Correlating Ki67 and other prognostic markers with Oncotype DX recurrence score in early estrogen receptor-positive breast cancer.
Decisions regarding adjuvant chemotherapy for early breast cancer are complex. Ki67 is increasingly used, in conjunction with conventional prognostic markers, to help decide the use of adjuvant chemotherapy for early breast cancer. Ki67 has been proposed as an economical alternative to Oncotype DX recurrence score (RS), which is a validated prognostic marker for disease recurrence and predictive marker for benefit from chemotherapy. This study aimed to determine in patients where conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy, whether Ki67 could be a substitute for RS. We reviewed all cases of luminal-type node-negative early breast cancer (T1-2, N0-1mi, M0, estrogen receptor positive, HER2 negative) referred for Oncotype DX testing by the multidisciplinary team at an Australian tertiary private hospital from 14th December 2006 to 31st December 2013, when conventional prognostic markers did not provide a clear recommendation for adjuvant chemotherapy. RS was correlated with Ki67, along with other conventional prognostic markers including tumor size, grade, mitotic rate and lymphovascular invasion. Spearman's rank order correlation coefficient and Pearson product-moment correlation coefficient (r) were used for ordinal and continuous variables, respectively. A total of 58 patients were analyzed, median Ki67 was 15% (range 2-50%) and the median RS was 16 (range 3-65). There was no positive correlation between Ki67 and RS (r = 0.01, P = 0.93). No single conventional prognostic marker was shown to significantly correlate with RS, including tumor size (r = -0.02, P = 0.88), grade (r = 0.10, P = 0.44), mitotic rate (r = -0.07, P = 0.69) and lymphovascular invasion (r = -0.12, P = 0.39). Ki67 and conventional prognostic markers do not correlate with Oncotype DX RS. In the setting where conventional prognostic markers do not show a clear indication for or against adjuvant chemotherapy as determined by consensus in a multidisciplinary team, Ki67 is not a substitute for Oncotype DX testing. RS may provide additional information to aid decision making for adjuvant chemotherapy.


Serum pancreatic secretory trypsin inhibitor in pancreatic disease.
The clinical usefulness of serum pancreatic secretory trypsin inhibitor (PSTI) in pancreatic diseases was evaluated. The mean serum PSTI level of 41 healthy normal persons was 9.4 ng/ml (ranging from 5.2 to 16.7 ng/ml). Serum PSTI levels were abnormally raised in all patients with acute pancreatitis ranging from 35.0 to 4500 ng/ml, but were almost within normal range in patients with chronic pancreatitis, pancreatic cyst, acute abdominal emergencies such as perforated ulcer and intestinal obstruction, and macroamylasemia. There was no correlation between serum PSTI levels and total or pancreatic-type isoamylase activity. Patients with acute pancreatitis in whom the elevation of serum PSTI was transient and occurred after that of serum amylase activity had relatively mild symptoms and recovered along with normalization of serum PSTI levels. On the other hand, patients whose serum PSTI values became increased coincidentally with serum amylase activity and remained elevated, had severe clinical symptoms and unfavorable clinical outcome. Of 2 patients who underwent partial pancreatectomy, the serum PSTI level increased markedly in one who developed postoperative pancreatitis but not in the other without pancreatitis. In contrast to patients with acute pancreatitis, the serum response to the secretin stimulation in patients with chronic pancreatitis, was only small and transient, reaching the maximum at 10 min after administration of secretin. These results suggest that measurement of serum PSTI concentration may be useful in the diagnosis of acute pancreatitis and that the degree of rise and the duration of the elevated levels of serum PSTI are closely related to the severity of acute pancreatitis.


Double-Wound O-Ring Retraction for Chylothorax Surgery in Dogs.
A suitable wound retraction is crucial for open surgical treatment of chylothorax in dogs. A single paracostal approach for transabdominal/transdiaphragmatic thoracic duct ligation and cisterna chyli ablation is an effective procedure. For the procedure, the use of stay sutures and handheld or automatic soft tissue retractors is recommended. However, it is often necessary to adjust the retractors several times during the surgery to provide sufficient exposure of the thoracic duct. This prolongs the operation and increases infection risk. In this report, we describe the modified application of two o-ring elastic wound retractors (O-WRs) in three large breed dogs with idiopathic chylothorax. We conclude that the O-WRs provide a static circumferential vision of the operation field and good access to the cisterna chyli, especially to the thoracic duct. The usage of other surgical instruments is not hampered by the O-WRs, and the elastic rings are not damaged by the metal instruments. Once placed in the diaphragmatic area, indeed, they do not require further manual retraction.


The connective connection: interstitial cells of Cajal (ICC) and ICC-like cells establish synapses with immunoreactive cells. Electron microscope study in situ.
We present transmission electron microscope (TEM) evidence that ICC and ICC-like cells frequently establish close contacts (synapses) with several types of immunoreactive cells (IRC): lymphocytes, plasma cells, eosinophils, basophils, macrophages and mast cells. Such synapses were found in various organs: human mammary gland and myometrium, as well as rat stomach, gut, bladder and uterus. Specimens were observed by conventional TEM on ultrathin sections. Based on morphometric analyses and computer-aided 3-D reconstructions from serial sections, we propose an operational definition of ICC-IRC synapses: cell-to-cell close contacts where the two cells are separated by only approximately 15 nm, equivalent to twice the plasmalemmal thickness. Two types of such synapses were found: (i) uniform ('plain') synapses (PS). close contact extending for >200 nm, and (ii) multi-contact ('kiss and run') synapses (MS)--with multiple, focal, close-contact points alternating with regions of wider intermembrane distance. For instance, a typical PS between a rat bladder ICC-like cell and an eosinophil was 2.48 microm long and 11+/-4 nm wide. By contrast, a MS synapse in rat myometrium (between an ICC-like cell and an eosinophil) was 8.64 microm long and had 13 contact points. The synaptic cleft measured 15+/-8 nm at contact points and approximately 100 nm or more in wider areas. These synapses are different from gap junctions usually seen between ICC and between ICC and smooth muscle cells. We previously proposed that ICC-like cells might represent stromal progenitor cells, participate in juxtacrine/paracrine signaling and play a role in immune surveillance. The nanoscopic distances between the two contiguous membranes suggest a juxtacrine cell-to-cell signaling (chemical synapse), via juxtacrinins, a specific case of phenomenins. However, the (micro)vesicles found in the synaptic cleft may correspond to an exosome-based mechanism.


X-interface is not the explanation for the slow disassembly of N-cadherin dimers in the apo state.
In spite of structural similarities Epithelial- (E-) and Neural- (N-) cadherins are expressed at two types of synapses and differ significantly in dimer disassembly kinetics. Recent studies suggested that the formation of an X-dimer intermediate in E-cadherin is the key requirement for rapid disassembly of the adhesive dimer (Harrison et al., Nat Struct Mol Biol 2010;17:348-357 and Hong et al., J Cell Biol 2011;192:1073-1083). The X-interface in E-cadherin involves three noncovalent interactions, none of which is conserved in N-cadherin. Dimer disassembly is slow at low calcium concentration in N-cadherin, which may be due to the differences in the X-interface residues. To investigate the origin of the slow disassembly kinetics we introduced three point mutations into N-cadherin to provide the opportunity for the formation of X-interface interactions. Spectroscopic studies showed that the triple mutation did not affect the stability or the calcium-binding affinity of the X-enabled N-cadherin mutant. Analytical size exclusion chromatography was used to assay for the effect of the mutation on the rate of dimer disassembly. Contrary to our expectation, the disassembly of dimers of the X-enabled N-cadherin mutant was as slow as seen for wild-type N-cadherin in the apo-state. Thus, the differences in the X-interface residues are not the origin of slow disassembly kinetics of N-cadherin in the apo-state.


Physico-chemical characterization of benzocaine-beta-cyclodextrin inclusion complexes.
Local anesthetics are able to induce pain relief by binding to the sodium channel of excitable membranes, blocking the influx of sodium ions and the propagation of the nervous impulse. Benzocaine (BZC) is a local anesthetic whose low water-solubility limits its application to topical formulations. The present work focuses on the characterization of inclusion complexes of BZC in beta-cyclodextrin (beta-CD). Differential scanning calorimetry and electron microscopy gave evidences of the formation and the morphology of the complex. Fluorescence spectroscopy showed a BZC/beta-CD 1:1 stoichiometry. Phase-solubility diagrams allowed the determination of the association constants between BZC and beta-CD (549 M(-1)) and revealed that a three-fold increase in BZC solubility can be reached upon complexation with beta-CD. The details of BZC/beta-CD molecular interaction were analyzed by 1H 2D NMR allowing the proposition of an inclusion model for BZC into beta-CD where the aromatic ring of the anesthetic is located near the head of the beta-CD cavity. Moreover, in preliminary toxicity studies, the complex seems to be less toxic than BZC alone, since it induced a decrease in the in vitro oxidation of human hemoglobin. These results suggest that the BZC/beta-CD complex represents an effective novel formulation to enhance BZC solubility in water, turning it promising for use outside its traditional application, i.e., in infiltrative anesthesia.


Chromosome aberrations, micronuclei and sister-chromatid exchanges in blood lymphocytes after occupational exposure to low levels of styrene.
Chromosome aberrations, micronuclei and sister-chromatid exchanges were analysed in blood lymphocytes of 21 reinforced plastic workers, exposed to styrene from 1 to 25 years, and 21 control persons. Occupational hygienic measurements showed personal exposure to styrene to range from 34 to 263 mg/m3 air, the average was 98 mg/m3. Urinary mandelic acid levels of the workers varied from below detection limit to 7 mM/1 l urine. No increase was detected in the frequency of any of the cytogenetic endpoints studied. No correlations between the number of aberrations, micronuclei or SCEs on one hand and the extent or duration of exposure to styrene on the other could be detected.


Optimization of dropping process of Xuesaitong dropping pills based on quality by design concept and machine vision.
The drooping process of the Xuesaitong dropping pills (XDPs) was optimized based on quality by design concept. Meanwhile, a machine vision (MV) technology was creatively introduced in this study to predict the critical quality attributes (CQAs) rapidly and accurately. This study improves the understanding of dropping process, and has reference value for the guidance of pharmaceutical process research and industrial production. The study mainly consisted of three stages: the first stage involved the prediction model to establish and evaluate the CQAs, and the second stage involved assessing the quantitative relationships between critical process parameters (CPPs) and CQAs by the mathematical models that were established through the Box-Behnken experimental design. Finally, a probability-based design space for the dropping process was calculated and verified according to the qualification criteria of each quality attribute. The results show that the prediction accuracy of the random forest (RF) model was high and met the analysis requirements, and the CQAs of dropping pills can meet the standard by running in the design space. The MV technology developed in this study can be applied to the optimization process of the XDPs. In addition, the operation in the design space can not only ensure the quality of XDPs to meet the criteria, but also help to improve the consistency of XDPs.


