MDMA to Treat PTSD in Adults.
Post-traumatic stress disorder (PTSD) has become one of the most common psychiatric diagnosis in the United States specifically within the veteran population. The current treatment options for this debilitating diagnosis include trauma-focused psychotherapies along with selective serotonin reuptake inhibitors (SSRI) and serotonin-norepinephrine reuptake inhibitors (SNRI).1 MDMA has recently been shown as a novel therapeutic agent with promisingly results in the treatment of PTSD. MDMA is a psychoactive compound traditionally categorized as a psychedelic amphetamine that deemed a Schedule I controlled substance in the 1980s. Prior to its status as a controlled substance, it was used by psychotherapists for an array of psychiatric issues. In more recent times, MDMA has resurfaced as a potential therapy for PTSD and the data produced from randomized, controlled trials back the desire for MDMA to be utilized as an effective pharmacologic therapy in conjunction with psychotherapy.2.


Meta-analysis of intermittent Pringle manoeuvre versus no Pringle manoeuvre in elective liver surgery.
Intermittent Pringle manoeuvre (IPM) is frequently used during liver surgery. This meta-analysis aimed to review the impact on blood loss, operating time and morbidity and mortality with and without use of IPM. An electronic search was performed of the MEDLINE, EMBASE, PubMed databases using both subject headings (MeSH) and truncated word searches to identify all articles published that related to this topic. Pooled risk ratios were calculated for categorical outcomes, and mean differences (MDs) for secondary continuous outcomes, using the fixed-effects and random-effects models for meta-analysis. Four randomized controlled trials encompassing 392 patients were analysed to achieve a summated outcome. Pooled data analysis showed the use of IPM resulted in reduced transection time/cm(2) (MD -0.53 (-0.88, -0.18) min/cm(2) (P = 0.003)) but with comparable blood loss (mL/cm(2)) (MD -1.67 (-4.41, 1.08) mL/cm(2), P = 0.23), overall blood loss (MD -20.42 (-89.42, 48.58) mL), blood transfusion requirements (risk ratio 0.78 (0.40, 1.52, P = 0.47)) and morbidity and mortality compared to no Pringle manoeuvre. In addition, there was no significant difference in the post-operative hospital stay (MD 0.37 (-0.60, 1.34) days). There is no evidence that the routine use of IPM improves perioperative and post-operative outcomes compared to no Pringle manoeuvre and its routine may not be recommended.


Post COVID-19 opportunistic candida retinitis: A case report.
A 42-year-old male patient presented with profound impairment of vision in both eyes, just as he was recovering from COVID-19. A known diabetic and hypertensive, he suffered from COVID-19 pneumonia further complicated by ARDS, septicaemia and acute kidney injury. His vision on presentation was finger counting close to face bilaterally with multiple, yellowish lesions at the posterior pole. Based on the clinical findings and previous blood culture report, it was diagnosed as candida retinitis and treated with oral and intravitreal anti-fungals. The lesions were regressing at follow-up. This is a post COVID-19 presumed candida retinitis case report.


Influence of hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA and antigens.
Various genotypes of the hepatitis B virus (HBV) induce liver disease of distinct severity, but the underlying virological differences are not well defined. Huh7 cells were transfected with plasmids carrying 1.24-fold the HBV genome of different genotypes/subgenotypes (2 strains each for Aa/A1, Ae/A2, Ba/B2 and D; 3 each for Bj/B1 and C). HBV DNA levels in cell lysates, determined by Southern hybridization, were the highest for C followed by Bj/Ba and D/Ae (P < .01), and the lowest for Aa (P < .01), whereas in culture media, they were the highest for Bj, distantly followed by Ba/C/D and further by Ae/Aa (P < .01). The intracellular expression of core protein was more than 3-fold lower for Ae/Aa than the others. Hepatitis B e antigen (HBeAg) was excreted in a trend similar to that of HBV DNA with smaller differences. Secretion of hepatitis B surface antigen (HBsAg) was most abundant for Ae followed by Aa, Ba, Bj/C and remotely by D, which was consistent with mRNA levels. Cellular stress determined by the reporter assay for Grp78 promoter was higher for C and Ba than the other genotypes/subgenotypes (P < .01). Severe combined immunodeficiency mice transgenic for urokinase-type plasminogen activator (uPA/SCID), with the liver replaced for human hepatocytes, were inoculated with virions passed in mouse and recovered from culture supernatants. HBV DNA levels in their sera were higher for C than Ae by 2 logs during 4-7 weeks after inoculation. In conclusion, virological differences among HBV genotypes were demonstrated both in vitro and in vivo. These differences may influence HBV infections with distinct genotypes in clinical and epidemiological settings.


Dose-response association of uncontrolled blood pressure and cardiovascular disease risk factors with hyperuricemia and gout.
First-line therapy of hypertension includes diuretics, known to exert a multiplicative increase on the risk of gout. Detailed insight into the underlying prevalence of hyperuricemia and gout in persons with uncontrolled blood pressure (BP) and common comorbidities is informative to practitioners initiating antihypertensive agents. We quantify the prevalence of hyperuricemia and gout in persons with uncontrolled BP and additional cardiovascular disease (CVD) risk factors. We performed a cross-sectional study of non-institutionalized US adults, 18 years and older, using the National Health and Nutrition Examination Surveys in 1988-1994 and 1999-2010. Hyperuricemia was defined as serum uric acid >6.0 mg/dL in women; >7.0 mg/dL in men. Gout was ascertained by self-report of physician-diagnosed gout. Uncontrolled BP was based on measured systolic BP≥140 mmHg and diastolic BP≥90 mmHg. Additional CVD risk factors included obesity, reduced glomerular filtration rate, and dyslipidemia. The prevalence of hyperuricemia was 6-8% among healthy US adults, 10-15% among adults with uncontrolled BP, 22-25% with uncontrolled BP and one additional CVD risk factor, and 34-37% with uncontrolled BP and two additional CVD risk factors. Similarly, the prevalence of gout was successively greater, at 1-2%, 4-5%, 6-8%, and 8-12%, respectively, across these same health status categories. In 2007-2010, those with uncontrolled BP and 2 additional CVD risk factors compared to those without CVD risk factors had prevalence ratios of 4.5 (95% CI 3.5-5.6) and 4.5 (95% CI: 3.1-6.3) for hyperuricemia and gout respectively (P<0.01). Health care providers should be cognizant of the incrementally higher prevalence of hyperuricemia and gout among patients with uncontrolled BP and additional CVD risk factors. With one in three people affected by hyperuricemia among those with several CVD risk factors, physicians should consider their anti-hypertensive regimens carefully and potentially screen for hyperuricemia or gout.


Seal-promoting solutions and pipette perfusion for patch clamping plant cells.
Patch-clamp technology has greatly increased our knowledge of plant membrane transport. However, the success of patch clamping crucially relies on establishing a high resistance (G omega) seal between the membrane and the patch-clamp pipette. This can prove problematic in many plant-cell preparations. It is therefore of great importance to develop protocols for protoplast isolation, maintenance and seal formation that improve seal rate. This study investigated whether the pH and the K+ and the Cl(-)concentration of the pipette solution had an effect on the seal formation. High pH and absence of K+ significantly promoted membrane sealing, whereas the concentration of Cl- had no effect. To reap the benefit of seal-promoting pipette solutions and yet retain the option to adjust this solution to experimental requirements, a pipette perfusion apparatus was implemented. The perfusion system was successfully applied in cell-attached patch, excised-patch and whole-cell configurations, using plasma membrane and tonoplast of three different species. The system enables complete solution exchange within minutes and is potentially of great benefit in the study of channel selectivity, the application of (cytoplasmic) channel blockers and the study of primary and secondary transport.


CXCL17 Chemokine-Dependent Mobilization of CXCR8+CD8+ Effector Memory and Tissue-Resident Memory T Cells in the Vaginal Mucosa Is Associated with Protection against Genital Herpes.
Circulating conventional memory CD8+ T cells (i.e., the CD8+ effector memory T [TEM] cell and CD8+ central memory T [TCM] cell subsets) and the noncirculating CD8+ tissue-resident memory T (TRM) cell subset play a critical role in mucosal immunity. Mucosal chemokines, including the recently discovered CXCL17, are also important in mucosal immunity because they are homeostatically expressed in mucosal tissues. However, whether the CXCL17 chemokine contributes to the mobilization of memory CD8+ T cell subsets to access infected mucosal tissues remains to be elucidated. In this study, we report that after intravaginal HSV type 1 infection of B6 mice, we detected high expression levels of CXCL17 and increased numbers of CD44highCD62LlowCD8+ TEM and CD103highCD8+ TRM cells expressing CXCR8, the cognate receptor of CXCL17, in the vaginal mucosa (VM) of mice with reduced genital herpes infection and disease. In contrast to wild-type B6 mice, the CXCL17-/- mice developed 1) fewer CXCR8+CD8+ TEM and TRM cells associated with more virus replication in the VM and more latency established in dorsal root ganglia, and 2) reduced numbers and frequencies of functional CD8+ T cells in the VM. These findings suggest that the CXCL17/CXCR8 chemokine pathway plays a crucial role in mucosal vaginal immunity by promoting the mobilization of functional protective CD8+ TEM and CD8+ TRM cells, within this site of acute and recurrent herpes infection.


Differential incorporation of docosahexaenoic and arachidonic acids by the yolk sac membrane of the avian embryo.
During avian development, lipoproteins derived from yolk lipid are assembled in the yolk sac membrane (YSM) for secretion into the embryonic circulation. To investigate how yolk polyunsaturated fatty acids, essential for the development of certain tissues, are distributed among the lipid classes of the lipoproteins, pieces of YSM were incubated in vitro with [14C]arachidonic and [14C]docosahexaenoic acids (DHA). There was a marked difference in the partitioning of these two precursors among the lipid classes of the tissue. Of the radioactivity incorporated into total lipid from [14C]-arachidonic acid during 1 h of incubation, 67.3% was esterified as phospholipid and 29.5% as triacylglycerol. In contrast, only 14.6% of the label incorporated from [14C]-DHA was esterified as phospholipid, whereas 73.2% was recovered in triacylglycerol. This pattern of differential partitioning was observed at all time points and across a 20-fold range of fatty acid concentrations. There was no evidence for conversion of the radioactive arachidonic and DHAs to other fatty acids prior to incorporation into tissue lipids. It is suggested that the selective incorporation of yolk-derived DHA into the triacylglycerol of secreted lipoproteins represents part of a mechanism for directing this polyunsaturate to particular embryonic tissues.


