Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial.
The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear. We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04-1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79-1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14-1.49). The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events. http://www.clinicaltrials.gov. Unique identifier: NCT00391872.


The efficacy and safety of hydroxychloroquine in pregnant patients with IgA nephropathy: A retrospective cohort study.
Hydroxychloroquine (HCQ) is used to control proteinuria in IgA Nephropathy (IgAN) However, its efficacy and safety in pregnant IgAN patients remains unknown. This study aimed to verify the safety of HCQ in pregnant IgAN patients and compare renal function and pregnancy outcomes with those of patients not treated with HCQ. We retrospectively reviewed medical records of all pregnant IgAN patients and singleton gestations at Peking University First Hospital from 2003-2021. Patients who did and did not receive HCQ treatment during pregnancy were compared. We found no significant pre- or post-pregnancy differences in proteinuria or renal function between the two groups. However, the HCQ (+) group had higher proteinuria at the time of kidney biopsy (2.04 [1.26, 2.56] g/d vs. 0.80 [0.44, 1.11] g/d, P < .001); the proteinuria level at HCQ therapy initiation was also higher than that at the beginning of pregnancy (1.87 [1.30, 2.59] g/d vs. 1.08 [0.75, 1.50] g/d, P = .001). Despite no difference in preterm birth, birth weight, preeclampsia or postpartum haemorrhage, the proportion of patients with a previous history of spontaneous abortion was higher in the HCQ (+) group than in the HCQ (-) group (48.0% vs. 20.6%, P = .010). The eGFR (regression coefficient, 0.981; 95%CI 0.964-0.998) was a predictive factor for obstetrical complications. HCQ is safe for IgAN treatment during pregnancy with effective reduction of proteinuria. HCQ might also be helpful in patients with a history of spontaneous abortion.


Epidemiologic features of recent trends in coronary heart disease in the Soviet Union.
Beginning in the mid 1960s the Soviet Union experienced a sharp increase in the mortality rate for men over the age of 20 and for women 50 to 64 years. The principal cause of this increase appears to be the rising rates of coronary heart disease. The rate of increase in coronary heart disease for men in the 30 to 59 year age group over the years 1966 to 1972 was almost 7% per year. Rural death rates have increased at a faster rate than those in cities, although the absolute level remains somewhat lower. Mortality from other major cardiovascular diseases has also increased. It would appear that the coronary heart disease epidemic has been particularly severe in the USSR and there is no evidence that it has abated.


Osseodensification -- A systematic review and qualitative analysis of published literature.
The recently introduced technique of osseodensification for dental implant involves the use of special drills (Densah) run in a counter-clockwise direction at the osteotomy site. It is claimed that this causes expansion of the osteotomy site, and increases density of the bone in immediate vicinity of the osteotomy. We reviewed published papers on the primary stability attained using this drilling technique. As a secondary finding, the bone to implant contact (BIC) and the bone area fraction occupancy (BAF) was also compared between the conventional drilling protocol and the osseodensification protocol, among these articles. A Systematic search was performed in PubMed-Medline, Embase and Google Scholar for clinical/animal studies up to November 2018. A total of 12 articles, from a database of 132 articles, consisting of 8 animal histologic studies, 2 human based clinical studies, 1 case series and 1 case report were assessed. 10/12 articles measured the insertion torque values, 7/12 articles measured the BIC and 6/12 articles estimated the BAF between the two techniques. Quality assessment of 8 studies performed using ARRIVE guidelines showed that 6/8 studies had a high score. An average increase in the insertion torque, BIC and BAF was noted in the osseodensification group as compared to the conventional drilling group. Since most of these studies are non-clinical, it can be inferred that osseodensification is an efficient way to enhance primary stability of implants in low density bone in an animal model. However, extrapolation to long term clinical success cannot be ascertained until further evidence becomes available.


Multiplexed immunofluorescence analysis of CAF-markers, EZH2 and FOXM1 in gastric tissue: associations with clinicopathological parameters and clinical outcomes.
The aim of this study is to explore the expression and clinical relevance of CAF-associated markers, EZH2 and FOXM1 in gastric samples. Protein expression were detected and evaluated by multi-plex immunofluorescence (mIF) in 93 cases of gastric cancer (GC) and 31 cases of gastric intraepithelial neoplasia (GIN). The correlation among their expression, and the relationship of them with clinicopathological parameters and prognosis in GC were then analyzed. FAP was specific expressed in the CAFs of GC samples, and thus be utilized as a CAF-associated marker in our subsequently analysis. The immunostaining of EZH2, FOXM1 and FAP were significantly upregulated in patients with GC tissues than in those normal gastric mucosa or GIN tissues. The average fluorescence intensity of FAP was slightly positively correlated with EZH2 in GC, GIN and normal samples, whereas the percentage of FAP positive cells has no correlation with that of EZH2. Both the percentage of positive cells and the average fluorescence intensity of FOXM1 were positively correlated with that of FAP and EZH2 in GC, GIN and normal samples, except for FOXM1 and EZH2 expression in normal tissue samples. No significant association was observed between FAP expression and any clinicopathological parameters, whereas the positive frequency of EZH2 and FOXM1 were correlated with tumor location significantly and tumor invasion depth, respectively. In addition, there was strong positive correlations between FAP protein expression and overall survival (OS) and disease-free survival (DFS), and EZH2 expression was positively associated with OS in patients with GC. Furthermore, EZH2 and FAP protein expression was an independent prognostic factor for OS and DFS, respectively. These results suggest that both EZH2 and FOXM1 expression was positively associated with CAFs abundance in GC. They may be potential cellular target for therapeutic intervention, especially in patients with a large number of CAFs.


Competitive solubilization of cholesterol and phytosterols in nonionic microemulsions studied by pulse gradient spin-echo NMR.
The actual mechanism of cholesterol reduction by phytosterols is yet to be explored. One hypothesis states that cholesterol and phytosterols compete on the solubilization locus within gastric bile salt micelles. In this study competitive solubilization within microemulsions as vehicles for dietary intake of cholesterol and phytosterols was studied by pulse gradient spin-echo nuclear magnetic resonance. The loaded microemulsions undergo phase transitions as a function of dilution, the type of solubilized sterol, and the weight ratio of the cosolubilized sterols. Microemulsions containing 10-20 wt% of aqueous phase, show similar diffusivity of the oil and aqueous phases in all examined systems (excluding PS-loaded one) reflecting the minor influence of these solubilizates on the structure of the inner and the outer phases. The closeness of these structures enables the mobility of water molecules between them. Upon further dilution (>20 wt% aqueous phase), significant differences in decrease rate of the oil and increase of the water phases mobilities (occurring upon inversion), were detected within the studied systems. It was concluded that the solubilized sterols influence the structural transitions based on their location within the structures and their competitive solubilization. The phytosterols solubilized mostly in the continuous oil phase and between the surfactant tails. Cholesterol is solubilized in the vicinity of the surfactant headgroups and affects the surface curvature. In mixtures of cholesterol and phytosterols, structural changes are dictated mostly by the presence of the cholesterol.


HIV-1 integrase inhibitors: 2003-2004 update.
The integration of viral cDNA into the host genome is an essential step in the HIV-1-life cycle and is mediated by the virally encoded enzyme, integrase (IN). Inhibition of this process provides an attractive strategy for antiviral drug design. The discovery of beta-diketo acid inhibitors played a major role in validating IN as a legitimate antiretroviral drug target. Over a decade of research, a plethora of IN inhibitors have been discovered and some showed antiviral activity consistent with their effect on IN. To date, at least two compounds have been tested in human but none are close to the FDA approval. In this review, we provide a comprehensive report of all small-molecule IN inhibitors discovered during the years 2003 and 2004. Compilation of such data will prove beneficial in developing QSAR, virtual screening, pharmacophore hypothesis generation, and validation.


Patterns of participation and enjoyment in adolescents with Down syndrome.
This study aimed to determine participation and enjoyment in young people with Down syndrome (DS) in Taiwan and to assess how participation varies across gender, cognitive, and motor function variables. Using the Children's Assessment of Participation and Enjoyment, data on participation were collected from 997 adolescents with DS and their families. Findings indicated limited diversity and intensity of participation, with proportionately greater involvement in informal activities. Youth with better cognitive and motor functions participated more often in activities and reported higher enjoyment and social engagement with these. These findings provide a foundation for an improved understanding of activity participation of youth with DS. Service providers and families could provide and plan activities to ensure more satisfying and meaningful participation.


Grip strength is more sensitive to changes in elbow position than isolated wrist extension strength in patients with lateral elbow tendinopathy.
This is an observational study. Because isometric wrist extension minimizes the effects of other muscles, the sensitivity of wrist extension strength testing on patients with lateral elbow tendinopathy (LET) should be evaluated. The purpose of the study was to compare the effects of the elbow position on wrist extension and grip strength in patients with LET. Patients were screened for at least 2 of 5 clinical tests for LET. Between-day intraclass correlation coefficients (ICC3, 1) for healthy individuals were examined for both grip and wrist extension strength at 0° and 90°. To compare the effects of elbow position on wrist extension strength to grip strength, a repeated measure analysis of variance was run using 2 within-group factors, test angles (0° and 90°), and the test type (wrist extension and grip). Nineteen patients with LET and twenty-one healthy participants were included. The between-day intrarater reliability for both wrist extension and grip strength was excellent for the healthy subjects across the 0° and 90° positions (ICC > .95). The analysis of variance yielded a significant interaction between the type of test and the angle of testing (P = .00). Both wrist extension strength and grip strength are reliable between-day measures. For patients with LET, there was a significant decrease in grip strength when testing at 0° compared with 90°. In patients with LET, clinicians can expect wrist extension strength at 0° and 90° to be similar. Grip strength testing may be a more relevant clinical test at the initial evaluation.


Kunitz-type proteinase inhibitors derived by limited proteolysis of the inter-alpha-trypsin inhibitor, VII. Determination of the amino-acid sequence of the trypsin-released inhibitor from bovine inter-alpha-trypsin inhibitor.
An acid-labile proteinase inhibitor, quite similar to human inter-alpha-trypsin inhibitor, was isolated from bovine serum. An acid-resistant 30-kDa inhibitor, exhibiting properties similar to human HI-30, was also isolated. Upon limited proteolysis of both bovine inhibitors, active 14-kDa domains are released which are identical with respect to molecular mass and acid resistance. The amino-acid sequence determination of these fragments revealed a strong homology to the corresponding human inhibitor HI-14 which is characterized by two covalently linked Kunitz-type domains. The reactive-site residue is leucine in the N-terminal domain (in the human inhibitor methionine) and arginine in the C-terminal domain in both bovine and human inhibitor.


