Determinants of late and/or inadequate use of prenatal healthcare in high-income countries: a systematic review.
Prenatal healthcare is likely to prevent adverse outcomes, but an adequate review of utilization and its determinants is lacking. To review systematically the evidence for the determinants of prenatal healthcare utilization in high-income countries. Search of publications in EMBASE, CINAHL and PubMed (1992-2010). Studies that attempted to study determinants of prenatal healthcare utilization in high-income countries were included. Two reviewers independently assessed the eligibility and methodological quality of the studies. Only high-quality studies were included. Data on inadequate use (i.e. late initiation, low-use, inadequate use or non-use) were categorized as individual, contextual and health behaviour-related determinants. Due to the heterogeneity of the studies, a quantitative meta-analysis was not possible. Ultimately eight high-quality studies were included. Low maternal age, low educational level, non-marital status, ethnic minority, planned pattern of prenatal care, hospital type, unplanned place of delivery, uninsured status, high parity, no previous premature birth and late recognition of pregnancy were identified as individual determinants of inadequate use. Contextual determinants included living in distressed neighbourhoods. Living in neighbourhoods with higher rates of unemployment, single parent families, medium-average family incomes, low-educated residents, and women reporting Canadian Aboriginal status were associated with inadequate use or entering care after 6 months. Regarding health behaviour, inadequate use was more likely among women who smoked during pregnancy. Evidence for determinants of prenatal care utilization is limited. More studies are needed to ensure adequate prenatal care for pregnant women at risk.


Enhanced interaction of patients' lymphocytes with human dermal microvascular endothelial cell cultures in active Adamantiades-Behçet disease.
To elucidate the role of lymphocyte/endothelial cell interactions in patients with Adamantiades-Behçet disease (ABD), we studied 16 patients of German and Turkish nationality (aged 18-57 years), all with active ABD, and 12 healthy volunteers (controls) of similar age and nationality. Peripheral blood lymphocytes (PBL) of patients were coincubated with human dermal microvascular endothelial cells (HDMEC) and human keratinocytes (HK) in vitro; interactions of PBL with HDMEC and HK were investigated using an established fluorometric assay. Interactions of patients' PBL with HDMEC, HK, or both were the main outcome measures. A significant increase of fluorescence with increasing PBL/HDMEC ratios was seen in patients and controls (P < .001); patients showed a significantly higher increase of fluorescence at higher PBL/HDMEC ratios (P < .05). The PBL/HK coincubation did not show significant alterations compared with the basal fluorescence signals of HK monolayers alone. Peripheral blood lymphocyte and HDMEC fluorescence values that were more than 2 SDs of controls (defined as positive result of assay) were found in a significantly higher number of patients with 2 or more active symptoms at the time of investigation (83%) compared with patients with only 1 active symptom (10%) (P = .008). Other clinical data did not correlate with the results of the PBL/HDMEC coincubation assay. Our results indicate enhanced in vitro interaction of PBL from patients with ABD with HDMEC, which was additionally shown to be a marker of the activity of the disease.


p63 expression correlates with sensitivity to the Eg5 inhibitor ZD4877 in bladder cancer cells.
Antimitotics such as taxanes are being considered as alternatives to conventional cisplatin-based chemotherapy in patients with bladder cancer, but the molecular determinants of sensitivity or resistance to these agents in bladder cancer cells have not been defined. Here we examined the cytotoxic effects of a novel antimitotic, the Eg5 inhibitor AZD4877, in a molecularly diverse panel of human bladder cancer cell lines. The cells displayed heterogeneous responses to the drug that correlated closely with sensitivity to docetaxel but not with sensitivity to cisplatin. Global gene expression profiling identified p63 as the top gene that was differentially expressed between sensitive and resistant cell lines. Stable knockdown of p63 inhibited cell death induced by either AZD4877 or docetaxel and was associated with decreased proliferation and decreased expression of c-myc. Furthermore, c-myc knockdown also rendered cells resistant to AZD4877 or docetaxel. Together, our results implicate p63 and its downstream target c-myc as determinants of sensitivity to anti-mitotics in bladder cancer cells. Our data also suggest that anti-mitotics and cisplatin target different subsets of bladder cancer cells, a conclusion that may have important implications for the therapy of muscle-invasive bladder cancers.


Measuring negative publicity.
Measuring the impact of negative news coverage on a hospital's image is an important first step in repairing the damage. That was the task at hand for a group of East Coast hospitals following a series of unfavorable newspaper stories. This article shows how public opinion research helped the hospitals to gauge the extent to which the negative press coverage affected their reputations and to identify targeted corrective action.


Azidohomoalanine: A Minimally Invasive, Versatile, and Sensitive Infrared Label in Proteins To Study Ligand Binding.
The noncanonical amino acid azidohomoalanine (Aha) is known to be an environment-sensitive infrared probe for the site-specific investigation of protein structure and dynamics. Here, the capability of that label is explored to detect protein-ligand interactions by incorporating it in the vicinity of the binding groove of a PDZ2 domain. Circular dichroism and isothermal titration calorimetry measurements reveal that the perturbation of the protein system by mutation is negligible, with minimal influence on protein stability and binding affinity. Two-dimensional infrared spectra exhibit small (1-3 cm-1) but clearly measurable red shifts of the Aha vibrational frequency upon binding of two different peptide ligands, while accompanying molecular dynamics simulations suggest that these red shifts are induced by polar contacts with side chains of the peptide ligands. Hence, Aha is a versatile and minimally invasive vibrational label that is not only able to report on large structural changes during, e.g., protein folding, but also on very subtle changes of the electrostatic environment upon ligand binding.


Developing a vaccine for human rhinoviruses.
Rhinoviruses (RV's) are common human pathogens of the respiratory tract being the most frequent cause of mild diseases of the upper respiratory tract (common cold) but more importantly they are a major initiator of acute exacerbations of chronic airway diseases. Infections can be life threatening in the latter context however RV -induced common colds have an associated economic cost from loss of productivity due to absence from work or school. There are no appropriate antiviral therapies available and vaccine strategies have failed because of the large number of viral serotypes and the lack of cross-serotype protection generated. Here, approaches past and present for development of a vaccine to these widespread human pathogens are highlighted.


Regulation of renal ion transport and cell growth by sodium.
Intracellular sodium has been implicated in a variety of cellular processes including regulation of Na+-K+-ATPase activity, mitogen-induced cell growth, and proliferation and stimulation of Na+-K+-ATPase by aldosterone. In renal epithelial cells a rise in sodium uptake across the apical membrane increases intracellular sodium concentration, which in turn stimulates the turnover rate of Na+-K+-ATPase and thereby enhances sodium efflux across the basolateral membrane. A prolonged increase in sodium uptake causes dramatic hypertrophy and hyperplasia and a rise in the quantity of Na+-K+-ATPase in the basolateral membrane. These structural and functional changes occur in the kidney in the absence of alterations in plasma aldosterone and vasopressin levels. Several mitogens induce growth and proliferation by initiating a cascade of events, which include a rise in intracellular sodium. Accordingly, an increase in the sodium concentration within renal epithelial cells may elicit a "mitogen-like" effect by initiating the cascade at the sodium step, even in the absence of a mitogen. A rise in cell sodium may also stimulate the production of autocrine growth factors that directly or indirectly regulate cell growth and proliferation, by modifying the response to mitogens or to changes in the ionic composition of the extracellular fluid. In this review we will examine the evidence that supports a role for intracellular sodium in regulating these cellular events in renal epithelial cells.


[EFFECTIVENESS COMPARISON OF ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION BY LONG FIBULAR MUSCLE TENDON AND HAMSTRING TENDON].
To compare the effectiveness of anterior cruciate ligament (ACL) reconstruction between by long fibular muscle tendon and by hamstring tendon under arthroscopy after ACL rupture. Between February 2010 and December 2012, 56 cases of ACL rupture underwent ACL reconstruction under arthroscopy. The long fibular muscle tendon was used in 26 cases (group A) and the hamstring tendon was used in 30 cases (group B). There was no significant difference in gender, age, side, disease duration, and preoperative Lachman test, Lysholm score, and the International Knee Documentation Committee (IKDC) score between 2 groups (P > 0.05). The treatment after operation was identical in 2 groups. Primary healing of incision was obtained after operation in 2 groups. There was no major neurovascular injury and knee synovitis. There was no significant difference in operation time, hospitalization time, and postoperative 24-hour drainage volume between 2 groups (P > 0.05). The patients were followed up 25-32 months (mean, 28 months) in group A, and 27-37 months (mean, 31 months) in group B. There was no related complication at donor site in 2 groups. MRI examination showed good ACL reconstruction. The Lysholm score and the IKDC score of group A at 6 months after operation were significantly better than those of group B (P < 0.05), but no significant difference was found between 2 groups at 2 years after operation (P > 0.05). There was no significant difference in Lachman score between 2 groups at 6 months and 2 years after operation (P > 0.05). The long fibular muscle tendon for arthroscopic reconstruction of ACL has much simpler operation, earlier knee function recovery, and better subjective satisfaction than the hamstring tendon.


"Doctors ready to be posted are jobless on the street…" the deployment process and shortage of doctors in Tanzania.
The World Health Organization advocates that health workforce development is a continuum of three stages of entry, available workforce and exit. However, many studies have focused on addressing the shortage of numbers and the retention of doctors in rural and remote areas. The latter has left the contribution of the entry stage in particularly the deployment process on the shortage of health workforce less understood. This study therefore explored the experiences of medical doctors (MDs) on the deployment process after the internship period in Tanzania's health sector. A qualitative case study that adopted chain referral sampling was used to conduct 20 key informant interviews with MDs who graduated between 2003 and 2009 from two Medical Universities in Tanzania between February and April 2016. These MDs were working in hospitals at different levels and Medical Universities in eight regions and five geo-political zones in the country. Information gathered was analysed using a qualitative content analysis approach. Experiences on the deployment process fall into three categories. First, "uncertainties around the first appointment" attributed to lack of effective strategies for identification of the pool of available MDs, indecision and limited vacancies for employment in the public sector and private sector and non-transparent and lengthy bureaucratic procedures in offering government employment. Second, "failure to respect individuals' preferences of work location" which were based on the influence of family ties, fear of the unknown rural environment among urbanized MDs and concern for career prospects. Third, "feelings of insecurity about being placed at a regional and district level" partly due to local government authorities being unprepared to receive and accommodate MDs and territorial protectionism among assistant medical officers. Experiences of MDs on the deployment process in Tanzania reveal many challenges that need to be addressed for the deployment to contribute better in availability of equitably distributed health workforce in the country. Short-term, mid-term and long-term strategies are needed to address these challenges. These strategies should focus on linking of the internship with the first appointment, work place preferences, defining and supporting career paths to health workers working under the local government authorities, improving the working relationships and team building at the work places and fostering rural attachment to medical students during medical training.


