Screening for chronic hepatitis B and C in migrants from Afghanistan, Iran, Iraq, the former Soviet Republics, and Vietnam in the Arnhem region, The Netherlands.
Migrants born in hepatitis B virus (HBV) and hepatitis C virus (HCV) endemic countries are at increased risk of being infected with these viruses. The first symptoms may arise when liver damage has already occurred. The challenge is to identify these infections early, since effective treatment has become available. In 2011 we conducted a screening project in first-generation migrants (FGMs) born in Afghanistan, Iran, Iraq, the former Soviet Republics, and Vietnam and living in Arnhem and Rheden. All participants were offered free blood screening for HBV and HCV. In total 959 participants were tested, with the country of origin known for 927, equating to 28·7% of all registered FGMs from the chosen countries. Nineteen percent (n = 176) had serological signs of past or chronic HBV infection and 2·2% (n = 21) had chronic HBV infection. The highest prevalence of chronic HBV infection was found in the Vietnamese population (9·5%, n = 12). Chronic HCV was found in two persons from the former Soviet Republics and one from Vietnam. Twenty-four percent (n = 5) of the newly identified patients with chronic HBV and one of the three patients with chronic HCV received treatment. Three of the patients, two with HCV and one with HBV, already had liver cirrhosis. The highest (9·5%) HBV prevalence was found in FGMs from Vietnam, indicating a high need for focusing on that particular immigrant population in order to identify more people with silent HBV infection. The fact that three patients already had liver cirrhosis underlines the necessity of early identification of HBV and HCV infection in risk groups.


The digestion of total and cell wall monosaccharides of alfalfa by sheep.
The effect of dietary starch on the digestibility of total and cell wall (CW) monosaccharides of alfalfa hay, was examined in sheep equipped with rumen and duodenal cannulas. The experiment consisted of two treatments. In one of them the sheep received 803 g dry matter (DM) of alfalfa hay (A), and in the second, 242 g DM alfalfa hay + 553 g of a purified starchy concentrate mixture (A + conct ). Rumen volume was not significantly different between treatments, but the mean retention time of markers in the rumen was shorter, and their rate of passage was faster in the A treatment than in the A + conct treatment. The overall digestibility of total CWs and CW constituents was not depressed in the A + conct treatment, the values for total CW being: 58.2 and 58.9% for the A and A + conct treatments, respectively. However, the digestion of CW monosaccharides in the rumen of the A + conct sheep was reduced despite the 100% longer retention time of particles in the rumen. The complimentary digestion of the potentially digestible CW monosacharides has been completed in the hindgut. The digestibility of CW glucose was higher (72%) than that of xylose (57%) in both treatments. CW glucuronic acid was the least digestible constituent (40%). Soluble uronic acids, representing the pectic material, were highly digestible (86.5% in A), but this was reduced to 80.3 in the A + conct treatment.


Eating jellyfish: safety, chemical and sensory properties.
People's preference for fish with a high trophic level, like Atlantic cod and tuna, leads to a large food footprint. Responsible seafood consumption should include underutilised local products; hence the culinary use of edible jellyfish can be an effective contribution. The present work focused on Catostylus tagi to contribute to the consumption of edible jellyfish in the West. A questionnaire conducted with 192 young people showed an interest in tasting jellyfish-based food (64.6%). The resulting product, obtained by an alternative cooking process to traditional Asian ones, was chemically characterised and underwent microbiological and heavy metals control. The results indicated its non-toxicity. Patients who were allergic to seafood as well as non-allergic volunteers revealed no allergic reaction to the jellyfish umbrella product (intakes up to 5 mg/kg body weight and 8 mg/kg, respectively). Seafood-trained panellists defined the product's main impact on the mouth as freshness (72 mg/kg body weight). The preliminary snack, a pâté, was positively accepted by allergic (7 in 9; n = 20) and non-allergic volunteers (6 in 7; n = 21). The present study confirmed that jellyfish intake is safe, even for allergic individuals, and its organoleptic properties were accepted by the study population. © 2018 Society of Chemical Industry.


Interaction between angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin-converting enzyme inhibition on survival in hemodialyzed patients.
The association between ACE (angiotensin-converting enzyme) gene insertion/deletion (I/D) polymorphism and mortality has been inconsistently observed in earlier studies in patients on maintenance hemodialysis. We hypothesized that the effect of ACE gene I/D polymorphism on mortality may be influenced by concurrent ACE inhibitor therapy in this population. In this prospective, multicenter cohort, observational study, data was collected from 716 prevalent chronic hemodialysis patients, blood samples were genotyped for I/D single nucleotide polymorphism. Patient mortality was assessed in tree genotype groups insertion/insertion, insertion/deletion and deletion/deletion (I/I, I/D, and D/D) using multivariate Cox proportional hazard models. The most frequent genotype was I/D (42.6%), followed by D/D (37.7%) and I/I (19.7%) genotypes. The mean age was 54.9±15.5 years, 53.2% of all patients were male and in the total group the prevalence of diabetes was 19.3%. ACE inhibitor therapy was prescribed for 47.9% of all patients. The median duration of dialysis before blood sampling was 23.8 months (IQR 11.2-47.1). Patients were followed for 10 years, the median follow-up time was 29.8 months (IQR 12.6-63.4). Patient characteristics were well balanced among the genotype groups. D/D genotype, was associated with inferior survival (I/I vs D/D: log-rank test: P=0.04) in patients not receiving ACE inhibitor therapy, and the presence of this therapy diminished this difference. There was no difference in survival among unselected patients with different genotypes. In multivariate Cox regression models, D/D genotype (compared to I/I) was a significant predictor of mortality only in patients without ACE inhibitor therapy (HR 0.67, 95% CI 0.46-0.97, P=0.03). Our data suggests that hemodialyzed patients with the deletion/deletion (D/D) genotype might have inferior outcome, and ACE inhibitor therapy may be associated with improved survival in this subgroup.


CLINICAL AND EPIDEMIOLOGICAL CHARACTERIZATION OF INFLUENZA A/H1N1PDM AND B AMONG HOSPITALIZED CHILDREN, GEORGIA, SEASON 2010-2011.
The aim of the study was to describe, analyze and compare clinical and epidemiological characteristics of laboratory confirmed influenza A(H1N1)pdm and B cases in hospitalized children during post pandemic season. Between 1st January and 1st May, 2011 retrospective observational study was conducted in M. Iashvili Children's Central Hospital. From 1028 patients with influenza like illness hospitalized at Children's Hospital 871 specimens were collected and 360 tested positive for influenza: A(H1N1)pdm - 139 and B - 221. Data were obtained for 290 cases: A(H1N1)pdm - 122 and B - 168. At the time of hospital admission, influenza A(H1N1)pdm and B cases had similar median age of 2 years. The median length of hospital stay was 5 days for both influenza types. Predominant clinical symptoms were fever (98.3%), cough (82.4%) and running nose (68.6%). 39.7% (115/290) of patients suffered with lower respiratory tract infection: A(H1N1)pdm - 41% (50/122) and B - 38.7% (65/168). 19% (55/290) developed pneumonia of which 12 with primary diagnosis of acute respiratory failure were admitted to ICU: A(H1N1)pdm - 4.9% (6/122) and B - 3.6% (6/168). Median length in ICU stay was 6 days. Only two patients with A(H1N1)pdm required artificial ventilation with one fatal outcome. Almost equally (31%) patients with influenza A or B viruses suffered with at least one pre-existing condition. Statistically significant association was revealed between neurological pre-existing conditions and developing pneumonia (OR=5.6; p=0.00) and ICU requirement (OR=17.5, p=0.00). Congenital malformations were also associated with sever course of disease (OR=9.1; p=0.01). Treatment with antiviral oseltamivir was prescribed to 29.5% (36/122) A(H1N1)pdm and 8.3% (14/168) B cases among whom only 24% cases received antiviral within 48 hours after symptoms onset. None of the patients was vaccinated against influenza. Our study revealed no significant difference between influenza A(H1N1)pdm and influenza B in terms of age distribution, clinical manifestation, hospital stay or complications in hospitalized children during post pandemic season. Pre-existing conditions such as neurological disorders and congenital malformations represented risk factors for severe course of influenza, therefore timely antiviral treatment and annual influenza vaccination is recommended to avoid complications.


Effect of dialyzer reprocessing methods on complement activation and hemodialyzer-related symptoms.
The effects of different dialyzer processing methods and of reuse on complement activation and dialyzer-related symptoms were studied in 96 maintenance hemodialysis patients. New dialyzers were either unprocessed (Group 1) or machine-washed with bleach and stored in formaldehyde (Group 2). Reused dialyzers were manually cleansed using the combination of bleach and formaldehyde (Group 3), or machine-washed in formaldehyde (Group 4) or peracetic acid (Group 5). Prewashed new dialyzers (Group 2) were associated with greater complement activation during dialysis when compared with unprocessed, new dialyzers (Group 1) (p less than 0.05). Reused, unbleached but formaldehyde-treated or peracetic acid-treated dialyzers (Groups 4 and 5) were associated with reduced complement activation (p less than 0.05). Complement activation was not reduced when bleach was used for reprocessing (Group 3). The percentage of patients without symptoms during dialysis was significantly greater with reused dialyzers than with new dialyzers (Groups 3 through 5 versus Groups 1 and 2; 39 versus 25%; p = 0.035). The severity of total symptoms correlated significantly (p = 0.0004) with complement activation. Our results suggest that total symptoms during dialysis are correlated with the degree of complement activation. However, trends in the data pertaining to chest pain suggest that factors other than complement activation may be important in the pathogenesis of some dialyzer-related symptoms.


Propofol protects against blood-spinal cord barrier disruption induced by ischemia/reperfusion injury.
Propofol has been shown to exert neuroprotective effects on the injured spinal cord. However, the effect of propofol on the blood-spinal cord barrier (BSCB) after ischemia/reperfusion injury (IRI) is poorly understood. Therefore, we investigated whether propofol could maintain the integrity of the BSCB. Spinal cord IRI (SCIRI) was induced in rabbits by infrarenal aortic occlusion for 30 minutes. Propofol, 30 mg/kg, was intravenously infused 10 minutes before aortic clamping as well as at the onset of reperfusion. Then, 48 hours later, we performed histological and mRNA/protein analyses of the spinal cord. Propofol decreased histological damage to the spinal cord, attenuated the reduction in BSCB permeability, downregulated the mRNA and protein expression levels of matrix metalloprotease-9 (MMP-9) and nuclear factor-κB (NF-κB), and upregulated the protein expression levels of occludin and claudin-5. Our findings suggest that propofol helps maintain BSCB integrity after SCIRI by reducing MMP-9 expression, by inhibiting the NF-κB signaling pathway, and by maintaining expression of tight junction proteins.


Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships.
Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145 + 2T > C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed.


A Hydroethanolic Leaf Extract of Persicaria lanigera Possesses Antinociceptive Activity through Cytokine and Glutamatergic Pathways In Vivo.
Persicaria lanigera is used traditionally to treat pain. The antinociceptive properties of the hydroethanolic leaf extract of Persicaria lanigera (PLE) were evaluated in rats and mice. Mice were pretreated orally with PLE (30, 100, and 300 mg kg-1) and evaluated for antinociceptive effects in the acetic acid-, glutamate-, and formalin-induced nociception models. Additionally, mechanical hyperalgesia models were used to evaluate PLE's influence on TNF-α- and IL-1β-induced hyperalgesia in rats. In the acetic acid-induced nociception model, 100 mg kg-1 PLE exhibited the highest antinociceptive activity of 95.13 ± 9.52% at p < 0.0001, followed by the 300 mg kg-1 (85.44 ± 5.75%; p < 0.0001) and then the 30 mg kg-1 (67.95 ± 18.55%; p < 0.01), compared to morphine 3 mg kg-1 i.p. (86.97 ± 9.52; p < 0.0001). PLE (30, 100, and 300 mg kg-1) also showed significant (p < 0.05) antinociceptive effect in phase two of the formalin-induced nociception with % inhibitions of 66.88 ± 12.17, 75.12 ± 9.01, and 89.12 ± 4.32%, respectively, compared to 3 mg/kg morphine (97.09 ± 2.84%). Similarly, PLE (30, 100, and 300 mg kg-1) significantly reduced pain in the glutamate-induced nociception model with % inhibitions of 79.28 ± 8.17, 90.54 ± 5.64, and 96.49 ± 1.43%, respectively, whereas ketamine (5 mg/kg i.p.) reduced nociception to be 59.94 ± 18.14%. All doses of PLE significantly reduced nociceptive scores in TNF-α- and IL-1β-induced mechanical hyperalgesia (p < 0.01). Similarly, PLE significantly inhibited bradykinin-induced nociception. The hydroethanolic extract of Persicaria lanigera has antinociceptive effects; this is the first scientific report providing evidence to validate its traditional use for the management of pain.


Compounding of vitamin A, D3, E and K3 supplements for cystic fibrosis patients: formulation and stability study.
Cystic fibrosis (CF) patients suffer from malabsorption of fat-soluble vitamins (A, D, E and K). These vitamins are available as water-dispersible (A, D(3) and E) or water-soluble grades (K(3)), which is favoured in CF patients as they fail to absorb oil-based products. The objective of this study was to determine stability of these raw materials after opening the original package and to develop a compounded formulation of acceptable quality, stability and taste, allowing flexible dose adaptation and being appropriate for administration to children and elderly people. The raw materials were stored after opening their original package for 8 months at 8 degrees C and room temperature (RT). Stability was assessed using a validated HPLC method after extraction of the vitamin from the cold water-soluble matrix (vitamin A acetate, D(3) and E) or using a spectrophotometrical method (vitamin K(3)). These materials were mixed with an appropriate lactose grade (lactose 80 m for vitamins A and D(3); lactose 90 m for vitamin E, lactose very fine powder for vitamin K(3)) and filled in hard gelatin capsules. Mass and content uniformity were determined and stability of the vitamins in the capsules was assessed after 2 months storage at 8 degrees C and RT. All raw materials showed good stability during storage in the opened original package for 8 months storage at 8 degrees C as well as RT (>95% of the initial content). The compounded formulations complied with the requirements of the European Pharmacopoeia for mass and content uniformity and can be stored for 2 months at 8 degrees C or RT while maintaining the vitamin content between 90% and 110%. As these fat-soluble vitamins are not commercially available on the Belgian market, compounded formulations are a valuable alternative for prophylactic administration of these vitamins to CF patients, i.e. a stable formulation, having an acceptable taste, allowing flexible dose adaptation and being appropriate for administration to children and elderly people.


Monocyte-mediated lysis of HIV-infected tumor cells.
Peripheral blood monocytes (PBM) can selectively lyse malignant or virus-infected cells. We investigated the effects of target cell infection with HIV-1 on PBM cytolytic function. Cytokine-activated PBM lysed uninfected, HSV-1-infected or vaccinia virus-infected tumor cells, but did not lyse the same cell lines when infected with the human immunodeficiency virus type 1 (HIV-1). HIV did not impair PBM viability, and actinomycin D (Act D) pretreatment of HIV-infected target cells restored their susceptibility to PBM-mediated lysis. Either antibody to CD4 (Leu3a) or a recombinant vaccinia virus that induces expression of the HIV envelope protein, also inhibited target cell lysis by PBM. These studies indicate that CD4 can function as a mediator of PBM cytolytic function, and that target cell expression of the HIV-1 envelope protein may inhibit monocyte-mediated antitumor responses.


A Reproducibility-Based Computational Framework Identifies an Inducible, Enhanced Antiviral State in Dendritic Cells from HIV-1 Elite Controllers.
Human immunity relies on the coordinated responses of many cellular subsets and functional states. Inter-individual variations in cellular composition and communication could thus potentially alter host protection. Here, we explore this hypothesis by applying single-cell RNA-sequencing to examine viral responses among the dendritic cells (DCs) of three elite controllers (ECs) of HIV-1 infection. To overcome the potentially confounding effects of donor-to-donor variability, we present a generally applicable computational framework for identifying reproducible patterns in gene expression across donors who share a unifying classification. Applying it, we discover a highly functional antiviral DC state in ECs whose fractional abundance after in vitro exposure to HIV-1 correlates with higher CD4+ T cell counts and lower HIV-1 viral loads, and that effectively primes polyfunctional T cell responses in vitro. By integrating information from existing genomic databases into our reproducibility-based analysis, we identify and validate select immunomodulators that increase the fractional abundance of this state in primary peripheral blood mononuclear cells from healthy individuals in vitro. Overall, our results demonstrate how single-cell approaches can reveal previously unappreciated, yet important, immune behaviors and empower rational frameworks for modulating systems-level immune responses that may prove therapeutically and prophylactically useful.


Contraception in diabetic women.
There is a very strong need for an effective and reliable method of contraception in the diabetic woman. An unplanned pregnancy that occurs when her diabetes is not under good control can have disastrous consequences, ranging from abortion to a congenitally malformed fetus. The most important factor in the contraceptive decision for the diabetic patient, especially the IDDM patient, is that the choice be made not by the clinician alone or the patient alone, but through a carefully through-out process that involves both patient and physician.


Compatibility of staining protocols for bone tissue with Raman imaging.
We report the use of Raman microscopy to image mouse calvaria stained with hematoxylin, eosin and toluidine blue. Raman imaging of stained specimens allows for direct correlation of histological and spectral information. A line-focus 785 nm laser imaging system with specialized near-infrared (NIR) microscope objectives and CCD detector were used to collect approximately 100 x 450 micro m Raman images. Principal components analysis, a multivariate analysis technique, was used to determine whether the histological stains cause spectral interference (band shifts or intensity changes) or result in thermal damage to the examined tissue. Image analysis revealed factors for tissue components and the embedding medium, glycol methacrylate, only. Thus, Raman imaging proved to be compatible with histological stains such as hematoxylin, eosin and toluidine blue.


Behavioral Counseling for Skin Cancer Prevention: Evidence Report and Systematic Review for the US Preventive Services Task Force.
Exposure to UV radiation, especially in childhood, increases skin cancer risk. To systematically review the evidence on the benefits and harms of behavioral counseling for skin cancer prevention to inform the US Preventive Services Task Force (USPSTF). Cochrane Central Register of Controlled Trials, MEDLINE, and PubMed were searched for studies published from January 2009 to March 31, 2016, for skin cancer prevention and from August 2005 to March 31, 2016, for skin self-examination. Surveillance in targeted publications was conducted through February 14, 2018. Studies included in previous USPSTF reports were reevaluated for inclusion. Fair- and good-quality studies of primary care-relevant behavioral interventions focused on improving skin cancer outcomes, intermediate outcomes, or skin cancer prevention and self-examination behaviors. Two investigators independently reviewed abstracts and full-text articles and extracted data into evidence tables. Results were qualitatively summarized but not pooled because of heterogeneity of measures. Skin cancer, sunburn, precursor skin lesions, sun protection behaviors, and any harms from interventions. Twenty-one trials in 27 publications were included (N = 20 561). No studies assessed skin cancer outcomes in pediatric populations; 1 adult trial (n = 1356) promoting skin self-examination found no significant difference in participants diagnosed with melanoma in the intervention group vs the control group at 12-month follow-up (0 vs 1 diagnosis). There was no consistent improvement in prevention of sunburn for children (3 trials [n = 2508]) or adults (6 trials [n = 3959]). There were small to moderate increases in sun protection behavior in pediatric populations (6 trials [n = 4252]) and adults (12 trials [n = 13 099]) and small increases in skin self-examination in adults (11 trials [n = 7771]; odds ratios, 1.16-2.6). One of 3 trials of indoor tanning found an intervention effect; an appearance-focused intervention (n = 430) resulted in a smaller increase in mean indoor tanning sessions at 6 months in the intervention group vs the control group. Harms were rarely reported: 1 trial of skin self-examination (n = 1356) found an increase in skin procedures in the intervention group vs the control group at 6 months (8.0% vs 3.6%, P < .001) but not between 6 and 12 months (3.9% vs 3.3%, P = .50), and 1 trial (n = 217) found no between-group difference in skin cancer worry (28.9% vs 18.4%, P = .16). Behavioral interventions can increase sun protection behavior, but there is no consistent evidence that interventions are associated with a reduction in the frequency of sunburn in children or adults and minimal evidence on skin cancer outcomes. Intervention can increase skin self-examination in adults but may lead to increased skin procedures without detecting additional atypical nevi or skin cancers.