Tuning electronic properties of transition-metal dichalcogenides via defect charge.
Defect engineering is a promising route for controlling the electronic properties of monolayer transition-metal dichalcogenide (TMD) materials. Here, we demonstrate that the electronic structure of MoS2 depends sensitively on the defect charge, both its sign and magnitude. In particular, we study shallow bound states induced by charged defects using large-scale tight-binding simulations with screened defect potentials and observe qualitative changes in the orbital character of the lowest lying impurity states as function of the impurity charge. To gain further insights, we analyze the competition of impurity states originating from different valleys of the TMD band structure using effective mass theory and find that impurity state binding energies are controlled by the effective mass of the corresponding valley, but with significant deviations from hydrogenic behaviour due to unconventional screening of the defect potential.


Age-associated changes in the proliferative response of rat intestinal intraepithelial leukocytes to bacterial antigens.
Intraepithelial leukocytes (IELs) residing in the intestinal epithelium are thought to recognize bacterial antigens and play an important role in providing protection against the invasion of microorganisms through the intestinal wall. This report studies the effect of various bacterial antigens on the proliferation of cultured IELs. Bacterial antigens mycobacterial heat shock protein (hsp) 60 or 70, staphylococcal enteroxin A (SEA), or purified protein derivative (PPD) from Mycobacterium tuberculosis were added to mixed cultures of IELs and irradiated syngeneic or allogeneic spleen cells, and the proliferative response was evaluated. Monoclonal antibodies to CD4, CD8, and major histocompatibility complex class I or class II molecules were added to assess the role of these proteins in the proliferative response. The proliferation of IELs isolated from mature rats in mixed culture was significantly enhanced by the addition of PPD, hsp 60, hsp 70, or SEA. The proliferation of mixed cultures of IELs isolated from young rats was enhanced only by the addition of SEA. In mixed cultures of mature rat IELs and syngeneic spleen cells containing PPD, proliferating populations were of the CD4-CD8+ and CD4+CD8+ phenotypes. Addition of anti-CD4 monoclonal antibody suppressed the proliferative response to PPD to control levels. IELs isolated from mature rats contain mycobacterial antigen-specific T cells, and these cells may be selected by long-term exposure to common intestinal bacterial antigens such as hsp. These cells may contain populations that recognize bacterial antigens in a CD4-dependent manner.


A new model for measuring breeding genetic distance.
A model is proposed for measuring the genetic 'distance' between two populations having gene frequencies p and p. The measure of distance is based on a hypothetical selection process as follows: From population P a subpopulation P can be selected having gene frequency p. Let Po be the largest subpopulation yielding gene frequency p, then the relative size of Po to p--denoted by thetao (p,p)--is a measure of the 'closeness' of populations having gene frequencies p and p, and 1-thetao (p,p) whould be a reasonable measure of genetic distance. We show that the calculation of thetao (p,p) is a special case of the linear programming problem and derive algebraic expressions for thetao (p,p) in the two-allele case. We discuse some of the implications of the use of this measure of distance and compare it to others which have been proposed. We use linear programming methods to calculate genetic distance for three alleles.


Homogeneous stalled ribosome nascent chain complexes produced in vivo or in vitro.
Cotranslational protein maturation is often studied in cell-free translation mixtures, using stalled ribosome-nascent chain complexes produced by translating truncated mRNA. This approach has two limitations: (i) it can be technically challenging, and (ii) it only works in vitro, where the concentrations of cellular components differ from concentrations in vivo. We have developed a method to produce stalled ribosomes bearing nascent chains of a specified length by using a 'stall sequence', derived from the Escherichia coli SecM protein, which interacts with residues in the ribosomal exit tunnel to stall SecM translation. When the stall sequence is expressed at the end of nascent chains, stable translation-arrested ribosome complexes accumulate in intact cells or cell-free extracts. SecM-directed stalling is efficient, with negligible effects on viability. This method is straightforward and suitable for producing stalled ribosome complexes in vivo, permitting study of the length-dependent maturation of nascent chains in the cellular milieu.


Long-term outcomes of chemoradiotherapy versus radiotherapy alone in patients with intermediate-risk nasopharyngeal carcinoma: a population-based analysis.
To investigate the efficacy of chemotherapy among intermediate-risk (stage II/T3N0) nasopharyngeal carcinoma (NPC) patients receiving radiotherapy (RT). We identified stage II/T3N0 NPC patients who received radiotherapy with or without chemotherapy from the Surveillance, Epidemiology and End Results database (2004-2019). Overall survival (OS) and cancer-specific survival (CSS) were assessed using the Kaplan-Meier method with log-rank test and Cox proportional hazards models to evaluate the efficacy of chemotherapy. Subgroup analysis was also conducted based on the baseline characteristics. Propensity score matching (PSM) was performed to balance the intergroup covariates. A total of 1623 patients were enrolled in the study, 1444 received chemoradiotherapy (CRT) and 179 received RT alone. CRT, compared to RT alone, was independently associated with a better OS (HR 0.57, 95% CI 0.45-0.71) and CSS (HR 0.55, 95% CI 0.39-0.79). After PSM, similar results were obtained, and CRT was superior to RT alone in terms of OS (HR 0.60, 95% CI 0.39-0.92) and CSS (HR 0.60, 95% CI 0.40-0.91). Subgroup analysis revealed that OS benefits from CRT were mainly observed in T0-2N1(HR 0.51, 95% CI 0.38-0.70) and T3N0 (HR 0.64, 95% CI 0.42-0.98) rather than T2N0 (HR 1.00, 95% CI 0.51-1.94). Interestingly, after PSM, OS benefits were still seen in T0-2N1 (HR 0.44, 95% CI 0.24-0.82), while not seen in T2N0 (HR 1.83, 95% CI 0.56-5.97) and T3N0 (HR 0.56, 95% CI 0.28-1.12). For T0-2N1 NPC patients, CRT was superior to RT alone with better survival, whereas, for T2-3N0 patients, CRT was comparable to RT alone. Prospective large studies should be encouraged to verify the results.


Compartment Syndrome in Tibial Plateau Fractures: Do Previously Established Predictors Have External Validity?
To test previously established radiographic predictors of compartment syndrome in tibial plateau fractures and determine whether novel measurements may further improve a surgeon's ability to identity patients at high risk for developing this outcome. Retrospective review. Academic Level I trauma center. Five hundred thirteen patients with tibial plateau fractures treated operatively over a 10-year period (OTA/AO 41B1-3 & 41C1-3; Schatzker I-VI). Previously established plain film radiographic measurements and novel computed tomography soft tissue measurements. Acute compartment syndrome (ACS). Schatzker VI fractures (odds ratio 5.72, confidence interval 2.55-12.83, P < 0.001), high-energy mechanism (3.10, 1.26-7.58, P = 0.0096), fibular fracture (8.14, 3.33-19.96, P < 0.0001), fracture length (9.70, 2.45-37.69, P = 0.0014), and plateau-shaft combined injury (2.97, 1.15-7.70, P = 0.019) were all associated with the development of compartment syndrome. The depth of the posterior compartment was also predictive of CS (1.06, 1.02-1.09, P = 0.0025). Patients with 3 and 4 predictive markers demonstrated a 20% and 27% chance of developing ACS respectively. This study confirms that several factors are associated with the development of ACS. The presence of each independent predictor had a cumulative effect such that when more than one variable is present, the chance of ACS increases. This information may be used to alert providers regarding injuries that require vigilant evaluation. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


Bascom's operation in the day-surgical management of symptomatic pilonidal sinus.
Many treatments for symptomatic pilonidal sinus disease have been described. Ambulatory treatment with minimal morbidity and a rapid return to normal activity is desirable. Bascom's operation fulfils these requirements. This paper describes the operative technique and results of treatment. Some 218 patients of mean age 27 years were treated as day cases. The mean duration of symptoms was 2.4 years. Sixty-eight per cent of patients had complex disease with more than two midline pits and/or a lateral discharging sinus. One hundred and eighty-three patients (84 per cent) were operated on under local anaesthesia. Ninety-five per cent of patients have been followed up for a mean of 12.1 (range 1-60) months. All except one midline wound healed. Lateral wounds healed after a mean of 4.0 (range 1-15) weeks. Postoperative complications were few, including bleeding in 4 per cent and abscess formation treated by reopening the lateral incision in 6 per cent. Twenty-one patients (10 per cent) have had recurrence and have needed reoperation. Bascom's operation is simple and results in considerable financial savings with minimal social disruption and an early return to work. Recurrent disease is no more frequent than after other treatments.


The Relationship Between Risk Factors and Alcohol and Marijuana Use Outcomes Among Concurrent Users: A Comprehensive Examination of Protective Behavioral Strategies.
Among college samples, both alcohol and marijuana protective behavioral strategies (PBS) have been shown to mediate the effects of known risk factors (i.e., sex, age at substance use onset, college substance use beliefs, substance use motives, and impulsivity-like traits) on alcohol and marijuana outcomes. However, it is unknown whether PBS use would operate similarly for both substances among concurrent users. The present study examined which risk factors relate to alcohol/marijuana outcomes via alcohol/marijuana PBS use among a large group of concurrent alcohol/marijuana users. Participants were college students who consumed both alcohol and marijuana at least 1 day in the previous month (n = 2,034; 69.08% female). Across both substances, PBS use significantly mediated the effects of sex (women reported higher PBS use), age at first use (having an older age at first use was associated with more PBS use), and college substance use beliefs (higher beliefs was associated with lower PBS use). Unique to alcohol outcomes, alcohol PBS use significantly mediated the effects of negative urgency, social motives, and enhancement motives (all associated with lower PBS use). Unique to marijuana outcomes, marijuana PBS use mediated the effects of coping, expansion (both associated with lower PBS use), and conformity motives (associated with more PBS use). Our results suggest that PBS for both alcohol and marijuana can help explain why some risk factors are associated with alcohol/marijuana outcomes. Taken together, PBS use seems to be an important intervention target for alcohol/marijuana concurrent users.