Systemic and topical use of monoclonal antibodies to prevent the sexual transmission of HIV.
: Passive immunization, the transfer of antibodies to a nonimmune individual to provide immunological protection, has been used for over 100 years to prevent and treat human infectious diseases. The introduction of techniques to produce human mAbs has revolutionized the field, and a large number of human mAbs have been licensed for the treatment of cancer, autoimmune and inflammatory diseases. With the recent discovery and production of highly potent broadly neutralizing and other multifunctional antibodies to HIV, mAbs are now being considered for HIV therapy and prophylaxis. In this review, we briefly present recent advances in the anti-HIV mAb field and outline strategies for the selection, engineering and production of human mAbs, including the modification of their structure for optimized stability and function. We also describe results from nonhuman primate studies and phase 1 clinical trials that have tested the safety, tolerability, pharmacokinetics, and efficacy of mAb-based HIV prevention strategies, and discuss the future of parenteral and topical mAb administration for the prevention of HIV transmission.


Finding New Targets for the Treatment of Heart Failure: Endoplasmic Reticulum Stress and Autophagy.
Heart failure is a progressive disease with an annual mortality rate of about 10% and is the end-stage stage of various heart diseases, which places a huge socioeconomic burden on the healthcare system. The development of heart failure has received increasing attention as a potential way to improve the treatment of this disease. Many studies have shown that endoplasmic reticulum stress and autophagy play an important role in the occurrence and development of heart failure. With the in-depth study of endoplasmic reticulum stress and autophagy, both are considered promising targets for pharmacological interventions to treat heart failure, but the mechanism of heart failure between the two is not clear. This review will highlight the effects of endoplasmic reticulum stress, autophagy, and their interactions in the development and development of heart failure, thereby helping to provide direction for the future development of targeted therapies for patients with heart failure. CLINICAL RELEVANCE: This study explored the new targets for the treatment of heart failure: endoplasmic reticulum stress and autophagy. Targeted drug therapy for endoplasmic reticulum stress and autophagy is expected to provide a new intervention target for the treatment of heart failure.


Best available technologies and treatment trains to address current challenges in urban wastewater reuse for irrigation of crops in EU countries.
Conventional urban wastewater treatment plants (UWTPs) are poorly effective in the removal of most contaminants of emerging concern (CECs), including antibiotics, antibiotic resistant bacteria and antibiotic resistance genes (ARB&ARGs). These contaminants result in some concern for the environment and human health, in particular if UWTPs effluents are reused for crop irrigation. Recently, stakeholders' interest further increased in Europe, because the European Commission is currently developing a regulation on water reuse. Likely, conventional UWTPs will require additional advanced treatment steps to meet water quality limits yet to be officially established for wastewater reuse. Even though it seems that CECs will not be included in the proposed regulation, the aim of this paper is to provide a technical contribution to this discussion as well as to support stakeholders by recommending possible advanced treatment options, in particular with regard to the removal of CECs and ARB&ARGs. Taking into account the current knowledge and the precautionary principle, any new or revised water-related Directive should address such contaminants. Hence, this review paper gathers the efforts of a group of international experts, members of the NEREUS COST Action ES1403, who for three years have been constructively discussing the efficiency of the best available technologies (BATs) for urban wastewater treatment to abate CECs and ARB&ARGs. In particular, ozonation, activated carbon adsorption, chemical disinfectants, UV radiation, advanced oxidation processes (AOPs) and membrane filtration are discussed with regard to their capability to effectively remove CECs and ARB&ARGs, as well as their advantages and drawbacks. Moreover, a comparison among the above-mentioned processes is performed for CECs relevant for crop uptake. Finally, possible treatment trains including the above-discussed BATs are discussed, issuing end-use specific recommendations which will be useful to UWTPs managers to select the most suitable options to be implemented at their own facilities to successfully address wastewater reuse challenges.


[Justifying hyperbaric oxygenation use for medical correction in individuals working in extreme conditions].
Experimental studies were conducted to justify possibility of hyperbaric oxygenation to correct functional state in individuals working in extreme conditions. Studies were aimed to determine stress resistance in apparently healthy individuals, to choose hyperbaric oxygenation method and mode.


Improved leptin sensitivity as a potential candidate responsible for the spontaneous food restriction of the Lou/C rat.
The Lou/C rat, an inbred strain of Wistar origin, was described as a model of resistance to age- and diet-induced obesity. Although such a resistance involves many metabolic parameters described in our previous studies, Lou/C rats also exhibit a spontaneous food restriction due to decreased food consumption during the nocturnal period. We then attempted to delineate the leptin sensitivity and mechanisms implicated in this strain, using different protocols of acute central and peripheral leptin administration. A first analysis of the meal patterns revealed that Lou/C rats eat smaller meals, without any change in meal number compared to age-matched Wistar animals. Although the expression of the recognized leptin transporters (leptin receptors and megalin) measured in the choroid plexus was normal in Lou/C rats, the decreased triglyceridemia observed in these animals is compatible with an increased leptin transport across the blood brain barrier. Improved hypothalamic leptin signaling in Lou/C rats was also suggested by the higher pSTAT3/STAT3 (signal transducer and activator of transcription 3) ratio observed following acute peripheral leptin administration, as well as by the lower hypothalamic mRNA expression of the suppressor of cytokine signaling 3 (SOCS3), known to downregulate leptin signaling. To conclude, spontaneous hypophagia of Lou/C rats appears to be related to improved leptin sensitivity. The main mechanism underlying such a phenomenon consists in improved leptin signaling through the Ob-Rb leptin receptor isoform, which seems to consequently lead to overexpression of brain-derived neurotrophic factor (BDNF) and thyrotropin-releasing hormone (TRH).


Influence of surfactant on the thermal behavior of marigold oil emulsions with liquid crystal phases.
Vegetable oils have been largely consumed owing to the interest of pharmaceutical and cosmetic industries in using natural raw materials. The production of stable emulsions with vegetable oils challenges formulators due to its variability in composition and fatty acids constitution within batches produced. In the present work, it was studied that the influence of the size of carbon chain and the number of ethylene oxide moieties of the surfactant on the thermal behavior of eight emulsions prepared with marigold oil stabilized by liquid crystal phases. Differential scanning calorimetry (DSC) was used to determine the thermal behavior of the emulsions. The ratio of bound water was calculated, being between 29.0 and 42.0%, confirming the extension of the liquid-crystalline net in the external phase. Changing the lipophilic surfactant from Ceteth-2 to Steareth-2, there was an increase in the temperature of phase transition of the liquid crystal influencing the system stability. Calorimetric study is very useful in understanding the performance of liquid crystals with the increase of temperature and to estimate emulsions stability.


Mycobacterium tuberculosis SigF regulates genes encoding cell wall-associated proteins and directly regulates the transcriptional regulatory gene phoY1.
Mycobacterium tuberculosis SigF is homologous to stress response and sporulation sigma factors in many bacteria. Consistent with a possible role in mycobacterial survival under stress conditions, M. tuberculosis sigF is strongly induced within cultured human macrophages and upon nutrient starvation, and SigF has been implicated in M. tuberculosis entry into stationary phase. On the other hand, SigF appears to contribute to the immune pathology of tuberculosis (TB), and a sigF-deficient mutant has altered cell membrane properties. Using an M. tuberculosis sigF deletion mutant, we show here that sigF is not required for bacillary survival under nutrient starvation conditions and within activated murine macrophages or for extracellular persistence in an in vivo granuloma model of latent TB infection. Using a chemically inducible recombinant strain to conditionally overexpress sigF, we did not observe arrest or retardation of growth in exponentially growing cultures or reduced susceptibility to rifampin and isoniazid. Consistent with our hypothesis that SigF may mediate TB immunopathogenesis by altering cell membrane properties, we found that overexpression of sigF resulted in the differential regulation of many cell wall-associated proteins, including members of the MmpL, PE, and PPE families, several of which have been shown to influence host-pathogen interactions. The most highly upregulated gene by quantitative reverse transcription-PCR at all time points following sigF induction was Rv3301c (phoY1), which encodes a probable transcriptional regulatory protein homologous to PhoU proteins involved in regulation of phosphate uptake. Using in vitro transcription analysis, we show that SigF directly regulates phoY1, whose proposed promoter sequence is GGATTG-N(16)-GGGTAT.


An antibody which binds to the membrane-proximal end of influenza virus haemagglutinin (H3 subtype) inhibits the low-pH-induced conformational change and cell-cell fusion but does not neutralize virus.
A monoclonal antibody, LMBH6, was derived from mice which had been sequentially immunized with bromelain-cleaved haemagglutinin (BHA) from influenza virus A/Aichi/2/68, A/Victoria/3/75 and A/Philippines/2/82 (all H3N2). LMBH6 recognizes the haemagglutinin (HA) of all H3N2 influenza A strains tested, which were isolated between 1968 and 1989. HA in the low-pH-induced conformation is not recognized, and cleavage of the HA0 precursor to HA1 and HA2 is needed to obtain efficient binding. Compared to other monoclonal antibodies, binding of LMBH6 to virus and to virus-infected cells is weak, while binding to BHA is comparable. Electron microscopy demonstrates binding to the membrane proximal end of the stem structure. The antibody shows no haemagglutination-inhibition activity, but inhibits polykaryon formation and the low-pH-induced conformational change of BHA. However, LMBH6 cannot prevent infection of MDCK cells but slows the growth of virus when included in a plaque assay overlay.


