Giant growth hormone-secreting pituitary adenomas from the endocrinologist's perspective.
Since giant (≥40 mm) GH-secreting pituitary adenomas are rarely encountered, data on their characteristics and treatment outcomes are limited. We aimed to investigate the characteristics of giant GH-secreting pituitary adenomas and to compare their clinical, biochemical, imaging and histopathological features with non-giant macroadenomas. We have evaluated 15 (six female/nine male) and 57 (29 female/28 male) patients with acromegaly in giant and <40 mm adenoma groups, respectively. Patients with <40 mm adenoma were further divided into subgroups with adenoma size 20-29 mm and 30-39 mm. In giant adenoma group, median (IQR) preoperative maximal diameter of adenoma was 40 mm (5 mm), median preoperative GH level was 40 (153.4) ng/mL and median baseline IGF-1 level was 2.19 (1.88) × ULN for age and sex. The number of surgeries was significantly higher in giant adenoma group (median 2, IQR 2) in which 66.7% of patients underwent repeated surgeries (p = 0.014). Residual tumor was detected after last operation in all patients with giant adenoma. Total number of treatment modalities administered postoperatively increased as adenoma size increased (p = 0.043). After a median follow-up duration of 10 years (IQR 10), hormonal remission was achieved in six patients (40%) of giant adenoma group, while the rate of hormonal remission in non-giant adenoma group was 37%. Although preoperative GH and IGF-1 levels and Ki-67 index tended to be higher with increasing adenoma size, there was no statistically significant difference between groups in terms of these variables, as well as age, sex and invasion status. Hormonal remission rates of acromegaly patients with ≥20 mm pituitary macroadenoma were comparable. However, giant GH-secreting pituitary adenomas require an aggressive multimodal treatment approach.


Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross-sectional study.
Neuroendocrine factors may predict which athletes develop amenorrhea and which athletes remain eugonadal. Specifically, ghrelin and leptin have been implicated in regulation of GnRH secretion, with ghrelin having inhibitory and leptin, facilitatory effects. We hypothesized that adolescent athletes with amenorrhea (AA) would have higher ghrelin and lower leptin levels than eumenorrheic athletes (EA) and would predict levels of gonadal steroids. Cross-sectional. We enrolled 58 girls, 21 AA, 19 EA and 18 nonathletic controls 12-18 years old. Fasting blood was drawn for active ghrelin, leptin, E(2) and testosterone. Athletes were > 85% of ideal body weight for age based on body mass index (BMI). AA girls had lower BMI than EA and controls (P = 0.003). Log ghrelin was higher in AA than in EA and controls (P < 0.0001), and remained higher after controlling for BMI Z-scores. Leptin was lower in AA than in the other groups (P < 0.0001), however, the differences did not persist after controlling for BMI Z-scores. Testosterone was lower in AA than in EA and controls (P = 0.002) and log E(2) trended lower in AA (P = 0.07). We observed inverse associations of log active ghrelin with testosterone (P = 0.01), and positive associations of leptin with testosterone and log E(2) (P = 0.02 and 0.009). Higher ghrelin levels, even after controlling for BMI, and lower leptin in AA compared with EA and controls, and their inverse and positive associations, respectively, with gonadal steroids suggest endocrine perturbations that may explain why hypogonadism occurs in some but not all athletes.


Interaction of N-methyl-D-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm.
Behavioral flexibility or 'set-shifting' refers to the ability to modify ongoing behavior in response to changing goals or environmental contingencies. Impaired behavioral flexibility is associated with disorders such as schizophrenia and addiction. Hypofunction of N-methyl-D-aspartate (NMDA) receptors has been implicated in these impairments. Metabotropic glutamate 5 (mGlu5) receptors closely interact with NMDA receptors and may provide a feasible pharmacological target for indirect manipulation of NMDA receptor function in disease states. The aim of this study was to examine the impact of NMDA and mGlu5 receptors on set-shifting ability. We developed a computer-controlled, operant-based set-shifting task that requires rats to learn sequential discrimination rules based on two distinct perceptual dimensions. Using this task, we found that administration of the NMDA receptor antagonist MK801, both systemically and intracortically, significantly impaired task performance, whereas stimulation or inhibition of mGlu5 receptors did not impair task performance. However, when administered after MK801, potentiation of mGlu5 receptor function reduced the performance impairments observed with MK801 alone. These results suggest an interaction between NMDA and mGlu5 receptors in cognitive flexibility and may provide a novel therapeutic approach for treating disorders associated with aberrant NMDA function.


Facile Surface Modification of Polyethylene Film via Spray-Assisted Layer-by-Layer Self-Assembly of Graphene Oxide for Oxygen Barrier Properties.
The oxygen barrier properties are essential for the food packaging systems that preserve perishable food. In this research, the facile surface modification method for oxygen barrier properties is introduced by using spray assisted layer-by-layer (LbL) self-assembly. The nano-sized graphene oxide (GO-) multilayer films were developed and characterized. Positively charged amine-functionalized GO+ was synthesized using the negatively charged GO- dispersion, ethylenediamine, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (EDC). Alternating layers of GO- and GO+ were deposited onto the flexible polyethylene (PE) substrate which has no intrinsic gas barrier properties. This method is able to modify surfaces which are challenging for the conventional dipping LbL method. The oxygen transmittance rate of coated PE film (3511.5 cc/m2·day) decreased significantly to 1091 cc/m2·day after a GO film with a thickness of only 60 nm was deposited. The light transmittance in the visible light range was not significantly decreased after coating of GO films, thus ensuring transparency for PE packaging applications.


Proteomic profiles of Zika virus-infected placentas bearing fetuses with microcephaly.
Zika virus (ZIKV) transmission to the fetus during pregnancy could enable a collection of severe fetal malformations like microcephaly (MC), termed Congenital Zika Syndrome (CZS). The mechanisms involved in ZIKV transplacental transmission are not fully understood. Here we aim to identify in placental tissues the deregulated proteins associated with ZIKV-induced MC using label-free proteomics. We found proteins associated with DNA damage and gene expression inhibition up-regulated in infected placentas with no MC fetuses (Z+) compared to the control group (Ctr). Actin filament organization and the immune response were also found deregulated in the Z+ group. In ZIKV-positive placentas bearing fetuses with MC (MC+) was detected an increase in T cell activation, indicating an elevated immune response. A comparison between MC+ and Z+ groups showed a higher abundance of proteins related to endocytosis and autophagy in MC+, suggesting a higher transcytosis of vesicles with ZIKV particles across the maternal-fetal interface. Our results suggest that higher expression of integrins in MC+ might be associated with high internalization of the virus since these proteins are known as virus receptors. Similarly, an increased immune response in the placenta and higher infiltration of the virus to the fetus could contribute to the neurological malformation of the CZS.


Prolactin, fructose, and zinc levels found in human seminal plasma.
Fructose, zinc, and prolactin determinations were performed on the seminal plasma of normospermic (n = 30), oligospermic (n = 30), and azoospermic (n = 30) men to determine whether there was a correlation between any of these substances and seminal quality. None of these azoospermic men had congenital bilateral absence of the vasa, but in a separate group of such men (n = 10) these same studies were performed. Fructose was determined photometrically, zinc by atomic absorption, and prolactin by radioimmunoassay. Zinc and fructose levels in all three groups showed no statistical differences. Prolactin was found to be significantly higher in the seminal plasma of normospermic men than was found in the seminal plasma of oligospermic or azoospermic men. In men with congenital bilateral absence of the vasa and seminal vesicles, zinc was elevated, fructose was absent, and prolactin was markedly depressed.


Suppression of chronic-relapsing experimental allergic encephalomyelitis in strain-13 guinea pigs by administration of liposome-associated myelin basic protein.
Juvenile strain-13 guinea pigs were challenged with isologous spinal cord in CFA. After recovery from the first EAE episode the animals were treated with guinea pig MBP inserted into liposomes, with cytochrome-c-liposomes, with MBP in saline or with MBP in IFA. Guinea pigs treated with MBP-liposomes showed a striking reduction in clinical signs and in the number and intensity of relapses. They displayed virtually no demyelinating lesions, and had comparatively little parenchymal inflammation in the spinal cord. Early T rosette levels showed an inverse correlation with the severity of histological lesions in the spinal cord but correlation with the clinical status at the time of rosette assay was less well defined.


Alpha-naphthyl-acetate-esterase activity in cerebrospinal fluid cells.
Mono-histiocytes and T-lymphocytes were assessed by the cytochemical alpha-naphthyl-acetate-esterase (ANAE) stain in 50 CSF samples of patients with various neurological diseases. The ANAE-activity of lymphocytes was decreased in multiple sclerosis and subacute sclerosing panencephalitis, while the activity of mono-histiocytes was increased in the group of infarctions and bacterial and viral infections of the central nervous system. In bacterial meningitis and viral meningo-encephalo-radiculitis the number of ANAE-positive lymphocytes increased after treatment and clinical improvement. ANAE staining appears to be a useful additional tool in CSF cytology in these conditions.


Effect of serum on cells cultured from human mammary tumors.
Clusters of cells derived from biopsy specimens of human mammary ductal carcinomas form two morphologically distinct epithelial colonies in culture, designated as E and E'. The proportion of E' cell clusters that attached and formed colonies ranged from 0.3 to 13.0% with different tumors. Attachment was independent of tumor grade. Microscopic observations revealed that the survival of E' cell colonies was limited to approximately 10 days with rapid cell degeneration commencing about 7 days. A comparison of sera showed that colony formation by cells from malignant tumors during the 1st week of culture was maximum in the presence of fetal bovine serum. Human serum alone was 70 to 100% less effective in promoting E' colonies. The most significant finding was that human serum from normal donors inhibited E' colony development in the presence of FBS. Although human serum was less effective than FBS in promoting colony formation by clusters of E cells, an inhibition was not observed. Inhibitory activity could not be attributed to either antagonistic hormones or the source of human serum. These results demonstrate that normal human serum contains a factor(s) that exhibits an inhibitory activity specific for human epithelial cells (E') derived from malignant tumors.


Pathology, diagnosis and pathogenesis of AA amyloidosis.
Amyloid is defined as a proteinaceous tissue deposit that shows a typical green birefringence in polarised light after staining with Congo red, the presence of non-branching linear fibrils of indefinite length with an approximate diameter of 10-12 nm and a distinct X-ray diffraction pattern consistent with Pauling's model of a cross-beta fibril. Approximately 45% of generalised amyloidoses are secondary or reactive (AA) amyloidosis. Among the causes of AA amyloidosis are rheumatic diseases, idiopathic diseases, inherited diseases, infectious diseases and malignant tumours. Recent decades have provided significant advances in our understanding of the pathology and pathogenesis of AA amyloidosis. Its pathogenesis is multifactorial involving many variables such as primary structure of the precursor protein, acute phase response, the presence of non-fibril proteins (e.g. amyloid P component, apolipoprotein E, glycosaminoglycans, proteoglycans and basement membrane proteins), receptors, lipid metabolism and proteases. Study of the pathogenesis of AA amyloidosis has provided many insights into the nature of conformational diseases, which may help in the understanding of other members of this particularly heterogeneous group of diseases, such as Alzheimer's disease and transmissible spongiform encephalopathies.


