Demographic Characteristics, Survival and Prognostic Factors of Early Breast Cancer Patients with Type 2 Diabetes Mellitus: A Hospital-Based Cohort Study
Objective: With increasing prevalence of type 2 diabetes mellitus and breast cancer in Iran, we aimed to search hospital registries of breast cancer patients to investigate type 2 diabetes mellitus association with survival outcomes of early breast cancer after adjustment of confounding factors. Methods: In a retrospective cohort study conducted from July 2003 to Feb 2014 and followed up until death or December 2016, female patients with early breast cancer who have been treated for the first time at the Cancer Institute of Iran, were divided to diabetic and non-diabetic groups. Primary and secondary outcomes were relapse free survival (RFS) and overall survival (OS). SPSS version 23 was used for analysis of data. Other variables included age, tumor stage, hormone receptor status, tumor subtype, and patient's body mass index (BMI). Result: From a total of 1021 patients, 218 (21.4%) had type 2 diabetes mellitus. Diabetic patients had a higher mean age (53.31 vs 47.00), higher mean BMI (31.13 vs 29.15), lower HER2 expression (20.8% vs 32.1%) and higher frequency of luminal A subtype (61.1% vs 51.0). Overall, after adjustment of other variables, diabetes status did not affect RFS or OS independently. However, in luminal A subgroup, patients with diabetes mellitus had significantly lower survival outcomes of OS (135.277 vs 154.701) and RFS (114.107 vs 133.612) as well as OS higher hazard ratio of 1.830 and RFS hazard ratio of 1.663 compared to non-diabetic patients. BMI, hormone receptor status and tumor stage significantly affected the survival of the patients. Conclusion: In the present study, in addition to known breast cancer risk factors, BMI and type 2 diabetes mellitus had an independent impact on survival of the patients, highlighting the importance of health issues such as obesity and diabetes suboptimal performance in the treatment outcomes of early breast cancer patients in Iran.


Analysis of the unfused tetanus course in fast motor units of the rat medial gastrocnemius muscle.
The course of unfused tetani with the sag effect in fast motor units of rat medial gastrocnemius was studied. The analysis of the course of successive contractions within these tetani showed that the high peak force at the beginning of tetanus before the sag resulted from temporary, very efficient sum mation of contractions at this phase, both in FF (fast fatigable) and FR (fast resistant to fatigue) units. The process of summation developed in spite of parallel shortening of the contraction and relaxation. The peak of tetanus force was visible on the average at the 2nd contraction in FF units and at the 5th contraction in FR units. After the tetanus peak the process of the efficient summation was completed and the force decreased what was visible as a sag. In the following part of the tetanus, mainly in FF units, the potentiation occurred and the force of successive contractions increased. The rise of force was visible in spite of shortening of the contraction time and was due to prolongation of the relaxation in this part of the tetanus. These observations indicated that the processes of the summation of successive contractions before sag and during the potentiation underwent different mechanisms discussed in this paper. Considerable release of Ca2+ ions from the sarcoplasmic reticulum was proposed as a possible mechanism responsible for a very efficient summation at the beginning of the tetanus whereas phosphorylation of regulatory light chain of myosin (RLC) in muscle fibers was considered as the reason of potentiation. Moreover, the present analysis revealed that previously found differences in tetani profiles between FF and FR units resulted from faster development of described changes in the course of contractions summating into the tetanus in FF motor units.


Metformin Plus Insulin for Preexisting Diabetes or Gestational Diabetes in Early Pregnancy: The MOMPOD Randomized Clinical Trial.
Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on a composite adverse neonatal outcome. This randomized clinical trial in 17 US centers enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation between April 2019 and November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was completed in May 2022. Metformin 1000 mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery. The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. Prespecified secondary outcomes included maternal hypoglycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy. Of the 831 participants randomized, 794 took at least 1 dose of the study agent and were included in the primary analysis (397 in the placebo group and 397 in the metformin group). Participants' mean (SD) age was 32.9 (5.6) years; 234 (29%) were Black, and 412 (52%) were Hispanic. The composite adverse neonatal outcome occurred in 280 (71%) of the metformin group and in 292 (74%) of the placebo group (adjusted odds ratio, 0.86 [95% CI 0.63-1.19]). The most commonly occurring events in the primary outcome in both groups were preterm birth, neonatal hypoglycemia, and delivery of a large-for-gestational-age infant. The study was halted at 75% accrual for futility in detecting a significant difference in the primary outcome. Prespecified secondary outcomes and subgroup analyses were similar between groups. Of individual components of the composite adverse neonatal outcome, metformin-exposed neonates had lower odds to be large for gestational age (adjusted odds ratio, 0.63 [95% CI, 0.46-0.86]) when compared with the placebo group. Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation. ClinicalTrials.gov Identifier: NCT02932475.


The effects of co-administration of butter on the absorption, metabolism and excretion of catechins in rats after oral administration of tea polyphenols.
In Southwest China, tea polyphenols are usually utilized by way of butter tea. Tea polyphenols inhibit the absorption and biosynthesis of fatty acids in vivo, but the effects of butter on the pharmacokinetics of tea polyphenols have drawn less concern. A rapid UHPLC-MS/MS method was used to quantitatively determine the catechins in the plasma, feces and bile of rats after the oral administration of tea polyphenol or its combination with butter. In comparison with the single tea polyphenol treatment, the maximum plasma concentrations (Cmax) of the free EGCG, EGC, EC, GCG, GC and ECG significantly decreased after the co-administration of butter. The mean residence times (MRT) of the free EGCG, EGC, EC, GC and ECG were also significantly prolonged. When the plasma samples were treated with β-glucuronidase and arylsulfatase, the pharmacokinetic parameters of the total catechins (free and conjugated forms) were not affected by the co-administration of butter. These results indicated that the total absorption of catechins was not affected by butter, but the metabolism of catechins had been changed. Furthermore, the fecal catechins were significantly increased by butter. The total fecal amount and excretion ratio of all catechins were increased highly. The biliary excretion of EGCG, EGC, EC, GCG and GC was significantly increased by the co-administration of butter. To sum up, the butter changed the metabolism of catechins in vivo by decreasing the plasma concentration of the free catechins but increasing the conjugated catechins.


The Role of KV7.3 in Regulating Osteoblast Maturation and Mineralization.
KCNQ (KV7) channels are voltage-gated potassium (KV) channels, and the function of KV7 channels in muscles, neurons, and sensory cells is well established. We confirmed that overall blockade of KV channels with tetraethylammonium augmented the mineralization of bone-marrow-derived human mesenchymal stem cells during osteogenic differentiation, and we determined that KV7.3 was expressed in MG-63 and Saos-2 cells at the mRNA and protein levels. In addition, functional KV7 currents were detected in MG-63 cells. Inhibition of KV7.3 by linopirdine or XE991 increased the matrix mineralization during osteoblast differentiation. This was confirmed by alkaline phosphatase, osteocalcin, and osterix in MG-63 cells, whereas the expression of Runx2 showed no significant change. The extracellular glutamate secreted by osteoblasts was also measured to investigate its effect on MG-63 osteoblast differentiation. Blockade of KV7.3 promoted the release of glutamate via the phosphorylation of extracellular signal-regulated kinase 1/2-mediated upregulation of synapsin, and induced the deposition of type 1 collagen. However, activation of KV7.3 by flupirtine did not produce notable changes in matrix mineralization during osteoblast differentiation. These results suggest that KV7.3 could be a novel regulator in osteoblast differentiation.


Synthesis and anticoagulant activity of bioisosteric sulfonic-Acid analogues of the antithrombin-binding pentasaccharide domain of heparin.
Two pentasaccharide sulfonic acids that were related to the antithrombin-binding domain of heparin were prepared, in which two or three primary sulfate esters were replaced by sodium-sulfonatomethyl moieties. The sulfonic-acid groups were formed on a monosaccharide level and the obtained carbohydrate sulfonic-acid esters were found to be excellent donors and acceptors in the glycosylation reactions. Throughout the synthesis, the hydroxy groups to be methylated were masked in the form of acetates and the hydroxy groups to be sulfated were masked with benzyl groups. The disulfonic-acid analogue was prepared in a [2+3] block synthesis by using a trisaccharide disulfonic acid as an acceptor and a glucuronide disaccharide as a donor. For the synthesis of the pentasaccharide trisulfonic acid, a more-efficient approach, which involved elongation of the trisaccharide acceptor with a non-oxidized precursor of the glucuronic acid followed by post-glycosidation oxidation at the tetrasaccharide level and a subsequent [1+4] coupling reaction, was elaborated. In vitro evaluation of the anticoagulant activity of these new sulfonic-acid derivatives revealed that the disulfonate analogue inhibited the blood-coagulation-proteinase factor Xa with outstanding efficacy; however, the introduction of the third sulfonic-acid moiety resulted in a notable decrease in the anti-Xa activity. The difference in the biological activity of the disulfonic- and trisulfonic-acid counterparts could be explained by the different conformation of their L-iduronic-acid residues.


Effects of Passiflora nitida Kunth leaf extract on digestive enzymes and high caloric diet in rats.
The present study investigated inhibition of pancreatic lipase and metabolic effects of high caloric diet in rats. The Passiflora nitida hydroethanol leaf extract (PNE) was used in in vitro assays or administered to rats to study dyslipidemia. Inhibition of lipase in vitro was studied by a spectrophotometric assay using orlistat as the positive control. The effects of PNE on reduction of postprandial triglyceride were studied by oral fat-overloading in rats. Metabolic alterations were induced using the cafeteria diet and 4 weeks post-treatment with PNE or orlistat and blood samples were collected and biochemical analyses were performed. Liver and retroperitoneal fat tissues were obtained to analyze weight and steatosis. IC50 (lg/mL) values for pancreatic lipase inhibition were 21.2 ± 0.8 and 0.1 ± 0.01 for PNE and orlistat, respectively. Oral administration of lipid emulsion resulted in postprandial hypertriglyceridemia at 3 h postadministration and when rats were then administered PNE and orlistat there was decreased of triglyceride levels by 15 % compared to control. Although the energy consumption by the cafeteria diet had been higher, there was no significant weight gain observed in the study groups. The cafeteria diet resulted in a significant increase of weight in the retroperitoneal fat and hypertriglyceridemia levels that could be significantly reduced by PNE and orlistat treatment. We hypothesized that PNE administration prevented the hypertriglyceridemia in rats with a high caloric diet, possibly owing to reduction of lipid absorption and pancreatic lipase inhibition.


