A Mushroom P450-Monooxygenase Enables Regio- and Stereoselective Biocatalytic Synthesis of Epoxycyclohexenones.
An epoxycyclohexenone (ECH) moiety occurs in natural products of both bacteria and ascomycete and basidiomycete fungi. While the enzymes for ECH formation in bacteria and ascomycetes have been identified and characterized, it remained obscure how this structure is biosynthesized in basidiomycetes. In this study, we i) identified a genetic locus responsible for panepoxydone biosynthesis in the basidiomycete mushroom Panus rudis and ii) biochemically characterized PanH, the cytochrome P450 enzyme catalyzing epoxide formation in this pathway. Using a PanH-producing yeast as a biocatalyst, we synthesized a small library of bioactive ECH compounds as a proof of concept. Furthermore, homology modeling, molecular dynamics simulation, and site directed mutation revealed the substrate specificity of PanH. Remarkably, PanH is unrelated to ECH-forming enzymes in bacteria and ascomycetes, suggesting that mushrooms evolved this biosynthetic capacity convergently and independently of other organisms.


How Can Autonomy Support from a Coach, Basic Psychological Needs, and the Psychological Climate Explain Ego and Task Involvement?
The aim of this study was to consider the relationships among the autonomy support an athlete perceives from their coach, the three basic psychological needs (autonomy, competence, and relatedness), the psychological motivational climate of the team (a task or ego climate), and the athlete's motivational orientation (ego or task involvement). No other studies have investigated this. My three hypotheses were as follows: autonomy support from a coach will have an impact on motivational involvement, all three basic needs will have an impact on motivational involvement, and motivational involvement will be explained by the motivational climate. A total of 175 elite male ice hockey players from Norway, ranging in age from 15 to 18 years old, answered questionnaires about autonomy support, perceived motivational climate, achievement goal orientation, and basic psychological needs. A multiple regression analysis was conducted to predict ego-task involvement using autonomy support from the coach, the need for autonomy, the need for competence, the need for relatedness, the task climate, and the ego climate. The only two variables that statistically significantly predicted ego-task involvement were the autonomy support from the coach (std. beta = 0.28, sign = 0.05) and the ego climate (std. beta = 0.34, sign = 0.01). The analysis revealed that the athletes had a higher score on task (M = 4.85) than ego (M = 3.34) involvement, but when these were transformed into two variables (high and low) for task and ego involvement, we found that most players scored high for both task and ego involvement. We found that autonomy support from the coach had a positive relationship with a high score for players on both task and ego involvement. We also found that the three basic psychological needs had no impact on the motivational involvement of the athletes. Lastly, we found that the ego climate had an impact on motivational involvement. There was a positive relationship between a high score for the ego climate and a high score for both ego and task involvement.


Production and utilization of pyochelin by clinical isolates of Pseudomonas cepacia.
Forty-three Pseudomonas cepacia isolates were screened for the production of pyochelin. Twenty-one (49%) produced pyochelin, and 22 (51%) were pyochelin negative. Of the 21 strains producing pyochelin, 18 were from patients with severe infections, 11 of which resulted in death. Of the 22 strains which did not produce pyochelin, 13 were from patients with mild or moderate infections. Pyochelin production by P. cepacia isolates infecting cystic fibrosis patients correlates with morbidity and mortality in these patients. Pyochelin was shown to stimulate the in vitro growth of P. cepacia in the presence of transferrin. P. cepacia isolates were able to accumulate 59Fe-pyochelin regardless of whether they produced this siderophore.


Different aspects of atrial fibrillation genetics.
Atrial fibrillation (AF) is a consequence of a complex interplay of genetic, epigenetic and environmental factors. In addition, AF is a major contributor to stroke, heart failure, and mortality. Several family studies have shown a strong polygenetic predisposition for AF but, so far, most of the linkage analysis and candidate gene studies have discovered only monogenic, rare, deleterious mutations. While research in human genetics has moved from monogenic to oligogenic to complex diseases, its pharmacogenetics branch has followed, usually a few years behind. The present paper reviews the potential contributions of genetic approaches to AF.


Early changes in inositol lipids and their metabolites induced by platelet-derived growth factor in quiescent Swiss mouse 3T3 cells.
Inositol lipid turnover was studied in quiescent Swiss mouse 3T3 cells stimulated by platelet-derived growth factor (PDGF). Stimulation of the cells by PDGF for 10 min at 37 degrees C induced the following changes in lipids: in cells prelabelled with [32P]Pi, a 28% decrease in [32P]phosphatidylinositol 4,5-bisphosphate, a 41% decrease in [32P]phosphatidylinositol 4-phosphate and a 1.7-fold increase in the 32P-labelling of phosphatidic acid; in cells prelabelled with [3H8]arachidonic acid, a 17.9-fold increase in [3H]phosphatidic acid, a 20% decrease in [3H]phosphatidylinositol (PtdIns), an 8.6-fold increase in [3H]arachidonic acid released into the medium, a 57-fold increase in [3H]prostaglandin E2 in the medium, and a 5.3-fold increase in [3H]monoacylglycerol released into the medium (the last was identified as the 2-acyl derivative); in cells prelabelled with [2-3H]glycerol, a 1.7-fold increase in [3H]diacylglycerol, a 6.7-fold increase in [3H]phosphatidic acid, a 1.6-fold increase in [3H]lysophosphatidylcholine (lysoPtdCho), a 9% decrease in [3H]PtdIns, and a 1.6-fold increase in [3H]monoacylglycerol released into the medium. PDGF stimulated the formation of inositol tris-, bis- and mono-phosphates in the cells prelabelled with myo-[2-3H]inositol. These results indicate that, in Swiss 3T3 cells stimulated by PDGF, diacylglycerol produced by the hydrolysis of inositol lipids is partly degraded to 2-acylglycerol and partly converted into phosphatidic acid. The increase in lysoPtdCho indicates that a portion of arachidonic acid released from the stimulated cells is formed by the hydrolysis of PtdCho with a phospholipase A2. Different values of half-maximal doses of the partially purified PDGF used in this study were found for the various responses of quiescent Swiss 3T3 cells to PDGF. The values for half-maximal doses suggest that activation of a fraction of the cell-surface receptor for PDGF is sufficient for mitogenesis and for an increase in the cytoplasmic free Ca2+ concentration, and that the PGDF-stimulated lipid metabolism is probably proportional to the number of receptor sites activated by PDGF.


Competition between covalent and noncovalent bond cleavages in dissociation of phosphopeptide-amine complexes.
Interactions between quaternary amino or guanidino groups with anions are ubiquitous in nature and have been extensively studied phenomenologically. However, little is known about the binding energies in non-covalent complexes containing these functional groups. Here, we present a first study focused on quantifying such interactions using complexes of phosphorylated A(3)pXA(3)-NH(2) (X = S, T, Y) peptides with decamethonium (DCM) or diaguanidinodecane (DGD) ligands as model systems. Time- and collision energy-resolved surface-induced dissociation (SID) of the singly charged complexes was examined using a specially configured Fourier transform ion cyclotron resonance mass spectrometer (FTICR-MS). Dissociation thresholds and activation energies were obtained from RRKM modeling of the experimental data that has been described and carefully characterized in our previous studies. For systems examined in this study, covalent bond cleavages resulting in phosphate abstraction by the cationic ligand are characterized by low dissociation thresholds and relatively tight transition states. In contrast, high dissociation barriers and large positive activation entropies were obtained for cleavages of non-covalent bonds. Dissociation parameters obtained from the modeling of the experimental data are in excellent agreement with the results of density functional theory (DFT) calculations. Comparison between the experimental data and theoretical calculations indicate that phosphate abstraction by the ligand is rather localized and mainly affected by the identity of the phosphorylated side chain. The hydrogen bonding in the peptide and ligand properties play a minor role in determining the energetics and dynamics of the phosphate abstraction channel.


[Effect of mutations of Escherichia coli K-12 chromosome on the integration of bacteriophage Mu introduced into cells by infection or conjugation].
We present the detailed research on the previously described Escherichia coli K-12 Mud- mutants with impaired development of bacteriophage Mu. The ability of Mu phage DNA to penetrate into mutant cells on infection was shown. If introduced into the cells or combined with mud mutation by recombination, the prophage may be induced, which results in phage Mu lythic development and phage burst from mutant cells. In the course of conjugative transfer into the mutant cells, within a DNA fragment of the lysogenic donor chromosome, MupAp1 prophage is not inherited by recombinants. At the same time, Mu prophage deficient in genes A and B, whose products are required for transposition, is inherited by the mutant with the usual frequency. These data enable us to conclude that the mud mutations disturb the stage of conservative transposition which is connected with the insertion of the Mu prophage into the chromosome, after excision from the linear DNA introduced into the cells via infection or conjugation.


Potentiation of chemotherapy in companion animals with spontaneous large neoplasms by application of biphasic electric pulses.
The objectives of this phase I/II study were: i) to determine whether electrochemotherapy (intralesional bleomycin + electric pulses) could be effective in companion animals with different, large neoplasms compared to chemotherapy (conventional intralesional bleomycin); ii) to identify potential toxicities; iii) to preliminarily assess the electric field requirements. Twenty-two patients received intralesional bleomycin + administration of permeabilizing electric pulses. Specifically, after the injection of the drug, sequences of 8 biphasic electric pulses lasting 50 + 50 micros each, with 1 ms interpulse intervals, were delivered in bursts of 1300 V/cm for cutaneous and soft tissue lesions, and of 800 V/cm for oral mucosal and exposed soft tissue neoplasms, using caliper electrodes. The treatment was well tolerated and side effects were infrequent. Nevertheless, two previously unreported toxicities (drug-induced vasculitis and pulmonary thromboembolism) have been identified. A high response rate (complete remission + partial remission: > 80%), often long lasting (> 40%) was obtained. Furthermore, results of this trial were compared to a subset of veterinary cancer patients treated with bleomycin single agent, observing a remarkable superiority of the combined treatment (p < 0.01). Altogether, results suggest that electrochemotherapy is a potentially advantageous rescue protocol for bulky, even relapsing neoplasms of companion animals. Further investigations in this field might allow developing improved protocols for the treatment of down-staged relapsing cancer in pets as well as in humans.


