Expression, engineering and characterization of the tumor-targeting heterodimeric immunocytokine F8-IL12.
Proinflammatory cytokines have been used for several years in patients with advanced cancer but their administration is typically associated with severe toxicity hampering their application to therapeutically active regimens. This problem can be overcome by using immunocytokines (cytokines fused to antibody or antibody fragments) which selectively deliver the active cytokine to the tumor environment. Preclinical and recent clinical results confirmed that this approach is a very promising avenue to go. We designed an immunocytokine consisting of the scFv(F8) specific to extra-domain A of fibronectin and the very potent human cytokine interleukin-12 (IL12). The heterodimeric nature of IL12 allows the engineering of various immunocytokine formats, based on different combinations of the two subunits (p35 and p40) together with the scFv. In comparison to monomeric or homodimeric cytokines, the construction of a heterodimeric immunocytokine poses many challenges, e.g. gene dosing, stable high-yield expression as well as good manufacture practice (GMP) purification and characterization. In this paper, we describe the successful construction, characterization and production of the heterodimeric immunocytokine F8-IL12. The positive outcome of this feasibility study leads now to GMP production of F8-IL12, which will soon enter clinical trials.


Prevalence of symptoms in relation to androgen concentrations in women using estrogen plus progestogen and women using estrogen alone.
Women using estrogen plus progestogen therapy sometimes report difficult to describe symptoms, eg, changes in libido, mood, and memory, that may be related to decreased androgens. To evaluate the prevalence of such symptoms and relate these symptoms to androgen levels in women using estrogen plus progestogen therapy, data from the Women's Health in the Lund Area Study were analyzed. A total of 2,816 women using estrogen plus progestogen therapy were asked to complete a questionnaire consisting of questions concerning sexual well-being and different aspects of quality of life. Serum concentrations of testosterone, androstendione, sex hormone-binding globulin, and estradiol were measured. A total of 2,048 questionnaires were eligible for evaluation. Almost 40% of the women reported decreased libido. Approximately 70% were satisfied with their current sex life. Eight percent reported that intercourse was unpleasant because of vaginal dryness. No evident associations were found between libido and serum hormone concentrations. The most positive effects of estrogen plus progestogen therapy concerning memory and urinary tract and vaginal complaints were found in women with the highest and/or moderate testosterone levels (P < 0.05). We found no strong association between symptoms related to sexual well-being or quality of life and androgen concentrations in this study. Estrogen plus progestogen therapy did not seem to affect symptoms that might be related to low levels of androgens in the group of climacteric women whom we studied.


5-Chloro-2-methyl-sulfanyl-6-(naphtha-len-1-yl-oxy)-1H-benzimidazole methanol monosolvate.
In the title compound, C18H13ClN2OS·CH3OH, the dihedral angle between the benzimidazole group and the naphth-yloxy moiety [82.89 (5)°] very near to orthogonality. The H atom in the five-membered ring is disordered with equal occupancies at the two N atoms and the H atom of the methano-lic hy-droxy group is disordered with equal occupancies over two sites at the O atom. The methanol mol-ecule acts as a hydrogen-bond acceptor for the amino H atom and donates a hydrogen bond to the nonprotonated ring N atom. As a result, chains are formed running along the a axis.


Effectivity of dexamethasone in patients undergoing off-pump coronary artery bypass surgery.
Based on our previous pilot study, systemic inflammatory response syndrome is more common in off-pump compared to on-pump coronary artery bypass. Therefore, we conducted a clinical trial of dexamethasone in patients undergoing off-pump coronary artery bypass. Sixty consecutive patients undergoing off-pump coronary artery bypass were enrolled from August 2018 to January 2019 and randomized to a dexamethasone or placebo group of 30 each. Clinical outcomes were analyzed. There was a lower incidence of major adverse cardiac events in the dexamethasone group compared to the placebo group (17% versus 43%, p = 0.024). Clinical outcomes in the dexamethasone group were better than those in the placebo group, in terms of duration of mechanical ventilation (p = 0.029), intensive care unit stay (p = 0.028), hospital stay (p = 0.04), and vasoactive-inotropic score (p = 0.045). There were significant differences in inflammatory markers between the two groups: interleukin-6 (p = 0.0001), procalcitonin (p = 0.0001), and C-reactive protein (p = 0.0001) were lower in the dexamethasone group. There was a significant association between the incidence of major adverse cardiac events and both interleukin-6 (p = 0.005) and procalcitonin (p = 0.007). Preoperative dexamethasone in patients undergoing off-pump coronary artery bypass is effective in improving clinical outcomes and controlling the postoperative inflammatory reaction.


Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes: association analyses in 9,518 subjects.
Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001).


Genomewide search and genetic localization of a second gene associated with autosomal dominant branchio-oto-renal syndrome: clinical and genetic implications.
Branchio-oto-renal (BOR) syndrome is characterized by ear malformations, cervical fistulas, hearing loss, and renal anomalies. It is an autosomal dominant disorder with variable clinical manifestations. The most common features of BOR syndrome are branchial, hearing, and renal anomalies. However, many affected subjects have been observed with branchial-cleft anomalies and hearing loss but without renal anomalies, a condition called "branchio-otic" (BO) syndrome. It is logical to question whether the BOR and BO syndromes are allelic or whether they represent distinct genetic entities. We identified a very large extended family whose members had branchial and hearing anomalies associated with commissural lip pits that segregated in an autosomal dominant fashion. Using a genomewide search strategy, we identified genetic linkage, with a maximum LOD score of 4.81 at recombination fraction 0, between the BO phenotype and polymorphic marker D1S2757 in the genetic region of chromosome 1q31. This is the first report of linkage for a second gene associated with BOR syndrome. The findings have important clinical implications and will provide insight into the genetic basis of BOR syndrome.


Single-molecule imaging at high fluorophore concentrations by local activation of dye.
Single-molecule fluorescence microscopy is a powerful tool for observing biomolecular interactions with high spatial and temporal resolution. Detecting fluorescent signals from individual labeled proteins above high levels of background fluorescence remains challenging, however. For this reason, the concentrations of labeled proteins in in vitro assays are often kept low compared to their in vivo concentrations. Here, we present a new fluorescence imaging technique by which single fluorescent molecules can be observed in real time at high, physiologically relevant concentrations. The technique requires a protein and its macromolecular substrate to be labeled each with a different fluorophore. Making use of short-distance energy-transfer mechanisms, only the fluorescence from those proteins that bind to their substrate is activated. This approach is demonstrated by labeling a DNA substrate with an intercalating stain, exciting the stain, and using energy transfer from the stain to activate the fluorescence of only those labeled DNA-binding proteins bound to the DNA. Such an experimental design allowed us to observe the sequence-independent interaction of Cy5-labeled interferon-inducible protein 16 with DNA and the sliding via one-dimensional diffusion of Cy5-labeled adenovirus protease on DNA in the presence of a background of hundreds of nanomolar Cy5 fluorophore.


Circadian Rhythm and Endocrinological Control on the Swimming and Sand Burrowing Behaviors of Japanese Sand Lances Ammodytes spp. (Uranoscopiformes, Ammodytidae).
In diurnal and nocturnal organisms, daily activity is regulated by the perception of environmental stimuli and circadian rhythms, which enable organisms to maintain their essential behaviors. The Japanese sand lances genus Ammodytes are coastal marine fish that exhibit unique nocturnal sand burrowing behavior. To elucidate the extrinsic and intrinsic regulation of this behavior and its endocrinological basis, we conducted a series of rearing experiments under various light conditions and hormone administrations. Under a light-dark photoperiod, the fish showed three types of behavior: sand buried, head-exposed from sand, and swimming/feeding. During the transition from dark to light periods, the fish first showed head exposure, followed by swimming and foraging, and buried themselves in the sand immediately after shifting to the dark period. Under constant light conditions, fish exhibited swimming behavior during the period corresponding to the acclimated light period. In addition, swimming did not occur under constant dark conditions but head exposure was observed at the time of the dark-light transition during acclimation. These observations indicate that the essential behavior of sand lances is regulated by both light and circadian rhythms. Subsequently, a melatonin-containing diet promoted the onset of burrowing in 10 to 120 min in a dose-dependent manner at 0.3-128 µg/g-diet, suggesting the direct behavioral regulation by this hormone. These findings suggest that the behavior of sand lances is strictly regulated by an intrinsic mechanism and that melatonin is a regulatory endocrine factor that induces burrowing behavior.


Cost analysis of current therapies for limited coronary artery revascularization.
Single or double (limited) coronary artery revascularization using percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass (CAB) surgery has recently been enhanced with further innovation in intracoronary stenting and the emergence of minimally invasive direct coronary artery bypass (MIDCAB) grafting. Resource allocation for all modalities is directly dependent on hospitalization costs, length of stay, and clinical results. Four groups of 25 consecutive patients over 9 months at a single center received either PTCA, stenting, MIDCAB, or conventional CAB for single-vessel coronary disease, primarily of the left anterior descending circulation. Day, supply, and procedural charges were evaluated, along with the total hospital charge. Postprocedural length of stay was calculated and compared with a national database. MIDCAB surgery day charges were less than stenting but greater than PTCA, MIDCAB supply charges were the least of all groups, and MIDCAB procedural charges were less than for conventional CAB. Total charges for MIDCAB grafting were less than for stenting but greater than for PTCA. Postprocedural length of stay for MIDCAB patients was equivalent to PTCA patients and significantly less than for stenting or for conventional CAB. MIDCAB grafting provides a new surgical approach that is comparable in charges to catheter-based interventions. The technique markedly reduces length of stay and perioperative morbidity. The selection of medical or surgical limited coronary revascularization can now be based primarily on clinical outcomes without consideration for associated resource allocation.


