Adult-onset motor neuron disease in three cats.
Motor neuron diseases of domestic animals have rarely been described. Three cats with adult-onset, chronic, progressive generalized muscle weakness characterized initially by trembling on exertion and later by extreme difficulty in walking, cervical ventroflexion, dysphagia, and marked muscle atrophy were elevated. Spinal reflexes were evident early but were nondetectable as the disease progressed. Electromyography revealed fibrillation potentials, with nerve conduction velocities within the reference range. Histologic examination of muscle specimens revealed denervation. Marked neuron loss and gliosis were detected in the ventral horns of the spinal cord, with atrophy of ventral nerve rootlets. Less dramatic neuron loss was seen in brain stem motor nuclei. Electron microscopic examination of the ventral horns disclosed hypertrophied astrocytes, with densely arrayed intermediate filaments, swollen axons with large filamentous accumulations, and many macrophages with lipofuscin-like inclusions. Clinical and pathologic findings were consistent with a progressive neurodegenerative disease affecting spinal and some bulbar motor nuclei.


Ligand and structure based hierarchical virtual screening cascade for finding novel epidermal growth factor receptor inhibitors.
The epidermal growth factor receptor (EGFR) tyrosine kinase plays an important role in tumor formation and growth by mediating cell growth and other physiological processes. Therefore, EGFR is a promising target for the treatment of cancer. In this work, we combined ligand-based and structure-based virtual screening methods to identify novel EGFR inhibitors from a library of more than 103 thousand compounds. We first obtained hundreds of compounds with similar physiochemical properties through 3D molecular shape and electrostatic similarity screening with potent inhibitors AEE788 and Afatinib as queries. Next, we identified compounds with strong binding affinities to the EGFR pocket through molecular docking, which makes good use of the structure information of the receptor. After molecular scaffold analysis, our bioassay confirmed 13 compounds with EGFR inhibitory activity and three compounds had IC50 values below 1000 nM. In addition, we collected 5371 EGFR inhibitors from online databases, and clustered them into 7 groups by K-means method using their ECFP4 fingerprints as input. Each cluster had typical molecular fragments and corresponding activity characteristics, which could guide the design of EGFR inhibitors, and we concluded that the fragments from some of the hits are indicated in the highly active scaffolds.


Effect of a prodrug of the green tea polyphenol (-)-epigallocatechin-3-gallate on the growth of androgen-independent prostate cancer in vivo.
Epigallocatechin-3-gallate (EGCG) is the major and most potent polyphenol compound of green tea that has been shown to have anticancer effects against various types of cancers. In this study, in addition to the EGCG compound, a synthetic derivative, the peracetate of EGCG (EGCG-P), was used to investigate the inhibitory effects on growth of androgen-independent prostate cancer in vivo. The advantage of EGCG-P is that it may act as a prodrug, leading to higher bioavailability than EGCG itself. The aim of our study was to compare the differences between EGCG and EGCG-P on their inhibitory effect on androgen-independent prostate cancer, CWR22R, xenograft model in nude mice. The mice were administrated daily with solvent dimethyl sulfoxide, EGCG, and EGCG-P separately through intraperitoneal injection for 20 days. Tumor volume and body weight of nude mice were recorded daily. Serum prostate-specific antigen (PSA) levels were also measured before and after the treatment. The effects of both EGCG and EGCG-P on tumor cell proliferation were assessed by immunohistochemical (IHC) method using antibodies against Ki-67 and proliferating cell nuclear antigen. The apoptotic effect was evaluated by IHC against B-cell non-Hodgkin lymphoma-2 and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay by in situ apoptosis detection kit. Moreover, the potential suppression of angiogenesis by EGCG and EGCG-P on prostate cancer was examined by IHC against CD31. Our results revealed that treatment of EGCG and EGCG-P compounds suppressed the growth of CWR22R xenografts without causing any detectable side effects in nude mice. The suppression of growth of the tumor was correlated with the decrease of serum PSA level together with the reduction in tumor angiogenesis and an increase in apoptosis on prostate cancer cells. The results showed that treatment of EGCG and EGCG-P inhibited tumor growth and angiogenesis while promoting apoptosis of the prostate cancer cells in vivo. Our results suggest that EGCG-P may be a more stable and useful compound for increasing the therapeutic anticancer effects in androgen-independent prostate cancer.


[Stewart-Bluefarb syndrome (kaposiform arteriovenous fistula with bone changes)].
In a 14-year-old female patient with arteriovenous shunts (Stewart-Bluefarb syndrome), fist-sized cutaneous swelling, venous dilatation, blue-brown pigmentation and painful subcutaneous fingertip-sized nodules were noted on the right lower thigh. In addition to an arteriovenous malformation, bone hypertrophy, bone atrophy and after bone defects were observed in the involved area on X-ray examination. Histological examination revealed increased vascularity and vascular cavernous structures with endothelial swelling and extravasation of erythrocytes, but no malignant changes.


[Socio-professional evaluation of 184 patients with hand injuries treated at an emergency microsurgery service].
184 consecutive patients were operated for severe industrial injuries of the hand. Microsurgical techniques were used in 86% of cases, with 41% of replantation (with about 1/3 of failures), and revascularization, and 17% of sutures of median and ulnar nerves. These patients were examined by medical experts from the French National Health Service, independently of their surgeons, in order to determine under which conditions they could resume their professional activities (changes of their working conditions or not, reduction in their wages or not, etc.). Moreover the duration of work interruption, as well as the percentage of professional disabilities, were known for more than 90% of the 115 patients who underwent an official assessment. The average percentage of professional disability was 19%, whereas without specialized surgery it used to be roughly 30 to 40% for the same lesions. The value of microsurgical techniques was obvious when considering the ability of the patients to resume their previous activities, especially as 96% of them were manual workers. Only 12% of the patients did not resume their work (5% were unemployed, and 7% retired or were too disabled to work). 18% were able to return to work, but with modifications of their working conditions or their wages. But, most important, 70% of the patients resumed their previous work with the same pay. On average, they had to stay for ten days in the surgical department and had to stop work for 3 months. This may be due to our great concern with early rehabilitation, aimed at manual work, with early transfer of patients to specialized rehabilitation centers.(ABSTRACT TRUNCATED AT 250 WORDS)


Synthesis and physicochemical properties of 2'-deoxy-2',2''-difluoro-beta-D-ribofuranosyl and 2'-deoxy-2',2''-difluoro-alpha-D-ribofuranosyl oligonucleotides.
We present procedures for nucleoside and oligonucleotide synthesis, binding affinity (Tm) and structural analysis (CD spectra) of 2'-deoxy-2',2''-difluoro-alpha-D-ribofuranosyl and 2'-deoxy-2',2''-difluoro-beta-D-ribofuranosyl oligothymidylates. Possible reasons for the thermal instability of duplexes formed between these compounds and RNA or DNA targets are discussed.


Microstructure of white and dark turkey meat batters as affected by pH.
1. The effect of increasing the pH (4.5 to 7.5) of white and dark comminuted turkey meat on the microstructure of cooked batters was studied. 2. Both scanning and transmission electron micrographs revealed that low pH caused the formation of a dense aggregated gel matrix while increasing the pH resulted in more open structures. 3. At pH 7.5 both the white and dark meat exhibited superior water holding capacity (both raw and cooked) compared to the low pH treatments; all adjusted to 14% protein. 4. The high pH also resulted in a higher gel strength, while the low pH (4.5) produced a soft and crumbly texture. As pH was raised, gel strength gradually increased reaching a maximum at pH 7.5. Decreasing the pH resulted in lighter meat batters in both the white and dark turkey meat. 5. Muscle fibre microstructure appeared to be better preserved at the low pH treatments.


[Development of polymeric nanoparticles in the targeting drugs carriers].
This review presents the most outstanding contribution in the field of polymeric nanoparticles used as targeting drugs delivery systems. Nanoparticles barrier is a novel kind of controlled release system for drugs which can effectively deliver the drug to a target site and increase the bioavailability and therapeutic benefit, while minizing the side effects. In this paper the applications of nanoparticles in the active, passive and physical targeting drugs carriers are reviewed.


Elevated blood markers 1 year before manifestation of malignant glioma.
We detected distinct plasma concentration profiles of S100B, neuropeptide Y, and secretagogin in 3 of 191 patients enrolled in a previous study investigating brain-tissue-related markers in the blood of patients with atrial fibrillation. Intriguingly, 2 of these 3 patients, both of whom were without neurological symptoms at the time of blood sampling, were diagnosed with malignant glioma (MG) approximately 1 year later. To our knowledge, this is the first report indicating that distinct blood biomarker profiles may be detected long before clinical manifestation of MG.


Expanding Clinical Assessment for Traumatic Brain Injury and Comorbid Post-Traumatic Stress Disorder: A Retrospective Analysis of Virtual Environment Tasks in the Computer-Assisted Rehabilitation Environment.
The objective of this study was to determine whether physical performance during virtual environment (VE) tasks in the Computer-Assisted Rehabilitation Environment (CAREN) could differentiate between service members (SMs) with a history of traumatic brain injury (TBI) with and without comorbid post-traumatic stress disorder (PTSD). Data were obtained by independent review of clinical notes, objective outcomes, and validated questionnaires from 214 SMs (208 males) with a history of TBI assessed in the CAREN from 2010 to 2015. Three preliminary VEs acclimatized patients to the CAREN: Balance Balls, weight shifting on a static platform (timed); Balance Cubes, step shifting with and without platform motion (timed); and Continuous Road, flat ambulation (self-selected speed). Multiple regression analyses revealed that patients with comorbid TBI-PTSD were significantly slower in completing the VE tasks than patients without PTSD. Logistic regression showed that the Balance Cubes VE without platform motion significantly predicted diagnostic category (i.e., no PTSD vs. comorbid PTSD). In conclusion, in SMs with a history of TBI, physical performance on the CAREN effectively distinguished those with comorbid PTSD, as their performance was significantly slower than SMs without PTSD. These results portray the potential of the CAREN as a novel assessment tool in SMs with a history of TBI.


Computer use in schools for the blind in Japan.
In a school for the blind, computer use and feelings toward computers by 34 visually impaired students receiving secondary education and by their 42 teachers were investigated with a questionnaire. Most subjects used computers effectively, but some students who had low vision did not wish to use them to avoid strain on their eyes. The computers allowed use of Kanji (Chinese characters) by the blind students, providing a new tool in their learning of Kanji. In classes, it is necessary to maintain and customize the computers continuously.


