First Report of Alternaria alternata Causing Leaf Spots of Tea (Camellia sinensis) in China.
Tea is the most popular non-alcoholic beverage crop in the world, which originated in China and has been cultivated in over 45 countries. In recent years, a leaf spot disease of unknown etiology has been observed on young leaves of tea trees (Camellia sinensis) grown in Luotian county, Hubei Province, China. Observed symptoms display grayish brown to white spots (about 1 cm in diameter) surrounded by brown edges. Over 20% of the young leaves were affected on surveyed trees. To identify the pathogen, six symptomatic tea leaves were collected from six individual tea trees of unknown variety in August 2012. A thin section (3 to 5 mm) of symptomatic tissue was sterilized in a bleach solution of 3% hypochlorite and placed on potato dextrose agar (PDA) medium at 25°C in darkness for isolation. Six fungal colonies displaying gray-brown and gray-white aerial mycelia were consistently recovered from lesions of the six leaves, termed as T1 to T6, respectively. Conidia produced on the colonies were olive brown, obpyriform, short conical beak at the tip, 0 to 3 vertical and 1 to 6 transverse septa, and length × width of 7.1 to 31.7 (avg. 20.1) × 2.9 to 12.7 (avg. 7.2) μm. T1 to T6 were identified as Alternaria alternata on the basis of morphological characterization, respectively (2). Confirmation of the species identification was obtained by molecular characterization of their internal transcribed spacer (ITS) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) regions amplified from the genomic DNAs using the universal primers (1). The results revealed identical sequences of ITS (GenBank Accession No. KF699530) and GAPDH among the six isolates. BLAST searches showed that they had the highest similarity with A. alternata strains, with 98.3% for ITS (AJ276055) and 96.2% for GAPDH (EF513205), deposited in fungus database ( http://www.mycobank.org/ ). Pathogenicity tests were conducted on the detached leaves expanding for 10 to 20 days of two tea varieties (cvs. Fudingdabai and Taicha No. 12) in triplicate by placing 4 mm diameter discs from 5-day-old PDA plates of T3 and T6, which were incubated in an incubator at 25°C with a 12-h photoperiod for 7 days. All inoculated leaves with or without wound treatment developed brown spots similar to the original ones at 7 days post inoculation (dpi) while the control leaves inoculated with non-colonized PDA plugs remained asymptomatic. Isolates recovered from diseased samples were of the same morphology and ITS sequence as the inoculated ones. Alternaria alternata had been described on C. sinensis in China (3), but it was only reported as a severe foliar fungal pathogen of tea in North Bengal, India (1), and to our knowledge, this is the first report of A. alternata causing leaf spots on tea leaves (C. sinensis) in China. In addition to quantity loss, the species may result in a decrease of quality of tea crop considering that it can produce Alternaria toxins related to animal and public health. The etiologic identification of the disease is expected to provide useful information for its control. References: (1) B. N. Chakraborty et al. Plant Pathol. 55:303, 2006. (2) E. G. Simmons. Page 1 in: Alternaria Biology, Plant Diseases and Metabolites. J. Chelchowski and A. Visconti, eds. Elsevier, Amsterdam, 1992. (3) F. L. Tai. Page 1527 in: Sylloge Fungorum Sinicorum. eds. Sci. Press Acad. Sin. Beijing, 1979. (4) B. S. Weir et al. Stud. Mycol. 73:115, 2012.


Dry fermented sausages of Southern Italy: a comparison of free amino acids and biogenic amines between industrial and homemade products.
This paper compares some important parameters and the free amino acid and biogenic amine contents of cured industrial and homemade meat products. To this aim, industrial and homemade "soppressata" and "salsiccia", typical dry fermented sausages produced in Southern Italy, were analyzed. The homemade sausages showed a higher level of free biogenic amines than that manufactured industrially, most likely because biogenic amine formation in industrial products is limited by the use of starter cultures. The industrial sausages are characterized by a higher total free amino acid content than the homemade products. Overall, free amino acid and biogenic amine contents demonstrated that appreciable differences exist between homemade and industrial sausages.


Parental exposure to elevated pCO2 influences the reproductive success of copepods.
Substantial variations are reported for egg production and hatching rates of copepods exposed to elevated carbon dioxide concentrations (pCO2). One possible explanation, as found in other marine taxa, is that prior parental exposure to elevated pCO2 (and/or decreased pH) affects reproductive performance. Previous studies have adopted two distinct approaches, either (1) expose male and female copepoda to the test pCO2/pH scenarios, or (2) solely expose egg-laying females to the tests. Although the former approach is more realistic, the majority of studies have used the latter approach. Here, we investigated the variation in egg production and hatching success of Acartia tonsa between these two experimental designs, across five different pCO2 concentrations (385-6000 µatm pCO2). In addition, to determine the effect of pCO2 on the hatching success with no prior parental exposure, eggs produced and fertilized under ambient conditions were also exposed to these pCO2 scenarios. Significant variations were found between experimental designs, with approach (1) resulting in higher impacts; here >20% difference was seen in hatching success between experiments at 1000 µatm pCO2 scenarios (2100 year scenario), and >85% at 6000 µatm pCO2. This study highlights the potential to misrepresent the reproductive response of a species to elevated pCO2 dependent on parental exposure.


ON THE RELATION BETWEEN MEASUREMENTS OF INTENSITY DISCRIMINATION AND OF VISUAL ACUITY IN THE HONEY BEE.
1. Bees respond by a characteristic reflex to a movement of their visual field. By confining the field to a series of parallel stripes of two alternating different brightnesses it is possible to determine for any width of stripe, at any brightness of one of the two sets of stripes, the brightness of the second at which the bee will first respond to a displacement of the field. Thus the relations between visual acuity and intensity discrimination can be studied. 2. For each width of stripe and visual angle subtended by the stripe the discrimination power of the bee's eye for different brightnesses was studied. For each visual acuity the intensity discrimination varies with illumination in a characteristic, consistent manner. The discrimination is poor at low illuminations; as the intensity of illumination increases the discrimination increases, and reaches a constant level at high illuminations. 3. From the intensity discrimination curves obtained at different visual acuities, visual acuity curves can be reconstructed for different values of DeltaI/I. The curves thus obtained are identical in form with the curve found previously by direct test for the relation between visual acuity and illumination.


Systemic testing on Bradley-Terry model against nonlinear ranking hierarchy.
We take a system point of view toward constructing any power or ranking hierarchy onto a society of human or animal players. The most common hierarchy is the linear ranking, which is habitually used in nearly all real-world problems. A stronger version of linear ranking via increasing and unvarying winning potentials, known as Bradley-Terry model, is particularly popular. Only recently non-linear ranking hierarchy is discussed and developed through recognition of dominance information contents beyond direct dyadic win-and-loss. We take this development further by rigorously arguing for the necessity of accommodating system's global pattern information contents, and then introducing a systemic testing on Bradley-Terry model. Our test statistic with an ensemble based empirical distribution favorably compares with the Deviance test equipped with a Chi-squared asymptotic approximation. Several simulated and real data sets are analyzed throughout our development.


Extracochlear Electrode Insertion in the Petrous Area in Cochlear Implantation.
Cochlear implantation is a reliable and safe tool to rehabilitate patients with severe-to-profound sensorineural hearing loss, who get limited benefits from traditional hearing aids. Electrode misplacement is a rare but significant problem that fails to provide benefits and may cause injury to the nearby structures. We present a case that underwent mastoidectomy first to remove cholesteatoma, followed by cochlear implantation with electrode misplacement into the petrous area, with sustained hearing benefits and without any injury to the surrounding structures.


In situ hybridization analysis of acquisition and loss of the human multidrug-resistance gene.
The extent of multidrug-resistance of human KB carcinoma cell lines has been shown to be proportional to the level of expression of the MDR1 gene. Using an in situ hybridization analysis with 35S-labeled RNA probes, we have found that there is some heterogeneity in expression of the MDR1 gene from cell to cell, but that the average level of expression is proportional to the resistance of the cell line. In the absence of selective pressure, a colchicine-selected multidrug-resistant population with a highly amplified MDR1 gene loses its resistance in parallel with the loss of the amplified gene. Loss of resistance also parallels a decrease in MDR1 RNA expression in the whole cell population. Loss of MDR1 expression in this population is highly heterogeneous, with small clusters of cells maintaining expression even after the population as a whole has become relatively sensitive. This heterogenous loss of expression of the MDR1 gene is consistent with random segregation of amplified DNA segments in the selected cells. The analysis of MDR1 RNA expression by in situ hybridization which is validated by this study should be useful in the study of normal human tissue and tumor samples expressing the MDR1 gene.


Spinopelvic Adaptations in Standing and Sitting Positions in Patients With Adult Spinal Deformity.
Purpose To describe spinopelvic adaptations in the standing and sitting positions in patients with adult spinal deformity (ASD). Methods Ninety-five patients with ASD and 32 controls completed health-related quality of life (HRQOL) questionnaires: short form 36 (SF36), Oswestry Disability Index (ODI), and visual analog scale (VAS) for pain. They underwent biplanar radiography in both standing and sitting positions. Patients with ASD were divided into ASD-front (frontal deformity Cobb > 20°, n = 24), ASD-sag (sagittal vertical axis (SVA) > 50 mm, pelvic tilt (PT) > 25°, or pelvic incidence (PI)-lumbar lordosis (LL) > 10°, n = 40), and ASD-hyper thoracic kyphosis (TK >60°, n = 31) groups. Flexibility was defined as the difference (Δ) in radiographic parameters between the standing and sitting positions. The radiographic parameters were compared between the groups. Correlations between HRQOL scores were evaluated. Results All participants increased their SVA from standing to sitting (ΔSVA<0), except for patients with ASD-sag, who tended to decrease their SVA (78-62 mm) and maximize their pelvic retroversion (27-40° vs 10-34° in controls, p<0.001). They also showed reduced thoracic and lumbar flexibility (ΔLL = 3.4 vs 37.1°; ΔTK = -1.7 vs 9.4° in controls, p<0.001). ASD-hyperTK showed a decreased PT while sitting (28.9 vs 34.4° in controls, p<0.001); they tended to decrease their LL and TK but could not reach values for controls (ΔLL = 22.8 vs 37.1° and ΔTK = 5.2 vs 9.4°, p<0.001). The ASD-front had normal standing and sitting postures. ΔSVA and ΔLL were negatively correlated with the physical component scale (PCS of SF36) and ODI (r = -0.39 and r = -0.46, respectively). Conclusion Patients with ASD present with different spinopelvic postures and adaptations from standing to sitting positions, with those having sagittal malalignment most affected. In addition, changes in standing and sitting postures were related to HRQOL outcomes. Therefore, surgeons should consider patient sitting adaptations in surgical planning and spinal fusion. Future studies on ASD should evaluate whether physical therapy or spinal surgery can improve sitting posture and QOL, especially for those with high SVA or PT.


