Disruptions in maternal and child health service utilization during COVID-19: analysis from eight sub-Saharan African countries.
The coronavirus-19 pandemic and its secondary effects threaten the continuity of essential health services delivery, which may lead to worsened population health and a protracted public health crisis. We quantify such disruptions, focusing on maternal and child health, in eight sub-Saharan countries. Service volumes are extracted from administrative systems for 63 954 facilities in eight countries: Cameroon, Democratic Republic of Congo, Liberia, Malawi, Mali, Nigeria, Sierra Leone and Somalia. Using an interrupted time series design and an ordinary least squares regression model with facility-level fixed effects, we analyze data from January 2018 to February 2020 to predict what service utilization levels would have been in March-July 2020 in the absence of the pandemic, accounting for both secular trends and seasonality. Estimates of disruption are derived by comparing the predicted and observed service utilization levels during the pandemic period. All countries experienced service disruptions for at least 1 month, but the magnitude and duration of the disruptions vary. Outpatient consultations and child vaccinations were the most commonly affected services and fell by the largest margins. We estimate a cumulative shortfall of 5 149 491 outpatient consultations and 328 961 third-dose pentavalent vaccinations during the 5 months in these eight countries. Decreases in maternal health service utilization are less generalized, although significant declines in institutional deliveries, antenatal care and postnatal care were detected in some countries. There is a need to better understand the factors determining the magnitude and duration of such disruptions in order to design interventions that would respond to the shortfall in care. Service delivery modifications need to be both highly contextualized and integrated as a core component of future epidemic response and planning.


Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinases, inhibits platelet aggregation and arterial thrombosis.
Resting platelets rely on oxidative phosphorylation (OXPHOS) and aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen) to generate adenosine triphosphate, whereas activated platelets exhibit a high level of aerobic glycolysis, suggesting the existence of metabolic flexibility in platelets. Mitochondrial pyruvate dehydrogenase kinases (PDK 1-4) play a pivotal role in metabolic flexibility by inhibiting pyruvate dehydrogenase complex. We determined whether metabolic reprogramming, diverting metabolism from aerobic glycolysis back to OXPHOS, would inhibit platelet function. PDKs activity in human and mouse platelets was inhibited with dichloroacetic acid (DCA), a potent inhibitor of all 4 forms of PDK. Human and mouse platelets pretreated with DCA exhibited decreased platelet aggregation to suboptimal doses of collagen, convulxin, thrombin, and adenosine diphosphate concomitant with decreased glucose uptake. Bioenergetics profile revealed that platelets pretreated with DCA exhibited decreased aerobic glycolysis in response to convulxin only. Furthermore, DCA inhibited ATP secretion, thromboxane A2 generation, and tyrosine phosphorylation of Syk and PLCγ2 in response to collagen or convulxin in human and mouse platelets (P < .05 vs vehicle treated). In the flow chamber assay, human and mouse blood pretreated with DCA formed smaller thrombi when perfused over collagen for 10 minutes at an arterial shear rate of 1500 s-1 (P < .05 vs control). Wild-type mice pretreated with DCA were less susceptible to thrombosis in the FeCl3-induced carotid and laser injury-induced mesenteric artery thrombosis models (P < .05 vs vehicle control), without altering hemostasis. Targeting metabolic plasticity with DCA may be explored as a novel strategy to inhibit platelet function.


Autophagy is essential for maintaining the growth of a human (mini-)organ: Evidence from scalp hair follicle organ culture.
Autophagy plays a crucial role in health and disease, regulating central cellular processes such as adaptive stress responses, differentiation, tissue development, and homeostasis. However, the role of autophagy in human physiology is poorly understood, highlighting a need for a model human organ system to assess the efficacy and safety of strategies to therapeutically modulate autophagy. As a complete, cyclically remodelled (mini-)organ, the organ culture of human scalp hair follicles (HFs), which, after massive growth (anagen), spontaneously enter into an apoptosis-driven organ involution (catagen) process, may provide such a model. Here, we reveal that in anagen, hair matrix keratinocytes (MKs) of organ-cultured HFs exhibit an active autophagic flux, as documented by evaluation of endogenous lipidated Light Chain 3B (LC3B) and sequestosome 1 (SQSTM1/p62) proteins and the ultrastructural visualization of autophagosomes at all stages of the autophagy process. This autophagic flux is altered during catagen, and genetic inhibition of autophagy promotes catagen development. Conversely, an anti-hair loss product markedly enhances intrafollicular autophagy, leading to anagen prolongation. Collectively, our data reveal a novel role of autophagy in human hair growth. Moreover, we show that organ-cultured scalp HFs are an excellent preclinical research model for exploring the role of autophagy in human tissue physiology and for evaluating the efficacy and tissue toxicity of candidate autophagy-modulatory agents in a living human (mini-)organ.


Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis.
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43-positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the approximately 25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.


Genotype analysis of varicella-zoster virus isolates from suburban Shanghai Municipal Province, China.
To determine the predominant genotype of the varicella-zoster virus (VZV) in suburban Shanghai Municipal Province, specimens were collected from the lesions of 95 outpatients clinically diagnosed with varicella or herpes zoster. Of these, 69 patients (72.6%) were positive for VZV DNA. The 69 isolates were all genotyped as the genotype J1/clade 2. Based on sequencing of the 447 bp sequence in ORF22, 66 isolates were identified as genotype J/clade 2 strains and three were identified as type M2/clade 4 strains. To confirm the classification of these three strains, we determined the presence of 27 single-nucleotide polymorphisms (SNPs) and found that isolates 1270/1450 shared seven SNPs that differed from those of clade 2, in which three SNPs were unique to clade 3 and another three were unique to clade 4. Isolate 1456 had two markers of clade 4 that differed from clade 2. The phylogenetic tree showed that our isolates clustered primarily with clade 2 and that the three M2/J1 strains clustered between clades 2 and 4. It is likely that isolates 1270/1450/1446 may represent a new subclade of either clade 2 or 4, or some recombinant events. In addition, our isolates were WT strains. We also observed significant inter-strain variations.


Multicohort Analysis of Whole-Blood Gene Expression Data Does Not Form a Robust Diagnostic for Acute Respiratory Distress Syndrome.
To identify a novel, generalizable diagnostic for acute respiratory distress syndrome using whole-blood gene expression arrays from multiple acute respiratory distress syndrome cohorts of varying etiologies. We performed a systematic search for human whole-blood gene expression arrays of acute respiratory distress syndrome in National Institutes of Health Gene Expression Omnibus and ArrayExpress. We also included the Glue Grant gene expression cohorts. We included investigator-defined acute respiratory distress syndrome within 48 hours of diagnosis and compared these with relevant critically ill controls. We used multicohort analysis of gene expression to identify genes significantly associated with acute respiratory distress syndrome, both with and without adjustment for clinical severity score. We performed gene ontology enrichment using Database for Annotation, Visualization and Integrated Discovery and cell type enrichment tests for both immune cells and pneumocyte gene expression. Finally, we selected a gene set optimized for diagnostic power across the datasets and used leave-one-dataset-out cross validation to assess robustness of the model. We identified datasets from three adult cohorts with sepsis, one pediatric cohort with acute respiratory failure, and two datasets of adult patients with trauma and burns, for a total of 148 acute respiratory distress syndrome cases and 268 critically ill controls. We identified 30 genes that were significantly associated with acute respiratory distress syndrome (false discovery rate < 20% and effect size >1.3), many of which had been previously associated with sepsis. When metaregression was used to adjust for clinical severity scores, none of these genes remained significant. Cell type enrichment was notable for bands and neutrophils, suggesting that the gene expression signature is one of acute inflammation rather than lung injury per se. Finally, an attempt to develop a generalizable diagnostic gene set for acute respiratory distress syndrome showed a mean area under the receiver-operating characteristic curve of only 0.63 on leave-one-dataset-out cross validation. The whole-blood gene expression signature across a wide clinical spectrum of acute respiratory distress syndrome is likely confounded by systemic inflammation, limiting the utility of whole-blood gene expression studies for uncovering a generalizable diagnostic gene signature.


Characterization of the genomic features and expressed fusion genes in micropapillary carcinomas of the breast.
Micropapillary carcinoma (MPC) is a rare histological special type of breast cancer, characterized by an aggressive clinical behaviour and a pattern of copy number aberrations (CNAs) distinct from that of grade- and oestrogen receptor (ER)-matched invasive carcinomas of no special type (IC-NSTs). The aims of this study were to determine whether MPCs are underpinned by a recurrent fusion gene(s) or mutations in 273 genes recurrently mutated in breast cancer. Sixteen MPCs were subjected to microarray-based comparative genomic hybridization (aCGH) analysis and Sequenom OncoCarta mutation analysis. Eight and five MPCs were subjected to targeted capture and RNA sequencing, respectively. aCGH analysis confirmed our previous observations about the repertoire of CNAs of MPCs. Sequencing analysis revealed a spectrum of mutations similar to those of luminal B IC-NSTs, and recurrent mutations affecting mitogen-activated protein kinase family genes and NBPF10. RNA-sequencing analysis identified 17 high-confidence fusion genes, eight of which were validated and two of which were in-frame. No recurrent fusions were identified in an independent series of MPCs and IC-NSTs. Forced expression of in-frame fusion genes (SLC2A1-FAF1 and BCAS4-AURKA) resulted in increased viability of breast cancer cells. In addition, genomic disruption of CDK12 caused by out-of-frame rearrangements was found in one MPC and in 13% of HER2-positive breast cancers, identified through a re-analysis of publicly available massively parallel sequencing data. In vitro analyses revealed that CDK12 gene disruption results in sensitivity to PARP inhibition, and forced expression of wild-type CDK12 in a CDK12-null cell line model resulted in relative resistance to PARP inhibition. Our findings demonstrate that MPCs are neither defined by highly recurrent mutations in the 273 genes tested, nor underpinned by a recurrent fusion gene. Although seemingly private genetic events, some of the fusion transcripts found in MPCs may play a role in maintenance of a malignant phenotype and potentially offer therapeutic opportunities.


