The effects of stimulating protease-activated receptor-1 and -2 in A172 human glioblastoma.
Human glioblastoma cell line A172 expressed protease-activated receptor-1 and -2 (PAR-1 and PAR-2). We investigated the effects of the stimulation of these receptors by receptor-activating agonist peptides on the Ca2+ signaling, protein kinase C translocation, cell morphology and cell proliferation in A172. Both PAR-1 agonist SFLLRN and PAR-2 agonist SLIGKV induced an increase in [Ca2+]i. The prior treatment of A172 with PAR-2 agonist SLIGKV did not influence the [Ca2+]i response to PAR-1 agonist SFLLRN or thrombin, however, the prior treatment with PAR-1 agonist SFLLRN or thrombin completely abolished the second response to PAR-2 agonist SLIGKV. Treatment with each agonist peptide produced thinner and fewer processes in A172. The PAR-2 agonist inhibited the proliferation of A172 significantly while PAR-1 agonist did not. PKC-alpha and gamma were translocated from cytosol to membrane with either PAR-1 or PAR-2 stimulation, however, L was specifically translocated with SFLLRN, and lambda with SLIGKV, respectively. These results indicated that PAR-1 and PAR-2 stimulation produced a similar [Ca2+]i response and morphological changes in A172 glioblastoma while the effects on the cell proliferation and activation of PKC isozymes were distinct, suggesting that different signal transduction pathways were activated by these receptors. The uni-directional cross desensitization implies a functional linkage between PAR-1 and PAR-2 receptors.


Cloning and sequencing of full-length cDNA encoding the precursor of human complement component C1r.
The sequencing of human liver cDNA clones encoding the entire C1r precursor protein has confirmed the previously determined peptide sequence and has shown that there is a leader peptide which is 17 amino acids long. A residue tentatively identified as beta-hydroxyaspartic acid [Arlaud, Willis & Gagnon (1986) Biochem. J., in the press] located in the C1r A-chain, within an epidermal-growth-factor consensus sequence, was found to be encoded as asparagine. Two sequence elements, tandemly located in the A-chain, are related to a sequence widespread among proteins which interact with C3b or C4b. Structural comparisons between different clones indicate that multiple polyadenylation sites are responsible for the length heterogeneity observed for C1r mRNA from liver and Hep G2 cells.


Airway ion transport on the first postnatal day in infants delivered vaginally or by elective cesarean section.
To determine airway ion transport in term infants on the first day of postnatal life, and to test the hypothesis that infants born without labor have reduced sodium absorption, we measured nasal potential difference using a modified perfusion protocol suitable for newborn infants. We examined maximal stable baseline potential difference, the change after perfusion with 10(-4) M amiloride (Deltaamil), and the change after perfusion with a zero-chloride solution (Deltazero Cl-) in infants born after elective cesarean section (n = 21) or normal labor (n = 20). Maximal stable baseline potential difference was not different in the two cohorts (-24.0 mV, range -9 to -64 mV versus -25.5 mV, range -6 to -44 mV). The majority of infants in both cohorts showed a substantial fall in potential difference after amiloride perfusion, and there was little capacity for chloride secretion. These results demonstrate a fluid absorptive pattern in the airways on the first postnatal day. In these well infants, the ion transport phenotype was not dependent on the presence or absence of labor.


Repeated seizures in an elderly patient with alcohol dependence and mild cognitive impairment.
A 69-year-old man with alcohol dependence and mild cognitive impairment (MCI) suffered from repeated tonic-clonic seizures. The seizures typically occurred several hours after his last alcohol intake at home (early withdrawal seizure) and 22 days after his last intake of alcohol (14 days after the last dose of diazepam substituting for alcohol: late withdrawal seizure) on the ward. Psychiatrists in charge of this patient found it difficult to attribute his seizures to alcohol withdrawal syndrome (AWS) because of the atypical onset. The patient responded to diazepam resumption and valproate combination. This case highlights the need to always consider AWS as a possible cause of seizures and to gradually decrease diazepam as a substitute for alcohol. Moreover, in this patient, MCI may have induced vulnerability in the brain for AWS and the patients' older age might have decreased liver function leading to delayed onset of the seizures after diazepam withdrawal.


Stressful and traumatic life events as disruptors to antiretroviral therapy adherence.
Stressful and traumatic life events (STLEs) are common among HIV-infected individuals and may affect health behaviors such as adherence to antiretroviral (ARV) therapy, with important implications for treatment outcomes. We examined the association between STLEs and ARV adherence among 289 US-based participants enrolled between 7/1/2010 and 9/1/2013 in a study of depression treatment for HIV-infected patients. Participants received monthly telephone calls to assess STLEs and pill count-based ARV adherence. Inverse probability of observation weighting was combined with multiple imputation to address missing data. Participants were mostly male (71%) and black (63%), with a median age of 45 years. Median monthly adherence was 96% (interquartile range (IQR): 85-100%). Participants experienced a mean of 2.48 STLEs (range: 0-14) in the previous month. The presence of ≥2 STLEs was associated with a mean change in adherence of -3.67% (95% confidence interval (CI): -7.12%, -0.21%) and decreased likelihood of achieving ≥95% adherence (risk ratio (95% CI) = 0.82 (0.71, 0.95)). For each additional STLE, the mean adherence change was -0.90% (95% CI: -1.79%, 0.00%). STLEs were associated with poorer ARV adherence, including decreased likelihood of adhering to ≥95% of ARV doses. This level of adherence has a critical role in regimen effectiveness and prevention of resistance.


STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes.
Tumor-associated macrophages (TAMs) are of major importance in cancer-related immune suppression, and tumor infiltration by CD163pos TAMs is associated with poor outcome in most human cancers. Therefore, therapeutic strategies for reprogramming TAMs from a tumor-supporting (M2-like) phenotype towards a tumoricidal (M1-like) phenotype are of great interest. Activation of the transcription factor STAT3 within the tumor microenvironment is associated with worse prognosis, and STAT3 activation promotes the immunosuppressive phenotype of TAMs. Therefore, we aimed to develop a drug for inhibition of STAT3 specifically within human TAMs by targeting the endocytic CD163 scavenger receptor, which is highly expressed on TAMs. Here, we report the first data on a CD163-targeted STAT3-inhibitory drug consisting of corosolic acid (CA) packaged within long-circulating liposomes (LCLs), which are CD163-targeted by modification with monoclonal anti-CD163 antibodies (αCD163)-CA-LCL-αCD163. We show, that activation of STAT3 (by phosphorylation) was inhibited by CA-LCL-αCD163 specifically within CD163pos cells, with minor effect on CD163neg cells. Furthermore, CA-LCL-αCD163 inhibited STAT3-regulated gene expression of IL-10, and increased expression of TNFα, thus indicating a pro-inflammatory effect of the drug on human macrophages. This M1-like reprogramming at the mRNA level was confirmed by significantly elevated levels of pro-inflammatory cytokines (IFNγ, IL-12, TNFα, IL-2) in the culture medium. Since liposomes are attractive vehicles for novel anti-cancer drugs, and since direct TAM-targeting may decrease adverse effects of systemic inhibition of STAT3, the present results encourage future investigation of CA-LCL-αCD163 in the in vivo setting.


Growth factor receptor tyrosine kinases acutely regulate neuronal sodium channels through the src signaling pathway.
Growth factor receptor tyrosine kinase (RTK)-activated signaling pathways are well established regulators of neuronal growth and development, but whether these signals provide mechanisms for acute modulation of neuronal activity is just beginning to be addressed. We show in pheochromocytoma (PC12) cells that acute application of ligands for both endogenous RTKs [trkA, basic FGF (bFGF) receptor, and epidermal growth factor (EGF) receptor] and ectopically expressed platelet-derived growth factor (PDGF) receptors rapidly inhibits whole-cell sodium channel currents, coincident with a hyperpolarizing shift in the voltage dependence of inactivation. Sodium channel inhibition by trkA and PDGF receptors is mutually occlusive, suggestive of a common signal transduction mechanism. Furthermore, specific inhibitors for trkA and PDGF RTK activities abrogate sodium channel inhibition in response to NGF and PDGF, respectively, showing that the intrinsic RTK activity of these receptors is necessary for sodium channel inhibition. Use of PDGF receptor mutants deficient for specific signaling activities demonstrated that this inhibition is dependent on RTK interaction with Src but not with other RTK-associated signaling molecules. Inhibition was also compromised in cells expressing dominant-negative Ras. These results suggest a possible mechanism for acute physiological actions of RTKs, and they indicate regulatory functions for Ras and Src that may complement the roles of these signaling proteins in long-term neuronal regulation.


Recent advances in 2D materials for photocatalysis.
Two-dimensional (2D) materials have attracted increasing attention for photocatalytic applications because of their unique thickness dependent physical and chemical properties. This review gives a brief overview of the recent developments concerning the chemical synthesis and structural design of 2D materials at the nanoscale and their applications in photocatalytic areas. In particular, recent progress on the emerging strategies for tailoring 2D material-based photocatalysts to improve their photo-activity including elemental doping, heterostructure design and functional architecture assembly is discussed.


The relationship between ambient air pollution and heart rate variability differs for individuals with heart and pulmonary disease.
Associations between concentrations of ambient fine particles [particulate matter < 2.5 microm aerodynamic diameter (PM2.5)] and heart rate variability (HRV) have differed by study population. We examined the effects of ambient pollution on HRV for 18 individuals with chronic obstructive pulmonary disease (COPD) and 12 individuals with recent myocardial infarction (MI) living in Atlanta, Georgia. HRV, baseline pulmonary function, and medication data were collected for each participant on 7 days in fall 1999 and/or spring 2000. Hourly ambient pollution concentrations were obtained from monitoring sites in Atlanta. The association between ambient pollution and HRV was examined using linear mixed-effect models. Ambient pollution had opposing effects on HRV in our COPD and MI participants, resulting in no significant effect of ambient pollution on HRV in the entire population for 1-, 4-, or 24-hr moving averages. For individuals with COPD, interquartile range (IQR) increases in 4-hr ambient PM2.5 (11.65 microg/m3)) and nitrogen dioxide (11.97 ppb) were associated with 8.3% [95% confidence interval (CI), 1.7-15.3%] and 7.7% (95% CI, 0.1-15.9%) increase in the SD of normal R-R intervals (SDNN), respectively. For individuals with MI, IQR increases in 4-hr PM2.5 (8.54 microg/m3) and NO2 (9.25 ppb) were associated with a nonsignificant 2.9% (95% CI, -7.8 to 2.3) and significant 12.1 (95% CI, -19.5 to -4.0) decrease in SDNN. Beta-blocker and bronchodilator intake and baseline forced expiratory volume in 1 sec modified the PM-SDNN association significantly, with effects consistent with those by disease group. Results indicate heterogeneity in the autonomic response to air pollution due to differences in baseline health, with significant associations for ambient NO2 suggesting an important role for traffic-related pollution.