HSV-1 amplicon-mediated post-transcriptional inhibition of Rad51 sensitizes human glioma cells to ionizing radiation.
Standard treatment for glioblastoma multiforme and other brain tumors consists of surgical resection followed by combined radio-/chemotherapy. However, radiation resistance of tumor cells limits the success of this treatment, and the tumors invariably recur. Therefore, the selective inhibition of molecular mediators of radiation resistance may provide therapeutic benefit to the patient. One of these targets is the Rad51 protein, which is a key component of the homologous recombinational repair of DNA double-strand breaks. Here, we investigated whether post-transcriptional silencing of Rad51 by herpes simplex virus-type 1 (HSV-1) amplicon vector-mediated short interfering RNA expression can enhance the antitumor effect of radiation therapy. We demonstrate that these vectors specifically and efficiently inhibited the radiation-induced recruitment of Rad51 into nuclear foci in human glioma cells. The combination of vector-mediated silencing of Rad51 expression and treatment with ionizing radiation resulted in a pronounced reduction of the survival of human glioma cells in culture. In athymyc mice, a single intratumoral injection of Rad51-specific HSV-1 amplicon vector followed by a single radiation treatment resulted in a significant decrease in tumor size. In control animals, including mice that received an intratumoral injection of Rad51-specific amplicon vector but no radiation treatment, the tumor sizes increased.


Safety of intravenous dipyridamole for stress testing with thallium imaging.
Cardiac and noncardiac side effects were studied in 293 consecutive patients referred for nonexercise stress thallium imaging with intravenous dipyridamole. Six minutes after the initiation of infusion, there was a mean 9-beat/min increase in heart rate and a mean 12-mm Hg decrease in systolic blood pressure. The largest increase in heart rate exceeded 20 beats/min in only 13% of patients and the largest decrease in systolic blood pressure exceeded 20 mm Hg in 31%. Noncardiac side effects were headache (11%), lightheadedness or dizziness (5%) and nausea (4%). Only 9 patients required intravenous aminophylline for relief of noncardiac side effects: severe headache in 7 and nausea in 2. Cardiac side effects included chest pain in 76 patients (26%), of whom 70% were given aminophylline for relief of symptoms. Sixty patients (20%) had ischemic ST-segment depression and 56 (19%) had arrhythmias (ventricular in 50 and atrial in 6). There were no deaths, myocardial infarctions or sustained arrhythmias due to dipyridamole administration. Among 62 patients also undergoing cardiac catheterization, side effects except for arrhythmias were unrelated to the number of vessels with coronary artery disease. Intravenous dipyridamole is safe for nonexercise stress testing and has few serious side effects. However, the possibility of ischemia requires careful selection of patients and monitoring of vital signs and the electrocardiogram during the test.


Nonius alignment apparatus for measuring vergence.
The present paper describes an apparatus designed for the assessment of vergence. Based on the Nonius alignment system of viewing dichoptic stimuli, this apparatus provides a compact, portable, easily constructed, and easily maintained piece of equipment. It can be used for the assessment of vergence under a wide variety of viewing conditions and laboratory demands. Also included are an example of one way in which the apparatus may be set up, the equations for finding vergence angle using that set-up, and data concerning the validity and reliability of measurements made with the apparatus.


Perceptions of caregivers about health and nutritional problems and feeding practices of infants: a qualitative study on exclusive breast-feeding in Kwale, Kenya.
Despite the significant positive effect of exclusive breast-feeding on child health, only 32% of children under 6 months old were exclusively breast-fed in Kenya in 2008. The aim of this study was to explore perceptions and feeding practices of caregivers of children under 6 months old with special attention to the caregivers' indigenous knowledge, perceptions about the health and nutritional problems of their infants, and care-seeking behaviors that affect feeding practices. The study was exploratory and used an inductive approach. In all, 32 key informants, including mothers, mothers-in-law, and traditional healers, were interviewed in-depth. The number of participants in free-listing of perceived health problems of babies, in ranking of the perceived severity of these health problems, and in free-listing of food and drink given to children under 6 months old were 29, 28, and 32, respectively. Additionally, 28 babies under 6 months old were observed at home with regard to feeding practices. Data obtained using these methods were triangulated to formulate an ethnomedical explanatory model for mothers who do not practice exclusive breast-feeding. The informants stated that various types of food, drink, and medicine were given to infants under 6 months old. Direct observation also confirmed that 2- to 3-month-old babies were given porridge, water, juice, herbal medicine, and over-the-counter medicine. Mothers' perceptions of insufficient breast milk production and a lack of proper knowledge about the value of breast milk were identified in key informant interviews, free-listing, and ranking as important factors associating with the use of food and drink other than breast milk; in addition, perceived ill health of babies appears to be associated with suboptimal practice of exclusive breast-feeding. Caregivers used various folk and popular medicines from the drugstore, their own backyard or garden, and traditional healers so that the mother or child would not be exposed to perceived risks during the vulnerable period after birth. Mothers should be advised during their antenatal and postnatal care about exclusive breast-feeding. This should be done not as a single vertical message, but in relation to their concerns about the health and nutritional problems of their babies.


Longitudinal data in peripheral blood confirm that PM20D1 is a quantitative trait locus (QTL) for Alzheimer's disease and implicate its dynamic role in disease progression.
While Alzheimer's disease (AD) remains one of the most challenging diseases to tackle, genome-wide genetic/epigenetic studies reveal many disease-associated risk loci, which sheds new light onto disease heritability, provides novel insights to understand its underlying mechanism and potentially offers easily measurable biomarkers for early diagnosis and intervention. We analyzed whole-genome DNA methylation data collected from peripheral blood in a cohort (n = 649) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and compared the DNA methylation level at baseline among participants diagnosed with AD (n = 87), mild cognitive impairment (MCI, n = 175) and normal controls (n = 162), to identify differentially methylated regions (DMRs). We also leveraged up to 4 years of longitudinal DNA methylation data, sampled at approximately 1 year intervals to model alterations in methylation levels at DMRs to delineate methylation changes associated with aging and disease progression, by linear mixed-effects (LME) modeling for the unchanged diagnosis groups (AD, MCI and control, respectively) and U-shape testing for those with changed diagnosis (converters). When compared with controls, patients with MCI consistently displayed promoter hypomethylation at methylation QTL (mQTL) gene locus PM20D1. This promoter hypomethylation was even more prominent in patients with mild to moderate AD. This is in stark contrast with previously reported hypermethylation in hippocampal and frontal cortex brain tissues in patients with advanced-stage AD at this locus. From longitudinal data, we show that initial promoter hypomethylation of PM20D1 during MCI and early stage AD is reversed to eventual promoter hypermethylation in late stage AD, which helps to complete a fuller picture of methylation dynamics. We also confirm this observation in an independent cohort from the Religious Orders Study and Memory and Aging Project (ROSMAP) Study using DNA methylation and gene expression data from brain tissues as neuropathological staging (Braak score) advances. Our results confirm that PM20D1 is an mQTL in AD and demonstrate that it plays a dynamic role at different stages of the disease. Further in-depth study is thus warranted to fully decipher its role in the evolution of AD and potentially explore its utility as a blood-based biomarker for AD.


Use of consensus oligonucleotides for detecting and isolating nucleic acids encoding calcium binding domains of the troponin C superfamily.
Proteins belonging to the troponin C superfamily (troponin C, calmodulin, myosin light chains, and parvalbumin) are involved in a wide variety of cellular activities mediated by calcium ions. Most of these proteins bind ionic calcium, and all have calcium binding domains that are conserved to some extent at the nucleic acid level. We made use of the conservation in the third calcium binding domain to synthesize two consensus sequence oligonucleotide probes, one 43 bases and the other 25 bases long. By using cDNA and genomic clones encoding calmodulin, troponin C, parvalbumin, and the sea urchin Spec proteins, we show that these probes hybridize with nucleic acid sequences representing calcium binding domains. In an RNA gel blot analysis of embryonic RNA from the sea urchin Strongylocentrotus purpuratus, we show that transcripts which have previously been shown to encode troponin C like proteins hybridize with the consensus sequence probes. Screening sea urchin cDNA and genomic libraries with the 43-base consensus oligonucleotide shows that the probe can be used to isolate cloned nucleic acids. Two such genomic clones from a Lytechinus pictus library were isolated and characterized. One clone encodes part of an L. pictus calmodulin gene, and the other encodes a member of the superfamily that has not been characterized previously. The consensus oligonucleotides should be valuable probes in the diagnosis and isolation of nucleic acids encoding proteins of the troponin C superfamily.


Maternal mid-upper arm circumference is associated with birth weight among HIV-infected Malawians.
The authors examined the relationship of maternal anthropometry to fetal growth and birth weight among 1005 human immunodeficiency virus (HIV)-infected women in Lilongwe, Malawi, who consented to enrollment in the Breastfeeding, Antiretrovirals, and Nutrition Study (www.thebanstudy.org). Anthropometric assessments of mid-upper arm circumference (MUAC), arm muscle area (AMA), and arm fat area (AFA) were collected at the baseline visit between 12 and 30 weeks' gestation and in up to 4 follow-up prenatal visits. In longitudinal analysis, fundal height increased monotonically at an estimated rate of 0.92 cm/wk and was positively and negatively associated with AMA and AFA, respectively. These latter relationships varied over weeks of follow-up. Baseline MUAC, AMA, and AFA were positively associated with birth weight (MUAC: 31.84 g/cm(2), 95% confidence interval [CI], 22.18-41.49 [P < .01]; AMA: 6.88 g/cm(2), 95% CI, 2.51-11.26 [P < .01]; AFA: 6.97 g/cm(2), 95% CI, 3.53-10.41 [P < .01]). In addition, MUAC and AMA were both associated with decreased odds for low birth weight (LBW; <2500 g) (MUAC: odds ratio [OR] = 0.85, 95% CI, 0.77-0.94 [P < .01]; AMA: OR = 0.95, 95% CI, 0.91-0.99 [P < .05]). These findings support the use of MUAC as an efficient, cost-effective screening tool for LBW in HIV-infected women, as in HIV-uninfected women.