Towards general network architecture design criteria for negative gas adsorption transitions in ultraporous frameworks.
Switchable metal-organic frameworks (MOFs) have been proposed for various energy-related storage and separation applications, but the mechanistic understanding of adsorption-induced switching transitions is still at an early stage. Here we report critical design criteria for negative gas adsorption (NGA), a counterintuitive feature of pressure amplifying materials, hitherto uniquely observed in a highly porous framework compound (DUT-49). These criteria are derived by analysing the physical effects of micromechanics, pore size, interpenetration, adsorption enthalpies, and the pore filling mechanism using advanced in situ X-ray and neutron diffraction, NMR spectroscopy, and calorimetric techniques parallelised to adsorption for a series of six isoreticular networks. Aided by computational modelling, we identify DUT-50 as a new pressure amplifying material featuring distinct NGA transitions upon methane and argon adsorption. In situ neutron diffraction analysis of the methane (CD4) adsorption sites at 111 K supported by grand canonical Monte Carlo simulations reveals a sudden population of the largest mesopore to be the critical filling step initiating structural contraction and NGA. In contrast, interpenetration leads to framework stiffening and specific pore volume reduction, both factors effectively suppressing NGA transitions.


Report of the Committee on the classification and diagnostic criteria of diabetes mellitus.
In 1995, the Japan Diabetes Society (JDS) appointed the Committee for the Classification and Diagnosis of Diabetes Mellitus. The Committee presented a final report in May 1999 in Japanese. This is the English version with minor modifications for readers outside Japan. Diabetes mellitus represents a group of diseases of heterogeneous etiology, characterized by chronic hyperglycemia and other metabolic abnormalities, which are due to deficiency of insulin effect. After a long duration of metabolic derangement, specific complications of diabetes (retinopathy, nephropathy, and neuropathy) may occur. Arteriosclerosis is also accelerated. Depending on the severity of the metabolic abnormality, diabetes may be asymptomatic, or may be associated with symptoms (thirst, polyuria, and weight loss), or may progress to ketoacidosis and coma. Both etiological classification and staging of pathophysiology by the degree of deficiency of insulin effect need to be considered. The etiological classification of diabetes and related disorders of glycemia includes, (1) type 1; (2) type 2; (3) those due to specific mechanisms and diseases; and (4) gestational diabetes mellitus. Type 1 is characterized by destructive lesions of pancreatic beta cells either by an autoimmune mechanism or of unknown cause. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Category (3) includes two subgroups; subgroup A is diabetes in which specific mutations have been identified as a cause of genetic susceptibility, while subgroup B is diabetes associated with other pathologic conditions or diseases. The staging of glucose metabolism includes normal, borderline and diabetic stages. The diabetic stage is further classified into three substages; non-insulin requiring, insulin-requiring for glycemic control, and insulin-dependent (ID) for survival. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment. The confirmation of chronic hyperglycemia is a prerequisite for the diagnosis of diabetes mellitus. The state of glycemia may be classified within three categories, diabetic type; borderline type; and normal type. Diabetic type is defined when fasting plasma glucose (FPG) is 7.0 mmol/l (126 mg/dl) or higher, and/or plasma glucose 2 h after 75 g glucose load (2hPG) is 11.1 mmol/l (200 mg/dl) or higher. A casual plasma glucose (PG) > or =11.1 mmol/l (200 mg/dl) also indicates diabetic type. Normal type is defined when FPG is below 6.1 mmol/l (110 mg/dl) and 2hPG below 7.8 mmol/l (140 mg/dl). Borderline type includes those who are neither diabetic nor normal types. These cutoff values are for venous PG measurements. The persistence of 'diabetic type' in a subject indicates that he or she has diabetes. For children, a dose of 1.75 g/kg (maximum, 75 g) is used for oral glucose tolerance test (OGTT). The procedure for clinical diagnosis is as follows. Diabetes mellitus is diagnosed when hyperglycemia meeting the criteria for 'diabetic type' is shown on two or more occasions examined on separate days. Diabetes can be diagnosed by a single PG test of 'diabetic type' if one of the following three conditions co-exists, (1) typical symptoms of diabetes mellitus; (2) HbA1c > or =6.5% by a standardized method; or (3) unequivocal diabetic retinopathy. If the above conditions ((1) or (2)) have been present in the past and well documented, the subject is diagnosed either to have diabetes or to be suspected of diabetes, even if the present level of glycemia does not reach that of 'diabetic type'. If the diagnosis of diabetes cannot be established by these procedures, re-testing of PG is recommended after an appropriate interval. The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions. In order to determine the prevalence of diabetes in a population, 'diabetic type' may be regarded as 'diabetes'. The use of 2hPG cutoff level of > or =11.1 mmol/l (200 mg/dl) is recommended. If this is difficult, the FPG cutoff level of > or =7.0 mmol/l (126 mg/dl) can be used, but is likely to lead to under-ascertainment. For screening, the most important point is not to overlook 'diabetes'. In addition to parameters of hyperglycemia, clinical information such as family history, obesity etc., should be regarded as indications for further testing. Only FPG and 2hPG are adopted as cutoff values, but in clinical situations, it is recommended to measure PG also at 30 and 60 min during 75 g OGTT. Among people with normal type, those with 1hPG higher than 10.0 mmol/l (180 mg/dl) are at higher risk to develop diabetes than those with lower 1hPG. When OGTT is performed, the borderline type corresponds to the sum of impaired fasting glycemia (IFG) plus impaired glucose tolerance (IGT) according to the new WHO report. Subjects in this category are at higher risk of developing diabetes than those with 'normal type'. Those with low insulinogenic index (the ratio of increment of plasma insulin to that of PG at 30 min during OGTT) are at particularly high risk to develop diabetes. Microvascular complications are rare but arteriosclerotic complications are fairly frequent in this category. The current definition of GDM is ' any glucose intolerance developed or detected during pregnancy'. We adopt the proposal of the Japan Society of Gynecology and Obstetrics for the diagnosis of GDM (1984). GDM is defined when two or more values during a 75 g OGTT are higher than the following cutoff levels; FPG > or =5.5 mmol/l (100 mg/dl), 1hPG > or =10.0 mmol/l (180 mg/dl) and 2hPG > or =8.3 mmol/l (150 mg/dl). As a screening test, subjects with casual PG > or =5.5 mmol/l (100 mg/dl) are recommended for further testing. Patients who have had documented glucose intolerance before pregnancy, and who present as 'diabetic type' should be under closer supervision than those who develop GDM during pregnancy for the first time. HbA1c: There is a large overlap in the distribution of HbA1c between groups with 'normal type' and 'borderline type' and mild 'diabetic type'. Therefore, HbA1c is not a suitable parameter to detect mild glucose intolerance. HbA1c higher than 6.5% suggests diabetes, but HbA1c below 6.5% alone should not be taken as evidence against the diagnosis of diabetes. COMPARISON WITH REPORTS OF AMERICAN DIABETES ASSOCIATION (ADA) IN 1997 AND WHO IN 1999: The present report is unique in the following points when compared with those of the ADA 'Diabetes Care 20 (1997) 1183' and WHO 'Report of a WHO Consultation (1999)'. (1) Diabetes due to specific mechanisms and diseases is divided into two subgroups; diabetes in which genetic susceptibility is clarified at the DNA level and diabetes associated with other diseases or conditions. (2) Cutoff PG levels are the same as those of ADA and WHO, but a term 'type' is added to each glycemic category, because a single coding of 'diabetic type' hyperglycemia does not define diabetes. Diabetes is diagnosed when 'diabetic type' hyperglycemia is shown on two or more occasions. (3) A single 'diabetic type' hyperglycemia is considered sufficient for the diagnosis of diabetes, if the patient has typical symptoms, HbA1c > or =6.5%, or diabetic retinopathy. (4) OGTT is recommended for those with mild hyperglycemia, because FPG criteria alone would overlook many subjects with 'diabetic type' in Japan. High 1hPG without elevation of FPG and 2hPG is also considered to be a risk factor for future diabetes. (5) Borderline type in the present report corresponds to the sum of IFG and IGT by WHO when OGTT is performed. (6) New criteria for GDM by OGTT are proposed.


Accommodating measurements below a limit of detection: a novel application of Cox regression.
In environmental epidemiology, measurements of exposure biomarkers often fall below the assay's limit of detection. Existing methods for handling this problem, including deletion, substitution, parametric regression, and multiple imputation, can perform poorly if the proportion of "nondetects" is high or parametric models are mis-specified. We propose an approach that treats the measured analyte as the modeled outcome, implying a role reversal when the analyte is a putative cause of a health outcome. Following a scale reversal as well, our approach uses Cox regression to model the analyte, with confounder adjustment. The method makes full use of quantifiable analyte measures, while appropriately treating nondetects as censored. Under the proportional hazards assumption, the hazard ratio for a binary health outcome is interpretable as an adjusted odds ratio: the odds for the outcome at any particular analyte concentration divided by the odds given a lower concentration. Our approach is broadly applicable to cohort studies, case-control studies (frequency matched or not), and cross-sectional studies conducted to identify determinants of exposure. We illustrate the method with cross-sectional survey data to assess sex as a determinant of 2,3,7,8-tetrachlorodibenzo-p-dioxin concentration and with prospective cohort data to assess the association between 2,4,4'-trichlorobiphenyl exposure and psychomotor development.


