Ephedrine in the cat lung vasculature.
Ephedrine is one of the most commonly used non-catecholamine sympathomimetic agents. It is used in operating rooms and critical care settings worldwide. While it has many side effects, its ability to rapidly raise blood pressure makes it an ideal agent to maintain homeostasis as well as in emergency situations. While its effects are known to be mediated by an alpha-mediated mechanism, the exact alpha subtype is unknown. In addition, no studies using ephedrine have been performed in the pulmonary vascular bed of the cat. The effects of phentolamine, a non-selective alpha-receptor blocker, and prazosin, an alpha1-selective antagonist, were investigated on pulmonary arterial responses to ephedrine, phenylepherine, norepinephrine, and U-46619. Lobar arterial perfusion pressure was continuously monitored, electronically averaged, and recorded with constant flow in the isolated left lower lobe vascular bed of the cat. Phentolamine and prazosin significantly reduced vasoconstrictor pulmonary perfusion pressure increases induced by ephedrine. Ephedrine has significant vasopressor activity in the pulmonary vascular bed of the cat meditated predominantly by alpha1 adrenergic receptor activation.


Changes in liver and spleen volumes in alcoholic liver disease.
Liver and spleen volumes were determined using computed tomography in 57 subjects with alcoholic liver disease and 76 subjects with nonalcoholic liver disease, in order to clarify the clinical characteristics and pathogenetic mechanisms of portal hypertension in alcoholic liver disease. The liver volumes in alcoholic liver disease were significantly larger than those in nonalcoholic liver disease, except in cases of decompensated liver cirrhosis. The increase in liver volume in alcoholic liver disease showed a significant correlation with the degree of hepatocytic ballooning. Overlapping of values for liver volume between alcoholic and nonalcoholic liver disease was quite small, suggesting that determination of liver volumes could be helpful for making etiological diagnoses in chronic liver disease. Spleen volumes were increased in the advanced cases of both alcoholic and nonalcoholic liver disease. The correlations between liver and spleen volumes were quite different between alcoholic and nonalcoholic liver disease. In nonalcoholic liver disease, a negative correlation was obtained, while, on the other hand, it was significantly positive in alcoholic liver disease. This appears to suggest that the pathogenetic mechanism of portal hypertension may differ between the diseases. After abstinence from alcohol, the decrease in liver and spleen volumes showed a statistically significant correlation, suggesting that ballooning of the hepatocytes may play a role in the augmentation of portal hypertension in alcoholic liver disease.


The Genetic Diversity, Haplotype Analysis, and Phylogenetic Relationship of Aedes albopictus (Diptera: Culicidae) Based on the Cytochrome Oxidase 1 Marker: A Malaysian Scenario.
The global expansion of Ae. albopictus from its native range in Southeast Asia has been implicated in the recent emergence of dengue endemicity in Malaysia. Genetic variability studies of Ae. albopictus are currently lacking in the Malaysian setting, yet are crucial to enhancing the existing vector control strategies. The study was conducted to establish the genetic variability of maternally inherited mitochondrial DNA encoding for cytochrome oxidase subunit 1 (CO1) gene in Ae. albopictus. Twelve localities were selected in the Subang Jaya district based on temporal indices utilizing 120 mosquito samples. Genetic polymorphism and phylogenetic analysis were conducted to unveil the genetic variability and geographic origins of Ae. albopictus. The haplotype network was mapped to determine the genealogical relationship of sequences among groups of population in the Asian region. Comparison of Malaysian CO1 sequences with sequences derived from five Asian countries revealed genetically distinct Ae. albopictus populations. Phylogenetic analysis revealed that all sequences from other Asian countries descended from the same genetic lineage as the Malaysian sequences. Noteworthy, our study highlights the discovery of 20 novel haplotypes within the Malaysian population which to date had not been reported. These findings could help determine the genetic variation of this invasive species, which in turn could possibly improve the current dengue vector surveillance strategies, locally and regionally.


Genetics of the induction of antigen-specific immunity in anti-idiotype-treated mice and derivation of monoclonal Ab3 antibodies.
Antiidiotypic antibodies can be used as a means other than antigen of clone-specific intervention in the immune system. In a number of cases, antiidiotypic antibodies induce potent, antigen-specific responses without exposure of the recipient animals to antigen, and a better understanding of such responses will aid in the application of idiotype manipulation to both immunological and practical problems. The Ia. 7 system expresses a major, cross-reactive idiotype on antibodies to an epitope of the mouse I-E antigen. Here, we examine genetic control of the I-E-specific response to anti-idiotype in this model system. Results demonstrate that both heavy chain allotype-linked and non-allotype-linked loci contribute to the control of this response. In addition, monoclonal antibodies representing the non-antigen-specific portion of the Ab3 response were derived. Two idiotype-positive clones were demonstrated to be of IgM isotype, contrasting with previous data showing that the serum Ab3 response is predominantly IgG1.


Development of a two-part biomaterial adhesive strategy for annulus fibrosus repair and ex vivo evaluation of implant herniation risk.
Intervertebral disc (IVD) herniation causes pain and disability, but current discectomy procedures alleviate pain without repairing annulus fibrosus (AF) defects. Tissue engineering strategies seal AF defects by utilizing hydrogel systems to prevent recurrent herniation, however current biomaterials are limited by poor adhesion to wetted tissue surfaces or low failure strength resulting in considerable risk of implant herniation upon spinal loading. Here, we developed a two-part repair strategy comprising a dual-modified (oxidized and methacrylated) glycosaminoglycan that can chemically adsorb an injectable interpenetrating network hydrogel composed of fibronectin-conjugated fibrin and poly (ethylene glycol) diacrylate (PEGDA) to covalently bond the hydrogel to AF tissue. We show that dual-modified hyaluronic acid imparts greater adhesion to AF tissue than dual-modified chondroitin sulfate, where the degree of oxidation is more strongly correlated with adhesion strength than methacrylation. We apply this strategy to an ex vivo bovine model of discectomy and demonstrate that PEGDA molecular weight tunes hydrogel mechanical properties and affects herniation risk, where IVDs repaired with low-modulus hydrogels composed of 20kDa PEGDA failed at levels at or exceeding discectomy, the clinical standard of care. This strategy bonds injectable hydrogels to IVD extracellular matrix proteins, is optimized to seal AF defects, and shows promise for IVD repair.


Cyclooxygenase (COX)-2 and cell cycle activity in a transgenic mouse model of Alzheimer's disease neuropathology.
Prior studies have shown that cyclooxygenase (COX)-2, an enzyme involved in inflammatory mechanisms as well as neuronal activities, is up-regulated in the Alzheimer's disease (AD) brain and may represent a therapeutic target for anti-inflammatory treatments. We report the effect of neuronal overexpression of human (h)COX-2 in a murine model of AD neuropathology. Transgenic mice expressing both the human amyloid precursor protein mutation (APPswe) and the human presenilin (PS1-A246E) mutation, with resultant AD plaque pathology, were crossed with transgenic mice expressing human (h)COX-2 in neurons. At 12 months of age, the APPswe/PS1-A246E/hCOX-2 triple-transgenic mice showed an elevation in the number of phosphorylated retinoblastoma (pRb) tumor suppressor protein and active caspase-3 immunopositive neurons, compared to double APPswe/PS1-A246E or single hCOX-2 transgenic controls. No detectable influence of neuronal hCOX-2 on AD neuropathology was found in the brain of APPswe/PS1-A246E/hCOX-2 triple-transgenic mice, compared to double APPswe/PS1-A246E. In vitro studies revealed that hCOX-2 overexpression in primary cortico-hippocampal neurons derived from the hCOX-2 transgenics accelerates beta-amyloid (Abeta)(1-42)-mediated apoptotic damage which was prevented by the cell cycle dependent (CDK) inhibitor, flavoperidol. The data indicates that COX-2 overexpression causes alteration of neuronal cell cycle in a murine model of AD neuropathology, and provides a rational basis for targeting neuronal COX-2 in therapeutic research aimed at slowing the clinical progression of AD.


Hair transplantation: using a power punch in the recipient area.
A useful technique for using a motorized punch for cutting recipient holes is presented. This technique minimizes the possibility of entangling surrounding hairs. It is easy to perform and requires no special instruments.


Multiple-parallel-protease digestion coupled with high-resolution mass spectrometry: An approach towards comprehensive peptide mapping of therapeutic mAbs.
Therapeutic monoclonal antibodies (mAbs) are structurally large and complex molecules. To be safe and efficacious, a biosimilar mAb must show high similarity to its reference product in Critical Quality Attributes (CQA). mAbs are highly sensitive to protein expression, production, manufacturing, supply chain, and storage conditions. All these factors make biosimilar mAbs intrinsically susceptible for variability during production. Accordingly, several lots of references and tests are required to establish the biosimilarity of a test mAb. The primary structure is a CQA of a mAb affecting its safety and efficacy. Here, we apply peptide mapping as an analytical method to decipher the primary structure and associated modifications for a quick quality assessment of TrastuzumAb and RituximAb innovator and biosimilar. A multiple-parallel-protease digestion strategy followed by high-resolution mass spectrometric analysis consistently achieved 100% sequence coverage along with reliable detection of post-translational modifications. Additionally, the use of supporting methods such as intact mass analysis and circular dichroism helped us to decipher the primary and higher order structures of these mAbs. We identify discernible variations in the profile of the innovator and biosimilar mAbs and validate the method for quick yet deep comparability analysis of the primary structure of biosimilar mAbs sold in the market. SIGNIFICANCE: Peptide mapping using bottom-up approach is one of the most common methods for the characterization of therapeutic monoclonal antibodies. Herein, we describe a multi-parallel-protease digestion strategy using a combination of five different proteases followed by high-resolution mass spectrometric analysis with TrastuzumAb and RituximAb as an example. This resulted in a comprehensive identification of peptides with increased reliability and identification of different PTMs. Additional supporting orthogonal methods like intact mass and higher-order structure analysis helped evaluate broader conformational properties.


D-serine antagonized phencyclidine- and MK-801-induced stereotyped behavior and ataxia.
D-Serine, a selective agonist at the strychnine-insensitive glycine binding site, antagonized PCP-induction of stereotyped behavior and ataxia in a dose-dependent manner. At intraventricular doses of 0.1, 0.5 and 1 mumol/rat, D-serine significantly attenuated PCP-induction of stereotyped behavior in rats. Only doses of 0.5 and 1.0 mumol/rat of D-serine antagonized PCP-induction of ataxia. D-Serine (0.5 mumol/rat) also antagonized MK-801 induced stereotyped behavior and ataxia. These results suggest that agonists at the strychnine-insensitive glycine site may be clinically useful as a novel class of atypical antipsychotic agents.