[Is pancreatectomy with resection of the retro-pancreatic vessels for cancer justified?].
Tumoural invasion of the retropancreatic vessels and particularly of the superior mesentericoportal vein confluence (SMPV) is often considered as a contraindication to resection of malignant tumours of the pancreas. The aim of this retrospective study is to report a series of 20 patients and to demonstrate that resection of the vessels supposed to be involved is justified when it is the only barrier to a complete tumoural resection. Twenty patients, 11 men and nine women (mean age: 61.7 years) underwent a right (n = 14), left (n = 2) or total (n = 4) pancreatic resection for pancreatic adenocarcinoma (n = 19) or cystadenocarcinoma (n = 1) associated with partial resection of SMPV (n = 17), inferior vena cava (n = 1), right hepatic artery (n = 1) and common hepatic artery (n = 1). The veins were reconstructed in all cases by end to end anastomosis and the arteries by direct suture in one patient and venous or artery graft in two patients. Tumoural invasion was histologically present in the vascular wall in nine patients, in the perivascular area in six and negative in five. The in-hospital mortality was nil. One patient had an early venous thrombosis of the repaired SMPV which was reoperated and treated with success by desobstruction and venous graft. The 3-year actuarial survival rate was 16%. Segmental venous resection of the SMPV confluence can be performed safely. Localised invasion of the vascular wall, considered as the only obstacle for a complete tumoural resection, is not associated with a poor prognosis. In case of tight adhesions between tumour and SMPV (inflammatory or tumoural) the venous resection may be included in a deliberate surgical strategy. On the other hand, total obstruction of SMPV, extrapancreatic tumoural extension, tumoural invasion of superior mesenteric artery or coeliac trunk are contraindications to pancreatic resection.


Prevalence and impact of Streptococcus pneumoniae in adult cystic fibrosis patients: a retrospective chart review and capsular serotyping study.
Cystic fibrosis (CF) is a genetic disease characterized by complex polymicrobial communities within the lower respiratory tract. S. pneumoniae, while a well-defined pathogen in the general population, has rarely been identified in CF. Furthermore, prevalence studies on Pneumococcus in CF have predominantly focused on the infant and pediatric populations, and outcome data is lacking. Through a review of our comprehensive clinical and microbiologic database from a single adult CF center in Canada from 1978-2013 we sought to determine the incidence, prevalence, serotype and clinical impact of Pneumococcus in adults with CF. Only fifteen of 318 adult CF patients (5%) were ever found to have transient Pneumococcus colonization, and none developed persistent infection although length of carriage varied. As all isolates were stored, capsular serotyping could be performed using a multiplex PCR panel. Capsular serotyping revealed a varied distribution of several serotypes within these isolates. Lung function testing at time of incident Pneumococcus isolation was compared with values before and after isolation and showed no significant reduction in spirometry values, nor was there an increased need for rescue antibacterial therapy. Within our center, incident Pneumococcus infection is neither common, associated with a disproportionate clinical deterioration nor results in chronic infection.


The impact of hepatic steatosis on portal hypertension.
Studies in animal models have suggested that hepatic steatosis impacts on portal pressure, potentially by inducing liver sinusoidal endothelial dysfunction and thereby increasing intrahepatic resistance. Thus, we aimed to evaluate the impact of hepatic steatosis on hepatic venous pressure gradient (HVPG) in patients with chronic liver disease. 261 patients undergoing simultaneous HVPG measurements and controlled attenuation parameter (CAP)-based steatosis assessment were included in this retrospective study. The majority of patients had cirrhosis (n = 205; 78.5%) and n = 191 (73.2%) had clinically significant portal hypertension (CSPH; HVPG≥10mmHg). Hepatic steatosis (S1/2/3; CAP ≥248dB/m) was present in n = 102 (39.1%). Overall, HVPG was comparable between patients with vs. without hepatic steatosis (15.5±7.5 vs. 14.8±7.7mmHg; p = 0.465). Neither in patients with HVPG (<6mmHg; p = 0.371) nor in patients with mild portal hypertension (HVPG 6-9mmHg; p = 0.716) or CSPH (HVPG≥10mmHg; p = 0.311) any correlation between CAP and HVPG was found. Interestingly, in patients with liver fibrosis F2/3, there was a negative correlation between CAP and HVPG (Pearson's ρ:-0.522; p≤0.001). In multivariate analysis, higher CAP was an independent 'protective' factor for the presence of CSPH (odds ratio [OR] per 10dB/m: 0.92, 95% confidence interval [CI]:0.85-1.00; p = 0.045), while liver stiffness was associated with the presence of CSPH (OR per kPa: 1.26, 95%CI: 1.17-1.36; p≤0.001). In 78 patients, in whom liver biopsy was performed, HVPG was neither correlated with percentage of histological steatosis (p = 0.714) nor with histological steatosis grade (p = 0.957). Hepatic steatosis, as assessed by CAP and liver histology, did not impact on HVPG in our cohort comprising a high proportion of patients with advanced chronic liver disease. However, high CAP values (i.e. pronounced hepatic steatosis) might lead to overestimation of liver fibrosis by 'artificially' increasing transient elastography-based liver stiffness measurements.


An improvised mould for vaginoplasty.
The use of a simple, improvised mould for vaginoplasty is described. It is made of rubber foam rolled over a winged infusion cannula and covered over by condoms. It offers a number of advantages over conventional moulds, the main ones being its simplicity of construction and its ease of application and removal from the neo-vagina.


[A search for mutations in the DIA1 gene in case of hereditary methemoglobinemia type I in the iakut population].
In the patients with enzymopenic hereditary methemoglobinemia type I, a disease widely distributed on the territory of Yakutia, a search for the mutations in exons 3 and 4 of the DIA1 gene encoding NADH-cytochrome b5 reductase was carried out. It was shown that Yakut patients have none of three missence mutations, Arg57Gln, Leu72Pro, and Val105Met, described in case of this disease in the neighboring populations, Chinese and Japanese, inhabiting the territories south of Yakutia.


Ligand-induced rapid redistribution of lysosomes is temporally distinct from endosome translocation.
When many ligands bind to cell-surface receptors, ligand-receptor complexes are internalized via clathrin coated pits by a process called receptor-mediated endocytosis. The cytoplasmic fate of ligands internalized within endocytic vesicles or endosomes is variable. For example, maternal immunoglobulins are transported through the cytoplasm of neonatal intestinal epithelial cells and are exocytosed at the basolateral surface. However, other ligands are degraded as a result of their delivery to the lysosomal compartment of cells. Although the translocation of endosomes to the Golgi region in the cell centre seems to be a general phenomenon presumably coupled to ligand degradation by lysosomes and endosomes and lysosomes undergo saltatory movements within the cytoplasm, the spatial control of interaction between the two structures is not understood. To address this problem we have begun to examine the spatial and temporal intracellular distribution of endosomes and lysosomes. Utilizing a new fluorescent microscopic approach, we have now been able simultaneously to visualize endosome and lysosome populations in living cells. Our results suggest that a specific relocation of lysosomes is rapidly induced upon binding of different types of ligands to the cell surface; this migration of lysosomes to the Golgi region of the cell precedes the translocation of endosomes into the same area.


A comparison of internal fixation and prosthetic replacement in the treatment of displaced subcapital fractures.
This paper presents a retrospective review of 348 operations performed for subcapital fractures of the neck of the femur. A similar proportion of satisfactory results was obtained with internal fixation and prosthetic replacement. The mortality was higher in those treated by prosthetic replacement and careful selection of patients for this treatment is required.


Identification and functional characterization of the putative polysaccharide biosynthesis protein (CapD) of Enterococcus faecium U0317.
Most bacterial species produce capsular polysaccharides that contribute to disease pathogenesis through evasion of the host innate immune system and are also involved in inhibiting leukocyte killing. In the present study, we identified a gene in Enterococcus faecium U0317 with homologies to the polysaccharide biosynthesis protein CapD that is made up of 336 amino acids and putatively catalyzes N-linked glycosylation. A capD deletion mutant was constructed and complemented by homologous recombination that was confirmed by PCR and sequencing. The mutant revealed different growth behavior and morphological changes compared to wild-type by scanning electron microscopy, also the capD mutant showed a strong hydrophobicity and that was reversed in the reconstituted mutant. For further characterization and functional analyses, in-vitro cell culture and in-vivo a mouse infection models were used. Antibodies directed against alpha lipotechoic acid (αLTA) and the peptidyl-prolyl cis-trans isomerase (αPpiC), effectively mediated the opsonophagocytic killing in the capD knock-out mutant, while this activity was not observed in the wild-type and reconstituted mutant. By comparison more than 2-fold decrease was seen in mutant colonization and adherence to both T24 and Caco2 cells. However, a significant higher bacterial colonization was observed in capD mutant during bacteremia in the animal model, while virulence in a mouse UTI (urinary tract infection) model, there were no obvious differences. Further studies are needed to elucidate the function of capsular polysaccharide synthesis gene clusters and its involvement in the disease pathogenesis with the aim to develop targeted therapies to treat multidrug-resistant E. faecium infections.


Input-specific synaptic depression shapes temporal integration in mouse visual cortex.
Efficient sensory processing requires the nervous system to adjust to ongoing features of the environment. In primary visual cortex (V1), neuronal activity strongly depends on recent stimulus history. Existing models can explain effects of prolonged stimulus presentation but remain insufficient for explaining effects observed after shorter durations commonly encountered under natural conditions. We investigated the mechanisms driving adaptation in response to brief (100 ms) stimuli in L2/3 V1 neurons by performing in vivo whole-cell recordings to measure membrane potential and synaptic inputs. We find that rapid adaptation is generated by stimulus-specific suppression of excitatory and inhibitory synaptic inputs. Targeted optogenetic experiments reveal that these synaptic effects are due to input-specific short-term depression of transmission between layers 4 and 2/3. Thus, brief stimulus presentation engages a distinct adaptation mechanism from that previously reported in response to prolonged stimuli, enabling flexible control of sensory encoding across a wide range of timescales.


The impact of false-positive newborn screening results on families: a qualitative study.
Newborn screening leads to improved treatment and disease outcomes, but false-positive newborn screening results may cause distress for parents. The purpose of this study was to describe the experiences of families who receive a false-positive newborn screening result in an attempt to discover ways to help improve the newborn screening communication process for families. This was a qualitative study using two methods of data collection: in-depth, semistructured interviews and focus groups. Participants (N = 27) were parents whose children (ages 6-16 months) underwent follow-up testing after newborn screening and whose follow-up test results indicated that the newborn screening result was a false-positive. Our analysis found that parents who have a false-positive newborn screening result experience five distinct stages. Most parents did not report long-term negative impacts of the experience, but some experienced some residual worry. Participants described effective provider communication as key in mitigating stress. Some parents identified the experience as leading to positive outcomes. Identifying best practices for communication between the health care providers and parents is an essential component in improving the newborn screening process. Further research is needed to discover best practices for communication to minimize potential harm and maximize the benefits of newborn screening.