Altered glycosylated PrP proteins can have different neuronal trafficking in brain but do not acquire scrapie-like properties.
N-Linked glycans have been shown to have an important role in the cell biology of a variety of cell surface glycoproteins, including PrP protein. It has been suggested that glycosylation of PrP can influence the susceptibility to transmissible spongiform encephalopathy and determine the characteristics of the many different strains observed in this particular type of disease. To understand the role of carbohydrates in influencing the PrP maturation, stability, and cell biology, we have produced and analyzed gene-targeted murine models expressing differentially glycosylated PrP. Transgenic mice carrying the PrP substitution threonine for asparagine 180 (G1) or threonine for asparagine 196 (G2) or both mutations combined (G3), which eliminate the first, second, and both glycosylation sites, respectively, have been generated by double replacement gene targeting. An in vivo analysis of altered PrP has been carried out in transgenic mouse brains, and our data show that the lack of glycans does not influence PrP maturation and stability. The presence of one chain of sugar is sufficient for the trafficking to the cell membrane, whereas the unglycosylated PrP localization is mainly intracellular. However, this altered cellular localization of PrP does not lead to any overt phenotype in the G3 transgenic mice. Most importantly, we found that, in vivo, unglycosylated PrP does not acquire the characteristics of the aberrant pathogenic form (PrPSc), as was previously reported using in vitro models.


Effects of swim training alone and in combination with clonidine and rilmenidine on blood pressure, plasma electrolytes, vasopressin, and renin activity in spontaneously hypertensive rats.
Adaptations to the effects of clonidine (CL) and rilmenidine (R) were studied during a 12-week training program (swimming) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. Systolic blood pressure (SBP) was regularly measured during this period. Body weight (BW) was determined at the beginning and at the 12th week. Plasma parameters, cardiac determinations, vasopressin (pAVP), and plasma renin activity (PRA) were measured only at the end of the experiment. Both SBP and ponderal benefit were reduced by CL, R, and training. Contrary to beta-adrenoceptor blocking agents, we found no inhibition of the beneficial effect on SBP of training in combination with CL or R. Plasma and hypothalamic vasopressin were reduced by both drugs but only CL increased plasma renin activity (PRA) although its mechanisms of action are still not clearly understood. Our results suggest that CL and R as well as swim training can be considered as an effective countermeasure in SHR. Moreover, the heterogeneity of action of CL and R on some of the parameters tested is in favor of different pharmacological properties for these drugs.


INCB-13739, an 11beta-hydroxysteroid dehydrogenase type 1 inhibitor for the treatment of type 2 diabetes.
INCB-13739, being developed by Incyte Corp, is a novel, first-in-class 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitor for the potential treatment of metabolic disorders, including type 2 diabetes mellitus (T2DM) and obesity. INCB-13739 has high selectivity for 11beta-HSD1 over other dehydrogenases and glucocorticoid and mineralocorticoid receptors, with prolonged pharmacodynamic activity and good pharmacokinetic/pharmacodynamic properties. INCB-13739 demonstrated improved hepatic and peripheral insulin sensitivity with a satisfactory reduction in fasting plasma glucose and cholesterol after 28 days of treatment in patients with T2DM, with a dose-dependent weight loss, decrease in triglyceride levels and an improvement in blood pressure. Clinical data demonstrated that INCB-13739 had a better efficacy to tolerability ratio compared with potential competitors. The unique differentiation of INCB-13739 is its effects on both glucose and lipid parameters coupled with its effects on body weight and hypertension. The results from phase III clinical trials will be pivotal; however, the available data suggest that INCB-13739 has potential for success in the market.


Antinuclear antibodies by indirect immunofluorescence : optimum screening dilution for diagnosis of systemic lupus erythematosus.
Antinuclear antibodies (ANA) are serological hallmark of systemic lupus erythematosus (SLE). Conventionally, the test is carried out on human epithelial cells (HEp2) by indirect immunofluorescence (IIF) technique. Since culturing and maintaining HEp2 cells in the laboratory are labour intensive, in-house assays have given way to kits manufactured by commercial companies. The reference screening dilutions provided by the manufacturers are based on different ethnic population than ours. Therefore, it becomes mandatory for every laboratory to have its own screening dilutions for the local population that distinguishes best between healthy and diseased state. As, there is paucity of such data, we aimed to define the optimum screening dilution that distinguishes the patient with SLE from healthy individuals. Sera of patients fulfilling ACR criteria for diagnosis of SLE, idiopathic inflammatory polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA), and age and sex matched healthy individuals were tested for ANA by IIF using a commercial kit (Euroimmun, Germany) at 5 dilutions, namely 1:40, 1:80, 1:160, 1:320 and 1:640. Receiver operator characteristics (ROC) curve were constructed to define the optimum dilution that distinguished healthy sera from the diseased ones. Test was performed on 213 sera from 94 healthy individuals, and 43 SLE, 37 RA and 39 DM/PM patients. In healthy individuals, ANA at dilutions 1:40, 1:80, 1:160, 1:320 and 1:640 was positive in 13.8, 4.3, 2.1, 2.1 and 0 per cent respectively, whereas in SLE it was positive in 95.3, 95.3, 65.1, 53.5 and 23.3 per cent respectively. ROC curves analysis showed that at 1:40 dilution, sera of 95.3 per cent of SLE and 13.8 per cent of normal individuals were (ANA) positive, whereas at 1:80 dilution it was 95.3 per cent for SLE and 4.3 per cent for healthy individuals. A fluorescent intensity of > or =2 was more specific for SLE. The best discrimination between healthy individuals and the SLE patients was found at screening dilution of 1:80 and fluorescent intensity of > or =2 in our laboratory.


Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model.
Chronic liver disease may result in a sequential progression through fibrosis, cirrhosis and lead, eventually, to hepatocellular carcinoma (HCC). Hepatic stellate cells (HSC) seem to be responsible for the fibrogenic response through the activation of an autocrine loop involving the chemokine receptor, CCR5. However, the role of CCR5 in HCC remains poorly understood. Since this receptor is also one of the main ports of entry for the human immunodeficiency virus (HIV), several CCR5 inhibitors are being used in the clinic to reduce viral load. We used one of these inhibitors, maraviroc (MVC), in a mouse model of diet-induced HCC to investigate whether this intervention would reduce disease progression. Animals treated with MVC on top of a normal control diet did not present any evidence of toxicity or any morphological change when compared with non-treated mice. Animals treated with MVC presented higher survival, less liver fibrosis, lower levels of liver injury markers and chemokines, less apoptosis, lower proliferation index, and lower tumor burden than their counterparts receiving only the hepatotoxic diet. In addition, MVC inhibits HSC activation markers such as phosphorylation of p38 and ERK, and increases hepatocyte survival. This study suggests that MVC, a well tolerated and clinically characterized drug, may be used as a preventative treatment for HCC. Clinical studies are needed to demonstrate the efficacy of this drug, or other CCR5 inhibitors, in patients with high risk of developing HCC.


Sex- and age-related differences in bilirubin concentrations in serum.
The relation between age and sex and the concentration of bilirubin in serum was evaluated in 6740 men and 11 215 women, ages 13 to 96 years. Mean serum bilirubin concentrations in the men significantly exceeded values in the women over all age groups examined. Further, mean serum bilirubin concentrations were greatest both in males and females in the 19-24 years age group and then declined to former values, which persisted throughout life. Pearson correlation coefficients for bilirubin with liver function indices (albumin and total protein) and with hemoglobin were low in all ages and in both sexes, suggesting that bilirubin concentrations do not correlate with those liver functions not directly concerned with bile pigment processing.


Quinoline-8-ol and its derivatives as preconcentration agents in flow injection analysis coupled to atomic and molecular spectrometric techniques.
Quinoline-8-ol, one of the most popular and versatile organic reagents, is known to react with several metals, because it has both a basic nitrogen and a phenolic group. Hence, quinoline-8-ol and its derivatives have been widely used as chelating and/or sorbent extraction agents in on-line flow injection analysis (FIA) along with a suitable detection technique. The state of the art for using quinoline-8-ol and its derivatives in FIA was studied in terms of the selectivity, sensitivity and precision. Emphasis was placed on validating these procedures by analyzing certified reference materials and applying these analytical methodologies to real samples for the determination of inorganics.


High-Dose Intravenous Immunoglobulin in Skin Autoimmune Disease.
The immunomodulatory potential and low incidence of severe side effects of high-dose intravenous immunoglobulin (IVIg) treatment led to its successful application in a variety of dermatological autoimmune diseases over the last two decades. IVIg is usually administered at a dose of 2 g per kg body weight distributed over 2-5 days every 4 weeks. They are most commonly used as a second- or third-line treatment in dermatological autoimmune disease (pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, dermatomyositis, systemic vasculitis, and systemic lupus erythematosus). However, first-line treatment may be warranted in special circumstances like concomitant malignancy, a foudroyant clinical course, and contraindications against alternative treatments. Furthermore, IVIg can be considered first line in scleromyxedema. Production of IVIg for medical use is strictly regulated to ensure a low risk of pathogen transmission and comparable quality of individual batches. More common side effects include nausea, headache, fatigue, and febrile infusion reactions. Serious side effects are rare and include thrombosis and embolism, pulmonary edema, renal failure, aseptic meningitis, and severe anaphylactic reactions. Regarding the mechanism of action, one can discriminate between functions of the Fcγ region and the F(ab)2 region and their effects on a cellular level. These functions are not mutually exclusive, and more than one pathway may contribute to the beneficial effects. Here, we present a historical background, details on manufacturing, hypotheses on the mechanisms of action, information on the clinical application in the abovementioned conditions, and a brief outlook on future directions of IVIg treatment in dermatology.