Muscle wasting in a rat model of long-lasting sepsis results from the activation of lysosomal, Ca2+ -activated, and ubiquitin-proteasome proteolytic pathways.
We studied the alterations in skeletal muscle protein breakdown in long lasting sepsis using a rat model that reproduces a sustained and reversible catabolic state, as observed in humans. Rats were injected intravenously with live Escherichia coli; control rats were pair-fed to the intake of infected rats. Rats were studied in an acute septic phase (day 2 postinfection), in a chronic septic phase (day 6), and in a late septic phase (day 10). The importance of the lysosomal, Ca2+ -dependent, and ubiquitin-proteasome proteolytic processes was investigated using proteolytic inhibitors in incubated epitrochlearis muscles and by measuring mRNA levels for critical components of these pathways. Protein breakdown was elevated during the acute and chronic septic phases (when significant muscle wasting occurred) and returned to control values in the late septic phase (when wasting was stopped). A nonlysosomal and Ca2+ -independent process accounted for the enhanced proteolysis, and only mRNA levels for ubiquitin and subunits of the 20 S proteasome, the proteolytic core of the 26 S proteasome that degrades ubiquitin conjugates, paralleled the increased and decreased rates of proteolysis throughout. However, increased mRNA levels for the 14-kD ubiquitin conjugating enzyme E2, involved in substrate ubiquitylation, and for cathepsin B and m-calpain were observed in chronic sepsis. These data clearly support a major role for the ubiquitin-proteasome dependent proteolytic process during sepsis but also suggest that the activation of lysosomal and Ca2+ -dependent proteolysis may be important in the chronic phase.


Survival among children with "Lethal" congenital contracture syndrome 11 caused by novel mutations in the gliomedin gene (GLDN).
Biallelic GLDN mutations have recently been identified among infants with lethal congenital contracture syndrome 11 (LCCS11). GLDN encodes gliomedin, a protein required for the formation of the nodes of Ranvier and development of the human peripheral nervous system. We report six infants and children from four unrelated families with biallelic GLDN mutations, four of whom survived beyond the neonatal period into infancy, childhood, and late adolescence with intensive care and chronic respiratory and nutritional support. Our findings expand the genotypic and phenotypic spectrum of LCCS11 and demonstrate that the condition may not necessarily be lethal in the neonatal period.


Sexual Health and Well-being Among Older Men and Women in England: Findings from the English Longitudinal Study of Ageing.
We describe levels of sexual activity, problems with sexual functioning, and concerns about sexual health among older adults in the English Longitudinal Study of Ageing (ELSA), and associations with age, health, and partnership factors. Specifically, a total of 6,201 core ELSA participants (56 % women) aged 50 to >90 completed a comprehensive Sexual Relationships and Activities questionnaire (SRA-Q) included in ELSA Wave 6 (2012/13). The prevalence of reporting any sexual activity in the last year declined with age, with women less likely than men at all ages to report being sexually active. Poorer health was associated with lower levels of sexual activity and a higher prevalence of problems with sexual functioning, particularly among men. Difficulties most frequently reported by sexually active women related to becoming sexually aroused (32 %) and achieving orgasm (27 %), while for men it was erectile function (39 %). Sexual health concerns most commonly reported by women related to their level of sexual desire (11 %) and frequency of sexual activities (8 %). Among men it was level of sexual desire (15 %) and erectile difficulties (14 %). While the likelihood of reporting sexual health concerns tended to decrease with age in women, the opposite was seen in men. Poor sexual functioning and disagreements with a partner about initiating and/or feeling obligated to have sex were associated with greater concerns about and dissatisfaction with overall sex life. Levels of sexual activity decline with increasing age, although a sizable minority of men and women remain sexually active until the eighth and ninth decades of life. Problems with sexual functioning were relatively common, but overall levels of sexual health concerns were much lower. Sexually active men reported higher levels of concern with their sexual health and sexual dissatisfaction than women at all ages. Older peoples' sexual health should be managed, not just in the context of their age, gender, and general health, but also within their existing sexual relationship.


Transcription factor ΔFosB acts within the nucleus of the solitary tract to increase mean arterial pressure during exposures to intermittent hypoxia.
ΔFosB is a member of the activator protein-1 family of transcription factors. ΔFosB has low constitutive expression in the central nervous system and is induced after exposure of rodents to intermittent hypoxia (IH), a model of the arterial hypoxemia that accompanies sleep apnea. We hypothesized ΔFosB in the nucleus of the solitary tract (NTS) contributes to increased mean arterial pressure (MAP) during IH. The NTS of 11 male Sprague-Dawley rats was injected (3 sites, 100 nl/site) with a dominant negative construct against ΔFosB (ΔJunD) in an adeno-associated viral vector (AAV)-green fluorescent protein (GFP) reporter. The NTS of 10 rats was injected with AAV-GFP as sham controls. Two weeks after NTS injections, rats were exposed to IH for 8 h/day for 7 days, and MAP was recorded using telemetry. In the sham group, 7 days of IH increased MAP from 99.8 ± 1.1 to 107.3 ± 0.5 mmHg in the day and from 104.4 ± 1.1 to 109.8 ± 0.6 mmHg in the night. In the group that received ΔJunD, IH increased MAP during the day from 95.9 ± 1.7 to 101.3 ± 0.4 mmHg and from 100.9 ± 1.7 to 102.8 ± 0.5 mmHg during the night (both IH-induced changes in MAP were significantly lower than sham, P < 0.05). After injection of the dominant negative construct in the NTS, IH-induced ΔFosB immunoreactivity was decreased in the paraventricular nucleus ( P < 0.05); however, no change was observed in the rostral ventrolateral medulla. These data indicate that ΔFosB within the NTS contributes to the increase in MAP induced by IH exposure. NEW & NOTEWORTHY The results of this study provides new insights into the molecular mechanisms that mediate neuronal adaptations during exposures to intermittent hypoxia, a model of the hypoxemias that occur during sleep apnea. These adaptations are noteworthy as they contribute to the persistent increase in blood pressure induced by exposures to intermittent hypoxia.


The rs1801133 polymorphism of methylenetetrahydrofolate reductase gene- the association with 5-year survival in patients with ST-elevation myocardial infarction.
Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in endothelial nitric oxide synthase (eNOS) coupling and homocysteine metabolism. The rs1801133 polymorphism of the MTHFR gene affects risk of coronary artery disease. We assessed its influence on 5-year survival of patients with ST-elevation acute myocardial infarction (STEMI). The study group comprised consecutive patients with STEMI. Genotyping was performed with a TaqMan SNP Genotyping Assay using the ABI 7500 Real Time PCR System (Applied Biosystems). The analyzed end-point was all-cause 5-year survival. The study group comprised 637 patients (mean age 62.3 ± 11.9 years; 25.1% females, n=160; 5-year mortality 16.3%, n=104). The percentages of TT, CT and CC genotypes were: 10.8 (n=69), 39.7 (n=253) and 49.45 (n=315), respectively. No significant differences in clinical characteristics were identified between the genotypes (p>0.05 for all parameters). Eleven (15.9%) TT homozygotes, 40 (15.8%) heterozygotes and 53 (16.8%) CC homozygotes died during follow up (p=0.99 log-rank test). TT homozygotes presented only weak and insignificant tendency towards higher mortality rates in subgroups of patients ≤75 years old (15.6 vs. 11.54%, p=0.35) or with intermediate risk according to the GRACE risk score (13.3% vs. 8.76%, p=0.42). The rs1801133 polymorphism did not show significant association with 5-year survival.


Extension of lymphocyte viability for radiation biodosimetry: Potential implications for radiological/nuclear mass casualty incidents.
Dicentric chromosome assay (DCA) is routinely used for estimating the absorbed radiation dose in exposed humans. Optimal lymphocyte viability is crucial for reliable dose estimation and most cytogenetic laboratories prefer the receipt of blood samples within 24 to 36 hours after collection. Delays in the shipment/receipt of samples can occur sometimes under certain unforeseen circumstances: (1) Adverse weather conditions, (2) distant location of blood collection sites, and (3) shipping and handling of a large number of samples after radiological/nuclear mass casualty incident(s). To circumvent some of these limitations, we evaluated the suitability of ex vivo irradiated blood samples stored in the presence of phytohemagglutinin (PHA) for 7 days at ambient temperature (22-24°C) for radiation biodosimetry. Blood samples stored in the presence of PHA for up to 7 days showed a higher mitotic index than blood samples stored without PHA. To verify the use of stored blood samples for DCA, frequencies of X-rays induced dicentric chromosomes were analyzed in the blood samples that were cultured either 24 hours after exposure or 7 days later after storage. Our results indicate that storage of ex vivo irradiated blood samples in the presence of PHA at ambient temperature was found optimal for DCA and that the radiation doses estimated by dicentric chromosome frequencies were grossly similar between the fresh and stored blood samples. Our study suggests that reliable and accurate biodosimetry results can be obtained for triage using blood samples stored for up to a week at ambient temperature in the presence of PHA.


Bone mineral density and bone turnover in postmenopausal women treated for breast cancer.
Chemotherapy and endocrine treatments for breast cancer are believed to increase risk of osteoporosis by causing early menopause in premenopausal women and by further depleting estrogen levels in postmenopausal women. Multivariate analyses were used to evaluate the contributions of 7 predictors (age, body mass index [BMI], family history of osteoporosis, months since menopause, past use of chemotherapy, and current use of tamoxifen or aromatase inhibitors) in explaining variability in bone mineral density (BMD) at the hip and the spine and bone turnover in 249 postmenopausal women who are breast cancer survivors. This report was an analysis of baseline data from a federally funded (1 R01 NR07743-01A1) intervention study on osteoporosis prevention. Mean age of the women was 58.5 years, and average BMI was 26.7 kg/m; 98% were white. All had measurable bone loss, 167 had chemotherapy, 76 were on tamoxifen, and 21 were on aromatase inhibitors. Women with higher BMI had higher BMD at the hip (P < .001) and the spine (P = .004). Women on tamoxifen had lower measures of bone formation (Alkphase B) (P < .001), suggesting less bone turnover, and higher BMD at the hip (P = .035). There was a trend for women who had received chemotherapy to have lower BMD at the spine (P = .06). The implications of these findings are discussed in the article.