Frigocyclinone, a novel angucyclinone antibiotic produced by a Streptomyces griseus strain from Antarctica.
A new angucyclinone antibiotic, frigocyclinone, was isolated from Streptomyces griseus strain NTK 97, consisting of a tetrangomycin moiety attached through a C-glycosidic linkage with the aminodeoxysugar ossamine. Frigocyclinone showed antibacterial activities against Gram-positive bacteria.


Design, synthesis, and SAR studies of novel 4-methoxyphenyl pyrazole and pyrimidine derivatives as potential dual tyrosine kinase inhibitors targeting both EGFR and VEGFR-2.
Guided by the pharmacophoric features of both EGFR and VEGFR-2 antagonists, two novel series of 4-methoxyphenyl pyrazole and pyrimidine derivatives [(4a-c) and (5a-c, 6, 7a-c, 8, 9, 10, 11a,c, 12, 13a-c, 14a-c, and 15a,b)], respectively, were designed and synthesized as dual EGFR/VEGFR-2 inhibitors. Interestingly, compound 12 showed very strong antiproliferative effects towards all the five studied cell lines (HepG-2, MCF-7, MDA-231, HCT-116, and Caco-2) with IC50 values of 3.74, 7.81, 4.85, 2.96, and 9.27 µM, respectively. Also, it achieved the highest inhibitory activities against both EGFR and VEGFR-2 as well (IC50 = 0.071 and 0.098 µM) compared to the two reference drugs, erlotinib (IC50 = 0.063 µM) and sorafenib (IC50 = 0.041 µM), respectively. Moreover, four compounds (4a, 7a, 7c, and 12) were selected for further evaluation through cell cycle analysis and Annexin V-based flow cytometry assay in the HepG-2 cell line. In addition, deep computational studies including molecular docking, physicochemical properties, profiling pharmacokinetics, ADMET studies, and toxicity predictions were performed for the designed compounds to evaluate the prospective drug candidates. Finally, analyzing the structure-activity relationship (SAR) of the new derivatives gives us a lot of interesting promising results which could help medicinal chemists to design more potent drug candidates soon as well.


5-substituted pyrimidine L-2'-deoxyribonucleosides: synthetic, quantum chemical, and NMR studies.
As a part of an ongoing medicinal chemistry, we report here the synthesis and structure evaluation of 1-(2-deoxy-3,5-di-O-acetylpentofuranosyl)-5-[(3-methyl-5-oxo-1-phenyl-4,5-dihydro-4H-pyrazol-4-ylidene) pyrimidine-2,4(1H,3H)-dione 5 and 5-[bis(3-methyl-5-oxo-1-phenyl-4,5-dihydro-4H-pyrazol-4-yl)methyl-1-(2-deoxy-3,5-di-O-acetylpentofuranosyl)pyrimidine-2,4(1H,3H)-dione 6 derived from 3',5'-di-O-acetyl-5-formyl-2'-deoxy-β-L-uridine 1. Base hydrolysis of compounds 1 and 6 furnished their deacetylated analogues in good yields, whereas hydrolysis of 5 was troublesome. Structural features of these molecules are discussed by NMR spectra analyses and density functional theory quantum chemical calculations. The newly synthesized L-analogues show no significant activity against vaccinia and cowpox viruses.


Familial aggregation of congenital dislocation of the hip in a Norwegian population.
Previous studies of congenital dislocation of the hip have not used adequate control groups in estimating the level of genetic influence on that trait. Furthermore, it could not be demonstrated that alleged maternal effects were not an artifact of reporting bias. To that end, information was obtained on the presence of the anomaly in the families of adult twins and their spouses participating in the Norwegian Twin Registry. The prevalence odds ratio for having that disorder in first degree relatives was 10.0. Stratifying by class of relatives, the prevalence odds ratio was 8.1 for fathers, 35.8 for mothers, 12.7 for siblings, and 3.3 for offspring. The increased prevalence odds ratio for mothers over that of fathers suggests a maternal effect. Since both males and females reported on the anomaly for each parental type, it is unlikely that the difference in prevalence odds ratios is due to general reporting bias.


Bone microstructure and its associated genetic variability in 12 inbred mouse strains: microCT study and in silico genome scan.
MicroCT analysis of 12 inbred strains of mice identified 5 novel chromosomal regions influencing skeletal phenotype. Bone morphology varied in a compartment- and site-specific fashion across strains and genetic influences contributed to the morphometric similarities observed in femoral and vertebral bone within the trabecular bone compartment. Skeletal development is known to be regulated by both heritable and environmental factors, but whether genetic influence on peak bone mass is site- or compartment-specific is unknown. This study examined the genetic variation of cortical and trabecular bone microarchitecture across 12 strains of mice. MicroCT scanning was used to measure trabecular and cortical bone morphometry in the femur and vertebra of 12 strains of 4-month-old inbred male mice. A computational genome mapping technique was used to identify chromosomal intervals associated with skeletal traits. Skeletal microarchitecture varied in a compartment- and site-specific fashion across strains. Genome mapping identified 13 chromosomal intervals associated with skeletal traits and 5 of these intervals were novel. Trabecular microarchitecture in different bone sites correlated across strains and most of the chromosomal intervals associated with these trabecular traits were shared between skeletal sites. Conversely, no chromosomal intervals were shared between the trabecular and cortical bone compartments in the femur, even though there was a strong correlation for these different bone compartments across strains, suggesting site-specific regulation by environmental or intrinsic factors. In summary, these data confirm that there are distinct genetic determinants that define the skeletal phenotype at the time when peak bone mass is being acquired, and that genomic regulation of bone morphology is specific for skeletal compartment.


The Impact of the First and Second Wave of the COVID-19 Pandemic on Eating Symptoms and Dysfunctional Eating Behaviours in the General Population: A Systematic Review and Meta-Analysis.
The aim of this systematic review and meta-analysis was to examine the prevalence of feeding and eating disorder (FED) symptoms or dysfunctional eating behaviours (DEB) in the general population during the COVID-19 outbreak. We searched eligible articles in biomedical databases from 1 January 2020 to 31 March 2022. Prevalence rates of FED or DEB changes between pre-pandemic and pandemic time and correlation with psychological distress were pooled with a meta-analysis using a random-effects model. Heterogeneity was tested using I-squared (I2) statistics. A total of 186 studies with 406,076 participants met the inclusion criteria. The more prevalent FED or DEB during the COVID-19 outbreak were: body image concerns (52%, 95% CI 0.38, 0.66), binge eating (40%, 95% CI 0.25, 0.55), and overeating (40%, 95% CI = 0.32-0.48). Pooled data of longitudinal studies (k = 8) only showed a significant difference in the prevalence of weight gain from pre-pandemic to the pandemic time. Finally, increased levels of psychological distress (k = 35) positively correlated with some ED symptoms. This meta-analysis evidenced a negative impact of the pandemic on eating symptoms and DEB in the general population.


Effects of prenatal testosterone propionate treatment on saccharin preference of adult rats exposed to ethanol in utero.
Prenatal exposure to alcohol feminizes saccharin consumption patterns in adult male rats. To study the involvement of testosterone in this effect, testosterone propionate (TP) was administered to pregnant dams in an attempt to reverse that feminized saccharin consumption pattern in the male offspring. Female offspring were also studied to determine the effect of TP on saccharin preference in normal males and females. During the last week of gestation, dams were administered a liquid diet containing 35% ethanol derived calories, an isocaloric liquid diet containing no ethanol, or Purina Lab Chow. Half of the dams in each group received twice daily injections of TP, the other half were injected with the oil vehicle. Saccharin consumption of adult fetal alcohol exposed (FAE) males from dams administered oil or TP was significantly greater than controls, indicating that the feminized pattern of saccharin consumption of FAE males cannot be overcome with TP administration during the prenatal period. In controls, prenatal TP exposure alone was found to increase adult saccharin consumption in both sexes. Prenatal administration of TP was also found to markedly depress body weight of offspring of dams receiving the liquid diets compared to offspring from dams receiving the same diets plus oil injections. Body weights of offspring from TP or oil injected dams receiving the chow fed diets during pregnancy did not differ.


In vitro metabolic studies on the selective metabotropic glutamate receptor sub-type 5 (mGluR5) antagonist 3-[(2-methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP).
Metabotropic glutamate receptors (mGluR) are G-protein-coupled receptors that play a major role in modulatory pathways in the CNS and have been suggested to have pharmacological implications in pain, psychiatric disorders and other neurological states. 3-[(2-Methyl-1,3-thiazol-4-yl) ethynyl]-pyridine (MTEP) is a specific and selective antagonist for the mGluR sub-type 5. Previous studies using rat liver microsomes showed that the major oxidative metabolites of MTEP are a hydroxymethyl metabolite (M1), two oxides (M2 and M4), a thiazole-ring opened metabolite (M3) and CO(2) (M5). In the present study, we examined the metabolism of MTEP in liver microsomes and expressed rat and human CYP isoforms. In rat liver microsomes, metabolic stability studies accurately predicted the in vivo clearance for MTEP. Incubation of MTEP with expressed rat and human CYP isoforms showed that CYP1A and CYP2C isoforms are primarily responsible for the metabolism of this compound. The results suggest that species differences in MTEP metabolism is possible and could contribute to specie-differences in biological effects of the compound.


Incidental findings during ultrasound of thyroid, breast, testis, uterus and ovary in healthy term neonates.
Incidental sonographic findings in thyroid and estrogen-responsive organs have been described in children and adults, but no publications describe incidental findings of these organs in infancy. We describe ultrasound features in thyroid, breast buds, testes, uterus, and ovaries in infants up to 32 weeks old that vary from the expected tissue architecture. Infants described in this paper were enrolled as healthy term neonates in a longitudinal study of normal feeding practices. Radiology reports for ultrasound exams in these infants described a range of findings that are similar to those reported in older populations. Knowledge of these asymptomatic variants occurring in infancy may guide radiologists in interpretation of these findings during clinical exams.


Prevalence of Epstein-Barr virus DNA in different T-cell lymphoma entities in a European population.
The Epstein-Barr virus (EBV) has been classically associated with nasopharyngeal carcinoma and Burkitt's lymphoma, a monoclonal B-cell non-Hodgkin's lymphoma. Since the EBV genome has also been found in post-transplant lymphomas and lymphomas arising in individuals infected with the human immunodeficiency virus, evidence has now accumulated that EBV might be the initiator of a multi-step process leading from polyclonal B-cell hyperplasias to monoclonal lymphoma. In a retrospective study of 60 T-cell lymphomas of various types, we found EBV DNA in 21 (35%) using Southern- and/or dot-blot techniques. Eight of 14 nodal samples of angio-immunoblastic lymphadenopathy (57%) were shown to harbour detectable EBV DNA. The tumour with the next highest frequency, 47% (7/15 cases analyzed) was pleomorphic T-cell lymphoma, medium- and large-cell type; EBV was found both in nodal and in extranodal lymphomas of this type. Lymphoepitheloid (Lennert's) lymphoma and large-cell anaplastic lymphoma were positive in 2/5 and 3/8, respectively, of the cases analyzed. No viral DNA could be demonstrated in 3 T-immunoblastic and 5 T-lymphoblastic lymphomas. Clonotypic analysis revealed monoclonal as well as oligoclonal virus populations. Our data suggest that, at least in some of these entities, the presence of the EBV genome might be due to secondary mechanisms such as escape from immune surveillance.