Compliance and loss to follow up of HIV negative and positive mothers recruited from a PMTCT programme in Zimbabwe.
To describe the methodological challenges of a nine months follow up study of mothers recruited from a national Prevention of Mother To Child Transmission (PMTCT) programme with regards to defaulters, drop outs and compliance. Nested case control study. Three peri-urban clinics in Zimbabwe namely: Epworth, St Mary's, Seke North. Pregnant women who enrolled at 36 weeks of gestation were recruited for a follow up of mother and child from delivery, six weeks, four and nine months post partum. Follow up trend of these women was compared between the HIV positive and negative mothers with regards to defaulting, drop outs, full and partial compliance. Statistical significance was computed using the Chi-square test. Of the enrolled 1050 pregnant women with a known HIV status (594 HIV negative and 456 HIV positive) 851 (457 HIV negative and 394 HIV positive) showed up at one or more visits scheduled up to nine months. The denominator was dropping at each point and time. The overall dropout rate was 19% without a significant difference between the HIV positive and negative women at delivery. At six weeks the drop out rate was 35 (7.7%) for the HIV positive versus 75 (12.9%) p=0.010 and at four months 12 (2.9%) versus 39 (7.7%) p=0.002 respectively. However, at nine months the drop out rate was not different (p=0.747). The defaulter rate was significantly different at every stage between the HIV positive and negative mothers from delivery to six weeks, becoming even more significant at the four and nine months visit (p=<0.001). The overall full compliance at nine months was 46.1% with a significant difference between the HIV positive (55.6%) versus (37.9%) for the HIV negative (p=<0.001). Drop out is highest among the HIV negative as opposed to the HIV positive with the peak period being at "six weeks". There is high defaulting among the HIV negative compared to the HIV positive with the peak being at "four months". The study has shown that the HIV negative women are more likely to drop out whereas the HIV positive were twice as likely to fully comply. It is surprising that the peak drop out period, "six weeks visit" is a cardinal existing national scheduled visit where both mother and baby undergo a full medical examination with the mother having a pap smear taken.


Spondylodiscitis: a rare complication of button battery ingestion in a 10-month-old boy.
Nowadays, button battery ingestion accounts for one of the common foreign body ingestions among pediatric population. Unexpected manifestations in this setting, particularly after late removal, are confusing and might be misleading and postpone the proper management. We report a case of button battery ingestion in a 10-month-old boy who was primarily considered uncomplicated. However, he was readmitted with neck stiffness, which later turned to be due to spondylodiscitis. Based on this report, we strongly recommend considering spondylodiscitis as a late but serious complication of button battery ingestion in any patient who presents with restricted neck movement following foreign body ingestion.


Colonization of the upper genital tract by vaginal bacterial species in nonpregnant women.
The objective of the study was to evaluate the upper genital tract (UGT) presence of vaginal bacterial species using sensitive molecular methods capable of detecting fastidious bacterial vaginosis (BV)-associated bacteria. Vaginal swabs were collected prior to hysterectomy. The excised uterus was sterilely opened and swabs collected from the endometrium and upper endocervix. DNA was tested in 11 quantitative polymerase chain reaction (PCR) assays for 12 bacterial species: Lactobacillus iners, L crispatus, L jensenii, Gardnerella vaginalis, Atopobium vaginae, Megasphaera spp, Prevotella spp, Leptotrichia/Sneathia, BVAB1, BVAB2, BVAB3, and a broad-range16S ribosomal ribonucleic acid gene assay. Endometrial fluid was tested with Luminex and an enzyme-linked immunosorbent assay for cytokines and defensins and tissue for gene expression of defensins and cathelicidin. We enrolled 58 women: mean aged 43±7 years, mostly white (n=46; 79%) and BV negative (n=43; 74%). By species-specific quantitative PCR, 55 (95%) had UGT colonization with at least 1 species (n=52) or were positive by 16S PCR (n=3). The most common species were L iners (45% UGT, 61% vagina), Prevotella spp (33% UGT, 76% vagina) and L crispatus (33% UGT, 56% vagina). Median quantities of bacteria in the UGT were lower than vaginal levels by 2-4 log10 ribosomal ribonucleic acid gene copies per swab. There were no differences in the endometrial inflammatory markers between women with no bacteria, Lactobacillus only, or any BV-associated species in the UGT. Our data suggest that the endometrial cavity is not sterile in most women undergoing hysterectomy and that the presence of low levels of bacteria in the uterus is not associated with significant inflammation.


Framework for monitoring equity in access and health systems issues in antiretroviral therapy Programmes in southern Africa.
Universal provision of antiretroviral therapy (ART), while feasible, is expensive. In light of this limitation, the World Health Organisation (WHO) has launched the 3 × 5 initiative, to provide ART to 3 million people by the end of the year 2005. In Southern Africa, large-scale provision of ART will likely be achieved through fragile public health systems. ART programmes should therefore be developed and expanded in ways that will not aggravate inequities or result in the inappropriate withdrawal of resources from other health interventions or from other parts of the health system. This paper, proposes a framework for monitoring equity in access and health systems issues in ART programmes in Southern Africa. It proposes that an equity monitoring system should comprise seven thematic areas. These thematic areas encompass a national monitoring system which extends beyond one agency or single data collection method. Together with monitoring of targets in terms of numbers treated, there should also be monitoring of health systems impacts and issues in ART expansion, with reporting both nationally and to a regional body.


Energy metabolism as part of the anticonvulsant mechanism of the ketogenic diet.
The efficacy of the ketogenic diet (KD) develops gradually over a period of 1-3 weeks, suggesting that adaptive changes in gene expression are involved in its anticonvulsant effects. Previously, microarrays were employed to define patterns of gene expression in the hippocampus of rats maintained on either a KD or a control diet for 3 weeks. The density of mitochondria in hippocampal tissue was assessed by electron microscopy. Levels of selected energy metabolites, enzyme activities, and the effect of low glucose on synaptic transmission were also investigated in hippocampal tissue taken from either KD- or control-fed animals. We found a coordinated up-regulation of transcripts encoding energy metabolism enzymes and a dramatic 46% increase in the density of mitochondria observed in neuronal processes. These changes were accompanied by an increased phosphocreatine (PCr):creatine (Cr) energy-store ratio. Consistent with heightened energy reserves, hippocampal synaptic transmission in KD-fed animals was maintained approximately 50% longer compared to controls after exposure to a mild metabolic stressor. Taken together, several lines of evidence indicate that the KD enhances energy production in the brain. As a consequence, brain tissue appears to become more resistant to metabolic stress. It is proposed...that the observed KD-induced enhancements in energy metabolism help to compensate for the metabolic deficits exhibited (interictally) within epileptic foci and transient failures of gamma-aminobutyric acid (GABA) ergic inhibition, which would otherwise favor the initiation and propagation of seizure activity.


Social network analysis of biomedical research growth at a primarily undergraduate institution.
The National Institutes of Health Institutional Development Award Programs support the establishment and growth of biomedical research infrastructure in states that receive a low level of federal funding for biomedical research. The purpose of this investigation was to analyze the growth in research productivity over time. This program fostered an environment in which a biomedical research program could be developed and allowed to grow at Boise State University, a primarily undergraduate institution. The growth of the biomedical research community can be visualized through social network analysis.


Pathways to comorbidity: the transition of pure mood, anxiety and substance use disorders into comorbid conditions in a longitudinal population-based study.
To describe transitions to comorbidity within a 3-year period in three cohorts of subjects with at baseline a 12-month pure mood, anxiety or substance use disorder but no lifetime history of any other disorder category. To assess the role of personal and social vulnerability factors, life events, clinical factors and functional disability in the pathway to comorbidity. Data were derived from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), a prospective epidemiologic study of a representative sample of 7076 adults aged 18-65, interviewed in three waves (baseline, 1 and 3 years after baseline) with the Composite International Diagnostic Interview. 15.2% of 99 pure mood, 10.5% of 220 anxiety and 6.8% of 192 substance use disorder cases became comorbid. Comorbid transition from pure mood disorder was multivariately associated with higher age, external mastery and severity of the disorder. Comorbidity developing from pure anxiety disorder was associated with past and recent stressful life circumstances (childhood trauma, negative life events) and physical functional disability. Predictors of comorbid transition from pure substance use disorder were personal and social vulnerability variables only (high neuroticism, low social support). Although NEMESIS was performed among a substantial number of cases, the number of cases with a pure disorder at baseline subsequently developing comorbidity was low. This limited analysing determinants of different comorbid conditions. Risk factors for comorbid transitions vary depending on whether subjects have a primary mood, anxiety or substance use disorder. Interventions aimed at primary prevention of comorbidity to reduce psychiatric burden in populations with a history of pure disorders are indicated in response to clearly identified risk factors.


Taxifolin reduces the cholesterol oxidation product-induced neuronal apoptosis by suppressing the Akt and NF-κB activation-mediated cell death.
The taxifolin effect on the cholesterol oxidation product-induced neuronal apoptosis was investigated using differentiated PC12 cells and human neuroblastoma SH-SY5Y cells. 7-ketocholesterol induced phosphorylation of Akt, and increase in the levels of cytosolic and nuclear NF-κB p65, cytosolic NF-κB p50 and cytosolic phosphorylated-IκB-α in PC12 cells. The cholesterol oxidation products also induced a decrease in the levels of Bid and Bcl-2, increase in the levels of p53 and Bax, loss of the mitochondrial transmembrane potential, release of cytochrome c, activation of caspases (-8, -9 and -3), production of reactive oxygen species, depletion of GSH and cell death in both cell lines. Taxifolin, N-acetylcysteine, trolox, Akt inhibitor and Bay11-7085 attenuated the cholesterol oxidation product-induced changes in the apoptosis-related protein levels, activation of the Akt and NF-κB, reactive oxygen species production, GSH depletion and cell death. These results show that taxifolin may reduce the cholesterol oxidation product-induced neuronal apoptosis by suppressing the Akt and NF-κB activation-mediated cell death. The suppressive effect appears to be attributed to the inhibition of reactive oxygen species production and GSH depletion.


Dynamics of benzene guest inside a self-assembled cylindrical capsule: a combined solid-state 2H NMR and molecular dynamics simulation study.
The reorientational dynamics of benzene-d(6) molecules hosted into the cavity of a cavitand-based, self-assembled capsule was investigated by Molecular Dynamics (MD) simulations and temperature-dependent solid-state (2)H NMR spectroscopy. MD simulations were preliminarily performed to assess the motional models of the guest molecules inside the capsules. An in-plane fast reorientation of the benzene guest around the C(6) symmetry axis (B1 motion), characterized by correlation times of the order of picoseconds, was predicted with an activation barrier ( approximately 8 kJ/mol) very similar to that found for neat benzene in the liquid state. An out-of-plane reorientation corresponding to a nutation of the C(6) symmetry axis in a cone angle of 39 degrees (B2 motion, 373 K) with an activation barrier ( approximately 39 kJ/mol) definitely larger than that of liquid benzene was also anticipated. In the temperature range 293-373 K correlation times of the order of a nanosecond have been calculated and a transition from fast to slow regime in the (2)H NMR scale has been predicted between 293 and 173 K. (2)H NMR spectroscopic analysis, carried out in the temperature range 173-373 K on the solid capsules containing the perdeuterated guest (two benzene molecules/capsule), confirmed the occurrence of the B1 and B2 motions found in slow exchange in the (2)H NMR time scale. Line shape simulation of the (2)H NMR spectral lines permitted defining a cone angle value of 39 degrees at 373 K and 35 degrees at 173 K for the nutation axis. The T(1) values measured for the (2)H nuclei of the encapsulated aromatic guest gave correlation times and energetic barrier for the in-plane motion B1 in fine agreement with theoretical calculation. The experimental correlation time for B2 as well as the corresponding energetic barrier are in the same range found for B1. A molecular mechanism for the encapsulated guest accounting for the B1 and B2 motions was also provided.


