Treatment and metabolic findings in extreme short-bowel syndrome with 11 cm jejunal remnant.
A full term girl survived nonresected, subtotal small-bowel gangrene. The length of the small-bowel remnant (only jejunum) measured 11 cm. Anastomosis was performed with insertion of a 3-cm-long antiperistaltic segment. The ileocecal valve remained intact. The jejunal remnant showed an increase in length of at least 1 m. The resorptive functions of the bowel residue recovered incompletely, particularly the ileal functions. Disturbances of calcium and phosphorus metabolism are now in the foreground; nevertheless, the child now manages to live without parenteral feeding.


Recurrent radial head subluxation treated with annular ligament reconstruction. A case report and follow-up study.
Radial head subluxation secondary to traumatic rupture of the annular ligament has been well described in the literature. Annular ligament reconstruction utilizing fascia lata graft has been proposed and described, but no follow-up reports have been published. A 21-year-old man was treated by annular ligament reconstruction for recurrent radial head subluxation with a good result and no recurrent subluxation at more than four years postoperatively. The operative technique is as follows: a fascia lata graft 1.5 x 12 cm was anchored through a drill hole in the posterolateral ulna, passed around the radial neck, and sutured back onto itself to reconstruct an annular ligament.


Assessment of supportive care needs among cervical cancer patients under treatment in Nepal: a cross-sectional study.
The perceived supportive care needs (SCNs) of cancer patients are essential components of a care program. The first step in planning and intervening for supportive care is the proper identification of the SCNs of cancer patients. Cervical cancer (CC) is the most prevalent cancer among Nepali women. The authors assess SCNs and their predictors among CC patients under treatment by using a validated Nepali version supportive care need survey short form (SCNS- SF 34 N). This descriptive cross-sectional study was conducted in 5 cancer treatment hospitals in Nepal. A culturally adapted and psychometrically validated Nepali version SCNS -SF- 34 N was completed by a convenience sample of 218 CC patients. Data were analyzed by using descriptive (frequency, percentage, mean, median) and inferential (Chi-square P-value and binary logistic regression analysis) statistics. The study showed that 99% of the respondents were in need of some level (low, moderate, high) of supportive care. The psychological domain, physical daily living, health system information, patient care support and sexuality domain ranked from first to fifth for SCNs with mean and standard deviations 70.29 ± 18.84, 63.25 ± 23.15, 57.90 ± 21.11, 56.46 ± 21.92 and 46.06 ± 34.16, respectively. Binary logistic regression found causal association between SCNs and variables "occupation (p-value = 0.007), and type of hospital (p-value = 0.000)" at a 95% confidence level. Nepali CC patients perceive and experience many unmet SCNs, with psychological SCNs being the first priority. It is essential that the SCNs of patients may need to be known by their close family members, care providers, CC related program. so that they can offer intervention as per patients' needs.


Advanced practice in case management: An essential element in the new complex chronicity care model.
The increased prevalence of complex chronic diseases in all stages of life, the progressive aging of the population, the prevalence of multimorbidity, polypharmacy, and loss of autonomy, have given rise to new needs in society. The current model of care is failing to meet these needs in an effective or sustainable way. People with complex chronic diseases are vulnerable, they deteriorate as diseases progress, and they require individualized and coordinated professional care that takes into account the progression of the disease, transitions and people's preferences. It is essential to determine a new care paradigm as a framework for the projects and actions that should be promoted to reach transversal, sustainable and quality care directed at people with complex and advanced chronic diseases in all stages of life. Different studies show that case management is an added value in terms of quality, safety and cost-effectiveness. However, its implementation in Spain is uneven and heterogeneous, and no regulations have yet been developed to give stability to this new nurse figure. The Ministry and the Autonomous Communities now have the responsibility to create regulations and institutionalize the figure of case management nurses/advanced practice nurses, with a clear definition of their professional competences and functions, as has been done in other countries.


Targeting BCL6 in Gastrointestinal Stromal Tumor Promotes p53-Mediated Apoptosis to Enhance the Antitumor Activity of Imatinib.
Imatinib mesylate (IM) has revolutionized the treatment of gastrointestinal stromal tumor (GIST). However, most patients inevitably acquire IM resistance. Second- and third-line treatments exhibit modest clinical benefits with a median time to disease progression of 4 to 6 months, highlighting the urgency for novel therapeutic approaches. Here, we report that the expression of BCL6, a known oncogenic driver and transcriptional repressor, was significantly induced in GIST cells following IM treatment. Elevated BCL6 levels suppressed apoptosis and contributed to IM resistance. Mechanistically, BCL6 recruited SIRT1 to the TP53 promoter to modulate histone acetylation and transcriptionally repress TP53 expression. The reduction in p53 subsequently attenuated cell apoptosis and promoted tolerance of GIST cells to IM. Concordantly, treatment of GIST cells showing high BCL6 expression with a BCL6 inhibitor, BI-3802, conferred IM sensitivity. Furthermore, BI-3802 showed striking synergy with IM in IM-responsive and IM-resistant GIST cells in vitro and in vivo. Thus, these findings reveal a role for BCL6 in IM resistance and suggest that a combination of BCL6 inhibitors and IM could be a potentially effective treatment for GIST. BCL6 drives resistance to imatinib by inhibiting p53-mediated apoptosis and can be targeted in combination with imatinib to synergistically suppress tumor growth, providing a therapeutic strategy for treating gastrointestinal stromal tumor.


The effect of LncRNA SNHG16 on vascular smooth muscle cells in CHD by targeting miRNA-218-5p.
To explore the role of SNHG16 in coronary heart disease (CHD) and its effect on vascular smooth muscle cells via miR-218-5p. A quantitative real time polymerase chain reaction (qRT-PCR) assay was carried out to determine the expression of serum SNHG16 and miR-218-5p in the observation group before and after treatment and in the control group. Then, receiver operating characteristic (ROC) curves were drawn to analyze the value of SNHG16 and miR-218-5p in the diagnosis and prognosis prediction of CHD. Furthermore, purchased coronary artery smooth muscle cells (HCASMC) were transfected with SNHG16 mimics, SNHG16 inhibitor, miR-218-5p mimics, miR-218-5p inhibitor, or negative control, and then the cell proliferation, migration, apoptosis, and apoptosis-related proteins (Bax, Bcl-2, and Caspase-3) and Wnt/β-catenin signaling pathway-related proteins (c-myc and β-catenin) in the cells were detected. Both SNHG16 and miR-218-5 had good predictive value for the development and recurrence of CHD (P < 0.001). In addition, cell experiments showed that inhibition of SNHG16 weakened the proliferation and migration of HCASMC cells and intensified their apoptosis, SNHG16 and miR-218-5p had the same binding sites, and the dual luciferase reporter assay revealed that the fluorescence activity of HG16-WT was inhibited by transfected miR-mimics, but enhanced by transfected miR-inhibitor (both P < 0.050). Furthermore, the rescue experiment revealed that the effect of inhibiting SNHG16 on HCASMC cells was completely reversed by miR-218-5p (P > 0.050). Highly expressed SNHG16 targetedly regulates miR-218-5p and promotes the proliferation and migration of HCASMC via the Wnt/β-catenin signaling pathway, giving rise to CHD.


Achieving better indoor air quality with IoT systems for future buildings: Opportunities and challenges.
With the development of IoT technology and low-cost indoor air quality (IAQ) sensors, the IoT-based IAQ monitoring platform has garnered significant research interest and demonstrated its potential in enhancing IAQ management. This study presents a comprehensive review of previous research on the development and application of IoT-based IAQ platforms in different built environments. It offers detailed insights into the design and implementation of recent IoT-based IAQ platforms. The findings indicate that the IoT-based IAQ platforms are able to provide reliable information for IAQ monitoring. To ensure quality control of the IoT-based IAQ platform, it is suggested to replace the sensors every 4-6 months for reliable monitoring. In another aspect, integrating data-driven technology into the platform is crucial for IAQ prediction and efficient control of ventilation systems, leveraging the wealth of data available from the IoT platform. According to recent studies that applied data-driven algorithms for IAQ management, it can be confirmed that the data-driven algorithms are able to prompt IAQ by providing either more information or a control strategy. However, it should be noted that only 9.1 % of the developed platforms integrated data-driven models for IAQ management. Based on our findings, current challenges and further opportunities are discussed. Future studies should focus on integrating data-driven algorithms into IoT-based IAQ platforms and developing digital twins that can be used for real building IAQ management. However, there is obvious tension between controlling ventilation for energy efficiency versus better air quality. It is important to make a balance between energy efficiency and better air quality according to the current situations of specific built environments. Also, the next generation of IoT-based IAQ platforms should include occupants in the loop to create a more occupant-centric IAQ management approach.


Studies on the quality of pancreatic preparations: enzyme content, prospective bioavailability, bile acid pattern, and contamination with purines.
Of the 72 pancreatic preparations currently on the market 24 were randomly selected for study and compared with 3 US preparations with different dosage forms. The activities of amylase, lipase, and proteases were measured with natural substrates. Prospective bioavailability was determined using amylase as indicator enzyme. Total bile acid content and distribution pattern were analyzed. The risk of renal changes due to prolonged ingestion of purines was estimated by qualitative and quantitative determination of these contaminants. Enzyme activities differed up to 16-fold. At pH 6, the drugs released the indicator enzyme with very different velocities. The efficacy of the drugs varied between 0.78% and 80.9%. The bioavailability of capsules was generally better than that of coated tablets; pellet capsules were not absolutely superior in this regard. All pancreatic preparations contained the purine bases guanine and hypoxanthine; only one drug had no adenine. Fifteen drugs contained 2.2%-10.6% bile acids by weight. Monohydroxy bile acids, which should not be administered to patients with liver disease, were detected in eight of these preparations.