Quantitative analysis of high-resolution trypsin-giemsa bands on human prometaphase chromosomes.
We have constructed ideograms of human prometaphase chromosomes from synchronized and from standard 72-h lymphocyte cultures. G banding was achieved by a trypsin-Giemsa (or Wright's stain) method. In addition to light (white) and dark (black) bands, we have distinguished three different shades of grey. This distinction is essential for proper identification of the increasing number of bands displayed by high-resolution chromosomes. The relative amount of chromatin in each category of staining intensity has been calculated and expressed as 'light value.' The ideograms represent the maximal number of bands discernible with some consistency on prometaphase chromosomes, i.e., 721 euchromatic and 62 'variable' heterochromatic or heteromorphic bands. The ideograms are based on measurements. On selected printed copies of each chromosome derived from different cells and different individuals, the relative width of each band was measured in relation to the length of the respective chromosome arm. The measurements per chromosome were averaged and used for construction of the ideograms. The distance of each border between bands or sub-bands from the centromere has been calculated on a relative scale, with positions 0 at the centromere and 1.0 at the p terminus of q terminus. The numbering system for bands and sub-bands follows the Paris Conference (1971) recommendations.


Optimization of adhesive conditions for neural differentiation of murine embryonic stem cells using hydrogels functionalized with continuous Ile-Lys-Val-Ala-Val concentration gradients.
Stem cell therapies, which aim to restore neurological function after central nervous system injury, have shown increased efficacy when a tissue engineering matrix is implanted with cells compared to implantation of the cells alone. However, much work still needs to be done to characterize materials that can be used to facilitate and direct the differentiation of implanted cells. In the current study, polyethylene glycol hydrogels functionalized with continuous Ile-Lys-Val-Ala-Val (IKVAV) concentration gradients were fabricated and utilized to systematically study and optimize the adhesive conditions for neural differentiation of mouse embryonic stem cells in two- and three-dimensional environments. The results suggest that 570 μM and 60 μM are the optimal IKVAV concentrations for 2D and 3D neural differentiation, respectively, to maximize mRNA expression of neuron-specific markers and neurite extension while minimizing apoptotic activities in cultured cells compared to those exposed to higher IKVAV concentrations. The combinatorial approach presented in this work demonstrates that hydrogels functionalized with bioactive peptides provide a defined and tunable platform that can be employed to characterize and improve culture conditions for superior survival, maturation and integration of implanted cells, leading to enhanced restoration of neurological function for those receiving stem cell therapies after traumatic brain and spinal cord injuries.


Sulfate-reducing bacteria-dominated biofilms that precipitate ZnS in a subsurface circumneutral-pH mine drainage system.
The microbial diversity of ZnS-forming biofilms in 8 degrees C, circumneutral-pH groundwater in tunnels within the abandoned Piquette Zn, Pb mine (Tennyson, Wisconsin, USA) has been investigated by molecular methods, fluorescence in situ hybridization (FISH), and cultivation techniques. These biofilms are growing on old mine timbers that generate locally anaerobic zones within the mine drainage system. Sulfate-reducing bacteria (SRB) exclusively of the family Desulfobacteriaceae comprise a significant fraction of the active microbiota. Desulfosporosinus strains were isolated, but could not be detected by molecular methods. Other important microbial clusters belonged to the beta-, gamma-, and epsilon-Proteobacteria, the Cytophaga/Flexibacter/Bacteroides-group (CFB), Planctomycetales, Spirochaetales, Clostridia, and green nonsulfur bacteria. Our investigations indicated a growth dependence of SRB on fermentative, cellulolytic, and organic acid-producing Clostridia. A few clones related to sulfur-oxidizing bacteria were detected, suggesting a sulfur cycle related to redox gradients within the biofilm. Sulfur oxidation prevents sulfide accumulation that would lead to precipitation of other sulfide phases. FISH analyses indicated that Desulfobacteriaceae populations were not early colonizers in freshly grown and ZnS-poor biofilms, whereas they were abundant in older, naturally established, and ZnS-rich biofilms. Gram-negative SRB have been detected in situ over a period of 6 months, supporting the important role of these organisms in selective ZnS precipitation in Tennyson mine. Results demonstrate the complex nature of biofilms responsible for in situ bioremediation of toxic metals in a subsurface mine drainage system.


Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects.
To determine whether the metabolic benefits of hypoabsorptive surgeries are associated with changes in the gut endocannabinoidome (eCBome) and microbiome. Biliopancreatic diversion with duodenal switch (BPD-DS) and single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) were performed in diet-induced obese (DIO) male Wistar rats. Control groups fed a high-fat diet (HF) included sham-operated (SHAM HF) and SHAM HF-pair-weighed to BPD-DS (SHAM HF-PW). Body weight, fat mass gain, fecal energy loss, HOMA-IR, and gut-secreted hormone levels were measured. The levels of eCBome lipid mediators and prostaglandins were quantified in different intestinal segments by LC-MS/MS, while expression levels of genes encoding eCBome metabolic enzymes and receptors were determined by RT-qPCR. Metataxonomic (16S rRNA) analysis was performed on residual distal jejunum, proximal jejunum, and ileum contents. BPD-DS and SADI-S reduced fat gain and HOMA-IR, while increasing glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) levels in HF-fed rats. Both surgeries induced potent limb-dependent alterations in eCBome mediators and in gut microbial ecology. In response to BPD-DS and SADI-S, changes in gut microbiota were significantly correlated with those of eCBome mediators. Principal component analyses revealed connections between PYY, N-oleoylethanolamine (OEA), N-linoleoylethanolamine (LEA), Clostridium, and Enterobacteriaceae_g_2 in the proximal and distal jejunum and in the ileum. BPD-DS and SADI-S caused limb-dependent changes in the gut eCBome and microbiome. The present results indicate that these variables could significantly influence the beneficial metabolic outcome of hypoabsorptive bariatric surgeries.


Improved immunomagnetic enrichment of CD34(+) cells from umbilical cord blood using the CliniMACS cell separation system.
CD34(+) enrichment from cord blood units (CBU) is used increasingly in clinical applications involving ex vivo expansion. The CliniMACS instrument from Miltenyi Biotec is a current good manufacturing practice (cGMP) immunomagnetic selection system primarily designed for processing larger numbers of cells: a standard tubing set (TS) can process a maximum of 60 billion cells, while the larger capacity tubing set (LS) will handle 120 billion cells. In comparison, most CBU contain only 1-2 billion cells, raising a question regarding the optimal tubing set for CBU CD34(+) enrichment. We compared CD34(+) cell recovery and overall viability after CliniMACS processing of fresh CBU with either TS or LS. Forty-six freshly collected CBU (≤ 36 h) were processed for CD34(+) enrichment; 22 consecutive units were selected using TS and a subsequent 24 processed with LS. Cell counts and immunophenotyping were performed pre- and post-selection to assess total nucleated cells (TNC), viability and CD34(+) cell content. Two-sample t-tests of mean CD34(+) recovery and viability revealed significant differences in favor of LS (CD34(+) recovery, LS = 56%, TS = 45%, P = 0.003; viability, LS = 74%, TS = 59%, P = 0.011). Stepwise linear regression, considering pre-processing unit age, viability, TNC and CD34(+) purity, demonstrated statistically significant correlations only with the tubing set used and age of unit. For CD34(+) enrichment from fresh CBU, LS provided higher post-selection viability and more efficient recovery. In this case, a lower maximum TNC specification of TS was not predictive of better performance. The same may hold for smaller scale enrichment of other cell types with the CliniMACS instrument.


Cancer development in patients hospitalized with systemic lupus erythematosus: A population-level data linkage study.
To explore the association between systemic lupus erythematosus (SLE) with the risk of cancer development and subsequent 5-year mortality in Western Australia (WA). Population-level, data linkage study of SLE patients (n = 2111) and general population comparators (n = 21 110) hospitalized between 1980 and 2014. SLE patients (identified by ICD-9-CM: 695.4, 710.0, and ICD-10-AM: L93.0, M32.0) were nearest matched (10:1) for age, sex, Aboriginality, and temporality. Follow up was from time zero (index SLE hospitalization) to cancer development, death or 31 December 2014. We assessed the risk of cancer development and subsequent 5-year mortality between SLE patients and comparators with univariate and multivariate-adjusted Cox proportional hazards regression models. SLE patients had similar multivariate-adjusted risk (adjusted hazard ratio [aHR] 1.03, 95% confidence interval [CI] 0.93-1.15; p = .583) of cancer development. Cancer development risk was higher in SLE patients <40 years old (aHR 1.58, 95% CI 1.29-1.94; p < .001), and from 1980 to 1999 (aHR 1.16, 95% CI 1.02-1.31; p < .001). SLE patients had higher risk of developing cancer of the oropharynx (aHR 2.13, 95% CI 1.30-3.50), vulvo-vagina (aHR 3.22, 95% CI 1.34-7.75), skin (aHR 1.20, 95% CI 1.01-1.43), musculoskeletal tissues (aHR 2.26, 95% CI 1.16-4.40), and hematological tissues (aHR 1.78 95% CI 1.25-2.53), all p < .05. After cancer development, SLE patients had increased risk of 5-year mortality (aHR 1.31, 95% CI 1.06-1.61); highest in patients <50 years old (aHR 2.03, 95% CI 1.03-4.00), and in those with reproductive system and skin cancers. Hospitalized SLE patients had increased risk of multiple cancer sub-types. Following cancer development, SLE patients had increased risk of 5-year mortality. There is scope to improve cancer prevention and surveillance in SLE patients. Not applicable. This low-risk risk study used de-identified administrative linked health data.


