Health and Disease Imprinted in the Time Variability of the Human Microbiome.
The animal microbiota (including the human microbiota) plays an important role in keeping the physiological status of the host healthy. Research seeks greater insight into whether changes in the composition and function of the microbiota are associated with disease. We analyzed published 16S rRNA and shotgun metagenomic sequencing (SMS) data pertaining to the gut microbiotas of 99 subjects monitored over time. Temporal fluctuations in the microbial composition revealed significant differences due to factors such as dietary changes, antibiotic intake, age, and disease. This article shows that a fluctuation scaling law can describe the temporal changes in the gut microbiota. This law estimates the temporal variability of the microbial population and quantitatively characterizes the path toward disease via a noise-induced phase transition. Estimation of the systemic parameters may be of clinical utility in follow-up studies and have more general applications in fields where it is important to know whether a given community is stable or not. IMPORTANCE The human microbiota correlates closely with the health status of its host. This article analyzes the microbial composition of several subjects under different conditions over time spans that ranged from days to months. Using the Langevin equation as the basis of our mathematical framework to evaluate microbial temporal stability, we proved that stable microbiotas can be distinguished from unstable microbiotas. This initial step will help us to determine how temporal microbiota stability is related to a subject's health status and to develop a more comprehensive framework that will provide greater insight into this complex system.


Oral health condition in an Italian preschool population.
This was to describe caries experience in Sardinian kindergarten children and the possible association with social, behavioural and dietary factors. 418 kindergarten children (209 males, 209 females), aged 2.5-6.5 years, were enrolled. Dental status (dmft, dmfs) and presence of plaque were recorded by one calibrated examiner. Social, behavioural and dietary factors were investigated with an ad hoc prepared questionnaire. These were descriptive and associations between caries experience and background variables were tested using chi square test. Logistic regression models were built up to assess the odds ratios (ORs) of caries prevalence and background variables. The caries experience rate was 29.9% of the total sample. The mean dmfs index was 3.26+/-7.37. The ds mean value was statistically higher in males at 3.41 versus 2.23 in females. Dmfs and sub indices were very high skewed in the total sample and in all age groups. Presence of plaque was recorded in 142 subjects (34.0%) and it was related to caries experience (20.1% without caries and 13.9% with caries) but not statistically significant. In logistic analysis, the socioeconomic status families were positively associated with caries experience OR=1.4 (95% CI: 1.2-1.9). Subjects with high sweet foods consumption showed a higher risk (60%) of caries experience than those not OR=1.6 (95% CI: 1.1-2.3). Children who cared for themselves regarding oral hygiene habits showed a lower risk for caries (OR=0.4 95% CI: 0.2-0.7). This study documented widespread neglect of dental health of preschool children in Sardinia. Untreated decayed teeth dominated the dmfs score among examined population, indicating a high rate of treatment needs.


Multiple chemical sensitivity: on the scent of central sensitization.
Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by recurrent, non-specific symptoms in response to chemically unrelated exposures in non-toxic concentrations. Although the pathophysiology of MCS remains unknown, central sensitization may be an important factor contributing to the clinical manifestations. To use quantitative sensory testing (QST) to study central hyperexcitability and multiple aspects of central sensory processing in MCS patients without comorbid overlapping disorders and to compare the results with those among matched controls. 15 MCS patients and 15 healthy matched controls underwent QST to assess the following aspects of pain: capsaicin-induced secondary punctate hyperalgesia, stimulus response function (SRF) to punctate mechanical stimuli before and after capsaicin injection, temporal summation to punctate stimuli post capsaicin injection, pressure pain thresholds, heat pain thresholds, tonic heat stimulation and conditioning pain modulation (CPM: formerly known as diffuse noxious inhibitory control or DNIC). The mean area of capsaicin-induced secondary punctate hyperalgesia was significantly larger in MCS patients than in controls at 5, 30 and 60 min post capsaicin injection (p=0.01). In addition MCS patients reported higher ratings in response to punctate mechanical stimuli assessed by SRF compared with controls (p<0.001). The CPM test induced significantly higher pain ratings in patients than in controls (p=0.002). We found no group differences in pressure pain and heat pain thresholds, temporal summation to punctate stimuli post capsaicin injection, capsaicin and tonic heat pain ratings or CPM effect. Increased capsaicin-induced secondary punctate hyperalgesia was demonstrated in MCS patients without comorbid, overlapping disorders, suggesting facilitated central sensitization in MCS.


Valence holes observed in nanodiamonds dispersed in water.
Colloidal dispersion is essential for most nanodiamond applications, but its influence on nanodiamond electronic properties remains unknown. Here we have probed the electronic structure of oxidized detonation nanodiamonds dispersed in water by using soft X-ray absorption and emission spectroscopies at the carbon and oxygen K edges. Upon dispersion in water, the π* transitions from sp(2)-hybridized carbon disappear, and holes in the valence band are observed.


Fluid administration prevents renal dysfunction during hypotension under spinal anesthesia in a rat model.
Severe hypotension deteriorates renal functions and renal hemodynamics especially renal cortical blood flow. Systemic hypotension following high level spinal anesthesia may impair renal functions in spite of the blockade of renal sympathetic nerves that may help prevent vasoconstriction. Fluid loading is clinically applied for preventing hypotension but the effects on the changes of renal functions have not been studied. This study was designed to investigate the effects of fluid loading on systemic hemodynamics, renal hemodynamics and functions especially the blood distribution to renal cortex. A rat model was used in our study. Intravenous normal saline infusion was started in both control group (5 ml/kg/h, 8 rats) and fluid loading group (15 ml/kg/h, 8 rats) 30 min before spinal anesthesia. A high level (above T4) spinal anesthesia was conducted via a preset intrathecal catheter with 0.5% hyperbaric bupivacaine. Blood pressure, heart rate and renal cortical microvascular blood flow (CMBF) were measured via a laser Doppler probe firmly contacted on renal cortex and recorded continuously after spinal anesthesia. Renal functions including glomerular filtration rates (GFR, by inulin clearance), effective renal plasma flow (ERPF, by P-aminohippurate clearance), urine flow rate (UFR) and electrolytes excretion were measured every 30 min after spinal anesthesia. Severe hypotension was notable within 5-10 min after intrathecal anesthesia and recovered with 30 min in both groups but the difference was not significant between groups. In the control group, GFR and ERPF decreased significantly in the first 30 min by 51.9 +/- 19.8% and 44.3 +/- 13.7% respectively (P < 0.05) and recovered after 60 min. Also the deteriorations of UFR and CMBF were significantly longer (over 60 min). In fluid loading group, ERPF, UFR and CMBF could maintain throughout the experiment but only GFR was affected in the first 30 min. Fluid administration did not prevent hypotension following high level spinal anesthesia but might have beneficial effects on renal hemodynamics especially on the renal cortical circulation and urine flow rate.


Analysis of factorial time-course microarrays with application to a clinical study of burn injury.
Time-course microarray experiments are capable of capturing dynamic gene expression profiles. It is important to study how these dynamic profiles depend on the multiple factors that characterize the experimental condition under which the time course is observed. Analytic methods are needed to simultaneously handle the time course and factorial structure in the data. We developed a method to evaluate factor effects by pooling information across the time course while accounting for multiple testing and nonnormality of the microarray data. The method effectively extracts gene-specific response features and models their dependency on the experimental factors. Both longitudinal and cross-sectional time-course data can be handled by our approach. The method was used to analyze the impact of age on the temporal gene response to burn injury in a large-scale clinical study. Our analysis reveals that 21% of the genes responsive to burn are age-specific, among which expressions of mitochondria and immunoglobulin genes are differentially perturbed in pediatric and adult patients by burn injury. These new findings in the body's response to burn injury between children and adults support further investigations of therapeutic options targeting specific age groups. The methodology proposed here has been implemented in R package "TANOVA" and submitted to the Comprehensive R Archive Network at http://www.r-project.org/. It is also available for download at http://gluegrant1.stanford.edu/TANOVA/.


The invasive shrub, Lonicera maackii, reduces growth and fecundity of perennial forest herbs.
Effects of invasive plant species on native plant species are frequently assumed or inferred from comparisons, but rarely quantified experimentally. Such quantification is important to assessing risks and impacts of invasives. We quantified the effects of Lonicera maackii, an exotic shrub invasive in many eastern North American forests, on survival, growth, and reproduction of three perennial herbs: Allium burdickii, Thalictrum thalictroides , and Viola pubescens. We predicted that the spring ephemeral, A. burdickii , would be most impacted, due to early leaf expansion of L. maackii. Field experiments were carried out in two deciduous forest stands, one (Gregg's Woodlot, GW) disturbed and the other (Western Woods, WW) relatively undisturbed. In each stand, individual herbs were transplanted into a blocked design of 60 plots where L. maackii was present, absent, or removed, and monitored for 5 growing seasons. Lonicera maackii did not affect survival of transplants, but reduced growth and final size of individuals of all three species. For two of the species, A. burdickii and V. pubescens, L. maackii reduced the proportion of live plants flowering in both stands, and reduced the seed or fruit number per flowering individual in GW. For T. thalictroides the proportion flowering was not affected, but seed number per flowering plant was reduced by L. maackii in both stands. For all three species, cumulative seed production over the course of the study was reduced by L. maackii. Overall, effects on the spring ephemeral, A. burdickii, were similar to effects on the other herbs. Because mortality of these established individuals was not affected, short-term studies might conclude forest herbs are unaffected by invasive shrubs. However, the growth and reproduction impacts documented here suggest that populations are impacted in the long-term.


