The Chlamydomonas cell wall and its constituent glycoproteins analyzed by the quick-freeze, deep-etch technique.
Using the quick-freeze, deep-etch technique, we have analyzed the structure of the intact cell wall of Chlamydomonas reinhardi, and have visualized its component glycoproteins after mechanical shearing and after depolymerization induced by perchlorate or by the wall-disrupting agent, autolysin. The intact wall has previously been shown in a thin-section study (Roberts, K., M. Gurney-Smith, and G. J. Hills, 1972, J. Ultrastruct. Res. 40:599-613) to consist of a discrete central triplet bisecting a meshwork of fibrils. The deep-etch technique provides additional information about the architecture of each of these layers under several different experimental conditions, and demonstrates that each layer is constructed from a distinct set of components. The innermost layer of the central triplet proves to be a fibrous network which is stable to perchlorate but destabilized by autolysin, disassembling into fibrillar units we designate as "fishbones." The medial layer of the triplet is a loose assemblage of large granules. The outer layer is a thin, crystalline assembly that is relatively unaffected by autolysin. It depolymerizes into two glycoprotein species, one fibrous and one globular. The wall glycoproteins prove to be structurally similar to two fibrous proteins that associate with the flagellar membrane, namely, the sexual agglutinins and the protomers of a structure we designate a "hammock." They are also homologous to some of the fibrous components found in the extracellular matrices of multicellular plants and animals. The quick-freeze, deep-etch technique is demonstrated to be a highly informative way to dissect the structure of a fibrous matrix and visualize its component macromolecules.


Racial discrimination among children in the United States from 2016 to 2020: an analysis of the National Survey of Children's Health.
Sociological research has linked racism and discrimination among children to poorer health outcomes and social conditions later in life. Given the change in the political climate in the United States, highly publicized deaths of Black men and women by police, and the rise in hate crimes against Asian Americans from 2016 through 2020, our primary objective was to assess trends in racial or ethnic discrimination among children in the United States. We conducted a cross-sectional analysis of the National Survey of Children's Health (NSCH), a nationally representative survey, utilizing data from 2016 to 2020. We calculated yearly population estimates of whether a child had experienced discrimination based on race/ethnicity via a parent-reported item. We further divided the estimates by race/ethnicity and plotted linear trends over time. Data from the NSCH show that racial/ethnic discrimination reported by parents of children who are minorities increased from 6.7% in 2016 to approximately 9.3% in 2020. Indigenous children were reported to experience discrimination at high rates ranging from 10.8% in 2016 to 15.7% in 2020, as well as Black children ranging from 9.69% in 2018 to 15.04% in 2020. The percent of Asian, Hawaiian or Pacific Islander, and Hispanic children reported to have experience discrimination was between 4.4 and 6.8% during this time. Discrimination negatively impacts the developmental experiences of children, disproportionately affecting those identifying as Indigenous and Black. Therefore, addressing harmful stereotyping of Indigenous and Black cultures is necessary, especially in media targeted toward children. Providing culturally competent healthcare, critically in the Indigenous and Black pediatric population, may improve long-term outcomes by reducing discriminatory barriers to healthcare access.


The effect of kangaroo care on neurodevelopmental outcomes in preterm infants.
Preterm birth is associated with long-term deficits in executive functioning and cognitive performance. As advances in neonatal care enable more preterm infants to survive, development of strategies to address high rates of neurodevelopmental disabilities and poor academic achievement in preterm infants are crucial. Evidence suggests that infants' brains are plastic in nature and, therefore, can be shaped by the environment. Kangaroo care has become popularized as a means of modifying the stress of the NICU environment. However, few studies have examined whether kangaroo care affects neurodevelopmental outcomes in preterm infants. This review examined available literature that investigated the effect of kangaroo care on cognition in preterm infants. Current evidence suggests that short-term benefits of kangaroo care are associated with improved neurodevelopment. However, few studies have examined the long-term impact of kangaroo care on cognitive outcomes in preterm infants. To address neurological disparities in children born preterm, research using kangaroo care as a strategy to improve neurodevelopment in preterm infants is warranted.


Autophagy and Akt promote survival in glioma.
Signaling through phosphatidylinositol 3-kinase (PtdIns3K)-Akt-mTOR is frequently activated in cancers including glioblastoma multiforme (GBM), where this kinase network regulates survival. It is thus surprising that inhibitors of these pathways induce minimal cell death in glioma. We showed that the dual PtdIns3K-mTOR inhibitor PI-103 induces autophagy in therapy-resistant, PTEN-mutant glioma, with blockade of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) contributing independently to autophagy. Inhibition of autophagosome maturation synergizes with PI-103 to induce apoptosis through the Bax-dependent intrinsic mitochondrial pathway, indicating that PI-103 induces autophagy as a survival pathway in this setting. Not all inhibitors of PtdIns3K-Akt-mTOR signaling synergize with inhibitors of autophagy. The allosteric mTORC1 inhibitor rapamycin fails to induce apoptosis in conjunction with blockade of autophagy, due to feedback-activation of Akt. Apoptosis in the setting of rapamycin therapy requires concurrent inhibition of both autophagy and of PtdIns3K-Akt. Moreover, the clinical PtdIns3K-mTOR inhibitor NVP-BEZ235 cooperates with the clinical lysosomotropic autophagy inhibitor chloroquine to induce apoptosis in PTEN-mutant glioma xenografts in vivo, offering a therapeutic approach translatable to patients.


The synthesis of mono-alkyl phosphates and their derivatives: an overview of their nature, preparation and use, including synthesis under plausible prebiotic conditions.
Nucleic acids, phospholipids and other organic phosphates play central roles in biological pathways. n-Alkyl phosphates and their derivatives have been recognized as amphiphilic molecules for nearly two centuries. In the last 50 years, n-alkyl phosphate derivatives such as di-alkyl phosphates, mono-alkyl phosphatidyl ethanol amines and mono-alkyl phosphocholines have become predominant compounds with applications in different areas, from food chemistry to life science. The aim of this review is to summarize the most relevant progress made in the field of the synthesis of these molecules and to provide a concise perspective on the use of these amphiphiles as possible prebiotic membrane constituents. The first part of the review is dedicated to the analysis of the most relevant syntheses carried out in recent years with respect to those reported from the second half of the nineteenth century. The second part is dedicated to a description of the latest reports on prebiotic synthesis of mono-alkyl phosphates. In this part, the authors did not report the phosphorylation of other relevant biomolecules, such as nucleosides, which have been excellently reviewed elsewere.


Nanotechnology for breast cancer therapy.
Breast cancer is the field of medicine with the greatest presence of nanotechnological therapeutic agents in the clinic. A pegylated form of liposomally encapsulated doxorubicin is routinely used for treatment against metastatic cancer, and albumin nanoparticulate chaperones of paclitaxel were approved for locally recurrent and metastatic disease in 2005. These drugs have yielded substantial clinical benefit, and are steadily gathering greater beneficial impact. Clinical trials currently employing these drugs in combination with chemo and biological therapeutics exceed 150 worldwide. Despite these advancements, breast cancer morbidity and mortality is unacceptably high. Nanotechnology offers potential solutions to the historical challenge that has rendered breast cancer so difficult to contain and eradicate: the extreme biological diversity of the disease presentation in the patient population and in the evolutionary changes of any individual disease, the multiple pathways that drive disease progression, the onset of 'resistance' to established therapeutic cocktails, and the gravity of the side effects to treatment, which result from generally very poor distribution of the injected therapeutic agents in the body. A fundamental requirement for success in the development of new therapeutic strategies is that breast cancer specialists-in the clinic, the pharmaceutical and the basic biological laboratory-and nanotechnologists-engineers, physicists, chemists and mathematicians-optimize their ability to work in close collaboration. This further requires a mutual openness across cultural and language barriers, academic reward systems, and many other 'environmental' divides. This paper is respectfully submitted to the community to help foster the mutual interactions of the breast cancer world with micro- and nano-technology, and in particular to encourage the latter community to direct ever increasing attention to breast cancer, where an extraordinary beneficial impact may result. The paper initiates with an introductory overview of breast cancer, its current treatment modalities, and the current role of nanotechnology in the clinic. Our perspectives are then presented on what the greatest opportunities for nanotechnology are; this follows from an analysis of the role of biological barriers that adversely determine the biological distribution of intravascularly injected therapeutic agents. Different generations of nanotechnology tools for drug delivery are reviewed, and our current strategy for addressing the sequential bio-barriers is also presented, and is accompanied by an encouragement to the community to develop even more effective ones.


Child or family assessed measures of activity performance and participation for children with cerebral palsy: a structured review.
There is a need to measure children's 'activity performance and participation' as defined in the World Health Organization's International Classification of Functioning, Disability and Health for Children and Youth (WHO ICF). The aim of this review is to identify instruments that are suitable for use in postal surveys with families of children with cerebral palsy. We conducted a structured review of instruments that use child or family self-assessment of 'activity performance and participation'. The review involved a systematic search for instruments using multiple published sources. Appraisal of the instruments used the predefined criteria of appropriateness, validity, reliability, responsiveness, precision, interpretability, acceptability and feasibility. There are relatively few child or family assessed instruments appropriate for measuring children's activities and participation. Seven instruments were identified that could potentially be administered by mail. The Assessment of Life Habits for Children (LIFE-H) was the most appropriate instrument as assessed by its content but the reliability of child or family self-assessment is not known. If the LIFE-H were shown to be a reliable self-report measure then the LIFE-H would be the recommended choice. Currently, the Activities Scale for Kids and the condition-specific Lifestyle Assessment Questionnaire for cerebral palsy (LAQ-CP) provide the broadest description of what and how frequently children with cerebral palsy perform a range of activities and thereby indicate participation. The LAQ-CP also provides additional contextual information on the impact of any disability on the participation of the family unit. There remains much scope for developing valid and reliable self-assessed measures corresponding to the WHO ICF dimensions of activities and participation.