Maximal lymph flow in the ovine fetus.
This study was designed to determine the maximal left thoracic duct lymph flow rate in late-gestation ovine fetuses. Chronically catheterized sheep fetuses (n = 8) with indwelling left thoracic lymph duct and vascular catheters were studied > or = 5 days after surgery at 136 +/- 1 (SE) days' gestation. To increase lymph flow rate, 4 L of warm lactated Ringer's solution were infused intravenously into the fetus over 4 hours, because this causes mild edema as determined ultrasonographically. During a 1-hour preinfusion period lymph flow rate was 0.53 +/- 0.06 ml/min. During the infusion increases occurred in fetal arterial (7.6 +/- 1.0 mm Hg) and venous (2.4 +/- 0.3 mm Hg) pressures (p < 0.001). Lymph flow rate increased and reached a plateau after 1 hour at 339% +/- 30% of preinfusion values (p < 0.001). When the infusion was terminated, fetal arterial and venous pressures rapidly returned to preinfusion levels. Lymph flow rate gradually decreased during the first 30 minutes and stabilized at 97% +/- 17% above control during the subsequent 30 minutes. Analysis of lymph flow rate as a function of outflow pressure revealed that the increases in flow occurred because of an upward shift in the plateau flow rate with no change in the stop-flow pressure. (1) Fetal left thoracic duct lymph flow rate can increase significantly above basal values and therefore is an important safety factor against fetal edema formation. (2) The maximal lymph flow rate appears to be 3.4 times normal when venous pressure is elevated and two times normal when venous pressure is normal.


Jugular bulb diverticulum associated with lower cranial nerve palsy and multiple aneurysms.
Jugular bulb diverticulum is a rare condition that has never been reported in association with lower cranial nerve palsy. A 54-year-old woman developed acute swallowing disturbance and hoarseness. Neuroradiological examinations demonstrated a jugular bulb diverticulum as well as unruptured internal carotid and basilar tip aneurysms on the same side. Laboratory data for both serum and cerebrospinal fluid were normal. Steroids were given, and the cranial nerve palsy disappeared within 1 month. The aneurysms were successfully clipped. During the follow-up period of more than 1 year, the patient has done well and has no neurological deficit. This is the first reported case of jugular bulb diverticulum associated with a lower cranial nerve palsy and multiple aneurysms. We recommend close observation of patients with this condition regardless of its clinical presentation.


Patients with acute chest pain who leave emergency departments against medical advice: prevalence, clinical characteristics, and natural history.
The study group identified 107 patients who left against advice from the emergency departments of three university and four community hospitals after presenting for evaluation of acute chest pain. In comparison with other emergency department patients with acute chest pain, patients who left against advice had findings that suggested they were at higher risk for myocardial infarction than patients for whom admission was not recommended but at lower risk than patients who consented to be admitted. Specific follow-up plans were made at the time of evaluation for 45 patients (42%). Survival data were obtained at 48-72 hours for 104 patients (97%) and at one month for 101 patients (94%). Fourteen patients (12%) were hospitalized within three days of their original emergency department visits, and three patients had documented acute myocardial infarctions. The only death within one month was that of a patient who died suddenly out-of-hospital later on the day of his emergency department visit. The authors conclude that patients who left against medical advice had presentations and prognoses that were in between those of patients for whom admission was not recommended and those of patients who consented to be admitted.


The inhibitory effect of ErbB2 on epidermal growth factor-induced formation of clathrin-coated pits correlates with retention of epidermal growth factor receptor-ErbB2 oligomeric complexes at the plasma membrane.
By constructing stably transfected cells harboring the same amount of epidermal growth factor (EGF) receptor (EGFR), but with increasing overexpression of ErbB2, we have demonstrated that ErbB2 efficiently inhibits internalization of ligand-bound EGFR. Apparently, ErbB2 inhibits internalization of EGF-bound EGFR by constitutively driving EGFR-ErbB2 hetero/oligomerization. We have demonstrated that ErbB2 does not inhibit phosphorylation or ubiquitination of the EGFR. Our data further indicate that the endocytosis deficiency of ErbB2 and of EGFR-ErbB2 heterodimers/oligomers cannot be explained by anchoring of ErbB2 to PDZ-containing proteins such as Erbin. Instead, we demonstrate that in contrast to EGFR homodimers, which are capable of inducing new clathrin-coated pits in serum-starved cells upon incubation with EGF, clathrin-coated pits are not induced upon activation of EGFR-ErbB2 heterodimers/oligomers.


Different interdigestive antroduodenal motility patterns in chronic antral gastritis with and without Helicobacter pylori infection.
Fasting antroduodenal motor activity was studied in 15 dyspeptic patients with chronic superficial antral gastritis and Helicobacter pylori infection (group A), 10 dyspeptic patients with chronic superficial antral gastritis without Helicobacter pylori infection (group B), and eight healthy control subjects (group C) by manometric recording of phases of the interdigestive migrating motor complex (MMC) prolonged over 240 min. A significantly lower incidence of activity fronts (phase III of MMC) starting from the antrum was observed in patients with gastritis and Helicobacter pylori infection vs patients without bacterial colonization (P = 0.013) and in these latter vs control subjects (P = 0.013). Likewise, the overall number of activity fronts was smaller in patients with gastritis than in healthy subjects (P = 0.034). Symptomatic evaluation was performed in the two groups of dyspeptic patients, without detecting any differences in frequency and severity of complaints. Our results show a significant reduction in the occurrence of interdigestive antral phase III of MMC in chronic gastritis associated with Helicobacter pylori infection, suggesting a possible relationship between fasting motility and bacterial colonization.


Anion movements across lamprey (Lampetra fluviatilis) red cell membrane.
Chloride and bicarbonate movements across lamprey red cell membrane were investigated. The halftime for equilibration of radioactive chloride across the red cell membrane was 2.46 h, and apparent permeability for chloride-36 was approximately 10(-9) cm X s-1, a value similar to that observed for lipid bilayers. Chloride movements were not affected by the anion exchange inhibitor, 4,4'-diisothiocyano-stilbene-2,2'-disulfonic acid (DIDS). Furthermore, intracellular buffering is effectively isolated from the extracellular compartment, as shown by the fact that practically no pH recovery occurred in the unbuffered extracellular medium after either acidification or alkalinization. These observations show that lamprey red cell membrane is quite impermeable to bicarbonate and other acid/base equivalents.


Toxicokinetics of the four stereoisomers of the nerve agent soman in atropinized rats--influence of a soman simulator.
The toxicokinetics of the four stereoisomers of C(+/-)P(+/-)-soman were investigated in anesthetized, atropinized, and artificially ventilated rats at iv doses of 6 (495 micrograms/kg) and 3 LD50. By integration of a thermodesorption/cold trap injector into our GLC analysis, the soman stereoisomers could be followed in rat blood down to a minimum detectable concentration, i.e., 1.5 pg/ml (8.3 pM), 55-fold lower than that published previously. This new detection limit is probably near or below the minimum concentration relevant for survival. Whereas C(+)P(+)-soman disappears in vivo from rat blood within 0.25 min, the toxicokinetics of C(-)P(+)-soman could be described by a two-compartment model, with a biological half-life of 1-1.5 min. The extremely toxic C(+/-)P(-)-isomers could be followed in rat blood for greater than 4 and 2 hr at doses of 6 and 3 LD50, respectively. The toxicokinetics of the P(-)-isomers are best described with a three-compartment model, with terminal half-lives of 40-64 and 16-22 min at doses of 6 and 3 LD50, respectively. Administration of a 13.6-fold molar excess of the soman simulator 1,2,2-trimethylpropyl dimethylphosphinate (PDP) 10 min prior to administration of 6 LD50 of C(+/-)P(+/-)-soman reduces the terminal half-lives of the C(+/-)P(-)-isomers to the values measured at the dose of 3 LD50 without PDP pretreatment. Previous investigations showed that, without PDP pretreatment, rats suffer from endogenous reintoxication 4-6 hr after initially successful therapy, at C(+/-)P(+/)-soman doses greater than or equal to 6 LD50. Both this reintoxication phenomenon due to the presence of toxicologically significant C(+/-)P(-)-soman levels up to 4 hr after intoxication and its antagonism via PDP pretreatment can be understood on the basis of our toxicokinetic measurements. This shows that such investigations can contribute to insight into the toxicology of C(+/-)P(+/-)-soman and to a better treatment of intoxications with this agent.


Community people-pet programs that work.
Excellent models exist for people-pet programs in institutions and in the community. Veterinarians should assess the needs of their local communities and adapt a model program to fit these needs.


Absolute Configuration Assignment of a Paraconic Acid Derivative via Vibrational Circular Dichroism Spectroscopy and Density Functional Theory Calculation.
Density functional theory calculation of the vibrational circular dichroism spectrum was used to assign the absolute configuration of an all-carbon quaternary β-stereocenter of a γ-butyrolactone recently synthesized through an asymmetric organocatalytic tandem aldol/lactonization sequence. Comparison with the experimental spectrum is satisfactory, on account of the fact that spectroscopic features are weak due to the presence of multiple conformers. As a result, the (R) absolute configuration was assigned to the (+) optical isomer.


Dexamethasone-induced hepatomegaly in three children.
High-dose treatment with dexamethasone led to reversible hepatomegaly with disturbance of liver function in three children. After withdrawal of dexamethasone, liver size and function returned to normal. These observations were compared with previously published data. The authors conclude that if this condition occurs, dexamethasone should be discontinued.


Characterization of both dopamine uptake systems in rat striatal slices by specific pharmacological tools.
Previous results have shown that modifications of dopamine (DA) high-affinity uptake1 and those of DA low-affinity uptake2 in rat striatal slices were different after autoxidation of this model and in the presence of antioxidants. The aim of this study was to determine whether these two DA uptake systems correspond to two different dopamine transporters or rather to a single one. A lesion into the substantia nigra of animals by injection of 6-hydroxydopamine, a neurotoxic substance of nigrostriatal dopaminergic neurons led to the suppression of both DA uptake systems. These two DA uptake systems were not modified when animals were treated by reserpine or tetrabenazine, which inhibit the vesicular monoamine transporter. Moreover, they were sodium- and temperature-dependent. Experiments with specific inhibitors showed that 1-[2-(diphenylmethoxy) ethyl]-4-(3-phenylpropyl)-piperazine dihydrochloride (GBR-12935) and (E)-N-(3-iodoprop-2-enyl)-2beta-carbomethoxy-3beta-(4'-tolyl ) nortropane chloride (PE2I), two selective DA uptake inhibitors, were significantly more potent than fluoxetine and nisoxetine (selective serotonin and norepinephrine uptake inhibitors respectively) in both DA uptake systems. However, the concentrations of these products inhibiting low-affinity uptake2 by 50% were much greater than those for high-affinity uptake1. Our data indicate that both DA uptake systems are neuronal, independent of the vesicular monoamine transporter, active and specific for dopamine. Our results suggest that high-affinity uptake1 and low-affinity uptake2 correspond to the same dopamine transporter, but would be situated at different levels in the striatal slice model. Uptake1 could take place at the periphery of the slice whereas uptake2 in the depth of the slice.