Suicide by motor vehicle.
Five suicides by motor vehicle drivers are reported. Possible frequency of such incidents and methods for their investigation, as well as patterns and characteristics of suicidal behavior, are discussed. Published reports of suicide by motor vehicle are scarce. Proven cases should be reported by medical examiners and coroners to help establish the patterns of such deaths.


Mitonuclear interactions alter sex-specific longevity in a species without sex chromosomes.
Impaired mitochondrial function can lead to senescence and the ageing phenotype. Theory predicts degenerative ageing phenotypes and mitochondrial pathologies may occur more frequently in males due to the matrilineal inheritance pattern of mitochondrial DNA observed in most eukaryotes. Here, we estimated the sex-specific longevity for parental and reciprocal F1 hybrid crosses for inbred lines derived from two allopatric Tigriopus californicus populations with over 20% mitochondrial DNA divergence. T. californicus lacks sex chromosomes allowing for more direct testing of mitochondrial function in sex-specific ageing. To better understand the ageing mechanism, we estimated two age-related phenotypes (mtDNA content and 8-hydroxy-20-deoxyguanosine (8-OH-dG) DNA damage) at two time points in the lifespan. Sex differences in lifespan depended on the mitochondrial and nuclear backgrounds, including differences between reciprocal F1 crosses which have different mitochondrial haplotypes on a 50 : 50 nuclear background, with nuclear contributions coming from alternative parents. Young females showed the highest mtDNA content which decreased with age, while DNA damage in males increased with age and exceed that of females 56 days after hatching. The adult sex ratio was male-biased and was attributed to complex mitonuclear interactions. Results thus demonstrate that sex differences in ageing depend on mitonuclear interactions in the absence of sex chromosomes.


The extreme lateral approach for treatment of thoracic and lumbar vertebral body metastases.
In addition to radiotherapy, the utility of surgical decompression and stabilization in patients with metastatic vertebral body tumors causing cord compression, progressive deformity and/or intractable pain has been well demonstrated. Minimally invasive approaches are an attractive alternative to traditional procedures as they may reduce the degree of disruption of normal anatomy, decrease blood loss, shorten hospital stays and reduce the risk of infection or wound dehiscence. The extreme lateral approach is a procedure that provides access to the anterior spine through a small incision along the flank utilizing a unique retractor system without disruption of posterior vertebral elements, spinal musculature and ligaments. A review of two senior surgeons' databases was performed between June 2010 and October 2014 to identify patients with metastatic vertebral body tumors who were treated surgically at the University of Miami during this period. We report the results of eight cases in which the extreme lateral approach was employed to perform a corpectomy and cage reconstruction for metastatic disease of the thoracic and lumbar vertebral bodies. Each case was supplemented by posterior percutaneous or less commonly open pedicle screw instrumentation. Postoperative imaging demonstrated excellent decompression of neural elements as well as deformity correction, and all patients maintained or improved neurologic function. There were no instances of wound dehiscence or infection. Our results indicate that the extreme lateral approach can be effectively used to excise metastatic vertebral body lesions of the thoracolumbar spine causing spinal cord and/or nerve root compression and spinal deformity.


[The role of core decompression for the treatment of femoral head avascular necrosis in renal transplant recipients].
Avascular bone necrosis is a relatively rare but significant complication in renal transplant recipients because it causes progressive pain and invalidity. It can be the consequence of the action of numerous causative factors, but it is mostly connected to corticosteroid treatment.The underlying pathophysiologic mechanism is a diminished blood flow to the bone leading to necrosis and bone destruction. During the past 25-years period, 570 renal transplantations and five combined kidney and pancreas transplantations were performed in our centre. A part of the patients was lost to follow-up due to the separation of Croatia from the former Republic of Yugoslavia. After transplantation, we revealed aseptic necrosis of the femoral head in five female patients. All patients had a history of treatment with pulse doses of corticosteroids. At transplantation the average age of the patients was 52.2 yrs (range 46 to 62 yrs), and dialytic treatment before transplantation lasted in average 9.2 yrs (range 2.5 to 21.2 yrs). The period between renal transplantation and the development of clinical signs of avascular bone necrosis lasted in average 1.2 yrs (range 0.3 to 2.3 yrs). We will demonstrate our 62-year old female patient with terminal renal failure caused by post-streptococcal glomerulonephritis, who was treated with peritoneal dialysis 2.5 years before renal transplantation. Twenty months before renal transplantation the patient received pulse doses of corticosteroids, together with immunoglobulins and plasmapheresis, for the treatment of an acute polyradiculoneuritis Guillaine Barré. After transplantation a standard immunosuppressive protocol was applied which included tacrolimus, mycophenolate mofetil, corticosteroids and induction with basiliximab. Four months after transplantation the patient started to feel pain in the right hip after longer standing, in addition to the earlier long-lasting problems caused by bilateral coxarthrosis. The pelvic radiograph showed subchondral radiolucencies in the lateral part of the head circumference spreading into the proximal part of the neck of the right femur, which indicated the presence of aseptic necrosis, but these changes could have also been caused by coxarthrosis. Unexpectedly, magnetic resonance imaging (MRI) did not reveal changes characteristic for avascular bone necrosis. Due to the progressively worsening of pain and the radiographic finding, the patient was submitted to decompression surgery of the femoral head. The surgical procedure was performed under diascopic guidance (C-arm) which allowed the correct positioning of a Kuerschner wire. A cannulated drill (diameter 4.0 mm) was placed over the wire and we performed two drillings of the spongiosis of the femoral head through to the subchondral area. Postoperatively, the patient was soon verticalized and advised to walk with crooks during a period of six weeks. This time is necessary to allow the mineralisation and strengthening of the bone which is now better vascularised. The patient recovered well and had no more pain. In renal transplant recipients it is most important to raise suspicion and verify the presence of avascular bone necrosis early, because timely bone decompression surgery can eliminate pain and cure the patient or it can prevent or delay bone destruction. When clinical signs of avascular bone necrosis arise and radiographic or standard MRI findings are negative, additional investigations (i.e. SPECT or MRI with contrast) should be performed to confirm or exclude the diagnosis. In latter phases of the disease, surgical decompression of the femoral head cannot lead to permanent amelioration, and it is inevitable to perform more invasive surgical procedures like "resurfacing" or bone grafting in younger patients, or the implantation of total hip endoprotheses.


Good to excellent Quality of Life in patients suffering from severe obesity post bariatric surgery - A single-center retrospective study report using BAROS Questionnaire.
Despite the positive outcomes reported in terms of weight loss and resolution of co-morbidities, the impact of bariatric surgery on patient-reported outcomes of quality of life (QoL) still remains scarce, particularly in the Indian population. The present study was conducted to evaluate the efficacy of laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB) procedures in patients with severe obesity over a period of 2 years in terms of weight loss, resolution of comorbidities, safety and changes in QoL using the Bariatric analysis and reporting outcome system (BAROS). The data of 100 patients who underwent RYGB and LSG between March 2014 and December 2017 were analyzed. The study endpoints such as QoL, major and minor complication rates, co-morbidity resolutions and the percentage of excess weight loss (%EWL) were measured using the Moorehead-Ardelt BAROS questionnaire II. At a follow-up point of 2 years, patients achieved a mean %EWL of 79.2 (±28.9) % and the mean postoperative body mass index decreased to 31.7 (±6.22) kg/m2. No major complications were reported to have occurred. Excellent global BAROS outcome was obtained in 20% of patients, very good in 47%, good in 29%, fair 2% and failure in 2% patients 24 months post-surgery. The mean BAROS score was 5.8 ± 1.73, and a 'good' to 'excellent' QoL outcome was observed in 96% of patients. RYGB and LSG are safe and effective bariatric procedures. These procedures provided substantial results in good to excellent health-related QoL, weight loss and medical conditions.


The demise of drug design litigation: death by federal preemption.
For over half a century, courts and commentators have disagreed as to the standards governing liability for drug design cases. In the last several years, the United States Supreme Court decided two cases that will have a profound effect on whether drug design defect cases, in general, are federally preempted. In PLIVA v. Mensing and Mutual Pharmaceutical Co. v. Bartlett, the Court preempted product liability actions for failure to warn and design defect against the manufacturers of generic drugs that met the FDA standard for the brand name drug. In these cases, the Court made wide-ranging statements that are applicable to brand name drugs as well. This Essay finds the Bartlett Court erred in having read New Hampshire law too narrowly. At the same time, the Court's reasoning has opened a debate as to the scope of federal preemption for brand name drugs. This Essay argues that the sweeping language in these two cases leads to the conclusion that common law drug design cases involving brand name drugs will fall prey to federal preemption.


Targeting the affordability of cigarettes: a new benchmark for taxation policy in low-income and-middle-income countries.
To investigate the appropriateness of tax incidence (the percentage of the retail price occupied by taxes) benchmarking in low-income and-middle-income countries (LMICs) with rapidly growing economies and to explore the viability of an alternative tax policy rule based on the affordability of cigarettes. The paper outlines criticisms of tax incidence benchmarking, particularly in the context of LMICs. It then considers an affordability-based benchmark using relative income price (RIP) as a measure of affordability. The RIP measures the percentage of annual per capita GDP required to purchase 100 packs of cigarettes. Using South Africa as a case study of an LMIC, future consumption is simulated using both tax incidence benchmarks and affordability benchmarks. I show that a tax incidence benchmark is not an optimal policy tool in South Africa and that an affordability benchmark could be a more effective means of reducing tobacco consumption in the future. Although a tax incidence benchmark was successful in increasing prices and reducing tobacco consumption in South Africa in the past, this approach has drawbacks, particularly in the context of a rapidly growing LMIC economy. An affordability benchmark represents an appropriate alternative that would be more effective in reducing future cigarette consumption.