Anthropometry, physical activity, and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition.
Tobacco smoking is the only established risk factor for pancreatic cancer. Results from several epidemiologic studies have suggested that increased body mass index and/or lack of physical activity may be associated with an increased risk of this disease. We examined the relationship between anthropometry and physical activity recorded at baseline and the risk of pancreatic cancer in the European Prospective Investigation into Cancer and Nutrition (n = 438,405 males and females age 19-84 years and followed for a total of 2,826,070 person-years). Relative risks (RR) were calculated using Cox proportional hazards models stratified by age, sex, and country and adjusted for smoking and self-reported diabetes and, where appropriate, height. In total, there were 324 incident cases of pancreatic cancer diagnosed in the cohort over an average of 6 years of follow-up. There was evidence that the RR of pancreatic cancer was associated with increased height [RR, 1.74; 95% confidence interval (95% CI), 1.20-2.52] for highest quartile compared with lowest quartile (P(trend) = 0.001). However, this trend was primarily due to a low risk in the lowest quartile, as when this group was excluded, the trend was no longer statistically significant (P = 0.27). A larger waist-to-hip ratio and waist circumference were both associated with an increased risk of developing the disease (RR per 0.1, 1.24; 95% CI, 1.04-1.48; P(trend) = 0.02 and RR per 10 cm, 1.13; 95% CI, 1.01-1.26; P(trend) = 0.03, respectively). There was a nonsignificant increased risk of pancreatic cancer with increasing body mass index (RR, 1.09; 95% CI, 0.95-1.24 per 5 kg/m(2)), and a nonsignificant decreased risk with total physical activity (RR, 0.82; 95% CI, 0.50-1.35 for most active versus inactive). Future studies should consider including measurements of waist and hip circumference, to further investigate the relationship between central adiposity and the risk of pancreatic cancer.


Effect of target spatial frequency on accommodative response in myopes and emmetropes.
This study investigates whether systematic differences exist between the accommodation response/stimulus curves of emmetropes and myopes when the targets are sinusoidal gratings, in particular whether myopic accommodation is relatively less effective when presented with targets of high spatial frequency due to increased tolerance to defocus blur. Ten emmetropes (overall mean sphere +0.19 D, range -0.37 to +1.37 D) and 10 myopes (overall mean sphere -2.89 D, range -1.13 to -6.63 D) viewed Gabor targets with dominant frequencies 1, 4, 8 and 16 c/deg. Maximal grating contrast was 80% and the full, green, stimulus field was 6 deg. Subjects were aged between 18 and 37 years. A further high-contrast 6/30 optotype target was included for comparison purposes. Viewing was monocular, the other eye being occluded. Stimulus demand was varied with trial lenses over the nominal range 0 to 6.0 D and the corresponding accommodation responses were recorded with an open-view, Shin-Nippon SRW-5000 auto-refractor. The resulting accommodation response/stimulus curves were characterized by their slopes over the stimulus range 1.5 to 6.0 D and by an "error index" indicating the extent to which the responses differed from the ideal 1:1 response/stimulus line. No significant differences were found between the mean accommodative behavior of the two refractive groups for any target. There were, however, substantial inter-subject differences. Some subjects in both groups showed more accurate responses with the higher spatial-frequency targets, while others showed optimal response at intermediate frequencies. Although it has been reported in the literature that, in comparison to emmetropes, myopes have reduced sensitivity to blur and response/stimulus curves of lower slope, the present study failed to demonstrate any reduction in their responses to gratings of relatively high spatial frequency. For each target the two refractive groups showed similar accommodative behavior.


A change point model for estimating the onset of cognitive decline in preclinical Alzheimer's disease.
Dementia is characterized by accelerated cognitive decline before and after diagnosis as compared to normal ageing. Determining the time at which that rate of decline begins to accelerate in persons who will develop dementia is important both in describing the natural history of the disease process and in identifying the optimal time window for which treatments might be useful. We model that time at which the rate of decline begins to accelerate in persons who develop dementia relative to those who do not by using a change point in a mixed linear model. A profile likelihood method is proposed to draw inferences about the change point. The method is applied to data from the Bronx Ageing Study, a cohort study of 488 initially non-demented community-dwelling elderly individuals who have been examined at approximately 12-month intervals over 15 years. Cognitive function was measured using the Buschke Selective Reminding test, a memory test with high reliability and known discriminative validity for detecting dementia. We found that the rate of cognitive decline as measured by this test in this cohort increases on average 5.1 years before the diagnosis of dementia.


Randomized comparison of the influence of dietary management and/or physical exercise on ovarian function and metabolic parameters in overweight women with polycystic ovary syndrome.
To compare the influence of dietary management and/or physical exercise on ovarian function and metabolic variables in women with polycystic ovary syndrome (PCOS). Randomized 4-month trial with three interventions and a long-term follow-up. Women's health clinical research unit at a university hospital. Fifty-seven overweight/obese women with PCOS. Dietary management, physical exercise, or both, using programs individually adapted and supervised by a dietician and/or a physical therapist. Ovarian function, endocrinologic, and metabolic status and body composition. On average, body mass index was reduced 6% by the dietary management, 3% by the exercise, and 5% by the combined interventions. Lower body fat and lean body mass were significantly decreased in the dietary groups, whereas upper body fat was lowered and lean body mass maintained by exercise alone. The menstrual pattern was significantly improved in 69% and ovulation confirmed in 34% of the patients, with no differences among the groups. The strongest predictor of resumed ovulation was a high serum level of insulin-like growth factor-binding protein 1 after the intervention. Follow-up of one-half of the patients for a median of 2.8 years revealed sustained weight reduction and improvement in menstrual pattern. Dietary management and exercise, alone or in combination, are equally effective in improving reproductive function in overweight/obese women with PCOS. The underlying mechanisms appear to involve enhanced insulin sensitivity. Supportive individualized programs for lifestyle change could exert long-term beneficial effects.


Improved word comprehension in Global aphasia using a modified semantic feature analysis treatment.
Limited research has investigated treatment of single word comprehension in people with aphasia, despite numerous studies examining treatment of naming deficits. This study employed a single case experimental design to examine efficacy of a modified semantic feature analysis (SFA) therapy in improving word comprehension in an individual with Global aphasia, who presented with a semantically based comprehension impairment. Ten treatment sessions were conducted over a period of two weeks. Following therapy, the participant demonstrated improved comprehension of treatment items and generalisation to control items, measured by performance on a spoken word picture matching task. Improvements were also observed on other language assessments (e.g. subtests of WAB-R; PALPA subtest 47) and were largely maintained over a period of 12 weeks without further therapy. This study provides support for the efficacy of a modified SFA therapy in remediating single word comprehension in individuals with aphasia with a semantically based comprehension deficit.


A novel sLRP6E1E2 inhibits canonical Wnt signaling, epithelial-to-mesenchymal transition, and induces mitochondria-dependent apoptosis in lung cancer.
Aberrant activation of the Wnt pathway contributes to human cancer progression. Antagonists that interfere with Wnt ligand/receptor interactions can be useful in cancer treatments. In this study, we evaluated the therapeutic potential of a soluble Wnt receptor decoy in cancer gene therapy. We designed a Wnt antagonist sLRP6E1E2, and generated a replication-incompetent adenovirus (Ad), dE1-k35/sLRP6E1E2, and a replication-competent oncolytic Ad, RdB-k35/sLRP6E1E2, both expressing sLRP6E1E2. sLRP6E1E2 prevented Wnt-mediated stabilization of cytoplasmic β-catenin, decreased Wnt/β-catenin signaling and cell proliferation via the mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways. sLRP6E1E2 induced apoptosis, cytochrome c release, and increased cleavage of PARP and caspase-3. sLRP6E1E2 suppressed growth of the human lung tumor xenograft, and reduced motility and invasion of cancer cells. In addition, sLRP6E1E2 upregulated expression of epithelial marker genes, while sLRP6E1E2 downregulated mesenchymal marker genes. Taken together, sLRP6E1E2, by inhibiting interaction between Wnt and its receptor, suppressed Wnt-induced cell proliferation and epithelial-to-mesenchymal transition.


Lymphoepithelial cyst of the pancreas: report of a case.
An extremely rare case of a lymphoepithelial cyst (LEC) of the pancreas is described herein. A pancreatic cystic tumor was initially detected in a 50-year-old man at a medical checkup. On admission, his serum carbohydrate antigen (CA) 19-9 level was 8100 U/ml and a computed tomography scan revealed a well-circumscribed multilocular cystic tumor in the pancreatic head and body. Magnetic resonance cholangiopancreatography showed no communication between the pancreatic ducts and the tumor. A distal pancreatectomy with lymph node dissection was performed because the lesion was suspected to be a mucinous cystadenoma or cystadenocarcinoma of the pancreas. However, histological examination revealed that the cyst was lined by stratified squamous epithelium and surrounded by lymphoid tissue. thereby confirming the diagnosis of LEC of the pancreas. The superficial layer of squamous epithelium and the cystic contents were found to be immunohistologically positive for CA19-9. Establishing a preoperative diagnosis of LEC is quite difficult because it resembles other cystic neoplasms of the pancreas in radiographic features and is frequently associated with an elevation of serum tumor markers such as CA19-9.


Ambidentate coordination in hydrogen bonded dimethyl sulfoxide, (CH3)2SO...H3O+, and in dichlorobis(dimethyl sulfoxide) palladium(II) and platinum(II) solid solvates, by vibrational and sulfur K-edge X-ray absorption spectroscopy.
The strongly hydrogen bonded species (CH3)2SO...H3O+ formed in concentrated hydrochloric acid displays a new low energy feature in its sulfur K-edge X-ray absorption near edge structure (XANES) spectrum. Density Functional Theory-Transition Potential (DFT-TP) calculations reveal that the strong hydrogen bonding decreases the energy of the transition S(1s) --> LUMO, which has antibonding sigma*(S-O) character, with about 0.8 eV. Normal coordinate force field analyses of the vibrational spectra show that the SO stretching force constant decreases from 4.72 N cm(-1) in neat liquid dimethyl sulfoxide to 3.73 N cm(-1) for the hydrogen bonded (CH3)2SO...H3O+ species. The effects of sulfur coordination on the ambidentate dimethyl sulfoxide molecule were investigated for the trans-Pd((CH3)2SO)2Cl2, trans-Pd((CD3)2SO)2Cl2 and cis-Pt((CH3)2SO)2Cl2 complexes with square planar coordination of the chlorine and sulfur atoms. The XANES spectra again showed shifts toward low energy for the transition S(1 s) --> LUMO, now with antibonding sigma*(M-Cl, M-S) character, with a larger shift for M = Pt than Pd. DFT-TP calculations indicated that the differences between the XANES spectra of the geometrical cis and trans isomers of the M((CH3)2SO)2Cl2 complexes are expected to be too small to allow experimental distinction. The vibrational spectra of the palladium(II) and platinum(II) complexes were recorded and complete assignments of the fundamentals were achieved. Even though the M-S bond distances are quite similar the high covalency especially of the Pt-S bonds induces significant increases in the S-O stretching force constants, 6.79 and 7.18 N cm(-1), respectively.