The role of telomerase expression and telomere length maintenance in human and mouse.
The molecular regulation of telomere length has been well elucidated by a series of elegant studies over the past decade. More recently, experimental evidence has accrued that addresses the challenging question of if and how telomere length regulation may contribute to normal human aging or to human disease. Recent studies in mice have provided a mammalian precedent indicating that telomerase deficiency can lead to in vivo dysfunction, most probably as a consequence of progressive telomere shortening. In humans, the evidence that telomere shortening might lead to in vivo dysfunction is far less direct, although the recent description of telomerase deficiency and telomere shortening associated with the DKC syndrome is suggestive of such a link. Methodologies exist and continue to be developed that are increasingly capable of manipulating telomerase activity and telomere length in human cells. It remains to be determined whether scientifically rigorous and (equally important) medically ethical approaches will emerge to directly assess the ability of telomere length modulation to correct functional disorders of human cellular function ex vivo or more challenging still, in vivo.


Facile synthesis of 2D CuO nanoleaves for the catalytic elimination of hazardous and toxic dyes from aqueous phase: a sustainable approach.
This article reports for the first time a facile, green synthesis of 2D CuO nanoleaves (NLs) using the amino acid, namely aspartic acid, and NaOH by a microwave heating method. The amino acid acts as a complexing/capping agent in the synthesis of CuO NLs. This method resulted in the formation of self-assembled 2D CuO NLs with an average length and width of ~300-400 and ~50-82 nm, respectively. The as-synthesized 2D CuO NLs were built up from the primary CuO nanoparticles by oriented attachment growth mechanism. The CuO NLs were characterized by an X-ray diffraction (XRD) method, transmission electron microscopy (TEM), selected-area electron diffraction (SAED) pattern, and Fourier transform infrared spectroscopy (FT-IR). The optical properties were investigated using UV-visible spectroscopy. For the first time, rose bengal and eosin Y dyes were degraded photochemically by solar irradiation using CuO NLs as a photocatalyst. The synthesized CuO NLs act as an efficient photocatalyst in the degradation of rose bengal and eosin Y dye under direct sunlight. The degradation of both the dyes, namely rose bengal and eosin Y, took place within 120 and 45 min, respectively, using CuO NLs as a photocatalyst, whereas commercial CuO, SnO2 quantum dots (QDs), and commercial SnO2 took more than 120 and 45 min for the degradation of rose bengal and eosin Y, respectively. The synthesized CuO NLs showed a superior photocatalytic activity as compared to that of commercial CuO, SnO2 QDs, and commercial SnO2. The reusability of the CuO NLs as a photocatalyst in the degradation of dyes was investigated, and it was evident that the catalytic efficiency decreases to a small extent (5-6 %) after the fifth cycle of operation.


Secretase as a target for Alzheimer's disease.
The amyloid-beta peptide (Abeta) is the major protein component of the characteristic cerebral plaques of Alzheimer s disease (AD), and a large body of evidence supports a pathogenic role for this peptide. Thus, the proteases beta- and gamma-secretase that are responsible for carving Abeta out of its precursor protein are considered prime targets for therapeutic design. beta-Secretase is a membrane-anchored aspartyl protease of the pepsin family, while gamma-secretase is much more complex. gamma-Secretase requires presenilin, a multipass membrane protein that is the site of dozens of missense mutations that alter Abeta formation and cause hereditary AD. Two conserved aspartates in presenilin are required for gamma-secretase activity, and aspartyl protease transition-state analogue inhibitors of gamma-secretase bind directly to presenilins, strong evidence that presenilin is the catalytic component of a novel membrane aspartyl protease. gamma-Secretase appears to be a multi-component complex of integral membrane proteins, and so far presenilin and a single-pass membrane protein called nicastrin have been identified as members of this complex. A closely similar or identical protease activity is essential for a signaling pathway critical for embryogenesis and hematopoiesis, raising concerns about gamma-secretase as a target. The development of potent and selective inhibitors with good pharmacokinetic properties may soon address these concerns.


In vitro tests and ethnopharmacological investigations: wound healing as an example.
In vitro tests are now widely employed in ethnopharmacological research because of ethical reasons and their usefulness in bioactive-guided fractionation and determination of active compounds. For many disease conditions, a variety of in vitro tests can now be employed as the biochemical mechanisms underlying disease and healing processes are understood. Approaches to the in vitro investigations of wound healing processes are exemplified by studies on extracts of Buddleja species and three Ghanaian species Spathodea campanulata, Commelina diffusa and Secamone afzelii. Most studies have been carried out on Buddleja officinalis or Buddleja globosa. The extracts have been shown to have anti-inflammatory and antioxidant properties due to flavonoids, triterpenoids, diterpenoids and caffeic acid derivatives. There appears to a slight effect on proliferation of fibroblasts at lower concentrations, but this was not significant, and higher concentrations appeared to be cytotoxic. Novel findings are the ability of Buddleja globosa leaf extracts to induce differentiation in keratinocytes and to alter the profile of proteins produced by cultured fibroblasts. Extracts also had some effect on lattice contraction. The three Ghanaian species examined show a mixture of antimicrobial and antioxidant activities. The evolution over recent years of tests for wound healing, from in vivo tests to cell-based systems and chemical reactions and on to investigations into effects on secondary messengers and protein expression, is described.


Early warning scores predict outcome in acute pancreatitis.
The Early Warning Score (EWS) is a widely used general scoring system to monitor patient progress with a varying score of 0-20 in critically unwell patients. This study evaluated the EWS system compared with other established scoring systems in patients with acute pancreatitis. EWS scores were compared with APACHE scores, Imrie scores, computed tomography grading scores, and Ranson criteria for 110 admissions with acute pancreatitis. A favorable outcome was considered to be survival without intensive therapy unit admission or surgery. Nonsurvivors, necrosectomy, and critical care admission were considered adverse outcomes. EWS was the best predictor of adverse outcome in the first 24 hours of admission (receiver operating curve, 0.768). The most accurate predictor of mortality overall was EWS on day 3 of admission (receiver operating curve, 0.920). EWS correlated with duration of intensive therapy unit stay and number of ventilated days (P < 0.05) and selected those who went on to develop pancreas-specific complications such as pseudocyst or ascites. EWS of 3 or above is an indicator of adverse outcome in patients with acute pancreatitis. EWS can accurately and reliably select both patients with severe acute pancreatitis and those at risk of local complications.


Photosensitization of DNA by β-carbolines: kinetic analysis and photoproduct characterization.
β-Carbolines (βCs) are a group of alkaloids present in many plants and animals. It has been suggested that these alkaloids participate in a variety of significant photosensitized processes. Despite their well-established natural occurrence, the main biological role of these alkaloids and the mechanisms involved are, to date, poorly understood. In the present work, we examined the capability of three important βCs (norharmane, harmane and harmine) and two of its derivatives (N-methyl-norharmane and N-methyl-harmane) to induce DNA damage upon UV-A excitation, correlating the type and extent of the damage with the photophysical characteristics and DNA binding properties of the compounds. The results indicate that DNA damage is mostly mediated by a direct type-I photoreaction of the protonated βCs after non-intercalative electrostatic binding. Reactive oxygen species such as singlet oxygen and superoxide are not involved to a major extent, as indicated by the only small influence of D(2)O and of superoxide dismutase on damage generation. An analysis with repair enzymes revealed that oxidative purine modifications such as 8-oxo-7,8-dihydroguanine, sites of base loss and single-strand breaks (SSB) are generated by all βCs, while only photoexcited harmine gives rise to the formation of cyclobutane pyrimidine dimers as well.


Hemoglobin Gavello - alpha 2 beta 2 47 (CD6) Asp replaced by Gly. A new hemoglobin variant from Polesine (Italy).
During a survey for abnormal hemoglobins in Polesine (a region north of the Po river, where beta-thalassemia is very frequent) a slow moving variant was noted in a 79-yr-old woman living in Gavello, a small town in the province of Rovigo. Structural studies demonstrated a previously undescribed amino acid substitution, beta47 Asp replaced by Gly. This new variant has been named Hb Gavello.


Platelet Count and Major Bleeding in Patients Receiving Vitamin K Antagonists for Acute Venous Thromboembolism, Findings From Real World Clinical Practice.
The outcome of patients with acute venous thromboembolism (VTE) and abnormal platelet count (PlC) at baseline has not been consistently studied. In real-world clinical practice, a number of patients with abnormal PlC receive vitamin K antagonists (VKAs) to treat acute VTE despite their higher risk of bleeding.We used the Registro Informatizado de Enfermedad TromboEmbólica registry database to compare the rate of major bleeding in patients receiving VKA for long-term therapy of acute VTE according to PlC levels at baseline. Patients were categorized as having very low (<100,000/μL), low (100,000-150,000/μL), normal (150,000-300,000/μL), high (300,000-450,000/μL), or very high (>450,000/μL) PlC at baseline.Of 55,369 patients recruited as of January 2015, 37,000 (67%) received long-term therapy with VKA. Of these, 611 patients (1.6%) had very low PlC, 4006 (10.8%) had low PlC, 25,598 (69%) had normal PlC, 5801 (15.6%) had high PlC, and 984 (2.6%) had very high PlC at baseline. During the course of VKA therapy (mean, 192 days), there were no differences in the duration or intensity (as measured by international normalized ratio levels) of treatment between subgroups. The rate of major bleeding was 3.6%, 2.1%, 1.9%, 2.1%, and 3.7%, respectively, and the rate of fatal bleeding was 0.98%, 0.17%, 0.29%, 0.34%, and 0.50%, respectively. Patients with very low or very high PlC levels were more likely to have severe comorbidities.We found a nonlinear "U-shaped" relationship between PlC at baseline and major bleeding during therapy with VKA for VTE. Consistent alteration of PlC values at baseline suggested a greater frailty.


[Stimulated sweating in order to improve the water-and-salt balance in hemodialysis patients. A case report].
Obtaining the desired dry weight in dialysis patients is challenging once residual diuresis has disappeared, considering the trend of increasing dietary salt intake and shortening dialysis time over the last 40 years. We describe the case of a 55-year-old patient of Sudanese origin, who presented excessive interdialytic weight gain and hypertension on maintenance hemodialysis. After failure of conservative measures, a therapy of daily hot water baths of 30 minutes each on non-dialysis days was introduced. All clinical parameters improved, including potassium profile. In this article, we review the history, pathophysiological mechanisms, efficacy and possible side effects of this interesting, somewhat forgotten technique.