Oropharyngeal pH monitoring for the detection of liquid and aerosolized supraesophageal gastric reflux.
The association between gastroesophageal reflux disease (GERD) and extraesophageal symptoms is poorly understood and difficult to document. pH monitoring in this group of patients has resulted in conflicting data due to lack of diagnostic sensitivity. Recently, a new sensitive pH device for detection of liquid and aerosolized droplets in the oropharynx (The Dx-pH Measurement System [Dx-pH]) has become available. Our hypothesis is that we will be able to improve our ability to identify and understand this group of patients with this device. The aim of this preliminary observation study was to compare the results of this new device to the standard esophageal and pharyngeal pH probes in a small group of patients with extraesophageal symptoms. Patients with suspected extraesophageal GER symptoms underwent traditional 24-hour esophago-pharyngeal pH monitoring (24pH) simultaneous with Dx-pH monitoring in the oropharynx. Tracings were reviewed for comparison and correlation between the two probes, with an event in the Dx-pH Probe being defined as a rapid drop >3 standard deviation from baseline. Fifteen patients (10 females, 5 males) with mean age of 57.5 years (range, 25-75) were studied. The predominant chief complaint included 12/15 chronic cough, 2/15 asthma; and 1/15 throat clearing. All Dx-pH events were preceded and associated with distal esophageal pH drops in a progressive ante grade manner. Ten patients had 1-13 abnormal oropharyngeal pH events as measured by Dx-pH monitoring with a total of 48 events. The median pH of reflux events had a statistically significant increase from 3.1 at the distal esophageal probe to 5.2 at the pharynx and 5.6 at the oropharynx, the latter being 80% higher than the distal esophageal probe (P<0.001). The percentage of acid events decreased in a cephalad manner from 66.7% at distal esophagus to 25% at the pharynx and only 6.25% at the oropharyngeal Dx-pH Probe, with the remaining events being weakly acidic. Dx-pH Probe is a new sensitive oropharyngeal pH device whose values correlate well with the gold-standard 24-hour pH device, and appears to accurately detect pH events that begin at the distal esophagus and travel upward to the oropharynx. This device suggests that supraesophageal events manifest themselves as rapid pH drops (>10%), which are likely not to be identified using the standard criteria of pH <4 due to the gradient of increasing pH from the lower esophagus to the oropharynx.


Dual-Inhibition of mTOR and Bcl-2 Enhances the Anti-tumor Effect of Everolimus against Renal Cell Carcinoma In Vitro and In Vivo.
Renal cell carcinoma (RCC) is the predominant type of kidney cancer. Mammalian target of rapamycin (mTOR) inhibitor everolimus is currently used as a second-line therapy for sorafenib or sunitinib-refractory metastatic RCC patients. The clinical limitation confronted during everolimus therapy is the onset of drug resistance that decreases the efficacy of the drug. Elevated level of anti-apoptotic Bcl-2 protein is proposed to be an emerging feedback loop for the acquired drug-resistance in various cancer types. In this study, the Bcl-2 inhibitor ABT-737 was used in combination with everolimus to enhance its anti-tumor effectiveness in everolimus-resistant RCC cell lines. Everolimus and ABT-737 combination synergistically led to a decrease in the proliferation of primary site A-498 and metastatic site Caki-1 RCC cell lines, which was accompanied by a reduction in protein levels of cell cycle and mTOR pathway proteins. In both RCC cell lines, everolimus-ABT-737 combination not only induced apoptosis, caspase and PARP-1 cleavage but also a decrease in Bcl-2 protein levels in parallel with a concomitant increase in Bim and Noxa levels. In order to confirm our in vitro findings, we have generated everolimus-resistant RenCa cell line (RenCares) to establish a RCC mouse xenograft model. Animals co-treated with everolimus and ABT-737 exhibited a complete suppression of tumor growth without any notable toxicity. This study thus proposes the everolimus-ABT-737 combination as a novel therapeutic strategy for the treatment of RCC to overcome the current clinical problem of everolimus resistance.


Calculation of control coefficients of metabolic pathways. A flux-oriented graph-theoretic approach.
Within the premises of the flux-oriented theory of Crabtree & Newsholme [(1987) Biochem. J. 247, 113-120], I have used a graph-theoretic approach for calculating the Control Coefficients of metabolic pathways. It is shown that a directed graph representing the control structure of a metabolic pathway can be constructed in a heuristic manner directly from the reaction diagram of the pathway, without the necessity of writing down the governing equations for the Control Coefficients. The Control Coefficients are derived from an analysis of the topology of the directed graph. The graph-theoretic approach also provides a visual framework for analysing the functional relationships of the individual enzymes. The control structures of the following pathways are examined here: (a) a simple unbranched pathway with four enzymes, (b) a simple branched pathway with three enzymes, and (c) a branched pathway with both carbon and energy (ATP) fluxes.


Digital photography for mapping Mohs micrographic surgery sections.
Instant photographic print images have been used to diagram tissue sections excised for Mohs micrographic surgery (MMS). This approach is limited by the size of the print image, the potential difficulty of writing on a glossy photo print, and the cost of film. We describe the use of digital photographic images as templates for making maps of tissue excised for MMS. Digital photographic images of patients undergoing MMS are downloaded to a computer and printed onto plain paper. A map of the tissue excised for MMS is drawn directly onto the digital print. Several methods of creating MMS maps using digital photographic print images are described. Advantages of using digital photographs in MMS include speed of producing images, low cost of materials, greater accuracy of depicting the MMS excision defect, and ease of correlating the MMS map to the patient for subsequent stages of excision.


Eukaryotic initiation factor 5A dephosphorylation is required for translational arrest in stationary phase cells.
The protein known as eIF5A (eukaryotic initiation factor 5A) has an elusive role in translation. It has a unique and essential hypusine modification at a conserved lysine residue in most eukaryotes. In addition, this protein is modified by phosphorylation with unknown functions. In the present study we show that a phosphorylated state of eIF5A predominates in exponentially growing Trypanosoma cruzi cells, and extensive dephosphorylation occurs in cells in stationary phase. Phosphorylation occurs mainly at Ser(2), as shown in yeast eIF5A. In addition, a novel phosphorylation site was identified at Tyr(21). In exponential cells, T. cruzi eIF5A is partially associated with polysomes, compatible with a proposed function as an elongation factor, and becomes relatively enriched in polysomal fractions in stationary phase. Overexpression of the wild-type eIF5A, or eIF5A with Ser(2) replaced by an aspartate residue, but not by alanine, increases the rate of cell proliferation and protein synthesis. However, the presence of an aspartate residue instead of Ser(2) is toxic for cells reaching the stationary phase, which show a less-pronounced protein synthesis arrest and a decreased amount of eIF5A in dense fractions of sucrose gradients. We conclude that eIF5A phosphorylation and dephosphorylation cycles regulate translation according to the growth conditions.


Inflammation and TCR signal strength determine the breadth of the T cell response in a bim-dependent manner.
Generating a diverse T cell memory population through vaccination is a promising strategy to overcome pathogen epitope variability and tolerance to tumor Ags. The effector and memory pool becomes broad in TCR diversity by recruiting high- and low-affinity T cells. We wanted to determine which factors dictate whether a memory T cell pool has a broad versus focused repertoire. We find that inflammation increases the magnitude of low- and high-affinity T cell responses equally well, arguing against a synergistic effect of TCR and inflammatory signals on T cell expansion. We dissect the differential effects of TCR signal strength and inflammation and demonstrate that they control effector T cell survival in a bim-dependent manner. Importantly, bim-dependent cell death is overcome with a high Ag dose in the context of an inflammatory environment. Our data define the framework for the generation of a broad T cell memory pool to inform future vaccine design.


Culture- and quantitative IS900 real-time PCR-based analysis of the persistence of Mycobacterium avium subsp. paratuberculosis in a controlled dairy cow farm environment.
The aim of this study was to monitor the persistence of Mycobacterium avium subsp. paratuberculosis in environmental samples taken from a Holstein farm with a long history of clinical paratuberculosis. A herd of 606 head was eradicated, and mechanical cleaning and disinfection with chloramine B with ammonium (4%) was carried out on the farm; in the surrounding areas (on the field and field midden) lime was applied. Environmental samples were collected before and over a period of 24 months after destocking. Only one sample out of 48 (2%) examined on the farm (originating from a waste pit and collected before destocking) was positive for M. avium subsp. paratuberculosis by cultivation on solid medium (Herrold's egg yolk medium). The results using real-time quantitative PCR (qPCR) showed that a total of 81% of environmental samples with an average mean M. avium subsp. paratuberculosis cell number of 3.09 × 10(3) were positive for M. avium subsp. paratuberculosis before destocking compared to 43% with an average mean M. avium subsp. paratuberculosis cell number of 5.86 × 10(2) after 24 months. M. avium subsp. paratuberculosis-positive samples were detected in the cattle barn as well as in the calf barn and surrounding areas. M. avium subsp. paratuberculosis was detected from different matrices: floor and instrument scrapings, sediment, or scraping from watering troughs, waste pits, and cobwebs. M. avium subsp. paratuberculosis DNA was also detected in soil and plants collected on the field midden and the field 24 months after destocking. Although the proportion of positive samples decreased from 64% to 23% over time, the numbers of M. avium subsp. paratuberculosis cells were comparable.


Bicruciate retaining total knee arthroplasty: current state and future promise.
Total knee arthroplasty (TKA) is a well-known surgical procedure performed to address end stage osteoarthritis. The main goal is to relieve pain, recover articular function and return to normal function as soon as possible. Over the years it is frequently performed in the elderly, but lately there is an increased demand in a younger and more active population. Up to 25% of patients feel dissatisfied about their TKA. The anterior cruciate ligament (ACL) is considered the main anteroposterior stabilizer of the knee; nevertheless the ACL is usually sacrificed during conventional TKA. Research shows this might be an unnecessary sacrifice in certain cases. The considerable dissatisfaction rate in mainly high-demanding patients, together with the literature reports on the importance of the ACL function, were the two main reasons for the development of bicruciate retaining (BCR) total knee arthroplasty. BCR TKA may offer superior knee kinematics and proprioception, through anterior cruciate ligament preservation, but requires a higher level of attention to obtain an accurate and precise component orientation to reach proper ligamentous balancing and restore the native knee biomechanics. Many surgeons abandoned its use due to its challenging technique and inconsistent results. Recent new BCR implant designs are promising. This systematic literature review aims to summarize the current state of BCR TKA and what to expect in the future.


