Melatonin induces autophagy via an mTOR-dependent pathway and enhances clearance of mutant-TGFBIp.
The hallmark of granular corneal dystrophy type 2 (GCD2) is the deposit of mutant transforming growth factor-β (TGF-β)-induced protein (TGFBIp) in the cornea. We have recently shown that there is a delay in autophagic degradation of mutant-TGFBIp via impaired autophagic flux in GCD2 corneal fibroblasts. We hypothesized that melatonin can specifically induce autophagy and consequently eliminate mutant-TGFBIp in GCD corneal fibroblasts. Our results show that melatonin activates autophagy in both wild-type (WT) and GCD2-homozygous (HO) corneal fibroblast cell lines via the mammalian target of rapamycin (mTOR)-dependent pathway. Melatonin treatment also led to increased levels of beclin 1, which is involved in autophagosome formation and maturation. Furthermore, melatonin significantly reduced the amounts of mutant- and WT-TGFBIp. Treatment with melatonin counteracted the autophagy-inhibitory effects of bafilomycin A1, a potent inhibitor of autophagic flux, demonstrating that melatonin enhances activation of autophagy and increases degradation of TGFBIp. Cotreatment with melatonin and rapamycin, an autophagy inducer, had an additive effect on mutant-TGFBIp clearance compared to treatment with either drug alone. Treatment with the selective melatonin receptor antagonist luzindole did not block melatonin-induced autophagy. Given its ability to activate autophagy, melatonin is a potential therapeutic agent for GCD2.


Sticky eye, tricky diagnosis.
Infective conjunctivitis is common and mostly responds well to supportive management and/or empiric antibiotic treatment. At times the differential diagnosis includes more serious conditions that potentially threaten vision. Recurrence and treatment failures are relatively common. To outline the usual clinical appearance of conjunctivitis and its management. To explore the clinical appearance (with the help of case studies) of conditions that have been mistaken for conjunctivitis, and to consider some of the conditions that may coexist that contribute to recurrence and nonresponsiveness. Empiric treatment for presumed bacterial conjunctivitis remains an appropriate course of action. Care must be taken in certain groups who are at high risk of complications. Careful review of the clinical appearance and consideration of other possible diagnoses is mandatory in nonresponding patients.


Gender differences in the relationship between anxiety symptoms and physical inactivity in a community-based sample of adults with type 2 diabetes.
To examine the association between physical inactivity and anxiety symptoms in a community-based sample of men and women with type 2 diabetes mellitus. Eligibility criteria included residents of Quebec, Canada aged between 40 and 75 years, having a diagnosis of type 2 diabetes (≤10 years), being insulin-naive and having participated in a previous telephone-based survey of diabetes treatments. Of the 2028 eligible respondents, 1953 (96.3%) provided information on anxiety symptoms and were included in this analysis. Participants were interviewed and provided information on diabetes-related clinical and sociodemographic factors. A total of 27.3% of participants reported being physically inactive. The prevalence of mild to severe anxiety symptoms was 22.9%. Persons with mild anxiety symptoms and moderate to severe anxiety symptoms were 1.4 times and 1.7 times more likely to report being inactive than persons without anxiety symptoms, respectively. Subgroup analyses according to gender revealed that women who had mild anxiety symptoms were 1.5 times more likely to report being inactive compared with women who did not have anxiety symptoms, whereas men who had moderate to severe anxiety symptoms were 2.5 times more likely to be inactive than men who did not have anxiety symptoms. Anxiety symptoms in the mild and moderate to severe range are a relevant clinical comorbidity in persons with type 2 diabetes, and men may represent a particularly vulnerable subgroup. Future research is recommended to further assess the relationship between anxiety symptoms and diabetes-related health behaviours.


Responsiveness of different rating instruments in spinocerebellar ataxia patients.
To determine the longitudinal metric properties of recently developed clinical assessment tools in spinocerebellar ataxia (SCA). A subset of 171 patients from the EUROSCA natural history study cohort (43 SCA1, 61 SCA2, 37 SCA3, and 30 SCA6) were examined after 1 year of follow-up. Score changes and effect size indices were calculated for clinical scales (Scale for the Assessment and Rating of Ataxia [SARA], Inventory of Non-Ataxia Symptoms [INAS]), functional tests (SCA Functional Index [SCAFI] and components), and a patient-based scale for subjective health status (EQ-5D visual analogue scale [EQVAS]). Responsiveness was determined in relation to the patient's global impression (PGI) of change and reproducibility described as retest reliability for the stable groups and smallest detectable change. Within the 1-year follow-up period, SARA, INAS, and SCAFI but not EQVAS indicated worsening in the whole group and in the groups with subjective (PGI) worsening. SCAFI and its 9-hole pegboard (9HPT) component also deteriorated in the stable groups. Standardized response means were highest for 9HPT (-0.67), SARA (0.50), and SCAFI (-0.48) with accordingly lower sample size estimates of 143, 250, or 275 per group for a 2-arm interventional trial that aims to reduce disease progression by 50%. SARA and EQVAS performed best to distinguish groups classified as worse by PGI. All scales except EQVAS reached the criterion for retest reliability. While both the Scale for the Assessment and Rating of Ataxia and the SCA Functional Index (SCAFI) (and its 9-hole pegboard component) had favorable measurement precision, the clinical relevance of SCAFI and 9-hole pegboard score changes warrants further exploration. The EQ-5D visual analogue scale proved insufficient for longitudinal assessment, but validly reflected patients' impression of change.


Maternal Flt-1 and endoglin expression by circulating monocyte subtype and polarization in preeclampsia and fetal growth restriction.
Circulating levels of the anti-angiogenic factors sFlt-1 and sEndoglin are elevated in preeclampsia (PE) and fetal growth restriction (FGR), mainly secreted from placental trophoblast. This study aims to identify the contributory role of monocyte Flt-1 and endoglin expression in PE and FGR. A prospective cross-sectional study was conducted and patients recruited from four clinical groups including normal pregnancy, PE, FGR and PE + FGR. Peripheral blood samples and cord blood were collected from 54 pregnant women between 24-40 weeks of gestation. Monocyte subset distribution was assessed using CD14 and CD16 expression and the surface expression of Flt-1, endoglin, CD86 and CD163 assessed by flow cytometry. We compared these factors between (1) clinical groups. (2) monocyte subset (3) monocyte polarization and (4) gestational age. Across all clinical groups, Flt-1 was mainly expressed by classical and intermediate monocytes, but no differences between clinical groups were observed. Surface expression of endoglin was higher on intermediate and non-classical monocytes and decreased in PE + FGR total monocytes. Flt-1 and endoglin expression correlated with increasing gestational age as well as higher CD86/CD163 ratio favouring M1 polarisation. The fetal monocyte endoglin expression was increased in FGR. We conclude that monocyte Flt-1 and endoglin expression increase with gestational age and with M1 polarization suggesting their upregulation with inflammatory changes in monocytes. Endoglin expression by M1 monocytes may play a part in increased cardiovascular risk associated with preeclampsia. Endoglin expression on fetal monocytes is increased in FGR as a likely response to placental injury.


Multi-responsive nanocomposite hydrogels with high strength and toughness.
Multi-responsive hydrogels with high strength have great significance for potential applications in smart soft devices. However, it remains a challenge to incorporate multiple responsive moieties with energy dissipation mechanisms. Herein, multi-responsive nanocomposite hydrogels with high compressive strength and toughness were synthesized via in situ copolymerization of N-isopropylacrylamide (NIPAM) and acryloyloxyethyltrimethyl ammonium chloride (DAC) in an aqueous dispersion of exfoliated LAPONITE® RDS with a minute amount of N,N'-methylenebisacrylamide (MBAA) as a crosslinker. The combined use of clay and MBAA is demonstrated to be favorable for the high strength and toughness, and helped in avoiding precipitation of clay nanosheets, which otherwise occurred upon addition of cationic DAC. The effect of the NIPAM/DAC molar ratio, MBAA and clay contents on the properties of the hydrogels has been systematically investigated. Compression tests showed a compressive strength up to 6.2 MPa, with fracture strain higher than 90%. The presence of ionic DAC moieties in the hydrogels rendered a very high swelling ratio up to 40 (g g-1). These hydrogels were responsive to temperature changes due to the presence of NIPAM units, with the transition temperature (Ttrans) dependent on the molar ratio of NIPAM and DAC monomers. The internal electrostatic repulsion of the NIPAM/DAC copolymer network changed upon exposure to solutions with different pH and/or ion strength. Cyclic swelling-shrinking was demonstrated by shuttling the gels between pure water and 0.1 mol L-1 NaCl solution.


Seedling Disease of Corn Caused by Pythium Increases With Proximity of Rye.
Yield loss of corn following a winter rye cover crop (CC) has been associated with increases in seedling disease caused by Pythium spp. We hypothesized that physical separation between the CC and corn could reduce the risk of seedling disease, and benefit corn growth and development. In a growth chamber experiment, corn seedlings were planted at 0 cm and 8 to 10 cm from terminated winter rye plants. Root rot severity was assessed at crop development stage V2, and quantitative PCR was used to estimate the abundance of Pythium clade B and clade F members present in corn roots. Radicle and seminal root rot severity was numerically greater when seedlings were planted 0 cm from terminated rye plants compared with seedlings planted 8 to 10 cm away. Moreover, a greater abundance of Pythium clade B was detected in corn grown within the terminated winter rye compared with corn planted further away (P = 0.0003). No effect of distance between corn and winter rye was detected for Pythium clade F. These data contribute to our understanding of the effect of a winter rye cover crop on corn and will inform field trial management practices for farmers to reduce occasional yield loss of corn following a winter rye cover crop.


High heritability of telomere length and low heritability of telomere shortening in wild birds.
Telomere length and telomere shortening predict survival in many organisms. This raises the question of the contribution of genetic and environmental effects to variation in these traits, which is still poorly known, particularly for telomere shortening. We used experimental (cross-fostering) and statistical (quantitative genetic "animal models") means to disentangle and estimate genetic and environmental contributions to telomere length variation in pedigreed free-living jackdaws (Corvus monedula). Telomere length was measured twice in nestlings, at ages 4 (n = 715) and 29 days (n = 474), using telomere restriction fragment (TRF) analysis, adapted to exclude interstitial telomeric sequences. Telomere length shortened significantly over the nestling period (10.4 ± 0.3 bp day-1 ) and was highly phenotypically (rP = 0.95 ± 0.01) and genetically (rG > 0.99 ± 0.01) correlated within individuals. Additive genetic effects explained a major part of telomere length variation among individuals, with its heritability estimated at h2 = 0.74 on average. We note that TRF-based studies reported higher heritabilities than qPCR-based studies, and we discuss possible explanations. Parent-offspring regressions yielded similar heritability estimates for mothers and fathers when accounting for changes in paternal telomere length over life. Year effects explained a small but significant part of telomere length variation. Heritable variation for telomere shortening was low (h2 = 0.09 ± 0.11). The difference in heritability between telomere length (high) and telomere shortening (low) agrees with evolutionary theory, in that telomere shortening has stronger fitness consequences in this population. Despite the high heritability of telomere length, its evolvability, which scales the additive genetic variance by mean telomere length, was on average 0.48%. Hence, evolutionary change of telomere length due to selection is likely to be slow.