Pesticides exposure in pregnant Argentinian women: Potential relations with the residence areas and the anthropometric neonate parameters.
Intrauterine environment is the first chemical exposure scenario in life, through transplacental transfer. In this study, the aim was to determine concentrations of organochlorine pesticides (OCPs) and selected current use pesticides in the placentas of pregnant women from Argentina. Socio-demographic information, the mother's lifestyle and neonatal characteristics were also analysed and related to pesticides residue concentrations. Thus, 85 placentas were collected at birth, from an area of intensive fruit production for the international market, in Patagonia Argentina. Concentrations of 23 pesticides including, trifluralin (herbicide), the fungicides chlorothalonil and HCB, and the insecticides chlorpyrifos, HCHs, endosulfans, DDTs, chlordanes, heptachlors, drins and metoxichlor, were determined by GC-ECD and GC-MS. Results were first analysed all together and then grouped by their residential settings, in urban and rural groups. Total mean pesticide concentration was 582.6 ± 1034.4 ng/g lw, where DDTs (325.9 ± 950.3 ng/g lw) and chlorpyrifos (188.4 ± 365.4 ng/g lw) showed a high contribution. Pesticide levels found exceeded those reported in low, middle and high income countries from Europe, Asia and Africa. In general, pesticides concentrations were not associated with neonatal anthropometric parameters. When the results were analysed by residence place, significantly higher concentrations of total pesticides and chlorpyrifos (Mann Whitney test p = 0.0003 and p = 0.032, respectively) were observed in placentas collected from mothers living in rural settings compared to urban areas. Rural pregnant women presented the highest pesticide burden (5.9 μg), where DDTs and chlorpyrifos were the major constituents. These results suggested that all pregnant women are highly exposed to complex pesticide mixtures, including banned OCPs and the widely used chlorpyrifos. Based on the pesticide concentrations found, our results warn of possible health impacts from prenatal exposure through transplacental transfer. This is one of the first reports of both chlorpyrifos and chlorothalonil concentrations in placental tissue, and contributes to the knowledge of current pesticide exposure in Argentina.


Flexible PET/ITO electrode array for implantable biomedical applications.
Flexible PET/ITO (PolyEthylene Terephthalate/ Indium Tin Oxide) implantable electrode array for spinal cord stimulation and retina prosthesis have been developed. The electrode array is fabricated on a thin PET/ITO substrate and encapsulated with insulating material, SU-8. The PET substrate made electrodes flexible so that they could shape to contoured tissues. A layer of gold on the stimulation sites served to reduce the electrode/tissue interface impedance. Prototypes of 1 × 8 and 3 × 8 electrode arrays are fabricated for monophasic and biphasic stimulation of spinal cord respectively. The exposed electrode dimensions are 3 mm² for monophasic and 6 mm² for biphasic stimulation with 100 μm of interconnection paths. The prototype of 4 × 4 electrode arrays were also fabricated with the same process for retinal prosthesis with exposed electrode diameter of 125 μm. To verify the functionality of the subdural electrodes, the electrochemical impedance spectroscopy was measured. The electrode/tissue impedance was 500 Ω at 1KHz for 3 mm² area.


Effect of zinc chloride on picrotoxin-induced hyperkinesis depends on its concentration in solution injected into rat neostriatum.
The hyperkinekic effect (increase in spontaneous activity and development of choreomyoclonic hyperkinesis of the extremities and body) of picrotoxin injected into the rostral neostriatum of rats in a dose of 2 μg was reduced if the drug was injected together with ZnCl(2) in a concentration of 0.1 μg/μl. ZnCl(2) in a concentration of 1 μg/μl did not modulate the effects of picrotoxin, while in a concentration of 3 μg/μl it increased spontaneous motor activity in the open field test without affecting the symptoms of choreomyoclonic hyperkinesis.


Triterpenoids and Flavonoids from the Leaves of Astragalus membranaceus and Their Inhibitory Effects on Nitric Oxide Production.
Four new cycloartane triterpenes, named huangqiyegenins V and VI and huangqiyenins K and L (1-4, resp.), together with nine known triterpenoids, 5-13, and eight flavonoids, 14-21, were isolated from a 70%-EtOH extract of Astragalus membranaceus leaves. The structures of the new compounds were elucidated by detailed spectroscopic analyses, and the compounds were identified as (9β,11α,16β,20R,24S)-11,16,25-trihydroxy-20,24-epoxy-9,19-cyclolanostane-3,6-dione (1), (9β,16β,24S)-16,24,25-trihydroxy-9,19-cyclolanostane-3,6-dione (2), (3β,6α,9β,16β,20R,24R)-16,25-dihydroxy-3-(β-D-xylopyranosyloxy)-20,24-epoxy-9,19-cyclolanostan-6-yl acetate (3), and (3β,6α,9β,16β,24E)-26-(β-D-glucopyranosyloxy)-16-hydroxy-3-(β-D-xylopyranosyloxy)-9,19-cyclolanost-24-en-6-yl acetate (4). All isolated compounds were evaluated for their inhibitory activities against LPS-induced NO production in RAW264.7 macrophage cells. Compounds 1-3, 14, 15, and 18 exhibited strong inhibition on LPS-induced NO release by macrophages with IC50 values of 14.4-27.1 μM.


Hindbrain V2a neurons in the excitation of spinal locomotor circuits during zebrafish swimming.
During locomotion in vertebrates, reticulospinal neurons in the hindbrain play critical roles in providing descending excitation to the spinal cord locomotor systems. However, despite the fact that many genes that are used to classify the neuronal identities of neurons in the hindbrain have been identified, the molecular identity of the reticulospinal neurons that are critically involved in locomotor drive is not well understood. Chx10-expressing neurons (V2a neurons) are ipsilaterally projecting glutamatergic neurons in the spinal cord and the hindbrain. Many of the V2a neurons in the hindbrain are known to project to the spinal cord in zebrafish, making hindbrain V2a neurons a prime candidate in descending locomotor drive. We investigated the roles of hindbrain V2a neurons using optogenetic and electrophysiological approaches. The forced activation of hindbrain V2a neurons using channelrhodopsin efficiently evoked swimming, whereas the forced inactivation of them using Archearhodopsin3 or Halorhodpsin reliably stopped ongoing swimming. Electrophysiological recordings of two populations of hindbrain reticulospinal V2a neurons showed that they were active during swimming. One population of neurons, small V2a neurons in the caudal hindbrain, fired with low rhythmicity, whereas the other population of neurons, large reticulospinal V2a neurons, called MiV1 neurons, fired more rhythmically. These results indicated that hindbrain reticulospinal V2a neurons play critical roles in providing excitation to the spinal locomotor circuits during swimming by providing both tonic and phasic inputs to the circuits.


Massive necrotizing pancreatitis in an immunosuppressed renal transplant recipient (successful therapy).
Severe pancreatitis may be associated with massive necrosis of the pancreas and/or retroperitoneal adipose tissue. Toxicity results from the dead tissue and secondary infection. A 45 year old patient, while fully immunosuppressed, developed this complication following cadaveric renal transplantation. He survived continued immunosuppression, 16 operative debridements of the retroperitoneum, and maintained a functioning renal transplant. In view of the previously reported high mortality rates from mild pancreatitis after transplantation, the current experience warrants further evaluation of the open method of treatment.


Effects of experimental bilateral cryptorchidism and castration on the plasma gonadotropins in male rats during sexual maturation.
The effect of bilateral cryptorchidism and castration on serum LH and FSH was assessed in rats throughout their sexual maturation. After short time (4 days) castration marked elevations of FSH and increases of LH in plasma are recorded in all developmental stages. Bilateral cryptorchidism caused after 4 days in different age groups elevations of LH regardless of the sexual maturation. FSH was elevated in these cryptorchid animals only in more mature animals.


MiSearch adaptive pubMed search tool.
MiSearch is an adaptive biomedical literature search tool that ranks citations based on a statistical model for the likelihood that a user will choose to view them. Citation selections are automatically acquired during browsing and used to dynamically update a likelihood model that includes authorship, journal and PubMed indexing information. The user can optionally elect to include or exclude specific features and vary the importance of timeliness in the ranking. http://misearch.ncibi.org. Supplementary data are available at Bioinformatics online.


Environment of TyrZ in photosystem II from Thermosynechococcus elongatus in which PsbA2 is the D1 protein.
The main cofactors that determine the photosystem II (PSII) oxygen evolution activity are borne by the D1 and D2 subunits. In the cyanobacterium Thermosynechococcus elongatus, there are three psbA genes coding for D1. Among the 344 residues constituting D1, there are 21 substitutions between PsbA1 and PsbA3, 31 between PsbA1 and PsbA2, and 27 between PsbA2 and PsbA3. Here, we present the first study of PsbA2-PSII. Using EPR and UV-visible time-resolved absorption spectroscopy, we show that: (i) the time-resolved EPR spectrum of Tyr(Z)(•) in the (S(3)Tyr(Z)(•))' is slightly modified; (ii) the split EPR signal arising from Tyr(Z)(•) in the (S(2)Tyr(Z)(•))' state induced by near-infrared illumination at 4.2 K of the S(3)Tyr(Z) state is significantly modified; and (iii) the slow phases of P(680)(+) reduction by Tyr(Z) are slowed down from the hundreds of μs time range to the ms time range, whereas both the S(1)Tyr(Z)(•) → S(2)Tyr(Z) and the S(3)Tyr(Z)(•) → S(0)Tyr(Z) + O(2) transition kinetics remained similar to those in PsbA(1/3)-PSII. These results show that the geometry of the Tyr(Z) phenol and its environment, likely the Tyr-O···H···Nε-His bonding, are modified in PsbA2-PSII when compared with PsbA(1/3)-PSII. They also point to the dynamics of the proton-coupled electron transfer processes associated with the oxidation of Tyr(Z) being affected. From sequence comparison, we propose that the C144P and P173M substitutions in PsbA2-PSII versus PsbA(1/3)-PSII, respectively located upstream of the α-helix bearing Tyr(Z) and between the two α-helices bearing Tyr(Z) and its hydrogen-bonded partner, His-190, are responsible for these changes.