Regulation of gonadotropin secretion by monitoring energy availability.
Nutrition is a principal environmental factor influencing fertility in animals. Energy deficit causes amenorrhea, delayed puberty, and suppression of copulatory behaviors by inhibiting gonadal activity. When gonadal activity is impaired by malnutrition, the signals originating from an undernourished state are ultimately conveyed to the gonadotropin-releasing hormone (GnRH) pulse generator, leading to suppressed secretion of GnRH and luteinizing hormone (LH). The mechanism responsible for energetic control of gonadotropin release is believed to involve metabolic signals, sensing mechanisms, and neuroendocrine pathways. The availabilities of blood-borne energy substrates such as glucose, fatty acids, and ketone bodies, which fluctuate in parallel with changes in nutritional status, act as metabolic signals that regulate the GnRH pulse generator activity and GnRH/LH release. As components of the specific sensing system, the ependymocytes lining the cerebroventricular wall in the lower brainstem integrate the information derived from metabolic signals to control gonadotropin release. One of the pathways responsible for the energetic control of gonadal activity consists of noradrenergic neurons from the solitary tract nucleus in the lower brainstem, projecting to the paraventricular nucleus of the hypothalamus. Further studies are needed to elucidate the mechanisms underlying energetic control of reproductive function.


[Protective effect of tetrandrine on pancreatic islet cells damaged by alloxan in rats].
Tetrandrine (TET, 100 mg/kg) injected intraperitoneally could prevent rats from diabetes induced by alloxan. After 48 h of injection of alloxan, the blood sugar of the preventive group decreased from the control value of 25.46 +/- 1.21 mmol/L to 7.63 +/- 0.44 mmol/L (P < 0.001) while the serum insulin level increased to 11.33 +/- 1.97 microU/ml and the plasma glucagon concentration to 66.85 +/- 5.07 pg/ml respectively from the control group's value of 7.13 +/- 0.45 microU/ml and 90.35 +/- 8.33 pg/ml. In glucose tolerance test, TET 100 mg/kg showed that the abnormal glucose tolerance induced by alloxan could be improved. The blood sugar area under the glucose tolerance curve of the preventive group decreased from the control groups level of 113.28 +/- 5.02 mmol.h/L to 29.45 +/- 1.63 mmol.h/L (P < 0.001). Immunohistochemical observation of islet beta cells confirmed that TET could markedly prevent beta cells from injuries induced by alloxan and there was no obvious change in the appearance of islet beta cells in the preventive group. The above results suggested that TET could protect pancreatic islet beta cells from injuries caused by Alloxan.


Tocotrienol suppresses adipocyte differentiation and Akt phosphorylation in 3T3-L1 preadipocytes.
In vivo studies show that alpha-tocotrienol and gamma-tocotrienol accumulate in adipose tissue. Furthermore, a recent study reports that the oral administration of gamma-tocotrienol from a tocotrienol-rich fraction from palm oil (TRF) decreases body fat levels in rats. The objective of this study was to evaluate the effect of TRF and its components on adipocyte differentiation in 3T3-L1 preadipocytes, which differentiated into adipocytes in the presence of 1.8 micromol/L insulin. TRF suppressed the insulin-induced mRNA expression of adipocyte-specific genes such as PPARgamma, adipocyte fatty acid-binding protein (aP2), and CCAAT/enhancer-binding protein-alpha (C/EBPalpha) compared with the differentiation of 3T3-L1 preadipocytes into adipocytes only in the presence of insulin. To confirm the suppressive effect of TRF, the major components of TRF, such as alpha-tocotrienol, gamma-tocotrienol, and alpha-tocopherol, were investigated. Alpha-tocotrienol and gamma-tocotrienol decreased the insulin-induced PPARgamma mRNA expression by 55 and 90%, respectively, compared with insulin, whereas alpha-tocopherol increased the mRNA expression. In addition, gamma-tocotrienol suppressed the insulin-induced aP2 and C/EBPalpha mRNA expression, triglyceride accumulation, and PPARgamma protein levels compared with insulin. The current results also revealed that gamma-tocotrienol inhibited the insulin-stimulated phosphorylation of Akt but not extracellular signal-regulated kinase (ERK)1/2 in the insulin signaling pathway of 3T3-L1 preadipocytes. Thus, the antiadipogenic effect of TRF depends on alpha-tocotrienol and gamma-tocotrienol, and gamma-tocotrienol may be a more potent inhibitor of adipogenesis than alpha-tocotrienol. Therefore, the results of this study suggest that tocotrienol suppresses insulin-induced differentiation and Akt phosphorylation in 3T3-L1 preadipocytes. Furthermore, tocotrienol could act as an antiadipogenic vitamin in the nutrient-mediated regulation of body fat through its effects on differentiation.


Medicine should reorder its priorities.
Although many entities contribute to the escalating cost of health care, the author of this opinion article believes physicians have two significant alternatives when it comes to health care costs: They can continue to be a major part of the problem, or they can take the lead in rolling back the cost of medical care.


Comparing effects in regular practice of e-communication and Web-based self-management support among breast cancer patients: preliminary results from a randomized controlled trial.
While Web-based interventions have been shown to assist a wide range of patients successfully in managing their illness, few studies have examined the relative contribution of different Web-based components to improve outcomes. Further efficacy trials are needed to test the effects of Web support when offered as a part of routine care. Our aim was to compare in regular care the effects of (1) an Internet-based patient provider communication service (IPPC), (2) WebChoice, a Web-based illness management system for breast cancer patients (IPPC included), and (3) usual care on symptom distress, anxiety, depression, (primary outcomes), and self-efficacy (secondary outcome). This study reports preliminary findings from 6 months' follow-up data in a 12-month trial. We recruited 167 patients recently diagnosed with breast cancer and undergoing treatment from three Norwegian hospitals. The nurse-administered IPPC allowed patients to send secure e-messages to and receive e-messages from health care personnel at the hospital where they were treated. In addition to the IPPC, WebChoice contains components for symptom monitoring, tailored information and self-management support, a diary, and communication with other patients. A total of 20 care providers (11 nurses, 6 physicians, and 3 social workers) were trained to answer questions from patients. Outcomes were measured with questionnaires at study entry and at study months 2, 4, and 6. Linear mixed models for repeated measures were fitted to compare effects on outcomes over time. Patients were randomly assigned to the WebChoice group (n=64), the IPPC group (n=45), or the usual care group (n=58). Response rates to questionnaires were 73.7% (123/167) at 2 months, 65.9 (110/167) at 4 months, and 62.3% (104/167) at 6 months. Attrition was similar in all study groups. Among those with access to WebChoice, 64% (41/64) logged on more than once and 39% (25/64) sent e-messages to care providers. In the IPPC group, 40% (18/45) sent e-messages. Linear mixed models analyses revealed that the WebChoice group reported significantly lower symptom distress (mean difference 0.16, 95% CI 0.06-0.25, P=.001), anxiety (mean difference 0.79, 95% CI 0.09-1.49, P=.03), and depression (mean difference 0.79, 95% CI 0.09-1.49, P=.03) compared with the usual care group. The IPPC group reported significant lower depression scores compared with the usual care group (mean difference 0.69, 95% CI 0.05-1.32, P=.03), but no differences were observed for symptom distress or anxiety. No significant differences in self-efficacy were found among the study groups. In spite of practice variations and moderate use of the interventions, our results suggest that offering Web support as part of regular care can be a powerful tool to help patients manage their illness. Our finding that a nurse-administered IPPC alone can significantly reduce depression is particularly promising. However, the multicomponent intervention WebChoice had additional positive effects. Clinicaltrials.gov:NCT00971009; http://clinicaltrials.gov/show/NCT00971009 (Archived by WebCite at http://www.webcitation.org/6USKezP0Y).


Classification of developmental delays.
Developmental delay is frequently used to identify children with delay in meeting developmental milestones in one or more streams of development. There is no consensus on the specific definition. Developmental delay is best viewed generically as a chief complaint rather than a diagnosis. A child suspected to have delays should always be assessed in each of the major streams of development: expressive and receptive language, including social communication; visual problem solving (nonverbal cognition); motor development; neurobehavioral development; and social-emotional development. A model developed by the National Center for Medical Rehabilitation Research is used to compare existing classifications of developmental delays. This model defines the five domains in the disability process: pathophysiology, impairment, functional limitation, disability, and societal limitation. An etiology domain is added. This model is used to illustrate how existing classification systems of cerebral palsy, mental retardation, autism, and language delay draw on information from one or more domains. The model illustrates some of the conflicts between different systems. For example, most classification systems for cerebral palsy emphasize only impairment (spasticity, dyskinesias, and topography). The current definition and classification system for mental retardation focuses on functional limitations (IQ), disability, and societal limitations, ignoring pathophysiology and details of impairment. Given the complexity of neurodevelopmental disabilities, it is unlikely that a single classification system will fit all needs.


Capillary rise of superspreaders.
Trisiloxane surfactants, known as 'superspreaders', are commonly employed in numerous applications where enhanced wetting is of the utmost importance. The underlying mechanisms of superspreader wetting have been a focus of scientific interest for ca. 2 decades, and a number of mechanisms have been proposed to explain the unique trisiloxane dynamics. We have studied trisiloxane behaviour in thin capillaries to get further insight into their interfacial activity. Additionally, our knowledge of the capillary rise of superspreaders is surprisingly limited, and the effect of this extraordinary group of surfactants on capillary phenomena has been largely overlooked. Diffusion was confirmed to be the limiting factor of trisiloxane behaviour. A tentative theoretical explanation for the phenomenon studied and an appropriate mathematical model are presented. It is concluded that the enhancement of wetting due to surfactant addition is also a function of geometry: the effect is clear for a sessile drop, but more complex and less beneficial in a capillary.