A murine model for oral infection with a primate rotavirus (simian SA11).
Simian rotavirus SA11 was shown to replicate in the gastrointestinal tracts of infant mice after oral inoculation. Clinical symptoms, histopathological changes in the small intestinal mucosa, and the type-specific humoral immune response were all characteristic of rotavirus-induced gastroenteritis. The availability of this small animal model for the study of a primate rotavirus infection should expedite analysis of the immune response necessary for protection against challenge.


The nitrate-reduction gene cluster components exert lineage-dependent contributions to optimization of Sinorhizobium symbiosis with soybeans.
Receiving nodulation and nitrogen fixation genes does not guarantee rhizobia an effective symbiosis with legumes. Here, variations in gene content were determined for three Sinorhizobium species showing contrasting symbiotic efficiency on soybeans. A nitrate-reduction gene cluster absent in S. sojae was found to be essential for symbiotic adaptations of S. fredii and S. sp. III. In S. fredii, the deletion mutation of the nap (nitrate reductase), instead of nir (nitrite reductase) and nor (nitric oxide reductase), led to defects in nitrogen-fixation (Fix- ). By contrast, none of these core nitrate-reduction genes were required for the symbiosis of S. sp. III. However, within the same gene cluster, the deletion of hemN1 (encoding oxygen-independent coproporphyrinogen III oxidase) in both S. fredii and S. sp. III led to the formation of nitrogen-fixing (Fix+ ) but ineffective (Eff- ) nodules. These Fix+ /Eff- nodules were characterized by significantly lower enzyme activity of glutamine synthetase indicating rhizobial modulation of nitrogen-assimilation by plants. A distant homologue of HemN1 from S. sojae can complement this defect in S. fredii and S. sp. III, but exhibited a more pleotropic role in symbiosis establishment. These findings highlighted the lineage-dependent optimization of symbiotic functions in different rhizobial species associated with the same host.


Impact of Ixekizumab on Work Productivity in Patients with Ankylosing Spondylitis: Results from the COAST-V and COAST-W Trials at 52 Weeks.
Patients with ankylosing spondylitis (AS) are burdened with symptoms impacting work productivity measured by presenteeism, absenteeism, overall work impairment, and activity impairment. Ixekizumab, a high-affinity monoclonal antibody selectively targeting interleukin-17A, has been demonstrated to improve disease signs and symptoms in two phase 3 trials of AS. This study investigated for 52 weeks the effect of ixekizumab treatment on work productivity in patients with active AS. COAST-V (NCT02696785) and COAST-W (NCT02696798) were phase 3, multicenter, randomized, controlled trials investigating the efficacy of ixekizumab 80 mg every 4 weeks (Q4W) and every 2 weeks (Q2W) in patients with AS naïve to biologic disease-modifying antirheumatic drugs (bDMARDs; COAST-V) or who were inadequate responders or intolerant to tumor necrosis factor inhibitors (TNFi; COAST-W). Work productivity was measured with the Work Productivity and Activity Impairment Questionnaire for Spondyloarthritis at weeks 16 and 52. Absenteeism, presenteeism, and overall work impairment were assessed for patients reporting paid work. Activity impairment was assessed regardless of work status. At baseline, 66.2% (434/656) of patients reported paid work. At week 16, bDMARD-naïve patients treated with both ixekizumab dose regimens and TNFi-experienced patients treated with ixekizumab Q2W reported significant improvements in activity impairment (p < 0.01 and p < 0.05, respectively). TNFi-experienced patients treated with ixekizumab showed significant improvements versus placebo in presenteeism and overall work impairment (p < 0.05); bDMARD-naïve patients had numeric improvements. After week 16, patients initially on placebo switched to ixekizumab and patients already treated with ixekizumab continued treatment. Improvements in work productivity and daily activity were sustained through week 52 for both bDMARD-experienced and -naïve patients. Both bDMARD-naïve and TNFi-experienced patients with AS had greater improvements in work productivity and activity impairment when receiving ixekizumab compared to placebo at week 16. Improvements in work productivity and activity impairment achieved at week 16 were sustained through week 52 with ixekizumab treatment.


Correlation between Vitamin D receptor gene FOKI and BSMI polymorphisms and the susceptibility to pulmonary tuberculosis in an Indonesian Batak-ethnic population.
To explore the role of FokI and BsmI polymorphisms the VDR gene in the susceptibility to pulmonary tuberculosis (PTB) in an Indonesian Batak ethnic population. Matched case-control study was conducted on 76 PTB patients and 76 healthy normal control. Genetic polymorphisms of Vitamin D Receptor (VDR) gene were analysed using PCR-RFLP. The frequencies of FokI genotypes were FF 35.5%, Ff 55.3%, ff 9.2% for PTB patients and FF 39.5%, Ff 44.7.% and ff 15.8% for normal control. The BsmI genotypes frequencies were BB 0%, Bb 68.4%, bb 31.6% for TB patients and BB 2.6%, Bb 23.7% and bb 73.7% for control. There was no significant association between FokI genotype and PTB (OR 1.39, 95% CI: 0.69-2.77 for Ff genotype and OR 0.64, 95% CI: 0.22-1.86 for ff genotype). There was a significant association between BsmI genotype and PTB; the bb genotype was associated with a decreased risk to PTB (OR 0.22, 95% CI: 0.11-0.45). In Indonesian Batak ethnic population, there was no association between FokI polymorphism of VDR gene with host susceptibility to PTB. There was a significant association between BsmI polymorphism of VDR gene; bb genotype was associated with a decreased risk to PTB.


Failure of vaccines to protect salmon from vibriosis enzootic in Puget Sound, Washington.
Juvenile chinook salmon in fresh water were vaccinated either orally or parenterally with heat- or formalin-killed bacterins prepared with Vibrio anguillarum. Subsequent exposure to naturally occuring vibriosis in the marine waters of Puget Sound (Washington State) indicated that no protection resulted. It was demonstrated, however, that protection could be achieved with the passive transfer of immune serum.


Glucose oxidase as label in histological immunoassays with enzyme-amplification in a two-step technique: coimmobilized horseradish peroxidase as secondary system enzyme for chromogen oxidation.
A sensitive staining procedure for glucose oxidase (GOD) as marker in immunohistology is described. The cytochemical procedure involves a two-step enzyme method in which GOD and horseradish peroxidase (HRP) are coimmobilized onto the same cellular sites by immunological bridging or by the principle of avidin-biotin interaction. In this coupled enzyme technique, H2O2 generated during GOD reaction is the substrate for HRP and is utilized for the oxidation of chromogens such as 3,3'-diaminobenzidine or 3-amino-9-ethylcarbazole. Due to the immobilization of the capture enzyme HRP in close proximity to the marker enzyme (GOD), more intense and specific staining is produced than can be obtained with soluble HRP as coupling enzyme in the substrate medium. Indirect antibody labelled and antibody bridge techniques including the avidin (streptavidin)-biotin principle have proven the usefulness of this GOD labelling procedure for antigen localization in paraffin sections. Antigens such as IgA in tonsil, alpha-fetoprotein in liver and tissue polypeptide antigen in mammary gland served as models. The immobilized two-step enzyme procedures have the same order of sensitivity and specificity as comparable immunoperoxidase methods. The coupled GOD-HRP principle can be superior to conventional immunoperoxidase labelling for the localization of biomolecules in tissue preparations rich in endogenous peroxidase activities.


A Novel del(20q) in Aggressive Nodal Marginal Zone Lymphoma.
This is a case report of a previously undescribed 20q chromosomal deletion (del(20q)) in marginal zone lymphoma (MZL). A 54-year-old Caucasian male presented with an enlarging neck mass and multiple violaceous skin nodules over his chest. Biopsy of the neck mass and cervical lymph nodes revealed MZL. Cytogenetic evaluation of both lymph node and bone marrow tissue revealed del(20q). This was an unexpected finding, as del(20q) is associated with myelodysplastic syndromes and myeloproliferative neoplasms and rarely seen in diffuse large B-cell lymphoma, follicular lymphoma, and T-cell lymphoma, but has not previously been described in MZL. We describe the case presentation and histologic findings and discuss the significance of this novel finding.


CRP Enhances the Innate Killing Mechanisms Phagocytosis and ROS Formation in a Conformation and Complement-Dependent Manner.
Phagocytosis and the formation of reactive oxygen species (ROS) in phagocytic leukocytes are an effective killing mechanism of the innate host defense. These cellular processes of innate immunity function in a complex interplay with humoral factors. C-reactive protein (CRP) in its activated, monomeric isoform (mCRP) has been shown to activate immune cells via the classical complement pathway. We investigated the complement-dependent effects of monomeric CRP (mCRP) on neutrophils and monocyte subtypes using complement-specific inhibitors by both flow cytometry and confocal fluorescence microscopy. We demonstrate that CRP-induced ROS generation is a conformation-specific and complement-dependent process in leukocyte subsets with classical monocytes as the primary source of ROS amongst human monocyte subsets. Elucidation of this complex interplay of CRP and complement in inflammation pathophysiology might help to improve anti-inflammatory therapeutic strategies.


Resveratrol-mediated reduction of collagen by inhibiting proliferation and producing apoptosis in human hypertrophic scar fibroblasts.
Hypertrophic scar (HS) is a dermal fibroproliferative disorder characterized by excessive deposition of extracellular matrix. Here, to investigate the regulative effects of resveratrol, a natural antioxidant compound, on fibroblasts from human skin HS tissue, a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay was used to evaluate the inhibitory effect of resveratrol on cells. Cellcycle progression and apoptosis were measured by flow cytometry and Hoechst 33258 staining respectively. The hydroxyproline content and mRNA expression levels of type I and III procollagen were measured separately by ELISA and reverse transcription-polymerase chain reaction (RT-PCR). The results indicated that resveratrol significantly inhibited cell growth, arresting the cell cycle at the G1 phase and inducing apoptosis in the fibroblasts, decreasing hydroxyproline (or collagen) levels, and downregulating the expression levels of type I and III procollagen mRNA. Taken together, these data indicate that resveratrol-mediated reduction of collagen in fibroblasts is at least partially effected by causing inhibitory cell growth, cellcycle arrest, and apoptosis, and they suggest that resveratrol is a potential agent for HS treatment.