Therapeutic miR-21 Silencing Ameliorates Diabetic Kidney Disease in Mice.
Diabetic nephropathy is the main cause of end-stage renal disease. MicroRNAs are powerful regulators of the genome, and global expression profiling revealed miR-21 to be among the most highly regulated microRNAs in kidneys of mice with diabetic nephropathy. In kidney biopsies of diabetic patients, miR-21 correlated with tubulointerstitial injury. In situ PCR analysis showed a specific enrichment of miR-21 in glomerular cells. We identified cell division cycle 25a (Cdc25a) and cyclin-dependent kinase 6 (Cdk6) as novel miR-21 targets in mesangial cells. miR-21-mediated repression of Cdc25a and Cdk6 resulted in impaired cell cycle progression and subsequent mesangial cell hypertrophy. miR-21 increased podocyte motility by regulating phosphatase and tensin homolog (Pten). miR-21 antagonism in vitro and in vivo in streptozotocin-induced diabetic mice decreased mesangial expansion, interstitial fibrosis, macrophage infiltration, podocyte loss, albuminuria, and fibrotic- and inflammatory gene expression. In conclusion, miR-21 antagonism rescued various functional and structural parameters in mice with diabetic nephropathy and, thus, might be a viable option in the treatment of patients with diabetic kidney disease.


Selection on male sex pheromone composition contributes to butterfly reproductive isolation.
Selection can facilitate diversification by inducing character displacement in mate choice traits that reduce the probability of maladaptive mating between lineages. Although reproductive character displacement (RCD) has been demonstrated in two-taxa case studies, the frequency of this process in nature is still debated. Moreover, studies have focused primarily on visual and acoustic traits, despite the fact that chemical communication is probably the most common means of species recognition. Here, we showed in a large, mostly sympatric, butterfly genus, a strong pattern of recurrent RCD for predicted male sex pheromone composition, but not for visual mate choice traits. Our results suggest that RCD is not anecdotal, and that selection for divergence in male sex pheromone composition contributed to reproductive isolation within the Bicyclus genus. We propose that selection may target olfactory mate choice traits as a more common sensory modality to ensure reproductive isolation among diverging lineages than previously envisaged.


Excitation of surface waves by events in southern algeria.
Surface-wave magnitudes (M(8)) of 4.1 and 3.2 are determined for two events in southern Algeria. The corresponding body-wave magnitudes (m(b)) are 5.8 and 4.9, respectively. The surface waves from these events are much smaller than would be expected from most earthquakes of comparable body-wave magnitudes, which fact suggests that these waves were generated by underground explosions.


Abdominal tuberculosis in children.
Abdominal tuberculosis (TB) includes infection of the gastrointestinal tract, peritoneum, mesentery, abdominal lymph nodes, liver, spleen, and pancreas. The most common forms of abdominal TB in children are adhesive peritonitis and nodal disease. We report our experience with abdominal TB treated in our hospital from 1995 to 2008. Thirteen patients (3 boys and 10 girls) of mean age 9.8 years were diagnosed as having abdominal TB. Eight patients presented with abdominal distension and abdominal pain. Fever was seen in 4 patients. One patient had surgical abdominal pain and 2 had abdominal mass. Two patients had coexisting pleural effusion and 1 of them had multifocal TB. Abdominal TB involved peritoneum in 9, abdominal lymph nodes in 7, gastrointestinal tract in 3, spleen in 2 patients, and liver in 1. Ascitic fluid analysis of 9 patients showed exudative fluid with predominately lymphocytes. Laparotomy was performed in 3 patients. The diagnosis of abdominal TB was confirmed histopathologically in 5 patients and microbiologically in 3. The remaining patients had been diagnosed by ascitic fluid diagnostic features, abdominal imaging, tuberculin skin test, history of exposure, and a positive response to antituberculous treatment. Twelve patients completed the antituberculous therapy without any complications. One patient with multifocal TB had neurological sequelae. In the areas with a high prevalence of tuberculosis and confirmatory investigations are inadequately available, treatment may be initiated, based on strong clinical diagnosis and supportive investigations. In such situations, it is the response to therapy that indirectly proves the diagnosis.


Ultra-low-dose CT combined with noise reduction techniques for quantification of emphysema in COPD patients: An intra-individual comparison study with standard-dose CT.
Phantom studies in CT emphysema quantification show that iterative reconstruction and deep learning-based noise reduction (DLNR) allow lower radiation dose. We compared emphysema quantification on ultra-low-dose CT (ULDCT) with and without noise reduction, to standard-dose CT (SDCT) in chronic obstructive pulmonary disease (COPD). Forty-nine COPD patients underwent ULDCT (third generation dual-source CT; 70ref-mAs, Sn-filter 100kVp; median CTDIvol 0.38 mGy) and SDCT (64-multidetector CT; 40mAs, 120kVp; CTDIvol 3.04 mGy). Scans were reconstructed with filtered backprojection (FBP) and soft kernel. For ULDCT, we also applied advanced modelled iterative reconstruction (ADMIRE), levels 1/3/5, and DLNR, levels 1/3/5/9. Emphysema was quantified as Low Attenuation Value percentage (LAV%, ≤-950HU). ULDCT measures were compared to SDCT as reference standard. For ULDCT, the median radiation dose was 84 % lower than for SDCT. Median extent of emphysema was 18.6 % for ULD-FBP and 15.4 % for SDCT (inter-quartile range: 11.8-28.4 % and 9.2 %-28.7 %, p = 0.002). Compared to SDCT, the range in limits of agreement of emphysema quantification as measure of variability was 14.4 for ULD-FBP, 11.0-13.1 for ULD-ADMIRE levels and 10.1-13.9 for ULD-DLNR levels. Optimal settings were ADMIRE 3 and DLNR 3, reducing variability of emphysema quantification by 24 % and 27 %, at slight underestimation of emphysema extent (-1.5 % and -2.9 %, respectively). Ultra-low-dose CT in COPD patients allows dose reduction by 84 %. State-of-the-art noise reduction methods in ULDCT resulted in slight underestimation of emphysema compared to SDCT. Noise reduction methods (especially ADMIRE 3 and DLNR 3) reduced variability of emphysema quantification in ULDCT by up to 27 % compared to FBP.


De novo assembly of a chromosome-scale reference genome for the northern flicker Colaptes auratus.
The northern flicker, Colaptes auratus, is a widely distributed North American woodpecker and a long-standing focal species for the study of ecology, behavior, phenotypic differentiation, and hybridization. We present here a highly contiguous de novo genome assembly of C. auratus, the first such assembly for the species and the first published chromosome-level assembly for woodpeckers (Picidae). The assembly was generated using a combination of short-read Chromium 10× and long-read PacBio sequencing, and further scaffolded with chromatin conformation capture (Hi-C) reads. The resulting genome assembly is 1.378 Gb in size, with a scaffold N50 of 11 and a scaffold L50 of 43.948 Mb. This assembly contains 87.4-91.7% of genes present across four sets of universal single-copy orthologs found in tetrapods and birds. We annotated the assembly both for genes and repetitive content, identifying 18,745 genes and a prevalence of ∼28.0% repetitive elements. Lastly, we used fourfold degenerate sites from neutrally evolving genes to estimate a mutation rate for C. auratus, which we estimated to be 4.007 × 10-9 substitutions/site/year, about 1.5× times faster than an earlier mutation rate estimate of the family. The highly contiguous assembly and annotations we report will serve as a resource for future studies on the genomics of C. auratus and comparative evolution of woodpeckers.


Mineral elements, lipoxygenase activity, and antioxidant capacity of okara as a byproduct in hydrothermal processing of soy milk.
Minerals and antioxidative capacity of raw okara that was obtained as a byproduct from six soybean varieties during hydrothermal cooking (HTC) of soy milk were assessed. Lipoxygenase (Lox), an enzyme deteriorating the sensory characteristics of okara, was also investigated. All genotypes had very similar concentrations of Lox (4.32-5.62%). Compared to raw soybeans, the applied HTC significantly reduced Lox content in okara (0.54-0.19%) and lowered its activity to 0.004-0.007 μmol g(-1) min (-1). Correlation between the content of Lox in soybeans and that in okara (r = 0.21;p < 0.05) was not registered. This indicates that the content of this enzyme in okara depended much more on the technological process than on soybean genotype. Very strong correlation (r = 0.99; p < 0.05) between okara Lox content and its activity was found. The most abundant minerals in raw okara were potassium (1.04-1.21 g/100g), phosphorus (0.45-0.50 g/100 g), calcium (0.26-0.39 g/100 g), and iron (5.45-10.95 mg/100 g). A very high antioxidant capacity (19.06-29.36 mmol Trolox kg(-1)) contributes to the nutritional value of raw okara.


[Neurosurgery with a CO2 laser. Evaluation of 61 operations].
The authors present the results of their over two years experience with CO2 Laser neurosurgical unit. They explicit the indications and the technical data followed during intra-cranial (N = 44), intra-spinal (N = 12) and intra-orbital (N = 5) procedures. Meningiomas, neurinomas and adenomas are the best indications for tumoral CO2 Laser neurosurgery. In other respects sterilization and cranialization of aeric sinuses are simplified by the use of CO2 Laser: it assures vaporization of the mucosa and carbonization of the walls more easily than an electric coagulator. At last the use of CO2 Laser for dissection and removal of intra-orbital tumors is quite demonstrative. Thus owing to its physical and thermical qualities CO2 Laser is often a very useful, sometimes irreplaceable, apparatus: provided that its indications are precise and rigorous.