Biodistribution, dosimetry and metabolism of 11beta-methoxy-(17alpha,20E/Z)-[123I]iodovinylestradiol in healthy women and breast cancer patients.
The biodistribution and dosimetry of the 20E and 20Z stereoisomers of 11 beta-methoxy-(17alpha,20)-[123I]iodovinylestradiol (MIVE) were evaluated in six healthy women. Tumor uptake and metabolism of the 20Z isomer were evaluated in 13 women referred after abnormal mammography or after discovery of a suspect mass at physical examination. The radiopharmaceuticals were prepared from their corresponding stannyl intermediates and administrated intravenously. Blood samples were drawn at different time intervals and urine was collected for up to 24 h. Metabolites were detected by radiochromatography. Tissue distribution was followed for up to 24 h by scintigraphic imaging. The dosimetry was computed according to the Medical Internal Radiation Dose scheme. The 20E and 20Z isomers exhibit similar biodistribution and dosimetry patterns. Chromatographic analysis of plasma samples of healthy volunteers and cancer patients, as well as in vitro plasma incubations, confirmed the in vivo stability of (20Z)-[123I]MIVE. Radioactivity was rapidly cleared from the blood by the liver and excreted through the gut, which received the highest radiation dose (0.211 mGy/MBq). The effective doses for the adult female and male phantom were 0.054 and 0.046 mSv/MBq, respectively. Among the 13 patients imaged with (20Z)-[123I]MIVE, 3 had fibrocystic disease with no focal uptake, 8 had good agreement with in vitro estrogen receptor determination and 2 were false-positive. The radiation dose after intravenous administration of 20E- or (20Z)-[123I]MIVE at imaging dose levels is within acceptable limits. There was a good correlation between uptake of (20Z)-[123I]MIVE and the presence of estrogen receptors in breast cancer patients.


Values of serum carcinoembryonic antigen and elastase 1 in diagnosis of pancreatic carcinoma.
Carcinoembryonic antigen (CEA) and elastase 1 in the serum were determined by enzyme immunoassay and radioimmunoassay, respectively, in 224 healthy subjects, 49 patients with pancreatitis, 53 patients with pancreatic carcinoma and 129 patients with cancer in other organs. The CEA concentrations in the serum were significantly higher in patients with pancreatic carcinoma than in those with pancreatitis, but this concentration was not a satisfactory indicator of pancreatic carcinoma localised to allow irradication by resection as it was raised in only 47% of the patients. High CEA concentrations were also slightly, but not significantly, more frequent in patients with cancer of the pancreatic body or tail, and unresectable cancer or cancer of more than 6.0 cm in longest diameter than in those with cancer of the pancreatic head, resectable cancer or cancer of less than 6.0 cm diameter. Serum elastase 1 was raised in only 42% of the patients with pancreatic carcinoma and could not be used to distinguish patients with pancreatic carcinoma from those with pancreatitis. In contrast with CEA, however, its concentration was abnormally high significantly more frequently in patients with cancer of less than 6.0 cm in longest diameter than in those with larger tumours. It was also raised slightly, but not significantly, more frequently in those with cancer of the pancreatic head and in patients with resectable cancer than in those with unresectable cancer. A combination of these two tests raised the diagnostic rate of pancreatic carcinoma to 77% without a remarkable decrease in the specificity for pancreatic carcinoma. In particular, it raised the diagnostic rates of cases of cancer of the pancreatic head, resectable cancer and cancers of less than 3.0 cm and 3.0-6.0 cm in longest diameter. Therefore, a combination of measurements of CEA and elastase 1 in the serum is very useful for early detection of pancreatic carcinoma.


Interplay between COVID-19 and Secukinumab treatment in Spondylarthritis patients during the omicron surge: a retrospective cohort study.
The objective of this retrospective cohort study was to assess the relationship between Corona Disease 2019 (COVID-19) and Secukinumab treatment in patients with Spondylarthritis (SpA) in China during the omicron surge. Researchers retrieved 1018 medical records of Secukinumab-treated patients between January 2020 and January 2023 from the West China Hospital of Sichuan University. Out of these, 190 SpA patients from the rheumatology clinic were selected for the study. Guided phone questionnaires were administered by research staff to collect baseline characteristics, SpA disease status, and COVID-19 clinical outcomes. Cohabitants served as the control group and provided COVID-19 related data. Of the 190 potential SpA patients, 122 (66%) completed the questionnaire via phone, along with 259 cohabitants. 84.4% of SpA patients were diagnosed with Ankylosing Spondylitis (AS), and 15.6% were diagnosed with Psoriatic Arthritis (PsA). The rate of SARS-CoV-2 infection was 83.6% in the Secukinumab group and 88.8% in the cohabitants control group, with no significant difference (OR = 0.684, CI 0.366-1.275). One instance of severe COVID-19 was observed in the Secukinumab group, while two were identified in the cohabitants control group. Patients in the Secukinumab group had less time with fever caused by COVID-19 (p = 0.004). Discontinuing Secukinumab after SARS-CoV-2 infection did not significantly affect the course of COVID-19 or worsen SpA status according to our data. Our study suggests that administering Secukinumab to SpA patients does not increase their susceptibility to contracting SARS-CoV-2, and may have a positive effect on the course of SARS-CoV-2 infection.


[Characterization of cold-adapted influenza strain A/HongKong/1/68/162/35 as a potential donor of attenuation and high reproduction].
Live and inactivated vaccines are currently produced using virus reassortants originating from various gene donors of internal proteins. Based on the pandemic virus A/Hong Kong/1/68 (H3N2), a cold-adapted thermo-sensitive strain A/Hong Kong/1/68/162/35 was generated. It is distinguished for its high reproductive capacity (9-9.5 lg EID50), and hemagglutinating activity (1:1024-1:2048). The strain has ts and ca phenotype: reproductive capacity at t = 39 degrees C is 1.0 lg EID50; at t = 26 degrees C, 8.5 lg EID50. A total of 16 mutations have emerged from comprehensive sequencing of the virus genome. Among them 10 mutations were located in the genes of polymerase complex and NP, with respective amino-acid substitutions. The stability of strain characteristics, such as attenuation to humans and high reproductive capacity, were confirmed by repeated sequencing of the genome after tenfold passing of the virus in chicken embryos. Reassortants of the strain A/Hong Kong/1/68/162/35 with the wild-type viruses have inherited useful features of donor virus.


Association of Folate Level in Blood with the Risk of Schizophrenia.
The aim of this study was to evaluate the association between folate level and the risk of schizophrenia and to identify possible biomarker for schizophrenia. Data about folate were extracted from 16 high quality studies. The association of folate level in blood and schizophrenia was evaluated using standardized mean difference (SMD) and 95% confidence interval (CI). Totally 1183 (52.1%) cases and 1089 (47.9%) controls were included in the current metaanalysis. Folate level in schizophrenia patients was significantly lower than that in healthy controls (SMD= -0.65; 95% CI: [-0.86, -0.45]; P <0.00001). Subgroup analysis demonstrated that the decreased folate level was found in both Asian and European patients (SMD=-0.86, P<0.00001; SMD=-0.44, P<0.00001, respectively), while there were no significant differences in patients from other areas (P>0.05). Sensitivity analysis confirmed that these results were stable and reliable, no publication bias existed in our meta-analysis based on Egger's and Begg's tests (P=0.48 and 0.30, respectively). These results suggest that decreased folate may be a risk factor for schizophrenia. More epidemiological and biochemistry studies are required to describe how folate or folate supplementation play roles in the progress of schizophrenia.


Toward a Universal μ-Agonist Template for Template-Based Alignment Modeling of Opioid Ligands.
Opioid ligands are a large group of G-protein-coupled receptor ligands possessing high structural diversity, along with complicated structure-activity relationships (SARs). To better understand their structural correlations as well as the related SARs, we developed the innovative template-based alignment modeling in our recent studies on a variety of opioid ligands. As previously reported, this approach showed promise but also with limitations, which was mainly attributed to the small size of morphine as a template. With this study, we set out to construct an artificial μ-agonist template to overcome this limitation. The newly constructed template contained a largely extended scaffold, along with a few special μ-features relevant to the μ-selectivity of opioid ligands. As demonstrated in this paper, the new template showed significantly improved efficacy in facilitating the alignment modeling of a wide variety of opioid ligands. This report comprises of two main parts. Part 1 discusses the general construction process and the structural features as well as a few typical examples of the template applications and Part 2 focuses on the template refinement and validation.


Monitoring of the folic acid supplementation program in the Netherlands.
In November of 1993, the Dutch government recommended daily folic acid supplementation of 0.4 or 0.5 mg for all women planning pregnancy, starting 4 weeks before conception until 8 weeks after. In 1995, a one-time mass media campaign was conducted, and due to this campaign, the use of folic acid in this recommended period increased from 4.8% in 1995 to 21% in 1996. Subsequently, no structural strategies were undertaken until 2003, and at that time, 22% of lower-educated women used folic acid in the recommended period. The prevalence of neural tube defects (NTD) decreased from 11.44/10,000 before the official recommendations to 6.52/10,000 thereafter. Currently, community pharmacies proactively approach women before their first pregnancy on the subject of folic acid supplementation. This is done by means of a sticker placed on packages of oral contraceptives with the text "Child wish?*". "Ask for information about folic acid in your pharmacy," and a brochure (leaflet) containing detailed information about folic acid. (*"Child wish" refers to women who plan to become pregnant.) Data from an explorative, comparative study strongly suggest that this intervention is effective. Sustainable education programs through which women are informed repeatedly to take folic acid supplements during the periconceptional period are urgently needed.


