D-cis-diltiazem hydrochloride increased incrementally from 21 to 54 mg/kg in a divided dose (8 AM and 8 PM) administered by intraperitoneal (i.p.) injection for 21 days, beginning on days of age 10 through 12. Saline-treated line 1 rats (n = 6) received i.p. injections of an equal volume of 0.9% saline. Analysis on day 35 of age included dark-adapted corneal electroretinogram (ERG) b- and a-waves recorded from threshold to 0.63 log candela-seconds [cd-s]/m2, saturated a-waves elicited with a 2.1 log cd-s/m2 flash, and morphometry of the outer nuclear layer (ONL) and rod outer segments (ROS). ONL width and cell counts of diltiazem-treated and saline-treated animals at 35 days were reduced to 64%-68% of 15-day-old untreated P23H line 1 retinas. No photoreceptor rescue was found by measuring ONL width (P = 0.84), cell count (P = 0.42), or ROS length (P = 0.85). Functional assays by ERG b-wave threshold (P = 0.57), b-wave maximum amplitude (P = 0.46), and saturated a-wave amplitude (P = 0.59) also showed no rescue. D-cis-Diltiazem did not rescue photoreceptors of Pro23His rhodopsin mutation line 1 rats treated according to the protocol used in rd mouse.


Matrix-assisted laser desorption ionization time-of-flight mass spectrometry for fast and accurate identification of clinically relevant Aspergillus species.
New Aspergillus species have recently been described with the use of multilocus sequencing in refractory cases of invasive aspergillosis. The classical phenotypic identification methods routinely used in clinical laboratories failed to identify them adequately. Some of these Aspergillus species have specific patterns of susceptibility to antifungal agents, and misidentification may lead to inappropriate therapy. We developed a matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS)-based strategy to adequately identify Aspergillus species to the species level. A database including the reference spectra of 28 clinically relevant species from seven Aspergillus sections (five common and 23 unusual species) was engineered. The profiles of young and mature colonies were analysed for each reference strain, and species-specific spectral fingerprints were identified. The performance of the database was then tested on 124 clinical and 16 environmental isolates previously characterized by partial sequencing of the β-tubulin and calmodulin genes. One hundred and thirty-eight isolates of 140 (98.6%) were correctly identified. Two atypical isolates could not be identified, but no isolate was misidentified (specificity: 100%). The database, including species-specific spectral fingerprints of young and mature colonies of the reference strains, allowed identification regardless of the maturity of the clinical isolate. These results indicate that MALDI-TOF MS is a powerful tool for rapid and accurate identification of both common and unusual species of Aspergillus. It can give better results than morphological identification in clinical laboratories.


Unusual Sites of Cutaneous Tuberculosis: A Report of Two Cases.
Cutaneous tuberculosis (CTB) is an uncommon small subset of extrapulmonary tuberculosis, comprising 1-1.5% of all extrapulmonary tuberculosis manifestations, which manifests only in 8.4-13.7% of all tuberculosis cases. Lupus vulgaris (LV) and tuberculosis verrucosa cutis (TBVC) are forms of reinfection tuberculosis and often occur in presensitized patients, by exogenous inoculation. We report two cases of cutaneous tuberculosis at unusual sites. A 35-year-old female having a forehead lesion for 2 years was diagnosed as having tuberculosis verrucosa cutis and another 16-year-old girl with lesion in left axilla for 10 years was proven to have lupus vulgaris. The delayed diagnosis was possibly due to lower clinical suspicion due to the presentation of CTB at unusual sites. This highlights the importance of keeping TB as an important differential as misdiagnosis or delayed diagnosis of this entity can lead to prolonged morbidity.