Potential mechanisms of Na+/K+-ATPase attenuation by heat and pesticides co-exposure in goldfish: role of cellular apoptosis, oxidative/nitrative stress, and antioxidants in gills.
In this study, we examined the dose-dependent effects of an environmentally relevant pesticide cocktail (metalachlor, linuron, isoproturon, tebucanazole, aclonifen, atrazine, pendimethalin, and azinphos-methyl) and temperature change (22 vs. 32 °C for 4-week exposure) on Na+/K+-ATPase, 3-nitrotyrosine protein (NTP), dinitrophenyl protein (DNP), catalase (CAT), and superoxide dismutase (SOD) expressions in gills of goldfish (Carassius auratus). Histopathological analysis showed widespread damage to gill in elevated temperature (32 °C) and pesticide co-exposure groups, including fusion of secondary lamellae, club-shaped primary lamellae, rupture of epithelial layer, loss of normal architecture, and hemorrhaging. Immunohistochemical and qRT-PCR analyses showed significant decreases in Na+/K+-ATPase protein and mRNA expressions in gills exposed to higher temperature and pesticides; however, combined exposure to heat and pesticides significantly increases NTP, DNP, CAT, and SOD expressions. In situ TUNEL assay revealed elevated levels of apoptotic cells in response to combined exposure. Collectively, our results suggest the combined effects of heat and pesticide stress cause cellular damage, upregulate oxidative/nitrative stress biomarkers, and increase apoptotic cells, downregulate Na+/K+-ATPase expression in gills. This provides new evidence for oxidant/antioxidant-dependent mechanisms for downregulation of Na+/K+-ATPase expression in gills during combined exposure.


Wavelength adjustment using an eye model from aberrometry data.
We developed a method to convert aberrometry data obtained in one wavelength to the corresponding data in another wavelength using an eye model. A single map of aberrometry data is used to construct a free-form one-surface eye model. A general algorithm for the surface construction is described and implemented for real aberrometry data. Our method can handle varying conjugate distances of the measurement plane of the aberrometer and can also manage the chief ray prism that may be present. The algorithm is validated with the aid of an artificial plastic eye. The wavefronts in different wavelengths are compared through the Zernike analysis not only for lower-order aberrations, but also for higher-order aberrations. The results show that the changes of the Zernike aberration coefficients due to wavelengths are non-uniform. The defocus term has the highest effect from wavelength changes, which is consistent with the previous literature. Our method is compared with two approximate semi-analytical algorithms. The wavelength adjustments from a multi-surface eye model are contrasted with our method. We prove analytically that the conventional method of wavelength adjustment is based on paraxial analysis. In addition, we provide a method of finding the chief ray using back-projection in some cases and discuss different meanings of prism.


Diabetic gastroparesis: diagnosis and management.
Gastric emptying is frequently abnormal in patients with long-standing type 1 and type 2 diabetes mellitus. Symptoms commonly associated with disordered gastric emptying include nausea, vomiting, bloating and epigastric pain, while patients are also at risk of malnutrition, weight loss, impaired drug absorption, disordered glycaemic control and poor quality of life. Although often attributed to the presence of irreversible autonomic neuropathy, acute hyperglycaemia represents a potentially reversible cause of gastric dysfunction in diabetes. Scintigraphy represents the gold standard for measuring gastric emptying. The management of diabetic gastroparesis is less than optimal, partly because the pathogenesis has not been clearly defined. Treatment approaches include dietary modification and optimization of glycaemia, and the use of prokinetic drugs, while novel therapies such as gastric electrical stimulation are the subject of ongoing investigation.


Regulation of the collagen IV network by the basement membrane protein perlecan is crucial for squamous epithelial cell morphogenesis and organ architecture.
All epithelia have their basal side in contact with a specialized extracellular matrix, the basement membrane (BM). During development, the BM contributes to the shaping of epithelial organs via its mechanical properties. These properties rely on two core components of the BM, collagen type IV and perlecan/HSPG2, which both interact with another core component, laminin, the initiator of BM assembly. While collagen type IV supplies the BM with rigidity to constrain the tissue, perlecan antagonizes this effect. Nevertheless, the number of organs that has been studied is still scarce, and given that epithelial tissues exhibit a wide array of shapes, their forms are bound to be regulated by distinct mechanisms. This is underscored by mounting evidence that BM composition and assembly/biogenesis is tissue-specific. Moreover, previous reports have essentially focused on the mechanical role of the BM in morphogenesis at the tissue scale, but not the cell scale. Here, we took advantage of the robust conservation of core BM proteins and the limited genetic redundancy of the Drosophila model system to address how this matrix shapes the wing imaginal disc, a complex organ comprising a squamous, a cuboidal and a columnar epithelium. With the use of a hypomorphic allele, we show that the depletion of Trol (Drosophila perlecan) affects the morphogenesis of the three epithelia, but particularly that of the squamous one. The planar surface of the squamous epithelium (SE) becomes extremely narrow, due to a function for Trol in the control of the squamous shape of its cells. Furthermore, we find that the lack of Trol impairs the biogenesis of the BM of the SE by modifying the structure of the collagen type IV lattice. Through atomic force microscopy and laser surgery, we demonstrate that Trol provides elasticity to the SE's BM, thereby regulating the mechanical properties of the SE. Moreover, we show that Trol acts via collagen type IV, since the global reduction in the trol mutant context of collagen type IV or the enzyme that cross-links its 7S -but not the enzyme that cross-links its NC1- domain substantially restores the morphogenesis of the SE. In addition, a stronger decrease in collagen type IV achieved by the overexpression of the matrix metalloprotease 2 exclusively in the BM of the SE, significantly rescues the organization of the two other epithelia. Our data thus sustain a model in which Trol counters the rigidity conveyed by collagen type IV to the BM of the SE, via the regulation of the NC1-dependant assembly of its scaffold, allowing the spreading of the squamous cells, spreading which is compulsory for the architecture of the whole organ.


Congenital dislocation of the hip. Recent advances and current problems.
This article reviews changes that have occurred in the understanding and treatment of congenital dislocation of the hip (CDH). It is now recognized that CDH is a spectrum of diseases with differing etiologies, pathologies, and natural histories that, as a result, require different treatment approaches. The etiology of CDH involves genetic, hormonal, mechanical, and environmental influences. This recognition of mechanical factors that predispose to CDH has allowed the identification of high-risk patients. Screening for CDH in the new born has resulted in many more patients being diagnosed earlier. Ultrasonography has added a new dimension to CDH diagnosis, since it has demonstrated abnormal hips in otherwise normal children. In the newborn, the use of ultrasonography may be the single most important recent contribution to the study of this disease. The natural history of CDH is well-known: The disease often can lead to early coxarthrosis. However, avascular necrosis is a complication of treatment and results in a hip that may be worse than one not treated at all. Treatment of CDH includes gentle closed reduction in the majority of patients. In patients under six months of age, this can usually be achieved with the Pavlik harness. Up to the age of three years, gentle manipulative closed reduction after traction is successful in the majority of patients. The trend toward the use of home traction and away from inpatient skeletal traction has been documented by many centers to be successful. Open reduction is becoming infrequently required and has specific indications.(ABSTRACT TRUNCATED AT 250 WORDS)


Multimode interference tapered fiber refractive index sensors.
Real-time monitoring of the fabrication process of tapering down a multimode-interference-based fiber structure is presented. The device is composed of a pure silica multimode fiber (MMF) with an initial 125 μm diameter spliced between two single-mode fibers. The process allows a thin MMF with adjustable parameters to obtain a high signal transmittance, arising from constructive interference among the guided modes at the output end of the MMF. Tapered structures with waist diameters as low as 55 μm were easily fabricated without the limitation of fragile splices or difficulty in controlling lateral fiber alignments. The sensing device is shown to be sensitive to the external environment, and a maximum sensitivity of 2946 nm/refractive index unit in the refractive index range of 1.42-1.43 was attained.


An update on the use of cerebrospinal fluid analysis as a diagnostic tool in multiple sclerosis.
Intrathecal B-lymphocyte activation is a hallmark of multiple sclerosis (MS), a multi-factorial inflammatory-demyelinating disease of the central nervous system. Such activation has a counterpart in the cerebrospinal fluid (CSF) oligoclonal IgG bands (OCB), whose diagnostic role in MS has been downgraded within the current McDonald's criteria. With a theoretico-practical approach, the authors review the physiopathological basis of the CSF dynamics, and the state-of-the-art of routine CSF analysis and CSF biomarkers in MS. Areas covered: The authors discuss pros and cons of CSF analysis, including critical evaluations of both well-established, and promising diagnostic and prognostic laboratory tools. New acquisitions on the CSF and cerebral interstitial fluid dynamics are also presented. The authors searched the PubMed database for English-language articles reported between January 2010 and June 2016, using the key words 'multiple sclerosis', 'cerebrospinal fluid', 'oligoclonal bands'. Reference lists of relevant articles were scanned for additional studies. Expert commentary: The availability of performing high-quality, routine CSF tests in specialized laboratories, the emerging potential of novel CSF biomarkers, and the trend for early treatments should induce a reappraisal of CSF analysis for diagnostic and prognostic purposes in MS. Further procedural and methodological improvements seem to be necessary in both research and translational diagnostic CSF settings.


Blood pressure excursions in acute ischemic stroke patients treated with intravenous thrombolysis.
To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA). We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER. The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75 min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P = 0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR = 0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR = 0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR = 0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR = 0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR = 0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR = 1.26, 95% CI: 1.04-1.53). BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.


Flavonoids and PI3K/Akt/mTOR Signaling Cascade: A Potential Crosstalk in Anticancer Treatment.
Cancer is one of the leading causes of death worldwide. A slight decline in mortality has been noted, but the currently available treatment options did not give an expected outcome and are associated with several side effects resulting a substantial economic burden. The advent of plant-based treatment is rising because of its ease of use, ready availability, cost-effectiveness, and low/no toxicity. In recent years, flavonoids with their diverse physico-biological properties have gained the scientific community's attention for the treatment of various forms of cancer. Different flavonoids, especially, flavonols (quercetin, kaempferol, fisetin, and isorhamnetin), flavanones (hesperidin and naringin), and anthocyanins, have shown potent anticancer activities affecting various signaling cascades. Among those, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/ mammalian target of rapamycin (mTOR) signaling pathway is widely known to play a significant role in different physio-cellular activities, which triggers malignant transformation and is considered a key target for anticancer compounds. This pathway plays a vital role in regulating the cell cycle, metabolism, survival, and proliferation. The flavonoids exhibit their anticancer activity via different molecular pathways, including PI3K/Akt/mTOR. In the current piece of paper, our focus is to underpin the action of the above-mentioned flavonoids against different cancers, mainly covering in-vitro data, through PI3K/Akt/mTOR targeting.