Synthetic response of stimulated respiratory epithelium: modulation by prednisolone and iKK2 inhibition.
The airway epithelium plays a central role in wound repair and host defense and is implicated in the immunopathogenesis of asthma. Whether there are intrinsic differences between the synthetic capacity of epithelial cells derived from subjects with asthma and healthy control subjects and how this mediator release is modulated by antiinflammatory therapy remains uncertain. We sought to examine the synthetic function of epithelial cells from different locations in the airway tree from subjects with and without asthma and to determine the effects of antiinflammatory therapies upon this synthetic capacity. Primary epithelial cells were derived from 17 subjects with asthma and 16 control subjects. The release of 13 cytokines and chemokines from nasal, bronchial basal, and air-liquid interface differentiated epithelial cells before and after stimulation with IL-1β, IL-1β and interferon-γ, or Poly-IC (Toll-like receptor 3 agonist) was measured using MesoScale discovery or enzyme-linked immunosorbent assay, and the effects of prednisolone and an inhibitor of nuclear factor κ-B2 (IKK2i) were determined. The pattern of release of cytokines and chemokines was significantly different between nasal, bronchial basal, and differentiated epithelial cells but not between health and disease. Stimulation of the epithelial cells caused marked upregulation of most mediators, which were broadly corticosteroid unresponsive but attenuated by IKK2i. Synthetic capacity of primary airway epithelial cells varied between location and degree of differentiation but was not disease specific. Activation of epithelial cells by proinflammatory cytokines and toll-like receptor 3 agonism is attenuated by IKK2i, but not corticosteroids, suggesting that IKK2i may represent an important novel therapy for asthma.


Orthostatic intolerance and syncope associated with Chiari type I malformation.
The Chiari type I malformation (CM1) is characterized by herniation of cerebellar tonsils to at least 3-5 mm below the plane of foramen magnum and can present with a wide variety of clinical symptoms, frequently including occipital headaches, secondary to bulbar and/or medullary distress. Rarely, syncopal episodes have also been described and attributed to either compression of the midbrain ascending reticular system, or vascular compromise (vertebrobasilar artery compression, hypotension). We report the first case of a CM1 patient with frequently recurring syncope due to postural orthostatic tachycardia syndrome (POTS), a form of orthostatic intolerance, whose symptoms resolved completely after surgical intervention. It is important to stress that it is not clear whether the described association of POTS and CM1 in our patient is a fortuitous finding in an isolated case or a reflection of a more systematic association between the two pathologies.


Drive in the Moment: An evaluation of a web-based tool designed to reduce smartphone use among young drivers.
Young drivers are overrepresented in road traffic crashes and fatalities. Distracted driving, including use of a smartphone while driving (SWD), is a major risk factor for crashes for this age group. We evaluated a web-based tool (Drive in the Moment or DITM) designed to reduce SWD among young drivers. A pretest-posttest experimental design with a follow-up was used to assess the efficacy of the DITM intervention on SWD intentions and behaviors, and perceived risk (of having a crash and of being apprehended by the police) associated with SWD. One hundred and eighty young drivers (aged 17-25 years old) were randomly assigned to either the DITM intervention or a control group where participants completed an unrelated activity. Self-reported measures of SWD and perceptions of risk were obtained pre-intervention, immediately post-intervention and at a follow-up 25 days after the intervention. Participants who engaged with the DITM showed a significant reduction in the number of times they used their SWD at follow-up compared to their pre-intervention scores. Future intentions to SWD were also reduced from pre-intervention to post-intervention and follow-up. There was also an increase in the perceived risk of SWD following the intervention. Our evaluation of DITM suggests that the intervention had an impact on reducing SWD among young drivers. Further research is needed to establish which particular elements of the DITM are associated with reductions in SWD and whether similar findings would be identified in other age groups.


Asthma and Allergies in Children With Autism Spectrum Disorders: Results From the CHARGE Study.
Immune aberrations are often noted in children with autism spectrum disorder (ASD), but whether asthma and allergy are related to ASD is not well defined. This study examined asthma and allergies in association with ASD and phenotypic subsets. Participants were 560 children with confirmed ASD and 391 typically developing children from the CHildhood Autism Risks from Genetics and the Environment study. Maternally reported child asthma and allergy was compared between cases and controls, and in association with cognitive and behavioral test scores. Prevalence of asthma and overall allergies did not differ between cases and controls, but overall allergy in children with ASD was associated with higher stereotypy scores as measured by the Aberrant Behavior Checklist. In addition, reported food allergies were significantly associated with ASD (adjusted odds ratio = 2.23, 95% confidence interval 1.28, 3.89). Our results suggest food allergies and sensitivities may be more common in children with ASD, and that these issues may correlate with other behaviors.


[Recipient capacity of B. alcalescens strains in the conjugation transfer of R-factors to them for E. coli strains].
Unlike many enterobacteria the strains of B. alkalescens isolated from patients with the intestine dysfunction and healthy persons preserved sensitivity to the antibiotics used in the medical practice. This served as a basis for the study of the recipient competence for reception of R-factors from E. coli by 6 strains of the alkali producer. The strains of E. coli with the derepressive R-factors J 5-3 R1, J 5-3 R64 and CSH-2 R1-19 were introduced into the conjugation mixture as the donors. Only I strain of E. coli, i.e. J 5-3 R1 with multiple antibiotic resistance proved to be a competent donor. A possibility of transfering on1 I determinant of resistance (to neomycin) to 3 out of 6 strains of B. alkalescens at a low rate of10-7 and 10-9 was shown. The R+ conjugants appeared to be immune to further reception of R-factors of both the competent and the incompetent donors. The low recipient capacity of the strains of B. alkalescens must, to some extent promote circulation mainly of antibiotic sensitive strains of the microbes under natural conditions.


GRP78 Overexpression Triggers PINK1-IP3R-Mediated Neuroprotective Mitophagy.
An experimental model of spinal root avulsion (RA) is useful to study causal molecular programs that drive retrograde neurodegeneration after neuron-target disconnection. This neurodegenerative process shares common characteristics with neuronal disease-related processes such as the presence of endoplasmic reticulum (ER) stress and autophagy flux blockage. We previously found that the overexpression of GRP78 promoted motoneuronal neuroprotection after RA. After that, we aimed to unravel the underlying mechanism by carrying out a comparative unbiased proteomic analysis and pharmacological and genetic interventions. Unexpectedly, mitochondrial factors turned out to be most altered when GRP78 was overexpressed, and the abundance of engulfed mitochondria, a hallmark of mitophagy, was also observed by electronic microscopy in RA-injured motoneurons after GRP78 overexpression. In addition, GRP78 overexpression increased LC3-mitochondria tagging, promoted PINK1 translocation, mitophagy induction, and recovered mitochondrial function in ER-stressed cells. Lastly, we found that GRP78-promoted pro-survival mitophagy was mediated by PINK1 and IP3R in our in vitro model of motoneuronal death. This data indicates a novel relationship between the GRP78 chaperone and mitophagy, opening novel therapeutical options for drug design to achieve neuroprotection.


New approaches to the diagnosis of heparin-induced thrombocytopenia.
Heparin-induced thrombocytopenia (HIT) is a clinicopathologic syndrome that is most reliably diagnosed when a patient with a clinical scenario that is consistent with heparin-induced immunization is shown to have antiplatelet factor 4/heparin, platelet-activating IgG antibodies. A Bayesian diagnostic approach is discussed, wherein the physician estimates the pretest probability of HIT (eg, the timing and severity of thrombocytopenia in relation to heparin treatment and associated thrombosis) and determines the posttest probability using the results of HIT antibody testing. By this approach, the magnitude of a positive test result determines its likelihood ratio in influencing the posttest probability of HIT.


Interactions of sodium-proton exchange mechanism in dog red blood cells with N-phenylmaleimide.
Dog red blood cells (RBC) have a Na-H exchanger that is reversibly activated by cell shrinkage. The Na-H exchanger can be fixed in the on or off mode by treating the cells with N-phenylmaleimide. This action depends on the volume of the cells at the time of exposure to N-phenylmaleimide and also on the concentration of the reagent per number of cells. If the cells are swollen in hypotonic media during N-phenylmaleimide exposure, the Na-H exchanger becomes irreversibly inactivated, so that on subsequent shrinkage of the cells, no amiloride-sensitive Na flux is seen. This effect is maximal at N-phenylmaleimide concentrations of greater than 20 mumol/g hemoglobin. If the cells are shrunken in hypertonic media during N-phenylmaleimide exposure, the response of the Na-H exchanger depends critically on the concentration of the reagent. At N-phenylmaleimide concentrations of less than 20 mumol/g hemoglobin, the Na-H exchanger is fixed in the activated state, so that even when the volume stimulus is removed by subsequent cell swelling, an amiloride-sensitive flux is seen. Higher concentrations of N-phenylmaleimide applied to shrunken cells inhibit the Na-H exchanger. The results are accounted for in a model that envisions a volume-responsive switching mechanism for Na-H exchange that has two functional groups capable of reacting with N-phenylmaleimide. The accessibility of these groups is determined by cell volume.