T-DM1 Activity in Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancers That Received Prior Therapy With Trastuzumab and Pertuzumab.
Purpose Ado-trastuzumab emtansine (T-DM1) is currently approved for treatment in patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (MBC) who previously received trastuzumab and a taxane. However, there are no data on the activity of T-DM1 in patients who received prior pertuzumab, which is now included as standard first-line therapy. The goal of this study was to assess the efficacy of T-DM1 in routine clinical practice in a contemporary patient population that received both prior trastuzumab and pertuzumab. Patients and Methods We identified all patients with HER2-positive MBC who received T-DM1 after trastuzumab and pertuzumab between March 1, 2013, and July 15, 2015, via electronic pharmacy records and departmental databases at three institutions: MD Anderson Cancer Center, Smilow Cancer Hospital at Yale, and The James Cancer Hospital at the Ohio State University. We reviewed medical records of each case to confirm treatment sequencing and outcome. Results Of patients, 82 were identified and 78 were available for outcome analysis; 32% received T-DM1 as first- and second-line line therapy, and 48% received it as fourth-line treatment or later. Rate of prolonged duration on therapy, defined as duration on therapy ≥ 6 months, was 30.8% (95% CI, 20.6% to 41.1%), and tumor response rate was 17.9% (95% CI, 9.4% to 26.4%). Median duration on therapy was 4.0 months (95% CI, 2.7 to 5.1; range, 0 to 22.5 months). T-DM1 was discontinued for disease progression in 84% of patients and for toxicity in 10%. Conclusion Tumor response rates were lower than in prior reports of trastuzumab-resistant, HER2-positive MBC, but one third of patients received therapy with T-DM1 for ≥ 6 months, which suggests a clinically relevant benefit in patients who received prior pertuzumab.


A new family of giardial cysteine-rich non-VSP protein genes and a novel cyst protein.
Since the Giardia lamblia cyst wall is necessary for survival in the environment and host infection, we tested the hypothesis that it contains proteins other than the three known cyst wall proteins. Serial analysis of gene expression during growth and encystation revealed a gene, "HCNCp" (High Cysteine Non-variant Cyst protein), that was upregulated late in encystation, and that resembled the classic Giardia variable surface proteins (VSPs) that cover the trophozoite plasmalemma. HCNCp is 13.9% cysteine, with many "CxxC" tetrapeptide motifs and a transmembrane sequence near the C-terminus. However, HCNCp has multiple "CxC" motifs rarely found in VSPs, and does not localize to the trophozoite plasmalemma. Moreover, the HCNCp C-terminus differed from the canonical VSP signature. Full-length epitope-tagged HCNCp expressed under its own promoter was upregulated during encystation with highest expression in cysts, including 42 and 21 kDa C-terminal fragments. Tagged HCNCp targeted to the nuclear envelope in trophozoites, and co-localized with cyst proteins to encystation-specific secretory vesicles during encystation. HCNCp defined a novel trafficking pathway as it localized to the wall and body of cysts, while the cyst proteins were exclusively in the wall. Unlike VSPs, HCNCp is expressed in at least five giardial strains and four WB subclones expressing different VSPs. Bioinformatics identified 60 additional large high cysteine membrane proteins (HCMp) containing > or = 20 CxxC/CxC's lacking the VSP-specific C-terminal CRGKA. HCMp were absent or rare in other model or parasite genomes, except for Tetrahymena thermophila with 30. MEME analysis classified the 61 gHCMp genes into nine groups with similar internal motifs. Our data suggest that HCNCp is a novel invariant cyst protein belonging to a new HCMp family that is abundant in the Giardia genome. HCNCp and the other HCMp provide a rich source for developing parasite-specific diagnostic reagents, vaccine candidates, and subjects for further research into Giardia biology.


The minimum amount of "matrix" needed for matrix-assisted pulsed laser deposition of biomolecules.
The ability of matrix-assisted pulsed laser evaporation (MAPLE) technique to transfer and deposit high-quality thin organic, bioorganic, and composite films with minimum chemical modification of the target material has been utilized in numerous applications. One of the outstanding problems in MAPLE film deposition, however, is the presence of residual solvent (matrix) codeposited with the polymer material and adversely affecting the quality of the deposited films. In this work, we investigate the possibility of alleviating this problem by reducing the amount of matrix in the target. A series of coarse-grained molecular dynamics simulations are performed for a model lysozyme-water system, where the water serves the role of volatile "matrix" that drives the ejection of the biomolecules. The simulations reveal a remarkable ability of a small (5-10 wt %) amount of matrix to cause the ejection of intact bioorganic molecules. The results obtained for different laser fluences and water concentrations are used to establish a "processing map" of the regimes of molecular ejection in matrix-assisted pulsed laser deposition. The computational predictions are supported by the experimental observation of the ejection of intact lysozyme molecules from pressed lysozyme targets containing small amounts of residual water. The results of this study suggest a new approach for deposition of thin films of bioorganic molecules with minimum chemical modification of the molecular structure and minimum involvement of solvent into the deposition process.


Combinatorial roles of heparan sulfate proteoglycans and heparan sulfates in Caenorhabditis elegans neural development.
Heparan sulfate proteoglycans (HSPGs) play critical roles in the development and adult physiology of all metazoan organisms. Most of the known molecular interactions of HSPGs are attributed to the structurally highly complex heparan sulfate (HS) glycans. However, whether a specific HSPG (such as syndecan) contains HS modifications that differ from another HSPG (such as glypican) has remained largely unresolved. Here, a neural model in C. elegans is used to demonstrate for the first time the relationship between specific HSPGs and HS modifications in a defined biological process in vivo. HSPGs are critical for the migration of hermaphrodite specific neurons (HSNs) as genetic elimination of multiple HSPGs leads to 80% defect of HSN migration. The effects of genetic elimination of HSPGs are additive, suggesting that multiple HSPGs, present in the migrating neuron and in the matrix, act in parallel to support neuron migration. Genetic analyses suggest that syndecan/sdn-1 and HS 6-O-sulfotransferase, hst-6, function in a linear signaling pathway and glypican/lon-2 and HS 2-O-sulfotransferase, hst-2, function together in a pathway that is parallel to sdn-1 and hst-6. These results suggest core protein specific HS modifications that are critical for HSN migration. In C. elegans, the core protein specificity of distinct HS modifications may be in part regulated at the level of tissue specific expression of genes encoding for HSPGs and HS modifying enzymes. Genetic analysis reveals that there is a delicate balance of HS modifications and eliminating one HS modifying enzyme in a compromised genetic background leads to significant changes in the overall phenotype. These findings are of importance with the view of HS as a critical regulator of cell signaling in normal development and disease.


Towards local motion detection by the use of analog self electro-optic effect device.
We demonstrated the use of the analog self electro-optic effect device (SEED) as part of an artificial retina chip for the detection and estimation of local motion. The characterization was performed by comparing our chip to biological and computational models and to other artificial retina chips. Its main unique feature is the optical output, since most chips have electrical output. By combining the response of the chip with temporal information about the input image, it is possible to estimate the velocity perpendicular to an edge, including its direction.


Tyrosine kinase inhibition activates intratumoral ϒδ T cells in gastrointestinal stromal tumor.
γδ T cells are a rare but potent subset of T cells with pleiotropic functions. They commonly reside within tumors but the response of γδ T cells to tyrosine kinase inhibition is unknown. To address this, we studied a genetically engineered mouse model of gastrointestinal stromal tumor (GIST) driven by oncogenic Kit signaling that responds to the Kit inhibitor imatinib. At baseline, γδ T cells were anti-tumoral, as blockade of either γδ TCR or IL17A increased tumor weight and decreased antitumor immunity. However, imatinib therapy further stimulated intratumoral γδ T cells, as determined by flow cytometry and single-cell RNA sequencing. Imatinib expanded a highly activated γδ T-cell subset with increased IL17A production and higher expression of immune checkpoints and cytolytic effector molecules. Consistent with the mouse model, γδ T cells produced IL17A in fresh human GIST specimens, and imatinib treatment increased γδ T-cell gene signatures, as measured by bulk tumor RNA sequencing. Furthermore, tumor γδ T cells correlated with survival in GIST patients. Our findings highlight the interplay between tumor cell oncogene signaling and antitumor immune responses and identify γδ T cells as targets for immunotherapy in GIST.


An inexpensive dual-chamber particle monitor: laboratory characterization.
In developing countries, high levels of particle pollution from the use of coal and biomass fuels for household cooking and heating are a major cause of ill health and premature mortality. The cost and complexity of existing monitoring equipment, combined with the need to sample many locations, make routine quantification of household particle pollution levels difficult. Recent advances in technology, however, have enabled the development of a small, portable, data-logging particle monitor modified from commercial smoke alarm technology that can meet the needs of surveys in the developing world at reasonable cost. Laboratory comparisons of a prototype particle monitor developed at the University of California at Berkeley (UCB) with gravimetric filters, a tapered element oscillating microbalance, and a TSI DustTrak to quantify the UCB particle monitor response as a function of both concentration and particle size and to examine sensor response in relation to changes in temperature, relative humidity, and elevation are presented here. UCB particle monitors showed good linearity in response to different concentrations of laboratory-generated oleic acid aerosols with a coarse (mass median diameter, 2.1 microm) and fine (mass median diameter, 0.27-0.42 microm) size distributions (average r2 = 0.997 +/- 0.005). The photoelectric and ionization chamber showed a wide range of responses based on particle size and, thus, require calibration with the aerosol of interest. The ionization chamber was five times more sensitive to fine rather than coarse particles, whereas the photoelectric chamber was five times more sensitive to coarse than fine. The ratio of the response between the two sensors has the potential for mass calibration of individual data points based on estimated parameters of the size distribution. The results demonstrate the significant potential of this monitor, which will facilitate the evaluation of interventions (improved fuels, stoves, and ventilation) on indoor air pollution levels and research on the impacts of indoor particle levels on health in developing countries.