Urban legend series: mucous membrane pemphigoid.
Mucous membrane pemphigoid (MMP) is a heterogeneous group of autoimmune subepithelial blistering diseases affecting primarily mucous membranes showing marked degree of clinical and immunological variability. We investigated four controversial topics: (i) Does oral pemphigoid (OP) really exist as a separate entity? (ii) Is mucous membrane pemphigoid curable? (iii) What is the best therapeutic option for MMP? (iv) Does exclusive oral IgA dermatitis exist as a distinct entity from MMP? Results from extensive literature searches suggested that (i) it is still unclear whether patients with OP could be considered as a distinct subset of MMP with specific clinical and immunological features; (ii) it is uncertain whether treatment regimens that get MMP under control can be eliminated to allow patients to be in drug-free remission or they should be continuously administered in some capacities; (iii) there is a concerning paucity of good-quality trials on MMP and available recommendations are solely based on generally small patients' cohorts or case series. Some of the 2002 consensus experts' opinions should be possibly updated, particularly regarding the safety of sulfa drugs; (iv) we did not find any strong evidence to support an exclusive oral (and perhaps also mucosal) form of LAD as a separate entity.


Quantification of heteroplasmic mitochondrial DNA mutations for DNA samples in the low picogram range by nested real-time ARMS-qPCR.
In many mitochondrial diseases, different clinical manifestations are related to tissue-specific distribution of mutated mitochondrial DNA (mtDNA). In this study, we describe an assay for the determination of mutated mtDNA copy number in small clinical samples, using standard polymerase chain reaction (PCR) followed by SYBR Green real-time allelic-specific PCR [amplification refractory mutation system-quantitative PCR (ARMS-qPCR)]. To assess the degree of heteroplasmy in a patient harboring 2 cosegregating mtDNA mutations (4415A>G and 9922A>C) starting from picogram amounts of DNA, we first amplified the mutated target sequence by standard PCR, and then analyzed it by real-time ARMS-qPCR. To validate this method, we analyzed by real-time ARMS-qPCR the PCR amplification products derived from different mixtures containing known proportions of mutant and wild-type cloned mtDNA fragments. The correlation coefficient of 0.994 between expected and observed values for the percentage of mutant A4415G confirms that the relative proportion of mutated and wild-type mtDNA was maintained after the first PCR amplification. This method allows the precise quantification of heteroplasmic mutations in DNA samples extracted from hairs, urine, small stomach biopsies, and, more importantly, single-muscle fiber, with a limit of detection close to 0.5%. This nested real-time ARMS-PCR represents a rapid, efficient, and less expensive method for the detection and quantification of heteroplasmic mutant mtDNA, even in very small clinical samples.


A novel solid state non-dispersive infrared CO2 gas sensor compatible with wireless and portable deployment.
This paper describes development of a novel mid-infrared light emitting diode (LED) and photodiode (PD) light source/detector combination and use within a non-dispersive infrared (NDIR) carbon dioxide gas sensor. The LED/PD based NDIR sensor provides fast stabilisation time (time required to turn on the sensor from cold, warm up, take and report a measurement, and power down again ≈1 second), longevity (>15 years), low power consumption and low cost. Described performance is compatible with "fit and forget" wireless deployed sensors in applications such as indoor air quality monitoring/control & energy conservation in buildings, transport systems, horticultural greenhouses and portable deployment for safety, industrial and medical applications. Fast stabilisation time, low intrinsic power consumption and cycled operation offer typical energy consumption per measurement of mJ's, providing extended operation using battery and/or energy harvesting strategies (measurement interval of ≈ 2 minutes provides >10 years operation from one AA battery). Specific performance data is provided in relation to measurement accuracy and noise, temperature performance, cross sensitivity, measurement range (two pathlength variants are described covering ambient through to 100% gas concentration), comparison with NDIR utilizing thermal source/pyroelectric light source/detector combination and compatibility with energy harvesting. Semiconductor based LED/PD processing together with injection moulded reflective optics and simple assembly provide a route to low cost high volume manufacturing.


Suicidal behavior as communication in a cultural context: a comparative study between Uganda and Norway.
In this study, we attempt to even out some of the imbalance in suicide research caused by the fact that most such research has been conducted in the Western part of the world with the corresponding common disregard of the potential problems in generalizing findings to different cultural settings. Our point of departure was to look at suicidal behavior as communication and our main purpose was to investigate whether Qvortrup's semiotic four-factor model, which has been empirically supported in the West, would be applicable in an African context, exemplified by Uganda. Interviews of patients admitted to hospital following an act of nonfatal suicidal behavior were conducted in Uganda and Norway and the data were compared. The results showed that the four-factor structure found in the West was not applicable in the Ugandan context, but that two by two of these factors were collapsed into a two-factor model in Uganda: One factor regarding the external dialog and one factor regarding the internal dialog. Some differences and some similarities were found between Norway and Uganda when suicidal behavior was considered as a communicative act. The results are discussed in terms of the differences in the psychological characteristics of the suicidal persons in the two countries, as well as the different cultural settings of the study.