Prediction of calcaneal bone competence from biomechanical accommodation variables measured during weighted walking.
Carrying weight while walking is a common activity associated with increased musculoskeletal loading, but not all individuals accommodate to the weight in the same way. Different accommodation strategies could lead to different skeletal forces, stimuli for bone adaptation and ultimately bone competence. The purpose of the study was to explore the relationships between calcaneal bone competence and biomechanical accommodation variables measured during weighted walking. Twenty healthy men and women (10 each; age 27.8 ± 6.8 years) walked on a treadmill at 1.34 m/s while carrying 0, 44.5 and 89 N weights with two hands in front of the body. Peak vertical ground reaction force and sagittal plane angular displacements of the trunk and left lower extremity during weight acceptance were measured and used to quantify accommodation. Calcaneal bone stiffness index T-score (BST) was measured using quantitative ultrasound. Correlation and stepwise multiple regression were used to predict calcaneal BST from the accommodation variables. Accommodations of the foot and ankle explained 29 and 54% (p ≤ .015) of the variance in calcaneal BST in different regression models. Statistical resampling using 1000 replications confirmed the strength and consistency of relationships, with the best model explaining 94% of the variance in calcaneal BST. Individuals who change foot and ankle function when carrying heavier weight likely alter the control of gravitational and muscular forces, thereby affecting calcaneal loading, bone adaptation and bone competence. These novel findings illustrate the importance of gait accommodation strategies and highlight a potential clinical consequence that requires further investigation.


Investigating the effect of carbon source on rabies virus glycoprotein production in Pichia pastoris by a transcriptomic approach.
Several factors affect protein expression in Pichia pastoris, one among them is the carbon source. In this work, we studied the effect of this factor on the expression level of rabies virus glycoprotein (RABV-G) in two recombinant clones harboring seven copies of the gene of interest. The expression was driven either by the constitutive glyceraldehyde-3-phosphate dehydrogenase (GAP) promoter or the inducible alcohol oxidase1 (AOX1) promoter. Clones were compared in terms of cell physiology and carbon source metabolism. The transcription levels of 16 key genes involved in the central metabolic pathway, the methanol catabolism, and the oxidative stress were investigated in both clones. Cell size, as a parameter reflecting cell physiological changes, was also monitored. Our results showed that when glucose was used as the sole carbon source, large cells were obtained. Transcript levels of the genes of the central metabolic pathway were also upregulated, whereas antioxidative gene transcript levels were low. By contrast, the use of methanol as a carbon source generated small cells and a shift in carbon metabolism toward the dissimilatory pathway by the upregulation of formaldehyde dehydrogenase gene and the downregulation of those of the central metabolic. These observations are in favor of the use of glucose to enhance the expression of RABV-G in P. pastoris.


Adaptive multiple-frame image super-resolution based on U-curve.
Image super-resolution (SR) reconstruction has been a hot research topic in recent years. This technique allows the recovery of a high-resolution (HR) image from several low-resolution (LR) images that are noisy, blurred and down-sampled. Among the available reconstruction frameworks, the maximum a posteriori (MAP) model is widely used. In this model, the regularization parameter plays an important role. If the parameter is too small, the noise will not be effectively restrained; conversely, the reconstruction result will become blurry. Therefore, how to adaptively select the optimal regularization parameter has been widely discussed. In this paper, we propose an adaptive MAP reconstruction method based upon a U-curve. To determine the regularization parameter, a U-curve function is first constructed using the data fidelity term and prior term, and then the left maximum curvature point of the curve is regarded as the optimal parameter. The proposed algorithm is tested on both simulated and actual data. Experimental results show the effectiveness and robustness of this method, both in its visual effects and in quantitative terms.


Expression of the Escherichia coli glutamate dehydrogenase gene in the cyanobacterium Synechococcus PCC6301 causes ammonium tolerance.
The unicellular cyanobacterium Synechococcus PCC6301 lacks a hybridisable homologue of the strongly conserved gdhA gene of E. coli that encodes NADP-specific glutamate dehydrogenase. This is consistent with the failure to find this enzyme in extracts of the cyanobacterium. The E. coli gdhA gene was transferred to Synechococcus PCC6301 by transformation with an integrative vector. High levels of glutamate dehydrogenase activity, similar to those found in ammonium grown E. coli cells, were found in these transformants. These transformed cyanobacteria displayed an ammonium tolerant phenotype, consistent with the action of their acquired glutamate dehydrogenase activity as an ammonium detoxification mechanism. Minor differences in colony size and in growth at low light intensity were also observed.


Skeletal responsiveness to parathyroid hormone in pseudohypoparathyroidism.
Although there have been some case reports suggesting that bone in patients with pseudohypoparathyroidism (PHP) might respond to parathyroid hormone (PTH), no information is available as to whether serum PTH concentration is related to bone metabolic markers or to bone mineral density (BMD) in PHP. To address these relationships, by comparing intact serum PTH, bone metabolic markers and BMD in patients with PHP with those in patients with idiopathic hypoparathyroidism (IHP) and postoperative hypoparathyroidism (OHP). Intact serum PTH, bone metabolic markers (osteocalcin, tartrate-resistant acid phosphatase, pyridinoline, deoxypyridinoline) and BMD by dual-energy X-ray absorptiometry or single-photon absorptiometry were measured in patients with PHP Ia (n=2) and PHP Ib (n=8). The results were compared with those in patients with IHP (n=5) and OHP (n=14). All bone metabolic markers measured were present in significantly greater amounts in patients with PHP Ib than in those with IHP+OHP. The Z score (standard deviation of average BMD at each age) of the BMD of femoral neck was significantly lower in patients with PHP Ib than in those with IHP+OHP. The Z scores of BMD of lumbar spine and radius were also lower in patients with PHP Ib than in those with IHP+OHP, but the difference was not significant. Moreover, the intact serum PTH concentrations were significantly and positively related to bone metabolic marker levels in all patients, and the intact serum PTH concentrations were significantly and negatively related to BMD of lumbar spine in PHP patients. These results suggest that PTH stimulates bone turnover in PHP Ib patients, resulting in a relatively lower BMD in PHP Ib patients than in IHP+OHP patients. The present study indicates that bones of most cases of PHP could respond to PTH.


Xylazine potentiates the lethal but not the rewarding effects of fentanyl in mice.
Fentanyl is commonly laced with xylazine. People who use this combination report heightened effects, but it also increases death risk. Although no medication has been approved to counteract overdoses produced by fentanyl and xylazine, naloxone is frequently used. This paper studies the preclinical rewarding and lethal effects of fentanyl combined with xylazine and the efficacy of yohimbine or naloxone to prevent death. Male Swiss Webster mice were treated with (in mg/kg, i.p.) xylazine (0.3, 1, 3, or 5.6), fentanyl (0.01, 0.3, or 0.1), or 1 xylazine plus 0.01 (non-effective) or 0.1 (effective) fentanyl doses during the conditioned-place preference (CPP) test. In addition, independent groups received (in mg/kg, i.p.): xylazine (31.6, 60, 74.2, or 100), fentanyl (3.1 or 10), or both substances at two doses: 31.6 xylazine + 3.1 fentanyl, or 60 xylazine + 10 fentanyl to analyze lethal effects. We determined whether yohimbine or naloxone (each medication tested at 10 or 30mg/kg) could prevent the lethality produced by fentanyl/xylazine combinations. Female mice were also tested in key experiments. Xylazine neither induced CPP nor altered fentanyl's rewarding effects. In contrast, lethality was potentiated when fentanyl was combined with xylazine. Naloxone, but not yohimbine, effectively prevented the lethality of the fentanyl/xylazine combinations. At the doses tested, xylazine does not increase the rewarding effect of fentanyl on the CPP in male mice but potentiates the risk of fatal overdose in male and female mice. A high naloxone dose prevents death induced by coadministration of fentanyl and xylazine in both sexes.


Developmental biology of pterobranch hemichordates: history and perspectives.
Hemichordates, like echinoderms and chordates, are deuterostomes, and study of their developmental biology could shed light on chordate origins. To date, molecular developmental studies in hemichordates have been confined to the enteropneusts or acorn worms. Here, we introduce the developmental biology of the other group of hemichordate, the pterobranchs. Pterobranchs generally live in cold, deep waters; this has hampered studies of this group. However, about 40 years ago, the colonial pterobranchs Rhabdopleura compacta and R. normani were discovered from shallow water, which has facilitated their study. Using Rhabdopleura compacta from south-west England, we have initiated molecular developmental studies in pterobranchs. Here, we outline methods for collecting adults, larvae, and embryos and demonstrate culturing of larvae under laboratory conditions. Given that the larval and adult forms differ from enteropneusts, we suggest that molecular developmental studies of pterobranchs may offer new insights into chordate origins.


Extreme disruption of heterochromatin is required for accelerated hematopoietic aging.
Loss of heterochromatin has been proposed as a universal mechanism of aging across different species and cell types. However, a comprehensive analysis of hematopoietic changes caused by heterochromatin loss is lacking. Moreover, there is conflict in the literature around the role of the major heterochromatic histone methyltransferase Suv39h1 in the aging process. Here, we use individual and dual deletion of Suv39h1 and Suv39h2 enzymes to examine the causal role of heterochromatin loss in hematopoietic cell development. Loss of neither Suv39h1 nor Suv39h2 individually had any effect on hematopoietic stem cell function or the development of mature lymphoid or myeloid lineages. However, deletion of both enzymes resulted in characteristic changes associated with aging such as reduced hematopoietic stem cell function, thymic involution and decreased lymphoid output with a skewing toward myeloid development, and increased memory T cells at the expense of naive T cells. These cellular changes were accompanied by molecular changes consistent with aging, including alterations in nuclear shape and increased nucleolar size. Together, our results indicate that the hematopoietic system has a remarkable tolerance for major disruptions in chromatin structure and reveal a role for Suv39h2 in depositing sufficient H3K9me3 to protect the entire hematopoietic system from changes associated with premature aging.