Schizophrenia as a disorder of developmentally reduced synaptic connectivity.
Recent postmortem and neuroimaging studies of schizophrenia delineate changes in brain structure and volume that appear to arise from a reduction of neuritic processes (such as dendrites and synapses) rather than loss of neuronal or glial cell bodies. To account for these findings, we propose a pathophysiological model of reduced synaptic connectivity arising from disturbances of brain development active during perinatal and adolescent periods. We review a computer simulation of the elimination of the synaptic connections that models normal cognitive development and psychotic symptom formation. We describe the model's key parameters and discuss how they can account for important aspects of schizophrenia, including its unique symptoms, short- and long-term course, typical age of onset, neurodevelopmental deficits, limited neurodegenerative progression, sex differences, and more. We discuss some of the model's predictions and questions raised for basic research, early detection, and preventive intervention.


Physiological regulation of hypothalamic neuropeptide Y release in lean and obese rats.
The paraventricular nucleus (PVN) of the hypothalamus is an important site for the regulation of feeding behavior. Neuropeptide Y (NPY) injected into this nucleus strongly stimulates food intake. In the current study we measured NPY release in the PVN of unrestrained rats through the push-pull technique. The rats were placed in their habitual environment and conditions of life. NPY release was augmented by > 40% (P < 0.01) in Long-Evans rats deprived of food for 12 h. It returned to the baseline as measured in ad libitum-fed rats 90 min after food access. Its stimulation by 55 mM KCl in refed animals indicated that the whole stock of NPY was not used during a short fast. During the light-dark transition, when feeding behavior is initiated. NPY release in lean Zucker rats showed a peak 20 min after lights off and then declined. It corresponded well with the first feeding episodes. In the obese Zucker rats, this peak was absent. NPY release was totally anarchic but at a high level. The feeding behavior of the obese rats was not as time delimited as in the lean rats. This study performed in very physiological conditions therefore indicates that NPY release could drive feeding behavior in the normal life. Its dysregulation in obese rats could participate in overeating and absence of feeding rhythm measured in these rats and speed up the development of their obesity.


Unexpected diversity in the catfish Pseudancistrus brevispinis reveals dispersal routes in a Neotropical center of endemism: the Guyanas Region.
Neotropical freshwater fishes have reached an unrivalled diversity, organized into several areas of endemism, yet the underlying processes are still largely unknown. The topographical and ecological characteristics of the Guyanas Region make it an ideal area of endemism in which to investigate the forces that have shaped this great diversity. This region is thought to be inhabited by species descending from Amazonian ancestors, which would have used two documented routes that, however, hardly explain the entrance of species adapted to running waters. Here, we investigate the evolutionary history of Pseudancistrus brevispinis, a catfish endemic to this region and exclusively found in running waters, thus making it an ideal model for investigating colonization routes and dispersal in such habitats. Our analyses, based on mitochondrial and nuclear markers, revealed an unexpected diversity consisting of six monophyletic lineages within P. brevispinis, showing a disjoint distribution pattern. The lineages endemic to Guyanas coastal rivers form a monophyletic group that originated via an ancestral colonization event from the Amazon basin. Evidence given favours a colonization pathway through river capture between an Amazonian tributary and the Upper Maroni River. Population genetic analyses of the most widespread species indicate that subsequent dispersal among Guyanas coastal rivers occurred principally by temporary connections between adjacent rivers during periods of lower sea level, yet instances of dispersal via interbasin river captures are not excluded. During high sea level intervals, the isolated populations would have diverged leading to the observed allopatric species. This evolutionary process is named the sea level fluctuation (SLF) hypothesis of diversification.


Effect of an image-sharing network on CT utilization for transferred trauma patients: a 5-year experience at a level I trauma center.
The aim of this study was to evaluate the influence of an image-sharing network established between referring hospitals and a level I trauma center on CT utilization at the trauma center. This retrospective study was approved by the local institutional review board. The requirement for informed consent was waived. Harborview Medical Center's trauma registry was linked to billing department data, and detailed information on all resources utilized during each patient's hospitalization was obtained. Negative binomial regression was used to evaluate body region-specific CT utilization between direct-admit and transfer patients after adjustment for potential confounding variables. Special attention was paid to 2005 as the year internet-based image sharing between Harborview Medical Center and referring hospitals was established. A total of 81,159 trauma patients were admitted to Harborview Medical Center (44% transfers) during the study period. The utilization of head CT slightly increased from 1996 to 2005, with no significant difference between direct-admit and transfer patients. Between 2005 and 2010, utilization remained relatively unchanged; however, significantly higher utilization rates were observed for direct-admit patients. A relatively similar pattern was observed for pelvic CT; however, between 2005 and 2010, CT use was greater for direct-admit compared with transfer patients. Abdominal and thoracic CT was relatively unchanged between 2005 and 2010. However, both studies had significantly higher utilization rates for direct-admit patients. The utilization rates of CT of different body regions have been higher for direct-admit trauma patients compared with transfer patients since 2005; however, decreasing utilization trends have been observed in recent years.


Extended trimethoprim/sulfamethoxazole prophylaxis for implant reconstruction in the previously irradiated chest wall.
Patients who have undergone prior chest wall irradiation can present as challenging candidates for implant reconstruction because of troublesome rates of infectious complications. The issue of antibiotic prophylaxis remains controversial, and evidence-based postoperative strategies to reduce implant infections have not been well described in the literature. The purpose of this study was to determine the efficacy of extended trimethoprim/sulfamethoxazole therapy in preventing implant infections in the irradiated chest wall. A retrospective chart review of hospital and office records was performed on all patients undergoing implant reconstruction performed by a single surgeon (J.M.S.) from August of 2005 to March of 2008. Before 2007, the senior author used 5 to 7 days of cephalosporin prophylaxis. Subsequent to this period, the prophylactic regimen was amended to provide patients with previous chest wall irradiation prophylactic trimethoprim/sulfamethoxazole for 30 days after implant insertion. Fifty-one implant reconstructions, in the setting of prior ipsilateral chest wall irradiation, were performed. The mean follow-up time was 39 months. The infection rate for the routine cephalosporin group was 35 percent as compared with 8 percent for the extended trimethoprim/sulfamethoxazole group (p = 0.038). After multivariate analysis, extended trimethoprim/sulfamethoxazole remained the only significant factor that influenced the rate of infection (p = 0.05). The mean time to infection was 13 weeks for the routine cephalosporin group and 1.5 weeks for the extended trimethoprim/sulfamethoxazole group (p = 0.044). Extended trimethoprim/sulfamethoxazole therapy demonstrates preliminary evidence as an effective adjunctive measure for reducing the rate of implant infections in breast reconstruction. Therapeutic, III.


Detection of JC virus in two African cases of progressive multifocal leukoencephalopathy including identification of JCV type 3 in a Gambian AIDS patient.
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating central nervous system (CNS) infection, affecting mainly oligodendrocytes, but also occasional astrocytes. In the USA, Europe and Asia, PML is caused by the human polyomavirus JC virus (JCV) and in autopsy series occurs in about 4-7% of AIDS patients. In Africa, the prevalence of PML in AIDS patients is uncertain and the causative agent is unknown. This study reports immunocytochemical and PCR confirmation of PML in the CNS of an AIDS patient dying in Uganda, East Africa (case 1). In a Gambian patient infected with HIV-2 who died 3 months after onset of AIDS/PML in Germany (case 2), it was possible to confirm the identity of the virus by DNA sequencing of the PCR amplified JCV product. This African genotype of the virus (type 3) showed an unusual re-arrangement of the regulatory region, and could be distinguished at several sites from East African and African-American JCV strains described previously. This study has confirmed that PML is a complication of African AIDS as it is in Europe and the USA, and that JCV type 3 is pathogenic in African AIDS patients. Furthermore, the finding of an African genotype of JCV in a patient dying in Germany suggests that in this individual JCV represented a latent infection acquired in Africa.


Harnessing combinational phototherapy via post-synthetic PpIX conjugation on nanoscale metal-organic frameworks.
Nanomaterial-mediated phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is an effective anticancer intervention that relies on light activation of photoactive nanomaterials localized in tumors. Recently, combinational PDT/PTT offered a practical pathway to relieve resistance of monotherapy, surmount undesirable side effects and provide a synergistic effect to enhance phototherapeutic efficiency. Herein, we report a facile strategy to integrate protoporphyrin IX (PpIX) into nanoscale metal-organic frameworks (NMOFs) and control their photoactive properties for combinational cancer PDT and PTT. With optimized PpIX conjugation, the as-fabricated nanoparticles (nPCU NPs) exhibit (1) improved dispersibility and particle stability, (2) simultaneous generation of reactive oxygen species and heat effectively through activation by a single-wavelength laser of 635 nm, and (3) maintenance of porosity for further application as drug delivery vehicles. Moreover, in vitro investigation of nPCU NPs demonstrates effective cellular uptake, successful endosomal escape and enhanced phototherapeutic efficacy under both normoxic and hypoxic conditions. Therefore, this study developed a novel type of phototherapeutic nanoplatform with optimal properties for applicable cancer phototherapy.


Induced maturation of frog mast cells by nerve growth factor during ontogenesis.
The effect of nerve growth factor (NGF) on ontogenesis of frog mast cells was investigated in vivo by histochemical, morphometric, and ultrastructural analysis. Three groups of tadpoles at various stages of development were used. In the first group, the larvae received i.p. injections of 1 ng NGF/g; the second group received 10 ng NGF/g, while the control group received only the vehicle. The first recognizable mast cells arose symmetrically in the tongue at stage 26 of Witschi's standard table. At stages 26 and 29, the mast cell number in the NGF-injected tadpoles was significantly higher than the control group. From stage 29 onward, the mast cell number rapidly increased in all groups. No significant differences in mast cell number were observed between the control group and the NGF-injected groups at stages 31 and 33. Electron microscopy revealed that at metamorphic climax (stage 33), the mast cells in the NGF-treated groups were more mature than those in the control group. Therefore, nerve growth factor at early stages of tadpole development is likely to induce differentiation of mast cell precursors, while at later stages it is likely to induce maturation of immature mast cells. The close anatomical association between mast cells and perineurium, observed during nerve development, is intriguing. Already in the early stages of nerve development, the mast cells form a network around Schwann cell-axon complexes, together with the perineurial cells. At climax, the mast cells are located between the perineurial layers, suggesting that they may play a role in the tissue-nerve barrier of the perineurium. Nerve growth factor also seems to induce perineurial cell maturation.