Immunochemical localization of calretinin in the retina of the turbot (Psetta maxima) during development.
The expression of the calcium-binding protein calretinin was analysed by immunohistochemistry techniques in the retina of turbot (Psetta maxima) from embryonic to juvenile stages. Calretinin immunoreactivity was first detected in retinae from newly hatched larvae, in which the anlage of the inner plexiform layer and a subset of amacrine and ganglion cells displayed a faint immunolabelling. First appearance of photoreceptors during larval life coincided with an increase in the intensity of the labelling. During subsequent larval development, the expression of calretinin affected distinctive retinal components. The inner plexiform layer, optic fiber layer, and a population of amacrine and ganglion cells were invariably labelled. Occasional bipolar cells were labelled at the end of the larval period. By metamorphosis, calretinin is sequentially expressed in horizontal cells, and bipolar immunoreactive cells become numerous. The pattern of calretinin immunoreactivity of the inner plexiform layer changes from the larval to juvenile period. In all cases, calretinin immunoreactivity exhibited variations between the peripheral retina, which contains the most recently differentiated retinal components, and the remainder of the differentiated retina. Our results suggest that the progressive expression of calretinin in the turbot retina appears associated with some degree of neuronal differentiation. Once the definitive pattern of calretinin immunoreactivity is established in the turbot retina, both similarities and differences with the calretinin location in the retina of other vertebrates can be demonstrated.


Targeting those with decreased meaning and peace: a supportive care opportunity.
To evaluate if an individual's level of meaning/peace (M/P) predicts various quality of life (QOL) and mental well-being measures. To identify targets that might enhance the overall spiritual well-being and QOL of ovarian cancer patients. Multi-site analysis of women with newly diagnosed stages II-IV ovarian, primary peritoneal, or fallopian tube cancer. Patients completed the following surveys: Functional Assessment of Chronic Illness Therapy-Ovarian (FACT-O), Functional Assessment of Chronic Illness Therapy-Spiritual (FACIT-Sp), Edmonton Symptom Assessment System (ESAS), Hospital Anxiety and Depression Scale (HADS), Templer's Death Anxiety Scale (DAS), Herth Hope Index (HHI), and Brief Multidimensional Measure of Religiousness/Spirituality (BMMRS). Linear regression models were created to examine the effect of M/P (FACIT-Sp) upon QOL, symptoms, and other measures of mental well-being. These models adjusted for the effect of site, race, age, stage, anaphylaxis to chemotherapy, and partner status as potential confounders. This study enrolled 104 patients from three separate sites. After adjusting for potential confounders, it was found that higher M/P predicted better QOL (FACT-O) (p < 0.0001). Higher M/P also predicted decreased death anxiety, depression, and anxiety (p ≤ 0.005). Finally, higher M/P predicted increased hope and coping scores (p ≤ 0.0005). Level of M/P is associated with several important mental and physical health states. This information may allow providers to identify patients at increased risk for mental/physical distress and may facilitate early referral to targeted psychotherapy interventions focused on improving patient QOL and decreasing anxiety and depression.


Influenza in the United Kingdom 1977-1981.
The laboratory surveillance of influenza in the UK has continued to demonstrate the regularity of influenza outbreaks each winter even in the absence of increase in the other indices which reflect the morbidity and mortality associated with influenza. The period of five years from 1976 to 1981 has seen the appearance of a second sub-type of influenza. A with the return of the historic H1N1 virus; and the continued circulation of H3N2 concurrently with H1N1 virus. Variants of both these influenza A viruses have been demonstrated as well as further changes in the strains of influenza B virus isolated during this time.


Immuno-pathotyping of Karnal bunt (Tilletia indica) isolates of wheat using anti-mycelial antibodies.
Two types of polyclonal antibodies raised against whole lyophilized (LMA) and fractionated mycelial antigen (FMA) of most virulent, Pantnagar isolate of T. indica were used for the development of immunoassay systems, viz. dot immuno-binding assay (DIBA) and indirect enzyme linked immuno-sorbent assay (ELISA) procedures. The immuno-assays were developed by performing antigen concentration kinetics and antibody dilution curves analyses. These assays were employed for immuno-analysis of diversity amongst KB pathogen based on antibodies reactivity pattern and subsequently categorization into distinct sero-groups. The reactivity of two polyclonal antibodies was tested with 15 (P1-P15) isolates of T. indica. When anti-LMA antibodies were tested, four serologically distinct groups were formed based on percent reactivity (>75%, highly reactive; 60-75%; moderately reactive, <50-25%; low reactive and <25%, non-reactive). However, when anti-FMA antibodies were used, two distinct sero-groups were formed based on reactivity patterns (group I, highly reactive P1, P3, P4, P11 and P13, group II, less reactive P2, P4, P5, P6, P7, P8, P9, P10, P12, P14 and P15).


A chiral Brønsted acid-catalyzed highly enantioselective Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines.
A chiral phosphoric acid-catalyzed asymmetric Mannich-type reaction of α-diazo esters with in situ generated N-acyl ketimines, derived from 3-hydroxyisoindolinones has been demonstrated in this communication. A variety of isoindolinone-based α-amino diazo esters bearing a quaternary stereogenic center were afforded in high yields (up to 99%) with excellent enantioselectivities (up to 99% ee). Furthermore, the synthetic utility of the products has been depicted by the hydrogenation of the diazo moiety of adducts.


[Misinformation among physicians about dangers of fetal x-ray exposure].
A survey among 20 gynecologists and 86 family physicians and general practitioners revealed that only 46% (70% of the gynecologists and 41% of the others) knew that exposure of a pregnant woman to common diagnostic x-ray is not an indication for therapeutic abortion (the opinion of a consensus of experts). This lack of basic information by those who advise pregnant women points to a serious public health problem. Pregnant women are frightened, and in a sense abortions are "coerced" by increasing the unwarranted anxiety. It is incumbent upon individuals and institutions to ensure that physicians, nurses and others in the health professions be well-informed and not supply misinformation.


Kostmann syndrome: oral aspects and 10-year follow-up case report.
Kostmann syndrome (KS) is an autosomal recessive disorder characterized by a low neutrophil count and recurrent bacterial infections, including periodontal disease. This report describes the case of a 5-year-old female KS patient treated with regular infusions of granulocyte stimulating factor (granulokine), with primary complaint of gingival bleeding and tooth mobility, and followed up for 10 years. Conventional periodontal treatment and some extractions were performed, after neutrophil function tests using flow cytometry. The invasive procedures were carried out at an outpatient clinic under antibiotic prophylaxis due to a low neutrophil count and an impaired neutrophil function presented. During the 10-year follow-up period, despite episodes of recurrent gingivitis and periodontitis the present report describes the positive outcome of dental treatment of a patient with KS.


Human epididymis: structural pattern, total length and inner surface area.
The organ epididymis is secured the name considering it functioned as an appendix to the testis; earlier testis was called as didymi. Regarding the length of human epididymis, several values are attributed by different authors. The present study was aimed to find out the pattern, total length and inner surface area of human epididymis. The study was conducted by employing microsurgical procedures on five testes from unclaimed human dead bodies. Caput was formed by few tubes interconnecting at three levels. These tubes led to corpus, which in turn was having more number of tubes interconnecting at different levels. Tubules were many looking like a mesh. United tubes of corpus form the single tube to form cauda. Epididymis length was 30.48 cm. Inner surface area was 818.16 mm2. Reported values of others seem to be a modified version from that of animals. Authors believe that organic revolutionary changes in man led to a reduction in the length of epididymis.


Impact of Thromboprophylaxis Intensity on Patients' Mortality Among Hospitalized Patients with COVID-19: A Propensity-Score Matched Study.
Venous thromboembolism (VTE), a major complication that has been reported in patients with COVID-19, is associated with an increased risk of mortality. The purpose of this study was to compare in-hospital mortality among hospitalized patients with COVID-19 who received high-intensity versus standard-intensity thromboprophylactic anticoagulation. A secondary database analysis was conducted using data for adult patients who were hospitalized for COVID-19 in Saudi Arabia and received enoxaparin for thromboprophylaxis during their hospitalization. While enoxaparin 40 mg daily is considered the standard-intensity, doses higher than the standard but not to reach the therapeutic dose were considered as high-intensity. The primary outcome in the study was in-hospital mortality, and the secondary outcomes included intensive care unit (ICU) and hospital length of stay. Chi-square and t-tests were used to assess the difference between the two independent groups, and propensity score matching was performed to adjust for baseline characteristics. From 3508 patients who received high- or standard-intensity enoxaparin, 1422 patients, 711 in each group, were included in the analyses after propensity score matching. The mean age of the participants was 57.2 years, and around 30% of them were female. About 72% of the patients were admitted to the ICU. No difference was observed between the two groups in the in-hospital mortality outcome (36% vs 33.5% in the high-intensity and the standard group, respectively; RR=1.06, 95% CI 0.95-1.18). However, patients who received high-intensity thromboprophylaxis had a significantly longer duration of hospitalization (15.6 days vs 13.6 days; p=0.003) and ICU stay (12.3 days vs 10.8 days; p=0.039) compared to patients who received the standard dose. The use of high-intensity thromboprophylaxis was not associated with a reduction in mortality. Therefore, our results do not support the routine use of high-intensity prophylactic anticoagulation in both ICU and non-ICU patients with COVID-19.


Personality characteristics of men with liberal sex-role attitudes.
The present study was conducted to provide some initial information on the personality attributes of men oriented toward liberal sex-role views. Fifty-one male college students were given the Attitudes Toward Women Scale and divided into conservative, moderate, and liberal groups. Personality differences among the groups were assessed by comparing scores on nine scales from the Adjective Check List. Findings for liberal men were found to parallel results reported for liberal women on some personality dimensions and complement them on others. As with liberal women, liberal men were found to be more spontaneous, action oriented, risk taking, individualistic, and unconventional than the other male groups. There were also some indications of less self-control. Sex-role attitudes and heterosexuality were curvillinearly related. In direct opposition to results for liberal women, male liberals evidenced the least need for achievement and dominance.


