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Aims: The safety of continuing metformin during a hospital admission has not been robustly demonstrated. We evaluated the association of continuing metformin in hospital with the risk for a hospital-acquired complication (HAC)., Methods: This is a retrospective observational study of patients admitted to a medical or surgical ward. We considered those with diabetes who continued metformin (DM/MET group), those who discontinued metformin upon admission (DM/MET-STOP), and those with diabetes not on metformin just prior to and during admission (DM/NoMET). We prepared propensity score-matched (PSM) control groups from admitted patients without diabetes. The likelihood of a HAC was determined using a Kaplan-Meier survival analysis. A Cox proportional hazards model was employed to calculate the hazard ratio, adjusted for covariates., Results: Of the 4446 (14%) patients with diabetes, 3331 (10%) were prescribed metformin on admission, and it was continued in 2557 patients. HAC occurred in 5.5% of DM/MET group and 6.4% of the PSM control group. Continuation of metformin was associated with a lower likelihood of HAC, adjusted hazard ratio 0.85 (95% CI 0.69, 1.04), p = 0.117 compared to a PSM-matched control group without diabetes. The DM/NoMET and DM/MET-STOP groups had an increased risk for HAC, adjusted HR 1.77 (1.44, 2.18), p < 0.001 and 2.57 (2.10, 3.13), p < 0.001, as compared to their respective PSM control groups., Conclusion: An individualized assessment to continue metformin during hospital admission was associated with a reduced likelihood of HAC, with the caveat that there was limited matching to non-diabetes controls. This finding warrants further exploration., (© 2024 The Author(s). Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

Addition of an active surveillance virtual glucose management (VGM) system to usual consultation-based diabetes inpatient care at our hospital was associated with a decrease in hospital-acquired infection from 8.7% (17/196) to 3.5% (6/172) with an adjusted odds ratio of 0.17 (95%CI: 0.05-0.61), and a reduction in hypoglycemic and hyperglycemic patient-stay days., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Sue Mei Lau reports financial support was provided by South Eastern Sydney Local Health District. Sue Mei Lau reports financial support was provided by Diabetes Australia Research Trust]., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The risk of adverse outcomes in recurrent GDM pregnancy has not been well documented, particularly in women who have already had an adverse outcome. The aim of this study was to compare the risk of recurrent adverse delivery outcome (ADO) or adverse neonatal outcome (ANO) between consecutive gestational diabetes (GDM) pregnancies., Methods: In this retrospective study of 424 pairs of consecutive ("index" and "subsequent") GDM pregnancies, we compared the risk of ADO (instrumental delivery, emergency Caesarean section) and ANO (large for gestational age (LGA and small for gestational age (SGA)) in women with and without a history of adverse outcome in their index pregnancy., Results: Subsequent pregnancies had higher rates of elective Caesarean (30.4% vs 17.0%, p < 0.001) and lower rates of instrumental delivery (5% vs 13.9%, p < 0.001), emergency Caesarean (7.1% vs 16.3%, p < 0.001) and vaginal delivery (62.3% vs 66.3%, p = 0.01). Index pregnancy adverse outcome was associated with a higher risk of repeat outcome: RR 3.09 (95%CI:1.30,7.34) for instrumental delivery, RR 2.20 (95%CI:1.06,4.61) for emergency Caesarean, RR 4.55 (95%CI:3.03,6.82) for LGA, and RR 5.01 (95%CI:2.73,9.22) for SGA). The greatest risk factor for subsequent LGA (RR 3.13 (95%CI:2.20,4.47)) or SGA (RR 4.71 (95%CI:2.66,8.36)) was having that outcome in the index pregnancy., Conclusion: A history of an adverse outcome is a powerful predictor of the same outcome in the subsequent GDM pregnancy. These high-risk women may warrant more directed management over routine GDM care such as altered glucose targets or increased frequency of ultrasound assessment., (© 2023. Crown.)

Bimodal bilingual (spoken and sign language) programming has been recommended to promote the language and social development of deaf and hard of hearing (DHH) students as advances in auditory technologies and inclusion placements have opened up opportunities for access to spoken language (Mitchiner et al., 2012). The authors report preliminary findings of a small-scale, service-oriented bimodal bilingual (Macau Sign Language and spoken Cantonese) project at a deaf service center with four preschool deaf children who had underlying neurological conditions. Using a qualitative multiple case study design, the authors document yearlong language and social growth along with caregiver and administrator commentary. Recommendations are made for future empirical studies investigating bimodal bilingual programming in Macau and other Asian jurisdictions with deaf residents.

Aims/hypothesis: Numerous adaptations of the maternal immune system are necessary during pregnancy to maintain immunological tolerance to the semi-allogeneic fetus. Several complications of pregnancy have been associated with dysregulation of these adaptive mechanisms. While gestational diabetes mellitus (GDM) has been associated with upregulation of circulating inflammatory factors linked to innate immunity, polarisation of the adaptive immune system has not been extensively characterised in this condition. We aimed to characterise pro- and anti-inflammatory CD4 + (T helper [Th]) T cell subsets in women with GDM vs women without GDM (of similar BMI), during and after pregnancy, and examine the relationship between CD4 + subsets and severity of GDM., Methods: This is a prospective longitudinal case-control study of 55 women with GDM (cases) and 65 women without GDM (controls) at a tertiary maternity hospital. Quantification of proinflammatory (Th17, Th17.1, Th1) and anti-inflammatory (regulatory T cell [Treg]) CD4 + T cell subsets was performed on peripheral blood at 37 weeks gestation and 7 weeks postpartum, and correlated with clinical characteristics and measures of blood glucose., Results: Women with GDM had a significantly greater percentage of Th17 (median 2.49% [interquartile range 1.62-4.60] vs 1.85% [1.13-2.98], p = 0.012) and Th17.1 (3.06% [1.30-4.33] vs 1.55% [0.65-3.13], p = 0.006) cells compared with the control group of women without GDM. Women with GDM also had higher proinflammatory cell ratios (Th17:Treg, Th17.1:Treg and Th1:Treg) in pregnancy compared with the control group of women without GDM. In the control group, there was a statistically significant independent association between 1 h glucose levels in the GTT and Th17 cell percentages, and also between 2 h glucose levels and percentage of Th17 cells. The percentage of Th17 cells and the Th17:Treg ratio declined significantly after delivery in women with GDM, whereas this was not the case with the control group of women. Nevertheless, a milder inflammatory phenotype persisted after delivery (higher Th17:Treg ratio) in women with GDM vs women without., Conclusions/interpretation: Dysregulation of adaptive immunity supports a novel paradigm of GDM that extends beyond hyperglycaemia and altered innate immunity.