Evidence of Rentian Scaling of Functional Modules in Diverse Biological Networks.
Biological networks have long been known to be modular, containing sets of nodes that are highly connected internally. Less emphasis, however, has been placed on understanding how intermodule connections are distributed within a network. Here, we borrow ideas from engineered circuit design and study Rentian scaling, which states that the number of external connections between nodes in different modules is related to the number of nodes inside the modules by a power-law relationship. We tested this property in a broad class of molecular networks, including protein interaction networks for six species and gene regulatory networks for 41 human and 25 mouse cell types. Using evolutionarily defined modules corresponding to known biological processes in the cell, we found that all networks displayed Rentian scaling with a broad range of exponents. We also found evidence for Rentian scaling in functional modules in the Caenorhabditis elegans neural network, but, interestingly, not in three different social networks, suggesting that this property does not inevitably emerge. To understand how such scaling may have arisen evolutionarily, we derived a new graph model that can generate Rentian networks given a target Rent exponent and a module decomposition as inputs. Overall, our work uncovers a new principle shared by engineered circuits and biological networks.


Increased risk for primary liver cancer among women exposed to solvents.
An earlier case-referent study by the same authors [Int Arch Occup Environ Health 54 (1984) 147-153] reported that solvent-exposed women, but not men, had an increased risk for primary liver cancer. The present study was undertaken to verify these results. The relatives of deceased patients, ie, 377 liver cancer cases, 385 coronary infarction referents, and 476 stomach cancer referents, responded to a questionnaire on past employment and potentially relevant covariables, the response rates being 71.7, 72.7, and 69.0%, respectively. The information was assessed for solvent exposure by two occupational hygienists without knowledge of the patients' diagnoses. Seven male and seven female liver cancer cases had been exposed to solvents, the odds ratio being less than 1 for the men but greater than 3 for the women irrespective of the reference group used for comparison. The results confirm the authors' earlier findings. When both materials were combined, the odds ratio was 7.8 for the female liver cancer cases as compared with the infarction referents. In the combined material, nine female liver cancer cases, two stomach cancer referents, but no infarction referent had had at least probable exposure to chlorinated hydrocarbons. Such exposure was rare among all of the men in the study. This finding may explain why the increased liver cancer risk occurred only for the women, although a sex difference in sensitivity cannot be completely ruled out.


N-acetylcysteine inhibits bacterial lipopeptide-mediated neutrophil transmigration through the choroid plexus in the developing brain.
The etiology of neurological impairments associated with prematurity and other perinatal complications often involves an infectious or pro-inflammatory component. The use of antioxidant molecules have proved useful to protect the neonatal brain from injury. The choroid plexuses-CSF system shapes the central nervous system response to inflammation at the adult stage, but little is known on the neuroimmune interactions that take place at the choroidal blood-CSF barrier during development. We previously described that peripheral administration to neonatal mice of the TLR2 ligand PAM3CSK4 (P3C), a prototypic Gram-positive bacterial lipopeptide, induces the migration of innate immune cells to the CSF. Here we showed in neonatal rats exposed to P3C that the migration of neutrophils into the CSF, which occurred through the choroid plexuses, is abolished following administration of the antioxidant drug N-acetylcysteine. Combining light sheet microscopy imaging of choroid plexus, a differentiated model of the blood-CSF barrier, and multiplex cytokine assays, we showed that the choroidal epithelium responds to the bacterial insult by a specific pattern of cytokine secretion, leading to a selective accumulation of neutrophils in the choroid plexus and to their trafficking into CSF. N-acetylcysteine acted by blocking neutrophil migration across both the endothelium of choroidal stromal vessels and the epithelium forming the blood-CSF barrier, without interfering with neutrophil blood count, neutrophil tropism for choroid plexus, and choroidal chemokine-driven chemotaxis. N-acetylcysteine reduced the injury induced by hypoxia-ischemia in P3C-sensitized neonatal rats. Overall, the data show that a double endothelial and epithelial check point controls the transchoroidal migration of neutrophils into the developing brain. They also point to the efficacy of N-acetylcysteine in reducing the deleterious effects of inflammation-associated perinatal injuries by a previously undescribed mechanism, i.e. the inhibition of innate immune cell migration across the choroid plexuses, without interfering with the systemic inflammatory response to infection.


Medial Arterial Calcification: JACC State-of-the-Art Review.
Medial arterial calcification (MAC) is a chronic systemic vascular disorder distinct from atherosclerosis that is frequently but not always associated with diabetes mellitus, chronic kidney disease, and aging. MAC is also a part of more complex phenotypes in numerous less common diseases. The hallmarks of MAC include disseminated and progressive precipitation of calcium phosphate within the medial layer, a prolonged and clinically silent course, and compromise of hemodynamics associated with chronic limb-threatening ischemia. MAC increases the risk of complications during vascular interventions and mitigates their outcomes. With the exception of rare monogenetic defects affecting adenosine triphosphate metabolism, MAC pathogenesis remains unknown, and causal therapy is not available. Implementation of genetics and omics-based approaches in research recognizing the critical importance of calcium phosphate thermodynamics holds promise to unravel MAC molecular pathogenesis and to provide guidance for therapy. The current state of knowledge concerning MAC is reviewed, and future perspectives are outlined.


Association of facial massage, dry needling, and laser therapy in Temporomandibular Disorder: case report.
This case report aims to evaluate the treatment of Temporomandibular Disorder (TMD) of muscular origin by associating facial massage (FM), dry needling (DN), and low-level laser therapy (LLLT). The pre- and post-treatment evaluations consisted of clinical examinations based on the Research Diagnostic Criteria (RDC) for TMD, pain intensity quantification by means of the Visual Analog Scale (VAS), mandibular movement measurement, and electromyographic (EMG) analysis of the masseter and temporal muscles. Post-therapy assessment indicated a decrease in pain sites of 58%, in pain intensity mean (1.3), and an increase in the maximum aperture of 10 mm, in addition to normalization of EMG signals. We conclude that, after application of the treatment protocol, there was a decrease in painful sites, gain in amplitude of mandibular movements, and normalization of EMG activity.


Vaccine protection of chimpanzees against challenge with HIV-1-infected peripheral blood mononuclear cells.
Because human immunodeficiency virus (HIV) can be transmitted as cell-free virus or as infected cells (cell-associated virus), vaccines must protect against infection by both viral forms. Vaccine-mediated protection of nonhuman primates against low doses of cell-free HIV-1, HIV-2, or simian immunodeficiency virus (SIV) has been demonstrated. It is now shown that multiple immunizations of chimpanzees with HIV-1 antigens protected against infection with cell-associated virus. Protection can persist for extended periods (one animal had not been exposed to viral antigens for 1 year before challenge). These results show that it is possible to elicit long-lasting protective immunity against cell-associated HIV-1.


Interactions between Local Anaesthetic Agents and Poly(N-isopropyl acrylamide) through Phase Behavior, Surface Tension, and Adsorption Measurement.
The interaction between the local anaesthetic agents prilocaine and lidocaine, on one hand, and poly(N-isopropyl acrylamide) (pNIPAM), on the other, is investigated through studies of the polymer phase behavior and through surface tension and adsorption measurements. In particular, the cloud points (CP) for pNIPAM in the presence of lidocaine and prilocaine under different conditions were compared to the effects of electrolytes and alcohols. It was found that the electrolytes affect the CP of pNIPAM in a lyotropic manner, whereas alcohols depress the CP of pNIPAM in an alkyl chain length dependent way; i.e., the longer the chain, the larger the decrease in CP. Lidocaine and prilocaine affect the CP of pNIPAM in a pH-dependent manner. Below the pK(a) of lidocaine and prilocaine, these cosolutes do not substantially affect the CP in the concentration range investigated, but rather behave analogous to simpler electrolytes. Above the pK(a), on the other hand, they strongly depress the CP already at low concentrations. In parallel, at low pH, the surface tension reduction due to lidocaine or prilocaine is marginal, whereas at high pH the surface tension is reduced considerably. Thus, the poor solubility of prilocaine and lidocaine at high pH causes these to become more surface active and simultaneously interact in a more pronounced way with pNIPAM. Furthermore, it was found from ellipsometry that an adsorbed pNIPAM layer contracts when lidocaine is added, presumably due to a lidocaine-pNIPAM interaction similar to that causing pNIPAM to phase separate. Analogous to this, it was demonstrated that an adsorbed pNIPAM layer shrinks and swells reversibly when the temperature is cycled above and beneath the CP. Copyright 2001 Academic Press.


Endoscopic approach to fourth ventricle cysticercosis.
Neurocysticercosis is the most frequently observed parasitosis of the central nervous system worldwide. The fourth ventricle is the most frequent site of intraventricular infestation, a location that carries a higher risk for CSF blockage and intracranial hypertension due to CSF blockage. A great number of patients become shunt dependent which carries a poorer prognosis. We report on a case of a patient with symptomatic obstructive hydrocephalus due to cysticercus in the fourth ventricle where an endoscopic approach via a frontal burr hole was performed. Although there is no consensus in the literature for the optimal treatment of this disease, this method seemed adequate for treatment of fourth ventricle cysticercosis in patients with hydrocephalus, aqueductal and foramen of Monro dilatations.


Hypoxia and oxidative stress in breast cancer. Hypoxia and tumourigenesis.
The microenvironmental hypoxia that arises as a consequence of the development of a solid tumour also acts to promote tumour growth. Hypoxia induces the expression of key components of the angiogenic and apoptotic signalling cascades, the glycolytic pathway and various cell-cycle control proteins. At the cellular level it mediates the infiltration and accumulation of tumour-associated macrophages within avascular tumour regions. Complex interactions between tumour cell and macrophage hypoxia-regulated gene products and their associated pathways form the basis for the hypoxic promotion of tumourigenesis and malignant progression.