Expression of the tumour-associated antigen CA-242 in transitional cell bladder tumours: a comparison with CA-50.
The tissue expression of carbohydrate antigen CA-242 was analysed in formalin-fixed biopsy specimens from 147 transitional cell bladder tumours. The staining was related to established prognostic factors and survival during a mean follow-up of over 12 years and the staining results were also compared to expression of CA-50 antigen. Forty-one percent (60/147) of the tumours were negative for CA-242 and 59% (87/147) were positive. Normal bladder mucosa was positive for CA-242 and the umbrella cells in particular showed intense positive staining. In tumours, the umbrella cells were usually positive (when present) and in tumour tissue, positive cells appeared either as individual positive cells or in groups. None of the tumours was entirely positive for CA-242. The tissue expression of CA-242 could not be significantly related to TNM classification, papillary status, WHO grade or quantitative variables (DNA ploidy, S phase fraction, mitotic frequency, nuclear factors). The tissue expression of CA-242 was significantly weaker than the expression of CA-50. The expression of CA-242 was related to favourable prognosis in survival analysis (P = 0.04). The results show that the expression of the novel tumour marker antigen CA-242 as determined in paraffin-embedded material is a weak prognostic factor as compared with established prognostic factors in transitional cell bladder tumours.


High-dose whole abdominal and pelvic irradiation for treatment of ovarian carcinoma: long-term toxicity and outcomes.
To evaluate the role of high-dose whole abdominal and pelvic irradiation (WART) in the treatment of epithelial ovarian carcinoma. A retrospective review was performed on 71 patients with Stage I-III ovarian carcinoma who were treated with WART using an open field technique after total abdominal hysterectomy and bilateral oophorectomy with or without omentectomy. Whole abdominal doses greater than typically recommended were used in a series of patients to enhance local control and to decrease abdominal recurrence. None of the patients had received chemotherapy before RT. Thirty-one patients received Alkeran or cyclophosphamide and two received cisplatin-based chemotherapy after WART. The median whole abdominal dose was 36 Gy (range 9-45.5), delivered in a median of 30 fractions (range 8-46). A pelvic boost was delivered using AP-PA fields during whole abdominal RT to a total midline pelvic dose of 200 cGy/d. The median pelvic dose was 51 Gy (range 16-59). The right lobe and a portion of the left lobe of the liver were shielded with custom blocks at a median dose of 25 Gy (range 9-41). The kidneys were shielded either AP-PA or PA from the first day of RT. The median dose to the kidneys was 19 Gy (range 4-30). The 5-year overall survival rate was 93%, 48%, and 29% for Stage I, II, and III patients, respectively. On multivariate analysis, stage and the extent of residual disease were independent prognostic factors. The 5- and 10-year overall survival rate for the 46 patients in the intermediate-risk group was 61% and 54%, respectively. For this group, a total abdominal dose of > or /=36 Gy was associated with a longer overall survival independent of stage, grade, and the amount of residual disease. This was most likely due to a significant reduction in the incidence of abdominal recurrence in patients receiving >36 Gy to the whole abdomen (18% vs. 49%, p = 0.006). Multivariate analysis revealed that grade (p = 0.023) and abdominal dose (p = 0.018) were independent factors influencing the rate of abdominal recurrence. Pelvic recurrence was rare as a first site of failure (6%). Twenty-one percent (n = 15) of the patients developed Grade 3 or 4 (Radiation Therapy Oncology Group [RTOG] criteria) chronic small or large bowel toxicity. Eleven percent of all patients had a small bowel obstruction requiring surgery. A whole abdominal dose >30 Gy and a pelvic dose >50 Gy were associated with a significant increase in small bowel obstruction (p = 0.01) independent of other factors. Chronic Grade 3 or 4 (Common Toxicity Criteria) anemia, thrombocytopenia, and leukopenia were seen in 7%, 1%, and 4% of the patients, respectively. Transient liver enzyme elevation was common (62%). Two patients had Grade 3 (RTOG) hepatic toxicity. Grade 3 or 4 renal toxicity (RTOG) was observed in 4%, and 2 patients (3%) were diagnosed with pelvic insufficiency fractures that were managed conservatively. Survival after RT for ovarian carcinoma rivals that achieved with systemic chemotherapy. The results of this study suggest a possible dose-control relationship between the whole abdominal dose and the risk of abdominal recurrence; however, a higher rate of small bowel obstruction was observed when greater abdominal doses and greater pelvic doses were combined. Careful attention to balancing toxicity and efficacy is imperative if RT is to have a future role in the treatment of this disease.


Differences in occupational stress by smoking intensity and gender in cross-sectional study of 59 355 Japanese employees using the Brief Job Stress Questionnaire (BJSQ): the Niigata Wellness Study.
It has been hypothesised that smoking intensity may be related to occupational stress. This study aimed to investigate whether stress, including problems with superiors or co-workers, is a driver of smoking. Cross-sectional study. 59 355 employees (34 865 men and 24 490 women) across multiple occupations who completed a self-reported questionnaire-based occupational stress survey between April 2016 and March 2017 in Niigata Prefecture. Stress scores for the Brief Job Stress Questionnaire subscales summed up after assigning high points for high stress and converted to Z-scores based on the mean of all participants. Heavy smokers (HS) smoked ≥15 cigarettes/day and light smokers (LS) smoked <15 cigarettes/day and were compared with non-smokers (NS) by gender. The main subscale items that were significantly associated with smoking status in both genders included 'physical burden', 'irritation' and 'physical symptoms'. In the analysis that included smoking intensity, the stress score for 'co-workers' support' was significantly lower for LS men than NS men (NS 0.091±0.98, LS -0.027±1.00, HS 0.033±0.99), and was significantly higher for HS women than NS women (NS -0.091±1.00, LS -0.080±1.05, HS 0.079±1.03). However, the stress score for 'co-workers' support' was low among LS women aged ≤39 years in the manufacturing industry. It was speculated that LS men and some LS women gained 'co-workers' support' using smoking as a communication tool while reducing the degree of smoking. The existence of such 'social smokers' suggested that to promote smoking cessation, measures are essential to improve the communication between workers in addition to implementing smoking restrictions in the workplace.


Dynamic Notch signaling in neural progenitor cells and a revised view of lateral inhibition.
In the developing mammalian nervous system, neural progenitor cells first express the Notch effector Hes1 at variable levels and then proneural genes and Notch ligands in salt-and-pepper patterns. Recent real-time imaging analysis indicates that Hes1 expression in these cells oscillates with a period of about 2-3 h. Furthermore, the proneural gene Neurogenin-2 (Ngn2) and the Notch ligand gene Deltalike-1 (Dll1) are expressed cyclically in neural progenitor cells under the control of Hes1 oscillation but are expressed continuously in postmitotic neurons, which lose Hes1 expression. Hes1-driven Ngn2 and Dll1 oscillations seem to be advantageous for maintenance of a group of cells in an undifferentiated state by mutual activation of Notch signaling. This dynamic mode of gene expression would require a revision of the traditional view of how Notch-mediated lateral inhibition operates in the developing mammalian nervous system.


Suicide surveillance and health systems in Nepal: a qualitative and social network analysis.
Despite increasing recognition of the high burden of suicide deaths in low- and middle-income countries, there is wide variability in the type and quality of data collected and reported for suspected suicide deaths. Suicide data are filtered through reporting systems shaped by social, cultural, legal, and medical institutions. Lack of systematic reporting may underestimate public health needs or contribute to misallocation of resources to groups most at risk. The goal of this study was to explore how institutional structures, cultural perspectives on suicide, and perceived criminality of self-harm influence the type and quality of suicide statistics, using Nepal as an example because of its purported high rate of suicide in the public health literature. Official documentation and reporting networks drawn by police, policy makers, and health officials were analyzed. Thirty-six stakeholders involved in various levels of the death reporting systems in Nepal participated in in-depth interviews and an innovative drawn surveillance system elicitation task. Content analysis and social network analysis revealed large variation across the participants perceived networks, where some networks were linear pathways dominated by a single institution (police or community) with few nodes involved in data transmission, while others were complex and communicative. Network analysis demonstrated that police institutions controlled the majority of suicide information collection and reporting, whereas health and community institutions were only peripherally involved. Both health workers and policy makers reported that legal codes criminalizing suicide impaired documentation, reporting, and care provision. However, legal professionals and law review revealed that attempting suicide is not a crime punishable by incarceration. Another limitation of current reporting was the lack of attention to male suicide. Establishment and implementation of national suicide prevention strategies will not be possible without reliable statistics and comprehensive standardized reporting practices. The case of Nepal points to the need for collaborative reporting and accountability shared between law enforcement, administrative, and health sectors. Awareness of legal codes among health workers, in particular dispelling myths of suicide's illegality, is crucial to improve mental health services and reporting practices.


Epidermal proteins of cultured human and bovine keratinocytes.
Bovine and human epidermal cells were cultured on mitomycin C treated fibroblasts. The cells were carried through four passages and found to synthesize fibrous proteins and insoluble cell envelopes. Acid buffer soluble fibrous protein, prekeratin, and urea soluble fibrous protein were both identified and the latter was the major component in older cultures. Some of the prekeratin polypeptides of intact tissue were not found in cultured cells, but the ones that were present corresponded to those of whole tissue. X-ray diffraction, amino acid analysis and immunological techniques were used to establish that the polypeptides were keratins. The insoluble cell envelopes had a higher proline and 1/2 cystine content than the fibrous protein, similar to what is found in whole epidermis. Histidase, a characteristic enzyme marker of whole epidermis, was not observed in cultured cells. These studies indicate that differentiation occurs in cultured cells but it may not be as complete as in intact tissue.


Trypanosoma cruzi: maintenance of parasite-specific T cell responses in lymph nodes during the acute phase of the infection.
Mice infected with 5 x 10(3) forms of Trypanosoma cruzi showed a transient, but severe impairment of in vitro spleen cell responses to parasite antigens and to Concanavalin A (Con A). In contrast, inguinal and periaortic lymph node (LN) cells displayed high parasite-specific proliferative responses and only a partial reduction of the Con A-induced proliferation during the acute and chronic phases of infection. Lymphocytes that underwent blastic transformation in T. cruzi-stimulated cell cultures were of the L3T4+ phenotype. Suppression of spleen cell responses occurred in the acute phase whether mice were infected with high (3 x 10(5] or low (5 x 10(3] doses of T. cruzi by intraperitoneal or subcutaneous route. Suppression of the T. cruzi-specific proliferative response of LN cells was only observed in mice infected with high subcutaneous inocula. This suppression, however, was restricted to the LNs draining the site of inoculation without affecting distant LNs. Supernatants from parasite-stimulated proliferating LN cells displayed low or undetectable T cell growth factor (TCGF) activity, in contrast with the high TCGF levels found in supernatants of the same cells stimulated with Con A. Low levels of TCGF were also detected in cultures of LN cells from mice immunized with T. cruzi extracts. Neither the T. cruzi antigen used for in vitro stimulation nor the LN cell supernatants from infected mice inhibited TCGF activity. These findings indicate that (1) parasite-specific responses are present in the LN compartment throughout the acute phase of T. cruzi infection in mice and (2) the proliferative response of L3T4+ LN cells from infected mice to T. cruzi antigens is not associated with a high TCGF secretory response.