Secondary primary malignancy risk among patients with esophageal cancer in Taiwan: a nationwide population-based study.
To evaluate the risk and sites of metachronous secondary primary malignancies (SPMs) among patients with esophageal cancer. Newly diagnosed esophageal cancer patients between 1997 and 2011 were recruited. To avoid surveillance bias, SPMs that developed within one year were excluded. Standardized incidence ratios (SIRs) of metachronous SPMs in these patients were calculated by comparing to the cancer incidence in the general population. Risk factors for SPM development, included age, sex, comorbidities and cancer-related treatments, were estimated by Cox proportional hazards models. During the 15-year study period, 870 SPMs developed among 18,026 esophageal cancer patients, with a follow-up of 27,056 person-years. The SIR for all cancers was 3.53. The SIR of follow-up period ≥ 10 years was 3.56; 5-10 years, 3.14; and 1-5 years, 3.06. The cancer SIRs of head and neck (15.83), stomach (3.30), lung and mediastinum (2.10), kidney (2.24) and leukemia (2.72), were significantly increased. Multivariate analysis showed that age ≥ 60 years (hazard ratio [HR] 0.74), being male (HR 1.46) and liver cirrhosis (HR 1.46) were independent factors. According to the treatments, major surgery (HR 1.24) increased the risk, but chemotherapy was nearly significant. Patients with esophageal cancer were at increased risk of developing metachronous SPMs. The SIR remained high in follow-up > 10 years, so that close monitoring may be needed for early detection of SPM among these esophageal cancer patients.


A longitudinal study of resolution of allergy to well-cooked and uncooked egg.
Egg allergy is common and although resolution to uncooked egg has been demonstrated, there is lack of evidence to guide reintroduction of well-cooked egg. To examine the rate of resolution to well-cooked, compared with uncooked egg in children, and safety of egg challenges. A longitudinal study of egg-allergic children from 2004 to 2010, who underwent challenge with well-cooked and if negative, uncooked egg. Participants underwent repeat annual challenges and egg-specific IgE measurement. One hundred and eighty-one open egg challenges were performed in 95 children whose median age of allergy onset was 12 months. Fifty-three of 95 (56%) had at least one annual repeat challenge. Pre-study historical reactions occurred to baked egg in five (5%), lightly cooked in 58 (61%) and uncooked in nine (9%); respiratory reactions occurred in 11 (12%) and seven (7%) had anaphylaxis; adrenaline was used during five reactions. There were 77 well-cooked and 104 uncooked egg challenges. Tolerance was gained twice as rapidly to well-cooked than uncooked egg (median 5.6 vs. 10.3 years; P<0.0001) and continued to 13 years; hazard ratio 2.23 (95% confidence interval 1.6-3.9). Nearly 1/3 had resolved allergy to well-cooked egg at 3 years and 2/3 at 6 years. Of 28/77 (37%) positive well-cooked egg challenges, 65% had cutaneous symptoms, 68% gastrointestinal and 39% rhinitis, with no other respiratory reactions. Adrenaline was not required. CONCLUSIONS AND CLINICAL RELEVANCE RESOLUTION: of egg allergy takes place over many years, with children outgrowing allergy to well-cooked egg approximately twice as quickly as they outgrow allergy to uncooked egg. There were no severe reactions to well-cooked egg challenge, and adrenaline was not required. Our data support initiation of home reintroduction of well-cooked egg from 2 to 3 years of age in children with previous mild reactions and no asthma. Resolution continues to occur in older children, so that despite an earlier positive challenge, attempts at reintroduction should be continued.


The cellular pathology of experimental hypertension. VI. Alterations in retinal vasculature.
The ultrastructure of retinal arterial vessels from rats with severe renal hypertension has been studied. The permeability of retinal vessels has also been examined by means of vascular labeling technics utilizing horseradish peroxidase and microperoxidase as tracer substances. Small retinal arteries and arterioles exhibit foci of smooth muscle necrosis characterized initially by fragmentation of medial smooth muscle cells, and subsequently by loss of myofilaments and release of free vesicles, vacuoles and other cytoplasmic organelles extracellularly. Evidence for increased permeability is observed occasionally in retinal capillaries and less frequently in arteries and arterioles. The enzymatic tracers penetrate the tight junctions of the endothelial cells and are found in the basement membranes adjacent to endothelial and smooth muscle cells, as well as in expanded extracellular spaces around the capillaries. The alterations in the ultrastructure and permeability of retinal vessels in experimental hypertension have been compared with that of visceral and cerebral cortical vessels.


Alcohol use and HIV sexual risk among MSM in Chennai, India.
Men who have sex with men (MSM) in India are a core risk group for HIV. Heavy alcohol consumption is associated with increased sexual risk-taking behaviours in many cultures, in particular among MSM. However, no studies to date have explored alcohol use and HIV risk among MSM in India. MSM in Chennai, India (n = 210) completed an interviewer-administered behavioural and psychosocial assessment. Bivariate and multivariable logistic regression procedures examined behavioural and demographic associations with weekly alcohol consumption. Twenty-eight percent of the sample (n = 58) reported using alcohol at least weekly to the point of being buzzed/intoxicated, which was associated with older age, being married to a woman, being panthi (masculine appearing, predominantly insertive partners) versus kothi (feminine acting/appearing and predominantly receptive partners), weekly tobacco use, unprotected anal sex and unprotected vaginal sex in the three months prior to study enrollment (all P < 0.05). In a multivariable model, unprotected vaginal sex in the previous three months and being married to a women were unique variables associated with weekly alcohol use (all P < 0.01). Further investigation of alcohol use within the context of sexual risk taking is warranted among Indian MSM. Panthis and MSM who are married to women may be particularly likely to benefit from interventions to decrease alcohol intake and concurrent unsafe sex.


Organization of transcriptional signals in plasmids pBR322 and pACYC184.
Electron microscopic analysis of in vitro transcriptional complexes of pBR322 and pACYC184 revealed five and six major transcriptional units, respectively, in these two plasmid vectors. These units are transcribed with various efficiencies, depending upon the individual promoter strengths, which differ in pBR322 up to 10-fold. A most interesting signal arrangement was found at the beginning of the tetracycline resistance region, where two partially overlapping promoters (P1 and P2) initiate transcription crosswise in opposite directions. Whereas P2 is known to promote tetracycline resistance and to be inactivated by HindIII cleavage, P1 is able to transcribe DNA integrated at that site and probably contributes to the expression of the beta-lactamase gene in pBR322. In pACYC184, besides P1, P2, and the cat (chloramphenicol resistance) promoter (P5), two initiation sites (P3 and P4) were mapped in a region that appears to be part of insertion sequence 1. The maps of transcription signals permit a more predictable utilization of these cloning vehicles and also allow the reinterpretation of earlier cloning results.


Timing and number of antenatal care contacts in low and middle-income countries: Analysis in the Countdown to 2030 priority countries.
The 2016 World Health Organization (WHO) guidelines for antenatal care (ANC) shift the recommended minimum number of ANC contacts from four to eight, specifying the first contact to occur within the first trimester of pregnancy. We quantify the likelihood of meeting this recommendation in 54 Countdown to 2030 priority countries and identify the characteristics of women being left behind. Using 54 Demographic and Health Surveys (DHS) and Multiple Indicator Cluster Surveys (MICS) since 2012, we reported the proportion of women with timely ANC initiation and those who received 8-10 contacts by coverage levels of ANC4+ and by Sustainable Development Goal (SDG) regions. We identified demographic, socio-economic and health systems characteristics of timely ANC initiation and achievement of ANC8+. We ran four multiple regression models to quantify the associations between timing of first ANC and the number and content of ANC received. Overall, 49.9% of women with ANC1+ and 44.3% of all women had timely ANC initiation; 11.3% achieved ANC8+ and 11.2% received no ANC. Women with timely ANC initiation had 5.2 (95% confidence interval (CI) = 5.0-5.5) and 4.7 (95% CI = 4.4-5.0) times higher odds of receiving four and eight ANC contacts, respectively (P < 0.001), and were more likely to receive a higher content of ANC than women with delayed ANC initiation. Regionally, women in Central and Southern Asia had the best performance of timely ANC initiation; Latin America and Caribbean had the highest proportion of women achieving ANC8+. Women who did not initiate ANC in the first trimester or did not achieve 8 contacts were generally poor, single women, with low education, living in rural areas, larger households, having short birth intervals, higher parity, and not giving birth in a health facility nor with a skilled attendant. Timely ANC initiation is likely to be a major driving force towards meeting the 2016 WHO guidelines for a positive pregnancy experience.


HDL proteomics: pot of gold or Pandora's box?
In this issue of the JCI, Vaisar et al. studied the proteome of HDL (see the related article beginning on page 746). They reveal, quite unexpectedly, that HDL is enriched in several proteins involved in the complement cascade, as well as in a variety of protease inhibitors, supporting the concept that HDL plays a role in innate immunity and in the regulation of proteolytic cascades involved in inflammatory and coagulation processes. The protein makeup of HDL also appears to be altered in patients with coronary artery disease. HDL proteomics is in its infancy, and preliminary findings will need to be confirmed using standardized approaches in larger clinical samples. However, this approach promises to better elucidate the relationship of HDL to atherosclerosis and its complications and could eventually help in the development of biomarkers to predict the outcome of interventions that alter HDL levels and functions.


[Nursing education: building up the integrality of care].
In this study it was aimed to understand the nursing teaching towards the integrality of healthcare. A qualitative approach study with data obtained from interviews with members of the teaching staff, student nurses and nurses of services. The transcribed interviews were submitted to discourse analysis. Intentionalities shown by the research participants regarding the professional training from the perspective of the integrality of healthcare in a movement of overcoming the flexnerian paradigm towards a possibility of critical and reflective education were seen. It was concluded that the nursing training points at reflections on the changing movement on the pedagogical practices and healthcare as fundamental strategy in order to build the integrality of healthcare.