What skills should new internal medicine interns have in july? A national survey of internal medicine residency program directors.
The transition from medical student to intern may cause stress and burnout in new interns and the delivery of suboptimal patient care. Despite a formal set of subinternship curriculum guidelines, program directors have expressed concern regarding the skill set of new interns and the lack of standardization in that skill set among interns from different medical schools. To address these issues, the Accreditation Council for Graduate Medical Education's Next Accreditation System focuses on the development of a competency-based education continuum spanning undergraduate, graduate, and continuing medical education. In 2010, the Clerkship Directors in Internal Medicine subinternship task force, in collaboration with the Association of Program Directors in Internal Medicine survey committee, surveyed internal medicine residency program directors to determine which competencies or skills they expected from new medical school graduates. The authors summarized the results using categories of interest. In both an item rank list and free-text responses, program directors were nearly uniform in ranking the skills they deemed most important for new interns-organization and time management and prioritization skills; effective communication skills; basic clinical skills; and knowing when to ask for assistance. Stakeholders should use the results of this survey as they develop a milestone-based curriculum for the fourth year of medical school and for the internal medicine subinternship. By doing so, they should develop a standardized set of skills that meet program directors' expectations, reduce the stress of transitions across the educational continuum, and improve the quality of patient care.


Lateral interdot carrier transfer in an InAs quantum dot cluster grown on a pyramidal GaAs surface.
InAs quantum dot clusters (QDCs), which consist of three closely spaced QDs, are formed on nano-facets of GaAs pyramidal structures by selective-area growth using metal-organic chemical vapor deposition. Photoluminescence (PL) and time-resolved PL (TRPL) experiments, measured in the PL linewidth, peak energy and QD emission dynamics indicate lateral carrier transfer within QDCs with an interdot carrier tunneling time of 910 ps under low excitation conditions. This study demonstrates the controlled formation of laterally coupled QDCs, providing a new approach to fabricate patterned QD molecules for optical computing applications.


The interaction of two complex loci, zeste and bithorax in Drosophila melanogaster.
It has been found that certain alleles of the zeste locus (z(a) 1-1.0) have no phenotype of their own, but interact with certain alleles at the bithorax locus (bx 3-58.8). This interaction takes the form of an enhancement of the homeotic bx phenotype to a more extreme form-i.e., the metathorax is transformed into mesothorax in varying degrees depending on the bx allele used. This enhancement is somewhat reminiscent of the transvection effect described by Lewis (1954). The characterization of the interaction thus far has shown that the enhancement only effects bx alleles which arise spontaneously, whereas the origin of the z(a) allele is unimportant. The gene claret nondisjunctional was used for the production of gynandromorphs which showed that the enhancing ability of z(a), like the eye pigment change caused by z, is autonomous. The enhancement of one specific allele (bx(34e)), which is temperature-sensitive, has allowed a delineation of the temperature-sensitive period of the bithorax locus to a period extending from the middle of the second larval instar to the middle of the third larval instar. These results, as well as those of other enhancer and suppressor systems in Drosophila, have revealed the possibility of the involvement of heterocyclic compounds in the control of cell determination and fate in Drosophila melanogaster.


Advances in the study of biomarkers of idiopathic pulmonary fibrosis in Japan.
Idiopathic pulmonary fibrosis is an intractable disease with a median survival time of 2 to 3 years. Serum levels of Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) are useful biomarkers for idiopathic pulmonary fibrosis and they are widely used in Japan. Based on clinical use in Japan, a combination of KL-6, SPA, and SP-D is useful at diagnosing interstitial lung diseases and predicting the prognoses for patients with these diseases. However, the differential diagnosis of idiopathic pulmonary fibrosis from other interstitial lung diseases is still challenging. Several other biomarkers have been identified and are being studied in Japan.


Comparison between informant-observed and actigraphic assessments of sleep-wake rhythm disturbances in demented residents of homes for the elderly.
Sleep-wake rhythm disturbances frequently occur in demented elderly and are of clinical relevance because they herald accelerated functional decline and institutionalization. Assessment of sleep-wake rhythm disorders is therefore of significant importance and can be performed by questionnaires or actigraphy, i.e., the recording of wrist activity. The present study investigates the relation of these two types of measurement by simultaneously assessing actigraphy and the Circadian Sleep Inventory for Normal and Pathological States (CSINAPS). Seventy-eight elderly subjects, mean age 85+/-6 years, living in group care facilities of 12 homes for the elderly, wore an actigraph for two weeks. Caregivers completed the nurse informant CSINAPS. Spearman rank correlations and Mann-Whitney U tests were calculated over the equivalent sleep-wake rhythm parameters as derived from actigraphy and from the CSINAPS. Good correlations were found between questionnaire items about habitual timing of sleep and wakefulness and their actigraphic counterparts. Caregivers overestimated the actual sleep time between sleep onset and offset by 96 minutes. Questionnaire reports of sleep disturbances like wandering at night were also reflected in actigraphy parameters. However, the questionnaire and actigraphy variables correlate only modestly and may complement each other. In our study, both actigraphy and the CSINAPS seemed to miss the previously established high prevalence of sleep-disordered breathing (SDB) and leg movements during sleep (LM). The assessment of sleep and wake disturbances in demented elderly is best served by parallel use of a questionnaire like the CSINAPS and actigraphy. Moreover, if SDB and LM are a focus of interest, additional assessments are needed.


Assessment of the passivation capabilities of two different covalent chemical modifications on GaP(100).
Gallium phosphide is a semiconductor material that can be used for the fabrication of optoelectronic devices. The report compares the ability of two similar organic molecules to form covalent bonds with the GaP(100) surface. Undecenoic acid (UDA) is a terminal alkene that can potentially form Ga-C bonds, and mercaptoundecanoic acid (MUA) is a thiol that can be used to generate Ga-S bonds. The chemical passivation capabilities of the functionalized surfaces exposed to different media were investigated by contact angle measurements, atomic force microscopy (AFM), and X-ray photoelectron spectroscopy (XPS). Toxicity levels, which are important for sensing applications, were evaluated by inductively coupled plasma mass spectrometry (ICP-MS) on the media in which surfaces were stored in order to identify any gallium leaching from the substrates. Both molecules formed fairly disordered monolayers demonstrated by comparable oxide thicknesses. The UDA molecules demonstrated better stability compared to MUA molecules based on contact angle measurements and tilt angle data extracted from XPS results. According to the XPS data, the UDA molecules formed a more dense adlayer compared to MUA molecules. With respect to toxicity, the UDA-functionalized GaP provided better passivation which was confirmed by less gallium leaching into water and saline solutions. Overall, the superior passivation provided by UDA demonstrates that alkene grafting has better potential for modifying GaP based devices such as implantable sensors.


Effects of Polymyxin B on Clinical Signs, Serum TNF-α, Haptoglobin and Plasma Lactate Concentrations in Experimental Endotoxaemia in Sheep.
The experiment evaluated the effects of intravenous administration of polymyxin B on experimental endotoxaemia in sheep. Twenty clinically healthy fat-tailed sheep were randomly divided into: a group treated with 6,000 U/kg of polymyxin B, a group at 12,000 U/kg, and positive and negative controls. Endotoxaemia was induced by intravenous administration of lipopolysaccharide (LPS) from E. coli serotype O55:B5 at 0.5 μg/kg. polymyxin was infused intravenously along with 2.5 L of isotonic intravenous fluids at 20 mL/kg/h. The positive control group received LPS and 2.5 L of isotonic fluids, the negatives receiving just 2.5 L of isotonic fluids. Clinical signs were evaluated before and at 1.5, 3, 4.5, 6, 24, and 48 h after LPS administration. Blood was also sampled at the denoted hours and serum haptoglobin, tumour necrosis factor-α (TNF-α), and plasma lactate concentrations were assayed. The serum concentration of TNF-α in the positive control group increased significantly up to 48 h after LPS administration. The concentration of TNF-α was significantly different from those of the polymyxin B and positive control groups from 3 to 48 h; also, the concentrations of haptoglobin at different times in the polymyxin groups were lower than those of the positive control group and were significant at hours 3 to 48 (P < 0.05). Following the LPS administration, haptoglobin and TNF-α concentrations changed without significant difference between the two polymyxin B groups. Polymyxin B (6,000 U/kg) restrained blood lactate concentrations. Furthermore, it significantly improved the clinical signs in endotoxaemic animals, including rectal temperature and heart and respiratory rates. Polymyxin B may be an antiendotoxic in fat-tailed sheep.


Binding of low density lipoproteins to lipoprotein lipase is dependent on lipids but not on apolipoprotein B.
Lipoprotein lipase (LPL) efficiently mediates the binding of lipoprotein particles to lipoprotein receptors and to proteoglycans at cell surfaces and in the extracellular matrix. It has been proposed that LPL increases the retention of atherogenic lipoproteins in the vessel wall and mediates the uptake of lipoproteins in cells, thereby promoting lipid accumulation and plaque formation. We investigated the interaction between LPL and low density lipoproteins (LDLs) with special reference to the protein-protein interaction between LPL and apolipoprotein B (apoB). Chemical modification of lysines and arginines in apoB or mutation of its main proteoglycan binding site did not abolish the interaction of LDL with LPL as shown by surface plasmon resonance (SPR) and by experiments with THP-I macrophages. Recombinant LDL with either apoB100 or apoB48 bound with similar affinity. In contrast, partial delipidation of LDL markedly decreased binding to LPL. In cell culture experiments, phosphatidylcholine-containing liposomes competed efficiently with LDL for binding to LPL. Each LDL particle bound several (up to 15) LPL dimers as determined by SPR and by experiments with THP-I macrophages. A recombinant NH(2)-terminal fragment of apoB (apoB17) bound with low affinity to LPL as shown by SPR, but this interaction was completely abolished by partial delipidation of apoB17. We conclude that the LPL-apoB interaction is not significant in bridging LDL to cell surfaces and matrix components; the main interaction is between LPL and the LDL lipids.