Integrating Biological Covariates into Gene Expression-Based Predictors of Radiation Sensitivity.
The use of gene expression-based classifiers has resulted in a number of promising potential signatures of patient diagnosis, prognosis, and response to therapy. However, these approaches have also created difficulties in trying to use gene expression alone to predict a complex trait. A practical approach to this problem is to integrate existing biological knowledge with gene expression to build a composite predictor. We studied the problem of predicting radiation sensitivity within human cancer cell lines from gene expression. First, we present evidence for the need to integrate known biological conditions (tissue of origin, RAS, and p53 mutational status) into a gene expression prediction problem involving radiation sensitivity. Next, we demonstrate using linear regression, a technique for incorporating this knowledge. The resulting correlations between gene expression and radiation sensitivity improved through the use of this technique (best-fit adjusted R2 increased from 0.3 to 0.84). Overfitting of data was examined through the use of simulation. The results reinforce the concept that radiation sensitivity is not driven solely by gene expression, but rather by a combination of distinct parameters. We show that accounting for biological heterogeneity significantly improves the ability of the model to identify genes that are associated with radiosensitivity.


Preclinical medical student training in radiology: the effect of early exposure.
The purpose of this study was to determine whether an integrated radiology curriculum in the first year of medical school changes medical students' attitudes toward radiology or affects their knowledge of radiologic principles. The first-year medical curriculum of a medical school was revised between the 2003 and 2004 academic years to introduce more didactic radiology teaching. Dedicated radiology lectures were introduced, and radiology consult sessions became integral to problem-based learning sessions. A survey was administered between the first and second years of training to assess first-year medical students' attitudes toward radiology and their knowledge of basic radiologic principles. Students who had undertaken the revised curriculum (class of 2008) were compared with students who had undertaken the traditional curriculum (class of 2007). Survey responses were compared with Mann-Whitney rank sum tests. Students exposed to the new curriculum stated that they were more familiar with radiology as a specialty and believed that radiology had greater importance to the overall practice of medicine. They stated that they were more likely to select radiology as a clinical elective, and more of them were considering radiology as a career option. The students who had been exposed to radiology performed better on the test of basic radiologic knowledge. All results were statistically significant. Exposing students to radiology in the first year of medical school improves their impression of radiology as a specialty and increases their interest in radiology as a career. Follow-up surveys will determine whether this effect persists through the clinical years of training and improves the overall impression of radiology within the medical community.


[Cascade of gene activation in Landouzy Dejerine muscular dystrophy].
Our laboratory studies the Landouzy Dejerine muscular dystrophy or FSHD, a genetic disease which affects 7 in 100,000 individuals. The genetic defect is a deletion on chromosome 4 that decreases the copy number of a repeated DNA element, disturbs chromatin structure and activates the expression of neighbouring genes. The originality of our team has been to identify a gene within the repeated element itself and to show its activation in FSHD muscle cells. This gene expresses DUX4, a transcription factor that targets tens of genes, some of which express other transcription factors which target other genes, leading to a general deregulation. This DUX4-mediated cascade recapitulates by itself the major pathological features of FSHD: muscle atrophy, differentiation defect, oxidative stress... The homologous DUX4c gene located 42 kb from the repeat array expresses a protein that triggers myoblast proliferation. Its high expression level in severe cases of FSHD most probably contributes to the pathology by interfering with myoblast fusion with the muscle fibers at the last steps of muscle regeneration. We are performing global analyses of proteins and metabolites in healthy and FSHD myotubes (collaboration R Wattiez and JM Colet, UMONS) to identify abnormalities and their links with DUX4 or DUX4C.


The patient and the dying psychiatrist.
In the last few years a great deal of attention has been paid to the dying patient and his relatives, but very little to the illness of the psychiatrist, particularly when it is of a terminal nature. This paper is about Jean Caron, M.D., a psychiatrist who suffered from leukemia, and his patients some of whom came to learn about it in an indirect fashion and others in a more open way. The knowledge of his illness and oncoming death, while first experienced as severe shock, became therapeutically useful in relieving previous losses and abandonments and completing unfinished mourning. It appears possible to mourn a person who is still living and through his help, mourn previous losses while this person is mourning his own life.


Relationship between left ventricular geometry and left atrial size and function in patients with systemic hypertension.
Arterial hypertension determines distinct adaptive left ventricular geometric responses, which may differently affect left ventricular function and left atrial performance. In this study, the effect of left ventricular geometry on left atrial size and function, and the relationship between left atrial size and left ventricular mass were assessed in 336 patients with systemic arterial hypertension who had undergone Doppler echocardiography. Patients were classified into concentric (110 patients with concentric left ventricular geometry defined as relative wall thickness > or = 0.44) and eccentric groups (226 patients with relative wall thickness < 0.44). Comparison to the latter, the former had greater left atrial size, left atrial ejection force, left ventricular mass and lower left ventricular midwall fractional shortening. Left ventricular concentric, rather than eccentric, geometry emerged by multivariate analysis as a factor independently associated with the highest degree of left atrial ejection force. Left atrial size was positively related to left ventricular mass in the whole population (r = 0.65, SEE = 6 ml, P < 0.00001). This relationship was maintained in the subgroups with concentric (r = 0.65, SEE = 6 ml, P < 0.00001) or eccentric geometry (r = 0.59, SEE = 6 ml, P < 0.00001). Our results indicate that the relationship of left ventricular geometry to both left atrial size and ejection force in hypertensive patients is relevant. Concentric left ventricular geometry is associated with greater left atrial size and ejection force than eccentric geometry, suggesting that increased left ventricular stiffness has a greater effect in stimulating left atrial performance than left ventricular end-systolic stress. The degree of left atrial enlargement similarly depends on left ventricular mass in patients with concentric and eccentric geometry.


Binding of an oligopeptide to a specific plane of ice.
The alpha-helical antifreeze protein (AFP) from winter flounder inhibits ice growth by binding to a specific set of pyramidal surface planes that are not otherwise macroscopically expressed. The 37-residue AFP contains three 11-amino acid repeats that make a stereo-specific fit to the ice lattice along the <01-12> direction of the (20-21) and equivalent binding planes. When the AFP was shortened to delete two of the three 11-amino acid ice-binding repeats, the resulting 15-residue peptide and its variants were less helical and showed no antifreeze activity. However, when the helicity of the peptide was reinforced by an internal lactam bridge between Glu-7 and Lys-11, the minimized AFP was able to stably express the pyramidal plane (20-21) on the surface of growing ice crystals. This dynamic shaping of the ice surface by a single ice-binding repeat provides evidence that AFP adsorption to the ice lattice is not an "all-or-nothing" interaction. Instead, a partial interaction can help develop the binding site on ice to which the remainder of the AFP (or other AFP molecules) can orient and bind.


Vidarabine monophosphate and human leukocyte interferon in chronic hepatitis B infection.
Ten young adult patients with chronic hepatitis B virus infection and positive hepatitis B e antigen and DNA polymerase (DNAP) levels were treated with alternating courses of seven to 28 days of 5 to 7.5 mg/kg of vidarabine monophosphate (adenine arabinoside monophosphate) and 28 days of human leukocyte interferon (IFN-alpha); three different regimens were given on an outpatient basis. All patients with a fall in their DNAP level, and the DNAP remained undetectable six months after treatment was stopped in one patient. The major side effect, which most often occurred in those patients receiving 7.5 mg/kg of vidarabine monophosphate, was severe muscular pains. This study demonstrated the feasibility of administering vidarabine monophosphate and interferon to outpatients. Based on data from this and other studies, it is now possible to use a relatively nontoxic regimen that includes 28 days of 5 mg/kg of vidarabine monophosphate in a larger controlled study to answer the question of efficacy.


CONVERSION FACTOR FROM DOSEMETER READING TO AIR KERMA FOR NUCLEAR WORKER USING ANTHROPOMORPHIC PHANTOM FOR FURTHER CONVERSION FROM AIR KERMA TO ORGAN-ABSORBED DOSE.
Estimation of cancer risk based on the organ-absorbed dose is underway for the Japanese Epidemiological Study on Low-Dose Radiation Effects (J-EPISODE). The reconstruction method for the organ-absorbed dose follows the approach adopted in the IARC 15-Country Collaborative Study, which examined the dosemeter response to photon exposure for the old film badge (FB) type, a multi-element FB and a thermoluminescence dosemeter. Until 2000, the dosemeters used in Japan were almost the same in the IARC study, so IARC study data could be used as they were. However, since 2000, the type of dosemeter has been replaced with active personal dosemeters (hereafter called electronic personal dosemeters), radio-photoluminescent glass dosemeters (Glass badge) and optically stimulated luminescence dosemeters (Luminess badge). Hence, it was necessary to collect these data again. A dosemeter response experiment was conducted using a device that irradiated an anthropomorphic phantom in the Japan Atomic Energy Agency calibration laboratories. The aim of the paper is to provide a conversion factor from reading in terms of Hp(10) to air kerma for realistic conditions for further conversion from air kerma to organ-absorbed dose. The obtained dosemeter responses for the dosemeter types currently used in Japan were consistent with those in the IARC study. These data will be utilized for J-EPISODE in reconstructing the organ-absorbed dose.


[Immunogenicity of retina in mice].
To evaluate the immunogenicity of retina. DBA/2 mice (MHCH-2d) were used as donors, C57BL/6 mice (MHC H-2d) or BALB/C mice (MHC H-2d) as recipients. Half retina of DBA/2 mouse was transplanted subcutaneously to a C57BL/6 or BALB/C mouse. The delayed-type hypersensitivity (DTH) and specific killing rate of cytotoxic T lymphocyte(CTL) were detected two weeks later. The results of DTH and specific killing rate of CTL in the retina of DBA/2 mice were significantly lower than the positive group(P < 0.01), but significantly higher than the negative group(P < 0.01). MHC Class I and Class II antigen and minor histocompatibility complex antigen(Minor HC) are expressed in the retina of the DBA/2 mouse, which stimulates immune system of recipient to produce weak cellular immune response. It is suggested that the retina has weak immunogenicity.


Diagnostic evaluation of a point-of-care test for culture and microbial susceptibility testing in canine dermatological infections in clinical practice.
Empirical antimicrobial therapy is frequently given in superficial bacterial folliculitis (SBF) and otitis externa (OE) in dogs, especially for the initial clinical presentation. Culture and subsequent antimicrobial susceptibility testing (AST) are generally limited to chronic cases with poor response to initial therapy. Several factors contribute to the failure to implement the use of AST in veterinary practice, i.e., long laboratory turnaround time or special requirements for sample shipping. Point-of-care (PoC) testing might reduce laboratory turnaround time and costs and the risk of emergence of multidrug-resistant pathogens. This study evaluated the Speed Biogram™ PoC test in canine SBF and OE compared with conventional methods for culture and AST. Thirty-four canine samples were analyzed: eleven from SBF, seven from bacterial OE, four from mixed OE, six from Malassezia spp. OE, and six negative controls. Sensitivity (Se) and specificity (Sp) of the PoC test and the agreement between the PoC test and conventional methods were evaluated. Se and Sp of PoC test in discriminating between healthy and unhealthy subjects were 100% (95% confidence interval [CI] 87.66-100.00) and 100% (95% CI 54.1-100.0), respectively. For bacterial identification, the k value was 0.532. Se and Sp of PoC tests for AST were 81.73% (95% CI 72.95-88.63) and 93.10% (95% CI 88.86-96.98), respectively with a total good agreement between tests (mean k=0.714), but major (8/27) and very major (19/27) errors were observed in 55% of bacterial conventional culture-positive samples. PoC test can identify dogs with SBF and OE, but AST is not sufficiently accurate. The lack of susceptibility testing for methicillin makes this test inappropriate for use in small animal practice.