Accumulation of C-terminal cleaved tau is distinctly associated with cognitive deficits, synaptic plasticity impairment, and neurodegeneration in aged mice.
C-terminal cleaved tau at D421 (∆D421-tau) accumulates in the brains of Alzheimer's disease (AD) patients. However, it is unclear how tau truncation, an understudied tau post-translational modification, contributes to AD pathology and progression. Utilizing an adeno-associated virus (AAV) gene delivery-based approach, we overexpressed full-length tau (FL-tau) and ∆D421-tau in 4- and 12-month-old mice for 4 months to study the neuropathological impact of accumulation in young adult (8-month) and middle-aged (16-month) mice. Overall, we show that independent of the tau species, age was an important factor facilitating tau phosphorylation, oligomer formation, and deposition into silver-positive tangles. However, mice overexpressing ∆D421-tau exhibited a distinct phosphorylation profile to those overexpressing FL-tau and increased tau oligomerization in the middle-age group. Importantly, overexpression of ∆D421-tau, but not FL-tau in middle-aged mice, resulted in pronounced cognitive impairments and hippocampal long-term potentiation deficits. While both FL-tau and ∆D421-tau induced neuronal loss in mice with age, ∆D421-tau led to significant neuronal loss in the CA3 area of the hippocampus and medial entorhinal cortex compared to FL-tau. Based on our data, we conclude that age increases the susceptibility to neuronal degeneration associated with ΔD421-tau accumulation. Our findings suggest that ΔD421-tau accumulation contributes to synaptic plasticity and cognitive deficits, thus representing a potential target for tau-associated pathologies.


PlateDesigner: a web-based application for the design of microplate experiments.
In biological assays, systematic variability, known as a batch effect, can often confound the effects of true biological conditions and has been well documented for a variety of high-throughput technologies. In microplate-based multiplex experiments, such as Luminex or OLINK assays, researchers need to consider both position and plate effects. Those effects can be easily accounted for if the experiments are properly designed, which includes randomization of the samples across multiple experimental runs. However, doing the ad hoc randomization becomes challenging when handling multiple samples. PlateDesigner is the first web-based application that provides randomization for microplate experiments, ensuring that the main principles of the experimental design, such as grouping samples from the same biological units and balancing the distribution of experimental conditions, are applied. Creating randomizations with PlateDesigner is simple and the results can be exported in a variety of formats, and easily integrated with microplate readers and statistical analysis software. PlateDesigner is written in R/Shiny and is hosted online by the Center of Biostatistics at the Icahn School of Medicine at Mount Sinai. This application is freely available at platedesigner.net.


Judgement post-stratification for designed experiments.
In many scientific studies, information that is not easily translated into covariates is ignored in the analysis. However, this type of information may significantly improve inference. In this research, we apply the idea of judgment post-stratification to utilize such information. Specifically, we consider experiments that are conducted under a completely randomized design. Sets of experimental units are formed, and the units in a set are ranked. Estimation is performed conditional on the sets and ranks. We propose a new estimator for a treatment contrast. We improve the new estimator by Rao-Blackwellization. Asymptotic distribution theory and corresponding inferential procedures for both estimators are developed. Simulation studies quantify the superiority of the new estimators and show their desirable properties for small and moderate sample sizes. The impact of the new techniques is illustrated with data from a clinical trial.


Infectious diarrhea in developed and developing countries.
Diarrhea from gastrointestinal infection remains a common problem. In industrialized countries, management is aimed at reducing morbidity and defining groups that may benefit from further investigation. Most infectious diarrhea is self-limiting and only requires supportive management. Viral agents are increasingly recognized as causative agents of epidemic and sporadic diarrhea. In developing countries, diarrhea is a major cause of mortality in children. Oral rehydration therapy, guided by a clinical assessment of the degree of dehydration, is cheap, simple, and effective and remains the mainstay of management of infant diarrhea. Controversies focus on the optimal formulation of oral rehydration solution. A vaccine against rotavirus has the potential to save millions of lives worldwide.


[Nursing of intubation].
Recent developments in noninvasive ventilation allow the intensivists to delay the time o intubation of the patient admitted to the ICU. This new possibility of a gain in time leads to the fact that those patients who are intubated in the ICLI, are patients with a very compromised hemodynamic and respiratory situation. For this reason, we developed a specific protocol regarding the intubation procedure of this kind of patients. This paper reviews our strategies for endotracheal tube positioning in critically ill patients and shows the fundamental role of the nurses during this procedure.


Differential Rates of Inadvertent Intravascular Injection during Lumbar Transforaminal Epidural Injections Using Blunt-Tip, Pencil-Point, and Catheter-Extension Needles.
To quantify the incidence of inadvertent vascular penetration during lumbosacral transforaminal epidural injections using blunt-tip, pencil-point, and catheter-extension needles. This is a prospective, observational, consecutive cohort study. Two hundred consecutive patients undergoing lumbosacral transforaminal epidural injections at an academic outpatient spine center. Four hundred seventy-five fluoroscopically guided lumbosacral transforaminal epidural injections were performed on consecutively consenting patients by one interventional spine physician, using three different needle types. The presence or absence of vascular uptake was determined during contrast injection under live fluoroscopy. Vascular uptake of contrast was observed in 58 of the total 475 injections, for an overall incidence of 12.2%. By needle type, the incidence of inadvertent vascular uptake was 16.6% (26/157) in the pencil-point group, 15.6% (24/154) in the blunt-tip group, and 4.9% (8/164) in the catheter-extension group. The difference in rates is statistically significant between the catheter-extension needle group and both the pencil-point group (P = 0.0009) and blunt-tip group (P = 0.0024). A secondary analysis was performed to quantify the incidence of functional pitfalls between needle groups, with a significantly lower incidence in the pencil-point group compared to both the catheter-extension (P = 0.0148) and blunt-tip needle (P = 0.0288) groups. Blunt-tip and pencil-point needles have comparable risk of inadvertent vascular injection during lumbosacral transforaminal injections. Catheter-extension needles demonstrated a reduce incidence of vascular uptake, but also result in a significantly higher rate of functional pitfalls that limits their usefulness in routine practice.


LncRNA NEAT1 regulate diffuse large B-cell lymphoma by targeting miR-495-3p/PD-L1 axis.
Diffuse large B-cell lymphoma (DLBCL) is a common lymphatic tumor in clinic. LncRNAs were reported to play a regulatory role in many cancers, including DLBCL. This study focused on the roles of NEAT1 in DLBCL. Real-time quantitative polymerase chain reaction (RT-qPCR) was carried out to detect mRNA expression. StarBase as well as TargetScan was used to predict targeting relationships, which was confirmed by the Dual Luciferase Reporter Assay and RNA pull-down assay. Cell Counting Kit 8 (CCK-8) were applied to measure cell viability. Flow cytometry assay was applied to detect cell apoptosis. Western blotting assay was conduct to determine protein expression. Lactate dehydrogenase (LDH) release assay were applied to evaluated cell cytotoxicity. NEAT1 was overexpressed in DLBCL patients. Knockdown of NEAT1 reduced the viability while enhanced the apoptosis of tumor cells. However, overexpression of NEAT1 exhibited an opposite effect. miR-495-3p was a target of NEAT1 and was decreased in DLBCL cells. However, inhibiting miR-495-3p reversed the effect of NEAT1 knock-down on DLBCL cells and induced the malignant behaviors of DLBCL cells. Moreover, NEAT1 functioned as a sponge of miR-495-3p to upregulate PD-L1. Our study demonstrated that a NEAT1/miR-495-3p/PD-L1 axis regulated the development of DLBCL. Therefore, NEAT1 may be a potential biomarker for DLBCL.


An AT-rich satellite DNA sequence, E180, in alfalfa (Medicago sativa).
A DNA fragment of approximately 750 bp was cloned from EcoRI-digested nuclear DNA of alfalfa (Medicago sativa). Southern blot and sequence analysis showed that the cloned DNA fragment represents a tetramer of a highly tandemly repeated DNA sequence of 185-188 bp (E180). The consensus sequence deduced from the four repeating units is 189 bp in length with an AT content of 67%. The copy number of the satellite DNA was estimated to be approximately 1.8 x 10(5) per genome and constitutes about 1% of the alfalfa genome. Sequence comparison revealed no identity to any repetitive DNA sequences that have been published to date. Digestion with HpaII and MspI indicated a high degree of methylation at the internal C of the restriction site CCGG within E180.


New concepts in vulvodynia.
Vulvodynia is chronic vulvar burning/pain without clear medical findings. The etiology of vulvodynia is unknown and health care professionals should thoroughly rule out specific, treatable causes or factors such as dermatoses or group B Streptococcus infections. Vulvodynia is divided into 2 classes: vulvar vestibulitis syndrome is vestibule-restricted burning/pain and is elicited by touch; dysesthetic vulvodynia is burning/pain not limited to the vestibule and may occur without touch/pressure. After diagnosis, critical factors in successful patient management include education and psychological support/counseling. Unfortunately, clinical trials on potential vulvodynia therapies have been few. Standard therapy includes treating neuropathic pain (eg, tricyclic medications, gabapentin) thought to play a role. Additional therapies may be considered: pelvic floor rehabilitation combined with surface electromyography, interferon alfa, estrogen creams, and surgery. Importantly, any therapy should be accompanied by patient education and psychological support. Because definitive data on effective therapies are lacking, further clinical investigations of treatment options are warranted.


Characterization of cardiac- and respiratory-driven cerebrospinal fluid motions using correlation mapping with asynchronous 2-dimensional phase contrast technique.
To investigate spatial distribution properties of the cardiac- and respiratory-driven cerebrospinal fluid (CSF) motions in the intracranial space, correlation mapping technique was conducted. Time series of CSF velocity were acquired in 7 healthy subjects of 26±5 years old under by asynchronous 2-dimensional phase contrast (2D-PC) method with 217-msec temporal resolution. The delay time and maximum correlation maps of the cardiac- and respiratory-driven CSF motions demonstrated clear differences in the propagation properties. When the reference region was set at anterior spinal subarachnoid space, the maximum correlation coefficients in the case of 6-sec respiratory period were 0.91±0.05 for cardiac-driven and 0.78±0.08 for respiratory-driven. They were 0.90±0.06 and 0.81±0.06 in the case of 10-sec period. The cardiac- and respiratory CSF motions differently distributed in intracranial space.