Biology and significance of alpha-fetoprotein in hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths globally due, in part, to the majority of patients being diagnosed with intermediate or advanced stage disease. Our increased understanding of the heterogeneous molecular pathogenesis of HCC has led to significant developments in novel targeted therapies. Despite these advances, there remains a high unmet need for new treatment options. HCC is a complex disease with multiple pathogenic mechanisms caused by a variety of risk factors, making it difficult to characterize with a single biomarker. In fact, numerous biomarkers have been studied in HCC, but alpha-fetoprotein (AFP) remains the most widely used and accepted serum marker since its discovery over 60 years ago. This review summarizes the most relevant studies associated with the regulation of AFP at the gene and protein levels; the pathophysiology of AFP as a pro-proliferative protein; and the correlation of AFP with molecular HCC subclasses, the vascular endothelial growth factor pathway and angiogenesis. Also described are the historical and current uses of AFP for screening and surveillance, diagnosis, its utility as a prognostic and predictive biomarker and its role as a tumour antigen in HCC. Taken together, these data demonstrate the relevance of AFP for patients with HCC and identify several remaining questions that will benefit from future research.


Advancements in pH-responsive nanocarriers: enhancing drug delivery for tumor therapy.
Tumors pose a significant global economic and health burden, with conventional cancer treatments lacking tumor specificity, leading to limited efficiency and undesirable side effects. Targeted tumor therapy is imminent. Tumor cells produce lactate and hydrogen ions (H+) by Warburg effect, forming an acidic tumor microenvironment (TME), which can be employed to design targeted tumor therapy. Recently, progress in nanotechnology has led to the development of pH-responsive nanocarriers, which have gathered significant attention. Under acidic tumor conditions, they exhibit targeted accumulation within tumor sites and controlled release profiles of therapeutic reagents, enabling precise tumor therapy. This review comprehensively summarize the principles underlying pH-responsive features, discussing various types of pH-responsive nanocarriers, their advantages, and limitations. Innovative therapeutic drugs are also examined, followed by an exploration of recent advancements in applying various pH-responsive nanocarriers as delivery systems for enhanced tumor therapy. pH-responsive nanocarriers have garnered significant attention for their capability to achieve targeted accumulation of therapeutic agents at tumor sites and controlled drug delivery profiles, ultimately increasing the efficiency of tumor eradication. It is anticipated that the employment of pH-responsive nanocarriers will elevate the effectiveness and safety of tumor therapy, contributing to improved overall outcomes.


A 3-D visualization method for image-guided brain surgery.
This paper deals with a 3D methodology for brain tumor image-guided surgery. The methodology is based on development of a visualization process that mimics the human surgeon behavior and decision-making. In particular, it originally constructs a 3D representation of a tumor by using the segmented version of the 2D MRI images. Then it develops an optimal path for the tumor extraction based on minimizing the surgical effort and penetration area. A cost function, incorporated in this process, minimizes the damage surrounding healthy tissues taking into consideration the constraints of a new snake-like surgical tool proposed here. The tumor extraction method presented in this paper is compared with the ordinary method used on brain surgery, which is based on a straight-line based surgical tool. Illustrative examples based on real simulations present the advantages of the 3D methodology proposed here.


Treatment patterns in patients with advanced gastric cancer in Taiwan.
To describe treatment patterns, outcomes and healthcare resource use in patients with metastatic and/or locally recurrent, unresectable gastric cancer (MGC) in Taiwan. Patients who had received first-line therapy (platinum and/or fluoropyrimidine) followed by second-line therapy or best supportive care (BSC) only were eligible. Participating physicians provided de-identified information from patient charts. Data were summarized descriptively and Kaplan-Meier analysis was used to describe time to events. Overall, 37 physicians contributed 122 patient charts. Of the 122 patients (median age, 61 years; 62% male), 43 (35%) received BSC only following first-line therapy, whereas 79 (65%) received second-line therapy. There was heterogeneity in second-line treatment, although fluoropyrimidine with or without a platinum agent was most frequently used. Median survival was 12.5 (interquartile range [IQR], 8.2-20.8) months from MGC diagnosis for patients receiving second-line therapy and 8.0 (IQR, 5.6-not reached) months for patients receiving BSC only. The most common treatment-related symptoms were nausea/vomiting (58%); the most common cancer-related symptoms were pain (61%), ascites (35%) and nausea/vomiting (33%). Inpatient and outpatient hospitalizations were numerically more common for patients receiving second-line therapy than for those receiving BSC only; the prevalence of hospice and skilled nursing facility stays were numerically more common for patients receiving BSC only. In this Taiwanese MGC population, 65% received active second-line therapy with heterogeneity seen in the regimen used. Clinical outcomes suggest an unmet medical need in this population. This study may help inform clinical practice and future research to ultimately improve patient outcomes in Taiwan.


Nonlinear dipole inversion (NDI) enables robust quantitative susceptibility mapping (QSM).
High-quality Quantitative Susceptibility Mapping (QSM) with Nonlinear Dipole Inversion (NDI) is developed with pre-determined regularization while matching the image quality of state-of-the-art reconstruction techniques and avoiding over-smoothing that these techniques often suffer from. NDI is flexible enough to allow for reconstruction from an arbitrary number of head orientations and outperforms COSMOS even when using as few as 1-direction data. This is made possible by a nonlinear forward-model that uses the magnitude as an effective prior, for which we derived a simple gradient descent update rule. We synergistically combine this physics-model with a Variational Network (VN) to leverage the power of deep learning in the VaNDI algorithm. This technique adopts the simple gradient descent rule from NDI and learns the network parameters during training, hence requires no additional parameter tuning. Further, we evaluate NDI at 7 T using highly accelerated Wave-CAIPI acquisitions at 0.5 mm isotropic resolution and demonstrate high-quality QSM from as few as 2-direction data.


Neuroinflammation in Alzheimer's disease.
Amyloid-β plaques and neurofibrillary tangles are the main neuropathological hallmarks in Alzheimer's disease (AD), the most common cause of dementia in the elderly. However, it has become increasingly apparent that neuroinflammation plays a significant role in the pathophysiology of AD. This review summarizes the current status of neuroinflammation research related to AD, focusing on the connections between neuroinflammation and some inflammation factors in AD. Among these connections, we discuss the dysfunctional blood-brain barrier and alterations in the functional responses of microglia and astrocytes in this process. In addition, we summarize and discuss the role of intracellular signaling pathways involved in inflammatory responses in astrocytes and microglia, including the mitogen-activated protein kinase pathways, nuclear factor-kappa B cascade, and peroxisome proliferator-activated receptor-gamma transcription factors. Finally, the dysregulation of the control and release of pro- and anti-inflammatory cytokines and classic AD pathology (amyloid plaques and neurofibrillary tangles) in AD is also reviewed.


Development of a foot care model to determine the risk of foot problems among homeless adults in Canada.
Foot care is a common problem for homeless adults in cities, who often receive fragmented foot care services, resulting in increased foot problems, health complications, hospitalisation, limb removal and disabilities. Among the health factors that negatively affect the homeless, foot health is essential, but often neglected. This study employed a descriptive, cross-sectional research design to assess the foot care of homeless people and develop recommendations for clinical practice. Using Inlow's 60-s foot screening method, the foot conditions of a purposive sample of 65 homeless adults were examined in British Columbia, Canada, in 2019-2020. Descriptive and inferential statistics were used to analyse the data. Determinants, such as sex and years of homelessness significantly contributed to homeless individuals' risk of developing foot problems. Differences in perceived and observed foot problems were influenced by equitable access to social health and healthcare services. Foot assessment is not well-covered by homeless health services and should be implemented as part of the standard medical review of homeless patients. Furthermore, foot assessment should be conducted by healthcare professionals, rather than relying on the standard practice of service users' self-report. Finally, foot care should be based on tailoring assessments and interventions for the individualised needs of homeless service users. Future research must seek ways to integrate homeless individuals' voices in the development, implementation and evaluation of foot care services.


The threat of a non-native oligochaete species in Iran's freshwater: Assessment of the diversity and origin of Eiseniella tetraedra (Savigny, 1826) and its response to climate change.
Oligochaetes are the most abundant benthic taxa in aquatic ecosystems that play an important role in food webs. The present study aims to assess the diversity and origin of Eiseniella tetraedra as a non-native species in the Lar National Park of Iran and also its response to current and future climate change. To this, we obtained the specimen from rivers and sequenced the mitochondrial gene Cytochrome Oxidase subunit I (COI) and combined them with 117 sequences from the Jajroud and Karaj rivers in Iran and native regions from GenBank (NCBI). We also run Species Distribution Modelings (SDMs) using an ensemble model approach that was estimated according to two Shared Socio-economic Pathways (SSPs): 126 and 585 of the MRI-ESM2 based on CMIP6. According to the results, all the samples examined in the current study originated from Spanish rivers, and no unique haplotype was found in the Lar National Park. Moreover, the results also show high haplotype diversity that can positively affect the success of this non-native species in different freshwater. Also, the results of SDMs depict that climate change would remarkably affect the distribution of E. tetraedra and it verifies the invasion power of E. tetraedra in Iran's freshwater ecosystems over time.


Hamstring muscle elasticity differs in specialized high-performance athletes.
The effect of training on hamstring flexibility has been widely assessed through the measurement of the maximal range of motion or passive torque. However, these global measures do not provide direct information on the passive muscle mechanical properties of individual muscle. This characterization is crucial to better understand the effect of interventions as selective adaptations may occur among synergist muscles. Taking advantage of shear wave elastography, we aimed to determine whether elite sport athletes exhibit different passive shear modulus of hamstring heads compared to controls. Passive shear modulus was measured on semitendinosus (ST), semimembranosus (SM), and biceps femoris (BF) using shear wave elastography with the knee flexed at 60° and 90°, and 90° of hip flexion. A total of 97 elite athletes from various sports including running sprint, figure skating, fencing, field hockey, taekwondo, basketball, and soccer and 12 controls were evaluated. The shear modulus measured at 60° of knee flexion was lower in SM for figure skating (P < .001; d = 1.8), taekwondo (P < .001; d = 2.1), fencing (P = .024; d = 1.0), and soccer (P = .011; d = 0.9) compared to controls, while no difference was found for athletic sprinters, field hockey, and basketball players. Shear modulus of the BF and ST muscle was not significantly different between controls and elite athletes, regardless of the sport specialization (all P values = 1). We provide evidence that the shear modulus of the SM is altered in athletes involved in elite sport practice performed over large range of motion and/or including substantial stretching program in training content (taekwondo, figure skating, fencing, and soccer).