Mouse preimplantation embryo responses to culture medium osmolarity include increased expression of CCM2 and p38 MAPK activation.
Mechanisms that confer an ability to respond positively to environmental osmolarity are fundamental to ensuring embryo survival during the preimplantation period. Activation of p38 mitogen-activated protein kinase (MAPK) occurs following exposure to hyperosmotic treatment. Recently, a novel scaffolding protein called Osmosensing Scaffold for MEKK3 (OSM) was linked to p38 MAPK activation in response to sorbitol-induced hypertonicity. The human ortholog of OSM is cerebral cavernous malformation 2 (CCM2). The present study was conducted to investigate whether CCM2 is expressed during mouse preimplantation development and to determine whether this scaffolding protein is associated with p38 MAPK activation following exposure of preimplantation embryos to hyperosmotic environments. Our results indicate that Ccm2 along with upstream p38 MAPK pathway constituents (Map3k3, Map2k3, Map2k6, and Map2k4) are expressed throughout mouse preimplantation development. CCM2, MAP3K3 and the phosphorylated forms of MAP2K3/MAP2K6 and MAP2K4 were also detected throughout preimplantation development. Embryo culture in hyperosmotic media increased p38 MAPK activity in conjunction with elevated CCM2 levels. These results define the expression of upstream activators of p38 MAPK during preimplantation development and indicate that embryo responses to hyperosmotic environments include elevation of CCM2 and activation of p38 MAPK.


Discontinuation of Infliximab in Patients With Ulcerative Colitis Is Associated With Increased Risk of Relapse: A Multinational Retrospective Cohort Study.
Infliximab is a safe and effective therapy for ulcerative colitis (UC). We conducted a multicenter retrospective cohort study that included 7 European countries and Israel to examine whether infliximab discontinuation can be considered for patients who achieve sustained remission. We performed a retrospective cohort study, collecting medical records from 13 tertiary care referral inflammatory bowel disease centers of all patients with UC treated with infliximab (n = 193). We compared the disease course of patients with at least 12 months of clinical remission who discontinued infliximab (n = 111) with that of patients who continued scheduled treatment (controls, n = 82). We examined the incidence rates of relapse, hospitalization and colectomy, the comparative effectiveness of different therapeutic strategies after discontinuation, and assessed the rates of response, remission, and adverse effects after infliximab re-initiation. Statistical analyses used time-to-event methods. In the entire cohort, 67 patients (34.7%) relapsed during the follow-up period. The incidence rate of relapse was significantly higher after discontinuation (23.3 per 100 person-years) compared with the control group (7.2 per 100 person-years) in univariable analysis (log-rank P < .001; hazard ratio, 3.41; 95% confidence interval, 1.88-6.20) and multivariable analysis (hazard ratio, 3.70; 95% confidence interval, 2.02-6.77). Rates of hospitalization and colectomy did not differ between groups. Thiopurines appeared to be the best treatment option after infliximab discontinuation (incidence of relapse: 15.0 per 100 person-years for thiopurines, 27.4 per 100 person-years for thiopurines plus aminosalicylates, and 31.2 per 100 person-years for aminosalicylates alone; log-rank P = .032). Response was regained in 77.1% of patients and remission in 51.4% of patients who re-initiated infliximab. However, 17.1% had infusion reactions and 17.1% reported other adverse events. In a multinational retrospective cohort study of patients with UC in sustained clinical remission, we associated discontinuation of infliximab with an increased risk of relapse. Treatment re-initiation is effective and safe.


Separation of photo-induced radical pair in cryptochrome to a functionally critical distance.
Cryptochrome is a blue light receptor that acts as a sensor for the geomagnetic field and assists many animals in long-range navigation. The magnetoreceptor function arises from light-induced formation of a radical pair through electron transfer between a flavin cofactor (FAD) and a triad of tryptophan residues. Here, this electron transfer is investigated by quantum chemical and classical molecular dynamics calculations. The results reveal how sequential electron transfer, assisted by rearrangement of polar side groups in the cryptochrome interior, can yield a FAD-Trp radical pair state with the FAD and Trp partners separated beyond a critical distance. The large radical pair separation reached establishes cryptochrome's sensitivity to the geomagnetic field through weakening of distance-dependent exchange and dipole-dipole interactions. It is estimated that the key secondary electron transfer step can overcome in speed both recombination (electron back-transfer) and proton transfer involving the radical pair reached after primary electron transfer.


Polyamine metabolism: a potential therapeutic target in trypanosomes.
alpha-Difluoromethylornithine (RMI 71,782), a specific irreversible inhibitor of the first step in polyamine biosynthesis, that is, the formation of putrescine from ornithine by ornithine decarboxylase, cures mice infected with a virulent, rodent-passaged strain of Trypanosoma brucei brucei. This parasite is closely related to the trypanosomes that cause human sleeping sickness. The drug, which is remarkably nontoxic, was effective when administered in drinking water or by intubation. The ability of the compound to inhibit ornithine decarboxylase in vitro was demonstrated by the reduced amounts of putrescine synthesized from tritiated ornithine in Trypanosoma brucei suspensions. These observations direct attention to polyamine metabolism as a target for chemotherapy of parasitic diseases.


Xenon arc panretinal photocoagulation for central retinal vein occlusion: a randomised prospective study.
Thirty-three patients with central vein occlusion were evaluated for the effects of scatter xenon arc panretinal photocoagulation. Thirty-four eyes (2 eyes of 1 patient) were randomly divided into a treatment (15 eyes) and a nontreatment group (19 eyes). The average follow-up per eye has been 29 months. The visual prognosis was not significantly better in either group. There was no difference in the development of fundus neovascularisation between groups. None of the patients in the treated group developed rubeosis or neovascular glaucoma. Two patients in the nontreatment group initially had rubeosis and 3 developed it after entry. All 5 involved eyes developed neovascular glaucoma. A significantly greater amount of central retinal capillary drop-out was present in the untreated eyes that developed rubeosis than those untreated eyes which did not. The eyes in the treated group had a similar range of capillary drop-out area, but none of these eyes developed rubeosis or neovascular glaucoma. Panretinal photocoagulation prevented the development of rubeosis and neovascular glaucoma in susceptible eyes.


A novel study on association between untreated hearing loss and cognitive functions of older adults: Baseline non-verbal cognitive assessment results.
Age-related hearing loss (ARHL) is highly prevalent in older adults, and more than two-thirds above age of 70 years suffer from ARHL. Recent studies have established a link between ARHL and cognitive impairment; however, most of the studies have used verbally loaded cognitive measures to investigate the association between ARHL and cognition. It is possible that due to hearing impairment, the elderly may experience difficulty in following verbal instructions or completing tasks that heavily rely on hearing during cognitive assessments. This may result in overestimation of cognitive impairment in such individuals. This baseline cross-sectional study investigated the associations between untreated hearing loss and a number of cognitive functions using a battery of non-verbal cognitive tests. Further, association between hearing loss and psychological status of older adults was examined. Prospective case-controlled study. A total of 119 participants (54 males, M=66.33±10.50 years; 65 females M=61.51±11.46 years) were recruited. All participants completed a hearing assessment, a computerised test battery of non-verbal cognitive functions and the depression, anxiety and stress scale. Hierarchical multiple regression analysis results revealed that hearing thresholds significantly associated with the working memory (P<0.05), paired associative learning scores (P<0.05), depression (P<0.001), and anxiety (P<0.001) and stress (P<0.001) scores. Analysis of covariance results revealed that participants with moderately-severe hearing loss performed significantly poorer in paired associative learning and working memory tasks and psychological function tests compared to those with normal hearing. Results of the current study suggest a significant relationship between ARHL and both cognition and psychological status. Our results also have some implications for using non-verbal cognitive tests to evaluate cognitive functions in post-lingually hearing impaired ageing adults, at least for those with more than moderately-severe levels of hearing loss.


Organized Violence and Institutional Child Delivery: Micro-Level Evidence From Sub-Saharan Africa, 1989-2014.
The conditions under which a mother gives birth greatly affect the health risk of both the mother and the child. This article addresses how local exposure to organized violence affects whether women give birth in a health facility. We combine geocoded data on violent events from the Uppsala Conflict Data Program with georeferenced survey data on the use of maternal health care services from the Demographic and Health Surveys. Our sample covers 569,201 births by 390,574 mothers in 31 countries in sub-Saharan Africa. We use a mother fixed-effects analysis to estimate the effect of recent organized violence events within a radius of 50 km of the home of each mother on the likelihood that her child is born in a health facility. The results indicate that geographical and temporal proximity to organized violence significantly reduces the likelihood of institutional births. Although the level of maternal health care overall is lower in rural areas, the negative effect of violence appears to be stronger in urban areas. The study further underscores the importance of household and individual resilience, indicating that the effect of organized violence on institutional child delivery is greater among poor and less-educated mothers.


Microparasites and Placental Invasiveness in Eutherian Mammals.
Placental invasiveness-the number of maternal tissue layers separating fetal tissues from maternal blood-is variable across mammalian species. Although this diversity is likely to be functionally important, variation in placental invasiveness remains unexplained. Here we test the hypothesis that increased risk of transplacental transmission of pathogens from the mother to the fetus promotes the evolution of non-invasive placentation, the most likely derived condition in eutherian mammals. Specifically, we predict that non-invasive placentation is associated with increased microparasite species richness relative to more invasive placental types, based on the assumption that higher numbers of microparasites in a population reflects greater risk of transplacental transmission to fetuses. As predicted, higher bacteria species richness is associated with non-invasive placentation. Protozoa species richness, however, shows the opposite pattern. Because invasive placentae facilitate the transfer of maternal antibodies to the fetus, we propose that the ancestral condition of invasive placentation is retained under selection for protection of newborns from higher risk of postnatal protozoan infection. Hence, our findings suggest that a tradeoff exists between protection against bacterial infection prenatally and protozoan infection postnatally. Future studies are needed to investigate how maternal prevalence of infection and the relative pre- versus postnatal risk of fetal infection by different microparasite groups vary among mammalian hosts in relation to placental invasiveness.