Vitreous hemorrhage in pediatric age group.
Purpose. To identify and study causes of vitreous hemorrhage (VH) in pediatric age group and to investigate factors predicting visual and anatomical outcomes. Procedure. A retrospective review of patients aged 16 years or less with the diagnosis of vitreous hemorrhage from January 2005 until December 2010. Results. A total number of 230 patients (240 eyes) were identified. Traumatic vitreous hemorrhage accounted for 82.5%. In cases of accidental trauma, final visual acuity of 20/200 was significantly associated with visual acuity of ≥20/200 at presentation and the absence of retinal detachment at last follow-up. Patients with nontraumatic vitreous hemorrhage were significantly younger with higher rates of enucleation/evisceration/exenteration and retinal detachment at last follow-up compared to traumatic cases. Conclusion. Trauma is the most common cause of VH in pediatric age group. In this group, initial visual acuity was the most important predictor for visual outcome, and the presence of retinal detachment is a negative predictor for final good visual outcome. The outcome is significantly worse in nontraumatic cases compared to traumatic cases.


Deposits from Creams Containing 20% (w/w) Urea and Suppression of Crystallization (Part 2): Novel Analytical Methods of Urea Accumulated in the Stratum Corneum by Tape stripping and Colorimetry.
The transfer of urea from a urea formulation to the stratum corneum varies with the formulation base and form, and impacts the formulation's therapeutic effect. Consequently, determining the amount of urea transferred is essential for developing efficient formulations. This study assessed a simple method for measuring the amount of urea accumulated in the stratum corneum. Conventional methods rely on labeling urea used in the formulation with radiocarbon ((14)C) or other radioactive isotopes (RIs), retrieving the transferred urea from the stratum corneum by tape stripping, then quantitating the urea. The handling and use of RIs, however, is subject to legal regulation and can only be performed in sanctioned facilities, so methods employing RIs are neither simple nor convenient. We therefore developed a non-radiolabel method "tape stripping-colorimetry (T-C)" that combines tape stripping with colorimetry (urease-glutamate dehydrogenase (GLDH)) for the quantitative measurement of urea. Urea in the stratum corneum is collected by tape stripping and measured using urease-GLDH, which is commonly used to measure urea nitrogen in blood tests. The results indicate that accurate urea measurement by the T-C method requires the application of 1400 mg (on hairless rats) of a 20% urea solution on a 50 cm(2) (5×10 cm) area. Further, we determined the amount of urea accumulated in the stratum corneum using formulations with different urea concentrations, and the time course of urea accumulation from formulations differing in the rate of urea crystallization. We demonstrate that the T-C method is simple and convenient, with no need for (14)C or other RIs.


pH-mediated upregulation of AQP1 gene expression through the Spi-B transcription factor.
Bicarbonate-based peritoneal dialysis (PD) fluids enhance the migratory capacity and damage-repair ability of human peritoneal mesothelial cells by upregulating AQP1. However, little is known about the underlying molecular mechanisms. Here we used HEK-293T cells to investigate the effect of pH on AQP1 gene transcription levels. We found that AQP1 mRNA levels increases with pH. Transfection of HEK-293T cells with luciferase reporter vectors containing different regions of the AQP1 promoter identified an upstream region in the AQP1 gene between - 2200 and - 2300 bp as an enhancer required for pH-mediated regulation of AQP1 expression. Site-directed mutagenesis of this specific promoter region revealed a critical region between - 2257 and - 2251 bp, and gene knock-down experiments and ChIP assays suggested that the Spi-B transcription factor SPIB is involved in pH-mediated regulation of AQP1 expression. We identified an upstream region in the AQP1 gene and the transcription factor SPIB that are critically involved in pH-mediated regulation of AQP1 expression. These findings provide the basis for further studies on the pH- and buffer-dependent effects of PD fluids on peritoneal membrane integrity and function.


[Does gender exert influence on stroke?].
Stroke morbidity increases with age. That is the reason why it affects especially the middle aged and elderly. Life expectancy is longer for females than males by 10 years, that is why stroke is a major problem in women. Women die twice more frequently from stroke than men (16% vs. 8%). Stroke risk factors are basically the same in spite of gender. The most important are hypertension, diabetes, dyslipidaemia, atrial fibrillation, coronary heart disease, previous stroke, smoking, alcohol abuse, obesity and lack of physical activity. Their impact, however, is different in males and females. Women with diabetes, atrial fibrillation, myocardial infarction, obese, drinking excessive amounts of alcohol and smoking are more likely to suffer of stroke than males with the same burden. A less favourable outcome after stroke has been observed in female patients--higher mortality rates and disability. It is possible that poor prognosis is related to a drop in blood estrogen concentration after menopause. Estrogen replacement therapy has not proved to be beneficial in preventing stroke and improving outcome. There are several specific conditions: pregnancy, migraine in women associated with the occurrence of stroke.


Pediatric concussion: biomechanical differences between outcomes of transient and persistent (> 4 weeks) postconcussion symptoms.
OBJECTIVE Currently, little is known about the biomechanics of head impact for concussion in youths (ages 5 to 18 years). Even less is known about the biomechanical characteristics and variables related to head impacts that may be useful in differentiating between transient and persistent postconcussion symptoms in a youth population. The purpose of this research was to examine the differences in biomechanics of youth head impact for transient postconcussion symptoms (TPCSs) and persistent postconcussion symptoms (PPCSs) by using data from a hospital population. METHODS In a laboratory setting and using physical, computational, and finite element models, the authors reconstructed falling events in a large cohort of patients who had sustained a brain injury that resulted in transient or persistent postconcussion symptoms. The falling events and resulting concussions for the TPCS and PPCS patient groups were analyzed in terms of force, energy, peak resultant linear and rotational accelerations, and maximum principal strain in the gray and white matter of the brain, as well as measurements of cumulative strain damage. RESULTS The results indicated that there were no significant differences between the groups for any of the variables analyzed. CONCLUSIONS With methods derived for use in an adult population, the magnitudes of peak linear acceleration for the youth data set were determined to be above the 50% risk of injury. The youth data set showed higher brain tissue strain responses for lower energy and impact velocities than measured in adults, suggesting that youths are at higher risk of concussive injury at lower event severities. A trend shown by some variables indicated that larger magnitudes of response were associated with PPCSs, but no single measurement variable consistently differentiated between the TPCS and PPCS groups. It is possible that using the biomechanics of head and brain responses to predict a subjective symptom load may not be appropriate. To enhance future biomechanical analyses, further investigations should include the use of quantifiable measures of brain injury linked to clinical outcomes and possible confounding factors such as history of brain injury and patient predisposition.


[The development of radiation caries after high doses of irradiation].
39 patients, who were irradiated with doses of 50 to 70 Gy for ENT-tumors over a period of 3.5 months to three years prior to the examination, showed a rapidly progressing caries of the teeth inside the target volume. The teeth outside the target volume developed a caries of less extent. Radiation induced xerostomia, effects of the irradiation of the soft tissues, nutrition habits and hygiene are discussed as causes for the damage of the teeth.


Patient Handoff Education: Are Medical Schools Catching Up?
Communication errors during shift-to-shift handoffs are a leading cause of preventable adverse events. Nevertheless, handoff skills are variably taught at medical schools. The authors administered questionnaires on handoffs to interns during orientation. Questions focused on medical school handoff education, experiences, and perceptions. The majority (546/718) reported having some form of education on handoffs during medical school, with 48% indicating this was 1 hour or less. Most respondents (98%) reported that they believe patients experience adverse events because of inadequate handoffs, and more than one third had witnessed a patient safety issue. Results show that medical school graduates are not receiving adequate handoff training. Yet graduates are expected to conduct safe patient handoffs at the start of residency. Given that ineffective handoffs pose a significant patient safety risk, medical school graduates should have a baseline competency in handoff skills. This will require medical schools to develop, implement, and study handoff education.


What really matters in cancer?: Putting people back into the heart of cancer policy.
Twenty-first century cancer is framed by the biomedical revolution. The cancer patient today enters a world dominated by the success and failures of biomedical science from gene to statistic. By any measure, bibliometric, financial, media profile or simply the lingua franca of everyday discourse about cancer, biomedicine occupies the majority of the cultural discourse around cancer. Yet the reality is that patients are people who are diagnosed, treated, survive and die with cancer in a world bounded by their personal and social experiences. Others they have known with the disease shape their values and concepts. The social determinants of cancer are of far greater importance in terms of prevention, treatment and care than is acknowledged in policy terms. In light of the demographic trend of a rapidly ageing population, increasing costs of healthcare and the urgent need to be able to deliver affordable cancer care set against the population's almost insatiable ability to absorb all types of healthcare, there is an urgent need to redress policy balance in terms of both understanding the social determinants of cancer and bringing new insights into evidence-based national cancer planning and delivery of services.


[Pathological tolerance to glucose and breast neoplasia].
Thirty non diabetic women with breast cancer and five with benign breast disease have been evaluated by oral glucose tolerance test. 40% showed a diabetic-like curve. The positive women had a metastatic disease. The positive correlation between a pathologic glucose tolerance and the metastatic disease are stressed. The conclusion is drawn that the research of a latent glycidic alteration as monitor of breast cancer evolution is useful.


Anticancer and Immunomodulatory Effects of Lactobacillus plantarum LS/07, Inulin and Melatonin in NMU-induced Rat Model of Breast Cancer.
Chemopreventive activity of a new probiotic strain Lactobacillus plantarum LS/07 (PRO) and prebiotic oligofructose-enriched inulin (PRE) in rat mammary carcinogenesis induced by procarcinogen 7,12-dimethylbenz[a]anthracene has been reported before. This study evaluated the anticancer and immunomodulatory efficacy of PRO, PRE, PRO+PRE (PRO/PRE) and combination with melatonin (PRO+PRE+MEL) in a rat model, when breast cancer was induced by a direct-acting carcinogen N-nitroso-N-methylurea (NMU). Daily administration of PRO (at a dose of 8.4×10(8) colony-forming units (c.f.u.)/rat), PRE (in the diet, 20 g/kg) and MEL (in tap water, 20 mg/l) started 14 days before the first NMU dose and lasted for 16 weeks. Although tumor growth was not altered, a marked decrease in the ratio of high-/low-grade carcinomas and in tumoral Ki-67 expression was found after PRO+PRE treatment; melatonin augmented these effects. PRO+PRE+MEL combination enhanced CD4(+) and CD8(+) T-cell tumor infiltration induced by PRO/PRE and increased CD25(+)FoxP3(+) regulatory T-cells in tumors. In mammary carcinogenesis, Lactobacillus plantarum LS/07 and inulin exert prodifferentiating, antiproliferative and immunomodulatory activities, which are significantly amplified by melatonin co-administration.