Purification of retrovirus particles using heparin affinity chromatography.
Retroviral vectors have been used as gene delivery vehicles for more than two decades and continue to be the best available tool for stable and efficient transfer of therapeutic genes into various cell types. Although most gene therapy preclinical studies presently use crude or concentrated retroviral vector supernatants, purification to eliminate serum and host-derived impurities contained in these stocks will be a necessary requirement for clinical applications. Chromatography is deemed the most promising technology for large-scale purification of viral vectors. Heparin affinity chromatography offers the possibility to selectively and efficiently purify retroviruses. This chapter gives a simple, reproducible, and scaleable protocol for the purification of bioactive VSV-G pseudotyped retroviral vectors that employs membrane and chromatography technologies. The protocol can be easily adapted for the purification of different retroviral vector pseudotypes and lentiviral vectors. The purification techniques described here represent a significant improvement over the conventional sucrose density gradient methodology used for retrovirus purification and will hopefully contribute to the technological progress in the field of gene therapy.


Carcinoma of the cardia and proximal third of the stomach. Results of surgical treatment in 91 consecutive patients.
In the present retrospective study, 79 percent of the patients were men with a median age of 65.5 years. Of 91 patients, 84 were surgically explored. Excision of the tumor was carried out in 57 patients (63 percent) and was curative in 28 cases and palliative in 29 cases. Curative resection included proximal gastrectomy in 5 patients and total gastrectomy in 23 patients, which was extended to the spleen and distal pancreas in 18 patients. Lymph node metastases were found in 67 percent of the patients treated by resection. According to the TNM classification, 18 percent of the patients undergoing resection had stage I tumor, 28 percent had stage II tumor, 40 percent had stage III tumor, and 14 percent had stage IV tumor. The postoperative mortality rate was 16 percent for the entire series, 21 percent for patients undergoing palliative resection, and only 4 percent for patients undergoing curative resection. Three patients had an obvious anastomotic leak, one of whom died. Median survival time was 5 months for patients who had exploration only, 6 months for patients who had palliative resection, and 36 months for patients who had potentially curative resection. The 5 year actuarial survival rate was 20 percent for patients having resection and 40 percent for patients having curative resection. Survival was closely related to tumor stage. These results indicate that total gastrectomy with complete abdominal lymph node dissection can give comparatively good long-term results when performed for cure. Nevertheless, only one of three patients in this series could have a potentially curative resection. The only way to increase the curative resection rate and to improve survival is to detect the cancer at an early stage.


Curcumin inhibits connective tissue growth factor gene expression in activated hepatic stellate cells in vitro by blocking NF-kappaB and ERK signalling.
Gene expression of connective tissue growth factor (CTGF) is induced in activated hepatic stellate cells (HSC), the major effectors in hepatic fibrosis, and production of extracellular matrix (ECM) is consequently increased. We previously reported that curcumin, the yellow pigment in curry, suppressed ctgf expression, leading to decreased production of ECM by HSC. The purpose of this study is to evaluate signal transduction pathways involved in the curcumin suppression of ctgf expression in HSC. Transient transfection assays were performed to evaluate effects of activation of signalling pathways on the ctgf promoter activity. Real-time PCR and Western blotting analyses were conducted to determine expression of genes. Suppression of ctgf expression by curcumin was dose-dependently reversed by lipopolysaccharide (LPS), an NF-kappaB activator. LPS increased the abundance of CTGF and type I collagen in HSC in vitro. Activation of NF-kappaB by dominant active IkappaB kinase (IKK), or inhibition of NF-kappaB by dominant negative IkappaBalpha, caused the stimulation, or suppression of the ctgf promoter activity, respectively. Curcumin suppressed gene expression of Toll-like receptor-4, leading to the inhibition of NF-kappaB. On the other hand, interruption of ERK signalling by inhibitors or dominant negative ERK, like curcumin, reduced NF-kappaB activity and in ctgf expression. In contrast, the stimulation of ERK signalling by constitutively active ERK prevented the inhibitory effects of curcumin. These results demonstrate that the interruption of NF-kappaB and ERK signalling by curcumin results in the suppression of ctgf expression in activated HSC in vitro.


Nickel-titanium versus stainless-steel finger spreaders in curved canals.
Placement of endodontic spreaders to within 1 to 2 mm of the root canal working length has been advocated for optimum gutta-percha obturation. Due to their stiffness, stainless-steel (SS) spreaders will often fail to achieve this position in curved canals. Newly marketed nickel-titanium (NiTi) spreaders may offer an advantage in this regard due to the increased flexibility of these instruments. Seventy mesial and distal mandibular molar canals were instrumented to a #35 master apical file size. Measurements of the canal curvature were made from preoperative radiographs. Canal curvature angles ranged from 0 to 51 degrees. The teeth were placed in a radiographic mount to ensure a constant focal length, and postoperative radiographs were exposed with comparably sized SS and NiTi spreaders inserted into each prepared canal. Measurements of spreader tip to apex distance were made with a micrometer to the nearest 0.02 mm on the radiographs. Using a t test for paired samples, it was shown that NiTi spreaders penetrated to a significantly greater depth than SS spreaders in curved canals (p < 0.001).


The effect of acute maximal exercise on the regional distribution of ventilation using ventilation MRI in CF.
The importance of exercise in the management of people with CF is well recognised, yet the effect of exercise on lung function is not well understood. FEV1 is insensitive to the detection of small changes in lung function. Ventilation MRI and LCI are both more sensitive to mild lung disease than FEV1 and may be better suited to assess the effects of exercise. Here we assessed the short-term effects of maximal exercise on the distribution of ventilation using ventilation MRI and LCI. Patients with CF and a range of lung disease were assessed. Baseline LCI and ventilation MRI was followed by a maximal cardio-pulmonary exercise test (CPET). Repeated ventilation MRI was performed within 30 minutes of exercise termination, followed by LCI and finally by FEV1. 13 patients were recruited and completed all assessments. Mean (SD) age was 25 (10) years and mean (SD) FEV1 z-score was -1.8 (1.7). Mean LCI at baseline was 8.2, mean ventilation defect percentage on MRI (VDP) was 7.3%. All patients performed maximal CPET. Post-exercise, there was a visible change in lung ventilation in 85% of patients, including two patients with increased ventilation heterogeneity post-CPET who had normal FEV1. VDP and LCI were significantly reduced post-exercise (p < 0.05) and 45% of patients had a significant change in VDP. Acute maximal exercise directly affects the distribution of ventilation on ventilation MRI in patients with CF. This suggests that exercise is beneficial in CF and that ventilation MRI is suitable to assess airway clearance efficacy.


Mumps vaccine hesitancy: Current evidence and an evidence-based campaign in Japan.
Mumps is still endemic in Japan because mumps vaccination is voluntary. In this study, we investigated associations of parental socioeconomic status, family structure, and knowledge/belief about mumps and mumps vaccine with parental decision to vaccinate their children. We also evaluated effectiveness of a campaign based on survey results. We conducted a cross-sectional survey of parents with children aged 1-6 years attending preschools or kindergartens in Tokamachi City, Japan. We assessed the association of parental factors with their decision to vaccinate their children using multivariable logistic regression analyses. We designed a campaign based on the survey results, and compared the number of annual vaccinations at Tokamachi Hospital per the child population aged 1-6 years in Tokamachi City before and after the campaign using a trend test. In total, 1391 of 1617 (86%) eligible parents completed the survey. Among these parents, 229 (16%) vaccinated their children. In multivariable analyses, higher parental education [odds ratio (OR) = 2.21; 95% CI, 1.59-3.08; P < 0.001], greater knowledge about mumps and the mumps vaccine (OR = 1.88; 95% CI, 1.60-2.21; P < 0.001), and living without grandparents (OR = 1.44; 95% CI, 1.05-1.99; P = 0.024) were significantly associated with parental decision to vaccinate their children. The number of annual vaccinations per the child population significantly increased following the campaign (P < 0.001). Our study showed several sociodemographic factors significantly associated with mumps vaccination. Further research is needed to examine the relevance of our findings to the uptake of other voluntary vaccines among children.


AMX - the highly automated macromolecular crystallography (17-ID-1) beamline at the NSLS-II.
The highly automated macromolecular crystallography beamline AMX/17-ID-1 is an undulator-based high-intensity (>5 × 1012 photons s-1), micro-focus (7 µm × 5 µm), low-divergence (1 mrad × 0.35 mrad) energy-tunable (5-18 keV) beamline at the NSLS-II, Brookhaven National Laboratory, Upton, NY, USA. It is one of the three life science beamlines constructed by the NIH under the ABBIX project and it shares sector 17-ID with the FMX beamline, the frontier micro-focus macromolecular crystallography beamline. AMX saw first light in March 2016 and started general user operation in February 2017. At AMX, emphasis has been placed on high throughput, high capacity, and automation to enable data collection from the most challenging projects using an intense micro-focus beam. Here, the current state and capabilities of the beamline are reported, and the different macromolecular crystallography experiments that are routinely performed at AMX/17-ID-1 as well as some plans for the near future are presented.


Intra-crown variation in leaf herbivory and seed production in striped maple, Acer pensylvanicum L. (Aceraceae).
Patterns of spatial variation in leaf herbivory and the effects of this variation on seed production and twig growth were studied in striped maple, Acer pensylvanicum (Aceraceae). Experimental removal of 25% of the leaf area from each of four leaves directly subtending a developing infructescence significantly reduced seed number in that infructescence. When leaf area was removed from leaves neighboring to, but not directly subtending developing infructescences, no reduction in seed production occurred. Together, these results suggest that only photosynthate from leaves directly subtending infructescences contributes to seed production in nearby infructescences. Effects of the experimental removal of leaf area did not persist the second year, suggesting that mobilization of storage products the following spring occurred independent of prior treatment. There was probably little negative impact of leaf herbivores on this plant species during the study year due to (1) low occurrence of localized damage within the crowns of censused trees and (2) delay of leaf area loss until completion of fruit development.


Primary sutureless repair and anterior translocation of the atrial septum for cardiac total anomalous pulmonary venous connection.
The incidence of pulmonary vein stenosis after correction of a cardiac total anomalous pulmonary venous connection in neonates may be underestimated because of the small population of patients; however, it is associated with significant mortality and morbidity. This report describes a primary sutureless repair and anterior translocation of the atrial septum to create a large left atrial cavity and avoid post-repair pulmonary vein stenosis.