Predictive Biomarkers of Overall Survival in Patients with Metastatic Renal Cell Carcinoma Treated with IFNα ± Bevacizumab: Results from CALGB 90206 (Alliance).
CALGB 90206 was a phase III trial of 732 patients with metastatic renal cell carcinoma (mRCC) comparing bevacizumab plus IFNα (BEV + IFN) with IFNα alone (IFN). No difference in overall survival (OS) was observed. Baseline samples were analyzed to identify predictive biomarkers for survival benefit. A total of 32 biomarkers were assessed in 498 consenting patients randomly assigned into training (n = 279) and testing (n = 219) sets. The proportional hazards model was used to test for treatment arm and biomarker interactions of OS. The estimated coefficients from the training set were used to compute a risk score for each patient and to classify patients by risk in the testing set. The resulting model was assessed for predictive accuracy using the time-dependent area under the ROC curve (tAUROC). A statistically significant three-way interaction between IL6, hepatocyte growth factor (HGF), and bevacizumab treatment was observed in the training set and confirmed in the testing set (P < 0.0001). The model based on IL6, HGF, and bevacizumab treatment was predictive of OS (P < 0.001), with the high- and low-risk groups having a median OS of 10.2 [95% confidence interval (CI), 8.0-13.8] and 34.3 (95% CI, 28.5-40.5) months, respectively. The average tAUROC for the final model of OS based on 100 randomly split testing sets was 0.78 (first, third quartiles = 0.77, 0.79). IL6 and HGF are potential predictive biomarkers of OS benefit from BEV + IFN in patients with mRCC. The model based on key biological and clinical factors demonstrated predictive efficacy for OS. These markers warrant further validation in future anti-VEGF and immunotherapy in mRCC trials. See related commentaries by Mishkin and Kohn, p. 2722 and George and Bertagnolli, p. 2725.


Neuropeptide levels in nasal secretions from patients with and without chronic cough.
The pathophysiology of upper airway cough syndrome is not well understood. To investigate the levels of neuropeptides found in nasal mucus of subjects with and without the complaint of chronic cough. Preformed nasal mucus from 26 subjects complaining of postnasal drip with chronic cough and 17 without self-reported chronic cough was collected at the time of presentation. The nasal secretions were assayed for 3 neuropeptides-substance P (SP), calcitonin gene-related peptide (CGRP), and Neurokinin A (NKA)-that have been previously linked to chronic cough. Coughing subjects with postnasal drip have significantly higher levels of CGRP and SP than noncoughing subjects with postnasal drip (69.0 ng vs 4.6 ng, P < .001 and 4.5 ng vs 3.4 ng, P = .004). The differences in NKA levels in nasal secretions between coughing and noncoughing subjects did not reach statistical significance (16.3 ng vs 3.4 ng, P = .067). Both CGRP and SP levels are elevated in preformed nasal secretions of coughing subjects when compared with noncoughing subjects. Additional studies are needed to clarify whether CGRP and SP levels in preformed nasal secretions may assist in diagnosis or predicting treatment response in patients presenting with chronic cough.


Does Preoperative Surgical Delay Lead to Increased Postsurgical Length of Stay or Reoperation in Patients With Severe Odontogenic Infections?
While severe odontogenic infections can be life-threatening and emergent surgery can be required more often, surgical management in the operating room (OR) is completed as soon as feasible. However, provider schedules and OR availability can occasionally lead to longer delays before surgery, but their effect on outcomes is unknown. The purpose of this study was to determine the association of preoperative surgical delay with postsurgical length of stay (LOS) and reoperation in patients with severe odontogenic infections. The authors conducted a retrospective cohort study consisting of all adult patients treated in the OR with incision and drainage for odontogenic infections from 1/1/2015 to 7/30/2021 at a large, urban academic hospital. The primary predictor variable was the length of presurgical delay-the number of hours between arrival in the emergency department and the start of surgery. The primary outcome variable was the postsurgical LOS and the secondary outcome variable was the rate of reoperation. Demographics, medical history, exam findings, diagnosis, and treatment-related variables were also analyzed. Descriptive and bivariate analyses were performed along with multivariable linear and logistic regression. A P value of < .05 was considered significant. There were 401 patients included in the study with 50.9% men and a mean age of 39.1 years. Increased length of presurgical delay (hours) was associated with a decreased postsurgical LOS (β = -0.05 days, P = .01) and length of presurgical delay was not associated with reoperation (P = .51) in the unadjusted analyses. However, length of presurgical delay was not found to be associated with either LOS (β = -0.02, 95% confidence interval (CI) -0.05 to 0.01, P = .12) or reoperation (adjusted odds ratio (aOR) 1.0, 95% CI 0.96 to 1.02, P = .67) in the adjusted analyses. The association of decreased length of presurgical delay with increased postsurgical LOS in the unadjusted analysis could reflect the practice of rapid intervention for the most ill patients. After adjusting for number of spaces, a primary indicator of infection severity, length of presurgical delay was not associated with either LOS or return to the operating room.


Modeling of the biodynamic responses distributed at the fingers and palm of the hand in three orthogonal directions.
The objectives of this study were to develop models of the hand-arm system in the three orthogonal directions (xh, yh , and zh ) and to enhance the understanding of the hand vibration dynamics. A four-degrees-of-freedom (DOF) model and 5-DOF model were used in the simulation for each direction. The driving-point mechanical impedances distributed at the fingers and palm of the hand reported in a previous study were used to determine the parameters of the models. The 5-DOF models were generally superior to the 4-DOF models for the simulation. Hence, as examples of applications, the 5-DOF models were used to predict the transmissibility of a vibration-reducing glove and the vibration transmissibility on the major substructures of the hand-arm system. The model-predicted results were also compared with the experimental data reported in two other recent studies. Some reasonable agreements were observed in the comparisons, which provided some validation of the developed models. This study concluded that the 5-DOF models are acceptable for helping to design and analyze vibrating tools and anti-vibration devices. This study also confirmed that the 5-DOF model in the zh direction is acceptable for a coarse estimation of the biodynamic responses distributed throughout the major substructures of the hand-arm system. Some interesting phenomena observed in the experimental study of the biodynamic responses in the three directions were also explained in this study.


Chronic ingestion of cadmium and lead alters the bioavailability of essential and heavy metals, gene expression pathways and genotoxicity in mouse intestine.
Chronic ingestion of environmental heavy metals such as lead (Pb) and cadmium (Cd) causes various well-documented pathologies in specific target organs following their intestinal absorption and subsequent accumulation. However, little is known about the direct impact of the non-absorbed heavy metals on the small intestine and the colon homeostasis. The aim of our study was to compare the specific bioaccumulation and retention of Cd and Pb and their effect on the essential metal balance in primary organs, with those occurring specifically in the gastrointestinal tract of mice. Various doses of Cd (5, 20 and 100 mg l(-1)) and Pb (100 and 500 mg l(-1)) chloride salts were provided in drinking water for subchronic to chronic exposures (4, 8 and 12 weeks). In contrast to a clear dose- and time-dependent accumulation in target organs, results showed that intestines are poor accumulators for Cd and Pb. Notwithstanding, changes in gene expression of representative intestinal markers revealed that the transport-, oxidative- and inflammatory status of the gut epithelium of the duodenum, ileum and colon were specifically affected by both heavy metal species. Additionally, in vivo comet assay used to evaluate the impact of heavy metals on DNA damage showed clear genotoxic activities of Cd, on both the upper and distal parts of the gastrointestinal tract. Altogether, these results outline the resilience of the gut which balances the various effects of chronic Cd and Pb in the intestinal mucosa. Collectively, it provides useful information for the risk assessment of heavy metals in gut homeostasis and further disease's susceptibility.


Differential effects of single fatty acids and fatty acid mixtures on the phosphoinositide 3-kinase/Akt/eNOS pathway in endothelial cells.
Dietary fat composition is an important modulator of vascular function. Non-esterified fatty acids (NEFA) enriched in saturated fatty acids (SFA) are thought to reduce vascular reactivity by attenuating insulin signalling via vasodilator pathways (phosphoinositide 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS)) and enhancing signalling via pro-inflammatory pathways. To examine the effects of fatty acids on these pathways, human aortic endothelial cells were incubated with single fatty acids, and mixtures of these fatty acids to mimic typical NEFA composition and concentrations achieved in our previous human study. RNA was extracted to determine gene expression using real-time RT-PCR and cell lysates prepared to assess protein phosphorylation by Western blotting. Oleic acid (OA, 100 µM) was shown to down regulate expression of the insulin receptor, PTEN and a PI3K catalytic (p110β) and regulatory (p85α) subunit compared to palmitic, linoleic and stearic acids (P < 0.04), and promote greater eNOS phosphorylation at Ser1177. Both concentration and composition of the SFA and SFA plus n-3 polyunsaturated fatty acids (PUFA) mixtures had significant effects on genes involved in the PI3K/Akt pathway. Greater up-regulation was found with 800 than 400 µM concentration (respective of concentrations in insulin resistant and normal individuals), whereas greater down-regulation was evident with SFA plus n-3 PUFA than SFA mixture alone. Our findings provide novel insights into the modulation of the PI3K/Akt/eNOS pathway by single fatty acids and fatty acid mixtures. In particular, OA appears to promote signalling via this pathway, with further work required to determine the primary molecular site(s) of action.


Comparative metabolite fingerprinting of legumes using LC-MS-based untargeted metabolomics.
Legumes are a well-known source of phytochemicals and are commonly believed to have similar composition between different genera. To date, there are no studies evaluating changes in legumes to discover those compounds that help to discriminate for food quality and authenticity. The aim of this work was to characterize and make a comparative analysis of the composition of bioactive compounds between Cicer arietinum L. (chickpea), Lens culinaris L. (lentil) and Phaseolus vulgaris L. (white bean) through an LC-MS-Orbitrap metabolomic approach to establish which compounds discriminate between the three studied legumes. Untargeted metabolomic analysis was carried out by LC-MS-Orbitrap from extracts of freeze-dried legumes prepared from pre-cooked canned legumes. The metabolomic data treatment and statistical analysis were realized by using MAIT R's package, and final identification and characterization was done using MSn experiments. Fold-change evaluation was made through Metaboanalyst 4.0. Results showed 43 identified and characterized compounds displaying differences between the three legumes. Polyphenols, mainly flavonol and flavanol compounds, were the main group with 30 identified compounds, followed by α-galactosides (n = 5). Fatty acyls, prenol lipids, a nucleoside and organic compounds were also characterized. The fold-change analysis showed flavanols as the wider class of discriminative compounds of lentils compared to the other legumes; prenol lipids and eucomic acids were the most discriminative compounds of beans versus other legumes and several phenolic acids (such as primeveroside salycilic), kaempferol derivatives, coumesterol and α-galactosides were the most discriminative compounds of chickpeas. This study highlights the applicability of metabolomics for evaluating which are the characteristic compounds of the different legumes. In addition, it describes the future application of metabolomics as tool for the quality control of foods and authentication of different kinds of legumes.


A case report of myasthenia gravis associated with Hashimoto's thyroiditis.
An unusual case of myasthenia gravis is presented. The disease was clinically established in a 71-year-old Japanese woman by an electromyographic, pharmacologic test and anti-acetylcholine receptor (anti-AChR) antibodies demonstrated in the circulating blood. The coexistence of Hashimoto's thyroiditis was diagnosed by the presence of a diffuse thyroid enlargement, anti-thyroglobulin and anti-microsomal antibodies and a lowered thyroidal 131I uptake. A delusion of persecution developed during the treatment with pyridostigmine and ephedrine chloride, but the symptom disappeared after discontinuing the use of ephedrine chloride.