Role of calcium in exocytosis induced by hypotonic swelling.
We studied the influence of Ca(2+) on exocytosis induced by hypotonic shock using the fluorescent dyes acridine orange FM1-43 and FM2-10. It was shown using acridine orange that lowering osmolarity to 230 mOsm/L induces exocytosis both in calcium-containing and calcium-free media. By contrast, we were able to demonstrate calcium dependence of exocytosis using styryl dyes. Lowering osmolarity leads to an increase of neurotransmitter release in a calcium-independent manner. Thus, our data suggest that hypotonic swelling induces calcium-independent exocytosis. Calcium influx mediated by stretch channels is able to switch mode of exocytosis from "kiss and run" to full fusion.


Development of an LC-MS/MS method for determining the pharmacokinetics of clonidine following oral administration of Zhenju antihypertensive compound.
Zhenju antihypertensive compound (ZJAHC) is a combined Chinese-Western medicine formula including clonidine (CLO), hydrochlorothiazide (HCT), rutin, Chrysanthemum indicum extract and pearl powder. Compared with CLO preparations, ZJAHC shows improved activities and decreased adverse effects. It is believed that the side effects of CLO are caused by its high peak plasma concentration. Hence, study of the influence of ZJAHC on the pharmacokinetic behaviors of clonidine seems essential. In present study, the plasma concentrations of CLO were determined with a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The MS/MS transitions monitored for clonidine and internal standard were 230.2 → 213.1 and 152.2 → 110.2, respectively. The analyte was quantified in a single run within 3 min. The pharmacokinetic study showed that the area under the plasma concentration-time curve of CLO in ZJAHC (60 µg/kg CLO) was similar to that of CLO-HCT-high (120 µg/kg CLO) but the peak concentration was much lower than that in CLO-HCT-high. ZJAHC could enhance the bioavailability without greatly increasing peak concentration of clonidine. This comprehensive effect of enhancing the bioavailability and avoiding the high peak plasma concentration for CLO might mainly result from the co-contribution of Western medicine and traditional Chinese medicine (TCM), while the effect of TCM was stronger than that of Western medicine.


HIV-1 subtype diversity based on envelope C2V3 sequences from Kenyan patients on highly active antiretroviral therapy.
There is a continuous need to genetically characterize the HIV strains in circulation in order to assess interventions and inform vaccine discovery. We partially sequenced the envelope C2V3 gene from a total of 59 Kenyan patients on highly active antiretroviral treatment (HAART) and determined HIV subtypes using both the JPHMM subtyping tool and the phylogenetic method. HIV-1 subtype A1 was the predominant strain in circulation, representing 65.5% and 74.5% of all isolates as determined by JPHMM and phylogenetic methods, respectively. Subtypes C and D were the next most prevalent pure strains at 9.1% each by both methods. JPHMM identified 9.1% of the isolates as recombinant. Four isolates had short sequences not covering the entire C2V3 region and were thus not subtyped. From this study, subtype A viruses are still the predominant HIV-1 strains in local circulation in Kenya. Constant surveillance is needed to update molecular trends under continuing HAART scale-up.


Targeted endothelial nanomedicine for common acute pathological conditions.
Endothelium, a thin monolayer of specialized cells lining the lumen of blood vessels is the key regulatory interface between blood and tissues. Endothelial abnormalities are implicated in many diseases, including common acute conditions with high morbidity and mortality lacking therapy, in part because drugs and drug carriers have no natural endothelial affinity. Precise endothelial drug delivery may improve management of these conditions. Using ligands of molecules exposed to the bloodstream on the endothelial surface enables design of diverse targeted endothelial nanomedicine agents. Target molecules and binding epitopes must be accessible to drug carriers, carriers must be free of harmful effects, and targeting should provide desirable sub-cellular addressing of the drug cargo. The roster of current candidate target molecules for endothelial nanomedicine includes peptidases and other enzymes, cell adhesion molecules and integrins, localized in different domains of the endothelial plasmalemma and differentially distributed throughout the vasculature. Endowing carriers with an affinity to specific endothelial epitopes enables an unprecedented level of precision of control of drug delivery: binding to selected endothelial cell phenotypes, cellular addressing and duration of therapeutic effects. Features of nanocarrier design such as choice of epitope and ligand control delivery and effect of targeted endothelial nanomedicine agents. Pathological factors modulate endothelial targeting and uptake of nanocarriers. Selection of optimal binding sites and design features of nanocarriers are key controllable factors that can be iteratively engineered based on their performance from in vitro to pre-clinical in vivo experimental models. Targeted endothelial nanomedicine agents provide antioxidant, anti-inflammatory and other therapeutic effects unattainable by non-targeted counterparts in animal models of common acute severe human disease conditions. The results of animal studies provide the basis for the challenging translation endothelial nanomedicine into the clinical domain.


2012 Liver resections in the 21st century: we are far from zero mortality.
Recent improvements in surgical technique have extended the indications for liver resection. The aims of this study were to assess whether this extension is associated with a changing patient profile and to evaluate how this potential shift has influenced mortality after liver resection in order to define standard expectations for hepatectomy. The characteristics and postoperative outcomes of all patients undergoing elective hepatectomy from 2000 to 2009 were reviewed retrospectively. Multivariate analysis was conducted to determine the factors associated with mortality in the subgroup of patients with malignant disease. Among the 2012 patients in whom hepatectomies were performed, the percentage of patients operated for malignancy increased from 66.4% in 2000 to 82.3% in 2009 (P < 0.001). These patients experienced higher mortality (4.5% versus 0.7%; P < 0.001), were significantly older, and displayed greater comorbidity and underlying parenchymal disease compared with those with benign lesions. Mortality over the entire study period was 3.5% and was fairly stable, dropping from 3.8% in 2000 to 3.1% in 2009 (P = 0.686). On multivariate analysis, age of >60 years, an American Society of Anesthesiologists score of ≥3, major resection, vascular procedure, severe fibrosis (F3-F4) and steatosis of >30% were associated with increased mortality in patients with malignant disease. The profile of patients undergoing liver resection has changed and now includes more high-risk patients with diseased parenchyma undergoing major hepatectomy for malignancy. This change in patient profile is responsible for the stability in mortality rates over the years.


Steroid avoidance in pediatric heart transplantation results in excellent graft survival.
Maintenance steroid (MS) use in pediatric heart transplantation (HT) varies across centers. The purpose of this study was to evaluate the impact of steroid-free maintenance immunosuppression (SF) on graft outcomes in pediatric HT. Patients younger than 18 years in the United States undergoing a first HT during 1990 to 2010 were analyzed for conditional 30-day graft loss (death or repeat HT) and death based on MS use by multivariable analysis. A propensity score was then given to each patient using a logistic model, and propensity matching was performed using pre-HT risk factors, induction therapy, and nonsteroid maintenance immunosuppression. Kaplan-Meier graft and patient survival probabilities by MS use were then calculated. Of 4894 patients, 3962 (81%) were taking MS and 932 (19%) SF. Of the 4530 alive at 30 days after HT, 3694 (82%) and 836 (18%) were in the MS and SF groups, respectively. Unmatched multivariable analysis showed no difference in 30-day conditional graft survival between MS and SF groups (hazard ratio=1.08, 95% confidence interval=0.93-1.24; P=0.33). Propensity matching resulted in 462 patients in each MS and SF group. Propensity-matched Kaplan-Meier survival analysis showed no difference in graft or patient survival between groups (P=0.3 and P=0.16, respectively). We found no difference in graft survival between SF patients and those taking MS. An SF regimen in pediatric HT avoids potential complications of steroid use without compromising graft survival, even after accounting for pre-HT risk factors.


Impression Smear Agreement with Acetate Tape Preparation for Cytologic Sampling.
Cutaneous cytologic sampling techniques are used to detect bacteria, yeast, and inflammatory cells for diagnosis and therapeutic monitoring. Studies have examined slide evaluation techniques, ear swab cytology staining methods, and observer variations; few studies compare common clinical sampling techniques. The primary aim of this study was to measure detection of microorganisms and neutrophils by impression smear compared to acetate tape preparation; comparison of agreement between two acetate tape staining methods was a secondary aim. Thirty lesions consistent with superficial pyoderma were sampled via impression smear and acetate tape preparation. Acetate tape preparations were either stained with modified Romanowksy stain solutions two and three or solution three alone. Impression smears were stained in the standard manner. Bacteria, yeast, and neutrophils were evaluated using a semi-quantitative scale [0-4]. Quantities were aggregated and compared using Cohen's kappa to measure agreement between methods. When impression smears were compared to acetate tape, the lowest agreement occurred for neutrophils, with impression smears detecting more neutrophils. Comparison of acetate tape staining methods had the highest agreement for yeast detection. Sampling technique and staining method did not differ for detection of bacteria. Impression smears detected more neutrophils, and yeast detection appeared equivalent for acetate tape staining methods.


Clinical whole-genome sequencing from routine formalin-fixed, paraffin-embedded specimens: pilot study for the 100,000 Genomes Project.
Fresh-frozen (FF) tissue is the optimal source of DNA for whole-genome sequencing (WGS) of cancer patients. However, it is not always available, limiting the widespread application of WGS in clinical practice. We explored the viability of using formalin-fixed, paraffin-embedded (FFPE) tissues, available routinely for cancer patients, as a source of DNA for clinical WGS. We conducted a prospective study using DNAs from matched FF, FFPE, and peripheral blood germ-line specimens collected from 52 cancer patients (156 samples) following routine diagnostic protocols. We compared somatic variants detected in FFPE and matching FF samples. We found the single-nucleotide variant agreement reached 71% across the genome and somatic copy-number alterations (CNAs) detection from FFPE samples was suboptimal (0.44 median correlation with FF) due to nonuniform coverage. CNA detection was improved significantly with lower reverse crosslinking temperature in FFPE DNA extraction (80 °C or 65 °C depending on the methods). Our final data showed somatic variant detection from FFPE for clinical decision making is possible. We detected 98% of clinically actionable variants (including 30/31 CNAs). We present the first prospective WGS study of cancer patients using FFPE specimens collected in a routine clinical environment proving WGS can be applied in the clinic.