Cost of the Otolaryngology Residency Application Process: Comparison With Other Specialties and Equity Implications.
This study aims to assess trends in applicant-reported costs of the otolaryngology residency application process between 2019 and 2021 and evaluate the impact of application costs on number of interview offers. Cross-sectional study. US allopathic and osteopathic medical schools. Survey data from applicants were obtained from the Texas STAR database (Seeking Transparency in Application to Residency) for the years 2019 to 2021. Outcomes included total cost, interview cost, other costs, application fees, and number of interview offers. Simple and multivariable linear regression was used to identify novel predictors of cost and assess the correlation between cost and interview offers. Among 363 otolaryngology applicants, there was a 74% reduction in total costs and a 97% reduction in interview costs in the 2021 cycle vs the 2020 cycle. Significant predictors of total cost among otolaryngology applicants included the number of away rotations (P < .01), the number of research experiences (P = .04), and couples matching (P < .01). During the 2019 and 2020 application cycles, there was a significant association between applicant-reported total spending and number of otolaryngology interview offers (P < .01), which was not present during the 2021 cycle (P = .35). Number of otolaryngology interview offers appears to be directly correlated with applicant-reported total costs regardless of number of applications or interviews attended, which may be a source of inequality in the application process. There was a drastic reduction in total costs, interview costs, and other costs during the COVID-19 pandemic, which was likely driven by virtual interviewing and the absence of away rotations.


Modulation of central glucocorticoid receptors in short- and long-term experimental hyperthyroidism.
Hyperthyroidism is associated with a significant increase in circulating glucocorticoid levels and hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. The aim of this study was to examine whether the HPA axis hyperactivity observed in hyperthyroidism may be explained by a disturbed feedback inhibition of endogenous glucocorticoids through two specific intracellular receptors in the brain: the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Cytosolic receptor binding and gene expression was assessed in rats with short (7 days) and long standing (60 days) eu- and hyperthyroidism. Glucocorticoid receptor number and binding affinity (Kd) in the hippocampus were measured using [(3)H2]-dexamethasone radioreceptor assay. In situ hybridization was employed to examine the effects of hyperthyroidism on the GR and MR mRNA levels in the hippocampus and the pituitary. Both short- and long-term hyperthyroid rats showed pronounced reduction in the concentration of cytosolic GR in the hippocampus, without changes in binding affinity or changes in GR expression. In contrast, GR mRNA in the pituitary increased after 7 days and decreased after 60 days of thyroxin treatment. MR mRNA was moderately affected. Hyperthyroidism is associated with significant decreases in hippocampal GR levels supporting the hypothesis that hyperactivity of the HPA axis observed in experimentally induced hyperthyroidism may be attributed, at least in part, to decreased negative feedback at the level of the hippocampus. These findings further support the notion that a central locus is principally responsible for the hyperactivity of the HPA axis observed in hyperthyroidism.


Low pathogenicity of anti-desmoglein 3 immunoglobulin G autoantibodies contributes to the atypical clinical phenotypes in pemphigus.
The clinical phenotypes of pemphigus can be explained by the desmoglein (Dsg) compensation theory. However, some atypical cases such as cutaneous pemphigus vulgaris (cPV), in which patients have anti-Dsg3 antibodies without oral erosions, do not conform to this theory. To explain the discrepancy between clinical phenotypes and anti-Dsg antibody profiles, the pathogenic strength of immunoglobulin (Ig)G autoantibodies against Dsg3 must be taken into consideration. We analyzed the epitopes and blister-inducing pathogenic strength of the sera from three patients having IgG against Dsg3 without oral erosions with domain-swapped recombinant proteins and dissociation assay using cultured normal human epidermal keratinocytes. The results showed that all sera contained IgG directed against the amino terminal EC1 domain of Dsg3, as is found in most PV sera. However, dissociation assays revealed that the pathogenic strength of the anti-Dsg3 antibodies in all three cases was extremely lower than that of typical PV cases with mucosal involvement. In conclusion, when anti-Dsg3 IgG antibodies are not sufficient to inhibit the expression of Dsg3 in the oral mucosa, but can inhibit the expression in the skin, skin blisters can result. Therefore, the pathogenicity of anti-Dsg3 antibodies should be regarded as a key factor contributing to the clinical phenotype in pemphigus patients with conflicting antibody profiles.


Mutant mice lacking the p53 C-terminal domain model telomere syndromes.
Mutations in p53, although frequent in human cancers, have not been implicated in telomere-related syndromes. Here, we show that homozygous mutant mice expressing p53Δ31, a p53 lacking the C-terminal domain, exhibit increased p53 activity and suffer from aplastic anemia and pulmonary fibrosis, hallmarks of syndromes caused by short telomeres. Indeed, p53Δ31/Δ31 mice had short telomeres and other phenotypic traits associated with the telomere disease dyskeratosis congenita and its severe variant the Hoyeraal-Hreidarsson syndrome. Heterozygous p53+/Δ31 mice were only mildly affected, but decreased levels of Mdm4, a negative regulator of p53, led to a dramatic aggravation of their symptoms. Importantly, several genes involved in telomere metabolism were downregulated in p53Δ31/Δ31 cells, including Dyskerin, Rtel1, and Tinf2, which are mutated in dyskeratosis congenita, and Terf1, which is implicated in aplastic anemia. Together, these data reveal that a truncating mutation can activate p53 and that p53 plays a major role in the regulation of telomere metabolism.


A comparison of delay discounting in adolescents and adults in treatment for cannabis use disorders.
Delay discounting is associated with problematic substance use and poorer treatment outcomes in adolescents and adults with substance use disorders. Although some research has addressed delay discounting among individuals with cannabis use disorders (CUDs), results have been equivocal, and no study has examined whether discounting rates differ between adolescent and adult cannabis users. The aim of this study was to compare discounting rates between adolescents and adults in treatment for CUD to determine whether discounting at intake or changes in discounting across treatment differed between age groups. Participants were 165 adolescents and 104 adults enrolled in treatment for CUD. Participants completed a delay discounting task at intake and end of treatment for 2 commodities (money and cannabis) at 2 different magnitudes ($100 and $1,000). Repeated measures mixed models examined differences in discounting rates by commodity and magnitude across age groups at intake and changes in discounting across treatment. At intake, adolescents discounted money more than adults whereas adults showed greater discounting at $100 magnitude than $1,000. In addition, adults had greater decreases in discounting of cannabis over the course of treatment. Overall, adolescents appeared less sensitive to changes in magnitude of rewards, discounted money at higher rates, and showed less improvement in discounting over the course of treatment compared to adults. Comparing delay discounting in adolescents and adults with CUD can contribute to a better understanding of how development influences the effect of discounting on substance use to better inform treatment for substance use disorders.


Direct Patterning of Highly Conductive PEDOT:PSS/Ionic Liquid Hydrogel via Microreactive Inkjet Printing.
The gelation of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) has gained popularity for its potential applications in three dimensions, while possessing tissue-like mechanical properties, high conductivity, and biocompatibility. However, the fabrication of arbitrary structures, especially via inkjet printing, is challenging because of the inherent gel formation. Here, microreactive inkjet printing (MRIJP) is utilized to pattern various 2D and 3D structures of PEDOT:PSS/IL hydrogel by in-air coalescence of PEDOT:PSS and ionic liquid (IL). By controlling the in-air position and Marangoni-driven encapsulation, single droplets of the PEDOT:PSS/IL hydrogel as small as a diameter of ≈260 μm are fabricated within ≈600 μs. Notably, this MRIJP-based PEDOT:PSS/IL has potential for freeform patterning while maintaining identical performance to those fabricated by the conventional spin-coating method. Through controlled deposition achieved via MRIJP, PEDOT:PSS/IL can be transformed into different 3D structures without the need for molding, potentially leading to substantial progress in next-generation bioelectronics devices.


Isoniazid-resistant tuberculosis in children: a systematic review.
Isoniazid resistance is an obstacle to the treatment of tuberculosis disease and latent tuberculosis infection in children. We aim to summarize the literature describing the risk of isoniazid-resistant tuberculosis among children with tuberculosis disease. We did a systematic review of published reports of children with tuberculosis disease who had isolates tested for susceptibility to isoniazid. We searched PubMed, Embase and LILACS online databases up to January 12, 2012. Our search identified 3403 citations, of which 95 studies met inclusion criteria. These studies evaluated 8351 children with tuberculosis disease for resistance to isoniazid. The median proportion of children found to have isoniazid-resistant strains was 8%; the distribution was right-skewed (25th percentile: 0% and 75th percentile: 18%). High proportions of isoniazid resistance among pediatric tuberculosis patients have been reported in many settings suggesting that diagnostics detecting only rifampin resistance are insufficient to guide appropriate treatment in this population. Many children are likely receiving substandard tuberculosis treatment with empirical isoniazid-based regimens, and treating latent tuberculosis infection with isoniazid may not be effective in large numbers of children. Work is needed urgently to identify effective regimens for the treatment of children sick with or exposed to isoniazid-resistant tuberculosis and to better understand the scope of this problem.


Cardiovascular magnetic resonance imaging in suspected cardiac tumour: a multicentre outcomes study.
Cardiovascular magnetic resonance (CMR) imaging is a key diagnostic tool for the evaluation of patients with suspected cardiac tumours. Patient management is guided by the CMR diagnosis, including no further testing if a mass is excluded or if only a pseudomass is found. However, there are no outcomes studies validating this approach. In this multicentre study of patients undergoing clinical CMR for suspected cardiac tumour, CMR diagnoses were assigned as no mass, pseudomass, thrombus, benign tumour, or malignant tumour. A final diagnosis was determined after follow-up using all available data. The primary endpoint was all-cause mortality. Among 903 patients, the CMR diagnosis was no mass in 25%, pseudomass in 16%, thrombus in 16%, benign tumour in 17%, and malignant tumour in 23%. Over a median of 4.9 years, 376 patients died. Compared with the final diagnosis, the CMR diagnosis was accurate in 98.4% of patients. Patients with CMR diagnoses of pseudomass and benign tumour had similar mortality to those with no mass, whereas those with malignant tumour [hazard ratio (HR) 3.31 (2.40-4.57)] and thrombus [HR 1.46 (1.00-2.11)] had greater mortality. The CMR diagnosis provided incremental prognostic value over clinical factors including left ventricular ejection fraction, coronary artery disease, and history of extracardiac malignancy (P < 0.001). In patients with suspected cardiac tumour, CMR has high diagnostic accuracy. Patients with CMR diagnoses of no mass, pseudomass, and benign tumour have similar long-term mortality. The CMR diagnosis is a powerful independent predictor of mortality incremental to clinical risk factors.