A synthesis of terrestrial mercury in the western United States: Spatial distribution defined by land cover and plant productivity.
A synthesis of published vegetation mercury (Hg) data across 11 contiguous states in the western United States showed that aboveground biomass concentrations followed the order: leaves (26μgkg(-1))~branches (26μgkg(-1))>bark (16μgkg(-1))>bole wood (1μgkg(-1)). No spatial trends of Hg in aboveground biomass distribution were detected, which likely is due to very sparse data coverage and different sampling protocols. Vegetation data are largely lacking for important functional vegetation types such as shrubs, herbaceous species, and grasses. Soil concentrations collected from the published literature were high in the western United States, with 12% of observations exceeding 100μgkg(-1), reflecting a bias toward investigations in Hg-enriched sites. In contrast, soil Hg concentrations from a randomly distributed data set (1911 sampling points; Smith et al., 2013a) averaged 24μgkg(-1) (A-horizon) and 22μgkg(-1) (C-horizon), and only 2.6% of data exceeded 100μgkg(-1). Soil Hg concentrations significantly differed among land covers, following the order: forested upland>planted/cultivated>herbaceous upland/shrubland>barren soils. Concentrations in forests were on average 2.5 times higher than in barren locations. Principal component analyses showed that soil Hg concentrations were not or weakly related to modeled dry and wet Hg deposition and proximity to mining, geothermal areas, and coal-fired power plants. Soil Hg distribution also was not closely related to other trace metals, but strongly associated with organic carbon, precipitation, canopy greenness, and foliar Hg pools of overlying vegetation. These patterns indicate that soil Hg concentrations are related to atmospheric deposition and reflect an overwhelming influence of plant productivity - driven by water availability - with productive landscapes showing high soil Hg accumulation and unproductive barren soils and shrublands showing low soil Hg values. Large expanses of low-productivity, arid ecosystems across the western U.S. result in some of the lowest soil Hg concentrations observed worldwide.


Phase I study of glypican-3-derived peptide vaccine therapy for patients with refractory pediatric solid tumors.
The carcinoembryonic antigen glypican-3 (GPC3) is a good target of anticancer immunotherapy against pediatric solid tumors expressing GPC3. In this non-randomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3-peptide vaccination in patients with pediatric solid tumors. Eighteen patients with pediatric solid tumors expressing GPC3 underwent GPC3-peptide vaccination (intradermal injections every 2 weeks), with the primary endpoint being the safety of GPC3-peptide vaccination and the secondary endpoints being immune response, as measured by interferon (IFN)-γ enzyme-linked immunospot assay and Dextramer staining, and the clinical outcomes of tumor response, progression free survival (PFS), and overall survival (OS). Our findings indicated that GPC3 vaccination was well tolerated. We observed disease-control rates [complete response (CR)+partial response+stable disease] of 66.7% after 2 months, and although patients in the progression group unable to induce GPC3-peptide-specific cytotoxic T lymphocytes (CTLs) received poor prognoses, patients in the partial-remission and remission groups or those with hepatoblastoma received good prognoses. The GPC3-peptide vaccine induced a GPC3-specific CTL response in seven patients, with PFS and OS significantly longer in patients with high GPC3-specific CTL frequencies than in those with low frequencies. Furthermore, we established GPC3-peptide-specific CTL clones from a resected-recurrent tumor from one patient, with these cells exhibiting GPC3-peptide-specific cytokine secretion. The results of this trial demonstrated that the GPC3-peptide-specific CTLs induced by the GPC3-peptide vaccine infiltrated tumor tissue, and use of the GPC3-peptide vaccine might prevent the recurrence of pediatric solid tumors, especially hepatoblastomas, after a second CR.


Allele-specific gene expression uncovered.
Genetic variation in populations can result in variation in levels of gene expression but the extent to which this occurs has been unclear. In this article, recent studies of allele-specific expression among autosomal non-imprinted genes are reviewed. These new data provide evidence that differential expression is relatively common and that allelic differences are heritable and can be highly context specific.


Construction of new EST-SSRs for Fusarium resistant wheat breeding.
Surveying Fusarium resistance in wheat with easy applicable molecular markers such as simple sequence repeats (SSRs) is a prerequest for molecular breeding. Expressed sequence tags (ESTs) are one of the main sources for development of new SSR candidates. Therefore, 18.292 publicly available wheat ESTs were mined and genotyping of newly developed 55 EST-SSR derived primer pairs produced clear fragments in ten wheat cultivars carrying different levels of Fusarium resistance. Among the proved markers, 23 polymorphic EST-SSRs were obtained and related alleles were mostly found on B and D genome. Based on the fragment profiling and similarity analysis, a 327bp amplicon, which was a product of contig 1207 (chromosome 5BL), was detected only in Fusarium head blight (FHB) resistant cultivars (CM82036 and Sumai) and the amino acid sequences showed a similarity to pathogen related proteins. Another FHB resistance related EST-SSR, Contig 556 (chromosome 1BL) produced a 151bp fragment in Sumai and was associated to wax2-like protein. A polymorphic 204bp fragment, derived from Contig 578 (chromosome 1DL), was generated from root rot (FRR) resistant cultivars (2-49; Altay2000 and Sunco). A total of 98 alleles were displayed with an average of 1.8 alleles per locus and the polymorphic information content (PIC) ranged from 0.11 to 0.78. Dendrogram tree with two main and five sub-groups were displayed the highest genetic relationship between FRR resistant cultivars (2-49 and Altay2000), FRR sensitive cultivars (Seri82 and Scout66) and FHB resistant cultivars (CM82036 and Sumai). Thus, exploitation of these candidate EST-SSRs may help to genotype other wheat sources for Fusarium resistance.


Vascular patterns in the heads of crocodilians: blood vessels and sites of thermal exchange.
Extant crocodilians are a highly apomorphic archosaur clade that is ectothermic, yet often achieve large body sizes that can be subject to higher heat loads. Therefore, the anatomical and physiological roles that blood vessels play in crocodilian thermoregulation need further investigation to better understand how crocodilians establish and maintain cephalic temperatures and regulate neurosensory tissue temperatures during basking and normal activities. The cephalic vascular anatomy of extant crocodilians, particularly American alligator (Alligator mississippiensis) was investigated using a differential-contrast, dual-vascular injection technique and high resolution X-ray micro-computed tomography (μCT). Blood vessels were digitally isolated to create representations of vascular pathways. The specimens were then dissected to confirm CT results. Sites of thermal exchange, consisting of the oral, nasal, and orbital regions, were given special attention due to their role in evaporative cooling and cephalic thermoregulation in other diapsids. Blood vessels to and from sites of thermal exchange were studied to detect conserved vascular patterns and to assess their ability to deliver cooled blood to neurosensory tissues. Within the orbital region, both the arteries and veins demonstrated consistent branching patterns, with the supraorbital, infraorbital, and ophthalmotemporal vessels supplying and draining the orbit. The venous drainage of the orbital region showed connections to the dural sinuses via the orbital veins and cavernous sinus. The palatal region demonstrated a vast plexus that comprised both arteries and veins. The most direct route of venous drainage of the palatal plexus was through the palatomaxillary veins, essentially bypassing neurosensory tissues. Anastomotic connections with the nasal region, however, may provide an alternative route for palatal venous blood to reach neurosensory tissues. The nasal region in crocodilians is probably the most prominent site of thermal exchange, as it offers a substantial surface area and is completely surrounded by blood vessels. The venous drainage routes from the nasal region offer routes directly to the dural venous sinuses and the orbit, offering evidence of the potential to directly affect neurosensory tissue temperatures. The evolutionary history of crocodilians is complex, with large-bodied, terrestrial, and possibly endothermic taxa that may have had to deal with thermal loads that likely provided the anatomical building-blocks for such an extensive vascularization of sites of thermal exchange. A clear understanding of the physiological abilities and the role of blood vessels in the thermoregulation of crocodilians neurosensory tissues is not available but vascular anatomical patterns of crocodilian sites of thermal exchange indicate possible physiological abilities that may be more sophisticated than in other extant diapsids.


[Permanent tunneled drainage for malignant ascites: initial experience with the PleurX® catheter].
The most common treatment in recurrent malignant ascites is generally temporary peritoneal drainage. We present our experience in placing permanent tunneled catheters in a series of patients and analyze the safety and efficacy of the treatment. We used total aseptic measures in the interventional ultrasonography suite to place permanent tunneled catheters in 10 patients under ultrasonographic guidance and local anesthesia. The catheters remained patent for a median of 52 days in the nine patients who died. In one of these, the catheter was withdrawn while still patent due to generalized sepsis. At the end of the study, one patient still had a permeable catheter 124 days after placement. Although the low number of patients in our series precludes generalizations, tunneled peritoneal catheters seem to be a safe and effective minimally invasive treatment for malignant ascites in terminal oncologic patients. This approach facilitates the draining of the ascites at home, obviating the need for repeated hospital visits and punctures and the risks involved therein. Nevertheless, further experience and prospective randomized trials are necessary.


Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration.
Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10(-8)] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10(-9)). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD.