Association of longitudinal alcohol consumption trajectories with coronary heart disease: a meta-analysis of six cohort studies using individual participant data.
Studies have shown that alcohol intake trajectories differ in their associations with biomarkers of cardiovascular functioning, but it remains unclear if they also differ in their relationship to actual coronary heart disease (CHD) incidence. Using multiple longitudinal cohort studies, we evaluated the association between long-term alcohol consumption trajectories and CHD. Data were drawn from six cohorts (five British and one French). The combined analytic sample comprised 35,132 individuals (62.1% male; individual cohorts ranging from 869 to 14,247 participants) of whom 4.9% experienced an incident (fatal or non-fatal) CHD event. Alcohol intake across three assessment periods of each cohort was used to determine participants' intake trajectories over approximately 10 years. Time to onset for (i) incident CHD and (ii) fatal CHD was established using surveys and linked medical record data. A meta-analysis of individual participant data was employed to estimate the intake trajectories' association with CHD onset, adjusting for demographic and clinical characteristics. Compared to consistently moderate drinkers (males: 1-168 g ethanol/week; females: 1-112 g ethanol/week), inconsistently moderate drinkers had a significantly greater risk of incident CHD [hazard ratio (HR) = 1.18, 95% confidence interval (CI) = 1.02-1.37]. An elevated risk of incident CHD was also found for former drinkers (HR = 1.31, 95% CI = 1.13-1.52) and consistent non-drinkers (HR = 1.47, 95% CI = 1.21-1.78), although, after sex stratification, the latter effect was only evident for females. When examining fatal CHD outcomes alone, only former drinkers had a significantly elevated risk, though hazard ratios for consistent non-drinkers were near identical. No evidence of elevated CHD risk was found for consistently heavy drinkers, and a weak association with fatal CHD for inconsistently heavy drinkers was attenuated following adjustment for confounding factors. Using prospectively recorded alcohol data, this study has shown how instability in drinking behaviours over time is associated with risk of CHD. As well as individuals who abstain from drinking (long term or more recently), those who are inconsistently moderate in their alcohol intake have a higher risk of experiencing CHD. This finding suggests that policies and interventions specifically encouraging consistency in adherence to lower-risk drinking guidelines could have public health benefits in reducing the population burden of CHD. The absence of an effect amongst heavy drinkers should be interpreted with caution given the known wider health risks associated with such intake. ClinicalTrials.gov, NCT03133689 .


The Pyramid Trough Wetland: environmental and biological diversity in a newly created Antarctic protected area.
The Pyramid Trough (Lat 78°S) has recently gained protection under the Antarctic Treaty system, owing to its wetland values. Here, we describe the microbial diversity of this system, with emphasis on cyanobacteria, and evaluate environment-biota relationships. Geochemistry separates ponds along hydrological gradients receiving recent inflows of dilute meltwater, from a second group that is rarely inundated and where chemistry is dominated by evaporation. Cyanobacteria-based microbial mats dominated the biota throughout. Mats were characterized by light-microscopy, pigment analysis, automated ribosomal intergenic spacer analysis and 16S rRNA gene clone libraries. A total of 17 morphotypes and 21 ribotypes were identified, mostly Oscillatoriales and several taxa that are usually rare in continental Antarctica, including Chroococcales and scytomin-rich Calothrix/Dichothrix, were abundant. There was a general decline in cyanobacterial diversity with increasing conductivity, but weak support for either differences in community composition between the two groups of ponds or sorting of taxa along the hydrological gradients with the pond groups. This implies a broad environmental tolerance and a prevalence of neutral assembly mechanisms in cyanobacterial communities of Antarctic wetland ecosystems.


Large tumour-derived extracellular vesicles as prognostic indicators of metastatic cancer patient survival.
Extracellular vesicles (EVs) are released by all cells and produced at particularly high levels by many cancer cells, often inducing pro-tumorigenic effects. Since these cancer EVs carry tumour proteins and RNAs, they can potentially be used at biomarkers. The heterogeneity of surface markers and cargos carried by EVs, however, presents some challenges to developing such approaches. Nanou et al. [1] found that automated counting of large tumour-derived EVs (tdEVs) performed at least as effectively as counting circulating tumour-derived cells (CTCs) and with higher sensitivity, in distinguishing the survival of patients with castration-resistant prostate cancer (CRPC), metastatic colorectal cancer (mCRC) and metastatic breast cancer (MBC), but not for non-small cell lung cancer (NSCLC). Subsequent work has suggested that these tdEVs may also be used to assess tumour subtype and that the number of large EVs produced by endothelial cells can also be increased in cancer patients. While by itself, the tdEV imaging approach used by Nanou et al. [1] is not specific enough to predict the survival of individual patients, in combination with other EV-associated assays, this test, perhaps enhanced through the inclusion of other tumour antigens, could prove invaluable in predicting cancer survival and other outcomes in the clinic.


Intravitreal devices for the treatment of vitreous inflammation.
The eye is a well-suited organ for local delivery of therapeutics to treat vitreous inflammation as well as other pathologic conditions that induce visual loss. Several conditions are particularly challenging to treat and often require chronic courses of therapy. The use of implantable intravitreal devices for drug delivery is an emerging field in the treatment of vitreous inflammation as well as other ophthalmologic diseases. There are unique challenges in the design of these devices which include implants, polymers, and micro- and nanoparticles. This paper reviews current and investigational drug delivery systems for treating vitreous inflammation as well as other pathologic conditions that induce visual loss. The use of nonbiodegradable devices such as polyvinyl alcohol-ethylene vinyl acetate polymers and polysulfone capillary fibers, and biodegradable devices such as polylactic acid, polyglycolic acid, and polylactic-co-glycolic acid, polycaprolactones, and polyanhydrides are reviewed. Clinically used implantable devices for therapeutic agents including ganciclovir, fluocinolone acetonide, triamcinolone acetonide, and dexamethasone are described. Finally, recently developed investigational particulate drug delivery systems in the form of liposomes, microspheres, and nanoparticles are examined.


Cellular uptake of drug loaded spider silk particles.
Medical therapies are often accompanied by un-wanted side-effects or, even worse, targeted cells can develop drug resistance leading to an ineffective treatment. Therefore, drug delivery systems are under investigation to lower the risk thereof. Drug carriers should be biocompatible, biodegradable, nontoxic, non-immunogenic, and should show controllable drug loading and release properties. Previous studies qualified spider silk particles as drug delivery carriers, however, cellular uptake was only tested with unloaded spider silk particles. Here, the effect of drug loading on cellular uptake of previously established spider silk-based particles made of eADF4(C16), eADF4(C16)RGD, eADF4(C16)R8G and eADF4(κ16) was investigated. Fluorescently labelled polyethylenimine was used as a model substance for loading eADF4(C16), eADF4(C16)RGD or eADF4(C16)R8G particles, and fluorescently labelled ssDNA was used for loading eADF4(κ16) particles. Upon loading polyanionic eADF4(C16) and eADF4(C16)RGD particles with polycationic polyethylenimine the cellular uptake efficiency was increased, while the uptake of eADF4(C16)R8G and polycationic eADF4(κ16) particles was decreased upon substance loading. The latter could be circumvented by coating substance-loaded eADF4(κ16) particles with an additional layer of eADF4(κ16) (layer-by-layer coating). Further, it could be shown that eADF4(C16)RGD and eADF4(κ16) uptake was based on clathrin-mediated endocytosis, whereas macropinocytosis was more important in case of eADF4(C16) and eADF4(C16)R8G particle uptake. Finally, it was confirmed that drugs, such as doxorubicin, can be efficiently delivered into and released within cells when spider silk particles were used as a carrier.


Acute and preventive pharmacologic treatment of cluster headache.
Cluster headache (CH) is a rare and disabling primary headache disorder. CH attacks are unilateral, short, severe headaches associated with ipsilateral autonomic symptoms that occur in a periodic fashion. We provide a systematic review and meta-analysis of existing trials of pharmacotherapy for CH and evidence-based suggestions for acute abortive treatment and preventive therapy for cluster headache. Prospective, double-blind, randomized controlled trials of any pharmacologic agent for the symptomatic relief or prevention of CH were included in this evidence-based review. The main outcomes considered were headache response and pain-free response at 15 and 30 minutes for acute treatment trials, and the cessation of CH attacks within a specific time period or the number of days on which CH attacks occurred for preventive trials. Twenty-seven trials were included in the analysis. The American Academy of Neurology quality criteria were used to assess trial quality and to grade advisements. Based on the evidence, for acute treatment of CH, Level A advice can be given for subcutaneous sumatriptan 6 mg, zolmitriptan nasal spray 5 mg and 10 mg, and 100% oxygen 6-12 L/min. Level B advice can be given for sumatriptan nasal spray 20 mg and oral zolmitriptan 5 mg and 10 mg. For the prevention of CH, Level B advice can be given for intranasal civamide 100 microg daily and suboccipital steroid injections, and Level C advice can be given for verapamil 360 mg, lithium 900 mg, and melatonin 10 mg.


Plasma neurofilament light chain and glial fibrillary acidic protein predict stroke in CADASIL.
Stroke remains the most cumbersome disease burden in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). This study aimed to investigate whether plasma biomarkers can reflect disease severity and predict stroke recurrence in CADASIL patients. Sixty-three CADASIL patients (mean age 58.9 ± 9.3 years old, male 63%) from a multicenter registry and 17 controls were recruited. Plasma biomarkers, namely neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), tau, and ubiquitin carboxy-terminal hydrolase L1 (UCHL1), were measured using an ultra-sensitive single molecule array at baseline. Neuroimaging markers assessed included the Fazekas scale of white matter hyperintensity, numbers of lacunes, and cerebral microbleeds (CMBs). Cox proportional hazards regression models were applied to calculate the hazard ratio (HR) of plasma biomarkers at baseline for predicting incident stroke during follow-up. Plasma NfL, GFAP, and UCHL1 levels were significantly elevated in the CADASIL patients than in the controls. Among the CADASIL patients, both plasma NfL and GFAP levels positively correlated with the numbers of CMBs (r = 0.32 and r = 0.37, respectively; both p < 0.05). Higher plasma levels of NfL and GFAP were associated with any stroke (odds ratio 2.02, 95% confidence interval [CI] 1.06-3.87) and ICH (odds ratio 2.06, 95% CI 1.26-3.35) at baseline, respectively. Within a mean follow-up period of 3.1 ± 2.1 years, 10 patients (16%) had incident stroke and 6 of them were ICH. Higher baseline NfL (HR 1.93, 95% CI 1.19-3.13) predicted any incident stroke, whereas higher GFAP (HR 2.80, 95% CI 1.21-6.53) predicted incident ICH. In CADASIL patients, plasma NfL can be a promising biomarker for monitoring incident stroke, whereas GFAP may have a role in cerebral hemorrhage.