Antibiotic resistance among indicator bacteria isolated from healthy pigs in New Zealand.
To determine the resistance to antibiotics among the indictor bacteria, Escherichia coli and Enterococcus spp, isolated from the faeces of healthy pigs on three conventional pig farms and one organic farm in the North Island of New Zealand. Faecal samples, collected at intervals between March and October 2001, were plated onto MacConkey agar and Slanetz-Bartley agar and examined after 1-3 days incubation for colonies resembling E. coli and Enterococcus spp, respectively. Typical colonies were subcultured for further identification and storage. The isolates were tested for antibiotic resistance, using disc diffusion, to ampicillin, gentamicin, streptomycin, and tetracycline. Escherichia coli isolates were also tested for resistance to ciprofloxacin, cotrimoxazole and neomycin. Enterococcus spp isolates were also tested for resistance to vancomycin, erythromycin and virginiamycin. A total of 296 E. coli and 273 Enterococcus spp isolates were obtained from the three conventional farms, and 79 E. coli and 80 Enterococcus spp isolates were obtained from the organic farm. All the E. coli isolates from both the conventional and organic pig farms were susceptible to ciprofloxacin, and all the Enterococcus spp isolates were susceptible to ampicillin, gentamicin and vancomycin. Isolates of E. coli from conventional pig farms were resistant to gentamicin (0.7%), neomycin (0.7%), ampicillin (2.7%), cotrimoxazole (11%), streptomycin (25%) and tetracycline (60%). Enterococcus spp isolates from the same farms were resistant to erythromycin (68%), tetracycline (66%), streptomycin (54%) and virginiamycin (49%). By contrast, for the organic pig farm <or=5% of either the E. coli or the Enterococcus spp isolates were resistant to any of the antibiotics tested. On commercial pig farms which used antimicrobial agents, there was a higher level of antimicrobial resistance in the E. coli and Enterococcus spp cultured from the faeces of pigs compared with an organic farm which used no antibiotics. Overall levels of antibiotic resistance in the indicator bacteria isolated from conventional pig farms in this study were similar to those reported for indicator bacteria from pigs in Europe.


Obesity in Infertile Women, a Cross-Sectional Study of the United States Using NSFG 2011-2019.
Reproductive health can be affected by obesity through various mechanisms. Obesity-associated inflammatory markers and altered hormones can have direct and indirect impacts on female reproductive health. However, little is known about obesity prevalence and trend among infertile women and obesity association with infertility in reproductive-age women of the U.S. In a cross-sectional study, we sought to conduct a secondary analysis of National Survey of Family Growth (NSFG) data from 2011 to 2019. A total of 6,035 infertile and non-pregnant fecund women aged 20-44 years were included in a nationally representative sample of the U.S. The weighted prevalence of obesity (BMI ≥ 30) among infertile women was 41.63% for the period 2011-2019. Obese women had 62% higher odds of infertility (95% CI 1.24, 2.17) compared to non-obese women of reproductive age (20-44 years). However, there was no specific trend of obesity among infertile and non-pregnant fecund women aged 20-44 years in the U.S. from 2011 to 2019. Given the negative impact of obesity on female reproductive health and in light of our results, it is important to counsel obese infertile reproductive-age women of the U.S. about behavioral changes that include weight management. Future longitudinal studies are needed to evaluate the risk of infertility among obese women.


Effects of honey, sucrose and glucose on blood glucose and C-peptide in patients with type 1 diabetes mellitus.
This study was a case control cross sectional study that was conducted on 50 patients with type 1 diabetes mellitus and 30 controls without diabetes. The mean age of patients was 10.02 years. Oral sugar tolerance tests using glucose, sucrose and honey and measurement of fasting and postprandial serum C-peptide levels were done for all subjects in three separate sittings. The glycemic index (GI) and the peak incremental index (PII) were then calculated for each subject. Honey, compared to sucrose, had lower GI and PII in both patients and controls (P < 0.01). In both patients and controls, the increase in the level of C-peptide after honey was significant when compared with either glucose or sucrose (P < 0.01). Because of its possible stimulatory effect on diseased beta cells, honey might be considered in future therapeutic trials targeting beta cells of pancreas.


The Effect of Combined Therapy ICS/LABA and ICS/LABA plus Montelukast in Patients with Uncontrolled Severe Persistent Asthma Based on the Serum IL-13 and FEV1.
IL-13 is one of many cytokines responsible for the chronic inflammation of asthma. The aim of this study was to determine the effect of combined therapy ICS/LABA and ICS/LABA plus Montelukast in patients with uncontrolled severe persistent asthma by analyzing of serum IL-13 and FEV1 before the treatment and after 6 months of therapy. In study we included two groups. First group with 27 patients were treated with ICS/LABA. Second group with 29 patients were treated with ICS/LABA plus Montelukast. In each of them were measured serum IL-13 levels by the ELISA method and FEV1 before and after 6 months of treatment. Results were statistically analyzed according to the Wilcoxon Pairs Test and T-test. The obtained results in both groups showed that the serum IL-13 before the start of therapy were much higher and after 6 months of treatment significantly reduces their value, which in the second group were more expressed. The difference in the average value of FEV1 in both groups before and after therapy was statistically significant. Treatment with ICS/LABA plus Montelukast proved superior compared to therapy of ICS/LABA in patients with uncontrolled severe persistent asthma and allows achievement of well controlled of asthma with subjective clinical improvement.


Rapid analysis of meat floss origin using a supervised machine learning-based electronic nose towards food authentication.
Authentication of meat floss origin has been highly critical for its consumers due to existing potential risks of having allergic diseases or religion perspective related to pork-containing foods. Herein, we developed and assessed a compact portable electronic nose (e-nose) comprising gas sensor array and supervised machine learning with a window time slicing method to sniff and to classify different meat floss products. We evaluated four different supervised learning methods for data classification (i.e., linear discriminant analysis (LDA), quadratic discriminant analysis (QDA), k-nearest neighbors (k-NN), and random forest (RF)). Among them, an LDA model equipped with five-window-extracted feature yielded the highest accuracy values of >99% for both validation and testing data in discriminating beef, chicken, and pork flosses. The obtained e-nose results were correlated and confirmed with the spectral data from Fourier-transform infrared (FTIR) spectroscopy and gas chromatography-mass spectrometry (GC-MS) measurements. We found that beef and chicken had similar compound groups (i.e., hydrocarbons and alcohol). Meanwhile, aldehyde compounds (e.g., dodecanal and 9-octadecanal) were found to be dominant in pork products. Based on its performance evaluation, the developed e-nose system shows promising results in food authenticity testing, which paves the way for ubiquitously detecting deception and food fraud attempts.


Natural cytotoxicity of haemopoietic cell populations against murine lymphoid tumours.
Homozygous nude and normal mice of 3 strains, BALB/c, CBA and C57BL, were used as sources of nucleated haemopoietic "natural killer" (NK) cells. These killer cells could lyse a wide range of syngeneic and allogeneic lymphoid tumour cell lines in vitro, and it was found that cell suspensions from nude mice were always significantly more active than those from normal mice, and that the most active effector population was a polymorph-enriched peritoneal-exudate cell suspension. Eosinophils did not appear to be involved in the phenomenon, and mononuclear peritoneal-exudate cell suspensions were actually highly inhibitory. Three non-lymphoid tumours, a carcinoma, a fibrosarcoma and a mastocytoma, were totally resistant to in vitro lysis. Although all susceptible tumour cell lines were C-type virus-associated, not all of these tumours were killed by all strain sources of spleen cells, indicating a specificity of killing.


Immunomodulation of neutrophils and platelets by TNF blockage in patients with juvenile idiopathic arthritis.
Juvenile idiopathic arthritis (JIA) is a multifactorial autoimmune disease mediated by both adaptive and innate immunity. The role of neutrophils in the pathogenesis of autoimmune diseases is well-established; however, in JIA they are still markedly understudied. Here, we explored the neutrophil features and role of platelet-neutrophil aggregates in JIA patients and assessed the effect of TNF inhibitor (TNFi) therapy. We provide evidence of dysbalanced neutrophil subsets in JIA patients, with a shift towards immature and suppressive subpopulations that lack the cell-adhesion molecules. Correspondingly, patient sera contained high amounts of neutrophil- and platelet-related products. Transcriptomic analysis revealed neutrophil degranulation as the most affected process by TNFi therapy, which was mirrored by the decrease in degranulation products in the patient sera. Toll-like receptors -4, -7, and - 8 signaling pathways are particularly hyperresponsive in patients, but are strongly suppressed by TNFi. Overall, our study demonstrates augmented neutrophil and platelet responses in JIA patients.


Endoscopic assisted antral window approach for type III nasopharyngeal angiofibroma with infratemporal fossa extension.
To assess the efficacy and safety of endoscopic assisted antral window approach in advanced nasopharyngeal angiofibroma with infratemporal fossa extension. Sixteen cases diagnosed as juvenile nasopharyngeal angiofibroma type III with infratemporal fossa extension were surgically managed using endoscopic assisted antral window approach (group A) and compared with another group of similar number that were managed using endoscopic assisted midfacial degloving (group B). Inclusion criteria were type III JNA with infratemporal fossa extension and a minimum follow-up of 2 years. Operative time, blood loss, adverse events and recurrences were recorded in all cases. The amount of blood lost in group A was significantly less than group B. The operative time of group A was significantly less than group B. No major complications were seen in both groups. Twenty-eight patients showed complete tumor clearance. Four recurrences were seen: two in group A and two in group B. Endoscopic assisted antral window approach provides a safe, reliable, effective and minimally invasive technique in management of type III JNA with infratemporal fossa extension. Preoperative embolization is a safe measure in the experienced hands that helps to reduce intraoperative blood loss and improves the quality of the surgical field.