Direct stimulation of adult neural stem/progenitor cells in vitro and neurogenesis in vivo by salvianolic acid B.
Small molecules have been shown to modulate the neurogenesis processes. In search for new therapeutic drugs, the herbs used in traditional medicines for neurogenesis are promising candidates. We selected a total of 45 natural compounds from Traditional Chinese herbal medicines which are extensively used in China to treat stroke clinically, and tested their proliferation-inducing activities on neural stem/progenitor cells (NSPCs). The screening results showed that salvianolic acid B (Sal B) displayed marked effects on the induction of proliferation of NSPCs. We further demonstrated that Sal B promoted NSPCs proliferation in dose- and time-dependent manners. To explore the molecular mechanism, PI3K/Akt, MEK/ERK and Notch signaling pathways were investigated. Cell proliferation assay demonstrated that Ly294002 (PI3K/Akt inhibitor), but neither U0126 (ERK inhibitor) nor DAPT (Notch inhibitor) inhibited the Sal B-induced proliferation of cells. Western Blotting results showed that stimulation of NSPCs with Sal B enhanced the phosphorylation of Akt, and Ly294002 abolished this effect, confirming the role of Akt in Sal B mediated proliferation of NSPCs. Rats exposed to transient cerebral ischemia were treated for 4 weeks with Sal B from the 7th day after stroke. BrdU incorporation assay results showed that exposure Sal B could maintain the proliferation of NSPCs after cerebral ischemia. Morris water maze test showed that delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. Sal B could maintain the NSPCs self-renew and promote proliferation, which was mediated by PI3K/Akt signal pathway. And delayed post-ischemic treatment with Sal B improved cognitive impairment after stroke in rats. These findings suggested that Sal B may act as a potential drug in treatment of brain injury or neurodegenerative diseases.


Impact of presenting stroke severity and thrombolysis on outcomes following urgent carotid interventions.
Carotid interventions are increasingly performed in select patients following acute stroke. We aimed to determine the effects of presenting stroke severity (National Institutes of Health Stroke Scale [NIHSS]) and use of systemic thrombolysis (tissue plasminogen activator [tPA]) on discharge neurological outcomes (modified Rankin scale [mRS]) after urgent carotid endarterectomy (uCEA) and urgent carotid artery stenting (uCAS). Patients undergoing uCEA/uCAS at a tertiary Comprehensive Stroke Center (January 2015 to May 2022) were divided into two cohorts: (1) no thrombolysis (uCEA/uCAS only) and (2) use of thrombolysis before the carotid intervention (tPA + uCEA/uCAS). Outcomes were discharge mRS and 30-day complications. Regression models were used to determine an association between tPA use and presenting stroke severity (NIHSS) and discharge neurological outcomes (mRS). Two hundred thirty-eight patients underwent uCEA/uCAS (uCEA/uCAS only, n = 186; tPA + uCEA/uCAS, n = 52) over 7 years. In the thrombolysis cohort compared with the uCEA/uCAS only cohort, the mean presenting stroke severity was higher (NIHSS = 7.6 vs 3.8; P = .001), and more patients presented with moderate to severe strokes (57.7% vs 30.2% with NIHSS >4). The 30-day stroke, death, and myocardial infarction rates in the uCEA/uCAS only vs tPA + uCEA/uCAS were 8.1% vs 11.5% (P = .416), 0% vs 9.6% (P < .001), and 0.5% vs 1.9% (P = .39), respectively. The 30-day stroke/hemorrhagic conversion and myocardial infarction rates did not differ with tPA use; however, the difference in deaths was significantly higher in the tPA + uCEA/uCAS cohort (P < .001). There was no difference in neurological functional outcome with or without thrombolysis use (mean mRS, 2.1 vs 1.7; P = .061). For both minor strokes (NIHSS ≤4 vs NIHSS >4: relative risk, 1.58 vs 1.58, tPA vs no tPA, respectively, P = .997) and moderate strokes (NIHSS ≤10 vs NIHSS >10: relative risk, 1.94 vs 2.08, tPA vs no tPA, respectively; P = .891), the likelihood of discharge functional independence (mRS score of ≤2) was not influenced by tPA. Patients with a higher presenting stroke severity (NIHSS) had worse neurological functional outcomes (mRS). Patients presenting with minor and moderate strokes were more likely to have discharge neurological functional independence (mRS of ≤2), regardless of whether they received tPA or not. Overall, presenting NIHSS is predictive of discharge neurological functional autonomy and is not influenced by the use of thrombolysis.


Immunologic evidence that staphylococcal alpha toxin is oriented on membranes.
Antibodies to staphylococcal alpha toxin were separated into two distinct populations. One population prevented binding of alpha toxin onto erythrocyte membranes. The other population neutralized after the toxin was bound onto erythrocytes and thereby brought about an indirect hemagglutination reaction. The data suggest that alpha toxin has a membrane-binding region.


Management of Recurrent Aphthous Stomatitis: An Indian Expert Consensus.
Recurrent aphthous stomatitis (RAS) is characterized by painful, oral mucosal ulcers with wide range of prevalence ranging from 2 to 78%. Etiology of RAS is idiopathic and multifactorial. There are numerous gaps in assessment and management of RAS and the absence of guidelines or a consensus document makes the treatment further difficult. The aim of this document is to provide an Indian expert consensus for management of RAS. Experts from different specialties such as Otorhinolaryngology, Oral Medicine/Dentistry and Internal Medicine from India were invited for face to face and online meetings. After a deliberate discussion of current literature, evidence and clinical practice during advisory meetings, experts developed a consensus for management of RAS. We identify that the prevalence of RAS may lie between 2 and 5%. In defining RAS, we advocate three or more recurrences of aphthous ulcers per year as criterion for RAS. Investigation should include basic hematological (complete blood count) and nutritional (serum vitamin B12, and iron studies) parameters. Primary aim of treatment is to reduce the pain, accelerate ulcer healing, reduce the recurrences and improve the quality of life. In treating RAS, initial choice of medications is determined by pain intensity, number and size of ulcers and previous number of recurrences. Topical and systemic agents can be used in combination for effective relief. In conclusion, this consensus will help physicians and may harmonize effective diagnosis and treatment of RAS.


Assessment methods of an undergraduate psychiatry course at a saudi university.
In Arab countries there are few studies on assessment methods in the field of psychiatry. The objective of this study was to assess the outcome of different forms of psychiatric course assessment among fifth year medical students at King Faisal University, Saudi Arabia. We examined the performance of 110 fifth-year medical students through objective structured clinical examinations (OSCE), traditional oral clinical examinations (TOCE), portfolios, multiple choice questions (MCQ), and a written examination. The score ranges in TOCE, OSCE, portfolio, and MCQ were 32-50, 7-15, 5-10 and 22-45, respectively. In regression analysis, there was a significant correlation between OSCE and all forms of psychiatry examinations, except for the MCQ marks. OSCE accounted for 65.1% of the variance in total clinical marks and 31.5% of the final marks (P = 0.001), while TOCE alone accounted for 74.5% of the variance in the clinical scores. This study demonstrates a consistency among the students' assessment methods used in the psychiatry course, particularly the clinical component, in an integrated manner. This information would be useful for future developments in undergraduate teaching.


Prevention of fluphenazine-induced changes in dopaminergic and muscarinic receptors by lithium.
Co-administration of lithium carbonate to mice through their diet prevented the increase in dopamine receptor binding and the decrease in muscarinic receptor binding normally produced in striatum by chronic (12 week) administration of the neuroleptic, fluphenazine. The lithium treatment failed to prevent the muscarinic down-regulation induced by the muscarinic agonist pilocarpine in the hippocampus. These results (along with previous data) suggest that fluphenazine-induced striatal muscarinic receptor down-regulation and its reversal by lithium may be the consequence of changes in dopamine receptors in this brain region.


D14 repeat polymorphism of the asporin gene is associated with primary osteoarthritis of the knee in a Mexican Mestizo population.
Asporin is a novel extracellular matrix protein (ECM) with an important role in the development of osteoarthritis (OA), because it has been reported that functional polymorphisms in the aspartic acid repeat (D) of the asporin gene (ASPN) are associated with susceptibility to OA. This study was planned to investigate the association of the ASPN polymorphism with primary OA of the knee in a Mexican population, including several countryside regions. We conducted a case-control study in which 93 cases with primary OA of the knee and 118 controls were included. Cases included patients > 40 years of age, with a body mass index (BMI) ≤ 27 and a radiologic score for OA of the knee of ≥ 2. Controls were subjects > 40 years of age with a radiologic score of < 2. The D repeat polymorphism was genotyped and logistic regression was developed to evaluate risk magnitude. The D14 allele was more common in our cases and was associated with an increased risk for developing OA, while the frequencies of the remaining alleles did not exhibit differences. Our data suggest that the D14 allele of the ASPN polymorphism could exert an influence on primary OA of the knee etiology in a Mexican Mestizo population.


The human brain networks mediating the vestibular sensation of self-motion.
Vestibular Agnosia - where peripheral vestibular activation triggers the usual reflex nystagmus response but with attenuated or no self-motion perception - is found in brain disease with disrupted cortical network functioning, e.g. traumatic brain injury (TBI) or neurodegeneration (Parkinson's Disease). Patients with acute focal hemispheric lesions (e.g. stroke) do not manifest vestibular agnosia. Thus, brain network mapping techniques, e.g. resting state functional MRI (rsfMRI), are needed to interrogate functional brain networks mediating vestibular agnosia. Hence, we prospectively recruited 39 acute TBI patients with preserved peripheral vestibular function and obtained self-motion perceptual thresholds during passive yaw rotations in the dark and additionally acquired whole-brain rsfMRI in the acute phase. Following quality-control checks, 26 patient scans were analyzed. Using self-motion perceptual thresholds from a matched healthy control group, 11 acute TBI patients were classified as having vestibular agnosia versus 15 with normal self-motion perception thresholds. Using independent component analysis on the rsfMRI data, we found altered functional connectivity in bilateral lingual gyrus and temporo-occipital fusiform cortex in the vestibular agnosia patients. Moreover, regions of interest analyses showed both inter-hemispheric and intra-hemispheric network disruption in vestibular agnosia. In conclusion, our results show that vestibular agnosia is mediated by bilateral anterior and posterior network dysfunction and reveal the distributed brain mechanisms mediating vestibular self-motion perception.


Training providers at a university health center in substance use screening.
NYU MAINSTREAM fellows collaborated with a student health center. An objective structured clinical evaluation (OSCE) was conducted by the fellows for the center's personnel.