Background: Dengue remains a serious public health problem in Southeast Asia and has increased 37-fold in Malaysia compared to decades ago. New strategies are urgently needed for early detection and control of dengue epidemics., Methods: We conducted a two year study in a high human density dengue-endemic urban area in Selangor, where Gravid Ovipositing Sticky (GOS) traps were set up to capture adult Aedes spp. mosquitoes. All Aedes mosquitoes were tested using the NS1 dengue antigen test kit. All dengue cases from the study site notified to the State Health Department were recorded. Weekly microclimatic temperature, relative humidity (RH) and rainfall were monitored., Results: Aedes aegypti was the predominant mosquito (95.6%) caught in GOS traps and 23% (43/187 pools of 5 mosquitoes each) were found to be positive for dengue using the NS1 antigen kit. Confirmed cases of dengue were observed with a lag of one week after positive Ae. aegypti were detected. Aedes aegypti density as analysed by distributed lag non-linear models, will increase lag of 2-3 weeks for temperature increase from 28 to 30 °C; and lag of three weeks for increased rainfall., Conclusion: Proactive strategy is needed for dengue vector surveillance programme. One method would be to use the GOS trap which is simple to setup, cost effective (below USD 1 per trap) and environmental friendly (i.e. use recyclable plastic materials) to capture Ae. aegypti followed by a rapid method of detecting of dengue virus using the NS1 dengue antigen kit. Control measures should be initiated when positive mosquitoes are detected.

Objectives: To identify consumer information needs about paracetamol, the most commonly used analgesic and antipyretic worldwide., Design: Retrospective analysis of medicines questions from the public., Setting: Australian consumer medicines call centre., Participants: Callers to National Prescribing Service Medicines Line between September 2002 and June 2010 (n=123 217)., Main Outcome Measures: Enquiry profile: demographics, enquiry type and concurrent medicines included in paracetamol calls; question themes derived from subset of call narratives., Results: Paracetamol comprised part of the enquiry in 5.2% of calls (n=6367). The caller age distribution for paracetamol calls was skewed towards a younger cohort, with 45.2% made by those aged 25-44 vs 37.5% in 'rest of calls'. Significantly more paracetamol-related calls were made for a child (23.7%) compared with 'rest of calls' (12.7%, p<0.001). The most frequent concurrently asked about medicines were codeine (11%, n=1521) and ibuprofen (6.4%, n=884). Questions underpinned by paracetamol risk (interaction, use in pregnancy/lactation or other safety concerns) predominated (55.8%). When individual paracetamol enquiry types were compared with 'rest of calls', efficacy was most frequent (24.9% vs 22.8%); however, interaction (21.5% vs 14.8%), administration (15.5% vs 11%) and pregnancy/lactation (13.8% vs 8.3%) categories were more prevalent for paracetamol calls (all p<0.001). Enquiry type frequency also varied by patient age group, with questions about administration more common in younger groups and efficacy dominating in those over 45. Narrative analysis of over-represented paracetamol enquiry types showed specific concerns relevant to life stages: young children, those of reproductive age and the elderly., Conclusions: Consumers have many concerns about the use of paracetamol that may be under-recognised by healthcare providers, with the nature of enquiries differing across life stages. These concerns are not adequately addressed by available consumer information. Improving access to targeted information about paracetamol would promote the safe and effective use of this common medicine., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Between 2009 and 2012, 22 adolescents of age 15-20 from a day school in Macau were diagnosed with tuberculosis. Detection of multiple molecular clusters may suggest the presence of concurrent outbreaks, and could reflect also ongoing transmissions in the community. Careful interpretation of molecular epidemiology data is crucial in contact investigations., (© The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To determine the effectiveness of using sticky traps and the NS1 dengue antigen kit for the surveillance of Aedes mosquitoes for dengue control., Methods: Apartments were selected in a dengue-endemic area, and sticky traps were set to capture adult Aedes mosquitoes. NS1 dengue antigen kit was used to detect dengue antigen in mosquitoes, and positive mosquitoes were serotyped using real-time RT-PCR., Results: The sticky traps were effective in capturing Aedes aegypti, and a minimum of three traps per floor was sufficient. Multiple serotypes were found in individual mosquitoes., Conclusion: The sticky trap and the NS1 dengue antigen test kit can be used as surveillance tool in dengue control programmes. This proactive method will be better suited for control programmes than current reactive methods., (© 2015 John Wiley & Sons Ltd.)

Aims: This study sought to understand the relationship between Type 2 diabetes in pregnancy and previous gestational diabetes (GDM), and determine whether a previous pregnancy with GDM was associated with subsequent better pregnancy planning., Methods: A retrospective review of medical records of women with Type 2 diabetes in pregnancy was conducted at three teaching hospitals to ascertain whether they had earlier GDM, and to determine whether this is associated with differences in measures of pregnancy planning and diabetes management., Results: Of 172 index pregnancies affected by Type 2 diabetes, in 76 (44%) cases, the mother had a previous history of GDM. Within this cohort, a diagnosis of 'overt diabetes in pregnancy', made on the basis of a GTT result during pregnancy in the WHO diabetic range with persistent diabetes post partum, was more common among women who had previous GDM than women who had not had GDM (20% vs 7%, P = 0.02). Women who previously had GDM did not exhibit a higher incidence of preconception planning or folate supplementation., Conclusions: It is common for women with Type 2 diabetes in pregnancy to have had GDM previously. The diagnosis of GDM is an opportunity to improve future pregnancy planning and outcomes for women with Type 2 diabetes in pregnancy. This goal is yet to be realized., (© 2015 The Authors. Diabetic Medicine © 2015 Diabetes UK.)