Carbon-coated Fe3O4 core-shell super-paramagnetic nanoparticle-based ferrofluid for heat transfer applications.
Herein, we report the investigation of the electrical and thermal conductivity of Fe3O4 and Fe3O4@carbon (Fe3O4@C) core-shell nanoparticle (NP)-based ferrofluids. Different sized Fe3O4 NPs were synthesized via a chemical co-precipitation method followed by carbon coating as a shell over the Fe3O4 NPs via the hydrothermal technique. The average particle size of Fe3O4 NPs and Fe3O4@C core-shell NPs was found to be in the range of ∼5-25 nm and ∼7-28 nm, respectively. The thickness of the carbon shell over the Fe3O4 NPs was found to be in the range of ∼1-3 nm. The magnetic characterization revealed that the as-synthesized small average-sized Fe3O4 NPs (ca. 5 nm) and Fe3O4@C core-shell NPs (ca. 7 nm) were superparamagnetic in nature. The electrical and thermal conductivities of Fe3O4 NPs and Fe3O4@C core-shell NP-based ferrofluids were measured using different concentrations of NPs and with different sized NPs. Exceptional results were obtained, where the electrical conductivity was enhanced up to ∼3222% and ∼2015% for Fe3O4 (ca. 5 nm) and Fe3O4@C core-shell (ca. 7 nm) NP-based ferrofluids compared to the base fluid, respectively. Similarly, an enhancement in the thermal conductivity of ∼153% and ∼116% was recorded for Fe3O4 (ca. 5 nm) and Fe3O4@C core-shell (ca. 7 nm) NPs, respectively. The exceptional enhancement in the thermal conductivity of the bare Fe3O4 NP-based ferrofluid compared to that of the Fe3O4@C core-shell NP-based ferrofluid was due to the more pronounced effect of the chain-like network formation/clustering of bare Fe3O4 NPs in the base fluid. Finally, the experimental thermal conductivity results were compared and validated against the Maxwell effective model. These results were found to be better than results reported till date using either the same or different material systems.


Point-of-critical-care diagnostics for sepsis enabled by multiplexed micro and nanosensing technologies.
Sepsis is responsible for the highest economic and mortality burden in critical care settings around the world, prompting the World Health Organization in 2018 to designate it as a global health priority. Despite its high universal prevalence and mortality rate, a disproportionately low amount of sponsored research funding is directed toward diagnosis and treatment of sepsis, when early treatment has been shown to significantly improve survival. Additionally, current technologies and methods are inadequate to provide an accurate and timely diagnosis of septic patients in multiple clinical environments. For improved patient outcomes, a comprehensive immunological evaluation is critical which is comprised of both traditional testing and quantifying recently proposed biomarkers for sepsis. There is an urgent need to develop novel point-of-care, low-cost systems which can accurately stratify patients. These point-of-critical-care sensors should adopt a multiplexed approach utilizing multimodal sensing for heterogenous biomarker detection. For effective multiplexing, the sensors must satisfy criteria including rapid sample to result delivery, low sample volumes for clinical sample sparring, and reduced costs per test. A compendium of currently developed multiplexed micro and nano (M/N)-based diagnostic technologies for potential applications toward sepsis are presented. We have also explored the various biomarkers targeted for sepsis including immune cell morphology changes, circulating proteins, small molecules, and presence of infectious pathogens. An overview of different M/N detection mechanisms are also provided, along with recent advances in related nanotechnologies which have shown improved patient outcomes and perspectives on what future successful technologies may encompass. This article is categorized under: Diagnostic Tools > Biosensing.


Multiplexed analysis of biomarkers related to obesity and the metabolic syndrome in human plasma, using the Luminex-100 system.
The complex pathology of disease has sparked the development of novel protein expression profiling techniques that require validation in clinical settings. This study focuses on multiplexed analyses of adipocytokines and biomarkers linked to the metabolic syndrome, diabetes, and cardiovascular disease. Multiplexed immunoassays using fluorescent microspheres and the Luminex-100 system were performed on plasma from 80 obese patients (40 with the metabolic syndrome) before and after 6-8 weeks of diet-induced weight loss. Leptin, insulin, C-peptide, monocyte chemoattractant protein-1 (MCP-1), eotaxin, interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-alpha), and IL-6 concentrations measured with multiplex panels from 3 different manufacturers were compared with results from commercial ELISAs. Detection limits and between- and within-run imprecision were determined for each analyte. Bland-Altman analysis was used to determine agreement between multiplexed immunoassays and ELISAs. Correlation between the Luminex multiplexed assays and ELISAs was good for leptin (Linco), insulin (Linco), MCP-1 (Biosource and Upstate), and eotaxin (Biosource) with correlation coefficients of 0.711-0.895; fair for eotaxin (Upstate) and C-peptide (Linco) with correlation coefficients of 0.496-0.582; and poor for TNF-alpha, IL-8, and IL-6 (Linco, Biosource, Upstate, and R&D) with correlation coefficients of -0.107 to 0.318. Within- and between-run imprecision values for the multiplex method were generally <15%. Relative changes in plasma leptin and insulin concentrations after diet-induced weight loss were similar whether assessed by multiplex assay or ELISA. Although this technology appears useful in clinical research studies, low assay sensitivity and poor correlations with conventional ELISA methods for some analytes with very low plasma concentrations should be considered when using the Luminex platform in clinical studies.


Management of the Patient After Heart Transplant.
Cardiac transplantation is a highly effective therapy for selected patients with end-stage cardiac disease. The management of the patient after heart transplant involves three main strategies: optimization of immunosuppressive therapy, prevention of complications resulting from the transplant or the immunosuppressive agents, and treatment of those complications when they arise. For most patients, optimal current immunosuppression in the first year after transplantation consists of combination therapy with a calcineurin inhibitor (eg, cyclosporine or tacrolimus), corticosteroids, and an antimetabolite agent (eg, azathioprine or mycophenolate mofetil). Ideally, the corticosteroid is weaned and discontinued 1 to 2 years following transplantation and the patient is managed chronically with a two-drug immunosuppressive regimen. The major complications that occur following cardiac transplantation include infection, hypertension, diabetes, dyslipidemia, osteoporosis, graft coronary disease, renal insufficiency, and malignancy. Preventive efforts focused on infection, osteoporosis, renal insufficiency, and malignancy include minimization of immunosuppression. Once established, treatment of any of the above conditions generally relies on standard pharmacologic therapies; however, an understanding of potential drug interactions is critical. In addition, although standard nonpharmacologic therapies may be used to treat several of these conditions, one must be cognizant of special issues related to the post-transplant state.


Conceptual framework for defining disease modification in systemic lupus erythematosus: a call for formal criteria.
Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE.We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on 'disease manifestations' (ie, signs, symptoms and patient-reported outcomes) and on 'disease outcomes' (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested.Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE.


Effect of Long-Acting Insulin Analogs on the Risk of Cancer: A Systematic Review of Observational Studies.
Observational studies examining the association between long-acting insulin analogs and cancer incidence have produced inconsistent results. We conducted a systematic review of these studies, focusing on their methodological strengths and weaknesses. We systematically searched MEDLINE and EMBASE from 2000 to 2014 to identify all observational studies evaluating the relationship between the long-acting insulin analogs and the risk of any and site-specific cancers (breast, colorectal, prostate). We included cohort and case-control studies published in English on insulin glargine and detemir and any cancer incidence among patients with type 1 or 2 diabetes. The methodological assessment involved the inclusion of prevalent users, inclusion of lag periods, time-related biases, and duration of follow-up between insulin initiation and cancer incidence. A total of 16 cohort and 3 case-control studies met our inclusion criteria. All studies evaluated insulin glargine, and four studies also examined insulin detemir. Follow-up ranged from 0.9 to 7.0 years. Thirteen of 15 studies reported no association between insulin glargine and detemir and any cancer. Four of 13 studies reported an increased risk of breast cancer with insulin glargine. In the quality assessment, 7 studies included prevalent users, 11 did not consider a lag period, 6 had time-related biases, and 16 had short (<5 years) follow-up. The observational studies examining the risk of cancer associated with long-acting insulin analogs have important methodological shortcomings that limit the conclusions that can be drawn. Thus, uncertainty remains, particularly for breast cancer risk.


Identification and treatment of Nepal 2015 earthquake survivors with posttraumatic stress disorder by nonspecialist volunteers: An exploratory cross-sectional study.
In April 2015, a major earthquake struck northern regions of Nepal affecting one-third of the population, and many suffered mental health problems. This study aimed to conduct a preliminary investigation of prevalence and feasibility of brief therapy for posttraumatic stress disorder (PTSD) among earthquake survivors. This is an exploratory cross-sectional study of prevalence and feasibility of brief trauma-focused therapy for PTSD among survivors 3 and 11 months after the earthquake in affected areas near Kathmandu. A team of local nonspecialist mental health volunteers was trained to identify survivors with PTSD using the PTSD checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (PCL-5) (cutoff score 38). They were trained to deliver either shortened versions of narrative exposure therapy (NET)-revised or group-based control-focused behavioral treatment (CFBT). Altogether, 333 survivors were surveyed (130 in July 2015 and 203 in March 2016) with PCL-5 as the screening instrument, using the cutoff score of 38 or more for diagnosing PTSD. A PTSD prevalence of 33% was noted in 2015 and 28.5% in 2016. This drop of 4.5% prevalence in the intervening 8 months suggests that a significant number of survivors are still suffering from PTSD. Most participants were female, aged 40 or above, married, and poorly educated. Compared to the brief (four sessions) individual NET-revised, a group-based CFBT was found more acceptable and affordable. PTSD is common following earthquake trauma, and if untreated, survivors continue to suffer for a long time. Management of PTSD should be included in future disaster management plans.


A tRNA fragment, tRF5-Glu, regulates BCAR3 expression and proliferation in ovarian cancer cells.
Ovarian cancer is a complex disease marked by tumor heterogeneity, which contributes to difficulties in diagnosis and treatment. New molecular targets and better molecular profiles defining subsets of patients are needed. tRNA fragments (tRFs) offer a recently identified group of noncoding RNAs that are often as abundant as microRNAs in cancer cells. Initially their presence in deep sequencing data sets was attributed to the breakdown of mature tRNAs, however, it is now clear that they are actively generated and function in multiple regulatory events. One such tRF, a 5' fragment of tRNA-Glu-CTC (tRF5-Glu), is processed from the mature tRNA-Glu and is shown in this study to be expressed in ovarian cancer cells. We confirmed that tRF5-Glu binds directly to a site in the 3'UTR of the Breast Cancer Anti-Estrogen Resistance 3 (BCAR3) mRNA thereby down regulating its expression. BCAR3 has not previously been studied in ovarian cancer cells and our studies demonstrate that inhibiting BCAR3 expression suppresses ovarian cancer cell proliferation. Furthermore, mimics of tRF5-Glu were found to inhibit proliferation of ovarian cancer cells. In summary, BCAR3 and tRF5-Glu contribute to the complex tumor heterogeneity of ovarian cancer cells and may provide new targets for therapeutic intervention.