Systematic review of the use of "magnitude-based inference" in sports science and medicine.
Magnitude-based inference (MBI) is a controversial statistical method that has been used in hundreds of papers in sports science despite criticism from statisticians. To better understand how this method has been applied in practice, we systematically reviewed 232 papers that used MBI. We extracted data on study design, sample size, and choice of MBI settings and parameters. Median sample size was 10 per group (interquartile range, IQR: 8-15) for multi-group studies and 14 (IQR: 10-24) for single-group studies; few studies reported a priori sample size calculations (15%). Authors predominantly applied MBI's default settings and chose "mechanistic/non-clinical" rather than "clinical" MBI even when testing clinical interventions (only 16 studies out of 232 used clinical MBI). Using these data, we can estimate the Type I error rates for the typical MBI study. Authors frequently made dichotomous claims about effects based on the MBI criterion of a "likely" effect and sometimes based on the MBI criterion of a "possible" effect. When the sample size is n = 8 to 15 per group, these inferences have Type I error rates of 12%-22% and 22%-45%, respectively. High Type I error rates were compounded by multiple testing: Authors reported results from a median of 30 tests related to outcomes; and few studies specified a primary outcome (14%). We conclude that MBI has promoted small studies, promulgated a "black box" approach to statistics, and led to numerous papers where the conclusions are not supported by the data. Amidst debates over the role of p-values and significance testing in science, MBI also provides an important natural experiment: we find no evidence that moving researchers away from p-values or null hypothesis significance testing makes them less prone to dichotomization or over-interpretation of findings.


[Experimental study on the preventive and treatment function of cortex mori for peripheral nervous lesion at the early stage of diabetes rats].
To observe the preventive function of cortex mori for peripheral nervous lesion at the early stage in diabetes rats, and probe into the mechanism of that formula. Set up the diabetes rat model evoked by alloxan. According to different blood sugar values, randomly divide the rats into normal group, model group, cortex mori(high dosage and low dosage) group and methylcobalamin control group, respectively administer the rats with saline and cortex mori of different dosages by ig (1.875 g/kg, 0.625 g/kg), while 300 microg/kg methylcobalamin for control group, one time each day. Two months after the administration, determine the FBG, body weight, SOD and MDA in blood serum of rats in each group, observe the changes on final product of glycosylation, CGMP and CAMP of sciatic nerve and the synapsin of rats' sciatic nerves. Conduct the pathological observation on area of myelin sheath, extramedullary fiber and the cross section of myelin sheath of sciatic nerves. And observe the changes of ultrafine form of sciatic nerve through transmission electron microscope. In the mean time, determine the MNCV, SNVC and SL, and the tail-flicking test should be undertaken for checking the sensory nerve. Cortex mori can effectively enlarge the area of myelin sheath, extramedullary fiber and the cross section of myelin sheath. Cortex mori can obviously ease up the pathological changes of peripheral nerve at the early stage of the diabetes rats, and the overall curative effect is better than that of methylcobalamin.


[Atypical meningocele localization in the new-born. A report on one case (author's transl)].
A case is reported of a new-born infant presenting with a voluminous laterofacial tumor which had literally blown up the right side of the face. The tumor was found to be a meningocele. Treatment was applied in such a way as to cause the least surgical trauma possible and to use the natural flexibility of the tissues in an infant of this age. The rare nature of this localization is emphasized.


Non specific magnetic resonance features of chondromyxoid fibroma of the iliac bone.
Chondromyxoid fibroma is a benign cartilaginous neoplasm. The tumor is rare, perhaps the rarest of all bone tumors. It is more common in long bones and rare in pelvic bones. We report a case of a 31-year-old woman with chondromyxoid fibroma arising from the iliac bone and presenting with leg pain due to compression on the femoral nerve. Magnetic resonance imaging (MRI) features were non specific for chondromyxoid fibroma. We emphasize the need to consider it in the differential diagnosis of chondrosarcoma.


Failure to protect Mus musculus against Plasmodium berghei with footpad injections of killed parasites incorporated in complete Freund's adjuvant.
The stimulation of cell-mediated immunity by the injection of antigen from killed parasites incorporated in complete Freund's adjuvant did not protect Mus musculus from the erythrocytic stages of Plasmodium berghei. Agglutinating antibodies could not be detected, but delayed hypersensitivity was demonstrable. Apparently thymocyte sensitization alone was not sufficient to afford protection.


Time-resolved fluorescence study of a calcium-induced conformational change in prothrombin fragment 1.
The wavelength dependent fluorescence decay properties of bovine prothrombin fragment 1 have been investigated employing a picosecond time-correlated single photon counting technique. All observations are discussed with using the crystal structure (Soriano-Garcia et al., Biochemistry 31:2554-2566, 1992). Fluorescence lifetimes distribution and conventional multiexponential analysis, as well as acrylamide quenching studies lead to the identification of six distinguishable tryptophan excited-states. Accessibility to the quencher and the known structure are used to associate a fluorescence decay of the tryptophan present in the Gla domain (Trp42) with two red shifted components (2.3 and 4.9 ns). The two kringle domain tryptophans (Trp90 and Trp126) exhibit four decay times (0.06, 0.24, 0.68, and 2.3 ns), which are blue shifted. The calcium-induced fluorescence quenching is a result of static quenching: the five decay times remain unchanged, whereas the fluorescence intensity of Trp42 is decreased. The static quenching process is a consequence of a ground state interaction between the Cys18-Cys23 disulfide bridge and Trp42. The monomolecular equilibrium constant for this disulfide-pi-electron interaction is found as 4.8.


Electrolyte Disturbances in Critically Ill Cancer Patients: An Endocrine Perspective.
Electrolyte disturbances are frequently encountered in critically ill oncology patients. Hyponatremia and hypernatremia as well as hypocalcemia and hypercalcemia are among the most commonly encountered electrolyte abnormalities. In the intensive care unit, management of critical electrolyte disturbances is focused on initial evaluation and immediate treatment plan to prevent severe complications. A PubMed search was performed to identify best available evidence for evaluation and management of dysnatremias, hypocalcemia, and hypercalcemia. Current literature was reviewed regarding the management of electrolyte disturbances. The role of new therapeutic options, for example, vaptans for hyponatremia, teriparatide for hypocalcemia, and denosumab for hypercalcemia, is discussed. Early diagnosis and appropriate management are expected to reduce adverse outcomes.


Low-Molecular-Weight NGF Mimetic Corrects the Cognitive Deficit and Depression-like Behavior in Experimental Diabetes.
Based on the comorbidity of diabetes, depression, and dementia and recognizing that a deficiency of the nerve growth factor (NGF) is involved in all of these kinds of pathologies, we studied the effect of the mimetic of dimeric dipeptide NGF loop 4, GK-2, on a model of streptozotocin-induced type 2 diabetes in C57Bl/6 mice. GK-2 [hexamethylenediamide bis-(N-monosuccinyl-glutamyl-lysine)] was synthesized at the V.V. Zakusov Scientific Research Institute of Pharmacology. The study revealed the ability of GK-2 to ameliorate hyperglycemia induced by streptozotocine (STZ 100 mg/kg i.p.) in C57Bl/6 mice, to restore learning ability in the Morris Water Maze test, and to overcome depression after both intraperitoneal (0.5 mg/kg) and peroral (5 mg/kg) long-term administration. The presence of the listed properties and their preservation in the case of peroral treatment determines the prospects of research. Taking into account the previous findings on the ability of GK-2 to selectively activate PI3K/Akt, these data suggest that Akt-signaling is sufficient for pancreatic beta cell function. GK-2 has been shown to exhibit pronounced neuroprotective activity. The coexistence of neuroprotective and antidiabetic effects is in agreement with the fundamental concept holding that the function of neurons and pancreatic beta cells is controlled by similar mechanisms.


Platycodin D suppressed LPS-induced inflammatory response by activating LXRα in LPS-stimulated primary bovine mammary epithelial cells.
Platycodin D (PLD), a triterpenoid saponin derived from the root of Platycodon grandiflorum, has been reported to possess anti-inflammatory activity. However, the protective effect of PLD on mastitis has not been reported. In the present study, we aim to investigate the anti-inflammatory feature of PLD on the primary bovine mammary epithelial cells (bMEC) challenged with LPS. The cell viability of bMEC was measured by MTT assay. The quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the gene expression of pro-inflammatory cytokines and western blotting was carried out to measure the expression of LXRα and NF-κB. The results showed that PLD inhibited LPS-induced TNF-α, IL-1β, and IL-6 expression in LPS-stimulated bEMC. Meanwhile, PLD suppressed LPS-induced NF-κB activation. Furthermore, PLD was found to up-regulate the expression of LXRα. The inhibition of PLD on NF-κB activation and inflammatory cytokines production were reversed by GGPP, the inhibitor of LXRα. In conclusion, our results suggested that PLD inhibited LPS-induced inflammatory response in bMEC by activating LXRα. PLD may be a potential therapeutic drug for mastitis.


Rapid transmission and tight bottlenecks constrain the evolution of highly transmissible SARS-CoV-2 variants.
Transmission bottlenecks limit the spread of novel mutations and reduce the efficiency of natural selection along a transmission chain. Many viruses exhibit tight bottlenecks, and studies of early SARS-CoV-2 lineages identified a bottleneck of 1-3 infectious virions. While increased force of infection, host receptor binding, or immune evasion may influence bottleneck size, the relationship between transmissibility and the transmission bottleneck is unclear. Here, we compare the transmission bottleneck of non-variant-of-concern (non-VOC) SARS-CoV-2 lineages to those of the Alpha, Delta, and Omicron variants. We sequenced viruses from 168 individuals in 65 multiply infected households in duplicate to high depth of coverage. In 110 specimens collected close to the time of transmission, within-host diversity was extremely low. At a 2% frequency threshold, 51% had no intrahost single nucleotide variants (iSNV), and 42% had 1-2 iSNV. In 64 possible transmission pairs with detectable iSNV, we identified a bottleneck of 1 infectious virion (95% CI 1-1) for Alpha, Delta, and Omicron lineages and 2 (95% CI 2-2) in non-VOC lineages. The latter was driven by a single iSNV shared in one non-VOC household. The tight transmission bottleneck in SARS-CoV-2 is due to low genetic diversity at the time of transmission, a relationship that may be more pronounced in rapidly transmissible variants. The tight bottlenecks identified here will limit the development of highly mutated VOC in typical transmission chains, adding to the evidence that selection over prolonged infections in immunocompromised patients may drive their evolution.


Tandem Radical Cyclization for the Construction of Difluoro-Containing Oxindoles and Quinoline-2,4-diones.
Cu-catalyzed direct difluoromethylation of activated alkenes through a difluoromethyl radical addition/cyclization to afford difluorinated oxindoles and quinoline-2,4-diones has been developed. This method provides convenient access to a variety of oxindoles and quinoline-2,4-diones under mild conditions via a proposed tandem radical cyclization process, while tolerating various functional groups well. Moreover, a facile method to construct diverse difluorinated quinoline-2,4-diones by visible-light photoredox catalysis under mild conditions was presented.