Context: Maternal pregnancy-associated plasma protein-A (PAPP-A) is measured at nuchal translucency scanning to assess the risk of fetal chromosomal disorders., Objective: The aim of this study was to examine whether PAPP-A might also be a predictor of gestational diabetes (GDM), type 2 diabetes (T2D), or large-for-gestational-age (LGA) births., Design: PAPP-A levels were measured in serum from 1664 women at their 10-14-week nuchal translucency scan at a tertiary referral hospital. Maternal diabetes was categorized as T2D, "early GDM" (GDM diagnosed < 22 wk), and "late GDM" (GDM diagnosed ≥ 22 wk). The relationship between PAPP-A multiples of the median (MoM), maternal diabetes, and LGA was examined with multivariate regression models., Results: PAPP-A MoM was significantly lower in women with T2D and women who developed GDM than in nondiabetic women. PAPP-A MoM was 41.3% lower in T2D, 22.6% lower in early GDM, and 8.6% lower in late GDM. Women in the lowest quartile of PAPP-A MoM were 2.7 times more likely to have early GDM (odds ratio [OR], 2.74; 95% confidence interval [CI], 1.2-6.1) compared with the highest quartile. Birth weight had a positive linear association with PAPP-A MoM. Women in the highest PAPP-A MoM quartile were twice as likely to have an LGA baby (OR, 2.2; 95% CI, 1.39-3.46; P = .0007)., Conclusions: Routinely tested first-trimester PAPP-A is a novel biomarker for maternal diabetes and LGA. PAPP-A decreased with increasing severity of maternal diabetes. Although this cannot infer causality, low PAPP-A may help identify women at risk of GDM, and high PAPP-A may help identify pregnancies at risk of LGA.

Background: Myeloproliferative neoplasms (MPNs) are a group of haematological malignancies that can be characterised by a somatic mutation (JAK2V617F). This mutation causes the bone marrow to produce excessive blood cells and is found in polycythaemia vera (~95%), essential thrombocythaemia and primary myelofibrosis (both ~50%). It is considered as a major genetic factor contributing to the development of these MPNs. No genetic association study of MPN in the Hong Kong population has so far been reported. Here, we investigated the relationship between germline JAK2 polymorphisms and MPNs in Hong Kong Chinese to find causal variants that contribute to MPN development. We analysed 19 tag single nucleotide polymorphisms (SNPs) within the JAK2 locus in 172 MPN patients and 470 healthy controls. Three of these 19 SNPs defined the reported JAK2 46/1 haplotype: rs10974944, rs12343867 and rs12340895. Allele and haplotype frequencies were compared between patients and controls by logistic regression adjusted for sex and age. Permutation test was used to correct for multiple comparisons. With significant findings from the 19 SNPs, we then examined 76 additional SNPs across the 148.7-kb region of JAK2 via imputation with the SNP data from the 1000 Genomes Project., Results: In single-marker analysis, 15 SNPs showed association with JAK2V617F-positive MPNs (n = 128), and 8 of these were novel MPN-associated SNPs not previously reported. Exhaustive variable-sized sliding-window haplotype analysis identified 184 haplotypes showing significant differences (P < 0.05) in frequencies between patients and controls even after multiple-testing correction. However, single-marker alleles exhibited the strongest association with V617F-positive MPNs. In local Hong Kong Chinese, rs12342421 showed the strongest association signal: asymptotic P = 3.76 × 10-15, empirical P = 2.00 × 10-5 for 50,000 permutations, OR = 3.55 for the minor allele C, and 95% CI, 2.59-4.87. Conditional logistic regression also signified an independent effect of rs12342421 in significant haplotype windows, and this independent effect remained unchanged even with the imputation of additional 76 SNPs. No significant association was found between V617F-negative MPNs and JAK2 SNPs., Conclusion: With a large sample size, we reported the association between JAK2V617F-positive MPNs and 15 tag JAK2 SNPs and the association of rs12342421 being independent of the JAK2 46/1 haplotype in Hong Kong Chinese population.

We recorded gestational weight gain (GWG) and change in body mass index (BMI) at 28 weeks gestation in 343 vs. 339 women with and without gestational diabetes (GDM). GDM was associated with a greater increment in BMI, but not with increased GWG in kilograms., (Crown Copyright © 2014. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Replacing β-cells by islet-transplantation can cure type 1 diabetes, but up to 70% of β-cells die within 10 days of transplantation. ARNT (Aryl hydrocarbon Receptor Nuclear Translocator) regulates β-cell function, and potentially survival. Lack of ARNT impairs the ability of β-cells to respond to physiological stress and potentiates the onset of diabetes, but the exact role of ARNT in graft outcome is unknown., Aim: To investigate the effect of β-cell deletion of ARNT on graft outcomes., Methods: Islets were isolated from donor mice which had β-cell specific ARNT-deletion (β-ARNT) or littermate floxed controls. The islets were transplanted into diabetic SCID recipients in ratios of (a) 3 donors: 1 recipient, (b) 1 donor: 1 recipient or (c) ½ of the islets from 1 donor: 1 recipient. After 28 days, the kidney containing the graft was removed (nephrectomy) to exclude regeneration of the endogenous pancreas., Results: In the supra-physiological-mass model (3:1), both groups achieved reasonable glycaemia, with slightly higher levels in β-ARNT-recipients. In adequate-mass model (1:1), β-ARNT recipients had poor glucose control versus floxed-control recipients and versus the β-ARNT donors. In the low-β-cell-mass model (½:1) β-ARNT transplants completely failed, whereas controls had good outcomes. Unexpectedly, there was no difference in the graft insulin content or β-cell mass between groups indicating that the defect was not due to early altered β-cell survival., Conclusion: Outcomes for islet transplants lacking β-cell ARNT were poor, unless markedly supra-physiological masses of islets were transplanted. In the 1:1 transplant model, there was no difference in β-cell volume. This is surprising because transplants of islets lacking one of the ARNT-partners HIF-1α have increased apoptosis and decreased islet volume. ARNT also partners HIF-2α and AhR (aryl hydrocarbon receptor) to form active transcriptional complexes, and further work to understand the roles of HIF-2α and AhR in transplant outcomes is needed.