Nexus between epidermolysis bullosa and transcriptional regulation by thyroid hormone in epidermal keratinocytes.
Abstract Thyroid hormone, T3, through the interaction of its receptor with the recognition sequences in the DNA, regulates gene expression. This regulation includes the promoter activity of keratin genes. The receptor shares coregulators with other members of the nuclear receptor family, including RXR. Intending to define the transcriptional effects of thyroid hormones in keratinocytes, we used Affymetrix microarrays to comprehensively compare the genes expressed in T3-treated and untreated human epidermal keratinocytes. The transcriptomes were compared at 1, 4, 24, 48, and 72 hours. Surprisingly, T3 induced only 9 and suppressed 28 genes, much fewer than expected. Significantly, genes associated with epidermolysis bullosa, a set of inherited blistering skin diseases, were found statistically highly overrepresented among the suppressed genes. These genes include Integrin beta4, Plectin, Collagen XVII, MMP1, MMP3, and MMP14. The data imply that in keratinocytes T3 could suppresses the remodeling by, attachment to, and production of extracellular matrix. The results suggest that topical treatment with T3 may be effective for alleviation of symptoms in patients with epidermolysis bullosa.


Aspirin in patients undergoing noncardiac surgery.
There is substantial variability in the perioperative administration of aspirin in patients undergoing noncardiac surgery, both among patients who are already on an aspirin regimen and among those who are not. Using a 2-by-2 factorial trial design, we randomly assigned 10,010 patients who were preparing to undergo noncardiac surgery and were at risk for vascular complications to receive aspirin or placebo and clonidine or placebo. The results of the aspirin trial are reported here. The patients were stratified according to whether they had not been taking aspirin before the study (initiation stratum, with 5628 patients) or they were already on an aspirin regimen (continuation stratum, with 4382 patients). Patients started taking aspirin (at a dose of 200 mg) or placebo just before surgery and continued it daily (at a dose of 100 mg) for 30 days in the initiation stratum and for 7 days in the continuation stratum, after which patients resumed their regular aspirin regimen. The primary outcome was a composite of death or nonfatal myocardial infarction at 30 days. The primary outcome occurred in 351 of 4998 patients (7.0%) in the aspirin group and in 355 of 5012 patients (7.1%) in the placebo group (hazard ratio in the aspirin group, 0.99; 95% confidence interval [CI], 0.86 to 1.15; P=0.92). Major bleeding was more common in the aspirin group than in the placebo group (230 patients [4.6%] vs. 188 patients [3.8%]; hazard ratio, 1.23; 95% CI, 1.01, to 1.49; P=0.04). The primary and secondary outcome results were similar in the two aspirin strata. Administration of aspirin before surgery and throughout the early postsurgical period had no significant effect on the rate of a composite of death or nonfatal myocardial infarction but increased the risk of major bleeding. (Funded by the Canadian Institutes of Health Research and others; POISE-2 ClinicalTrials.gov number, NCT01082874.).


Young female drivers in fatal crashes: recent trends, 1995-2004.
Motor vehicle crashes are the leading cause of death for 15-to 20-year-olds. In 2004, nearly 8,000 15to 20-year-old drivers were killed in crashes. Epidemiologic studies repeatedly identify overrepresentation of young males in fatal crashes. Recent studies of young females and risk-taking behaviors (drug use, violent crime, risky sexual behavior) show unfavorable trends. The objective of this study is to study the extent of contribution of young female drivers to national fatal crashes over and to uncover unfavorable trends linked to risky driving behavior. Data from the National Highway Traffic Safety Administration's Fatal Analysis Reporting System (FARS) on drivers in crashes with one or more fatalities during 1995-2004 were studied. Five age groups were used: 16, 17, 18, 19-20, and 21-24 years. Linear regression was used to measure trends over time. The regression results represent differences in proportions and changes in proportion of crashes that fell into specified categories. The FARS multiple imputation data sets was used to estimate the proportion of drivers with positive blood alcohol, and variance estimates were corrected for the imputation procedure. In all, 139,000 fatal crashes involving the noted age groups occurred over 10 years. Safety restraint use: Females had more safety restraint use (by 17.8%) but a smaller increase in use over time. Driver's license validity: The percentage of valid licensure decreased over the study for young males and females both in the general population and among drivers in fatal crashes. Single-vehicle crashes: A lower proportion of female drivers (8.9% fewer) were involved in single-vehicle fatal crashes. This proportion changed little over the study period. Alcohol use: Females had a 16.7% lower proportion than males of alcohol involvement in fatal crashes. This lower proportion was seen throughout the age groups. When accounting for change over the study period, female drivers had a similar to male increase in alcohol-involved fatal crashes. Presence of peer passengers: Female drivers were less likely to have age peers as passengers. While young male drivers surpass young females in number of fatal crashes, there are unfavorable trends linked to crash fatalities in young females. Our results suggest a smaller increase in safety restraint use, proportional decrease in license validity, and an increase in rate of alcohol-involved fatal crashes that approaches that seen in young males. These findings have considerable implications for future traffic safety social marketing campaigns, programs, and interventions.


Contralateral and ipsilateral disorders of visual attention in patients with unilateral brain damage.
To explain the prevalence of unilateral spatial neglect in patients with right brain damage, Heilman et al have suggested that the attentional neurons of the right parietal lobe might have bilateral receptive fields, whereas the homologous cells of the left hemisphere would have strictly contralateral receptive fields. One implication of this theory is that patients with right brain damage should show a prevalence of disorders of visual attention not only in the half space contralateral to the damaged hemisphere, but also in the ipsilateral one. To check this theory, 50 control subjects, 102 right and 125 left brain-damaged patients were given a drawing completion task in which patients were requested to complete the missing parts of a star, a cube and a house. Omissions of lines lying on the sides of the models contralateral and ipsilateral to the damaged hemisphere were taken separately into account. Results did not confirm the hypothesis, since right brain-damaged patients failed to complete the contralateral sides of the models much more frequently than patients with left brain injury, but no difference was found between the two hemispheric groups when ipsilateral disorders of visual attention were taken into account. Furthermore, no correlation was found between omissions of lines lying on the sides of the models contralateral and ipsilateral to the damaged hemisphere. This finding suggests that contralateral and ipsilateral disorders of visual attention are not due to the same mechanism in right brain-damaged patients. The alternative hypothesis viewing ipsilateral disorders as resulting from a widespread lowering of general attention (and only contralateral neglect reflecting a specific disorder of visual attention) was supported by results obtained on a verbal memory test, used to evaluate the general cognitive and attention level of the patients. Patients with clear-cut ipislateral inattention obtained very low scores on this test, whereas patients with severe contralateral neglect, but not ipislateral inattention scored within the normal range on the verbal memory test.


The weight-based heparin dosing nomogram compared with a "standard care" nomogram. A randomized controlled trial.
To determine whether an intravenous heparin dosing nomogram based on body weight achieves therapeutic anticoagulation more rapidly than a "standard care" nomogram. Randomized controlled trial. Two community teaching hospitals in Phoenix, Arizona, and Rochester, New York. One hundred fifteen patients requiring intravenous heparin treatment for venous or arterial thromboembolism or for unstable angina. Patients were randomized to the weight-based nomogram (starting dose, 80 units/kg body weight bolus, 18 units/kg per hour infusion) or the standard care nomogram (starting dose, 5000-unit bolus, 1000 units per hour infusion). Activated partial thromboplastin time (APTT) values were monitored every 6 hours, and heparin dose adjustments were determined by the nomograms. Activated partial thromboplastin times were measured using a widely generalizable laboratory method. The primary outcomes were the time to exceed the therapeutic threshold (APTT > 1.5 times the control) and the time to achieve therapeutic range (APTT, 1.5 to 2.3 times the control). Bleeding complications and recurrent thromboembolism were also compared. Kaplan-Meier curves for the primary outcomes favored the weight-based nomogram (P < 0.001 for both). In the weight-based heparin group, 60 of 62 patients (97%) exceeded the therapeutic threshold within 24 hours, compared with 37 of 48 (77%) in the standard care group (P < 0.002). Only one major bleeding complication occurred (in a standard care patient). Recurrent thromboembolism was more frequent in the standard care group; relative risk, 5.0 (95% CI, 1.1 to 21.9). The weight-based heparin nomogram is widely generalizable and has proved to be effective, safe, and superior to one based on standard practice.


Sleep quality, chronotypes and preferential timing of attacks in migraine without aura.
Clinical observations show that migraine attacks have a seasonal, menstrual and circadian timing, suggesting a role of chronobiological mechanisms and their alterations in the disease, but little experimental data exists about this issue. The aim of this study was to estimate sleep quality chronotypes and the possible circadian timing of attacks in migraneurs. One hundred patients suffering from migraine without aura according to the IHS criteria (2004), and 30 controls were enrolled. Morning and evening type subjects were more represented in migraine patients than in controls and showed a tendency towards worse sleep quality and higher disability. Forty-two percent of migraineurs presented more than 75% of their attacks at night. Morning and evening types rather than intermediate and differences between real and preferred times may represent stressors that can worsen the disease. A preferential timing for occurrence of migraine attacks during the night and early morning hours was documented.


Risk attitudes in a changing environment: An evolutionary model of the fourfold pattern of risk preferences.
A striking feature of human decision making is the fourfold pattern of risk attitudes, involving risk-averse behavior in situations of unlikely losses and likely gains, but risk-seeking behavior in response to likely losses and unlikely gains. Current theories to explain this pattern assume particular psychological processes to reproduce empirical observations, but do not address whether it is adaptive for the decision maker to respond to risk in this way. Here, drawing on insights from behavioral ecology, we build an evolutionary model of risk-sensitive behavior, to investigate whether particular types of environmental conditions could favor a fourfold pattern of risk attitudes. We consider an individual foraging in a changing environment, where energy is needed to prevent starvation and build up reserves for reproduction. The outcome, in terms of reproductive value (a rigorous measure of evolutionary success), of a one-off choice between a risky and a safe gain, or between a risky and a safe loss, determines the risk-sensitive behavior we should expect to see in this environment. Our results show that the fourfold pattern of risk attitudes may be adaptive in an environment in which conditions vary stochastically but are autocorrelated in time. In such an environment the current options provide information about the likely environmental conditions in the future, which affect the optimal pattern of risk sensitivity. Our model predicts that risk preferences should be both path dependent and affected by the decision maker's current state.