Vascular injury related to lumbar disk surgery.
This report summarizes the Walter Reed Army Medical Center experience with six patients operated on from 1949 through 1982 for vascular injury related to lumbar disk surgery. All had common iliac artery injuries generated by L4-5 disk operations. Four patients had isolated arterial injuries and two had combined arteriovenous injuries. Three underwent vascular repair acutely, two with shock and one with a false aneurysm. Delay in diagnosis occurred in two patients who presented 6 weeks and 3 years postinjury with minimally symptomatic arteriovenous fistulae. A sixth patient had a known arterial injury and was operated on after a 1-month delay. All patients survived. Two patients had had repeated back operations, suggesting that this may be a risk factor for perforation of the anterior spinal ligament by an operative rongeur.


The salvage role of allogeneic hematopoietic stem-cell transplantation in relapsed/refractory diffuse large B cell lymphoma.
To clarify the role of allogeneic hematopoietic stem-cell transplantation (allo-HSCT) in the chimeric antigen receptor T-cell therapy era, we analyzed the clinical characteristics and outcomes of 52 patients treated with allo-HSCT with relapsed/refractory diffuse large B cell lymphoma. Most enrolled patients had previously undergone intensive treatments, the median number of chemotherapy lines was 4, and the median time from diagnosis to allo-HSCT was 27.1 months. Patients were divided into remission-achieved (n = 30) and active-disease (n = 22) groups before allo-HSCT. Over a median follow-up period of 38.3 months, overall survival (OS) and event-free survival (EFS) rates were 38.4% and 30.6%, respectively. The cumulative incidence of relapse (CIR) and the non-relapsed mortality (NRM) were 36.7% and 32.7%, respectively. OS, EFS, and graft-versus-host disease-free, relapse-free survival (GRFS) outcomes were significantly superior in the remission-achieved group with lower CIR. In a multivariate analysis, a shorter interval from diagnosis to allo-HSCT reflected relatively rapid disease progression and showed significantly poor OS and EFS with higher CIR. Patients with active disease had significantly lower EFS, GRFS, and higher CIR. Previous autologous stem-cell transplantation was associated with better GRFS. Allo-HSCT is an established modality with a prominent group of cured patients and still has a role in the CAR T-cell era, particularly given its acceptable clinical outcomes in young patients with chemo-susceptible disease.


Rapid isolation of human stem cells (connective tissue progenitor cells) from the proximal humerus during arthroscopic rotator cuff surgery.
Bone-to-tendon healing in the shoulder can be unpredictable. Biologic augmentation, through the implementation of adult mesenchymal stem cells, may improve this healing process. The purpose of this study was to (1) arthroscopically obtain bone marrow aspirates from the proximal humerus during rotator cuff repair, (2) purify and concentrate the connective tissue progenitor cells (CTPs) in the operating room efficiently, and (3)confirm these are stem cells through their ability to differentiate into bone cells. We hypothesize that CTPs can be quickly and efficiently isolated from bone marrow during arthroscopic surgery and that these cells are capable of osteogenesis. Cohort study; Level of evidence, 3; and Descriptive laboratory study. Bone marrow aspirates were harvested through the anchor tunnel of the humeral head during arthroscopic rotator cuff repair in 23 patients. Twenty-three matched controls were selected from a clinical registry to evaluate for increased incidence of complication. Connective tissue progenitor cells were isolated using 2 accepted methods and compared with a novel, rapid method designed for use in the operating room. Osteogenic potential was assessed by cytochemical and molecular analysis. Reverse transcription polymerase chain reaction analysis and cellular staining confirmed the osteogenic potential of these CTPs. There was no statistical significant difference in the Single Assessment Numeric Evaluation score (aspirate, 86.3 +/- 10.5; control, 83.6 +/- 15.1; P = .54), range of motion measures (postoperative external rotation: aspirate, 65.0 degrees +/- 20.4 degrees ; control, 62.5 degrees +/- 17.1 degrees ; P = .67; postoperative forward elevation: aspirate, 163.0 degrees +/- 30.6 degrees ; control, 145.7 degrees +/- 41.4 degrees ; P = .12), or postoperative strength measures between groups (median, 5; range, 4-5 in the aspirate group compared with median, 5; range, 4-5 in the control group; P > .05). Connective tissue progenitor cells can be safely and efficiently aspirated from the proximal humerus using the anchor tunnel created during arthroscopic rotator cuff surgery. These cells may play an important role in cell-based therapies involving rotator cuff repair. We have established a reliable, reproducible protocol for isolating CTPs in the operating room. These cells may have the potential to enhance the healing process after rotator cuff repair.


Effects of ID-540 on averaged photopalpebral reflex in man.
Effects of ID-540, a recently introduced benzodiazepine derivative, on the averaged photopalpebral reflex (PPR), subjective symptoms and serum levels of ID-540 and its principal metabolite, N-desmethyl-ID-540 following an oral dose of 0.5 mg were investigated in 4 healthy male Japanese students in their early twenties. Both the latencies of PPR, P1 and P2 latency, showed a prolongation and maximum level at 2-2.5 hours after administration and tended to decline thereafter to control levels. The serum concentration of ID-540 showed a peak level at 2 hours after dosing, then showed a decline at 4 hours. The N-desmethyl-ID-540 exhibited a slow, gradual rise in the serum over the first 4 hours and there was a tendency toward a continued rise even at 24 hours. These parameters were of striking resemblance in the time-course of changes after oral dosing. Thus the PPR test may be a useful means of determining the clinical effects of anxiolytic agents. ID-540 appears to be an agent with remarkable anxiolytic effects.


[Analysis of prescription patterns of antipsychotic agents in psychiatry].
We describe the different diseases in which conventional and second generation antipsychotic (APS) prescriptions are made. Observational, retrospective, multicenter study based on the review of 300 clinical records of public and private sites, hospital and out-patient clinics, located in Salamanca, Vigo, Bilbao, Barcelona, Valencia, Oviedo and Malaga. The mean age of the population studied was 42 +/- 17 years; 56.6 % were men. Atypical drugs (67 %) were used basically versus classical ones (33 %). Classical APS are basically prescribed in bipolar disorder with/without psychotic symptoms (20.6 %), schizophrenia (18.3%) and delusional disorder (11.5 %). Atypical APS are fundamentally prescribed in schizophrenia (31.5 %), bipolar disorders with/without psychotic symptoms (12.5 %) and other psychotic disorders (8.9 %). When the psychotic disorders are considered by groups (schizophrenia, bipolar disorder with psychotic symptoms, delusional disorder and other psychotic disorders), classical APS are used in 47.4 % and atypical APS in 62.5%. APS were used ((outside the indication)) (off-label) in 32.8%, including resistant depressions, serious obsessive-compulsive disorder and borderline personality disorder, with similar percentages for both conventional and atypical ones. In dementia, atypical APS were used in 5.1 % versus 1.5 % of the conventional ones. The most frequent reasons for prescription of classical APS were control of psychotic symptoms (33.6 %), aggressiveness-agitation (31.3 %), severe insomnia (16 %), impulsivity (6.9 %) and severe anxiety (6.1 %). Atypical APS were preferably used in the control of psychotic symptoms (58.8%) and aggressiveness-agitation (25.5%). The use of APS basically occurs within their authorized indications (67.2 %). The off-label use (32.8 %) occurs both for the classical as well as atypical APS and occurs in serious diseases in which there are no alternative treatments.


Transformation of human diploid cells by adenovirus type 4 irradiated with ultraviolet light.
Inoculation of ultraviolet (UV)-irradiated adenovirus type 4 (Ad4) led to in vitro transformation of human diploid cells (HDC). Two transformed cell lines could be established: cell line H 1418, from HDC inoculated with the 10(-3) dilution of Ad4 UV-irradiated for 20 min at a distance of 20 cm, co-cultivated with uninfected HDC, and cell line H 1557, from HDC inoculated with the 10(-2) dilution of Ad4 irradiated at the same distance for 12 min. Both transformed cell lines were resistant to superinfection with homologous virus. Virus-specific antigen could be made evident by the indirect immunofluorescence technique in the nuclei of both H 1418 and H 1557 cells.


Cobalt-catalyzed carbocyclization of o-iodobenzaldehydes and o-iodophenylketones with alkynes.
[reaction: see text] Treatment of various o-iodobenzaldehydes and o-iodophenyl ketones with alkynes in the presence of Co(dppe)I(2) and Zn powder in acetonitrile at 80 degrees C afforded the corresponding indenols in moderate to excellent yields with exceedingly high regioselectivity. For most unsymmetrical alkynes tested, the carbocyclization gave a single regioisomer.


Wearable deep body thermometers and their uses in continuous monitoring for daily healthcare.
This paper introduces noninvasive deep body thermometers suitable for continuous deep body temperature (DBT) measurement. On the basis of their features, they were used in DBT monitoring for daily healthcare. A thermometer based on the dual-heat-flux method (T_DHFM), and an aural canal thermistor (ACT), were used in two studies of daily healthcare. The medical device CoreTemp by Terumo, based on the zero-heat-flux method, was also used for a DBT reference. The first study focused on preventing heat stroke in a high-temperature and high-humidity environment, while the other focused on the temperature monitoring of patients with spinal cord injuries. In the first study, CoreTemp and T_DHFM were used, whereas T_DHFM and ACT were used in the second study. Using the results from these two studies, we discuss the availability and performance of each thermometer and indicate the necessity of an appropriate method of measuring DBT.


Erectile dysfunction and angiographic extent of coronary artery disease in type II diabetic patients.
Some studies observed an association between erectile dysfunction (ED) and coronary artery disease (CAD) extent in the general population, but others did not. There are no specific studies in diabetic populations. The aim of the present study was to evaluate whether ED is correlated with the extent of angiographic CAD in a large group of type II diabetic patients. We recruited 198 consecutive type II diabetic males undergoing an elective coronary angiography to evaluate chest pain or suspected CAD. Presence and degree of ED were assessed by the International Index Erectile Function - 5 (IIEF-5) questionnaire. ED was considered present, when IIEF-5 score was < or =21. Moreover, each domain of IIEF-5 was considered. Angiographic CAD extent was expressed both by the number of vessels diseased and by the Gensini scoring system. The percentage of subjects with ED was significantly higher (45.8 versus 15.8%; P=0.0120) in patients with (n=179) than in those without (n=19) significant angiographic CAD (stenosis of the lumen > or =50%). No significant association of CAD extent with presence of ED, total IIEF-5 score and each domain of IIEF-5 was observed. Our study shows that ED was significantly more prevalent in type II diabetic males with angiographic CAD than in those with normal arteries. However, no correlation was found between the extent of angiographic CAD and the presence or the severity of ED.