Evaluation of the first-generation AAOS clinical guidelines on the prophylaxis of venous thromboembolic events in patients undergoing total joint arthroplasty: experience with 3289 patients from a single institution.
Patients undergoing total hip or total knee arthroplasty have risks that include venous thromboembolism. The American Academy of Orthopaedic Surgeons has promulgated guidelines for the preoperative assessment of patients with the primary objective of preventing pulmonary embolism. We aimed to evaluate and establish the utility of the first-generation American Academy of Orthopaedic Surgeons guidelines for the prophylaxis of venous thromboembolism in patients undergoing total joint arthroplasty at a single institution. A prospective analysis of 3289 consecutive patients managed with total hip or total knee arthroplasty at the Connecticut Joint Replacement Institute between June 1, 2009, and April 30, 2011, was conducted. Data on age, sex, body mass index, American Society of Anesthesiologists classification, and a personal or family history of blood clots requiring long-term warfarin use were analyzed, as were data on a personal history of a malignant tumor, a bleeding disorder, gastrointestinal bleeding, or a hemorrhagic cerebrovascular accident. All patients were managed prophylactically with a specific algorithm based on the American Academy of Orthopaedic Surgeons guidelines. All of the patients were mobilized on postoperative day one, and pneumatic foot-pump compression was used for the duration of the hospitalization. Thirty-six major venous thromboembolic events were documented with Doppler ultrasound or computed tomography angiography, for a ninety-day incidence of 1.1% (95% confidence interval, 0.8% to 1.5%). A personal history of blood clots was significantly associated with a blood clot in the proximal part of the thigh or a pulmonary embolism, but a family history of blood clots and a personal history of a malignant tumor did not show a significant relationship with venous thromboembolism. The ninety-day incidence of venous thromboembolism was significantly different between total hip arthroplasty patients (0.56%; 95% confidence interval, 0.30% to 1.15%) and total knee arthroplasty patients (1.46%; 95% confidence interval, 1.01% to 2.10%). The risk was greater in high-risk total knee arthroplasty patients compared with high-risk total hip arthroplasty patients despite comparable prophylaxis with enoxaparin sodium for twenty-eight days. The prospective use of the first-generation American Academy of Orthopaedic Surgeons guidelines resulted in a low incidence of clinically important thromboembolic events in total hip and total knee arthroplasty patients. When properly used in these patients, the guidelines to minimize adverse outcomes are executable and effective. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


DISCRIMINATION OF Burkholderia mallei/pseudomallei FROM Burkholderia thailandensis BY SEQUENCE COMPARISON OF A FRAGMENT OF THE RIBOSOMAL PROTEIN S21 (RPSU) GENE.
Discrimination of Burkholderia (B.) pseudomallei and B. mallei from environmental B. thailandensis is challenging. We describe a discrimination method based on sequence comparison of the ribosomal protein S21 (rpsU) gene.The rpsU gene was sequenced in ten B. pseudomallei, six B. mallei, one B. thailandensis reference strains, six isolates of B. pseudomallei, and 37 of B. thailandensis. Further rpsU sequences of six B. pseudomallei, three B. mallei, and one B. thailandensis were identified via NCBI GenBank. Three to four variable base-positions were identified within a 120-base-pair fragment, allowing discrimination of the B. pseudomallei/mallei-cluster from B. thailandensis, whose sequences clustered identically. All B. mallei and three B. pseudomallei sequences were identical, while 17/22 B. pseudomallei strains differed in one nucleotide (78A>C). Sequences of the rpsU fragment of 'out-stander' reference strains of B. cepacia, B. gladioli, B. plantarii, and B. vietnamensis clustered differently.Sequence comparison of the described rpsU gene fragment can be used as a supplementary diagnostic procedure for the discrimination of B. mallei/pseudomallei from B. thailandensis as well as from other species of the genus Burkholderia, keeping in mind that it does not allow for a differentiation between B. mallei and B. pseudomallei.


Copper levels in patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic, autoimmune-based disease of the connective tissue with still unknown etiology. Numerous studies have indicated the association between Copper (Cu) and ceruloplasmin (Cp) concentrations and pathogenesis of RA. To compare the concentrations of Cu and Cp in different biological samples and their correlation with the inflammatory process, between a group of patients with RA and a control group of healthy individuals. The study enrolled 74 Caucasian patients (20 men and 54 women), aged 29-50 (mean age 39.8±6.1 years) diagnosed with RA. The control group consisted of 30 healthy Caucasian individuals. Copper levels were assessed by atomic absorption spectroscopy. Among RA patients the mean Cu level was significantly higher in serum and hair compartments and significantly lower in erythrocytes, compared with the control group (p<0.01). The Cp concentration was also higher in serum of RA patients (p<0.001). A statistically significant, positive correlation between the Cp serum concentration and the ESR values (r(s)=0.38; p<0.007) was found. No significant influence of pharmaceutical treatment (methotrexate, non-steroidal anti-inflammatory drugs, glucocorticoids, calcium, vitamin D3 and sulphasalazine) on serum Cu was found. It seems that the 'copper status' in patients with RA, based on the measurement of Cu and Cp levels in blood serum is correlated with presence of the inflammatory process. The hair could serve as a useful, additional diagnostic material. Some other factors, different from the applied treatment, can probably influence the Cu levels in patients with RA.


Multiple sclerosis and anti-Plasmodium falciparum innate immune response.
Several epidemiological investigations conducted in Sardinia, insular Italy, indicate that the strong selective pressure of malaria along the centuries may have concurred to the elevated genetic MS-risk in this region. To test such hypothesis in an experimental setting, we have compared the immune response to P. falciparum (the causative agent of malaria) in Sardinian MS patients relative to their ethnic healthy controls and control MS patients of different ethnicity. To this purpose, the P. falciparum-driven peripheral mononuclear cell proliferation, the production of pro-inflammatory cytokines of the innate immunity such as TNF-alpha, IL-6 and IL-12 and the ability to inhibit the parasite growth have been tested in relation to HLA-DR alleles and TNF promoter polymorphisms known of being associated to MS. We found that P. falciparum-induced proliferation, cytokine production and parasite killing are significantly augmented in Sardinian MS patients as compared to controls (p<0.01). Additionally, a correlation is found with genes associated to Sardinian MS, namely the TNF(-376A) promoter polymorphism and the class II HLA-DRB1*0405 allele. In conclusion, we have found evidences that some genetic traits formerly selected to confer a protective responses to P. falciparum now partially contribute to the elevated MS susceptibility amongst Sardinians.


Methylobacterium gossipiicola sp. nov., a pink-pigmented, facultatively methylotrophic bacterium isolated from the cotton phyllosphere.
A pink, aerobic, facultatively methylotrophic, motile, Gram-negative rod, designated Gh-105(T), was isolated from the phyllosphere of cotton from Coimbatore (Tamilnadu, India). 16S rRNA gene sequence analysis showed clearly that the isolate belonged to the Methylobacterium cluster. Strain Gh-105(T) was most closely related to Methylobacterium adhaesivum AR27(T) (99% 16S rRNA gene sequence similarity) and Methylobacterium iners 5317S-33(T) (97.5%). The isolate grew with C(1) compounds such as methanol and dichloromethane, but not with formaldehyde, formate, methylamine, trimethylamine or methane, as sole carbon sources and carried mxaF, which encodes methanol dehydrogenase and supports methylotrophic metabolism. The major fatty acid was C(18:1)ω7c and the G+C content of the genomic DNA was 64.2 mol%. Physiological and biochemical data and DNA-DNA relatedness with M. adhaesivum KACC 12195(T) and M. iners KACC 11765(T) revealed clear phenotypic and genotypic differences. For this reason, we propose that strain Gh-105(T) (=CCM 7572(T) =NRRL B-51692(T)) represents the type strain of a novel species, with the name Methylobacterium gossipiicola sp. nov.


Dietary interventions for autism spectrum disorder: An updated systematic review of human studies.
Autism is a complex spectrum of disorders with genetic, epigenetic, autoimmune, oxidative stress, and environmental etiologies. Treatment of ASD using dietary approach is a promising strategy, especially owing to its safety and availability. Our study critically analysed the roles and efficacy of antioxidants, probiotics, prebiotics, camel milk and vitamin D. This systematic review provides an updated synopsis of human studies that investigated therapeutic benefits of these dietary interventions in autism. A total of 943 papers were identified out of which 21 articles were included in the systematic review. The selected studies investigated the impact of 5 different dietary supplementations in ASD symptom and behaviours. These agents include; antioxidants/polyphenolic compounds, probiotics, prebiotics, camel milk and vitamin D. From the results of the present review, antioxidants/polyphenolic compounds decreased the levels of inflammatory cytokines and improved behavioural symptoms. Probiotics improved behavioural and GI symptoms as well as restored gut microbiota equilibrium. Prebiotics decreased levels of inflammatory cytokines, improved behavioural and GI symptoms and improved gut microbiota. Vitamin D improved behavioural symptoms and offered protective effects against neurotoxicity. Camel milk reduced inflammatory responses and oxidative stress. Given the chronic nature as well as early onset of ASD, dietary supplements become useful to complement nutritional deficiencies in children with ASD. Key benefits of these agents stem from their ability to target multiple physiological areas via the gut brain-axis and are devoid of potential harmful or aggravating effects on ASD patients. The evidence collated in this review propose that dietary intervention may provide a new platform for the management of autism.


The influence of medial and lateral placement of orthotic wedges on loading of the plantar aponeurosis.
Repetitive trauma and overuse of the plantar aponeurosis are believed to be causal factors of plantar fasciitis. Therefore, it is important to know how an orthosis influences loading of the plantar aponeurosis. The aim of this study was to quantify strain in the plantar aponeurosis in cadaveric feet with the use of various combinations of orthotic wedges. An in vitro test that simulated static stance was used to determine the loading characteristics of the plantar aponeurosis. A differential variable reluctance transducer was operatively implanted into the plantar aponeurosis of nine fresh-frozen cadaveric lower limbs. Each specimen was mounted in an electromechanical testing machine that applied an axial load of as much as 900 newtons to the tibia. Eight different combinations of test conditions, in which wedges (each with a 6-degree incline) were or were not positioned under the medial and lateral aspects of the forefoot and hindfoot, were evaluated, with the plantigrade foot used as a neutral control. Each of the test conditions that involved a wedge under the forefoot resulted in strain that was significantly different from that in the neutral control. A wedge under the lateral aspect of the forefoot decreased strain in the plantar aponeurosis, and a wedge under the medial aspect increased strain (p < 0.05). The test conditions that involved a wedge under the hindfoot but not under the forefoot resulted in strains that were not significantly different from those in the neutral control (p > 0.05). A wedge under the lateral aspect of the forefoot transmits loads through the lateral support structures of the foot, locking the calcaneocuboid joint and decreasing strain in the plantar aponeurosis. A wedge under the medial aspect of the forefoot transmits loads through the medial support structures of the foot, which produces a truss-like action that increases strain in the plantar aponeurosis.