Restoration of digestive continuity after Hartmann's procedure.
Reestablishment of colonic continuity (RDC) following Hartmann's procedure is associated with high morbidity (anastomotic leak 4-16%) and mortality (0-4%) rates. The aim of this retrospective study is to evaluate the morbidity of RDC following Hartmann's procedure, and to analyze the various factors which may be able to influence the rate of complications. From 1996 to 2002, 74 patients were treated by Hartmann's colectomy. Of these 74 patients, 40 patients underwent a reestablishment of colonic continuity (54% of all the Hartmann's procedures). The common factor of indications is the presence of infection in the abdominal cavity, combined with a distended or prepared intestine, or both. The mean age was 60 years (33-90). The mean delay between Hartmann's operation and the RDC was 139 days (range: 25-450 days) and 15.5 days (8-57 days) was the mean duration of the hospital stay. The mortality rate was 0% and incidence of anastomotic stricture was 2.5%. The morbidity was 45%. The majority of patients presenting complications had an ASA score of III (44.4%), and the patients without complications were for the majority classified as ASA I (45.5%) The RDC is an intervention performed safely after a 3 to 5-month delay with an acceptable morbidity and a negligible mortality. The ASA score is a determining factor for the risk for complications (p<0.05), unlike the age. However, patients younger than 50 years benefit from a protective factor against complications.


Association of Genetic Variants of CYP2C19 and CYP2D6 with Esophageal Squamous Cell Carcinoma Risk in Northern India, Kashmir.
Genetic polymorphism in xenobiotic metabolizing enzymes (XMEs) is associated with various malignancies. However, the association of esophageal cancer with XMEs is mixed. The current study was aimed to explore the association of genetic polymorphisms of cytochrome (CYP) 2C19 and CYP2D6 genotypes with esophageal squamous cell carcinoma (ESCC) risk in Kashmir, India. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing methods were used for genotyping of 492 ESCC cases and equal number of individually matched controls. Conditional logistic regression models were used to assess odds ratios (ORs) and 95% confidence intervals. Increased ESCC risk was observed in subjects with variant genotypes of CYP2C19 (OR = 3.3) or CYP2D6 (OR = 2.1) and risk was higher (OR = 4.6) in subjects who harbored both the genotypes. Almost same but higher risk turned when subjects were smokers and carried a variant genotype of CYP2C19 (OR = 4.4) or CYP2D6 (OR = 4.7). Risk was appreciably increased in subjects who had family history of any cancer and also harbored a variant genotype of either CYP2C19 (OR = 15.5) or CYP2D6 (OR = 9.7). Subjects harboring a variant genotype of CYP2D6 showed an added risk when they used biomass as fuel (OR = 4.6). In conclusion, variant genotypes of CYP2C19 and CYP2D6 are associated with an increased risk of ESCC.


The Triple-Decker Complex [Cp*Fe(µ,η⁵:η⁵-P₅)Mo(CO)₃] as a Building Block in Coordination Chemistry.
Although the triple-decker complex [Cp*Fe(µ,η⁵:η⁵-P₅)Mo(CO)₃] (2) was first reported 26 years ago, its reactivity has not yet been explored. Herein, we report a new high-yielding synthesis of 2 and the isolation of its new polymorph (2'). In addition, we study its reactivity towards AgI and CuI ions. The reaction of 2 with Ag[BF₄] selectively produces the coordination compound [Ag{Cp*Fe(µ,η⁵:η⁵-P₅)Mo(CO)₃}₂][BF₄] (3). Its reaction with Ag[TEF] and Cu[TEF] ([TEF]- = [Al{OC(CF₃)₃}₄]-) leads to the selective formation of the complexes [Ag{Cp*Fe(µ,η⁵:η⁵-P₅)Mo(CO)₃}₂][TEF] (4) and [Cu{Cp*Fe(µ,η⁵:η⁵-P₅)Mo(CO)₃}₂][TEF] (5), respectively. The X-ray structures of compounds 3⁻5 each show an MI ion (MI = AgI, CuI) bridged by two P atoms from two triple-decker complexes (2). Additionally, four short MI···CO distances (two to each triple-decker complex 2) participate in stabilizing the coordination sphere of the MI ion. Evidently, the X-ray structure for compound 3 shows a weak interaction of the AgI ion with one fluorine atom of the counterion [BF₄]-. Such an Ag···F interaction does not exist for compound 4. These findings demonstrate the possibility of using triple-decker complex 2 as a ligand in coordination chemistry and opening a new perspective in the field of supramolecular chemistry of transition metal compounds with phosphorus-rich complexes.


The association between perseverative negative cognitive processes and negative affect in people with long term conditions: a protocol for systematic review and meta-analysis.
Depression is common in people with long term conditions (LTCs) and is associated with worse medical outcomes. Understanding the mechanisms underpinning this relationship could help predict who is at increased risk of adverse medical outcomes, and lead to the development of novel interventions. Perseverative negative cognitive processes, such as worry and rumination, involve repetitive and frequent thoughts about oneself and one's concerns. These processes have been associated with negative affect, and also adverse medical outcomes. The results of prospective studies, which would allow causal inferences to be drawn, are more equivocal however. Furthermore, the majority of studies have been conducted in physically healthy individuals, and we do not know to what extent these findings will generalise to people with LTCs. Electronic databases will be searched using a search strategy including controlled vocabulary and text words related to perseverative negative cognitive processes (such as worry and rumination) and negative affect (including depression and anxiety). Records will be hand-searched for terms related to LTCs. Citation and bibliography searching will be conducted, and authors of included studies will be contacted to identify unpublished studies. Studies will be included if they contain a standardised measure of the prospective association between perseverative negative cognitive processes and negative affect, or vice versa, in people with LTCs. Narrative and meta-analytic methods will be used to synthesize the data collected. This review will identify and synthesise studies of the prospective association between perseverative negative cognitive processes and negative affect among people with LTCs. The findings will help to identify whether worry and rumination could cause depression and anxiety in people with LTCs, and might indicate whether perseverative negative cognitive processes are appropriate targets for treatment.


Temperature anomalies of oscillating diffusion in ac-driven periodic systems.
We analyze the impact of temperature on the diffusion coefficient of an inertial Brownian particle moving in a symmetric periodic potential and driven by a symmetric time-periodic force. Recent studies have revealed the low-friction regime in which the diffusion coefficient shows giant damped quasiperiodic oscillations as a function of the amplitude of the time-periodic force [I. G. Marchenko et al., Chaos 32, 113106 (2022)1054-150010.1063/5.0117902]. We find out that when temperature grows the diffusion coefficient increases at its minima; however, it decreases at the maxima within a finite temperature window. This curious behavior is explained in terms of the deterministic dynamics perturbed by thermal fluctuations and mean residence time of the particle in the locked and running trajectories. We demonstrate that temperature dependence of the diffusion coefficient can be accurately reconstructed from the stationary probability to occupy the running trajectories.


[Animal experimental studies on the biocompatibility of resorbable gelatin sponges and dry fibrin foam].
Histologic specimens taken from the implantation site and the regional lymph nodes up to four weeks after subcutaneous implantation of Gelastypt S (Höchst AG), Gelfoam (Upjohn), and Fibrospum (Promonta) into the upper hind leg of guinea pigs were examined. Similar tissue reactions were observed with Gelastypt S and Gelfoam; the reactions did not differ appreciably from those normally occurring in the context of wound healing. The predominance of round cell infiltrate and the appearance of giant cells in connection with Fibrospum may indicate an immunogenetic potency of the substance. No signs of beginning resorption could be observed four weeks later.


Detection of Zn-binding in domain E of the porcine estradiol receptor.
A 32 kDa fragment of the porcine estradiol receptor, which contains the entire hormone-binding domain E and parts of the adjacent domains D and F, binds 65Zn with high affinity. Nonradioactive Zn and Cu are equally potent competitors, Co and Ni are less effective. The capacity for Zn-binding is pH-dependent, it is abolished by the ethoxycarboxylation of imidazole, but remains unimpaired after the modification of sulfhydryls by vinylpyridine. The presence of a HDXXH motif in domain E of the receptor and the significance of its similarity with the HEXXH zinc-binding motif of metallo-proteases are discussed.


Low molecular weight glutenins in wheat-dependant, exercise-induced anaphylaxis: allergenicity and antigenic relationships with omega 5-gliadins.
Adults suffering from wheat-dependant, exercise-induced anaphylaxis (WDEIA) develop IgE directed against wheat omega5-gliadins (major allergens for this allergy) and against wheat low-molecular weight glutenin subunits (LMW-GS). However, the ability of LMW-GS to trigger an inflammatory response is still unknown. It also remains to be determined if IgE from these patients bind the same epitopes on LMW-GS and omega5-gliadins or if the epitopes are independent. WDEIA patients were selected and skin prick tests (SPTs) were performed on them using commercial gluten, wheat flour extracts, prolamin fractions and a purified natural LMW-GS P42. The IgE-binding ability of natural and recombinant wheat prolamins was verified by immunoblot experiments. Cross-reactivity between LMW-GS and omega5-gliadins was studied by immunoblot inhibition experiments, using purified natural omega5-gliadin as an inhibitor. Patients developed positive SPTs with natural LMW-GS fractions and/or with the purified LMW-GS P42. Natural and recombinant LMW-GS were highly reactive with patient IgE in immunoblot experiments, as was omega5-gliadin. However, differences in reactivity were evident within the LMW-GS group. Except for one recombinant LMW-GS (P73), IgE cross-reactivity between LMW-GS and natural omega5-gliadin was only partial. LMW-GS are able to promote local inflammation and they share common epitopes with omega5-gliadins. The nature of these epitopes is discussed. LMW-GS also carried specific epitopes, completely independent from the omega5-gliadin epitopes. Thus, LMW-GS behaved partly as independent allergens.