Reproductive health and quality of life of young Burmese refugees in Thailand.
Of the 140,000 Burmese* refugees living in camps in Thailand, 30% are youths aged 15-24. Health services in these camps do not specifically target young people and their problems and needs are poorly understood. This study aimed to assess their reproductive health issues and quality of life, and identifies appropriate service needs. We used a stratified two-stage random sample questionnaire survey of 397 young people 15-24 years from 5,183 households, and 19 semi-structured qualitative interviews to assess and explore health and quality of life issues. The young people in the camps had very limited knowledge of reproductive health issues; only about one in five correctly answered at least one question on reproductive health. They were clear that they wanted more reproductive health education and services, to be provided by health workers rather than parents or teachers who were not able to give them the information they needed. Marital status was associated with sexual health knowledge; having relevant knowledge of reproductive health was up to six times higher in married compared to unmarried youth, after adjusting for socio-economic and demographic factors. Although condom use was considered important, in practice a large proportion of respondents felt too embarrassed to use them. There was a contradiction between moral views and actual behaviour; more than half believed they should remain virgins until marriage, while over half of the youth experienced sex before marriage. Two thirds of women were married before the age of 18, but two third felt they did not marry at the right age. Forced sex was considered acceptable by one in three youth. The youth considered their quality of life to be poor and limited due to confinement in the camps, the limited work opportunities, the aid dependency, the unclear future and the boredom and unhappiness they face. The long conflict in Myanmar and the resultant long stay in refugee camps over decades affect the wellbeing of these young people. Lack of sexual health education and relevant services, and their concerns for their future are particular problems, which need to be addressed. Issues of education, vocational training and job possibilities also need to be considered.*Burmese is used for all ethnic groups.


Looking beyond recurrence: comorbidities in cancer survivors.
Cancer recurrence is a very real concern for cancer survivors. Surveillance for recurrence and vigilance for development of new cancers are top priorities during follow-up visits after active treatment ends. However, the cancer survivor also is at risk for the development of comorbid conditions. These conditions, including obesity, diabetes, dyslipidemia, menopause, decreased bone mass, hypertension, and hypothyroidism, are discussed with their relevance for general health and their relationships to disease-specific cancers. All of these conditions should be routinely addressed as part of the patient's survivorship care when appropriate. The oncology nurse is in a prime position to educate survivors about the risks for these conditions, both through evidence-based practice guidelines specific to each condition and also through the use of a treatment summary and care plan. This article discusses these selected comorbidities and offers strategies for nurses to address them with survivors during follow-up visits. Clinical practice guidelines for comorbidities are included, along with oncology implications and relevance for survivors. Recommendations for modifiable risk factors and healthy living also are included, along with Web sites for survivorship care plans.


Care of the self and American physicians' place in the "war on terror": a Foucauldian reading of senator Bill Frist, MD.
American physicians are increasingly concerned that they are losing professional control. Other analysts of medical power argue that physicians have too much power. This essay argues that current analyses are grounded in a structuralist reading of power. Deploying Michel Foucault's "care of the self" and rhetorician Raymie McKerrow's "critical rhetoric," this essay claims that medical power is better understood as a way that medical actors take on power through rhetoric rather than a force that has power over medical actors. Through a close reading of an essay by Senator Bill Frist, this paper argues that physicians experience a process of "subjection" wherein they are both agents of and objects of medical power as it is combined with state and corporate power in the American "war on terror." This alternative mode of analyzing medical power has implications for our collective understanding of its operations and the means by which we propose alternative enactments of medical power.


Effect of optional home initiation of HIV care following HIV self-testing on antiretroviral therapy initiation among adults in Malawi: a randomized clinical trial.
Self-testing for HIV infection may contribute to early diagnosis of HIV, but without necessarily increasing antiretroviral therapy (ART) initiation. To investigate whether offering optional home initiation of HIV care after HIV self-testing might increase demand for ART initiation, compared with HIV self-testing accompanied by facility-based services only. Cluster randomized trial conducted in Blantyre, Malawi, between January 30 and November 5, 2012, using restricted 1:1 randomization of 14 community health worker catchment areas. Participants were all adult (≥16 years) residents (n = 16,660) who received access to home HIV self-testing through resident volunteers. This was a second-stage randomization of clusters allocated to the HIV self-testing group of a parent trial. Clusters were randomly allocated to facility-based care or optional home initiation of HIV care (including 2 weeks of ART if eligible) for participants reporting positive HIV self-test results. The preplanned primary outcome compared between groups the proportion of all adult residents who initiated ART within the first 6 months of HIV self-testing availability. Secondary outcomes were uptake of HIV self-testing, reporting of positive HIV self-test results, and rates of loss from ART at 6 months. A significantly greater proportion of adults in the home group initiated ART (181/8194, 2.2%) compared with the facility group (63/8466, 0.7%; risk ratio [RR], 2.94, 95% CI, 2.10-4.12; P < .001). Uptake of HIV self-testing was high in both the home (5287/8194, 64.9%) and facility groups (4433/8466, 52.7%; RR, 1.23; 95% CI, 0.96-1.58; P = .10). Significantly more adults reported positive HIV self-test results in the home group (490/8194 [6.0%] vs the facility group, 278/8466 [3.3%]; RR, 1.86; 95% CI, 1.16-2.97; P = .006). After 6 months, 52 of 181 ART initiators (28.7%) and 15 of 63 ART initiators (23.8%) in the home and facility groups, respectively, were lost from ART (adjusted incidence rate ratio, 1.18; 95% CI, 0.62-2.25, P = .57). Among Malawian adults offered HIV self-testing, optional home initiation of care compared with standard HIV care resulted in a significant increase in the proportion of adults initiating ART. clinicaltrials.gov Identifier: NCT01414413.


Randomized trial of fenretinide to prevent second breast malignancy in women with early breast cancer.
Fenretinide, a vitamin A analogue, has been shown to inhibit breast carcinogenesis in preclinical studies. We determined the efficacy of fenretinide in preventing a second breast malignancy in women with breast cancer. We randomly assigned 2972 women, aged 30-70 years, with surgically removed stage I breast cancer or ductal carcinoma in situ to receive for 5 years either fenretinide orally (200 mg/day) or no treatment. The primary end point was the incidence of contralateral breast cancer or ipsilateral breast cancer 7 years after randomization. Other end points considered post hoc were the same outcomes stratified by menopausal status, incidence of distant metastases, overall mortality, and tumors in other organs. The hazards of breast cancer occurrence were determined by Cox proportional hazards regression analysis. Statistical tests were two-sided. At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P =.642) or ipsilateral breast cancer (P =.177) between the two arms. However, an interaction was detected between fenretinide treatment and menopausal status in both outcomes (P for interaction in both outcomes =.045), with a possible beneficial effect in premenopausal women (contralateral breast cancer: adjusted hazard ratio [HR] = 0.66, and 95% confidence interval [CI] = 0.41-1.07; ipsilateral breast cancer: adjusted HR = 0.65, and 95% CI = 0.46-0. 92) and an opposite effect in postmenopausal women (contralateral breast cancer: adjusted HR = 1.32, and 95% CI = 0.82-2.15; ipsilateral breast cancer: adjusted HR = 1.19, and 95% CI = 0.75-1. 89). There were no statistically significant differences between the two arms in tumors in other organs, incidence of distant metastasis, and all-cause mortality. Fenretinide treatment of women with breast cancer for 5 years appears to have no statistically significant effect on the incidence of second breast malignancies overall, although a possible benefit was detected in premenopausal women. These studies, particularly the post hoc analyses, are considered exploratory and need to be confirmed.


Alternative Runx1 promoter usage in mouse developmental hematopoiesis.
The interest in stem cell based therapies has emphasized the importance of understanding the cellular and molecular mechanisms by which stem cells are generated in ontogeny and maintained throughout adult life. Hematopoietic stem cells (HSCs) are first found in clusters of hematopoietic cells budding from the luminal wall of the major arteries in the developing mammalian embryo. The transcription factor Runx1 is critical for their generation and is specifically expressed at sites of HSC generation, prior to their formation. To understand better the transcriptional hierarchies that converge on Runx1 during HSC emergence, we have initiated studies into its transcriptional regulation. Here we systematically analyzed Runx1 P1 and P2 alternative promoter usage in hematopoietic sites and in sorted cell populations during mouse hematopoietic development. Our results indicate that Runx1 expression in primitive erythrocytes is largely P2-derived, whilst in definitive hematopoietic stem and/or progenitor cells from the yolk sac or AGM and vitelline and umbilical arteries both the distal P1 and proximal P2 promoters are active. After cells have migrated to the fetal liver, the P1 gradually becomes the main hematopoietic promoter and remains this into adulthood. In addition, we identified a novel P2-derived Runx1 isoform.


Profiling microbial communities in manganese remediation systems treating coal mine drainage.
Water discharging from abandoned coal mines can contain extremely high manganese levels. Removing this metal is an ongoing challenge. Passive Mn(II) removal beds (MRBs) contain microorganisms that oxidize soluble Mn(II) to insoluble Mn(III/IV) minerals, but system performance is unpredictable. Using amplicon pyrosequencing, we profiled the bacterial, fungal, algal, and archaeal communities in four MRBs, performing at different levels, in Pennsylvania to determine whether they differed among MRBs and from surrounding soil and to establish the relative abundance of known Mn(II) oxidizers. Archaea were not detected; PCRs with archaeal primers returned only nontarget bacterial sequences. Fungal taxonomic profiles differed starkly between sites that remove the majority of influent Mn and those that do not, with the former being dominated by Ascomycota (mostly Dothideomycetes) and the latter by Basidiomycota (almost entirely Agaricomycetes). Taxonomic profiles for the other groups did not differ significantly between MRBs, but operational taxonomic unit-based analyses showed significant clustering by MRB with all three groups (P < 0.05). Soil samples clustered separately from MRBs in all groups except fungi, whose soil samples clustered loosely with their respective MRB. Known Mn(II) oxidizers accounted for a minor proportion of bacterial sequences (up to 0.20%) but a greater proportion of fungal sequences (up to 14.78%). MRB communities are more diverse than previously thought, and more organisms may be capable of Mn(II) oxidation than are currently known.