Improving plant stress tolerance and yield production: is the tonoplast aquaporin SlTIP2;2 a key to isohydric to anisohydric conversion?
Anisohydric plants are thought to be more drought tolerant than isohydric plants. However, the molecular mechanism determining whether the plant water potential during the day remains constant or not regardless of the evaporative demand (isohydric vs anisohydric plant) is not known. Here, it was hypothesized that aquaporins take part in this molecular mechanism determining the plant isohydric threshold. Using computational mining a key tonoplast aquaporin, tonoplast intrinsic protein 2;2 (SlTIP2;2), was selected within the large multifunctional gene family of tomato (Solanum lycopersicum) aquaporins based on its induction in response to abiotic stresses. SlTIP2;2-transformed plants (TOM-SlTIP2;2) were compared with controls in physiological assays at cellular and whole-plant levels. Constitutive expression of SlTIP2;2 increased the osmotic water permeability of the cell and whole-plant transpiration. Under drought, these plants transpired more and for longer periods than control plants, reaching a lower relative water content, a behavior characterizing anisohydric plants. In 3-yr consecutive commercial glasshouse trials, TOM-SlTIP2;2 showed significant increases in fruit yield, harvest index and plant mass relative to the control under both normal and water-stress conditions. In conclusion, it is proposed that the regulation mechanism controlling tonoplast water permeability might have a role in determining the whole-plant ishohydric threshold, and thus its abiotic stress tolerance.


Inhibiting wear particles-induced osteolysis with doxycycline.
To study the effect of doxycycline (DOX) on osteoclastogenesis, mature osteoclast fate and function, wear particles-induced osteoeolysis, and to provide some foundation for treating aseptic loosening and osteolysis after joint arthroplasty. Osteoclasts were generated from mouse bone marrow monocytes with the receptor activator of NF-kappaB ligand and the macrophage colony stimulating factor. DOX at a concentration of 5, 10, 15, and 20 microg/mL was respectively added to the medium. Seven days later, the osteoclasts were determined through tartrate-resistant acid phosphatase (TRAP) staining. Mature osteoclasts were isolated from newborn rabbits and cultured for 3 d in 24-well plates or on bone slices. DOX at a concentration of 5, 10, 15, and 20 microg/mL was respectively added to the medium. After TRAP staining, the osteoclasts were counted, resorption on bone slices was quantified, and the area was calculated after toluidine blue and Mayer-hematoxylin staining. Polymethyl methacrylate (PMMA) or ultra-high molecular weight polyethylene (UHMWPE) particles were implanted on the calvariae of C57BL/J6 mice. DOX, at a dose of 2 and 10 mg x kg(-1) x d(-1), was respectively given intraperitoneally for 7 d. Seven days later, the calvariae were removed and processed for pathological analysis. DOX treatment effectively inhibited in vitro osteoclastogenesis, affected the fate of mature osteoclasts, and inhibited mature osteoclasts, causing bone resorption. In vivo data indicated that DOX strongly inhibited PMMA or UHMWPE-induced osteolysis and osteoclastogenesis. DOX can effectively inhibit osteoclastogenesis and affect mature osteoclast fate and suppress wear particles induced by osteolysis and osteoclastogenesis. DOX might be useful in the treatment or prevention of wear particles-induced osteolysis and aseptic loosening for its effect on osteoclast generation and mature osteoclast fate and function.


Immunophenotype of human HT29 colon cancer cell metastases in the lungs of scid mice: spontaneous versus artificial metastases.
The aim of this study was to compare the immunophenotype of the human colon cancer cell line HT29 tumour deposits in the lung which occurred spontaneously after subcutaneous implantation with those which arose after intravenous injection into severe combined immunodeficient (scid) mice. Irrespective of the route of implantation the colon cancer cells were readily observed in the lungs of the scid mice. Similar patterns of immunoreactivity for the proliferative markers (MiB-1, PCNA), and for the tumour suppressor gene (p53) were detected in both groups, and for carcinoembryonic antigen, with only minor quantitative differences in levels of marker expression. Whereas the marker CD44 variant 6 gave very little reaction after either route, cytokeratin expression varied amongst the different cytokeratins (CK 7, 18 or 20), and with the route of implantation. CA125 and E-cadherin were weakly expressed after intravenous injection, but generally not after subcutaneous implantation. Vimentin was not demonstrated in any of the specimens examined. In general, the expression of proliferative markers, and of oncogenes, appears to be independent of the implantation route, whilst expression of cell adhesion molecules can be dependent on the route of implantation.


[Prevalence of gastro-oesophageal reflux disease in general practice].
While there is an ever rising prevalence of gastro-oesophageal reflux disease among people in the western world, the actual number are usually underestimated, because many afflicted persons do not seek medical care. This study was undertaken to determine the frequency of unrecognized reflux disease among an unselected patient cohort in general practice. In addition, answers by these patients to a questionnaire were evaluated. 162 consecutive patients of a general practice without known gastro-oesophageal reflux took part. After the questionnaire had been filled in a history was obtained with semi-quantitative grading of dyspeptic symptoms, and all underwent a physical examination. A gastroscopy was offered to all patients. Gastro-oesophageal reflux was diagnosed when endoscopy revealed typical oesophageal lesions and/or there were at least moderately severe reflux symptoms that had reduced the patient's quality of life. 82 patients (51%) had reflux disease. 121 patients underwent endoscopy. Structural changes (reflux oesophagitis, Barrett metaplasia) were seen in 28 of the 82 patients with reflux disease (34%), 17% of the entire cohort. Axial hiatus hernia, positive family history, advancing age, over-weight, female gender and treatment with NSAIDs or aspirin were significant risk factors in the development of reflux disease. Patients with reflux disease significantly more frequently suffered from hoarseness and/or cough. Positive or negative predictability of the questionnaire regarding the diagnosis of reflux disease was 94% each way. The prevalence of unrecognized gastro-oesophageal reflux disease in the population is extraordinarily high. One quarter to one third of those with reflux disease have cough or hoarseness. The disease can apparently be reliably diagnosed by a standardized questionnaire.


Orthologous CRISPR/Cas9 systems for specific and efficient degradation of covalently closed circular DNA of hepatitis B virus.
Covalently closed circular DNA (cccDNA) of hepatitis B virus (HBV) is the major cause of viral persistence and chronic hepatitis B. CRISPR/Cas9 nucleases can specifically target HBV cccDNA for decay, but off-target effects of nucleases in the human genome limit their clinical utility. CRISPR/Cas9 systems from four different species were co-expressed in cell lines with guide RNAs targeting conserved regions of the HBV genome. CRISPR/Cas9 systems from Streptococcus pyogenes (Sp) and Streptococcus thermophilus (St) targeting conserved regions of the HBV genome blocked HBV replication and, most importantly, resulted in degradation of over 90% of HBV cccDNA by 6 days post-transfection. Degradation of HBV cccDNA was impaired by inhibition of non-homologous end-joining pathway and resulted in an erroneous repair of HBV cccDNA. HBV cccDNA methylation also affected antiviral activity of CRISPR/Cas9. Single-nucleotide HBV genetic variants did not impact anti-HBV activity of St CRISPR/Cas9, suggesting its utility in targeting many HBV variants. However, two or more mismatches impaired or blocked CRISPR/Cas9 activity, indicating that host DNA will not likely be targeted. Deep sequencing revealed that Sp CRISPR/Cas9 induced off-target mutagenesis, whereas St CRISPR/Cas9 had no effect on the host genome. St CRISPR/Cas9 system represents the safest system with high anti-HBV activity.


A general mathematical method for investigating the thymic microenvironment, thymocyte development, and immunopathogenesis.
T-lymphocyte (T-cell) development constitutes one of the basic and most vital processes in immunology. The process is profoundly affected by the thymic microenvironment, the dysregulation of which may be the pathogenesis or the etiology of some diseases. On the basis of a general conceptual framework, we have designed the first biophysical model to describe thymocyte development. The microclimate within the thymus, which is shaped by various cytokines, is first conceptualized into a growth field lambda and a differentiation field mu, under the influence of which the thymocytes mature. A partial differential equation is then derived through the analysis of an infinitesimal element of the flow of thymocytes. A general method is presented to estimate the two fields based on experimental data obtained by flow cytometric analysis of the thymus. Numerical examples are given for both normal and pathologic conditions. Our results are quite good, and even the time varying fields can be accurately estimated. Our method has demonstrated its great potential for the study of immunopathogenesis. The plan for implementation of the method is addressed.


Ependymal development, proliferation, and functions: a review.
A survey of the literature shows that proliferation of ependyma occurs largely during the embryonic and early postnatal periods of development in most species. Differentiation of these cells proceeds along particular regional and temporal gradients as does the expression of various cytoskeletal (vimentin, cytokeratins, glial fibrillary acidic protein) and secretory proteins (S-100). Turnover declines significantly postnatally, and only low levels of residual activity persist into adulthood under normal conditions. Although the reported response of ependyma to injury is somewhat equivocal, only limited regenerative capacity appears to exist and to varying degrees in different regions of the neuraxis. Proliferation has been most often observed in response to spinal cord injury. Indeed, the ependyma plays a significant role in the initiation and maintenance of the regenerative processes in the spinal cord of inframammalian vertebrates. In the human, however, ependyma appears never to regenerate at any age nor re-express cytoskeletal proteins characteristic of immature cells. The functions of ependyma including tanycytes, a specialized form of ependymal cell that persists into adulthood within circumscribed regions of the nervous system, are still largely speculative. Fetal unlike mature ependyma is believed to be secretory and is believed to play a role in neurogenesis, neuronal differentiation/axonal guidance, transport, and support. In the adult brain, mature ependyma is not merely an inert lining but may regulate the transport of ions, small molecules, and water between the cerebrospinal fluid and neuropil and serve an important barrier function that protects neural tissue from potentially harmful substances by mechanisms that are still incompletely understood.