Adolescent anxiety disorders and the developing brain: comparing neuroimaging findings in adolescents and adults.
Adolescence is the peak period for the incidence of anxiety disorders. Recent findings have revealed the immaturity of neural networks underlying emotional regulation in this population. Brain vulnerability to anxiety in adolescence is related to the unsynchronised development of anxiety-relevant brain functional systems. However, our current knowledge on brain deficits in adolescent anxiety is mainly borrowed from studies on adults. Understanding adolescent-specific brain deficits is essential for developing biomarkers and brain-based therapies targeting adolescent anxiety. This article reviews and compares recent neuroimaging literature on anxiety-related brain structural and functional deficits between adolescent and adult populations, and proposes a model highlighting the differences between adolescence and adulthood in anxiety-related brain networks. This model emphasises that in adolescence the emotional control system tends to be hypoactivated, the fear conditioning system is immature, and the reward and stress response systems are hypersensitive. Furthermore, the striatum's functional links to the amygdala and the prefrontal cortex are strengthened, while the link between the prefrontal cortex and the amygdala is weakened in adolescence. This model helps to explain why adolescents are vulnerable to anxiety disorders and provides insights into potential brain-based approaches to intervene in adolescent anxiety disorders.


Sectional porcelain veneers for a maxillary midline diastema closure: a case report.
Diastema closure is a frequently requested, technique-sensitive cosmetic procedure. There are many techniques and materials that can be employed to close diastemas. While direct composite techniques can be economical and successful, they do present challenges in achieving satisfactory clinical and esthetic results. Traditional porcelain veneer placement may offer an excellent esthetic result, but typically requires the removal of tooth structure; as such, this is an irreversible procedure. The present article reports the case of a maxillary midline diastema closure in a healthy dentition by means of sectional porcelain veneers simply cemented onto the natural teeth and without tooth preparation. A step-bystep procedure is proposed for illustrating the proper implementation of an additive-only and noninvasive indirect technique that yields a satisfactory clinical and esthetic outcome for clinician and patient.


Histological and Urodynamic Effects of Autologous Stromal Vascular Fraction Extracted from Fat Tissue with Minimal Ex Vivo Manipulation in a Porcine Model of Intrinsic Sphincter Deficiency.
To evaluate the healing abilities of autologous stem cell therapy (stromal vascular fraction) prepared from adipose tissue we used an automated system without an ex vivo culture phase in a pig model of intrinsic sphincteric deficiency. A total of 15 pigs underwent endoscopic section of the urethral sphincter. Animals were then randomly assigned to 3 groups, including 1) controls without stromal vascular fraction injection, 2) early injection with stromal vascular fraction 2 to 3 days after section and 3) late stromal vascular fraction injection delivery 30 days after injury. Extraction and stromal vascular fraction injection were performed as a single procedure. The stromal vascular fraction was characterized by flow cytometry. Mesenchymal stem cell-like cells were enumerated by clonogenicity (cfu fibroblast) assay. Study end points included histological assessment of the urethral injury surface and urodynamics to determine maximum urethral pressure. Flow cytometry analysis revealed a mesenchymal stem cell-like phenotype in a mean ± SD of 47.3% ± 11.8% of stromal vascular fraction cells. The cfu fibroblast frequency was 1.3 to 6.6/100 stromal vascular fraction cells (1.3% to 6.6%). Stromal vascular fraction injection was associated with a reduction of the urethral injury surface in the early and late injection groups compared with the respective controls (7% vs 17% and 1% vs 13%, p = 0.050 and 0.029, respectively). On day 30 after injection maximum urethral pressure was significantly higher in the injected groups than in the control group, that is 64% vs 50% of maximum urethral pressure on day 0 (p = 0.04). These data demonstrate the ability of an autologous stromal vascular fraction to improve the urethral healing process in a large animal model of intrinsic sphincteric deficiency.


A TEST OF THE ROLE OF EPISTASIS IN DIVERGENCE UNDER UNIFORM SELECTION.
Five populations of Drosophila melanogaster have previously been shown to be replicably different in their responses to artificial selection for knockdown resistance to ethanol fumes (Cohan and Hoffmann, 1986). The present study tests whether this divergence could be attributed to the epistatic mechanism assumed by Wright's shifting-balance model of evolution, in which alleles favored in the genetic background of one population are not favored in that of another. If this were the mechanism of divergence, crosses between selected lines from different populations would be expected to yield an epistatic loss of the selected phenotype. However, all such crosses showed a good fit to an additive model with dominance. Divergence by an epistatic mechanism may also be associated with epistatic variance within populations, but no evidence for such epistasis was found. The populations therefore appear to have responded in different ways to selection not because of epistasis but because knockdown-resistance alleles that were common in some populations were absent (or at least less common) in others.


Effects of rabbit platelets on vascular smooth muscle cell DNA synthesis.
During platelet aggregation a factor is released which stimulates DNA synthesis in vascular smooth muscle cells. We have examined the capacity of plasma free suspensions of intact rabbit platelets to stimulate DNA synthesis in vascular smooth muscle cells in tissue culture. Platelet-rich plasma was obtained by low-speed centrifugation of citrated blood and passed through sterile columns of sepharose 2B beads. The resultant plasma-free platelet suspension was adjusted to 400,000 platelets/mm3. An aliquot was completely aggregated with thrombin, centrifuged and the supernatant examined for ability to stimulate incorporation of [3H]thyrmidine into DNA by cultured vascular smooth muscle cells. Sonication of an aliquot of platelet suspension released an equivalent amount of this stimulating factor. Another aliquot of platelet suspension of identical volume was added directly to the test smooth muscle cells. Stimulation by intact platelets co-cultured with smooth muscle cells was more than twice as great as that of the thrombin-aggregated supernatant. The latter was not increased by increasing the thrombin concentration nor by increasing the time of exposure. The potency of intact platelets was decreased only slightly by segregating them in Millipore chambers indicating the direct contact was not responsible for its enhancement.


Mechanical Properties and Friction Dynamics of Organogels Solidified with Rice Paraffin.
Raw materials suitable for a sustainable society have attracted interest in the cosmetics industry. We focused on rice bran as a sustainable material and evaluated the gelation behavior of paraffin extracted from rice bran (rice paraffin) against liquid paraffin, squalane, jojoba oil, and silicone oil. In addition, the frictional properties of the prepared organogel on an artificial skin surface were evaluated using a sinusoidal motion friction evaluation system. Rice paraffin solidified all oils even at the lowest wax concentration of 5 wt%. The hardness and kinetic friction coefficient μ k increased with an increase in the wax composition. The hardness and μ k of organogels solidified with rice paraffin were smaller than those of gels solidified with petroleum-derived paraffin. These differences are caused by the smaller carbon amount of rice paraffin. The friction parameters depended on the type of oil: the μ k of RLG composed of rice and liquid paraffin was greater than that of the other three oils (R, L, and G denote rice paraffin, liquid paraffin, and gel, respectively). These findings promote the development of lipsticks and cleansing gels consisting of sustainable development goal-responsive raw materials.


Cerebrovascular disease and stroke.
Stroke and cerebrovascular disorders are important causes of morbidity and mortality in children; they are already amongst the top 10 causes of childhood death and are probably increasing in prevalence. Acute treatment of stroke syndromes in adults is now evidence based. However, paediatric stroke syndromes are far less common and the differential diagnosis is very wide, but the individual health resource implications are much greater because of the life-long treatment costs in survivors. Recognition and consultation with a paediatric neurologist should be rapid so that children can benefit from regional services with emergency neurological, neuroradiological and neurosurgical intervention and paediatric intensive care. This review focuses on the epidemiology, presentation, differential diagnosis, generic/specific emergency management and prognosis of acute stroke in children. Its aim is to educate and guide management by general paediatricians and to emphasise the importance of local guidelines for the initial investigation and treatment and appropriate transfer of these children.


Study of prevalence and risk factors of chemotherapy-induced mucositis in gastrointestinal cancer using machine learning models.
Chemotherapy-induced mucositis (CIM) significantly impacts clinical outcomes and diminishes the quality of life in patients with gastrointestinal cancer. This study aims to prospectively determine the incidence, severity, and underlying risk factors associated with CIM in this patient population. To achieve this objective, we introduce a novel Machine Learning-based Toxicity Prediction Model (ML-TPM) designed to analyze the risk factors contributing to CIM development in gastrointestinal cancer patients. Within the winter season spanning from December 15th, 2018 to January 14th, 2019, we conducted in-person interviews with patients undergoing chemotherapy for gastrointestinal cancer. These interviews encompassed comprehensive questionnaires pertaining to patient demographics, CIM incidence, severity, and any supplementary prophylactic measures employed. The study encompassed a cohort of 447 participating patients who provided complete questionnaire responses (100%). Of these, 328 patients (73.4%) reported experiencing CIM during the course of their treatment. Notably, CIM-induced complications led to treatment discontinuation in 14 patients (3%). The most frequently encountered CIM symptoms were diarrhea (41.6%), followed by nausea (37.8%), vomiting (25.1%), abdominal pain (21%), gastritis (10.5%), and oral pain (10.3%). Supplementary prophylaxis was administered to approximately 62% of the patients. The analysis revealed significant correlations between the overall incidence of CIM and gender (p=0.015), number of chemotherapy cycles exceeding one (p=0.039), utilization of platinum-based regimens (p=0.039), and administration of irinotecan (p=0.003). Specifically, the incidence of diarrhea exhibited positive correlations with prior surgical history (p=0.037), irinotecan treatment (p=0.021), and probiotics usage (p=0.035). Conversely, diarrhea incidence demonstrated an adverse correlation with platinum-based treatment (p=0.026). In conclusion, this study demonstrates the successful implementation of the ML-TPM model for automating toxicity prediction with accuracy comparable to conventional physical analyses. Our findings provide valuable insights into the identification of CIM risk factors among gastrointestinal cancer patients undergoing chemotherapy. Furthermore, the results underscore the potential of machine learning in enhancing our understanding of chemotherapy-induced mucositis and advancing personalized patient care strategies.