Sensitivity of human lymphocytes to acetaldehyde: comparison between alcoholic and control subjects.
The action of acetaldehyde (ACH), the first metabolite of ethanol, was studied on human lymphocytes stimulated in vitro by phytohemagglutinin (PHA) or Concanavalin A (Con A). ACH caused a dose-dependent decrease of [3H]thymidine uptake in lymphocytes from both alcoholic and control subjects. The area under the curve of [3H]thymidine incorporation as a function of ACH concentration was determined for each subject and referred to as the lymphocyte sensitivity index. Indexes for alcoholic subjects were found to be higher than those for controls, indicating a lower sensitivity to ACH of lymphocytes from alcoholics. We also found a wide range of sensitivity indexes within the same group. These results are consistent with the current hypothesis that not everybody is at equal risk to develop alcohol related disorders.


Mutual Relations between Substituent Effect, Hydrogen Bonding, and Aromaticity in Adenine-Uracil and Adenine-Adenine Base Pairs.
The electronic structure of substituted molecules is governed, to a significant extent, by the substituent effect (SE). In this paper, SEs in selected nucleic acid base pairs (Watson-Crick, Hoogsteen, adenine-adenine) are analyzed, with special emphasis on their influence on intramolecular interactions, aromaticity, and base pair hydrogen bonding. Quantum chemistry methods-DFT calculations, the natural bond orbital (NBO) approach, the Harmonic Oscillator Model of Aromaticity (HOMA) index, the charge of the substituent active region (cSAR) model, and the quantum theory of atoms in molecules (QTAIM)-are used to compare SEs acting on adenine moiety and H-bonds from various substitution positions. Comparisons of classical SEs in adenine with those observed in para- and meta-substituted benzenes allow for the better interpretation of the obtained results. Hydrogen bond stability and its other characteristics (e.g., covalency) can be significantly changed as a result of the SE, and its consequences are dependent on the substitution position. These changes allow us to investigate specific relations between H-bond parameters, leading to conclusions concerning the nature of hydrogen bonding in adenine dimers-e.g., H-bonds formed by five-membered ring nitrogen acceptor atoms have an inferior, less pronounced covalent nature as compared to those formed by six-membered ring nitrogen. The energies of individual H-bonds (obtained by the NBO method) are analyzed and compared to those predicted by the Espinosa-Molins-Lecomte (EML) model. Moreover, both SE and H-bonds can significantly affect the aromaticity of adenine rings; long-distance SEs on π-electron delocalization are also documented.


[New immunomodulators in treatment of Graves'ophtalmopathy].
Treatment of severe Graves'ophtalmopathy (GO) is a complex therapeutic challenge and spite any efforts, about one third of patients are disappointed with the outcome of treatment. Intravenous glucocorticoids (GCIV), orbital radiotherapy, or the combination of both are most frequently used for their immunosuppressive effects. The anti-CD 20 monoclonal antibody rituximab (RTX) induces transient B-cell depletion that may potentially modify the active inflammatory phase of thyroid-associated ophtalmopathy (TAO). A preliminary study in nine patients with TAO treated with RTX and twenty patients treated with GCIV was reported by Salvi and al. All patients attained peripheral B-cell depletion after the first RTX infusion. At the end of follow-up, clinical activity score values decreased more significantly compared with GCIV. Proptosis and the degree of inflammation decrease significantly in response to RTX. Relapse of active TAO are not observed in patients treated with RTX but occurred in 10 % of those treated with GCIV. If these results are confirmed in large controlled studies, RTX may represent a useful therapeutic tool in patients with active TAO.


Comparative neurotoxicity and pyrrole-forming potential of 2,5-hexanedione and perdeuterio-2,5-hexanedione in the rat.
2,5-Hexanedione (2,5-HD), the neurotoxic metabolite of n-hexane, reacts with protein amines to form alkylpyrrole adducts. Pyrrolylation of neurofilament protein may be the initiating molecular event in 2,5-HD neuropathy. The present study compares the neurotoxic and pyrrole-forming potentials of 2,5-HD with those of perdeuterio-2,5-HD ([D10]-2,5-HD) in the rat. Due to a requirement for C-H bond breaking in the reaction mechanism, the latter derivative was expected to exhibit a primary isotope effect, thus forming the pyrrole at a slower rate. In vitro studies confirmed that [D10]-2,5-HD pyrrolylated protein at only one-third of the initial rate seen with native 2,5-HD. Prolonged incubation resulted in similar pyrrole concentrations with both derivatives. Adult, male Wistar rats were administered daily (5 days/week) ip doses of either 3.5 mmol 2,5-HD or [D10]-2,5-HD/kg/day for 17 days or 2.5 mmol/kg/day for 38 days. At termination, animals administered 2,5-HD and [D10]-2,5-HD exhibited 27 and 8% body weight loss, respectively. Moderate to severe hindlimb paralysis was present in the 2,5-HD groups while only mild effects were seen in [D10]-2,5-HD-dosed rats. Neuropathological changes were prominent in spinal cord sections from 2,5-HD-treated animals, while no effects were present in rats given the deuterated derivative. Pyrrole adduct concentrations in serum and axonal cytoskeletal proteins from 2,5-HD-treated animals were two- to threefold higher than in rats given equimolar doses of [D10]-2,5-HD. Levels of covalent crosslinking of axonal cytoskeletal proteins (assessed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis) appeared to correlate with pyrrole concentrations. Tissue concentrations of each diketone isomer were not significantly different, indicating similar uptake of native and deuterated 2,5-HD. Mass spectrometry revealed rapid back exchange of the terminal (methyl) but not of the internal (methylene) deuteriums of [D10]-2,5-HD in vivo. These findings support an absolute requirement for pyrrole formation in gamma-diketone neurotoxicity.


The ontogeny of gene expression of progestin receptors in the female rat brain.
The postnatal development of the progestin receptor (PR) system in the rat brain is a region-specific and stage-related process. In an attempt to analyze the molecular mechanism by which the dramatic change of gene expression of the PR occurs we have examined the level of PR mRNAs in the hypothalamus-preoptic area (HPOA) and cerebral cortex in development from fetal to postnatal stages of female rats. We used polymerase chain reaction to clone, from uterine cDNA, the cDNA corresponding to the steroid-binding domain of the PR forms 'A' and 'B' mRNA as well as the region around the translation-initiation site (ATG1) of the putative PR form 'B' mRNA. A quantitative reverse transcription-polymerase chain reaction assay was used to measure the level of mRNAs for PR forms 'A' and 'B' (total PR mRNAs) and PR form 'B'. There was a regional difference in the intracerebral distribution between the total and form 'B' mRNAs, indicating possible distinct mechanisms responsible for regulating the expression of the PR mRNAs. The PR mRNAs in the brain, already detectable 2 days before birth, increased at early neonatal stages. The total PR mRNAs in the cortex developed in a manner essentially similar to the PR protein at the early stages, but, surprisingly, unlike the receptor, the messages remained high at the later stages from day 18 to 8 weeks of life. On the other hand, the ontogeny of the cortical mRNA for form 'B', which predominantly existed in the region, resembled that of the cortical PR protein. In the HPOA the postnatal development of the form 'B' mRNAs was also roughly similar to the PR. These results suggest region-specific and stage-related gene expression of the PR isoform system in the developing brain: gene expression of form 'B' seems to be predominantly, first, "turned on" around birth, followed by form 'A' mRNA expression around days 8-12. Moreover, lowered levels of the cortical PR mRNAs in the propylthiouracil-induced hypothyroid rat, together with suppressed PR level, indicate a possible regulatory role of thyroid hormone on gene expression of the cortical receptor.


Cidofovir for cytomegalovirus reactivation in pediatric patients after hematopoietic stem cell transplantation.
Cidofovir (CDV) is a nucleotide analogue with broad antiviral activity. This drug has a very favorable pharmacokinetic profile that enables intermittent dosing, but the potential for nephrotoxicity has hitherto restricted its use in stem cell transplant recipients. Data on pediatric patients are limited. To report the efficacy and toxicity of CDV in a group of pediatric patients with cytomegalovirus (CMV) reactivation after allogeneic stem cell transplantation. Prospective evaluation of safety and efficacy of CDV used pre-emptively for CMV reactivation in 10 out of 30 children who underwent allogeneic hematopoietic stem cell transplantation from January 2000 to December 2001. In all the patients but one, CDV was used as second-line therapy (after foscarnet or ganciclovir) of CMV reactivation. Overall, 12 courses of CDV were administered with a median 5 doses per course, range 1-6 (two patients were treated twice). Considering the first CDV treatment episode, 8 out of 10 patients had positive CMV antigenemia assay when they started CDV. Five of eight antigenemic patients responded completely while three were switched to foscarnet or ganciclovir, respectively, due to increasing (one) or persistent CMV antigenemia (two). Overall, the therapy with CDV was well tolerated, but it was withdrawn in one patient due to a two-fold increase in the baseline creatinine level. This patient concurrently had a high tacrolimus blood level. Safety is the major concern regarding the use of CDV but the adoption of probenicid, intravenous hydration and anti-emetic therapy improved its tolerability profile. Our data suggest that CDV has an acceptable toxicity and would deserve further controlled studies in the setting of pre-emptive therapy for CMV.


[Study of the interaction of MTPN11 mycobacteriophage with host cells based on electron microscopy, fluorimetry, and electro-oriented spectroscopy].
According to electron-microscopic data, various cells in the M. smegmatis ATCC607 population interact differently with phage MTPH11. Fluorometric studies of phage-host interactions were performed using a membranotropic fluorescent probe, 8-anilino-1-naphthalene sulfonate (ANS). Changes in the electric characteristics of mycobacterial cells infected with the phage were studied by electro-orientational (EO) spectroscopy. The problem of the employment of fluorometry and EO spectroscopy for rapid phage typing of mycobacteria is discussed.


Diffuse large B-cell lymphoma variants: an update.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma, representing approximately one-third of all cases worldwide. In the World Health Organization (WHO) classification of lymphomas, most cases of DLBCL are designated as not otherwise specified (NOS). About 20% of cases, however, are designated as specific variants of DLBCL. These variants, 13 in total, are specified on the basis of distinctive morphological or immunophenotypic findings or distinctive biological or clinical issues associated with their diagnoses. In this review we discuss the following variants: T-cell/histiocyte-rich large B-cell lymphoma; ALK-positive large B-cell lymphoma; plasmablastic lymphoma; intravascular large B-cell lymphoma; large B-cell lymphoma with IRF4 rearrangement; primary mediastinal large B-cell lymphoma; primary cutaneous diffuse large B-cell lymphoma, leg type; primary diffuse large B-cell lymphoma of the central nervous system; diffuse large B-cell lymphoma associated with chronic inflammation; lymphomatoid granulomatosis; primary effusion lymphoma; and HHV8-positive diffuse large B-cell lymphoma, NOS. Two additional variants recognised in the WHO classification, EBV-positive diffuse large B-cell lymphoma and EBV-positive mucocutaneous ulcer are discussed elsewhere in another review within this issue of Pathology. Although not recognised as a specific variant in the current WHO classification, primary testicular diffuse large B-cell lymphoma also has unique biological features and requires some modification of the standard treatment approach for patients with DLBCL. Therefore, we suggest that primary testicular diffuse large B-cell lymphoma also should be recognised as a specific variant of DLBCL in a future version of the WHO classification.