Forecasting Tidal Disruption Events for Binary Black Holes with an Outer Tertiary.
We discuss the gravitational wave (GW) emission and the orbital evolution of a hierarchical triple system composed of an inner binary black hole (BBH) and an outer tertiary. Depending on the kick velocity at the merger, the merged BBH could tidally disrupt the tertiary. Even though the fraction of BBH mergers accompanied by such disruptions is expected to be much smaller than unity, the existence of a tertiary and its basic parameters (e.g., semimajor axis, projected mass) can be examined for more than 10^{3} BBHs with the follow-on missions to the space GW detector LISA. This allows us to efficiently prescreen the targets for the follow-up searches for the tidal disruption events (TDEs). The TDE probability would be significantly higher for triple systems with aligned orbital- and spin-angular momenta, compared with random configurations.


The direction of the difference between Canadian and American erythrocyte folate concentrations is dependent on the assay method employed: a comparison of the Canadian Health Measures Survey and National Health and Nutrition Examination Survey.
Fortification of select grain products with folic acid and periconceptional supplementation recommendations in Canada and the USA have improved folate status, and have been associated with a reduced risk of neural tube defects. In the present study, we aimed to conduct a comparison of erythrocyte folate concentrations from the 2007-9 Canadian Health Measures Survey (CHMS) and the 2007-8 US National Health and Nutrition Examination Survey (NHANES). Erythrocyte folate concentration was assessed in participants aged 6-79 years (CHMS, n 5248; NHANES, n 7070). To account for different folate assays employed - Immulite 2000 immunoassay (CHMS) and microbiological assay (NHANES) - a conversion equation was generated (n 152 adults) to adjust the CHMS data. t Tests were used to examine country differences. Median Canadian erythrocyte folate concentrations (method-adjusted) were lower than those of Americans (988 and 1100 nmol/l, respectively), but unadjusted median Canadian erythrocyte folate concentrations were higher (1250 nmol/l). The upper 95% CI boundary of the method-adjusted Canadian erythrocyte folate distribution overlapped that of the American erythrocyte folate concentrations, while the lower 95% CI boundary of the method-adjusted Canadian erythrocyte folate data was below the American distribution. In summary, the fact that erythrocyte folate concentrations were either higher or lower in Canadians compared with Americans, depending on whether an adjustment was made to account for assay differences, suggests that caution must be exercised in evaluating erythrocyte folate data from different countries because analytical methods are not readily comparable. Furthermore, we cannot unequivocally conclude that there are true differences in erythrocyte folate concentrations between the Canadian and American populations in the post-fortification era.


Straylight effects with aging and lens extraction.
To assess possible gains and losses in straylight values among the population to consider straylight as added benefit of lens extraction. In this cross-sectional design, data from a multicenter study on visual function in automobile drivers were analyzed. On both eyes of 2,422 subjects, visual acuity (logarithm of the minimum angle of resolution [logMAR] in steps of 0.02 log units), straylight on the retina (psychophysical compensation comparison method), and lens opacity (slit-lamp scoring using the Lens Opacities Classification System III [LOCS III] system) were determined. Three groups were defined: 220 pseudophakic eyes, 3,182 noncataractous eyes (average LOCS III score, <1.5), and 134 cataractous eyes (average LOCS III score, >3.0). Noncataractous straylight values increases strongly with age as: log(s) = constant + log(1 + (age / 65)(4)), doubling by the age of 65 years, and tripling by the age of 77 years. Population standard deviation around this age norm was approximately 0.10 log units. The cataract eyes (in this active driver group) had relatively mild straylight increase. In pseudophakia, straylight values may be very good, better even than in the noncataract group. Visual acuity and straylight were found to vary quite independently. Lens extraction holds promise not only to improve on the condition of the cataract eye, but also to improve on the age-normal eye. Lens extraction potentially reverses the strong age increase in straylight value, quite independently from visual acuity.


High-temperature Fe oxidation coupled with redistribution of framework cations in lobanovite, K2Na(Fe2+4Mg2Na)Ti2(Si4O12)2O2(OH)4 - the first titanosilicate case.
The high-temperature (HT) behaviour of lobanovite, K2Na(Fe2+4Mg2Na)Ti2(Si4O12)2O2(OH)4, was studied using in situ powder X-ray diffraction in the temperature range 25-1000°C and ex situ single-crystal X-ray diffraction of 17 crystals quenched from different temperatures. HT iron oxidation associated with dehydroxylation starts at 450°C, similar to other ferrous-hydroxy-rich heterophyllosilicates such as astrophyllite and bafertisite. A prominent feature of lobanovite HT crystal chemistry is the redistribution of Fe and Mg+Mn cations over the M(2), M(3), M(4) sites of the octahedral (O) layer that accompanies iron oxidation and dehydroxylation. This HT redistribution of cations has not been observed in titanosilicates until now, and seems to be triggered by the need to maintain bond strengths at the apical oxygen atom of the TiO5 pyramid in the heteropolyhedral (H) layer during oxidation-dehydroxylation. Comparison of the HT behaviour of lobanovite with five-coordinated Ti and astrophyllite with six-coordinated Ti shows that the geometry of the Ti polyhedron plays a key role in the HT behaviour of heterophyllosilicates. The thermal expansion, geometrical changes and redistribution of site occupancies which occur in lobanovite under increasing temperature are reported. A brief discussion is given of minerals in which the cation ordering (usually for Fe and Mg) occurs together with iron oxidation-dehydroxylation at elevated temperatures: micas, amphiboles and tourmalines. Now this list is expanded by the inclusion of titanosilicate minerals.


Propagating wave based on transition of interaction within animal group.
Propagating waves, information transfers of direction of travel in collective groups, have been observed in animal groups of insects, birds, fish, and mammals. Nevertheless, although many previously proposed models of group behaviors have elucidated various aspects of collective motion, none has directly shown the propagating wave constructively. These models consisted of flocking algorithms in which individuals modify their positions or velocities through average responses to their neighbors. The algorithms involve the function of diluting local fluctuations, individual motions, or social cues that initiate coherent decision-making of where to travel and which spread through a group in the form of a wave. The present study challenged physics-inspired models based solely on average interaction and instead proposed a combination with pair interaction: the 'copy' mechanism. By the mechanism, individuals specially attend and mimic the motion of the largest turning neighbor. The model comprises three modes (base, copy, and align modes) that sequentially switch among themselves, depending on the degree of variance in direction. The model therefore involves propagating waves that produce rapid collective responses and quick turning motions of a group. This proposal is an attempt to uncover the mechanisms of self-organized waves in simulation studies of coordinated groups, without explicit signals such as alarm calls. Understanding such mechanisms is expected to contribute to the 'collective mind' metaphor, answering the question of how animal groups obtain higher-order computational capabilities from local inter-individual interactions.


SkQ1 treatment and food restriction--two ways to retard an aging program of organisms.
Effects of the mitochondria-targeted antioxidant SkQ1 and food restriction are compared. In both cases there is a remarkable increase in the median lifespan of organisms belonging to many different taxonomic ranks. Essentially, both SkQ1 treatment and restriction in food intake retard development of numerous adverse traits of senescence. This relationship could be predicted assuming that SkQ1 and food restriction inhibit the execution of an aging program. It is hypothesized that food restriction is perceived by organisms as a signal of starvation, which can be catastrophic for the population. Under these conditions, the organism switches off an aging program that is favorable for evolvability of the species but counterproductive for the individual. Unfortunately, food restriction is accompanied by some other effects, e.g., constant anxiety and attempts to scan as large a space as possible looking for food. Such side effects seem to be absent in the case of inhibition of the aging program by SkQ1.


Thioredoxin redox regulates ATPase activity of magnesium chelatase CHLI subunit and modulates redox-mediated signaling in tetrapyrrole biosynthesis and homeostasis of reactive oxygen species in pea plants.
The chloroplast thioredoxins (TRXs) function as messengers of redox signals from ferredoxin to target enzymes. In this work, we studied the regulatory impact of pea (Pisum sativum) TRX-F on the magnesium (Mg) chelatase CHLI subunit and the enzymatic activation of Mg chelatase in vitro and in vivo. In vitro, reduced TRX-F activated the ATPase activity of pea CHLI and enhanced the activity of Mg chelatase reconstituted from the three recombinant subunits CHLI, CHLD, and CHLH in combination with the regulator protein GENOMES UNCOUPLED4 (GUN4). Yeast two-hybrid and bimolecular fluorescence complementation assays demonstrated that TRX-F physically interacts with CHLI but not with either of the other two subunits or GUN4. In vivo, virus-induced TRX-F gene silencing (VIGS-TRX-F) in pea plants did not result in an altered redox state of CHLI. However, simultaneous silencing of the pea TRX-F and TRX-M genes (VIGS-TRX-F/TRX-M) resulted in partially and fully oxidized CHLI in vivo. VIGS-TRX-F/TRX-M plants demonstrated a significant reduction in Mg chelatase activity and 5-aminolevulinic acid synthesizing capacity as well as reduced pigment content and lower photosynthetic capacity. These results suggest that, in vivo, TRX-M can compensate for a lack of TRX-F and that both TRXs act as important redox regulators of Mg chelatase. Furthermore, the silencing of TRX-F and TRX-M expression also affects gene expression in the tetrapyrrole biosynthesis pathway and leads to the accumulation of reactive oxygen species, which may also serve as an additional signal for the transcriptional regulation of photosynthesis-associated nuclear genes.


Phase II clinical evaluation of AZQ in colorectal cancer.
Thirty patients with measurable metastatic colorectal cancer refractory to 5-fluorouracil-containing regimens, received AZQ (1,4-cyclohexadiene-1,4-dicarbamic acid, 2,5-bis(1-aziridinyl)3,6,dioxo,diethylester, NSC 182986) on a 5-day intravenous schedule administered every 4 weeks. Good risk patients received AZQ at the starting daily dose of 8 mg/m2, while patients who had had therapy with radiation or myelosuppressive drugs such as mitomycin C or a nitrosourea compound received an initial daily dose of 6 mg/m2. There were no complete or partial remissions. Only one of 27 evaluable patients had objective tumor regression. Five additional patients had disease stabilization. The dose-limiting toxicity was myelosuppression, with thrombocytopenia being more severe than neutropenia. The myelosuppression occurred late in the treatment cycle (day 20), was more severe with repeated treatments, and was more severe in patients who had poor bone marrow reserves. AZQ administered by the 5-day dose schedule as used in this study is not effective against colorectal cancer.