[Efficacy and safety of cefbuperazone in severe infections complicating hematologic diseases Hanshin Infection Study Group].
Cefbuperazone (CBPZ) was administered to patients with severe infections complicating hematologic diseases to assess its efficacy and safety under such clinical conditions. Primary diseases in this series of 78 cases included; acute leukemia in 41 cases, chronic leukemia in 6 cases, other leukemia in 9 cases, malignant lymphoma in 13 cases, multiple myeloma in 3 cases, aplastic anemia in 5 cases and 1 other case. Types of infection included sepsis; proven or suspected, in 59 cases, pulmonary infection in 8 cases, upper respiratory infection in 5 cases, and other cases. CBPZ was infused by an intravenous drip method at a dosage of 4-8 g daily. Patients' ages ranged from 14 to 85 years. Clinical response to the CBPZ regimen was excellent in 24 cases, good in 22 cases, fair in 2 cases, and poor in 30 cases. Thus the overall efficacy rate (percentage of cases showing an excellent or good response) was 59.0%. Efficacy rates for individual types of infection were: documented sepsis 16.7%, suspected sepsis 58.5%, lower respiratory infection 62.5%, and upper respiratory infection 100%. CBPZ also proved to be effective in 61.0% of cases with a neutrophil count of less than 500/mm3 prior to therapy. Side effects encountered were diarrhea in 1 case, gastric discomfort in 1 case and hepatic dysfunction in 5 cases. These side effects, however, were not dose-related, and none were serious. These results indicate that CBPZ has a high therapeutic efficacy even in patient with compromised immunodefenses.


The heart of Detroit study: a window into urban middle-aged and older African Americans' daily lives to understand psychosocial determinants of cardiovascular disease risk.
Cardiovascular disease disproportionately affects African Americans. Psychosocial factors, including the experience of and emotional reactivity to racism and interpersonal stressors, contribute to the etiology and progression of cardiovascular disease through effects on health behaviors, stress-responsive neuroendocrine axes, and immune processes. The full pathway and complexities of these associations remain underexamined in African Americans. The Heart of Detroit Study aims to identify and model the biopsychosocial pathways that influence cardiovascular disease risk in a sample of urban middle-aged and older African American adults. The proposed sample will be composed of 500 African American adults between the ages of 55 and 75 from the Detroit urban area. This longitudinal study will consist of two waves of data collection, two years apart. Biomarkers of stress, inflammation, and cardiovascular surrogate endpoints (i.e., heart rate variability and blood pressure) will be collected at each wave. Ecological momentary assessments will characterize momentary and daily experiences of stress, affect, and health behaviors during the first wave. A proposed subsample of 60 individuals will also complete an in-depth qualitative interview to contextualize quantitative results. The central hypothesis of this project is that interpersonal stressors predict poor cardiovascular outcomes, cumulative physiological stress, poor sleep, and inflammation by altering daily affect, daily health behaviors, and daily physiological stress. This study will provide insight into the biopsychosocial pathways through which experiences of stress and discrimination increase cardiovascular disease risk over micro and macro time scales among urban African American adults. Its discoveries will guide the design of future contextualized, time-sensitive, and culturally tailored behavioral interventions to reduce racial disparities in cardiovascular disease risk.


Hemangioma Mimicking Left Atrial Mass in the Posterior Mediastinum.
Primary hemangioma of the mediastinum is extremely rare. Herein, we present a unique case of hemangioma mimicking left atrial mass in the posterior mediastinum. We reviewed the literature and found 17 other hemangiomas in the posterior mediastinum. Herein, we summarize the age, gender, symptoms, diagnostic methods, image diagnosis, size, treatments, histologic features, outcomes, and follow-up of 17 cases. Most of the cases were asymptomatic and were accidentally detected in chest radiographs. Diagnostic methods mainly included chest X-ray, computed tomography (CT), and magnetic resonance imaging (MRI). All patients underwent surgical resection, recovered well, and had no recurrence during follow-up.


[A survey of sleeping difficulties in an urban Latin American population].
To report the results of the first regional survey on the prevalence of sleep disturbances in an urban Latin American population. Door-to-door and telephone interviews in main urban areas were performed in two phases. In phase one, 1776 adults, aged 18 to 70 were interviewed in Buenos Aires and São Paulo. In phase two, adults aged 18 to 77 were interviewed in Buenos Aires, São Paulo and Mexico City (n = 300 in each city). Two-thirds of those surveyed in phase 1, regardless of age and gender, reported some type of sleep problem within the last 12 months. Up to 25 % of individuals surveyed in phase 2 reported being severely affected or moderately affected by their sleep problems. The severity of the condition increased with age, women being more severely affected than men. On average, individuals reported suffering from sleep difficulties for a period of 5 years and were affected 15.5 nights per month. Although 8.2 hours of sleep was most desired, Latin Americans were sleeping on average 5.8 hours per night. Those severely affected lost about 3 hours per night. Individuals reported stress and worry as the primary trigger for their sleep problems, followed by health concerns. All respondents reported the negative impact of poor sleep on their health and quality of life. The survey indicates that the prevalence of sleep difficulties in an urban Latin America population is high.


A systematic pan-cancer study demonstrates the oncogenic function of heterogeneous nuclear ribonucleoprotein C.
Although complex links between heterogeneous nuclear ribonucleoprotein C (HNRNPC) and numerous types of cancer have been shown in both cell and animal models, a comprehensive pan-cancer investigation on the features and activities of HNRNPC is still lacking. Based on the Cancer Genome Atlas and Gene Expression Omnibus datasets, we investigated the possible oncogenic effects of HNRNPC in thirty-three cancers. HNRNPC expression was detected in the majority of cancers, and its expression level was shown to be significantly linked with cancer patient prognosis. HNRNPC increased the phosphorylation of S220, which was detected in various cancers, including ovarian cancer and colon cancer. HNRNPC expression was also shown to be related to cancer-associated cell infiltration, most notably in uveal melanoma, testicular germ cell tumors, and thymoma. Additionally, the signaling pathway for vascular endothelial growth factors and RNA transport were implicated in HNRNPC's functioning processes. In short, HNRNPC may further influence cancer progression through gene mutation, protein phosphorylation, cancer associated fibroblasts infiltration and related molecular pathways. This work was intended to provide a relatively thorough knowledge of the oncogenic activities of HNRNPC across a variety of tumor types by performing a systematic pan-cancer investigation.


[Italian male nurses called to arms in World War II: the letters of the years of imprisonment].
During the Second World War the male staff of assistance in the Italia hospitals was called to arms.This work concerns the letters sent by the male nurses who were captured by the Germans and put in prison. The aim is to know whether their profession had somehow affected their living condition in jail and had favoured their release or not. 88 personal files of nurses on duty in Ospedale Maggiore and sent to the front during the period between 1940 and 1945 have been studied. The documents are kept in the historical archive of the Ospedale Maggiore of Milan and the research covered the period from December to January 2013. The sources have been analyzed according to Chabod's method of historical research (2012). 4 prisoners have been found among the 88 files of soldiers and handwritten letter has been selected for each one. These letters the attempt of the prisoners to reassure their loved ones emerges. Moreover, in the files of the prisoners' formal request for their release sent by hospital board were found. As a result one of the prisoners was released. This paper suggests that the fact of being a nurse in a hospital influenced the conditions during tha period of captivity. Much is still to be found to shed light on a dramatic period of our country and to restore the memory of the contribution given by the profession.


Increased Cardiovascular Mortality Risk in Women Discontinuing Postmenopausal Hormone Therapy.
Current guidelines recommend annual discontinuation of postmenopausal hormone therapy (HT) to evaluate whether a woman could manage without the treatment. The impact of HT on cardiovascular health has been widely studied, but it is not known how the withdrawal of HT affects cardiovascular risk. We evaluated the risk of cardiac or stroke death after the discontinuation of HT. Design, Patients, Interventions, and Main Outcome Measures: Altogether 332 202 Finnish women discontinuing HT between 1994 and 2009 (data from National Reimbursement register) were followed up from the discontinuation date to death due to cardiac cause (n = 3177) or stroke (n = 1952), or to the end of 2009. The deaths, retrieved from the national Cause of Death Register, were compared with the expected number of deaths in the age-standardized background population. In a subanalysis we also compared HT stoppers with HT users. Within the first posttreatment year, the risk of cardiac death was significantly elevated (standardized mortality ratio; 95% confidence interval 1.26; 1.16-1.37), whereas follow-up for longer than 1 year was accompanied with a reduction (0.75; 0.72-0.78). The risk of stroke death in the first posttreatment year was increased (1.63; 1.47-1.79), but follow-up for longer than 1 year was accompanied with a reduced risk (0.89; 0.85-0.94). The cardiac (2.30; 2.12-2.50) and stroke (2.52; 2.28-2.77) death risk elevations were even higher when compared with HT users. In women who discontinued HT at age younger than 60 years, but not in women aged 60 years or older, the cardiac mortality risk was elevated (1.94; 1.51-2.48). Increased cardiovascular death risks question the safety of annual HT discontinuation practice to evaluate whether a woman could manage without HT.


Visual search for apparent-length targets is modulated by the Müller-Lyer illusion.
Is apparent object size represented in pre-attentive vision and can it influence visual search for size-defined targets in a spatially parallel manner? This question was investigated, using the Müller-Lyer illusion. Observers searched for a target line that was longer than the distractor lines. Test lines could be presented without context arrows (control); be adjoined by obtuse-angle context arrows (arrow heads pointing inward), making the lines appear longer; or by acute-angle arrows (heads pointing outward), making the lines appear shorter. These apparent-length modulations were larger for the target than for the distractor lines, thereby increasing and, respectively, decreasing the target-distractor length contrast. In line with these changes in contrast, target detection was found to be expedited by obtuse-angle arrows and impeded by acute-angle arrows, independently of the number of elements in the display. This finding provides further evidence for the pre-attentive processing of apparent object size.


Ecologically driven selection of nonstructural carbohydrate storage in oak trees.
Leaf habit is a major axis of plant diversity that has consequences for carbon balance since the leaf is the primary site of photosynthesis. Nonstructural carbohydrates (NSCs) produced by photosynthesis can be allocated to storage and serve as a resiliency mechanism to future abiotic and biotic stress. However, how leaf habit affects NSC storage in an evolutionary context has not been shown. Using a comparative physiological framework and an analysis of evolutionary model fitting, we examined if variation in NSC storage is explained by leaf habit. We measured sugar and starch concentrations in 51 oak species (Quercus spp.) growing in a common garden and representing multiple evolutions of three different leaf habits (deciduous, brevideciduous and evergreen). The best fitting evolutionary models indicated that deciduous oak species are evolving towards higher NSC concentrations than their brevideciduous and evergreen relatives. Notably, this was observed for starch (the primary storage molecule) in the stem (a long-term C storage organ). Overall, our work provides insight into the evolutionary drivers of NSC storage and suggests that a deciduous strategy may confer an advantage against stress associated with a changing world. Future work should examine additional clades to further corroborate this idea.