Housing, neighbourhood and sociodemographic associations with adult levels of physical activity and adiposity: baseline findings from the ENABLE London study.
The neighbourhood environment is increasingly shown to be an important correlate of health. We assessed associations between housing tenure, neighbourhood perceptions, sociodemographic factors and levels of physical activity (PA) and adiposity among adults seeking housing in East Village (formerly London 2012 Olympic/Paralympic Games Athletes' Village). Cross-sectional analysis of adults seeking social, intermediate and market-rent housing in East Village. 1278 participants took part in the study (58% female). Complete data on adiposity (body mass index (BMI) and fat mass %) were available for 1240 participants (97%); of these, a subset of 1107 participants (89%) met the inclusion criteria for analyses of accelerometer-based measurements of PA. We examined associations between housing sector sought, neighbourhood perceptions (covariates) and PA and adiposity (dependent variables) adjusted for household clustering, sex, age group, ethnic group and limiting long-standing illness. Participants seeking social housing had the fewest daily steps (8304, 95% CI 7959 to 8648) and highest BMI (26.0 kg/m2, 95% CI 25.5kg/m2 to 26.5 kg/m2) compared with those seeking intermediate (daily steps 9417, 95% CI 9106 to 9731; BMI 24.8 kg/m2, 95% CI 24.4 kg/m2 to 25.2 kg/m2) or market-rent housing (daily steps 9313, 95% CI 8858 to 9768; BMI 24.6 kg/m2, 95% CI 24.0 kg/m2 to 25.2 kg/m2). Those seeking social housing had lower levels of PA (by 19%-42%) at weekends versus weekdays, compared with other housing groups. Positive perceptions of neighbourhood quality were associated with higher steps and lower BMI, with differences between social and intermediate groups reduced by ~10% following adjustment, equivalent to a reduction of 111 for steps and 0.5 kg/m2 for BMI. The social housing group undertook less PA than other housing sectors, with weekend PA offering the greatest scope for increasing PA and tackling adiposity in this group. Perceptions of neighbourhood quality were associated with PA and adiposity and reduced differences in steps and BMI between housing sectors. Interventions to encourage PA at weekends and improve neighbourhood quality, especially among the most disadvantaged, may provide scope to reduce inequalities in health behaviour.


Functional anatomy of the ligaments of the elbow.
Dissections of 10 fresh cadaver specimens revealed an important insertion of the posterior portion of the lateral collateral ligament to the ulna at the crista supinatoris. The humeral origin of the medial ligament attachments was found to lie posterior to the axis of elbow flexion; in this position a cam effect is created so that ligament tension varies with elbow flexion. The three-dimensional distance between the origin and the insertion of the anterior portion of the medial collateral ligament was found to increase slightly from extension to approximately 60 degrees of flexion; thereafter, it remained nearly constant. The distance of the posterior portion increased by about 9 mm from 60 degrees to 120 degrees of flexion. The flexion axis was shown to pass through the origin of the lateral collateral ligament, so the length of this structure was not changed during elbow flexion.


The citrullinated/native index of autoantibodies against hnRNP-DL predicts an individual "window of treatment success" in RA patients.
There is a need for biomarker to identify patients "at risk" for rheumatoid arthritis (risk-RA) and to better predict the therapeutic response and in this study we tested the hypothesis that novel native and citrullinated heterogeneous nuclear ribonucleoprotein (hnRNP)-DL autoantibodies could be possible biomarkers. Using protein macroarray and ELISA, epitope recognition against hnRNP-DL was analysed in sera from different developed RA disease and diagnosed SLE patients. Toll-like receptor (TLR) 7/9 and myeloid differentiation primary response gene 88 (MyD88)-dependency were studied in sera from murine disease models. HnRNP-DL expression in cultivated cells and synovial tissue was analysed by indirect immunofluorescence, immunoblot and immunohistochemistry. HnRNP-DL was highly expressed in stress granules, citrullinated in the rheumatoid joint and targeted by autoantibodies either as native or citrullinated proteins in patient subsets with different developed RA disease. Structural citrullination dependent epitopes (SCEs) of hnRNP-DL were detected in 58% of the SLE patients although 98% of these sera were α-CCP-2-negative. To obtain a specific citrullinated signal value, we subtracted the native antibody value from the citrullinated signal. The citrullinated/native index of autoantibodies against hnRNP-DL (CNDL-Index) was identified as a new value for an "individual window of treatment success" in early RA and for the detection of RF IgM/α-CCP-2 seronegative RA patients (24-46%). Negative CNDL-index was found in SLE patients, risk-RA and early RA cohorts such as EIRA where the majority of these patients are DAS28-responders to methotrexate (MTX) treatment (87%). High positive CNDL-values were associated with more severe RA, shared epitope and parenchymal changes in the lung. Specifically, native α-hnRNP-DL is TLR7/9-dependent, associated with pain and ROC analysis revealed an association to initial MTX or etanercept treatment response, especially in seronegative RA patients. CNDL-index defines people at risk to develop RA and the "window of treatment success" thereby closing the sensitivity gap in RA.


NLRP3-Inflammasome Inhibition with IZD334 Does Not Reduce Cardiac Damage in a Pig Model of Myocardial Infarction.
NLRP3-inflammasome-mediated signaling is thought to significantly contribute to the extent of myocardial damage after myocardial infarction (MI). The purpose of this study was to investigate the effects of the NLRP3-inflammasome inhibitor IZD334 on cardiac damage in a pig model of myocardial infarction. Prior to in vivo testing, in vitro, porcine peripheral blood mononuclear cells and whole blood were treated with increasing dosages of IZD334, a novel NLRP3-inflammasome inhibitor, and were stimulated with lipopolysaccharide (LPS) and adenosine triphosphate (ATP). After determination of the pharmacological profile in healthy pigs, thirty female Landrace pigs were subjected to 75 min of transluminal balloon occlusion of the LAD coronary artery and treated with placebo or IZD334 (1 mg/kg, 3 mg/kg, or 10 mg/kg once daily) in a blinded randomized fashion. In vitro, NLRP3-inflammasome stimulation showed the pronounced release of interleukin (IL)-1β that was attenuated by IZD334 (p < 0.001). In vivo, no differences were observed between groups in serological markers of inflammation nor myocardial IL-1β expression. After 7 days, the ejection fraction did not differ between groups, as assessed with MRI (placebo: 45.1 ± 8.7%, 1 mg/kg: 49.9 ± 6.1%, 3 mg/kg: 42.7 ± 3.8%, 10 mg/kg: 44.9 ± 6.4%, p = 0.26). Infarct size as a percentage of the area at risk was not reduced (placebo: 73.1 ± 3.0%, 1 mg/kg: 75.5 ± 7.3%, 3 mg/kg: 80.3 ± 3.9%, 10 mg/kg: 78.2 ± 8.0%, p = 0.21). In this pig MI model, we did not observe attenuation of the inflammatory response after NLRP3-inflammasome inhibition in vivo. Consecutively, no difference was observed in IS and cardiac function, while in vitro inhibition successfully reduced IL-1β release from stimulated porcine blood cells.


Identification and fine mapping of nuclear and nucleolar localization signals within the human ribosomal protein S17.
Human ribosomal protein S17 (RPS17) is mutated in Diamond-Blackfan Anemia (DBA), a bone marrow disorder that fails to produce sufficient red blood cells leading to anemia. Recently, an RPS17 protein sequence was also found to be naturally inserted in the genome of hepatitis E virus (HEV) from patients chronically-infected by HEV. The role of RPS17 in HEV replication and pathogenesis remains unknown due to the lack of knowledge about how RPS17 functions at a molecular level. Understanding the biological function of RPS17 is critical for elucidating its role in virus infection and DBA disease processes. In this study we probed the subcellular distribution of normal and mutant RPS17 proteins in a human liver cell line (Huh7). RPS17 was primarily detected within the nucleus, and more specifically within the nucleoli. Using a transient expression system in which RPS17 or truncations were expressed as fusions with enhanced yellow fluorescent protein (eYFP), we were able to identify and map, for the first time, two separate nuclear localization signals (NLSs), one to the first 13 amino acids of the amino-terminus of RPS17 and the other within amino acids 30-60. Additionally, we mapped amino acid sequences required for nucleolar accumulation of RPS17 to amino acids 60-70. Amino acids 60-70 possess a di-RG motif that may be necessary for nucleolar retention of RPS17. The results from this study enhance our knowledge of RSP17 and will facilitate future mechanistic studies about the roles of RSP17 in hepatitis E and DBA disease processes.


Clinical significance of serum insulin-like growth factor-1 (IGF-1) and insulinlike growth factor binding protein-3 (IGFBP-3) in patients with epithelial ovarian cancer.
Insulin-like growth factor-1 (IGF-1) and its primary binding protein IGFBP-3 play an important role in cellular proliferation, differentiation, and apoptosis in many tumors, including ovarian cancer. The objective of this study was to determine the clinical significance of the serum levels of IGF-1 and IGFBP-3 in epithelial ovarian cancer (EOC) patients. A total of 50 patients with a pathologically confirmed diagnosis of EOC were enrolled into this study. Serum IGF-1 and IGFBP-3 levels were determined by the solid-phase sandwich ELISA method. Twenty age- and sex-matched healthy controls were included in the analysis. Median age of patients was 56.5 years old (range 22 to 83 years). Majority of the patients had advanced disease (FIGO stage III-IV; 90%). No significant difference was observed in baseline serum IGF-1 and IGFBP-3 levels between EOC patients and healthy controls (p = 0.99 and p = 0.80, respectively). The young patients had higher serum IGF-1 and IGFBP-3 concentrations (p = 0.04 and p = 0.02, respectively). Patients with normal CA-125 levels had higher serum IGFBP-3 concentrations compared with those with higher CA-125 levels (p = 0.008). However, no other clinical variables including histology, tumor grade, stage of disease, and response to chemotherapy were found to be correlated with serum IGF assays (p > 0.05). A trend to significant relationship was found between the serum levels of IGF-1 and IGFBP-3 (r(s) = 0.212, p = 0.07). The patients with elevated serum IGF-1 levels had favorable progression-free and overall survivals than those with lower levels (p = 0.04 and p = 0.03, respectively). However, serum IGFBP-3 concentrations were found to have no prognostic role for both survivals (p = 0.12 and p = 0.26, respectively). In conclusion, elevated serum level of IGF-1 is associated with favorable progression-free and overall survivals in EOC patients.