Sex difference in the mediation roles of an inflammatory factor (hsCRP) and adipokines on the relationship between adiposity and blood pressure.
Mounting evidence shows that adiposity is closely related to elevated blood pressure (BP); however, the underlying mechanism of this relationship is not clearly understood. We aimed to assess the mediating effects of an inflammatory factor (high sensitivity C-reactive protein, hsCRP) and adipokines, as well as any sex differences, on the relationship between adiposity and BP among Chinese overweight or obese adults. A total of 1221 overweight or obese subjects aged 20-55 years who lived in Beijing for at least 1 year were recruited in 2014. The percentage of body fat (PBF) was examined using dual energy X-ray absorptiometry (DXA). Mediation analyses were conducted to examine the mediation of hsCRP, leptin, and adiponectin on the relationship between adiposity and BP by sex. Serum hsCRP and leptin levels were positively associated with PBF (P < 0.001) in males and females. Adiponectin and leptin levels were associated with systolic BP (SBP), but only in males, while in females, the hsCRP level was associated with SBP and diastolic BP (DBP). In males, leptin mediated 22.5% of the relationship between adiposity and SBP and 31.4% for DBP (mediation effect = 0.059 and 0.068, respectively, P < 0.05). However, in females, hsCRP mediated 30.2% of the relationship between adiposity and SBP and 29.5% for DBP (mediation effect = 0.058 and 0.063, respectively, P < 0.001). There are sex differences in the mediation roles of hsCRP and adipokines on the relationship between adiposity and BP. Leptin mediated part of the relationship between adiposity and BP in males, while hsCRP mediated the relationship in females. Our results provide evidence for adiposity-related high BP control measures in a sex-specific manner and provide hints for exploring the potential mechanisms of obesity-related hypertension.


In vitro human epidermal and polyethylene membrane penetration and retention of the sunscreen benzophenone-3 from a range of solvents.
To study epidermal and polyethylene membrane penetration and retention of the sunscreen benzophenone-3 (BP) from a range of single solvent vehicles and evaluate solvent effects on permeability parameters. The solubility of BP was measured in a number of solvents. Penetration of BP across human epidermis and high density polyethylene (HDPE) membranes was studied from 50% saturated solutions in each solvent. Maximal BP fluxes from the solvents across the two membranes varied widely. Highest fluxes were observed from 90% ethanol (EtOH) for epidermis and from isopropyl myristate (IPM) and C12-15 benzoate alcohols (C12-15 BA) for HDPE membrane. Both the flux and estimated permeability coefficient and skin-vehicle partitioning of BP appeared to be related to the vehicle solubility parameter (delta(v)). The major effects of solvents on BP flux appear to be via changes in BP diffusivity through the membranes. Minimal penetration of sunscreens such as BP is best achieved by choosing vehicles with a delta(v) substantially different to the solubility parameter of the membrane.


INFRAFRONTIER: a European resource for studying the functional basis of human disease.
Ageing research and more generally the study of the functional basis of human diseases profit enormously from the large-scale approaches and resources in mouse functional genomics: systematic targeted mutation of the mouse genome, systemic phenotyping in mouse clinics, and the archiving and distribution of the mouse resources in public repositories. INFRAFRONTIER, the European research infrastructure for the development, systemic phenotyping, archiving and distribution of mammalian models, offers access to sustainable mouse resources for biomedical research. INFRAFRONTIER promotes the global sharing of high-quality resources and data and thus contributes to data reproducibility and animal welfare. INFRAFRONTIER puts great effort into international standardisation and quality control and into technology development to improve and expand experimental protocols, reduce the use of animals in research and increase the reproducibility of results. In concert with the research community and the International Mouse Phenotyping Consortium (IMPC), INFRAFRONTIER is currently developing new pilot platforms and services for the research on ageing and age-related diseases.


Recognition and differential diagnosis of enlarged extraocular muscles in computed tomography.
We found enlargement of the extraocular muscles in 70 patients out of 603 orbit studies, of whom 310 had exophthalmos. The majority (46 of 70) had the eye signs of Graves' disease. Arteriovenous malformations and carotid cavernous fistulas can cause enlargement of the extraocular muscles by a diffuse increase in orbital venous pressure, Acute orbital myositis can be distinguished from other forms of pseudotumor by the presence of a single enlarge extraocular muscle with associated inflammatory findings which responds to corticosteroid therapy. Neoplasms may invade extraocular muscles or compress their venous drainage causing secondary muscle enlargement. In all these patients the presence of a mass was correctly identified. The ability of the computed tomography scanner to recognize abnormalities of the extraocular muscles represents a significant advance in classification and diagnosis of the causes of exophthalmos.


Is metallothionein involved in deposition of cadmium in bile?
1. By use of our metallothionein (Mt) antibody in Western blotting and techniques for investigating protein metal-binding capacity, the form and content of Mt in bile, collected from cadmium (Cd) treated rats, were studied. 2. It was found that bile is an excretory pathway for Mt from the liver. 3. However, only immunoreactive proteins of higher molecular weight, probably representing polymerized forms of Mt or Mt bound to other proteins, were detected. 4. No monomeric Mt was found. 5. Excretion of Mt is probably not of importance in biliary metal transport.


Fat in liver/muscle correlates more strongly with insulin sensitivity in rats than abdominal fat.
Intrahepatic or intramuscular lipid (IHL/IML) content has been reported to be correlated with insulin resistance. Visceral fat has also been shown to be associated with insulin resistance. Thus, we investigated whether IHL/IML or visceral fat content is more closely associated with insulin resistance. Twenty Sprague-Dawley rats were divided into two groups based on regular chow diet (RCD) or high-fat diet (HFD; 40% fat). The insulin-sensitivity index (ISI) was determined by euglycemic glucose clamp study, the amount of visceral fat by computed tomography (CT), and the IHL/IML content by magnetic resonance spectroscopy (MRS). Weight, food, and water intake, physical activity, energy expenditure, lipid profile, adiponectin, and high-sensitivity C-reactive protein (hsCRP) levels were measured. At the study end point, visceral fat, and the IHL/IML content were higher in the HFD group than in the RCD group. The IHL/IML content was more highly correlated with ISI than was visceral fat amount. Stronger correlations were also found between adiponectin or hsCRP level and IML/IHL content than visceral fat, especially in the HFD group. Furthermore, the IHL/IML content was significantly associated with the ISI in the multiple regression models but visceral fat was not. There was clear discrimination between RCD and HFD groups in scatter plots of IML/IHL against the ISI, but substantial overlap in that of visceral fat against the ISI. This result suggests that IHL/IML contents are closely related with insulin resistance or atherosclerosis and is a better metabolic index of insulin sensitivity than the visceral fat.


Inferring the phase response curve from observation of a continuously perturbed oscillator.
Phase response curves are important for analysis and modeling of oscillatory dynamics in various applications, particularly in neuroscience. Standard experimental technique for determining them requires isolation of the system and application of a specifically designed input. However, isolation is not always feasible and we are compelled to observe the system in its natural environment under free-running conditions. To that end we propose an approach relying only on passive observations of the system and its input. We illustrate it with simulation results of an oscillator driven by a stochastic force.


Buccinator synkinesis treated by botulinum toxin in facial palsy and hemifacial spasms.
To assess botulinum toxin treatment for buccinator muscle synkinesis including: how often the synkinesis was troublesome; who benefitted and how from the treatment; and what were the adverse effects, ideal dosage, and injection site. Facial palsy (FP) patients and patients with hemifacial spasms who were attending for multiple site botulinum-toxin treatment for facial sequelae were assessed for buccinator synkinesis. The study group comprises those experiencing buccinator synkinesis with associated bothering symptoms who were willing to try injection also to the buccinator muscle. During 9/2017-12/2019, 126 different patients with facial sequelae were treated with multiple-site botulin-toxin injections by the author. Of them, 83 (66%) received injection also for buccinator synkinesis and 66/82 (80%) wanted to continue with the buccinator injections. The most remarkable results were seen with FP patients biting the mucus membrane of their cheek: usually the biting ceased totally. Patients with powerful hemifacial cheek spasms also experienced cessation of the spasms, contrasting any previous treatments. Adverse effects were mostly mild: slight weakness of the corner of the mouth or additional leakage of saliva or liquids. Only a few patients experienced more pronounced adverse effects. The most posterior contracting part of the buccinator muscle proved to be the best site for the injection. Buccinator synkinesis was very common and its treatment gave many patients additional relief from facial sequelae symptoms. Professionals treating patients with synkinesis and hemifacial spasms should add well-tolerated buccinator injections to their repertoire of injection sites.


Effects of dibromothymoquinone on mung bean mitochondrial electron transfer and membrane fluidity.
The effects of the quinone analog dibromothymoquinone on electron transfer in isolated mung bean mitochondria are described. Both the main, cyanide-sensitive and the alternate, cyanide-insensitive pathways are inhibited by dibromothymoquinone but in markedly different fashions. Half-maximal inhibition appeared at 40 microM and 20 microM dibromothymoquinone for the cyanide-sensitive and alternate pathways, respectively. With succinate as the electron donor, dibromothymoquinone inhibited the alternate pathway at a single site; showing a mixed, non-competitive type inhibition. On the succinate, cyanide-sensitive pathway dibromothymoquinone showed two sites of inhibition and neither coincides with the site of inhibition associated with the alternate pathway. With malate as the electron donor, two sites of inhibition by dibromothymoquinone were observed regardless of the pathway measured. Dibromothymoquinone also inhibited the rate of valinomycin-induced swelling of isolated mung bean mitochondria. Steady-state kinetics showed the inhibition to be non-competitive with respect to valinomycin. Additionally dibromothymoquinone was observed to increase the fluorescence polarization associated with the hydrophobic probe 1,6-diphenylhexatriene. The results indicated that dibromothymoquinone decreased the fluidity of the inner mitochondrial membrane and suggested that the inhibition of mitochondrial electron transfer by dibromothymoquinone may be associated with this decrease in membrane fluidity. The relationship of the multisite nature of the inhibition of electron transfer by dibromothymoquinone and the possible role of mobile electron carriers such as ubiquinone on the main and alternate respiratory pathways of higher plants is discussed.


Biliary enteric fistulas. Management of 47 cases in native Americans.
The management of 47 patients with spontaneous biliary fistulas is reported. Thirteen did not have surgery, and another 8, although operated on, did not have the fistulas closed. In none of these patients have recurrent biliary symptoms developed. The 26 patients who did have surgical closure of the fistula were operated on, in nearly every instance, for symptoms of residual cholelithiasis or choledocholithiasis, and in only 4 of these patients was the fistula known to exist preoperatively.


[Study of individual variations of the composition of human parotid saliva collected under stimulation].
Human parotid saliva was studied for its qualitative and quantitative composition; alpha-amylase activity, immunoglobulin A and composition were investigated and showed significant variations from one individual sample to another. The same phenomenon was observed with the inorganic components: CA, P, K, Mg, Na, Cl. The influence of the frequency and length of collection of parotid saliva is discussed.