Aims: Insulin secretion increases in normal pregnancy to meet increasing demands. Inability to increase beta-cell function results in gestational diabetes mellitus (GDM). We have previously shown that the expression of the transcription factor ARNT (Aryl-hydrocarbon Receptor Nuclear Translocator) is reduced in the islets of humans with type 2 diabetes. Mice with a beta-cell specific deletion of ARNT (β-ARNT mice) have impaired glucose tolerance secondary to defective insulin secretion. We hypothesised that ARNT is required to increase beta-cell function during pregnancy, and that β-ARNT mice would be unable to compensate for the beta-cell stress of pregnancy. The aims of this study were to investigate the mechanisms of ARNT regulation of beta-cell function and glucose tolerance in pregnancy., Methods: β-ARNT females were mated with floxed control (FC) males and FC females with β-ARNT males., Results: During pregnancy, β-ARNT mice had a marked deterioration in glucose tolerance secondary to defective insulin secretion. There was impaired beta-cell proliferation in late pregnancy, associated with decreased protein and mRNA levels of the islet cell-cycle regulator cyclinD2. There was also reduced expression of Irs2 and G6PI. In contrast, in control mice, pregnancy was associated with a 2.1-fold increase in ARNT protein and a 1.6-fold increase in cyclinD2 protein, and with increased beta-cell proliferation., Conclusions: Islet ARNT increases in normal murine pregnancy and beta-cell ARNT is required for cyclinD2 induction and increased beta-cell proliferation in pregnancy.

A high proportion of β-cells die within days of islet transplantation. Reports suggest that induction of hypoxia-inducible factor-1α (HIF-1α) predicts adverse transplant outcomes. We hypothesized that this was a compensatory response and that HIF-1α protects β-cells during transplantation. Transplants were performed using human islets or murine β-cell-specific HIF-1α-null (β-HIF-1α-null) islets with or without treatment with deferoxamine (DFO) to increase HIF-1α. β-HIF-1α-null transplants had poor outcomes, demonstrating that lack of HIF-1α impaired transplant efficiency. Increasing HIF-1α improved outcomes for mouse and human islets. No effect was seen in β-HIF-1α-null islets. The mechanism was decreased apoptosis, resulting in increased β-cell mass posttransplantation. These findings show that HIF-1α is a protective factor and is required for successful islet transplant outcomes. Iron chelation with DFO markedly improved transplant success in a HIF-1α-dependent manner, thus demonstrating the mechanism of action. DFO, approved for human use, may have a therapeutic role in the setting of human islet transplantation.

Compared with conventional diuretic (CD) therapy, ultrafiltration (UF) is associated with greater weight loss and fewer re-hospitalizations in patients admitted with decompensated heart failure (HF). Concerns have been raised regarding its safety and efficacy in patients with more advanced heart failure. The authors conducted a single-center, prospective, randomized controlled trial in patients with advanced HF admitted to an intensive care unit for hemodynamically guided therapy, comparing UF (n=17) with CD (n=19) at admission. The primary end point was the time required for pulmonary capillary wedge pressure (PCWP) to be maintained at a value of ≤18 mm Hg for at least 4 consecutive hours. Secondary end points included levels of cytokines and neurohormones, as well as several clinical outcomes. In our study cohort, the time to achieve the primary end point was lower in the UF group but did not reach statistical significance (P = .08). UF resulted in greater weight reduction, higher total volume removed, and shorter hospital length of stay. There were no differences in kidney function, biomarkers, or adverse events. In patients with advanced HF under hemodynamically tailored therapy, UF can be safely performed to achieve higher average volume removed than CD therapy without leading to adverse outcomes., (© 2011 Wiley Periodicals, Inc.)

Aims/hypothesis: Diabetes in pregnancy is linked to development of obesity in the offspring, but the mechanisms are not fully understood. Gestational diabetes mellitus (GDM) occurs when beta cells are unable to compensate for the normal insulin resistance of late pregnancy. In this study, we used a murine model of beta cell dysfunction to examine the effects of maternal GDM on phenotype in male offspring with and without an inherited predisposition for beta cell dysfunction., Methods: Beta cell-specific aryl-hydrocarbon receptor nuclear translocator-null (βArnt) mice develop GDM from beta cell dysfunction. βArnt and control female mice were used to induce GDM and non-diabetic pregnancies, respectively., Results: Offspring from GDM pregnancies became spontaneously obese on a normal-chow diet. They were heavier than offspring from non-diabetic pregnancies, with increased body fat. Respiratory exchange ratio (RER) was higher, indicating decreased capacity to switch to lipid oxidation. Metabolic rate in GDM offspring was decreased prior to onset of obesity. The phenotype was more pronounced in βArnt GDM offspring than in GDM offspring of control genotype, demonstrating an interaction between genotype and pregnancy exposure. βArnt GDM offspring had increased hypothalamic neuropeptide Y (Npy) and decreased pro-opiomelanocortin (Pomc) expression. Weight, body fat, insulin sensitivity and RER in all mice, and hypothalamic Npy in βArnt mice were significantly correlated with AUC of maternal late pregnancy glucose tolerance tests (p < 0.01), but not with litter size, maternal weight, triacylglycerol or pre-pregnancy glycaemia., Conclusions/interpretation: In βArnt mice, exposure to GDM and inheritance of genetic beta cell dysfunction had additive effects on male offspring obesity; severity of the offspring phenotype correlated with maternal glycaemia.