Paediatric subglottic stenosis - Have things changed? Our experience from a developing tertiary referral centre.
Paediatric airway disorders are common, particularly in the context of improved ventilation methods for neonates in intensive care units. Management is not standardised. To assess the number, severity, management and outcomes of all patients diagnosed with subglottic stenosis at a developing tertiary referral centre. 19 month prospective longitudinal study. All patients who underwent microlaryngobronchoscopy (MLB) were included. Subglottic stenosis (SGS) was graded intraoperatively using the Myer-Cotton classification. 102 patients underwent MLB during this period. 33 of 102 patients (32.4%) were diagnosed with SGS+/-other co-pathologies. Mean and median age at diagnostic procedure were 24.7 months (SD 23.5) and 18 months, respectively. At their first MLB, 22 of 33 patients (66.7%) were found to have a Grade 1 SGS, 7 of 33 (21.2%) were Grade 2 and the remaining 4 of 33 (12.1%) were Grade 3. We had no patients with Grade 4 SGS. During this period, these patients with SGS underwent 73 MLBs+/-interventions (2.21 per patient) such as incision and balloon dilatation, tracheostomy (2 of 33) or ultimately, laryngotracheal reconstruction (LTR) (2 of 33). A further 3 patients have since undergone LTR. No significant unexpected events occurred. These findings suggest that subglottic stenosis may be evolving in terms of its presentation and management. Management can more often be endoscopic and perhaps avoid tracheostomy or laryngotracheal reconstruction. Further long term prospective studies are required.


Stress-stones-stress-recurrent stones: a self-propagating cycle? Difficulties in solving this dichotomy.
Numerous studies have reported an association between stress and urolithiasis. Although urinary risk factors have been measured in several of these, compelling evidence of a causal relationship has not been established. A shortcoming is that alterations in single urinary parameters rather than ratios and quotients, which provide a more synergistic risk evaluation, have been measured. Recently, we speculated about a possible association between chronic stress and stone recurrence. This presents an intriguing dichotomy of whether stress causes stones or vice versa, or whether they are linked in a self-propagating stress-stones-stress-recurrence cycle. We investigated the latter hypothesis in a retrospective case-control designed study in which we calculated urinary ratios and quotients which are regarded as diagnostic indicators of stone risk. These included Ca/Cr, Ox/Cr, Mg/Cr, Cit/Cr, urate/Cr and citrate-magnesium-calcium ratios, activity product quotient for calcium oxalate (CaOx) and relative supersaturation of CaOx, brushite and uric acid. Overnight urinary data from 128 participants comprising 31 first time (FS), 33 recurrent (RS) CaOx stone formers and 64 controls were used. All subjects had been previously assessed for chronic stress dimensions, as well as for stress caused by their stone episodes per se. Conditional and unconditional logistic regression (with a Bonferroni correction for multiple tests) and simple linear regression were used to analyse various components of the data. Although RS had more stressful life events, with greater intensity of perception than FS, there were no significant differences between the groups regarding any of the urinary risk factors. No significant association between stressful life events and any of the urinary ratios or quotients was observed. A direct causal link between stress and stone recurrence was not indicated. We believe that future studies should shift their focus from traditional urinary risk factors to other stone-forming mechanisms. However, we recognize that there is an inherent problem in attempting to solve the stress-stones dichotomy as it would be impossible to disentangle alterations in risk factors which arise from lifestyle stress and those arising from stone episodes themselves.


Emerging studies of the urinary proteome: the end of the beginning?
Urinary proteomics is a rapidly growing field, holding the promise of discovery of biomarkers of various disease processes and elucidation of pathophysiologic mechanisms of disease states. This may be true not only for renal disease but for diseases of other organs and systemic disorders. Recent advances in separation technologies and rapid, high-throughput, and accurate protein detection and identification now permit rigorous examination of complex biological fluids. This review sketches the progress achieved in recent years and the existing hurdles in describing a normal urinary proteome, its aberrations in pathological conditions, and the search for biomarkers of several renal and non-renal diseases. The first wave of urinary proteomic studies has now arrived and their results are summarized. Future lines of investigation are delineated.


Clinical pharmacology and neuroprotection in Parkinson's disease.
There has been significant progress in the study of the causes, the pathogenesis, and the mechanism of cell death in Parkinson's disease (PD). Mutations in single genes have been shown to cause PD, and accumulation of alpha-synuclein seems to be a clue to the pathogenesis of neurodegeneration. However, mutations of single genes account for only a small number of cases. Environmental factors seem to play a large role in the majority of cases of sporadic PD. Genetic factors may predispose patients to develop PD if combined with other gene mutations or environmental toxins. In an attempt to design a neuroprotective therapy, the pathogenesis of neurodegeneration, and the mechanism of cell death have been studied. Aggregation of insoluble alpha-synuclein, oxidant stress, mitochondrial dysfunction, excitotoxicity, and glia and inflammatory processes are all thought to contribute to the cell death process and agents that interfere with these events may be neuroprotective. The final culmination of these events is supposed to be the induction of apoptosis in nigral dopaminergic neurons and this too offers opportunities for providing neuroprotection. A large number of different approaches are under discussion in the hope of developing a neuroprotective therapy, using clinical indices and neuroimaging markers of nigral dopaminergic neurons. Conventional approaches to studies that use large numbers of patients in search of small effects are costly and time consuming, and it would be impossible to test all the potentially valuable neuroprotective agents because of a lack of time, money, or subjects. As a translational research, it is more profitable to test agents in a small number of selected patients in search of a more neuroprotective effect. Well designed translational research might allow us to reduce the risk of missing a powerful neuroprotective treatment.


Nomogram based on preoperative CT imaging predicts the EGFR mutation status in lung adenocarcinoma.
Tyrosine kinase inhibitors (TKIs) provide clinical benefits to the lung cancer patients with epidermal growth factor receptor (EGFR) mutations. However, non-invasively determine EGFR mutation status in patients before targeted therapy remains a challenge. This study aimed to develop and validate a nomogram for preoperative prediction of EGFR mutation status in patients with lung adenocarcinoma. The medical records of 403 patients with lung adenocarcinoma confirmed by histology from January 2016 to June 2020 were retrospectively collected. We combined CT features and clinical risk factors and used them to build a prediction nomogram. The performance of the nomogram was evaluated in terms of calibration, discrimination, and clinical usefulness. The nomogram was further validated in an independent external cohort. Finally, a nomogram that contained CT features and clinical risk factors, which could conveniently and non-invasively predict EGFR mutation status in patients with lung adenocarcinoma before surgery.


Synthesis, spectral and oxidase studies of a new diamide copper(II) complex with pendant benzimidazolyl groups.
A new benzimidazole-based diamide ligand-N,N'-bis(alanine-2-benzimidazolyl) hexanediamide (ABHA) has been synthesized and utilized to prepare Cu(II) complexes of general composition [Cu(ABHA)X2].nH2O,where X is an exogenous anionic ligand (X=Cl-,NO3-). Low temperature EPR spectra has been obtained that shows gparallel>gperpendicular>2.0024, indicating a tetragonal geometry in the solution state. The complexes display a quasi-reversible redox wave due to the Cu(II)/Cu(I) reduction process. E1/2 values shift anodically as NO3-<Cl-, indicating that the bound NO3- stabilizes the Cu(II) ion while the bonded Cl- destabilizes it. The complex [Cu(ABHA)Cl2] has been found to oxidize dopamine to dopachrome or aminochrome, both in a methanolic and a reverse-miceller system. The oxidation of dopamine to aminochrome is reminiscent of the functioning of Prostglandin H-synthetase in brain cells which requires dopamine as a cofactor for catalytic activity.


Clonidine reverses the amnesia induced by dopamine beta hydroxylase inhibition.
The role of noradrenergic (NE) mechanisms in amnesia induced by the dopamine-beta-hydroxylase (DBH) inhibitor, diethyldithiocarbamate (DEDTC) was examined by studying the antiamnestic characteristics of the alpha-NE receptor stimulator clonidine. DEDTC (250 mg/kg) administered 3 hr prior to training to C57BL/6J mice resulted in marked deficits when retention of a multiple trial food motivated spatial discrimination task was measured 24 hr after learning. Investigation of the temporal aspects of recovery indicated that the agonist was an effective antiamnestic agent when administered 0, 1, 3, 21 and 23 hr after training. No recovery was observed when the drug was administered 6 and 18 hr posttraining. A dose response study of the effectiveness of clonidine administered 1 hr prior to testing indicated recovery of memory at doses ranging from 10-500 microgram/kg. The clonidine induced recovery was not a result of general performance facilitation, but specific to the memory tested. In addition, the clonidine effect was pharmacologically specific to its actions on NE receptors, as recovery was blocked by pre-treatment with the alpha-NE antagonist, phentolamine. No recovery from DEDTC induced amnesia was seen with post-training or pre-test injection of d-amphetamine.


Everyday classism in medical school: experiencing marginality and resistance.
To explore the medical school experiences of students who self-identify as coming from a working-class or impoverished family background. A questionnaire was administered to Year 3 medical students at a Canadian medical school and in-depth interviews were held with 25 of these students (cohort 1). The same methods were repeated with another Year 3 class 3 years later (cohort 2). While having (or not having) money was the most obvious impact of social class differences, students also discussed more subtle signs of class that made it easier or more difficult to fit in at medical school. Students from working-class or impoverished backgrounds were significantly less likely to report that they fitted in well, and more likely to report that their class background had a negative impact in school. They were also more likely to indicate awareness that a patient's social class may affect their health care treatment. Students from working-class or impoverished backgrounds may experience alienation in medical school. Through the commonplace interactions of 'everyday classism' they may experience marginalisation, isolation, disrespect and unintentional slights. At the same time, they suggest that their experiences of exclusion may strengthen their clinical practice.


Moist wound healing compared with standard care of treatment of primary closed vascular surgical wounds: a prospective randomized controlled study.
This study was a randomized-controlled trial comparing the standard type of dry dressing, Mepore, with moist wound healing, using a hydrofiber dressing, Aquacel, in primary closed wounds after vascular surgery. The endpoints were patient comfort, cost-effectiveness, infections, wound complications, and length of hospital stay. One hundred and sixty patients were randomized to receive either Mepore or Aquacel dressing. There was no significant difference in patient comfort between the two groups, but a higher cost in the Aquacel group despite significantly fewer changes of dressings in these patients. No difference in the infection rate (13% vs. 11%, p=0.73), length of hospital stay, or wound complications was noted between the two groups. We conclude that although the Aquacel dressing needed significantly fewer changes than the conventional dressing, this did not influence the patient comfort. Moreover, the traditional dressing scheme was significantly less expensive.