Histological Underpinnings of Grey Matter Changes in Fibromyalgia Investigated Using Multimodal Brain Imaging.
Chronic pain patients present with cortical gray matter alterations, observed with anatomical magnetic resonance (MR) imaging. Reduced regional gray matter volumes are often interpreted to reflect neurodegeneration, but studies investigating the cellular origin of gray matter changes are lacking. We used multimodal imaging to compare 26 postmenopausal women with fibromyalgia with 25 healthy controls (age range: 50-75 years) to test whether regional gray matter volume decreases in chronic pain are associated with compromised neuronal integrity. Regional gray matter decreases were largely explained by T1 relaxation times in gray matter, a surrogate measure of water content, and not to any substantial degree by GABAA receptor concentration, an indirect marker of neuronal integrity measured with [18F] flumazenil PET. In addition, the MR spectroscopy marker of neuronal viability, N-acetylaspartate, did not differ between patients and controls. These findings suggest that decreased gray matter volumes are not explained by compromised neuronal integrity. Alternatively, a decrease in neuronal matter could be compensated for by an upregulation of GABAA receptors. The relation between regional gray matter and T1 relaxation times suggests decreased tissue water content underlying regional gray matter decreases. In contrast, regional gray matter increases were explained by GABAA receptor concentration in addition to T1 relaxation times, indicating perhaps increased neuronal matter or GABAA receptor upregulation and inflammatory edema. By providing information on the histological origins of cerebral gray matter alterations in fibromyalgia, this study advances the understanding of the neurobiology of chronic widespread pain. Regional gray matter alterations in chronic pain, as detected with voxel-based morphometry of anatomical magnetic resonance images, are commonly interpreted to reflect neurodegeneration, but this assumption has not been tested. We found decreased gray matter in fibromyalgia to be associated with T1 relaxation times, a surrogate marker of water content, but not with GABAA receptor concentration, a surrogate of neuronal integrity. In contrast, regional gray matter increases were partly explained by GABAA receptor concentration, indicating some form of neuronal plasticity. The study emphasizes that voxel-based morphometry is an exploratory measure, demonstrating the need to investigate the histological origin of gray matter alterations for every distinct clinical entity, and advances the understanding of the neurobiology of chronic (widespread) pain.


The importance of greater speed in drug development for advanced malignancies.
It takes on average 6-12 years to develop new anticancer drugs from discovery to approval. Effective new agents prolong survival. To demonstrate the importance of rapid drug approval, we calculated life-years potentially saved if selected agents were approved more rapidly. As illustrative examples, we used 27 trials documenting improvements in survival. We multiplied improvement in median survival by numbers of patients dying annually and multiplied this by number of years from drug discovery until approval. For every year by which time to drug approval could have been shortened, there would have been a median number of life-years potentially saved of 79,920 worldwide per drug. Median number of life-years lost between time of drug discovery and approval was 1,020,900 per example. If we were able to use available opportunities to decrease the time required to take a drug from discovery to approval to 5 years, the median number of life-years saved per example would have been 523,890 worldwide. Various publications have identified opportunities to speed drug development without sacrificing patient safety. While many investigational drugs prove to be ineffective, some significantly prolong survival and/or reduce suffering. These illustrative examples suggest that a substantial number of life-years could potentially be saved by increasing the efficiency of development of new drugs for advanced malignancies.


Effects of neem seed derivatives on behavioral and physiological responses of the Cosmopolites sordidus (Coleoptera: Curculionidae).
Both in a choice and multi-choice laboratory tests, fewer adults of the banana root borer, Cosmopolites sordidus (Germar), settled under the corms of the susceptible banana "Nakyetengu" treated with 5% aqueous extract of neem seed powder or cake or 2.5 and 5% emulsified neem oil than on water-treated corms. Feeding damage by larvae on banana pseudostem discs treated with 5% extract of powdered neem seed, kernel, or cake, or 5% emulsified neem oil was significantly less than on untreated discs. The larvae took much longer to locate feeding sites, initiate feeding and bore into pseudostem discs treated with extract of powdered neem seed or kernel. Few larvae survived when confined for 14 d on neem-treated banana pseudostems; the survivors weighed two to four times less than the larvae developing on untreated pseudostems. Females deposited up to 75% fewer eggs on neem-treated corms. In addition, egg hatching was reduced on neem-treated corms. The higher the concentration of neem materials the more severe the effect.


Conserving large populations of lions - the argument for fences has holes.
Packer et al. reported that fenced lion populations attain densities closer to carrying capacity than unfenced populations. However, fenced populations are often maintained above carrying capacity, and most are small. Many more lions are conserved per dollar invested in unfenced ecosystems, which avoid the ecological and economic costs of fencing.


Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism.
Obesity and diabetes in humans are associated with increased rates of anxiety and depression. To understand the role of the gut microbiome and brain insulin resistance in these disorders, we evaluated behaviors and insulin action in brain of mice with diet-induced obesity (DIO) with and without antibiotic treatment. We find that DIO mice have behaviors reflective of increased anxiety and depression. This is associated with decreased insulin signaling and increased inflammation in in the nucleus accumbens and amygdala. Treatment with oral metronidazole or vancomycin decreases inflammation, improves insulin signaling in the brain and reduces signs of anxiety and depression. These effects are associated with changes in the levels of tryptophan, GABA, BDNF, amino acids, and multiple acylcarnitines, and are transferable to germ-free mice by fecal transplant. Thus, changes in gut microbiota can control brain insulin signaling and metabolite levels, and this leads to altered neurobehaviors.


Placental lactogen and GH receptors in sheep liver: striking differences in ontogeny and function.
To determine whether changes in the relative biological potencies of ovine placental lactogen (oPL) and ovine growth hormone (oGH) during development derive from ontogenetic changes in the binding of these hormones to hepatic receptors, we have compared the binding of 125I-oPL and 125I-oGH to hepatic membranes from fetal lambs and pregnant sheep at mid- and late gestation and from postnatal sheep at 1 day to 7 mo of age. Specific high-affinity 125I-oPL binding sites in ovine fetal liver were detected as early as day 70 of gestation (term = 145 days), and the number of fetal 125I-oPL binding sites increased progressively throughout the latter half of gestation, reaching a maximum (11.2 fmol/mg protein) at 3-7 days before parturition. The potency of oPL (Kd 0.27 nM) in competing for 125I-oPL binding sites was 90 and 1,300 times greater than that of oGH and ovine prolactin, respectively. Although the number of fetal 125I-oPL binding sites increased throughout pregnancy, there was little or no specific binding of 125I-oGH noted in the fetus. Treatment of fetal liver membranes with 4 M MgCl2 did not enhance the subsequent specific binding of 125I-oGH, suggesting that the low specific binding of oGH did not result from occupation of hepatic receptors by endogenous circulating oPL or oGH. In contrast, MgCL2 treatment markedly increased the apparent number of fetal 125I-oPL binding sites, suggesting that oPL receptors in fetal liver are partly saturated in vivo by oPL.(ABSTRACT TRUNCATED AT 250 WORDS)


Paradoxical evolution of a cerebellar tuberculosis abscess after surgical drainage and antibiotic therapy.
Involvement of the central nervous system (CNS) by a tuberculosis abscess is a rare form of extra-pulmonary tuberculosis. With proper treatment, the abscess most commonly follows a pattern of continued reduction in size. A 71-year-old male with a past medical history of kidney transplant on immunosuppressive therapy, presented to the hospital with a 1-day history of headache. On physical examination, the patient had no focal neurological symptoms. Initial laboratory reports were unremarkable. Contrast enhanced magnetic resonance imaging (MRI) was performed, which showed a ring enhancing mass and perilesional edema in the left cerebellar hemisphere. The patient underwent a left posterior fossa biopsy and drainage. The lesion was encapsulated with a purulent center. Cultures revealed pan-sensitive mycobacterium tuberculosis and the patient was started on rifampicin, isoniazid, pyrazinamide, ethambutol, and B6. The patient was monitored carefully and brain MRIs were obtained at 1, 4, 9, 11, and 14 months. It was noted that the tuberculosis abscess had grown in size from month 4 to month 9 of treatment. Since the patient's neurologic examination and symptoms were stable at that time, the drug regimen was not changed. The 14-month follow up MRI showed that the abscess had nearly resolved. Rarely, the pattern of CNS tuberculosis abscess evolution may include growth, even with proper treatment. This pattern does not necessarily signify treatment failure, as our abscess resolved without change in treatment. Given the possibility of asymptomatic abscess enlargement, close clinical and imaging follow up are crucial in management of these cases.


Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis.
Allele-specific expression (ASE) of the Adenomatous Polyposis Coli (APC) gene occurs in up to one-third of families with adenomatous polyposis (FAP) that have screened mutation-negative by conventional techniques. To advance our understanding of the genomic basis of this phenomenon, 54 APC mutation-negative families (21 with classical FAP and 33 with attenuated FAP, AFAP) were investigated. We focused on four families with validated ASE and scrutinized these families by sequencing of the blood transcriptomes (RNA-seq) and genomes (WGS). Three families, two with classical FAP and one with AFAP, revealed deep intronic mutations associated with pseudoexons. In all three families, intronic mutations (c.646-1806T>G in intron 6, c.1408+729A>G in intron 11, and c.1408+731C>T in intron 11) created new splice donor sites resulting in the insertion of intronic sequences (of 127 bp, 83 bp, and 83 bp, respectively) in the APC transcript. The respective intronic mutations were absent in the remaining polyposis families and the general population. Premature stop of translation as the predicted consequence as well as co-segregation with polyposis supported the pathogenicity of the pseudoexons. We conclude that next generation sequencing on RNA and genomic DNA is an effective strategy to reveal and validate pseudoexons that are regularly missed by traditional screening methods and is worth considering in apparent mutation-negative polyposis families.


Conversion of linoleic acid and alpha-linolenic acid to long-chain polyunsaturated fatty acids (LCPUFAs), with a focus on pregnancy, lactation and the first 2 years of life.
Over the past two decades, there has been a marked shift in the fatty acid composition of the diets of industrialized nations towards increased intake of the n-6 fatty acid linoleic acid (LA, 18:2n-6), largely as a result of the replacement of saturated fats with plant-based polyunsaturated fatty acid (PUFA). While health agencies internationally continue to advocate for high n-6 PUFA intake combined with increased intakes of preformed n-3 long-chain PUFAs (LCPUFA) docosahexaenoic acid (DHA, 22:6n-3) and eicosapentaenoic acid (EPA, 20:5n-3) to reduce the incidence of cardiovascular disease (CVD), there are questions as to whether this is the best approach. LA competes with alpha-linolenic acid (18:3n-3) for endogenous conversion to the LC derivatives EPA and DHA, and LA also inhibits incorporation of DHA and EPA into tissues. Thus, high-LA levels in the diet generally result in low n-3 LCPUFA status. Pregnancy and infancy are developmental periods during which the fatty acid supply is particularly critical. The importance of an adequate supply of n-3 LCPUFA for ensuring optimal development of infant brain and visual systems is well established, and there is now evidence that the supply of n-3 LCPUFA also influences a range of growth, metabolic and immune outcomes in childhood. This review will re-evaluate the health benefits of modern Western diets and pose the question of whether the introduction of similar diets to nations with emerging economies is the most prudent public health strategy for improving health in these populations.