Hypoxia-inducible factor-1alpha (HIF-1alpha) is a transcription factor that regulates cellular stress responses. While the levels of HIF-1alpha protein are tightly regulated, recent studies suggest that it can be active under normoxic conditions. We hypothesized that HIF-1alpha is required for normal beta cell function and reserve and that dysregulation may contribute to the pathogenesis of type 2 diabetes (T2D). Here we show that HIF-1alpha protein is present at low levels in mouse and human normoxic beta cells and islets. Decreased levels of HIF-1alpha impaired glucose-stimulated ATP generation and beta cell function. C57BL/6 mice with beta cell-specific Hif1a disruption (referred to herein as beta-Hif1a-null mice) exhibited glucose intolerance, beta cell dysfunction, and developed severe glucose intolerance on a high-fat diet. Increasing HIF-1alpha levels by inhibiting its degradation through iron chelation markedly improved insulin secretion and glucose tolerance in control mice fed a high-fat diet but not in beta-Hif1a-null mice. Increasing HIF-1alpha levels markedly increased expression of ARNT and other genes in human T2D islets and improved their function. Further analysis indicated that HIF-1alpha was bound to the Arnt promoter in a mouse beta cell line, suggesting direct regulation. Taken together, these findings suggest an important role for HIF-1alpha in beta cell reserve and regulation of ARNT expression and demonstrate that HIF-1alpha is a potential therapeutic target for the beta cell dysfunction of T2D.

Objective: To estimate the prevalence and course of antenatal anxiety and depression across different stages of pregnancy, risk factors at each stage, and the relationship between antenatal anxiety and depression and postpartum depression., Methods: A consecutive sample of 357 pregnant women in an antenatal clinic in a regional hospital was assessed longitudinally at four stages of pregnancy: first trimester, second trimester, third trimester, and 6 weeks postpartum. The antenatal questionnaire assessed anxiety and depression (using the Hospital Anxiety and Depression Scale) and demographic and psychosocial risk factors. The postpartum questionnaire assessed postpartum depression with the Edinburgh Postnatal Depression Scale., Results: More than one half (54%) and more than one third (37.1%) of the women had antenatal anxiety and depressive symptoms, respectively, in at least one antenatal assessment. Anxiety was more prevalent than depression at all stages. A mixed-effects model showed that both conditions had a nonlinear changing course (P<.05 for both), with both being more prevalent and severe in the first and third trimesters. Risk factors were slightly different at different stages. Both antenatal anxiety (adjusted odds ratio [OR] 2.66, P=.004 in the first trimester; adjusted OR 3.65, P<.001 in the second trimester; adjusted OR 3.84, P<.001 in the third trimester) and depression (adjusted OR 4.16, P<.001 in the first trimester; adjusted OR 3.35, P=.001 in the second trimester; adjusted OR 2.67, P=.009 in the third trimester) increased the risk of postpartum depression., Conclusion: Antenatal anxiety and depression are prevalent and serious problems with changing courses. Continuous assessment over the course of pregnancy is warranted. Identifying and treating these problems is important in preventing postpartum depression., Level of Evidence: II.

This study examined the distribution of organisms and their antimicrobial resistance in patients admitted due to acute bacteremic and non-bacteremic community-acquired urinary tract infection (UTI). During a period of 1 year and 1 month, a total of 201 patients and 253 bacterial isolates were studied. Fever higher than 38.5 degrees C was significantly more common in the bacteremic group than the non-bacteremic group (68% vs 48%; p<0.05). Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis were the most common organisms isolated. E. coli was the leading pathogen and it was significantly more predominant in bacteremic UTI than non-bacteremic UTI (73% vs 49%; p<0.01). Bacteria other than E. coli (i.e., K. pneumoniae, P. aeruginosa, Proteus spp., Morganella morganii, Enterobacter cloacae, Citrobacter spp., Acinetobacter baumannii, Serratia marcescens, and Providencia spp.) were more common in non-bacteremic UTI than bacteremic UTI (44% vs 22%; p<0.01). E. coli isolated from both bacteremic and non-bacteremic patients had a high rate of resistance to ampicillin (80%), cephalothin (59%), gentamicin (29%), piperacillin (61%), trimethoprim-sulfamethoxazole (56%), amoxicillin-clavulanic acid (34%), and ticarcillin-clavulanic acid (36%). Isolates of P. aeruginosa, K. pneumoniae, and Proteus spp. from the non-bacteremic group showed a higher proportion of resistance to extended-spectrum cephalosporins, aminoglycosides (netilmicin and amikacin) and ciprofloxacin. The emergence of a high rate of resistance to commonly used antimicrobials (ampicillin, cephalothin, gentamicin, trimethoprim-sulfamethoxazole, piperacillin, amoxicillin-clavulanic acid and ticarcillin-clavulanic acid) may have an impact on the antibiotic treatment of patients admitted due to acute community-acquired bacteremic or non-bacteremic UTI in Taiwan. Further studies are needed to clarify the impact of antimicrobial resistance on the outcome in these conditions.

Modulated thermogravimetic analysis (MTGA) is evaluated for the rapid estimation of thermal stability using several penicillin antibiotics as model compounds. The MTGA technique utilizes an oscillatory temperature program to obtain Arrhenius kinetic parameters through a mass loss during thermal degradation. To evaluate the reliability of this technique, activation energies (E(a)), log pre-exponential factor (logZ), and log first order rate constants (logk) obtained by MTGA for the thermal decomposition of ampicillin anhydrous, ampicillin trihydrate, ampicillin sodium salt, and penicillin G potassium salt are compared to existing literature values. The logk values estimated by MTGA agreed well with literature values when the weight loss observed by MTGA was shown to be due to the first decomposition step of the compound. The E(a) and logZ values determined by MTGA did not consistently agree with literature values as these parameters increased with decreasing heating rate (beta). The increase in E(a) and logZ values with decreasing beta seemed to offset each other to some extent to yield a relatively consistent logk estimate regardless of beta.