Care seeking for fatal illness episodes in neonates: a population-based study in rural Bangladesh.
Poor neonatal health is a major contributor to under-five mortality in developing countries. A major constraint to effective neonatal survival programme has been the lack of population level data in developing countries. This study investigated the consultation patterns of caregivers during neonatal fatal illness episodes in the rural Matlab sub-district of eastern Bangladesh. Neonatal deaths were identified through a population-based demographic surveillance system in Matlab ICDDR,B maternal and child health (MCH) project area and an adjoining government service area. Trained project staff administered a structured questionnaire on care seeking to mothers at home who had experienced a neonatal death. Univariate, bivariate and binary multivariate logistic regressions were performed to describe care seeking during the fatal illness episode. Of the 365 deaths recorded during 2003 and 2004, 84% died in the early (0-7 days) neonatal period, with the remaining deaths occurring over the subsequent 8 to 28 days. The first resort of care by parents was a qualified doctor or paramedic in 37% of cases, followed by traditional and unqualified health care providers in 25%, while 38% sought no care. Thus, almost two thirds (63%) of neonates who died received only traditional and unqualified care or no care at all during their final illness episode. About 22% sought care from more than one provider, including 6% from 3 or more providers. Such plurality in care seeking was more likely among male infants, in the late neonatal period, and in the MCH project area. The high proportion of neonatal deaths that had received traditional care or no medical care in a rural area of Bangladesh highlights the need to develop community awareness about prompt medical care seeking for neonatal illnesses and to improve access to effective health care. Integration of traditional care providers into mainstream health programs should also be considered.


Sleep and environmental context: interactive effects for memory.
Sleep after learning is often beneficial for memory. Reinstating an environmental context that was present at learning during subsequent retrieval also leads to superior declarative memory performance. This study examined how post-learning sleep, relative to wakefulness, impacts upon context-dependent memory effects. Thirty-two participants encoded word lists in each of two rooms (contexts), which were different in terms of size, odour and background music. Immediately after learning and following a night of sleep or a day of wakefulness, memory for all previously studied words was tested using a category-cued recall task in room one or two alone. Accordingly, a comparison could be made between words retrieved in an environmental context which was the same as, or different to, that of the learning phase. Memory performance was assessed by the difference between the number of words remembered at immediate and delayed retrieval. A 2 × 2 × 2 mixed ANOVA revealed an interaction between retrieval context (same/different to learning) and retention interval (sleep/wakefulness), which was driven by superior memory after sleep than after wake when learning and retrieval took place in different environmental contexts. Our findings suggest a sleep-related reduction in the extent to which context impacts upon retrieval. As such, these data provide initial support for the possibility that sleep dependent processes may promote a decontextualisation of recently formed declarative representations.


Opposite Polarity Surface Photovoltage of MoS2 Monolayers on Au Nanodot versus Nanohole Arrays.
We prepared MoS2 monolayers on Au nanodot (ND) and nanohole (NH) arrays. Both these sample arrays exhibited enhanced photoluminescence intensity compared with that of a bare SiO2/Si substrate. The reflectance spectra of MoS2/ND and MoS2/NH had clear features originating from excitation of localized surface plasmon and propagating surface plasmon polaritons. Notably, the surface photovoltages (SPV) of these hybrid plasmonic nanostructures had opposite polarities, indicating negative and positive charging at MoS2/ND and MoS2/NH, respectively. Surface potential maps, obtained by Kelvin probe force microscopy, suggested that the potential gradient led to a distinct spatial distribution of photo-generated charges in these two samples under illumination. Furthermore, the local density of photo-generated excitons, as predicted from optical simulations, explained the SPV spectra of MoS2/ND and MoS2/NH. We show that the geometric configuration of the plasmonic nanostructures modified the polarity of photo-generated excess charges in MoS2. These findings point to a useful means of optimizing optoelectronic characteristics and improving the performance of MoS2-based plasmonic devices.


Immunocytochemical localization of the synapse-associated protein SAP102 in the rat retina.
An elaborate network of transmitter receptors, synapse associated proteins (SAPs), and cytoskeletal elements, generally known as the postsynaptic density, is involved with efficient synaptic signaling. The localization of the synapse associated protein SAP102 was studied in the rat retina by using immunocytochemical methods. Immunofluorescence for SAP102 was most prominent in the inner plexiform layer (IPL). It had a punctate appearance, suggesting a synaptic clustering of SAP102 in the IPL. Electron microscopy by use of pre-embedding immunocytochemistry showed that SAP102 is concentrated in the IPL in processes which are postsynaptic at bipolar cell ribbon synapses (dyads). As a rule, only one of the two postsynaptic members of the dyad was labeled for SAP102. Double-labeling experiments were performed in order to find out whether SAP102 is involved with the clustering the N-methyl-D-aspartate (NMDA) receptor 2A subunit (NR2A). Only a fraction (approximately 23%) of the SAP102 clusters expressed NR2A, suggesting SAP102 is also associated with other subunits or receptors. Distinct SAP102 labeling was also present in horizontal cell processes in the outer plexiform layer (OPL), which are inserted as lateral elements into photoreceptor ribbon synapses (triads). The optic nerve fibre layer was also diffusely immunoreactive for SAP102. The postsynaptic aggregation of SAP102 at bipolar cell dyads and at photoreceptor triads suggests SAP102 is associated with the clustering of transmitter receptors. However, the labeling of the optic nerve fibre layer indicates additional functions of SAP102 in the retina.


New York City's window guard policy: four decades of success.
Preventing child falls from windows is easily accomplished by installing inexpensive window-limiting devices but window falls remain a common cause of child injuries. This article describes the history and evolution of the New York City (NYC) window guard rule,which requires building owners to install window guards in apartments housing children aged ≤10 years. The NYC window guard rule was the first directive of its kind in the USA when it was adopted in 1976, and it has led to a dramatic and long-lasting reduction in child window fall-related injuries and deaths. Data about the history of the window guard rule were obtained by reviewing programmatic records, correspondence, legal decisions and the published literature. In addition, key informant interviews were conducted with programme staff. This article describes each stage of policy development, starting with epidemiological studies defining the scope of the problem in the 1960s and pilot-testing of the window guard intervention. We describe the adoption, implementation and enforcement of the rule. In addition, we show how the rule was modified over time and document the rule's impact on window fall incidence in NYC. We describe litigation that challenged the rule's constitutionality and discuss the legal arguments used by opponents of the rule. Finally, we discuss criminal and tort liability as drivers of compliance and summarise lessons learnt.


Identification of DVA interneuron regulatory sequences in Caenorhabditis elegans.
The identity of each neuron is determined by the expression of a distinct group of genes comprising its terminal gene battery. The regulatory sequences that control the expression of such terminal gene batteries in individual neurons is largely unknown. The existence of a complete genome sequence for C. elegans and draft genomes of other nematodes let us use comparative genomics to identify regulatory sequences directing expression in the DVA interneuron. Using phylogenetic comparisons of multiple Caenorhabditis species, we identified conserved non-coding sequences in 3 of 10 genes (fax-1, nmr-1, and twk-16) that direct expression of reporter transgenes in DVA and other neurons. The conserved region and flanking sequences in an 85-bp intronic region of the twk-16 gene directs highly restricted expression in DVA. Mutagenesis of this 85 bp region shows that it has at least four regions. The central 53 bp region contains a 29 bp region that represses expression and a 24 bp region that drives broad neuronal expression. Two short flanking regions restrict expression of the twk-16 gene to DVA. A shared GA-rich motif was identified in three of these genes but had opposite effects on expression when mutated in the nmr-1 and twk-16 DVA regulatory elements. We identified by multi-species conservation regulatory regions within three genes that direct expression in the DVA neuron. We identified four contiguous regions of sequence of the twk-16 gene enhancer with positive and negative effects on expression, which combined to restrict expression to the DVA neuron. For this neuron a single binding site may thus not achieve sufficient specificity for cell specific expression. One of the positive elements, an 8-bp sequence required for expression was identified in silico by sequence comparisons of seven nematode species, demonstrating the potential resolution of expanded multi-species phylogenetic comparisons.


Diffuse Colour Discrimination as Marker of Afferent Visual System Dysfunction in Amyotrophic Lateral Sclerosis.
Abnormalities of the inner and intermediate retinal structures in patients with amyotrophic lateral sclerosis (ALS) have been described using optical coherence tomography and histopathology. Colour vision is a potential marker of these structural changes. The purpose of this study is to test the hypothesis that colour vision impairment is associated with ALS. Monocular (right eye) colour vision was assessed in subjects with definite or probable ALS (n = 25, aged 50-80 years) and control (n = 21, aged 46-89 years) subjects with corrected near visual acuity of at least 20/40 using the L'Anthony D15 color test (desaturated), scored by c-index, a measure of diffuse colour discrimination. Of ALS subjects, 16/25 (64%) had impaired colour vision (c-index >1.8). Comparing with our normal subjects and accounting for age, 72% (n = 18) of ALS subjects had colour vision below the 50th percentile, 52% (n = 13) had colour vision below the 25th percentile, 24% (n = 6) had colour vision below the 10th percentile, and 8% (n = 2) had colour vision below the 2nd percentile. In multivariate models of ln(c-index) and age, the intercept was higher and the slope was flatter in ALS subjects, suggesting that colour vision deficits are more prominent in younger ALS patients. Diffuse colour discrimination deficits are detected in ALS subjects at younger ages than in control subjects. Further study is needed to confirm these findings and to determine if the ALS colour discrimination abnormalities correlate with structural markers of retinal involvement and ALS disease severity.


Long-term follow-up of 500 patients with mild to moderate hypertension who had successfully completed a 3-month general practice study of a timolol-bendrofluazide combination ('Prestim').
A sample of 500 patients with mild to moderate hypertension, who had been successfully controlled on once daily timolol/bendrofluazide at the end of a 3-month general practice study, was followed up after approximately 1 year of treatment. Physicians who had participated in the trial were questioned on the current status of these patients. Out of 479 reports received, data showed that 358 (75%) patients were still normotensive 47 weeks after starting treatment with timolol/bendrofluazide and in a further 8 patients other antihypertensive agents had been added to this therapy. Of the 113 patients no longer receiving timolol/bendrofluazide, only 38 (7.9%) had stopped therapy due to adverse effects. It is concluded that the results are a further indication that timolol/bendrofluazide offers an acceptable and balanced long-term form of therapy in hypertension for both the patient and the physician.