Newly described clinical features in two siblings with MACS syndrome and a novel mutation in RIN2.
The disorder comprising Macrocephaly, Alopecia, Cutis laxa, and Scoliosis has been designated MACS syndrome. It is a rare condition, inherited in an autosomal recessive pattern. Three families from different ethnic origins have so far been reported and were all linked to homozygous mutations in RIN2, a gene encoding the Ras and Rab interactor 2 protein involved in cell trafficking. We describe herein the fourth family with MACS syndrome in two siblings carrying a novel homozygous mutation, c.1878_1879insC in exon 8 of the RIN2 gene, which predicts p.Ile627Hisfs*7. We also report on additional findings not previously described in MACS syndrome, including bronchiectasis and hypergonadotropic hypogonadism. Finally, our overall data support the argument that RIN2 syndrome is a more appropriate name for the disorder.


Interaction between the estrogen receptor and fibroblast growth factor receptor pathways in non-small cell lung cancer.
The estrogen receptor (ER) promotes non-small cell lung cancer (NSCLC) proliferation. Since fibroblast growth factors (FGFs) are known regulators of stem cell markers in ER positive breast cancer, we investigated whether a link between the ER, FGFs, and stem cell markers exists in NSCLC. In lung preneoplasias and adenomas of tobacco carcinogen exposed mice, the anti-estrogen fulvestrant and/or the aromatase inhibitor anastrozole blocked FGF2 and FGF9 secretion, and reduced expression of the stem cell markers SOX2 and nanog. Mice administered β-estradiol during carcinogen exposure showed increased FGF2, FGF9, SOX2, and Nanog expression in airway preneoplasias. In normal FGFR1 copy number NSCLC cell lines, multiple FGFR receptors were expressed and secreted several FGFs. β-estradiol caused enhanced FGF2 release, which was blocked by fulvestrant. Upon co-inhibition of ER and FGFRs using fulvestrant and the pan-FGFR inhibitor AZD4547, phosphorylation of FRS2, the FGFR docking protein, was maximally reduced, and enhanced anti-proliferative effects were observed. Combined AZD4547 and fulvestrant enhanced lung tumor xenograft growth inhibition and decreased Ki67 and stem cell marker expression. To verify a link between ERβ, the predominant ER in NSCLC, and FGFR signaling in patient tumors, mRNA analysis was performed comparing high versus low ERβ expressing tumors. The top differentially expressed genes in high ERβ tumors involved FGF signaling and human embryonic stem cell pluripotency. These results suggest interaction between the ER and FGFR pathways in NSCLC promotes a stem-like state. Combined FGFR and ER inhibition may increase the efficacy of FGFR inhibitors for NSCLC patients lacking FGFR genetic alterations.


[Age changes in interalveolar septa and their relationship to a decrease in gas exchange].
External respiration and interalveolar septa ultrastructure were examined in healthy men aged 45-49 and 60-70 years. Involution reduction of static lung volumes, decrease in lung ventilation capacity and deceleration of gas exchange in the respiratory portion of the lung were noted. Age changes in interalveolar septa capillary network structure, air-blood barrier and the interstitium have been established. In the elderly people, the capillary network was found to lose some small loops, which were substituted by a connective tissue. The thickness of air-blood barrier was shown to increase, thus causing a deceleration of oxygen diffusion from alveolar lumen into the blood of pulmonary capillaries. The interstitial connective tissue was found to contain a larger proportion of collagen and, particularly, of elastic fibers per unit volume. In the aged persons interalveolar septa underwent obvious sclerotic changes, and the disappearance of Kohn pores could be considered as one of their manifestations. All these changes seem to disturb the uniformity of intraacinar ventilation and may significantly influence gas exchange conditions.


[Medical support of the Armed Forces of the Russian Federation: the results of the activities and the main tasks for 2015].
Presented the directions of activity of the medical service in the past year, including improving the legal framework, the optimization of medical management software, improving combat and mobilization readiness of units of the army, the optimization of therapeutic and preventive activities, implementation of innovative technologies, increasing mobility of units and subunits, their level of equipping with modern samples of property, training of qualified personnel, intensify research and etc. Analyzed and formulated directions of development of military medicine in 2015, including improvement of combat and mobilization readiness of the management body, military and medical organizations and departments, improving the legal framework of the military health care, holding among the troops interventions for the prevention morbidity of personnel by pneumonia and meningitis, work with commanders at all levels to ensure the preservation and strengthening of health of servicemen, improving of the system of early and active detection of diseases in the military, providing a guaranteed level of care to all contingent Ministry of Defense, improving the quality and accessibility of sanatorium treatment, maintaining constant readiness of medical special forces to carry out tasks for the purpose, improvement of professional training of personnel of the medical service, providing qualitative preparation of government medical service to participate in the training of troops, implementation of unexpected problems, equipping of army medical service with modern medical equipment finishing of the construction and renovation of military medical organizations facilities, improvement of social protection of personnel and many others.


Mitochondrial ion channels as targets for cardioprotection.
Acute myocardial infarction (AMI) and the heart failure (HF) that often result remain the leading causes of death and disability worldwide. As such, new therapeutic targets need to be discovered to protect the myocardium against acute ischaemia/reperfusion (I/R) injury in order to reduce myocardial infarct (MI) size, preserve left ventricular function and prevent the onset of HF. Mitochondrial dysfunction during acute I/R injury is a critical determinant of cell death following AMI, and therefore, ion channels in the inner mitochondrial membrane, which are known to influence cell death and survival, provide potential therapeutic targets for cardioprotection. In this article, we review the role of mitochondrial ion channels, which are known to modulate susceptibility to acute myocardial I/R injury, and we explore their potential roles as therapeutic targets for reducing MI size and preventing HF following AMI.


The Ca2+/calmodulin binding domain of the Ca2+-ATPase linked to the Na+,K+-ATPase alters transport stoichiometry.
Using Xenopus oocytes as an expression system, we have investigated ion-transport and ouabain-binding properties of a chimeric ATPase (alpha1-CBD; Ishii and Takeyasu (1995) EMBO J. 14, 58-67) formed by the alpha1-subunit of chicken Na+,K(+)-ATPase (alpha1) and the calmodulin binding domain (CBD) of the rat plasma membrane Ca2(+)-ATPase. alpha1-CBD can be expressed and transported to the oocyte plasma membrane without the beta-subunit, and shows ouabain binding. In contrast to ouabain binding, this chimera requires the beta-subunit for its cation (Na+ and K+) transport activity. alpha1-CBD exhibits an altered stoichiometry of Na(+)-K+ exchange. A detailed analysis of 22Na+ efflux, 86Rb+ uptake, pump current and ouabain binding suggests that the chimeric molecule can operate in an electrically silent 2Na(+)-2K+ exchange mode and, with much lower probability, in its normal 3Na(+)-2K+ exchange mode.


Exome sequencing and digital PCR analyses reveal novel mutated genes related to the metastasis of pancreatic ductal adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant cancers with more than 94% mortality rate mainly due to the widespread metastases. To find out the somatically mutated genes related to the metastasis of PDAC, we analyzed the matched tumor and normal tissue samples from a patient diagnosed with liver metastatic PDAC using intensive exome capture-sequencing analysis (> 170× coverage). Searching for the somatic mutations that drive the clonal expansion of metastasis, we identified 12 genes with higher allele frequencies (AFs) of functional mutations in the metastatic tumor, including known genes KRAS and TP53 for metastasis. Of the 10 candidate genes, 6 (ADRB1, DCLK1, KCNH2, NOP14, SIGLEC1, and ZC3H7A), together with KRAS and TP53, were clustered into a single network (p value = 1 × 10(-22)) that is related to cancer development. Moreover, these candidate genes showed abnormal expression in PDAC tissues and functional impacts on the migration, proliferation, and colony formation abilities of pancreatic cancer cell lines. Furthermore, through digital PCR analysis, we revealed potential genomic mechanisms for the KRAS and TP53 mutations in the metastatic tumor. Taken together, our study shows the possibility for such personalized genomic profiling to provide new biological insight into the metastasis of PDAC.


The central role of CD4(+) T cells in the antitumor immune response.
The induction of optimal systemic antitumor immunity involves the priming of both CD4(+) and CD8(+) T cells specific for tumor-associated antigens. The role of CD4(+) T helper cells (Th) in this response has been largely attributed to providing regulatory signals required for the priming of major histocompatibility complex class I restricted CD8(+) cytolytic T lymphocytes, which are thought to serve as the dominant effector cell mediating tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor indicates a far broader role for CD4(+) T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4(+) T cells activate eosinophils as well as macrophages that produce both superoxide and nitric oxide. Both of these cell types then collaborate within the site of tumor challenge to cause its destruction.


Israeli Arabs develop diverticulitis at a younger age and are more likely to require surgery than Jews.
Only few studies have examined the impact of racial differences on the age of onset, course and outcomes of diverticulitis. To provide data about the epidemiology of diverticulitis in northern Israel, and to determine whether ethnicity is a predictor of age of onset, complications, and need for surgery. Was conducted a retrospective review of the charts of all patients diagnosed with a first episode of diverticulitis in our hospital between 2005 and 2012. Were found 638 patients with a first episode of acute diverticulitis in the eight year interval. Israeli Arabs developed a first episode of diverticulitis at a younger age compared to Jews (51.2 vs 63.8 years, p<0.01). Arabs living in rural areas developed diverticulitis at a younger age than Arabs living in urban centers (49.4 vs 54.5 years, P=0.03). Jewish and Arabic men developed diverticulitis at younger age compared to their female counterparts (59.9 vs 66.09, p<0.01, and 47.31 vs 56.93, p<0.01, respectively). Arabs were more likely [odds ratio (OR)=1.81 ,95% confidence interval (CI)1.12-2.90, p=0.017] than Jews to require surgical treatment (urgent or elective) for diverticulitis. Israeli Arabs tend to develop diverticulitis at a younger age and are more likely to require surgical treatment for diverticulitis compared to Jews. Arabs living in rural areas develop diverticulitis at a younger age than Arabs living in urban centers. These findings highlight a need to address the root cause for ethnic differences in onset, course and outcome of acute diverticulitis.