[Corticosteroids in community acquired pneumonia: Where are we in 2018?]
Community-acquired pneumonia (CAP) is a common infectious disease and one of the main causes of mortality worldwide. Despite an improvement in management globally, mortality remains high especially in severe forms of CAP. Adequate early antibiotics remain the cornerstone of the treatment but adjuvant corticosteroid administration is being considered to counterbalance the systemic inflammatory reaction and modulate the immune response. In the last ten years, several clinical trials and meta-analyses have been conducted in severe and non-severe CAP to assess the efficacy of corticosteroids. The benefits on the duration of hospitalization and the time to clinical stability are quite small and early mortality does not seem to be improved. Corticosteroids should not, therefore, be used routinely in patients with CAP, even in severe cases. However, new therapeutic trials are currently underway.


Work in progress: transcatheter embolization of renal cell carcinoma with radioactive infarct particles.
Treatment by radioactive infarct implant is advocated for patients who have renal cell carcinoma with distant metastases. The radioactive infarct implants were placed into the primary tumor, and when feasible into metastases, by transcatheter embolization. Metastases to the skeleton, liver, lungs, adrenals, and retroperitoneal muscles were also seeded; metastases to the central nervous system, pancreas, and spleen, as well as most pulmonary metastases, proved inaccessible to this approach. The effectiveness of this treatment modality was shown by improved cumulative survival rates (59% for patients with metastases and at risk at two years and 50% for those at risk at five years). The best results were obtained when treating patients who had skeletal metastases (90% survival of those at risk at two years and 60% at five years). Measurable palliation factors, such as decrease in the size of the primary lesion, weight gain, and control of bleeding and pain, were indicators of treatment response and were observed in the majority of patients. Remissions were signaled by weight gain, normalization of the erythrocyte sedimentation rate, and disappearance or decrease of tumor markers. Some evidence suggests that the salutary results may be based on significant reduction of tumor burden, temporary local control of tumor, and improved general immunocompetence.


Septins regulate border cell surface geometry, shape, and motility downstream of Rho in Drosophila.
Septins self-assemble into polymers that bind and deform membranes in vitro and regulate diverse cell behaviors in vivo. How their in vitro properties relate to their in vivo functions is under active investigation. Here, we uncover requirements for septins in detachment and motility of border cell clusters in the Drosophila ovary. Septins and myosin colocalize dynamically at the cluster periphery and share phenotypes but, surprisingly, do not impact each other. Instead, Rho independently regulates myosin activity and septin localization. Active Rho recruits septins to membranes, whereas inactive Rho sequesters septins in the cytoplasm. Mathematical analyses identify how manipulating septin expression levels alters cluster surface texture and shape. This study shows that the level of septin expression differentially regulates surface properties at different scales. This work suggests that downstream of Rho, septins tune surface deformability while myosin controls contractility, the combination of which governs cluster shape and movement.


Pneumocystis jirovecii pneumonia in HIV-negative patients, a frequently overlooked problem. A case series from a large Italian center.
Pneumocystis jirovecii pneumonia (PCP) still has substantial morbidity and mortality. For non-HIV patients, the course of infection is severe, and management guidelines are relatively recent. We collected all PCP cases (European Organization for Research and Treatment of Cancer criteria) diagnosed in HIV-negative adult inpatients in 2019-2020 at our center in northern Italy. Of 20 cases, nine had microbiologic evidence of probable (real-time polymerase chain reaction, RT-PCR) and 11 proven (immunofluorescence) PCP on respiratory specimens. Half were female; the median age was 71.5 years; 14 of 20 patients had hematologic malignancies, five had autoimmune/hyperinflammatory disorders, and one had a solid tumor. RT-PCR cycle threshold (Ct) was 24-37 for bronchoalveolar lavage (BAL) and 32-39 for sputum; Ct was 24-33 on BAL proven cases. Of 20 cases, four received additional diagnoses on BAL. At PCP diagnosis, all patients were not on anti-pneumocystis prophylaxis. We retrospectively assessed prophylaxis indications: 9/20 patients had a main indication, 5/9 because of prednisone treatment ≥ 20 mg (or equivalents) for ≥4 weeks. All patients underwent antimicrobial treatment according to guidelines; 18/20 with concomitant corticosteroids. A total of 4/20 patients died within 28 days from diagnosis. Despite appropriate treatment, PCP is still associated to high mortality (20%) among non-HIV patients. Strict adherence to prophylaxis guidelines, awareness of gray areas, and prompt diagnosis can help manage this frequently overlooked infection.


Understanding how stress responses and stress-related behaviors have evolved in zebrafish and mammals.
Stress response is essential for the organism to quickly restore physiological homeostasis disturbed by various environmental insults. In addition to well-established physiological cascades, stress also evokes various brain and behavioral responses. Aquatic animal models, including the zebrafish (Danio rerio), have been extensively used to probe pathobiological mechanisms of stress and stress-related brain disorders. Here, we critically discuss the use of zebrafish models for studying mechanisms of stress and modeling its disorders experimentally, with a particular cross-taxon focus on the potential evolution of stress responses from zebrafish to rodents and humans, as well as its translational implications.


Suprachoroidal hemorrhage after glaucoma filtering surgery.
We reviewed a series of 305 consecutive glaucoma filtering procedures performed by one surgeon. Five eyes (1.6%) had a postoperative suprachoroidal hemorrhage. All five eyes were aphakic, and four had undergone a partial or complete vitrectomy before the glaucoma surgery. The incidence of this complication was 13% (five of 37) among the aphakic eyes and 33% (four of 12) in the aphakic, vitrectomized eyes in this series. Despite drainage of the hemorrhage and reformation of the anterior chamber, three patients had a poor visual outcome.


Induction of the metastatic phenotype in a mouse tumor model by 5-azacytidine, and characterization of an antigen associated with metastatic activity.
The murine Lewis lung carcinoma is a long-term grafted tumor that, after subcutaneous inoculation, forms metastases to the lungs. Forty-two cell lines were established from a primary tumor site and 40 were established from lung metastatic foci. Cloned sublines were established from the original 82 lines, and 2 sublines among 405 were found to be tumorigenic but not metastatic (T+/M-), whereas the remaining 403 sublines were both tumorigenic and metastatic (T+/M+). The T+/M- phenotype was shown to be stable for greater than 2 yr. However, treatment of the T+/M- cell lines for 3 days with 3 microM 5-azacytidine resulted in reexpression of the metastatic phenotype in otherwise stable T+/M- lines. Also, 5-azacytidine treatment could result in loss of the metastatic phenotype in lines that had been stable T+/M+. The changes in tumorigenic and metastatic phenotypes were not associated with altered immunogenicity of the cells. Monoclonal antibodies were generated against T+/M+ cells, and one antibody ( M36D3 ) was found to bind only to T+/M+ cells. Reactivity of the antibody was found to co-vary with expression of the metastatic phenotype. The antigen recognized by M36D3 antibody thus seems to be associated with metastatic capability. The antigen was found by two-dimensional gel electrophoretic analysis to be a cellular protein of Mr approximately equal to 45,000 and pI approximately equal to 6.7.


Entry Studies of New World Arenaviruses.
Identification of cell moieties involved in viral binding and internalization is essential since their expression would render a cell susceptible. Further steps that allow the uncoating of the viral particle at the right subcellular localization have been intensively studied. These "entry" steps could determine cell permissiveness and often define tissue and host tropism. Therefore applying the right and, when possible, straightforward experimental approaches would shorten avenues to the complete knowledge of this first and key step of any viral life cycle. Mammarenaviruses are enveloped viruses that enter the host cell via receptor-mediated endocytosis. In this chapter we present a set of customized experimental approaches and tools that were used to describe the entry of Junín virus (JUNV), and other New World mammarenavirus members, into mammalian cells.


Metabolism of cyclic AMP in non-pathogenic Mycobacterium smegmatis.
The intracellular concentration of cyclic AMP reached a maximum in 3.5-day old cultures of Mycobacterium smegmatis grown in the presence of glycerol as the main source of carbon. Glucose-grown cells exhibited decreased cyclic AMP levels at all stages of growth. When M. smegmatis cells were incubated with various metabolites, pyruvate increased whereas glucose, ctric acid, succinic acid and lactic acid decreased intracellular cyclic AMP levels. No cyclic AMP was detected in the incubation medium. The presence of a cyclic AMP-binding protein was demonstrated in cell-free extracts of M. smegmatis.


Recognition memory models and binary-response ROCs: a comparison by minimum description length.
Model comparison in recognition memory has frequently relied on receiver operating characteristics (ROC) data. We present a meta-analysis of binary-response ROC data that builds on previous such meta-analyses and extends them in several ways. Specifically, we include more data and consider a much more comprehensive set of candidate models. Moreover, we bring to bear modern developments in model selection on the current selection problem. The new methods are based on the minimum description length framework, leading to the normalized maximum likelihood (NML) index for assessing model performance, taking into account differences between the models in flexibility due to functional form. Overall, NML results for individual ROC data indicate a preference for a discrete-state model that assumes a mixture of detection and guessing states.


[Chronic pain and regional anesthesia in children].
Chronic pain is usually underestimated in children, due to lack of knowledge and its specific signs. In addition to suffering, chronic pain causes a physical, psychological, emotional, social, and financial burden for the child and his family. Practitioners may find themselves in a situation of failure with depletion of medical resources. Some types of chronic pain are refractory to conventional systemic treatment and may require the use of regional anesthesia. Cancer pain is common in children and its medical management is sometimes insufficient. It is accessible to neuroaxial or peripheral techniques of regional anesthesia if it is limited to an area accessible to one of these techniques and no contraindications (e.g., thrombopenia) are present. Complex regional pain syndrome 1 is not rare in children and adolescents, but it often goes undiagnosed. Regional anesthesia may contribute to the treatment of complex regional pain syndrome 1, mainly in case of recurrence, because it provides rapid effective analgesia and allows rapid implementation of intensive physiotherapy. These techniques have also shown interest in phantom limb pain after limb amputation, but they remain controversial for erythromelalgia pain or chronic abdominopelvic pain. Finally, the treatment of postdural puncture headache due to cerebrospinal fluid leak can be treated by performing an epidural injection of the patient's blood, called a blood-patch. Finally, the management of children with chronic pain should be multidisciplinary (pediatrician, physiotherapist, psychologist, surgeon, anesthesiologist) to support the child and her problem in its entirety.