Investigations into the relationship of selected blood components to nutrition and fertility of the dairy cow under commercial farm conditions.
Blood chemistry, nutrition, productivity and fertility were monitored and their interrelationship examined in groups of cows from 15 commercial dairy herds. Plasma urea, albumin, glucose, non-esterified fatty acids (NEFA), acetone, calcium, magnesium, inorganic phosphorus (IP), blood copper, haemoglobin and packed cell volume were examined in relation to the intakes of starch equivalent (SE) digestible crude protein (DCP), calcium, phosphorus, magnesium, sodium, potassium, copper and manganese. The most consistent correlations were found for the regressions of SE intake as a percentage of requirements (I/R per cent) on plasma non-esterified fatty acids, the ratio of SE intake over DCP intake on plasma urea, DCP I/R per cent on plasma urea and phosphorus I/R per cent on plasma IP, but factors other than nutrition accounted for a large part of the variation in all cases. The mean plasma glucose concentration within +/- three days before or after first service of cows which held was higher than that of cows which returned, but the difference was only approaching significance at the 5% level and it is doubtful whether it could be of practical value. No other differences in blood component levels were demonstrated for first or second service. It is concluded that, within the nutritional ranges encountered, the levels of the selected blood components did not show a consistent relationship to nutrient balance or potential fertility. In this context a multiple analytical scheme employing these components would appear to be of limited value, particularly if samples are taken on only one occasion. The technique is more appropriately regarded as an aid to the conventional approach involving the examination of feeding systems and feedstuffs, herd records, management and clinical conditions.


The L1 adhesion molecule normalizes neuritogenesis in Rett syndrome-derived neural precursor cells.
Therapeutic intervention is an important need in ameliorating the severe consequences of Rett Syndrome (RTT), a neurological disorder caused by mutations in the X-linked gene methyl-CpG-binding protein-2 (MeCP2). Following previously observed morphological defects in induced pluripotent stem cell (iPSC)-derived neurons obtained from female RTT patients, we hypothesized that transfection with the L1 cell adhesion molecule (L1) could contribute to normalizing a pathological male cell system bearing a nonsense mutation of MeCP2. We found a decreased expression of L1 in RTT iPSCs-derived neural precursor cells (RTT NPCs) and decreased neuritogenesis. Expression of wild-type MeCP2 in RTTNPCs revealed a positive correlation between the levels of MeCP2 and L1, and normalization of cell survival. Expression of L1 in RTTNPCs enhanced neuritogenesis and soma size. Knock-down of MeCP2 in wild type NPCs reduced neuritogenesis. L1 expression is regulated by the MeCP2 promoter. These results suggest that a deficiency in L1 may partially account for RTT phenotypes.


Longtime administration of growth hormone-releasing hormone (GHRH) does not restore the reduced efficiency of GHRH on sleep endocrine activity in 2 old-aged subjects--a preliminary study.
Aging results in a more shallow sleep accompanied by a blunted growth hormone (GH) secretion. In young male normal controls repetitive administration of GH-releasing hormone (GHRH) at the beginning of the night results in an increased secretion of GH, a blunting of cortisol and a stimulation of slow-wave sleep (SWS). In healthy elderly men and women, however, GHRH exerts only weak effects on sleep-endocrine activity. In a previous report continuous treatment of healthy elderly males by repetitive administration of GHRH (during 12 days administration with 100 micrograms GHRH i.v. at 9.00 h every second day, "priming") enhanced GHRH stimulated GH secretion at daytime markedly. We tested if priming with GHRH results in a more distinct modulation of the nocturnal hormone secretion and of the sleep EEG than acute administration of the peptide. Two elderly male controls spent first three consecutive nights in the sleep laboratory, the first of which served for adaptation to laboratory conditions. During the two other nights (at days 1 and 2) sleep EEG was recorded and blood was sampled for determining the secretion of GH, cortisol and ACTH. In one of the nights the subjects received 50 micrograms GHRH hourly between 22.00 h and 1.00 h (4 x 50 micrograms) or placebo. The next examination followed after the priming period at day 14 and the last was performed two weeks after treatment at day 28. After the baseline administration of 4 x 50 micrograms GHRH before priming no clear changes of sleep EEG towards improved sleep were detectable, whereas GH secretion was increased. After priming sleep period time and SWS time were lower compared to the baseline night with GHRH administration, whereas REM time duration increased. GHRH induced GH secretion was not enhanced after priming. ACTH secretion was markedly enhanced compared to baseline stimulation. We conclude that priming with GHRH has no sleep improving effect and does not change hormone secretion in elderly normal subjects. Hence in the elderly priming with GHRH is not capable to induce a rejuvenation of sleep endocrine activity.


Heritable Variants in the Chromosome 1q22 Locus Increase Gastric Cancer Risk via Altered Chromatin Looping and Increased UBAP2L Expression.
Genome-wide association studies (GWAS) have implicated the 1q22 gastric cancer risk locus in disease, but little is known about its underlying oncogenic functions. This study represents a systematic investigation of the biological significance and potential mechanism associated with the gastric cancer risk of SNP rs2075570(C>T) in 1q22. We identified two functional germline variations (rs2049805-C and rs2974931-G) in an active enhancer in a 64.8 kb high-linkage disequilibrium block of rs2075570. The enhancer upregulated ubiquitin associated protein 2 like (UBAP2L) gene expression over a 960 kb distance by chromatin looping. Gastric cancer tissues expressed significantly higher levels of UBAP2L than was observed in the matched noncancerous tissues, and the UBAP2L expression was negatively correlated with patient survival. Downregulation of UBAP2L inhibited the proliferation and invasion of human gastric cancer cells in vitro and in a xenograft mouse model. Notably, the two mutant variations significantly enforced the enhancer activity and UBAP2L expression. In conclusion, this study revealed two causal variations in the 1q22 region using tag-SNP rs2075570 as a genetic marker. These variations may affect the occurrence and progression of gastric cancer by reinforcing the expression of the 1q22-Enh enhancer-regulated UBAP2L target gene. IMPLICATIONS: Our study provides an important clue of how noncoding germline variations contribute to gastric cancer, which gives a novel insight into understanding the genetic mechanism of gastric cancer.


Electrophysiological characterization of murine HL-5 atrial cardiomyocytes.
HL-5 cells are cultured murine atrial cardiomyocytes and have been used in studies to address important cellular and molecular questions. However, electrophysiological features of HL-5 cells have not been characterized. In this study, we examined such properties using whole cell patch-clamp techniques. Membrane capacitance of the HL-5 cells was from 8 to 62 pF. The resting membrane potential was -57.8 +/- 1.4 mV (n = 51). Intracellular injection of depolarizing currents evoked action potentials (APs) with variable morphologies in 71% of the patched cells. Interestingly, the incidence of successful, current-induced APs positively correlated with the hyperpolarizing degrees of resting membrane potentials (r = 0.99, P < 0.001). Only a few of the patched cells (4 of 51, 7.8%) exhibited spontaneous APs. The muscarinic agonist carbachol activated the acetylcholine-activated K(+) current and significantly shortened the duration of APs. Immunostaining confirmed the presence of the muscarinic receptor type 2 in HL-5 cells. The hyperpolarization-activated cation current (I(f)) was detected in 39% of the patched cells. The voltage to activate 50% of I(f) channels was -73.4 +/- 1.2 mV (n = 12). Voltage-gated Na(+), Ca(2+), and K(+) currents were observed in the HL-5 cells with variable incidences. Compared with the adult mouse cardiomyocytes, the HL-5 cells had prolonged APs and small outward K(+) currents. Our data indicate that HL-5 cells display significant electrophysiological heterogeneity of morphological appearance of APs and expression of functional ion channels. Compared with adult murine cardiomyocytes, HL-5 cells show an immature phenotype of cardiac AP morphology.


Effect of antibiotics on urine leakage in women with refractory detrusor overactivity: A phase IIb randomized trial.
Because bacterial cystitis is common in women with refractory detrusor overactivity, the aim was to compare the efficacy of 6 weeks of rotating antibiotics versus placebo, in conjunction with an anticholinergic, in controlling the symptoms of urge incontinence. In a multicenter phase IIb double-blinded randomized placebo-controlled trial, women with urodynamically proven refractory detrusor overactivity were randomized in a 2:1 ratio of antibiotics versus placebo for 6 weeks, in addition to darifenacin for 6 months. Any woman with disabling cystitis symptoms was given appropriate antibiotics ("clinical override"). The primary outcome was the degree of urge incontinence change at 6 weeks and 6 months on 24-h pad test. Secondary outcomes were changes in leaks and voids per day measured on 3-day bladder diary and quality of life measures. Microbiological data were collected at all visits. Although 278 women were screened, only 36 were randomized and 33 (91.7%) completed the trial. Leakage on 24-h pad test decreased at 6 months by 75 g in patients receiving antibiotics versus 35 g in placebo. Cure of urge incontinence occurred at 6 months in 10/21 (48%) of antibiotics versus 2/12 (17%) of placebo. Clinical override, necessitating treatment of cystitis, occurred in 41.6% of placebo versus 16.7% of the antibiotic group by 6 months. Despite the small sample size, the study showed a significant reduction in pad leakage and leaks per day over 24 h in the active treatment group over a 6-month period. Nearly half of patients on placebo had disabling urinary tract infection symptoms that required clinical override treatment.


[Occupational hazard evaluation in exposure to pesticides].
In the world there are several models of occupational hazard evaluation in exposure to pesticides, including the German calculation model as the most popular one. Natural investigations in Russia have not confirmed the basic idea of the German model, according to which there is a direct relation between the amount of active pesticide ingredient and the exposure of an operator to it. The use of Russian model implies establishing actual pesticide exposures and correlating them with hygienic regulations.


Management of enteroatmospheric fistulae.
A small-bowel enteroatmospheric fistula (EAF) is an especially challenging complication for patients with open abdomens (OAs) and their surgeons. Manipulation of the bowel during treatment (e.g. dressing changes) is one of the risk factors for developing these openings between the atmosphere and the gastrointestinal tract. Unlike enterocutaneous fistulae, EAFs have neither overlying soft tissue nor a real fistula tract, which reduces the likelihood of their spontaneous closure. Surgical closure is necessary but not always easy to do in the OA environment. Negative pressure wound therapy (NPWT) has been used successfully as an adjunct therapy to heal the wound around EAFs. This review discusses many aspects of managing EAFs in patients with OAs, and presents techniques that have been developed to isolate the fistula and divert effluent while applying NPWT to the surrounding wound bed.