Age and Obesity Promote Methylation and Suppression of 5α-Reductase 2: Implications for Personalized Therapy of Benign Prostatic Hyperplasia.
In men with symptomatic benign prostatic hyperplasia 5α-reductase inhibitors are a main modality of treatment. More than 30% of men do not respond to the therapeutic effects of 5α-reductase inhibitors. We have found that a third of adult prostate samples do not express 5α-reductase type 2 secondary to epigenetic modifications. We evaluated whether 5α-reductase type 2 expression in benign prostatic hyperplasia specimens from symptomatic men was linked to methylation of the 5α-reductase type 2 gene promoter. We also identified associations with age, obesity, cardiac risk factors and prostate specific antigen. Prostate samples from men undergoing transurethral prostate resection were used. We determined 5α-reductase type 2 protein expression and gene promoter methylation status by common assays. Clinical variables included age, body mass index, hypertension, hyperlipidemia, diabetes, prostate specific antigen and prostate volume. Univariate and multivariate statistical analyses were performed followed by stepwise logistic regression modeling. Body mass index and age significantly correlated with methylation of the 5α-reductase type 2 gene promoter (p <0.05) whereas prostate volume, prostate specific antigen or benign prostatic hyperplasia medication did not correlate. Methylation highly correlated with 5α-reductase protein expression (p <0.0001). In a predictive model increasing age and body mass index significantly predicted methylation status and protein expression (p <0.01). Increasing age and body mass index correlate with increased 5α-reductase type 2 gene promoter methylation and decreased protein expression in men with symptomatic benign prostatic hyperplasia. These results highlight the interplay among age, obesity and gene regulation. Our findings suggest an individualized epigenetic signature for symptomatic benign prostatic hyperplasia, which may be important to choose appropriate personalized treatment options.


Machine Learning for Brain Images Classification of Two Language Speakers.
The image analysis of the brain with machine learning continues to be a relevant work for the detection of different characteristics of this complex organ. Recent research has observed that there are differences in the structure of the brain, specifically in white matter, when learning and using a second language. This work focuses on knowing the brain from the classification of Magnetic Resonance Images (MRIs) of bilingual and monolingual people who have English as their common language. Different artificial neural networks of a hidden layer were tested until reaching two neurons in that layer. The number of entries used was nine hundred and the classifier registered a high percentage of effectiveness. The training was supervised which could be improved in a future investigation. This task is usually carried out by an expert human with Tract-Based Spatial Statistics analysis and fractional anisotropy expressed in different colors on a screen. So, this proposal presents another option to quantitatively analyse this type of phenomena which allows to contribute to neuroscience by automatically detecting bilingual people of monolinguals by using machine learning from MRIs. This reinforces what is reported in manual detections and the way that a machine can do it.


Assessment Causality in Associations Between Serum Uric Acid and Risk of Schizophrenia: A Two-Sample Bidirectional Mendelian Randomization Study.
Although increasing lines of evidence showed associations between serum uric acid (UA) levels and schizophrenia, the causality and the direction of the associations remain uncertain. Thus, we aimed to assess whether the relationships between serum UA levels and schizophrenia are causal and to determine the direction of the association. Two-sample bidirectional Mendelian randomization (MR) analyses and various sensitivity analyses were performed utilizing the summary data from genome-wide association studies within the Global Urate Genetics Consortium and the Psychiatric Genomics Consortium. Secondary MR analyses in both directions were conducted within summary data using genetic risk scores (GRSs) as instrumental variables. Three MR methods provided no causal relationship between serum UA and schizophrenia. Furthermore, GRS approach showed similar results in the three MR methods after adjustment for heterogeneity. By contrast, inverse variance weighted method, weighted median and GRS approach suggested a causal effect of schizophrenia risk on serum UA after adjustment for heterogeneity (per 10-symmetric percentage increase in schizophrenia risk, beta: -0.039, standard error (SE): 0.013, P = 0.003; beta: -0.036, SE: 0.018, P = 0.043; beta: -0.039, SE: 0.013, P = 0.002; respectively). Moreover, in both directions' analyses, the heterogeneity and sensitivity tests suggested no strong evidence of bias due to pleiotropy. Schizophrenia may causally affect serum UA levels, whereas the causal role of serum UA concentrations in schizophrenia was not supported by our MR analyses. These findings suggest that UA may be a useful potential biomarker for monitoring treatment or diagnosis of schizophrenia rather than a therapeutic target for schizophrenia.