Serogroups and antimicrobial susceptibility among Escherichia coli isolated from farmed mink (Mustela vison Schreiber) in Denmark.
Escherichia coli is commonly found in outbreaks of diarrhoea in mink during the production season although its role as a primary causal organism remains unclear. The present study was undertaken to determine the serogroups and antimicrobial susceptibility of E. coli isolates from healthy and diarrhoeic mink. Rectal swabs were taken from healthy and diseased animals, on six different farms, once at the onset of disease and again approximately 2 weeks later. The swabs were subjected to bacteriological investigation; a total of 210 E. coli were isolated, 98 from healthy animals and 112 from diseased. All isolates were serotyped and MICs were determined for nine antimicrobial compounds. Non-haemolytic isolates numbered 147, whereas 63 were haemolytic. Both haemolytic and non-haemolytic isolates were isolated from both healthy and diseased animals.A wide range of serogroups was detected, the most frequent being O2 (11.0%), O78 (11.0%), O153 (7.1%), O25 (5.7%), O6 (4.8%), and O15 (4.8%), but diarrhoea was not associated with specific serogroups. All isolates were sensitive to enrofloxacin, neomycin, gentamicin and colistin. In contrast, considerable variations in susceptibility were found among the six mink farms, for tetracycline (0-46.4%, average 21.9), ampicillin (2.9-50.0%, average 23.3), spectinomycin (8.0-35.7%, average 21.9), sulfamethoxazole (8.6-57.7%, average 30.0) and trimethoprim (0-35.7%, average 9.5). Resistance to tetracycline was statistically more prevalent among haemolytic than among non-haemolytic strains.In conclusion, serogrouping and haemolysin testing failed to identify any association with diarrhoeal disease and antimicrobial resistance was highly variable between different mink farms.


HOXA1 Mutations are Not Commonly Associated with Non-Syndromic Deafness.
Homozygous homeobox A1 (HOXA1) mutations cause a spectrum of abnormalities in humans including bilateral profound deafness. This study evaluates the possible role of HOXA1 mutations in familial, non-syndromic sensorineural deafness. Forty-eight unrelated Middle Eastern families with either consanguinity or familial deafness were identified in a large deafness clinic, and the proband from each family was evaluated by chart review, audiogram, neuroimaging, and HOXA1 sequencing. All 48 probands had normal neuro-ophthalmologic and general medical examinations except for refractive errors. All had congenital non-syndromic sensorineural hearing loss that was symmetric bilaterally and profound (>90 dBHL) in 33 individuals and varied from 40 to 90 dBHL in the remainder. Thirty-nine of these individuals had neuroimaging studies, all documenting normal internal carotid arteries and normal 6th, 7th, and 8th cranial nerves bilaterally. Of these, 27 had normal internal ear structures with the remaining 12 having mild to modest developmental abnormalities of the cochlea, semicircular canals, and/or vestibular aqueduct. No patient had homozygous HOXA1 mutations. None of these patients with non-syndromic deafness had HOXA1 mutations. None had major inner ear anomalies, obvious cerebrovascular defects, or recognized congenital heart disease. HOXA1 is likely not a common cause of non-syndromic deafness in this Middle Eastern population.


Palladium-catalyzed direct C-H functionalization of benzoquinone.
A direct Pd-catalyzed C-H functionalization of benzoquinone (BQ) can be controlled to give either mono- or disubstituted BQ, including the installation of two different groups in a one-pot procedure. BQ can now be directly functionalized with aryl, heteroaryl, cycloalkyl, and cycloalkene groups and, moreover, the reaction is conducted in environmentally benign water or acetone as solvents.


Screening for cancer-related distress: Summary of evidence from tools to programmes.
A number of studies have addressed the development and testing of tools for measuring cancer-related distress. Except for studies of diagnostic validity, knowledge on the effect of screening for psychological distress on psychological well-being is limited. We aimed to describe and critically discuss the findings of randomized trials of the effect of screening and to identify components necessary for future studies of the effectiveness of screening programmes. A search was made of the Embase/Medline and Web of Knowledge abstract databases from inception to September 2010. Our inclusion criterion was randomized controlled trials concerning the effect of screening for psychological distress on psychological outcomes. We compared the randomized trials on the following aspects: design and methods, setting and sample, screening and intervention, effects on psychological distress, staff utilization of screening results, possible confounding factors and other methodological limitations. Of the seven identified randomized trials of the effect of screening for psychological distress, three showed an effect on psychological well-being, one showed an effect only among patients depressed at baseline, and three studies showed no effect. Several of the trials had methodological weaknesses and they were heterogeneous in design and content making direct comparisons difficult. Future randomized trials are needed to examine comparative validity of different screening approaches and to evaluate the benefits of screening linked with associated treatment. Trials should include distress as a patient outcome, use appropriate samples, include a detailed, theory-based distress management plan, offer staff training and ideally track staff and patient use of subsequent interventions. Provisional work suggests that screening for psychological distress holds promise and is often clinically valuable, but it is too early to conclude definitively that psychological screening itself affects the psychological well-being of cancer patients.


St. Louis encephalitis and the substantia nigra: MR imaging evaluation.
Neuroimaging findings in cases of St. Louis encephalitis (StLE) have yet to be reported despite the relatively high frequency of this entity. An epidemic permitted the documentation of isolated hyperintensity of the substantia nigra on T2-weighted images in two patients with StLE. This distribution of MR imaging abnormality in cases of StLE mirrors the reports presented in the literature that implicate the substantia nigra as peculiarly susceptible to the StLE virus. Isolated lesions of the substantia nigra revealed by T2-weighted imaging should suggest the possibility of StLE.


[Contractile function of the myocardium and oxygen metabolism in diabetes mellitus].
Myocardial contractility was studied by the radionuclide cardiography method and oxygen exchange and ABB by Astrup's method in 42 patients with insulin dependent and 50 patients with insulin independent diabetes mellitus. Indicators of tissue oxygenation and hemodynamics were correlated in both types of diabetes mellitus. At the start of disease tissue hypoxia causes compensatory change of hemodynamics, and the hyperkinetic type of the disease develops. Further development of diabetes mellitus results in disorder of myocardial contractility and deterioration of tissue oxygenation.


A comparison of ML Flow serology and slit skin smears to assess the bacterial load in newly diagnosed leprosy patients in Brazil.
The ML Flow test is an immunochromatographic assay that detects IgM antibodies against M. leprae-specific anti-phenolic glycolipid I (PGL-I). In addition to slit skin smears stained by the Ziehl-Neelsen technique, it can be helpful in the operational classification of leprosy patients for treatment purposes. This work studied the relationship between antibody levels as detected by semi-quantitative ML Flow serologic test and bacterial load as quantified by slit skin smear. 135 patients with newly detected leprosy at the reference service in Sanitary Dermatology in Brazil had slit skin smears (registered as bacillary index - BI) and an ML Flow test (registered qualitatively and semi-quantitatively) performed at admission. A logistic regression and agreement measures (kappa index) were calculated. Slit skin smears were positive in 35.9% of patients and 57% of patients were seropositive for PGL-1 antibodies. Among the seropositive patients, 416% had five or fewer skin lesions, and 65.8% had more than one peripheral nerve involved. Slit skin smears were positive in only three seronegative patients (5.6%), and negative in 41.9% of seropositive patients. Patients with a BI of 4 + had an OR of 33 for being seropositive in comparison to those with a low BI. There is a correlation between serologic test and slit skin smear results. Therefore, an ML Flow test may become a useful tool in the clinical classification of leprosy, besides slit skin smears, which require a proper laboratory infrastructure and experienced personnel.


An engineered interdomain disulfide bond stabilizes human blood coagulation factor VIIIa.
The blood coagulation disorder, hemophilia A, is caused by deficiency of coagulation factor (F)VIII. Hemophilia A is now treated by infusions of pure FVIII, but the activity of FVIII is limited because it is unstable following activation by thrombin. This instability of activated FVIII is the result of dissociation of the A2 subunit. To obtain increased stability in FVIIIa, a disulfide bond between the A2 domain and the A3 domain, preventing A2 subunit dissociation, has been engineered. Structural analysis of the FVIII A domain homology model allowed us to identify residues 664 and 1826 as a potential disulfide bond pair. A FVIII mutant containing Cys664 and Cys1826 was produced and purified (C664-C1826 FVIII). Immunoblotting showed that a disulfide bond did form to link covalently the A2 and the A3 domains. Following activation of the recombinant C664-C1826 FVIII by thrombin, the mutant FVIIIa had increased stability and retained more than 90% of its clotting activity at a time at which wild-type FVIIIa lost more than 90% of its activity. This remarkably stable C664-C1826 FVIIIa provides a unique approach for studies of the cofactor activity of FVIIIa and also for new, improved therapy for hemophilia A.


Hepatic abnormalities in patients with chronic granulomatous disease.
Chronic granulomatous disease (CGD) is a rare congenital disorder characterized by repeated bacterial and fungal infections. Aside from a high incidence of liver abscess, little is known about hepatic involvement in CGD. The aim of this study was to describe the spectrum of liver abnormalities seen in CGD. The charts of 194 patients with CGD followed at the NIH were reviewed, with a focus on liver abnormalities. Liver enzyme elevations occurred on at least one occasion in 73% of patients during a mean of 8.9 years of follow-up. ALT elevations were generally transient. Although transient alkaline phosphatase (ALP) elevations were also common, persistent ALP elevations lasting up to 17.6 years were seen in 25% of patients. Liver abscess occurred in 35% of patients. Drug-induced hepatotoxicity was documented in 15% of patients but likely occurred more frequently. Hepatomegaly was found in 34% and splenomegaly in 56% of patients. Liver histology showed granulomata in 75% and lobular hepatitis in 90% of specimens. Venopathy of the portal vein was common (80%) and associated with splenomegaly. Venopathy of the central vein was also common (63%) and was associated with the number of abscess episodes. Nodular regenerative hyperplasia (NRH) was seen in 9 patients, including 6 of 12 autopsy specimens. Liver enzyme abnormalities occur frequently in patients with CGD. In addition to liver abscesses and granulomata, drug hepatotoxicity is likely underappreciated. Vascular lesions such as venopathy and--to a lesser extent--NRH are common. The cause and clinical consequences of venopathy await prospective evaluation.