The multidimensional and developmental nature of infidelity: practical applications.
When a partner has been unfaithful, an important therapeutic task is to assess factors that contributed to the affair and that may affect the individual's and couple's healing. This article provides a framework to assess multiple factors and their influence on an affair over time, as well as on responses to an affair. We address factors related to the person involved in an affair, his or her partner, their relationship, and the external context. These factors are considered across six phases of an affair: predisposition, approach, initial involvement, maintenance, disclosure or discovery, and response. A case study is presented to illustrate the usefulness of the framework in working with couples in which there has been an affair.


Editorial: Closing in on causal links between environmental exposures and human development using observational data - "confound those confounders!"
A central goal of developmental psychopathology research is to understand the mechanisms linking environmental exposures in childhood to variations in mental health and development across the lifespan. The Journal of Child Psychology & Psychiatry has featured many influential studies and reviews addressing this important topic. This month's issue of the journal presents papers which address several specific environmental exposures, including prenatal factors, parenting and adverse childhood experiences, and illustrate important principles that should be used as a basis for taking the field forward.


Prediction of patient survival in cases of acute paraquat poisoning.
Paraquat concentration-time data have been used to predict the clinical outcome following ingestion. However, these studies have included only small populations, although paraquat poisoning has a very high mortality rate. The purpose of this study was to develop a simple and reliable model to predict survival according to the time interval post-ingestion in patients with acute paraquat poisoning. Data were retrospectively collected for patients who were admitted with paraquat poisoning to Soonchunhyang University Choenan Hospital between January 2005 and December 2012. Plasma paraquat levels were measured using high-performance liquid chromatography. To validate the model we developed, we used external data from 788 subjects admitted to the Presbyterian Medical Center, Jeonju, Korea, between January 2007 and December 2012. Two thousand one hundred thirty six patients were included in this study. The overall survival rate was 44% (939/2136). The probability of survival for any specified time and concentration could be predicted as (exp(logit))/(1+exp(logit)), where logit = 1.3544+[-3.4688 × log10(plasma paraquat μg/M[Formula: see text])]+[-2.3169 × log10(hours since ingestion)]. The external validation study showed that our model was highly accurate for the prediction of survival (C statics 0.964; 95% CI [0.952-0.975]). We have developed a model that is effective for predicting survival after paraquat intoxication.


Mechanisms of GABA release from human astrocytes.
We have previously demonstrated that human astrocytes are GABAergic cells. Throughout the adult human brain, they express the GABA synthesizing enzyme GAD 67, the GABA metabolizing enzyme GABA-T, and the GABA(A) and GABA(B) receptors. GABA modulates the actions of microglia, indicating an important role for astrocytes beyond that of influencing neurotransmitter function. Here we report on the mechanisms by which astrocytes release GABA. Astrocytes were found to express the mRNA and protein for multiple GABA transporters, and multiple receptors for glutamate, GABA, and glycine. In culture, untreated human astrocytes maintained an intracellular GABA level of 2.32 mM. They exported GABA into the culture medium so that an intracellular-extracellular gradient of 3.64 fold was reached. Inhibitors of the GABA transporters GAT1, GAT2, and GAT3, significantly reduced this export in a Ca(2+)-independent fashion. Intracellular GABA levels were enhanced by treatment with the GABA-T inhibitors gabaculine or vigabatrin. Treatment with glutamate increased GABA release in a concentration-dependent fashion. This was partially inhibited by blockers of N-methyl-D-aspartate and kainate receptors. Conversely, glycine and D-serine, co-agonists of NMDA receptors, enhanced the GABA release. GABA release was accompanied by an increase in intracellular Ca(2+) concentration ([Ca(2+)](i)) and was reduced by adding the Ca(2+) chelator, BAPTA-AM to the medium. These data indicate that astrocytes continuously synthesize GABA and that there are multiple mechanisms which can mediate its release. Each of these may play a role in the physiological functioning of astrocytes.


Clustering of water bodies in unpolluted and polluted environments based on Escherichia coli phylogroup abundance using a simple interaction database.
Different types of water bodies, including lakes, streams, and coastal marine waters, are often susceptible to fecal contamination from a range of point and nonpoint sources, and have been evaluated using fecal indicator microorganisms. The most commonly used fecal indicator is Escherichia coli, but traditional cultivation methods do not allow discrimination of the source of pollution. The use of triplex PCR offers an approach that is fast and inexpensive, and here enabled the identification of phylogroups. The phylogenetic distribution of E. coli subgroups isolated from water samples revealed higher frequencies of subgroups A1 and B23 in rivers impacted by human pollution sources, while subgroups D1 and D2 were associated with pristine sites, and subgroup B1 with domesticated animal sources, suggesting their use as a first screening for pollution source identification. A simple classification is also proposed based on phylogenetic subgroup distribution using the w-clique metric, enabling differentiation of polluted and unpolluted sites.


Reversible absorptive defects in anticonvulsant megaloblastic anaemia.
Two cases of anticonvulsant megaloblastic anaemia are described, showing features of unusual interest. Though both cases were apparently deficient in folic acid, the Figlu tests were negative. One patient had an extremely low serum B(12) concentration apparently associated with defective B(12) absorption due to deficiency of intrinsic factor, and both showed impaired intestinal absorption of D-xylose. There was, however, no evidence of permanent gastro-intestinal dysfunction, and the absorptive defects disappeared completely after treatment with folic acid. Possible reasons for the findings are discussed. It is suggested that absorptive defects produced by the drugs may play some part in initiating anticonvulsant megaloblastic anaemia, and that once deficiencies of haemopoietic factors are established, a vicious circle may be set up owing to the effects of these deficiencies on the gastro-intestinal tract.


Intrinsic lipid preferences and kinetic mechanism of Escherichia coli MurG.
MurG, the last enzyme involved in the intracellular phase of peptidoglycan synthesis, is a membrane-associated glycosyltransferase that couples N-acetyl glucosamine to the C4 hydroxyl of a lipid-linked N-acetyl muramic acid derivative (lipid I) to form the beta-linked disaccharide (lipid II) that is the minimal subunit of peptidoglycan. Lipid I is anchored to the bacterial membrane by a 55 carbon undecaprenyl chain. Because this long lipid chain impedes kinetic analysis of MurG, we have been investigating alternative substrates containing shortened lipid chains. We now describe the intrinsic lipid preferences of MurG and show that the optimal substrate for MurG in the absence of membranes is not the natural substrate. Thus, while the undecaprenyl carrier lipid may be critical for certain steps in the biosynthetic pathway to peptidoglycan, it is not required-in fact, is not preferred-by MurG. Using synthetic substrate analogues and products containing different length lipid chains, as well as a synthetic dead-end acceptor analogue, we have also shown that MurG follows a compulsory ordered Bi Bi mechanism in which the donor sugar binds first. This information should facilitate obtaining crystals of MurG with substrates bound, an important goal because MurG belongs to a major superfamily of NDP-glycosyltransferases for which no structures containing intact substrates have yet been solved.


Localization of enterobacterial common antigen:immunogenic and nonimmunogenic enterobacterial common antigen-containing Escherichia coli.
In rabbits immunized with intact bacteria, the immune response to the enterobacterial common antigen (ECA) predominantly consists of the production of immunoglobulin M antibodies. This is not dependent on whether the animals are immunized for a short (2 weeks) or a long (3 months) period of time. The highest ECA-specific immunoglobulin G titers were observed after a short immunization with living bacteria. ECA-specific antisera were obtained by absorption with appropriate ECA-negative mutants. The absorbed antisera were then separated on Sephadex G-200. The resulting immunoglobulin G fractions were conjugated to ferritin by glutardialdehyde and used to visualize the distribution of ECA in E. coli. Bacterial strains either possessing the immunogenic form of ECA (F470, 2387) or solely the nonimmunogenic form (F614) or being devoid of both (ECA-negative mutants F1283 and F1327) were labeled with the conjugates. Freezeetchings of ferritin-labeled strains showed a dense labeling of the outer membrane in case of ECA-immunogenic strains, an essentially weaker labeling of the non-immunogenic ECA mutant and, as expected, no labeling of ECA-negative mutants. Comparable results were obtained with the indirect immunofluorescence technique: the whole cell envelope of strain F470 showed a brilliant fluorescence, whereas a much lesser, spotty distribution of fluorescence was noted with strain F614 and none at all was noted with the ECA-negative strains. These data show that ECA is localized in the outer membrane of ECA-containing strains and further demonstrate that there is more in the immunogenic strains than in the nonimmunogenic ones.


Human relaxin in the amnion, chorion, decidua parietalis, basal plate, and placental trophoblast by immunocytochemistry and northern analysis.
Immunocytochemistry and Northern analysis were used to show that relaxin is a product of intrauterine tissues of pregnancy. In addition, tissues from a patient without ovaries had similar results on both immunocytochemistry and Northern analysis as tissues from intact patients. The parietal decidua was clearly the major source of relaxin within the uterus and the relaxin mRNA (1.2 kilobases) from this tissue was detected with a 48-mer oligonucleotide probe designed to hybridize with both H1 and H2 relaxin gene transcripts. The mRNA isolated from the placental trophoblast was slightly smaller (1.1 kilobases), and the placental basal plate which has both maternal and fetal cells contained relaxin mRNAs of both sizes. Two monoclonal antibodies (Mabs) raised to synthetic human relaxin (H2) gave different patterns of localization in the fetal membranes, decidua and placenta. One Mab (RLX8) stained the chorionic cytotrophoblast in the fetal membranes and all of the cells in the placental basal plate. The other Mab (RLX6) stained the chorionic cytotrophoblast in some instances and selectively stained the decidua-like cells of the placental syncytiotrophoblast, whereas Mab RLX8 failed to detect this relaxin. Tissues obtained after spontaneous labor and delivery contained significantly less relaxin mRNA than tissues obtained at elective cesarean section without labor, but their hormone contents, as judged by immunocytochemistry, were not different. We conclude that the relaxin gene (H2) is expressed in intrauterine tissues, but that expression and hormone synthesis are not ubiquitous. Whether the relaxin gene H1 is expressed has not been determined.