Fundamental properties of oligo double-stranded DNA/single-walled carbon nanotube nanobiohybrids.
Fundamental properties of single-walled carbon nanotubes (SWNTs) that are individually dissolved using twenty base paired-double-stranded (ds) DNA, (dA)(20)/(dT)(20), as well as single-stranded (ss) twenty-mers of oligo DNAs, adenine (dA)(20) and thymine (dT)(20), for comparison are described. In this study, unbound oligo DNAs are fully removed from the hybrid aqueous solutions using size-exclusion chromatography (SEC)-HPLC. Each SEC chromatogram of the solutions shows two separated peaks; one is the free oligo DNAs and the others are the oligo DNA/SWNT hybrids. The earlier eluent fractions (the hybrids) are separated into four size-separated fractions, and then their stability is evaluated by the re-injection of the fractions. The chromatograms of the earlier eluent fractions are almost identical to those of the original ones even after storage for one month, indicating the high stability of the dsDNA/SWNTs and ssDNA/SWNTs hybrids in water. The results free us from considering the desorption of the bound-oligo dsDNA or oligo ssDNA from their nanohybrids with the SWNTs, which is of significant advantage to the utilization of oligo DNA/SWNT nanobiohybrids in wide areas of science. We also investigated the near-IR absorption and photoluminescence (PL) spectral behaviors of the fractionated oligo DNA/SWNTs hybrids not containing corresponding free oligo DNA.


Evidence from the lamarck granodiorite for rapid late cretaceous crust formation in california.
Strontium and neodymium isotopic data for rocks from the voluminous 90-million-year-old Lamarck intrusive suite in the Sierra Nevada batholith, California, show little variation across a compositional range from gabbro to granite. Data for three different gabbro intrusions within the suite are identical within analytical error and are consistent with derivation from an enriched mantle source. Recognition of local involvement of enriched mantle during generation of the Sierran batholith modifies estimates of crustal growth rates in the United States. These data indicate that parts of the Sierra Nevada batholith may consist almost entirely of juvenile crust added during Cretaceous magmatism.


Free drug samples in the United States: characteristics of pediatric recipients and safety concerns.
Free drug samples frequently are given to children. We sought to describe characteristics of free sample recipients, to determine whether samples are given primarily to poor and uninsured children, and to examine potential safety issues. We analyzed data on 10295 US residents <18 years of age from the 2004 Medical Expenditure Panel Survey, a nationally representative survey that includes questions on receipt of free drug samples. We performed bivariate and multivariate analyses to evaluate characteristics associated with receipt of >or=1 free drug sample in 2004. We identified the most frequently reported sample medications and reviewed potential safety issues. Ten percent of children who received prescription medications and 4.9% of all children received >or=1 free drug sample in 2004. In bivariate analyses, poor children (family incomes of <200% of the federal poverty level) were no more likely to receive free samples than were those with incomes of >or=400% of the poverty level (3.8% vs 5.9%). Children who were uninsured for part or all of the year were no more likely to receive free samples than were those who were insured all year (4.5% vs 5.1%); 84.3% of all sample recipients were insured. In multivariate analyses, routine access to health care (>or=3 provider visits in 2004) was associated with free sample receipt. The 15 most frequently distributed pediatric free samples in 2004 included 2 schedule II controlled medication, Adderall (amphetamine/dextroamphetamine) [corrected] and 4 medications that received new or revised black box warnings between 2004 and 2007, Elidel (pimecrolimus), Advair (fluticasone/salmeterol), Strattera (atomoxetine), and Adderall (amphetamine/dextroamphetamine). Poor and uninsured children are not the main recipients of free drug samples. Free samples do not target the neediest children selectively, and they have significant safety considerations.