Benign breast biopsy diagnosis and subsequent risk of breast cancer.
We examine benign breast biopsy diagnoses as reported by community pathologists in New Mexico and investigate associations with future breast cancer development. Using data collected between 1992 and 2000 by the New Mexico Mammography Project and cancer data through 2003 from the New Mexico Tumor Registry, we calculated breast cancer rates following 14,602 benign breast biopsies for women ages 30 to 89 years. For comparison, we also calculated the breast cancer rate following 215,283 normal screening mammograms. Hazard ratios (HR) are presented. We identified 480 subsequent breast cancer diagnoses among 14,602 women with benign breast biopsies and 4,402 breast cancer diagnoses among 215,283 women with mammograms assigned a "negative" or "benign finding" assessment. Histologic diagnoses in absence of atypia had an age-adjusted HR of 1.95 [95% confidence interval (95% CI), 1.77-2.15]. Among low-risk histologic diagnoses, the strongest associations with subsequent breast cancer development included adenosis, apocrine metaplasia, calcifications, and ductal hyperplasia. Fibroadenoma, inflammation, and cysts did not exhibit an association with breast cancer development. Women with low-risk diagnoses and breast tissue characterized as fatty or with scattered densities had a HR of 2.09 (95% CI, 1.68-2.60), whereas women with low-risk histologic diagnoses and dense breasts had a HR of 3.36 (95% CI, 2.83-3.99). The observed breast cancer occurrence contributes to evidence of increased risk following benign biopsy. The risk associated with histologic diagnoses in absence of atypia was twice the risk experienced by women with normal mammogram evaluations and may be modified by breast density.


Vascular expression, activity and function of indoleamine 2,3-dioxygenase-1 following cerebral ischaemia-reperfusion in mice.
Indoleamine 2,3-dioxygenases-1 (Ido1) and -2 initiate the kynurenine pathway of tryptophan metabolism. In addition to the established immune regulatory effects of Ido1 and the ability of nitric oxide to regulate Ido1 activity, it is now also known that Ido1-mediated metabolism of tryptophan to kynurenine can modulate vascular tone. Ido activity is reportedly elevated in stroke patients and correlates with increased risk of death. Thus, the present goals were to test whether, following cerebral ischaemia, Ido activity and cerebrovascular Ido1 expression are altered and whether expression of Ido1 contributes to stroke outcome. Transient cerebral ischaemia was induced in wild-type and Ido1 gene-deficient (Ido1 (-/-)) mice. Mice were pre-treated with vehicle, the Ido1 inhibitor, 1-methyl-D-tryptophan (1-MT; 50 mg/kg i.p.) or the inducible nitric oxide synthase (Nos2) inhibitor, aminoguanidine (AG, 100 mg/kg i.p.). At 24 h, neurological function, brain infarct size and swelling were assessed. In addition, Ido activity was estimated by plasma kynurenine and tryptophan, and Ido1 expression was examined in cerebral arterioles. Cerebral ischaemia-reperfusion in wild-type mice increased Ido activity and its expression in cerebral arterioles. Ido1 (-/-) and 1-MT-treated wild-type mice had lower Ido activity but similar post-stroke neurological function and similar total brain infarct volume and swelling, relative to control mice. Inhibition of Nos2 with AG also did not affect Ido activity or outcome following stroke. This study provides molecular and pharmacological evidence that the expression and the activity of Ido1 increase following stroke. However, such Ido1 expression does not appear to affect overall outcome following acute ischaemic stroke, and furthermore, a regulatory role of Nos2-derived nitric oxide on Ido activity following cerebral ischaemia-reperfusion appears unlikely.


Enhanced fluorescence of phthalimide compounds induced by the incorporation of electron-donating alicyclic amino groups.
Due to their high thermal and environmental stability, polyimides (PIs) are one of the most attractive candidates for novel highly fluorescent polymers, though photophysical studies of PIs are challenging owing to their poor solubility in common solvents. To overcome these problems, we have synthesized and examined a series of low molecular weight model imide compounds: substituted N-cyclohexylphthalimides with alicyclic amino groups at the 3 or 4-positions of the benzene rings (x-NHPIs). Their photophysical properties were systematically investigated by steady-state UV/Visible absorption, fluorescence, and time-resolved fluorescence techniques. In solution, unsubstituted N-cyclohexylphthalimide (NHPI) showed almost no emission, while x-NHPIs exhibited enhanced fluorescence emission depending on the solvent polarity. Analysis of the solvatochromism of the x-NHPIs via Lippert-Mataga plots indicated the generation of large dipole moments in the excited singlet states originating from the intramolecular charge-transfer (ICT) states. The significant difference in the fluorescence quantum yields (Φ) between the 3-substituted (3Pi and 3Pyr) and 4-substituted NHPIs (4Pi and 4Pyr) strongly suggests that the former form a twisted ICT (TICT) state, whereas the latter form a planar ICT (PICT) state when excited. 4-Substituted NHPIs also show high fluorescence yields in the crystalline state. A particularly large Φ value was obtained for the 4Pi crystal, which we explain by the large intermolecular distances and the arrangement of molecules minimizing intermolecular interactions as well as the small non-radiative deactivation rate. These facts clearly demonstrate that the introduction of an alicyclic amino group into NHPI at the 4-position enhances the fluorescence quantum yields significantly, which suggests a new pathway for the development of novel, highly fluorescent PIs.


Children's emotional security and sleep: longitudinal relations and directions of effects.
We examined longitudinal relations between children's sleep and their emotional security in the mother-child, father-child, and parental marital relationships, with the goal of explicating the direction of association over time. Gender-related effects were also examined. Sleep duration was examined through actigraphy, and sleep quality was assessed via both actigraphy and self-reports. Children were in 3rd (T1) and 5th (T2) grades. The sample was composed of 78 boys and 98 girls at T1, and 62 boys and 80 girls at T2. Security in the child-mother, child-father, and marital relationships at T1 were predictive of sleep problems two years later even after controlling for children's sleep at T1. Collectively, results were more supportive of security predicting sleep parameters than the other direction of effects. Results highlight the important associations between family functioning and children's sleep, and extend the literature through the longitudinal design.


[Urinary excretion of neopterin and plasma levels of interferon gamma in patients with multiple myeloma].
Neopterin, a pteridine derivate, is produced and released by lymphocytes and monocytes/macrophages after stimulation by T-cell derived interferon (IFN) gamma. The urinary excretion of neopterin and plasma IFN-gamma levels were measured in 35 patients with multiple myeloma (MM) and 21 patients with other monoclonal gammapathies (MG). Significantly higher excretion of neopterin was found in patients with MM in the time of diagnosis and/or progressive phase of disease (median 963,7 mumol/mol creatinine, range 183,9-2 376,3) comparing the patients in stable phase of MM (median 407,4, range 184,3-826,4), monoclonal gammapathy of undetermined significance (406,2, 226,9-1 689,3) and other MG (452,5, 240, 4-913,6) (p < 0,05). Elevation of urinary neopterin levels preceded changes of other parameters of disease activity by several months, persistent high urinary excretion was associated with refractory disease respectively. The differences of neopterin levels between patients of various clinical stages of MM was observed in newly diagnosed and progressive disease (III. vs. I and II. clinical stage, p < 0.05), but not in stable phase of MM. The plasma concentration of IFN-gama were insignificantly higher in MM than in health controls, however, the difference between all groups of patients was not found. We conclude, that neopterin is a good marker of disease activity in patients with MM. The plasma levels of its regulatory cytokine, IFN-gama, did not correlate with urine neopterin levels in our study.


Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group.
In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.


RNA synthesis inhibitors alter the subnuclear distribution of DNA topoisomerase I.
The acute effect of RNA and DNA synthesis inhibitors on DNA topoisomerase (topo) I localization within cells was examined. Indirect immunofluorescence revealed that topo I was distributed throughout the nuclei but was concentrated in nucleoli of untreated K562 leukemia cells and A549 non-small cell lung cancer cells. Treatment with the DNA polymerase inhibitor aphidicolin did not alter this distribution. In contrast, 30-60 min after addition of the RNA synthesis inhibitor 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (DRB) at concentrations that inhibited [3H]uridine incorporation into RNA by > or = 50%, topo I was visible throughout the nuclei without nucleolar accentuation. Western blotting and activity assays confirmed that the amount of topo I polypeptide and topo I activity were unaltered by the brief DRB treatment. Within 30 min of DRB removal, topo I relocalized to the nucleoli in the absence or presence of the protein synthesis inhibitor cycloheximide. Collectively, these results suggest a reversible translocation of topo I out of the nucleoli when RNA synthesis is inhibited. Treatment with the topo I poisons topotecan or camptothecin, agents that also inhibit RNA synthesis, likewise caused redistribution of topo I to nonnucleolar regions of the nucleus in a variety of cell types. In DC3F hamster lung fibroblasts, 2.5 microM topotecan or 1.25 microM camptothecin was sufficient to cause this topo I redistribution. In DC3F/C-10 cells that contain a mutant camptothecin-resistant topo I, topo I relocalization required 50-fold higher concentrations of topotecan or camptothecin but not DRB. These observations not only suggest that accumulation of topo I in the nucleolus is related to ongoing RNA synthesis but also raise the possibility of screening for some types of camptothecin resistance at the single-cell level using a rapid immunofluorescence-based assay.


[The primary and secondary prevention of ischemic cardiopathy].
The aim of this paper was to summarize the most important clinical issues on coronary artery disease prevention, in order to provide the best advice to cardiologists, and facilitate their work on primary and secondary prevention. Although in recent years the knowledge of the beneficial effects of major risk factor modification has been increasing, most physicians still concentrate only on patients with overt coronary artery disease. Many high-risk individuals are not adequately advised and treated, whilst a great effort should be made by national institutions and individual doctors to implement primary prevention schemes. Indeed, the potential for preventive measures is greatest in high-risk groups. Specific international task forces have issued official recommendations on the prevention of coronary heart disease in clinical practice, which have been intended to encourage the development and revision of national guidelines on coronary prevention. The challenge for cardiologists in the year 2000 is to realize the potential for coronary prevention in all patients, and to contribute to reduce the enormous socio-economic burden of cardiovascular disease.