Alteration of Chain Length Selectivity of Candida antarctica Lipase A by Semi-Rational Design for the Enrichment of Erucic and Gondoic Fatty Acids.
Biotechnological strategies using renewable materials as starting substrates are a promising alternative to traditional oleochemical processes for the isolation of different fatty acids. Among them, long chain mono-unsaturated fatty acids are especially interesting in industrial lipid modification, since they are precursors of several economically relevant products, including detergents, plastics and lubricants. Therefore, the aim of this study was to develop an enzymatic method in order to increase the percentage of long chain mono-unsaturated fatty acids from Camelina and Crambe oil ethyl ester derivatives, by using selective lipases. Specifically, the focus was on the enrichment of gondoic (C20:1 cisΔ11) and erucic acid (C22:1 cisΔ13) from Camelina and Crambe oil derivatives, respectively. The pursuit of this goal entailed several steps, including: (i) the choice of a suitable lipase scaffold to serve as a protein engineering template (Candida antarctica lipase A); (ii) the identification of potential amino acid targets to disrupt the binding tunnel at the adequate location; (iii) the design, creation and high-throughput screening of lipase mutant libraries; (iv) the study of the selectivity towards different chain length p-nitrophenyl fatty acid esters of the best hits found, as well as the analysis of the contribution of each amino acid change and the outcome of combining several of the aforementioned residue alterations and, finally, (v) the selection and application of the most promising candidates for the fatty acid enrichment biocatalysis. As a result, enrichment of C22:1 from Crambe ethyl esters was achieved either, in the free fatty acid fraction (wt, 78%) or in the esterified fraction (variants V1, 77%; V9, 78% and V19, 74%). Concerning the enrichment of C20:1 when Camelina oil ethyl esters were used as substrate, the best variant was the single mutant V290W, which doubled its content in the esterified fraction from approximately 15% to 34%. A moderately lower increase was achieved by V9 and its two derived triple mutant variants V19 and V20 (27%).


Gastroenteritis in children under 5 years of age in England and Wales.
Gastroenteritis is a major cause of illness in young children worldwide. The magnitude of this problem is underestimated, as many cases may not present for medical treatment and many that do present are not asked to provide a faecal specimen. In this study, laboratory reports of pathogens responsible for gastroenteritis in children under 5 years in England and Wales reported to the PHLS Communicable Disease Surveillance Centre from January 1990 to December 1994 were analysed. These reports were compared with food poisoning notifications and mortality attributable to gastroenteritis collated by the Office of Population Censuses and Surveys in the same age group over the same period. Thirty-nine per cent of the 167630 laboratory faecal identifications were of rotavirus. Reports were commonest in children under 1 year of age during the winter months. Salmonellas and campylobacters were isolated from 16% and 15% of the specimens reported respectively. During the study period salmonella reporting rates rose by 48% in this age group. Improving the microbiological quality of food and raising standards of food hygiene, together with increasing parental awareness of the possibility of food poisoning in young children, will help to reduce morbidity in this age group. The majority of childhood deaths attributable to gastroenteritis were associated with rotavirus infection. The introduction of recently developed vaccines against rotavirus could substantially reduce the level of morbidity in this age group.


Intravitreal bevacizumab for retinal neovascularizations associated with myelinated nerve fibers.
To report the effects of intravitreal bevacizumab injection (IVBI) in a patient affected by retinal neovascularizations (RNVs) associated with myelinated nerve fibers (MNF) and complicated by vitreous hemorrhage. A 23-year-old female was referred because of sudden visual acuity deterioration in the left eye. Nine years earlier, the subject underwent retinal laser photocoagulation for recurrent vitreous hemorrhages related to the development of RNV associated with MNF. The ophthalmological evaluation revealed a new recurrence of vitreous hemorrhage associated with fluorescein leakage from RNV. After careful discussion, the patient underwent IVBI. One month after the injection, the best corrected visual acuity (BCVA) improved from 20/400 to 20/100, with a vitreous hemorrhage resolution, and cessation of fluorescein leakage. Over the 24-month follow-up, 2 additional IVBIs were administered due to further vitreous hemorrhage associated with fluorescein leakage from RNV, achieving a final BCVA of 20/80. IVBI may temporarily counteract the vascular hyperpermeability typical of RNV associated with MNF, leading to the cessation of fluorescein leakage, but does not result in RNV regression.


Investigation of feasibility of bamboo charcoal as solid-phase extraction adsorbent for the enrichment and determination of four phthalate esters in environmental water samples.
This paper demonstrates, for the first time, that adsorptive potential of bamboo charcoal for solid-phase extraction of phthalate esters was investigated. The four phthalate esters, dimethyl phthalate (DMP), diethyl phthalate (DEP), butyl benzyl phthalate (BBP) and di-n-butyl phthalate (DBP), are quantitatively adsorbed on a bamboo charcoal packed cartridge, then the analytes retained on the cartridge are quantitatively desorbed with optimum amounts of acetone. Finally, the analytes in the eluant acetone are determined by high-performance liquid chromatography-ultraviolet detectior. Important parameters influencing the extraction efficiency, such as eluant and its volume, flow rate of sample, sample volume, pH, the amount of adsorbent and ionic strength were investigated and optimized in detail. Under the optimum conditions, the limits of detection were 0.35-0.43 microg/L for four phthalate esters. The proposed method has been applied to the analysis of rainwater and tap water samples. And satisfactory spiked recoveries were obtained in the range of 75.0-114.2%. All the results indicated that the bamboo charcoal has great potential as a novel adsorbent material for the enrichment and determination of phthalate esters in real environmental water samples.


[Giant gastric ulcers].
In 43 patients with giant gastric ulcer treated in the last 20 years in the Centenario Hospital, Rosario, we have verified important loss of weight and high incidence of ulcer's complications. "Pseudotumoral ulcers" were present in 30% and carcinoma rate reached 7%. We emphasize the importance of histologic study of the ulcer.


HIV self-testing as part of a differentiated HIV testing approach: exploring urban and rural adult experiences from KwaZulu-Natal, South Africa using a cross-over study design.
Suboptimal HIV testing rates through available testing approaches such as HIV counselling and testing have directed research efforts toward recognizing the potential of HIV self-testing as an additional testing method. However, HIV self-testing is not readily available within HIV testing facilities and data on how HIV self-testing and HIV counselling and testing will co-exist within HIV testing facilities is limited. Therefore, this study sought to fill this knowledge gap. Forty consenting adults were exposed to HIV counselling and testing and HIV self-testing using a cross-over study design between February 2016 and February 2017 resulting in 80 (20,20) interviews. Participants were randomly exposed to HIV counselling and testing first, followed by self-testing, or HIV self-testing first, followed by counselling and testing. In-depth interviews were conducted at baseline, and after each testing exposure, using a semi-structured interview guide. Interviews were transcribed and translated prior to doing the framework analysis. Support through counselling played a central role in the HIV testing process for some participants who desired support or were not confident to perform unsupervised HIV self-testing. The complementary relationship between HIV self-testing and HIV counselling and testing requires a combination of benefits such as availability of counselling, confidence, convenience and confidentiality (4 Cs) derived from HIV self-testing and HIV counselling and testing. Implementation of the 4 Cs will depend on the availability of unsupervised HIV self-testing and/or supervised self-testing with support from HIV counselling and testing. As treatment and prevention efforts expand, the reasons for and frequency of testing is changing and there is a need to develop differentiated models for providing HIV testing services to meet client's needs. HIV self-testing is an important addition to enhance HIV testing efforts and should be offered in combination with HCT.


The Cancer Research Institute 2013 Annual Symposium: Dynamics of host-tumor interaction.
The 21st annual Cancer Research Institute (CRI) cancer immunotherapy symposium, entitled "Dynamics of Host-Tumor Interaction," was held in New York City from September 30 through October 2, 2013. The symposium comprised 27 presentations, organized into five sessions and exploring such topics as the role of chronic inflammation in creating a protumorigenic microenvironment, the interactions between the cancer stroma and immune cells in trafficking and cancer metastasis, the role of the host microbiota in immune responses to cancer, and the interactions between cancer cells and immunoregulatory elements, including regulatory T cells and T-cell checkpoint proteins. The conference began with a keynote address by Michael Karin, recipient of the 2013 Coley Award, who discussed the role of inflammation as a Janus-faced process in the body's fight against cancer-both tumor destroying and tumor promoting. The conference concluded with a session on therapeutics and translational research aimed at improving existing cancer immunotherapies.


Self-consistent nonlocal feedback theory for electrocatalytic swimmers with heterogeneous surface chemical kinetics.
We present a self-consistent nonlocal feedback theory for the phoretic propulsion mechanisms of electrocatalytic micromotors or nanomotors. These swimmers, such as bimetallic platinum and gold rods catalyzing decomposition of hydrogen peroxide in aqueous solution, have received considerable theoretical attention. In contrast, the heterogeneous electrochemical processes with nonlocal feedback that are the actual "engines" of such motors are relatively neglected. We present a flexible approach to these processes using bias potential as a control parameter field and a locally-open-circuit reference state, carried through in detail for a spherical motor. While the phenomenological flavor makes meaningful contact with experiment easier, required inputs can also conceivably come from, e.g., Frumkin-Butler-Volmer kinetics. Previously obtained results are recovered in the weak-heterogeneity limit and improved small-basis approximations tailored to structural heterogeneity are presented. Under the assumption of weak inhomogeneity, a scaling form is deduced for motor speed as a function of fuel concentration and swimmer size. We argue that this form should be robust and demonstrate a good fit to experimental data.


Pulse oximetry of body cavities and organs.
The focus of this paper will be in the development and in vivo applications of new custom made photoplethysmographic (PPG) and pulse oximetry optical and fiber optic sensors and instrumentation in an effort to investigate their suitability in the estimation of blood oxygen saturation and their contribution in the assessment of organ/tissue perfusion and viability. The paper describes the development of optical and fiber optic PPG and blood oxygen saturation (SpO2) sensors and covers examples of application areas including real-time PPG monitoring from body cavities (esophagus) and solid or hollow organs (bowel, liver, stomach, brain, etc). The clinical studies presented successfully demonstrated the feasibility in acquiring PPGs and estimating blood oxygen saturation values from a variety of organs and tissues. The technological developments and the measurements presented in this work pave the way in a new era of pulse oximetry where direct and continuous monitoring of blood oxygen saturation of internal organs and tissues could be made possible.


Social learning of vocal structure in a nonhuman primate?
Non-human primate communication is thought to be fundamentally different from human speech, mainly due to vast differences in vocal control. The lack of these abilities in non-human primates is especially striking if compared to some marine mammals and bird species, which has generated somewhat of an evolutionary conundrum. What are the biological roots and underlying evolutionary pressures of the human ability to voluntarily control sound production and learn the vocal utterances of others? One hypothesis is that this capacity has evolved gradually in humans from an ancestral stage that resembled the vocal behavior of modern primates. Support for this has come from studies that have documented limited vocal flexibility and convergence in different primate species, typically in calls used during social interactions. The mechanisms underlying these patterns, however, are currently unknown. Specifically, it has been difficult to rule out explanations based on genetic relatedness, suggesting that such vocal flexibility may not be the result of social learning. To address this point, we compared the degree of acoustic similarity of contact calls in free-ranging Campbell's monkeys as a function of their social bonds and genetic relatedness. We calculated three different indices to compare the similarities between the calls' frequency contours, the duration of grooming interactions and the microsatellite-based genetic relatedness between partners. We found a significantly positive relation between bond strength and acoustic similarity that was independent of genetic relatedness. Genetic factors determine the general species-specific call repertoire of a primate species, while social factors can influence the fine structure of some the call types. The finding is in line with the more general hypothesis that human speech has evolved gradually from earlier primate-like vocal communication.