[Maturity-onset diabetes of the young--MODY. Molecular-genetic, pathophysiological and clinical characteristics].
Maturity-onset diabetes of the young (MODY) is a genetically and clinically heterogeneous subtype of type 2 diabetes characterised by an early onset, an autosomal dominant inheritance, and a primary defect in insulin secretion. MODY comprises 2-5% of cases of type 2 diabetes. So far, six MODY genes have been identified (MODY1-6): hepatocyte nuclear factor (HNF-4 alpha), glucokinase, HNF-1 alpha, HNF-1 beta, insulin promoter factor 1(IPF-1), and neurogenic differentiation factor 1 (NEUROD1). MODY2 and MODY3 are the most common forms of MODY. Mutations in glucokinase/MODY2 result in a mild form of diabetes. In contrast, MODY3 and some of the other MODY forms are characterised by major insulin secretory defects and severe hyperglycaemia associated with microvascular complications. About 25% of known MODY is caused by mutations in yet unknown genes and present results suggest that other monogenic forms of type 2 diabetes might exist. The diagnosis of MODY has implications for the clinical management of the patient's diabetes. The identification of MODY genes also opens new perspectives in the understanding of the molecular basis of diabetes and may probably contribute to the definition of novel targets for drug development and gene therapy.


[A glossary for discussion about abortion].
Abortion and its diverse possible legal regulations is one of the major and toughest social controversies. This debate is even more problematic due to biases, prejudgments, different ideologies, beliefs, religious doctrines and political pressures. Chile has recently begun a new national discussion with an evident confusion, both in juridical and clinical terminology, which makes very difficult to achieve the necessary plural debate for a social and political consensus. The authors structured an academic collaborative project to create a glossary as a contribution for a discussion based on clearly defined notions about the different terms used in the abortion debate. Twenty-two concepts were selected and their definitions were reviewed and discussed by more than 50 different specialists. The final version of this glossary in Spanish language is presented.


Cardiovascular disease is associated with high-fat-diet-induced liver damage and up-regulation of the hepatic expression of hypoxia-inducible factor 1α in a rat model.
CVD (cardiovascular disease) is associated with abnormal liver enzymes, and NAFLD (non-alcoholic fatty liver disease) is independently associated with cardiovascular risk. To gain insights into the molecular events underlying the association between liver enzymes and CVD, we developed an HFD (high-fat diet)-induced NAFLD in the SHR (spontaneously hypertensive rat) and its control WKY (Wistar-Kyoto) rat strain. We hypothesized that hepatic induction of Hif1a (hypoxia-inducible factor 1α) might be the link between CVD and liver injury. Male SHRs (n=13) and WKY rats (n=14) at 16 weeks of age were divided into two experimental groups: standard chow diet and HFD (10 weeks). HFD-fed rats, irrespective of the strain, developed NAFLD; however, only HFD-SHRs had focus of lobular inflammation and high levels of hepatic TNFα (tumour necrosis factor α). SHRs had significantly higher liver weight and ALT (alanine aminotransferase) levels, irrespective of NAFLD. Liver abundance of Hif1a mRNA and Hif1α protein were overexpressed in SHRs (P<0.04) and were significantly correlated with ALT levels (R=0.50, P<0.006). This effect was not reverted by a direct acting splanchnic vasodilator (hydralazine). Angiogenesis may be induced by the HFD, but the disease model showed significantly higher hepatic Vegf (vascular endothelial growth factor) levels (P<0.025) even in absence of dietary insult. Hif1a mRNA overexpression was not observed in other tissues. Liver mRNA of Nr1d1 (nuclear receptor subfamily 1, group D, member 1; P<0.04), Ppara [Ppar (peroxisome-proliferator-activated receptor) α; P<0.05], Pparg (Pparγ; P<0.001) and Sirt1 (Sirtuin 1; P<0.001) were significantly upregulated in SHRs, irrespective of NAFLD. Sirt1 and Hif1a mRNAs were significantly correlated (R=0.71, P<0.00002). In conclusion, CVD is associated with Hif1a-related liver damage, hepatomegaly and reprogramming of liver metabolism, probably to compensate metabolic demands.


Regulation of Trypanosoma cruzi-induced myocarditis by programmed death cell receptor 1.
Trypanosoma cruzi infection causes intense myocarditis, leading to cardiomyopathy and severe cardiac dysfunction. Protective adaptive immunity depends on balanced signaling through a T cell receptor and coreceptors expressed on the T cell surface. Such coreceptors can trigger stimulatory or inhibitory signals after binding to their ligands in antigen-presenting cells (APC). T. cruzi modulates the expression of coreceptors in lymphocytes after infection. Deregulated inflammation may be due to unbalanced expression of these molecules. Programmed death cell receptor 1 (PD-1) is a negative T cell coreceptor that has been associated with T cell anergy or exhaustion and persistent intracellular infections. We aimed to study the role of PD-1 during T. cruzi-induced acute myocarditis in mice. Cytometry assays showed that PD-1 and its ligands are strongly upregulated in lymphocytes and APC in response to T. cruzi infection in vivo and in vitro. Lymphocytes infiltrating the myocardium exhibited high levels of expression of these molecules. An increased cardiac inflammatory response was found in mice treated with blocking antibodies against PD-1, PD-L1, and to a lesser extent, PD-L2, compared to that found in mice treated with rat IgG. Similar results in PD-1(-/-) mice were obtained. Moreover, the PD-1 blockade/deficiency led to reduced parasitemia and tissue parasitism but increased mortality. These results suggest the participation of a PD-1 signaling pathway in the control of acute myocarditis induced by T. cruzi and provide additional insight into the regulatory mechanisms in the pathogenesis of Chagas' disease.


Conducting a multi-country online alcohol survey in the time of the COVID-19 pandemic: Opportunities and challenges.
This contribution provides insights into the methodology of a pan-European population-based online survey, performed without external funding during the COVID-19 pandemic. We present the impact of different dissemination strategies to collect data from a non-probabilistic convenience sample and outline post-stratification weighting schemes, to provide guidance for future multi-country survey studies. Description and comparison of dissemination strategies for five exemplary countries (Czechia, Germany, Lithuania, Norway, Spain) participating in the Alcohol Use and COVID-19 Survey. Comparison of the sample distribution with the country's actual population distribution according to sociodemographics, and development of weighting schemes. The dissemination of online surveys through national newspapers, paid social media adverts and dissemination with the support of national health ministries turned out to be the most effective strategies. Monitoring the responses and adapting dissemination strategies to reach under-represented groups, and the application of sample weights were helpful to achieve an analytic sample matching the respective general population profiles. Reaching a large pan-European convenience sample, including most European countries, in a short time was feasible, with the support of a broad scientific network.


The effect of pregnancy on survival in a low-grade glioma cohort.
OBJECTIVE The impact of pregnancy on survival in female patients with low-grade glioma (LGG) is unknown and controversial. The authors designed a retrospective cohort study on prospectively collected registry data to assess the influence of pregnancy and child delivery on the survival of female patients with LGG. METHODS In Norway, the reporting of all births and cancer diagnoses to the Medical Birth Registry of Norway (MBRN) and the Cancer Registry of Norway (CRN), respectively, is compulsory by law. Furthermore, every individual has a unique 11-digit identification number. The CRN was searched to identify all female patients with a histologically confirmed diagnosis of World Health Organization (WHO) Grade II astrocytoma, oligoastrocytoma, oligodendroglioma, or pilocytic astrocytoma who were 16-40 years of age at the time of diagnosis during the period from January 1, 1970, to December 31, 2008. Obstetrical information was obtained from the MBRN for each patient. The effect of pregnancy on survival was evaluated using a Cox model with parity as a time-dependent variable. RESULTS The authors identified 65 patients who gave birth to 95 children after an LGG diagnosis. They also identified 281 patients who did not give birth after an LGG diagnosis. The median survival was 14.3 years (95% CI 11.7-20.6 years) for the entire study population. The effect of pregnancy was insignificant in the multivariate model (HR 0.71, 95% CI 0.35-1.42). CONCLUSIONS Pregnancy does not seem to have an impact on the survival of female patients with LGG.


CysView: protein classification based on cysteine pairing patterns.
CysView is a web-based application tool that identifies and classifies proteins according to their disulfide connectivity patterns. It accepts a dataset of annotated protein sequences in various formats and returns a graphical representation of cysteine pairing patterns. CysView displays cysteine patterns for those records in the data with disulfide annotations. It allows the viewing of records grouped by connectivity patterns. CysView's utility as an analysis tool was demonstrated by the rapid and correct classification of scorpion toxin entries from GenPept on the basis of their disulfide pairing patterns. It has proved useful for rapid detection of irrelevant and partial records, or those with incomplete annotations. CysView can be used to support distant homology between proteins. CysView is publicly available at http://research.i2r.a-star.edu.sg/CysView/.


The use of risk and need factors in forensic mental health decision-making and the role of gender and index offense severity.
Canadian legislation makes Review Boards (RBs) responsible for rendering dispositions for individuals found Not Criminally Responsible on account of Mental Disorder (NCRMD) after considering public safety, the mental condition of the accused, and his/her potential for community reintegration. We reviewed 6,743 RB hearings for 1,794 individuals found NCRMD in the three largest Canadian provinces to investigate whether items from two empirically supported risk assessment measures, the Historical Clinical Risk Management-20 and the Violence Risk Appraisal Guide, were considered. Less than half the items were included in expert reports or in RBs' reasons for dispositions, and consideration of these items differed according to gender and index offense severity of the accused. These items included evidence-based risk factors and/or legally specified criteria: mental health, treatment, and criminal history. These results illustrate the gap between research on risk factors and the integration of this evidence into practice. In particular, we recommend the implementation of structured measures to reduce the potential for clinicians to be unduly influenced by gender and offense severity.