HIV-1 protease inhibition potential of functionalized polyoxometalates.
Polyoxometalates (POMs) are interesting biomedical agents due to their versatile anticancer and antiviral properties, such as remarkable anti-HIV activity. Although POMs are tunable and easily accessible inorganic drug prototypes in principle, their full potential can only be tapped by enhancing their biocompatibility, for example, through organic functionalization. We have therefore investigated the HIV-1 protease inhibition potential of functionalized Keggin- and Dawson-type POMs with organic side chains. Their inhibitory performance was furthermore compared to other POM types, and the buffer dependence of the results is discussed. In addition, chemical shift mapping NMR experiments were performed to exclude POM-substrate interactions. Whereas the introduction of organic side chains into POMs is a promising approach in principle, the influence of secondary effects on the reaction system also merits detailed investigation.


Local distortion energy and coarse-grained elasticity of the twist-bend nematic phase.
The recently discovered twist-bend nematic phase of achiral bent-shaped molecules, NTB, has a doubly degenerate ground-state with a periodically modulated heliconical structure and unusual distortion elasticity, the theoretical description of which is still debated. We show that the NTB phase has the same macroscopic symmetry as another periodic mesophase, the chiral smectic-A, SmA*. Based on this NTB/SmA* analogy, we develop a coarse-grained elastic model for the NTB phase. Adopting one of the existing microscopic NTB elastic models, we calculate the coarse-grained elastic constants, coherence and penetration lengths in terms of a few Frank-like nematic elastic coefficients that can be measured in macroscopic experiments. The same coarse-grained approach, applied to different local elastic models, may provide an efficient experimental test of their validity. We show that the anisotropy of the NTB coarse-grained elasticity is opposite to that of the SmA*, leading probably to different configurations of some of the defects of the "layered" NTB structure. Moreover, we argue that the intrinsic chiral frustration of the NTB phase may be resolved by penetration of the twist field into the bulk through a network of screw dislocations of the NTB pseudo-layers, resulting in a twist-bend analogue of the twist grain boundary phase TGBA.


Impact of malaria on hematological parameters in people living with HIV/AIDS attending the Laquintinie Hospital in Douala, Cameroon.
People living with HIV/AIDS (PLWHA) frequently have abnormal blood counts including anemia, leucopenia and thrombocytopenia. The role of infection with plasmodia on these hematological parameters in PLWHA is not well known. In this study we compared selected hematological parameters between malaria positive and negative PLWHA. We conducted a cross-sectional study of PLWHA attending the Douala Laquintinie hospital. After obtaining consent, demographic and clinical data were obtained via a standardized questionnaire. Blood samples collected for hematological assays were run using an automated full blood counter. Malaria parasitaemia was determined by blood smear microscopy. A total of 238 adult PLWHA were enrolled, 48.3% of who were on antiretroviral therapy and 24.8% of whom had malaria parasitaemia. The respective mean (±SD) of hemoglobin level, RBC count, WBC count, platelet count, lymphocyte count and CD4+ T cell counts in malaria co-infected patients versus non-infected patients were: 10.8(±1.9) g/dl versus 11.4(±2.0) g/dl; 3,745,254(±793,353) cells/µl versus 3,888,966(±648,195) cells/µl; 4,403(±1,534) cells/µl versus 4,920(±1,922) cells/µl; 216,051(±93,884) cells/µl versus 226,792(±98,664) cells/µl; 1,846(±711) cells/µl versus 2,052(±845) cells/µl and 245(±195) cells/µl versus 301(±211) cells/µl. All these means were not statistically significantly different from each other. There was no significant difference in studied hematological parameters between malaria positive and negative PLWHA. These data suggest little or no impact of malaria infection. Hematological anomalies in PLWHA in this area need not be necessarily attributed to malaria. These need to be further investigated to identify and treat other potential causes.


DensiTree: making sense of sets of phylogenetic trees.
Bayesian analysis through programs like BEAST (Drummond and Rumbaut, 2007) and MrBayes (Huelsenbeck et al., 2001) provides a powerful method for reconstruction of evolutionary relationships. One of the benefits of Bayesian methods is that well-founded estimates of uncertainty in models can be made available. So, for example, not only the mean time of a most recent common ancestor (tMRCA) is estimated, but also the spread. This distribution over model space is represented by a set of trees, which can be rather large and difficult to interpret. DensiTree is a tool that helps navigating these sets of trees. The main idea behind DensiTree is to draw all trees in the set transparently. As a result, areas where a lot of the trees agree in topology and branch lengths show up as highly colored areas, while areas with little agreement show up as webs. This makes it possible to quickly get an impression of properties of the tree set such as well-supported clades, distribution of tMRCA and areas of topological uncertainty. Thus, DensiTree provides a quick method for qualitative analysis of tree sets. DensiTree is freely available from http://compevol.auckland.ac.nz/software/DensiTree/. The program is licensed under GPL and source code is available. email@example.com


Motion aftereffect elicits smooth pursuit eye movements.
A moving stimulus is normally required to elicit smooth pursuit eye movements that serve to keep the retinal image of moving objects on the fovea. Recent experiments have shown that in cases where motion cues are ambiguous, pursuit eye movements tend to agree in direction and speed with the percept of motion. Here, we exploit the motion aftereffect (MAE) to show for the first time that smooth pursuit eye movements can also be elicited by the illusory motion of a stationary stimulus. After prolonged exposure to a moving stimulus, subjects show reliable pursuit of a physically stationary stimulus that is perceived to be moving. Conversely, the eyes remain stationary when viewing a physically moving stimulus that is perceived to be stationary. The MAE biases smooth eye movements in a way that agrees with the constant offset that is required to null the MAE perceptually. The agreement between perception and pursuit holds over a variety of stimulus conditions that modulate the magnitude of the MAE.


The effect of balance training on balance performance in individuals poststroke: a systematic review.
Stroke is a leading cause of long-term disability, and impaired balance after stroke is strongly associated with future function and recovery. Until recently there has been limited evidence to support the use of balance training to improve balance performance in this population. Information about the optimum exercise dosage has also been lacking. This review evaluated recent evidence related to the effect of balance training on balance performance among individuals poststroke across the continuum of recovery. On the basis of this evidence, we also provide recommendations for exercise prescription in such programs. A systematic search was performed on literature published between January 2006 and February 2010, using multiple combinations of intervention (eg, "exercise"), population (eg, "stroke"), and outcome (eg, "balance"). Criteria for inclusion of a study was having at least 1 standing balance exercise in the intervention and 1 study outcome to evaluate balance. Twenty-two published studies met the inclusion criteria. We found moderate evidence that balance performance can be improved following individual, "one-on-one" balance training for participants in the acute stage of stroke, and either one-on-one balance training or group therapy for participants with subacute or chronic stroke. Moderate evidence also suggests that in the acute stage, intensive balance training for 2 to 3 times per week may be sufficient, whereas exercising for 90 minutes or more per day, 5 times per week may be excessive. This review supports the use of balance training exercises to improve balance performance for individuals with moderately severe stroke. Future high-quality, controlled studies should investigate the effects of balance training for individuals poststroke who have severe impairment, additional complications/comorbidities, or specific balance lesions (eg, cerebellar or vestibular). Optimal training dosage should also be further explored. Studies with long-term follow-up are needed to assess outcomes related to participation in the community and reduction of fall risk.


Effect of nocturnal haemodialysis on body composition.
Haemodialysis patients have a high risk of malnutrition which is associated with increased mortality. Nocturnal haemodialysis (NHD) is associated with a significant increase in protein intake compared with conventional haemodialysis (CHD). It is unclear whether this leads to improved nutritional status. Therefore, we studied whether 1 year of NHD is associated with a change in body composition. Whole-body composition using dual-energy X-ray absorptiometry (DEXA) and normalised protein catabolic rate (nPCR) were measured in 11 adult patients before and 1 year after the transition from CHD (12 h dialysis/week) to NHD (28-48 h dialysis/week). Similar measurements were performed in a matched control group of 13 patients who stayed on CHD. Differences between groups were analysed with linear mixed models. At baseline, nPCR, total mass, fat-free mass, and fat mass did not differ significantly between the CHD and NHD groups. nPCR increased in the NHD group (from 0.96 ± 0.23 to 1.12 ± 0.20 g/kg/day; p = 0.027) whereas it was stable in the CHD group (0.93 ± 0.21 at baseline and 0.87 ± 0.09 g/kg/day at 1 year, n.s.). The change in nPCR differed significantly between the two groups (p = 0.027). We observed no significant differences in the course of total mass, fat-free mass, and fat mass during the 1-year observation period between the NHD and CHD groups. One year of NHD had no significant effect on body composition in comparison with CHD, despite a significantly higher protein intake in patients on NHD.