The Harmonized Alert Sensing Technology (HASTE) device was developed to overcome the primary shortcomings of interval based noninvasive blood pressure (BP) monitoring. This study was conducted to assess the reliability of the HASTE system compared with standard cuff BP values in patients on hemodialysis. A total of 1,370 HASTE measurements were compared with oscillometric standard cuff systolic BP values in 42 sessions of 15 patients on hemodialysis. The average discrepancy between the HASTE and cuff systolic BP was 1.41 +/- 16.90 mm Hg. Compared with cuff measurements, 31% of systolic BP fell within a range of 5 mm Hg difference, 57% of systolic BP fell within 10 mm Hg, and 73% of systolic BP fell within a 15 mm Hg band. According to British Hypertension Society standards or Association for the Advancement of Medical Instrumentation criteria, the current HASTE method did not perform well. Technology to provide noninvasive hemodynamic monitoring is, however, in its developmental stage. The effort at continuous systolic pressure monitoring using existing, readily available, and frequently used techniques is exciting. Although the HASTE system as currently configured and calibrated did not adequately perform, variations in site analysis and conversion factors may increase pressure sensitivity and tracking over the course of a standard dialysis treatment.

Primary plasma cell leukaemia (PPCL) is a rare form of plasma cell dyscrasia. Conventional melphalan-based treatment is often ineffective, with a reported median survival of 2-7 months only. We report a 53-year-old man with PPCL who was treated with four cycles of combination chemotherapy including vincristine, adriamycin and dexamethasone that resulted in a good partial remission. High-dose melphalan 200 mg/m2 and autologous peripheral blood stem cell (PBSC) rescue was then given 6 months after diagnosis. Maintenance interferon-alpha was started 8 weeks after transplantation with good drug compliance. Complete remission was achieved and molecular remission was documented 11 months after autologous PBSC transplantation. In conclusion, high-dose therapy followed by autologous stem cell rescue is a feasible option for PPCL that can result in a reasonably sustained remission.

Through the development and application of a liquid chromatography-mass spectrometry-based procedure for measuring the transport of complex organic molecules by vacuolar membrane vesicles in vitro, it is shown that the mechanism of uptake of sulfonylurea herbicides is determined by the ligand, glucose, or glutathione, to which the herbicide is conjugated. ATP-dependent accumulation of glucosylated chlorsulfuron by vacuolar membrane vesicles purified from red beet (Beta vulgaris) storage root approximates Michaelis-Menten kinetics and is strongly inhibited by agents that collapse or prevent the formation of a transmembrane H(+) gradient, but is completely insensitive to the phosphoryl transition state analog, vanadate. In contrast, ATP-dependent accumulation of the glutathione conjugate of a chlorsulfuron analog, chlorimuron-ethyl, is incompletely inhibited by agents that dissipate the transmembrane H(+) gradient but completely abolished by vanadate. In both cases, however, conjugation is essential for net uptake because neither of the unconjugated parent compounds are accumulated under energized or nonenergized conditions. That the attachment of glucose to two naturally occurring phenylpropanoids, p-hydroxycinnamic acid and p-hydroxybenzoic acid via aromatic hydroxyl groups, targets these compounds to the functional equivalent of the transporter responsible for chlorsulfuron-glucoside transport, confirms the general applicability of the H(+) gradient dependence of glucoside uptake. It is concluded that H(+) gradient-dependent, vanadate-insensitive glucoside uptake is mediated by an H(+) antiporter, whereas vanadate-sensitive glutathione conjugate uptake is mediated by an ATP-binding cassette transporter. In so doing, it is established that liquid chromatography-mass spectrometry affords a versatile high-sensitivity, high-fidelity technique for studies of the transport of complex organic molecules whose synthesis as radiolabeled derivatives is laborious and/or prohibitively expensive.

The Jerusalem artichoke (Helianthus tuberosus) xenobiotic inducible cytochrome P450, CYP76B1, catalyzes rapid oxidative dealkylation of various phenylurea herbicides to yield nonphytotoxic metabolites. We have found that increased herbicide metabolism and tolerance can be achieved by ectopic constitutive expression of CYP76B1 in tobacco (Nicotiana tabacum) and Arabidopsis. Transformation with CYP76B1 conferred on tobacco and Arabidopsis a 20-fold increase in tolerance to linuron, a compound detoxified by a single dealkylation, and a 10-fold increase in tolerance to isoproturon or chlortoluron, which need successive catalytic steps for detoxification. Two constructs for expression of translational fusions of CYP76B1 with P450 reductase were prepared to test if they would yield even greater herbicide tolerance. Plants expressing these constructs had lower herbicide tolerance than CYP76B1 alone, which is apparently a consequence of reduced stability of the fusion proteins. In all cases, increased herbicide tolerance results from more extensive metabolism, as demonstrated with exogenously fed phenylurea. Beside increased herbicide tolerance, expression of CYP76B1 has no other visible phenotype in the transgenic plants. Our data indicate that CYP76B1 can function as a selectable marker for plant transformation, allowing efficient selection in vitro and in soil-grown plants. Plants expressing CYP76B1 may also be a potential tool for phytoremediation of contaminated sites.