Association of comorbidities with clinical outcomes in patients after acute myocardial infarction.
Multimorbidity becomes more prevalent in patients admitted for acute myocardial infarction (AMI). We investigated the association of an increasing number of comorbidities with the excess risk of in-hospital mortality and other clinically outcomes in hospitalized AMI patients. In this population-based cohort study, we analyzed 104'906 admissions for AMI between 2012 and 2018 in Switzerland. We stratified patients based on four different age categories and investigated the association of the number of five common comorbidities (diabetes, chronic kidney-, chronic obstructive pulmonary-, cerebrovascular-, and peripheral artery disease) and risk of in-hospital mortality and other outcomes. A total of 5'029 admitted AMI patients (4.8%) died during the hospital stay. We found a stepwise increase in mortality risk with each additional comorbidity. Compared to AMI patients with no comorbidity, comorbid patients had a 26% increased risk for mortality (adjusted odds ratio [OR] 1.26, 95% confidence interval [CI] 1.20 to 1.33) with a pronounced association in younger patients. The overall risk for ICU admission, prolonged length of hospital stay (LOS), and 30-day readmission was higher in comorbid patients as compared to those without a comorbidity of interest (ICU: OR 1.19, 95% CI 1.16 to 1.22; LOS: OR 1.84, 95% CI 1.79 to 1.89; Readmission: OR 1.23, 95% CI 1.19 to 1.28), respectively. Again, the association of the numbers of prevalent comorbidities with adverse outcomes was strongest in the youngest patient population. In patients with AMI, the burden of comorbidities has a strong association with in-hospital mortality and other adverse outcomes - especially in younger patients.


Coexistence of the stigmoid body and estrogen receptor in some neuronal groups involved in rat reproductive functions.
Recent immunohistochemical studies have suggested that the forebrain distribution of stigmoid bodies, marked by an antibody against placental aromatase-associated antigen X-P2 (PAX), overlaps with that of the common binding sites of androgen and estrogen. In the present light- and electron-microscopy study the coexistence of stigmoid bodies and estrogen receptors (EsR) is immunohistochemically examined and quantitatively analyzed in the medial preoptic region, part of the bed nucleus of the stria terminalis and part of the medial amygdaloid nucleus of young female rats. Light microscopy with double immunostaining for PAX and EsR in all three regions indicates that 75-84% of the total of PAX-immunoreactive stigmoid structures are present in neurons which also contain EsR-immunoreactive nuclei, and that 75-78% of EsR-immunoreactive neurons contain PAX-immunoreactive inclusions. Electron microscopic analysis confirms that 70-80% of stigmoid body-containing neurons have EsR-immunoreactive nuclei. These results indicate that the majority of the stigmoid bodies and EsRs intimately coexist, strongly suggesting a functional interrelationship in brain regions which are involved in rat reproductive functions. Stigmoid bodies may play a role in subneuronal EsR mechanisms associated with aromatization in these sex steroid targets in rat brain.


Carbamazepine and phenytoin in epilepsies refractory to barbiturates: efficacy, toxicity and mental function.
A group of 51 patients with chronic cryptogenic or symptomatic localized epilepsy refractory to therapy with barbiturates underwent progressive substitution with phenytoin or carbamazepine, in standardized and randomized fashion. After drug changes were completed two thirds of the patients remained seizure free during a period of 6 months. A clearer effect of phenytoin and carbamazepine was seen on secondary generalized than on partial seizures. The frequency of severe side effects decreased after the change to phenytoin and carbamazepine. The group on carbamazepine improved in immediate and late recall, and in immediate and late recognition of pictures. The group on phenytoin improved significantly in the Stroop test. Patients changed to phenytoin, but not those changed to carbamazepine, became significantly more aggressive, anxious and depressive than when on phenobarbital, as measured by subjective scales. The results indicate that patients should not be considered refractory to antiepileptic drug therapy while on barbiturates. Cognitive dysfunction and mood changes observed in epilepsy may be temporary and dependent on the presence of seizures and/or on use of barbiturates.


Sequential immunological targeting of chronic experimental arterial allograft.
Arterial wall is the main site involved in the chronic rejection process. The rat aortic allograft model was used here to characterize and describe the sequential evolution of the different targets and effectors of arterial wall immunological injury and response during arterial allograft rejection. Rat abdominal aortae were isografted or allografted from Brown-Norway to Lewis rats. Endothelial and smooth muscle cell injury and humoral and cellular immunological effectors were characterized from 0 to 60 days after transplantation using a battery of specific antibodies. The intimal proliferative response was also characterized over this time. Isografted Brown-Norway aorta adventitia had very few cellular components, which suggests that donor adventitia would be poorly antigenic in allografts. In contrast, allograft adventitia was the site of a major inflammatory cell invasion in which the expression of an adhesion molecule by colonizing capillary endothelial cells could play a main role. This adventitial infiltration continued as long as medial smooth muscle persisted. The luminal endothelial cells disappeared early, probably associated with macrophage margination. In contrast, medial smooth muscle cell disappearance occurred later and was specifically targeted by immunoglobulins. Intimal proliferation was the most delayed phenomenon, involving both inflammatory cell infiltration at an early stage and later myofibroblastic proliferation, and could be related to the specific expression of growth factors in this layer. The rat aortic allograft model appeared useful for characterizing specific targets and effectors of chronic arterial graft rejection, demonstrating an early stage of endothelial injury and the presence of immunoglobulins involved in chronic medial smooth muscle cell injury.


National Database for Autism Research (NDAR): Big Data Opportunities for Health Services Research and Health Technology Assessment.
The National Database for Autism Research (NDAR) is a US National Institutes of Health (NIH)-funded research data repository created by integrating heterogeneous datasets through data sharing agreements between autism researchers and the NIH. To date, NDAR is considered the largest neuroscience and genomic data repository for autism research. In addition to biomedical data, NDAR contains a large collection of clinical and behavioral assessments and health outcomes from novel interventions. Importantly, NDAR has a global unique patient identifier that can be linked to aggregated individual-level data for hypothesis generation and testing, and for replicating research findings. As such, NDAR promotes collaboration and maximizes public investment in the original data collection. As screening and diagnostic technologies as well as interventions for children with autism are expensive, health services research (HSR) and health technology assessment (HTA) are needed to generate more evidence to facilitate implementation when warranted. This article describes NDAR and explains its value to health services researchers and decision scientists interested in autism and other mental health conditions. We provide a description of the scope and structure of NDAR and illustrate how data are likely to grow over time and become available for HSR and HTA.


Cancer Research UK procedures in manufacture and toxicology of radiotracers intended for pre-phase I positron emission tomography studies in cancer patients.
Radiolabelled compounds formulated for injection (radiopharmaceuticals), are increasingly being employed in drug development studies. These can be used in tracer amounts for either pharmacokinetic or pharmacodynamic studies. Such radiotracer studies can also be carried out early in man, even prior to conventional Phase I clinical testing. The aim of this document is to describe procedures for production and safety testing of oncology radiotracers developed for imaging by positron emission tomography in cancer patients. We propose strategies for overcoming the inability to produce compounds in sufficient quantities via the radiosynthetic routes for full chemical characterisation and toxicology testing including (i) independent confirmation as far as possible that the stable compound associated with the radiopharmaceutical is identical to the non-labelled compound, (ii) animal toxicity studies with > or = 10 times (typically 100 times) the intended tracer dose in humans scaled by body surface area, and (iii) patient monitoring during the radiotracer positron emission tomography clinical trial.


Developmental regulation of the male urogenital papilla in the male marine teleost black rockfish, Sebastes schlegelii (Hilgendorf, 1880)†.
The male external genitalia of the black rockfish (Sebastes schlegelii Hilgendorf, 1880) is a fleshy protrusion known as the urogenital papilla (UGP), which functions to deliver sperm into the female reproductive tract for internal fertilization. It is not known which genes regulate the development of the UGP. The aim of this study was to identify key genes that regulate the development of the UGP in black rockfish and to determine the distribution of androgen receptor gene (ar) in the UGP. A total of 26 adult males and 560 juvenile fish were used in the experiment, in which we divided all normally developing juveniles into normal development and androgen groups. We added methyltestosterone solution (100 μg/l) to the androgen group-treated fish tank, soaked for 2 h per day for 38 days, and sampled 5~10 samples each time every 5 days during the culture process. Gene expression changes related to UGP were analyzed with tissue specificity between control and androgen groups during sex differentiation, adult male maturation, and the copulation stage (September to December) using real-time quantitative polymerase chain reaction. The expression of ar was also localized by two-color in situ hybridization in the UGP region of juvenile fish. Androgen treatment enhanced ar expression levels and the ar signal was stronger in the UGP region of both adult breeding fish and androgen-treated juvenile fish. This study provides insights into the regulation of the external genitalia of black rockfish and presents vital information for the artificial breeding of viviparous fish.


Two-dimensional DOSY experiment with Excitation Sculpting water suppression for the analysis of natural and biological media.
The Bipolar Pulse Pair Stimulated Echo NMR pulse sequence was modified to blend the original Excitation Sculpting water signal suppression. The sequence is a powerful tool to generate rapidly, with a good spectrum quality, bidimensional DOSY experiments without solvent signal, thus allowing the analysis of complex mixtures such as plant extracts or biofluids. The sequence has also been successfully implemented for a protein at very-low concentration in interaction with a small ligand, namely the salivary IB5 protein binding the polyphenol epigallocatechine gallate. The artifacts created by this sequence can be observed, checked and removed thanks to NPK and NMRnotebook softwares to give a perfect bidimensional DOSY spectrum.


Polymorphisms in the immunoregulatory genes are associated with hematopoietic recovery and increased susceptibility to bacterial infections in patients with thalassaemia major undergoing matched related hematopoietic stem cell transplantation.
In this study, the impact of polymorphisms in the genes of proinflammatory (IL-β, TNF-α, IL-6, IFN-γ), anti-inflammatory (transforming growth factor [TGF]-β, IL-10, IL-Ra), and other immunoregulatory factors (FcγRIIa, NOS3) along with the conventional risk factors on the rate of hematopoietic recovery and first episodes of bacterial, viral, or invasive fungal infections in 102 patients with β-thalassaemia major who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with relatively uniform protocols at our center from June 1995 to June 2004 with a minimum follow-up of at least 2 years were studied retrospectively for 180 days after hematopoietic stem cell transplantation (HSCT). Our data show that (1) donor IL-1RN∗2/2 (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.17-5.09; P = .018) and FCγRIIA +4481G/G genotypes (HR, 3.1; 95% CI, 1.56-6.31; P = .001) increased the incidence of bacterial infection; (2) fungal infection was increased in recipients with whose donors had IFN-γ +874T/T genotype (HR, 3.8; 95% CI, 1.08-13.62; P = .037); (3) time to neutrophil recovery was shorter in splenectomized patients (HR, 3.1; 95% CI, 1.70-5.64; P < .001), donors without IL-10 -1082A, -819T, and -592A haplotype (HR, 1.6; 95% CI, 1.02-2.39; P = .039), and recipients with IFN-γ +874A/A genotype (HR, 1.6; 95% CI, 1.05-2.56; P = .029); and (4) time to platelet recovery was shorter in patients with IL-10 -1082A/A genotype (HR, 1.8; 95% CI, 1.14-2.68; P = .010) and with donors having TNF-α -308G/G genotypes (HR, 1.8; 95% CI, 1.06-2.93; P = .028). These data suggest that outcome after allogeneic stem cell transplantation could be affected by many factors. The mechanisms by which they bring about such impact needs further evaluation.