Information seeking behavior and perceived health literacy of family caregivers of persons living with a chronic condition. The case of spinal cord injury in Switzerland.
To examine the information seeking behavior and health literacy of caregivers of individuals living with spinal cord injury in Switzerland and their impact on the caregiving experience. Nationwide survey of family caregivers of people with spinal cord injury (N = 717). Caregivers aged 18+ who assisted with activities of daily living were included. Self-reported information seeking behavior, including topics, preferred sources, and health literacy were assessed and analyzed. Health professionals were the most trusted source of information. Among information-seekers, higher health literacy levels were shown to be associated with lower subjective caregiver burden and, in turn, with higher caregivers' satisfaction with own health. Caregivers use information on different topics and coming from different sources. In order for information to improve the caregiving experience, however, caregivers need health literacy skills to make sense of it. Building health literacy is a promising approach to support caregivers in their activities, reduce their subjective burden, and even to improve their health. Interventions should consider involving health professionals, as the most trusted source of information, and address both health-related and more practical issues.


Anti-idiotypic antibodies bear the internal image of a human tumor antigen.
Goat antibodies to idiotypes (anti-idiotypic antibodies; Ab2) that recognize an idiotype associated with the combining site of a BALB/c mouse IgG2a monoclonal antibody (Ab1) to human gastric carcinoma were used to immunize BALB/c mice and rabbits. A monoclonal anti-anti-idiotypic antibody (Ab3) of IgG1 isotype was obtained after immunization of mice. The Ab3 and the Ab1 showed identical binding specificities and bound with similar avidities to the same tumor antigen. The induction of Ab1-like Ab3 by Ab2 was not restricted to mice, since Ab3 could also be induced in rabbits. Both the mouse- and the rabbit-derived Ab3 bound the same gastrointestinal cancer-associated antigen as Ab1. These findings indicate that Ab2 induced the formation of antigen-specific Ab3, probably because it bears the internal image of the tumor-associated antigen. This Ab2 may therefore have potential for modulating the immune response of cancer patients to their tumors.


Chia (Salvia hispanica L) gel can be used as egg or oil replacer in cake formulations.
This study determined the overall acceptability, sensory characteristics, functional properties, and nutrient content of cakes made using chia (Salvia hispanica L) gel as a replacement for oil or eggs. Chia gel was used to replace 25%, 50%, and 75% of oil or eggs in a control cake formulation. Seventy-five untrained panelists participated in rating cakes on a seven-point hedonic scale. Analysis of variance conducted on the sensory characteristics and overall acceptability indicated a statistically significant effect when replacing oil or eggs for color, taste, texture, and overall acceptability (P<0.05). Post hoc analysis (using Fisher's least significant difference method) indicated that the 25% chia gel cakes were not significantly different from the control for color, taste, texture, and overall acceptability. The 50% oil substituted (with chia gel) cake, compared to control, had 36 fewer kilocalories and 4 g less fat per 100-g portion. Cake weight was not affected by chia gel in the formulation, although cake volume was lower as the percentage of substitution increased. Symmetry was generally not affected. This study demonstrates that chia gel can replace as much as 25% of oil or eggs in cakes while yielding a more nutritious product with acceptable sensory characteristics.


Depletion of intracellular polyamines relieves inward rectification of potassium channels.
Two different approaches were used to examine the in vivo role of polyamines in causing inward rectification of potassium channels. In two-microelectrode voltage-clamp experiments, 24-hr incubation of Xenopus oocytes injected with 50 nl of difluoromethylornithine (5 mM) and methylglyoxal bis(guanylhydrazone) (1 mM) caused an approximate doubling of expressed Kir2.1 currents and relieved rectification by causing an approximately +10-mV shift of the voltage at which currents are half-maximally inhibited. Second, a putrescine auxotrophic, ornithine decarboxylase-deficient Chinese hamster ovary (O-CHO) cell line was stably transfected with the cDNA encoding Kir2.3. Withdrawal of putrescine from the medium led to rapid (1-day) loss of the instantaneous phase of Kir2.3 channel activation, consistent with a decline of intracellular putrescine levels. Four days after putrescine withdrawal, macroscopic conductance, assessed using an 86Rb+ flux assay, was approximately doubled, and this corresponded to a +30-mV shift of V1/2 of rectification. With increasing time after putrescine withdrawal, there was an increase in the slowest phase of current activation, corresponding to an increase in the spermine-to-spermidine ratio over time. These results provide direct evidence for a role of each polyamine in induction of rectification, and they further demonstrate that in vivo modulation of rectification is possible by manipulation of polyamine levels using genetic and pharmacological approaches.


The effects of feedback on focal epileptic discharges in man. A preliminary report.
The history of the control of epileptic disturbances by conditioning techniques is reviewed. The preliminary results of a three year trial of feedback techniques in 13 epileptic patients are presented. Thirteen epileptic patients (age 2.5 leads to 39 mean, 15.1 years) with lateralized focal discharges in the EEG were given repeated trials of feedback, the focal discharges being used to trigger auditory and somatosensory stimuli. Dosages and serum levels of medication were unchanged throughout the experimental period. The number of epileptic spikes per 15 seconds was assessed by automatic trend analysis during 20 to 30 minute control, biofeedback and post-feedback epochs. On-going EEG activity was quantified by 8 channel frequency analysis over 10 second epochs. The patients made efforts to increase and decrease the number of spike discharges with and without feedback and the results of both triggered and random auditory, somatosensory, photic and combined stimulation were compared at various intervals over a period of up to three years. A marked reduction in the number of focal discharges was noted in eight (61.5%) patients during and immediately following the sessions. Intermittent biofeedback sessions were not associated with a serial reduction in the number of focal EEG discharges. There was a reduction in the number of clinical epileptic disturbances in six patients (46%) and possible reasons for this improvement are discussed. One patient suffered an increase in focal temporal lobe discharges during triggered and random auditory stimulation whereas there was a marked reduction in the number of discharges during minimal electrical stimulation of the contralateral arm. The need for careful assessment of each patient to determine appropriate feedback stimulation is stressed. One aim of this research has been to assess the feasibility of using miniature units for continuous feedback of focal discharges in epileptic patients.


[Shortage in admission capacity for acute cases].
According to Poolman et al. (this issue), 6% of patients visiting the casualty department of a large Amsterdam hospital and requiring hospital admission had to be transported elsewhere at the expense of a considerable administrative effort on the part of the emergency-care physicians. Contributing factors are the way the hospital handles capacity problems, discharge procedures and personnel shortages, and, at the level of the city, the system used to allocate budget for acute care according to the relative needs of the hospitals. However, the major factor is the overall capacity problem in Dutch health care resulting from tight budget control. Despite intense discussions, major changes in this system have yet to be implemented. In the near future lack of qualified medical and nursing personnel will be the main factor that will need to be addressed urgently.


The distribution and nature of responses to broadband sounds associated with pitch in the macaque auditory cortex.
The organisation of pitch-perception mechanisms in the primate cortex is controversial, in that divergent results have been obtained, ranging from a single circumscribed 'pitch centre' to systems widely distributed across auditory cortex. Possible reasons for such discrepancies include different species, recording techniques, pitch stimuli, sampling of auditory fields, and the neural metrics recorded. In the present study, we sought to bridge some of these divisions by examining activity related to pitch in both neurons and neuronal ensembles within the auditory cortex of the rhesus macaque, a primate species with similar pitch perception and auditory cortical organisation to humans. We demonstrate similar responses, in primary and non-primary auditory cortex, to two different types of broadband pitch above the macaque lower limit in both neurons and local field potential (LFP) gamma oscillations. The majority of broadband pitch responses in neurons and LFP sites did not show equivalent tuning for sine tones.


NR2B subunit blockade does not affect motor symptoms induced by 3-nitropropionic acid.
Broad-spectrum N-methyl D-aspartate (NMDA) antagonists, although proposed in therapies for several pathologies including Huntington's disease (HD), can produce dramatic side-effects. Thus, the therapeutic potential of subunit selective NMDA receptor antagonists warrants investigation. Overactivation of NMDA receptors containing the NR2B subunit plays a pathogenic role in HD, suggesting a neuroprotective potential of selective NR2B blockade. In the present study, we investigated whether the selective NR2B receptor antagonist, R-(R*,S*)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol, could also affect motor symptoms in mice intoxicated with 3-nitropropionic acid (3-NP), a phenotypic model of HD. NR2B subunit acute blockade had no effect on spontaneous activity, HD-like symptoms (clinical scale), and sensorimotor performances (beam task) in 3-NP intoxicated mice. These results suggest that selective NR2B antagonism has no acute symptomatic effect on motor and sensorimotor impairments due to 3-NP-induced striatal injury.


Precise measurement of the neutron magnetic form factor G(M)n in the few-GeV2 region.
The neutron elastic magnetic form factor was extracted from quasielastic electron scattering on deuterium over the range Q;{2}=1.0-4.8 GeV2 with the CLAS detector at Jefferson Lab. High precision was achieved with a ratio technique and a simultaneous in situ calibration of the neutron detection efficiency. Neutrons were detected with electromagnetic calorimeters and time-of-flight scintillators at two beam energies. The dipole parametrization gives a good description of the data.


Prevalence, symptomatology, and risk factors for depression among high school students in Saudi Arabia.
To assess the prevalence and pattern of depression in a secondary school sample of Saudi Arabia adolescents. Four hundred and ninety secondary school students, comprising 306 males (62.4%) and 184 females (37.6%), in the age group 16-20, were surveyed from January to May, 2005 in Taif, Saudi Arabia, using the Arabic Beck`s Depression Inventory (BDI) by a team consisting of a psychiatrist and psychologist. The prevalence of depression according to the Beck Depression Inventory (CBDI) (cut-off point: 19) was 110 (22.4%) for moderate (19-29), 36 (7.3%) for severe (30-40), and 18 (3.7%) as very severe (>40) in this study group, with a clear predominance of prevalence of depression in girls than in boys (1.5 times). Multivariate logistic regression analysis demonstrated that the most significant risk factors involved were: gender, birth order, history of psychiatric illness, history of relative loss, and familial history of chronic diseases. Factor analysis revealed that self-criticalness, agitation, and loss of energy had the highest scores in the total sample. In the male subgroup, loss of energy, self-criticalness, punishment feeling, and agitation had the highest score while in the female subgroup, self-criticalness, agitation, and crying had the highest scores. Our findings provide gender differences in the prevalence and presentation of depressive symptoms. The experience of stressful life events increases the risk of depression. Assessment using screening is recommended. The increased risk for the onset of depression in adolescents reinforces the importance of early recognition and intervention.