Use of zinc finger nuclease technology to knock out efflux transporters in C2BBe1 cells.
A limitation of the traditional Caco-2 cell assay for measuring transporter-mediated efflux of a given substrate is that it is not possible to determine which specific transporter is involved. The methods in this unit describe an approach for generating specific transporter knockout cell lines that can be used to test efflux with any desired substrates. In this approach, human C2BBe1 cells (a subclone of Caco-2 cells) are nucleofected with specific zinc finger nucleases (ZFN), which can be designed to target any gene of interest and generate a double-stranded break. The cell's normal repair mechanisms can then generate targeted deletions (or integrations). A single ZFN can be used to generate a single transporter knockout, or multiple ZFNs can be used to knock out more than one transporter. This unit provides all methods needed to design the required plasmids, generate and identify transporter knockout cell lines, verify their membrane integrity, and test them with functional transport assays.


The incidence and prevalence of crude and familial multiple sclerosis in Tehran, Iran in 2021.
Our registry-based cross-sectional study covered 27,508 PwMS in Tehran with a point incidence rate and prevalence of 7.87 and 194.62 per 100,000 in 2021, respectively. We found that the incidence and prevalence of MS in Tehran are still on an upward trend which requires general attention and measures to overcome. The proportion of men with a family history of MS was significantly higher. Whilst IMSS deals with economic difficulties, it continues to collect new PwMS to reach regional-level coverage in Tehran for better MS care services.


Production of 4-androstene-3,17-dione and 1,4-androstadiene-3,17-dione from rice germ and wheat germ extracts by Mycobacterium sp.
To study the biotransformation of phytosterol and phytosterol-containing rice germ and wheat germ ethanolic extracts to produce 4-androstene-3,17-dione (AD) and 1,4-androstadiene-3,17-dione (ADD) by Mycobacterium sp. DSM 2966 using phytosterol to hydroxypropyl-β-cyclodextrin (2:1, 1:1 and 1:2 mol/mol) and 2 % (w/v) Tween 80 as solubilizing agents. A maximum yield of 180 ± 27 mg AD l(-1) and 31 ± 11.4 mg ADD l(-1) with a total conversion of 65 % (day 12) was obtained using 1 g phytosterol l(-1) and hydroxypropyl-β-cyclodextrin (2 : 1 mol/mol) with 2 % (w/v) Tween 80 in the fermentation medium. The most appropriate conditions for rice germ extract and wheat germ extract which gave the maximum conversion of 22 and 43 % (day 14) were obtained by using 2 % (w/v) Tween 80. Phytosterol and wheat germ are effective sources for AD and ADD production while rice germ required further development. Hydroxypropyl-β-cyclodextrin (2 :1 mol/mol) and/or 2 % (w/v) Tween 80 in the biotransformation process could improve AD and ADD yields, depending on substrates and biotransformation conditions.


PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation.
P21-activated protein kinase1 (PAK1), a main downstream effector of small Rho GTPases, Rac1, and Cdc42, plays an important role in the regulation of cell morphogenesis, motility, mitosis, and angiogenesis. Despite its importance, the molecular mechanisms of PAK1 that contributed to colorectal carcinogenesis remain unclear. Our immunohistochemistry showed that PAK1 expression was increased with colorectal cancer (CRC) progression through the adenoma to carcinoma sequence. Furthermore, our results suggested a relationship between PAK1 nuclear localization and the Dukes staging. In the present study, we showed that PAK1 knockdown decreased proliferation and delayed the G1/S cell-cycle transition, and increased apoptosis in vivo and in vitro. In addition, PAK1 knock-down downregulated c-Jun amino terminal kinases (JNK) activity and the levels of cyclinD1, CDK4/6. Inhibition of the JNK activity by chemical inhibitor (SP600125) significantly reduced the effects of PAK1 on CRC proliferation via accumulation of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). In conclusion, our results demonstrate that knockdown of PAK1 could enhance the chemosensitivity of CRCs to 5-fluorouracil through G1 arrest. The mechanism by which PAK1 induced cancer growth might involve activation of JNK as well as downregulation of PTEN. Targeting PAK1 may represent a novel treatment strategy for developing novel chemotherapeutic agents.


Performance of graphene sheets as stationary phase for capillary gas chromatographic separations.
This work presents the investigation of graphene as a new type of stationary phase for capillary GC separations. Graphene capillary column (0.25 mm, i.d.) achieved column efficiency of 3100 plates/m determined by n-dodecane at 120 °C. The obtained McReynolds constants suggested the weakly polar nature of graphene sheets as GC stationary phase. As evidenced, graphene stationary phase differs from the conventional phase (5% phenyl polysiloxane) in its resolving ability and retention behaviors, and achieved better separation for the Grob and other mixtures. The advantages of graphene stationary phase may mainly originate from its specific π-π stacking interaction as well as H-bonding interaction. Furthermore, graphene column exhibited good repeatability with relative standard deviation (RSD%) in the range of 0.01-0.07% for run-to-run and 2.5-6.7% for column-to-column, respectively.


Dissecting aortic aneurysm involving a right-sided aortic arch.
In this case, the first reported instance of aortic dissection involving a right-sided arch, an anomalous fourth arch vessel, the left subclavian artery, arose from a congenital aortic diverticulum. This report emphasizes the need for precise anatomic definition with aortography to permit appropriate therapy when congenital anomalies of the aortic arch are complicated by dissecting hematoma.


Gasification of biomass in a fixed bed downdraft gasifier--a realistic model including tar.
This study presents a model for fixed bed downdraft biomass gasifiers considering tar also as one of the gasification products. A representative tar composition along with its mole fractions, as available in the literature was used as an input parameter within the model. The study used an equilibrium approach for the applicable gasification reactions and also considered possible deviations from equilibrium to further upgrade the equilibrium model to validate a range of reported experimental results. Heat balance was applied to predict the gasification temperature and the predicted values were compared with reported results in literature. A comparative study was made with some reference models available in the literature and also with experimental results reported in the literature. Finally a predicted variation of performance of the gasifier by this validated model for different air-fuel ratio and moisture content was also discussed.


Decision analysis in clinical cardiology: when is coronary angiography required in aortic stenosis?
Decision analysis offers a reproducible, explicit approach to complex clinical decisions. It consists of developing a model, typically a decision tree, that separates choices from chances and that specifies and assigns relative values to outcomes. Sensitivity analysis allows exploration of alternative assumptions. Cost-effectiveness analysis shows the relation between dollars spent and improved health outcomes achieved. In a tutorial format, this approach is applied to the decision whether to perform coronary angiography in a patient who requires aortic valve replacement for critical aortic stenosis.


Hypoxic oligodendrocyte precursor cell-derived VEGFA is associated with blood-brain barrier impairment.
Cerebral small vessel disease is characterised by decreased cerebral blood flow and blood-brain barrier impairments which play a key role in the development of white matter lesions. We hypothesised that cerebral hypoperfusion causes local hypoxia, affecting oligodendrocyte precursor cell-endothelial cell signalling leading to blood-brain barrier dysfunction as an early mechanism for the development of white matter lesions. Bilateral carotid artery stenosis was used as a mouse model for cerebral hypoperfusion. Pimonidazole, a hypoxic cell marker, was injected prior to humane sacrifice at day 7. Myelin content, vascular density, blood-brain barrier leakages, and hypoxic cell density were quantified. Primary mouse oligodendrocyte precursor cells were exposed to hypoxia and RNA sequencing was performed. Vegfa gene expression and protein secretion was examined in an oligodendrocyte precursor cell line exposed to hypoxia. Additionally, human blood plasma VEGFA levels were measured and correlated to blood-brain barrier permeability in normal-appearing white matter and white matter lesions of cerebral small vessel disease patients and controls. Cerebral blood flow was reduced in the stenosis mice, with an increase in hypoxic cell number and blood-brain barrier leakages in the cortical areas but no changes in myelin content or vascular density. Vegfa upregulation was identified in hypoxic oligodendrocyte precursor cells, which was mediated via Hif1α and Epas1. In humans, VEGFA plasma levels were increased in patients versus controls. VEGFA plasma levels were associated with increased blood-brain barrier permeability in normal appearing white matter of patients. Cerebral hypoperfusion mediates hypoxia induced VEGFA expression in oligodendrocyte precursor cells through Hif1α/Epas1 signalling. VEGFA could in turn increase BBB permeability. In humans, increased VEGFA plasma levels in cerebral small vessel disease patients were associated with increased blood-brain barrier permeability in the normal appearing white matter. Our results support a role of VEGFA expression in cerebral hypoperfusion as seen in cerebral small vessel disease.


Modeling and predicting interactions between the human amphiphysin SH3 domains and their peptide ligands based on amino acid information.
In this paper, VHESH, which was a novel set of amino acid descriptors including hydrophobic, electronic, steric, and hydrogen bond contribution properties, were proposed to characterize the structures of the decapeptides binding the human amphiphysin-1 Src homology 3 (SH3) domains, and QSAR model was constructed by partial least square (PLS) with genetic algorithm-variable selection. It was found that diversified properties of the residues between P(2) and P(-3) (including P(2) and P(-3)) of the decapeptide (P(4)P(3)P(2)P(1)P(0)P(-1)P(-2)P(-3)P(-4)P(-5)) may contribute remarkable effect to the interactions between the SH3 domain and decapeptides. Particularly, hydrogen bond and steric properties of P(2) and electronic properties, steric properties of P(-3) may provide relatively large positive contributions to the interactions. Based on the GA-PLS model, a series of decapeptides, with relatively high binding affinities were designed. These results showed that VHESH descriptors can well represent the decapeptides. Furthermore, the model obtained, which showed low computational complexity, correlated VHESH descriptors with the binding affinities as well as that VHESH may also be applied in QSAR studies of peptides.