Clinical Management of Financial Toxicity-Identifying Opportunities through Experiential Insights of Cancer Survivors, Caregivers, and Social Workers.
Perspectives of cancer survivors, caregivers, and social workers as key stakeholders on the clinical management of financial toxicity (FT) are critical to identify opportunities for better FT management. Semi-structured interviews (cancer survivors, caregivers) and a focus group (social workers) were undertaken using purposive sampling at a quaternary public hospital in Australia. People with any cancer diagnosis attending the hospital were eligible. Data were analysed using inductive-deductive content analysis techniques. Twenty-two stakeholders (n = 10 cancer survivors of mixed-cancer types, n = 5 caregivers, and n = 7 social workers) participated. Key findings included: (i) genuine concern for FT of cancer survivors and caregivers shown through practical support by health care and social workers; (ii) need for clarity of role and services; (iii) importance of timely information flow; and (iv) proactive navigation as a priority. While cancer survivors and caregivers received financial assistance and support from the hospital, the lack of synchronised, shared understanding of roles and services in relation to finance between cancer survivors, caregivers, and health professionals undermined the effectiveness and consistency of these services. A proactive approach to anticipate cancer survivors' and caregivers' needs is recommended. Future research may develop and evaluate initiatives to manage cancer survivors and families FT experiences and outcomes.


Associations of the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay diet with cardiac remodelling in the community: the Framingham Heart Study.
Normal cardiac function is directly associated with the maintenance of cerebrovascular health. Whether the Mediterranean-Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet, designed for the maintenance of neurocognitive health, is associated with cardiac remodelling is unknown. We evaluated 2512 Framingham Offspring Cohort participants who attended the eighth examination cycle and had available dietary and echocardiographic data (mean age 66 years; 55 % women). Using multivariable regression, we related the cumulative MIND diet score (independent variable) to left ventricular (LV) ejection fraction, left atrial emptying fraction, LV mass (LVM), E/e' ratio (dependent variables; primary), global longitudinal strain, global circumferential strain (GCS), mitral annular plane systolic excursion, longitudinal segmental synchrony, LV hypertrophy and aortic root diameter (secondary). Adjusting for age, sex and energy intake, higher cumulative MIND diet scores were associated with lower values of indices of LV diastolic (E/e' ratio: logβ = -0·03) and systolic function (GCS: β = -0·04) and with higher values of LVM (logβ = 0·02), all P ≤ 0·01. We observed effect modification by age in the association between the cumulative MIND diet score and GCS. When we further adjusted for clinical risk factors, the associations of the cumulative MIND diet score with GCS in participants ≥66 years (β = -0·06, P = 0·005) and LVM remained significant. In our community-based sample, relations between the cumulative MIND diet score and cardiac remodelling differ among indices of LV structure and function. Our results suggest that favourable associations between a higher cumulative MIND diet score and indices of LV function may be influenced by cardiometabolic and lifestyle risk factors.


A work sampling study of midlevel health professionals in a rural medical clinic.
A work sampling study was initiated to provide a comprehensive description of the tasks performed by midlevel health personnel in the rural component of an experimental medical care delivery system. The investigation determined the proportion of time spent on various activities by the staff members of a rural clinic which is linked to supervisory physicians in a distant urban medical center. Over 800 observations were recorded during ten randomly selected days in a two-month period on each of the three staff members. The family nurse practitioner spent one-third of her time in direct patient care activities with almost one-half of the day devoted to indirect patient care tasks. The laboratory aide allocated one-half of her day to providing direct patient services whereas the clerk-receptionist spent over 40 per cent of her day on patient records and billing. Work sampling results were considered within a comparative framework to qualitatively assess performance. The findings were coupled with proposed changes in administrative and medical policy to provide a quantitative basis for developing cost-reducing alternative staffing configurations.


Effect of ethanol on mouse cerebral cortical beta-adrenergic receptors.
Low concentrations of ethanol (10-100 mM), added to assays in vitro, altered agonist (isoproterenol) binding to mouse cerebral cortical beta-adrenergic receptors in a reversible manner. Ethanol decreased the affinity of the high affinity form of the receptor for isoproterenol but had no effect on the affinity of the low affinity form of the receptor, the proportion of high and low affinity forms of the receptor, the total number of agonist-binding sites, or antagonist binding. The selective effect of ethanol on the properties of the high affinity agonist-binding site suggested that ethanol alters the characteristics of the complex of the receptor and Gs, the guanine nucleotide-binding protein. In cerebral cortical membranes of mice that had ingested ethanol chronically, isoproterenol binding data were best fit by a one-site model, even in the absence of guanine nucleotides. This change, when considered together with previously reported changes in adenylate cyclase activity, is reminiscent of heterologous desensitization of the beta-adrenergic receptor. Thus, both acute and chronic ethanol administration may produce changes in adrenergic function in brain.


Multicenter Evaluation of the Cepheid Xpert Xpress SARS-CoV-2/Flu/RSV Test.
With the approach of respiratory virus season in the Northern Hemisphere, clinical microbiology and public health laboratories will need rapid diagnostic assays to distinguish severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from influenza virus and respiratory syncytial virus (RSV) infections for diagnosis and surveillance. In this study, the clinical performance of the Xpert Xpress SARS-CoV-2/Flu/RSV test (Cepheid, Sunnyvale, CA, USA) for nasopharyngeal swab specimens was evaluated in four centers: Johns Hopkins Medical Microbiology Laboratory, Northwell Health Laboratories, NYC Public Health Laboratory, and Los Angeles County/University of Southern California (LAC+USC) Medical Center. A total of 319 nasopharyngeal swab specimens, positive for SARS-CoV-2 (n = 75), influenza A virus (n = 65), influenza B virus (n = 50), or RSV (n = 38) or negative (n = 91) by the standard-of-care nucleic acid amplification tests at each site, were tested using the Cepheid panel test. The overall positive percent agreement for the SARS-CoV-2 target was 98.7% (n = 74/75), and the negative agreement was 100% (n = 91), with all other analytes showing 100% total agreement (n = 153). Standard-of-care tests to which the Cepheid panel was compared included the Cepheid Xpert Xpress SARS-CoV-2, Cepheid Xpert Xpress Flu/RSV, GenMark ePlex respiratory panel, BioFire respiratory panel 2.1 and v1.7, DiaSorin Simplexa COVID-19 Direct, and Hologic Panther Fusion SARS-CoV-2 assays. The Xpert Xpress SARS-CoV-2/Flu/RSV test showed high sensitivity and accuracy for all analytes included in the test. This test will provide a valuable clinical diagnostic and public health solution for detecting and differentiating SARS-CoV-2, influenza A and B virus, and RSV infections during the current respiratory virus season.


Crystallization and characterization of the prolidase from Pyrococcus furiosus.
The prolidase (proline-specific amino dipeptidase) from the hyperthermophilic archaeon Pyrococcus furiosus has been crystallized. The enzyme has been shown to be a homodimer and to require two Co atoms per subunit for optimum activity. Two crystal forms have been obtained under similar growth conditions. Both are monoclinic, space group P2(1). Form I has unit-cell parameters a = 130.4, b = 97.4, c = 129.9 A, beta = 118.3 degrees. Form II has a smaller unit cell, with a = 56.5, b = 97.3, c = 70.0 A, beta = 97.1 degrees. If the crystal density is assumed to lie near the center of the normal range then the form I crystals will have four dimers per asymmetric unit, whereas the form II crystals will have only one dimer in each asymmetric unit. Diffraction data have been recorded from native form I and form II crystals to resolutions of 3.2 and 1.95 A, respectively.


The Clinical and Psychosocial Outcomes for Women Who Received Unexpected Clinically Actionable Germline Information Identified through Research: An Exploratory Sequential Mixed-Methods Comparative Study.
Background Research identifying and returning clinically actionable germline variants offer a new avenue of access to genetic information. The psychosocial and clinical outcomes for women who have received this 'genome-first care' delivering hereditary breast and ovarian cancer risk information outside of clinical genetics services are unknown. Methods: An exploratory sequential mixed-methods case-control study compared outcomes between women who did (cases; group 1) and did not (controls; group 2) receive clinically actionable genetic information from a research cohort in Victoria, Australia. Participants completed an online survey examining cancer risk perception and worry, and group 1 also completed distress and adaptation measures. Group 1 participants subsequently completed a semi structured interview. Results: Forty-five participants (group 1) and 96 (group 2) completed the online survey, and 31 group 1 participants were interviewed. There were no demographic differences between groups 1 and 2, although more of group 1 participants had children (p = 0.03). Group 1 reported significantly higher breast cancer risk perception (p < 0.001) compared to group 2, and higher cancer worry than group 2 (p < 0.001). Some group 1 participants described how receiving their genetic information heightened their cancer risk perception and exacerbated their cancer worry while waiting for risk-reducing surgery. Group 1 participants reported a MICRA mean score of 27.4 (SD 11.8, range 9−56; possible range 0−95), and an adaptation score of 2.9 (SD = 1.1). Conclusion: There were no adverse psychological outcomes amongst women who received clinically actionable germline information through a model of 'genome-first' care compared to those who did not. These findings support the return of clinically actionable research results to research participants.


Helicobacter pylori infection in bleeding peptic ulcer patients after non-steroidal antiinflammatory drug consumption.
To establish the prevalence of Helicobacter pylori (H. pylori) infection in patients with a bleeding peptic ulcer after consumption of non-steroidal antiinflammatory drugs (NSAIDs). A very early upper endoscopy was performed to find the source of upper gastrointestinal bleeding and to take biopsy specimens for analysis of H. pylori infection by the rapid urease (CLO) test, histological examination, and bacterial culture. IgG anti-CagA were also sought. The gold standard for identifying H. pylori infection was positive culture of biopsy specimens or contemporary positivity of the CLO test and the presence of H. pylori on tissue sections. Eighty patients, 61 males (76.3%), mean age 61.2 ± 15.9 years, were consecutively enrolled. Forty-seven (58.8%) patients occasionally consumed NSAIDs, while 33 (41.3%) were on chronic treatment with low-dose aspirin (LD ASA). Forty-four (55.0%) patients were considered infected by H. pylori. The infection rate was not different between patients who occasionally or chronically consumed NSAIDs. The culture of biopsy specimens had a sensitivity of 86.4% and a specificity of 100%; corresponding figures for histological analysis were 65.9% and 77.8%, for the CLO test were 68.2% and 75%, for the combined use of histology and the CLO test were 56.8% and 100%, and for IgG anti-CagA were 90% and 98%. The highest accuracy (92.5%) was obtained with the culture of biopsy specimens. Patients with a bleeding peptic ulcer after NSAID/LD ASA consumption frequently have H. pylori infection. Biopsy specimen culture after an early upper gastrointestinal tract endoscopy seems the most efficient test to detect this infection.