[Stimulation of the healing of aseptic wounds using laser irradiation].
On the basis of experimental studies conducted on 535 albino Wistar rats and clinical observations over 125 patients, and from complex appraisal of morphological, biochemical, and tensiometric data the conclusion is drawn that optimal operative cutting of tissues is achieved by means of far infrared carbon dioxide laser beam with a wavelength of 10.6 microns. Comparison of these characteristics showed the strength of the postoperative scar to be much less in intraoperative tissue cutting with a steel scalpel or high-energy beam of an AIG laser with a wavelength of 1.06 microns. Low-intensity laser radiation increased the strength of the postoperative scar in the early periods in all groups. Tissue cutting with a high-energy carbon dioxide laser beam with a wavelength of 10.6 microns in combination with pre- and postoperative exposure of the zone of the incision to low-intensity 0.89 micron wavelength laser beam considerably increases the strength of the postoperative scar and is the method of choice in the treatment of aseptic wounds.


The representation of four personality disorders by the schedule for nonadaptive and adaptive personality dimensional model of personality.
This study examined the relationships of the Schedule for Nonadaptive and Adaptive Personality (SNAP) model of personality to 4 targeted personality disorders (PDs) in a large multisite sample of patients. Data were examined from 529 patients, who were assigned 1 of 5 primary diagnoses: borderline, schizotypal, avoidant, and obsessive-compulsive PDs and major depression without PD. Patients were administered the SNAP questionnaire and results were compared among diagnostic groups and between patient groups and nonclinical norms. Results indicated that the dimensions of the model appear to have considerable promise in differentiating normal from abnormal personality, particularly in the propensity of individuals with PDs to manifest negative affects and interpersonal detachment. Furthermore, the model appeared to successfully distinguish specific PDs, a property that represents a particular challenge for dimensional models of personality.


Adrenal Insufficiency at the Time of COVID-19: A Retrospective Study in Patients Referring to a Tertiary Center.
Coronavirus disease 2019 (COVID-19) represents a global health emergency, and infected patients with chronic diseases often present with a severe impairment. Adrenal insufficiency (AI) is supposed to be associated with an increased infection risk, which could trigger an adrenal crisis. Our primary aim was to evaluate the incidence of COVID-19 symptoms and complications in AI patients. We conducted a retrospective case-control study. All patients were on active follow-up and lived in Lombardy, Italy, one of the most affected areas. We enrolled 279 patients with primary and secondary AI and 112 controls (patients with benign pituitary lesions without hormonal alterations). All AI patients had been previously trained to modify their replacement therapy on stress doses. By administering a standardized questionnaire by phone, we collected data on COVID-19 suggestive symptoms and consequences. In February through April 2020, the prevalence of symptomatic patients (complaining at least 1 symptom of viral infection) was similar between the 2 groups (24% in AI and 22.3% in controls, P = 0.79). Highly suggestive COVID-19 symptoms (at least 2 including fever and/or cough) also occurred equally in AI and controls (12.5% in both groups). No patient required hospitalization and no adrenal crisis was reported. Few nasopharyngeal swabs were performed (n = 12), as indicated by sanitary regulations, limiting conclusions on the exact infection rate (2 positive results in AI and none in controls, P = 0.52). AI patients who are adequately treated and trained seem to display the same incidence of COVID-19-suggestive symptoms and disease severity as controls.


Recent developments in leprosy control.
Leprosy continues to be a major problem in the developing world with over 3.9 million cases registered in 1989. The control of leprosy had been considerably handicapped by the widespread occurrence of resistance of M. leprae to dapsone the most commonly used anti-leprosy drug. Together with problems of treatment compliance and social stigma this lead to leprosy control losing considerable ground. In response to the situation and taking advantage of the availability of more potent drugs, in 1981, WHO recommended standard multidrug therapy (MDT) regimens for treatment of leprosy in control programmes. The experience of implementating MDT all over the world over the last eight years has shown the regimens to be highly effective and acceptable. By 1990, nearly 50% of all the registered leprosy cases in the world were benefitting from MDT. The future prospects for leprosy control appear bright with major reductions in prevalence foreseen in the coming years.


Statistical molecular design: a tool to follow up hits from small-molecule screening.
In high-throughput screening (HTS) a robust assay is used to interrogate a large collection of small organic molecules in order to find compounds, hits, with a desired biological activity. The hits are then further explored by an iterative process where new compounds are designed, purchased, or synthesized, followed by an evaluation in one or more assays. Statistical molecular design (SMD) is a useful method to select a balanced, varied, and information-rich compound collection based on hits from HTS in order to create a foundation for development of optimized compounds with improved properties. In this chapter, we describe the use of SMD to explore a hit obtained from small-molecule screening.


Temporal pattern formation by heterochronic genes.
Heterochrony describes the phylogenetic variation in the relative timing of major developmental events. Such heterochronic variation has been noted across phylogeny, including closely related species, suggesting that particular genetic loci control global aspects of developmental timing, and that variation at those loci may play important roles in evolutionary change. Genetic analyses of heterochronic mutations in the nematode Caenorhabditis elegans reveal that control of temporal patterning is analogous to the dedicated genetic pathways that control the patterning of the spatial axes in Drosophila and other metazoans. These pathways generate graded or binary levels of regulatory factors that pattern particular axes of the developing animal. C. elegans heterochronic genes constitute a regulatory cascade that both generates a temporal decrease in the level of the LIN-14 and LIN-28 proteins and responds to the changes in these gene activities to coordinate the temporal sequence of many cell fates as the animal develops. The temporal regulation of lin-14 and lin-28 gene activities is posttranscriptional and mediated by the antisense RNA product of the lin-4 gene. Hormonal control of developmental timing is a common theme throughout phylogeny. Heterochronic genes that involve hormonal signaling have been identified in vertebrates as well as C. elegans.


Inhomogeneous kinetic effects related to intermittent magnetic discontinuities.
A connection between kinetic processes and two-dimensional intermittent plasma turbulence is observed using direct numerical simulations of a hybrid Vlasov-Maxwell model, in which the Vlasov equation is solved for protons, while the electrons are described as a massless fluid. During the development of turbulence, the proton distribution functions depart from the typical configuration of local thermodynamic equilibrium, displaying statistically significant non-Maxwellian features. In particular, temperature anisotropy and distortions are concentrated near coherent structures, generated as the result of the turbulent cascade, such as current sheets, which are nonuniformly distributed in space. Here, the partial variance of increments (PVI) method has been employed to identify high magnetic stress regions within a two-dimensional turbulent pattern. A quantitative association between non-Maxwellian features and coherent structures is established.


Identification and characterization of Clostridium perfringens beta toxin variants with differing trypsin sensitivity and in vitro cytotoxicity activity.
By producing toxins, Clostridium perfringens causes devastating diseases of both humans and animals. C. perfringens beta toxin (CPB) is the major virulence determinant for type C infections and is also implicated in type B infections, but little is known about the CPB structure-function relationship. Amino acid sequence comparisons of the CPBs made by 8 randomly selected isolates identified two natural variant toxins with four conserved amino acid changes, including a switch of E to K at position 168 (E168K) that introduces a potential trypsin cleavage site into the CPB protein of strain JGS1076. To investigate whether this potential trypsin cleavage site affects sensitivity to trypsin, a primary host defense against this toxin, the two CPB variants were assayed for their trypsin sensitivity. The results demonstrated a significant difference in trypsin sensitivity, which was linked to the E168K switch by using site-directed recombinant CPB (rCPB) mutants. The natural CPB variants also displayed significant differences in their cytotoxicity to human endothelial cells. This cytotoxicity difference was mainly attributable to increased host cell binding rather than the ability to oligomerize or form functional pores. Using rCPB site-directed mutants, differences in cytotoxicity and host cell binding were linked to an A300V amino acid substitution in the strain JGS1076 CPB variant that possessed more cytotoxic activity. Mapping of sequence variations on a CPB structure modeled using related toxins suggests that the E168K substitution is surface localized and so can interact with trypsin and that the A300V substitution is located in a putative binding domain of the CPB toxin.


Spectrum of clinical disease in a series of 135 hospitalised HIV-infected patients from north India.
Literature on the spectrum of opportunistic disease in human immunodeficiency virus (HIV)-infected patients from developing countries is sparse. The objective of this study was to document the spectrum and determine the frequency of various opportunistic infections (OIs) and non-infectious opportunistic diseases, in hospitalised HIV-infected patients from north India. One hundred and thirty five consecutive, HIV-infected patients (age 34 +/- 10 years, females 17%) admitted to a tertiary care hospital in north India, for the evaluation and management of an OI or HIV-related disorder between January 2000 and July 2003, were studied. Fever (71%) and weight loss (65%) were the commonest presenting symptoms. Heterosexual transmission was the commonest mode of HIV-acquisition. Tuberculosis (TB) was the commonest OI (71%) followed by candidiasis (39.3%), Pneumocystis jiroveci pneumonia (PCP) (7.4%), cryptococcal meningitis and cerebral toxoplasmosis (3.7% each). Most of the cases of TB were disseminated (64%). Apart from other well-recognised OIs, two patients had visceral leishmaniasis. Two cases of HIV-associated lymphoma were encountered. CD4+ cell counts were done in 109 patients. Majority of the patients (82.6%) had CD4+ counts <200 cells/microL. Fifty patients (46%) had CD4+ counts <50 cells/microL. Only 50 patients (37%) received antiretroviral therapy. Twenty one patients (16%) died during hospital stay. All but one deaths were due to TB (16 patients; 76%) and PCP (4 patients; 19%). A wide spectrum of disease, including both OIs and non-infectious opportunistic diseases, is seen in hospitalised HIV-infected patients from north India. Tuberculosis remains the most common OI and is the commonest cause of death in these patients.