Polypharmacy and older people--the GP perspective.
It is well known that problems with compliance rise exponentially when more that 4 drugs are prescribed. The rising use of prescription medicine forces the GP to balance the benefit of evidence group-based appropriate drug use against the problems arising when medication is given to older people and to consider different approaches when evaluating evidence of risk and benefit for the individual. Old people are facing a considerable risk of adverse drug reactions and recent initiatives, including the Continuous Medical Educational Efforts Programme, address issues of inappropriate prescribing practices. The authors recommend and present tools enabling the GP to focus on 'the core prescribing situation'. The logistics to optimise medication including compliance, the use of modern IT and better collaboration and communication between primary and secondary care are in focus. Since medication review is recommended at every encounter, and time consuming comprehensive follow-up will be demanded, 'polypharmacy consultations' surely will be built into GP contracts in the future. The authors state that a number of pharmacological regimens for older people are outperformed by non-pharmacological treatment alternatives involving competent individualised counselling and public provision of easy (transportation) possibilities for joining centres offering staff and equipment for physical and social activity (including basal aids for hearing and sight).


Structural modifications due to interface chemistry at metal-nitride interfaces.
Based on accurate first principles density functional theory (DFT) calculations, an unusual phenomenon of interfacial structural modifications, due to the interface chemistry influence is identified at two metal-nitride interfaces with strong metal-nitrogen affinity, Al/TiN {111} and Al/VN {111} interfaces. It is shown that at such interfaces, a faulted stacking structure is energetically preferred on the Al side of the interface. And both intrinsic and extrinsic stacking fault energies in the vicinity Al layers are negligibly small. However, such phenomenon does not occur in Pt/TiN and Pt/VN interfaces because of the weak Pt-N affinity. Corresponding to structural energies of metal-nitride interfaces, the linear elasticity analysis predicts characteristics of interfacial misfit dislocations at metal-nitride interfaces.


Simple centromere, complex kinetochore: linking spindle microtubules and centromeric DNA in budding yeast.
Although the budding yeast centromere is extremely short (125 bp) compared to those of other eukaryotes, the kinetochore that assembles on this DNA displays a rich molecular complexity. Here, we describe recent advances in our understanding of kinetochore function in budding yeast and present a model describing the attachment that is formed between spindle microtubules and centromeric DNA. This analysis may provide general principles for kinetochore function and regulation.


Different definitions of multimorbidity and their effect on prevalence rates: a retrospective study in German general practices.
Multimorbidity is common among general practice patients and increases a general practitioner's (GP's) workload. But the extent of multimorbidity may depend on its definition and whether a time delimiter is included in the definition or not. The aims of the study were (1) to compare practice prevalence rates yielded by different models of multimorbidity, (2) to determine how a time delimiter influences the prevalence rates and (3) to assess the effects of multimorbidity on the number of direct and indirect patient contacts as an indicator of doctors' workload. This retrospective observational study used electronic medical records from 142 German general practices, covering 13 years from 1994 to 2007. The four models of multimorbidity ranged from a simple definition, requiring only two diseases, to an advanced definition requiring at least three chronic conditions. We also included a time delimiter for the definition of multimorbidity. Descriptive statistics, such as means and correlation coefficients, were applied. The annual percentage of multimorbid primary care patients ranged between 84% (simple model) and 16% (advanced model) and between 74% and 13% if a time delimiter was included. Multimorbid patients had about twice as many contacts annually than the remainder. The number of contacts were different for each model, but the ratio remained similar. The number of contacts correlated moderately with patient age (r = 0.35). The correlation between age and multimorbidity increased from model to model up to 0.28 while the correlations between contacts and multimorbidity varied around 0.2 in all four models. Multimorbidity seems to be less prevalent in primary care practices than usually estimated if advanced definitions of multimorbidity and a temporal delimiter are applied. Although multimorbidity increases in any model a doctor's workload, it is especially the older person with multiple chronic diseases who is a challenge for the GP.


Cell polarity: new PARtners for Cdc42 and Rac.
Three recent papers have reported the surprising finding that Cdc42 and Rac1, both of which are known to be involved in maintaining apico-basolateral polarity of epithelial cells, can each bind to a protein complex containing Par6, Par3 and PKCzeta. These latter three proteins have known functions in the polarization of mother cells before asymmetric cell division in Caenorhabditis elegans. These latest results indicate a possible link between the mechanisms used to maintain cell polarity and to set up asymmetric cell divisions.


Two-year outcome of coping skills training, group support and information for spouses of alcoholics: a randomized controlled trial.
To evaluate three different intervention programmes for spouses of alcoholics. 39 spouses of alcoholics (36 women and 3 men) with an average age of 47 years (ranging from 23 to 60 years) were randomly assigned to one of the three interventions: Coping Skills Training, Group Support, and Information. Follow-up interviews were conducted 12 and 24 months after completing the programme. Coping Behaviour Scale, Symptom Checklist 90 (SCL-90), Hardship Scale and AUDIT at admission and at follow-up were compared. 38 of the 39 spouses completed the 24-month follow-up examination. Improvements of coping behaviour, psychiatric symptoms and hardship noted at the 12-month follow-up examination were still evident in all groups at the 24-month follow-up examination. The three groups scored similarly at 24 months on the four scales. A post hoc examination of subjects with SCL-90 scores above general population means, showed less improvement in the Information group than the two therapy groups combined (P < 0.05).


Matrix metalloproteinase-13 predominates over matrix metalloproteinase-8 as the functional interstitial collagenase in mouse atheromata.
Substantial evidence implicates interstitial collagenases of the matrix metalloproteinase (MMP) family in plaque rupture and fatal thrombosis. Understanding the compensatory mechanisms that may influence the expression of these enzymes and their functions, therefore, has important clinical implications. This study assessed in mice the relative effect of the 2 principal mouse collagenases on collagen content and other plaque characteristics. Apolipoprotein E-deficient (apoE(-/-)) mice, MMP-13(-/-) apoE(-/-), MMP-8(-/-) apoE(-/-) double knockout mice, and MMP-13(-/-) MMP-8(-/-) apoE(-/-) triple knockout mice consumed a high-cholesterol diet for 10 and 24 weeks. Both double knockout and triple knockout mice showed comparable atherosclerotic lesion formation compared with apoE(-/-) controls. Analysis of aortic root sections indicated that lesions of MMP-8/MMP-13-deficient and MMP-13-deficient mice accumulate more fibrillar collagen than apoE(-/-) controls and MMP-8(-/-) apoE(-/-) double knockout. We further tested the relative effect of MMPs on plaque collagenolysis using in situ zymography. MMP-13 deletion alone abrogated collagenolytic activity in lesions, indicating a predominant role for MMP-13 in this process. MMP-13 and MMP-13/MMP-8 deficiency did not alter macrophage content but associated with reduced accumulation of smooth muscle cells. These results show that among MMP interstitial collagenases in mice, MMP-13 prevails over MMP-8 in collagen degradation in atheromata. These findings provide a rationale for the identification and selective targeting a predominant collagenase for modulating key aspects of plaque structure considered critical in clinical complications, although they do not translate directly to human lesions, which also contain MMP-1.


Dorsal Hump Reduction and Osteotomies.
This article discusses the technique for planning, executing, and troubleshooting dorsal hump reduction for the cosmetic rhinoplasty patient. Details of the discussion include the necessary elements of the preoperative consultation with the patient, the specific instruments used to effectively and reproducibly create osteotomies, the anatomic and patient variables that require special attention, and the necessary measures to guard against potential complications.


Nano-SiO2 reinforced alginate-chitosan-gelatin nanocomposite hydrogels with improved physicochemical properties and biological activity.
Alginate (Alg) hydrogels possess desirable advantages for application in tissue engineering; however, they are limited by their weak mechanical properties, poor chronical stability in phosphate buffered saline, and absence of mammalian cell recognition sites, severely restricting their biomedical applications. To overcome these limitations, we integrated Alg hydrogels with nano-silica (SiO2) to produce nano-SiO2 reinforced Alg-chitosan-gelatin nanocomposite hydrogels (Alg/SiO2-CHI-GA NCH) for biomedical purposes, utilizing Chitosan (CHI) and gelatin (GA) in an alternate electrostatic adsorption. Specifically, we investigated the regulatory and promotional effects of the nano-SiO2 on the morphological structure, mechanical properties, thermal stability, rheological properties, swelling, biodegradability, biomineralization and cytocompatibility of the resultant Alg/SiO2-CHI-GA NCH. The experimental findings demonstrate that the constructed Alg/SiO2-CHI-GA NCH exhibited uniform morphology and a regular structure. Upon freeze-drying, the internal cross-sections of the NCH exhibited a honeycomb porous structure. Furthermore, the physicochemical properties and biological activities of the prepared Alg/SiO2-CHI-GA NCH were regulated to some extent by nano-SiO2 content. Notably, nano-SiO2 inclusion enhanced the attachment and viability of MG63 and MC3T3-E1 cells and induced three-dimensional cell growth in ALG/SiO2-CHI-GA NCH. Among the fabricated NCH, Alg/SiO2-CHI-GA NCH with 0.5% and 1.0% (w/v) nano-SiO2 exhibited significant proliferative activity, which is attributable to their high porosity and uniform cell adhesion. Furthermore, the alkaline phosphatase activity in the cells gradually increased with increasing of nano-SiO2 amount, indicating the favorable effect of nano-SiO2 on the osteogenic differentiation of MG63 and MC3T3-E1 cells. Our study findings provide a comprehensive foundation for the structural- and property-related limitations of Alg hydrogels in biomedicine, thereby expanding their potential applications in tissue engineering.


Autism: current theories regarding its pathogenesis and implications for rational pharmacotherapy.
Autism is a pervasive developmental disorder that is aetiologically and clinically heterogeneous. Twin and family-genetic studies provide evidence for strong genetic components. An international consortium using an affected sib pair strategy has found a promising linkage to a region on chromosome 7. In 10 to 15% of cases autism is due to associated medical conditions that affect normal brain functioning. Postmortem studies on small case series report cellular abnormalities in the limbic system and cerebellum. Between 10 and 20% of individuals with autism have macrocephalia, which is in accordance with magnetic resonance imaging (MRI) findings of an increased total brain tissue volume and enlargement most prominent in the occipital and parietal lobes. The most robust and well replicated neurobiological abnormality in autism is an elevation of whole blood serotonin (5-hydroxytryptamine; 5-HT) found in over 30% of patients. Pharmacological interventions with serotonin reuptake inhibitors or with atypical neuroleptics that block both dopamine (D2) and serotonin (5-HT2) receptors seem to offer clinical benefit and merit further study.