CX3CL1 and IL-15 Promote CD8 T cell chemoattraction in HIV and in atherosclerosis.
Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded.


Downregulation of miR-216a-5p by long noncoding RNA PVT1 suppresses colorectal cancer progression via modulation of YBX1 expression.
Increasing evidence has demonstrated that microRNAs (miRNAs) are closely related to the occurrence and development of tumors. MiR-216a-5p, located at 2p16.1, has been shown to suppress proliferation of cancerous cells. However, its expression and function in colorectal cancer (CRC) remain unclear. The significance of miR-216a-5p in CRC was studied by analyzing miR-216a-5p expression in CRC tissues and its association with clinicopathological parameters. CRC cells, stably overexpressing miR-216a-5p, were evaluated for cell proliferation and metastasis using cell counting kit-8 (CCK-8) and transwell assay methods. Epithelial-mesenchymal transition (EMT) pathway was analyzed by Western blotting. Bioinformatics, quantitative real-time polymerase chain reaction (RT-qPCR), and luciferase reporter assay were performed to define the regulation of PVT1/miR-216a-5p/Y Box Binding Protein 1 (YBX1) axis in CRC. The expression of miR-216a-5p was found to be significantly downregulated in CRC and was correlated with the various stages and differentiation degree of the tumors. Moreover, the overexpression of miR-216a-5p could significantly inhibit the tumor growth, metastasis, and EMT progression in CRC. Furthermore, the expression of miR-216a-5p was negatively correlated with the expression of PVT1, and PVT1 could reverse tumor suppressive effect of miR-216a-5p in CRC cells. Finally, YBX1 might be the key target of PVT1/miR-216a-5p axis in CRC. Downregulation of miR-216a-5p by PVT1 could suppress CRC progression via modulating YBX1 expression.


Protein-Polysaccharide Composite Materials: Fabrication and Applications.
Protein-polysaccharide composites have been known to show a wide range of applications in biomedical and green chemical fields. These composites have been fabricated into a variety of forms, such as films, fibers, particles, and gels, dependent upon their specific applications. Post treatments of these composites, such as enhancing chemical and physical changes, have been shown to favorably alter their structure and properties, allowing for specificity of medical treatments. Protein-polysaccharide composite materials introduce many opportunities to improve biological functions and contemporary technological functions. Current applications involving the replication of artificial tissues in tissue regeneration, wound therapy, effective drug delivery systems, and food colloids have benefited from protein-polysaccharide composite materials. Although there is limited research on the development of protein-polysaccharide composites, studies have proven their effectiveness and advantages amongst multiple fields. This review aims to provide insight on the elements of protein-polysaccharide complexes, how they are formed, and how they can be applied in modern material science and engineering.


Disciplinary reporting affects the interpretation of climate change impacts in global oceans.
Climate change is affecting marine ecosystems, but different investigative approaches in physical, chemical, and biological disciplines may influence interpretations of climate-driven changes in the ocean. Here, we review the ocean change literature from 2007 to 2012 based on 461 of the most highly cited studies in physical and chemical oceanography and three biological subdisciplines. Using highly cited studies, we focus on research that has shaped recent discourse on climate-driven ocean change. Our review identified significant differences in spatial and temporal scales of investigation among disciplines. Physical/chemical studies had a median duration of 29 years (n = 150) and covered the greatest study areas (median 1.41 × 10(7) km(2) , n = 148). Few biological studies were conducted over similar spatial and temporal scales (median 8 years, n = 215; median 302 km(2) , n = 196), suggesting a more limited ability to separate climate-related responses from natural variability. We linked physical/chemical and biological disciplines by tracking studies examining biological responses to changing ocean conditions. Of the 545 biological responses recorded, a single physical or chemical stressor was usually implicated as the cause (59%), with temperature as the most common primary stressor (44%). The most frequently studied biological responses were changes in physiology (31%) and population abundance (30%). Differences in disciplinary studies, as identified in this review, can ultimately influence how researchers interpret climate-related impacts in marine systems. We identified research gaps and the need for more discourse in (1) the Indian and other Southern Hemisphere ocean basins; (2) research themes such as archaea, bacteria, viruses, mangroves, turtles, and ocean acidification; (3) physical and chemical stressors such as dissolved oxygen, salinity, and upwelling; and (4) adaptive responses of marine organisms to climate-driven ocean change. Our findings reveal that highly cited biological studies are rarely conducted on scales that match those of physical and chemical studies. Rather, we suggest a need for measuring responses at biologically relevant scales.


Effect of lipopolysaccharide on the development of cell-mediated immunity to transplantation antigens.
Lipopolysaccharide (LPS) from Escherichia coli administered to allografted mice in a single dose of 20 microgram influenced the development of cell-mediated immunity to skin donor antigens. As an indicator of cell-mediated immunity, donor antigen-induced inhibition of cell migration from spleen explants of allografted animals was used. Cultures of spleen explants were established 16 days after grafting. The antigen-specific inhibition of migration was abolished when LPS was injected either 4 to 2 days before grafting and intensified when LPS was administered on the 2nd day after grafting.


[Modern methods of early screening for preeclampsia and pregnancy-induced hypertension--a review].
Preeclampsia remains to be a serious perinatal complication and early screening for this disease to identify the high risk population before the first symptoms develop constitutes a considerable clinical challenge. Modern methods of screening for preeclampsia and pregnancy-induced hypertension include patients history biochemical serum markers and foetal DNA and RNA in maternal serum. They aid the process of developing an optimal protocol to initiate treatment in early pregnancy and to reduce the rate of complications. Our review presents an overview of the novel methods and techniques used for early screening for preeclampsia and pregnancy-induced hypertension. Most of the research focuses on 11-13 weeks of gestation due to the fact that the first prenatal examination is performed at that time. The most important information seems to be: weight, mass, mean blood pressure, history of pregnancy-induced hypertension or preeclampsia at previous pregnancies as well as the ethnic origin. During an ultrasound scan, pulsatility index of the uterine arteries is measured. Blood samples are obtained during the last part of the examination. At the moment only a few markers seem to be strong predictors of hypertensive disorders during pregnancy: pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PIGF) and soluble fms-like tyrosine kinase-1 (sFlt-1). Also, fetal DNA and RNA in maternal plasma are helpful in the prediction of preeclampsia as they are markers of the trophoblast apoptosis. Researchers aim at identifying the population at high risk of pregnancy-induced hypertension and preeclampsia in order to offer appropriate antenatal care to these women. At the moment many drugs and diet supplements are investigated to reduce the prevalence of hypertensive disorders in pregnancy. These medications are usually administrated in early gestation (up to 16 week of gestation) before the first clinical symptoms present. Low doses of aspirin were found to decrease the risk of preeclampsia in high-risk groups. Moreover, according to some recent research, also essential omega-3 fatty acids reduce the incidence of preeclampsia. None of the other investigated diet supplements or antioxidants were proven to successfully reduce incidents of hypertensive disorders. So far, there is available evidence on the lack of any effect for vitamines C, D or E. Further studies are necessary to define clinical useful markers of gestational hypertension.


An examination of pay-for-performance in general practice in Australia.
This study examines the impact of Australia's pay-for-performance (P4P) program for general practitioners (GPs). The voluntary program pays GPs A$40 and A$100 in addition to fee-for-service payment for providing patients recommended diabetes and asthma treatment over a year, and A$35 for screening women for cervical cancer who have not been screened in 4 years. Three approaches were used to triangulate the program's impact: (1) analysis of trends in national claims for incentivized services pre- and postprogram implementation; (2) fixed effects panel regression models examining the impact of GPs' P4P program participation on provision of incentivized services; and (3) in-depth interviews to explore GPs' perceptions of their own response to the program. There was a short-term increase in diabetes testing and cervical cancer screens after program implementation. The increase, however, was for all GPs. Neither signing onto the program nor claiming incentive payments was associated with increased diabetes testing or cervical cancer screening. GPs reported that the incentive did not influence their behavior, largely due to the modest payment and the complexity of tracking patients and claiming payment. Monitoring and evaluating P4P programs is essential, as programs may not spark the envisioned impact on quality improvement.


Quality of pharmaceutical industry press releases based on original research.
Press releases are a popular vehicle to disseminate health information to the lay media. While the quality of press releases issued by scientific conferences and medical journals has been questioned, no efforts to assess pharmaceutical industry press releases have been made. Therefore, we sought to systematically examine pharmaceutical company press releases about original research for measures of quality. Press releases issued by the ten top selling, international pharmaceutical companies in the year 2005 were selected for evaluation. A total of 1028 electronic press releases were issued and 235 were based on original research. More than half (59%) reported results presented at a scientific meeting. Twenty-one percent of releases were not explicit about the source of original data. While harms or adverse events were commonly cited (76%), study limitations were rarely noted (6%). Almost one-third (29%) of releases did not quantify study results. Studies presented in abstract form were subsequently published within at least 20 months in 53% of cases. Pharmaceutical company press releases frequently report basic study details. However, readers should be cautioned by the preliminary nature of the data and lack of identified limitations. Methods to improve the reporting and interpretation of drug company press releases are desirable to prevent misleading media coverage.