[Exclusive breastfeeding and mixed feeding: knowledge, attitudes and practices of primiparous mothers].
We assessed the knowledge attitudes and practices of primiparous women with regard to exclusive breastfeeding and the use of formula milk. A total of 260 women were interviewed and the results showed that 41.5% of the women breastfed exclusively while 58.5% bottle-fed only or did so together with breastfeeding. Of those who breastfed, 43.0% did not do so soon after giving birth and did not know about colostrum. Overall, the knowledge, attitudes and practices of the mothers were unsatisfactory concerning the golden rules for successful breastfeeding, the ideal duration of exclusive breastfeeding and the food to include when introducing complementary feeding. This might be due to a low level of schooling and information, hence the need for improving strategies for maternal care during the antenatal and postnatal periods.


Genospirituality: genetic engineering for spiritual and religious enhancement.
The most frequently discussed role for genetic engineering is in relation to medicine, and a second area which provokes discussion is the use of genetic engineering as an enhancement technology. But one neglected area is the potential use of genetic engineering to increase human spiritual and religious experience - or genospirituality. If technologies are devised which can conveniently and safely engineer genes causal of spiritual and religious behaviours, then people may become able to choose their degree of religiosity or spiritual sensitivity. For instance, it may become possible to increase the likelihood of direct religious experience - i.e. 'revelation': the subjective experience of communication from the deity. Or, people may be able to engineer 'animistic' thinking, a mode of cognition in which the significant features of the world - such as large animals, trees, distinctive landscape features - are regarded as sentient and intentional beings; so that the individual experiences a personal relationship with the world. Another potentially popular spiritual ability would probably be shamanism; in which states of altered consciousness (e.g. trances, delirium or dreams) are induced and the shaman may undergo the experience of transformations, 'soul journeys' and contact with a spirit realm. Ideally, shamanistic consciousness could be modulated such that trances were self-induced only when wanted and when it was safe and convenient; and then switched-off again completely when full alertness and concentration are necessary. It seems likely that there will be trade-offs for increased spirituality; such as people becoming less 'driven' to seek status and monetary rewards - as a result of being more spiritually fulfilled people might work less hard and take more leisure. On the other hand, it is also possible that highly moral, altruistic, peaceable and principled behaviours might become more prevalent; and the energy and joyousness of the best churches might spread and be strengthened. Overall, genospirituality would probably be used by people who were unable to have the kind of spiritual or religious experiences which they wanted (or perhaps even needed) in order to lead the kind of life to which they aspired.


A review of geriatric education in Singapore.
The United Nations has identified the training and education of healthcare professionals and care providers involved in the care of older persons as a global priority. Singapore is no exception as it faces a rapidly ageing population. Older people have many medical needs of varying dimensions and their care requires a multidisciplinary healthcare team. The current status of geriatric education of health professionals involved in elderly care in Singapore is discussed in this paper. Important issues raised include the disparity between professions in the stages of development of geriatric education, questions on the adequacy of numbers and training of healthcare professionals providing geriatric care, as well as the need for geriatric education of caregivers.


Efficient oncolysis by a replicating adenovirus (ad) in vivo is critically dependent on tumor expression of primary ad receptors.
Replicating adenoviruses (Ads) are designed to replicate in and destroy cancer cells, generating viral progeny that spread within the tumor. To address the importance of the primary cellular receptor for Ads, the coxsackievirus and Ad receptor (CAR), in permitting intratumoral spread of a replicating Ad, we have used a pair of tumor cell lines differing only in the expression of a primary receptor for Ad5. This novel system thus allowed the first direct evaluation of the relationship between the efficacy of a replicating Ad and the primary receptor levels of the host cell without the confounding influence of other variable cellular factors. We demonstrate that the absence of the primary cellular receptor on the tumor cells restricts the oncolytic potency of a replicating Ad both in vitro and in vivo. Based on these findings, it is apparent that the potential therapeutic advantages afforded by viral replication would be negated by poor intratumoral spread of the viral progeny due to the failure to infect neighboring tumor cells. Because a number of studies have reported that primary cancer cells express only low levels of CAR, our results suggest that strategies to redirect Ads to achieve CAR-independent infection will be necessary to realize the full potential of replicating Ads in the clinical setting.


Optimal vein density in artificial and real leaves.
The long evolution of vascular plants has resulted in a tremendous variety of natural networks responsible for the evaporatively driven transport of water. Nevertheless, little is known about the physical principles that constrain vascular architecture. Inspired by plant leaves, we used microfluidic devices consisting of simple parallel channel networks in a polymeric material layer, permeable to water, to study the mechanisms of and the limits to evaporation-driven flow. We show that the flow rate through our biomimetic leaves increases linearly with channel density (1/d) until the distance between channels (d) is comparable with the thickness of the polymer layer (delta), above which the flow rate saturates. A comparison with the plant vascular networks shows that the same optimization criterion can be used to describe the placement of veins in leaves. These scaling relations for evaporatively driven flow through simple networks reveal basic design principles for the engineering of evaporation-permeation-driven devices, and highlight the role of physical constraints on the biological design of leaves.


Odorant receptor expression defines functional units in the mouse olfactory system.
Odorant receptors (ORs) mediate the interaction of odorous compounds with olfactory sensory neurons (OSNs) and influence the guidance of OSN axons to synaptic targets in the olfactory bulb (OB). OSNs expressing the same OR send convergent axonal projections to defined glomeruli in the OB and are thought to share the same odorant response properties. This expectation of functional similarity has not been tested experimentally, because it has not been possible to determine reproducibly the response properties of OSNs that express defined ORs. Here, we applied calcium imaging to characterize the odorant response properties of single neurons from gene-targeted mice in which the green fluorescent protein is coexpressed with a particular OR. We show that the odorants acetophenone and benzaldehyde are agonists for the M71 OR and that M71-expressing neurons are functionally similar in their response properties across concentration. Replacing the M71 coding sequence with that of the rat I7 OR changes the stimulus response profiles of this genetically defined OSN population and concomitantly results in the formation of novel glomeruli in the OB. We further show that the mouse I7 OR imparts a particular response profile to OSNs regardless of the epithelial zone of expression. Our data provide evidence that ORs determine both odorant specificity and axonal convergence and thus direct functionally similar afferents to form particular glomeruli. They confirm and extend the notion that OR expression provides a molecular basis for the formation and arrangement of glomerular functional units.


Molecular variation of human HSP90alpha and HSP90beta genes in Caucasians.
Understanding DNA variation within the human genome is fundamental to the identification and interpretation of genetic components underlying complex traits and diseases. Despite their role in many crucial cellular pathways and their reported involvement in many complex diseases no data are available on the molecular variability of the genes coding for Heat Shock Proteins 90Kda (HSP90). Towards this purpose we have used DHPLC methodology to survey, a sample of Caucasians for genetic polymorphisms in the exons and exon-flanking regions of the expressed genes of human HSP90 gene families, HSP90alpha (HSPCAL4, 14q31.3) and HSP90beta (HSPCB, 6p12). A total of 18 and 11 variants were found in the HSP90-alpha and -beta genes respectively, providing an initial view of human genetic variation in these important genes. Only three of the observed mutations altered the genic product. Interestingly, one of the variations observed was a missense mutation leading to the impairment of the hsp90alpha protein.


A lattice Monte Carlo simulation of the FePt alloy using a first-principles renormalized four-body interaction.
Although a lattice Monte Carlo method provides an effective, simple, and fast way to study thermodynamic properties of substitutional alloys, it cannot treat by itself the off-lattice effects, such as thermal vibrations and local distortions. Therefore, even if the interaction among atoms at lattice points is calculated accurately by means of first-principles calculations, the lattice Monte Carlo simulation overestimates the order-disorder phase transition temperature. In this paper, we treat this problem in the investigation of the FePt alloy, which has recently attracted considerable interest in its magnetic properties. We apply a simple version of the potential renormalization theory to determine the interaction among atoms, including partly the off-lattice effects by means of first-principles calculations. Then, we use the interaction to perform a lattice Monte Carlo simulation of the FePt alloy on a fcc lattice. From the results, we find that the transition temperature obtained after the present renormalization procedure becomes closer to the experimental value.


Scrub typhus with sepsis and acute respiratory distress syndrome.
Scrub typhus is a major infectious threat in the Asia-Pacific region. We report an unusual case of scrub typhus in a patient in Singapore who presented with sepsis and acute respiratory distress syndrome but lacked the pathognomonic eschar. The patient recovered after appropriate diagnosis and doxycycline treatment. Rickettsial diseases should be included in the differential diagnosis of febrile illnesses in regions where the diseases are endemic, and absence of eschar should not be the criterion used to rule out scrub typhus.


Thrombomodulin is silenced in malignant mesothelioma by a poly(ADP-ribose) polymerase-1-mediated epigenetic mechanism.
Malignant mesothelioma (MM) is often complicated by thromboembolic episodes, with thrombomodulin (TM) playing a critical role in the anticoagulant process. Heterogeneous expression of TM has been observed in cancer, and low or no TM expression in cancer cells is associated with poor prognosis. In this study, we analyzed TM expression in biopsies of MM patients and compared them with normal mesothelial tissue. The role of DNA methylation-associated gene silencing in TM expression was investigated. To evaluate poly(ADP-ribose) polymerase-1 (PARP1) as responsible for gene promoter epigenetic modifications, nonmalignant mesothelial cells (Met-5A) and MM cells (H28) were silenced for PARP1 and the DNA methylation/acetylation-associated TM expression evaluated. A correlation between low TM expression and high level of TM promoter methylation was found in MM biopsies. Low expression of TM was restored in MM cells by their treatment with 5-aza-2'-deoxycytidine and, to a lesser extent, with trichostatin, whereas the epigenetic agents did not affect TM expression in Met-5A cells. Silencing of PARP1 resulted in a strong down-regulation of TM expression in Met-5A cells, while restoring TM expression in H28 cells. PARP1 silencing induced TM promoter methylation in Met-5A cells and demethylation in MM cells, and this was paralleled by corresponding changes in the DNA methyltransferase activity. We propose that methylation of the TM promoter is responsible for silencing of TM expression in MM tissue, a process that is regulated by PARP1.