Sourdough fermentation or addition of organic acids or corresponding salts to bread improves nutritional properties of starch in healthy humans.
Postprandial blood glucose and insulin responses to barley bread containing organic acids or corresponding salts were evaluated in healthy human subjects. The satiety score and the rate and extent of in vitro starch digestion were also studied. Lactic acid was generated by use of a homofermentative starter culture or added to the dough. In addition, products were baked with Ca-lactate, or with Na-propionate at two different concentrations. Consumption of the product baked with a high concentration of Na-propionate significantly lowered the postprandial blood glucose and insulin responses, and significantly prolonged the duration of satiety compared with all other breads. When subjects consumed the breads baked with sourdough, lactic acid and Na-propionate, their glucose and insulin responses were reduced compared with the wholemeal bread alone. The rate of in vitro amylolysis was reduced only by ingestion of the breads containing lactic acid, suggesting that the beneficial impact of Na-propionate on metabolic responses and satiety was related to effects other than a reduced rate of starch hydrolysis. All bread products had a similar concentration of in vitro resistant starch of 1.3-2.1 g/100 g (starch basis). It is concluded that sourdough baking and other fermentation processes may improve the nutritional features of starch. The results also demonstrate that certain salts of organic acids may have metabolic effects.


Computational Modeling of Lipid Metabolism in Yeast.
Lipid metabolism is essential for all major cell functions and has recently gained increasing attention in research and health studies. However, mathematical modeling by means of classical approaches such as stoichiometric networks and ordinary differential equation systems has not yet provided satisfactory insights, due to the complexity of lipid metabolism characterized by many different species with only slight differences and by promiscuous multifunctional enzymes. Here, we present an object-oriented stochastic model approach as a way to cope with the complex lipid metabolic network. While all lipid species are treated objects in the model, they can be modified by the respective converting reactions based on reaction rules, a hybrid method that integrates benefits of agent-based and classical stochastic simulation. This approach allows to follow the dynamics of all lipid species with different fatty acids, different degrees of saturation and different headgroups over time and to analyze the effect of parameter changes, potential mutations in the catalyzing enzymes or provision of different precursors. Applied to yeast metabolism during one cell cycle period, we could analyze the distribution of all lipids to the various membranes in time-dependent manner. The presented approach allows to efficiently treat the complexity of cellular lipid metabolism and to derive conclusions on the time- and location-dependent distributions of lipid species and their properties such as saturation. It is widely applicable, easily extendable and will provide further insights in healthy and diseased states of cell metabolism.


Compensating for intraoperative soft-tissue deformations using incomplete surface data and finite elements.
Image-guided liver surgery requires the ability to identify and compensate for soft tissue deformation in the organ. The predeformed state is represented as a complete three-dimensional surface of the organ, while the intraoperative data is a range scan point cloud acquired from the exposed liver surface. The first step is to rigidly align the coordinate systems of the intraoperative and preoperative data. Most traditional rigid registration methods minimize an error metric over the entire data set. In this paper, a new deformation-identifying rigid registration (DIRR) is reported that identifies and aligns minimally deformed regions of the data using a modified closest point distance cost function. Once a rigid alignment has been established, deformation is accounted for using a linearly elastic finite element model (FEM) and implemented using an incremental framework to resolve geometric nonlinearities. Boundary conditions for the incremental formulation are generated from intraoperatively acquired range scan surfaces of the exposed liver surface. A series of phantom experiments is presented to assess the fidelity of the DIRR and the combined DIRR/FEM approaches separately. The DIRR approach identified deforming regions in 90% of cases under conditions of realistic surgical exposure. With respect to the DIRR/FEM algorithm, subsurface target errors were correctly located to within 4 mm in phantom experiments.


Perceived cognitive deficits and depressive symptoms in patients with multiple sclerosis: Perceived stress and sleep quality as mediators.
Multiple Sclerosis (MS), an autoimmune disorder marked by inflammation of the central nervous system, is associated with a myriad of symptoms. Individuals with MS are more likely to experience depressive symptoms, perhaps due to perceived cognitive impairments. Thus, we aimed to explore perceived stress and sleep deficits as potential mediators of the association between perceived cognitive deficits and depressive symptoms. We recruited a sample of 77 MS participants from an outpatient, university-based MS clinic in the United States. Participants ranged in age between 30 and 75 years old (M = 51.12; SD = 9.6), with more females than males (83% female; n = 64). Participants completed the Perceived Deficits Questionnaire, the Pittsburgh Sleep Quality Index, the Perceived Stress Scale, and the Center for Epidemiological Studies Depression Scale - Revised. Correlation analyses and mediation analyses were conducted with bootstrapping technique. Statistical analyses revealed that higher levels of perceived cognitive deficits were associated with lower quality of sleep, more perceived stress, and higher levels of depressive symptoms. Additionally, both perceived stress and sleep quality served as a significant mediator in the perceived cognitive impairments and depressive symptoms linkage. Our novel findings demonstrate the importance of underlying mechanisms (e.g., sleep quality and perceived stress) in the conceptualization of MS. Perceived stress and sleep quality are potentially modifiable factors, perhaps serving as a target for future treatment, to buffer risk of MS patients developing depression.


Honeybee nutrition is linked to landscape composition.
Declines in insect pollinators in Europe have been linked to changes in land use. Pollinator nutrition is dependent on floral resources (i.e., nectar and pollen), which are linked to landscape composition. Here, we present a stratified analysis of the nutritional composition of beebread in managed honeybee hives with a view to examining potential sources of variation in its nutritional composition. Specifically, we tested the hypothesis that beebread composition correlates with local land use and therefore available floral resources. The results demonstrated that the starch, lipid, and moisture contents of beebread are all highly conserved across hives, whereas levels of protein and nonreducing sugar increased as the year progressed, reducing sugars, however, decreased during the first half of the year and then increased toward the end. Local land use around hives was quantified using data from the Countryside Survey 2007 Land Cover Map. Bee-bread protein content was negatively correlated with increasing levels of arable and horticultural farmland surrounding hives and positively correlated with the cover of natural grasslands and broadleaf woodlands. Reducing sugar content was also positively correlated with the amount of broad-leaved woodland in a 3 Km² radius from the hives. Previous studies on a range of invertebrates, including honeybees, indicate that dietary protein intake may have a major impact on correlates of fitness, including longevity and immune function. The finding that beebread protein content correlates with land use suggests that landscape composition may impact on insect pollinator well-being and provides a link between landscape and the nutritional ecology of socially foraging insects in a way not previously considered.


Crystal and electrochemical properties of water dispersed CdS nanocrystals obtained via reverse micelles and arrested precipitation.
Different methods of synthesis for the production of electroactive nanocrystals (NCs) for use as labels in DNA sensing systems are presented. They are based on two general ways of controlling the formation and growth of the nanoparticles: (a) physical restriction of the volume available for the growth of the individual nanoparticles by using templates such as reverse micelles; (b) arrested precipitation that depends on exhaustion of one of the reactants. The water dispersed nanocrystals thus obtained are then characterized by optical or electrochemical techniques so as to evaluate the quality of the prepared NCs. A novel direct electrochemical stripping detection protocol that involves the use of a bismuth modified graphite epoxy composite electrode is developed and applied so as to quantify the CdS NCs. The electrochemical study revealed a linear dependency of the stripping current upon the concentration of CdS NCs with a detection limit of around 10(15) CdS NCs cm(-3). The obtained NCs are of great interest for future applications in electrochemical genosensors.


Acquisition of Ca(2+) and HCO3(-)/CO3(2-) for shell formation in embryos of the common pond snail Lymnaea stagnalis.
Embryos of the freshwater common pond snail Lymnaea stagnalis develop to hatch within 10 days under control conditions (22°C, Miami-Dade tap water) and this development is impaired by removal of ambient calcium. In contrast, embryos did not exhibit dependence upon an ambient HCO(3)(-)/CO(3)(2-) source, developing and hatching in HCO(3)(-)/CO(3)(2-)-free water at rates comparable to controls. Post-metamorphic, shell-laying embryos exhibited a significant saturation-type calcium uptake as a function of increasing ambient calcium concentration. However, changes in ambient bicarbonate concentration did not influence calcium or apparent titratable alkalinity uptake. There was a distinct shift from no significant flux in pre-metamorphic embryos to net uptake of calcium in post-metamorphic stages as indicated by an increased uptake from the micro-environment surrounding the egg mass and increased net uptake in 24-h, whole egg mass flux measurements. Furthermore, HCO(3)(-)/CO(3)(2-) acquisition as measured by titratable alkalinity flux is at least partially attributable to an endogenous carbonate source that is associated with acid extrusion. Thus, calcium requirements for embryonic shell formation are met via uptake but HCO(3)(-)/CO(3)(2-), which is also necessary for shell formation is acquired in part from endogenous sources with no detectable correlation to ambient HCO(3)(-)/CO(3)(2-) availability.


Dietary salt and blood pressure. A perspective.
Although dietary salt restriction is often valuable as sole or adjunctive therapy of hypertensive disorders, it is abundantly clear that hypertensive patients comprise a heterogeneous group with regard to salt sensitivity of blood pressure. This is apparent despite the many methodological obstacles to defining salt sensitivity in an individual patient. Currently, dietary trial is the only sure means of defining a given patient as responsive to salt restriction. Easily definable markers of salt sensitivity would allow appropriate targeting of this rather ponderous therapy. Promising leads include the assessment of membrane ion transporters such as sodium-lithium exchange and of the activity of the renin-angiotensin system, including the phenomenon of "non-modulating" hypertension and other volume regulatory hormones such as atrial natriuretic factor. Although less intensively studied than in hypertensive patients, the blood pressure response of normal subjects to salt restriction is also marked by great variability. Given the possibility of deleterious consequences of population-wide salt restriction for at least some people in a setting such as the United States, it seems imprudent to recommend such a policy before its proven worth has been demonstrated by clinical trial. Pending such evidence and the development of markers, salt restriction should be reserved for those in whom it is of demonstrated efficacy.