Ultrafast photoinduced charge separation in naphthalene diimide based multichromophoric systems in liquid solutions and in a lipid membrane.
The photophysical properties of multichromophoric systems consisting of eight red or blue naphthalene diimides (NDIs) covalently attached to a p-octiphenyl scaffold, as well as a blue bichromophoric system with a biphenyl scaffold, have been investigated in detail using femtosecond time-resolved spectroscopy. The blue octachromophoric systems have been recently shown to self-assemble as supramolecular tetramers in lipid bilayer membranes and to enable generation of a transmembrane proton gradient upon photoexcitation ( Bhosale, S. ; Sisson, A. L. ; Talukdar, P. ; Fürstenberg, A. ; Banerji, N. ; Vauthey, E. ; Bollot, G. ; Mareda, J. ; Röger, C. ; Würthner, F. ; Sakai, N. ; Matile, S. Science 2006, 313, 84 ). A strong reduction of the fluorescence quantum yield was observed when going from the single NDI units to the multichromophoric systems in methanol, the effect being even stronger in a vesicular lipid membrane. Fluorescence up-conversion measurements reveal ultrafast self-quenching in the multichromophoric systems, whereas the formation of the NDI radical anion, evidenced by transient absorption measurements, points to the occurrence of photoinduced charge separation. The location of the positive charge could not be established unambiguously from the transient absorption measurements, but energetic considerations indicate that charge separation should occur between two NDI units in the blue systems, whereas both an NDI unit and the p-octiphenyl scaffold could act as electron donor in the red system. The lifetime of the charge-separated state was found to increase from 22 to 45 ps by going from the bi- to the octachromophoric blue systems in methanol, while a 400 ps decay component was observed in the lipid membrane. This lifetime lengthening is explained in terms of charge migration that is most efficient when the octachromophoric systems are assembled as supramolecular tetramers in the lipid membrane. Furthermore, the average charge-separated state lifetime of the red system in methanol is even larger and amounts to 750 ps. This effect cannot be simply explained in terms of Marcus inverted regime as the driving force for charge recombination in the red system is only slightly larger than in the blue one. A better spatial separation of the charges in the red system stemming from the localization of the hole on the p-octiphenyl scaffold could additionally contribute to the slowing down of charge recombination.


Child day care, smoking by caregivers, and lower respiratory tract illness in the first 3 years of life. Group Health Medical Associates.
Day-care attendance has been associated with an increased risk of hospitalization for lower respiratory tract illnesses (LRIs). This study examines, in a health maintenance organization population of children, the associations between child day care and the occurrence of LRIs in the first 3 years of life. Smoking by caregivers and a possible protective effect of longer day-care enrollment in relation to LRIs are also addressed. Information on day-care arrangements was elicited from 1006 parents of infants for five age intervals in the first 3 years of life: birth through 3 months, 4 to 6 months, 6 to 12 months, 1 to 2 years, and 2 to 3 years. Data on LRIs in the first 3 years of life were recorded by pediatricians at the time of the acute illnesses. After controlling for other risk factors, the presence of three or more unrelated children in the care setting was associated with significant risks of LRI of up to twofold or more from 4 months of age to 3 years. Type of care setting was not a significant risk factor during this time period. In the third year of life, the risk of wheezing LRI in the presence of a smoking caregiver was more than threefold for those in another residential home setting. No significant protective effect against LRIs in the third year of life associated with longer prior day-care enrollment was demonstrated. The presence of three or more unrelated children in the care setting and the presence of a smoking caregiver were significant independent risk factors for LRIs during the first 3 years of life. Prolonged day-care did not protect against LRIs in the third year of life.


Genome-wide evidence for selection acting on single amino acid repeats.
Low complexity and homopolymer sequences within coding regions are known to evolve rapidly. While their expansion may be deleterious, there is increasing evidence for a functional role associated with these amino acid sequences. Homopolymer sequences are thought to evolve mostly through replication slippage and, therefore, they may be expected to be longer in regions with relaxed selective constraint. Within the coding sequences of eukaryotes, alternatively spliced exons are known to evolve under relaxed constraints in comparison to those exons that are constitutively spliced because they are not included in all of the mature mRNA of a gene. This relaxed exposure to selection leads to faster rates of evolution for alternatively spliced exons in comparison to constitutively spliced exons. Here, we have tested the effect of splicing on the structure (composition, length) of homopolymer sequences in relation to the splicing pattern in which they are found. We observed a significant relationship between alternative splicing and homopolymer sequences with alternatively spliced genes being enriched in number and length of homopolymer sequences. We also observed lower codon diversity and longer homocodons, suggesting a balance between slippage and point mutations linked to the constraints imposed by selection.


Identification of a target for CudA, the transcription factor which directs formation of the Dictyostelium tip organiser.
The tip of the Dictyostelium slug functions much like an embryonic organiser; when grafted onto the flank of a recipient slug, it recruits a mass of prespore cells and leads them away as part of a secondary slug. CudA is a nuclear protein which is expressed in prespore cells where it acts as a specific transcription factor. CudA is also expressed in an anteriorly located group of cells, the tip-organiser, that is believed to constitute the functional tip. We identify an expansin-like gene, expl7, that is expressed within the tip-organiser region and which is not expressed in a cudA null strain. The expl7 promoter contains a region that binds to CudA in vitro and this region is necessary for expression in the tip-organiser. These results provide an end-point for a previously defined signal transduction pathway in which regionalized expression of the ACA adenylyl cyclase within the tip-organiser leads to localised cAMP-induced activation of STATa and consequent binding of STATa to the cudA promoter. STATa then induces expression of cudA and cudA directs the transcription of target genes such as expl7.


Early detection of electromechanical dysfunction in patients with idiopathic premature ventricular contractions.
Premature ventricular contractions (PVCs) induced by subtle cardiac dysfunction are missed by echocardiography. We evaluated acoustic cardiography for detection of early electromechanical dysfunction in patients with idiopathic PVCs and normal left ventricular ejection fraction (LVEF), and investigated the impact of radiofrequency ablation (RFA) in reversing this adverse effect. Eighty-six patients with PVCs and 33 normal controls having normal LVEF were studied. Fifty PVC patients were in the ablation group and 36 in the nonablation group. %Electromechanical activation time (%EMAT), %left ventricular systolic time (%LVST), third (S3) and fourth heart sound (S4), and systolic dysfunction index (SDI) during sinus rhythm (SR) were measured by acoustic cardiography (Audicor, Inovise Medical, Inc., Beaverton, OR, USA) pre- and postablation. In 28 patients, acoustic parameters were compared during SR without PVCs, and SR with single PVC, ≥ 2 PVCs, or ventricular tachycardia over 10-second Audicor recording in a single patient at different times. Twenty-four-hour acoustic cardiographic and acoustic cardiographic Holter recording were used to assess the impact of PVC burden on electromechanical function in 41 patients. %EMAT, S3, S4, and SDI showed significant worsening in the PVC versus control group. %EMAT and SDI were worsened with increasing PVC number in a 10-second strip. %EMAT showed significant linear increment with increasing PVC burden. There was a significant improvement in %EMAT, %LVST, S3, S4, and SDI postablation in patients with PVCs. Acoustic cardiography can detect PVC-induced minor electromechanical dysfunction in patients with normal LVEF. RFA can reverse this adverse effect.


Online Prediction of Health Care Utilization in the Next Six Months Based on Electronic Health Record Information: A Cohort and Validation Study.
The increasing rate of health care expenditures in the United States has placed a significant burden on the nation's economy. Predicting future health care utilization of patients can provide useful information to better understand and manage overall health care deliveries and clinical resource allocation. This study developed an electronic medical record (EMR)-based online risk model predictive of resource utilization for patients in Maine in the next 6 months across all payers, all diseases, and all demographic groups. In the HealthInfoNet, Maine's health information exchange (HIE), a retrospective cohort of 1,273,114 patients was constructed with the preceding 12-month EMR. Each patient's next 6-month (between January 1, 2013 and June 30, 2013) health care resource utilization was retrospectively scored ranging from 0 to 100 and a decision tree-based predictive model was developed. Our model was later integrated in the Maine HIE population exploration system to allow a prospective validation analysis of 1,358,153 patients by forecasting their next 6-month risk of resource utilization between July 1, 2013 and December 31, 2013. Prospectively predicted risks, on either an individual level or a population (per 1000 patients) level, were consistent with the next 6-month resource utilization distributions and the clinical patterns at the population level. Results demonstrated the strong correlation between its care resource utilization and our risk scores, supporting the effectiveness of our model. With the online population risk monitoring enterprise dashboards, the effectiveness of the predictive algorithm has been validated by clinicians and caregivers in the State of Maine. The model and associated online applications were designed for tracking the evolving nature of total population risk, in a longitudinal manner, for health care resource utilization. It will enable more effective care management strategies driving improved patient outcomes.


Comprehensive, quantitative mapping of T cell epitopes in gluten in celiac disease.
Celiac disease is a genetic condition that results in a debilitating immune reaction in the gut to antigens in grain. The antigenic peptides recognized by the T cells that cause this disease are incompletely defined. Our understanding of the epitopes of pathogenic CD4(+ )T cells is based primarily on responses shown by intestinal T-cells in vitro to hydrolysates or polypeptides of gluten, the causative antigen. A protease-resistant 33-amino acid peptide from wheat alpha-gliadin is the immunodominant antigen, but little is known about the spectrum of T cell epitopes in rye and barley or the hierarchy of immunodominance and consistency of recognition of T-cell epitopes in vivo. We induced polyclonal gluten-specific T cells in the peripheral blood of celiac patients by feeding them cereal and performed a comprehensive, unbiased analysis of responses to all celiac toxic prolamins, a class of plant storage protein. The peptides that stimulated T cells were the same among patients who ate the same cereal, but were different after wheat, barley and rye ingestion. Unexpectedly, a sequence from omega-gliadin (wheat) and C-hordein (barley) but not alpha-gliadin was immunodominant regardless of the grain consumed. Furthermore, T cells specific for just three peptides accounted for the majority of gluten-specific T cells, and their recognition of gluten peptides was highly redundant. Our findings show that pathogenic T cells in celiac disease show limited diversity, and therefore suggest that peptide-based therapeutics for this disease and potentially other strongly HLA-restricted immune diseases should be possible.