Responsive social support serves important functions in clinical communication: Translating perspectives from relationship science to improve cancer clinical interactions.
Patient-clinician interactions are critical to patient-centered care, including in cancer care contexts which are often defined by multiple patient-clinician interactions over an extended period. Research on these dyadic interactions has been guided by perspectives in clinical communication science, but the study of clinical communication has not been fully integrated with perspectives on interpersonal interactions from relationship science research. An overlapping concept in both fields is the concept of responsive socialsupport. In this article, we discuss responsiveness as a concept that offers opportunities for connections between these two disciplines. Next, we focus on how relationship science can be applied to research in clinical settings. We discuss how three areas of relationship science define responsiveness and have potential for extension to clinical communication: (1) (in)visibility of social support, (2) attachment orientations, and (3) shared meaning systems. We also discuss how social biases can impede responsiveness and suggest research avenues to develop ideas and understand potential challenges in connecting these two fields. Many opportunities exist for interdisciplinary theory development that can generate momentum in understanding interpersonal processes in cancer care.


Regulation of mouse oocyte meiotic maturation: implication of a decrease in oocyte cAMP and protein dephosphorylation in commitment to resume meiosis.
Mouse oocytes are reversibly inhibited from resuming meiotic maturation in vitro by cAMP phosphodiesterase inhibitors such as 3-isobutyl-1-methyl xanthine (IBMX) and cAMP analogs such as dibutyryl cAMP (dbcAMP). Oocytes cultured in IBMX-containing medium were transferred to and cultured in IBMX-free medium for various periods of time prior to their return to either IBMX- or dbcAMP-containing medium. Results from these experiments defined a period of time in which oocytes became committed to resuming meiosis. Forskolin, which elevated the intracellular oocyte cAMP concentration, transiently inhibited oocytes from resuming meiosis. Levels of cAMP were determined in oocytes incubated in medium that allows resumption of meiosis. The level of oocyte cAMP decreased significantly during the time in which oocytes become committed to resuming meiosis. This decrease in oocyte cAMP was not observed in oocytes inhibited from resuming meiosis by IBMX. In addition, cAMP levels were determined in preovulatory antral follicles, cumulus cell-oocyte complexes, and oocytes during gonadotropin-induced resumption of meiosis in vivo. A decrease in oocyte cAMP preceded resumption of meiosis as manifested by germinal vesicle breakdown (GVBD). This decrease apparently occurred before or during a period of time in which follicle and cumulus cell cAMP were increasing. Associated with commitment to resume meiosis was a characteristic set of changes in oocyte phosphoprotein metabolism that preceded GVBD. These changes are, to date, some of the first reported biochemical changes that precede GVBD. Results from these experiments are discussed in terms of a possible role cAMP may play in regulation of resumption of meiosis in mammals.


Pirfenidone attenuates the profibrotic contractile phenotype of differentiated human dermal myofibroblasts.
Dysregulated wound healing after burn injury frequently results in debilitating hypertrophic scarring and contractures. Myofibroblasts, the main effector cells for dermal fibrosis, develop from normal fibroblasts via transforming growth factor beta 1 (TGF-β1). During wound healing, myofibroblasts produce extracellular matrix (ECM) proteins, modulate ECM stability, and contract the ECM using alpha smooth muscle actin (α-SMA) in contractile stress fibers. The antifibrotic pirfenidone has previously been shown to inhibit the initial differentiation of fibroblasts into myofibroblasts in vitro and act as a prophylactic measure against hypertrophic scar development in a mouse burn model. To test whether pirfenidone affects differentiated myofibroblasts, we investigated the in vitro effects of pirfenidone treatment after three to five days of stimulation with TGF-β1. In assays for morphology, protein and gene expression, and contractility, pirfenidone treatment produced significant effects. Profibrotic gene expression returned to near-normal levels, further α-SMA protein expression was prevented, and cell contraction within a stressed collagen matrix was reduced. These in vitro results promote pirfenidone as a promising antifibrotic agent to treat existing scars and healing wounds by mitigating the effects of differentiated myofibroblasts.


Revision of margins under frozen section in oral cancer: a retrospective study of involved margins in pT1 and pT2 oral cancers.
Operative assessment of the resection margins by frozen section is routine in many hospitals, but the usefulness of the technique relies on its sensitivity, specificity, sampling errors, and errors associated with relocation of involved margins. Its usefulness is indicated by assessment of overall survival and locoregional recurrence in patients whose margins were initially involved but were successfully revised after frozen section compared with those of the patients whose initially-involved margins were not revised. Patients with consecutive primary pT1, pT2 oral squamous cell carcinoma in whom initial resection resulted in involved margins were selected from the patients treated during the period January 2010 to December 2011 at a tertiary cancer hospital in India. The outcome of patients whose revision of margins after frozen section was successful was compared with that of patients who had "false negative" results after frozen section. Sixty-eight patients had involved margins after initial resection, of whom 42 (62%) had successful revision after frozen section (clear margins group). The remaining 26 patients (38%) had "false negative" results on frozen section, and had no further revision (invaded margins group). Local recurrence was more common in the invaded margins group, although not significantly so in this short retrospective series (p=0.08). The risk of death was greater in patients with local recurrence, hazard ratio (HR) 4.74 (95% CI 1.79 to 12.61, p=0.002). However, overall survival (p=0.73), incidence of locoregional recurrence (p=0.59) and neck recurrence (p=1.0), did not differ significantly between the groups.


MyoD or Myf-5 is required for the formation of skeletal muscle.
Mice carrying null mutations in the myogenic regulatory factors Myf-5 or MyoD have apparently normal skeletal muscle. To address whether these two factors functionally substitute for one another in myogenesis, mice carrying mutant Myf-5 and MyoD genes were interbred. While mice lacking both MyoD and Myf-5 were born alive, they were immobile and died soon after birth. Northern blot and S1 nuclease analyses indicated that Myf-5(-1-);MyoD(-1-) mice expressed no detectable skeletal muscle-specific mRNAs. Histological examination of these mice revealed a complete absence of skeletal muscle. Immunohistochemical analysis indicated an absence of desmin-expressing myoblast-like cells. These observations suggest that either Myf-5 or MyoD is required for the determination of skeletal myoblasts, their propagation, or both during embryonic development and indicate that these factors play, at least in part, functionally redundant roles in myogenesis.


Spinal epidural abscess in COVID-19 patients.
To report the peculiarity of spinal epidural abscess in COVID-19 patients, as we have observed an unusually high number of these patients following the outbreak of SARS-Corona Virus-2. We reviewed the clinical documentation of six consecutive COVID-19 patients with primary spinal epidural abscess that we surgically managed over a 2-month period. These cases were analyzed for what concerns both the viral infection and the spinal abscess. The abscesses were primary in all cases indicating that no evident infective source was found. A primary abscess represents the rarest form of spinal epidural abscess, which is usually secondary to invasive procedures or spread from adjacent infective sites, such as spondylodiscitis, generally occurring in patients with diabetes, obesity, cancer, or other chronic diseases. In all cases, there was mild lymphopenia but the spinal abscess occurred regardless of the severity of the viral disease, immunologic state, or presence of bacteremia. Obesity was the only risk factor and was reported in two patients. All patients but one were hypertensive. The preferred localizations were cervical and thoracic, whereas classic abscess generally occur at the lumbar level. No patient had a history of pyogenic infection, even though previous asymptomatic bacterial contaminations were reported in three cases. We wonder about the concentration of this uncommon disease in such a short period. To our knowledge, cases of spinal epidural abscess in COVID-19 patients have not been reported to date. We hypothesize that, in our patients, the spinal infection could have depended on the coexistence of an initially asymptomatic bacterial contamination. The well-known COVID-19-related endotheliitis might have created the conditions for retrograde bacterial invasion to the correspondent spinal epidural space. Furthermore, spinal epidural abscess carries a significantly high morbidity and mortality. It is difficult to diagnose, especially in compromised COVID-19 patients but should be kept in mind as early diagnosis and treatment are crucial.


The association between cortisol:C-reactive protein ratio and depressive fatigue is a function of CRP rather than cortisol.
Hormonal and inflammatory factors have been suggested as potentially influencing depressive state and depressive symptoms, but rarely compared for their relative contribution to these states and to specific depressive symptoms. This study examined cortisol:C-reactive protein (CRP) ratio, plus cortisol and CRP separately, as correlates of global depression and fatigue-related depression. One hundred and twenty-six community volunteers from rural Australia provided saliva and serum samples, and also completed a depression inventory. There was a significant correlation between cortisol:CRP ratio and depression-related fatigue, and this resolved to the effects of CRP rather than cortisol. Most of the variance in this association came from patients who were "depressed", and there were no significant gender associations. Inflammation, rather than HPA-axis activity, was associated with depression-related fatigue, supporting a model that places inflammation as a contributor to one of the major symptoms and predictors of depression. Individualization of therapy for depression-related fatigue in chronically stressed or physically ill patients might benefit from future research into cytokine therapy.


Fluoroscopy guided retrograde ureteral stent insertion in patients with a ureteroileal urinary conduit: method and results.
We evaluated retrograde double pigtail stent placement in patients with ureteroileal anastomosis. Procedures were performed under digital C-arm fluoroscopic guidance and the patient under sedation analgesia. Radiography of the conduit was done to delineate urinary diversion anatomy and identify ureteral reflux. A purpose designed, angled tip catheter was used to direct a straight glide wire across the ureteroileal anastomosis. The glide wire was exchanged for a stiff guide wire for stent placement. We retrospectively evaluated the clinical records of 7 men and 5 women with a mean age of 54.3 years in a 7-year period. In 11 patients a new stent was placed because of ureteroileal stricture in 5, anastomotic leakage in 3, ureterolithiasis in 2 and recurrent malignancy in 1. New stent placement was successful in 10 of the 11 patients (90.9%, 13 of 16 ureters or 81.3%). Stent placement was successful in the 8 ureters in which reflux was noted on radiography of the conduit and in 5 of the 9 (55.6%) in which no reflux was noted. Stent replacement was accomplished in all 22 ureters (6 patients) in which it was attempted. Mean radiological screening time for new stent placement was 13.3 minutes (range 4.7 to 19.7), while for exchange it was 6.4 minutes (range 0.8 to 15.1). There were no immediate complications. This technique represents a useful approach to the ureter and should be considered an alternative to percutaneous nephrostomy and surgical revision. The approach is also useful for other ureteral procedures, including stone or migrated stent retrieval.