Two tyrosine residues on the alpha subunit are crucial for benzodiazepine binding and allosteric modulation of gamma-aminobutyric acidA receptors.
Benzodiazepines (BZs) exert their therapeutic effects in the mammalian central nervous system at least in part by modulating the activation of gamma-aminobutyric acid (GABA)-activated chloride channels. To gain further insight into the mechanism of action of BZs on GABA receptors, we have been investigating structural determinants required for the actions of the BZ diazepam (dzp) on recombinant alpha1 beta2 gamma2 GABA(A) receptors. Site-directed mutagenesis was used to introduce point mutations into the alpha1 and gamma2 GABA(A) receptor subunits. Wild-type and mutant GABA(A) receptors were then expressed in Xenopus laevis oocytes or human embryonic kidney 293 (HEK 293) cells and studied using two-electrode voltage-clamp and ligand-binding techniques. With this approach, we identified two tyrosine residues on the alpha1 subunit (Tyr159 and Tyr209) that when mutated to serine, dramatically impaired modulation by dzp. The Y209S substitution resulted in a >7-fold increase in the EC50 for dzp, and the Y159S substitution nearly abolished dzp-mediated potentiation. Both of these mutations abolished binding of the high affinity BZ receptor antagonist [3H]Ro 15-1788 to GABA(A) receptors expressed in HEK 293 cells. These tyrosine residues correspond to two tyrosines of the beta2 subunit (Tyr157 and Tyr205) previously postulated to form part of the GABA-binding site. Mutation of the corresponding tyrosine residues on the gamma2 subunit produced only a slight increase in the EC50 for dzp (approximately 2-fold) with no significant effect on the binding affinity of [3H]Ro 15-1788. These data suggest that Tyr159 and Tyr209 of the alpha1 subunit may be components of the BZ-binding site on alpha1 beta2 gamma2 GABA(A) receptors.


Registration of acute stroke: validity in the Danish Stroke Registry and the Danish National Registry of Patients.
The validity of the registration of patients in stroke-specific registries has seldom been investigated, nor compared with administrative hospital discharge registries. The objective of this study was to examine the validity of the registration of patients in a stroke-specific registry (The Danish Stroke Registry [DSR]) and a hospital discharge registry (The Danish National Patient Registry [DNRP]). Assuming that all patients with stroke were registered in either the DSR, DNRP or both, we first identified a sample of 75 patients registered with stroke in 2009; 25 patients in the DSR, 25 patients in the DNRP, and 25 patients registered in both data sources. Using the medical record as a gold standard, we then estimated the sensitivity and positive predictive value of a stroke diagnosis in the DSR and the DNRP. Secondly, we reviewed 160 medical records for all potential stroke patients discharged from four major neurologic wards within a 7-day period in 2010, and estimated the sensitivity, specificity, positive predictive value, and negative predictive value of the DSR and the DNRP. Using the first approach, we found a sensitivity of 97% (worst/best case scenario 92%-99%) in the DSR and 79% (worst/best case scenario 73%-84%) in the DNRP. The positive predictive value was 90% (worst/best case scenario 72%-98%) in the DSR and 79% (worst/best case scenario 62%-88%) in the DNRP. Using the second approach, we found a sensitivity of 91% (95% confidence interval [CI] 81%-96%) and 58% (95% CI 46%-69%) in the DSR and DNRP, respectively. The negative predictive value was 91% (95% CI 83%-96%) in the DSR and 72% (95% CI 62%-80%) in the DNRP. The specificity and positive predictive value did not differ among the registries. Our data suggest a higher sensitivity in the DSR than the DNRP for acute stroke diagnoses, whereas the positive predictive value was comparable in the two data sources.


Identification of a vitamin D response element in the proximal promoter of the chicken carbonic anhydrase II gene.
The carbonic anhydrase II gene, whose transcription is enhanced by 1, 25-dihydroxyvitamin D3 (1,25-(OH)2D3), encodes an important enzyme in bone-resorbing cells derived from the fusion of monocytic progenitors. We analyzed the 1,25-(OH)2D3-mediated activation of the avian gene by transient transfection assays with promoter/reporter constructs into HD11 chicken macrophages and by DNA mobility shift assays. Deletion and mobility shift analyses indicated that the -62/-29 region confers 1,25-(OH)2D3 responsiveness and forms DNA-protein complexes. The addition of an anti-vitamin D receptor (VDR) antibody inhibited binding to this sequence, whereas anti-retinoid X receptor (RXR) antibody generated a lower mobility complex. Therefore, we concluded that this element binds a VDR.RXR heterodimer, but the addition of extra 1,25-(OH)2D3 had no effect on the formation of this complex. Moreover, the use of nuclear extracts from 1,25-(OH)2D3-treated macrophages led to the formation of an additional high mobility complex also composed of VDR.RXR heterodimer. Mutations provided evidence that the 1, 25-(OH)2D3-mediated activation of the carbonic anhydrase II gene is mediated by VDR.RXR heterodimers bound to a DR3-type vitamin D response element with sequence AGGGCAtggAGTTCG. This vitamin D response element is also functional in the ROS 17/2.8 osteoblasts.


Remembering your parents: reflections on the retrospective method.
In the present paper, I critique the use of the retrospective method when it is used as a proxy for actual longitudinal data on personality development. Studies on the constructive nature of memory cast strong doubts about the meaning of retrospective data. There are good reasons, both theoretical and empirical, to distrust the accuracy of such recall concerning parenting, whether recalled by parents, children, or siblings. Instead of using the method as a shortcut to developmental data, studies examining individual differences in accuracy and distortion and the factors that moderate them may inform us of the various meanings of retrospective data.


Separated and reunified: An apparent time investigation of the voice quality differences between Hong Kong Cantonese and Guangzhou Cantonese.
Hong Kong Cantonese (HKC) and Guangzhou Cantonese (GZC) are two major accents of Cantonese spoken in two geographically non-contiguous cities in Southern China. Previous studies were unable to identify the phonetic features that discern the two accents since they share the same phonological system. This study attempted to solve the puzzle by investigating the voice quality differences between the two accents through acoustic analysis on the speech output of 191 talkers in three age groups ranging from 18 to 65 years old. Among the various spectral and noise measurements of voice quality, we found that Cepstral Peak Prominence (CPP) was the best acoustic measure to discern the two accents. Based on the CPP measure, GZC had overall increased noise than HKC. Covariation of voice quality and tones was studied. The greatest CPP differences between the two accents were found in the two extreme tones: the high-level and the extra-low-level tones. Furthermore, creaky voice was found mainly tied to the extra-low-level tone in both accents. However, HKC exhibited higher frequency of creaky voice than GZC. The creaky voice in GZC was characterized by increased noise and increased tension, compared to those of HKC. Finally, age was found to be a mediating factor in the voice quality of the two accents. Adopting the Apparent Time Framework, voice quality in the two cities has undergone changes over time. The voice quality of the young generations of the two accents have become merged among the three low tones. Furthermore, the prevalence of creaky voice was increasing across age groups in both accents, and it increased at a faster rate in HKC than GZC.


Cytogenetical effects of sonication in mice and their modulations by actinomycin D and a homeopathic drug, Arnica 30.
Experiments were designed to examine if Actinomycin D, an antibiotic, and Amica 30, a homeopathic drug used against shock and injury, can ameliorate cytogenetic damage induced by single or multiple exposures to ultrasonication. Separate sets of healthy mice were directly exposed to sonication for two minutes either once or they received multiple exposures at an interval of 20 days. The mice were then assessed at different intervals, against suitable controls, using parameters like chromosome aberrations (CA), mitotic index (MI), sperm head anomaly (SHA) and micronucleated erythrocytes (MNE). Separate groups of sonicated mice were either orally administered with Arnica 30 (alcohol 30 in control) or injected intramuscularly with Actinomycin-D (AMD). Elevated frequencies of CA, MI, MNE and SHA were noted in sonicated series. AMD had genotoxic effects of its own and also had additive effects on sonication induced genotoxicity. Sonicated mice fed with Arnica 30 showed appreciably reduced genotoxicity as against alcohol 30 and distilled water fed controls, thereby showing ameliorating effect which may have human application.


Quality of steak restructured from beef trimmings containing microbial transglutaminase and impacted by freezing and grading by fat level.
The objective of this research was to evaluate the physico-chemical, microbiological and sensorial qualities of restructured steaks processed from beef trimmings (grade I and II) and frozen beef (fresh beef as control and frozen beef). Beef trimmings from commercial butcher were collected, designated into 4 treatments differing in beef trimmings grade and freezing, processed into restructured steaks with 1% microbial transglutaminase and then analyzed for product quality. The results showed that all meat from different groups could be tightly bound together via cross-linking of myosin heavy chain and actin as observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Microbial counts of psychrotrophic and mesophilic bacteria were not affected by treatments (p>0.05), and no detectable of thermophilic bacteria were found. Regarding effect of beef trimmings grade, steaks made from beef trimmings grade II (16.03% fat) showed some superior sensorial qualities including higher tenderness score (p<0.05) and tendency for higher scores of juiciness and overall acceptability (p<0.07) than those made from beef trimmings grade I (2.15% fat). Moreover, a hardness value from texture profile analysis was lower in steaks processed from beef trimmings grade II than those made from grade I (p< 0.05). Although some inferior qualities in terms of cooking loss and discoloration after cooking were higher in steaks made from beef trimmings grade II than those made from beef trimmings grade I (p<0.05), these differences did not affect the sensory evaluation. Frozen beef improved the soft texture and resulted in effective meat binding as considered by higher cohesiveness and springiness of the raw restructured product as compared to fresh beef (p<0.05). The results indicated the most suitable raw beef for producing restructured steaks without detrimental effect on product quality was beef trimmings grade II containing up to 17% fat which positively affected the sensory quality and that frozen beef trimmings increased tenderness and meat binding of restructured beef steaks.