Supporting cancer patients in Jamaica--a needs assessment survey.
Global cancer incidence is rising rapidly particularly in the developing world where a majority of people present with advanced disease. In the English-speaking Caribbean, there is very little published data on the needs of cancer patients, their caregivers or those of allied health professionals. The research team sought to redress this balance by undertaking a needs assessment survey in the South Eastern Health Region of Jamaica to identify unmet needs and to make recommendations for improved service delivery. A mixed methods, cross-sectional study design was used involving formal and semi-formal interviews and focus group discussions. The study results indicated that there were significant barriers to accessing healthcare. These included prohibitive costs of diagnosis and treatment, a mistrust of and poor communication with doctors, compounded by people's fears, belief in folk wisdom and lack of knowledge about cancer. Recommendations offered by the study participants focussed on a community-based model of support to address the multiple needs of people facing life-limiting illness and their caregivers. Healthcare practitioners recommended the development of specific policies, targeting, in particular improved drug availability and palliative care education in order to guide development of appropriate services for the large numbers of cancer patients in need. A multiplicity of unmet needs was identified by cancer patients, their caregivers and allied health professionals. Recommendations by study participants and the authors echoed the guidelines as set out by the World Health Organization (WHO) in its 1990 Public Health Model for the integration of palliative care into existing healthcare systems.


Sinusoidal Wave Estimation Using Photogrammetry and Short Video Sequences.
The objective of the work is to model the shape of the sinusoidal shape of regular water waves generated in a laboratory flume. The waves are traveling in time and render a smooth surface, with no white caps or foam. Two methods are proposed, treating the water as a diffuse and specular surface, respectively. In either case, the water is presumed to take the shape of a traveling sine wave, reducing the task of the 3D reconstruction to resolve the wave parameters. The first conceived method performs the modeling part purely in 3D space. Having triangulated the points in a separate phase via bundle adjustment, a sine wave is fitted into the data in a least squares manner. The second method presents a more complete approach for the entire calculation workflow beginning in the image space. The water is perceived as a specular surface, and the traveling specularities are the only observations visible to the cameras, observations that are notably single image. The depth ambiguity is removed given additional constraints encoded within the law of reflection and the modeled parametric surface. The observation and constraint equations compose a single system of equations that is solved with the method of least squares adjustment. The devised approaches are validated against the data coming from a capacitive level sensor and on physical targets floating on the surface. The outcomes agree to a high degree.


Blood-based diagnostics of Alzheimer's disease.
Introduction: This review is focused on the methods used for biomarker discovery for Alzheimer's disease (AD) in blood rather than on the nature of the biomarkers themselves. Areas covered: All biomarker discovery programs explicitly rely on contrasts in phenotype as a basis for defining differences. In this review, we explore the basis of contrasting choices as a function of the type of biomarker (genetic, protein, metabolite, non-coding RNA, or pathogenic epitope). We also provide an overview of the capacity to identify pathogenic epitopes with our new platform called Aptamarkers. It is suggested that a pre-existing hypothesis regarding the pathophysiology of the disease can act as a constraint to the development of biomarkers. Expert opinion: Limiting putative biomarkers to those that have a postulated role in the pathophysiology of disease imposes an unrealistic constraint on biomarker development. The understanding of Alzheimer's disease would be accelerated by agnostic, non-hypothesis-based biomarker discovery methods. There is a need for more complex contrasts and more complex mathematical models.


Reconstructing cerebrovascular networks under local physiological constraints by integer programming.
We introduce a probabilistic approach to vessel network extraction that enforces physiological constraints on the vessel structure. The method accounts for both image evidence and geometric relationships between vessels by solving an integer program, which is shown to yield the maximum a posteriori (MAP) estimate to a probabilistic model. Starting from an overconnected network, it is pruning vessel stumps and spurious connections by evaluating the local geometry and the global connectivity of the graph. We utilize a high-resolution micro computed tomography (μCT) dataset of a cerebrovascular corrosion cast to obtain a reference network and learn the prior distributions of our probabilistic model and we perform experiments on in-vivo magnetic resonance microangiography (μMRA) images of mouse brains. We finally discuss properties of the networks obtained under different tracking and pruning approaches.


Oscillations of heart rate and respiration synchronize during poetry recitation.
The objective of this study was to investigate the synchronization between low-frequency breathing patterns and respiratory sinus arrhythmia (RSA) of heart rate during guided recitation of poetry, i.e., recitation of hexameter verse from ancient Greek literature performed in a therapeutic setting. Twenty healthy volunteers performed three different types of exercises with respect to a cross-sectional comparison: 1). recitation of hexameter verse, 2). controlled breathing, and 3). spontaneous breathing. Each exercise was divided into three successive measurements: a 15-min baseline measurement (S1), 20 min of exercise, and a 15-min effect measurement (S2). Breathing patterns and RSA were derived from respiratory traces and electrocardiograms, respectively, which were recorded simultaneously using an ambulatory device. The synchronization was then quantified by the index gamma, which has been adopted from the analysis of weakly coupled chaotic oscillators. During recitation of hexameter verse, gamma was high, indicating prominent cardiorespiratory synchronization. The controlled breathing exercise showed cardiorespiratory synchronization to a lesser extent and all resting periods (S1 and S2) had even fewer cardiorespiratory synchronization. During spontaneous breathing, cardiorespiratory synchronization was minimal and hardly observable. The results were largely determined by the extent of a low-frequency component in the breathing oscillations that emerged from the design of hexameter recitation. In conclusion, recitation of hexameter verse exerts a strong influence on RSA by a prominent low-frequency component in the breathing pattern, generating a strong cardiorespiratory synchronization.


Neisseria meningitidis strains isolated from invasive infections in France (1999-2002): phenotypes and antibiotic susceptibility patterns.
Infections due to Neisseria meningitidis are a major public health concern. In France, during 1999-2002, a total of 2167 clinical isolates of N. meningitidis from invasive infections were studied at the National Reference Center for Meningococci (Paris). Serogroup B strains were the most common (58%), followed by serogroup C strains (29%) and serogroup W135 strains (8%). Various phenotypes were observed, reflecting heterogeneity in the meningococcal population. Strains were susceptible to antibiotics currently used for treatment and chemoprophylaxis of meningococcal infections. However, the prevalence of meningococci with reduced susceptibility to penicillin is increasing. Such strains were heterogeneous and accounted for approximately 30% of isolates during this period, warranting continued surveillance of this phenomenon.


A scoping review of health promotion interventions delivered via social media to women of reproductive age.
Adult women of reproductive age are highly engaged with social media, suggesting its utility for conveying health information to this population, at scale. This scoping review aimed to describe health promotion interventions conducted via social media and assess their effectiveness to improve health outcomes, engagement and acceptability in adult women of reproductive age. Six databases were searched on 13 May 2022. Two reviewers independently screened studies. Data were extracted and risk of bias assessed using the Joanna Briggs Critical Appraisal Tools. Eligible studies conducted an intervention primarily via social media, with or without a comparison intervention, and reported health-related outcomes/behaviours pre- and post-intervention. Results were presented in narrative form. Adult women (mean age 18-45 years). Nine eligible studies were identified: six randomised control trials, two quasi-experimental studies and one cross-sectional study. Interventions focused on prenatal, antenatal or postpartum health or physical activity. Seven studies utilised Facebook for intervention delivery, one conducted a digital campaign across four platforms and one used WeChat. Studies reported significant improvements in a range of outcomes, including increased parenting competence, longer duration of breast-feeding and higher rates of physical activity. Social media interventions had greater engagement than control interventions. We identified nine diverse health promotion interventions conducted via social media, which appear acceptable and effective for improving various health outcomes in adult women of reproductive age. While this supports the utility of social media to convey health information, further research is required to prove effectiveness and superiority over other intervention strategies.


Production of Obionin A and Derivatives by the Sooty Blotch Fungus Microcyclospora malicola.
A multitude of sooty blotch and flyspeck fungi, mainly belonging to the Ascomycetes order Capnodiales, causes dark blemishes and flyspeck-like spots on apples worldwide. Different sooty blotch and flyspeck fungi can coexist in the same orchard and even on a single fruit. Our preceding experiments revealed an activity of Microcyclospora malicola strain 1930 against the anthracnose fungus Colletotrichum fioriniae in dual culture assays. Extracts of M. malicola strain 1930 showed a broad bioactivity against filamentous fungus Mucor hiemalis and gram-positive bacterium Bacillus subtilis. A bioactivity-guided isolation led to the identification of obionin A (1) as the main active principle. In addition to 1, which was previously isolated from the marine fungus Leptosphaeria obiones, we isolated three derivatives. Metabolite 2 bears a keto function at C-6, besides the replacement of oxygen by nitrogen at position 10. Two more derivatives are adducts (3, 4) of acetone as work-up artifacts. Because obionin A (1) and its derivative 2 showed cytotoxic effects and antifungal activities, we propose a role of these secondary metabolites in the antagonism between M. malicola and other apple colonizing sooty blotch and flyspeck fungi, other epiphytes, or apple pathogens competing for the same ecological niche.


Active mode of excretion across digestive tissues predates the origin of excretory organs.
Most bilaterian animals excrete toxic metabolites through specialized organs, such as nephridia and kidneys, which share morphological and functional correspondences. In contrast, excretion in non-nephrozoans is largely unknown, and therefore the reconstruction of ancestral excretory mechanisms is problematic. Here, we investigated the excretory mode of members of the Xenacoelomorpha, the sister group to Nephrozoa, and Cnidaria, the sister group to Bilateria. By combining gene expression, inhibitor experiments, and exposure to varying environmental ammonia conditions, we show that both Xenacoelomorpha and Cnidaria are able to excrete across digestive-associated tissues. However, although the cnidarian Nematostella vectensis seems to use diffusion as its main excretory mode, the two xenacoelomorphs use both active transport and diffusion mechanisms. Based on these results, we propose that digestive-associated tissues functioned as excretory sites before the evolution of specialized organs in nephrozoans. We conclude that the emergence of a compact, multiple-layered bilaterian body plan necessitated the evolution of active transport mechanisms, which were later recruited into the specialized excretory organs.