Genome analysis and functional characterization of the E2 and RING-type E3 ligase ubiquitination enzymes of Arabidopsis.
Attachment of ubiquitin to substrate proteins is catalyzed by the three enzymes E1, E2 (ubiquitin conjugating [UBC]), and E3 (ubiquitin ligase). Forty-one functional proteins with a UBC domain and active-site cysteine are predicted in the Arabidopsis (Arabidopsis thaliana) genome, which includes four that are predicted or shown to function with ubiquitin-like proteins. Only nine were previously characterized biochemically as ubiquitin E2s. We obtained soluble protein for 22 of the 28 uncharacterized UBCs after expression in Escherichia coli and demonstrated that 16 function as ubiquitin E2s. Twelve, plus three previously characterized ubiquitin E2s, were also tested for the ability to catalyze ubiquitination in vitro in the presence of one of 65 really interesting new gene (RING) E3 ligases. UBC22, UBC19-20, and UBC1-6 had variable levels of E3-independent activity. Six UBCs were inactive with all RINGs tested. Closely related UBC8, 10, 11, and 28 were active with the largest number of RING E3s and with all RING types. Expression analysis was performed to determine whether E2s or E3s were expressed in specific organs or under specific environmental conditions. Closely related E2s show unique patterns of expression and most express ubiquitously. Some RING E3s are also ubiquitously expressed; however, others show organ-specific expression. Of all the organs tested, RING mRNAs are most abundant in floral organs. This study demonstrates that E2 diversity includes examples with broad and narrow specificity toward RINGs, and that most ubiquitin E2s are broadly expressed with each having a unique spatial and developmental pattern of expression.


Inhibitory activity of minor phlorotannins from Ecklonia cava on α-glucosidase.
α-Glucosidase is an enzyme that plays a key role in raising blood sugar level and is considered a good target for developing drugs to treat type 2 diabetes. This study was performed to evaluate the inhibition of the catalytic reaction of α-glucosidase by minor phlorotannin derivatives (1-5) from Ecklonia cava. These derivatives demonstrated inhibitory activity, with IC50 values ranging from 2.3 ± 0.1 to 59.8 ± 0.8 μM. Among the phlorotannins identified, compounds 2 and 3-5 were revealed to be non-competitive and competitive inhibitors, respectively. Furthermore, a fluorescence-quenching study of receptor-ligand binding was performed to calculate the kinetic parameters (Ksv, Kq, and K). These signal data indicated a 1:1 ratio of ligand-receptor binding. The binding conformations of the phlorotannin ligands were visually solved through molecular simulation. In conclusion, these minor phlorotannins may serve as α-glucosidase inhibitors targeted for the treatment of type 2 diabetes.


ST2 gene products critically contribute to cellular transformation caused by an oncogenic Ras mutant.
The ST2 gene was originally identified as a primary responsive gene, and the expressions of its gene products are induced by stimulation with growth factors and by oncogenic stresses. In this study, we observed that oncogenic Ras mutant induced the expression of ST2 and ST2L proteins. Interestingly, the enforced expression of ST2 gene products in NIH-3T3 murine fibroblasts remarkably enhanced Ras (G12V)-induced cellular transformation. Furthermore, when the expression of ST2 gene products was silenced by RNA-interference technique, Ras (G12V)-induced cellular transformation was drastically suppressed. According to these observations, it was indicated that the oncogenic Ras-induced expression of ST2 gene products is required for the acceleration of cellular transformation, and this seems to be independent of the stimulation with IL-33, a ligand for ST2/ST2L. Interestingly, knockdown of ST2 gene products caused a reduction in Rb phosphorylation in transformed murine fibroblasts, suggesting the functional involvement of ST2 gene products in cell cycle progression during cellular transformation. Our current study strongly suggests the importance of ST2 gene products in cellular transformation, and the presence of novel mechanism how ST2 gene products affect the cellular transformation and cell proliferation.


Effects of a gut-selective integrin-targeted therapy in male mice exposed to early immune activation, a model for the study of autism spectrum disorder.
To clarify the role of gut mucosal immunity in ASD, we evaluated, in the early-life immune activation (EIA) mouse model, the effects of administration of a monoclonal antibody directed against the integrin alpha4 beta7 (α4β7 mAb), blocking the leukocyte homing into the gut mucosa. EIA is a double-hit variant of the maternal immune-activation (MIA) model, including both prenatal (Poly I:C) and postnatal (LPS) immune challenges. In C57BL6/J EIA male adult offspring mice, IL-1β and IL-17A mRNA colonic tissue content increased when compared with controls. Cytofluorimetric analyses of lymphocytes isolated from mesenteric lymph-nodes (MLN) and spleens of EIA mice show increased percentage of total and CD4+α4β7+, unstimulated and stimulated IL-17A+ and stimulated IFN-γ+ lymphocytes in MLN and CD4+α4β7+ unstimulated and stimulated IL-17A+ and stimulated IFN-γ+ lymphocytes in the spleen. Treatment with anti-α4β7 mAb in EIA male mice was associated with colonic tissue IL-1β, and IL-17A mRNA content and percentage of CD4+ IL-17A+ and IFN-γ+ lymphocytes in MLN and spleens comparable to control mice. The anti-α4β7 mAb treatment rescue social novelty deficit showed in the three-chamber test by EIA male mice. Increased levels of IL-6 and IL-1β and decreased CD68 and TGF-β mRNAs were also observed in hippocampus and prefrontal cortex of EIA male mice together with a reduction of BDNF mRNA levels in all brain regions examined. Anti-α4β7 mAb treatment restored the expression of BDNF, TGF-β and CD68 in hippocampus and prefrontal cortex. Improvement of the gut inflammatory status, obtained by a pharmacological agent acting exclusively at gut level, ameliorates some ASD behavioral features and the neuroinflammatory status. Data provide the first preclinical indication for a therapeutic strategy against gut-immune activation in ASD subjects with peripheral increase of gut-derived (α4β7+) lymphocytes expressing IL-17A.


Mechano-chemical control of human endothelium orientation and size.
Human umbilical vein endothelial cells (EC) were grown on elastic silicone membranes subjected to cyclic stretch, simulating arterial wall motion. Stretching conditions (20% amplitude, 52 cycle/min) stimulated stress fiber formation and their orientation transversely to the strain direction. Cell bodies aligned along the same axis after the actin cytoskeleton. EC orientation response was inhibited by the adenylate cyclase activator, forskolin (10(-5) M), which caused stress fiber disassembly and the redistribution of F-actin to the cortical cytoplasm. Preoriented EC depleted of stress fibers by forskolin treatment retained their aligned state. Thus, stress fibers are essential for the process of EC orientation induced by repeated strain, but not for the maintenance of EC orientation. The monolayer formed by EC grown to confluence in conditions of intermittent strain consisted of uniform elongated cells and was resistant to deformation. In contrast, the monolayer assembled in stationary conditions was less compliant and exposed local denudations on initiation of stretching. When stretched in the presence of 10(-5) M forskolin it rapidly (3-4 h) reestablished integrity but gained a heterogeneous appearance since denuded areas were covered by giant cells. The protective effect of forskolin was because of the stimulation of EC spreading. This feature of forskolin was demonstrated while studying its action on EC spreading and repair of a scratched EC monolayer in conventional culture. Thus mechanical deformation and adenylate cyclase activity may be important factors in the control of endothelium morphology in human arteries.


An assessment of honeybee colony matrices, Apis mellifera (Hymenoptera: Apidae) to monitor pesticide presence in continental France.
The frequency of occurrence and relative concentration of 44 pesticides in apicultural (Apis mellifera) matrices collected from five French locations (24 apiaries) were assessed from 2002 to 2005. The number and nature of the pesticides investigated varied with the matrices examined-living honeybees, pollen loads, honey, and beeswax. Pollen loads and beeswax had the highest frequency of pesticide occurrence among the apiary matrices examined in the present study, whereas honey samples had the lowest. The imidacloprid group and the fipronil group were detected in sufficient amounts in all matrices to allow statistical comparisons. Some seasonal variation was shown when residues were identified in pollen loads. Given the results (highest frequency of presence) and practical aspects (easy to collect; matrix with no turnover, unlike with bees that are naturally renewed), pollen loads were the best matrix for assessing the presence of pesticide residues in the environment in our given conditions.


Quality of life assessment in the randomized PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) trial of patients at risk for stroke with nonvalvular atrial fibrillation.
This study sought to assess quality of life parameters in a subset of patients enrolled in the PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) trial. The PROTECT AF (Percutaneous Closure of the Left Atrial Appendage Versus Warfarin Therapy for Prevention of Stroke in Patients With Atrial Fibrillation) trial demonstrated that in patients with nonvalvular atrial fibrillation (AF) and CHADS2 (congestive heart failure, hypertension, age, diabetes mellitus, and prior stroke, transient ischemic attack, or thromboembolism) score ≥1, a left atrial appendage closure device is noninferior to long-term warfarin for stroke prevention. Given this equivalency, quality of life (QOL) indicators are an important metric for evaluating these 2 different strategies. QOL using the Short-Form 12 Health Survey, version 2, measurement tool was obtained at baseline and 12 months in a subset of 547 patients in the PROTECT AF trial (361 device and 186 warfarin patients). The analysis cohort consisted of patients for whom either paired quality of life data were available after 12 months of follow-up or for patients who died. With the device, the total physical score improved in 34.9% and was unchanged in 29.9% versus warfarin in whom 24.7% were improved and 31.7% were unchanged (p = 0.01). Mental health improvement occurred in 33.0% of the device group versus 22.6% in the warfarin group (p = 0.06). There was a significant improvement in QOL in patients randomized to device for total physical score, physical function, and in physical role limitation compared to control. There were significant differences in the change in total physical score among warfarin naive and not-warfarin naive subgroups in the device group compared to control, but larger gains were seen with the warfarin naive subgroup with a 12-month change of 1.3 ± 8.8 versus -3.6 ± 6.7 (p = 0.0004) device compared to warfarin. Patients with nonvalvular AF at risk for stroke treated with left atrial appendage closure have favorable QOL changes at 12 months versus patients treated with warfarin. (WATCHMAN Left Atrial Appendage System for Embolic Protection in Patients With Atrial Fibrillation [WATCHMAN PROTECT]; NCT00129545).