Thermal reactions of 7-d- and 8-d-bicyclo[4.2.0]oct-2-enes.
The gas phase thermal reactions exhibited by bicyclo[4.2.0]oct-2-ene and 7-d and 8-d analogues at 300 degrees C have been followed kinetically through GC and 2H NMR spectroscopic analyses. In contrast to the pattern of transformations exhibited by bicyclo[3.2.0]hept-2-ene and deuterium-labeled analogues, no reactions initiated by C1-C6 bond cleavage are seen, epimerization at C8 is much faster than [1,3] shifts leading to bicyclo[2.2.2]oct-2-ene, and the ratio of rate constants for [1,3] carbon migration with inversion versus migration with retention is approximately 1.4. Homolysis of C1-C8 to give a conformationally flexible diradical intermediate having a relatively long lifetime and multiple options for further reaction (re-formation of C1-C8 with or without net epimerization, fragmentation to 1,3-cyclohexadiene and ethylene, migration to the original C3 with inversion or retention) accords well with the observations. Clearly, orbital symmetry control does not govern stereochemistry for the [1,3] sigmatropic carbon shifts.


Thermodynamics of a Brownian particle in a nonconfining potential.
We consider the overdamped Brownian dynamics of a particle starting inside a square potential well which, upon exiting the well, experiences a flat potential where it is free to diffuse. We calculate the particle's probability distribution function (PDF) at coordinate x and time t, P(x,t), by solving the corresponding Smoluchowski equation. The solution is expressed by a multipole expansion, with each term decaying t^{1/2} faster than the previous one. At asymptotically large times, the PDF outside the well converges to the Gaussian PDF of a free Brownian particle. The average energy, which is proportional to the probability of finding the particle inside the well, diminishes as E∼1/t^{1/2}. Interestingly, we find that the free energy of the particle, F, approaches the free energy of a freely diffusing particle, F_{0}, as δF=F-F_{0}∼1/t, i.e., at a rate faster than E. We provide analytical and computational evidence that this scaling behavior of δF is a general feature of Brownian dynamics in nonconfining potential fields. Furthermore, we argue that δF represents a diminishing entropic component which is localized in the region of the potential, and which diffuses away with the spreading particle without being transferred to the heat bath.


Mechanisms of human immunodeficiency virus type 2 RNA packaging: efficient trans packaging and selection of RNA copackaging partners.
Human immunodeficiency virus type 2 (HIV-2) has been reported to have a distinct RNA packaging mechanism, referred to as cis packaging, in which Gag proteins package the RNA from which they were translated. We examined the progeny generated from dually infected cell lines that contain two HIV-2 proviruses, one with a wild-type gag/gag-pol and the other with a mutant gag that cannot express functional Gag/Gag-Pol. Viral titers and RNA analyses revealed that mutant viral RNAs can be packaged at efficiencies comparable to that of viral RNA from which wild-type Gag/Gag-Pol is translated. These results do not support the cis-packaging hypothesis but instead indicate that trans packaging is the major mechanism of HIV-2 RNA packaging. To further characterize the mechanisms of HIV-2 RNA packaging, we visualized HIV-2 RNA in individual particles by using fluorescent protein-tagged RNA-binding proteins that specifically recognize stem-loop motifs in the viral genomes, an assay termed single virion analysis. These studies revealed that >90% of the HIV-2 particles contained viral RNAs and that RNAs derived from different viruses were copackaged frequently. Furthermore, the frequencies of heterozygous particles in the viral population could be altered by changing a 6-nucleotide palindromic sequence at the 5'-untranslated region of the HIV-2 genome. This finding indicates that selection of copackaging RNA partners occurs prior to encapsidation and that HIV-2 Gag proteins primarily package one dimeric RNA rather than two monomeric RNAs. Additionally, single virion analyses demonstrated a similar RNA distribution in viral particles regardless of whether both viruses had a functional gag or one of the viruses had a nonfunctional gag, providing further support for the trans-packaging hypothesis. Together, these results revealed mechanisms of HIV-2 RNA packaging that are, contrary to previous studies, in many respects surprisingly similar to those of HIV-1.


Environmental implications of wireless technologies: news delivery and business meetings.
Wireless information technologies are providing new ways to communicate, and are one of several information and communication technologies touted as an opportunity to reduce society's overall environmental impacts. However, rigorous system-wide environmental impact comparisons of these technologies to the traditional applications they may replace have only recently been initiated, and the results have been mixed. In this paper, the environmental effects of two applications of wireless technologies are compared to those of conventional technologies for which they can substitute. First, reading newspaper content on a personal digital assistant (PDA) is compared to the traditional way of reading a newspaper. Second, wireless teleconferencing is compared to business travel. The results show that for both comparisons wireless technologies create lower environmental impacts. Compared to reading a newspaper, receiving the news on a PDA wirelessly results in the release of 32-140 times less CO2, several orders of magnitude less NOx and SOx, and the use of 26-67 times less water. Wireless teleconferencing results in 1-3 orders of magnitude lower CO2, NOx, and SO2 emissions than business travel.


Assessing family history of chronic disease in primary care: Prevalence, documentation, and appropriate screening.
To assess the proportion of primary care patients who report a family history (FH) of type 2 diabetes, coronary artery disease, breast cancer, or colorectal cancer (CRC); assess concordance of FH information derived from the electronic medical record (EMR) compared with patient-completed health questionnaires; and assess whether appropriate screening was informed by risk based solely on FH. Data from the BETTER (Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Primary Care) trial were used. Patients were mailed questionnaires. Baseline FH and screening data were obtained for enrolled patients from the EMR and health questionnaires. Ontario and Alberta. Randomly selected patients from 8 family practices. Agreement on FH between the EMR and questionnaire was determined; logistic regression was used to assess significant predictors of screening. In total, 775 of 789 (98%) patients completed the health questionnaire. The mean age of participants was 52.5 years and 72% were female. A minimum of 12% of patients (range 12% to 36%) had a reported FH of 1 of 4 chronic diseases. Among patients with positive FH, the following proportions of patients had that FH recorded in the EMR compared with the questionnaire: diabetes, 24% in the EMR versus 36% on the questionnaire, κ = 0.466; coronary artery disease, 35% in the EMR versus 22% on the questionnaire, κ = 0.225; breast cancer, 21% in the EMR versus 22% on the questionnaire, κ = 0.241; and CRC, 12% in the EMR versus 14% on the questionnaire, κ = 0.510. There was moderate agreement for diabetes and CRC. The presence of FH was a significant predictor of CRC screening (odds ratio 1.9, 95% CI 1.1 to 3.1). A moderate prevalence of FH was found for 4 conditions for which screening recommendations vary with risk based on FH. Having patients self-complete an FH was thought to be feasible; however, questions about FH accuracy and completeness from both self-report and EMR remain. Work is needed to determine how to facilitate the adoption of FH tools into practice as well as strategies linking familial risk to appropriate screening.Trial registration number ISRCTN07170460 (ISRCTN Registry).


Effects of work-related sleep restriction on acute physiological and psychological stress responses and their interactions: A review among emergency service personnel.
Emergency work can expose personnel to sleep restriction. Inadequate amounts of sleep can negatively affect physiological and psychological stress responses. This review critiqued the emergency service literature (e.g., firefighting, police/law enforcement, defense forces, ambulance/paramedic personnel) that has investigated the effect of sleep restriction on hormonal, inflammatory and psychological responses. Furthermore, it investigated if a psycho-physiological approach can help contextualize the significance of such responses to assist emergency service agencies monitor the health of their personnel. The available literature suggests that sleep restriction across multiple work days can disrupt cytokine and cortisol levels, deteriorate mood and elicit simultaneous physiological and psychological responses. However, research concerning the interaction between such responses is limited and inconclusive. Therefore, it is unknown if a psycho-physiological relationship exists and as a result, it is currently not feasible for agencies to monitor sleep restriction related stress based on psycho- physiological interactions. Sleep restriction does however, appear to be a major stressor contributing to physiological and psychological responses and thus, warrants further investigation.


Growth of the unilateral cleft lip.
Growth discrepancies have frequently been noted following surgery for the repair of clefts of the lip. A long lip is often noted months or years after LeMesurier, Tennison, or Asensio repair, whereas a short lip is noted after the Millard repair. We evaluated the problem by measuring 112 unrepaired unilateral completed cleft lips in a homogeneous population. Patients of all ages from newborn through adults were included. The study showed that a cleft lip has ten to twenty per cent greater growth in the transverse direction parallel with the orbicularis muscle than in the vertical direction perpendicular to the muscle. Thus, procedures such as those of LeMesurier and Asensio that transpose tissue from transverse to vertical will lead to excessive vertical growth. Lip growth is slightly decreased along the cleft margins but does not account for the short lip seen after the original Millard repair. Lip shortness occurs soon after repair because of scar contracture but tends to resolve with the passage of time.


Quality of life and sexual function of naturally postmenopausal women on an ultralow-concentration estriol vaginal gel.
This study aims to evaluate the sexual function and quality of life (QoL) of naturally postmenopausal women affected by genitourinary syndrome of menopause who were treated with an ultralow-concentration estriol vaginal gel (0.005%). Postmenopausal women with vulvovaginal atrophy symptoms and sexual disorders were enrolled in a case-control study. Women were treated with vaginal gel (containing 50 μg of estriol) daily for 3 weeks and then twice weekly up to 12 weeks. Determination of vaginal maturation index, evaluation of vaginal pH, and assessment of vaginal atrophy symptoms were carried out. QoL, sexual function, and distress were investigated using the Short Form 36, Female Sexual Function Index, and Female Sexual Distress Scale questionnaires. Changes between baseline and week 12 were assessed. Sixty-eight women were included in the study group, and 42 women were included in the control group. Women on estriol vaginal gel had a significant increase in vaginal maturation index and improvement of vaginal pH compared with baseline (P < 0.05). Mean total Female Sexual Function Index score improved, and Female Sexual Distress Scale score decreased from baseline to follow-up. Results from the Short Form 36 questionnaire showed a significant improvement in the overall index of somatic aspects (P < 0.05). The control group showed no changes from baseline evaluation (P = NS). Estriol vaginal gel (0.005%) therapy significantly improves the trophism of the vaginal mucosa and the sexual health and QoL of naturally postmenopausal women. These results confirm that low doses of vaginal estrogen must be considered as the first choice for the initial treatment of postmenopausal genitourinary symptoms.