Association between hospital onset of infection and outcomes in sepsis patients - A propensity score matched cohort study based on health claims data in Germany.
Hospital-acquired infections are a common source of sepsis. Hospital onset of sepsis was found to be associated with higher acute mortality and hospital costs, yet its impact on long-term patient-relevant outcomes and costs is unknown. We aimed to assess the association between sepsis origin and acute and long-term outcomes based on a nationwide population-based cohort of sepsis patients in Germany. This retrospective cohort study used nationwide health claims data from 23 million health insurance beneficiaries. Sepsis patients with hospital-acquired infections (HAI) were identified by ICD-10-codes in a cohort of adult patients with hospital-treated sepsis between 2013 and 2014. Cases without these ICD-10-codes were considered as sepsis cases with community-acquired infection (CAI) and were matched with HAI sepsis patients by propensity score matching. Outcomes included in-hospital/12-month mortality and costs, as well as readmissions and nursing care dependency until 12 months postsepsis. We matched 33,110 HAI sepsis patients with 28,614 CAI sepsis patients and 22,234 HAI sepsis hospital survivors with 19,364 CAI sepsis hospital survivors. HAI sepsis patients had a higher hospital mortality than CAI sepsis patients (32.8% vs. 25.4%, RR 1.3, p < .001). Similarly, 12-months postacute mortality was higher (37.2% vs. 30.1%, RR=1.2, p < .001). Hospital and 12-month health care costs were 178% and 22% higher in HAI patients than in CAI patients, respectively. Twelve months postsepsis, HAI sepsis survivors were more often newly dependent on nursing care (33.4% vs. 24.0%, RR=1.4, p < .001) and experienced 5% more hospital readmissions (mean number of readmissions: 2.1 vs. 2.0, p < .001). HAI sepsis patients face an increased risk of adverse outcomes both during the acute sepsis episode and in the long-term. Measures to prevent HAI and its progression into sepsis may be an opportunity to mitigate the burden of long-term impairments and costs of sepsis, e.g., by early detection of HAI progressing into sepsis, particularly in normal wards; adequate sepsis management and adherence to sepsis bundles in hospital-acquired sepsis; and an improved infection prevention and control.


Activity of the SNARE Protein SNAP29 at the Endoplasmic Reticulum and Golgi Apparatus.
Snap29 is a conserved regulator of membrane fusion essential to complete autophagy and to support other cellular processes, including cell division. In humans, inactivating SNAP29 mutations causes CEDNIK syndrome, a rare multi-systemic disorder characterized by congenital neuro-cutaneous alterations. The fibroblasts of CEDNIK patients show alterations of the Golgi apparatus (GA). However, whether and how Snap29 acts at the GA is unclear. Here we investigate SNAP29 function at the GA and endoplasmic reticulum (ER). As part of the elongated structures in proximity to these membrane compartments, a pool of SNAP29 forms a complex with Syntaxin18, or with Syntaxin5, which we find is required to engage SEC22B-loaded vesicles. Consistent with this, in HeLa cells, in neuroepithelial stem cells, and in vivo, decreased SNAP29 activity alters GA architecture and reduces ER to GA trafficking. Our data reveal a new regulatory function of Snap29 in promoting secretory trafficking.


Dissociative x-ray lasing.
X-ray lasing is predicted to ensue when molecules are pumped into dissociative core-excited states by a free-electron-laser pulse. The lasing is due to the population inversion created in the neutral dissociation product, and the process features self-trapping of the x-ray pulse at the gain ridge. Simulations performed for the HCl molecule pumped at the 2p(1/2)→6σ resonance demonstrate that the scheme can be used to create ultrashort coherent x-ray pulses.


Hepatitis in aviation personnel.
This study examines the specific etiologies and aeromedical outcomes of naval aviation personnel with hepatitis. We searched the Biomedical Database of the Naval Aerospace Medical Institute for waiver requests for hepatitis. We reviewed the records for specific etiologies, possible risk factors, and the aeromedical outcomes of aviators who received waivers for chronic hepatitis. We examined 48 initial and 95 follow-up waiver requests for hepatitis for naval aviation personnel from July 1988 to May 2001. Initial waiver requests were for chronic hepatitis C (HCV) in 23 (47.9%), chronic hepatitis B in 17 (35.4%), and other etiologies in 8 (16.7%). Asian Americans, who comprise 2% of the aviator population in the Biomedical Database, accounted for a disproportionate number of waiver requests for hepatitis: 7 (14.6%) of the total and 6 (35.3%) of the aviators with HBV. Of the 48 aviators with hepatitis, waivers were granted in 32 (66.7%) cases, all of whom were asymptomatic. Waivers were denied to 16 (33.3%) aviators. One aviator with Hodgkin's disease in remission and one aviator with chronic HCV who became asymptomatic after treatment with interferon later received waivers for a total of 34 (70.8%) waivers. Two waivers were later revoked because of symptomatic HCV requiring interferon in one and incomplete physical exam in another. Aviation personnel who receive waivers for asymptomatic hepatitis occasionally present with symptomatic hepatitis, but most waiver recipients remain asymptomatic during their aviation careers.


Quality characteristics of fresh blue crab meat held at 0 and 4 degrees C in tamper-evident containers.
There has been a regulatory movement toward the required use of tamper-evident containers for fresh blue crab meat. North Carolina passed tamper-evident regulations in 1993. Blue crab processors had little information on possible changes in head-space gases, microbial growth, chemical decomposition, sensory quality, or shelf life caused by the new containers. Chemical, microbiological, physical, and sensory changes in fresh crab meat were monitored during 18 days of storage in ice and 13 days of storage refrigerated at 4 degrees C. "Special" blue crab meat, chosen for the study, is the least expensive commercial form of white crab meat. The crab meat was packaged in four retail containers: copolymer polyethylene cups with polyethylene snap-on lids, copolymer polyethylene cups with snap-on polyethylene lids fastened to the cup with heat-shrink low-density polypropylene seals, copolymer polyethylene cans with aluminum easy-open ends, and copolymer polypropylene cups with a tamper-evident pull-tab on the lid. Control samples packaged in industry standard copolymer polyethylene cups maintained higher oxygen levels than meat stored in tamper-evident containers. No consistent differences in quality or shelf life were detected among the containers. Market shelf life was limited to 6 days for meat held at 4 degrees C and 15 days for meat held at 0 degrees C. Sensory quality deteriorated 6 days earlier for crab meat held at 4 degrees C than meat held at 0 degrees C. Collateral work showed that toxin production by Clostridium botulinum neither occurred following 18 days of storage at 4 degrees C nor after 15 days of storage at 10 degrees C. Definite spoilage occurred before any toxin production. The study suggests that blue crab processors can safely use the new tamper-evident packaging, which has little or no effect on product quality or shelf life. Processors may choose appropriate packaging options using price, packaging quality, market appearance, and ease of production as the deciding criteria.


Isolation of Escherichia coli mRNA and comparison of expression using mRNA and total RNA on DNA microarrays.
Bacterial messenger RNA (mRNA) is not coherently polyadenylated, whereas mRNA of Eukarya can be separated from stable RNAs by virtue of polyadenylated 3'-termini. We have developed a method to isolate Escherichia coli mRNA by polyadenylating it in crude cell extracts with E. coli poly(A) polymerase I and purifying it by oligo(dT) chromatography. Differences in lacZRNA levels were similar with purified mRNA and total RNA in dot blot hydridizations for cultures grown with or without gratuitous induction of the lactose operon. More broadly, changes in gene expression upon induction were similar when cDNAs primed from mRNA or total RNA with random hexanucleotides were hydridized to DNA microarrays for the E. coli genome. Comparable signal intensities were obtained with only 1% as much oligo(dT)-purified mRNA as total RNA, and hence in vitro poly(A) tailing appears to be selective for mRNA. These and additional studies of genome-wide expression with DNA microarrays provide evidence that in vitro poly(A) tailing works universally for E. coli mRNAs.


[Delayed hypersensitivity and nonspecific cellular immunity. The conditions determining the maximally expressed immunity activity].
In vivo experiments on the infection of mice with influenza A virus and Francisella tularensis and in vitro experiments on the bactericidal activity of macrophages have demonstrated the conditions leading to the maximally pronounced activation of immunity by means of preparations inducing delayed hypersensitivity (DH). The following conditions have been determined: the presence of pronounced DH previously to the injection of old tuberculin (OT) and staphylococcal phagolysate (SP) used as challenge antigens, the specificity and peculiar features of the antigenic structure of the challenge agent, the time of its administration after the course of multiple sensitizing injections of BCG and staphylococci, the dosage of OT and SP and the scheme of their administration, the desirability of their local use. The time of the maximum activation of cell-mediated immunity after the injection of OT and SP to sensitized animals with a high level of DH and the duration of such activation have been established.


Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs.
Consistent with its highest abundance in humans, cytochrome P450 (CYP) 3A is responsible for the metabolism of about 60% of currently known drugs. However, this unusual low substrate specificity also makes CYP3A4 susceptible to reversible or irreversible inhibition by a variety of drugs. Mechanism-based inhibition of CYP3A4 is characterised by nicotinamide adenine dinucleotide phosphate hydrogen (NADPH)-, time- and concentration-dependent enzyme inactivation, occurring when some drugs are converted by CYP isoenzymes to reactive metabolites capable of irreversibly binding covalently to CYP3A4. Approaches using in vitro, in silico and in vivo models can be used to study CYP3A4 inactivation by drugs. Human liver microsomes are always used to estimate inactivation kinetic parameters including the concentration required for half-maximal inactivation (K(I)) and the maximal rate of inactivation at saturation (k(inact)). Clinically important mechanism-based CYP3A4 inhibitors include antibacterials (e.g. clarithromycin, erythromycin and isoniazid), anticancer agents (e.g. tamoxifen and irinotecan), anti-HIV agents (e.g. ritonavir and delavirdine), antihypertensives (e.g. dihydralazine, verapamil and diltiazem), sex steroids and their receptor modulators (e.g. gestodene and raloxifene), and several herbal constituents (e.g. bergamottin and glabridin). Drugs inactivating CYP3A4 often possess several common moieties such as a tertiary amine function, furan ring, and acetylene function. It appears that the chemical properties of a drug critical to CYP3A4 inactivation include formation of reactive metabolites by CYP isoenzymes, preponderance of CYP inducers and P-glycoprotein (P-gp) substrate, and occurrence of clinically significant pharmacokinetic interactions with coadministered drugs. Compared with reversible inhibition of CYP3A4, mechanism-based inhibition of CYP3A4 more frequently cause pharmacokinetic-pharmacodynamic drug-drug interactions, as the inactivated CYP3A4 has to be replaced by newly synthesised CYP3A4 protein. The resultant drug interactions may lead to adverse drug effects, including some fatal events. For example, when aforementioned CYP3A4 inhibitors are coadministered with terfenadine, cisapride or astemizole (all CYP3A4 substrates), torsades de pointes (a life-threatening ventricular arrhythmia associated with QT prolongation) may occur.However, predicting drug-drug interactions involving CYP3A4 inactivation is difficult, since the clinical outcomes depend on a number of factors that are associated with drugs and patients. The apparent pharmacokinetic effect of a mechanism-based inhibitor of CYP3A4 would be a function of its K(I), k(inact) and partition ratio and the zero-order synthesis rate of new or replacement enzyme. The inactivators for CYP3A4 can be inducers and P-gp substrates/inhibitors, confounding in vitro-in vivo extrapolation. The clinical significance of CYP3A inhibition for drug safety and efficacy warrants closer understanding of the mechanisms for each inhibitor. Furthermore, such inactivation may be exploited for therapeutic gain in certain circumstances.