Evaluation for coastal reclamation feasibility using a comprehensive hydrodynamic framework: A case study in Haizhou Bay.
Coastal reclamation (CR) is a prevailing approach to solve the contradiction between the land shortage and the growing demand of living space for human beings. In general, environmental impact assessment (EIA) focuses on evaluating the feasibility of individual coastal reclamation project (CRP). However, few studies have investigated the cumulative effect of multiple CRPs on surrounding environment. In this study, an integrated framework based on coastal hydrodynamics was established, and then applied to the feasibility evaluation of multiple CRPs for future coastal management in Haizhou Bay, China. The results indicated that three out of five reclamation projects were feasible and the remaining two were forbidden in the study area, whereas EIA approves of all the CRPs. It provides a scientific reference for effective management of coastal reclamation and future environmental impact researches when new CRPs are proposed.


Endoscopic Endonasal Transpterygoid Approach for Resection of Carotid Sympathetic Plexus Schwannomas: A Cadaveric Stepwise Dissection, Technical Nuances and Surgical Outcomes.
Carotid sympathetic plexus (CSP) schwannomas are rare brain tumors located in a complex site around the cavernous sinus and carotid canal in the petrous bone. This study describes 3 cases of CSP schwannomas that underwent surgical removal of the tumor through an endoscopic endonasal transpterygoid approach. Between 2016 and 2021, 3 cases of CSP schwannomas were treated using an endoscopic endonasal transpterygoid approach. Preoperative tumor size, preoperative and postoperative symptoms, internal carotid artery (ICA) displacement, extent of tumor resection, intraoperative findings showing tumor origin, and surgical complications were evaluated in all patients. Two tumors were in the petrous region, and the other one was in both the petrous and cavernous regions. The median tumor diameter was 41.3 mm. In the 3 cases, the ICA was displaced to the superolateral side, the anterolateral side, and the posterior side, respectively. Near-total resection was achieved in all 3 cases via an endoscopic endonasal transpterygoid approach. There were no endonasal postoperative complications, and the cranial nerve disability improved in all 3 patients at 1-year follow-up. The surgical technique for CPS schwannoma using an endoscopic endonasal transpterygoid approach may be a viable option because endoscopy has been proven to offer better intraoperative visualization and reduce postoperative discomfort for patients. Tumors located medial and inferior to the ICA pars cavernous sinus or anterior, inferior, and medial to the paraclival ICA are ideal candidates for surgery using this endoscopic approach.


Determining the Accuracy of Self-Report Versus Informant-Report Using the Conners' Adult ADHD Rating Scale.
The present research examined the validity of self-report versus informant-report in relation to a performance-based indicator of adult ADHD. Archival data from 118 participants (52 males, 66 females) were used to compare Conners' Adult ADHD Rating Scale-Self-Report: Long Format (CAARS-S:L) and Conners' Adult ADHD Rating Scale-Observer Report: Long Format (CAARS-O:L) with discrepancy scores calculated between the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III) Verbal Comprehension Index - Working Memory Index (VCI - WMI) and Perceptual-Organizational Index - Processing Speed Index (POI - PSI) scaled scores. Neither the self- nor informant-report formats of the CAARS were better predictors of discrepancies between WAIS-III Index scores. Intercorrelations between the CAARS-S:L and CAARS-O:L revealed generally higher correlations between the same scales of different formats and among scales measuring externally visible symptoms. Furthermore, regression analysis indicated that both the CAARS-S:L and CAARS-O:L clinical scales contributed a significant proportion of variance in WAIS-III VCI - WMI discrepancy scores (14.7% and 16.4%, respectively). Results did not establish greater accuracy of self-report versus informant-report of ADHD symptomatology, rather demonstrate the need for multimodal assessment of ADHD in adults.


Autocatalytic synthesis of a tetranucleotide analogue.
As an approach to the study of the kind of chemical process that might have contributed to the origin of life, attempts have been made to develop purely chemical systems in which oligonucleotides self-replicate. Although performed oligonucleotides have been shown to facilitate the formation of their complements from activated mononucleotides, only a restricted range of oligomers are efficient templates and it will clearly be difficult to find a pair of complementary oligomers each of which will facilitate the formation of the other. Many of the difficulties facing the development of a self-replicating system could be overcome by using a pair of complementary substrate molecules that condense together more easily than ribonucleotides. It would also be helpful if each substrate molecule contained equal numbers of purine and pyrimidine bases as, otherwise, there is a tendency for purines to be overrepresented in the products. We have therefore explored the chemistry of 3'-amino-3'-deoxynucleotides and their dimers. We report here that the tetranucleoside triphosphoramidate GNHpCNHpGNHpCN3 acts as a template to catalyse the condensation of GNHpCNH2 and pGNHpCN3, forming further molecules of the template. The system is therefore autocatalytic, and in accordance with elementary theory the amount of product made increases with the square root of the template concentration.


Revisiting the design of minimal and no-preparation veneers: a step-by-step technique.
The concept of minimal preparation is more than 25 years old. Interest in conservative treatments is being revisited as dentistry embraces thinner ceramic veneers and adhesive bonding agents that keep preparations in enamel. Experience and professional knowledge help determine appropriate treatments based on patients' clinical situations and esthetic demands. This article reviews the veneer modality, its role as a conservative treatment, and the protocol to be implemented to ensure proper treatment planning and material selection.


Wax apple (Syzygium samarangense) fruit extract ameliorates endothelial dysfunction and liver damage in high cholesterol diet-fed rats.
Wax apple fruit (Syzygium samarangense) is one of the most popular tropical fruit in Asia, and contains several essential nutrients. Therefore, this study explored the effects of the wax apple fruit extract on a high-cholesterol diet-induced vascular endothelial dysfunction and fatty liver in rats. Male Sprague Dawley rats were fed a diet with 1.5% cholesterol (HCD) for 8 weeks, and were given wax apple fruit extract (50 and 100 mg/kg/day) orally for the last 4 weeks. After 8 weeks, blood sample, thoracic aorta, and liver were collected and processed for biochemical and histological analysis. Additionally, vascular endothelial function and the protein expression of oxidative stress markers in aortae were evaluated. Wax apple reduced serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), but increased high-density lipoprotein cholesterol (HDL-C) levels. Furthermore, the liver levels of TG and TC were reduced in wax apple-treated hypercholesterolemic rats. Histological studies revealed that wax apple ameliorated HCD-induced morphologic changes of aortic and liver tissues of rats. In aortic tissues, the impaired endothelium-dependent responses to acetylcholine, the reduced nitric oxide (NO) contents, the elevated endothelin (ET)-1 contents, and the increased expression of NADPH oxidase subunit p47phox and 4-hydroxynonenal in HCD-fed rats were reversed by wax apple treatment. These results suggest that oral administration of wax apple improves vascular dysfunction and damage in hypercholesterolemic rats possibly through increasing NO bioavailability, decreasing ET-1 levels and reducing oxidative stress. Furthermore, wax apple ameliorates the HCD-induced fatty liver in rats.


Occult Primary with Cervical Secondary-Role of CT Scan and Evaluation Under Anesthesia.
The potential of CT, MRI or both to detect a primary tumor ranges from 9.3 to 23% rising to 60% when suspicious radiological findings direct subsequent endoscopic biopsies (Zhuang et al. in Mol Clin Oncol 2:917-922, 2014). Prospective case Study. To know the sensitivity, specificity accuracy rate and P value of CT scan and upper aero digestive tract endoscopy with palpation of nasopharynx and oropharynx to search the primary site of cancer. 53 patient of occult primary with FNAC proved metastatic squamous cell carcinoma were evaluated to find out the sensitivity, specificity, accuracy rate and P value of imaging study and rigid endoscopic examination of upper aero digestive tract with through palpation of oropharynx, nasopharynx and evaluation under anesthesia (EUA). Punch biopsies were taken from suspicious areas and sent for histopathology examination (HPE). Taking HPE as a gold standard (Ishak et al in Rawal Med J 35:209-213, 2010) sensitivity of both EUA and imaging was found to be 100%, Specificity and diagnostic accuracy of EUA and imaging were 96.77, 83.87, 98.11 and 90.57% respectively. P value was <0.0000001 which is highly significant.


Plasma beta-thromboglobulin as a measure of platelet activity. Effect of risk factors and findings in ischemic heart disease and after acute myocardial infarction.
The plasma concentration of beta-thromboglobulin (BTG), a platelet-specific protein released during platelet aggregation, is considered a sensitive marker of in vivo platelet activity. The mean plasma level in 133 asymptomatic individuals was 32.3 +/- 1.1 ng/ml, and there was no difference between those with no risk factors (32.2 +/- 1.2 ng/ml, n = 56), those who smoked (31.8 +/- 1.8 ng/ml, n = 45), those with hyperlipidemia (32.8 +/- 1.7 ng/ml, n = 15), and those exposed to both of these risk factors (34.1 +/- 2.7 ng/ml, n = 17). The mean plasma BTG level in 104 patients with symptomatic ischemic heart disease was significantly elevated (40.9 +/- 1.4 ng/ml, p less than 0.01), but there was considerable overlap with normal levels. Although no difference was found between patients with no risk factors (38.1 +/- 4.0 ng/ml, n = 13) and those with only 1 risk factor (37.0 +/- 1.8 ng/ml, n = 44), patients with 2 or more risk factors ahd a significantly elevated plasma BTG level (45.2 +/- 2.2 ng/nl, n = 47, p less than 0.01). It is concluded that risk factors themselves do not increase platelet activity, but that patients with vascular disease have activated platelets that may contribute to the progression of the disease. Plasma BTG was also measured serially for 10 days in 29 patients after hospitalization with acute ischemic cardiac pain. Although the median plasma level was elevated above normal there were no acute changes in plasma BTG after either acute infarction (n = 22) or acute ischemia (n = 7), except in 2 patients in whom pericardial friction rubs developed. Thus, measurement of systemic plasma BTG did not detect platelet involvement in acute coronary occlusion or acute ischemia.