In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties.
We examined the leukemic stem cell potential of blasts at different stages of maturation in childhood acute lymphoblastic leukemia (ALL). Human leukemic bone marrow was transplanted intrafemorally into NOD/scid mice. Cells sorted using the B precursor differentiation markers CD19, CD20, and CD34 were isolated from patient samples and engrafted mice before serial transplantation into primary or subsequent (up to quaternary) recipients. Surprisingly, blasts representative of all of the different maturational stages were able to reconstitute and reestablish the complete leukemic phenotype in vivo. Sorted blast populations mirrored normal B precursor cells with transcription of a number of stage-appropriate genes. These observations inform a model for leukemia-propagating stem cells in childhood ALL.


The case for improved care and provision of treatment for people with first-episode mania.
The care of people with first-episode mania has been overlooked in comparison with the care of patients with other non-affective psychoses, despite evidence suggesting targeted treatments might be of benefit for this patient group. In this Personal View, we outline the general epidemiology of first-episode mania in the context of bipolar disorder, the natural history of mania (with an emphasis on its recurrent nature), current evidence for pharmacological, psychological, and service-level interventions, current guidelines for the treatment of first-episode mania, and provide a patient's point of view of the care pathway (appendix). We note the paucity of high-quality evidence for interventions in first-episode mania and the lack of agreement among treatment guidelines in relation to treatment, especially maintenance treatment. We suggest that, based on high morbidity and clinical need, research evidence to inform guideline development is necessary, and in the interim, clearer guidance on treatment and diagnosis should be given; specifically, we have suggested that patients should be cared for within a first-episode psychosis service, when such a service exists.


Comparison of some pharmacokinetic parameters of 5 angiotensin-converting enzyme inhibitors in normal beagles.
This study was designed to determine the degree of inhibition of the angiotensin-converting enzyme (ACE) in 5 normal dogs given single doses of conventionally used ACE inhibitors (ACEis). In addition the time required for that inhibition to return to 50% of the difference between maximum and zero (control values) was measured as an estimate of duration of action. The 5 ACEis (with dosages given in parentheses) were benazapril (0.5 mg/kg), captopril (2.0 mg/kg), enalapril (0.5 mg/kg), lisinopril (0.5 mg/kg), and ramipril (0.25 mg/kg). Blood samples for ACE activities were obtained before dosing and at 1.5, 3.0, 6.0, 12.0, and 24.0 hours after dosing. All ACEis except captopril decreased ACE activities to approximately 25% of control by the 1.5- to 3.0-hour sample, and ACE activities returned to 50% of the difference by the 12-hour sample. The value of AVE activity returned to normal by 24 hours for benazapril, whereas values for ACE activity remained below normal for enalapril, lisinopril, and ramipril at 24 hours. For captopril, however, ACE levels decreased to approximately 80% of control by the 1.5-hour recording, and returned to levels not different from control by the 3-hour recording. Based upon this study performed on normal dogs given a single dose, no pharmacokinetic advantage or disadvantage is apparent for any ACEi except captopril, which, at the dosage used, decreased ACE levels to a much lesser degree and shorter time.


Sirolimus-induced thrombotic microangiopathy is associated with decreased expression of vascular endothelial growth factor in kidneys.
The aim of this study was to examine the clinical characteristics, the histological features and the renal expression of vascular endothelial growth factor (VEGF) of five patients with sirolimus-associated thrombotic microangiopathy (TMA). Sirolimus-induced TMA occurs preferentially in kidneys with concomitant endothelial injury: it was observed in three patients with acute cellular rejection on calcineurin inhibitor-free regimen, in one patient with chronic graft rejection on a calcineurin inhibitor-free protocol and in one patient with chronic calcineurin inhibitor nephrotoxicity. We found that renal VEGF expression during sirolimus-induced TMA was significantly lower than VEGF expression in normal transplanted kidneys (p < 0.01). Decreased expression of VEGF seems to be a consequence of sirolimus treatment since (i) analysis of two biopsies performed after the switch of sirolimus to calcineurin inhibitor showed reappearance of VEGF expression, (ii) no decreased expression of VEGF was found in five kidneys with classical TMA and, (iii) an increased expression of VEGF was observed in seven kidneys with acute cellular rejection on a sirolimus-free immunosuppressive regimen (p < 0.01). The potential role of sirolimus-induced downregulation of VEGF as a predisposing factor to the development of TMA is discussed.


Plasma cell leukemia: case series from a tertiary center with review of literature.
Plasma cell leukemia is an unusual manifestation of multiple myeloma, reported to occur in 2% of newly diagnosed patients. It may either present at the time of diagnosis (primary) or evolve as a late feature in the course of multiple myeloma (secondary). Most clinical signs of myeloma are observed in plasma cell leukemia, although osteolytic lesions and bone pain are less frequent and lymphadenopathy, organomegaly and renal failure are more often present. The immunophenotype of plasma cell leukemia differs typically from that of myeloma by lack of aberrant CD56 expression. An abnormal karyotype is more frequently found in plasma cell leukemia and there is higher incidence of unfavourable cytogenetics. Plasma cell leukemia is an aggressive disease, characterized by a fulminant course and a short survival. We are reporting cases of this rare condition which presented at our center over 3 years along with review of literature.


Cortical Bone Porosity in Rabbit Models of Osteoporosis.
Cortical bone porosity is intimately linked with remodeling, is of growing clinical interest, and is increasingly accessible by imaging. Thus, the potential of animal models of osteoporosis (OP) to provide a platform for studying how porosity develops and responds to interventions is tremendous. To date, rabbit models of OP have largely focused on trabecular microarchitecture or bone density; some such as ovariectomy (OVX) have uncertain efficacy and cortical porosity has not been extensively reported. Our primary objective was to characterize tibial cortical porosity in rabbit-based models of OP, including OVX, glucocorticoids (GC), and OVX + GC relative to controls (SHAM). We sought to: (i) test the hypothesis that intracortical remodeling is elevated in these models; (ii) contrast cortical remodeling and porosity in these models with that induced by parathyroid hormone (1-34; PTH); and (iii) contrast trabecular morphology in the proximal tibia across all groups. Evidence that an increase in cortical porosity occurred in all groups was observed, although this was the least robust for GC. Histomorphometric measures supported the hypothesis that remodeling rate was elevated in all groups and also revealed evidence of uncoupling of bone resorption and formation in the GC and OVX + GC groups. For trabecular bone, a pattern of loss was observed for OVX, GC, and OVX + GC groups, whereas the opposite was observed for PTH. Change in trabecular number best explained these patterns. Taken together, the findings indicated rabbit models provide a viable and varied platform for the study of OP and associated changes in cortical remodeling and porosity. Intriguingly, the evidence revealed differing effects on the cortical and trabecular envelopes for the PTH model. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)..


[Basic studies on cancer pain control].
According to the World Health Organization (WHO) guidelines for patients with moderate or severe pain, morphine has been used as a "gold standard" treatment for cancer pain. Recent clinical experiences have demonstrated that when morphine is used to control pain in cancer patients, psychological dependence is not a major concern. However, undue anxiety about psychological dependence on morphine in cancer patients has caused physicians and patients to use inadequate doses of opioids. In basic research, we reported that the morphine-induced rewarding effects can be dramatically suppressed under a neuropathic pain-like state induced by sciatic nerve ligation and an inflammatory pain-like state produced by intraplantar injection of formalin or carrageenan in rodents. The use of morphine for the treatment of pain is sometimes accompanied with side effects such as emesis, constipation and drowsiness. We show that the lower doses of morphine produce emesis, whereas antinociceptive doses of morphine show no emetic responses in ferrets. These findings provide further evidence that an adequate dose of morphine is useful and safe in a clinical setting.


Cervical artery dissection expands the cardiovascular phenotype in FBN1-related Weill-Marchesani syndrome.
Weill-Marchesani syndrome (WMS) is a rare form of acromelic dysplasia that is characterized by distinctive skeletal, ocular, and cardiovascular abnormalities. Previously described cardiac manifestations of WMS include aortic and pulmonary valve stenosis, mitral valve prolapse, mitral stenosis, and QTc prolongation. Autosomal dominant forms of WMS result from heterozygous pathogenic variants in FBN1, a gene with a well characterized role in the pathogenesis of thoracic aortic aneurysm (TAA) in the context of Marfan syndrome. In contrast, only one patient has been reported with aortic disease in WMS. Although the risk of aortic dissection from preceding TAA remains the leading cause of morbidity for individuals with Marfan syndrome, rare reports of arterial dissection in the peripheral vasculature have been described. Peripheral artery dissection has not been previously reported in other FBN1-related diseases. We describe a three generation family with FBN1-related WMS whose cardiovascular manifestations include TAA and cervical artery dissection, thus expanding the cardiovascular phenotype of WMS. Further research is required to quantify these risks and establish appropriate recommendations for cardiovascular imaging, medical management, and prophylactic surgical intervention in individuals with FBN1--related acromelic dysplasia.


Low- and high-intensity treadmill exercise attenuates chronic morphine-induced anxiogenesis and memory impairment but not reductions in hippocampal BDNF in female rats.
Previous studies from our laboratory have shown that treadmill exercise alleviates the deficits in cognitive functions and anxiety behaviors induced by chronic exposure to morphine in male rats. In this study, we investigated the effects of low and high intensities of treadmill exercise on spatial memory, anxiety-like behaviors, and biochemical changes in the hippocampus and serum of morphine-treated female rats. The adult virgin female rats were injected with bi-daily doses (10mg/kg, at 12h intervals) of morphine over a period of 10days. Following these injections, the rats were exercised under low or high intensities for 30min per session on five days a week for four weeks. After exercise training, object location memory, anxiety profile, hippocampal BDNF, and serum corticosterone and BDNF were examined. Morphine-treated animals exhibited increased anxiety levels, impaired object location memory, and reduced hippocampal BDNF. Exercise alleviated these impairing effects on anxiety profile and memory but not hippocampal BDNF. The high-intensity exercise even further reduced the hippocampal BDNF. Additionally, both exercise regimens in the morphine group and the high exercise in the saline group reduced serum BDNF. Finally, the high-intensity exercise enhanced corticosterone serum. These findings indicate that the negative cognitive and behavioral effects of chronic exposure to morphine could be relieved by forced exercise in female rats. However, the exercise intensity is an important factor to be considered during exercise training. Finally, the correlation between changes of brain and serum BDNF and cognitive functions following morphine exposure needs further research.