Assessing bronchodilator responsiveness in infants using partial expiratory flow-volume curves.
Our objective was to compare the effectiveness of maximum forced expiratory flow measured at functional residual capacity (V'maxFRC) and the ratio of flow at 75% of the forced expiratory volume to peak forced expiratory flow (FEF(75)/FEF(peak)) for detecting bronchodilator-related changes in wheezy infants. In 55 infants (mean age, 7.8 +/- 3.1 months) with a history of recurrent wheezing, V'maxFRC and FEF(75)/FEF(peak) were measured at baseline and 15 min following nebulized albuterol. Mean results from 4 baseline and 4 postalbuterol partial expiratory flow-volume curves were compared at baseline and following bronchodilator challenge. The strength (relative effect size) of each measure for assessing change was quantified by dividing the mean of the pre- to postdifferences by the standard deviation of the differences. Mean percent predicted V'maxFRC was 41.3 +/- 34.3% at baseline and 44.4 +/- 34.0% following albuterol. Mean FEF(75)/FEF(peak) was 26.7 +/- 13.4% at baseline and 35.8 +/- 14.3% following albuterol. The mean percent change from baseline [(post-pre)/pre] in percent predicted V'maxFRC was 18.3 +/- 39.3, and for FEF(75)/FEF(peak), it was 44.1 +/- 36.8. The change in FEF(75)/FEF(peak) following albuterol was significantly greater than the change in V'maxFRC (P < 0.0001). The relative effect size for mean percent change from baseline in V'maxFRC was 0.47, and for FEF(75)/FEF(peak), 1.20. Changes in FEF(75)/FEF(peak) appear to differentiate changes in airway function following administration of a bronchodilator better than do changes in V'maxFRC.


Leveraging the electronic health record to improve dermatologic care delivery: The importance of finding structure in data.
The federal mandate for electronic health record (EHR) keeping for health care providers impacted the burden placed on dermatologists for medical documentation. The hope that EHR would improve care quality and efficiency and reduce health disparities has yet to be fully realized. Despite the significant time and effort spent on documentation, the majority of EHR clinical data remain unstructured and therefore, difficult to process and analyze. Structured data can provide a way for dermatologists and data scientists to make more effective use of clinical data-not only to improve the dermatologist's experience with EHRs, but also to manage technology-related administrative burden, accelerate understanding of disease, and enhance care delivery for patients. Understanding the importance of structured data will allow dermatologists to actively engage in how clinical data will be collected and used to advance patient care.


Clonal acquisition of inhibitory Ly49 receptors on developing NK cells is successively restricted and regulated by stromal class I MHC.
We report an in vitro stroma-dependent system for the clonal growth and differentiation of natural killer (NK) cells from lymphoid-restricted bone marrow progenitors or bone marrow NK1.1+ cells. Strikingly, the potential to initiate expression of specific Ly49 receptors becomes increasingly restricted as NK cells develop. Moreover, when NK cells express a Ly49 receptor specific for stromal cell class I MHC, they are less likely to initiate expression of another Ly49 receptor in the clonal culture system. The results indicate multiple roles for stromal cells in NK cell development, in supporting clonal growth, in initiation of Ly49 receptor expression, and in formation of the NK cell receptor repertoire.


T-cell-activation inhibitors in rheumatoid arthritis.
As rheumatoid arthritis (RA) is a chronic inflammatory disabling disease and a cure is not available, optimisation of therapeutic strategies is mandatory. Within recent years many new details of the inflammatory cascade(s) have been elaborated, leading to new therapeutic options such as neutralisation of tumour necrosis factor-alpha (TNFalpha). T-cell inhibition is another new approach to the treatment of RA. However, it is important to note two points: first, the role of T lymphocytes in the initiation and/or perpetuation of RA is still debated controversially. Second, there are few truly T-cell-specific agents that have proven to be effective and are established in the treatment of inflammatory disorders. Leflunomide may be considered one such agent; another in development is the fusion protein CTLA4-Ig. From a clinical perspective, studies demonstrating efficacy of these agents might represent the strongest support for a role of T cells in RA. In addition to leflunomide and CTLA4-Ig, therapeutic agents with activity against T cells, including anti-CD4 antibodies, cyclosporin, tacrolimus and T-cell receptor (TCR)-Vbeta-chain vaccination strategies, have been studied in patients with RA. Combination therapies including any of these T-cell-activation inhibitors with non-T-cell-specific agents such as methotrexate, antimalarials or anti-TNFalpha biologicals may prove the most effective strategies in controlling this complex disease.


Structural insights of the toxin-antitoxin system VPA0770-VPA0769 in Vibrio parahaemolyticus.
Toxin-antitoxin (TA) systems are involved in both normal bacterial physiology and pathogenicity, including gene regulation, antibiotic resistance, and bacteria persistence under stressful environments. In pathogenic Vibrio parahaemolyticus, however, TA interaction and assembly remain largely unknown. In this work, we identified a new RES-Xre type II TA module, encoded by gene cluster vpa0770-vpa0769 on chromosome II of V. parahaemolyticus. Ectopic expression of the VPA0770 toxin rapidly arrests the growth of E. coli cells, which can be neutralized by co-expression of the VPA0769 antitoxin. To decipher the action mechanism, we determined the crystal structure of the VPA0770-VPA0769 TA complex. VPA0770 and VPA0769 proteins can assemble into two types of large complexes, a W-shaped hetero-hexamer and a donut-like hetero-dodecamer, in a concentration-dependent manner in solution. Disruption of the TA interface results in a loss of the antitoxic phenotype. The toxicity of the VPA0770 toxin, which harbors a NAD+-binding pocket, may be largely ascribed to its highly effective capability to degrade intracellular NAD+. Our study provides a structural basis for a better understanding of diverse molecular mechanisms employed by human pathogens.


Ca2(+)-dependent adaptive properties in the solitary olfactory receptor cell of the newt.
The time-dependent decay of the olfactory receptor potential was analyzed with a solitary cell preparation by using the whole-cell patch clamp technique. During prolonged stimulation by 10 mM N-amylacetate under standard conditions, 17 out of 63 isolated olfactory cells responded with slow depolarization. Of these 17 cells, response amplitudes in 14 cells ('phasic/tonic' response) gradually decayed within 9 s, with a half-decay time of 1.71 +/- 1.10 s (mean +/- S.D.). The relative amplitude (ratio of tonic component to peak amplitude, Vtonic/Vmax) was 0.29 +/- 0.10. The response decay was attributed to the inactivation of the odorant-activated conductance. The recovery after inactivation, which was determined with double pulse experiments, was dependent on the resting interval. The inactivation of the odorant-activated conductance was found to be observed only when the external medium contained Ca2+. In addition, it was found that the odorant-activated conductance was capable of permeating Ca2+ (PCa/PNa = 6.5), and a rise in the internal EGTA concentration (to 50 mM) inhibited the inactivation. These observations suggest that the decay of the olfactory response to prolonged stimulation is mediated by Ca2+ influx.


Global contextual attention augmented YOLO with ConvMixer prediction heads for PCB surface defect detection.
To solve the problem of missed and false detection caused by the large number of tiny targets and complex background textures in a printed circuit board (PCB), we propose a global contextual attention augmented YOLO model with ConvMixer prediction heads (GCC-YOLO). In this study, we apply a high-resolution feature layer (P2) to gain more details and positional information of small targets. Moreover, in order to suppress the background noisy information and further enhance the feature extraction capability, a global contextual attention module (GC) is introduced in the backbone network and combined with a C3 module. Furthermore, in order to reduce the loss of shallow feature information due to the deepening of network layers, a bi-directional weighted feature pyramid (BiFPN) feature fusion structure is introduced. Finally, a ConvMixer module is introduced and combined with the C3 module to create a new prediction head, which improves the small target detection capability of the model while reducing the parameters. Test results on the PCB dataset show that GCC-YOLO improved the Precision, Recall, email@example.com, and email@example.com:0.95 by 0.2%, 1.8%, 0.5%, and 8.3%, respectively, compared to YOLOv5s; moreover, it has a smaller model volume and faster reasoning speed compared to other algorithms.


Intra- and postoperative predictors of stroke after coronary artery bypass grafting.
Stroke is a devastating complication of coronary artery bypass graft surgery. An individual's risk of stroke is based in part on preoperative characteristics but also on intra- and postoperative factors. We developed a risk prediction model for stroke based on factors in intra- and postoperative care, after adjusting for a patient's preoperative risk. We conducted a regional prospective study of 11,825 consecutive patients undergoing coronary artery bypass graft surgery surgery from 1996 to 2001. Data were collected on patient and disease characteristics, intra- and postoperative care and course, and outcomes. Stroke was defined as "a new focal neurologic deficit which appears and is still at least partially evident more than 24 hours after its onset." Logistic regression identified significant predictors of stroke. The incidence of stroke was 1.5%. The regression model significantly predicted the occurrence of stroke. As compared with cardiopulmonary bypass for less than 90 minutes, cardiopulmonary bypass for 90 to 113 minutes, odds ratio = 1.59, p = 0.022), cardiopulmonary bypass for 114 minutes or more (odds ratio = 2.36, p < 0.001), atrial fibrillation (odds ratio = 1.82, p < 0.001), and prolonged inotrope use (odds ratio = 2.59, p = 0.001) significantly improved our ability to predict stroke. Nearly 75% of all strokes occurred among the 90% of patients at low or medium preoperative risk. The inclusion of factors associated with intra- and postoperative care and course significantly improved the prediction model. Most strokes occurred among patients at low or medium preoperative risk, suggesting that many of these strokes may be preventable. Reduction in stroke risk may require modifications in intra- and postoperative care and course.


Radioisotopic and synthetic studies related to caroxazone metabolism in man.
Labelled 2-oxo-2H-1,3-benzoxazine-3(4H)-acetamide (caroxazone), has been synthesized by condensing N-(2-hydroxylbenzyl/glycinamide with 14C phosgene. Metabolic studies were performed administering the labelled drug to man and recovering metabolites from the urines. Beside the unchanged drug, five metabolites were identified and confirmed by synthesis, namely (3,4-dihydro-3-carboxamidomethyl-2-oxo-2H-1,3-benzoxazin-4-yl)urea (IX), N-carboxamidomethyl o-hydroxymethylphenyl carbamate (V), 4-methoxy-2-oxo-2H-1,3-benzoxazine-3(4H)acetamide (VIIIa), 2-oxo-2H-1,3-benzoxazine-3(4H)acetic acid (III) and 4-hydroxy-2-oxo-2H-1,3-benzoxazine-3(4H)acetamide (IV).


Glutamate dehydrogenase activity is markedly higher in a "Golgi-Bergmann"-like glial clone than in other astroglial cell lines.
Glutamate appears to be the neurotransmitter of granule cells, the major neuronal population of the cerebellar cortex. To determine the role of astroglial cells in the synthesis of glutamate, we have measured the specific activity of glutamate dehydrogenase (GDH) in clonal cell lines that might be the in vitro equivalents of the different cerebellum astroglial cell types. In conditions where GDH operates in the direction of glutamate synthesis, the specific activity of GDH measured in the "Golgi-Bergmann"-like clone was 4-6 times higher than in the "velate protoplasmic"- or "fibrous-like" astrocytic clones. These data correlate well with the intense immunoreactivity to GDH in Golgi-Bergmann astrocytes in vivo that has been recently reported.