Over a 6-year period, 42 patients with different underlying diseases developed Aeromonas bacteremia in our hospital. The male to female ratio was 2:1. The vast majority of these patients had underlying diseases, including various types of neoplasm (n = 14), liver cirrhosis (n = 11), biliary tract disorder (n = 10) and other illnesses (n = 7). Community-acquired bacteremia was predominant (33 cases, 79%). Aeromonas hydrophila was the most common species isolated (88%). Monomicrobial bacteremia was more common than polymicrobial bacteremia (64% vs 36%). Monomicrobial bacteremia was associated with neoplasm or liver cirrhosis in 80% of patients. Polymicrobial bacteremia was more common in patients with biliary tract disorder than in patients from other groups (60% vs 40%). Escherichia coli (60%) was the predominant concomitant organism isolated. The major clinical manifestations were fever (74%), jaundice (57%), and abdominal pain (45%). Recognized infection sites included biliary tract, soft tissue involvement, peritoneal involvement, while 50% of patients had no recognized infection site. Eight patients (80%) received cholecystectomy due to gall stone with acute cholecystitis. However, none of the cirrhotic patients with necrotizing fasciitis received surgical treatment. The mortality attributed to Aeromonas bacteremia was 70%. Patients with liver cirrhosis or malignancy had a higher acute mortality (death within 7 days after admission) than the other patients (89% vs 11%). We conclude that Aeromonas bacteremia can cause a rapidly fatal outcome and should be considered an important pathogen for septicemia in patients with liver cirrhosis or neoplasm.

By BLAST searching a large expressed sequence tag database for glutathione S-transferase (GST) sequences we have identified 25 soybean (Glycine max) and 42 maize (Zea mays) clones and obtained accurate full-length GST sequences. These clones probably represent the majority of members of the GST multigene family in these species. Plant GSTs are divided according to sequence similarity into three categories: types I, II, and III. Among these GSTs only the active site serine, as well as another serine and arginine in or near the "G-site" are conserved throughout. Type III GSTs have four conserved sequence patches mapping to distinct structural features. Expression analysis reveals the distribution of GSTs in different tissues and treatments: Maize GSTI is overall the most highly expressed in maize, whereas the previously unknown GmGST 8 is most abundant in soybean. Using DNA microarray analysis we observed increased expression among the type III GSTs after inducer treatment of maize shoots, with different genes responding to different treatments. Protein activity for a subset of GSTs varied widely with seven substrates, and any GST exhibiting greater than marginal activity with chloro-2,4 dinitrobenzene activity also exhibited significant activity with all other substrates, suggesting broad individual enzyme substrate specificity.

Anemia is generally attributed to zidovudine therapy in human immunodeficiency virus (HIV)-infected patients, although parvovirus B19 infection has been reported as a rare cause. We report on a 24-year-old homosexual man infected with HIV who presented with anemia. He had received aggressive daily antiretroviral therapy (zidovudine 600 mg, lamivudine 300 mg, and saquinavir 1,800 mg) for 2 years. At the time of admission, his CD4+ count was 10 x 10(6) cells/L. A bone marrow aspirate smear showed a marked decrease in erythropoiesis and immunocytochemical staining for parvovirus B19 was positive. Parvovirus B19 viral DNA was detected in the peripheral blood using a polymerase chain reaction-based assay. Serologic studies were positive for parvovirus B19 immunoglobulin (Ig)M antibodies, but negative for IgG antibodies. The patient was treated with packed red blood cell transfusion. Zidovudine was stopped and replaced with zalcitibine 2.25 mg daily after anemia occurred. He did not receive intravenous Ig therapy because of its cost. After discontinuation of zidovudine for 1 year, anemia persisted and the patient depended on regular blood transfusions to control the anemia. This case emphasizes that, in addition to drug-related causes, parvovirus B19 infection should be included in the differential diagnosis of chronic anemia in HIV-infected individuals.

Isoflavones have drawn much attention because of their benefits to human health. These compounds, which are produced almost exclusively in legumes, have natural roles in plant defense and root nodulation. Isoflavone synthase catalyzes the first committed step of isoflavone biosynthesis, a branch of the phenylpropanoid pathway. To identify the gene encoding this enzyme, we used a yeast expression assay to screen soybean ESTs encoding cytochrome P450 proteins. We identified two soybean genes encoding isoflavone synthase, and used them to isolate homologous genes from other leguminous species including red clover, white clover, hairy vetch, mung bean, alfalfa, lentil, snow pea, and lupine, as well as from the nonleguminous sugarbeet. We expressed soybean isoflavone synthase in Arabidopsis thaliana, which led to production of the isoflavone genistein in this nonlegume plant. Identification of the isoflavone synthase gene should allow manipulation of the phenylpropanoid pathway for agronomic and nutritional purposes.

A 70-year-old female farmer was admitted to the hospital because of fever, headache, and diarrhea for 7 days. Hypotension, right-sided pleural effusion with respiratory distress and leukocytosis were noted. She was initially treated as systemic bacterial infection by i.v. administration of ampicillin/sulbactam and amikacin. Because fever persisted in spite of aggressive treatment, a repeat thorough physical examination was done. An eschar was found over the left-sided labium majus and an enlarged lymph node was noted over the left inguinal region. Under the impression of scrub typhus, minocycline was administered. The patient's clinical condition improved dramatically within 3 days. The diagnosis was later confirmed by a serologic test for Rickettsia tsutsugamushi.

The signaling pathways activated by the macrophage colony-stimulating factor (M-CSF) to promote survival of monocyte and macrophage lineage cells are not well established. In an effort to elucidate these pathways, we have used two cell types responsive to M-CSF: NIH 3T3 fibroblasts genetically engineered to express human M-CSF receptors (3T3-FMS cells) and human monocytes. M-CSF treatment induced M-CSF receptor tyrosine phosphorylation and recruitment of the p85 subunit of phosphatidylinositol 3-kinase (PI3K) to these receptors. These M-CSF receptor events correlated with activation of the serine/threonine kinase Akt. To clarify that PI3K products activate Akt in response to M-CSF, NIH 3T3 fibroblasts expressing mutant human M-CSF receptors (3T3-FMS(Y809F)) that fail to activate Ras in response to M-CSF also exhibit increased Akt kinase activity in response to M-CSF challenge. Furthermore, Akt appears to be the primary regulator of survival in 3T3-FMS cells, as transfection of genes encoding dominant-negative Akt isoforms into these fibroblasts blocked M-CSF-induced survival. In normal human monocytes, M-CSF increased the levels of tyrosine-phosphorylated proteins and induced Akt activation in a PI3K-dependent manner. The PI3K inhibitor LY294002 blocked M-CSF-mediated monocyte survival, an effect that was partially restored by caspase-9 inhibitors. These data suggest that M-CSF may induce cell survival through Akt-induced suppression of caspase-9 activation.