Analysis of liver transplantation outcome in patients with MELD Score > or = 30.
Since July 2006, the liver graft allocation has been changed from the waiting time to the Model for End-stage Liver Disease (MELD), prioritizing the sickest patients, who have a higher risk of dying on the waiting list, and sometimes in such poor clinical condition that it compromises transplantation outcomes. The aim of this study was to analyze the impact of a MELD score > or = 30 on 30-day survival after liver transplantation (OLT). We prospectively collected the data on 178 liver transplants on 163 patients performed from March 2003 to August 2007. The subjects were divided in two groups according to their MELD scores: group 1, MELD > or = 30 (n = 15) and group 2, MELD < 30 (n = 96). The groups were compared with regard to hospital and intensive care unit (ICU) length of stay, intraoperative blood products transfusion, early survival (30 days), and need for retransplantation. We excluded, patients with prioritization criteria, those receiving extra points for any special situation, and six other patients without significant data for MELD calculation (of whom only one has died after transplantation). Patients under a "special situation" were those with hepatocelular carcinoma, hepatopulmonary syndrome, and metabolic diseases, who initially received a MELD/PELD score 20, and 24, and 29. The mean MELD score at group I was 34 (range, 30 to 42), and for group II it was 16 (range, 6 to 29). Group I displayed a mean hospital length of stay of 24 days (4 to 155), with 12.60 days (ranges, 1 to 103) in the ICU versus 15.55 (range, 1 to 48) and 5.13 (range, 1 to 45) days, respectively, for group II. The need for blood component transfusions were greater in group I; 25.28% of patients in group II did not receive any transfusion during the entire inpatient period. There were nine retransplants in group II, and none in group I. The 30-day survivals were 93.3% for group I and 84.37% for group II. Besides the increased complexity of these sickest patients, there was no negative impact on early survival rates.


Androgen synthesis and aromatization by equine corpus luteum microsomes.
Whereas mare corpus luteum does not produce androgens or estrogens in vivo, the incubation of mare corpus luteum microsomes with progesterone and NADPH resulted in 17 alpha-hydroxyprogesterone and estrogen production with a small yield of androstenedione. In the presence of an aromatase inhibitor (4-hydroxyandrostenedione), 17 alpha-hydroxyprogesterone and androstenedione were accumulated. Aromatization of testosterone and androstenedione occurred via stereospecific loss of the 1 beta, 2 beta hydrogen atoms and was inhibited by MgCl2, KCl, and EDTA. The Km of estrogen synthetase from equine corpus luteum for testosterone was 18.5 +/- 2.7 nM and for androstenedione was 11.5 +/- 1.5 nM. 19-Norandrogens were aromatized with a slightly higher efficiency than were androgens, but the affinity of the aromatase was lower for 19-norandrogens than for androgens. Our results suggest that aromatases from equine testis and corpus luteum are closely related enzymes. On the other hand, the question arises as to the relationship among the cell origin, the synthetizing abilities, and in vivo production of the corpus luteum in different mammalian species.


Use of photoretinoscopy as a screening technique in the assessment of anisometropia and significant refractive error in infants/toddlers/children and special populations.
The presence of significant refractive error and/or anisometropia can produce an irreversible decrease in visual function if not detected and treated at an early age. The general consensus is that the earlier a problem is detected, the easier the process of remediation. The authors have examined photoretinoscopy as a means of screening infant/toddlers and/or nonverbal persons for refractive anomalies. Fifty adults and fifty infants/toddlers/children were photographed and the estimated refractive error from review of the pictures was compared to the refractive error obtained from retinoscopy. The results indicate that photoretinoscopy is an effective screening procedure for the detection of significant refractive error and is extremely sensitive to anisometropia.


The EEG, brain function, and Thomson's sampling theory.
If the EEG is regarded as a measure of functional organisation in the brain, it may yet be possible to use it as an independent variable in psychological studies. The method of Maxwell et al. (1974) suggest how this relationship may be quantified. These authors develop the hypothesis that EEG power is proportional to p, the number of brain components involved in cognition. However, evidence is reviewed here to suggest an alternative hypothesis for the case of EEG alpha activity, namely that power is proportional to (1--p).


The function of the psoas major muscle: passive kinetics and morphological studies using donated cadavers.
This study was carried out to analyze the phasic heterogeneity in the function of the psoas major muscle (PMM) depending on the flexion angle at the hip joint. The study design was a passive kinetic experiment using 25 osteoligamentous specimens with the PMM tendon. We measured the flexion angle of the hip joint where the PMM tendon loses contact with the femoral head and pelvic surface. Ten osteoligamentous specimens were used for additional measurements of the tensile force and pressure exerted on the PMM and/or at the bone-tendon interface when the PMM tendon was gently pulled in line with the PMM origin in the supine position. The tension loading the PMM tendon was measured at seven different angled positions of hip joint flexion (0 degrees, 15 degrees, 30 degrees, 45 degrees, 60 degrees, 75 degrees, and 90 degrees ), using a load cell attached to a traction appliance. The pressure was measured at each of eight sites along the long axis of the PMM, using a pressure sensor. The PMM tendon lost contact with the femoral head at angled positions of 14 degrees (average) hip flexion, and lost contact with the iliopectineal eminence at positions of 54 degrees (average). The tension was stronger at angled positions of 0 degrees -30 degrees at the hip joint. The pressure on the femoral head and pelvic surface were stronger at positions of 0 degrees -30 degrees at the hip joint. The pressure on the femoral head was strongest at a hip flexion of 0 degrees. The tensile force markedly decreased at 45 degrees -60 degrees flexion at the hip joint, while the pressure on the femoral head gradually reduced to zero in the same phases. We concluded that the PMM works phasically: (1) as an erector of the lumbar vertebral column, as well as a stabilizer of the femoral head in the acetabulum at 0 degrees -15 degrees flexion at the hip joint; (2) less as a stabilizer, in contrast to maintaining its erector action, at 15 degrees -45 degrees; and (3) as an effective flexor of the lower extremity, at 45 degrees -60 degrees.


A problem-oriented independent studies programme in basic medical sciences.
An independent studies programme (ISP) in the basic medical sciences has been developed at the University of Rochester School of Medicine and Dentistry which involves sixteen students as a learning team working with ten medical teachers as a teaching team. The teachers serve as guides to learning rather than as sources of expert information and function as generalists in their educational roles. The programme, which is preferred by some students, has provided an alternative to the lecture-laboratory-conference format of the traditional curriculum. Some of the advantages of such an ISP are discussed and its effectiveness assessed.


Impact of COVID-19 pandemic on acute stroke care: facing an epidemiological paradox with a paradigm shift.
During the coronavirus disease 2019 (COVID-19) outbreak, a decrease of stroke's hospital admissions and reperfusion therapy has been reported worldwide. This retrospective observational study assessed the volume of stroke cases managed in the Emergency Department (ED) and reperfusion therapies in an Italian stroke network with a high incidence of COVID-19, particularly to evaluate if the in-hospital rerouting and the switch from a drip-and-ship to a mothership model could assure an adequate volume of acute treatments. We compared data from March 2020 with those from previous years and formulated five PICO questions regarding (1) incidence of stroke cases in the ED; (2) relation between stroke cases and COVID-19; (3) differences in the number of reperfusion therapies, (4) in the call-to-needle and door-to-needle times for intravenous thrombolysis, and (5) in the call-to-groin and door-to-groin times for thrombectomy. We found (1) a 28% decreased of confirmed stroke cases managed in the ED, (2) a negative correlation between stroke cases in ED and COVID-19 progression (rs = - .390, p = .030), and (3) a similar number of treatments in March 2020 and March 2019. The adoption of the mothership model (4) did not delay alteplase infusion (median call-to-needle p = .126, median door-to-needle p = .142) but led to (5) a significant reduction in median call-to-groin (p = .018) and door-to-groin times (p = .010). The "hospital avoidance" of stroke patients during the "stay-at-home" appeals needs to be considered for future public health campaigns. A prompt reorganization of the stroke network can guarantee optimal performances at times of crisis.


Testosterone induces up-regulation of mitochondrial gene expression in murine C2C12 skeletal muscle cells accompanied by an increase of nuclear respiratory factor-1 and its downstream effectors.
The reduction in muscle mass and strength with age, sarcopenia, is a prevalent condition among the elderly, linked to skeletal muscle dysfunction and cell apoptosis. We demonstrated that testosterone protects against H2O2-induced apoptosis in C2C12 muscle cells. Here, we analyzed the effect of testosterone on mitochondrial gene expression in C2C12 skeletal muscle cells. We found that testosterone increases mRNA expression of genes encoded by mitochondrial DNA, such as NADPH dehydrogenase subunit 1 (ND1), subunit 4 (ND4), cytochrome b (CytB), cytochrome c oxidase subunit 1 (Cox1) and subunit 2 (Cox2) in C2C12. Additionally, the hormone induced the expression of the nuclear respiratory factors 1 and 2 (Nrf-1 and Nrf-2), the mitochondrial transcription factors A (Tfam) and B2 (TFB2M), and the optic atrophy 1 (OPA1). The simultaneous treatment with testosterone and the androgen receptor antagonist, Flutamide, reduced these effects. H2O2-oxidative stress induced treatment, significantly decreased mitochondrial gene expression. Computational analysis revealed that mitochondrial DNA contains specific sequences, which the androgen receptor could recognize and bind, probably taking place a direct regulation of mitochondrial transcription by the receptor. These findings indicate that androgen plays an important role in the regulation of mitochondrial transcription and biogenesis in skeletal muscle.


[Experimental protection with tyrothrizin against herpes simplex virus infections in mice].
Using 12-day old baby mice, strain NMRI, the LD50 of a Herpes simplex virus type 1 was calculated. Intragastric inoculation of the mice was carried out applying a stomach tube. Lethality of the mice was reduced from 67% to 23% by pre-incubation of the virus suspension for 30 min at 37 degrees C in the presence of 0.2 mg tyrothricin/ml. The effect was statistically significant and could be produced only after direct contact between tyrothricin and virus. Under the same conditions there was no effect of lysozyme against virus infectivity.


Analysis of arrhythmic potential of embryonic stem cell-derived cardiomyocytes.
By directed differentiation using the hanging drop method, cardiomyocytes (CMs) can be derived from mouse embryonic stem cells. These spontaneously active CMs can then be isolated from the embryoid bodies and studied electrophysiologically for analysis of arrhythmic potential. This method is particularly advantangeous for studying CMs derived from genetically modified stem cells, in which mutations result in embryonic lethality.