The use of continuous surveys to generate and continuously report high quality timely maternal and newborn health data at the district level in Tanzania and Uganda.
The lack of high quality timely data for evidence-informed decision making at the district level presents a challenge to improving maternal and newborn survival in low income settings. To address this problem, the EQUIP project (Expanded Quality Management using Information Power) implemented a continuous household and health facility survey for continuous feedback of data in two districts each in Tanzania and Uganda as part of a quality improvement innovation for mothers and newborns. Within EQUIP, continuous survey data were used for quality improvement (intervention districts) and for effect evaluation (intervention and comparison districts). Over 30 months of intervention (November 2011 to April 2014), EQUIP conducted continuous cross-sectional household and health facility surveys using 24 independent probability samples of household clusters to represent each district each month, and repeat censuses of all government health facilities. Using repeat samples in this way allowed data to be aggregated at six four-monthly intervals to track progress over time for evaluation, and for continuous feedback to quality improvement teams in intervention districts.In both countries, one continuous survey team of eight people was employed to complete approximately 7,200 household and 200 facility interviews in year one. Data were collected using personal digital assistants. After every four months, routine tabulations of indicators were produced and synthesized to report cards for use by the quality improvement teams. The first 12 months were implemented as planned. Completion of household interviews was 96% in Tanzania and 91% in Uganda. Indicators across the continuum of care were tabulated every four months, results discussed by quality improvement teams, and report cards generated to support their work. The EQUIP continuous surveys were feasible to implement as a method to continuously generate and report on demand and supply side indicators for maternal and newborn health; they have potential to be expanded to include other health topics. Documenting the design and implementation of a continuous data collection and feedback mechanism for prospective description, quality improvement, and evaluation in a low-income setting potentially represents a new paradigm that places equal weight on data systems for course correction, as well as evaluation.


Method of analysing the performance of self-paced and engine induced cycling in children with cerebral palsy.
To develop a method of quantifying the features of cycling in children with CP by comparing them to typically developed children, and to demonstrate the applications of this tool for evaluating treatment effects in children with CP. Twenty-seven typically developed children and 51 with CP, classified by their gross motor function levels, were studied. Angular velocities were measured during self-paced active cycling and during passive cycling imposed by an electrically powered stationary cycle. Angular velocities were compared with the gross motor function levels, Modified Ashworth Scale and the Adductor Tone Rating. Significant differences between children with CP and those typically developed demonstrated in passive mode that the cycling task is sensitive to differences in resistance offered by the subjects. Active and passive cycling velocities differ significantly between groups classified by their functional levels (p < 0.01). Children with CP in the mild group showed no differences from typically developed children. The correlations between passive cycling and clinical tests were significant and higher at higher speeds (r = 0.62). Correlations with anthropometric measurements for the typically developed group associated the cycling task with growth and development, and for children with CP with motor control adjustments and impairments. Measuring of these two cycling modes could be applicable in assessing lower extremity function in children with CP and changes following interventions.


High-throughput identification of factors promoting neuronal differentiation of human neural progenitor cells in microscale 3D cell culture.
Identification of conditions for guided and specific differentiation of human stem cell and progenitor cells is important for continued development and engineering of in vitro cell culture systems for use in regenerative medicine, drug discovery, and human toxicology. Three-dimensional (3D) and organotypic cell culture models have been used increasingly for in vitro cell culture because they may better model endogenous tissue environments. However, detailed studies of stem cell differentiation within 3D cultures remain limited, particularly with respect to high-throughput screening. Herein, we demonstrate the use of a microarray chip-based platform to screen, in high-throughput, individual and paired effects of 12 soluble factors on the neuronal differentiation of a human neural progenitor cell line (ReNcell VM) encapsulated in microscale 3D Matrigel cultures. Dose-response analysis of selected combinations from the initial combinatorial screen revealed that the combined treatment of all-trans retinoic acid (RA) with the glycogen synthase kinase 3 inhibitor CHIR-99021 (CHIR) enhances neurogenesis while simultaneously decreases astrocyte differentiation, whereas the combined treatment of brain-derived neurotrophic factor and the small azide neuropathiazol enhances the differentiation into neurons and astrocytes. Subtype specification analysis of RA- and CHIR-differentiated cultures revealed that enhanced neurogenesis was not biased toward a specific neuronal subtype. Together, these results demonstrate a high-throughput screening platform for rapid evaluation of differentiation conditions in a 3D environment, which will aid the development and application of 3D stem cell culture models.


Essential-oil composition of Helichrysum italicum (ROTH) G.DON ssp. italicum from Elba Island (Tuscany, Italy).
The composition of 21 essential-oil samples isolated from Helichrysum italicum collected in seven locations of Elba Island (Tuscany, Italy), characterized by different soil types, during three different periods (January, May, and October 2010) was determined by GC-FID and GC/EI-MS analyses. In total, 115 components were identified, representing 96.8-99.8% of the oil composition. The oils were characterized by a high content of oxygenated monoterpenes (38.6-62.7%), while monoterpene and sesquiterpene hydrocarbons accounted for 2.3-41.9 and 5.1-20.1% of the identified constituents, respectively. The main oxygenated derivatives were nerol (2.8-12.8%) and its ester derivative neryl acetate (5.6-45.9%). To compare the chemical variability of the species within Elba Island and between the island and other localities within the Mediterranean area, studied previously, multivariate statistical analysis was performed. The results obtained showed a difference in the composition of the essential oils of H. italicum from Elba Island, mainly due to the environment where the plant grows, and, in particular, to the soil type. These hypotheses were further confirmed by the comparison of these oils with essential oils obtained from H. italicum collected on other islands of the Tuscan archipelago.


Contemporary Management of Hemorrhage After Minimally Invasive Radical Prostatectomy.
To describe contemporary management and outcomes of patients experiencing postoperative hemorrhage after minimally invasive radical prostatectomy. We retrospectively analyzed data from patients who underwent minimally invasive radical prostatectomy at our institution between January 2010 and January 2017. Clinically significant hemorrhage was defined as a decrease in hemoglobin of ≥30% or 4 g/dL from preoperative to 4 or 14 hours postoperative measurement, receiving a blood transfusion within 30 days, or undergoing a secondary procedure to control bleeding. Patients were analyzed in 3 groups: (1) serially monitored only, (2) received a blood transfusion, and (3) underwent a secondary procedure. Outcomes included imaging studies performed, length of stay, emergency room visits, hospital readmissions, complication rates, and functional outcomes. Of 3749 men, 4% (151/3749) had clinically significant hemorrhage, 1.6% (60/3749) received a transfusion; 0.32% (12/3749) underwent a secondary procedure to control bleeding. In a 30-day composite outcome, increased healthcare utilization (emergency room visit, readmission, or Grade ≥3 complications), was seen in 25% of the serial monitoring group, 65% of the transfusion group, and 100% in the secondary procedure group. This rate in 3598 men without hemorrhage was 12.5%. One-year erectile function was poorest in men who underwent a secondary procedure. Urinary functional outcomes were similar in the 3 groups. Most patients experiencing clinically significant hemorrhage will stabilize without transfusion, and a very small fraction require secondary intervention. Patients experiencing milder bleeding events utilized additional healthcare resources at approximately twice the rate of those who did not, warranting appropriate counseling and postoperative monitoring.


Autonomic neural control of intrathoracic airways.
Autonomic neural control of the intrathoracic airways aids in optimizing air flow and gas exchange. In addition, and perhaps more importantly, the autonomic nervous system contributes to host defense of the respiratory tract. These functions are accomplished by tightly regulating airway caliber, blood flow, and secretions. Although both the sympathetic and parasympathetic branches of the autonomic nervous system innervate the airways, it is the later that dominates, especially with respect to control of airway smooth muscle and secretions. Parasympathetic tone in the airways is regulated by reflex activity often initiated by activation of airway stretch receptors and polymodal nociceptors. This review discusses the preganglionic, ganglionic, and postganglionic mechanisms of airway autonomic innervation. Additionally, it provides a brief overview of how dysregulation of the airway autonomic nervous system may contribute to respiratory diseases.