A systematic review of the protective effects of silymarin/silibinin against doxorubicin-induced cardiotoxicity.
Although doxorubicin chemotherapy is commonly applied for treating different malignant tumors, cardiotoxicity induced by this chemotherapeutic agent restricts its clinical use. The use of silymarin/silibinin may mitigate the doxorubicin-induced cardiac adverse effects. For this aim, the potential cardioprotective effects of silymarin/silibinin against the doxorubicin-induced cardiotoxicity were systematically reviewed. In this study, we performed a systematic search in accordance with PRISMA guideline for identifying all relevant studies on "the role of silymarin/silibinin against doxorubicin-induced cardiotoxicity" in different electronic databases up to June 2022. Sixty-one articles were obtained and screened based on the predefined inclusion and exclusion criteria. Thirteen eligible papers were finally included in this review. According to the echocardiographic and electrocardiographic findings, the doxorubicin-treated groups presented a significant reduction in ejection fraction, tissue Doppler peak mitral annulus systolic velocity, and fractional shortening as well as bradycardia, prolongation of QT and QRS interval. However, these echocardiographic abnormalities were obviously improved in the silymarin plus doxorubicin groups. As well, the doxorubicin administration led to induce histopathological and biochemical changes in the cardiac cells/tissue; in contrast, the silymarin/silibinin co-administration could mitigate these induced alterations (for most of the cases). According to the findings, it was found that the co-administration of silymarin/silibinin alleviates the doxorubicin-induced cardiac adverse effects. Silymarin/silibinin exerts its cardioprotective effects via antioxidant, anti-inflammatory, anti-apoptotic activities, and other mechanisms.


Should informed consent for cancer treatment include a discussion about hospital outcome disparities?
Several studies have found disparities in the outcome of medical procedures across different hospitals--better outcomes have been associated with higher procedure volume. An Institute of Medicine workshop found such a "volume-outcome relationship" for two types of cancer surgery: resection of the pancreas and esophagus (http://www.iom.edu/?id=31508). This debate examines whether physicians have an ethical obligation to inform patients of hospital outcome disparities for these cancers.


Indications of an adaptive response in C57BL mice pre-exposed in vivo to low doses of ionizing radiation.
C57BL/6 mice were whole-body irradiated with 5 cGy/day ('adapting dose') on 4 consecutive days and their spleens removed on day 1, 3, 7, 12, 19 or 26 after the last irradiation. In vitro UV-light-induced unscheduled DNA synthesis (UDS) and mitomycin C (MMC)-induced sister-chromatid exchanges (SCEs) were scored in lymphocytes (UV-light and MMC being the 'challenging agents'), yielding higher UDS values and lower frequencies of induced SCEs than cells of non-adapted animals. On day 12 this effect could only be seen in half, on days 19 and 26 in none of the performed experiments. The results support those published by Tuschl et al. (1980, 1983) and Liu et al. (1987), showing that it is possible to induce the adaptive response in vivo.


Communicating HIV/AIDS through African American churches in North Carolina: implications and recommendations for HIV/AIDS faith-based programs.
This study explores HIV/AIDS communication strategies among church leaders at predominately African American churches in a metropolitan city and surrounding areas in North Carolina. The church leaders contacted for the study are members of an interfaith-based HIV/AIDS program. The researchers used semi-standardized interviews to explore how church leaders address HIV/AIDS in the church. The findings indicate that the seven church leaders who participated in the study use a variety of communication channels to disseminate HIV/AIDS information for congregants and their surrounding communities, which include both interpersonal and mass media.


Comparative affinities of the epimeric reaction-intermediate analogs 2- and 4-carboxy-D-arabinitol 1,5-bisphosphate for spinach ribulose 1,5-bisphosphate carboxylase.
2-Carboxy-3-keto-D-arabinitol 1,5-bisphosphate is a tightly bound intermediate of the carboxylase reaction of ribulosebisphosphate carboxylase/oxygenase. Two stereoisomers of an analog of this intermediate, 2-carboxy-D-arabinitol 1,5-bisphosphate (2CABP) and 4-carboxy-D-arabinitol 1,5-bisphosphate (4CABP), are exceptionally potent, virtually irreversible inhibitors of the spinach carboxylase, presumably due to their structural similarity to the gem-diol (hydrated carbonyl at C-3) form of the intermediate. Incubation of the enzyme with either leads to time-dependent loss of activity. Inhibition of the enzyme is biphasic, with initial dissociation constants of 0.47 and 0.19 microM and maximal rates for tight complex formation of 2.2 and 1.8 min-1 for 2CABP and 4CABP, respectively. These values give second-order rate constants for tight complex formation of 7.8 x 10(4) and 1.6 x 10(5) M-1 s-1. To determine the overall affinity of the spinach enzyme for 2CABP and 4CABP, the release rates were determined by dual isotope exchange (3H-inhibitor complex with free 14C-inhibitor). Exchange half-times of 1.82 and 530 days were observed for 4CABP and 2CABP, respectively. Overall dissociation constants of 28 pM (2.8 x 10(-11) M) and 190 fM (1.9 x 10(-13) M) were calculated from these dissociation rates together with the rates of association determined by inactivation kinetics. The difference in affinity of 2CABP and 4CABP corresponds to 2.9 kcal/mol, presumably reflecting the difference in interaction of the enzyme with the two hydroxyls of the intermediate's gem-diol. The kinetic behavior of these two inhibitors, in particular the rather slow maximal rates of association, are consistent with the expected behavior of analogs of a labile intermediate of an enzymic reaction that is far more stable than a transition state.


Stabilisation of plasma substrate concentrations: A model for conducting metabolic studies.
Metabolic studies involving changes in plasma substrate concentrations are frequently carried out after an overnight fast. This condition, however, is a transition between the post-prandial period and the beginning of starvation, and thus is associated with rapid changes in the plasma concentration of many substrates. Such alterations might interfere with the interpretation of modifications in plasma concentrations resulting from experimental manipulations. Infusion of glucose at a rate of 250 mg kg(-1) h(-1) for 1h and subsequently at 162 mg kg(-1) h(-1) together with amino-acids at 50 mg kg(-1) h(-1) is used to stabilise the plasma concentration of most substrates within 3 h, a condition which is maintained for the subsequent 5 h or more. This study offers a model which is more suitable for many metabolic investigations than overnight fasting and which takes little time or expense to prepare.


Ion transport and enteric nervous system (ENS) in rat rectal colon: mechanical stretch causes electrogenic Cl-secretion via plexus Meissner and amiloride-sensitive electrogenic Na-absorption is not affected by intramural neurons.
The initial phase of in vitro experiments in Ussing-type chambers on large intestine is characterized by short-circuit currents (ISC) declining from high starting values to a lower plateau within 0.5 h. The origin of this "initial ISC-transient" was investigated by ISC measurements on partially stripped segments of rat rectal colon. Transport was pre-stimulated in vivo by keeping animals in barbiturate-anesthesia for 5 h prior to tissue preparation. This procedure caused by endogenous aldosterone-liberation amiloride-sensitive Na-absorption to become the predominant electrogenic transport. The initial ISC-transient was abolished by tetrodotoxin (TTX, 1 microM), indicating a neuronal mediation of this phenomenon. In order to identify the transport which was subject to neuronal control, the amiloride-sensitive Na-absorption was measured during electrical field stimulation (bipolar rectangular pulses: 5 Hz, 1 ms, +/- 6 mA). There was no difference to unstimulated controls. In contrast, the initial ISC-transient was dependent on Cl in the bath following Michaelis-Menten-kinetics (KM = 20 mM) and could be prevented by 10 microM serosal bumetanide. Then, initial filling of the Ussing-chamber was imitated during the course of the experiment by removal and immediate re-addition of the bathing fluid. This procedure caused ISC-changes of similar appearance as the initial ISC-transient. To verify that indeed mechanical stretch is the sensory stimulus triggering the initial ISC-transient, the effect of small pressure oscillations was studied. This also produced an ISC-transient which was TTX-sensitive and was abolished after removal of the submucosal plexus Meissner by total stripping.(ABSTRACT TRUNCATED AT 250 WORDS)


In situ observation of fracture behavior of canine cortical bone under bending.
Cortical bone provides many important body functions and maintains the rigidness and elasticity of bone. A common failure mode for bone structure is fracture under a bending force. In the current study, the fracture behavior of canine cortical bone under three-point bending was observed in situ using an atomic force microscope (AFM), a scanning electron microscope (SEM), and an optical microscope to examine the fracture process in detail. Nanoindentation was carried out to determine the elastic modulus and hardness of different building blocks of the canine cortical bone. The results have shown that the special structure of Haversian systems has significant effects on directing crack propagation. Although Haversian systems contain previously believed weak points, and micro-cracks initiate within Haversian systems, our findings have demonstrated that macro-cracks typically form around the boundaries of Haversian systems, i.e. the cement lines. Micro-cracks that developed inside Haversian systems have the functions of absorbing and dissipating energy and slow down on expanding when interstitial tissue cannot hold any more pressure, then plastic deformation and fracture occur.


The protective effects of selenium on cadmium-induced oxidative stress and apoptosis via mitochondria pathway in mice kidney.
Selenium, an essential trace element, showed the significant protective effects against kidney damage induced by some heavy metals. Our previous research have found that the protection effects of selenium on ROS mediated-apoptosis by mitochondria dysfunction in cadmium (Cd)-induced LLC-PK1 cells. The present study as a continuation of our earlier one to investigate the protective effects and mechanism of selenium on Cd-induced apoptosis of kidney in vivo. Cadmium exposure increased the production of reactive oxygen species (ROS) and altered the levels of oxidative stress related biomarkers in kidney tissue. A concomitant by the loss of mitochondrial membrane potential, cytochrome c release and regulation of VDAC, Bcl-2 and Bax were observed. Apoptotic nature of cell death is confirmed by activation of caspase-3, which is also supported by histological examination. During the process, selenium played a beneficial role against Cd-induced renal damage. Pretreatment with selenium partially blocked Cd-induced ROS generation, inhibited Cd induced mitochondrial membrane potential collapse, prevented cytochrome c release, inhibited caspase activation and changed the level of VDAC, Bcl-2 and Bax. Combining all, results suggest that selenium has an ability to inhibit mitochondrial apoptotic pathway in oxidative stress mediated kidney dysfunction caused by cadmium.