Heterogeneity of hypothalamic rewarding sites possibly involved in temperature regulation.
The effect of hypothalamic self-stimulation on colonic temperature and the effect of cold and warm environments on self-stimulation rate were assessed in 97 rats. In most of the rats, self-stimulation induced a rise in colonic temperature. However, in seven animals the reverse occurred. In the whole sample self-stimulation was significantly depressed by the warm environment. The cold environment facilitated self-stimulation at some placements and inhibited it at others. From the first six placements most facilitated by the cold environment five were also most inhibited by the warm environment. When allowed to self-stimulate in the cold environment high rate self-stimulators had a significantly lower colonic temperature than when they self-stimulated at 25 degrees C while low rate self-stimulators had the same or a higher colonic temperature. Body temperature changes induced by self-stimulation on the one hand, and the effects of the cold and warm environments on self-stimulation on the other appear to be independent one from another. The results suggest that among distinct types of hypothalamic rewarding loci a few might be specifically related to temperature regulation.


Restoring vision using optogenetics without being blind to the risks.
Retinit is pigmentosa is an incurable degenerative disease that causes loss of light-sensitive cells in the retina and leads to severe vision impairment. The development of optogenetics has created great hype around its potential to treat retinitis pigmentosa by the introduction of light-sensitive proteins into other neural cells in the retina. The first-in-human studies of optogenetic treatment for this disease have recently been reported (NCT02556736 and NCT03326336). The treatment involves irreversible gene therapy and requires access to specially designed goggles to deliver light to the treated eye. These highly innovative and high-profile clinical trials raise numerous ethical issues that must be addressed during the early phases of research and clinical testing to ensure trial participants are treated fairly and can provide appropriate informed consent.


[Quality evaluation of Harpagophyton capsules].
Six samples of capsules Harpagophytum procumbens of different commercial origin have been examined by methods of the french Pharmacopoeia and measurement of the harpagoside by HPLC. The study showed variability of the quality of not pharmaceutical products.


Treatment selection in depression: the role of clinical judgment.
The selection of treatment in depression should be filtered by clinical judgment, taking into consideration a number of clinical variables, such as characteristics and severity of depressive episode, co-occurring symptomatology and problems (not necessarily syndromes), medical comorbidities, and patient's history with particular reference to treatment of previous episodes, if they occurred. Such information should be placed within what is actually available in the specific treatment setting and should be integrated with the patient's preferences. In clinical practice, on the one end, clinical decisions may be affected by irrational factors (eg, exposure to massive doses of pharmaceutical propaganda or familiarity with a specific psychotherapy or medication). On the other end, psychiatrists often use sophisticated forms of clinical judgment that are suitable for clinical challenges but are not addressed by current research strategies. There is increasing awareness of the need of differentiating depression according to specific subtypes, yet clear-cut indications for these subdivisions are still missing. The role of biomarkers, despite many promising research strategies, is still far from offering reliable clinical guidance. In the meanwhile, there are important indications that come from clinical research. Treatment of depression may be conceptualized as integrated treatment of the various components of symptomatology, lifestyle, and social adjustment. An integrated treatment model, discussed in detail elsewhere, is realistic and practical, and not just idealistic. It may be frustrating to those who like oversimplified biological models; however, approaches that integrate clinimetrics, patient priorities, lifestyle issues, and clinical judgment are more in keeping with the complexity of clinical situations and the challenge of depression treatment.


Genetic selection for growth drives differences in intestinal microbiota composition and parasite disease resistance in gilthead sea bream.
The key effects of intestinal microbiota in animal health have led to an increasing interest in manipulating these bacterial populations to improve animal welfare. The aquaculture sector is no exception and in the last years, many studies have described these populations in different fish species. However, this is not an easy task, as intestinal microbiota is composed of very dynamic populations that are influenced by different factors, such as diet, environment, host age, and genetics. In the current study, we aimed to determine whether the genetic background of gilthead sea bream (Sparus aurata) influences the intestinal microbial composition, how these bacterial populations are modulated by dietary changes, and the effect of selection by growth on intestinal disease resistance. To that aim, three different groups of five families of gilthead sea bream that were selected during two generations for fast, intermediate, or slow growth (F3 generation) were kept together in the same open-flow tanks and fed a control or a well-balanced plant-based diet during 9 months. Six animals per family and dietary treatment were sacrificed and the adherent bacteria from the anterior intestinal portion were sequenced. In parallel, fish of the fast- and slow-growth groups were infected with the intestinal parasite Enteromyxum leei and the disease signs, prevalence, intensity, and parasite abundance were evaluated. No differences were detected in alpha diversity indexes among families, and the core bacterial architecture was the prototypical composition of gilthead sea bream intestinal microbiota, indicating no dysbiosis in any of the groups. The plant-based diet significantly changed the microbiota in the intermediate- and slow-growth families, with a much lower effect on the fast-growth group. Interestingly, the smaller changes detected in the fast-growth families potentially accounted for more changes at the metabolic level when compared with the other families. Upon parasitic infection, the fast-growth group showed significantly lower disease signs and parasite intensity and abundance than the slow-growth animals. These results show a clear genome-metagenome interaction indicating that the fast-growth families harbor a microbiota that is more flexible upon dietary changes. These animals also showed a better ability to cope with intestinal infections. Video Abstract.


[Organizing printed copies from on-line scientific journals].
With recent advances in reference management software, bibliographic data can be down-loaded directly from PubMed and other databases. And then, the down-loaded full text of an article is immediately printed out. However, it is still a hassle to store, organize and search hard copies accumulated in piles.


Clinical performance of a novel bioprosthetic surgical aortic valve in a German high-volume center.
Bioprosthetic surgical aortic valve replacement (SAVR) is increasingly adopted in younger patients. We aimed to analyze mid-term follow-up data after SAVR to assess the performance of the prosthesis. Data were collected from a single-center series of 154 patients, who underwent SAVR with a bioprosthetic heart valve with the RESILIA tissue at our Heart Centre in Siegburg. All procedural and midterm patient outcomes were documented. Patients had a mean age of 56.8 ± 9.9 years, 35.7% were female, and the mean logistic European system for cardiac operative risk evaluation (EuroSCORE) was 3.4 ± 3.6%. Diabetes (12.3%), atrial fibrillation (10.4%), and chronic obstructive pulmonary disease (COPD) (5.8%) were common comorbidities. The mean surgery duration was 163.8 ± 73.4 min, with the 23 mm (34.4%) and 25 mm (33.8%) heart valves being most frequently implanted. At 3-year follow-up, mean pressure gradient was 13.9 ± 5.9 mmHg, peak gradient was 23.6 ± 7.7 mmHg, and effective orifice area (EOA) was 1.9 ± 0.4 cm². No patient died during the operation, 3 (2.1%) patients within 30 days, and 4 (2.7%) thereafter with an overall mortality of n = 7. Of the surviving patients, 97.8% were in New York Heart Association (NYHA) class I/II and none had structural valve deterioration (SVD). Results of our single-center study indicate favorable procedural outcomes. The safety outcomes confirm preliminary earlier results of this novel bioprosthesis but include more patients and a longer midterm follow-up.


Immunity to Environmental Crime, Harm and Violence: An Ongoing Pandemic and a Possible Narrative Vaccine.
As of June 2020, there have been at least 2,540 mass shootings since the Sandy Hook Elementary School shooting in Newtown, CT, on December 14, 2012. Some have suggested that the repeated trauma of these massacres has created a collective "emotional numbness," lessening our empathy. This article asks whether a similar phenomenon is occurring with respect to environmental crime and harm. It considers whether we have developed "compassion fatigue" regarding environmental violence and contemplates a "workout regimen" for empathy for Gaia's suffering. In so doing, it seeks to engage with emerging work in the penumbra of narrative criminology and green cultural criminology.


Composite Module Analyst: identification of transcription factor binding site combinations using genetic algorithm.
Composite Module Analyst (CMA) is a novel software tool aiming to identify promoter-enhancer models based on the composition of transcription factor (TF) binding sites and their pairs. CMA is closely interconnected with the TRANSFAC database. In particular, CMA uses the positional weight matrix (PWM) library collected in TRANSFAC and therefore provides the possibility to search for a large variety of different TF binding sites. We model the structure of the long gene regulatory regions by a Boolean function that joins several local modules, each consisting of co-localized TF binding sites. Having as an input a set of co-regulated genes, CMA builds the promoter model and optimizes the parameters of the model automatically by applying a genetic-regression algorithm. We use a multicomponent fitness function of the algorithm which includes several statistical criteria in a weighted linear function. We show examples of successful application of CMA to a microarray data on transcription profiling of TNF-alpha stimulated primary human endothelial cells. The CMA web server is freely accessible at http://www.gene-regulation.com/pub/programs/cma/CMA.html. An advanced version of CMA is also a part of the commercial system ExPlaintrade mark (www.biobase.de) designed for causal analysis of gene expression data.


Clinical symptoms and cognitive impairment associated with male schizophrenia relate to plasma manganese superoxide dismutase activity: a case-control study.
Several lines of evidence suggest that excessive reactive oxygen species-induced oxidative damage may underlie cognitive impairment in psychiatric disorders. A growing body of evidence show that oxidative damage may relate to the range of cognitive deficits associated with schizophrenia. In this study we examine one of the primary antioxidant defense enzymes manganese superoxide dismutase (MnSOD), and whether it relates to cognitive deficits in schizophrenia. We recruited 185 chronic male schizophrenia patients and 132 male controls and compared results from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and plasma MnSOD activity between groups. Symptom severity in patients with schizophrenia was assessed with the Positive and Negative Syndrome Scale (PANSS). Our results showed that MnSOD activities were significantly lower in patients than controls (p<0.05). Cognitive scores on the RBANS and nearly all of its five subscales (all p<0.001) except for the Visuospatial/Constructional index were significantly lower in schizophrenia patients than normal controls. MnSOD was negatively correlated with the general psychopathology subscale of PANSS, PANSS total score, positive symptoms and RBANS total score in patients with schizophrenia. Our findings add to growing evidence that oxidative stress may be involved in the psychopathology of male schizophrenia, and its associated cognitive impairment.