Joint association of smoking and physical activity with mortality in elderly hypertensive patients: A Chinese population-based cohort study in 2007-2018.
Although associations of physical activity and smoking with mortality have been well-established, the joint impact of physical activity and smoking on premature mortality among elderly hypertensive population was still unclear. This study aimed to assess association of physical activity, smoking, and their interaction with all-cause and cardiovascular disease (CVD) mortality risk in elderly hypertensive patients. We included 125,978 Chinese hypertensive patients aged 60-85 years [mean (SD) age, 70.5 (6.9) years] who had records in electronic health information system of Minhang District of Shanghai, China in 2007-2015. Cox regression was used to estimate individual and joint association of smoking and physical activity on all-cause and CVD mortality. Interactions were measured both additively and multiplicatively. Additive interaction was evaluated by relative excess risk due to interaction (RERI), attributable proportion due to interaction (AP) and synergy index (S). Among 125,978 elderly hypertensive patients (median age 70.1), 28,250 deaths from all causes and 13,164 deaths from CVD were observed during the follow-up up to 11 years. There was an additive interaction between smoking and physical inactivity [RERI: all-cause 0.19 (95% CI: 0.04-0.34), CVD 0.28 (0.06-0.50); AP: all-cause 0.09 (0.02-0.16), CVD 0.14 (0.04-0.23); S: all-cause 1.21 (1.04-1.42), CVD 1.36 (1.06-1.75)], while the concurrence of both risk factors was associated with more than 2-fold risk of death [hazard ratio (HR): all-cause 2.10 (1.99-2.21), CVD 2.19 (2.02-2.38)]. Our study suggested that smoking and physical inactivity together may have amplified association on premature death compared to the sum of their individual associations, highlighting the importance of improving behavioral factors in combination and promoting a comprehensive healthy lifestyle in hypertensive elderly.


Cohort Profile: The China Severe Trauma Cohort (CSTC).
PurposeTo establish a prospective hospital-based cohort, featured by detailed multidimensional data of trauma patients with active follow-ups, which can be a reliable data source for all studies focusing on the effects or underlying mechanistic pathways of environmental and biological factors on multiple interested trauma-related outcomes, particularly the incidence and trajectory of trauma-related psychopathology, in Chinese population.MethodsThe China Severe Trauma Cohort (CSTC) enrolled all traumatized individuals aged 12 to 80 years admitted to the Trauma Center of West China Hospital between 1st March 2020 and 8th July 2022. The bio-sample and detailed questionnaire data were collected at recruitment, and phone/internet follow-ups were scheduled at 1-, 3-, 6-, 12-months after the baseline. Long-term health outcomes are planned to be obtained from administrative databases through data linkage.ResultsA total of 2,500 trauma patients were enrolled (response rate=87.1%) with an average age of 46.01 years, and most of the participants were males(62.6%). The proportions of participants with blood and fecal sample collected at baseline were 93.8% and 66.3%, respectively. Upon 31st August 2022, the follow-up rate was 90.0%, 77.0%, 76.5%, and 89.0% for 1-, 3-, 6-, and 12-months follow-up, respectively. Fall/wrench (47.6%) and traffic accident (26.2%) were the top causes of current trauma. The most common psychopathology at recruitment was sleep disturbance(39.4%), followed by depression(22.6%), anxiety(18.2%), and acute stress reaction(7.8%), all of which showed recovering trajectories during the follow-up period, particularly the first 3 months after baseline.ConclusionsCSTC provides a platform with multidimensional data to study both short-term and long-term trauma-related health consequences, prompting early identification and intervention for individuals with high risk of health decline after trauma exposures.


Tetrodotoxin and manganese ion: effects on action potential of the frog heart.
Tetrodotoxin, which effectively suppresses the permeability of various tissues to sodium ions, has no effect on the calcium action potential of the fiber of barnacle muscle, which potential is produced by increase in permeability to calcium ions. Manganese ions, however, suppress the action potential. When applied to fiber of frog cardiac ventricle, tetrodotoxin suppresses the rate of rise of the action potential without affecting the overshoot; the suppressive effect of manganese ion is mainly on the overshoot of the action potential. This suggests that, in the action potential of the car-diac ventricle of the frog, the platealu phase is related primarily to the increase in permeability of the membrane to calcium ions.


Small bowel obstruction caused by Anisakis and Meckel's diverticulum: a rare case.
Anisakiasis is a parasitic infection caused by the ingestion of raw fish contaminated by larval nematodes of Anisakis species. Intestinal or extraintestinal manifestations are rated to > 4% and >1% respectively. A 61-year old patient was admitted to our General Surgical and Emergency Unit because of sudden abdominal pain, vomit and constipation. He had eaten raw fish 3 days before admission. Laboratory data showed high levels of WBC and PCR. CT scanning showed "dilation of jejunum and ileum loops, thickening of the terminal ileum and cecum and signs of inflammation of the intestinal wall and mesentery". The following emergency surgical procedure was performed: laparotomy with evidence of obstruction of the small bowels, a giant Meckel's diverticulum, resection of terminal ileum and cecum and ileocolonic anastomosis. At the microscopic examination, the intestinal wall appeared occupied by a transmural inflammatory infiltrate, mainly eosinophilic, edema and nematode larvae, referable to Anisakis, surrounded by necrotic-inflammatory material. Moreover, there was evidence of giant a Meckel's diverticulum. Normally, enteric anisakiasis exhibits leukocytosis with eosinophilia and high CRP levels. There are cases of successful medical treatment and other cases of endoscopic treatment avoiding surgical procedure. In our case, enteric Anisakias had not been taken into consideration at the moment of the operation and only histopathology could reveal Anisakis larvae inside the intestinal wall. Our surgical approach is considered in literature as the best one for this clinical presentation. Those patients need to be better studied and more attention should be paid to their history.


Validation of the Omron HEM-1040 Blood Pressure Monitor According to the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization 81060-2:2013 Protocol.
The accuracy of the Omron HEM-1040 automated oscillometric upper-arm blood pressure (BP) monitoring device, designed for home self-measurements in adult populations, was tested according to the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-2:2013 protocol. The requirements of this protocol were precisely followed with the recruitment of 85 individuals in whom sequential systolic BP (SBP) and diastolic BP (DBP) were measured in the same (left) arm and who fulfilled the inclusion criteria involving the ranges of arm circumference, SBP, and DBP. The mean device-observer difference in the 255 separate pairs of BP data was -2.7 ± 7.14 mmHg for SBP and -3.3 ± 5.70 mmHg for DBP. The data were in accordance with criterion 1 of the ANSI/AAMI/ISO 81060-2:2013 standard requirements (≤ 5 ± ≤ 8 mmHg). In addition, the mean device-observer difference in the 85 participants was -2.7 ± 5.89 mmHg for SBP and -3.3 ± 4.99 mmHg for DBP, fulfilling criterion 2 with a standard deviation of ≤ 6.39 mmHg for SBP and ≤ 6.09 mmHg for DBP. The OMRON HEM-1040 BP monitor fulfilled the requirements of the ANSI/AAMI/ISO validation standard.


Performance of epimysial stimulating electrodes in the lower extremities of individuals with spinal cord injury.
This study describes the performance of surgically-implanted epimysial stimulating electrodes in the muscles of the lower extremities for use in functional neuromuscular stimulation (FNS) systems for standing after spinal cord injury. A total of 86 epimysial electrodes were implanted in 13 volunteers with low tetraplegia or paraplegia receiving the Case Western Reserve University/Veteran Affairs (CWRU/VA)-implanted standing/transfer neuroprosthesis. The neuroprosthesis consisted of bilateral epimysial electrodes in the knee and hip extensors (vastus lateralis, gluteus maximus, and adductor magnus or semimembranosus) and intramuscular electrodes at the T12/L1 or L1/L2 spinal roots for trunk extension. Recruitment properties, stimulated knee and hip extension moments, standing performance, and mechanical integrity over time were measured for a period up to four years post-implantation. Stimulated thresholds were stable and recruitment was sufficient to generate joint moments adequate for standing, with up to 97% body weight supported by the legs. Four mechanical failures were observed, all in the posterior muscles of the thigh, leaving 95% of all electrodes operational at all followup intervals. Probability of 24-month survival is estimated to be 93% plateauing to a steady state of 90% at four years. These results indicate that epimysial designs are appropriate for long-term clinical use in the large muscles of the lower extremities with implanted motor system neuroprostheses.


Ndufs4 KO mice: A model to study comorbid mood disorders associated with mitochondrial dysfunction.
The Ndufs4 knockout (KO) mouse is a validated and robust preclinical model of mitochondrial diseases (specifically Leigh syndrome), that displays a narrow window of relative phenotypical normality, despite its inherent mitochondrial complex I dysfunction and severe phenotype. Preclinical observations related to psychiatric comorbidities that arise in patients with mitochondrial diseases and indeed in Leigh syndrome are, however, yet to be investigated in this model. Strengthening this narrative is the fact that major depression and bipolar disorder are known to present with deficits in mitochondrial function. We therefore screened the behavioural profile of male and female Ndufs4 KO mice (relative to heterozygous; HET and wildtype; WT mice) between postnatal days 28 and 35 for locomotor, depressive- and anxiety-like alterations and linked it with selected brain biomarkers, viz. serotonin, kynurenine, and redox status in brain areas relevant to psychiatric pathologies (i.e., prefrontal cortex, hippocampus, and striatum). The Ndufs4 KO mice initially displayed depressive-like behaviour in the tail suspension test on PND31 but not on PND35 in the forced swim test. In the mirror box test, increased risk resilience was observed. Serotonin levels of KO mice, compared to HET controls, were increased on PND36, together with increased tryptophan to serotonin and kynurenine turnover. Kynurenine to kynurenic acid turnover was however decreased, while reduced versus oxidized glutathione ratio (GSH/GSSG) was increased. When considering the comorbid psychiatric traits of patients with mitochondrial disorders, this work elaborates on the neuropsychiatric profile of the Ndufs KO mouse. Secondly, despite locomotor differences, Ndufs4 KO mice present with a behavioural profile not unlike rodent models of bipolar disorder, namely variable mood states and risk-taking behaviour. The model may elucidate the bio-energetic mechanisms underlying mood disorders, especially in the presence of mitochondrial disease. Studies are however required to further validate the model's translational relevance.