Cardiac study in thalassemic children.
Cardiac function was studied in 54 thalassemic children, aged 3 to 18 years. Abnormalities were found by echocardiography in 58%, by electrocardiography in 15%, and by chest film cardiomegaly in 24%. There was a correlation between the severity of anemia and the degree of cardiomegaly.


African trypanosomes.
African trypanosomes cause human African trypanosomiasis and animal African trypanosomiasis. They are transmitted by tsetse flies in sub-Saharan Africa. Although most famous for their mechanisms of immune evasion by antigenic variation, there have been recent important studies that illuminate important aspects of the biology of these parasites both in their mammalian host and during passage through their tsetse fly vector. This Primer overviews current research themes focused on these parasites and discusses how these biological insights and the development of new technologies to interrogate gene function are being used in the search for new approaches to control the parasite. The new insights into the biology of trypanosomes in their host and vector highlight that we are in a 'golden age' of discovery for these fascinating parasites.


Randomized, double-blind trial of an antibiotic-lock technique for prevention of gram-positive central venous catheter-related infection in neutropenic patients with cancer.
The aim of the present study was to determine the efficacy of an antibiotic-lock technique in preventing endoluminal catheter-related infection with gram-positive bacteria in neutropenic patients with hematologic malignancies. Patients with nontunneled, multilumen central venous catheters were assigned in a randomized, double-blinded manner to receive either 10 U of heparin per ml (57 patients) or 10 U of heparin per ml and 25 microg of vancomycin per ml (60 patients), which were instilled in the catheter lumen and which were allowed to dwell in the catheter lumen for 1 h every 2 days. Insertion-site and hub swabs were taken twice weekly. The primary and secondary end points of the trial were significant colonization of the catheter hub and catheter-related bacteremia, respectively. Significant colonization of the catheter hub occurred in nine (15.8%) patients receiving heparin (seven patients were colonized with Staphylococcus epidermidis, one patient was colonized with Staphylococcus capitis, and one patient was colonized with Corynebacterium sp.), whereas the catheter hubs of none of the patients receiving heparin and vancomycin were colonized (P = 0.001). Catheter-related bacteremia developed in four (7%) patients receiving heparin (three patients had S. epidermidis bacteremia and one patient had S. capitis bacteremia), whereas none of the patients in the heparin and vancomycin group had catheter-related bacteremia (P = 0.05). The times to catheter hub colonization and to catheter-related bacteremia by the Kaplan-Meier method were longer in patients receiving heparin and vancomycin than in patients receiving heparin alone (P = 0.004 and P = 0.06, respectively). Our study shows that a solution containing heparin and vancomycin administered by using an antibiotic-lock technique effectively prevents catheter hub colonization with gram-positive bacteria and subsequent bacteremia during chemotherapy-induced neutropenia in patients with hematologic malignancy.


Assessment of systemic inflammatory response index and other inflammatory indicators in retinal vein occlusion.
Retinal vein occlusion (RVO) is the second most common retinal vascular disease after diabetic retinopathy. The study aimed to evaluate the association and the predictive value of inflammatory indicators in RVO. Sixty patients with RVO and 60 healthy individuals were enrolled in this retrospective study. Inflammatory indicators and other hematological parameters obtained from the peripheral venous sample were analyzed and compared among groups. White blood cell count (P = .003), neutrophil (P < .001), neutrophil-to-lymphocyte ratio (NLR) (P < .001), monocyte-to-lymphocyte ratio (MLR) (P < .001), platelet-to-lymphocyte ratio (PLR) (P = .014), systemic immune-inflammation index (SII) (P < .001), and systemic inflammatory response index (SIRI) (P < .001) were significantly higher; the lymphocyte count (P < .001) was significantly lower in patients with RVO. According to receiver operating characteristic analysis, NLR was significant at the good level (area under the curve [AUC] = 0.817, P < .001); SIRI, SII, and MLR were significant at the fair level (AUC = 0.774, P < .001; AUC = 0.733, P < .001, and AUC = 0.724, P < .001, respectively) and PLR (AUC = 0.630, P = .014) was significant at the weak level in terms of RVO prediction. SIRI was superior to other indicators, except NLR, to predict RVO. SIRI, NLR, SII, MLR, and PLR can be used as predictors for identifying the risk of RVO.


The impact of childhood maltreatment: a review of neurobiological and genetic factors.
Childhood maltreatment represents a significant risk factor for psychopathology. Recent research has begun to examine both the functional and structural neurobiological correlates of adverse care-giving experiences, including maltreatment, and how these might impact on a child's psychological and emotional development. The relationship between such experiences and risk for psychopathology has been shown to vary as a function of genetic factors. In this review we begin by providing a brief overview of neuroendocrine findings, which indicate an association between maltreatment and atypical development of the hypothalamic-pituitary-adrenal axis stress response, which may predispose to psychiatric vulnerability in adulthood. We then selectively review the magnetic resonance imaging (MRI) studies that have investigated possible structural and functional brain differences in children and adults who have experienced childhood maltreatment. Differences in the corpus callosum identified by structural MRI have now been reliably reported in children who have experienced abuse, while differences in the hippocampus have been reported in adults with childhood histories of maltreatment. In addition, there is preliminary evidence from functional MRI studies of adults who have experienced childhood maltreatment of amygdala hyperactivity and atypical activation of frontal regions. These functional differences can be partly understood in the context of the information biases observed in event-related potential and behavioral studies of physically abused children. Finally we consider research that has indicated that the effect of environmental adversity may be moderated by genotype, reviewing pertinent studies pointing to gene by environment interactions. We conclude by exploring the extent to which the growing evidence base in relation to neurobiological and genetic research may be relevant to clinical practice and intervention.


Machine learning applied in patient-reported outcome research-exploring symptoms in adjuvant treatment of breast cancer.
Patient-reported outcome (PRO) data may help us better understand the life of breast cancer patients. We have previously collected PRO data in a national Danish breast cancer study in patients undergoing adjuvant chemotherapy. The aim of the present post-hoc explorative study is to apply Machine Learning (ML) algorithms using permutation importance to explore how specific PRO symptoms influence nonadherence to six cycles of planned adjuvant chemotherapy in breast cancer patients. We here investigate ePRO-data from the 347 patients. The ePRO presented 42 PROCTCAE questions on 25 symptoms. Patients completed the ePRO before each cycle of chemotherapy. Number of patients with completion of the scheduled six cycles of chemotherapy were registered. Two ML models were applied. One aimed at discovering the individual relative importance of the different questions in the dataset while the second aimed at discovering the relationships between the questions. Permutation importance was used. Out of 347 patients 238 patients remained in the final dataset, 15 patients dropped out. Two symptoms: aching joints and numbness/tingling, were the most important for dropout in the final dataset, each with an importance value of about 0.04. Model's average ROC-AUC-score being 0.706. In the second model a low performance score made the results very unreliable. In conclusion, this explorative data analysis using ML methodologies in an ePRO dataset from a population of women with breast cancer treated with adjuvant chemotherapy unravels that the symptoms aching joints and numbness/tingling could be important for drop out of planned adjuvant chemotherapy.


Impact of the Hydraulic Fracturing on Indoor Radon Concentrations in Ohio: A Multilevel Modeling Approach.
According to the United States Environmental Protection Agency (U.S. EPA), exposure to radon gas is the second leading cause of lung cancer after smoking. Extant research that has reported that fracking activity increases the radon levels. "Fracking" also known as hydraulic fracturing, which is a technology that is used to extract naturally occurring shale gas from the Marcellus and the Utica shales. Based on the data from the Ohio Radon Information System (ORIS) from 2007 to 2014 in Ohio, this research uses multilevel modeling (MLM) to examine the association between the incidences of hydraulic fracturing and elevated airborne radon levels. The ORIS data include information on 118,421 individual records of households geocoded to zip code areas. Individual records include radon concentrations, device types of the test, and seasons. Euclidean distances between zip code centroid to the 1,162 fracking wells are measured at the zip code level. Two additional zip code variables, namely the population density and urbanicity, are also included as control variables. Multilevel modeling results show that at the zip code level, distance to fracking wells and population density are significant and negative covariate of the radon concentration. By comparing with urban areas, urban clusters, and rural areas are significant which linked to higher radon concentrations. These findings lend support to the effect of hydraulic fracturing in influencing radon concentrations, and promote public policies that need to be geographically adaptable.


Comparison of the effect of nonactivated self-adjusting file system, Vibringe, EndoVac, ultrasonic and needle irrigation on apical extrusion of debris.
To compare the effects of Vibringe, EndoVac, nonactivated SAF and passive ultrasonic irrigation (PUI) with a conventional syringe on the amount of apically extruded debris. Seventy-five extracted human maxillary incisors were selected and randomly assigned to 5 groups (n = 15). The root canals were irrigated with Vibringe (Vibringe B. V. Corp, Amsterdam, Netherlands), EndoVac (Discus Dental, Smart Endodontics, Culver City, CA, USA), nonactivated SAF (ReDent-Nova, Ra'anana, Israel), passive ultrasonic irrigation (PUI) and conventional syringe. Distilled water was used as an irrigant, and debris was collected in pre-weighed glass vials. The tubes were then stored in an incubator at 37 °C for 10 days to evaporate the irrigant before weighing the dry debris. The mean weight of debris was assessed, and one-way analysis of variance was used for comparison of values and post hoc Tukey's test was used between groups (P = 0.05). The SAF group extruded significantly less debris than PUI and Vibringe groups (P < 0.05). There were no significant difference between needle, Vibringe and EndoVac groups (P > 0.05). All irrigation systems were associated with apical extrusion of debris. Nonactivated SAF extruded significantly less than Vibringe, EndoVac, passive ultrasonic and syringe irrigation.