Antipsychotic-induced akathisia in delirium: A systematic review.
Akathisia is a neuropsychiatric syndrome characterized by subjective and objective restlessness. It is a common side effect in patients taking antipsychotics and other psychotropics. Patients with delirium are frequently treated with antipsychotic medications that are well known to induce akathisia as a side effect. However, the prevalence, phenomenology, and management of akathisia in patients with delirium remain largely unknown. The purpose of this review was to examine the medical literature in order to establish the current state of knowledge regarding the prevalence of antipsychotic-induced akathisia in patients with delirium. A systematic review of the literature was conducted using the EMBASE, MEDLINE, PsycINFO, and CINAHL databases. Ten studies addressing the incidence of akathisia in patients taking antipsychotic medication for delirium were identified and included in our review. The included studies reported a variable prevalence of antipsychotic-induced akathisia. A higher prevalence was found in patients taking haloperidol. Among atypical antipsychotics, paliperidone and ziprasidone were associated with a higher risk of akathisia. The risk for akathisia appeared to be a dose-related phenomenon. Studies using specific scales for evaluation of akathisia in delirium are lacking. Some populations, such as patients with cancer or terminally ill patients in palliative care settings taking antipsychotics for the treatment of delirium, could be at higher risk for development of akathisia as a side effect.


Differential effects of naltrindole on morphine-induced tolerance and physical dependence in rats.
This study investigated the effect of delta opioid receptor blockade by naltrindole on the development of physical dependence and tolerance to the antinociceptive and respiratory depressive effects of morphine in rats. Chronic morphine was delivered either by s.c. injection of increasing amounts of morphine over 5 days or by s.c. implantation of morphine pellets. Animals were cotreated with saline or naltrindole. Antinociception and respiratory depression were assessed after administration of a challenge dose of morphine, and withdrawal signs were determined after naloxone challenge. Naltrindole significantly attenuated the development of antinociceptive tolerance after all three chronic treatment regimens. In addition, rats pretreated with naltrindole displayed significantly fewer withdrawal symptoms and less weight loss after a naloxone challenge. In contrast, naltrindole did not prevent the development of tolerance to morphine-induced respiratory depression. These results imply that tolerance to antinociception and physical dependence involves adaptations at interacting mu and delta receptor populations, whereas tolerance to respiratory depression reflects actions of independent mu and delta receptor populations. These findings suggest that delta antagonists may have potential clinical application for decreasing the rapid development of tolerance to opiate-induced analgesia, while allowing for the development of protective tolerance to respiratory depression.


Organ transplantation: a Sunni Islamic perspective.
This paper reviews the standpoints of Muslim jurists within the Sunni tradition on organ transplantation. Muslim jurists allowed different forms of bone grafts (autograft, allograft and xenograft) for widely broken bones. Ibn Sina in 1037 discussed this subject in Al-Kanoon 1000 years ago. In 1959, the Muftis of Egypt and Tunisia allowed, under specific conditions, corneal transplants from dead persons. Thereafter, many fatwas (jurisprudence) on organ trans-plantation have been issued from different parts of the Muslim world. In Amman, Jordan, the International Islamic Jurist Council recognized brain-death as a recognized sign of death in Islam in October 1986. This paved the way for organ transplantation from brain-dead persons, which started immediately in Saudi Arabia. In 1990 and 2003, the International Islamic Fiqh Academy (IIFA) and the Islamic Fiqh Academy (IFA) issued important fatwas on organ transplantation. By the end of 2008, more than 3600 organs were transplanted from brain-dead persons in Saudi Arabia.


Successes of a Focused Mothers' Own Milk (MOM) Program in Counteracting Unintended Effects of a Donor Milk Program on MOM Rates at Discharge.
Background: Avoidance of early formula feeding (EFF) and advancement of mother's own milk (MOM) in very low birth weight (VLBW) infants are important health influencers to decrease serious morbidities. Objective: To present the challenges and feeding strategy successes implemented to counteract a decline in MOM at discharge after initiation of donor milk (DM) to avoid EFF in racially and ethnically diverse VLBW infants. Patients and Methods: Retrospective review of prospectively tracked inborn surviving VLBW infants and their mothers admitted to neonatal intensive care unit from 2010 to 2020 during three feeding strategy implementations baby friendly (BF), DM program, and MOM bundle. Analysis included type of feeding (MOM, DM, or formula) and maternal with descriptive and comparative statistical analysis as indicated. Results: Analysis included 616 VLBW infants. Initiation of BF program resulted in 58.5% of infants discharged on MOM with 41.5% exposed to EFF. Initiation of the DM program resulted in a decline in EFF to 5% and decline in MOM at discharge to 26%. MOM bundle strategy resulted in an increase in MOM at discharge to 41% with sustained EFF exposure 0%. MOM at discharge varied among maternal racial and ethnic backgrounds in all epochs. Early DM use was not different among mothers by race or ethnicity with DM by African American (AA) mothers 89% > White mothers 83% > Other/Hispanic mothers 75%. MOM at discharge was lowest for AA mothers 33% < Hispanic mothers 40% < White mothers 55% < Asian/Other mothers at 60%. Conclusion: Changes in VLBW feeding strategies to avoid EFF utilizing DM can be successful among diverse maternal racial and ethnic populations. Nursing and maternal education coupled with early lactation support and attention to maternal individual long-term feeding plans were critical to improve MOM at discharge among mothers of all racial-ethnic backgrounds for successful attainment of MOM utilization in term corrected VLBW infants at discharge.


A 2-oxoglutarate-dependent dioxygenase from Ruta graveolens L. exhibits p-coumaroyl CoA 2'-hydroxylase activity (C2'H): a missing step in the synthesis of umbelliferone in plants.
Coumarins are important compounds that contribute to the adaptation of plants to biotic or abiotic stresses. Among coumarins, umbelliferone occupies a pivotal position in the plant phenylpropanoid network. Previous studies indicated that umbelliferone is derived from the ortho-hydroxylation of p-coumaric acid by an unknown biochemical step to yield 2,4-dihydroxycinnamic acid, which then undergoes spontaneous lactonization. Based on a recent report of a gene encoding a 2-oxoglutarate-dependent dioxygenase from Arabidopsis thaliana that exhibited feruloyl CoA 6'-hydroxylase activity (Bourgaud et al., 2006), we combined a bioinformatic approach and a cDNA library screen to identify an orthologous ORF (Genbank accession number JF799117) from Ruta graveolens L. This ORF shares 59% amino acid identity with feruloyl CoA 6'-hydroxylase, was functionally expressed in Escherichia coli, and converted feruloyl CoA into scopoletin and p-coumaroyl CoA into umbelliferone with equal activity. Its bi-functionality was further confirmed in planta: transient expression of JF799117 in Nicotiana benthamiana yielded plants with leaves containing high levels of umbelliferone and scopoletin when compared to control plants, which contained barely detectable traces of these compounds. The expression of JF799117 was also tightly correlated to the amount of umbelliferone that was found in UV-elicited R. graveolens leaves. Therefore, JF799117 encodes a p-coumaroyl CoA 2'-hydroxylase in R. graveolens, which represents a previously uncharacterized step in the synthesis of umbelliferone in plants. Psoralen, which is an important furanocoumarin in R. graveolens, was found to be a competitive inhibitor of the enzyme, and it may exert this effect through negative feedback on the enzyme at an upstream position in the pathway.


Biomass smoke COPD has less tomographic abnormalities but worse hypoxemia compared with tobacco COPD.
Special attention has emerged towards biomass smoke-induced chronic obstructive pulmonary disease (COPD), providing new knowledge for prevention and therapeutic approach of non-smoker COPD patients. However, the understanding of biomass smoke COPD is still limited and somewhat controversial. The aim of the present study was to compare COPD exclusively caused by tobacco smoking with COPD exclusively caused by environmental or occupational exposures. For this cross-sectional study, COPD patients were recruited from outpatient clinics and formed two groups: non-smoker COPD group (n=16) with exposure to biomass smoke who did not smoke cigarette and tobacco smoker COPD group (n=15) with people who did not report biomass smoke exposure. Subjects underwent pulmonary function tests, thoracic high-resolution computed tomography, 6-min walk test, and sputum induction. The non-smoker COPD group had biomass smoke exposure of 133.3±86 hour-years. The tobacco COPD group smoked 48.5±27.4 pack-years. Women were 62.5 and 66.7%, respectively, of non-smokers and smokers. The non-smoker COPD group showed higher prevalence of dyspnea, lower arterial oxygen tension (PaO2), and lower arterial oxygen saturation (SaO2%) with similar spirometry results, lung volumes, and diffusion capacity. Regarding inflammatory biomarkers, differences were detected in sputum number of lymphomononuclear cells and in sputum concentrations of interleukin (IL)-6 and IL-8 with higher values in the smoker group. Emphysema was more prevalent in the tobacco smoker group, which also showed higher relative bronchial wall thickness and lower lung density by quantitative analysis. Biomass smoke induced more hypoxemia compared to tobacco in COPD patients with similar severity.


[Treatment of invasive fungal infections with voriconazole. Evaluation of experience with compassionate use of voriconazole in Spain].
Although voriconazole shows an advantageous microbiological and pharmacological profile with respect to amphotericin B and other antifungals, the cumulative experience with the use of voriconazole in patients intolerant to other antifungals or with refractory invasive fungal infections is still limited. We performed a retrospective analysis of the charts of 48 patients in 26 Spanish hospitals who were diagnosed with invasive fungal infections due to filamentous fungi or yeasts and had received voriconazole (between 1999 and 2002) as part of a compassionate use program for a mean of 59.2 days (range 1-748 days). The favorable response rate in patients with invasive, refractory aspergillosis who were treated exclusively with voriconazole was 8/12 (66%). This response rate increased to 10/12 (83%) when two other cases treated with a combination of voriconazole plus caspofungin were included. In patients with invasive candidiasis the response rate was 66% (6/9). A favorable response was achieved in 12/17 (70%) patients with invasive fungal infections due to other difficult to treat fungi (Scedosporium spp., Fusarium spp., Blastoschizomyces spp.). The tolerability and safety profile of voriconazole was good; only four patients required discontinuation of treatment due to side effects. Voriconazole is a well-tolerated, effective antifungal for the treatment of patients with refractory invasive fungal infections due to Aspergillus spp., Candida spp. and fungi resistant or refractory to other treatments.