Medical Therapy for Secondary Prevention of Atherothrombotic Events in Peripheral Artery Disease.
Patients with peripheral artery disease (PAD) are at risk for severe morbidity and mortality, including ischaemic-related events. Furthermore, there is heterogeneity within the PAD population, where the drivers of risk for cardiovascular and limb-specific ischaemic events differ. Patients with PAD with concomitant coronary artery disease are at increased risk for cardiovascular ischaemic events, whereas patients with PAD with a prior history of lower-extremity revascularization are at increased risk for limb-specific ischaemic events. The current therapeutic challenge is identifying these risk factors to tailor therapy optimally for each patient. Additionally, the majority of our current medical therapeutics in patients with PAD have been shown to reduce atherothrombotic events, such as myocardial infarction, stroke and cardiovascular death, with a paucity of medical therapeutics specifically targeting a reduction in limb-specific ischaemic events. Over the past several years, there have been several contemporary clinical trials evaluating antithrombotic agents and their efficacy in reducing limb-specific ischaemic events. Specifically, rivaroxaban, with the addition of aspirin, has emerged as an efficacious therapeutic. In this article, we provide a review of the current clinical burden of PAD, the rationale behind current PAD medical therapeutics and the contemporary trials that have described the benefit of a novel therapeutic in PAD, rivaroxaban.


Convergence of a Reconstructed Density Matrix to a Pure State Using the Maximal Entropy Approach.
Impressive progress has been made in the past decade in the study of technological applications of varied types of quantum systems. With industry giants like IBM laying down their roadmap for scalable quantum devices with more than 1000-qubits by the end of 2023, efficient validation techniques are also being developed for testing quantum processing on these devices. The characterization of a quantum state is done by experimental measurements through the process called quantum state tomography (QST) which scales exponentially with the size of the system. However, QST performed using incomplete measurements is aptly suited for characterizing these quantum technologies especially with the current nature of noisy intermediate-scale quantum (NISQ) devices where not all mean measurements are available with high fidelity. We, hereby, propose an alternative approach to QST for the complete reconstruction of the density matrix of a quantum system in a pure state for any number of qubits by applying the maximal entropy formalism on the pairwise combinations of the known mean measurements. This approach provides the best estimate of the target state when we know the complete set of observables, which is the case of convergence of the reconstructed density matrix to a pure state. Our goal is to provide a practical inference of a quantum system in a pure state that can find its applications in the field of quantum error mitigation on a real quantum computer that we intend to investigate further.


Cortisol response in acute foetal distress.
Thirty neonates born after having acute intrapartum distress (study group) and 30 neonates matched for gestation, born without any clinical evidence of acute foetal distress (control group) were studied. Neonates with congenital malformation were excluded. Samples for cortisol estimation were taken from cord artery, cord vein at birth and from peripheral vein at 6 h of age. At birth maternal venous blood was also taken for cortisol estimation. Cortisol level was estimated by radioimmunoassay. Cord blood pH was measured immediately at birth in all neonates whereas base deficits were estimated in 20 neonates in the study group and 23 neonates in control group. Cortisol levels did not differ significantly in the groups with or without foetal distress. There was no significant correlation between cord blood pH and cord arterial cortisol levels. Significant positive correlation was found between cord arterial cortisol and maternal cortisol levels. We failed to find any significant cortisol response in acute foetal distress.


Different distribution of ELI-perikarya in rat mesencephalon using various injection sites for colchicine.
In the present work, using the indirect peroxidase-labelled antibody technique, we made a comparative study about the distribution of Met-enkephalin-like-immunoreactive (ELI)-cell bodies in rat mesencephalon; comparing animals that received colchicine into the lateral ventricle and animals that got the colchicine injected into different cerebral nuclei. We discuss the possibility that the local intracerebral injections are more effective than the intraventricular ones and we show that the results depend on the injection place. So, we think that there are possible met-enkephalinergic connections between the injected region and their corresponding immunoreactive mesencephalic nuclei.


[Effect on cryoablation of high-risk and locally recurrent prostate cancer: a Meta-analysis].
Objective: To discuss the curative effect and prognosis of cryoablation to high-risk and locally recurrent prostate cancer patients. Methods: Cryoablation related publications and relevant references were searched for potential pertinent articles until March, 2016.Articles were selected according to the exclusion criteria, Stata ver.11 was used to perform the statistical analysis. Results: 5-year biochemical disease-free survival of salvage ablation for prostate cancer was 45%(95% CI 0.43-0.47), in salvage radiotherapy of 45% (95% CI 0.44-0.47). The 5-year biochemical disease-free survival of high-risk prostate cancer cryoablation was 66%(95% CI 0.64-0.67). The result of high-risk prostate cancer radiotherapy and EBRT were respectively 61%(95% CI 0.60-0.63) and 54% (95% CI 0.52-0.56). Conclusions: The five-year biochemical recurrence of salvage cryoablation is similar to salvage radiotherapy. For high-risk prostate cancer, cryoablation shows an advantage than traditional EBRT radiation.


Multiple Sclerosis CSF Is Enriched With Follicular T Cells Displaying a Th1/Eomes Signature.
Tertiary lymphoid structures and aggregates are reported in the meninges of patients with multiple sclerosis (MS), especially at the progressive stage, and are strongly associated with cortical lesions and disability. Besides B cells, these structures comprise follicular helper T (Tfh) cells that are crucial to support B-cell differentiation. Tfh cells play a pivotal role in amplifying autoreactive B cells and promoting autoantibody production in several autoimmune diseases, but very few are known in MS. In this study, we examined the phenotype, frequency, and transcriptome of circulating cTfh cells in the blood and CSF of patients with relapsing-remitting MS (RRMS). The phenotype and frequency of cTfh cells were analyzed in the blood of 39 healthy controls and 41 untreated patients with RRMS and in the CSF and paired blood of 10 patients with drug-naive RRMS at diagnosis by flow cytometry. Using an in vitro model of blood-brain barrier, we assessed the transendothelial migratory abilities of the different cTfh-cell subsets. Finally, we performed an RNA sequencing analysis of paired CSF cTfh cells and blood cTfh cells in 8 patients sampled at their first demyelinating event. The blood phenotype and frequency of cTfh cells were not significantly modified in patients with RRMS. In the CSF, we found an important infiltration of Tfh1 cells, with a high proportion of activated PD1+ cells. We demonstrated that the specific subset of Tfh1 cells presents increased migration abilities to cross an in vitro model of blood-brain barrier. Of interest, even at the first demyelinating event, cTfh cells in the CSF display specific characteristics with upregulation of EOMES gene and proinflammatory/cytotoxic transcriptomic signature able to efficiently distinguish cTfh cells from the CSF and blood. Finally, interactome analysis revealed potential strong cross talk between pathogenic B cells and CSF cTfh cells, pointing out the CSF as opportune supportive compartment and highlighting the very early implication of B-cell helper T cells in MS pathogenesis. Overall, CSF enrichment in activated Tfh1 as soon as disease diagnosis, associated with high expression of EOMES, and a predicted high propensity to interact with CSF B cells suggest that these cells probably contribute to disease onset and/or activity.


Antibody-Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review.
Attaching a cytotoxic "payload" to an antibody to form an antibody-drug conjugate (ADC) provides a mechanism for selective delivery of the cytotoxic agent to cancer cells via the specific binding of the antibody to cancer-selective cell surface molecules. The first ADC to receive marketing authorization was gemtuzumab ozogamicin, which comprises an anti-CD33 antibody conjugated to a highly potent DNA-targeting antibiotic, calicheamicin, approved in 2000 for treating acute myeloid leukemia. It was withdrawn from the US market in 2010 following an unsuccessful confirmatory trial. The development of two classes of highly potent microtubule-disrupting agents, maytansinoids and auristatins, as payloads for ADCs resulted in approval of brentuximab vedotin in 2011 for treating Hodgkin lymphoma and anaplastic large cell lymphoma, and approval of ado-trastuzumab emtansine in 2013 for treating HER2-positive breast cancer. Their success stimulated much research into the ADC approach, with >60 ADCs currently in clinical evaluation, mostly targeting solid tumors. Five ADCs have advanced into pivotal clinical trials for treating various solid tumors-platinum-resistant ovarian cancer, mesothelioma, triple-negative breast cancer, glioblastoma, and small cell lung cancer. The level of target expression is a key parameter in predicting the likelihood of patient benefit for all these ADCs, as well as for the approved compound, ado-trastuzumab emtansine. The development of a patient selection strategy linked to target expression on the tumor is thus critically important for identifying the population appropriate for receiving treatment.


Rapid implementation of mobile technology for real-time epidemiology of COVID-19.
The rapid pace of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) presents challenges to the robust collection of population-scale data to address this global health crisis. We established the COronavirus Pandemic Epidemiology (COPE) Consortium to unite scientists with expertise in big data research and epidemiology to develop the COVID Symptom Study, previously known as the COVID Symptom Tracker, mobile application. This application-which offers data on risk factors, predictive symptoms, clinical outcomes, and geographical hotspots-was launched in the United Kingdom on 24 March 2020 and the United States on 29 March 2020 and has garnered more than 2.8 million users as of 2 May 2020. Our initiative offers a proof of concept for the repurposing of existing approaches to enable rapidly scalable epidemiologic data collection and analysis, which is critical for a data-driven response to this public health challenge.


Draft Genome Sequence of Psychrotrophic Acinetobacter sp. Strain MN12 (MTCC 10786), Which Produces a Low-Temperature-Active and Alkaline-Stable Peptidase.
We report here the draft genome sequence of Acinetobacter sp. strain MN12 (MTCC 10786), which is a psychrotrophic bacterium that produces an extracellular low-temperature-active and alkaline-stable peptidase. The draft genome assembly of Acinetobacter sp. MN12 has a size of 4.31 Mbp, with a G+C content of 40.75%.


Two Alkaloids From Delphinium brunonianum Royle, Their Anti-inflammatory and Anti-oxidative Stress Activity via NF-κB Signaling Pathway.
In this study, we isolated and identified four compounds in Delphinium brunonianum Royle, and they were Delbrunine (1), 4-O-α-D-Glucosyl benzoic acid (2), Kaempferol 3-O-β-D-glucopyranoside 7-O-α-L-rhamnopyranoside (3) and Eldeline (4). Furthermore, the anti-inflammatory activity of these compounds was screened in RAW264.7 cells. The results showed that the anti-inflammatory activities of compounds 2 and 3 were weak, and 1, 4 had good anti-inflammatory activity. The macrophage inflammation model was established by lipopolysaccharide (LPS). Then, the anti-inflammatory activity was evaluated by ELISA kits, qRT-PCR experiment and western blot experiment. And the anti-oxidative stress activity was assessed by flow cytometry. The results showed that compounds 1, 4 could significantly inhibit the elevation of inflammatory factors nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and also had obvious inhibitory effects on the production of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2). In addition, compounds 1 and 4 could effectively inhibit the overexpression of reactive oxygen species (ROS) in RAW264.7 cells that activated by LPS. These results indicated that compounds 1 and 4 may exert anti-inflammatory and anti-oxidative stress effects through the NF-κB signaling pathway.