Spectrum of exercise intolerance in 45 patients with Ebstein's anomaly and observations on exercise tolerance in 11 patients after surgical repair.
To determine the effects of definitive operation for Ebstein's anomaly on rest and exercise cardiorespiratory function, cycle exercise studies were performed on 38 patients with Ebstein's anomaly before definitive operation and on 11 patients after operation. An atrial septal defect was present in 29 of the 38 preoperative patients and in none of the postoperative patients. Seven of the postoperative patients had tricuspid valvuloplasty and four had valve replacement. Exercise tolerance, as defined by maximal oxygen uptake, was significantly greater in patients after operation for Ebstein's anomaly than in the preoperative patients. However, exercise tolerance for preoperative patients without an atrial septal defect was similar to that for postoperative patients. Tricuspid valve repair or replacement appeared to affect favorably cardiac output response to exercise. Rest systemic arterial oxygen saturation increased from 88 to 95% and exercise saturation from 77 to 93% after operation. Rest ventilatory equivalent for oxygen decreased from 48 +/- 13 preoperatively to 37 +/- 6 postoperatively, and exercise ventilatory equivalent for oxygen decreased from 53 +/- 23 preoperatively to 38 +/- 6 postoperatively. Definitive operation (tricuspid valvuloplasty or replacement and atrial septal defect closure) for Ebstein's anomaly results in significant improvement of exercise tolerance, normalization of systemic arterial oxygen saturation and reduction of excess ventilation at rest and during exercise.


Thyroid hormone levels and protein binding in patients on long-term diphenylhydantoin treatment.
The effect of long-term diphenylhydantoin (DPH) treatment on thyroid hormone concentrations and protein binding was determined in a randomized controlled trial. As has been demonstrated previously, total thyroxine (T4) concentrations were significantly depressed in patients on DPH. There was no significant effect on indirect indices of protein binding of thyroid hormones, and the free thyroxine index (FTI) was also significantly depressed. Triiodothyronine (T3) and thyrotrophin (TSH) concentrations were either unaffected, or only very slightly affected by DPH. Significant effects on the FTI were still apparent 4 weeks after discontinuing treatment. It is concluded that the depression of total T4 levels observed in vivo is not due solely to diminished protein binding, but may instead be largely explained by reports suggesting enhanced degradation of T4 following DPH therapy.


The effect of particulate air pollution on emergency admissions for myocardial infarction: a multicity case-crossover analysis.
Recently, attention has focused on whether particulate air pollution is a specific trigger of myocardial infarction (MI). The results of several studies of single locations assessing the effects of ambient particular matter on the risk of MI have been disparate. We used a multicity case-crossover study to examine risk of emergency hospitalization associated with fine particulate matter (PM) with aerodynamic diameter < 10 microm (PM10) for > 300,000 MIs during 1985-1999 among elderly residents of 21 U.S. cities. We used time-stratified controls matched on day of the week or on temperature to detect possible residual confounding by weather. Overall, we found a 0.65% [95% confidence interval (CI), 0.3-1.0%] increased risk of hospitalization for MI per 10 microg/m3 increase in ambient PM10 concentration. Matching on apparent temperature yielded a 0.64% increase in risk (95% CI, 0.1-1.2%). We found that the effect size for PM10 doubled for subjects with a previous admission for chronic obstructive pulmonary disease or a secondary diagnosis of pneumonia, although these differences did not achieve statistical significance. There was a weaker indication of a larger effect on males but no evidence of effect modification by age or the other diagnoses. We also found that the shape of the exposure-response relationship between MI hospitalizations and PM10 is almost linear, but with a steeper slope at levels of PM10 < 50 microg/m3. We conclude that increased concentrations of ambient PM10 are associated with increased risk of MI among the elderly.


Biosynthesis of the cell surface sialomucin complex of ascites 13762 rat mammary adenocarcinoma cells from a high molecular weight precursor.
Cell surfaces of metastatic 13762 ascites rat mammary adenocarcinoma cells are covered with a sialomucin complex composed of the high Mr sialomucin ASGP-1 (approximately 600,000) and a concanavalin A-binding, integral membrane glycoprotein ASGP-2 (120,000). Antibodies prepared against ASGP-2 and deglycosylated ASGP-1 react on immunoblots of ascites cells or their isolated microvilli with the Mr = 120,000 species and the high Mr sialomucin, respectively. No cross-reactivity was observed. Under complex dissociating conditions, anti-ASGP-2 immunoprecipitated primarily components of Mr = 120,000 and about 400,000 from lysates of cells labeled for 1 h with mannose, glucosamine, and threonine. Under similar conditions, anti-ASGP-1 immunoprecipitated the Mr = 400,000 component and a second major labeled component of about 330,000. Pulse-chase labeling with 35S-labeled amino acids followed by immunoprecipitation with anti-ASGP-2 indicated a precursor-product relationship for the Mr = 400,000 component, designated pSMC-1 (precursor, sialomucin complex), and ASGP-2. Similar pulse-chase analyses of threonine-labeled cells using anti-ASGP-1 showed equivalent amounts of immunoprecipitated pSMC-1 and pSMC-2, both of which disappeared with kinetics similar to those observed for pSMC-1 immunoprecipitated with anti-ASGP-2. A precursor-product relationship of both pSMC-1 and pSMC-2 to ASGP-1 was suggested by combined precipitations with anti-ASGP-1 and peanut agglutinin, which precipitates ASGP-1 specifically. Immunoblot and lectin blot analyses indicated that pSMC-1 and pSMC-2 from the immunoprecipitates bind anti-ASGP-2, anti-ASGP-1, and concanavalin A. Moreover, these three components can also be labeled with mannose; the mannose was removed from 30-min pulse-labeled anti-ASGP-2 immunoprecipitates by incubation with endo-beta-N-acetylglucosaminidase H, indicating the presence of only high mannose N-linked oligosaccharides in pSMC-1. One-dimensional peptide maps of 35S-labeled pSMC-1 and Mr = 120,000 ASGP-2 showed several corresponding bands. These results indicate that both ASGP-1 and ASGP-2 can be synthesized from a common high Mr precursor. We propose that complex is formed from pSMC-1 by proteolytic cleavage to yield Mr = 120,000 ASGP-2 plus the precursor to ASGP-1 early in the transit pathway from the endoplasmic reticulum to the cell surface.


Excretion of amines and their metabolites by two patients in hepatic coma treated with L-dopa.
Two patients in hepatic coma were treated with L-dopa. The first patient showed clear clinical improvement, but the second patient did not. Analyses of urinary metabolites indicated that L-dopa was not absorbed by the second patient. There was evidence that L-dopa had the following beneficial effects in the first patient: (1) increased production of urine, which could have been accompanied by increased excretion of toxins; (2) displacement of tyramine from transmitter sites (because increased excretion of p-hydroxyphenylacetic acid, a major metabolite of tyramine, occurred during L-dopa treatment in patient 1); (3) replenishment of dopamine, and to a much lesser extent, norepinephrine, at central or peripheral neuroeffector junctions; and (4) scavenging of methyl groups by L-dopa, because ratio of methylated amines to catecholamines was higher than normal in both comatose patients before L-dopa treatment, and this ratio decreased during L-dopa treatment in patient 1.


Enhanced lycopene productivity by manipulation of carbon flow to isopentenyl diphosphate in Escherichia coli.
Lycopene is a useful phytochemical that holds great commercial value. In our study the lycopene production pathway in E. coli originating from the precursor isopentenyl diphosphate (IPP) of the non-mevalonate pathway was reconstructed. This engineered strain of E. coli accumulated lycopene intracellularly under aerobic conditions. As a next step, the production of lycopene was enhanced through metabolic engineering methodologies. Various competing pathways at the pyruvate and acetyl-CoA nodes were inactivated to divert more carbon flux to IPP and subsequently to lycopene. It was found that the ackA-pta, nuo mutant produced a higher amount of lycopene compared to the parent strain. To further enhance lycopene production, a novel mevalonate pathway, in addition to the already existing non-mevalonate pathway, was engineered. This pathway utilizes acetyl-CoA as precursor, condensing it to form acetoacetyl-CoA and subsequently leading to formation of IPP. Upon the introduction of this new pathway, lycopene production increased by over 2-fold compared to the ackA-pta, nuo mutant strain.


Spectrin and calmodulin in spreading mouse blastomeres.
The role of spectrin and its association with calmodulin in spreading mouse blastomeres was investigated. Embryonic spectrin binds 125I-calmodulin in a calcium-dependent fashion in the blot overlay technique. Double-labeling experiments show coordinate redistribution of spectrin and calmodulin in blastomeres preparing to undergo active spreading movement. At this stage cortical spectrin staining is lost from the region of cell-substrate contact and spectrin and calmodulin become concentrated in two structures closely associated with the contacted region: a group of spherical bodies located on the cytoplasmic side of the cortical layer and a subcortical ring that marks the perimeter of the contacted region. The localization pattern of spectrin and calmodulin is also coordinated with that of actin and myosin. The results suggest that spectrin plays a role in the spreading of blastomeres and that this function may involve linkage of spectrin, calmodulin, and the cortical contractile apparatus.


Osteophyte formation and matrix mineralization in a TMJ osteoarthritis mouse model are associated with ectopic hedgehog signaling.
The temporomandibular joint (TMJ) is a diarthrodial joint that relies on lubricants for frictionless movement and long-term function. It remains unclear what temporal and causal relationships may exist between compromised lubrication and onset and progression of TMJ disease. Here we report that Proteoglycan 4 (Prg4)-null TMJs exhibit irreversible osteoarthritis-like changes over time and are linked to formation of ectopic mineralized tissues and osteophytes in articular disc, mandibular condyle and glenoid fossa. In the presumptive layer of mutant glenoid fossa's articulating surface, numerous chondrogenic cells and/or chondrocytes emerged ectopically within the type I collagen-expressing cell population, underwent endochondral bone formation accompanied by enhanced Ihh expression, became entrapped into temporal bone mineralized matrix, and thereby elicited excessive chondroid bone formation. As the osteophytes grew, the roof of the glenoid fossa/eminence became significantly thicker and flatter, resulting in loss of its characteristic concave shape for accommodation of condyle and disc. Concurrently, the condyles became flatter and larger and exhibited ectopic bone along their neck, likely supporting the enlarged condylar heads. Articular discs lost their concave configuration, and ectopic cartilage developed and articulated with osteophytes. In glenoid fossa cells in culture, hedgehog signaling stimulated chondrocyte maturation and mineralization including alkaline phosphatase, while treatment with hedgehog inhibitor HhAntag prevented such maturation process. In sum, our data indicate that Prg4 is needed for TMJ integrity and long-term postnatal function. In its absence, progenitor cells near presumptive articular layer and disc undergo ectopic chondrogenesis and generate ectopic cartilage, possibly driven by aberrant activation of Hh signaling. The data suggest also that the Prg4-null mice represent a useful model to study TMJ osteoarthritis-like degeneration and clarify its pathogenesis.