Association between organ dysfunction and cytokine concentrations during the early phases of septic shock.
To investigate the correlation of organ dysfunction and its progression with inflammatory response during the early phases of septic shock by assessing baseline cytokine concentrations. This study included patients over 18 years old with septic shock within the first 48 hours after the onset of organ dysfunction. Interleukin 6 (IL-6), interleukin 8 (IL-8), interleukin 10 (IL-10) and C-reactive protein levels were assessed at inclusion and after 24 hours, and the differences between these values were calculated. The progression of organ dysfunction was assessed using the Sequential Organ Failure Assessment (SOFA) score upon admission and 24 hours later for a delta-SOFA determination and were categorized as either worsened or improved. The results were expressed as means + standard deviation or median (25-75% percentiles). Values with descriptive p values of 0.05 or less were considered significant. Overall, we included 41 patients with median SOFA scores of 8.0 (6.5-10.0) upon admission (T0) and 8.0 (6.0-10.0) 24 hours later (T1). Worsened, improved or unchanged SOFA scores were observed in 11 (Group 1), 17 (Group 2) and 13 (Group 3) patients, respectively. For Group 1, the baseline IL-6, IL-8 and IL-10 values were higher, and a significant increase of IL-8 levels was found after 24 hours. The change in the SOFA score after 24 hours was significantly, although weakly, correlated with baseline IL-6 and IL-8 concentrations. Higher baseline IL-6, IL-8 and IL-10 levels are associated with unfavorable organ dysfunction outcomes. Increased IL-8 levels within the first 24 hours are correlated with a worsening dysfunction.


Association between single nucleotide polymorphisms on chromosome 17q and the risk of prostate cancer in a Chinese population.
In European populations, 7 single nucleotide polymorphisms (SNPs) on chromosome 17q, 3 SNPs on 17q12, and 4 SNPs on 17q24.3 were recently identified to be closely related to the risk of prostate cancer by a genome-wide association study. In Japanese populations, the correlation between 2 SNPs on 17q and the risk of prostate cancer and tumor aggressiveness was also confirmed by a large-scale experiment. However, whether 17q is associated with prostate cancer and its clinical manifestations in Chinese populations is still unknown. Therefore, we conducted a case-control study in a northern Chinese population and tested 2 SNPs, rs4430796 and rs1859962, on 17q in 124 prostate cancer patients and 111 controls using polymerase chain reaction-high resolution melting curve (PCR-HRM) combined with sequencing. We analyzed the association of the 2 SNPs with the risk of prostate cancer as well as patients' lifestyles, onset ages, Gleason scores, PSA levels, and pathologic stages. We found a significant difference in the G allele of SNP rs1859962 (P = 0.035, OR = 1.51, 95% CI = 1.03-2.21) but not in the rs4430796 genotype frequency or allele frequency distribution between prostate cancer patients and the controls (P > 0.05). Neither of the SNPs was significantly associated with the onset age, Gleason score, PSA level, pathologic stage, or other clinical indicators of patients with prostate cancer (P > 0.05). Our results show that polymorphism of the G allele of SNP rs1859962 is associated with the risk of prostate cancer in a Chinese population.


Role of the general practitioner in data collection and cross matching.
Dental records used in identification procedures are most often obtained from the offices of general practitioners. The family dentist is required to provide accurate and well documented data to assist in the identification process. The forensic team participating in a mass disaster identification may also utilize the services of general practitioners. They play an active role in the oral autopsy, the oral radiographic procedure, and the identification process itself.


Simultaneous occurrence of a congenital lateral upper lip sinus and congenital gingival cyst: a case report and discussion of pathogenesis.
The simultaneous occurrence of a congenital lateral sinus of the upper lip and of a congenital gingival cyst in a newborn boy is reported. The sinus extended to a depth of 10 mm and was lined by a parakeratinized squamous epithelium. The gingival cyst appeared as a 1 cm palatal enlargement lingual to the maxillary alveolar ridge and demonstrated a thin epithelial lining with localized plaquelike thickenings and occasional clear cells with vacuolated cytoplasm. There was no familial history of congenital deformities, and no additional abnormalities were noted. These two epithelium-lined structures show a clear topographic and morphologic relationship, and they may share a common embryologic origin. It is suggested that they derive from epithelium remaining subsequent to the union of the maxillary process and medial nasal process mesoderms.


Structure-activity relationship of alginate oligosaccharides in the induction of cytokine production from RAW264.7 cells.
Guluronate and mannuronate oligomers with various degree of polymerization were prepared from polyguluronate (PG) and polymannuronate (PM) with an alginate lyase from a Pseudoalteromonas sp., and their activities to induce cytokine secretion from mouse macrophage cell line RAW264.7 cells were examined. Enzymatically depolymerized unsaturated alginate oligomers induced tumor necrosis factor (TNF)-alpha secretion from RAW264.7 cells in a structure-depending manner, while the activities of saturated alginate oligomers prepared by acid hydrolysis were fairly low or only trace levels. These results suggest that unsaturated end-structure of alginate oligomers was important for the TNF-alpha-inducing activity. Among the unsaturated guluronate (G3-G9) and mannuronate (M3-M9) oligomers, G8 and M7 showed the most potent activity, respectively. Bio-Plex assay revealed that interleukin (IL)-1alpha, IL-1beta, and IL-6 secretion from RAW264.7 cells were also induced by unsaturated alginate oligomers with similar structure-activity relationship profiles as seen in TNF-alpha, and the most potent activities were observed with G8 and M7. These results suggest that G8 and M7 may have the most suitable molecular size or entire structural conformation as stimulant for cytokine secretion. Since antibodies to Toll-like receptor (TLR)2 and TLR4 effectively inhibited the G8- and M7-induced production of TNF-alpha, these alginate oligomers may stimulate innate immunity through the pattern recognition receptors on macrophages similar to microbial products.


Comparison of 3 T mpMRI and pelvic CT examinations for detection of lymph node metastases in patients with prostate cancer.
This study investigates preoperative lymph node metastases (LNM) detection accuracy by MRI and CT in patients with prostate cancer (PCA). All patients with preoperative MRI, CT or both and subsequent radical prostatectomy (RPE) and lymphadenectomy (LA) were included in this retrospective cohort study. Prostate specific antigen (PSA), PI-RADS, ISUP grade group, clinical and pathological tumor (T) stage was compared between negative and positive nodal (N) stage. LNM were assessed with size and localization and weather they were preoperatively detected or not. In patients with preoperative CT and MRI, the results were compared intermodally. The reference standard was the histopathological results after RPE and LA. A total of 228 patients were analysed including 24 patients with confirmed LNM (N1; 11%). PSA (median 9.7 vs. 14 ng/ml), PI-RADS (median 4 vs. 5), ISUP (median 2 vs. 4), and cT/pT-stage (median T2 vs. T3) was significantly higher in patients with LNM. No LNM were found in patients with ISUP-1-PCA. MRI was able to detect 67% of patients with LNM. Lymph node metastases presented on MRI predominantly small, round-shaped, located parailiacally with a minimum SAD of 4 mm (vs. CT SAD of 8 mm). In comparison, MRI was superior to CT in the detection of LNM (sensitivity 81% vs. 33%; specificity 99% vs. 97). LNM were very rare in patients with PSA < 10 ng/ml, PI-RADS ≤ 4, and ≤ cT2. MRI could detect LNM up to 4 mm with a moderate sensitivity and high specificity. Thus, MRI might optimise the preoperative diagnostic and therapy planning of patients with PCA, whereas CT was clearly limited for N-stage assessment.


Small pheochromocytomas: significance, diagnosis, and outcome.
To address the unique challenges in the diagnosis and management of small pheochromocytomas, the authors performed a retrospective study of 24 patients with small pheochromocytomas (≤ 3 cm) treated between 1995 and 2011, using 51 patients with larger pheochromocytomas (> 3 cm) as controls. Patient demographics were similar between the two groups. Small pheochromocytomas presented mainly as adrenal mass and hypertension and their major complication was hypertensive crisis during unrelated procedures in 4 patients (17%). Hypertension was improved in a quarter of the patients after pheochromocytoma resection. The biochemical marker levels in patients with small pheochromocytomas were generally lower than those with larger tumors and half of the patients exhibited modestly elevated or normal levels. The authors conclude that small pheochromocytomas are frequent and may not contribute to baseline hypertension, but can cause hypertensive crisis during unrelated medical procedures. Small pheochromocytomas should be removed to prevent hypertensive crisis and future complications of pheochromocytoma.


Differences in HIV-1 viral loads between male and female antiretroviral-untreated Mexican patients.
HIV-1 viral load is used to monitor AIDS progression and effect of antiretroviral therapy (ART). Several reports have indicated that the HIV-1 viral load of infected individuals is lower in females than in males. There are no reports exploring this issue in the Mexican population. We analyzed the relationship between sex and viral load in Mexican patients differing in CD4 T-cell count, age and treatment status. A retrospective study was performed in 3949 male and 696 female HIV-1-infected individuals. Statistical distributions were compared using the Mann-Whitney U nonparametric test. Among the antiretroviral-untreated group, females had a significantly lower viral load than males (0.52 female/male median viral load ratio, p = 0.008). When classified according to different ranges of CD4⁺ T cell counts, females had consistently lower viral loads than males, although statistical significance was achieved only for the group in the range of 201-350 (p = 0.014). Patients with the lowest CD4⁺ T-cell counts showed similar viral loads for both sexes. No differences were observed in the ART group. This study demonstrates a baseline difference in viral load between male and female ART-untreated Mexican patients. The overall tendency indicating a lower viral load in females in the same ranges of CD4⁺ T-cell counts than males, suggests that the lower viral load in females is not indicative of a lower risk of developing AIDS. These observations suggest a significant influence of sex on viral dynamics and immune response despite variations in demographic factors.


Development of a colloidal gold-immunochromatography assay to detect immunoglobulin G antibodies to Treponema pallidum with TPN17 and TPN47.
Syphilis remains a worldwide public health problem; it is necessary to develop a new diagnostic approach that is easier and faster than conventional tests. Here, we report a new testing method named colloidal gold-immunochromatography assay (GICA) to detect syphilis instead of fluorescent treponemal antibody-absorption (FTA-Abs). Syphilis-specific immunoglobulin G (IgG) antibody was detected with GICA established on syphilis-specific recombinant proteins, TPN17 and TPN47. FTA-Abs Treponema pallidum (TP)-IgG was set as the gold standard. A GICA test was performed to detect the serum of 14 967 subjects who took a serologic test for syphilis at the Xiamen Center of Clinical Laboratory, Fujian, China, from March 2009 to February 2010, among which 1326 cases were diagnosed as syphilitic. The results showed that the sensitivity, specificity, and positive predictive value were 99.38% (1279/1287), 99.96% (12,975/12,980), and 99.61% (1279/1284), respectively. The positive rate between the 2 test methods had no significant difference (χ(2) = 0.003, P > 0.05). Detection on 500 interference specimens indicated that the biologic false-positive rate of the GICA test was extremely low and free from other biologic and chemical factors. The characteristics of GICA TP-IgG correspond to that of FTA-Abs TP-IgG (EUROIMMUN Medizinische Labordiagnostika, Germany). The GICA test is convenient, fast, and inexpensive, and it can be used both as a confirmatory test and a screening indicator, instead of FTA-Abs TP-IgG.