Determination of trace impurities in high-purity zirconium dioxide by inductively coupled plasma atomic emission spectrometry using microwave-assisted digestion and wavelet transform-based correction procedure.
This paper describes a rapid, accurate and precise method for the determination of trace Fe, Hf, Mn, Na, Si and Ti in high-purity zirconium dioxide (ZrO2) powders by inductively coupled plasma atomic emission spectrometry (ICP-AES). The samples were dissolved by a microwave-assisted digestion system. Four different digestion programs with various reagents were tested. It was found that using a mixture of sulfuric acid (H2SO4) and ammonium sulfate ((NH4)2SO4), the total sample dissolution time was 30 min, much shorter than that required for conventional digestion in an opening system. The determination of almost all of the target analytes suffered from spectral interferences, since Zr shows a line-rich atomic emission spectrometry. The wavelet transform (WT), a recently developed mathematical technique was applied to the correction of spectral interference, and more accurate and precise results were obtained, compared with traditional off-peak background correction procedure. Experimental work revealed that a high Zr concentration would result in a significant decrease in peak height of the analyte lines, which was corrected by standard addition method. The performance of the developed method was evaluated by using synthetic samples. The recoveries were in the range of 87-112% and relative standard deviation was within 1.1-3.4%. The detection limits (3sigma) for Fe, Hf, Mn, Na, Si and Ti were found to be 1.2, 13.3, 1.0, 4.5, 5.8 and 2.0 microg g(-1), respectively. The results showed that with the microwave-assisted digestion and the WT correction, the detection limits have improved by a factor of about 5 for Fe, 4 for Mn and Ti, 3 for Si, and 2 for Hf and Na, respectively, in comparison with conventional open-system digestion and off-peak correction. The proposed technique was applied to the analysis of trace elements above-mentioned in three types of ZrO2 powders.


Prevalence and mortality of acute lung injury and ARDS after lung resection.
To describe the frequency and outcome of patients with acute lung injury (ALI) and ARDS who require mechanical ventilation (MV) after lung resection, and to analyze preoperative and perioperative variables associated with mortality. We retrospectively reviewed the case records of all patients who underwent lung resection and acquired ALI and/or ARDS and required invasive MV and ICU admission at a tertiary-care cancer center from January 1, 2002, to December 31, 2004. Preoperative and perioperative information including ICU-specific variables and outcome data were analyzed. Data are presented as median (range). During the study period, 2,039 patients underwent a total of 2,192 lung resections. ALI/ARDS developed in 50 patients (2.45%). The prevalence of ALI/ARDS by procedure was as follows: pneumonectomy, 7.9% (10 cases in 126 procedures); lobectomy/bilobectomy, 2.96% (31 cases in 1,047 procedures); and sublobar resection, 0.88% (9 cases in 1,019 procedures). There were 28 men (56%) and 22 women (44%). Median age was 68.5 years (range, 44 to 88 days). Median time of presentation to the ICU with ALI/ARDS following surgery was 4 days (range, 1 to 22 days). Median ICU length of stay was 10 days (range, 2 to 43 days), and median hospital LOS was 26.5 days (range, 6 to 93 days). During hospitalization, 20 of the 50 patients (40%) died: 16 in the ICU and 4 after ICU discharge. The mortality rate was highest after pneumonectomy (50%), followed by lobectomy (42%) and sublobar resections (22%). Although increased age was associated with a higher ICU mortality, none of the preoperative and perioperative variables were significantly associated with hospital mortality. There was a marginally significant association between mortality and time of presentation to the ICU after surgery (p = 0.06). Our results confirm that ALI/ARDS after lung resection is associated with a high mortality in patients who require invasive MV and ICU care.


Uterine rupture and dehiscence: ten-year review and case-control study.
Previous cesarean section, oxytocin administration, and fetal macrosomia increase the risk of uterine rupture or dehiscence (URD). All 25,718 deliveries at Riverside Regional Medical Center from January 1990 to June 2000 were reviewed to describe complications and identify risk factors for URD. Eleven uterine ruptures and 10 dehiscences occurred during this period (0.08%). One maternal death (5%) and three neonatal deaths (14%) occurred. Other complications included intrapartum nonreassuring fetal status (67%), 5-minute Apgar score < 7 (52%), maternal blood transfusion (24%), neonatal hypoxic injury (14%), hysterectomy (14%), and endometritis (10%). Uterine rupture/dehiscence was independently associated with fetal weight > or = 4,000 g, nonreassuring fetal status, use of oxytocin, and previous cesarean delivery; internal fetal monitoring reduced the risk of URD. To reduce the risk of URD, a delivery plan should include assessment of cesarean history and fetal macrosomia,judicious use of oxytocin, and intrapartum monitoring for nonreassuring fetal status.


Unique spatiotemporal activation pattern of Cdc42 by Gef1 and Scd1 promotes different events during cytokinesis.
The Rho-family GTPase Cdc42 regulates cell polarity and localizes to the cell division site. Cdc42 is activated by guanine nucleotide exchange factors (GEFs). We report that Cdc42 promotes cytokinesis via a unique spatiotemporal activation pattern due to the distinct action of its GEFs, Gef1 and Scd1, in fission yeast. Before cytokinetic ring constriction, Cdc42 activation, is Gef1 dependent, and after ring constriction, it is Scd1 dependent. Gef1 localizes to the actomyosin ring immediately after ring assembly and promotes timely onset of ring constriction. Gef1 is required for proper actin organization during cytokinesis, distribution of type V myosin Myo52 to the division site, and timely recruitment of septum protein Bgs1. In contrast, Scd1 localizes to the broader region of ingressing membrane during cytokinetic furrowing. Scd1 promotes normal septum formation, andscd1Δcells display aberrant septa with reduced Bgs1 localization. Thus we define unique roles of the GEFs Gef1 and Scd1 in the regulation of distinct events during cytokinesis. Gef1 localizes first to the cytokinetic ring and promotes timely constriction, whereas Scd1 localizes later to the ingressing membrane and promotes septum formation. Our findings are consistent with reports that complexity in GTPase signaling patterns enables exquisite precision over the control of cellular processes.


Identification of vesicle properties that enhance the antitumour activity of liposomal vincristine against murine L1210 leukemia.
The influence of vesicle lipid composition, size and drug-to-lipid ratio on the antitumour activity of liposomal vincristine was assessed in the murine L1210 ascitic leukemia model. A pH gradient-dependent entrapment procedure was used to encapsulate vincristine and allowed such vesicle properties to be independently varied. Free vincristine delivered i.v. at the maximum tolerated dose (2.0 mg/kg) resulted in a 27.8% increase in the life span (ILS) of mice inoculated i.p. with L1210 cells. Encapsulation of the drug in egg phosphatidylcholine/cholesterol vesicles did not significantly increase the antitumour efficacy of vincristine (ILS, 38.9%). In contrast, administration of vincristine entrapped in vesicles composed of distearoylphosphatidylcholine (DSPC)/cholesterol resulted in ILS values as high as 133%. This enhanced antitumour activity of the DSPC/cholesterol formulations was sensitive to the size of the liposomes; increasing the vesicle size from 100 nm to 1 micron decreased the ILS from 133.3% to 55.6% at a drug dose of 2.0 mg/kg. Decreasing the drug-to-lipid ratio from 0.1:1 to 0.05:1 (w/w) had negligible effects on the activity of liposomal vincristine; however, a further decrease in the drug-to-lipid ratio to 0.01:1 (w/w) decreased the antitumour potency at all drug doses studied. Pharmacology studies indicated that the antitumour activities of free and various liposomal forms of vincristine correlated well with the residence time of the drug in the circulation. These studies indicate that efforts to enhance the therapeutic activity of vincristine through liposome encapsulation must address not only the circulation lifetime of the vesicle systems but also the capacity of the liposomes to retain entrapped drug in vivo.


Analysis of factors affecting nonalcoholic fatty liver disease in Chinese steel workers and risk assessment studies.
The global incidence of nonalcoholic fatty liver disease (NAFLD) is rapidly escalating, positioning it as a principal public health challenge with significant implications for population well-being. Given its status as a cornerstone of China's economic structure, the steel industry employs a substantial workforce, consequently bringing associated health issues under increasing scrutiny. Establishing a risk assessment model for NAFLD within steelworkers aids in disease risk stratification among this demographic, thereby facilitating early intervention measures to protect the health of this significant populace. Use of cross-sectional studies. A total of 3328 steelworkers who underwent occupational health evaluations between January and September 2017 were included in this study. Hepatic steatosis was uniformly diagnosed via abdominal ultrasound. Influential factors were pinpointed using chi-square (χ2) tests and unconditional logistic regression analysis, with model inclusion variables identified by pertinent literature. Assessment models encompassing logistic regression, random forest, and XGBoost were constructed, and their effectiveness was juxtaposed in terms of accuracy, area under the curve (AUC), and F1 score. Subsequently, a scoring system for NAFLD risk was established, premised on the optimal model. The findings indicated that sex, overweight, obesity, hyperuricemia, dyslipidemia, occupational dust exposure, and ALT serve as risk factors for NAFLD in steelworkers, with corresponding odds ratios (OR, 95% confidence interval (CI)) of 0.672 (0.487-0.928), 4.971 (3.981-6.207), 16.887 (12.99-21.953), 2.124 (1.77-2.548), 2.315 (1.63-3.288), 1.254 (1.014-1.551), and 3.629 (2.705-4.869), respectively. The sensitivity of the three models was reported as 0.607, 0.680 and 0.564, respectively, while the precision was 0.708, 0.643, and 0.701, respectively. The AUC measurements were 0.839, 0.839, and 0.832, and the Brier scores were 0.150, 0.153, and 0.155, respectively. The F1 score results were 0.654, 0.661, and 0.625, with log loss measures at 0.460, 0.661, and 0.564, respectively. R2 values were reported as 0.789, 0.771, and 0.778, respectively. Performance was comparable across all three models, with no significant differences observed. The NAFLD risk score system exhibited exceptional risk detection capabilities with an established cutoff value of 86. The study identified sex, BMI, dyslipidemia, hyperuricemia, occupational dust exposure, and ALT as significant risk factors for NAFLD among steelworkers. The traditional logistic regression model proved equally effective as the random forest and XGBoost models in assessing NAFLD risk. The optimal cutoff value for risk assessment was determined to be 86. This study provides clinicians with a visually accessible risk stratification approach to gauge the propensity for NAFLD in steelworkers, thereby aiding early identification and intervention among those at risk.