Effect of cyclophosphamide and its analogs on collagen arthritis in rats.
The effects of cyclophosphamide (CY) and its structurally related analogs, ifosfamide (Ifo), sufosfamide (Sufo), and mafosfamide (Mafo), on collagen arthritis in Sprague-Dawley rats were examined. Prophylactic treatment with 7.5-10 mg/kg/day of CY. 15 mg/kg/day of Ifo, and 10-15 mg/kg/day of Sufo for the first 10 days starting on the same day as the type II collagen immunization suppressed arthritis induction as well as humoral immune response to type II collagen. Prophylactic treatment with Mafo at doses ranging from 10 to 40 mg/kg/day for 10 days was ineffective in suppressing the disease development. When drug treatment was started only during the immediate preclinical phase of arthritis, the development of arthritis was suppressed in the animals treated with 10 mg/kg/day of CY and 15 mg/kg/day of Ifo from Day 5 to Day 14. Additional studies demonstrated that treatment with 10 mg/kg/day of CY and 15 mg/kg/day of Ifo started at the time of disease onset significantly suppressed the severity of arthritis compared with the control group. These results show the effectiveness of Ifo and CY on this animal model of polyarthritis and suggest the possibility of clinical use of Ifo for the treatment of human arthritides similar to CY.


Substance P degrading systems of rat parotid and hypothalamus.
Inactivation of substance P and its C-terminal hexapeptide analog [p-Glu6]substance P6-11 was studied in rat parotid and hypothalamic slices. It was found that in the parotid slice system the decay of substance P induced K+ release occurs concurrently with a decrease in the biologically active concentration of the peptide in the medium. The inactivation was further studied using [p-Glu6]substance P6-11 as substrate in the parotid and in the hypothalamic slice systems. In both tissue preparations the hexapeptide is degraded to small peptide fragments by metalloendopeptidase. Separation of the peptide fragments by high performance liquid chromatography and determination of their amino acid composition showed that in the hypothalamic slice system the major cleavage of the hexapeptide analog occurs between Phe8-Gly9 with minor cleavage sites between Phe7-Phe8 and Gly9-Leu10. In the rat parotid slice system the major cleavage occurs between Gly9-Leu10 with a minor cleavage site between Phe7-Phe8. The degradation of the hexapeptide analog in the hypothalamic system was inhibited 77% and 67% by treatment with 1 mM p-chloromercuriphenylsulfonate and p-chloromercuribenzoate, respectively, whereas in the parotid system these reagents inhibited the degradation of the hexapeptide only by 15% and 8%. These results may indicate that different proteases in the parotid and hypothalamus are involved in degradation of substance P. Kinetic studies, including the use of various inhibitors as well as competition by the peptide hormones somatostatin, LHRH, TRH and Leu-enkephalin-NH2, revealed that in both tissues the hexapeptide analog is a preferred substrate for degradation by protease of considerable specificity towards the C-terminal sequence of substance P. It is suggested that this metalloendopeptidase may be important in the termination of the substance P response.


Cataract surgery at district hospital level.
Cataract remains the leading cause of blindness worldwide, curable though, by a simple procedure. The backlog of cataract patients in developing countries is mounting despite sustainable and downright efforts by health ministries, international voluntary and non-governmental organisations [1]. The current situation has put many developing countries in a difficult dilemma. The authors present a review of a pilot-project in decentralised eye-care in Mutasa District, Zimbabwe. Cataract surgery is performed by a district general doctor as an alternative to clearing the cataract back-log in developing countries, as suggested in several studies [2-5]. It is important to persuade the health ministries to adopt this simple and cheap policy [6,7].


Delayed diagnosis and treatment of acoustic neuroma.
The records of 25 patients who underwent excision of acoustic neuroma between 1980 and 1987 were reviewed. All patients originated from southern New England. Facial nerve function was preserved in 92% of all patients, and 42% of patients with tumors less than 2.0 cm retained residual hearing postoperatively. These rates compare favorably with those found in larger series. Our series demonstrated that 60% of patients complained of hearing loss for longer than 2 years prior to tumor diagnosis. The mean duration of hearing loss prior to diagnosis was 4.2 years. Although sophisticated diagnostic methods were generally available, early detection of tumors did not occur, despite the early onset of auditory symptoms. The emergence of sophisticated computer-assisted diagnostic tests and the development of technologically advanced operative methods have reduced operative morbidity, but interestingly, have had little influence on early tumor diagnosis. Late detection of acoustic neuroma in an otherwise medically sophisticated community suggests the need for improved awareness among patients and their primary care providers. Failure of early detection may occur more commonly than generally appreciated, despite the availability of technologically advanced methods of diagnosis.


TPPP orthologs are ciliary proteins.
Tubulin polymerization promoting protein, (TPPP/p25), was identified as a brain-specific protein. The potential function of this protein resembled that of MAPs. It is mainly expressed in oligodendrocytes; however, immunopositivity was also detected in glial and neuronal inclusions in synucleinopathies. Here, we show that TPPP gene(s) are conserved in the genomes of ciliated organisms, but are lacking from the nonciliated ones. This recognition is based upon homologous gene sequence analysis, in silico comparative genomic studies, bioinformatic search and experimental evidence. Cilia (flagella) are microtubule-based cellular extensions of sensory and/or motile function. TPPP orthologs are among the only 16 genes that can be found in all ciliated organisms, suggesting that TPPP orthologs may be associated with a basic function of cilia.


Psychometric properties of the Norwegian Person-centred Climate Questionnaire from a nursing home context.
The physical and psychosocial environments in nursing homes influence the residents' everyday life as well as their well-being and thriving. The staff's perceptions of and relationships with the residents are crucially important to quality care. Quality care is described often as person-centred. Few measurement tools exist that focus on person-centred care in nursing homes. The aim of this study was to evaluate the psychometric properties of the Norwegian version of the Person-centred Climate Questionnaire-Staff version (PCQ-S). This study had a cross-sectional survey design. Two hundred and nine healthcare and support staff in five nursing homes in the eastern part of Norway. The Swedish PCQ-S was translated into Norwegian with forward and backward translation. The relevance of the items included in the questionnaire was assessed by an expert panel of 10 nursing home care staff, because the questionnaire has not been used in this context previously. A psychometric evaluation using statistical estimates of validity and reliability was performed. The discriminatory capacity of the questionnaire was also tested. The content validity index was satisfactory (0.78). The PCQ-S showed high internal consistency reliability in that Cronbach's α was satisfactory for the total scale (0.92) and the three subscales (0.81, 0.89 and 0.87). The test-retest reliability was also satisfactory as evident from a Spearman's correlation coefficient of 0.76 (p < 0.01) between the total PCQ scores at test and retest. The Norwegian version retained the original factor structure of the Swedish version. As the psychometric evaluation showed satisfactory validity and reliability scores, this study supports the Norwegian version of the PCQ-S when applied to a sample of nursing home staff.


Growth hormone deficiency in children: role of magnetic resonance imaging in assessing aetiopathogenesis and prognosis in idiopathic hypopituitarism.
To search for the presence of morphostructural abnormalities of the hypothalamus-pituitary region in growth hormone deficient (GHD) children magnetic resonance imaging (MRI) was performed in 30 GHD patients (age 10.09 +/- 3.5 years) and in 15 healthy age-matched controls. MRI demonstrated a significantly small sella and pituitary volume compared to controls and normal literatures values. In 20 patients the structures were extremely small and an abnormal development of the pituitary stalk was observed, and in 18 of these patients the bright spot indicating the neurohypophysis was dislocated to the distal part of the maldeveloped stalk, although these children had a normal fluid balance. From a functional point of view hypothalamus and pituitary defects were equally distributed between the two morphological groups. The patients with multiple endocrine defects had the smallest pituitary volume and abnormal stalk. A possible pathogenetic role of perinatal trauma or dysembryogenic events are discussed. A careful follow up of patients with isolated GHD presenting MRI abnormalities of the pituitary is suggested for the possible evolution in panhypopituitarism.


ADCY5 Mutations and Benign Hereditary Chorea.
Investigators from the Institute of Neurology, London, UK, and centers in Italy, Germany, and Greece, studied 18 unrelated cases of benign hereditary chorea BHC (7 familial, 11 sporadic) who were negative for NKX2-1 mutations.


Risk factors for acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: retrospective analysis of 73 patients who received cyclosporin A.
Cyclosporin A (CsA) has been used most widely as an immunosuppressive agent for preventing graft-versus-host disease (GVHD). To explore the risk factors including CsA blood levels for grades II-IV acute GVHD, we retrospectively analyzed the data of patients who underwent allogeneic hematopoietic stem cell transplantation in our hospital between March 1989 and July 2001. Seventy-three patients (47 males and 26 females) received CsA and short-term methotrexate for GVHD prophylaxis. CsA 1.5 mg/kg was administered as a 3-h infusion twice daily from day 1 until the patient recovered from the toxic gastrointestinal complication. Methotrexate was given at a dose of 15 mg/m(2) on day 1 and 10 mg/m(2) on days 3, 6 and 11. Grades II-IV acute GVHD occurred in 18 patients (24.7%). Multivariate Cox regression analysis revealed that higher C(5) (the whole-blood CsA concentration at 5 h after the start of infusion) before the onset of acute GVHD reduced the onset of grades II-IV acute GVHD with a hazard ratio of 0.994 (95% confidence interval 0.989-0.999) for every increase of 1 ng/ml. Our data indicate that inadequate exposures of CsA can be a vital risk for developing acute GVHD. From our results, we consider that precise monitoring of CsA concentrations and adjustment of CsA dose using the concentration may be effective to prevent the onset of severe acute GVHD. To confirm this finding, further prospective study will be needed.