Rank-based spatial clustering: an algorithm for rapid outbreak detection.
Public health surveillance requires outbreak detection algorithms with computational efficiency sufficient to handle the increasing volume of disease surveillance data. In response to this need, the authors propose a spatial clustering algorithm, rank-based spatial clustering (RSC), that detects rapidly infectious but non-contagious disease outbreaks. The authors compared the outbreak-detection performance of RSC with that of three well established algorithms-the wavelet anomaly detector (WAD), the spatial scan statistic (KSS), and the Bayesian spatial scan statistic (BSS)-using real disease surveillance data on to which they superimposed simulated disease outbreaks. The following outbreak-detection performance metrics were measured: receiver operating characteristic curve, activity monitoring operating curve curve, cluster positive predictive value, cluster sensitivity, and algorithm run time. RSC was computationally efficient. It outperformed the other two spatial algorithms in terms of detection timeliness, and outbreak localization. RSC also had overall better timeliness than the time-series algorithm WAD at low false alarm rates. RSC is an ideal algorithm for analyzing large datasets when the application of other spatial algorithms is not practical. It also allows timely investigation for public health practitioners by providing early detection and well-localized outbreak clusters.


Screening of biochemical and molecular mechanisms of secondary injury and repair in the brain after experimental blast-induced traumatic brain injury in rats.
Abstract Explosive blast-induced traumatic brain injury (TBI) is the signature insult in modern combat casualty care and has been linked to post-traumatic stress disorder, memory loss, and chronic traumatic encephalopathy. In this article we report on blast-induced mild TBI (mTBI) characterized by fiber-tract degeneration and axonal injury revealed by cupric silver staining in adult male rats after head-only exposure to 35 psi in a helium-driven shock tube with head restraint. We now explore pathways of secondary injury and repair using biochemical/molecular strategies. Injury produced ∼25% mortality from apnea. Shams received identical anesthesia exposure. Rats were sacrificed at 2 or 24 h, and brain was sampled in the hippocampus and prefrontal cortex. Hippocampal samples were used to assess gene array (RatRef-12 Expression BeadChip; Illumina, Inc., San Diego, CA) and oxidative stress (OS; ascorbate, glutathione, low-molecular-weight thiols [LMWT], protein thiols, and 4-hydroxynonenal [HNE]). Cortical samples were used to assess neuroinflammation (cytokines, chemokines, and growth factors; Luminex Corporation, Austin, TX) and purines (adenosine triphosphate [ATP], adenosine diphosphate, adenosine, inosine, 2'-AMP [adenosine monophosphate], and 5'-AMP). Gene array revealed marked increases in astrocyte and neuroinflammatory markers at 24 h (glial fibrillary acidic protein, vimentin, and complement component 1) with expression patterns bioinformatically consistent with those noted in Alzheimer's disease and long-term potentiation. Ascorbate, LMWT, and protein thiols were reduced at 2 and 24 h; by 24 h, HNE was increased. At 2 h, multiple cytokines and chemokines (interleukin [IL]-1α, IL-6, IL-10, and macrophage inflammatory protein 1 alpha [MIP-1α]) were increased; by 24 h, only MIP-1α remained elevated. ATP was not depleted, and adenosine correlated with 2'-cyclic AMP (cAMP), and not 5'-cAMP. Our data reveal (1) gene-array alterations similar to disorders of memory processing and a marked astrocyte response, (2) OS, (3) neuroinflammation with a sustained chemokine response, and (4) adenosine production despite lack of energy failure-possibly resulting from metabolism of 2'-3'-cAMP. A robust biochemical/molecular response occurs after blast-induced mTBI, with the body protected from blast and the head constrained to limit motion.


Prevention-enhancing interactions: a Critical Interpretive Synthesis of the evidence about children who sexually abuse other children.
There is a growing interest in English-speaking jurisdictions, including Australia, North America, Canada, the United Kingdom and New Zealand, about the prevention of sexual abuse perpetrated by children against other children. The aim of this review was to identify opportunities for research, policy and practice which could enhance the prevention agenda relating to the perpetration of sexual abuse by children through conducting a Critical Interpretive Synthesis. Eleven electronic databases were searched in the period from 22 April to 23 May 2013 and included: SocINDEX, Social Services Abstracts, Applied Social Sciences Index and Abstracts, Family and Society Studies Worldwide, Project Muse, PsychINFO, Family and Society Plus, Jstor, Expanded Academic ASAP, Web of Science and Google Scholar. Key individual journals were also searched, including Child Abuse and Neglect and the Journal of Interpersonal Violence, as well as the grey literature. The search was guided by the research question: How could the prevention agenda relating to sexual abuse perpetrated by children be enhanced? The systematic literature search yielded 3323 titles, and 34 of these papers were included in the final synthesis. The authors identified five domains operating in the evidence base: characteristics, causes, communications, interventions and treatments. A synthesising construct emerged from the review: prevention-enhancing interactions. This construct referred to the potential for enhancing the prevention agenda which exists as the evidence domains interact with one another, and with the public health model of prevention. The authors consider this review to be a timely contribution to the current agenda pertaining to sexual abuse perpetrated by children. It provides researchers, policy makers and practitioners in the field with an evidence-informed conceptualisation of opportunities for enhancing prevention work.


Population pharmacokinetic analysis of tacrolimus in Chinese cardiac transplant recipients.
Usage of tacrolimus is complicated by its narrow therapeutic index and wide between- and within-subject pharmacokinetic variability. We aimed to obtain more information regarding the influence of various covariates on the disposition of tacrolimus in the early phase after cardiac transplantation using a population pharmacokinetic method, and provide information for the individualisation of drug dosing in the clinical setting. Routine therapeutic drug monitoring concentrations (897 observations) were retrospectively collected from 146 hospitalised patients. One compartment model with first-order absorption (absorption rate constant Ka was fixed as 4.48/hour) was employed to establish the population pharmacokinetic model using a non-linear mixed-effects modelling approach. Various demographic parameters, postoperative day and concomitant medications influencing drug clearance and distribution volume were investigated in this study. Bootstrap and prediction-corrected visual predictive check were employed to validate the final model. With the goal of tacrolimus trough concentrations within the therapeutic window, simulation was performed. Pharmacokinetic parameter population typical estimates for clearance (CL/F) and apparent distribution volume (V/F) were 14.23 L/hour and 760.80 L, respectively. Postoperative day and co-administration of Wuzhi capsules were identified as important factors affecting CL/F. Total body weight was significantly associated with the V/F. Results of model evaluation indicated a good stable and precise performance of the final model. Based on the simulation results, a simple-touse dosage regimen table to guide clinicians with drug dosing was created. The final population model could provide information for the individualised dosing of tacrolimus for cardiac transplant recipients.


Ocular histopathology in animals experimentally infected with Mycobacterium leprae and M. lepraemurium. 1. Mycobacterium leprae and M. lepraemurium infections in the mouse. 2. Mycobacterium leprae infections in the 9-banded armadillo (Dasypus novemcinctus L.).
At varying periods of time following the successful establishment of systemic infections with Mycobacterium leprae or M. lepraemurium in the mouse and the nine-banded armadillo eyes were examined by light microscopy. Inoculation of bacilli was by the intravenous or intraperitoneal route or directly into the hind footpads; eyes were not directly inoculated in this study. During periods of up to 3 years under laboratory conditions no animal showed evidence of impaired vision or blindness, and the external appearance of both eyes was normal. The ocular histopathology and the sites of accumulation of bacilli are described. In immunologically normal mice infected with M. lepraemurium bacilli were much commoner in extraorbital tissues, but they were, nevertheless, found in various tissues within the orbit, including the ciliary body and sclera. In immunologically normal mice (and one rat) injected with M. leprae of human origin no bacilli were found in the eye, but in mice immunologically depressed by thymectomy and total body irradiation considerable numbers of bacilli were present in the iris and ciliary body and also in the limbal cornea. In the armadillo bacilli were found in large numbers in virtually all tissues except the lens, retina, optic nerve, and aqueous and vitreous humours, but the uveal tract was heavily involved. Findings are discussed in relation to the great frequency of ocular involvement and the importance of immune-complex disease in patients with lepromatous leprosy, and to factors wihch may favour the localisation and multiplication of Mycobacterium leprae in the eye.


Depression and anxiety predict sex-specific cortisol responses to interpersonal stress.
Clinical theories posit interpersonal stress as an important factor in the emergence and exacerbation of depression and anxiety, while neuroendocrine research confirms the association of these syndromes with dysregulation in a major stress response system, the hypothalamic-pituitary-adrenal (HPA) axis. However, the proposal that depression and anxiety symptoms and diagnoses are associated with problematic HPA responses to close relationship stress has not been directly tested. We examined 196 heterosexual dating couples' depression and anxiety symptoms and diagnoses, assessed with questionnaires and diagnostic interviews, in relation to cortisol responses to discussion of an unresolved relationship conflict. Participants provided seven salivary samples in anticipation of and directly following the discussion, and throughout an hour-long recovery period, which were assayed for cortisol. Multilevel models of the HPA response predicted by symptoms or diagnoses showed that women's depressive symptoms predicted attenuated cortisol levels, with a flatter response curve. In contrast, men's depression symptoms and women's anxiety symptoms and diagnoses predicted higher cortisol levels. These findings highlight the importance of examining sex differences in responses to interpersonal stressors for understanding HPA dysregulation in internalizing psychopathology.


Can vitamin d suppress endothelial cells apoptosis in multiple sclerosis patients?
Multiple sclerosis (MS) is an autoimmune disease of central nerves system, in which neurological disabilities occur in young adults. Despite increasing number of studies on MS, some aspects of this disorder are still unclear. In the previous studies, it has been proven that there is direct relation between MS incidence and vitamin D deficiency. Thereby, strong evidence in MS pathogenesis suggests that endothelial cells (EC) could be harmed in MS. In addition, functional changes in EC and macrovascular injuries lead blood-brain barrier disruption in MS. Current study is the first investigation to elucidate positive influences of vitamin D against EC apoptosis in MS. Human umbilical vein endothelial cells (HUVECs) were cultured and then treated with sera from patients with active MS (in relapse) and sera from healthy volunteer participants as control group (each group n=15). 3-(4,5-dimethylthiazol-2-yl)-5- (3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assay for cell surveillance and cell-death detection kit for evaluating apoptosis were used in this study. There was a significant decrease in apoptosis rate by the serum of patients, just when 1,25(OH)2D3 applied before treating HUVECs with sera from active MS (in relapse). Furthermore, the cells surveillance increased markedly with the presence of 1,25(OH)(2)D(3) in culture, too. Withregard to increment in EC apoptosis rate, which treated by the sera from MS patients and decrement in apoptosis rate by the presence of vitamin D in culture media, it could be proposed that vitamin D pre-treatment can be used for MS patients, due to its beneficial effects on protecting EC apoptosis.