Diastolic dysfunction and thin filament dysregulation resulting from excitation-contraction uncoupling in a mouse model of restrictive cardiomyopathy.
Restrictive cardiomyopathy (RCM) has been linked to mutations in the thin filament regulatory protein cardiac troponin I (cTnI). As the pathogenesis of RCM from genotype to clinical phenotype is not fully understood, transgenic (Tg) mice were generated with cardiac specific expression of an RCM-linked missense mutation (R193H) in cTnI. R193H Tg mouse hearts with 15% stoichiometric replacement had smaller hearts and significantly elevated end diastolic pressures (EDP) in vivo. Using a unique carbon microfiber-based assay, membrane intact R193H adult cardiac myocytes generated higher passive tensions across a range of physiologic sarcomere lengths resulting in significant Ca(2+) independent cellular diastolic tone that was manifest in vivo as elevated organ-level EDP. Sarcomere relaxation and Ca(2+) decay was uncoupled in isolated R193H Tg adult myocytes due to the increase in myofilament Ca(2+) sensitivity of tension, decreased passive compliance of the sarcomere, and adaptive in vivo changes in which phospholamban (PLN) content was decreased. Further evidence of Ca(2+) and mechanical uncoupling in R193H Tg myocytes was demonstrated by the biphasic response of relaxation to increased pacing frequency versus the negative staircase seen with Ca(2+) decay. In comparison, non-transgenic myocyte relaxation closely paralleled the accelerated Ca(2+) decay. Ca(2+) transient amplitude was also significantly blunted in R193H Tg myocytes despite normal mechanical shortening resulting in myocyte hypercontractility when compared to non-transgenics. These results identify for the first time that a single point mutation in cTnI, R193H, directly causes elevated EDP due to a myocyte intrinsic loss of compliance independent of Ca(2+) cycling or altered cardiac morphology. The compound influence of impaired relaxation and elevated EDP represents a clinically severe form of diastolic dysfunction similar to the hemodynamic state documented in RCM patients.


Perstraction of Intracellular Pigments through Submerged Fermentation of Talaromyces spp. in a Surfactant Rich Media: A Novel Approach for Enhanced Pigment Recovery.
A high percentage of the pigments produced by Talaromyces spp. remains inside the cell, which could lead to a high product concentration inhibition. To overcome this issue an extractive fermentation process, perstraction, was suggested, which involves the extraction of the intracellular products out of the cell by using a two-phase system during the fermentation. The present work studied the effect of various surfactants on secretion of intracellular pigments produced by Talaromyces spp. in submerged fermentation. Surfactants used were: non-ionic surfactants (Tween 80, Span 20 and Triton X-100) and a polyethylene glycerol polymer 8000, at different concentrations (5, 20, 35 g/L). The highest extracellular pigment yield (16 OD500nm) was reached using Triton X-100 (35 g/L), which was 44% higher than the control (no surfactant added). The effect of addition time of the selected surfactant was further studied. The highest extracellular pigment concentration (22 OD500nm) was achieved when the surfactant was added at 120 h of fermentation. Kinetics of extracellular and intracellular pigments were examined. Total pigment at the end of the fermentation using Triton X-100 was 27.7% higher than the control, confirming that the use of surfactants partially alleviated the product inhibition during the pigment production culture.


Stomatal regulation and water potential variation in European beech: challenging the iso/anisohydry concept.
The iso/anisohydric continuum has been used to classify tree species' drought response strategies. The range over which stomata are regulating leaf water potential (ψl) before turgor loss occurs can be described with metrics such as the dependence of ψl on soil water potential (ψsoil) and the size of 'hydroscape area' (HA), but corresponding field data from adult trees are scarce. We examined the stomatal conductance (gs)-ψl relationship in its temporal (diurnal vs seasonal and interannual) and spatial (within-crown vs between-site) variation in European beech, using extensive ψl and gs measurements in the canopy of four beech stands across a precipitation gradient, and complemented the data set by published ψl and gs measurements in further Central European beech stands (including the extreme 2018 drought) in order to cover the full water potential operation space of the species. Both metrics characterize beech as a strictly anisohydric species with δψl/δψsoil >> 1 and HA = 4 MPa2. However, stomates close sensitively in response to increasing vapor pressure deficit, disproving the widely assumed dependence of large ψl variation on looser stomatal control. Characterizing the water status regulation mechanisms of trees requires separating diurnal from day-to-day variation in ψl and gs. The large diurnal and seasonal ψl variation in beech leaves is partly caused by a low leaf tissue elasticity, suggesting that a whole-plant perspective with consideration of osmotic and elastic tissue properties and stem and root hydraulics is needed for fully understanding ψl regulation and the drought tolerance strategy of trees.


The association between breast cancer and diet and other factors.
To explore the effects of diet and other factors on breast cancer development, a case-control study was conducted in Tianjin between 1986-87. After adjusting for confounding factors, it was found that factors associated with increased risk of breast cancer included --early age at menarche; late age at menopause; late age at first birth; high Qutelet's index; histories of breast wound, disease and benign tumor; and a family history of malignant tumor, high fat, high calorie, low vegetable intake; elevated serum cholesterol and LDL-cholesterol; and lower levels of serum HDL-cholesterol and whole blood selenium.


[Compared to whole body scanning thyroglobulin assay is reliable in the follow-up of thyroidectomized patients with thyroid carcinoma].
To determine whether it is reliable to do thyroglobulin measurements during thyroid hormone substitution (Tg ON) alone or whether it is also necessary to do 131I total body scanning (TBS) and Tg measurements after withdrawal of thyroid hormone substitution (Tg OFF) in the follow-up of patients with differentiated thyroid carcinoma. Retrospective. University Hospital Nijmegen. 202 Patients (151 females and 51 males, mean age 50.6 years) with differentiated thyroid carcinoma were examined in the period 1970-90. All patients had undergone total thyroidectomy and if necessary 131I ablation. 27 Patients with Tg antibodies were excluded (13.4%). In 175 patients Tg OFF levels were compared with TBS and clinical and radiological data. In 81 of them Tg ON levels were also compared. Specificity of Tg OFF and Tg ON measurement was 83 and 88%. Sensitivity of Tg OFF and Tg ON measurement was 100 and 92%. In detecting local residual thyroid tissue Tg OFF was superior to Tg ON. In detecting metastases Tg OFF and Tg ON were both superior to TBS. In the follow-up of patients with differentiated thyroid carcinoma it is reliable to do Tg measurements during thyroid hormone suppression. When Tg ON is detectable (> 3 pmol/l) TBS and Tg OFF measurement and if necessary further investigations have to be performed.


High-density lipoprotein facilitates in vivo delivery of α-tocopherol-conjugated short-interfering RNA to the brain.
We originally reported the use of vitamin E (α-tocopherol) as an in vivo vector of short-interfering RNA (siRNA) to the liver. Here, we apply our strategy to the brain. By combining high-density lipoprotein (HDL) as a second carrier with α-tocopherol-conjugated siRNA (Toc-siRNA) in the brain, we achieved dramatic improvement of siRNA delivery to neurons. After direct intracerebroventricular (ICV) infusion of Toc-siRNA/HDL for 7 days, extensive and specific knock-down of a target gene, β-site amyloid precursor protein cleaving enzyme 1 (BACE1), was observed in both mRNA and protein levels, especially in the cerebral cortex and hippocampus. This new delivery method achieved a much more prominent down-regulation effect than conventional silencing methods of the brain gene, i.e., ICV infusion of nonconjugated siRNA or oligonucleotides. With only 3 nmol Toc-siRNA with HDL, BACE1 mRNA in the parietal cortex could be reduced by ∼ 70%. We suppose that this dramatic improvement of siRNA delivery to the brain is due to the use of lipoprotein receptor-mediated endocytosis because the silencing efficiency was significantly increased by binding of Toc-siRNA to the lipoprotein, and in contrast, was clearly decreased in lipoprotein-receptor knockout mice. These results suggest exogenous siRNA could be used clinically for otherwise incurable neurological diseases.


Spontaneous gastrointestinal perforation in cats: a retrospective study of 13 cases.
The aim of this study was to describe the clinical characteristics and the frequency of malignant vs non-malignant causes for spontaneous gastrointestinal perforation in cats. The medical records of cats diagnosed as having gastrointestinal perforation between August 2010 and July 2013 were reviewed. Diagnosis was confirmed by exploratory surgery. Patients with incomplete records, perforation due to external trauma, leakage at previous enterotomy or anastomotic sites, or foreign bodies were excluded. Each record was examined for different information pertaining to signalment, medical history, clinical and clinicopathological data, imaging findings, abdominal fluid examination, surgical findings, histopathological examination, treatment received after surgery and outcome. Thirteen cats were included. Five of these cats had concurrent illnesses, including viral upper respiratory tract disease, pancreatitis and chronic kidney disease. Two cats had previously received non-steroidal anti-inflammatory drugs and four had received corticosteroids. Clinical signs and clinicopathological abnormalities were not specific. Six of 13 patients were diagnosed during surgery with gastric perforations, four patients with duodenal perforations and three patients with jejunal perforations. Histopathological examination of the ulcerated wall was performed in 11/13 cats. Alimentary lymphoma was diagnosed in six cats. Non-neoplastic lesions (lymphocytic- plasmacytic inflammatory bowel disease, necrotic suppurative enteritis) were observed in the other five cats. The major limitation of the study was the small sample size. Lymphoma may be a frequent cause of spontaneous perforation in cats. Therefore, histological examination of ulceration is essential in all cases. The direct and sole implication of anti-inflammatory administration in a gastrointestinal perforation is not clearly established in this study.


The socio-psychological factors of family planning with special reference to Iran: a theoretical appraisal.
Iran's explosive population growth, which increases the country's population by about 1.9 million people annually, is causing a considerable strain on resources and the environment, and the coming generations will be facing a serious situation unless this trend is reversed. The strength of cultural values has not encouraged a declining population growth rate in parallel with the Iranian wave of modernization before and after the revolution. A special cultural revolution is the prerequisite for a demographic revolution. This study is placing main emphasis on the social and psychological factors involved in family planning. The general findings of surveys conducted so far demonstrate that few people know anything about family planning and methods of contraception. Social, cultural, and religious institutions seem to inhibit the expansion of family planning. Moreover, the lack of economic and social security promotes a large family size and prevents contraceptive use. However, social change in Iranian society will eventually be brought about by urbanization, industrialization, and education, and the ensuing modernization of values is expected to increase the use of contraceptives and lead to changes in the associated social and cultural institutions.


Who is the real 12-HETrE?
Oxygenases, including lipoxygenases and cytochrome P450s, generate an array of structurally diverse oxylipins that modulate distinct biological responses in mammals. Depending on the source of tissues and enzymes, distinct oxylipins are generated with inherent cellular function. Here, we report structurally different forms of 12-HETrE, with distinct biological function in tissues as well as their derived enzymatic source.