Effects of CO2 adsorption on proton migration on a hydrated ZrO2 surface: an ab initio molecular dynamics study.
Hydration reactions on a carbonate-terminated cubic ZrO2(110) surface were analyzed using ab initio molecular dynamics (AIMD) simulations. After hydration reactions, carbonates were still present on the surface at 500 K. However, these carbonates are very weak conjugate bases and only act as steric hindrance in proton hopping processes between acidic chemisorbed H2O molecules (Zr-OH2) and monodentate hydroxyl groups (Zr-OH-). Similar to a carbonate-free hydrated surface, Zr-OH2, Zr-OH-, and polydentate hydroxyl groups ([double bond splayed left]OH+) were observed, while the ratio of acidic Zr-OH2 was significantly larger than that on the carbonate-free hydrated surface. A thermodynamic discussion and bond property analysis reveal that CO2 adsorption significantly decreases the basicity of surface oxide ions ([double bond splayed left]O), whereas the acidity of Zr-OH2 is not affected. As a result, protons released from [double bond splayed left]OH+ react with Zr-OH- to form Zr-OH2, leading to a deficiency of proton acceptor sites, which decreases the proton conductivity by the hopping mechanism.


Predicting PDZ domain mediated protein interactions from structure.
PDZ domains are structural protein domains that recognize simple linear amino acid motifs, often at protein C-termini, and mediate protein-protein interactions (PPIs) in important biological processes, such as ion channel regulation, cell polarity and neural development. PDZ domain-peptide interaction predictors have been developed based on domain and peptide sequence information. Since domain structure is known to influence binding specificity, we hypothesized that structural information could be used to predict new interactions compared to sequence-based predictors. We developed a novel computational predictor of PDZ domain and C-terminal peptide interactions using a support vector machine trained with PDZ domain structure and peptide sequence information. Performance was estimated using extensive cross validation testing. We used the structure-based predictor to scan the human proteome for ligands of 218 PDZ domains and show that the predictions correspond to known PDZ domain-peptide interactions and PPIs in curated databases. The structure-based predictor is complementary to the sequence-based predictor, finding unique known and novel PPIs, and is less dependent on training-testing domain sequence similarity. We used a functional enrichment analysis of our hits to create a predicted map of PDZ domain biology. This map highlights PDZ domain involvement in diverse biological processes, some only found by the structure-based predictor. Based on this analysis, we predict novel PDZ domain involvement in xenobiotic metabolism and suggest new interactions for other processes including wound healing and Wnt signalling. We built a structure-based predictor of PDZ domain-peptide interactions, which can be used to scan C-terminal proteomes for PDZ interactions. We also show that the structure-based predictor finds many known PDZ mediated PPIs in human that were not found by our previous sequence-based predictor and is less dependent on training-testing domain sequence similarity. Using both predictors, we defined a functional map of human PDZ domain biology and predict novel PDZ domain function. Users may access our structure-based and previous sequence-based predictors at http://webservice.baderlab.org/domains/POW.


Electroretinography and Pupillography in Unilateral Foveal Hypoplasia.
The authors describe a 3-year-old boy with unilateral foveal hypoplasia and an absence of other ocular or systemic findings. Electroretinography obtained predominantly affecting cones. Laterality of pupil constriction to red but not to blue light was observed. The colored-light pupil response can be used to predict the retinal state.


Recent advances in systemic lupus erythematosus genetics in an Asian population.
Recent advances in systemic lupus erythematosus (SLE) genetics in Asian populations have been achieved by genome-wide association studies (GWASs) and following replication studies, which expanded the genetic information about shared or population-specific risk genes between ethnic groups. Meta-analyses and multi-ethnic replication studies may be possible approaches that could demonstrate stronger or more suggestive evidence for multiple variants for SLE. In addition to the susceptibility of SLE itself, several genotype-phenotype analyses have shown that the specific phenotypes of SLE can also be influenced by genetic factors. Almost all SLE genetic loci are involved in the potential pathways of SLE pathogenesis, such as Toll-like receptor/type I interferon signaling, nuclear factor κB signaling, immune complex clearing mechanism, immune cell (B, T cell, neutrophil and monocyte) function and signaling, cell-cycle regulation, DNA methylation and autophagy. Further studies, including the next generation sequencing technology and the systematic strategy using bioinformatics, in addition to international collaboration among SLE genetic researchers, will give us better understanding of the genetic basis of SLE.


Global transcript profiling of potato tuber using LongSAGE.
Solanum tuberosum (potato) is the fourth major crop worldwide and is used for food, feed and biotechnological applications. To fully realize the biosynthetic potential for the production of starch, protein and metabolites, we conducted an extensive quantitative profiling of the expressed genes of mature potato tuber. A total of 58,322 serial analysis of gene expression (SAGE) tags of 19 nucleotides (nt), representing 22,233 different tags, were analysed. The 695 tags seen 10 or more times were assigned a tentative function by comparison with homologous genes. The identities of 12 'known' and 12 'unknown' transcripts were confirmed by rapid amplification of cDNA ends (RACE) cloning using the 19 nt tag as a primer. The SAGE and expressed sequence tag (EST) profiles of potato tuber were compared. Transcripts for four types of protease inhibitor, a metallothionein and a lipoxygenase were more prominent than patatin isoforms.


Increased Risk of CHD in the Presence of rs7865618 (A allele): Tehran Lipid and Glucose Study.
Recent genome-wide association studies (GWAS) in European populations have indicated that the rs12526453 polymorphism located in phosphatase and actin regulator 1 gene (PHACTR1), mapping to chromosome 6p24 and rs7865618 polymorphism in the cyclin-dependent kinase inhibitor B antisense RNA 1 gene (CDKN2B-AS1) on 9p21.3 are associated with coronary heart disease (CHD). This study was carried out to investigate the association of these polymorphisms and CHD in an Iranian population. In the present case-control study, 420 patients with CHD events were recruited from the population of the Tehran lipid and glucose study (TLGS); 407 healthy controls matched for age and sex were selected from the same population. The SNPs rs12526453 and rs7865618 were genotyped using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). The allele frequency of both SNPs deviated from Hardy-Weinberg equilibrium. The C allele frequency of the rs12526453 (68.5%, P = 0.11) and A allele of the rs7865618 (68.8%, P = 0.09) were the most prevalent alleles in both the case and control groups. The results indicated a significant association between the presence of risk alleles of rs7865618 and CHD in the TLGS population (P = 0.03; OR: 1.73; CI95%: 1.04 - 2.88). Due to the importance of chromosome 9p21 region and its relation with cardiovascular disease, the allelic pattern of its variation should be studied in different populations. The relation between this polymorphism and cardiovascular disease in the studied population confirms the importance of this region.


No increase in HIV incidence observed in a cohort of men who have sex with other men in Montreal.
To monitor HIV incidence we tested a cohort of men who have sex with men in Montreal for HIV every 6 months. Between 1996 and 2001, 17 out of 1244 participants seroconverted, for an HIV incidence of 0.56 per 100 person-years (py) (95% CL 0.29, 0.83). The incidence decreased over the study period, from 0.75 to 0.34 per 100 py; which was not statistically significant. An in-depth evaluation of the situation in Montreal could identify useful lessons for prevention efforts elsewhere.


Polypeptide-mediated switchable microarray of bacteria.
This paper describes a feasible solution for the bacterial cell death and contamination from cell division that occurs in microfluidic applications. The method adopts a smart thermoresponsive surface, highly resolved micropatterns, and surface-functionalized bacteria tagged with thermoresponsive molecules. We developed a method for controllable bacterial attachment and detachment using an elastin-like polypeptide (ELP). To create a smart surface with switchable properties, the surface of a glass substrate was conjugated with thermoresponsive ELP molecules. The attachment of bacterial cells to the ELP surface was induced by the hydrophobic affinity of the ELPs on the glass surface to tagged ELPs on the bacterial surface. A cell-repellent polymer was micropatterned to create a highly resolved space for specific bacterial adhesion. Reversible bacterial attachment and detachment was achieved by controlling the thermoresponsive phase transition of ELP molecules. Five different types of bacteria were successfully conjugated with ELPs and arrayed on the surface. The viability of the bacteria that had attached to the surface was evaluated by determining colony forming units of released bacteria on an agar plate.


Diffusion and ballistic transport in one-dimensional quantum systems.
It has been conjectured that transport in integrable one-dimensional systems is necessarily ballistic. The large diffusive response seen experimentally in nearly ideal realizations of the S=1/2 1D Heisenberg model is therefore puzzling and has not been explained so far. Here, we show that, contrary to common belief, diffusion is universally present in interacting 1D systems subject to a periodic lattice potential. We present a parameter-free formula for the spin-lattice relaxation rate which is in excellent agreement with experiment. Furthermore, we calculate the current decay directly in the thermodynamic limit using a time-dependent density matrix renormalization group algorithm and show that an anomalously large time scale exists even at high temperatures.


Acidosis induced by lactate, pyruvate, or HCl increases blood viscosity.
Serum lactate correlates with the severity of disease and the mortality in shock. It is not clear if lactate is only a marker or a mediator of disease. We tested the hypothesis that acidosis induced by lactate and pyruvate affects blood flow properties. Human blood was incubated with additional lactate (0-50 mmol/L) or pyruvate (0-25 mmol/L) for 1 hour at 37 degrees C. Blood viscosity was measured at high (94.5 s(-1)) and low (0.1 s(-1)) shear rate. Hematocrit was measured with an electronic particle counter as well as centrifugation. A total of 50 mmol/L additional lactate produced acidosis (pH 6.4) and increased whole-blood viscosity at high shear rate (94.5 s(-1): 6.53 +/- 0.51 mPa.s vs 4.94 +/- 0.18 mPa.s for control, n = 5, P <.001) and low shear rate (0.1 s(-1): 93.9 +/- 18.6 mPa.s vs 53.5 +/- 7.7 mPa.s, n = 5, P <.001). Simultaneously, an increased centrifuged hematocrit was observed (about 7% with 50 mmol/L lactate, P <.001), indicating eryth-rocyte swelling. These changes were reversible on removal of lactate. The addition of 25 mmol/L pyruvate also induced acidosis and increased blood viscosity and centrifuged hematocrit. When HCl was used to induce a comparable pH level decrease, a similar increase in blood viscosity and hematocrit were observed. Pronounced acidosis induced by either lactate, pyruvate, or HCl impairs blood flow properties, which may contribute to the understanding of the pathophysiology of critical illness.