Airway obstruction by vascular anomalies. Importance of telescopic bronchoscopy.
This review of 28 cases of airway obstruction by vascular anomalies in the past 6 years emphasizes the importance of these anomalies as causes of obstruction, stridor, and apnea in infants as well as the important contribution of telescopic bronchoscopy to the recognition of these lesions, especially compression of the trachea by the innominate artery. There were 20 patients with compression by the innominate artery; four were surgically corrected. Seven vascular ring anomalies were all corrected by operation as was an enlarged left atrium and malformed mitral valve in one patient. Vascular anomalies caused 26% of the obstructive airway lesions in a series of infants who had bronchoscopy for obstruction, stridor, or apnea. Failure to diagnose and treat these entities may result in progressive respiratory embarrassment and even death. Barium esophagogram and aortic arch arteriogram, the traditional modalities for diagnosing vascular rings, may fail to identify tracheal compression by enlarged cardiac chambers or the more common "anomalous" innominate artery. Telescopic bronchoscopy will identify tracheal compression by the innominate artery; furthermore, it will identify the area of compression by the vascular ring. Observation of the compressed area during corrective surgery ensures that the operative manipulations are appropriate and successful in relieving the obstruction. This observation can be facilitated by televised monitoring and videotaping.


Lymphatic sinusoids exist in chick but not in rabbit choroid.
Although it is generally thought that lymphatics do not exist in the choroid, there is mounting evidence that lymphatic-like structures do exist in primates and fowl. Our comparison of the ultrastructure of chick and rabbit outer choroid indicates that major differences exist in the non-vascular areas of the choroid: notably, the chick has large lymphatic sinusoids, whereas the rabbit only has a system of large vacuoles contained within the processes of individual fibroblasts. These results raise questions regarding the similarities or otherwise between species of the management of retinal metabolites, excess tissue fluid and choroidal homeostasis, especially during conditions of overload.


Extradural analgesia in the management of singleton breech delivery.
Ninety-four singleton vaginal breech deliveries conducted under extradural analgesia were compared with 277 singleton vaginal breech deliveries conducted without extradural analgesia. Mean duration of the first stage of labour was similar in both groups. Mean duration of the second stage of labour was prolonged and mean 1-min Apgar scores were less in fetuses weighing more than 2500 g in the extradural group. Mean 5-min Apgar scores, perinatal morbidity and maternal complications were similar in both groups.


Prostate cancer detection using magnetic resonance imaging-transrectal ultrasound fusion biopsy: A retrospective cohort study.
Transrectal ultrasound (TRUS) guided systematic prostate biopsy is conventionally used for the diagnosis of carcinoma prostate (CaP). However, magnetic resonance imaging (MRI) guided biopsies have been shown to have superior diagnostic performance. MRI-TRUS fusion biopsy improves the detection by combining the systematic and the targeted biopsies (TB). In this study, we evaluated the role of fusion biopsy in the detection of CaP as well as clinically significant carcinoma prostate (CsCaP). In this retrospective study, the patients who underwent fusion biopsy from January 2016 to July 2022 were evaluated. Patients underwent multiparametric MRI and the suspicious lesions were reported as per the Prostate Imaging Reporting and Data System (PIRADS) version 2. The clinical, imaging, and biopsy parameters were recorded and evaluated. A total of 330 patients with PIRADS ≥3 underwent MRI-TRUS fusion biopsy and prostate cancer was detected in 187 patients (56.67%). With an increase in the PIRADS score, there was a significant rise in the detection of CaP (P < 0.001) and CsCaP (P < 0.0000001). Prostatitis was observed in 13%-18.1% of the patients with a lesion on MRI irrespective of the PIRADS score. The systematic and TB were comparable for the detection of CaP (P = 0.88) and CsCaP (P = 0.26). With a prostate-specific antigen density (PSAD) cutoff of 0.15 ng/mL/cc and 0.22 ng/mL/cc, biopsy could be safely avoided in 14.2% and 20.3% of the patients, missing only 0.3% of CaP and 0.9% of CsCaP, respectively. Different subgroups based on PSA levels, prostate volume, lesion dimension, and PIRADS score did not show a significant difference between the systematic and the targeted cores for the detection of CsCaP. This single center study of MRI-TRUS fusion prostate biopsy shows that in men with clinical suspicion of prostate cancer a pre-biopsy MRI and MRI-TRUS fusion combined systematic and targeted prostate biopsy improves the detection of prostate cancer and CsCaP. Patients with a PIRADS 3 lesion with a PSA density <0.22 can safely avoid prostate biopsy, without a significant risk of missing clinically significant prostate cancer.


Demonstration and affinity labeling of a stereoselective binding site for a benzomorphan opiate on acetylcholine receptor-rich membranes from Torpedo electroplaque.
The interaction of an optically pure benzomorphan opiate, (-)-N-allyl-N-normetazocine [(-)-ANMC], with the nicotinic acetylcholine receptor from Torpedo electroplaque was studied by using radioligand binding and affinity labeling. The binding was complex with at least two specific components having equilibrium dissociation constants of 0.3 microM and 2 microM. The affinity of the higher affinity component was decreased by carbamoylcholine but not by alpha-bungarotoxin. The effect of carbamoylcholine was not blocked by alpha-bungarotoxin. In comparison, the affinity of [3H]phencyclidine, a well-characterized ligand for a high-affinity site for noncompetitive blockers on the acetylcholine receptor, is increased by carbamoylcholine and the increase is blocked by alpha-bungarotoxin. The binding of (-)-[3H]ANMC was inhibited by a number of other benzomorphans, with (-) isomers being 4- to 5-fold more potent than (+) isomers. Phencyclidine inhibits the binding of (-)-[3H]ANMC to its high-affinity site by a mechanism that is not competitive. UV-catalyzed affinity labeling indicated that the high-affinity-binding site for (-)-[3H]ANMC is at least partially associated with the delta subunit. Tryptic degradation of the Torpedo marmorata delta chain suggested that (-)-ANMC labeled a 16,000-dalton COOH-terminal portion of the subunit. In contrast, 5-azido-[3H]trimethisoquin, a photoaffinity label of the high-affinity site for noncompetitive blockers, labels a 47,000-dalton NH2-terminal fragment of the delta subunit. These results suggest that (-)-[3H]ANMC binds to sites completely distinct from the binding sites for acetylcholine. The high-affinity-binding site for (-)-ANMC and that for phencyclidine and 5-azidotrimethisoquin are allosterically coupled but are regulated differently and are probably physically distinct.


Dearomative logic in natural product total synthesis.
Covering: 2011 to 2022The natural world is a prolific source of some of the most interesting, rare, and complex molecules known, harnessing sophisticated biosynthetic machinery evolved over billions of years for their production. Many of these natural products represent high-value targets of total synthesis, either for their desirable biological activities or for their beautiful structures outright; yet, the high sp3-character often present in nature's molecules imparts significant topological complexity that pushes the limits of contemporary synthetic technology. Dearomatization is a foundational strategy for generating such intricacy from simple materials that has undergone considerable maturation in recent years. This review highlights the recent achievements in the field of dearomative methodology, with a focus on natural product total synthesis and retrosynthetic analysis. Disconnection guidelines and a three-phase dearomative logic are described, and a spotlight is given to nature's use of dearomatization in the biosynthesis of various classes of natural products. Synthetic studies from 2011 to 2021 are reviewed, and 425 references are cited.


Formyl peptide receptor-1 activation exerts a critical role for the dynamic plasticity of arteries via actin polymerization.
Several human diseases, include cancer and stroke are characterized by changes in immune system activation and vascular contractility. However, the mechanistic foundation of a vascular immuno-physiology network is still largely unknown. Formyl peptide receptor-1 (FPR-1), which plays a vital role in the function of the innate immune system, is widely expressed in arteries, but its role in vascular plasticity is unclear. We questioned why a receptor that is crucial for immune defense, and cell motility in leukocytes, would be expressed in vascular smooth muscle cells (VSMCs). We hypothesized that activation of FPR-1 in arteries is important for the temporal reorganization of actin filaments, and consequently, changes in vascular function, similar to what is observed in neutrophils. To address our hypothesis, we used FPR-1 knockout and VSMCs lacking FPR-1. We observed that FPR-1 activation induces actin polymerization in wild type VSMCs. Absence of FPR-1 in the vasculature significantly decreased vascular contraction and induced loss of myogenic tone to elevated intraluminal pressures via disruption of actin polymerization. Actin polymerization activator ameliorated these responses. In conclusion, we have established a novel role for FPR-1 in VSMC contractility and motility, similar to the one observed in sentinel cells of the innate immune system. This discovery is fundamental for vascular immuno-pathophysiology, given that FPR-1 in VSMCs not only functions as an immune system receptor, but it also has an important role for the dynamic plasticity of arteries.


Otitis Media with ANCA-associated Vasculitis: A New Concept and the Associated Criteria.
A previously healthy 77-year-old Japanese man presented with a 2-week history of daily fevers peaking at 38°C, chills, hearing loss, and almost 10 kg of unintentional weight loss over 2 months. Pure tone audiometry showed mixed conductive-sensorineural hearing loss: right, 63.6 dB, left, 80.0 dB. Blood tests after admission showed a high myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) level (>300 U/mL), so we suspected ANCA-related vasculitis. The Japanese Otorhinolaryngology Society has recently been advocating the concept of otitis media with ANCA-associated vasculitis (OMAAV). Our case met the criteria proposed, leading to our diagnosis.


Initial clinical experience with the selective phosphodiesterase-I isoenzyme inhibitor vinpocetine in the treatment of urge incontinence and low compliance bladder.
Current pharmacological treatment modalities for urge incontinence and low compliance bladder are limited by a low clinical efficacy and the significant side effects of the standard drugs available. Previous in vitro studies indicated a possible functional relevance of the intracellular phosphodiesterase (PDE)-1 isoenzyme in the regulation of human detrusor smooth muscle contractility. We therefore investigated the effect of the PDE-1 inhibitor vinpocetine in nonresponders to standard pharmacological therapy. In 11/19 patients (57.9%) clinical symptoms and/or urodynamic parameters were improved. Although these initial data are preliminary, they represent the first evidence that isoenzyme-selective PDE inhibition may be a novel approach to the treatment of lower urinary tract disorders.


[Morphogenic role of the underlying substrate of endothelial and mesothelial cells].
Endothelial and mesothelial cell form, cell surface microrelief and intercellular contacts were studied by scanning electron microscopy. The pattern of the underlying substrate (geometry and expressiveness of basal membrane) is shown to influence the endothelial and mesothelial cell morphology. The morphogenic role of the underlying substrate is discussed.