Cellular Diversity in Human Subgenual Anterior Cingulate and Dorsolateral Prefrontal Cortex by Single-Nucleus RNA-Sequencing.
Regional cellular heterogeneity is a fundamental feature of the human neocortex; however, details of this heterogeneity are still undefined. We used single-nucleus RNA-sequencing to examine cell-specific transcriptional features in the dorsolateral PFC (DLPFC) and the subgenual anterior cingulate cortex (sgACC), regions implicated in major psychiatric disorders. Droplet-based nuclei-capture and library preparation were performed on replicate samples from 8 male donors without history of psychiatric or neurologic disorder. Unsupervised clustering identified major neural cell classes. Subsequent iterative clustering of neurons further revealed 20 excitatory and 22 inhibitory subclasses. Inhibitory cells were consistently more abundant in the sgACC and excitatory neuron subclusters exhibited considerable variability across brain regions. Excitatory cell subclasses also exhibited greater within-class transcriptional differences between the two regions. We used these molecular definitions to determine which cell classes might be enriched in loci carrying a genetic signal in genome-wide association studies or for differentially expressed genes in mental illness. We found that the heritable signals of psychiatric disorders were enriched in neurons and that, while the gene expression changes detected in bulk-RNA-sequencing studies were dominated by glial cells, some alterations could be identified in specific classes of excitatory and inhibitory neurons. Intriguingly, only two excitatory cell classes exhibited concomitant region-specific enrichment for both genome-wide association study loci and transcriptional dysregulation. In sum, by detailing the molecular and cellular diversity of the DLPFC and sgACC, we were able to generate hypotheses on regional and cell-specific dysfunctions that may contribute to the development of mental illness.SIGNIFICANCE STATEMENT Dysfunction of the subgenual anterior cingulate cortex has been implicated in mood disorders, particularly major depressive disorder, and the dorsolateral PFC, a subsection of the PFC involved in executive functioning, has been implicated in schizophrenia. Understanding the cellular composition of these regions is critical to elucidating the neurobiology underlying psychiatric and neurologic disorders. We studied cell type diversity of the subgenual anterior cingulate cortex and dorsolateral PFC of humans with no neuropsychiatric illness using a clustering analysis of single-nuclei RNA-sequencing data. Defining the transcriptomic profile of cellular subpopulations in these cortical regions is a first step to demystifying the cellular and molecular pathways involved in psychiatric disorders.


Alzheimer's disease--immunological aspects.
Alzheimer's Disease (A.D.) is a multifarious, complex syndrome, which probably comprises different etiopathogenic subunits. Work by several authors has shown immunological disturbances in A.D. underlining the importance of immunological imbalance in the explanation of the etiopathogenesis and progress of some forms of A.D. An early diagnosis of A.D. is important because changes in central nervous system respond well to immunomodulatory treatment in the early course of disease. This justifies a search for diagnostic methods permitting an early diagnosis of the disease and establishment of immunological disturbances and consequently an early start of treatment. In the present paper, the literature regarding immunological disturbances observed in A.D. patients is reviewed.


Sympathetic activity and blood pressure are tightly coupled at 0.4 Hz in conscious rats.
Interactions of sympathetic nerve activity (SNA) with blood pressure (BP) and heart rate (HR) were assessed in conscious rats while they rested quietly in a cloth sock (n = 7), roamed freely in their home cage (n = 6), and then after anesthesia with pentobarbital (30 mg/kg; n = 7). The power and coherence spectra below 3 Hz were calculated from data collected for 9.56 min. In the conscious rat, SNA spectral power peaked at 0.4 Hz, whereas the majority of spectral power for both BP and HR occurred at frequencies lower than 0.4 Hz. However, there was an inconspicuous peak in the BP power spectra at 0.4 Hz that was not seen in the HR spectra. Coherence between SNA and BP peaked at a frequency of approximately 0.4 Hz, the same frequency at which the SNA spectral peaks occurred. In contrast, at frequencies below 0.4 Hz where maximum BP power occurred, the coherence was considerably lower. Anesthesia with pentobarbital lowered spectral power for BP, SNA, and HR but essentially did not change the coherence between SNA and BP. Interactions between respiration and each of the other variables were weak in the conscious rat. However, prominent respiratory interactions at approximately 1.2 Hz were evident after anesthesia. These data indicate a close coupling between SNA and BP at 0.4 Hz, raising the possibility that the BP spectral power at 0.4 Hz reliably reflects sympathetic activity.


Are annual fluctuations in hip fracture incidence dependent upon the underlying mortality rate?
There is substantial variation in hip fracture incidence rates from one year to the next. To determine whether this is related to varying mortality rates in the underlying population, we carried out an ecological analysis in Rochester and Olmsted County, Minnesota. In a given year, mortality in the general population was not related to hip fracture incidence nor did the fracture incidence rates influence the overall death rate. There was a negative correlation between hip fracture incidence and mortality in the preceding year among women, but not men; the trend was statistically significant among women less than 80 years of age. Both cervical and intertrochanteric hip fractures in women had a similar relationship to mortality in the population the year before. There was no consistent relationship between hip fracture incidence and mortality rates two or three years previously. Although many hip fractures occur in frail individuals near the end of life, patterns of mortality in the underlying population cannot account for the annual variation in hip fracture incidence.


Differential effect of immunoglobulin on the in vitro growth of several isolates of Plasmodium falciparum.
Immunoglobulin isolated from the sera of individuals living in a malarious area of Papua New Guinea was tested for an effect on the growth in vitro of four isolates of Plasmodium falciparum, three from Papua New Guinea and one from Thailand. The Papua New Guinea isolates were inhibited to the same degree by individual immunoglobulin preparations, and inhibition varied from 0 to 98% (assessed by a radioisotopic readout). Immunoglobulin preparations which inhibited the Papua New Guinea isolates caused less inhibition of the Thai parasites. Biosynthetically labeled parasite proteins were analyzed by two-dimensional gel electrophoresis, and differences were detected in the protein and antigenic composition of isolates which differed in their sensitivity to inhibitory immunoglobulin. Three acidic proteins (Mr 200,000, 150,000, and 65,000) were found only in the Papua New Guinea isolates. All Papua New Guinea isolates contained a high-molecular-weight basic protein with an Mr of 220,000 (Pf220), but the corresponding protein of the same molecular weight in the Thai isolate had a more acidic isoelectric point. Another isolate (from Africa) initially showed a degree of resistance to inhibition by Papua New Guinea immunoglobulin (although not to the same extent as the Thai parasite), but in later experiments, this isolate was susceptible to inhibition. During the course of this series of experiments, the antigenic composition of this (uncloned) isolate changed so that it became similar (but not identical) to the Papua New Guinea isolates.


Isomerization and fragmentation reactions of gaseous phenylarsane radical cations and phenylarsanyl cations. A study by tandem mass spectrometry and theoretical calculations.
The unimolecular reactions of radical cations and cations derived from phenylarsane, C6H5AsH2 (1) and dideutero phenylarsane, C6H5AsD2 (1-d2), were investigated by methods of tandem mass spectrometry and theoretical calculations. The mass spectrometric experiments reveal that the molecular ion of phenylarsane, 1*+, exhibits different reactivity at low and high internal excess energy. Only at low internal energy the observed fragmentations are as expected, that is the molecular ion 1*+ decomposes almost exclusively by loss of an H atom. The deuterated derivative 1-d2 with an AsD2 group eliminates selectively a D atom under these conditions. The resulting phenylarsenium ion [C6H5AsH]+, 2+, decomposes rather easily by loss of the As atom to give the benzene radical cation [C6H6]*+ and is therefore of low abundance in the 70 eV EI mass spectrum. At high internal excess energy, the ion 1*+ decomposes very differently either by elimination of an H2 molecule, or by release of the As atom, or by loss of an AsH fragment. Final products of these reactions are either the benzoarsenium ion 4*+, or the benzonium ion [C6H7]+, or the benzene radical cation, [C6H6]*+. As key-steps, these fragmentations contain reductive eliminations from the central As atom under H-H or C-H bond formation. Labeling experiments show that H/D exchange reactions precede these fragmentations and, specifically, that complete positional exchange of the H atoms in 1*+ occurs. Computations at the UMP2/6-311+G(d)//UHF/6-311+G(d) level agree best with the experimental results and suggest: (i) 1*+ rearranges (activation enthalpy of 93 kJ mol(-1)) to a distinctly more stable (DeltaH(r)(298) = -64 kJ mol(-1)) isomer 1 sigma*+ with a structure best represented as a distonic radical cation sigma complex between AsH and benzene. (ii) The six H atoms of the benzene moiety of 1 sigma*+ become equivalent by a fast ring walk of the AsH group. (iii) A reversible isomerization 1+<==>1 sigma*+ scrambles eventually all H atoms over all positions in 1*+. The distonic radical cation 1*+ is predisposed for the elimination of an As atom or an AsH fragment. The calculations are in accordance with the experimentally preferred reactions when the As atom and the AsH fragment are generated in the quartet and triplet state, respectively. Alternatively, 1*(+) undergoes a reductive elimination of H2 from the AsH2 group via a remarkably stable complex of the phenylarsandiyl radical cation, [C6H5As]*+ and an H2 molecule.


Do patients in a medical or surgical ICU benefit from a neurologic consultation?
Neurological complications are common in general medical and surgical intensive care units (ICU); they can prolong ICU and hospital stay and worsen outcome, including mortality. We performed a descriptive analysis of neurological consultations in non-neurological ICUs to determine the frequency of various neurological complications and to assess the diagnostic yield, therapeutic implications and prognostic benefit of these consultations. This is a retrospective single group cohort study of all neurological consultations for patients admitted to non-neurological (medical, respiratory care unit, cardiac, cardiothoracic, surgical and trauma) ICUs at Saint Marys Hospital (Mayo Clinic, Rochester) over a 24-month period (01 January 2010 to 31 December 2011). Equal numbers of neurological consultations (174, 50% each) were requested from medical ICUs and surgical ICUs. Altered consciousness (158, 45%), seizure (76, 22%) and focal deficits (75, 22%) were the most common reasons for consultations. Diagnostic, prognostic and therapeutic benefit was considered present in 89%, 38% and 39% patients respectively. Treatment change following neurological consultation occurred in 48% patients. Encephalopathy, stroke, seizure and anoxic brain injury were the most common causes of neurological complications in non-neurological ICUs with sedatives and opiates being the most common cause of encephalopathy. Almost half of the patients had change in treatment following neurological consultation. Neurological consultations in non-neurological ICU's are beneficial for patient's care in terms of diagnosis, treatment and prognosis.