Safety and efficacy of topical mitomycin C in myringotomy patency.
To develop an alternative method for prolonged middle ear ventilation using topical mitomycin C. Twenty guinea pigs with normal ears had bilateral myringotomies performed using the argon laser. After myringotomy, either mitomycin C (0.4 mg/mL) or saline pledgets were applied topically. Monitoring consisted of otomicroscopy and distortion-product otoacoustic emissions. Before myringotomy, all tympanic membranes were intact, and distortion-product otoacoustic emissions were measurable. After myringotomy, none (0%) of the saline-treated myringotomies were patent at day 7 as compared with 100% of the mitomycin C-treated myringotomies. At day 42, 10 (52.6%) of 19 mitomycin-treated myringotomies remained patent and 4 (28.6%) of 14 were patent at 131 days. Five (13.1%) ears developed purulent otorrhea; 3 were mitomycin C-treated and 2 were treated with saline solution.- Distortion-product otoacoustic emissions testing did not document any evidence of ototoxicity. Topical mitomycin C appears to be safe and effective at prolonging the duration of myringotomy patency in the guinea pig. Mitomycin C may be useful as an adjunct for preventing myringotomy closure.


Summation effects in receptive fields of the cat's pretectal neurons to stationary and moving visual stimuli.
1. Numerous investigations have shown that the cat's pretectal region (PR) is involved in performance of various visual habits, visually guided behaviour and learning processes. Thus, visually driven PR neurons must have abilities to integrate incoming sensory information. 2. Responses of 102 PR neurons to moving and stationary visual stimuli were investigated in cats. Special attention was paid to the comparative characteristics of summation processes in the same neuron elicited by stationary and moving visual stimuli. 3. The results indicate that only a small proportion (20%) of pretectal neurons revealed similar courses of summation for stationary and moving stimuli. The great majority of neurons (about 80%) showed differentiated courses of summation, depending on the type of visual stimuli used. 4. These data indicate that there are probably discrete mechanisms in the PR which contribute to integration of sensory information in the visually sensitive cells according to the different types of visual stimuli used.


Retroperitoneal vascular surgery for the treatment of giant growing teratoma syndrome.
To evaluate whether an aggressive surgical policy, which included vascular surgery with standard retroperitoneal lymph node dissection (RPLND), would be justified for managing bulky retroperitoneal growing teratoma syndrome (GTS). Data were collected retrospectively from a series of 12 patients who, from 1992 to 2010, underwent radical RPLND for bulky GTS (retroperitoneal mass≥10 cm in diameter). For complete resection, vascular procedures and nephrectomy were performed. Median tumor diameter was 100 mm before and 140 mm (range 100-300) after chemotherapy. Two patients underwent iterative RPLND. In addition to RPLND, patients underwent aortic section with aortic anastomosis (n=6), inferior vena cava resection (n=3), both the latter and the former (n=1), and aortic graft with left nephrectomy (n=2). There were no operative deaths; 3 patients had complications (25%), but none were related to extended procedures. The median hospital stay was 15 days. Median follow up was 59 months (range 10-162). One patient died of metastatic cutaneous melanoma 112 months after RPLND, 10 patients survived and are disease-free, and one patient had a para-aortic recurrence. A 100% complete resection rate, long-term survival, no mortality, and acceptable morbidity were achieved when vascular surgery and left nephrectomy were combined with standard RPLND for bulky GTS.


Evidence for sterol-independent regulation of low-density lipoprotein receptor activity in Hep-G2 cells.
The relationship between the serum factor(s)-mediated induction of low-density lipoprotein (LDL) receptor activity and changes in cellular cholesterol metabolism was examined in the human hepatoma cell line Hep-G2. Relative to incubation with serum-free media [Eagle's minimal essential medium (MEM) control], short-term (less than 8 h) incubation with medium containing 15% of either calf serum (MEM + serum) or the d greater than 1.25 fraction of calf serum (MEM + d greater than 1.25) produced a time- and concentration-dependent increase in the uptake of 125I-LDL. Immunoblotting with anti-(LDL receptor) antibodies demonstrated that this was correlated with a 2-fold increase in the amount of the mature 136,000 Da LDL receptor protein in detergent-solubilized Hep-G2 cell membranes. Incubation with MEM + serum, but not MEM + d greater than 1.25, increased the efflux of radiolabelled cholesterol from Hep-G2 cells. However, the induction of 125I-LDL uptake by MEM + d greater than 1.25 (2.3-fold) and MEM + serum (2.2-fold) was virtually identical. Addition of the d less than 1.063 lipoproteins of calf serum to MEM + d greater than 1.25 at their original or three times their serum concentration decreased the induction of 125I-LDL uptake by MEM + d greater than 1.25 by only 20-30%. Together, these results suggest that the stimulation of 125I-LDL uptake was not due to the presence of high-density lipoprotein, the absence of LDL or the stimulation of cholesterol efflux. MEM + serum stimulated 125I-LDL uptake in cells cholesterol-loaded by incubation with rat very-low-density lipoprotein with beta electrophoretic mobility (beta-VLDL). Compared to incubation with the MEM control, either MEM + serum or MEM + d greater than 1.25 produced time-dependent increases in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase which also occurred in cholesterol-loaded cells. However, cholesterol biosynthesis, whether measured from 3H2O, [14C]acetate or [3H]mevalonic acid, was not increased. Incubation with MEM + serum or MEM + d greater than 1.25 did not affect [3H]oleate incorporation into cellular cholesteryl esters, hydrolysis of intracellular [3H]cholesteryl esters or the cellular mass of unesterified or esterified cholesterol. Incubation with MEM + serum or MEM + d greater than 1.25 produced a transient increase in the level of LDL receptor mRNA, reaching a maximum of 5-10-fold by 2 h and decreasing to near baseline levels by 4 h. Actinomycin D blocked the serum-factor-mediated induction of LDL receptor mRNA.(ABSTRACT TRUNCATED AT 400 WORDS)


Trends in mortality rates comparing underlying-cause and multiple-cause coding in an English population 1979-1998.
Until recently, national coding and analysis of routine mortality statistics in most countries included only underlying cause of death. There were changes in the rules for selection and coding of underlying cause in England in 1984 and 1993. We report on trends in mortality rates in an English region from 1979 to 1998, comparing multiple-cause and underlying-cause coded rates, for individual diseases that were affected by coding changes. Among many others, these include pneumonia, venous thromboembolism, heart failure, respiratory distress syndrome, tuberculosis, diabetes, dementia, alcohol and drug abuse, epilepsy, multiple sclerosis, stroke, asthma, peptic ulcer, appendicitis, and cancers of the breast, colon and prostate. Comparisons over time of mortality rates based on underlying cause alone will be misleading when the time-period crosses years in which rules changed for selecting underlying cause.


Data processing method for the determination of accurate molecular weight distribution of polymers by SEC/MALDI-MS.
A novel data processing method for a hyphenated technique, size exclusion chromatography/matrix-assisted laser desorption/ionization-mass spectrometry (SEC/MALDI-MS), has been proposed to determine accurate molecular weight distributions on the basis of the individual oligomer species of a polymer. This method is based on the concept that the individual peak intensities of MALDI mass spectrum observed for every SEC fraction with narrow molecular weight distribution could be adjusted to the quantified values to reveal the accurate molecular weight distribution using the signal intensity of the corresponding fraction on the SEC chromatogram observed with a refractive index detector. At first, the theory of the proposed date processing is described in detail. Then, experimental verification of the method is described. This was performed through the characterization of mixtures of three kinds of monodispersed polystyrene reference materials (weight average molecular weight = ca. 6000, 10000, and 18000) as model samples. An accurate trimodal molecular weight distribution for the individual oligomer species of the sample was obtained without any influence of the chromatographic band broadening observed in the original SEC chromatogram. Moreover, the method for depicting the elution profiles of individual oligomer species during SEC separation was also obtained as a "mass chromatogram" using the data processing procedure.


Validation of the European Laryngological Society classification of glottic vascular changes as seen by narrow band imaging in the optical biopsy setting.
In 2016, the European Laryngological Society (ELS) proposed a classification for vascular changes occurring in glottic lesions as visible by narrow band imaging (NBI), based on the dichotomic distinction between longitudinal vessels (not suspicious) and perpendicular ones (suspicious). The aim of our study was to validate this classification assessing the interobserver agreement and diagnostic test performance in detecting the final histopathology. A retrospective study was carried out by reviewing clinical charts, preoperative videos, and final pathologic diagnosis of patients submitted to transoral microsurgery for laryngeal lesions in two Italian referral centers. In each institution, two physicians, independently re-assessed each case applying the ELS classification. The cohort was composed of 707 patients. The pathologic report showed benign lesions in 208 (29.5%) cases, papillomatosis in 34 (4.8%), squamous intraepithelial neoplasia (SIN) up to carcinoma in situ in 200 (28.2%), and squamous cell carcinoma (SCC) in 265 (37.5%). The interobserver agreement was extremely high in both institutions (k = 0.954, p < 0.001 and k = 0.880, p < 0.001). Considering the diagnostic performance for identification of at least SIN or SCC, the sensitivity was 0.804 and 0.902, the specificity 0.793 and 0.581, the positive predictive value 0.882 and 0.564, and the negative predictive value 0.678 and 0.908, respectively. The ELS classification for NBI vascular changes of glottic lesions is a highly reliable tool whose systematic use allows a better diagnostic evaluation of suspicious laryngeal lesions, reliably distinguishing benign ones from those with a diagnosis of papillomatosis, SIN or SCC, thus paving the way towards confirmation of the optical biopsy concept.


Core-Shell ZIF-8@ZIF-67-Derived Cobalt Nanoparticle-Embedded Nanocage Electrocatalyst with Excellent Oxygen Reduction Performance for Zn-Air Batteries.
Metal-nitrogen-carbon (M-N-C) catalysts obtained from zeolitic imidazolate frameworks (ZIFs) have great potential in the oxygen reduction reaction (ORR). Herein, based on the same three-dimensional (3D) topological structure of ZIF-67 and ZIF-8, ZIF-67 is grown on the ZIF-8 surface by the epitaxial growth method, and ZIF-8 is used as a sacrificial template to obtain a Co-embedded layered porous carbon nanocage (CoPCN) electrocatalyst. Meanwhile, the self-sacrificing template effectively improves the specific surface area of the porous structure and reduces the depletion of active sites. The CoPCN shows a high half-wave potential of 0.885 V and superior stability as well as excellent methanol resistance. Theoretical calculations demonstrate that the Co-N1-C2 sites of CoPCN effectively reduce the energy barrier of ORR. In addition, a zinc-air battery (ZAB) based on the CoPCN exhibits excellent peak power density (90 mW cm-2) and superior cycle performance. This work presents a novel idea in the design of ZIF precursor systems to synthesize efficient ORR catalysts.