Yes to Life: An Opportunity for Partnership Between Medicine and Religion.
Pope Francis recently spoke about perinatal palliative care and the dilemmas that parents of critically ill babies encounter. In his speech, the Pope beautifully captured what many parents feel. They love their baby even if they know that the baby cannot survive. They need compassionate care of the sort that will allow them to express that love, even if it is only for minutes or hours, and even if the expression of love takes the form of comforting the dying baby rather than intervening medically or surgically to try to prolong life. "Many times," the Pope said, "Those few hours in which a mother can cradle her child in her arms leave an unforgettable trace in her heart." For those who work in perinatal palliative care, this affirmation and endorsement of their efforts by the Church is a welcome offer for an important collaboration. Medicine and religion can work hand in hand, here, to help parents and doctors who struggle to do the right thing when all the choices seem bad.


Metastasizing chordoma in early childhood: a pathological and immunohistochemical study with review of the literature.
A 2 1/2-year-old female with a sphenooccipital-vertebral chordoma presented with neck pain, torticollis, fever, a lytic lesion of C2 vertebra, and bilateral nodular infiltrates in the lung. The lung biopsy revealed multiple tumor emboli by an enigmatic epithelioid-appearing neoplasm with immunohistochemical staining for vimentin, cytokeratin, and epithelial membrane antigen. A thorough roentgenographic evaluation disclosed a destructive, prepontine mass in the region of the clivus, erosion of the odontoid process, and compression of the cervical spinal cord. The patient died after a clinical course of 3 months. We identified 16 additional cases of metastasizing chordomas in the pediatric-age population; this case is the first to our knowledge with pathologically documented pulmonary metastasis at presentation.


Comparing community-preference-based and direct standard gamble utility scores: evidence from elective total hip arthroplasty.
Do utility scores based on patient preferences and scores based on community preferences agree? The purpose is to assess agreement between directly measured standard gamble (SG) utility scores and utility scores from the Health Utilities Index Mark 2 (HUI2) and Mark 3 (HUI3) systems. Patients were assessed repeatedly throughout the process of waiting to see a surgeon, waiting for surgery, and recovery after total hip arthroplasty (THA). Group mean scores are compared using paired t-tests. Agreement is assessed using the intraclass correlation coefficient (ICC). The mean SG, HUI2, and HUI3 (SD) scores at assessment 1 are 0.62 (0.31), 0.62 (0.19), and 0.52 (0.21); n=103. At assessment 2, the means are 0.67 (0.30), 0.68 (0.30), and 0.58 (0.22); n=84. There are no statistically significant differences between group mean SG and HUI2 scores. Mean SG and HUI3 scores are significantly different. ICCs are low. At the mean level for the group, SG and HUI2 scores match closely. At the individual level, agreement is poor. HUI2 scores were greater than HUI3 scores. HUI2 and HUI3 are appropriate for group level analyses relying on community preferences but are not a good substitute for directly measured utility scores at the individual level.


Phylogeography and environmental correlates of a cap on reproduction: teat number in a small marsupial, Antechinus agilis.
Natural selection should optimize litter size in response to the distribution and abundance of resources during breeding. In semelparous, litter-bearing antechinuses, teat number limits litter size. Consequently adaptation has been inferred in explaining intraspecific, geographic variability in teat number for several Antechinus spp. The phylogeography of teat number variation and associated genetic divergence were assessed in A. agilis using nine microsatellites and mitochondrial cytochrome b sequence data. Six-teat Otway Range animals were divergent in microsatellite allele identity and frequencies: samples from three Otway six-teat sites demonstrated significantly greater similarity genetically to those from six-teat animals approximately 250 km to the west, than to nearby Otway 10-teat samples, or to the six-teat animals at Wilsons Promontory. Gene flow between Otway phenotypes appears to have been limited for sufficient time to enable different microsatellite alleles to evolve. Nonetheless, nuclear genetic evidence suggested only incomplete reproductive isolation, and mitochondrial DNA (mtDNA) haplotypes showed no association with teat number. Other populations across the range were no more genetically differentiated from one another than expected from geographic separation. Principal components and distance-based redundancy analyses found an association between environmental variables and geographic distribution of A. agilis teat number - six-teat animals inhabit more temperate forests, whilst those with more teats experience greater seasonality. The apparent restricted breeding between phenotypically distinct animals, together with phylogenetically separate groups of six-teat animals in different locations with similar environments, are consistent with the hypothesis that adaptation to different habitats drives teat number variation in A. agilis.


[Growth of insulin-producing beta cells. Perhaps a new way to treat type 1 diabetes].
Insulin dependent diabetes mellitus (type 1-diabetes) results from a selective destruction of the insulin producing beta cells and a limited capacity of the remaining cells to regenerate in a compensatory manner. Increased knowledge of the factors involved in the regulation of beta-cell growth may lead to new ways of forming beta cells that in combination with selective immunosuppression could be used for treatment of type 1 diabetes. Physiological and pathophysiological conditions that induce beta-cell growth, different factors that have been implicated to regulate these processes and future perspectives concerning treatment of type 1 diabetes by expanding the beta-cell mass is discussed in this review article.


Assessing the impact of short-term surgical education on practice: a retrospective study of the introduction of mesh for inguinal hernia repair in sub-Saharan Africa.
Inguinal hernia repair is the most common general surgery operation performed globally. However, the adoption of tension-free hernia repair with mesh has been limited in low-income settings, largely due to a lack of technical training and resources. The present study evaluates the impact of a 2-day training course instructing use of polypropylene mesh for inguinal hernia repair on the practice patterns of sub-Saharan African physicians. A surgical training course on tension-free mesh repair of hernias was provided to 16 physicians working in rural Ghanaian and Liberian hospitals. Three physicians were requested to prospectively record all their inguinal hernia surgeries, performed with or without mesh, during the 14-month period following the training. Demographic variables, diagnoses, and complications were collected by an independent data collector for mesh and non-mesh procedures. Surgery with mesh increased significantly following intervention, from near negligible levels prior to the training to 8.1 % of all inguinal hernia repairs afterwards. Mesh repair accounted for 90.8 % of recurrent hernia repairs and 2.9 % of primary hernia repairs after training. Overall complication rates between mesh and non-mesh procedures were not significantly different (p = 0.20). Three physicians who participated in an intensive education course were routinely using mesh for inguinal hernia repair 14 months after the training. This represents a significant change in practice pattern. Complication rates between patients who underwent inguinal hernia repairs with and without mesh were comparable. The present study provides evidence that short-term surgical training initiatives can have a substantial impact on local healthcare practice in resource-limited settings.


Consequences of COVID-19 Confinement for Teachers: Family-Work Interactions, Technostress, and Perceived Organizational Support.
The confinement experienced due to the COVID-19 pandemic has prompted a rethink of the teaching-learning process to which teachers have responded without planning and instead used their resources. This study aimed to analyze the relationships between work-family interactions, technostress, and perceived organizational support in teachers during the confinement period in Spain that began in March 2020. An online survey was administered to 640 pre-school, primary, and secondary school teachers. Positive reciprocal work-family interactions and their relationship with organizational support were found, with differences according to gender, with women showing a more negative perception of the impact on the family. There were no marked levels of technostress in the overall sample, although higher levels of perceived ineffectiveness and skepticism were found in teachers aged 46 years or older. Teachers in private and subsidized schools showed a higher level of perceived support than those in public schools. There is a need to continue this work to verify the values of these dimensions in other contexts and to apply institutional measures and public policies to improve these indicators in this group.


Alpha-1-antitrypsin aerosolised augmentation abrogates neutrophil elastase-induced expression of cathepsin B and matrix metalloprotease 2 in vivo and in vitro.
Neutrophil elastase (NE) activity is increased in lung diseases such as alpha(1)-antitrypsin (A1AT) deficiency and pneumonia. It has recently been shown to induce expression of cathepsin B and matrix metalloprotease 2 (MMP-2) in vitro and in a mouse model. It is postulated that increased cathepsin B and MMP-2 in acute and chronic lung diseases result from high levels of extracellular NE and that expression of these proteases could be inhibited by A1AT augmentation therapy. Cathepsin and MMP activities were assessed in bronchoalveolar lavage (BAL) fluid from patients with A1AT deficiency, pneumonia and control subjects. Macrophages were exposed to BAL fluid rich in free NE from patients with pneumonia following pretreatment with A1AT. MMP-2, cathepsin B, secretory leucoprotease inhibitor (SLPI) and lactoferrin levels were determined in BAL fluid from A1AT-deficient patients before and after aerosolisation of A1AT. BAL fluid from both patients with pneumonia and those with A1AT deficiency containing free NE had increased cathepsin B and MMP-2 activities compared with BAL fluid from healthy volunteers. The addition of A1AT to BAL fluid from patients with pneumonia greatly reduced NE-induced cathepsin B and MMP-2 expression in macrophages in vitro. A1AT augmentation therapy to A1AT-deficient individuals also reduced cathepsin B and MMP-2 activity in BAL fluid in vivo. Furthermore, A1AT-deficient patients had higher levels of SLPI and lactoferrin after A1AT augmentation therapy. These findings suggest a novel role for A1AT inhibition of NE-induced upregulation of MMP and cathepsin expression both in vitro and in vivo.


Percutaneous absorption of 5 alpha-dihydrotestosterone in man. I. Plasma androgen and gonadotrophin levels in normal adult men after percutaneous administration of 5 alpha-dihydrotestosterone.
The distribution of 5 alpha-dihydrotestosterone to the blood following application of a solution of this androgen to the skin in a hydro-alcoholic gel was studied in order to evaluate the adequacy of the percutaneous route in correcting androgen deficiencies. In 14 adult men, daily percutaneous administration of 5 alpha-dihydrotestosterone (125 mg in 5 g gel) increases, on the average, 4 to 5 times its initial concentration in plasma. On the 14th day of treatment, repeated evaluations of plasma 5 alpha-dihydrotestosterone, between 2 and 21 h after final administration of gel, demonstrated the stability of diurnal 5 alpha-dihydrotestosterone levels and showed the regular distribution of the steroid from a presumably cutaneous reservoir. Plasma 5 alpha-androstane-3 alpha,17 beta-diol levels evolve parallel to those of 5 alpha-dihydrotestosterone. Plasma testosterone and luteinizing hormone, on the contrary, decrease considerably. No variation of follicle-stimulating-hormone is observed during treatment. The percutaneous absorption represents an interesting method for administration of a natural androgen in men, particularly because one avoids the deleterious effects of supra-physiological levels in the liver achieved with oral administration.