IL-17A causes depression-like symptoms via NFκB and p38MAPK signaling pathways in mice: Implications for psoriasis associated depression.
Psoriasis has been shown to be associated with an increased prevalence of comorbid major depression. IL-17A plays an important role in both depression and psoriasis. IL-17A has been shown to be elevated in systemic circulation of psoriatic patients. IL-17A released from different immune cells during psoriasis may be responsible for the development of neuropsychiatric symptoms associated with depression. Therefore, this study explored the association of systemic IL-17A with depression. The present study utilized imiquimod model of psoriatic inflammation as well as IL-17A administration in mice to investigate the effect of IL-17A on depression-like behavior. Psoriatic inflammation led to enhanced IL-17A expression in peripheral immune cells of both innate and adaptive origin. This was associated with increased NFκB/p38MAPK signaling and inflammatory mediators in different brain regions, and depression-like symptoms (as reflected by sucrose preference and tail suspension tests). The role of IL-17A was further confirmed by administering it alone for ten days, followed by assessment of the same parameters. IL-17A administration produced effects similar to psoriasis-like inflammation on neurobehavior and NFκB/p38MAPK pathways. Moreover, both NFκB and p38MAPK inhibitors led to attenuation in IL-17A associated with depression-like behavior via reduction in inflammatory mediators, such as MCP-1, iNOS, IL-6, and CXCL-2. Furthermore, anti-IL17A antibody also led to a reduction in imiquimod-induced depression-like symptoms, as well as NFκB/p38MAPK signaling. The present study shows that IL-17A plays an important role in comorbid depression associated with psoriatic inflammation, where both NFκB and p38MAPK pathways play significant roles via upregulation of inflammatory mediators in the brain.


Activation of p53 in cervical cancer cells by human papillomavirus E6 RNA interference is transient, but can be sustained by inhibiting endogenous nuclear export-dependent p53 antagonists.
p53 is degraded in cervical cancer cells by the human papillomavirus E6 and can be stabilized with short interfering RNA (siRNA) molecules targeting E6 mRNA. In this in vitro study, we show that E6 siRNA-induced p53 activation is transient in HeLa cervical cancer cells despite continuous suppression of E6 mRNA; activation can be sustained if the endogenous p53 antagonists COP1, MDM2, Pirh2, and c-Jun-NH(2)-kinase are also targeted by siRNAs or by inhibiting the nuclear export of p53 with leptomycin B. The direct targeting of any one of these four cellular p53 antagonists had no effect on p53 activity when E6 was intact, but inhibited the fading off of E6 siRNA-induced p53 activation in nonstress conditions. The effect was additive when multiple cellular antagonists were concomitantly inhibited, indicating that all these proteins degrade p53 when E6 is inactivated. The antiproliferative effect induced by E6 silencing was enhanced when the endogenous p53 antagonists were additionally targeted. In conclusion, if human papillomavirus E6 is inhibited under nonstress conditions, the subsequent p53 activation is quickly reversed by the endogenous p53 degenerative machinery. The present results indicate that several cellular p53 antagonists must be inhibited for sustained p53 activity if E6 siRNA therapy is attempted and if no combined genotoxic therapy is applied.


Introducing a Pseudocapacitive Lithium Storage Mechanism into Graphite by Defect Engineering for Fast-Charging Lithium-Ion Batteries.
The extreme fast-charging capability of lithium-ion batteries (LIBs) is very essential for electric vehicles (EVs). However, currently used graphite anode materials cannot satisfy the requirements of fast charging. Herein, we demonstrate that intrinsic lattice defect engineering based on a thermal treatment of graphite in CO2 is an effective method to improve the fast-charging capability of the graphite anode. The activated graphite (AG) exhibits a superior rate capability of 209 mAh g-1 at 10 C (in comparison to 15 mAh g-1 for the pristine graphite), which is attributed to a pseudocapacitive lithium storage behavior. Furthermore, the full cell LiFePO4||AG can achieve SOCs of 82% and 96% within 6 and 15 min, respectively. The intrinsic carbon defect introduced by the CO2 treatment succeeds in improving the kinetics of lithium ion intercalation at the rate-determining step during lithiation, which is identified by the distribution of relaxation times (DRT) and density functional theory (DFT) calculations. Therefore, this study provides a novel strategy for fast-charging LIBs. Moreover, this facile method is also suitable for activating other carbon-based materials.


Impairing memory reconsolidation with propranolol in healthy and clinical samples: a meta-analysis.
Reconsolidation impairment using propranolol is a novel intervention for mental disorders with an emotional memory at their core. In this systematic review and meta-analysis, we examined the evidence for this intervention in healthy and clinical adult samples. We searched 8 databases for randomized, double-blind studies that involved at least 1 propranolol group and 1 placebo group. We conducted a meta-analysis of 14 studies (n = 478) in healthy adults and 12 studies in clinical samples (n = 446). Compared to placebo, reconsolidation impairment under propranolol resulted in reduced recall of aversive material and cue-elicited conditioned emotional responses in healthy adults, as evidenced by an effect size (Hedges g) of -0.51 (p = 0.002, 2-tailed). Moreover, compared to placebo, reconsolidation impairment under propranolol alleviated psychiatric symptoms and reduced cue-elicited reactivity in clinical samples with posttraumatic stress disorder, addiction or phobia (g = -0.42, p = 0.010). Methodological differences between studies posed an obstacle for identifying sources of heterogeneity. Reconsolidation impairment is a robust, well-replicated phenomenon in humans. Its clinical use is promising and deserves further controlled investigation.


[Cellular chemiluminescence of activated phagocytes of whole blood].
Both, the phagocytic process and the activation of phagocytes with soluble stimuli are accompanied by increased production of reactive oxygen species (ROS). Chemiluminescence (CL) measurement is a simple and sensitive method for the detection of ROS generation. Phagocytes (mainly polymorphonuclear leukocytes, PMNL) were stimulated with soluble stimulus or via phagocytosis in diluted whole blood, and the generation of Luminol-enhanced CL was registered. The time dependence of CL, determined in whole blood, corresponds to the CL from isolated leukocytes. A relationship between peak CL and the number of leukocytes as well as of PMNL was observed. The specific CL, i.e. the CL response related to a defined PMNL number, increases with the age of investigated healthy individuals. No correlations were found between CL and the capacity of PMNL to ingest zymosan particles. Relations between CL and spontaneous platelet aggregation suggest, that reactivity of blood platelets may be a contributing factor to the kinetics of the CL signal in our test system. The inhibition of CL by the sulphydryl reagents diamide and fever few extract indicate the role of cellular sulphydryl groups for phagocyte function. Measurement of CL in whole blood is proved to be a simple assay for assessment of PMNL function and allows measurements in very small blood samples (greater than or equal to 10 ul).


The morphogenetic relationship of the temporal muscle to the coronoid process in human embryos and fetuses.
The purpose of this investigation was: (a) to study the developmental relationships of the temporal muscle and the coronoid process during the critical initial stages of morphogenesis and (b) to correlate the developmental stages of the muscle and the bone with data describing the functioning of the muscles of mastication in utero. The heads of 41 human embryos and fetuses, 6 to 11 weeks, estimated fertilization age, were sectioned and examined under light microscopy. The findings are described in terms of six successive stages, each characterized by a major developmental change occurring during that stage. The data indicate that the temporal and masseter muscle anlagen begin to develop prior to the skeleton to which they ultimately become attached. The coronoid process differentiates subsequently as a discrete entity within the mass of the temporal muscle anlage at an estimated fertilization age of 7 to 7.5 weeks (23-24 mm CRL). At approximately eight weeks of age, the coronoid process unites with the main portion of the mandibular ramus. The findings here presented do not support the conclusion that the coronoid process is self-differentiating as Washburn ('47) contended. Instead, the development of this feature of the human mandible represents a response that follows the differentiation of the temporal muscle. This conclusion is consistent with the observations drawn from a number of investigations concerning structural and functional development of the face.


Dynamical Timescale Explains Marginal Stability in Excitability Dynamics.
Action potentials, taking place over milliseconds, are the basis of neural computation. However, the dynamics of excitability over longer, behaviorally relevant timescales remain underexplored. A recent experiment used long-term recordings from single neurons to reveal multiple timescale fluctuations in response to constant stimuli, along with more reliable responses to variable stimuli. Here, we demonstrate that this apparent paradox is resolved if neurons operate in a marginally stable dynamic regime, which we reveal using a novel inference method. Excitability in this regime is characterized by large fluctuations while retaining high sensitivity to external varying stimuli. A new model with a dynamic recovery timescale that interacts with excitability captures this dynamic regime and predicts the neurons' response with high accuracy. The model explains most experimental observations under several stimulus statistics. The compact structure of our model permits further exploration on the network level.SIGNIFICANCE STATEMENT Excitability is the basis for all neural computations and its long-term dynamics reveal a complex combination of many timescales. We discovered that neural excitability operates under a marginally stable regime in which the system is dominated by internal fluctuation while retaining high sensitivity to externally varying stimuli. We offer a novel approach to modeling excitability dynamics by assuming that the recovery timescale is itself a dynamic variable. Our model is able to capture a wide range of experimental phenomena using few parameters with significantly higher predictive power than previous models.


Seasonal variations in birth weights and gender of infants born in a mission hospital in Benin City, Nigeria.
To examine the relationship, if any, between the geographical season in which a baby is born and the baby's birth weight and sex. The birth weights and sexes of 6141 babies delivered over a five- year period in a Nigerian mission hospital were prospectively recorded according to the month and year of delivery. The mean birth weights and sexes of infants born in the wet season (May to October) were compared with those of their counterparts born in the dry season (November to April). Comparison of the mean birth weight during the wet and dry seasons showed that for male infants it was 3333 (542)g versus 3197 (566)g (p<0.01), while for female infants it was 3203 (559)g versus 3110 (601)g (p<0.01). When both sexes were combined, the mean birth weights were 3249 (488)g and 3164 (524)g in wet and dry seasons respectively(p<0.01). Slightly more boys than girls were born in the dry season compared with the wet season (p>0. 05). Irrespective of gender, babies born during the wet season were significantly heavier than their counterparts born during the dry season. There was a higher probability of a boy birth in the dry season.


Genome Sequence of Corynebacterium ulcerans Strain 210932.
In this work, we present the complete genome sequence of Corynebacterium ulcerans strain 210932, isolated from a human. The species is an emergent pathogen that infects a variety of wild and domesticated animals and humans. It is associated with a growing number of cases of a diphtheria-like disease around the world.