The preproenkephalin (PPeK) and preprotachykinin (PPT) mRNA contents in 3-, 10- and 23-month-old rats in the striatum were measured by solution hybridization-RNase protection assay after 3 weeks of haloperidol injection. Haloperidol increased striatal PPek mRNA. There was no age-related difference in the response of striatal PPeK mRNA to chronic haloperidol treatment. The PPT mRNA decreased by 21% after the haloperidol treatment in young rats only. Meanwhile, age decreased the PPT mRNA by 27 and 24% in 10- and 23-month-old rats, respectively. It is concluded that there is a difference in the effects of aging on the response of PPek and PPT mRNA contents to haloperidol and that the loss of PPT mRNA response in 10- and 23-month-old rats might be due to the change of dopamine system of the striatum in these rats.

Septic sacroiliitis is an uncommon disease and is rarely reported as a complication of acupuncture. We present a case of unilateral septic sarcoiliitis, which developed as a complication of acupuncture because of failure to sterilise the skin properly before treatment. Bone scan and computed tomography were positive for sacroiliitis. After a course of antibiotics with oxacillin for 6 weeks, the condition was completely improved. This case report stresses the importance of sterilisation procedures before acupuncture therapy.

By solution-hybridization-RNase protection assay, the preproenkephalin (PPek) mRNA in the anterior pituitary (AL) of male rats was found to decrease by 42% after 3 weeks haloperidol treatment. It is concluded that dopamine may stimulate the AL enkephalinergic system at the level of gene expression.

Stimulation of several human and murine hematopoietically derived cell lines with anti-Fas antibodies induced increased tyrosine phosphorylation of a panel of proteins observed in whole-cell lysates. In the human T cell line Jurkat, the activity of a 56-kDa tyrosine kinase was likewise activated by anti-Fas antibodies. Immunoprecipitation studies of anti-Fas-stimulated human Jurkat and murine 2B4.11 T cells revealed activation of the Src-family tyrosine kinases Lck and Fyn. Fas receptor-induced tyrosine phosphorylation of p120 c-cbl proto-oncogene product was observed in Jurkat T cells. Pharmacological experiments demonstrated that pretreatment of Jurkat cells with tyrphostins inhibited Fas-induced apoptosis; likewise, Lck activity was inhibited by tyrphostins in a dose-dependent fashion. Finally, Lck derived from unstimulated Jurkat T cells formed stable complexes with the intracellular domain of the Fas receptor. These data are consistent with the notion that expression and activation of members of the Src-family kinases is required for Fas-induced cell death in T lymphocytes and consistent with recent findings demonstrating decreased Fas-mediated thymocytic death in Fyn-knockout mice.

1. Haloperidol increased the Met-enk level in the striatum at all age groups. However, the Met-enk level was decreased in AL of young and middle-aged rats by the drug. 2. Haloperidol elevated the beta-end level in AL and CCK level in NIL in young rats only. 3. The SP content in NIL was decreased by haloperidol in all age groups. 4. With regard to the effect of aging, Met-enk level in AL of middle-aged rats was higher than that in young rats. The beta-end level in AL also increased in old rats. 5. Aging modified the haloperidol effect on beta-end level in AL and CCK level in NIL as the effect was only observed in young rats. 6. In addition, aging caused a blunted response of Met-enk level to haloperidol in the striatum but an increased response of SP content to haloperidol in the NIL.

A cytochrome P-450 present in ripening avocado (Persea americana) fruit mesocarp (CYP71A1) had previously been shown to metabolize the monoterpenoids nerol and geraniol (Hallahan et al. (1992) Plant Physiol. 98, 1290-1297). Using DNA encoding CYP71A1 as a hybridization probe, we have shown by Southern analysis that a related gene is present in the catmint, Nepeta racemosa. RNA blot analysis, together with Western analysis of catmint leaf polypeptides using avocado cyt P-450 antiserum, showed that a closely related gene is expressed in catmint leaves. Cytochrome P-450 in catmint microsomes catalysed the specific hydroxylation of nerol and geraniol at C-10, whereas avocado CYP71A1, in either avocado microsomes or heterologously expressed in yeast, catalysed 2,3- or 6,7-epoxidation of these substrates. These results suggest that orthologous genes of the CYP71 family are expressed in these two plant species, but catalyse dissimilar reactions with monoterpenoid substrates.

A cytochrome P450 with low affinity (2.9 x 10(3) M-1) for CO appears to be the major microsomal P450 in some plant tissues. The presence of low CO affinity cytochrome P450 correlates with its lack of NADPH reducibility and with the presence of high levels of 13(S)-hydroperoxy-9(Z),11(E)-octadecadienoate peroxidase activity. This activity and low CO affinity are retained by purified tulip cytochrome P450, which appears to be catalytically identical to a flaxseed-derived fatty acid allene oxide synthase P450 described previously [Song, W.-C., & Brash, A.R. (1991) Science 253, 781-784]. Other heme-binding ligands, such as CN- and imidazoles, bind weakly to the allene oxide synthase P450s, suggesting that axial coordination in the heme distal pocket may be hindered. We conclude that low CO affinity is characteristic of the allene oxide synthase P450s and that these P450s constitute a major portion of the microsomal P450 in a variety of plant tissues, particularly from monocot species.