Overdose training and take-home naloxone for opiate users: prospective cohort study of impact on knowledge and attitudes and subsequent management of overdoses.
To examine the impact of training in overdose management and naloxone provision on the knowledge and confidence of current opiate users; and to record subsequent management of overdoses that occur during a 3-month follow-up period. Repeated-measures design to examine changes in knowledge and confidence immediately after overdose management training; retention of knowledge and confidence at 3 months; and prospective cohort study design to document actual interventions applied at post-training overdose situations. A total of 239 opiate users in treatment completed a pre-training questionnaire on overdose management and naloxone administration and were re-assessed immediately post-training, at which point they were provided with the take-home emergency supply of naloxone. Three months later they were re-interviewed. Significant improvements were seen in knowledge of risks of overdose, characteristics of overdose and appropriate actions to be taken; and in confidence in the administration of naloxone. A 78% follow-up rate was achieved (186 of 239) among whom knowledge of both the risks and physical/behavioural characteristics of overdose and also of recommended management actions was well retained. Eighteen overdoses (either experienced or witnessed) had occurred during the 3 months between the training and the follow-up. Naloxone was used on 12 occasions (a trained client's own supply on 10 occasions). One death occurred in one of the six overdoses where naloxone was not used. Where naloxone was used, all 12 resulted in successful reversal. With overdose management training, opiate users can be trained to execute appropriate actions to assist the successful reversal of potentially fatal overdose. Wider provision may reduce drug-related deaths further. Future studies should examine whether public policy of wider overdose management training and naloxone provision could reduce the extent of opiate overdose fatalities, particularly at times of recognized increased risk.


Rapid polymerization of Entamoeba histolytica actin induced by interaction with target cells.
Within 5 s of challenge of Entamoeba histolytica trophozoites with red blood cells (RBC), attachment and deformation of target cells occurred at multiple sites on the amoeba surface. Many trophozoite-target interfaces were outlined with a ring of polymerized amoeba actin, revealed by rhodamine-phalloidin staining of glutaraldehyde-fixed and Triton-X 100-extracted cells. The beginnings of phagocytic pseudopods rimmed many targets. The phagocytic membrane and underlying actin network grew uniformly about a target cell, which became dramatically elongated and constricted, sometimes severed, as it entered the amoeba. Total engulfment of RBC targets occurred within 10 s. By methanol extraction and spectrofluorimetric measurement of bound rhodamine-phalloidin we were able to quantitate polymerized actin in amoebae. Interaction with target cells was accompanied by a net increase of up to twofold in the average polymerized actin content of trophozoites. This reached a maximum during the period of most active phagocytosis (4 min after challenge at 25 degrees C), and declined as phagocytic activity diminished (8-16 min). Challenge with latex beads of similar size and number, which E. histolytica phagocytized more slowly than RBC, induced neither a detectable increase in polymerized actin content nor appearance of polymerized actin at the contact interface. RBC inhibited phagocytosis of latex beads, but the reverse did not occur. The results demonstrate a rapid, recognition-specific stimulation of reorganization of the actin cytoskeleton of E. histolytica induced by binding to target cells. Vigorous phagocytic activity is frequently an immediate consequence of cell-cell contact, which emphasizes the importance of this process in the contact-mediated attack mechanism of this pathogen. The quantitative assay of polymerized actin may be useful in further studies of this mechanism.


Electrical potential of gastroduodenal mucosa measured by endoscopy.
The gastroduodenal mucosa has a negative electrical potential with regard to the blood stream, as measured by a potentiometer connected to an intravenous and an intragastric electrode. The intragastric electrode can be positioned on various points of the gastroduodenal surface under direct vision through the forceps channel of the gastroduodenoscope. The values of potential differences were determined in various areas of the stomach and duodenum of normal humans and also over gastric ulcers, duodenal ulcers, gastritis and gastric erosions. A deflection of the potential difference value toward zero characterizes any disruption of the normal mucosa, even if only a few millimeters in diameter. Localized reproduce localized potential difference deflections. Atrophic lesions are represented by larger areas of abnormal potential difference levels. The direct multiple determinations of potential differences over mucosal areas in which lesions are suspected is a useful, simple tool for more objective gastroduodenoscopic diagnoses.


Drosophila kinesin: characterization of microtubule motility and ATPase.
Preparations of kinesin, a microtubule-based force-producing protein, have been isolated from Drosophila melanogaster embryos by incubation of microtubules with a nonhydrolyzable ATP analogue and gel filtration of proteins released from the microtubules by ATP. These preparations induced MgATP-dependent microtubule gliding in vitro with a Km for MgATP of 44 microM and a Vmax for gliding of 0.9 micron/sec. Samples of Drosophila proteins that were active in motility assays possessed an average ATPase activity in solution of 17 nmol/min per mg that increased to an average of 106 nmol/min per mg in the presence of microtubules. The major polypeptides that copurified with these activities showed relative molecular masses of 115 kDa and 58 kDa. An antiserum raised against the 115-kDa polypeptide also recognized the 110-kDa component of squid kinesin preparations and the 130-kDa component of sea urchin kinesin preparations.


Porous hyaluronic acid hydrogels for localized nonviral DNA delivery in a diabetic wound healing model.
The treatment of impaired wounds requires the use of biomaterials that can provide mechanical and biological queues to the surrounding environment to promote angiogenesis, granulation tissue formation, and wound closure. Porous hydrogels show promotion of angiogenesis, even in the absence of proangiogenic factors. It is hypothesized that the added delivery of nonviral DNA encoding for proangiogenic growth factors can further enhance this effect. Here, 100 and 60 μm porous and nonporous (n-pore) hyaluronic acid-MMP hydrogels with encapsulated reporter (pGFPluc) or proangiogenic (pVEGF) plasmids are used to investigate scaffold-mediated gene delivery for local gene therapy in a diabetic wound healing mouse model. Porous hydrogels allow for significantly faster wound closure compared with n-pore hydrogels, which do not degrade and essentially provide a mechanical barrier to closure. Interestingly, the delivery of pDNA/PEI polyplexes positively promotes granulation tissue formation even when the DNA does not encode for an angiogenic protein. And although transfected cells are present throughout the granulation tissue surrounding, all hydrogels at 2 weeks, pVEGF delivery does not further enhance the angiogenic response. Despite this, the presence of transfected cells shows promise for the use of polyplex-loaded porous hydrogels for local gene delivery in the treatment of diabetic wounds.


From book to bedside: putting evidence to use in the care of the elderly.
Infusion of research findings into clinical practice is a challenging part of the research process. Because the length of time between discovery and use of knowledge averages 20 years, methods are needed to speed translation of research findings into practice. Few efforts have been made to coordinate the generation of new knowledge with the dissemination of findings from research to improve care of the elderly. RESEARCH-BASED PRACTICE PROTOCOLS: The Research Development and Dissemination Core (RDDC) of the Gerontological Nursing Interventions Research Center (GNIRC) at the University of Iowa emphasizes development of research-based (RB) protocols, which requires collecting relevant literature, critiquing studies, and synthesizing research findings for practice. GNIRC-generated research is disseminated to nurses in practice, and the RDDC links nurses who identify clinical problems in care of the elderly with GNIRC scientists. Currently, 19 RB protocols are offered for dissemination through the RDDC, and 5 protocols are under development. Implementation and evaluation of research-based practices on "Split Thickness Skin Graft Donor Site Care" and "Nasogastric/Nasointestinal Tube Placement" are described. Lessons learned on the basis of experience in disseminating and implementing research-based practices include the necessity of tailoring them to the local needs of various clinical settings in which they are used, reinfusing them periodically to keep staff motivated, and making them consumer friendly. The challenge remains to integrate these practices into the fiber of organizations and to keep staff educated and motivated to carry out research-based practices to improve the care of the elderly.


Tumor microenvironment-activated NIR-II reagents for tumor imaging and therapy.
Second near-infrared window (NIR-II, 1000-1700 nm) absorption and fluorescent agents have attracted great attention because they can overcome the penetration limitation of the first near-infrared window (NIR-I, 750-1000 nm). However, these always "on" agents face the severe problem of being susceptible to retention and phagocytosis by the reticuloendothelial system after intravenous administration, which results in signal interference during diagnosis and side effects during treatment. Accordingly, tumor microenvironment-responsive smart agents (smart NIR-II agents), whose imaging and therapeutic functions can only be triggered in tumors, can overcome this limitation. Thus, NIR-II smart agents, which exhibit a combined response to the tumor microenvironment and NIR-II, make full use of the advantages of both triggers and improve the precision diagnosis and effective treatment of cancer. This review summarizes the recent advances in tumor microenvironment-activated NIR-II agents for tumor diagnosis and treatment, including smart NIR-II fluorescence imaging, photoacoustic imaging, photothermal therapy and photodynamic therapy. Finally, the challenges and perspectives of NIR-II smart agents for tumor diagnosis and treatment are proposed.


Postbiotics: An alternative and innovative intervention for the therapy of inflammatory bowel disease.
Inflammatory Bowel Disease (IBD) is a persistent gastrointestinal (GI) tract inflammatory disease characterized by downregulated mucosal immune activities and a disrupted microbiota environment in the intestinal lumen. The involvement of bacterium postbiotics as mediators between the immune system and gut microbiome could be critical in determining why host-microbial relationships are disrupted in IBD. Postbiotics including Short-chain fatty acids (SCFAs), Organic acids, Proteins, Vitamins, Bacteriocins, and Tryptophan (Trp) are beneficial bioactive compounds formed via commensal microbiota in the gut environment during the fermentation process that can be used to improve consumer health. The use of metabolites or fragments from microorganisms can be a very attractive treatment and prevention technique in modern medicine. Postbiotics are essential in the immune system's development since they alter the barrier tightness, and the gut ecology and indirectly shape the microbiota's structure. As a result, postbiotics may be beneficial in treating or preventing various diseases, even some for which there is no effective causative medication. Postbiotics may be a promising tool for the treatment of IBD in individuals of all ages, genders, and even geographical locations. Direct distribution of postbiotics may provide a new frontier in microbiome-based therapy for IBD since it allows both the management of host homeostasis and the correction of the negative implications of dysbiosis. Further studies of the biological effects of these metabolites are expected to reveal innovative applications in medicine and beyond. This review attempts to explore the possible postbiotic-based interventions for the treatment of IBD.


Harvey and Gurvir's Law: Ontario Bill for Quality Prenatal Information about Down Syndrome: Terminology, Feasibility, and Ethical Issues.
Harvey and Gurvir's Law is a bill proposed to the Legislative Assembly of Ontario (Canada) to reduce stigma and bias associated with Down syndrome, by developing and disseminating quality information about Down syndrome in the context of prenatal testing.