Health professionals' attitudes toward medications for opioid use disorder.
Background: Research has shown that medications, especially opioid agonist treatments, are an effective way to treat opioid use disorder (OUD); however, negative attitudes held by health professionals contribute to their underutilization. Methods: A 23-year review of studies that examined health professionals' attitudes toward medications for OUD (MOUD) was conducted to describe the current state of knowledge and to inform future research and interventions. Results: Studies examined attitudes toward the use of methadone, buprenorphine, and naltrexone among various types of health professionals: prescribers, non-prescribing clinicians, pharmacists, and administrators. The characteristics and findings of the included studies were reviewed and synthesized. Findings indicate that attitudes toward MOUD affect access and utilization by influencing prescribing practices, referrals, and adoption within programs. Exposure, knowledge, and treatment orientation were found to be important factors related to attitudes toward MOUD across multiple studies of various types of health professionals. Conclusions: To increase access and utilization, continued efforts are needed to increase positive attitudes toward MOUD among various types of health professionals. Findings indicate that interventions should seek to increase knowledge about MOUD and foster interprofessional communication related to MOUD, especially between prescribers and behavioral health providers.


[Group psychoeducational intervention in relatives of patients suffering from schizophrenia].
The present research paper aims at assessing the effectiveness of a psychoeducational intervention in relatives' groups of patients with schizophrenia or schizoaffective disorder. It examines the possible influence of the intervention on family members as well as on the course of the patient illness. Of a total of 131 relatives, 83 consisted the experimental group and 48 the control group. The relatives of the experimental group were divided into 5 groups and attended 18 psychoeducational sessions. Their patients as well s the patients and the relatives of the control group attended no specific intervention and continued their routine care. The psychoeducational intervention included education about the illness, communication skills training and training in problem-solving. It combined educational and psychotherapeutic techniques. The psychometric tools administered were: The Family Burden Scale, The Family Rituals Scale, The General Health Questionnaire GHQ-28, the Center for Epidemiological studies - Depression Scale (CES-D), the Opinions about Mental Illness Scale OMI, two scales concerning the knowledge about the illness, two questionnaires concerning expectations and feedback about the group process and questionnaires regarding sociodemographic characteristics of the sample and information about the illness. The number of hospitalizations of patients (n=91) during the research year was investigated. An interaction between group and measurement was found. While patient hospitalizations of both research groups did not differ significantly at the year before the study with X2=0.54, p=0.46), they differed when measured a year after the intervention, where patients in the intervention group had statistically significant fewer hospitalizations compared to the patients in the control group (x2=4.58, significant at p=0.032). As to the "compliance" in the medication, two statistical tests were conducted, taking into consideration that "compliance" by patients starting with a "very good" one can't be improved, while by those beginning with poor compliance can't be worsened. In the first investigation, which involved patients with possibility of amelioration or deterioration of "compliance", an improvement of patients (n=12) in the intervention group was recorded. This finding is statistically significant (p=0.0005). The second statistical test included all patients who were giving as an initial reply for the 'compliance' any value below "very good". In the intervention group there were 32 patients, 14 of whom showed improved "compliance" during the research year. This change is statistically significant (p=0.0014). The findings verify that the participation of relatives in psychoeducational groups leads to statistically significant improvement in the course of patient illness, as evident by the reduction in hospitalization rates and the improvement in adherence to pharmacotherapy. The study shows that relatives' psychoeducation constitutes a useful tool in improving the course of illness and empowering the family. The widespread implementation of relatives' psychoeducation in Greece is both necessary and challenging.


Safety Warning for ChAdOx1 nCov-19 Vaccine in Patients with Sickle Cell Disease.
Vaccines against acute respiratory syndrome Coronavirus 2(SARS-CoV2) are critical weapons to control the spread of the deadly Coronavirus 2019(COVId-19) virus worldwide. Although these vaccines are generally safe, their widespread use has produced reports of rare complications, including vaccine-induced immune thrombotic thrombocytopenia (VIITT), particularly in connection with ChAdOx1 nCov-19. We have identified three cases of sickle cell disease (SCD) experiencing a severe vaso-occlusive crisis (VOC) shortly after the vaccine. Despite being stable for a long time, they had fever with tachycardia, along with a significant rise in WBC, liver enzymes, particularly alkaline phosphate, with a remarkable drop in hemoglobin, and platelets and one of them had probably a fatal TTP like syndrome. Given these findings, physicians and patients should exercise caution when taking this type of vaccine and be aware of these safety concerns.


Empagliflozin for the treatment of type 2 diabetes.
Despite the availability of numerous anti-diabetes drugs and treatment guidelines, many patients with type 2 diabetes mellitus (T2DM) do not reach recommended targets for glycemic control. There remains an unmet need for effective and well-tolerated anti-diabetes agents that can be used as monotherapy or in combination with other therapies to improve glycemic control in patients with T2DM. Sodium glucose cotransporter 2 (SGLT2) inhibitors are a new class of treatment for T2DM that reduce hyperglycemia by reducing renal glucose reabsorption and thereby increasing urinary glucose excretion. This paper reviews the pharmacokinetic and pharmacodynamic properties of the SGLT2 inhibitor empagliflozin , the results of clinical trials investigating the efficacy of empagliflozin given as monotherapy or as add-on therapy on glycemic control, body weight, and blood pressure in patients with T2DM, and the safety and tolerability profile of empagliflozin. Empagliflozin offers good glycemic efficacy, weight loss, blood pressure reduction, and a low risk of hypoglycemia. These attributes, coupled with the ability to be used in virtually any combination with other anti-diabetes agents and at any stage in the disease process, provide a welcome new agent to our armamentarium of drugs to help manage T2DM.


Kinetic parameters from progress curves of competing substrates. Application to beta-lactamases.
The use of two substrates, one of them a reporter substrate, is often convenient. The time course of an enzymic reaction with competing substrates is given explicitly in the present paper. Kinetic parameters can be readily obtained. The method is applied to the hydrolysis of benzylpenicillin, with cephalosporin C as the reporter substrate, catalysed by a Pseudomonas beta-lactamase.


Positive Pelvic Lymph Nodes in Prostate Cancer Harbor Immune Suppressor Cells To Impair Tumor-reactive T Cells.
The impact of prostate cancer (PCa) metastases on pelvic lymph nodes in local antitumor immunity remains unknown. We prospectively enrolled ten hormone therapy-naïve men undergoing salvage pelvic lymph node dissection (sPLND) and analyzed their peripheral blood (PB) and positive pelvic lymph nodes (PPLNs) with PCa metastases for tumor-reactive CD8+ T cells and myeloid-derived suppressor cells (MDSCs) using flow cytometry. MDSCs were stratified into CD14+ monocytic and CD14- granulocytic types. PD-L1/2 expression was also analyzed for MDSCs. Relative to PB, tumor-reactive CD8+ T cells accumulated in PPLNs (p<0.01) yet had decreased proliferation, with low Ki67 expression (p<0.05). Both CD14+ monocytic and CD14- granulocytic MDSCs were found in PPLNs, but there was an increase in the proportion of CD8+ T cells in PPLNs compared to PB (p<0.01). The granulocytic MDSCs exhibited a high degree of immunosuppressive activity (as evidenced by high pSTAT3 levels) and high levels of B7-H1 (PD-L1) and B7-DC (PD-L2) expression. Thus, granulocytic MDSCs probably suppress tumor-reactive CD8+ T-cells in PPLNs and exhibit high expression of immune checkpoint molecules in PCa nodal metastases. The data suggest a relative immunosuppressive state in PPLNs. This provides a biologic rationale for sPLND beyond just tumor debulking, and calls for further investigation of immune checkpoint blockade. Prostate cancer metastases to lymph nodes may involve immunosuppressive cells that evade antitumor T-cells and create a relatively immunosuppressed state. This provides a rationale for treatment of such lymph nodes and/or for potential immunotherapy.


CNS-endocrine pancreas system. II. Response of dorsal nucleus of the vagus nerves to insulin deficiency.
Sensitivity of the vagal dorsal nucleus nerve cells to insulin deficiency was revealed in alloxan-diabetic rats by karyometry. Control measurements showed absence of similar changes in cell nuclear sizes of the adjoining area, the Nucltractus solitarii. The results provide evidence in favour of a selective response of the dorsal nucleus of the vagus nerves to insulin deficiency and allow assumption that not only the peripheral vagus but the central component of this cholinergic system contribute to endocrine pancreas control. It is suggested that the medial basal hypothalamus and the system of the vagus are links of a single control mechanism regulating endocrine pancreas and represented at different levels of the central and peripheral nervous system.


Unconventional protein secretion: membrane translocation of FGF-2 does not require protein unfolding.
Endoplasmic reticulum/Golgi-dependent protein secretion depends on signal peptides that mediate membrane translocation of nascent secretory proteins into the lumen of the endoplasmic reticulum. Classical secretory proteins are transported across the membrane of the endoplasmic reticulum in an unfolded conformation, which is similar to protein import into mitochondria. This process is mediated by Sec61, the protein-conducting channel of the endoplasmic reticulum. Employing both FACS-based in vivo transport assays and confocal microscopy, we now show that fibroblast growth factor 2 (FGF-2), a pro-angiogenic mediator exported from mammalian cells by an unconventional secretory pathway, does not need to be unfolded in order to be released into the extracellular space. These findings suggest that the molecular apparatus mediating export of FGF-2 is not only distinct from classical translocation machineries in terms of molecular identity but also operates in a mechanistically distinct manner that allows membrane translocation of FGF-2 in a folded conformation.


Therapeutic Perspectives for the Perioperative Period in Oral Squamous Cell Carcinoma (OSCC).
The perioperative period is the relatively short window of time, usually measured in days or weeks, around the surgical procedure. Despite its short duration, this time period is of great importance for cancer patients. From a biological point of view, the perioperative period is complex. Synchronous with primary tumor removal, surgery has local and distant consequences, including systemic and local inflammation, coagulation and sympathetic activation. Furthermore, the patients often present comorbidities and receive several medical prescriptions (hypnotics, pain killers, anti-emetics, hemostatics, inotropes, antibiotics). Because of the complex nature of the perioperative period, it is often difficult to predict the oncological outcome of tumor resection. Here, we review the biological consequences of surgery of Oral Squamous Cell Carcinoma (OSCC), the most frequent form of primary head and neck tumors. We briefly address the specificities and the challenges of the surgical care of these tumors and highlight the biological and clinical studies that offer insight into the perioperative period. The recent trials examining neoadjuvant immunotherapy for OSCC illustrate the therapeutic opportunities offered by the perioperative period.