Perspectives of Canadian Rural Consultant Pediatricians on Diagnosing Autism Spectrum Disorder: A Qualitative Study.
Consultant pediatricians represent a potential resource for increasing autism spectrum disorder (ASD) diagnostic capacity; however, little is known about how they perceive their roles in ASD diagnosis. The objective of this study was to examine the perspectives of rural consultant pediatricians regarding their perceived roles, facilitators, and barriers in ASD diagnosis. We performed a qualitative study using thematic analysis. Consultant pediatricians from 3 small-sized and medium-sized Ontario communities were recruited. Semistructured interviews were conducted, transcribed, coded, and analyzed. Fourteen pediatricians participated in this study. Participants all considered ASD diagnosis to be in their scope of practice. The major theme identified was the process of diagnosing ASD, which occurred in 3 stages: preassessment (gathering information before the first clinic visit), diagnosis, and service access. All these stages are influenced by ecological factors consisting of characteristics of the child, family, individual physician, pediatric group practice, and the broader system of ASD care. Consultant pediatricians practicing in nonurban Ontario communities see ASD diagnosis as part of their scope of practice and collaboratively work within groups to address the needs of their communities. Strategies aimed at increasing diagnostic capacity should target salaried group practices and improve the efficiency of assessments through preclinic information gathering.


Ubiquitin ligase Smurf1 controls osteoblast activity and bone homeostasis by targeting MEKK2 for degradation.
Bone is constantly resorbed and formed throughout life by coordinated actions of osteoclasts and osteoblasts. Here we show that Smurf1, a HECT domain ubiquitin ligase, has a specific physiological role in suppressing the osteogenic activity of osteoblasts. Smurf1-deficient mice are born normal but exhibit an age-dependent increase of bone mass. The cause of this increase can be traced to enhanced activities of osteoblasts, which become sensitized to bone morphogenesis protein (BMP) in the absence of Smurf1. However, loss of Smurf1 does not affect the canonical Smad-mediated intracellular TGFbeta or BMP signaling; instead, it leads to accumulation of phosphorylated MEKK2 and activation of the downstream JNK signaling cascade. We demonstrate that Smurf1 physically interacts with MEKK2 and promotes the ubiquitination and turnover of MEKK2. These results indicate that Smurf1 negatively regulates osteoblast activity and response to BMP through controlling MEKK2 degradation.


Antidepressants in the treatment of fibromyalgia.
Fibromyalgia syndrome is a chronic disease of widespread and debilitating pain whose cause is unknown and whose risk factors are poorly understood. It is often comorbid with rheumatoid and other pain disorders as well as psychiatric disorders such as anxiety and depression. Although they are not officially approved for this indication, antiepileptics and antidepressants are often used to treat fibromyalgia. The tricyclic antidepressants (TCAs), particularly amitriptyline, are among the most common treatment strategies. Because of the poor tolerability of the tricyclics, the newer antidepressants have been widely tested in fibromyalgia. The selective serotonin reuptake inhibitors (SSRIs) and the reversible monoamine oxidase inhibitors do not seem to be particularly helpful. The serotonin and norepinephrine reuptake inhibitors (SNRIs), duloxetine and milnacipran, on the other hand, have been shown in placebo-controlled trials to offer significant relief to patients suffering from fibromyalgia. Although no direct comparative studies have been performed, these compounds appear to be as effective as the TCAs but much better tolerated. The effectiveness of the SNRIs as well as other dual acting antidepressants, such as mirtazapine, but not the SSRIs, implies that a dysfunction of both serotonin and norepinephrine neurotransmission probably exists in fibromyalgia. The effectiveness of antidepressants appears to be independent of their effect on comorbid depression.


The efficacy of different sources of mesenchymal stem cells for the treatment of knee osteoarthritis.
Osteoarthritis (OA) is a common cause of chronic pain and disability. Regenerative therapies using mesenchymal stem cells (MSCs) provide an option for OA treatment as it could potentially regenerate the damaged cartilage. Bone marrow, adipose tissue and synovium are common MSC sources. The aim is to compare the therapeutic effect of MSCs from bone marrow, adipose tissue and synovium; combining its differentiation potential and accessibility, to decide the optimal source of MSCs for the treatment of knee OA. A comparison of preclinical and clinical studies using MSCs has been made with regard to treatment outcomes, isolation procedure and differentiation potential. All types of MSCs are effective at improving the clinical and structural condition of OA patients, but the longevity of the treatment, i.e. an effect that is maintained for at least 2 years, cannot be guaranteed. This review highlighted great variations in selection criteria and culture expansion conditions of MSCs between the literature and clinical trials. It also emphasised a substantial diversity and lack of consistency in the assessment mythology of clinical outcome after completion of MSC therapies procedures. A more cohesive methodology is required to evaluate the outcome of MSC treatments using quantitative and standardised frameworks in order to be able to directly compare results. Larger population of patients are recommended to assess the quality of MSC when designing studies and clinical trials to reaffirm the efficacy of MSC treatment prior to and within the clinical trials and follow up studies.


Age-modified factors associated with placental malaria in rural Burkina Faso.
Malaria in pregnancy can result in placental infection with fetal implications. This study aimed at assessing placental malaria (PM) prevalence and its associated factors in a cohort of pregnant women with peripheral malaria and their offspring. The data were collected in the framework of a clinical trial on treatments for malaria in pregnant women . Placental malaria (PM) was diagnosed by histopathological detection of parasites and/or malaria pigment on placenta biopsies taken at delivery. Factors associated with PM were assessed using logistic regression. Out of 745 biopsies examined, PM was diagnosed in 86.8 % of women. Acute, chronic and past PM were retrieved in 11 (1.5 %), 170 (22.8 %), and 466 (62.6 %) women, respectively. A modifying effect was observed in the association of gravidity or anemia at the study start with pooled PM (presence of parasites and/or malaria pigment). In women under 30, gravidity ≤ 2 was associated with an increased prevalence of pooled PM but in women aged 30 years or more, gravidity was no more associated with pooled PM (OR 6.81, 95 % CI 3.18 - 14.60; and OR 0.52, 95 % CI 0.10 - 2.76, respectively). Anemia was associated with pooled PM in women under 30 (OR 1.96, 95 % CI 1.03 - 3.72) but not in women aged 30 years or more (OR 0.68, 95 % CI 0.31 - 1.49). Similarly, the association of gravidity with past-chronic PM depended also on age. A higher prevalence of active PM was observed in women under 30 presenting with symptomatic malaria (OR 3.79, 95 % CI 1.55 - 9.27), while there was no significant increase in the prevalence of active PM (presence of parasites only) in women with symptomatic malaria when aged 30 years or more (OR 0.42, 95 % CI 0.10 - 1.75). In women with chronic PM, the prevalence of low birth weight or prematurity was the highest (31.2 %) as compared with past PM or no PM. Despite the rapid diagnosis and efficacious treatment of peripheral infection, the prevalence of placental malaria remained high in women with P. falciparum peripheral infection in Nanoro, especially in younger women This underlines the importance of preventive measures in this specific group.


Investigation of natural RIN4 variants reveals a motif crucial for function and provides an opportunity to broaden NLR regulation specificity.
Multiple bacterial effectors target RPM1-INTERACTING PROTEIN4 (RIN4), the biochemical modifications of which are recognized by several plant nucleotide-binding and leucine-rich repeat immune receptor (NLR) proteins. Recently, a comparative study of Arabidopsis and apple (Malus domestica) RIN4s revealed that the RIN4 specificity motif (RSM) is critical for NLR regulation. Here, we investigated the extent to which the RSM contributes to the functions of natural RIN4 variants. Functional analysis of 33 natural RIN4 variants from 28 plant species showed that the RSM is generally required yet sometimes dispensable for the RIN4-mediated suppression of NLR auto-activity or effector-triggered NLR activation. Association analysis of the sequences and fire blight resistance gene originating from Malus × robusta 5 (FB_MR5) activation functions of the natural RIN4 variants revealed H167 to be an indispensable residue for RIN4 function in the regulation of NLRs. None of the tested natural RIN4 variants could suppress RESISTANCE TO PSEUDOMONAS SYRINGAE PV. MACULICOLA1 (RPM1) auto-activity and activate FB_MR5. To engineer RIN4 to carry broader NLR compatibility, we generated chimeric RIN4 proteins, several of which could regulate RPM1, RESISTANT TO PSEUDOMONAS SYRINGAE2 (RPS2), and FB_MR5. We propose that the intrinsically disordered nature of RIN4 provides a flexible platform to broaden pathogen recognition specificity by establishing compatibility with otherwise incompatible NLRs.


Data-driven FDG-PET subtypes of Alzheimer's disease-related neurodegeneration.
Previous research has described distinct subtypes of Alzheimer's disease (AD) based on the differences in regional patterns of brain atrophy on MRI. We conducted a data-driven exploration of distinct AD neurodegeneration subtypes using FDG-PET as a sensitive molecular imaging marker of neurodegenerative processes. Hierarchical clustering of voxel-wise FDG-PET data from 177 amyloid-positive patients with AD dementia enrolled in the Alzheimer's Disease Neuroimaging Initiative (ADNI) was used to identify distinct hypometabolic subtypes of AD, which were then further characterized with respect to clinical and biomarker characteristics. We then classified FDG-PET scans of 217 amyloid-positive patients with mild cognitive impairment ("prodromal AD") according to the identified subtypes and studied their domain-specific cognitive trajectories and progression to dementia over a follow-up interval of up to 72 months. Three main hypometabolic subtypes were identified: (i) "typical" (48.6%), showing a classic posterior temporo-parietal hypometabolic pattern; (ii) "limbic-predominant" (44.6%), characterized by old age and a memory-predominant cognitive profile; and (iii) a relatively rare "cortical-predominant" subtype (6.8%) characterized by younger age and more severe executive dysfunction. Subtypes classified in the prodromal AD sample demonstrated similar subtype characteristics as in the AD dementia sample and further showed differential courses of cognitive decline. These findings complement recent research efforts on MRI-based identification of distinct AD atrophy subtypes and may provide a potentially more sensitive molecular imaging tool for early detection and characterization of AD-related neurodegeneration variants at prodromal disease stages.