Modified CBT for social anxiety and social functioning in young adults with autism spectrum disorder.
There is a strong research imperative to investigate effective treatment options for adolescents and adults with autism spectrum disorder (ASD). Elevated social anxiety, difficulties with social functioning and poor mental health have all been identified as core treatment targets for this group. While theoretical models posit a strong bidirectionality between social anxiety and ASD social functioning deficits, few interventions have targeted both domains concurrently. Of the two group interventions previously conducted with adolescents and adults with ASD, significant results have only been observed in either social anxiety or social functioning, and have not generalised to changes in overall mood. The aim of this study was to evaluate the potential benefit, tolerability and acceptability of a group cognitive-behaviour therapy (CBT) intervention in young adults with ASD. Primary treatment outcomes were social anxiety symptoms and social functioning difficulties; secondary outcomes were self-reported mood and overall distress. Ten groups of participants completed an eight-week, modified group CBT intervention targeting both social anxiety and social functioning, that included social skills training, exposure tasks and behavioural experiment components. Seventy-eight adolescents and young adults with ASD, without intellectual impairment, aged between 16 and 38 (M = 22.77; SD = 5.31), were recruited from the community, Headspace centres and the Autism Clinic for Translational Research at the Brain and Mind Centre, University of Sydney. Outcomes (social anxiety, social functioning and mood) were measured pre- and post-intervention via self-report questionnaires (administered either online or through the return of hard-copy booklets), and participants were invited to provide anonymous feedback on the intervention (at the mid-point and end of the intervention). Participants demonstrated statistically significant improvements on all outcome measures in response to the intervention. Specifically, social anxiety symptoms decreased (p < .001), and specific subdomains of social functioning improved post-intervention, particularly in social motivation (p = .032) and restricted interests and repetitive behaviours (p = .025). Self-reported symptom improvements also generalised to mood (depression, anxiety and stress; p < .05). All improvements demonstrated small effect sizes. Participant feedback was positive and indicated strong satisfaction with the program. The absence of a control group and follow-up measures, reliance on self-report instruments as outcome measures and the exclusion of those with intellectual disability represent significant limitations to this study. These findings indicate that a group CBT intervention appears to be a beneficial intervention for self-reported social anxiety, social functioning and overall mental health in adolescents and young adults with ASD. The stand-alone nature of the intervention combined with positive participant feedback indicates it was well tolerated, has potential clinical utility and warrants further study in a randomised-controlled, follow-up design.


Morphological identification of ganglion cells expressing the alpha subunit of type II calmodulin-dependent protein kinase in the macaque retina.
Expression of the alpha subunit of type II calmodulin-dependent protein kinase (alphaCamKII) distinguishes the koniocellular neurons of the primate lateral geniculate nucleus (LGN) from the primary parvo- and magnocellular neurons, but whether the same neurochemical signature distinguishes the retinal ganglion cells providing them input is not known. We find that, in the retina, alphaCamKII expression also differentiates two primary groups of ganglion cell, both characterized by broad, sparsely branching dendritic trees and cell bodies intermediate in size between the parvo- and magnocellular-projecting ganglion cells. Cells in the first group have three or four primary dendrites, a thick axon, and a rounded cell body and likely are made up of multiple types. In contrast, ganglion cells in the second group demonstrate a highly regular morphology, with strictly two primary dendrites and a thinner axon emanating from a smaller, elliptical cell body. This cell resembles the "large sparse" ganglion cell identified by others in retrograde labeling from the LGN and represents about 2% of all ganglion cells. In the optic nerve, alphaCamKII+ axons are also intermediate in size and form a bimodal distribution, correlating with the axonal sizes of the two groups of ganglion cell. For the LGN, we describe a group of alphaCamKII+ axon terminals with morphology consistent with terminals from retinal ganglion cells. These terminals form long, filamentous contacts with alphaCamKII+ relay cells and increase in frequency from the dorsal to the ventral koniocellular regions. Our results indicate that ganglion cells expressing alphaCamKII represent multiple projections to the brain, at least one of which provides input to one or more koniocellular regions of the LGN.


Wnt Signaling Cascades and Their Role in Coronary Artery Health and Disease.
The Wnt signaling is classified as two distinct pathways of canonical Wnt/β-catenin signaling, and the non-canonical pathways of planar cell polarity and Wnt/Ca2+ pathways. However, the scientific discoveries in recent years have shown that canonical and non-canonical Wnts pathways are intertwined and have complex interaction with other major signaling pathways such as hedgehog, Hippo and TOR signaling. Wnt signaling plays important roles in cell proliferation, differentiation and migration during embryonic development. The impairment of these pathways during embryonic development often leads to major congenital defects. In adult organisms Wnt expression is more restricted to proliferating tissues, where it plays a key role in tissue regeneration. In addition, the disruption of homeostatic processes of multicellular organisms may give rise to reactivation and/or altered activation of Wnt signaling, leading to development of malignant tumors and chronic diseases such as type-2 diabetes and adult cardiovascular diseases. Coronary artery disease (CAD) is the leading cause of death in the world. The disease is the consequences of two distinct disease processes: Atherosclerosis, a primarily inflammatory disease and plaque erosion, a disease process associated with endothelial cell defect and smooth muscle proliferation with only modest contribution of inflammatory cells. The atherosclerosis is itself a multifactorial disease that is initiated by lipid deposition and endothelial dysfunction, triggering vascular inflammation via recruitment and aggregation of monocytes and their transformation to foam cell by the uptake of modified low-density lipoprotein (LDL), culminating in an atheromatous plaque core formation. Further accumulation of lipids, infiltration and proliferation of vascular smooth muscle cells (VSMCs) and extracellular matrix deposition result in intimal hyperplasia. Myocardial infarction is the ultimate consequence of these processes and is caused by plaque rupture and hypercoagulation. In vivo studies have established the role of the Wnt pathway in all phases of atherosclerosis development, though much remains unknown or controversial. Less is known about the mechanisms that induce plaque erosion. The limited evidence in mouse models of Wnt coreceptor LRP6 mutation and heterozygous TCF7L2 knock out mice implicate altered Wnt signaling also in the pathogenesis of plaque erosion. In this article we focus and review the role of the Wnt pathway in CAD pathophysiology from clinical and experimental standpoints.


Invasive cutaneous angiomatosis and thrombocytopenia in a cat.
A 9-year-old 6.9-kg (15.18-lb) castrated male Siamese cat was evaluated because of a 3-year history of repeated hemorrhage from the right metacarpal pad. Physical examination findings were unremarkable except for a 2-mm-diameter erosion of the right metacarpal pad. A CBC revealed marked thrombocytopenia. Serum biochemical analyses, retroviral screening, thoracic radiography, and abdominal ultrasonography revealed no abnormalities. Via ultrasonographic examination, the vasculature in the right metacarpal pad appeared increased, compared with that of the left pad; an aberrant arterial plexus that was confined to the metacarpal pad was identified via arterial angiography. Surgical resection of the metacarpal pad (without digital pad transposition) with primary closure was performed. Histologic evaluation of the pad tissue revealed invasive cutaneous angiomatosis. The incision healed without complications, and limb function was considered normal. Administration of prednisone (2 mg/kg [0.91 mg/lb], PO, q 24 h) was initiated 4 weeks prior to surgery to treat suspected immune-mediated thrombocytopenia and continued afterwards with a tapering dosage. Platelet count was within reference limits 4 months after surgery; at 12 months, there was no evidence of recurrence of abnormal vasculature in the right metacarpal pad region. Complete resection of the metacarpal pad (without pad transposition) resulted in successful and well-tolerated treatment of cutaneous angiomatosis of the metacarpal pad of a cat. Recurrence of abnormal vasculature was not evident at a 12-month follow-up examination. Thrombocytopenia is commonly associated with vascular anomalies in humans and may have been a contributing factor in this cat.


The current epidemiological status of bovine theileriosis in eastern Zambia.
Results of a longitudinal study conducted in the eastern province of Zambia from 1994 to 1997 indicate that it is doubtful whether a state of endemic stability of East Coast fever (ECF) can be reached in the near future. Even in endemic areas, the mortality of Theileria parva infections is still estimated above 50%. The main factors limiting progress towards endemic stability are high innate susceptibility of the Zebu cattle, the virulence of the parasite and the climate. The unimodal rainfall pattern results in restricted activity of Rhipicephalus appendiculatus instars and year-to-year variation in rainfall causes fluctuations in tick phenology and T. parva transmission. Adult tick activity invariably peaks during the rains and is associated with the highest ECF incidence. Nymphal transmission of T. parva to cattle appears to be less important. Second periods of activity of both adult and nymphal instars are pronounced only when the climate is suitable. These second waves of tick activity ensure a more continuous and efficient transmission of T. parva and also play a key role in the dynamics of prolonged outbreaks in epidemic areas. ECF control methods may have an important influence on ECF epidemiology. Immunizations as well as chemotherapy of clinical cases create a reservoir of virulent parasites in susceptible cattle, resulting in artificial endemic stability.


[The brown line of Retzius in scanning electron microscopy].
A study in scanning electron microscopy of the striae of Retzius of human enamel, on longitudinal and transverse sections, has shown thin striae and relatively broad bands. The thin striae of Retzius consisted in narrow zones devoided of mineral material which extended obliquely through the prisms. These latter were interrupted at the level of the striae. A thin dense layer bordered sometimes unilaterally the striae of Retzius. The relatively large band-like structures involved several prism rows and can be considered as hypomineralized enamel.


Antigenemia, RNAemia, and innate immunity in children with acute rotavirus diarrhea.
Antigenemia is commonly detected in children with acute rotavirus diarrhea, but the prevalence of viremia has not been clearly defined. We examined antigenemia in plasma and RNAemia in peripheral blood mononuclear cells (PBMC) of children with acute diarrhea by EIA, RT-PCR, and Southern hybridization, using primers and a probe specific to rotavirus NSP4 gene. We detected the presence of rotavirus antigen in 33.3% and almost full-length NSP4 gene in 70.8% of the acute-phase plasma and PBMC, respectively. In contrast, antigenemia and RNAemia were detected in 0% and 4.2% of the convalescent-phase plasma and PBMC, respectively, which were similar to antigenemia (0%) and RNAemia (7.7%) in healthy controls. We demonstrated an increase in the proportions of activated myeloid dendritic cells (mDC) and activated plasmacytoid DC (pDC) in acute-phase PBMC of patients when compared to those in convalescent phase of patients and in PBMC of healthy controls. The activation of mDC peaked on days 2-4 after illness onset, and the activation of acute-phase pDC appeared to correlate with levels of antigenemia. High prevalence of NSP4 gene in acute-phase PBMC indicates possible rotavirus replication in white blood cells, and extraintestinal spread and the activation of DC may have implications for the prevention of rotavirus disease in children.