Feasibility of a Mobile Health Tool for Mothers to Identify Neonatal Illness in Rural Uganda: Acceptability Study.
A shortage of community health workers to triage sick neonates and poor recognition of neonatal illness by mothers contribute significantly toward neonatal deaths in low- and middle-income countries. Providing low-resource communities with the tools and knowledge to recognize signs of neonatal distress can lead to early care-seeking behavior. To empower and educate mothers to recognize signs of neonatal illness, we developed a neonatal health assessment device consisting of a smartphone app and a wearable sensor (the NeMo system). The aim of this study was to determine if mothers in rural Uganda were willing and able to use the NeMo system during the first week of their infant's life. We also assessed mothers' responses to the device's recommendation to seek care. A total of 20 mothers were enrolled in the study after giving birth in the Iganga District Hospital. Each mother was trained to use the NeMo system to assess her infant for signs of illness before leaving the hospital and was given the NeMo system to use at home for 1 week. Throughout the week, the smartphone tracked the mothers' usage of NeMo, and the study team visited twice to observe mothers' ability to use NeMo. Each mother was interviewed at the end of 1 week to gather qualitative feedback on her experience with the NeMo system. In total, 18 mothers completed the study; 2 mothers were withdrawn during the week because of extenuating health circumstances. Moreover, 1 day after enrollment and training, 75% (15/20) of mothers used NeMo properly with no mistakes. Three days after enrollment and training, only 1 mother placed the wearable sensor improperly on her infant. On the final study day, only 1 mother connected the device improperly. Mothers used NeMo an average of 11.67 (SD 5.70) times on their own at home during the 5 full study days. Although the frequency of use per day decreased from day 1 to day 5 of the study (P=.04), 72% (13/18) of mothers used NeMo at least once per day. In total, 64% (9/14) of mothers who received an alert from the NeMo system to seek care for their infants either called the health care professional working with the study team or reused the system immediately and found no danger signs. All 18 mothers agreed or strongly agreed that the NeMo system was easy to use and helped them know when to seek care for their babies. NeMo is a feasible and acceptable tool to aid mothers in rural Uganda to assess their infant's health.


The Mediterranean diet is associated with a reduction in premature mortality among middle-aged adults.
The available large prospective studies supporting an inverse association between better adherence to the Mediterranean diet and lower mortality have mainly included older adults. It is not clear whether this inverse association is also present among younger individuals at lower mortality risk. Our aim was to assess the association between adherence to the Mediterranean diet and total mortality in middle-aged adults from the Seguimiento Universidad de Navarra (SUN) Project. We followed 15,535 Spanish university graduates for a mean of 6.8 y. Their mean age was 38 ± 12 y, 59.6% were females, and all were initially free of cardiovascular disease, cancer, and diabetes. A validated FFQ was used to assess dietary habits. Adherence to the Mediterranean diet was categorized into 3 groups according to the Mediterranean Diet Score (low, 0-2 points; moderate, 3-5 points; and high, 6-9 points). The outcome variable was total mortality. Cox proportional hazards models were used to estimate HR and 95% CI. We adjusted the estimates for sex, age, years of university education, BMI, smoking, physical activity, television watching, history of depression and baseline hypertension, and hypercholesterolemia. We observed 125 deaths during 105,980 person-years of follow-up. The fully adjusted HR for moderate and high adherence were 0.58 (95% CI: 0.34, 0.99; P = 0.05) and 0.38 (95% CI: 0.21, 0.70; P = 0.002), respectively. For each 2-point increment in the Mediterranean Diet Score, the HR of death was 0.72 (95% CI: 0.58, 0.91; P = 0.006). Among highly educated, middle-aged adults, adherence to the traditional Mediterranean diet was associated with reduced risk of death.


CX3CR1 expression defines 2 KLRG1+ mouse NK-cell subsets with distinct functional properties and positioning in the bone marrow.
During development in the bone marrow (BM), NK-cell positioning within specific niches can be influenced by expression of chemokine or adhesion receptors. We previously demonstrated that the maintenance in the BM of selected NK-cell subsets is regulated by the CXCR4/CXCL12 axis. In the present study, we showed that CX3CR1 is prevalently expressed on KLRG1(+) NK cells, a subset considered terminally differentiated. Two KLRG1(+) NK-cell populations endowed with distinct homing and functional features were defined according to CX3CR1 expression. In the BM, KLRG1(+)/CX3CR1(-) NK cells were mainly positioned into parenchyma, while KLRG1(+)/CX3CR1(+) NK cells exhibited reduced CXCR4 expression and were preferentially localized in the sinusoids. We also showed that α(4) integrin plays a pivotal role in the maintenance of NK cells in the BM sinusoids and that α(4) neutralization leads to strong reduction of BM KLRG1(+)/CX3CR1(+) NK cells. Moreover, we found that KLRG1(+)/CX3CR1(+) cells originate from KLRG1(+)/CX3CR1(-) NK-cell population and display impaired capability to produce IFN-γ and to lyse YAC-1 target cells on cytokine stimulation. Altogether, our findings show that CX3CR1 represents a marker of a KLRG1(+) NK-cell population with unique properties that can irreversibly differentiate from the KLRG1(+)/CX3CR1(-) NK cells during steady state conditions.


Assessing the impact of anaesthetic and surgical task-shifting globally: a systematic literature review.
The global shortage of skilled anaesthesiologists, surgeons and obstetricians is a leading cause of high unmet surgical need. Although anaesthetic and surgical task-shifting are widely practised to mitigate this barrier, little is known about their safety and efficacy. This systematic review seeks to highlight the existing evidence on the clinical outcomes of patients operated on by non-physicians or non-specialist physicians globally. Relevant articles were identified by searching four databases (MEDLINE, EMBASE, CINAHL and Global Health) in all languages between January 2008 and February 2022. Retrieved documents were screened against pre-specified inclusion and exclusion criteria, and their qualities were appraised critically. Data were extracted by two independent reviewers and findings were synthesized narratively. In total, 40 studies have been included. Thirty-five focus on task-shifting for surgical and obstetric procedures, whereas four studies address anaesthetic task-shifting; one study covers both interventions. The majority are located in sub-Saharan Africa and the USA. Seventy-five per cent present perioperative mortality outcomes and 85% analyse morbidity measures. Evidence from low- and middle-income countries, which primarily concentrates on caesarean sections, hernia repairs and surgical male circumcisions, points to the overall safety of non-surgeons. On the other hand, the literature on surgical task-shifting in high-income countries (HICs) is limited to nine studies analysing tube thoracostomies, neurosurgical procedures, caesarean sections, male circumcisions and basal cell carcinoma excisions. Finally, only five studies pertaining to anaesthetic task-shifting across all country settings answer the research question with conflicting results, making it difficult to draw conclusions on the quality of non-physician anaesthetic care. Overall, it appears that non-specialists can safely perform high-volume, low-complexity operations. Further research is needed to understand the implications of surgical task-shifting in HICs and to better assess the performance of non-specialist anaesthesia providers. Future studies must adopt randomized study designs and include long-term outcome measures to generate high-quality evidence.


The effect of state early intervention eligibility policy on participation among a cohort of young CSHCN.
This purpose of this study was to describe differences in early intervention (EI) participation according to state among a cohort of young children with parent-reported developmental delays and disabilities. Data were obtained from the 2005-2006 National Survey of Children With Special Health Care Needs to describe state differences in EI participation. Multilevel modeling was used to estimate the relative contributions of child sociodemographic and developmental characteristics, and state EI eligibility policy on EI participation. The overall rate of EI participation was 45.7% (23.1%-83.3% across the states). EI participants were less likely to be Hispanic, live in a multiracial family, be poor, have a developmental delay, or have a less severe condition/delay. The predicted probability of receiving EI was lower for children who lived in states with more strict EI eligibility criteria than those with liberal criteria (.43 vs .52). Poverty influenced this association, with the adjusted probabilities of receiving EI for poor (<100% federal poverty level) and nonpoor (>185% federal poverty level) children being .18 and .36, respectively (P < .05). Among nonpoor children, those who lived in states with strict eligibility criteria were nearly as likely as poor children who lived in states with liberal eligibility criteria to receive EI (.33 vs .36; P < .05). The results of this study reveal marked disparities and unmet needs in EI participation as a function of both characteristics of the child and the state program. Improving developmental services for vulnerable populations requires addressing these sources of disparity.


A case report of tuberculous empyema: A tricky disease.
Extrapulmonary tuberculosis (TB) can rarely be transmitted to others. The disease mostly affects adults and immunocompromised individuals. A 26-year-old male presented with weight loss and occasional chest pain with a deep breath, but he was otherwise normal. The patient had a history of severe dry coughs, night sweats, fever, confusion, and dizziness for >3 weeks. The patient was initially misdiagnosed with an allergic cough and was treated with anti-allergic medications. Due to small and sticky effusion, the thoracentesis procedure failed, and the patient was referred to a thoracic surgeon for an open decortication. Pleural biopsy (PB) was negative for acid-fast bacilli, but the report showed necrotizing granulomatous inflammation. The patient was started on anti-TB treatment according to the WHO guidelines. The patient gained about 6% of the body weight at the end of the intensive phase and about 15% of the body weight at the end of the continuation phase. His chest pain subsided. Chest radiography showed improvement. The patient recovered, and no relapse occurred. This study recommends that a patient with dry coughs, night sweat, and fever for >3 weeks should be followed up with a chest X-ray for at least the next 3 months.