Augmented virtuality based on stereoscopic reconstruction in multimodal image-guided neurosurgery: methods and performance evaluation.
Displaying anatomical and physiological information derived from preoperative medical images in the operating room is critical in image-guided neurosurgery. This paper presents a new approach referred to as augmented virtuality (AV) for displaying intraoperative views of the operative field over three-dimensional (3-D) multimodal preoperative images onto an external screen during surgery. A calibrated stereovision system was set up between the surgical microscope and the binocular tubes. Three-dimensional surface meshes of the operative field were then generated using stereopsis. These reconstructed 3-D surface meshes were directly displayed without any additional geometrical transform over preoperative images of the patient in the physical space. Performance evaluation was achieved using a physical skull phantom. Accuracy of the reconstruction method itself was shown to be within 1 mm (median: 0.76 mm +/- 0.27), whereas accuracy of the overall approach was shown to be within 3 mm (median: 2.29 mm +/- 0.59), including the image-to-physical space registration error. We report the results of six surgical cases where AV was used in conjunction with augmented reality. AV not only enabled vision beyond the cortical surface but also gave an overview of the surgical area. This approach facilitated understanding of the spatial relationship between the operative field and the preoperative multimodal 3-D images of the patient.


Changes of ginsenoside content by mushroom mycelial fermentation in red ginseng extract.
To obtain microorganisms for the microbial conversion of ginsenosides in red ginseng extract (RGE), mushroom mycelia were used for the fermentation of RGE. After fermentation, total sugar contents and polyohenol contents of the RGEs fermented with various mushrooms were not a significant increase between RGE and the ferments. But uronic acid content was relatively higher in the fermented RGEs cultured with Lentus edodes (2155.6 μg/mL), Phelllinus linteus (1690.9 μg/mL) and Inonotus obliquus 26137 and 26147 (1549.5 and 1670.7 μg/mL) compared to the RGE (1307.1 μg/mL). The RGEs fermented by Ph. linteus, Cordyceps militaris, and Grifola frondosa showed particularly high levels of total ginsenosides (20018.1, 17501.6, and 16267.0 μg/mL, respectively). The ferments with C. militaris (6974.2 μg/mL), Ph. linteus (9109.2 μg/mL), and G. frondosa (7023.0 μg/mL) also showed high levels of metabolites (sum of compound K, Rh1, Rg5, Rk1, Rg3, and Rg2) compared to RGE (3615.9 μg/mL). Among four different RGE concentrations examined, a 20 brix concentration of RGE was favorable for the fermentation of Ph. linteus. Maximum biotransformation of ginsneoside metabolites (9395.5 μg/mL) was obtained after 5 days fermentation with Ph. linteus. Maximum mycelial growth of 2.6 mg/mL was achieved at 9 days, in which growth was not significantly different during 5 to 9 days fermentation. During fermentation of RGE by Ph. linteus in a 7 L fermenter, Rg3, Rg5, and Rk1 contents showed maximum concentrations after 5 days similar to flask fermentation. These results confirm that fermentation with Ph. linteus is very useful for preparing minor ginsenoside metabolites while being safe for foods.


GABA influences the development of the ventromedial nucleus of the hypothalamus.
The region that becomes the ventromedial nucleus of the hypothalamus (VMH) is surrounded by cells and fibers containing immunoreactive gamma-aminobutyric acid (GABA) by embryonic day 13 (E13), several days before the nucleus emerges in Nissl stains. As GABA plays many roles during neural development, we hypothesized that it influences VMH development, perhaps by providing boundary information for migrating neurons. To test this hypothesis we examined the VMH in embryonic mice in which the beta3 subunit of the GABA(A)-receptor, a receptor subunit that is normally highly expressed in this nucleus, was disrupted by gene targeting. In beta3 -/- embryos the VMH was significantly larger, and the distribution of cells containing immunoreactive estrogen receptor-alpha was expanded compared to controls. Using in vitro brain slices from wild-type C57BL/6J mice killed at E15 we found that treatment with the GABA(A) antagonist bicuculline increased the number of cells migrating per video field analyzed in the VMH. In addition, treatment with either bicuculline or the GABA(A) agonist muscimol altered the orientation of cell migration in particular regions of this nucleus. These data suggest that GABA is important for the organization of cells during VMH formation.


Using infectious intestinal disease surveillance data to explore illness aetiology; a cryptosporidiosis case study.
Infectious intestinal disease (IID) surveillance data are an under-utilised information source on illness geography. This paper uses a case study of cryptosporidiosis in England and Wales to demonstrate how these data can be converted into area-based rates and the factors underlying illness geography investigated. Ascertainment bias is common in surveillance datasets, and we develop techniques to investigate and control this. Rural areas, locations with many livestock and localities with poor water treatment had elevated levels of cryptosporidiosis. These findings accord with previous research validating the techniques developed. Their use in future studies investigating IID geography is therefore recommended.


Hybrid multiphoton and optoacoustic microscope.
We present a hybrid microscope combining multiphoton microscopy incorporating second-harmonic generation contrast and optical-resolution optoacoustic (photoacoustic) microscopy. We study the relative performance of the two systems and investigate the complementarity of contrast by demonstrating the label-free imaging capabilities of the hybrid microscope on zebrafish larvae ex vivo, concurrently visualizing the fish musculature and melanocytes. This implementation can prove useful in multiparametric microscopy studies, enabling broader information to be collected from biological specimens.


A gift and a burden: the purchase and distribution of duty-free tobacco and its potential impact upon Pacific people in New Zealand.
High smoking rates among Pacific people living within New Zealand (26.9%) are a significant and poorly understood problem. A proposed approach to tobacco control is to enhance restrictions on or ban duty-free sales, a pertinent notion for Pacific people given their frequent travel between New Zealand and the Pacific Islands. This study examines the purchase and distribution of duty-free tobacco by Pacific people, whether it is being used as a strategy to circumvent the tobacco excise tax increases and how duty-free cigarette sales are perceived within the Pacific community. We undertook a qualitative research study using six focus groups with Pacific smokers and non-smokers aged between 18 and 54 years. Half of the focus groups consisted of smokers and half non-smokers. We used a thematic analysis approach to identify, explore and report key themes within the data. Pacific smokers and non-smokers frequently purchase duty-free tobacco when travelling, and the usage of duty-free cigarettes for gift giving is a strongly embedded cultural value for Pacific peoples. However, nearly all participants strongly supported a proposal to reduce or ban duty-free tobacco sales. The findings suggest a ban on duty-free sales could be an important measure to help achieve the smokefree 2025 goal among Pacific communities in New Zealand. This measure would eliminate duty-free tobacco as a cheap form of supply, and efforts to denormalise the practice of gifting duty-free tobacco among Pacific people may also be helpful in reducing high prevalence rates within these communities.


Young children's after-school activities - there's more to it than screen time: a cross-sectional study of young primary school children.
Children can spend substantial amounts of leisure time in sedentary activities, dominated by TV/screen time. However, objective real-time measurement of activities after school among young school children is seldom described. School children (n = 246, 5-7 years old, mean 6.0) and their parents were recruited by random selection from 14 schools across Sydney, Australia. Parents used a real-time objective measure (Experience Sampling Method, ESM) to record children's activities and whether they were indoors or outdoors at 3 random times each day after school. Data were collected across 4 weekdays in 1 week and then, 13 weeks later, another 4 weekdays in 1 week. Results were based on 2940 responses from 214 child-parent dyads showed that 25% of behavior involved physical activity, 51% was spent in sedentary activities, and 22% was TV/screen time. Most instances (81%) occurred indoors. Despite a high proportion of TV/screen time, children were also engaged in a range of other sedentary and physically active pursuits after school. Hence TV/screen time is not a suitable proxy for all sedentary behavior, and it is important to gather information on other non-screen-based sedentary and physically active behaviors. Future research is warranted to further investigate after-school activities in young primary school children.


Design and evaluation of more accurate gradient operators on hexagonal lattices.
Digital two-dimensional images are usually sampled on square lattices, while the receptors of the human eye are following a hexagonal structure. It is the main motivation for adopting hexagonal lattices. The fundamental operation in many image processing algorithms is to extract the gradient information. As such, various gradient operators have been proposed for square lattices and have been thoroughly optimized. Accurate gradient operators for hexagonal lattices have, however, not been researched well enough, while the distance between neighbor pixels is constant. We therefore derive consistent gradient operators on hexagonal lattices and compare them with the existing optimized filters on square lattices. The results show that the derived filters on hexagonal lattices achieve a better signal-to-noise ratio than those on square lattices. Results on artificial images also show that the derived filters on hexagonal lattices outperform the square ones with respect to accuracy of gradient intensity and orientation detection.


A joint theoretical and experimental study for elastic electron scattering from 1,4-dioxane.
We present results of measurements and calculations of elastic electron scattering from 1,4-dioxane in the energy range of 0-1000 eV. Absolute differential and integral elastic cross sections have been measured using a crossed electron-molecule beam spectrometer and the relative flow technique, at four energies in the 10-30 eV range and for scattered electrons in the angular range 20°-129°. The measured cross sections are compared with results from R-matrix computations, at the static exchange plus polarization level, calculated at energies between 0-20 eV, and with calculations employing the independent atom model with the screening corrected additivity rule (IAM-SCAR). Those latter computations were conducted at energies between 1 and 1000 eV. Agreement between the measured and R-matrix cross sections was typically found to be good at all common energies, whereas agreement with IAM-SCAR was satisfactory only at 30 eV. To the best of our knowledge, the present results are the first absolute data to be published in the literature for this scattering system.