Effects of calcium and pH on the mucosal damage produced by deoxycholic acid in the rat colon.
A single pass perfusion system was used in anaesthetised, restrained rats to examine the effect of changing the composition of the perfusion fluid on the damage caused to the colonic epithelium by deoxycholic acid. Damage to the colonic surface was monitored with light microscopy, transmission and scanning electron microscopy and with measurements of deoxyribonucleic acid and carbohydrate in the perfusate. New scoring techniques for monitoring alterations in surface epithelium of light microscopy sections were used. The damaging effect of 5 mM deoxycholic acid to the colonic epithelium is inhibited by lowering the pH of the perfusion fluid from 7.9 to 5.5, or by increasing the calcium concentration from 0 to 4 mM. This inhibition is shown to be because of a decreased amount of bile acid in solution. Thus it is not the total concentration of deoxycholic acid in the colon that is responsible for the colonic damage, but the concentration in solution. Although extrapolation to the human situation must be made with caution, the concentration of bile acid in solution in the faecal water may be more relevant to colonic mucosal damage than total bile acid concentration.


Development and characterization of pomegranate peel extract-functionalized jackfruit seed starch-based edible films and coatings for prolonging the shelf life of white grapes.
In the current research, the pomegranate peel extract of varying concentrations (0.02, 0.04, 0.06, 0.08, and 0.1 g/mL) were incorporated into jackfruit seed starch (5 % w/w) based edible films and coatings for the evaluation their effects on the mechanical, physical, barrier and thermal properties. Furthermore, the effects of the optimized edible coating were investigated on the postharvest shelf life of white grapes at room storage (30 ± 5 °C, RH = 70 ± 5 %) conditions for up to 8 days. The obtained results showed a significant increment in thickness (p ≤ 0.05) with higher concentration (0.1 g/mL) of pomegranate peel extract (PPE), total phenolic content (959.33 ± 43.36 mg/100 g) and antioxidant activity (87.35 ± 1.64 %) of the prepared edible films but have negative impacts on the water vapor permeability (2.82 × 10-6 ± 6.48 × 10-7 g-1h-1pa-1) and oxygen permeability (1.62 × 10-14 ± 9.32 × 10-15 cm3·cm/cm2·s·cmHg), solubility (23.24 ± 3.21 %), and tensile strength (1.60 ± 0.43 MPa). The edible film enriched with 0.4 g/mL of PPE showed higher thermal stability in terms of glass transition temperature (98.2 ± 0.21 °C) and peak temperature (110.3 ± 0.35 °C). Additionally, the application of coating treatment significantly maintains the postharvest shelf life of white grapes throughout the storage period.


The impact of start strategy on start performance in alpine skiing exists on flat, but not on steep inclines.
Here, we explored the relationship between incline and start strategy during alpine skiing. Eight FIS skiers performed starts on a flat (3°) and steep (21°) incline employing five different strategies. Their times, trajectories and velocities were monitored with a GNSS system and video. A significant interaction was observed between slope incline and start strategy with respect to the skier's exit velocity (p < 0.001, ƞ2p = 0.716), but not for the start section time (p = 0.732, ƞ2p = 0.037). On the almost flat incline, both section time (p = 0.022, ƞ2p = 0.438) and exit velocity (p < 0.001, ƞ2p = 0.786) were influenced significantly by start strategy, with four V2 skate-pushes being optimal. On the steep incline, neither section time nor exit velocity was affected significantly by start strategy, the fastest section time and exit velocity being attained with four and two V2 skate-pushes, respectively. In conclusion, these findings demonstrate that the start strategy exerts considerable impact on start performance on almost flat inclines, with strategies involving three or more V2 skate-pushes being optimal. In contrast, start performance on the steep incline was not influenced by strategy.


Effects of hydrogen-rich water and ascorbic acid treatment on spontaneously hypertensive rats.
Hydrogen-rich water (HW) has been suggested to possess antioxidant properties of value in treatments of lifestyle diseases and for prevention of latent pathologies. To date, the potential benefits of HW against the deleterious effects of excessive salt intake and hypertension have not been investigated. Here, we first examined the effects of HW or HW supplemented with 0.1% ascorbic acid (HWA) on spontaneously hypertensive rats (SHR) that had been fed a normal diet. In comparison to control rats given distilled water (DW), we found that HW did not significantly influence systolic blood pressure (SBP) or diastolic blood pressure (DBP) in SHR; however, the increase in SBP and DBP were inhibited in the HWA group. Next, four groups of SHR were given DW, 0.1% ascorbic acid-added DW (DWA), HW, or HWA in combination with a 4% NaCl-added diet. SHR fed the 4% NaCl-added diet showed increased hypertension; HWA treatment resulted in a significant reduction in blood pressure. The HWA group tended to have lower plasma angiotensin II levels than the DW group. In addition, urinary volumes and urinary sodium levels were significantly lower in the HWA group than the DW group. Urinary isoprostane, an oxidative stress marker, was also significantly lower in the HWA group, suggesting that the inhibitory effect of HWA on blood pressure elevation was caused by a reduction in oxidative stress. These findings suggest a synergistic interaction between HW and ascorbic acid, and also suggest that HWA ingestion has potential for prevention of hypertension.


Prevalence of urinary stone disease in vegetarians.
A study was carried out to determine the effect of a low animal protein diet, such as taken by vegetarians, on the risk of urinary stone disease. A nation-wide survey of vegetarians in the UK showed that the prevalence of urinary stone formation is 40-60% of that predicted for a group of individuals taken from the general population and matched for age, sex and social class with the vegetarians. The findings support the hypothesis that a diet low in animal protein reduces the risk of urinary stone formation.


Tissue to air ratios for open-cut uranium mine employees: a simulation using circular plane sources.
Tissue to air ratios of absorbed dose have been measured for certain organs in an Alderson Rando radiotherapy phantom irradiated by simulated circular plane sources of degraded gamma rays from radium-226. The absorbed dose measurements were performed using thermoluminescent dosemeters. Factors were determined which relate the absorbed dose received by the organ, of interest to (i) the absorbed dose in air at the height of the organ, (ii) the absorbed dose measured by a personal monitor worn at the chest and waist, and (iii) the absorbed dose in air at 1 m above the source. Effective dose equivalents have been calculated using the above factors in conjunction with ICRP 26 weighting factors. The results indicate that a good estimate of the effective dose equivalent can be obtained irrespective of the wearing position of the personal monitor on the trunk.


Probabilistic consideration of consequences of long-duration accidental releases based on complete weather data.
This paper presents a method based on chronological weather data for estimating how variations in weather conditions during a radioactive release affect the consequences of the release. The modifications of the method made in the computer-based applications owing to the limited calculation resources are also studied. Additionally, the length of the chronological weather data observation period needed to satisfactorily support the assessments was tested. The results of the different duration times for the normalized concentration--which is the concentration divided by the release rate, and called here the dispersion factor--are presented and compared with the commonly used sector average model and the generic wind meandering method. The new method can be used for a variety of release durations and it makes realistic estimates, managing to avoid the weaknesses of the methods compared. The necessary length of the weather data is on the order of 1 y to get statistically satisfactory results.


A Small Dose Can Cause a Major Problem.
Baclofen is a presynaptic gamma-aminobutyric acid agonist, which has been used to treat muscle spasms. Due to its low cost and low addiction potential, baclofen has been the muscle relaxant of choice for many years. This drug is metabolized in the kidneys, posing a threat to patients with underlying renal dysfunction, with complications ranging from drug toxicity to death. We present a case of baclofen toxicity in a patient with renal failure on hemodialysis, who presented with signs and symptoms of baclofen overdose after consuming 10 mg of the medication. The highlight of this case is the detailed history taking, verifying all home medications, and thorough physical examination of the patient.


[Rat-bite fever].
Rat bite fever and Haverhill fever are caused by Streptobacillus moniliformis which is part of the natural oral flora of rats and other rodents. Fever accompanied by headache, nausea and myalgia develops within ten days. Complications can be fatal. A case of rat bite fever is described. A 48-year-old woman developed fever and malaise five days after being bitten by a pet rat. Two days later rash and arthritis in the hand and feet developed. Erythromycin was administered without effect. Ten days after the bite the patient was admitted to hospital and recovered after two weeks of intravenous penicillin therapy. S moniliformis was isolated from blood culture. On admission CRP was 231, ESR 88, ASAT 87, ALAT 218 and gamma-GT 461. Laboratory results normalized after therapy. In cases of fever after rodent bites, S moniliformis infection should always be considered. Diagnosis is made by blood culture or cultivation from pus from the bite wound. First choice therapy is penicillin, or in case of intolerance, tetracycline.


Evaluation of a new IR-guided system for mechanical QA of linear accelerators.
The authors report the development of a new procedure for mechanical quality assurance of linear accelerators using an infrared-guided system. The system consists of an infrared (IR) camera and an IR-reflective marker that can be attached to a gantry, a collimator, or a treatment table. The trace of this marker can be obtained in three dimensions (3D) for a full or partial rotation of the mechanical devices. The software is written to localize rotational axes of the gantry, collimator, and the treatment table based on the marker traces. The separation of these axes characterizes the size of the sphere defining the mechanical isocenter. Additional information on anomalies in gantry movement such as degree of gantry sag and hysteresis can also be obtained. An intrinsic uncertainty of the system to localize rotational axis is 0.35 mm or less. Tests on a linear accelerator demonstrated the ability of this system to detect the separation between rotational axes of less than 1 mm and to confirm orthogonality of the planes of gantry, collimator, and table rotation.