[Hemodynamic evaluation of the effectiveness of preservation of subvalvular structures in mitral valve prosthesis].
The article deals with the clinical evaluation of the results of mitral valve prosthetics with preservation of the subvalvular structures in 40 patients and comparative evaluation of the hemodynamic indices after prosthetics with preservation of the subvalvular structures of the posterior cusp and after routine mitral valve prosthetics. The authors show good clinical results in patients after valvar-preserving prosthetics of the mitral valve and essential improvement of left-ventricular contractile activity after such an operation. Comparative analysis showed that the total ejection fraction increased by 10.8 +/- 4.5% in the main group and reduced by 11.4 +/- 2.6% (p less than 0.01) in the control group. Left-ventricular end diastolic pressure did not change in the main group but increased significantly (p less than 0.05) in the control group. A conclusion is drawn that preservation of the subvalvular structures in mitral valve prosthetics is expedient even in patients with an initially grave condition because the method makes it possible to normalize intracardiac hemodynamics more rapidly in the postoperative period and essentially improve the contractility of the left ventricle.


Progress in filovirus vaccine development: evaluating the potential for clinical use.
Marburg and Ebola viruses cause severe hemorrhagic fever in humans and nonhuman primates. Currently, there are no effective treatments and no licensed vaccines; although a number of vaccine platforms have proven successful in animal models. The ideal filovirus vaccine candidate should be able to provide rapid protection following a single immunization, have the potential to work postexposure and be cross-reactive or multivalent against all Marburg virus strains and all relevant Ebola virus species and strains. Currently, there are multiple platforms that have provided prophylactic protection in nonhuman primates, including DNA, recombinant adenovirus serotype 5, recombinant human parainfluenza virus 3 and virus-like particles. In addition, a single platform, recombinant vesicular stomatitis virus, has demonstrated both prophylactic and postexposure protection in nonhuman primates. These results demonstrate that achieving a vaccine that is protective against filoviruses is possible; the challenge now is to prove its safety and efficacy in order to obtain a vaccine that is ready for human use.


Mitochondrial catalase induces cells transformation through nucleolin-dependent Cox-2 mRNA stabilization.
It's well documented that over-production of reactive oxygen species (ROS) causes detrimental damages to cells. While a low level of ROS, such as H2O2, functions as signaling transducer and motivates cell proliferation in both cancer and non-transformed stem cells. As a double-edged sword, the direct evidence for demonstrating the function of H2O2 in the cause of tumor is barely characterized in intact cells. In our current study, we found that targeted expression of mitochondrial catalase (mCAT), but not catalase, could significantly reduce the accumulation of H2O2 in mouse epithelial JB6 Cl41 cells, consequently led to the cell malignant transformation and anchorage-independent cell growth. Further study revealed that this reduction of H2O2 resulted in the translocation of nucleolin from the cytoplasm to nuclear, and maintaining the nucleolin nuclear location status, and in turn stabilizing the cox-2 mRNA and consequently leading to a COX-2 protein upregulation, as well as malignant transforming mCAT-overexpressed Cl41 cells. Collectively, our studies here provide direct experimental evidence demonstrating a novel function and molecular mechanisms of mCAT in transforming mouse Cl41 cells, and high significance insight into understanding the beneficial aspect of H2O2 in circumventing tumor promotion and the theoretical basis for the management of H2O2 in the clinic implementation as a chemotherapeutic strategy.


Molecular characterization of the SPL gene family in Populus trichocarpa.
SPLs, a family of transcription factors specific to plants, play vital roles in plant growth and development through regulation of various physiological and biochemical processes. Although Populus trichocarpa is a model forest tree, the PtSPL gene family has not been systematically studied. Here we report the identification of 28 full-length PtSPLs, which distribute on 14 P. trichocarpa chromosomes. Based on the phylogenetic relationships of SPLs in P. trichocarpa and Arabidopsis, plant SPLs can be classified into 6 groups. Each group contains at least a PtSPL and an AtSPL. The N-terminal zinc finger 1 (Zn1) of SBP domain in group 6 SPLs has four cysteine residues (CCCC-type), while Zn1 of SPLs in the other groups mainly contains three cysteine and one histidine residues (C2HC-type). Comparative analyses of gene structures, conserved motifs and expression patterns of PtSPLs and AtSPLs revealed the conservation of plant SPLs within a group, whereas among groups, the P. trichocarpa and Arabidopsis SPLs were significantly different. Various conserved motifs were identified in PtSPLs but not found in AtSPLs, suggesting the diversity of plant SPLs. A total of 11 pairs of intrachromosome-duplicated PtSPLs were identified, suggesting the importance of gene duplication in SPL gene expansion in P. trichocarpa. In addition, 18 of the 28 PtSPLs, belonging to G1, G2 and G5, were found to be targets of miR156. Consistently, all of the AtSPLs in these groups are regulated by miR156. It suggests the conservation of miR156-mediated posttranscriptional regulation in plants. A total of 28 full-length SPLs were identified from the whole genome sequence of P. trichocarpa. Through comprehensive analyses of gene structures, phylogenetic relationships, chromosomal locations, conserved motifs, expression patterns and miR156-mediated posttranscriptional regulation, the PtSPL gene family was characterized. Our results provide useful information for evolution and biological function of plant SPLs.


The health and social care needs of family carers supporting adults with autistic spectrum disorders.
The families of 26 adults with autistic spectrum disorders (ASDs) who either lived at home or maintained close contact with their families were interviewed about their social and psychological needs related to caring for the person with ASD. In contrast to previous studies of familial carers of children with ASDs, a strong association between parental emotional distress and unmet need was found. Parents also reported a need for more autism-specific intervention and support for adults with ASDs. The study illustrates the continuing and underreported role of families in supporting adults with ASDs.


Hormone-induced increase in free cytosolic calcium and glycogen phosphorylase activation in rat hepatocytes incubated in normal and low-calcium media.
The action of alpha 1-adrenergic agonists (noradrenaline in the presence of propranolol), vasopressin and angiotensin on the intracellular free Ca2+ concentration, [Ca2+]i, was determined by using the fluorescent dye quin2 in isolated rat liver cells. In the presence of external Ca2+ (1.8 mM), 1 microM-noradrenaline induced an increase in [Ca2+]i up to about 800 nM without apparent delay, whereas 10 nM-vasopressin and 1 nM-angiotensin increased [Ca2+]i to values higher than 1500 nM with a lag period of about 6s. The successive addition of the hormones and of their specific antagonists indicated that the actions of the three Ca2+-mobilizing hormones occurred without apparent desensitization (over 6 min) and via independent receptors. The relative contributions of internal and external Ca2+ pools to the cell response were determined by studying the hormone-mediated [Ca2+]i increase and glycogen phosphorylase activation in low-Ca2+ media (22 microM). In this medium: (1) [Ca2+]i was lowered and the hormones initiated a transient instead of a sustained increase in [Ca2+]i; subsequent addition (2 min) of a second hormone promoted a lesser increase in [Ca2+]i; in contrast, the subsequent addition (2 min) of Ca2+ (1.8 mM) caused [Ca2+]i to increase to a value close to that initiated by the hormone in control conditions, the amplitude of the latter response being dependent on the concentration of Ca2+ added to the medium; (2) returning to normal Ca2+ (1.8 mM) restored the resting [Ca2+]i and allowed the hormone added 2 min later to promote a large increase in [Ca2+]i whose final amplitude was also dependent on the concentration of Ca2+ added beforehand. Similar results were found when the same protocol was applied to the glycogen phosphorylase activation. It is concluded that Ca2+ influx is required for a maximal and sustained response and to reload the hormone-sensitive stores.


Medical treatment of congestive cardiac failure from cerebral arteriovenous fistulas at bicêtre hospital.
Arteriovenous fistulas create an increase in venous return and subsequent right heart overload. The result is right heart dilatation, pulmonary arterial hypertension, and increased pulmonary blood flow. Reduction in arterial diastolic pressure (as observed in arteriovenous shunt), an increase in end diastolic pressure (due to increased preload), a reduction in diastolic period (due to tachycardia) are all detrimental to myocardial perfusion and hence oxygen delivery and may precipitate left ventricular failure. Furthermore, the transition from a foetal circulatory pattern to an adult circulatory pattern is complex and both pulmonary and systemic circulations remain highly unstable during the first week after birth. This can explain a persistent transitional circulation with shunts through the ductus arteriosus, the foramen ovale and a pulmonary hypertension which worsen the systolic and diastolic wall stress. The clinical presentation depends on the size of the left-to-right shunt and its tolerance. The aims of symptomatic therapy are to improve oxygen delivery to the tissues and decrease tissue oxygen consumption. Measures that improve the patient's effective ventilation, arterial oxygen saturation, and hematocrit need to be the first steps. Diuretics are the first step for reducing preload. Cardiac output can be improved by increasing cardiac contractility with inotropic agents. Digoxin is the main agent used to increase myocardial contractility. However, its use in a hyperkinetic state due to arteriovenous fistulas remains controversial: pretreatment myocardial function indices may already be above normal, and there is no clear evidence that their further increase produces clinical benefit. Vasodilators are obviously contraindicated if systemic arterial pressure is low. If the failure cannot be controlled, embolisation of the lesion should be considered. The goal of this paper is to provide a rational approach to the treatment of circulatory failure due to cerebral arteriovenous shunts.


Additive or sequential nucleoside analogue therapy compared with continued zidovudine monotherapy in human immunodeficiency virus-infected patients with advanced disease does not prolong survival: an observational study.
To study the effect of sequential or additive use of zalcitabine or didanosine on survival in 308 human immunodeficiency virus-infected patients with advanced disease treated with zidovudine, an observational study using time-dependent Cox proportional hazards models was done. Changing to sequential or additive therapy was based on deterioration of a patient's health status, a significant drop in CD4 cell count, or intolerance for zidovudine. The median CD4 cell count at baseline was 110 x 10(6)/L; 42% of patients had AIDS. The median count before a change in therapy was 50 x 10(6)/L. Additive or sequential treatment was associated with an increased risk for death (relative hazard, 1.59; 95% confidence interval [CI], 1.01-2.49; and 1.58; 95% CI, 1.10-2.37, respectively). Adjustment of the models for prognostic factors failed to substantially affect this observation. Possibly the lack of benefit in this study is because patients switched therapy at advanced stages, whereas the switch may be more effective in early disease.