Effects of action on children's and adults' mental imagery.
The aim of this study was to investigate whether and which aspects of a concurrent motor activity can facilitate children's and adults' performance in a dynamic imagery task. Children (5-, 7-, and 9-year-olds) and adults were asked to tilt empty glasses, filled with varied amounts of imaginary water, so that the imagined water would reach the rim. Results showed that in a manual tilting task where glasses could be tilted actively with visual feedback, even 5-year-olds performed well. However, in a blind tilting task and in a static judgment task, all age groups showed markedly lower performance. This implies that visual movement information facilitates imagery. In a task where the tilting movement was visible but regulated by means of an on-and-off remote control, a clear age trend was found, indicating that active motor control and motor feedback are particularly important in imagery performance of younger children.


First records of tool-set use for ant-dipping by Eastern chimpanzees (Pan troglodytes schweinfurthii) in the Kalinzu Forest Reserve, Uganda.
Chimpanzees at numerous study sites are known to prey on army ants by using a single wand to dip into the ant nest or column. However, in Goualougo (Republic of Congo) in Central Africa, chimpanzees use a different technique, use of a woody sapling to perforate the ant nest, then use of a herb stem as dipping tool to harvest the army ants. Use of a tool set has also been found in Guinea, West Africa: at Seringbara in the Nimba Mountains and at nearby Bossou. There are, however, no reports for chimpanzees in East Africa. We observed use of such a tool set in Kalinzu, Uganda, for the first time by Eastern chimpanzees. This behavior was observed among one group of chimpanzees at Kalinzu (S-group) but not among the adjacent group (M-group) with partly overlapping ranging areas despite the fact that the latter group has been under intensive observation since 1997. In Uganda, ant-dipping has not been observed in the northern three sites (Budongo, Semliki, and Kibale) but has been observed or seems to occur in the southern sites (Kalinzu and Bwindi), which suggests that ant-dipping was invented by and spread from the southern region after the northern and southern forest blocks became separated. Use of a tool-set by only one group at Kalinzu further suggests that this behavior was recently invented and has not yet spread to the other group via migrating females.


Intratracheal Clara cell secretory protein (CCSP) administration in preterm infants with or at risk of respiratory distress syndrome.
Clara cell secretary protein (CCSP) is an immune-modulating and anti-inflammatory agent. CCSP is available synthetically as recombinant human Clara cell protein (rhCC10). It has been shown in animal models to reduce lung injury, improve pulmonary compliance and oxygenation, decrease systemic inflammation and up-regulate surfactant protein and vascular endothelial growth factor expression. These properties makes intratracheally administered CCSP a potential agent in prevention of chronic lung disease (CLD). To determine the effect of intratracheal CCSP administration compared to placebo or no treatment on morbidity and mortality in preterm infants with or at risk of respiratory distress syndrome (RDS). We searched CENTRAL (The Cochrane Library, October 2010), MEDLINE and PREMEDLINE (1950 to October 2010), EMBASE (1980 to October 2010) and CINAHL (1982 to October 2010). We searched proceedings of scientific meetings, Google Scholar and reference lists of identified studies, and contacted expert informants and surfactant manufacturers. Published, unpublished and ongoing randomised controlled, cluster-randomised or quasi-randomised trials of intratracheal CCSP administration, compared to placebo or no treatment on morbidity and mortality in preterm infants at risk of RDS. Two authors independently assessed studies for eligibility and quality, and extracted data. One pilot study was identified and included. This study enrolled 22 preterm infants 700 to 1300g with established RDS who required ventilation for surfactant administration. Infants received one intratracheal dose of placebo (n = 7), 1.5 mg/kg (n = 8) or 5 mg/kg (n = 7) rhCC10 within four hours of surfactant treatment. At either dose of rhCC10, no significant difference was reported in CLD (36 weeks postmenstrual age or 28 days), mortality, intraventricular haemorrhage, periventricular leukomalacia, patent ductus arteriosus, necrotising enterocolitis, sepsis or days supplemental oxygen compared to placebo. A significant increase in days mechanical ventilation was reported for infants receiving rhCC10 5mg/kg (mean difference 12.00, 95% confidence interval 0.39 to 23.61) but not at the lower dose. The study reported that a single intratracheal dose of rhCC10 was well tolerated and resulted in a significant reduction in tracheal aspirate neutrophil and total cell count, and lung protein concentration. There was no significant difference reported in tracheal aspirate cytokine levels between groups. There are insufficient data to determine the role of rhCC10 in clinical practice. Further studies are required to determine if rhCC10 reduces lung inflammation in infants at risk of CLD, and to determine dose and dosing strategy.


Precarious employment and mental health: a systematic review and meta-analysis of longitudinal studies.
Objectives Precarious employment (PE) is a term used to describe non-standard employment forms characterized by low security that may have negative effects on mental health. The objective of this review was to systematically review the evidence for effects of PE on mental health and identify important areas for further research. Methods A protocol was developed following PRISMA-P guidelines. Web of Science, PubMed and PsycINFO were searched up to 4 September 2017. All unique records were assessed for eligibility and quality by at least two reviewers. Data from included studies were summarized in forest plots and meta-analyses using a random-effects model. Evidence quality was rated using the GRADE method. Results We obtained 3328 unique records, of which 16 studies of sufficient quality met the inclusion criteria. Moderate quality evidence (GRADE score 3 of 4) was found for an adverse effect of job insecurity on mental health; summary odds ratio (OR) 1.52 [95% confidence interval (CI) 1.35-1.70]. There was very low quality (GRADE 1 of 4) evidence for effects of temporary employment or unpredictable work hours on mental health. Five studies on multidimensional exposures all showed adverse effects, weighted average OR 2.01 (95% CI 1.60-2.53). Conclusions Research on PE and mental health is growing, but high-quality prospective studies are still scarce. Job insecurity likely has an adverse effect on mental health. A clear multi-dimensional definition of PE is lacking, and harmonization efforts are needed. Further single-variable observational studies on job insecurity or temporary employment should not be prioritized.


Phenomenological theory of structural relaxation based on a thermorheologically complex relaxation time distribution.
The aim of this work is to explore the consequences on the kinetics of structural relaxation of considering a glass-forming system to consist of a series of small but macroscopic relaxing regions that evolve independently from each other towards equilibrium in the glassy state. The result of this assumption is a thermorheologically complex model. In this approach each relaxing zone has been assumed to follow the Scherer-Hodge model for structural relaxation (with the small modification of taking a linear dependence of configurational heat capacity with temperature). The model thus developed contains four fitting parameters. A least-squares search routine has been used to find the set of model parameters that fit simultaneously four DSC thermograms in PVAc after different thermal histories. The computer-simulated curves are compared with those obtained with Scherer-Hodge model and the model proposed by Gómez and Monleón. The evolution of the relaxation times during cooling or heating scans and also during isothermal annealing below the glass transition has been analysed. It has been shown that the relaxation times distribution narrows in the glassy state with respect to equilibrium. Isothermal annealing causes this distribution to broaden during the process to finally attain in equilibrium the shape defined at temperatures above Tg.


Mitochondria and the success of somatic cell nuclear transfer cloning: from nuclear-mitochondrial interactions to mitochondrial complementation and mitochondrial DNA recombination.
The overall success of somatic cell nuclear transfer (SCNT) cloning is rather unsatisfactory, both in terms of efficacy and from an animal health and welfare point of view. Most research activities have concentrated on epigenetic reprogramming problems as one major cause of SCNT failure. The present review addresses the limited success of mammalian SCNT from yet another viewpoint, the mitochondrial perspective. Mitochondria have a broad range of critical functions in cellular energy supply, cell signalling and programmed cell death and, thus, affect embryonic and fetal development, suggesting that inadequate or perturbed mitochondrial functions may adversely affect SCNT success. A survey of perinatal clinical data from human subjects with deficient mitochondrial respiratory chain activity has revealed a plethora of phenotypes that have striking similarities with abnormalities commonly encountered in SCNT fetuses and offspring. We discuss the limited experimental data on nuclear-mitochondrial interaction effects in SCNT and explore the potential effects in the context of new findings about the biology of mitochondria. These include mitochondrial fusion/fission, mitochondrial complementation and mitochondrial DNA recombination, processes that are likely to be affected by and impact on SCNT cloning. Furthermore, we indicate pathways that could link epigenetic reprogramming and mitochondria effects in SCNT and address questions and perspectives for future research.


Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting.
Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin]), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we aimed to confirm this observation in a third primary prevention randomized controlled trial. In addition, we assessed whether those at high genetic risk had a greater burden of subclinical coronary atherosclerosis. We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS [West of Scotland Coronary Prevention Study]; n=4910) and 2 observational cohort studies (CARDIA [Coronary Artery Risk Development in Young Adults] and BioImage; n=1154 and 4392, respectively). For each participant, we calculated a polygenic risk score derived from up to 57 common DNA sequence variants previously associated with coronary heart disease. We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of polygenic risk score) versus all others (WOSCOPS), as well as the association between the polygenic risk score and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage). Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% confidence interval [CI], 22-60; P<0.001), whereas in all others, the relative risk reduction was 24% (95% CI, 8-37; P=0.004) despite similar low-density lipoprotein cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others (P for heterogeneity=0.05). Across all 3 studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0-5.1) among those in the high genetic risk group and 1.3% (95% CI, 0.6-1.9) in all others. Each 1-SD increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7% higher (95% CI, 2.2-17.8) burden of carotid plaque. Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00738725 (BioImage) and NCT00005130 (CARDIA). WOSCOPS was carried out and completed before the requirement for clinical trial registration.