Prospective study of persistence and excretion of human herpesvirus-6 in patients with exanthem subitum and their parents.
To elucidate persistence of human herpesvirus-6 (HHV-6) in the blood and excretion of the virus into several body fluids of patients with exanthem subitum (ES), and to examine serologic and virologic findings of the parents caring for the patients in the family setting. During a 15-month period, 20 infants from 20 families (11 boys and 9 girls; mean age, 7.7 months; range, 4-11 months) with primary HHV-6 infection and a typical clinical course of ES, and 15 parents from the 20 families (2 males and 13 females; mean age, 28.2 years; range, 21-34 years) were enrolled in the study and examined clinically and virologically. Primary infection with HHV-6 was confirmed by isolation of the virus from peripheral blood mononuclear cells (MNCs), and seroconversion or a significant increase in the antibody titers to HHV-6 by a neutralization test. Viral persistence or excretion was examined by amplifying the viral deoxyribonucleic acid (DNA) in serially collected peripheral blood MNCs, plasma, saliva, stool, and urine samples with a nested polymerase chain reaction method. Data on saliva from the parents were compared with those of 21 age-matched controls. Twenty infants with virologically confirmed ES had HHV-6 DNA in MNCs persistently during and after the disease but in plasma only in the first 5 days of ES. The viral DNA was also detected persistently or intermittently in saliva and stool during and after the disease but rarely in urine. On the other hand, the 15 parents examined of the 20 infants had no HHV-6 viremia nor viral DNA in peripheral blood MNCs and plasma except 1, but half of them excreted viral DNA in saliva during and after ES. The frequency of excretion of viral DNA into saliva was not significantly different from that of 21 control parents. Only 1 of the 15 showed a fourfold increase in antibody titers to HHV-6 after possible exposure from their children. After systemic replication of HHV-6 in the blood of patients with ES during the first 5 days of the disease, the virus is excreted into saliva and stool persistently or intermittently but rarely into urine. The presence of HHV-6 DNA in plasma suggested active infection with the virus. Excretion of the virus into the saliva of infants with ES and their parents suggests the source and transmission route of infection with HHV-6.


Effects of Pre-Natal Vitamin D Supplementation with Partial Correction of Vitamin D Deficiency on Early Life Healthcare Utilisation: A Randomised Controlled Trial.
Some observational studies have suggested that higher prenatal Vitamin D intake may be associated with improved health outcomes in childhood. However there have been mixed results in this area with some negative studies, especially for effects on atopic and respiratory outcomes. We examined the effect of prenatal Vitamin D on healthcare utilisation in the first three years of life. In an ethnically stratified randomised controlled trial conducted at St Mary's Hospital London, 180 women at 27 weeks gestation were allocated to no Vitamin D, 800 IU ergocalciferol daily until delivery, or a single oral bolus of 200,000 IU cholecalciferol. Participants were randomised in blocks of 15 using computer-generated numbers and investigators were blinded to group assignment. Supplementation increased maternal and cord blood 25(OH) vitamin D concentrations, but levels remained lower than current recommendations. Primary health economic outcome was overall cost of unscheduled healthcare utilisation in the first three years of life as documented in the child's electronic health record. Secondary outcomes included cost attributable to: primary and secondary healthcare visits, respiratory and atopic complaints, cost in years 1, 2 and 3 of life and cost and frequency of prescribed medication. All costs were calculated as pounds sterling. Differences between groups were analysed using unpaired t-test or Mann-Whitney U test, and analysis of variance for adjusted analyses. We assessed 99/180 (55%) complete electronic health records, control (n = 31), daily (n = 36) and bolus (n = 32). We found no difference in total healthcare utilisation costs between the control and daily (mean difference in costs in pounds sterling 1.02, 95%CI -1.60, 1.65; adjusted 1.07, 95%CI -1.62, 1.86) or control and bolus groups (mean difference -1.58, 95%CI -2.63, 1.06; adjusted -1.40, 95%CI -2.45, 1.24). There were no adverse effects of supplementation reported during the trial. We found no evidence that prenatal vitamin D supplementation from 27 weeks gestation to delivery, at doses which failed to completely correct maternal vitamin D deficiency, influence overall healthcare utilisation in children in the first 3 years. Controlled-Trials.com ISRCTN68645785.


The cluster variation method for efficient linkage analysis on extended pedigrees.
Computing exact multipoint LOD scores for extended pedigrees rapidly becomes infeasible as the number of markers and untyped individuals increase. When markers are excluded from the computation, significant power may be lost. Therefore accurate approximate methods which take into account all markers are desirable. We present a novel method for efficient estimation of LOD scores on extended pedigrees. Our approach is based on the Cluster Variation Method, which deterministically estimates likelihoods by performing exact computations on tractable subsets of variables (clusters) of a Bayesian network. First a distribution over inheritances on the marker loci is approximated with the Cluster Variation Method. Then this distribution is used to estimate the LOD score for each location of the trait locus. First we demonstrate that significant power may be lost if markers are ignored in the multi-point analysis. On a set of pedigrees where exact computation is possible we compare the estimates of the LOD scores obtained with our method to the exact LOD scores. Secondly, we compare our method to a state of the art MCMC sampler. When both methods are given equal computation time, our method is more efficient. Finally, we show that CVM scales to large problem instances. We conclude that the Cluster Variation Method is as accurate as MCMC and generally is more efficient. Our method is a promising alternative to approaches based on MCMC sampling.


Socioeconomic indicators that matter for population health.
Increasing research and policy attention is being given to how the socioeconomic environment influences health. This article discusses potential indicators or metrics regarding the socioeconomic environment that could play a role in an incentive-based system for population health. Given the state of the research regarding the influence of socioeconomic contextual variables on health outcomes, the state of data and metrics for these variables at the local level, and the potential for program and policy intervention, we recommend a set of metrics related to the socioeconomic composition of a community (including poverty, unemployment, and public assistance rates); educational attainment and achievement; racial segregation; and social-capital indicators such as density of voluntary organizations and voter turnout. These indicators reflect the evidence that population health gains depend on improvements in many of the fundamental social determinants of health, including meaningful employment, income security, educational opportunities, and engaged, active communities.


Fragility, uncertainty, and healthcare.
Medicine seeks to overcome one of the most fundamental fragilities of being human, the fragility of good health. No matter how robust our current state of health, we are inevitably susceptible to future illness and disease, while current disease serves to remind us of various frailties inherent in the human condition. This article examines the relationship between fragility and uncertainty with regard to health, and argues that there are reasons to accept rather than deny at least some forms of uncertainty. In situations of current ill health, both patients and doctors seek to manage this fragility through diagnoses that explain suffering and provide some certainty about prognosis as well as treatment. However, both diagnosis and prognosis are inevitably uncertain to some degree, leading to questions about how much uncertainty health professionals should disclose, and how to manage when diagnosis is elusive, leaving patients in uncertainty. We argue that patients can benefit when they are able to acknowledge, and appropriately accept, some uncertainty. Healthy people may seek to protect the fragility of their good health by undertaking preventative measures including various tests and screenings. However, these attempts to secure oneself against the onset of biological fragility can cause harm by creating rather than eliminating uncertainty. Finally, we argue that there are good reasons for accepting the fragility of health, along with the associated uncertainties.


A method for producing precisely confocal resonators for scanning interferometers.
The desirability of using confocal cavities in scanning interferometers is discussed and a method for fabricating such cavities is described. This method makes use of the fact that in a confocal cavity the minimum spot size, and hence the extent of any combination of cavity modes, is stationary with respect to small changes in the cavity length. A method for reducing wedge in the cavity to small values is also presented. Tolerances are discussed and performance figures for two interferometers produced this way are given.


Plants used by native Amazonian groups from the Nanay River (Peru) for the treatment of malaria.
In order to evaluate the antimalarial potential of traditional remedies used in Peru, Indigenous and Mestizo populations from the river Nanay in Loreto were interviewed about traditional medication for the treatment of malaria. The survey took place on six villages and led to the collection of 59 plants. 35 hydro-alcoholic extractions were performed on the 21 most cited plants. The extracts were then tested for antiplasmodial activity in vitro on Plasmodium falciparum chloroquine resistant strain (FCR-3), and ferriprotoporphyrin inhibition test was also performed in order to assume pharmacological properties. Extracts from 9 plants on twenty-one tested (Abuta rufescens, Ayapana lanceolata, Capsiandra angustifolia, Citrus limon, Citrus paradise, Minquartia guianensis, Potalia resinífera, Scoparia dulcis, and Physalis angulata) displayed an interesting antiplasmodial activity (IC(50)<10 μg/ml) and 16 remedies were active on the ferriprotoporphyrin inhibition test. The results give scientific validation to the traditional medical knowledge of the Amerindian and Mestizo populations from Loreto and exhibit a source of potentially active plants.


OME-Zarr: a cloud-optimized bioimaging file format with international community support.
A growing community is constructing a next-generation file format (NGFF) for bioimaging to overcome problems of scalability and heterogeneity. Organized by the Open Microscopy Environment (OME), individuals and institutes across diverse modalities facing these problems have designed a format specification process (OME-NGFF) to address these needs. This paper brings together a wide range of those community members to describe the cloud-optimized format itself-OME-Zarr-along with tools and data resources available today to increase FAIR access and remove barriers in the scientific process. The current momentum offers an opportunity to unify a key component of the bioimaging domain-the file format that underlies so many personal, institutional, and global data management and analysis tasks.