Focused transcription from the human CR2/CD21 core promoter is regulated by synergistic activity of TATA and Initiator elements in mature B cells.
Complement receptor 2 (CR2/CD21) is predominantly expressed on the surface of mature B cells where it forms part of a coreceptor complex that functions, in part, to modulate B-cell receptor signal strength. CR2/CD21 expression is tightly regulated throughout B-cell development such that CR2/CD21 cannot be detected on pre-B or terminally differentiated plasma cells. CR2/CD21 expression is upregulated at B-cell maturation and can be induced by IL-4 and CD40 signaling pathways. We have previously characterized elements in the proximal promoter and first intron of CR2/CD21 that are involved in regulating basal and tissue-specific expression. We now extend these analyses to the CR2/CD21 core promoter. We show that in mature B cells, CR2/CD21 transcription proceeds from a focused TSS regulated by a non-consensus TATA box, an initiator element and a downstream promoter element. Furthermore, occupancy of the general transcriptional machinery in pre-B versus mature B-cell lines correlate with CR2/CD21 expression level and indicate that promoter accessibility must switch from inactive to active during the transitional B-cell window.


[The ABC of smoking cessation].
The professional support increased chances of success for smoking cessation and is an important goal in health politics. A short advice by pharmacists can make a significant contribution to this. This article describes tobacco dependence and the "stages of change-model". Afterwards we explain possible therapies: besides cognitive-behavioral intervention, different forms of medical treatment, e.g. nicotin replacement therapy, bupropion and varenicline, will be discussed.


Who are the support persons of haematological cancer survivors and how is their performance perceived?
To explore: (1) how haematological cancer survivors and their support persons perceive the overall performance of the support person; (2) disagreement between survivor and support person ratings; and (3) characteristics associated with support persons rating their performance poorly. This is a substudy of a larger project of Australian haematological cancer survivors and their support persons. For this substudy, haematological cancer survivors were recruited from 4 Australian population-based cancer registries and asked to pass on a questionnaire package to their support persons. Survivors who passed on a questionnaire package to their support person were asked to answer questions about the support person and how they perceived the support person's performance. Similarly, support persons answered questions on their own performance as a support person. A total of 924 haematological cancer survivors and 821 support persons were eligible for this study. Most survivors rated their support person as performing very well (84%) while less than half (48%) of support persons rated their own performance as very well. There was significant disagreement between survivor and their support person (dyad) ratings of the support person's performance. Support persons with above normal levels of depression (vs those with normal levels) had significantly higher odds of rating their own performance as "not well/somewhat well." Health care providers should consider providing additional education and skills-based interventions to support persons who experience increased symptoms of depression.


Nicotinamide n-Oxide Attenuates HSV-1-Induced Microglial Inflammation through Sirtuin-1/NF-κB Signaling.
HSV-1 is a typical neurotropic virus that infects the brain and causes keratitis, cold sores, and occasionally, acute herpes simplex encephalitis (HSE). The large amount of proinflammatory cytokines induced by HSV-1 infection is an important cause of neurotoxicity in the central nervous system (CNS). Microglia, as resident macrophages in CNS, are the first line of defense against neurotropic virus infection. Inhibiting the excessive production of inflammatory cytokines in overactivated microglia is a crucial strategy for the treatment of HSE. In the present study, we investigated the effect of nicotinamide n-oxide (NAMO), a metabolite mainly produced by gut microbe, on HSV-1-induced microglial inflammation and HSE. We found that NAMO significantly inhibits the production of cytokines induced by HSV-1 infection of microglia, such as IL-1β, IL-6, and TNF-α. In addition, NAMO promotes the transition of microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. More detailed studies revealed that NAMO enhances the expression of Sirtuin-1 and its deacetylase enzymatic activity, which in turn deacetylates the p65 subunit to inhibit NF-κB signaling, resulting in reduced inflammatory response and ameliorated HSE pathology. Therefore, Sirtuin-1/NF-κB axis may be promising therapeutic targets against HSV-1 infection-related diseases including HSE.


Effects of Commercial Apple Varieties on Human Gut Microbiota Composition and Metabolic Output Using an In Vitro Colonic Model.
Apples are a rich source of polyphenols and fiber. A major proportion of apple polyphenols escape absorption in the small intestine and together with non-digestible polysaccharides reach the colon, where they can serve as substrates for bacterial fermentation. Animal studies suggest a synergistic interaction between apple polyphenols and the soluble fiber pectin; however, the effects of whole apples on human gut microbiota are less extensively studied. Three commercial apple varieties-Renetta Canada, Golden Delicious and Pink Lady-were digested and fermented in vitro using a batch culture colonic model (pH 5.5-6.0, 37 °C) inoculated with feces from three healthy donors. Inulin and cellulose were used as a readily and a poorly fermentable plant fiber, respectively. Fecal microbiota composition was measured by 16S rRNA gene Illumina MiSeq sequencing (V3-V4 region) and Fluorescence in Situ Hybridization. Short chain fatty acids (SCFAs) and polyphenol microbial metabolites were determined. The three apple varieties significantly changed bacterial diversity, increased Actinobacteria relative abundance, acetate, propionate and total SCFAs (p < 0.05). Renetta Canada and Golden Delicious significantly decreased Bacteroidetes abundance and increased Proteobacteria proportion and bifidobacteria population (p < 0.05). Renetta Canada also increased Faecalibacterium prausnitzii, butyrate levels and polyphenol microbial metabolites (p < 0.05). Together, these data suggest that apples, particularly Renetta Canada, can induce substantial changes in microbiota composition and metabolic activity in vitro, which could be associated with potential benefits to human health. Human intervention studies are necessary to confirm these data and potential beneficial effects.


[The usefulness of ultrasonography in the diagnosis of acute appendicitis in children].
The main objective of the present report was the evaluation of the utility of echography as a diagnostic method in abdominal pain suspicious of acute appendicitis. A control-case study was performed in 165 children hospitalized for abdominal pain. Appendicitis histologically confirmed were considered cases (n = 110) while control (n = 55) were the not-operated patients (46 children) or the not-confirmed appendicitis after laparotomy (n = 9). The variables considered here were: the results of echography (Eco+ when echography showed signs of acute appendicitis: Eco- when not), the age of the patient (randomized at three groups; < 6, 6-9, > 9 years), and the conclusions of fisical exploration (conclusive or not as acute appendicitis). The results were analyzed statistically with the SPSS program, calculating the following predictive values; sensibility, specificity, positive predictive value, negative predictive value. Odds Radio before and after test and the global value of echography. Authors conclude that ultrasonography as method of support to abdominal exploration for diagnostic in acute appendicitis is manifest and present a global value of 70.90%.


Endotoxin and prevention of hypoxic pulmonary vasoconstriction.
Endotoxin is known both to stimulate prostaglandin production and to abolish the pulmonary vascular pressor response to hypoxia. The present study demonstrated that two inhibitors of prostaglandin synthesis, meclofenamate and indomethacin, prevent loss of pulmonary vasoconstriction due to hypoxia when sublethal doses of endotoxin are administered. This suggests that endotoxin may stimulate the production of a dilator prostaglandin which would oppose the hypoxic vasoconstriction, but other ways in which these inhibitor drugs might act are considered. Endotoxin damages platelets and leukocytes, both of which can form prostaglandins and could be the source of a dilator prostaglandin. However, in these experiments endotoxin abolished the hypoxic pressor response in dogs rendered severely thrombocytopenic by platelet antiserum. This suggests that platelets are not involved. In further experiments blood from anesthetized dogs was circulated through glass bead columns. Changes in the leukocyte count following perfusion were correlated with changes in the subsequent pressor response to hypoxia. The possibility that leukocytes may be involved in the effect of endotoxin on the hypoxic pressor response is considered.


Sometimes needs change minds: Interests and values as determinants of attitudes towards state support for the self-employed during the COVID-19 crisis.
This contribution investigates public attitudes toward providing financial help to the self-employed, a less well-researched area in the otherwise vibrant literature on welfare state attitudes. We analyse to what extent the self-employed themselves soften their general anti-statist stance in times of need, and how the public thinks about supporting those who usually tend to oppose government interventions. To answer these questions, we study public attitudes towards providing financial aid to the self-employed during the lockdowns adopted in response to the COVID pandemic in Switzerland, using survey data collected in the spring and in the autumn of 2020. The results show that most respondents favour the provision of financial support. In addition, the self-employed are the staunchest supporters of the more generous forms of help, like non-refundable payments. We conclude that, when exposed to significant economic risk, need and interests override ideological preferences for less state intervention.


Nanoparticle diffraction gratings for DNA detection on photopatterned glass substrates.
An ex situ nanoparticle DNA detection assay utilizing DNA-modified nanoparticles attached to DNA monolayer gratings on glass substrates is developed. The assay utilizes the simultaneous hybridization of a single stranded DNA (ssDNA) target molecule to both an amine-modified DNA oligonucleotide attached to an amine-reactive glass surface and a thiol-modified DNA oligonucleotide attached to a 13 nm gold nanoparticle. Surface plasmon resonance imaging measurements are used to characterize the two sequential hybridization adsorption processes employed in the assay, and fluorescence microscopy is used to characterize the formation of DNA monolayer gratings via the photopatterning of the amine-reactive glass slides. First order diffraction measurements utilizing incoherent collimated white light source and a 10 nm bandpass filter centered at 600 nm provided quantitative measurements of target ssDNA down to a concentration of 10 pM. Fourth order diffraction measurements employing a HeNe laser and avalanche photodiode were used to detect target ssDNA adsorption from 10 microl of a solution with a concentration as low as 10 fM, corresponding to 60,000 target DNA molecules. This simple yet sensitive grating-based nanoparticle DNA detection assay should be directly applicable for genetic screening, mRNA expression assays, and microRNA profiling.


Genomic consequences of ecological speciation in astyanax cavefish.
The cave environment is consistently radically different than the surface environment because it lacks light, and animals adapting to cave life are subject to strong selective forces much different than those experienced by their ancestors who evolved in the presence of light. As such, their divergence from surface ancestors and eventual speciation is likely to be driven by the shift in ecology. We report here that hybrids between cave and surface Astyanax mexicanus fishes produce offspring with allelic frequencies that differ significantly from Mendelian expectations both for transmission ratios and for independent assortment of unlinked markers. Comparison of allelic content of DNA from fin clips and sperm pools show that the transmission ratio distortion likely occurs during spermatogenesis. Departures from expectations of independent assortment are essentially epistatic phenomena generating linkage disequilibrium. A novel analysis of the epistatic interactions reveals an apparent network of interactions among genes known or suspected to be involved in cave adaptation, implying that the epistasis arose as a "by product" of the divergence due to cave adaptation.