Idiotype usage by polyclonally activated B cells in experimental autoimmunity and infection.
Both in animal models and in human systemic lupus erythematosus (SLE) the occurrence of nephritogenic autoantibodies bearing dominant idiotypes has been described. In this study we investigate the relation between the induction pathway of polyclonal B cell activation and the production and glomerular deposition of nephritogenic antibodies with shared dominant idiotype(s). Polyclonal B cell activation was induced in several experimental models characterized by glomerular immune deposit formation. We monitored the occurrence of dominant idiotypes among immunoglobulins deposited in the glomeruli. In addition, we studied the species specificity of the dominant idiotypes, by monitoring their presence in kidney sections of patients with an immunologically mediated kidney disease. Anti-idiotype antisera against two monoclonal anti-DNA autoantibodies were used, derived from MRL-lpr/lpr mice, i. e. clone H241 and clone H130. Autoantibodies with the H241 idiotype were present in immune complex depositions in all experimental models but not in humans. We therefore conclude that the presence of this dominant idiotype is independent of the induction pathway of polyclonal B cell activation. However, autoantibodies bearing the H130 idiotype were only detected in kidney sections of mice with spontaneous lupus.


In vitro and in vivo evaluations of topically applied capsaicin and nonivamide from hydrogels.
The purpose of this study was designed to investigate the in vitro and in vivo skin absorption of capsaicin and nonivamide from hydrogels. Various commercialized creams of capsaicin were also compared with hydrogels. Both skin stripping technique and Mexameter were applied to evaluate the level of capsaicin and nonivamide retained in stratum corneum (SC) and skin erythema in vivo. The partition of drug between skin and the hydrogel matrix was considered to play an important role in the permeation process. The in vitro permeation of capsaicin from hydrogels depends on the physicochemical nature and the concentration of the polymer used. The incorporation of nonionic Pluronic F-127 polymer into hydrogels resulted in a retarded release of capsaicin. On the other hand, the in vitro capsaicin permeation showed higher levels in cationic chitosan and anionic carboxymethyl cellulose (CMC) hydrogels than cream bases. The permeation of nonivamide was retarded at the late stage of in vitro application. The inter-subject variation was more significant in the in vivo study than in vitro skin permeation experiments. The cream induced in vivo skin erythema depending on the drug concentration, however, the dose-dependence was not observed in hydrogels. Nonivamide-treated skin showed stronger erythema than capsaicin-treated skin. The present study indicates that there is a moderate correlation between in vitro skin permeation and in vivo erythema responses of topically applied capsaicin and nonivamide. The correlation between drug amount in SC and skin erythema test in vivo was also observed.


Naked Hair Shafts as a Marker of Cicatricial Alopecia.
Naked hair shafts (NHS) are free-floating hair shafts devoid of surrounding epithelium, supporting structures, and/or embedded in inflammation that may result from destruction of hair follicles by scarring processes such as inflammation and fibroplasia. Extensive examination of NHS has not been performed in scalp biopsies of alopecia. We retrospectively evaluated 622 scalp biopsies of alopecia [345 cicatricial alopecias (central centrifugal cicatricial alopecia, lichen planopilaris, discoid lupus erythematosus, acne keloidalis nuchae, and folliculitis decalvans] and 277 non-cicatricial alopecias [alopecia areata, androgenic alopecia, telogen effluvium, and psoriatic alopecia)] for the presence of NHS. NHS occurred in 0.72% (2/277) of non-cicatricial alopecias (1/102 of alopecia areata, 1/150 of androgenic alopecia, 0/17 of telogen effluvium, and 0/8 of psoriatic alopecia) and 20% (72/345) of cicatricial alopecias (27/118 of central centrifugal cicatricial alopecia, 29/109 of lichen planopilaris, 2/75 of discoid lupus erythematosus, 11/16 of acne keloidalis nuchae, and 3/27 of folliculitis decalvans). The presence of NHS was significantly increased in cicatricial alopecias in comparison with non-cicatricial alopecias; P value <0.0001. Among the cicatricial alopecias, 26% (92/345) had mild inflammation and/or fibrosis, of which 9% (9/92) had NHS. There were 73% (253/345) that had moderate to severe inflammation and/or fibrosis, of which 24% (63/253) had NHS, indicating that as the severity of inflammation and fibrosis increases, so does the presence of NHS. NHS rarely occurs in non-cicatricial alopecias. This variation may result from destruction of hair follicles by the inflammatory and scarring processes. The presence of NHS may be a useful adjunctive histopathologic feature in the diagnosis of cicatricial alopecia.


The structures of mouse and human L1 elements reflect their insertion mechanism.
L1 is an abundant, interspersed repeated DNA element of mammalian genomes. It has achieved its high copy number via retrotransposition. Like other non-LTR retrotransposons, L1 insertion into chromosomal DNA apparently occurs by target-site primed reverse transcription, or TPRT. L1 retrotransposition often generates elements with 5' truncations that are flanked by a duplication of the genomic target site (TSD). It is typically assumed that the 5' truncated elements are the consequence of poor processivity of the L1 reverse transcriptase. However, we find that the majority of young L1 elements from both the human and mouse genomes are truncated at sequences that can basepair with the target site. Thus, to whatever extent truncation is a consequence of poor processivity, we suggest that truncation is likely to occur when target site sequence can basepair with L1 sequence. This finding supports a model for insertion that occurs by two sequential TPRT reactions, the second of which relies upon the homology between the target site and L1. Because perfect heteroduplex formation is not required for all insertions, a dynamic relationship between the primer, template and enzyme during reverse transcription is inferred. 5' truncation may be a successful evolutionary strategy that is exploited by L1 as a means to escape host suppression of transposition.


Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria.
It is established that chronic spirochetal infection can cause slowly progressive dementia, brain atrophy and amyloid deposition in late neurosyphilis. Recently it has been suggested that various types of spirochetes, in an analogous way to Treponema pallidum, could cause dementia and may be involved in the pathogenesis of Alzheimer's disease (AD). Here, we review all data available in the literature on the detection of spirochetes in AD and critically analyze the association and causal relationship between spirochetes and AD following established criteria of Koch and Hill. The results show a statistically significant association between spirochetes and AD (P = 1.5 × 10-17, OR = 20, 95% CI = 8-60, N = 247). When neutral techniques recognizing all types of spirochetes were used, or the highly prevalent periodontal pathogen Treponemas were analyzed, spirochetes were observed in the brain in more than 90% of AD cases. Borrelia burgdorferi was detected in the brain in 25.3% of AD cases analyzed and was 13 times more frequent in AD compared to controls. Periodontal pathogen Treponemas (T. pectinovorum, T. amylovorum, T. lecithinolyticum, T. maltophilum, T. medium, T. socranskii) and Borrelia burgdorferi were detected using species specific PCR and antibodies. Importantly, co-infection with several spirochetes occurs in AD. The pathological and biological hallmarks of AD were reproduced in vitro by exposure of mammalian cells to spirochetes. The analysis of reviewed data following Koch's and Hill's postulates shows a probable causal relationship between neurospirochetosis and AD. Persisting inflammation and amyloid deposition initiated and sustained by chronic spirochetal infection form together with the various hypotheses suggested to play a role in the pathogenesis of AD a comprehensive entity. As suggested by Hill, once the probability of a causal relationship is established prompt action is needed. Support and attention should be given to this field of AD research. Spirochetal infection occurs years or decades before the manifestation of dementia. As adequate antibiotic and anti-inflammatory therapies are available, as in syphilis, one might prevent and eradicate dementia.


A urinary biomarker for uptake of dietary isothiocyanates in humans.
Isothiocyanates (ITCs) are a family of biologically active compounds that are distributed widely in cruciferous vegetables. Although studies in rodents have shown that these compounds are effective and versatile inhibitors of tumorigenesis, the role of dietary ITCs in the protection against human cancers remains to be established. A prerequisite of human studies is to develop an uptake biomarker for dietary ITCs. In this study, we describe a rapid high-performance liquid chromatography-based assay to measure the total ITC level in human urine. This assay is based on a previously described reaction of ITCs or their thiol conjugates with 1,2-benzenedithiol to yield a cyclocondensation product, 1,3-benzodithiole-2-thione, which then can be quantified by reverse phase high-performance liquid chromatography with UV detection. This new assay was validated by analyzing urine samples from 14 subjects who had consumed a known amount of watercress or brown mustard in a controlled experiment. The N-acetylcysteine conjugates of phenethyl ITC and allyl ITC from watercress and brown mustard, respectively, were quantified and compared with the results obtained from the current assay. Results of the two methods were highly correlated (r = 0.978), indicating the specificity of this new assay for dietary ITCs. The feasibility of this assay for population-based studies was examined using stored urine samples collected from nine participants of a prospective cohort study in Shanghai, China, who indicated that they were daily consumers of dark green vegetables. There was a 10-fold variation in urinary ITC contents among these samples, ranging from 0.7 to 7.0 micromol/g creatinine. These results show the potential use of this uptake biomarker in epidemiological studies to identify the role of dietary ITCs in modifying cancer risks in humans.


Low-grade glioma on stereotactic biopsy: how often is the diagnosis accurate?
The objective of the present study was an evaluation of the incidence and risk factors for erroneous histopathological diagnosis of low-grade glioma after stereotactic biopsy. Twenty-eight tumors diagnosed as low-grade glioma after stereotactic biopsy and surgically resected thereafter were analyzed. There were 13 astrocytomas, 7 oligodendrogliomas, and 8 mixed gliomas. All neoplasms had a lobar location. Seven tumors had contrast enhancement on MRI. The number of tissue samples obtained during stereotactic biopsy was one in 19 cases, two in 4, and three or more in 5. Complete diagnostic agreement in tumor typing and grading after stereotactic biopsy and surgical resection was attained in 10 cases (36%). Agreement in tumor typing was marked in 16 cases (57%). Erroneous typing was more frequent in tumors with an MIB-1 index of less than 3% (P = 0.0629) and mixed gliomas (P = 0.0801). Overgrading of WHO grade I tumors was marked in 3 cases (11%) and undergrading of WHO grade III gliomas in 8 cases (28%). Tumor undergrading was more frequent in cases with an MIB-1 index of more than 3% (P = 0.0045). The MIB-1 index detected after stereotactic biopsy was nearly always lower compared with those established after surgical resection (P < 0.0001). In conclusion, the histopathological diagnosis of low-grade glioma established after stereotactic biopsy is associated with a substantial risk of inaccuracy. Tumors with low proliferative activity and mixed gliomas are especially susceptible for erroneous tumor typing. Undergrading of high-grade gliomas may be suspected if the MIB-1 index in the tumor specimen constitutes more, than 3%.