Microsatellite instability markers for identifying early-onset colorectal cancers caused by germ-line mutations in DNA mismatch repair genes.
Microsatellite instability (MSI) testing of colorectal cancer tumors is used as a screening tool to identify patients most likely to be mismatch repair (MMR) gene mutation carriers. We wanted to examine which microsatellite markers currently used to detect MSI best predict early-onset colorectal cancer caused by germ-line mutations in MMR genes. Invasive primary tumors from a population-based sample of 107 cases of colorectal cancer diagnosed before age 45 years and tested for germ-line mutations in MLH1, MSH2, MSH6, and PMS2 and MMR protein expression were screened for MSI using the National Cancer Institute panel and an expanded 10-microsatellite marker panel. The National Cancer Institute five-marker panel system scored 31 (29%) as (NCI)MSI-High, 13 (12%) as (NCI)MSI-Low, and 63 (59%) as (NCI)MS-Stable. The 10-marker panel classified 18 (17%) as (10)MSI-High, 17 (16%) as (10)MSI-Low, and 72 (67%) as (10)MS-Stable. Of the 26 cancers that lacked the expression of at least one MMR gene, 24 (92%) were positive for some level of MSI (using either microsatellite panel). The mononucleotide repeats Bat26, Bat40, and Myb were unstable in all (10)MSI-High cancers and all MLH1 and MSH2 mutation carriers (100% sensitive). Bat40 and Bat25 were unstable in all tumors of MSH6 mutation carriers (100% sensitive). Bat40 was unstable in all MMR gene mutation carriers (100% sensitive). By incorporating seven mononucleotide repeats markers into the 10-marker panel, we were able to distinguish the carriers of MSH6 mutations (all scored (10)MSI-Low) from the MLH1 and MSH2 mutation carriers (all scored (10)MSI-High). In early-onset colorectal cancer, a microsatellite panel containing a high proportion of mononuclear repeats can distinguish between tumors caused by MLH1 and MSH2 mutations from those caused by MSH6 mutations.


The nuclear receptor hepatocyte nuclear factor 4alpha acts as a morphogen to induce the formation of microvilli.
Microvilli are actin-based organelles found on apical plasma membranes that are involved in nutrient uptake and signal transduction. Numerous components, including ezrin/radixin/moesin (ERM) proteins, have been identified that link filamentous actins to transmembrane proteins, but the signals driving microvillus biogenesis are not known. In this study, we show that the conditional and/or ectopic expression of a nuclear receptor, hepatocyte nuclear factor 4alpha (HNF4alpha), triggers microvillus morphogenesis. We also demonstrate that HNF4alpha expression induces ERM-binding phosphoprotein 50 (EBP50) expression and that attenuation of EBP50 using RNA interference inhibits microvillus development. We conclude that HNF4alpha acts as a morphogen to trigger microvillus formation.


Aortic complications after bariatric surgery.
Obesity and its correlated comorbidities are nowadays considered a public health concern. In the last few years, a myriad of strategies searched an effective procedure to reduce weight and decreases related comorbidities. Among these strategies, the bariatric procedures have been achieved a significantly increase, being able to promote an expressive and lasting weight reduction. Diverse early and late complications are described and related to restrictive and malabsortive bariatric procedures. In this report we describe two cases of cardiovascular complications (aortic dissection and aneurysm) in the late postoperative period of the bariatric procedures.


The morphology of human conjunctival mucus.
Normal human conjuctival mucus was examined by permeable membrane filter (Millipore) surface biopsy and instillation of India ink. It exists in solution in the tear film, as clusters of granules, as granular sheets, and as strands, the latter often arranged as a network. This mucus network entraps exfoliated epithelial cells, miscellaneous surface debris, carbon particles (from the India ink) and bacteria, and stains positively for lipid. Blinking causes both collapse of this mucus network into a single strand and movement of this strand to the medial canthus, where it compacts and is pushed onto the skin surface. There it dries and either falls off or is removed by rubbing. It is suggested that the formation and collapse of this mucus network represents a system for removing exfoliated surface cells and debris, infection and foreign particles, and lipid-contaminated mucus from the surface of the normal eye.


Observed parenting behavior with teens: measurement invariance and predictive validity across race.
Previous reports supporting measurement equality between European American and African American families have often focused on self-reported risk factors or observed parent behavior with young children. This study examines equality of measurement of observer ratings of parenting behavior with adolescents during structured tasks; mean levels of observed parenting; and predictive validity of teen self-reports of antisocial behaviors and beliefs using a sample of 163 African American and 168 European American families. Multiple-group confirmatory factor analyses supported measurement invariance across ethnic groups for four measures of observed parenting behavior: prosocial rewards, psychological costs, antisocial rewards, and problem solving. Some mean-level differences were found: African American parents exhibited lower levels of prosocial rewards, higher levels of psychological costs, and lower problem solving when compared to European Americans. No significant mean difference was found in rewards for antisocial behavior. Multigroup structural equation models suggested comparable relationships across race (predictive validity) between parenting constructs and youth antisocial constructs (i.e., drug initiation, positive drug attitudes, antisocial attitudes, problem behaviors) in all but one of the tested relationships. This study adds to existing evidence that family-based interventions targeting parenting behaviors can be generalized to African American families.


Characteristics and postnatal development of the acid lipase activity of the rat small intestine.
Acid lipase was identified in the rat small intestine by using esters of 4-methylumbelliferone as substrates. Maximum activity towards the oleate ester was found at pH 4.0. In adult animals, the activity of acid lipase exhibited both latency and sedimentability, indicating a lyosomal localization. The activity of acid lipase was practically the same along the height of the villus, thus paralleling the distribution of acid beta-galactosidase. In adult rats, the activity of acid lipase in proximal (jejunum) and middle (mid-jejunum) sections of the small intestine was practically the same and exceeded the activity in the distal (ileum) section by a factor of 2. In suckling rats, the activity of the enzyme in the mid-jejunum exceeded that in the jejunum and ileum by 2.5- and 1.5-fold respectively. During postnatal development, the acid lipase activity of the mid-jejunum showed a peak between days 10 and 15, at which time it exceeded the adult mid-jejunum activity by 5--6-fold.


The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study.
In this study we analyzed the influence of human immunodeficiency virus (HIV) infection on the course of chronic hepatitis C through multivariate analysis including age, alcohol consumption, immune status, and hepatitis C virus (HCV)-related virologic factors. Eighty HIV-positive and 80 HIV-negative injection drug users included between 1980 and 1995 were matched according to age, gender, and duration of HCV infection and followed-up during 52 months. The progression to cirrhosis was the primary outcome measure. The impact of HIV on HCV-RNA load, histologic activity index, response to interferon therapy, and liver-related death was also considered. In HIV-positive patients, chronic hepatitis C was characterized by higher serum HCV-RNA levels (P =.012), higher total Knodell score (P =.011), and poorer sustained response to interferon therapy (P =.009). High serum HCV-RNA level was associated with low CD4-lymphocyte count (P =.001). Necroinflamatory score was higher in HIV-positive patients (P =.023) independently of the CD4-lymphocyte count, whereas increased fibrosis was related to decreased CD4-lymphocyte count (P =.011). The progression to cirrhosis was accelerated in HIV-positive patients with low CD4 cell count (RR = 4.06, P =.024) and in interferon-untreated patients (RR = 4.76, P =.001), independently of age at HCV infection (P =.001). Cirrhosis caused death in 5 HIV-positive patients. The risk of death related to cirrhosis was increased in heavy drinkers (RR = 10.8, P =.001) and in HIV-positive patients with CD4 cell count less than 200/mm(3) (RR = 11.9, P =.007). In this retrospective cohort study, HIV coinfection worsened the outcome of chronic hepatitis C, increasing both serum HCV-RNA level and liver damage and decreasing sustained response to interferon therapy. Age and alcohol were cofactors associated with cirrhosis and mortality. Interferon therapy had a protective effect against HCV-related cirrhosis no matter what the patient's HIV status was.


Heterologous encapsidation of recombinant pea early browning virus.
The coat protein gene of pea early browning virus (PEBV) was replaced with that of another tobravirus, tobacco rattle virus (TRV strain PPK20). The recombinant virus multiplied efficiently in the systemic host Nicotiana benthamiana and, on the local lesion host Phaseolus vulgaris, produced symptoms typical of PEBV rather than TRV showing that viral coat protein is not a determinant for lesion morphology. Both viral RNAs were encapsidated by TRV coat protein although the shorter particles (encapsidated RNA-2) did not form a discrete population. Evidence is presented to suggest involvement of nucleotide sequences upstream of the coat protein gene in virus particle assembly.


Changes of Small Non-coding RNAs by Severe Acute Respiratory Syndrome Coronavirus 2 Infection.
The ongoing pandemic of coronavirus disease 2019 (COVID-19), which results from the rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a significant global public health threat, with molecular mechanisms underlying its pathogenesis largely unknown. In the context of viral infections, small non-coding RNAs (sncRNAs) are known to play important roles in regulating the host responses, viral replication, and host-virus interaction. Compared with other subfamilies of sncRNAs, including microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs), tRNA-derived RNA fragments (tRFs) are relatively new and emerge as a significant regulator of host-virus interactions. Using T4 PNK-RNA-seq, a modified next-generation sequencing (NGS), we found that sncRNA profiles in human nasopharyngeal swabs (NPS) samples are significantly impacted by SARS-CoV-2. Among impacted sncRNAs, tRFs are the most significantly affected and most of them are derived from the 5'-end of tRNAs (tRF5). Such a change was also observed in SARS-CoV-2-infected airway epithelial cells. In addition to host-derived ncRNAs, we also identified several small virus-derived ncRNAs (svRNAs), among which a svRNA derived from CoV2 genomic site 346 to 382 (sv-CoV2-346) has the highest expression. The induction of both tRFs and sv-CoV2-346 has not been reported previously, as the lack of the 3'-OH ends of these sncRNAs prevents them to be detected by routine NGS. In summary, our studies demonstrated the involvement of tRFs in COVID-19 and revealed new CoV2 svRNAs.


Exploring the effect of anharmonicity of molecular vibrations on thermodynamic properties.
Thermodynamic properties of selected small and medium size molecules were calculated using harmonic and anharmonic vibrational frequencies. Harmonic vibrational frequencies were obtained by normal mode analysis, whereas anharmonic ones were calculated using the vibrational self-consistent field (VSCF) method. The calculated and available experimental thermodynamic data for zero point energy, enthalpy, entropy, and heat capacity are compared. It is found that the anharmonicity and coupling of molecular vibrations can play a significant role in predicting accurate thermodynamic quantities. Limitations of the current VSCF method for low frequency modes have been partially removed by following normal mode displacements in internal, rather than Cartesian, coordinates.