United Kingdom National Ophthalmology Database Study: Diabetic Retinopathy; Report 1: prevalence of centre-involving diabetic macular oedema and other grades of maculopathy and retinopathy in hospital eye services.
To report estimates of the prevalence of diabetic retinopathy (DR) and maculopathy grades for a large cohort of patients managed by the UK hospital eye service (HES). Anonymised data were extracted from 30 UK NHS hospital trusts using a single ophthalmic electronic medical record (EMR) for the period from April 2000 to November 2010 to create the National Ophthalmology Database (NOD). From 2007, the EMR facilitated capture of a nationally agreed-upon standardised data set (DR Structured Assessment) relating to the presence or absence of clinical signs of DR and maculopathy. An algorithm in the software automatically calculated the Early Treatment of Diabetic Retinopathy Study grades of retinopathy and maculopathy. Between 2007 and 2010, 307,538 patients had data on the NOD, with 76,127 (24.8%) patients having been recorded as having diabetes. The proportion of patients with diabetes who had a structured assessment increased from 50.7% (2007) to 86.8% (2010). In each NHS year, 12.6-20.6% of eyes with structured assessments had no DR; 59.6-67.3% had non-proliferative DR; and 18.3-20.9% had active or regressed proliferative DR. Clinically significant macular oedema was present in 15.8-18.1% of eyes, and in 8.7-10.0% of eyes, this involved the central macula. This study provides contemporary estimates of the prevalence of retinopathy and maculopathy grades in a large cohort of patients with diabetes managed by the UK HES. Centre-involving diabetic macular oedema, potentially amenable to anti-VEGF therapy, is present in the eyes of almost 10% of these patients. This information is useful for clinicians, health-care economists, and commissioners involved in planning and delivering diabetic eye services.


Introducing and Implementing HIV Self-Testing in Côte d'Ivoire, Mali, and Senegal: What Can We Learn From ATLAS Project Activity Reports in the Context of the COVID-19 Crisis?
Background: The ATLAS program promotes and implements HIVST in Côte d'Ivoire, Mali, and Senegal. Priority groups include members of key populations-female sex workers (FSW), men having sex with men (MSM), and people who use drugs (PWUD)-and their partners and relatives. HIVST distribution activities, which began in mid-2019, were impacted in early 2020 by the COVID-19 pandemic. Methods: This article, focusing only on outreach activities among key populations, analyzes quantitative, and qualitative program data collected during implementation to examine temporal trends in HIVST distribution and their evolution in the context of the COVID-19 health crisis. Specifically, we investigated the impact on, the adaptation of and the disruption of field activities. Results: In all three countries, the pre-COVID-19 period was marked by a gradual increase in HIVST distribution. The period corresponding to the initial emergency response (March-May 2020) witnessed an important disruption of activities: a total suspension in Senegal, a significant decline in Côte d'Ivoire, and a less pronounced decrease in Mali. Secondary distribution was also negatively impacted. Peer educators showed resilience and adapted by relocating from public to private areas, reducing group sizes, moving night activities to the daytime, increasing the use of social networks, integrating hygiene measures, and promoting assisted HIVST as an alternative to conventional rapid testing. From June 2020 onward, with the routine management of the COVID-19 pandemic, a catch-up phenomenon was observed with the resumption of activities in Senegal, the opening of new distribution sites, a rebound in the number of distributed HIVST kits, a resurgence in larger group activities, and a rebound in the average number of distributed HIVST kits per primary contact. Conclusions: Although imperfect, the program data provide useful information to describe changes in the implementation of HIVST outreach activities over time. The impact of the COVID-19 pandemic on HIVST distribution among key populations was visible in the monthly activity reports. Focus groups and individual interviews allowed us to document the adaptations made by peer educators, with variations across countries and populations. These adaptations demonstrate the resilience and learning capacities of peer educators and key populations.


General model for osmotic and pressure-induced flow in plant roots.
This paper presents a general model to describe coupled solute and water flow through plant roots when they are subjected to osmotic or hydrostatic pressure gradients, or both simultaneously. The model is based on well-established membrane transport equations derived from irreversible thermodynamic considerations. A variety of experimentally observed phenomena such as changes in root resistance with flow rate, apparent negative resistance effects, xylem sap dilution, and apparent non-osmotic water transport can be adequately explained with this model. The model also predicts that an exuding excised root system will be very insensitive to changes in the hydraulic conductivity coefficient. Previous work with a flat membrane of unit surface area and uniform properties is confirmed for a cylindrical coordinate system of nonuniform characteristics.


The epidemiology of community-acquired Clostridium difficile infection: a population-based study.
Clostridium difficile infection (CDI) is a common hospital-acquired infection with increasing incidence, severity, recurrence, and associated morbidity and mortality. There are emerging data on the occurrence of CDI in nonhospitalized patients. However, there is a relative lack of community-based CDI studies, as most of the existing studies are hospital based, potentially influencing the results by referral or hospitalization bias by missing cases of community-acquired CDI. To better understand the epidemiology of community-acquired C. difficile infection, a population-based study was conducted in Olmsted County, Minnesota, using the resources of the Rochester Epidemiology Project. Data regarding severity, treatment response, and outcomes were compared in community-acquired vs. hospital-acquired cohorts, and changes in these parameters, as well as in incidence, were assessed over the study period. Community-acquired CDI cases accounted for 41% of 385 definite CDI cases. The incidence of both community-acquired and hospital-acquired CDI increased significantly over the study period. Compared with those with hospital-acquired infection, patients with community-acquired infection were younger (median age 50 years compared with 72 years), more likely to be female (76% vs. 60%), had lower comorbidity scores, and were less likely to have severe infection (20% vs. 31%) or have been exposed to antibiotics (78% vs. 94%). There were no differences in the rates of complicated or recurrent infection in patients with community-acquired compared with hospital-acquired infection. In this population-based cohort, a significant proportion of cases of CDI occurred in the community. These patients were younger and had less severe infection than those with hospital-acquired infection. Thus, reports of CDI in hospitalized patients likely underestimate the burden of disease and overestimate severity.


A superhydrophobic chip based on SU-8 photoresist pillars suspended on a silicon nitride membrane.
We developed a new generation of superhydrophobic chips optimized for probing ultrasmall sample quantities by X-ray scattering and fluorescence techniques. The chips are based on thin Si3N4 membranes with a tailored pattern of SU-8 photoresist pillars. Indeed, aqueous solution droplets can be evaporated and concentrated at predefined positions using a non-periodic pillar pattern. We demonstrated quantitatively the deposition and aggregation of gold glyconanoparticles from the evaporation of a nanomolar droplet in a small spot by raster X-ray nanofluorescence. Further, raster nanocrystallography of biological objects such as rod-like tobacco mosaic virus nanoparticles reveals crystalline macro-domain formation composed of highly oriented nanorods.


Canopy phenology of a dry forest in western Brazil.
Dry forests are common, although highly threatened in the Neotropics. Their ecological processes are mostly influenced by rainfall pattern, hence their cycles exhibit contrasting phases. We studied the phenology of canopy trees in a primary dry forest in Western Brazil in the foothills of the Urucum mountain chain, in order to improve our knowledge on the functioning of these poorly-known forests. Leaf shedding started in the early dry season and was massive in the latter part of this period. Most leaf loss occurred in dry hills, while wet valleys remained evergreen. Anemochorich and autochorich species predominated in dry hills, presumably due to their tolerance to dry conditions and enhanced exposition to winds, which favour diaspores removal and dispersal. Conversely, zoochorich species dominated the wet valleys. Flowering was intense in the late dry season, the driest period of the year, while fruiting was massive just after the onset of rains, as well as flushing. Therefore, most flowering was unrelated to wet conditions, although such an abiotic factor, potentially, triggered the major fruiting episode, widely comprised by zoochorich species. Anemochorich and autochorich species flowered and fruited in the course of the long dry season. The contrasting environmental conditions present in the hills and valleys determine the arrangement of a mosaic in which patches of zoochorich and evergreen trees alternate with patches of non zoochorich and highly deciduous species. Consequently, species with such syndromes exhibited marked flowering and fruiting patterns, accordingly to the pronounced seasonality.


Hormones, herbal preparations and nutriceuticals for a better life after the menopause: part II.
Long-term estrogen replacement therapy with estrogen has benefits for many postmenopausal women. However, some women prefer non-steroidal substitution with herbal preparations. The effectivity against vasomotor symptoms has been evidenced for the extracts of pine bark, of linseed and of Lepidium meyenii (Maca), whereas there is controversy about the effectiveness of genistein-rich soy extract. The extracts of cruciferous vegetables such as Broccoli and of linseed induce changes in the metabolism of estrogens, and antioxidants may reverse altered epigenetic DNA methylation, possibly reducing the risk of breast cancer or its recurrence. Indirect evidence from the literature and from clinical trials supports that a nutriceutical composed of plant extracts, low-dose vitamins and minerals may improve the quality of life by delaying certain age-related diseases. On the basis of epidemiologic studies, physiopathological considerations and controlled prospectieve trials, it is suggested that transdermal substitution therapy with estradiol together with nutriceutical food supplementation may increase the number of quality-adjusted life years of postmenopausal women, but complementary, large-scale, prospective trials are still needed.


Small-scale analysis of exopolysaccharides from Streptococcus thermophilus grown in a semi-defined medium.
Exopolysaccharides (EPSs) produced by lactic acid bacteria are important for the texture of fermented foods and have received a great deal of interest recently. However, the low production levels of EPSs in combination with the complex media used for growth of the bacteria have caused problems in the accurate analysis of the EPS. The purpose of this study was to find a growth medium for physiological studies of the lactic acid bacterium Streptococcus thermophilus, and to develop a simple method for qualitative and quantitative analysis of EPSs produced in this medium. A semi-defined polysaccharide medium was developed and evaluated on six strains of Streptococcus thermophilus. The EPSs were analysed using a novel protocol incorporating ultracentrifugation for the removal of interfering sugars, hydrolysis and analysis of the monomer composition by High Performance Anion-Exchange Chromatography with pulsed amperometric detection. The medium and analysis method allowed accurate quantification and monomer analysis of 0.5 ml samples of EPSs from tube cultures. The presented medium should be useful for physiological studies of S. thermophilus, and, in combination with the method of analysis of EPS, will allow downscaling of physiological studies and screening for EPSs.