Liver-specific expression of the gene coding for human factor X, a blood coagulation factor.
Factor X is a vitamin K-dependent glycoprotein that plays an essential role in both the intrinsic and extrinsic pathways of blood coagulation. Studies on a recombinant lambda phage containing the 5'-flanking region of the human factor X gene showed that the factor X gene was linked to and was located at the 3' end of the factor VII gene: the initiation codon of the factor X gene was 2823 base pairs (bp) downstream from the polyadenylation site of the factor VII gene. This 2.8-kilobase intergenic region, and progressively deleted fragments of it, was fused to the chloramphenicol acetyltransferase gene, and transient expressions in HepG2 cells, human fibroblasts, and Chinese hamster ovary cells were measured. A liver-specific promoter element, FXP1-binding site, essential for hepatocyte-specific transcription was identified. This promoter sequence, further localized to -63 to -42 bp in DNase I footprint studies, was homologous to LF-A1 or hepatic nuclear factor-4 recognition sequence and was equally functional in the normal and inverse orientations. FXP1 site bound to nuclear protein(s) from HepG2 cells and complex formation was partially abolished by the presence of duplex oligonucleotides containing liver factor-A1 or hepatic nuclear factor-4-binding sequences. Two additional positive elements located upstream of the promoter region, spanning from -215 to -149 bp (FXP2 site), and -457 to -351 bp (FXP3 site), were also established by reporter gene assays.


Origin of acrocentric trisomies in spontaneous abortuses.
A total of 33 spontaneous abortuses with various acrocentric trisomies were studied for the origin of the extra chromosomes using Q- and R-band polymorphisms as markers. Eleven trisomic abortuses were informative: nine trisomic abortuses (one with trisomy 13, three with trisomy 21, and five with trisomy 22 including one with a 46,XX/47,XX,+22 mosaicism) originated at maternal first meiosis; a 21-trisomic abortus resulted from an error at maternal second meiosis (or first mitosis); and a 13-trisomic abortus was of maternal first or second meiotic origin. The abortus with mosaic trisomy 22 started as a 22-trisomic zygote resulting from an error at maternal first meiosis, followed by a mitotic (in vivo or in vitro) loss of the paternally derived chromosome 22.


Facile preparation of fluorescent nanodiamond based polymer nanoparticles via ring-opening polymerization and their biological imaging.
Fluorescent nanodiamond (ND) has been regarded as one of the most promising fluorescent nanoprobes owing to their chemical inert, biocompatibility, optical properties, and rich surface chemistry. The fluorescent ND has been mainly fabricated through high-energy ion beam irradiation of type Ib diamonds and subsequent thermal annealing. The generation of nitrogen-vacancy centers is the reason for the fluorescence. However, the physical method is relatively complicated and it need to expensive equipment as well as high cost. On the other hand, the resultant fluorescent ND particles are lack of functional groups and difficult to be dispersed in aqueous solution. Therefore, the development of facile methods to direct preparation of fluorescent ND and surface modification with functional polymers is of great research interest for expanding the biomedical applications of fluorescent ND. In this report, a facile strategy was reported for the first time to prepare hydrophilic polymers functionalized fluorescent ND (named as ND-PhE-PETOx) composites through the ring-opening polymerization and simultaneous simple nucleophilic substitution reaction using the non-fluorescent detonation ND as the raw material. The obtained fluorescent ND composites were characterized by various characterization techniques in details. The as-obtained ND-PhE-PETOx composites exhibit high water dispersibility, low toxicity and strong fluorescence intensity. Cell uptake results indicating that the fluorescent ND based composites can be effectively internalized by cells. Taken together, we have developed a novel and simple method for the preparation of fluorescent ND based composites, which show excellent physicochemical properties and great potential for biomedical applications.


Do low-risk nulliparous women with abnormal uterine artery Doppler in the third trimester have poorer perinatal outcomes? A longitudinal prospective study on uterine artery Doppler in low-risk nulliparous women and correlation with pregnancy outcomes.
To evaluate uterine artery (UtA) Doppler over the course of pregnancy in low-risk nulliparous women and to analyze whether an abnormal uterine artery pulsatility index (UtA-PI) at a 32-34 week' scan implies poorer perinatal outcomes. An observational prospective study was carried out including 616 low-risk nulliparous women. Women with any of the following were excluded: fetal abnormalities, multiple pregnancy, and heparin, metformin or hypotensive treatment. Maternal characteristics, mean arterial pressure measurements and UtA Doppler findings were recorded longitudinally. Complete pregnancy data were available for 489/616 women (79.3%). Of these, 385 women had a normal UtA-PI throughout pregnancy (Group 0), while 50 (10.1%) had an UtA-PI > 95th percentile in the first or the second trimester that normalized in the third trimester (Group 1), and 56 (11.4%) had an abnormal UtA-PI in the third trimester (Group 2). We found that the rate of pre-eclampsia (PE) was higher in Group 2 (7/56 versus 4/435, p = 0.003) as was the rate of intrauterine growth restriction (IUGR) (6/56 versus 14/435, p = 0.02). Low-risk nulliparous women with abnormal UtA Doppler findings in the third trimester are at a higher risk of developing PE and having a baby with IUGR.


Standardisation of glutaraldehyde-modified tyrosine-adsorbed tree pollen vaccines containing the Th1-inducing adjuvant, monophosphoryl lipid A (MPL).
a new range of allergy vaccines has been developed by the introduction of a relatively new Th1-inducing adjuvant known as 3-deacylated monophosphoryl lipid A (MPL). MPL adjuvant is of natural origin, derived from the lipopolysaccharide of Salmonella minnesota R595. This adjuvant is incorporated in a glutaraldehyde-modified pollen extract adsorbed to L-tyrosine (Pollinex Quattro). A major potential benefit provided by MPL adjuvant is the promotion of a Th1 response which enhances the efficacy of allergy vaccination and can consequently allow a reduction in the number of injections required for treatment. The standardisation of Pollinex Quattro tree pollen allergy vaccine is described and we include details of some innovative analytical procedures. an essential feature of the analytical strategy is the assay of the MPL adjuvant using a recently developed HPLC technique. The adjuvant has a complex chemical structure and the analysis is illustrated in detail. We give a full picture of the vaccine standardisation by describing biochemical and immunological characterisation of the allergen extract, together with some brief manufacturing details. a high overall level of standardisation is illustrated by a number of different tests applied to all stages of vaccine manufacture. Tree pollen allergen potency is measured following the pollen extraction, chemical modification and formulation as a tyrosine adsorbate. Good batch-to-batch reproducibility is shown. The HPLC assay for MPL adjuvant showed high quality resolution which did not vary when measuring raw material or when incorporated in the vaccine and the technically complex assay is shown to be reliable.


Molecular cloning and functional characterization of Physcomitrella patens UBC13-UEV1 genes required for Lys63-linked polyubiquitination.
Ubc13 and Ubc/E2 variant (Uev) form a stable heterodimer to mediate Lys63-linked polyubiquitination. Unicellular eukaryotic genomes often contain single UBC13 and UEV gene; however, multiple homologs were found in higher plants. As initial land plants, Physcomitrella patens occupies a key evolutionary position between green algae and higher plants. In this study, we report the identification and functional characterization of two UBC13 and three UEV1 genes from P. patens. Both PpUbc13s form heterodimers with PpUev1B or PpUev1C, which catalyze Lys63-linked polyubiquitination in vitro and functionally complement the yeast ubc13 mms2 null mutant from killing by DNA-damaging agents. In contrast, PpUev1A is unable to interact with Ubc13s and cannot complement the yeast mms2 mutant. Two single mutations, PpUev1A-D12N and ΔCT, barely have any effect; however, the corresponding double mutation makes PpUev1A functional in both heterodimer formation and complementation. This study identifies a critical Uev residue located in the Ubc13-Uev interface and reveals that mosses began to evolve multiple UBC13 and UEV orthologs in order to adapt to the terrestrial environment. The evolutionary significance of PpUEV1A is discussed.


Hypertension Prevalence and Control Among Adults: United States, 2011-2014.
Hypertension is a public health challenge in the United States because it directly increases the risk for cardiovascular disease (1). National and regional health initiatives, including Healthy People 2020, the Million Hearts Initiative, and the Community Preventive Services Task Force, have sought to increase public awareness of the health benefits of improving blood pressure control (2-4). This report presents updated estimates for the prevalence and control of hypertension in the United States for 2011-2014.


High penetrance of acute intermittent porphyria in a Spanish founder mutation population and CYP2D6 genotype as a susceptibility factor.
Acute intermittent porphyria (AIP) is a low-penetrant genetic metabolic disease caused by a deficiency of hydroxymethylbilane synthase (HMBS) in the haem biosynthesis. Manifest AIP (MAIP) is considered when carriers develop typical acute neurovisceral attacks with elevation of porphyrin precursors, while the absence of attacks is referred to as latent AIP (LAIP). Attacks are often triggered by drugs, endocrine factors, fasting or stress. Although AIP penetrance is traditionally considered to be around 10-20%, it has been estimated to be below 1% in general population studies and a higher figure has been found in specific AIP populations. Genetic susceptibility factors underlying penetrance are still unknown. Drug-metabolizing cytochrome P450 enzymes (CYP) are polymorphic haem-dependent proteins which play a role in haem demand, so they might modulate the occurrence of AIP attacks. Our aim was to determine the prevalence and penetrance of AIP in our population and analyse the main hepatic CYP genes to assess their association with acute attacks. For this, CYP2C9*2, *3; CYP2C19*2; CYP2D6*4, *5; CYP3A4*1B and CYP3A5*3 defective alleles were genotyped in fifty AIP carriers from the Region of Murcia, a Spanish population with a high frequency of the HMBS founder mutation c.669_698del30. AIP penetrance was 52%, and prevalence was estimated as 17.7 cases/million inhabitants. The frequency of defective CYP2D6 alleles was 3.5 times higher in LAIP than in MAIP. MAIP was less frequent among CYP2D6*4 and *5 carriers (p < 0.05). The urine porphobilinogen (PBG)-to-creatinine ratio was lower in these individuals, although it was associated with a lower prevalence of attacks (p < 0.05) rather than with the CYP2D6 genotype. AIP prevalence in our region is almost 3 times higher than that estimated for the rest of Spain. The penetrance was high, and similar to other founder mutation AIP populations. This is very relevant for genetic counselling and effective health care. CYP2D6*4 and *5 alleles may be protective factors for acute attacks, and CYP2D6 may constitute a penetrance-modifying gene. Further studies are needed to confirm these findings, which would allow a further progress in clinical risk profile assessment based on the CYP genotype, leading to predictive personalized medicine for each AIP carrier in the future.