Enhanced human CD4+ T cell engraftment in beta2-microglobulin-deficient NOD-scid mice.
Genetic crosses produced NOD/LtSz mice doubly homozygous for the severe combined immunodeficiency (scid) mutation and the beta2m (B2m) null allele. Both NOD/LtSz-scid/scid and NOD/LtSz-scid/scid B2m(null) mice lacked mature lymphocytes and serum Ig. However, homozygosity for the B2m(null) allele also resulted in the absence of MHC class I expression, loss of NK cell activity, accumulation of iron in the liver, and rapid clearance of human IgG1. NOD/LtSz-scid/scid B2m(null) mice supported markedly elevated levels of human T cell engraftment, compared with NOD/LtSz-scid/scid control animals, following injection with human PBMC. The increased engraftment was associated with a major increase in the number of human CD4+ T cells. Following injection with 20 million human PBMC, levels of human CD4+ T cells in the peripheral blood and spleen of NOD/ LtSz-scid/scid B2m(null) mice were 6- to 7-fold higher than those in NOD/LtSz-scid/scid mice and >50-fold higher than those in C.B-17-scid/scid mice. The resulting normalization of CD4+/CD8+ ratios in NOD/LtSz-scid/scid B2m(null) mice is in sharp contrast to that observed in NOD/LtSz-scid/scid mice or in C.B-17-scid/scid mice. Circulating human IgG was cleared 6-fold more rapidly in NOD/LtSz-scid/scid B2m(null) mice than in NOD/LtSz-scid/scid mice. This rapid IgG clearance suggested a failure of the engrafted human lymphoid cells to maintain high circulating levels of human IgG. The higher levels of human CD4+ T cells and the normalization of the CD4:CD8 ratio that are observed in human PBMC-engrafted NOD/LtSz-scid/scid B2m(null) mice suggest that this system may be an excellent model for studies of HIV pathogenesis.


Fish Skin Gelatin Hydrolysate Production by Ginger Powder Induces Glutathione Synthesis To Prevent Hydrogen Peroxide Induced Intestinal Oxidative Stress via the Pept1-p62-Nrf2 Cascade.
Gelatin hydrolysate was reported to contain large amounts of biologically active peptides with excellent antioxidant properties. However, its inducement of antioxidant response within cells and the underlying molecular mechanism are far from clear. Here, gelatin from Nile tilapia skin was hydrolyzed by ginger protease to produce antioxidant hydrolysate, and three fish skin gelatin hydrolysate fractions (FSGHFs) were obtained by ultrafiltration. Fractionation of the hydrolysate increased the free radical scavenging capacity of the FSGHFs, particularly FSGHF3, which showed the lowest molecular weight (below 1000 Da). Furthermore, FSGHF3 treatment prior to H2O2 exposure increased cell viability and membrane integrity in IPEC-J2 cells. H2O2-induced ROS production and epithelial barrier damage were suppressed by FSGHF3 pretreatment. FSGHF3 stimulated the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), along with increases in the mRNA and protein expression of catalytic and modulatory subunits of γ-glutamylcysteine ligase as well as in the level of glutathione. Silencing of Nrf2 or p62 (an upstream regulator of Nrf2) suppressed FSGHF3-induced Nrf2 activation and its protection against H2O2-induced oxidative stress. Moreover, oligopeptides in FSGHF3 may mediate the cytoprotective effect against oxidative stress, which was confirmed by the result that FSGHF3 failed to inhibit the ROS production in H2O2-exposed cells with the knockdown of Pept1 (an oligopeptide transporter). Therefore, FSGHF3 can induce glutathione synthesis and prevent oxidative stress through the Pept1-p62-Nrf2 cascade and thus may be a functional food for gastrointestinal dysfunction.


Geographic variation and physician specialization in the use of percutaneous biopsy for breast cancer diagnosis.
Preoperative diagnosis of breast cancer is a standard of care. We conducted a population-based study to determine the factors associated with the use of percutaneous needle biopsy to diagnose breast cancer in Ontario. We identified a total of 3644 women who underwent breast tissue sampling (percutaneous needle biopsy or surgical excision) that yielded a diagnosis of cancer between Apr. 1, 2002, and Dec. 31, 2002, and for whom we were able to obtain complete data. We performed univariate and multivariate analyses to examine the association between a number of variables and the use of percutaneous biopsy or surgery for diagnosis and the performance of biopsy with or without image guidance. The variables were age, local health integration network (LHIN), income quintile, urban or rural residence, access to a primary care provider, prior mammogram, prior regular screening mammography, screen-initiated biopsy, and surgeon and radiologist specialization in breast disease. A total of 2374 women (65%) underwent percutaneous biopsy to diagnose breast cancer. The use of percutaneous biopsy varied from 22% to 81% among LHINs. On multivariate analysis, no patient variables were associated with the use of percutaneous biopsy for diagnosis. Only the LHIN and surgeon and radiologist specialization were predictive of whether a woman received a percutaneous biopsy. These 2 variables, along with income quintile and screen-initiated biopsy, were associated with the use of image-guided biopsy as the method of choice. Geographic variation in the use of percutaneous biopsy, particularly image-guided biopsy, for the diagnosis of breast cancer exists across Ontario. The frequency of such biopsies may be a useful quality indicator. Strategies to improve uptake of organized evidence-based care may increase the use of percutaneous biopsy.


Pharmacokinetics and pharmacodynamics of high-dose human regular U-500 insulin versus human regular U-100 insulin in healthy obese subjects.
Human regular U-500 (U-500R) insulin (500 units/mL) is increasingly being used clinically, yet its pharmacokinetics (PK) and pharmacodynamics (PD) have not been well studied. Therefore, we compared PK and PD of clinically relevant doses of U-500R with the same doses of human regular U-100 (U-100R) insulin (100 units/mL). This was a single-site, randomized, double-blind, crossover euglycemic clamp study. Single subcutaneous injections of 50- and 100-unit doses of U-500R and U-100R were administered to 24 healthy obese subjects. Both overall insulin exposure (area under the serum insulin concentration versus time curve from zero to return to baseline [AUC(0-)(t)(')]) and overall effect (total glucose infused during a clamp) were similar between formulations at both 50- and 100-unit doses (90% [CI] of ratios contained within [0.80, 1.25]). However, peak concentration and effect were significantly lower for U-500R at both doses (P < 0.05). Both formulations produced relatively long durations of action (18.3 to 21.5 h). Time-to-peak concentration and time to maximum effect were significantly longer for U-500R than U-100R at the 100-unit dose (P < 0.05). Time variables reflective of duration of action (late tR(max50), tR(last)) were prolonged for U-500R versus U-100R at both doses (P < 0.05). Overall exposure to and action of U-500R insulin after subcutaneous injection were no different from those of U-100R insulin. For U-500R, peaks of concentration and action profiles were blunted and the effect after the peak was prolonged. These findings may help guide therapy with U-500R insulin for highly insulin-resistant patients with diabetes.


Acute kidney injury and intra-abdominal hypertension in burn patients in intensive care.
To evaluate the frequency of intra-abdominal hypertension in major burn patients and its association with the occurrence of acute kidney injury. This was a prospective cohort study of a population of burn patients hospitalized in a specialized intensive care unit. A convenience sample was taken of adult patients hospitalized in the period from 1 August 2015 to 31 October 2016. Clinical and burn data were collected, and serial intra-abdominal pressure measurements taken. The significance level used was 5%. A total of 46 patients were analyzed. Of these, 38 patients developed intra-abdominal hypertension (82.6%). The median increase in intra-abdominal pressure was 15.0mmHg (interquartile range: 12.0 to 19.0). Thirty-two patients (69.9%) developed acute kidney injury. The median time to development of acute kidney injury was 3 days (interquartile range: 1 - 7). The individual analysis of risk factors for acute kidney injury indicated an association with intra-abdominal hypertension (p = 0.041), use of glycopeptides (p = 0.001), use of vasopressors (p = 0.001) and use of mechanical ventilation (p = 0.006). Acute kidney injury was demonstrated to have an association with increased 30-day mortality (log-rank, p = 0.009). Intra-abdominal hypertension occurred in most patients, predominantly in grades I and II. The identified risk factors for the occurrence of acute kidney injury were intra-abdominal hypertension and use of glycopeptides, vasopressors and mechanical ventilation. Acute kidney injury was associated with increased 30-day mortality.


[Stability of a winter wheat population with high yield and high resource use efficiency].
Using the winter wheat cultivar Tainong 18 as the experimental material, we analyzed yield stability from 2012 to 2016 under three different treatments: T1(following typical local field management practices), T2(high-yield: high nitrogen and water were supplied to foster high grain yield), and T3(high-yield, high-efficiency: optimized field management including increasing plant density, reducing nitrogen input and delaying of the sowing date). Yield related phenotypic traits, including the number of ears on the main stem and tillers, leaf area index (LAI), photosynthetically active radiation (PAR) interception, dry matter accumulation and distribution, as well as grain yield, were analyzed over four seasons to determine their relationships with annual radiation, accumulated temperature and precipitation. We then determined grain yield stability for each of the three treatments. The amount and distribution of radiation, accumulated temperature, and precipitation varied greatly within each season. The ears on the main stem represented 38.9%, 58.7%, and 66.9% of the total ears, respectively, for wheat grown in the T1, T2 and T3 treatments, indicating that T1 ears originated mainly from the tillers, T2 ears from both the main stem and the tillers, and T3 ears from the main stem. The T2 and T1 treatments produced the highest and lowest amount of dry matter and grain yield, respectively. Although having relatively lower dry matter accumulation at maturity compared with T2, T3 led to higher grain yield due to high LAI, high PAR interception and utilization, high net canopy photosynthetic rate from booting (especially from 14 days after anthesis) to maturity and a higher harvest index. Among the three treatments, T3 resulted in the lowest annual range, standard deviation, and coefficient of variation for LAI, PAR interception, and dry matter accumulation. Thus, grain yield was most stable in wheat grown in the T3 treatment mainly due to stability in biological production during all four seasons.