Evaluating the biological safety on mice at 16 T static magnetic field with 700 MHz radio-frequency electromagnetic field.
This study evaluated the associated biological effects of radio-frequency (RF) exposure at 16 T magnetic resonance imaging (MRI) on mice health. A total of 48 healthy 8-week-old male C57BL/6 mice were investigated. A 16 T high static magnetic field (HiSMF) was generated by a superconducting magnet, and a radiofrequency (RF) electromagnetic field for hydrogen resonance at 16 T (700 MHz) was transmitted via a homemade RF system. The mice were exposed inside the 16 T HiSMF with the 700 MHz RF field for 60 min, and the body weight, organ coefficients, histomorphology of major organs, and blood indices were analyzed for the basal state of the mice on day 0 and day 14. The Heat Shock Protein 70 (HSP70), cyclooxygenase 2 (COX2), and interleukin- 6 (IL-6) were used to evaluate the thermal effects on the brain. Locomotor activity, the open field test, tail suspension test, forced swimming test, and grip strength test were used to assess the behavioral characteristics of the mice. The 16 T HiSMF with 700 MHz RF electromagnetic field exposure had no significant effects on body weight, organ coefficients, or histomorphology of major organs in the mice. On day 0, the expressions of HSP70 and COX2 in the brain were increased by 16 T HiSMF with 700 MHz RF electromagnetic field exposure. However, the expression of HSP70, COX2, and IL-6 had no significant difference compared with the sham group on day 14. Compared with the sham groups, the meancorpuscularvolume (MCV) on day 0 and the total protein (TP) on day 14 were increased significantly, whereas the other blood indices did not change significantly. The 16 T HiSMF with 700 MHz RF electromagnetic field exposure caused the mice to briefly circle tightly but had no effect on other behavioral indicators. In summary, 16 T HiSMF with 700 MHz RF electromagnetic field exposure for 60 min did not have severe effects on mice.


Bridging the gap: the village health worker as the cornerstone of the primary health care model.
The Alma-Ata Conference in 1978 reiterated the goal of 'Health for All by the Year 2000' and declared primary health care (PHC) the vehicle through which this lofty goal was to be achieved. National governments were recognized as responsible agents for developing and implementing PHC plans. The emphasis on community-oriented delivery of care places great importance on the village health worker (VHW), the individual who serves as the 'interface' between the formal health care system and the community. Despite the acknowledged importance of the VHW role, the question of whether the PHC model, with the VHW as the cornerstone can be effectively implemented without a "fundamental shift of wealth and power" (Sidel) continues to be asked. This paper examines the evolution and current status of the VHW role in Costa Rica, Nicaragua and Columbia, three Latin American nations which have adopted the PHC model. The authors discuss the evolution of the PHC model in each country with particular reference to the occurrence or non-occurrence of fundamental changes in the society. The conclude that the primary determiner of successful implementation of PHC is a national commitment to PHC including recognition of the importance of community participation which is best achieved through reliance on the village health worker.


Neighborhood stressors, perceived neighborhood quality, and child mental health in New York City.
This paper examines the relationship between neighborhood stressors, stressors related to parenting, children's evaluations of neighborhood quality, and child depression. One hundred and twenty-six young adolescents in three disadvantaged New York City neighborhoods completed surveys on neighborhood quality and child depression and the children's parents provided information on their mental health and parenting practices. Neighborhood stressors were measured through observations by outside raters. Children's evaluations of neighborhood quality were positively related to their assessments of depression and there was an unexpected positive association between the neighborhood drug/alcohol stressor and child depression. Moreover, the relationship between the drug/alcohol stressor and child depression was fully mediated by the children's assessments of neighborhood quality. Future directions for neighborhood and health research are discussed.


A monoclonal antibody specific to the non-epitope region of hepatitis B virus preS1 contributes to more effective HBV detection.
The hepatitis B virus (HBV) preS1 protein is divided into an epitope region and a non-epitope region based on the respective antigenicities of these regions. Most of the antibodies that are currently used to detect the large surface protein of HBV (HBV LHB) are specific to the epitope region of preS1, which may contribute to the false negative results of HBV LHB detection assays. Here, we established a mouse monoclonal antibody (mAb) that could improve the efficiency of HBV LHB detection. The HBV preS1 protein was expressed in E. coli strain BL21 and used to screen hybridoma clones. HBV preS1-specific mAb was produced by immunizing mice with a chemically synthesized peptide antigen derived from the non-epitope region of HBV preS1. The mAb was characterized by ELISA, Western blot, and immunocytochemistry and was subsequently used in serum sample tests. Based on in silico B cell epitope predictions, the HBV preS1 aa 91-117 peptide was synthesized as an antigen. Recombinant HBV preS1 was expressed in E. coli and identified by SDS-PAGE. The mAb D8 (IgG2b) recognized the recombinant preS1 protein in both ELISA and Western blot assays and also recognized the preS1 protein expressed in plasmid-transfected HepG2.2.15 cells by immunocytochemistry. Furthermore, the D8 mAb, which is specific for the non-epitope region of preS1, contributed to the improved sensitivity and specificity of HBV detection. We established an mAb that is specific to the non-epitope region of HBV preS1 and improved the detection of HBV LHB in an ELISA assay. This mAb could help increase the accuracy of the clinical measurement of preS1.


A new approach to assessing the obstetrician's posture and movement during an instrumental forceps delivery.
The number of deliveries by forceps decreases significantly in favour of the vacuum. Now, when the use of forceps is necessary, physicians less experimented with this procedure are likely to induce serious and preventable perineal or foetal injuries. Training therefore becomes essential. However, there are no clear recommendations on the technique to perform a delivery by forceps, namely the body posture and gesture to adopt. Our goal is then to provide a protocol that can help to determine if there is an optimal technique to perform a delivery by forceps. We will include voluntary participants whose level of experience and type of practice differ. We will propose to record their postures and gestures using an optoelectronic motion analysis system during a forceps delivery simulated on a mannequin. We will also measure the traction force produced by the subject on the forceps using force platforms and technical markers placed on the forceps. We will then perform a principal component analysis to look for similar motion patterns. We plan to analyse about fifty participants (25 seniors and 25 juniors). Our hypothesis is that the realism of the simulation will be deemed satisfactory by the participants, that the experimental conditions will not modify their gestures, and that the degree of experience will result in different techniques. A better knowledge on the posture and gesture to adopt to realise a forceps delivery should improve the safety of women and new-borns. The results of this study could also be a valuable contribution for the training of obstetricians.


Altitude as a risk factor for the development of hypospadias. Geographical cluster distribution analysis in South America.
Hypospadias is the most common congenital anomaly affecting the genitals. It has been established as a multifactorial disease with increasing prevalence. Many risk factors have been identified such as prematurity, birth weight, mother's age, and exposure to endocrine disruptors. In recent decades multiple authors using surveillance systems have described an increase in prevalence of hypospadias, but most of the published literature comes from developed countries in Europe and North America and few of the published studies have involved cluster analysis. Few large-scale studies have been performed addressing the effect of altitude and other geographical aspects on the development of hypospadias. Acknowledging this limitation, we present novel results of a multinational spatial scan statistical analysis over a 30-year period in South America and an altitude analysis of hypospadias distribution on a continent level. A retrospective review was performed of the Latin American collaborative study of congenital malformations (ECLAMC). A total of 4,020,384 newborns was surveyed between 1982 and December 2011 in all participating centers. We selected all patients with hypospadias. All degrees of clinical severity were included in the analysis. Each participating center was geographically identified with its coordinates and altitude above sea level. A spatial scan statistical analysis was performed using Kulldorf's methodology and a prevalence trend analysis over time in centers below and above 2000 m. During the study period we found 159 hospitals in six different countries (Colombia, Bolivia, Brazil, Argentina, Chile, and Uruguay) with 4,537 cases of hypospadias and a global prevalence rate of 11.3/10,000 newborns. Trend analysis showed that centers below 2000 m had an increasing trend with an average of 10/10,000 newborns as opposed to those centers above 2000 m that showed a reducing trend with an average prevalence of 7.8 (p = 0.1246). We identified clusters with significant increases of prevalence in five centers along the coast at an average altitude of 219.8 m above sea level (p > 0.0000). Reduction in prevalence was found in clusters located in two centers on the Andes mountains. Altitude of 2,000 m was associated with hypospadias (Figure), with an OR 0.59 (0.5-0.69). There are ethnic arguments to support our results supported by protective polymorphism distribution in high lands. Altitude above 2,000 m is suggested to have a protective effect for hypospadias. Specific clusters have been identified with increased risk for hypospadias. Environmental risk factors in these areas need to be further studied given the association seen between altitude and the distribution of more severe cases.


Salidroside reduces neuropathology in Alzheimer's disease models by targeting NRF2/SIRT3 pathway.
Neurite dystrophy is a pathologic hallmark of Alzheimer's disease (AD). However, drug discovery targeting neurite protection in AD remains largely unexplored. Aβ-induced neurite and mitochondrial damage assays were used to evaluate Aβ toxicity and the neuroprotective efficacy of a natural compound salidroside (SAL). The 5×FAD transgenic mouse model of AD was used to study the neuroprotective function of SAL. To verify the direct target of SAL, we used surface plasmon resonance and cellular thermal shift assays to analyze the drug-protein interaction. SAL ameliorates Aβ-mediated neurite damage in cell culture. We further reveal that SAL represses mitochondrial damage in neurites by promoting mitophagy and maintaining mitochondrial homeostasis, dependent on an NAD-dependent deacetylase SIRT3. In AD mice, SAL protects neurite morphology, mitigates Aβ pathology, and improves cognitive function, which are all SIRT3-dependent. Notably, SAL directly binds to transcription factor NRF2, inhibits its degradation by blocking its interaction with KEAP1 ubiquitin ligase, and then advances NRF2-mediated SIRT3 transcription. Overall, we demonstrate that SAL, a potential anti-aging drug candidate, attenuates AD pathology by targeting NRF2/SIRT3 pathway for mitochondrial and neurite protection. Drug discovery strategies focusing on SAL may thus provide promising therapeutics for AD.


The purification and preliminary characterization of UMP synthase from human placenta.
Orotate phosphoribosyltransferase (EC 184.108.40.206) and orotidine 5'-monophosphate decarboxylase (EC 18.104.22.168) are the final two of six enzymatic steps required in the de novo biosynthesis of uridine 5'-monophosphate (UMP). Earlier work of this laboratory showed that, in the mouse Ehrlich ascites carcinoma, both of these enzymatic activities were contained on the single multifunctional polypeptide chain, UMP synthase. We report here that the placenta provided an available human source for UMP synthase with 40-fold higher orotate phosphoribosyltransferase and orotidine 5'-monophosphate decarboxylase specific activities than erythrocytes, a human source previously used by others. By using the placenta as a source of UMP synthase and by developing a novel purification procedure different from that used in the purification of UMP synthase from the Ehrlich ascites carcinoma (the only other homogeneous preparation of a mammalian UMP synthase), we achieved the purification of human UMP synthase to apparent homogeneity. This represents the first publication to homogeneity of UMP synthase from a human source as well as from a source other than malignant cell lines. Contrary to earlier reports human placental UMP synthase was found to be a multifunctional protein containing both enzymatic activities on a single polypeptide of 51,000 molecular weight. Preliminary characterization of the human placental UMP synthase showed it to be similar to UMP synthase from the Ehrlich ascites carcinoma in subunit molecular weight, native molecular weight, isozyme pattern (although not absolute pI values), pH optima of enzymatic activities, and kinetic constants for orotidine 5'-monophosphate (Km) and 6-azauridine 5'-monophosphate (Ki) at the decarboxylase site.