In vitro and in vivo growth characteristics of two different cell populations in an established line of human neuroblastoma.
Two distinct cell morphologies were appreciated and separated in a long-established culture line (CHP-100) of human neuroblastoma. Both cell types carried chromosomal markers characteristic of neuroblastoma cells and the parent line; in addition, separate karyotypic changes in each cell type established them as separate and enriched populations. A small, refractile cell, designated CHP-100-S, was present and formed numerous cytoplasmic processes. A distinctly larger cell, CHP-100-L, was less refractile and lacked processes. The two cell types exhibited marked differences in adhesive properties in vitro. CHP-100-L adhered tightly to the culture flask and required enzymatic treatment for removal; CHP-100-S adhered loosely and could be harvested into the medium by simply tapping the flask. These two harvesting procedures were used to obtain highly enriched populations of each cell type, both of which proved to be tumorigenic in the nude mouse. In vitro, no significant difference in growth rates was observed between CHP-100-S (doubling time, 26 hr) and CHP-100-L (21 hr). However, in the nude mice, following inoculation of equal cell numbers, CHP-100-L cells grew much larger tumors than did CHP-100-S cells (3- to 100-fold increases over 25 days). Local invasion was also noted more frequently with the CHP-100-L explants. Reculturing of the mouse explants showed that the distinct cell morphologies were maintained even after multiple passages. The presence of heterogeneous cell populations in single tumors is of much potential importance for the clinical and biological behavior of neoplasms. The present data establish cultured human neuroblastomas as one model for studies of cell heterogeneity and suggest potentially important ramifications for the different cell types observed in the growth patterns of this neoplasm.


Different clinical presentation of community-onset bacteremia among human immunodeficiency virus-infected and human immunodeficiency virus-uninfected adults in the ED.
The objective of this study is to analyze the differences in clinical presentation and outcome of community-onset bacteremia between human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults visiting the emergency department (ED). A multicenter, case-control study with a ratio of 1:4 was conducted retrospectively over an 8-year period. Demographic characteristics, severity of illness, and clinical outcomes determined from chart records were analyzed. In total, 74 HIV-infected adults (case patients) and 288 HIV-uninfected adults (control patients) were examined. Significant differences in clinical presentation, severity, and the source of bacteremia as well as bacteremia-causing microorganisms between the case patients and control patients were observed by univariate analyses. Using multivariate analyses, the following variables were positively associated with case patients: male sex (odds ratio [OR], 3.42; P = .01), bacteremia due to endocarditis (OR, 7.68; P = .007), bacteremia due to Salmonella enteritidis (OR, 4.29; P = .03), and comorbidity with chronic hepatitis (OR, 5.65; P < .001). Moreover, several independent risk factors of 28-day mortality were discovered, including inappropriate empirical antibiotic therapy after the ED visit (OR, 9.01; P < .001), an initial syndrome with septic shock (OR, 5.37; P < .001); a Pittsburgh bacteremia score greater than or equal to 4 points at the ED (OR, 4.28; P = .002), severe underlying disease based on McCabe classification (rapid and ultimately fatal; OR, 3.31; P = .002), and bacteremia due to pneumonia (OR, 2.66; P = .03). Of note, HIV infection was not a significant factor affecting 28-day mortality. This study demonstrated that the clinical characteristics, the severity, and the character of bacteremia in HIV-infected and uninfected patients varied among community-onset bacteremic patients visiting the ED, despite the limited impact of HIV infection on short-term outcomes.


Tolerability of an Individualized Physical Rehabilitation Program in Patients Dependent on Inotropic Support With End-Stage Chronic Heart Failure.
Aim To assess the tolerability of an individualized physical rehabilitation program (PRP) in inotrope-dependent patients with end-stage chronic heart failure (CHF).Material and methods This prospective randomized study included 120 men aged 18-65 years with left ventricular ejection fraction ≤30 % and blood pressure ≥90 / 60 mm Hg. Patients who have received dobutamine or dopamine for ≥2 weeks were randomized into two groups: group 1, 40 patients who participated in the PRP and group 2, 40 patients who did not participate in the PRP. Group 3 included 40 patients without inotropic support who participated in the PRP.Results Patients of groups 1 and 3 attended >80 % of the scheduled classes without developing life-threatening adverse events (AEs) associated with exercise (E). After 6 months of the study, the exercising patients achieved a comparable (average) E intensity: 44 [35; 50]% and 45 [40;52]% of heart rate reserve and Borg scale scores 14 [12; 14] and 13 [11; 14] in groups 1 and 3, respectively (p>0.05). Initially, after 3 and 6 months at the peak of physical activity in groups 1 and 3, there was no decrease in arterial blood oxygen saturation according to pulse oximetry (SpO2) <93 %. At baseline, lactate levels in central venous blood at rest were normal in all groups. After 6 months, the lactate concentration was 1.1 mmol / l in group 1, 2.3 mmol / l in group 2, and 1.4 mmol / l in group 3 (р1-2=0.005; p2-3=0.008, respectively). At the E peak at baseline, after 3 and 6 months, comparable increases in lactate not exceeding 3 mmol / l were detected in groups 1 and 3.Conclusion The study allowed assessment of the tolerability of individualized PRP performed at the aerobic level of energy supply, in inotropic-dependent patients with CHF. Individualized 6-month PRP in inotropic-dependent patients with end-stage CHF, provided safety criteria are met, is well tolerated and does not increase the number of AEs associated with CHF and physical rehabilitation (PR). Continued inotropic support with dopamine or dobutamine should not be considered as a contraindication to PR in patients with CHF in the absence of E intolerance or life-threatening AEs.


Role of the adrenal cortex and sodium in the pathogenesis of human hypertension.
After 30 years of continuous research into the mechanisms of human hypertension, we summarize the results obtained by the members of the multidisciplinary research group on hypertension of the Clinical Research Institute of Montreal on the disturbances of minerlocorticoid activity in a rigorously selected group of patients with early, mild essential hypertension. We attempt to integrate these findings with those of many other groups working on other aspects of hypertensive cardiovascular diseases. On the assumption that the increased peripheral resistance responsible for hypertension results from an imbalance or a disturbance of the equilibrium between the sympathetic nervous system and norepinephrine on one hand, and the vascular tone, sensitivity and responsiveness of the arterial smooth muscle to norepinephrine and to angiotensin II on the other hand, three models that fit the experimental and clinical facts as known at present are described.


Implementation and assessment of an end-to-end Open Science & Data Collaborations program.
As research becomes more interdisciplinary, fast-paced, data-intensive, and collaborative, there is an increasing need to share data and other research products in accordance with Open Science principles. In response to this need, we created an Open Science & Data Collaborations (OSDC) program at the Carnegie Mellon University Libraries that provides Open Science tools, training, collaboration opportunities, and community-building events to support Open Research and Open Science adoption. This program presents a unique end-to-end model for Open Science programs because it extends open science support beyond open repositories and open access publishing to the entire research lifecycle. We developed a logic model and a preliminary assessment metrics framework to evaluate the impact of the program activities based on existing data collected through event and workshop registrations and platform usage. The combination of these evaluation instruments has provided initial insight into our service productivity and impact. It will further help to answer more in-depth questions regarding the program impact, launch targeted surveys, and identify priority service areas and interesting Open Science projects.


Malin: maximum likelihood analysis of intron evolution in eukaryotes.
Malin is a software package for the analysis of eukaryotic gene structure evolution. It provides a graphical user interface for various tasks commonly used to infer the evolution of exon-intron structure in protein-coding orthologs. Implemented tasks include the identification of conserved homologous intron sites in protein alignments, as well as the estimation of ancestral intron content, lineage-specific intron losses and gains. Estimates are computed either with parsimony, or with a probabilistic model that incorporates rate variation across lineages and intron sites. Malin is available as a stand-alone Java application, as well as an application bundle for MacOS X, at the website http://www.iro.umontreal.ca/~csuros/introns/malin/. The software is distributed under a BSD-style license.


The relation between green tea consumption and cardiovascular disease as evidenced by epidemiological studies.
Although substantial evidence from in vitro and animal studies indicates that green tea preparations inhibit cardiovascular disease processes, the possible protective role of green tea consumption against this disease in humans remains unclear. We conducted a population-based prospective cohort study (the Ohsaki Study) to examine the association between green tea consumption and mortality from cardiovascular disease (CVD), cancer, and all causes with 40,530 persons in Miyagi prefecture, in northern Japan. Previously published work has shown that green tea consumption was inversely associated with mortality from CVD and all causes. The inverse association of mortality from CVD was more pronounced in women (P = 0.08 for interaction with sex). In women, the multivariate hazard ratios (95% confidence intervals) of CVD mortality across increasing green tea consumption categories were 1.00, 0.84 (0.63-1.12), 0.69 (0.52-0.93), 0.69 (0.53-0.90) (P for trend = 0.004). Within CVD mortality, the stronger inverse association was observed for stroke mortality. Because our observational study has found the inverse association, I report here the results of a review of epidemiological evidence from randomized controlled trials (RCT) of the association between green tea or green tea extracts and CVD risk profiles. More than half of the RCT have demonstrated the beneficial effects of green tea on CVD risk profiles. These results from RCT suggest a plausible mechanism for the beneficial effects of green tea and provide substantial support for our observations.


The kleisin subunit controls the function of C. elegans meiotic cohesins by determining the mode of DNA binding and differential regulation by SCC-2 and WAPL-1.
The cohesin complex plays essential roles in chromosome segregation, 3D genome organisation, and DNA damage repair through its ability to modify DNA topology. In higher eukaryotes, meiotic chromosome function, and therefore fertility, requires cohesin complexes containing meiosis-specific kleisin subunits: REC8 and RAD21L in mammals and REC-8 and COH-3/4 in Caenorhabditis elegans. How these complexes perform the multiple functions of cohesin during meiosis and whether this involves different modes of DNA binding or dynamic association with chromosomes is poorly understood. Combining time-resolved methods of protein removal with live imaging and exploiting the temporospatial organisation of the C. elegans germline, we show that REC-8 complexes provide sister chromatid cohesion (SCC) and DNA repair, while COH-3/4 complexes control higher-order chromosome structure. High-abundance COH-3/4 complexes associate dynamically with individual chromatids in a manner dependent on cohesin loading (SCC-2) and removal (WAPL-1) factors. In contrast, low-abundance REC-8 complexes associate stably with chromosomes, tethering sister chromatids from S-phase until the meiotic divisions. Our results reveal that kleisin identity determines the function of meiotic cohesin by controlling the mode and regulation of cohesin-DNA association, and are consistent with a model in which SCC and DNA looping are performed by variant cohesin complexes that coexist on chromosomes.