Dental pain related to quality of life and mental health in South Korean adults.
High levels of stress, anxiety and depression have been reported in patients with orofacial pain. Dental pain has the potential to reduce quality of life (QOL), and pain relief is important aspect of QOL. The purpose of this study was to assess the relationships of dental pain with QOL and mental health using a nationally representative, population-based study. This study analyzed data from the 2012 Korea National Health and Nutrition Examination Survey (N = 5469). Oral health status was assessed using the oral health questionnaire, and oral examination was performed by trained dentists. Health-related QOL (HRQOL) was evaluated using EQ-5D and EQ-VAS, and mental health was evaluated by questionnaires. Logistic regression was applied to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI). Among 5469 adults, 1992 (36.42%) presented self-reported dental pain. Participants with anxiety/depression or pain/discomfort, and participants with stress, melancholy, suicidal thought or depression showed significantly higher prevalence of dental pain. After adjusting for covariates, five aspects of QOL and five aspects of mental health were related with dental pain. The AORs (95% CI) for dental pain were 1.39 (1.06-1.81) for mobility, 1.77 (1.19-2.63) for self-care, 1.38 (1.02-1.85) for usual activities, 1.73 (1.43-2.09) for pain/discomfort and 1.50 (1.13-1.98) for anxiety/depression. For mental health status factors, the AORs (95% CI) for dental pain were 1.29 (1.11-1.51) for stress, 1.37 (1.09-1.74) for melancholy, 1.26 (1.01-1.58) for suicidal thoughts, 1.43 (.93-2.19) for consultation to psychiatrist and 1.53 (1.07-2.19) for depression. This study showed that dental pain has an association with lower HRQOL and worse mental health status in South Korean adults.


[Histochemical localization of calcium in the colloid of rat thyroid vesicles (author's transl)].
With a Glyoxal bis 2-hydroxyanil alcoholic solution at -25 degrees C, the calcium was localized in frozen thyroid slices. The limited ionic movement permits seeing that the calcium situated principally in the colloid is resorbed at the same time by a low temperature stress.


Yeast culture collections of the world: meeting the needs of industrial researchers.
The importance of selecting optimal yeast strains for research or industrial applications is often underestimated. For example, utilizing a strain background that already provides the desired stress tolerance or nutrient utilization profile can eliminate costly strain optimization. Yeast culture collections can provide not only the yeast strains but also data and curator expertise to help narrow the search for the optimal strain. While some collections are known for a broad range of cultures and services, other "boutique" collections can provide a broader selection of strains of certain categories, a surprising amount of characterization data, and assistance in selecting strains. This article provides information on dozens of yeast collections of the world, profiles of selected yeast culture collections, and the services that they provide: e.g., strain preservation for patent or safe deposit purposes, species identification service, training workshops, and consulting on yeast identification and physiology. Utilization of these services can save industrial researchers valuable time and resources.


Developing Countries Vaccine Manufacturers Network: doing good by making high-quality vaccines affordable for all.
The Developing Countries Vaccine Manufacturers Network (DCVMN) is a unique model of a public and private international alliance. It assembles governmental and private organizations to work toward a common goal of manufacturing and supplying high-quality vaccines at affordable prices to protect people around the world from known and emerging infectious diseases. Together, this group of manufacturers has decades of experience in manufacturing vaccines, with technologies, know-how, and capacity to produce more than 40 vaccines types. These manufacturers have already contributed more than 30 vaccines in various presentations that have been prequalified by the World Health Organization for use by global immunization programmes. Furthermore, more than 45 vaccines are in the pipeline. Recent areas of focus include vaccines to protect against rotavirus, human papillomavirus (HPV), Japanese encephalitis, meningitis, hepatitis E, poliovirus, influenza, and pertussis, as well as combined pentavalent vaccines for children. The network has a growing number of manufacturers that produce a growing number of products to supply the growing demand for vaccines in developing countries.


The alteration of the pulmonary artery flow spectrum with pulmonary hypertension.
To research the alteration of pulmonary flow spectrum of patients with congenital heart disease and the relation between pulmonary flow spectrum and pulmonary artery pressure, 33 patients with congenital heart disease were examined by echocardiography and catheterization. The result showed that the spectrum peak early occurring in patients with pulmonary hypertension and the degree of the spectrum peak early occurring was related to pulmonary artery pressure positively. The result suggested that when the pulmonary artery systolic pressure was over 100 mmHg, the flow spectrum showed slender pattern usually. The slender pattern in pulmonary flow spectrum could be a semi-quantity parameter to predict that the pulmonary artery systolic pressure more than 100 mmHg.


Albumin adsorption on alkyl chain derivatized polyurethanes. II. The effect of alkyl chain length.
Linear alkyl chains containing 2, 10 and 18 carbon atoms were grafted to 10% of the urethane nitrogens in a polyether-polyurethane. The polyurethane was synthesized from methylene bis(p-phenyl isocyanate), 1,4-butanediol, and polytetramethylene oxide of 1000 molecular weight in a molar ratio of 3/2/1. Fourier transform infrared spectroscopy and attenuated total reflectance optics were used to study the adsorption of 5.0 mg/ml human serum albumin (HSA) at 37 degrees C to the derivatized and non-derivatized polymers. Both delipidized HSA and HSA containing 6.5 mol stearic acid per mol of albumin were used to study the effect of chain length upon the initial adsorption rate, the total amount adsorbed in 1 h, and the desorption rate. The initial adsorption rates revealed that non-specific adsorption was similar upon all four polymers. An increase in initial adsorption rate upon the C-18 derivatized polymer was attributed to a specific binding interaction between the HSA and the grafted alkyl chains. The conformational stability of the HSA also affected the adsorption rate. The total amount adsorbed after 1 h decreased as the alkyl chain length increased from 2 to 18 methylene groups. The desorption rate decreased in magnitude as the alkyl chain length increased from C-2 to C-18. These results support a hypothesis that alkyl chain length influences the interaction between albumin and an alkylated polymer system.


Sifting through course evaluations: medical student comments driving surgery curriculum changes.
Student empowerment of curriculum changes is a double-edged sword. When examining our third-year surgery course every year, we debate where the line is between improving education through student input against allowing the students to design "an easy course." Written student comments on end-of-course evaluations (from the academic years 2006-2007 to 2010-2011) were analyzed using the qualitative approach described by Miles and Huberman. We compared the grouped comments to the course changes that were made over these years to determine what extent were we listening to students. Finally, we took the course changes made and juxtaposed them with student grades and with student course perceptions provided by the end-of-course evaluation analysis. We identified 17 alterations to our curriculum since the year 2007-2008 and of those, 12 are directly related to student comments. Some examples of our changes were a grading-scale alteration, grouping of workshops, and adding a shelf examination review session. The overall course ratings by the students steadily rose over the 5-year period (2.57 to 3.39), while the percentages of A's earned by students decreased over that same time until the year 2010-2011 when the percent of A's earned increased by over 30%. Because of the fact that 12 of 17 course changes can be directly related back to the student comments, we feel confident that we are listening to students. The increase in perception of the course through the first 4 years did not coincide with higher grades. The changes made have been instrumental in the course winning the best clerkship award for the last 4 years.


CD4+ T-cell activation for immunotherapy of malignancies using Ii-Key/MHC class II epitope hybrid vaccines.
Active immunotherapy is becoming a reality in the treatment of malignancies. Peptide-based vaccines represent a simple, safe, and economic basis for cancer immunotherapeutics development. However, therapeutic efficacy has been disappointing. Some of the reasons for this, such as selection of patients with advanced disease and ignorance of the delayed activity of many immunotherapeutic vaccines, have hampered the entire field of cancer immunotherapy over the last decade. Another reason for this may be that most peptide regimens historically have focused on activation of CD8+ cytotoxic T lymphocytes, having little or only indirect CD4+ T helper (Th) cell activation. We review here evidence for the importance of specific CD4+ Th activation in cancer immunotherapy and the use of Ii-Key technology to accomplish this. Ii-Key (LRMK), a portion of the MHC class II-associated invariant chain (Ii protein), facilitates the direct charging of peptide epitopes onto MHC class II molecules. Directly linking Ii-Key to MHC class II peptide epitopes greatly enhances their potency in activating CD4+ T-cells. The Ii-Key hybrid AE37, generated by linking LRMK to the known HER2 MHC class II epitope HER2 (aa 776-790), has been shown to generate robust, long lasting HER2-specific immune responses both in patients with breast and prostate cancer. Interim data from a phase II study of AE37 in breast cancer patients suggest a possible improvement in clinical outcome. The Ii-Key hybrid technology is compared to other methods for enhancing the potency of peptide immunotherapy for cancer.


Prevalence of salt-losing among congenital adrenal hyperplasia patients.
Among clinic patients with congenital adrenal hyperplasia (CAH) the observed frequency of salt-losing has increased significantly over the past 30 years. Comparing estimates from various clinics, older estimates of the frequency of salt-losing are lower than estimates cited in more recent literature. Within the patient population of a single long-established clinic, an increase in the frequency of salt-losing can also be observed. It is likely that the increase in the frequency of salt-losing CAH reflects improved case finding and survival of salt-losing patients. Based on reports of recent populations of CAH patients, the frequency of salt-losing among CAH patients is approximately 66%.


Nonmalignant Features Associated with Inherited Colorectal Cancer Syndromes-Clues for Diagnosis.
Genetic diagnosis of affected individuals and predictive testing of their at-risk relatives, combined with intensive cancer surveillance, has an enormous cancer-preventive potential in these families. A lack of awareness may be part of the reason why the underlying germline cause remains unexplained in a large proportion of patients with CRC. Various extracolonic features, mainly dermatologic, ophthalmic, dental, endocrine, vascular, and reproductive manifestations occur in many of the cancer predisposition syndromes associated with CRC and polyposis. Some are mediated via the WNT, TGF-β, or mTOR pathways. However the pathogenesis of most features is still obscure. Here we review the extracolonic features of the main syndromes, the existing information regarding their prevalence, and the pathways involved in their pathogenesis. This knowledge could be useful for care managers from different professional disciplines, and used to raise awareness, enable diagnosis, and assist in the process of genetic testing and interpretation.


Clinical application of the P3 component of event-related potentials. II. Dementia, depression and schizophrenia.
Patients with dementia, schizophrenia and depression were tested with analogous auditory and visual event-related potential (ERP) paradigms designed to elicit a large P3. The patient groups were compared to age normative predictions derived from a large control sample for a number of ERP and behavioral variables. The results were similar for the auditory and visual paradigms. P3 latency was prolonged two or more S.D.s beyond that predicted by age for less than one-half of the demented patients. This latency prolongation was significant for the group as a whole but would result in too many false negatives if used diagnostically for individuals. Furthermore, increased P3 latency was not specific, as the schizophrenic patients also had later P3s. The amplitude of P3 was reduced in the demented patients, but it was also smaller in other patient groups. The only variable which distinguished the demented patients from both controls and from the other patients was the single trial P3 latency/RT correlation. The demented patients, as a group, had significantly lower P3 latency/RT correlations, but this effect also was not sensitive enough to be diagnostic for individuals. The data from these two paradigms suggest that the P3 amplitude and latency abnormalities observed reflect a common, rather than a diagnostically specific deficit. This study is in contrast to some others which report much more sensitivity and specificity in the use of P3 latency in the diagnosis of dementia. Differences in task demands, patient samples and ERP analysis techniques might explain some of the discrepancy.