The relationship between delay period eye movements and visuospatial memory.
We investigated whether overt shifts of attention were associated with visuospatial memory performance. Participants were required to study the locations of a set of visual objects and subsequently detect changes to the spatial location of one of the objects following a brief delay period. Relational information regarding the locations among all of the objects could be used to support performance on the task (Experiment 1) or relational information was removed during test and location manipulation judgments had to be made for a singly presented target item (Experiment 2). We computed the similarity of the fixation patterns in space during the study phase to the fixations made during the delay period. Greater fixation pattern similarity across participants was associated with higher accuracy when relational information was available at test (Experiment 1); however, this association was not observed when the target item was presented in isolation during the test display (Experiment 2). Similarly, increased fixation pattern similarity on a given trial (within participants) was associated with successful task performance when the relations among studied items could be used for comparison (Experiment 1), but not when memory for absolute spatial location was assessed (Experiment 2). This pattern of behavior and performance on the two tasks suggested that eye movements facilitated memory for the relationships among objects. Shifts of attention through eye movements may provide a mechanism for the maintenance of relational visuospatial memory.


Hepatitis C and progression of HIV disease.
Conflicting reports exist regarding the effect of hepatitis C virus (HCV) on the progression of human immunodeficiency virus (HIV) disease. To assess the effect of HCV infection on clinical and immunologic progression of HIV disease and immunologic response to highly active antiretroviral therapy (HAART). Prospective cohort study. University-based, urban HIV clinic in the United States. There were 1955 patients enrolled between January 1995 and January 2001 who were eligible for analysis because of having at least 1 return visit to the clinic and being free of acquired immunodeficiency syndrome (AIDS) at enrollment. Median (interquartile range) length of follow-up was 2.19 (1.00-3.50) years for HCV-infected and 2.00 (1.00-3.00) years for HCV-uninfected patients. Progression to an AIDS-defining illness, survival, and progression to a CD4 cell count below 200/microL; CD4 cell count change following initiation of effective HAART (resulting in a viral load of <400 copies/mL recorded at > or = 75% of measurements). No difference was detected in the risk of acquiring an AIDS-defining illness (HCV-infected patients, 231 events [26.4%] and HCV-uninfected patients, 264 events [24.4%]; relative hazard [RH], 1.03; 95% confidence interval [CI], 0.86-1.23) or in the risk of death (HCV-infected patients, 153 deaths [17.5%] and HCV-uninfected patients, 168 deaths [15.5%]; RH, 1.05; 95% CI, 0.85 -1.30). Although an increased risk of death was detected in the subgroup of 429 HCV-infected patients with a baseline CD4 cell count of 50/microL through 200/microL (RH, 1.51; 95% CI, 1.01-2.27), after adjustment for exposure to HAART and its effectiveness in a multivariate Cox regression analysis, death was not independently associated with HCV infection in this subgroup (RH, 1.01; 95% CI, 0.65-1.56). Similarly, in those receiving effective HAART (n = 208), there was no difference in the increase in CD4 cell count or CD4 percentage during HAART in HCV-infected compared with HCV-uninfected patients. Among patients in this urban US cohort, we did not detect evidence that HCV infection substantially alters the risk of dying, developing AIDS, or responding immunologically to HAART, especially after accounting for differences in its administration and effectiveness.


Lattice charge models and core level shifts in disordered alloys.
Differences in core level binding energies between atoms belonging to the same chemical species can be related to differences in their intra- and extra-atomic charge distributions, and differences in how their core holes are screened. With this in mind, we consider the charge-excess functional model (CEFM) for net atomic charges in alloys (Bruno et al 2003 Phys. Rev. Lett. 91 166401). We begin by deriving the CEFM energy function in order to elucidate the approximations which underpin this model. We thereafter consider the particular case of the CEFM in which the strengths of the 'local interactions' within all atoms are the same. We show that for binary alloys the ground state charges of this model can be expressed in terms of charge transfer between all pairs of unlike atoms analogously to the linear charge model (Magri et al 1990 Phys. Rev. B 42 11388). Hence, the model considered is a generalization of the linear charge model for alloys containing more than two chemical species. We then determine the model's unknown 'geometric factors' over a wide range of parameter space. These quantities are linked to the nature of charge screening in the model, and we illustrate that the screening becomes increasingly universal as the strength of the local interactions is increased. We then use the model to derive analytical expressions for various physical quantities, including the Madelung energy and the disorder broadening in the core level binding energies. These expressions are applied to ternary random alloys, for which it is shown that the Madelung energy and magnitude of disorder broadening are maximized at the composition at which the two species with the largest 'electronegativity difference' are equal, while the remaining species have a vanishing concentration. This result is somewhat counterintuitive with regards to the disorder broadening since it does not correspond to the composition with the highest entropy. Finally, the model is applied to CuPd and CuZn random alloys. The model is used to deduce the effective radii associated with valence electron charge transfer for Cu, Pd and Zn in these systems for use in the 'ESCA potential model' of x-ray photoelectron spectroscopy. The effective radii are found to be R1/3, where R1 is the nearest neighbor distance, with only small variations between chemical elements and between different systems. The model provides a framework for rationalizing the disorder broadenings in these systems: they can be understood in terms of an interplay between the broadening in the Madelung potentials and the broadening in the intra-atomic electrostatic potentials.


Purification and biochemical characterisation of human placental acid alpha-glucosidase.
An acid alpha-glucosidase (EC 22.214.171.124) has been purified to electrophoretic homogeneity from the soluble fraction of the human term placenta. In the presence of SDS, two doublets of 79 and 67 kDa were seen in addition to other bands of extremely low intensity. Each of these bands was seen to cross-react with polyclonal antiserum raised to the purified enzyme, thus confirming the homogeneity of the preparation. The purified enzyme exhibited a broad substrate specificity. The kinetic data revealed the possible presence of multiple substrate binding sites. Chemical modification using group specific reagents indicated the presence of a carboxyl group and tryptophan at the active site. Based on these results a possible structure for the active site of the human term placental acid alpha-glucosidase has been proposed.


Fusional vergence response to local peripheral stimulation.
Horizontal, convergent disparities were introduced between dichoptic stimuli confined to small regions of the peripheral retina. Stimuli were presented at 32 locations: radial positions varied in 5-deg increments up to 20 deg, while angular position varied in 45-deg steps. The stimulus size and disparity were scaled in accordance with the cortical magnification factor. Eye movements were objectively measured, and the relative contributions of the motor and nonmotor components to the fusional response were evaluated as a function of stimulus eccentricity and angular position. Vergence responses elicited by peripheral disparities had longer latencies and durations and were more asymmetric than the movements elicited by foveal disparities. The composition of the fusional response changed with the position of the stimulus. The largest percentage of motor compensation was observed for stimuli located either near the line of sight or directly above it. The variations in the size of the motor response with increasing eccentricity could not be explained by the cortical magnification factor.


A cognitively grounded measure of pronunciation distance.
In this study we develop pronunciation distances based on naive discriminative learning (NDL). Measures of pronunciation distance are used in several subfields of linguistics, including psycholinguistics, dialectology and typology. In contrast to the commonly used Levenshtein algorithm, NDL is grounded in cognitive theory of competitive reinforcement learning and is able to generate asymmetrical pronunciation distances. In a first study, we validated the NDL-based pronunciation distances by comparing them to a large set of native-likeness ratings given by native American English speakers when presented with accented English speech. In a second study, the NDL-based pronunciation distances were validated on the basis of perceptual dialect distances of Norwegian speakers. Results indicated that the NDL-based pronunciation distances matched perceptual distances reasonably well with correlations ranging between 0.7 and 0.8. While the correlations were comparable to those obtained using the Levenshtein distance, the NDL-based approach is more flexible as it is also able to incorporate acoustic information other than sound segments.


Adoption of Task-Specific Sets of Visual Attention.
Evidence from behavioral and physiological studies suggests attentional weighting of stimulus information from different sources, according to task demands. We investigated the adoption of task-specific attentional sets by administering a flanker task, which required responding to a centrally presented letter while ignoring two adjacent letters, and a same-different judgment task, which required a homogenous/heterogeneous classification concerning the complete three-letter string. To assess the distribution of attentional weights across the letter locations we intermixed trials of a visual search task, in which a target stimulus occurred randomly in any of these locations. Search task reaction times displayed a stronger center-to periphery gradient, indicating focusing of visual attention on the central location, when the search task was intermixed into blocks of trials of the flanker task than into blocks of trials of the same-different task (Experiment 1) and when a cue indicated the likely occurrence of the flanker task as compared to the likely occurrence the same-different task (Experiment 2). These findings demonstrate flexible adoption of task-specific sets of visual attention that can be implemented during preparation. In addition, responses in the intermixed search task trials were faster and (marginally significantly) more error-prone after preparation for a (letter) task repetition than for a task switch, suggesting that response caution is reduced during preparation for a task repetition.


A universal method for the rapid isolation of all known classes of functional silencing small RNAs.
Diverse classes of silencing small (s)RNAs operate via ARGONAUTE-family proteins within RNA-induced-silencing-complexes (RISCs). Here, we have streamlined various embodiments of a Q-sepharose-based RISC-purification method that relies on conserved biochemical properties of all ARGONAUTEs. We show, in multiple benchmarking assays, that the resulting 15-min benchtop extraction procedure allows simultaneous purification of all known classes of RISC-associated sRNAs without prior knowledge of the samples-intrinsic ARGONAUTE repertoires. Optimized under a user-friendly format, the method - coined 'TraPR' for Trans-kingdom, rapid, affordable Purification of RISCs - operates irrespectively of the organism, tissue, cell type or bio-fluid of interest, and scales to minute amounts of input material. The method is highly suited for direct profiling of silencing sRNAs, with TraPR-generated sequencing libraries outperforming those obtained via gold-standard procedures that require immunoprecipitations and/or lengthy polyacrylamide gel-selection. TraPR considerably improves the quality and consistency of silencing sRNA sample preparation including from notoriously difficult-to-handle tissues/bio-fluids such as starchy storage roots or mammalian plasma, and regardless of RNA contaminants or RNA degradation status of samples.