Rational emotive occupational health coaching for quality of work-life among primary school administrators.
This study aimed at investigating the effect of rational emotive occupational health coaching on quality of work-life among primary school administrators. This is a double blinded and randomized control design study. A total of 158 administrators were sampled, half of them were exposed to rational emotive occupational health treatment package that lasted for 12 sessions. Two self-report measures were utilized in assessing the participants using quality of work life scale. Data collected were analyzed using MANOVA statistical tool. The results showed that rational emotive occupational health coaching is effective in improving perception of quality of work-life among public administrators. A follow-up result showed that rational emotive occupational health coaching had a significant effect on primary school administrators' quality of work life. This study concluded rational emotive occupation health coaching is useful therapeutic strategy in improving quality of work of primary school administrators, hence, future researchers and clinical practitioners should adopt cognitive-behavioral techniques and principles in helping employers as well as employees. Based on the primary findings and limitations of this study, future studies, occupational psychotherapists should qualitatively explore the clinical relevance of rational emotive occupational health practice across cultures using different populations.


Platelet and hemorrhagic disorders associated with pregnancy: a review. Part I.
Disorders of coagulation remain an important potential cause of maternal morbidity and mortality. Bleeding disorders in pregnancy, unlike disorders of hypercoagulability, most often can have little impact on the mother but devastating consequences for the fetus. Further complicating the issue is that not all disorders of coagulation are inherited. Some are due to maternal illnesses unique to pregnancy, others are due to drug ingestion, and yet others remain idiopathic. In still other instances, thrombocytopenia is a minor consequence of a more severe disorder and will resolve when the inciting agent is removed or treated. A basic understanding of the pathophysiology of various conditions that lead to bleeding diathesis in pregnancy is necessary in order to effectively manage these varied clinical disorders. In addition, knowledge of whether the major morbidity is fetal or maternal or both can impact management. This review is concerned with the etiology, pathophysiology, diagnosis, and general management of commonly encountered disorders in pregnancy that place the mother and fetus at increased morbidity and mortality because of the potential for hemorrhage. Acutely acquired disorders and the resultant maternal manifestation versus a chronic disease process that is altered by the state of pregnancy are distinguished. Where possible, the incidence and prognosis of the disorder are provided. Actual cases are included to illustrate how similar presentations of distinctly different disorders can confuse and complicate an accurate diagnosis that is essential for appropriate management.


Variation within and between Frankliniella thrips species in host plant utilization.
Anthophilous flower thrips in the genus Frankliniella (Thysanoptera: Thripidae) exploit ephemeral plant resources and therefore must be capable of successfully locating appropriate hosts on a repeated basis, yet little is known of interspecific and intraspecific variation in responses to host plant type and nutritional quality. Field trials were conducted over two seasons to determine if the abundance of males and females of three common Frankliniella species, F. occidentalis (Pergande), F. tritici (Fitch) and F. bispinosa (Morgan), their larvae, and a key predator, Orius insidiosus (Say) (Hemiptera: Anthocoridae) were affected by host plant type and plant nutritional quality. Two host plants, pepper, Capsicum annuum L. (Solanales: Solanaceae) and tomato, Solanum lycopersicum L. that vary in suitability for these species were examined, and their nutritional quality was manipulated by applying three levels of nitrogen fertilization (101 kg/ha, 202 kg/ha, 404 kg/ha). F. occidentalis females were more abundant in pepper than in tomato, but males did not show a differential response. Both sexes of F. tritici and F. bispinosa were more abundant in tomato than in pepper. Larval thrips were more abundant in pepper than in tomato. Likewise, O. insidiosus females and nymphs were more abundant in pepper than in tomato. Only F. occidentalis females showed a distinct response to nitrogen fertilization, with abundance increasing with fertilization. These results show that host plant utilization patterns vary among Frankliniella spp. and should not be generalized from results of the intensively studied F. occidentalis. Given the different pest status of these species and their differential abundance in pepper and tomato, it is critical that scouting programs include species identifications for proper management.


[Functions of neuromediators in plants].
In plants, neurotransmitters play a major biological role in chemo-signaling, as regulating agents of growth and development, membrane permeability, etc. In the plant cells, there are also main elements of cholinergic and aminergic systems including the enzymes as well as functional analogues of cholino- and aminoreceptors. It is important that the systems should be taken into consideration in fertilizing and chemical interaction of the plant cells. Acetylcholine and cholinesterase were shown to be secreted in male sexual cells (the pollen). Depression of cholinesterase on the gene level correlates with male sterility. Preliminary treatment of a female gametophyte with antagonists of acetylcholine and histamine, prior to pollination, blocked the normal process of fertilizing. Cholinesterase was also found in secrets released from the pollen surface and pistil.


Inhibition of cholera toxin binding to membrane receptors by pig gastric mucin-derived glycopeptides: differential effect depending on the ABO blood group antigenic determinants.
The capacity of pig gastric mucin-derived glycopeptides to interfere with the binding of cholera toxin (CT) to membrane receptors was studied. Two types of glycopeptide preparations with or without human blood group A antigenic activity were assayed for comparison in a system in which the target for the toxin was rat erythrocyte ghosts. Blood group A-active glycopeptides (A+ glycopeptides) were more potent inhibitors for the toxin binding than those lacking group A activity (A- glycopeptides). The mean values of the 50% inhibitory dose revealed that the A+ glycopeptide preparations were 6.6-fold-more potent inhibitors than the A- ones (P less than 0.001). The inhibitory capacity of the different A+ glycopeptide preparations was not directly proportional to the group A antigenic titer. The A+ glycopeptides showed a higher capacity than the A- glycopeptides to interact with the toxin as revealed by CT-glycopeptide complex formation, which could be detected by Sephacryl S-400 chromatography. This result suggests that glycopeptide inhibition of CT binding to the erythrocyte ghosts is mediated by a competition between the GM1 receptors and the glycopeptides for the toxin. The differential effect between both types of glycoconjugates was independent of the way of measuring the amount of glycopeptides used (dry weight, carbohydrate or protein content). The existence in the gastrointestinal tract of mucins not carrying or carrying different ABO blood group determinants, which could behave as more or less potent inhibitors of CT binding to membrane receptors, may help to explain the relationship between ABO blood groups and severity of cholera.


Immunohistochemical localization of actin: applications in surgical pathology.
The contractile protein actin was demonstrated in formalin-fixed and paraffin-embedded human tissue by the peroxidase-antiperoxidase method of Sternberger. Both types of muscular cells and some other cell types showed positive staining. In skeletal muscle, the staining was seen diffusely in the cytoplasm with accentuation of cross-striations (I-bands). The cytoplasm of smooth muscle cells was also diffusely stained. Pericytes of blood vessels and myoepithelial cells of salivary glands and breast were clearly defined by positively stained smooth muscle cells and pericytes; this method proved superior to conventional elastic tissue staining for studying pathological conditions of blood vessels, such as vasculitides or invasion by neoplasms. Participation of myoepithelial cells in neoplasms of the breast and salivary glands could also be evaluated. This method can provide information about histogenesis and differentiation of a variety of soft-tissue neoplasms, in conjunction with other immunohistochemical methods for various tissue-specific markers.


Drosophila as a model to study the role of blood cells in inflammation, innate immunity and cancer.
Drosophila has a primitive yet effective blood system with three types of haemocytes which function throughout different developmental stages and environmental stimuli. Haemocytes play essential roles in tissue modeling during embryogenesis and morphogenesis, and also in innate immunity. The open circulatory system of Drosophila makes haemocytes ideal signal mediators to cells and tissues in response to events such as infection and wounding. The application of recently developed and sophisticated genetic tools to the relatively simple genome of Drosophila has made the fly a popular system for modeling human tumorigensis and metastasis. Drosophila is now used for screening and investigation of genes implicated in human leukemia and also in modeling development of solid tumors. This second line of research offers promising opportunities to determine the seemingly conflicting roles of blood cells in tumor progression and invasion. This review provides an overview of the signaling pathways conserved in Drosophila during haematopoiesis, haemostasis, innate immunity, wound healing and inflammation. We also review the most recent progress in the use of Drosophila as a cancer research model with an emphasis on the roles haemocytes can play in various cancer models and in the links between inflammation and cancer.


n-3 Polyunsaturated Fatty Acids and Their Derivates Reduce Neuroinflammation during Aging.
: Aging is associated to cognitive decline, which can lead to loss of life quality, personal suffering, and ultimately neurodegenerative diseases. Neuroinflammation is one of the mechanisms explaining the loss of cognitive functions. Indeed, aging is associated to the activation of inflammatory signaling pathways, which can be targeted by specific nutrients with anti-inflammatory effects. Dietary n-3 polyunsaturated fatty acids (PUFAs) are particularly attractive as they are present in the brain, possess immunomodulatory properties, and are precursors of lipid derivates named specialized pro-resolving mediators (SPM). SPMs are crucially involved in the resolution of inflammation that is modified during aging, resulting in chronic inflammation. In this review, we first examine the effect of aging on neuroinflammation and then evaluate the potential beneficial effect of n-3 PUFA as precursors of bioactive derivates, particularly during aging, on the resolution of inflammation. Lastly, we highlight evidence supporting a role of n-3 PUFA during aging.


Epidemiological Identification of A Novel Pathogen in Real Time: Analysis of the Atypical Pneumonia Outbreak in Wuhan, China, 2019-2020.
Virological tests have now shown conclusively that a novel coronavirus is causing the 2019-2020 atypical pneumonia outbreak in Wuhan, China. We demonstrate that non-virological descriptive characteristics could have determined that the outbreak is caused by a novel pathogen in advance of virological testing. Characteristics of the ongoing outbreak were collected in real time from two medical social media sites. These were compared against characteristics of eleven pathogens that have previously caused cases of atypical pneumonia. The probability that the current outbreak is due to "Disease X" (i.e., previously unknown etiology) as opposed to one of the known pathogens was inferred, and this estimate was updated as the outbreak continued. The probability (expressed as a percentage) that Disease X is driving the outbreak was assessed as over 29% on 31 December 2019, one week before virus identification. After some specific pathogens were ruled out by laboratory tests on 5 January 2020, the inferred probability of Disease X was over 49%. We showed quantitatively that the emerging outbreak of atypical pneumonia cases is consistent with causation by a novel pathogen. The proposed approach, which uses only routinely observed non-virological data, can aid ongoing risk assessments in advance of virological test results becoming available.