Antimetastatic effect of suicide gene therapy for mouse mammary cancers requires T-cell-mediated immune responses.
These experiments were conducted to investigate whether the antimetastatic effects of HSVtk/GCV therapy involve T-cell-mediated immune responses. In the first experiment, immunocompetent syngeneic mice were inoculated with metastatic mammary cancers, then given a direct intratumoral injection of a plasmid vector containing a suicide gene (pHSVtk) or control vector once a week for 8 weeks. Gene electrotransfer treatment was applied to the tumors, and mice were administered ganciclovir (GCV) using a mini-osmotic pump. At the end of the experiment, tumor volume was significantly lower in the pHSVtk/GCV group. Macrophage accumulations were frequently observed in the peripheries of the necrotic regions in pHSVtk-transfected mice. Levels of CD4 and CD8 proteins in tumors were higher in the pHSVtk/GCV group than in the control group. Interleukin (IL)-12 mRNA levels tended to be higher in tumors in the pHSVtk/GCV group, but there were large variations. Tumor microvessel density was significantly lower in the pHSVtk/GCV group. The numbers of dilated lymphatic vessels containing intraluminal tumor cells tended to be higher in the pHSVtk/GCV group. However, vascular endothelial growth factor (VEGF)-A and VEGF-C mRNA levels in tumors were similar in the control and pHSVtk/GCV groups. In the second experiment, tumor volume and metastatic parameters were compared for immunocompetent syngeneic mice and immunodeficient athymic mice (without an intact T-cell system) given pHSVtk/GCV therapy. Although tumor volumes were significantly smaller in both syngeneic and athymic mice given pHSVtk/GCV therapy, the inhibition ratios (relative to control mice) were much greater in syngeneic mice than in athymic mice. No suppression of metastasis to the lymph nodes and lungs was observed for athymic mice given pHSVtk/GCV therapy. Our data suggest that HSVtk/GCV suicide gene therapy exerts an antimetastatic effect via a T-cell-mediated immune response.


Antigenic determinants of two components of proteoglycan complex from bovine cartilage.
The immunological properties of a glycoprotein fraction and of proteoglycan subunits obtained from bovine nasal cartilage by nondisruptive methods of isolation have been studied. Using the techniques of hemagglutination and hemagglutination inhibition, we found that the glycoprotein contains most of the species-specific determinants, whereas the proteoglycan subunits contain most of the cross-reacting ones.


Preeclampsia Brings the Risk of Premature Cardiovascular Disease in Women Closer to That of Men.
It is not known if sex differences in the risk of premature cardiovascular disease (CVD) vary by whether a woman had preeclampsia or not. The current study determined whether prior preeclampsia brings a woman's risk of CVD closer to that of a male counterpart. A population-based cohort study was completed in Ontario, Canada, from 1993 to 2017. Participants were 55,186 women with prior preeclampsia, 110,372 randomly selected age- and region-matched men, and 110,372 similarly selected women who gave birth without prior preeclampsia. The primary outcome was a CVD composite outcome of any hospitalization or revascularization for coronary artery disease, cerebrovascular disease, peripheral artery disease, heart failure, and dysrhythmia. Median follow-up was approximately 16 years. Relative to women without prior preeclampsia (1193 events; 7.5 per 10,000 person-years), men had the highest risk of CVD (3706 events; 24.3 per 10,000 person-years) (adjusted hazard ratio [aHR], 2.52; 95% confidence interval [CI], 2.35-2.69). Women with a history of preeclampsia were also at higher risk (1252 events; 16.0 per 10,000 person-years) (aHR, 1.17; 95% CI, 1.08-1.28). Women with preeclampsia requiring preterm delivery were even more likely to experience CVD (21.5 per 10,000 person-years) (aHR, 1.44; 95% CI, 1.18-1.76). The absolute risk of CVD in men (22.5 per 10,000 person-years) was similar to the risk in women with preeclampsia and preterm delivery, but men had the highest aHR (2.48; 95% CI, 2.11-2.93). Although men remain at significantly higher risk of CVD, a history of preeclampsia, especially with preterm birth, elevates a woman's risk closer to that of a man.


Physical activity attenuates negative effects of short-term exposure to ambient air pollution on cognitive function.
As physical activity benefits brain health whereas air pollution damages it, the cognitive response to these exposures may interact. This study aimed to assess the short-term joint effect of physical activity and air pollution on cognitive function in a panel of healthy young adults. We followed ninety healthy subjects aged around 22 years from September 2020 to June 2021 and measured their personal exposure to fine particulate matter (PM2.5) (μg/m3) and daily accelerometer-based moderate-to-vigorous physical activity (MVPA) (min/day) in 4 one-week-long sessions over the study period. At the end of each measurement session, we assessed executive function using Stroop color-word test and collected resting-state electroencephalogram (EEG) signals. We found short-term PM2.5 exposure damaged executive function (βPM25 = 0.0064, p = 0.039) but physical activity could counterbalance it (βMVPA = -0.0047, p = 0.048), whereby beta-3 wave played as a potential mediating role. MVPA-induced improvement on executive function was larger in polluted air (βMVPA = -0.010, p = 0.035) than that in clean air (βMVPA = -0.003, p = 0.45). To offset the negative effect of air pollution on cognitive function, individuals should do extra 13.6 min MVPA every day for every 10 μg/m3 increase in daily PM2.5. This study implies that physical activity could be used as a preventive approach to compensate the cognitive damages of air pollution.


The Anti-Cancer Properties of the HIV Protease Inhibitor Nelfinavir.
Traditional cancer treatments may lose efficacy following the emergence of novel mutations or the development of chemoradiotherapy resistance. Late diagnosis, high-cost of treatment, and the requirement of highly efficient infrastructure to dispense cancer therapies hinder the availability of adequate treatment in low-income and resource-limited settings. Repositioning approved drugs as cancer therapeutics may reduce the cost and timeline for novel drug development and expedite the availability of newer, efficacious options for patients in need. Nelfinavir is a human immunodeficiency virus (HIV) protease inhibitor that has been approved and is extensively used as an anti-infective agent to treat acquired immunodeficiency syndrome (AIDS). Yet nelfinavir has also shown anti-cancer effects in in vitro and in vivo studies. The anti-cancer mechanism of nelfinavir includes modulation of different cellular conditions, such as unfolded protein response, cell cycle, apoptosis, autophagy, the proteasome pathway, oxidative stress, the tumor microenvironment, and multidrug efflux pumps. Multiple clinical trials indicated tolerable and reversible toxicities during nelfinavir treatment in cancer patients, either as a monotherapy or in combination with chemo- or radiotherapy. Since orally available nelfinavir has been a safe drug of choice for both adult and pediatric HIV-infected patients for over two decades, exploiting its anti-cancer off-target effects will enable fast-tracking this newer option into the existing repertoire of cancer chemotherapeutics.


The human platelet as an independent unit for sulfate conjugation.
The human platelets possess a full complement of enzymes capable of synthesizing N-acetyldopamine (NADA) 35sulfate from ATP, Mg++ and sodium 35sulfate. The pH optimum for this three-step overall sulfate conjugation (comprising of the ATP sulfurylase, APS kinase and phenolsulfotransferase reactions) is 8.6 and the reactions proceeded progressively for several hours. Both ATP and Mg++ ions, above their respective optimal concentrations of 5 and 7 mM, inhibited the sulfate conjugation of NADA. The apparent Km values for NADA as determined by the phenolsulfotransferase (PST) and overall reactions were similar in magnitude being 2.6 and 4.8 microM, respectively, while that for sodium 35sulfate was 202 microM. A comparison of these two activities in 62 platelet preparations of normal subjects showed that the rate of the PST reaction was generally higher than the overall reaction even though the PST assay was carried out at suboptimal concentration of PAPS. There was a positive correlation (r = 0.82) between the two sets of data, suggesting that the PST reaction probably has some control over the rate of overall sulfate conjugation.


Increased superoxide anion production in polymorphonuclear leucocytes on exposure to isobutyl-2-cyanoacrylate.
Alkyl-2-cyanoacrylates have been employed in a variety of surgical procedures, although the pathophysiological basis for their cytotoxicity has not been resolved. Previous reports indicated that leucocytes infiltrate the site of cyanoacrylate application in situ. Consequently, human polymorphonuclear leucocytes were treated with 0-200 mM cyanoacrylate isobutyl-2- and superoxide anion radical production, lactate dehydrogenase release, and intracellular reduced glutathione content were quantitated following this treatment. In addition, some cells were also treated with 0-20 mM ascorbic acid before exposure to the adhesive. Pretreatment with ascorbic acid resulted in a statistically significant decrease in superoxide production (up to 111%), decrease in lactate dehydrogenase release (up to 26.4%) and a like increase in glutathione content (up to 26.6%). These results indicated that the cytotoxic properties of isobutyl-2-cyanoacrylate were diminished in a dose-dependent manner with addition of ascorbic acid, a free radical trapping agent. Moreover, isobutyl-2-cyanoacrylate appeared to increase specifically the production of superoxide anion. These findings suggested that the cytotoxicity of this class of adhesives may be associated with the formation of reactive oxygen intermediates.


Characterization of mitotane (o,p'-DDD)--cyclodextrin inclusion complexes: phase-solubility method and NMR.
Mitotane (o,p'-dichlorodimethyl dichloroethane [o,p'-DDD]) is used for the treatment of adrenocortical cancer and occasionally Cushing's syndrome. This drug is very poorly soluble in water, and following oral administration, approximately 60% of the dose is recovered in the feces unaltered. The preparation of a soluble formulation (i.e. by complexation with cyclodextrins) with improved bioavailability is the aim of this work. The inclusion of mitotane in methyl-ß-cyclodextrins was studied using both phase-solubility methods and NMR experiments. To elucidate the inclusion mechanism, o,p'-DDD was compared to its regioisomer (i.e. p,p'-DDD). It was demonstrated that two dimethyl-ß-cyclodextrins (DMßCD) can complex with the aromatic rings. From the phase-solubility diagrams, we observe that both cases are very different: K(1:1) is between 37 000 and 85 000 mol.l(-1), whereas K(1:2) is between 5.3 and 32 mol.l(-1). The NMR experiments confirmed the inclusion but it also gave an insight into the kinetics of the dissociation: the ortho-chloro moiety is in slow exchange on the NMR time scale, whereas the para-chloro moiety is in fast exchange rate.