The Polycomb group gene Posterior Sex Combs encodes a chromosomal protein.
The Posterior Sex Combs (Psc) gene of Drosophila has been studied at the molecular level both because it is a Polycomb group (Pc-G) gene and hence required for the maintenance of segmental determination, and because it is the Drosophila homolog of the murine bmi-1 oncogene. Although genetic interactions indicated that Psc functioned as a Pc-G gene, the zygotic mutant phenotype of Psc showed little evidence of segmental transformations. We have examined mutant embryos derived from a mutant maternal germ line and found a stronger mutant phenotype, indicating that the weak zygotic phenotype of Psc is due to maternal rescue. We have found that Psc RNA accumulates in developing oocytes and this maternal RNA is presumably responsible for the maternal rescue. We have studied the expression of the Psc gene at both the RNA and protein levels. On northern blots, we find evidence for two Psc mRNAs and, on western blots, we find evidence for two Psc proteins that are altered either in abundance or size in Psc mutants. The Psc protein accumulates in all regions of the embryo and also in many tissues in a variety of developmental stages. In all cases, it is nuclear, as is its mammalian homolog, the bmi-1 protein. On polytene chromosomes, we find Psc at 45 chromosomal loci where two other Pc-G proteins are present.


Utility of socioeconomic status in predicting 30-day outcomes after heart failure hospitalization.
An individual's socioeconomic status (SES) is associated with health outcomes and mortality, yet it is unknown whether accounting for SES can improve risk-adjustment models for 30-day outcomes among Centers for Medicare & Medicaid Services beneficiaries hospitalized with heart failure. We linked clinical data on hospitalized patients with heart failure in the Get With The Guidelines-Heart Failure database (January 2005 to December 2011) with Centers for Medicare & Medicaid Services claims and county-level SES data from the 2012 Area Health Resources Files. We compared the discriminatory capabilities of multivariable models that adjusted for SES, patient, and hospital characteristics to determine whether county-level SES data improved prediction or changed hospital rankings for 30-day all-cause mortality and rehospitalization. After adjusting for patient and hospital characteristics, median household income (per $5000 increase) was inversely associated with odds of 30-day mortality (odds ratio, 0.97; 95% confidence interval, 0.95-1.00; P=0.032) and the percentage of people with at least a high school diploma (per 5 U increase) was associated with lower odds of 30-day rehospitalization (odds ratio, 0.95; 95% confidence interval, 0.91-0.99). After adjustment for county-level SES data, relative to whites, Hispanic ethnicity (odds ratio, 0.70; 95% confidence interval, 0.58-0.83) and black race (odds ratio, 0.57; 95% confidence interval, 0.50-0.65) remained significantly associated with lower 30-day mortality, but had similar 30-day rehospitalization. County-level SES did not improve risk adjustment or change hospital rankings for 30-day mortality or rehospitalization. County-level SES data are modestly associated with 30-day outcomes for Centers for Medicare & Medicaid Services beneficiaries hospitalized with heart failure, but do not improve risk adjustment models based on patient characteristics alone.


Synergy of Electrostatic and π-π Interactions in the Realization of Nanoscale Artificial Photosynthetic Model Systems.
In the scientific race to build up photoactive electron donor-acceptor systems with increasing efficiencies, little is known about the interplay of their building blocks when integrated into supramolecular nanoscale arrays, particularly in aqueous environments. Here, we describe an aqueous donor-acceptor ensemble whose emergence as a nanoscale material renders it remarkably stable and efficient. We have focused on a tetracationic zinc phthalocyanine (ZnPc) featuring pyrenes, which shows an unprecedented mode of aggregation, driven by subtle cooperation between electrostatic and π-π interactions. Our studies demonstrate monocrystalline growth in solution and a symmetry-breaking intermolecular charge transfer between adjacent ZnPcs upon photoexcitation. Immobilizing a negatively charged fullerene (C60 ) as electron acceptor onto the monocrystalline ZnPc assemblies was found to enhance the overall stability, and to suppress the energy-wasting charge recombination found in the absence of C60 . Overall, the resulting artificial photosynthetic model system exhibits a high degree of preorganization, which facilitates efficient charge separation and subsequent charge transport.


Identification and analysis of CXCR4-positive synovial sarcoma-initiating cells.
Synovial sarcoma accounts for almost 10% of all soft tissue sarcomas, and its prognosis is poor with 5-year survival rates at 36%. Thus, new treatments and therapeutic targets for synovial sarcoma are required. Tumor-initiating cells have been defined by the ability for self-renewal and multipotent differentiation, and they exhibit higher tumorigenic capacity, chemoresistance and radiation resistance, expecting to be a new therapeutic target. In synovial sarcoma, the presence of such stemness remains largely unclear; thus, we analyzed whether synovial sarcoma possessed tumor-initiating cells and explored specific markers, and we discovered that synovial sarcoma cell lines possessed heterogeneity by way of containing a sphere-forming subpopulation highly expressing NANOG, OCT4 and SOX2. By expression microarray analysis, CXCR4 was identified to be highly expressed in the sphere subpopulation and correlated with stem-cell-associated markers. Inhibition of CXCR4 suppressed the cell proliferation of synovial sarcoma cell lines in vitro. The tumor-initiating ability of CXCR4-positive cells was demonstrated by xenograft propagation assay. CXCR4-positive cells showed higher tumorigenicity than negative ones and possessed both self-renewal and multipotent differentiation ability. Immunohistochemical analysis of 39 specimens of synovial sarcoma patients revealed that CXCR4 strongly correlated with poor prognosis of synovial sarcoma. Thus, we conclude that CXCR4 is the marker of synovial sarcoma-initiating cells, a new biomarker for prognosis and a new potential therapeutic target.


Measurement of marine picoplankton cell size by using a cooled, charge-coupled device camera with image-analyzed fluorescence microscopy.
Accurate measurement of the biomass and size distribution of picoplankton cells (0.2 to 2.0 microns) is paramount in characterizing their contribution to the oceanic food web and global biogeochemical cycling. Image-analyzed fluorescence microscopy, usually based on video camera technology, allows detailed measurements of individual cells to be taken. The application of an imaging system employing a cooled, slow-scan charge-coupled device (CCD) camera to automated counting and sizing of individual picoplankton cells from natural marine samples is described. A slow-scan CCD-based camera was compared to a video camera and was superior for detecting and sizing very small, dim particles such as fluorochrome-stained bacteria. Several edge detection methods for accurately measuring picoplankton cells were evaluated. Standard fluorescent microspheres and a Sargasso Sea surface water picoplankton population were used in the evaluation. Global thresholding was inappropriate for these samples. Methods used previously in image analysis of nanoplankton cells (2 to 20 microns) also did not work well with the smaller picoplankton cells. A method combining an edge detector and an adaptive edge strength operator worked best for rapidly generating accurate cell sizes. A complete sample analysis of more than 1,000 cells averages about 50 min and yields size, shape, and fluorescence data for each cell. With this system, the entire size range of picoplankton can be counted and measured.


The association between cigarette smoking, virologic suppression, and CD4+ lymphocyte count in HIV-Infected Russian women.
Cigarette smoking among people living with HIV/AIDS is associated with significant morbidity and mortality, but findings regarding the association between cigarette smoking and HIV viral load and CD4+ lymphocyte counts have been inconsistent. This study characterized the prevalence of cigarette smoking among HIV-infected Russian women and examined the association between smoking frequency and quantity and HIV viral load and CD4+ lymphocyte counts. HIV-infected Russian women (N = 250; M age = 30.0) in St. Petersburg, Russia, completed an audio computer-assisted self-interview survey assessing cigarette use, antiretroviral medication adherence, and provided blood samples assayed for HIV viral load and CD4+ lymphocyte counts. The majority (60.4%) reported cigarette smoking in the past month; 49.0% of recent smokers were classified as moderate or heavy smokers, defined as smoking ≥10 cigarettes daily. Viral load status did not differ between infrequent smokers and regular smokers. However, moderate/heavy smokers (relative to light smokers) were more likely to have a detectable viral load (AOR = 2.3, 95% CI: 1.1, 5.1). There were no significant differences in CD4+ lymphocyte counts by smoking frequency or quantity of cigarettes smoked. Results highlight the need for additional research to examine the association between cigarette smoking and virologic suppression and markers of HIV disease progression. Adverse health consequences of cigarette smoking coupled with a potential link between heavy smoking and poor virologic suppression highlight the need for assessment of cigarette use and provision of evidence-based smoking-cessation interventions within HIV medical care.


Antibodies to AMPA receptors in Rasmussen's encephalitis.
Rasmussen's encephalitis is a rare progressive childhood disorder characterized by frequent severe seizures, hemiparesis, encephalitis and mental deterioration, and associated with severe unilateral neuroinflammation. Autoantibodies, particularly to the GluA3 subtype of the alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propinonic acid receptor (AMPAR) were reported in the 1990s but not always confirmed. To explore further, sera from 52 patients with Rasmussen's encephalitis were tested by cell-based assays for antibodies to AMPAR GluA1/2/3, N-methyl-d-aspartate (NMDA NR1/2b), γ-aminobutyric acid type A and B (GABAAR α1/γ2/β2 and GABABR b1/b2) receptors, for potassium channel complex proteins, and for binding to live cortical and hippocampal neuronal cultures. Two patients' sera (3.8%) bound to HEK cells co-transfected with the GluA2 and GluA3 subunits. One additional patient had a low level of VGKC-complex antibodies. These three, and seven additional, sera bound to hippocampal cultures. No other antibodies were detected. Thus, despite the rarity of GluA2/3 antibodies, 10 patients (19.2%) had evidence of antibodies to neuronal antigens. Whether these antibodies play a primary role in RE, or appear secondary to the neuro-inflammatory damage in this highly destructive disease, requires further study.