Neurotuberculosis: a review.
Tuberculosis is still a major cause of serious illness in many parts of the world. CNS involvement has frequently been found secondary to tuberculosis elsewhere in the body, particularly the lungs. The disease manifests itself as meningitis, tuberculoma and/or spinal tuberculosis. The presence of tuberculosis elsewhere in the body favors the diagnosis although its absence does not exclude it. While tuberculous meningitis is a disease of childhood, tuberculomas and spinal tuberculosis are invariably an adult manifestation. The great majority of patients with neurotuberculosis are diagnosed and treated early because of characteristic clinical, imaging, and CSF findings. Clinical response to antituberculous therapy in all forms of neurotuberculosis is excellent if the diagnosis is made early before irreversible neurological deficit is established.


The prevalence of angina pectoris and abnormal coronary arteriograms in severe aortic valvular disease.
In order to relate the frequency of angina pectoris to associated coronary artery disease, 66 consecutive patients with severe aortic valvular disease were studied by cardiac catheterization, including coronary angiography. Angina pectoris was found in 63 per cent of patients with predominant aortic stenosis, 62 per cent with aortic regurgitation, and 67 per cent with mixed disease. Associated coronary artery disease (larger than or equal to 75 per cent luminal stenosis) ranged from 14 to 28 per cent and averaged 20 per cent for the entire group of 66 patients. Only one patient without angina had significant coronary artery stenosis. Our studies indicate that angina pectoris is equally common in all forms of severe aortic valve disease and is usually not associated with significant coronary artery disease.


Optimized workflow for pulmonary vein isolation using 90-W radiofrequency applications: a comparative study.
Ninety-watt applications are more sensitive to catheter instability and produce lesions that are shallower and smaller in diameter than 50-W applications. These characteristics were considered for the development of a combined (90-50 W) pulmonary vein isolation (PVI) strategy which was prospectively compared to a 50 W-only ablation index (AI)-guided PVI strategy. One hundred fifty consecutive paroxysmal AF patients underwent PVI under general anesthesia using CARTO. In the first 75 patients, PVI was performed with a combined (90-50 W) strategy using the QDOT-MICRO catheter in a temperature-controlled mode. This strategy consisted of 90 W-4 s applications on the posterior LA wall (at sites of catheter stability and expectedly thin atrial tissue) with an interlesion distance (ILD) ≤ 4 mm and 50-W applications elsewhere (at sites of catheter instability or expectedly thick atrial tissue) with ILD < 6 mm. In the subsequent 75 patients, PVI was performed with a 50 W-only AI-guided strategy using the SmartTouch-SF catheter in a power-controlled mode. Both groups of patients had similar clinical characteristics and LA dimensions (123.1 ± 24.9 ml vs 119 ± 26.8 ml, P = 0.33). Total procedural times (61 [56-70] vs 65 [60-75] min, P = 0.12), first-pass PVI (82.6 vs 80%, P = 0.81), acute PV reconnection (0 vs 6.6%, P = 0.05), and 1-year SR maintenance (93.3 vs 90.6%, P = 0.57) rates were also similar in both groups of patients. There were no complications in the combined (90-50 W) group while only 2 groin hematomas were reported in the 50 W group. In paroxysmal AF patients, a combined (90-50 W) strategy for PVI did not improve safety, efficiency, or effectiveness compared to a 50 W-only AI-guided strategy.


Comparison of proteome alterations during aging in the temporal lobe of humans and rhesus macaques.
Rhesus macaques are widely used as animal models for studies of the nervous system; however, it is unknown whether the alterations in the protein profile of the brain during aging are conserved between humans and rhesus macaques. In this study, temporal cortex samples from old and young humans (84 vs. 34 years, respectively) or rhesus macaques (20 vs. 6 years, respectively) were subjected to tandem mass tag-labeled proteomic analysis followed by bioinformatic analysis. A total of 3861 homologous pairs of proteins were identified during the aging process. The conservatively upregulated proteins (n = 190) were involved mainly in extracellular matrix (ECM), focal adhesion and coagulation; while, the conservatively downregulated proteins (n = 56) were enriched in ribosome. Network analysis showed that these conservatively regulated proteins interacted with each other with respect to protein synthesis and cytoskeleton-ECM connection. Many proteins in the focal adhesion, blood clotting, complement and coagulation, and cytoplasmic ribosomal protein pathways were regulated in the same direction in human and macaque; while, proteins involved in oligodendrocyte specification and differentiation pathways were downregulated during human aging, and many proteins in the electron transport chain pathway showed differences in the altered expression profiles. Data are available via ProteomeXchange with identifier PXD013597. Our findings suggest similarities in some changes in brain protein profiles during aging both in humans and macaques, although other changes are unique to only one of these species.


[Multimodal Imaging of the Choroidal Melanoma, with Differential Diagnosis, Therapy (Radiation Planning) and Follow-up].
Imaging of intraocular tumors is multimodal, multi-purpose, and in continuous development. Therefore, imaging is indispensable for the detection, diagnosis, therapy and monitoring of intraocular tumours. A broad spectrum of imaging procedures is available for diagnostic testing and follow-up. This includes colour image acquisition, infrared imaging, autofluorescence imaging, fluorescence and indocyanine green angiography, optical coherence tomography (OCT) and sonography (US). In this article, the various investigations and their benefits are described using individual examples for the differential diagnosis of choroidal melanoma and retinal vascular tumours located in the fundus periphery.


Immunohistochemical analysis of Bax and AIF in colorectal tumors.
This study had three aims. The first was to determine whether Bax (Bcl-2-associated X protein) and AIF (apoptosis-inducing factor) are expressed in tissue sections of colorectal tumors. The second was to ascertain whether there is any difference in Bax and AIF expression between colorectal polyps, adenomas, and carcinomas. The third aim was to determine whether there is any difference between Bax and AIF expression in colorectal tumors. Bax and AIF expression were determined in 20 hyperplastic polyps (HPs), 20 adenomatous polyps (APs), 20 samples of colorectal carcinomas, and 20 samples of normal mucosa by immunohistochemical methods. The staining level of Bax and AIF in adenomas and carcinomas was significantly higher than in normal tissues (P<0.01). There was also a significant difference between HPs and APs (P<0.01). The level of Bax and AIF in carcinomas was higher than in adenomas, and the difference was of statistical significance (P<0.01). This study may be of interest in future research to confirm whether the changed expression of Bax and/or AIF between benign and malignant tumors can provide valuable information for the evaluation of colon or other tumors.


Modeling neurodevelopmental disorders using human pluripotent stem cells.
Neurodevelopmental disorders (NDs) are impairments that affect the development and growth of the brain and the central nervous system during embryonic and early postnatal life. Genetically manipulated animals have contributed greatly to the advancement of ND research, but many of them differ considerably from the human phenotype. Cellular in vitro models are also valuable, but the availability of human neuronal cells is limited and their lifespan in culture is short. Human pluripotent stem cells (hPSCs), including embryonic stem cells and induced pluripotent stem cells, comprise a powerful tool for studying developmentally regulated diseases, including NDs. We reviewed all recent studies in which hPSCs were used as in vitro models for diseases and syndromes characterized by impairment of neurogenesis or synaptogenesis leading to intellectual disability and delayed neurodevelopment. We analyzed their methodology and results, focusing on the data obtained following in vitro neural differentiation and gene expression and profiling of the derived neurons. Electrophysiological recording of action potentials, synaptic currents and response to neurotransmitters is pivotal for validation of the neuronal fate as well as for assessing phenotypic dysfunctions linked to the disease in question. We therefore focused on the studies which included electrophysiological recordings on the in vitro-derived neurons. Finally, we addressed specific issues that are critical for the advancement of this area of research, specifically in providing a reliable human pre-clinical research model and drug screening platform.


Endothelial dysfunction: causes and consequences in patients with diabetes mellitus.
Vascular endothelium plays a major role in maintaining cardiovascular homeostasis. Nitric oxide is the most powerful vasodilating compound. Diabetes disrupts endothelial integrity through an increased oxidative stress. Recent evidence indicates that there is a strong interaction between diabetes, the secretory proteins of adipocytes, called adipokines, and endothelium. Endothelial dysfunction may precede the development of overt DM, and a prolonged and repeated exposure to postprandial hyperglycemia may play an important role in the development of atherosclerosis, even in those who have normal fasting plasma glucose levels.


Comparison of Lupus Nephritis Induction Treatments in a Hispanic Population: A Single-center Cohort Analysis.
To evaluate response rates in an adult lupus nephritis (LN) cohort in Mexico City, Mexico. We analyzed 165 patients with biopsy-proven LN histological International Society of Nephrology/Renal Pathology Society classes III, IV, or V, distributed by treatment drug in 3 groups: mycophenolate mofetil (MMF; dosage > 2 g/day per 6 mos, n = 63), intravenous cyclophosphamide (IVC; 0.7 g/m(2) body surface area monthly per 6 pulses, n = 66), or azathioprine (AZA; dosage > 1.5 mg/kg/day per 6 mos, n = 36). Median followup was 31 ± 18 months. The primary endpoint was the proportion of patients achieving complete renal response (CR). Secondary endpoints included the proportion of patients achieving renal response (complete or partial), renal flare-free survival, doubling of serum creatinine, and progression to endstage renal disease (ESRD). MMF induction was superior to IVC (HR 2.00, 95% CI 1.23-3.25, p = 0.005) and AZA (HR 2.12, 95% CI 1.23-3.66, p = 0.007) in the primary endpoint. Censored CR rates at 6, 12, 24, and 36 months were 32.6%, 56.1%, 76.6%, and 94.1% for MMF; 24.2%, 34.4%, 57.9%, and 62.1% for IVC; and 8.4%, 39.8%, 49.7%, and 49.7% for AZA. MMF was also superior in renal response to treatment and renal flare-free survival outcomes. There were no differences between groups in doubling of serum creatinine or progression to ESRD. The induction treatment with MMF (HR 2.04, 95% CI 1.25-3.33, p = 0.005) and absence of vascular lesions on renal biopsy (HR 2.05, 95% CI 1.25-3.37, p = 0.004) were associated with CR, whereas proteinuria at the time of presentation was negatively associated with CR (HR 0.91, 95% CI 0.84-0.98, p = 0.013). MMF induction therapy is superior to IVC and AZA in patients with LN of Mexican-mestizo race.