Acute Lung Injury in Response to Intratracheal Instillation of Lipopolysaccharide in an Animal Model of Emphysema Induced by Elastase.
The response of lungs with emphysema to an acute lung injury (ALI) remains unclear. This study compared the lung response to intratracheal instillation of lipopolysaccharide (LPS) in rats with and without emphysema. Twenty-four Wistar rats were randomized to four groups: control group (C-G), ALI group (ALI-G), emphysema group (E-G), emphysema and ALI group (E-ALI-G). Euthanasia and the following analysis were performed 24 h after ALI induction: lung histology, bronchoalveolar lavage (BAL), mRNA expression of inflammatory mediators, and blood gas measures. The histological analysis showed that animals of ALI-G (0.55 ± 0.15) and E-ALI-G (0.69 ± 0.08) had a higher ALI score compared to C-G (0.12 ± 0.04) and E-G (0.16 ± 0.04) (p < 0.05). The analysis of each component of the score demonstrated that ALI-G and E-ALI-G had greater alveolar and interstitial neutrophil infiltration, as well as greater amount of alveolar proteinaceous debris. Comparing the two groups that received LPS, there was a trend of higher ALI in the E-ALI-G, specially due to a higher neutrophil infiltration in the alveolar spaces and a higher septal thickening. Total cell count (E-G = 3.09 ± 0.83; ALI-G = 4.45 ± 1.9; E-ALI-G = 5.9 ± 2.1; C-G = 0.73 ± 0.37 × 105) and neutrophil count (E-G = 0.69 ± 0.35; ALI-G = 2.53 ± 1.09; E-ALI-G = 3.86 ± 1.4; C-G = 0.09 ± 0.07 × 105) in the BAL were higher in the groups E-G, ALI-G, and E-ALI-G when compared to C-G (p < 0.05). The IL-6, TNF-α, and CXCL2 mRNA expressions were higher in the animals that received LPS (ALI-G and E-ALI-G) compared to the C-G and E-G (p < 0.05). No statistically significant difference was observed in the BAL cellularity and in the expression of inflammatory mediators between the ALI-G and the E-ALI-G. The severity of ALI in response to intratracheal instillation of LPS did not show difference in rats with and without intratracheal-induced emphysema.


High performance liquid chromatography-electrospray ionization mass spectrometric determination of tolterodine tartrate in human plasma.
A selective and sensitive high performance liquid chromatography-electrospray ionization mass spectrometry method has been developed for the determination of tolterodine tartrate in human plasma. With oxybutynin as internal standard, tolterodine tartrate was extracted from plasma with n-hexane: isopropanol (95:5, v/v). The organic layer was evaporated and the residue was redissolved in mobile phase comprised of acetonitrile-water (10 mM CH3COONH4, pH 3.0)=50:50 (v/v). An aliquot of 10 microl was chromatographically analyzed on a prepacked Shimadzu Shim-pack VP-ODS C18 column (150 mmx2.0 mm I.D.) by means of selected-ion monitoring (SIM) mode mass spectrometry. Standard curves were linear (r=0.9993) over the concentration range of 0.1-30.0 ng/ml and had good accuracy and precision. The within- and between-batch precisions were within 10% relative standard deviation. The limit of detection (LOD) was 0.05 ng/ml. The validated LC-ESI-MS method has been used successfully to study tolterodine tartrate pharmacokinetic, bioavailability and bioequivalence in 20 healthy male volunteers.


Spinal canal invasion as a predictor of neurological deficit in traumatic vertebral burst fractures.
This study correlated the extent of spinal canal compression from retropulsed traumatic burst cervical, thoracic, and lumbar spine fractures with the severity of neurological dysfunction. One hundred and sixty-nine patients with cervical, thoracic, or lumbar sub-axial traumatic burst fractures were seen in an emergency department from 2019 to 2021; 79.3% were men, averaging 37 years of age. The lumbar spine was most frequently involved (42%), followed by the thoracic (36.1%) and cervical (21.9%) levels. The extent of spinal canal compression was quantitated utilizing Hashimoto's method, and correlated with patients' extent of neurological injury based on their American Spinal Injury Association scores. There was a positive correlation between the extent of cervical and thoracic spinal cord compression due to retro pulsed burst fragments and the severity of the patients' neurological deficits, but this was not true for the lumbar spine. The extent of spinal cord compression from retropulsed cervical and thoracic traumatic burst fractures was readily correlated with the severity of patients' neurological dysfunction. However, there was no such correlation between the extent of cauda equina compression from retropulsed lumbar burst fractures and the severity of their cauda equina syndromes.


Risk factors for early-onset radiographical adjacent segment disease in patients with spondylolytic spondylolisthesis after single-level posterior lumbar interbody fusion.
The risk factors for radiographical adjacent segment disease (ASD) in patients with degenerative spondylolisthesis have been previously reported. However, there are only few reports on patients with spondylolytic spondylolisthesis who underwent single-level posterior lumbar interbody fusion (PLIF). The study aimed to investigate the risk factors for radiographical ASD in patients with L5-S1 spondylolytic spondylolisthesis who underwent single-level PLIF. A retrospective study PATIENT SAMPLE: This study retrospectively reviewed 135 consecutive patients (91 men and 44 women) with symptomatic L5-S1 spondylolytic spondylolisthesis who underwent single-level PLIF. The pre- and postoperative (at the final follow-up) spinopelvic parameters, % slip, sacral slope, lumbar lordosis (LL), pelvic tilt, pelvic incidence (PI), PI minus LL (PI - LL), lumbosacral angle, C7 sagittal vertical axis, and thoracic kyphosis were measured using standing radiographs. Radiographical ASD was defined as disc height loss (>3 mm), increase of posterior angulation (>5°), or progression of spondylolisthesis (>3 mm) between the pre- and postoperative radiographs. Pfirrmann's classification was used to evaluate disc degeneration. The radiographical parameters and changes between the pre- and postoperative values were evaluated and compared for the non-ASD and ASD groups. Binary logistic regression analysis was performed to evaluate the adjusted associations between each potential explanatory variable and ASD development. The radiographical ASD incidence was 11%. Additionally, 60% of the patients with ASD had radiographical ASD at 1 year and all cases of radiographical ASD in this follow-up period occurred within 3 years after the initial surgery. The mean period of ASD occurrence after initial surgery was 21.7 ± 12.6 months. No patients required reoperation for radiographical ASD. Multivariate analysis revealed that a preoperative (odds ratio [OR], 5.9; 95% confidence interval [CI], 1.2-28.9; p=.03) and a postoperative (OR, 6.5; 95% CI, 1.2-34.5; p=.03) PI - LL of ≥15° were risk factors for radiographical ASD. Pre- and postoperative PI - LL value mismatch was identified as significant independent risk factors for radiographical ASD in patients with L5-S1 spondylolytic spondylolisthesis. Obtaining larger lordosis at L5-S1 may be the key to preventing radiographical ASD.


Use of acute care hospitals by long-stay patients: who, how much, and why?
The effects of long-term hospitalizations can be severe, especially among older adults. In Manitoba, between fiscal years 1991/1992 and 1999/2000, 40 per cent of acute care hospital days were used by the 5 per cent of patients who had long stays, defined as stays of more than 30 days. These proportions were remarkably stable, despite major changes in the bed supply. Approximately two-thirds of long-stay patients were aged 75 or older. Medical record review for a small sample of long-stay medical patients aged 75 or older revealed that 42 per cent of the days spent in hospital were spent either awaiting transfer to another level of care (home care, nursing home, or chronic care), or were due to in-hospital factors, such as awaiting consults, tests, or treatments. Hospital information systems and early discharge planning may help to alleviate lengthy discharge delays and result in better care for these patients.


Actin polymerization regulates recruitment of Nck to CD3ε upon T-cell receptor triggering.
Following T-cell antigen receptor (TCR) engagement, rearrangement of the actin cytoskeleton supports intracellular signal transduction and T-cell activation. The non-catalytic region of the tyrosine kinase (Nck) molecule is an adapter protein implicated in TCR-induced actin polymerization. Further, Nck is recruited to the CD3ε subunit of the TCR upon TCR triggering. Here we examine the role of actin polymerization in the recruitment of Nck to the TCR. To this end, Nck binding to CD3ε was quantified in Jurkat cells using the proximity ligation assay. We show that inhibition of actin polymerization using cytochalasin D delayed the recruitment of Nck1 to the TCR upon TCR triggering. Interestingly, CD3ε phosphorylation was also delayed. These findings suggest that actin polymerization promotes the recruitment of Nck to the TCR, enhancing downstream signaling, such as phosphorylation of CD3ε.


Platelet-rich fibrin and piezoelectric surgery: a safe technique for the prevention of periodontal complications in third molar surgery.
The surgical removal of impacted mesioangular mandibular third molars (3Ms) may produce trauma to the soft tissues and bony structures. In particular, healing of postextractive socket may cause periodontal defects at the distal root of the second molar. The aim of the present prospective study was to assess the outcomes of a surgical protocol to remove 3Ms including the use of ultrasound bone surgery devices and platelet-rich fibrin (PRF) as a grafting material. Twenty-eight impacted mandibular 3Ms were removed. Fourteen 3Ms were removed by piezoelectric osteotomy and PRF application. Instead, the 14 3Ms of the control group were removed by piezoelectric osteotomy but without PRF application. Probing depth in the distal position for all the mandibular second molars was registered before and 6 months after surgery. No complications were encountered. In the study group, alveolar socket fulfillment was rated as sufficient in 4 cases and adequate in the remaining 10 cases, whereas in the control group, it was rated as insufficient in 3 cases, sufficient in 4 cases, and adequate in 7 cases. Mean preoperative periodontal probing in the control group was 3.78 mm, whereas in the study group, it was 3.93 mm.Six months after surgery, mean periodontal probing was 3.28 mm in the control group and 3.07 mm in the study group. Combined action of PRF and piezoelectric surgery can be considered a safe and fine technique for third molar surgery and alveolar socket healing.


The epidemiology of end-state renal disease: the six-year South-Central Los Angeles experience, 1980-85.
Using the End-Stage Renal Disease Medical Information System and 1980 census information, the crude cumulative incidence among Blacks, Hispanics, and Whites in south central Los Angeles was determined to be 160.1, 49.28, and 55.3 per 100,000 respectively. Sex-specific rates were slightly greater in males. Among Blacks, nephrosclerosis and diabetes represented 41.5 and 30.2 per cent of the cases respectively and increased during the period 1980-85.