Progress in spondylarthritis. Spondyloarthritis: lessons from imaging

The advent of magnetic resonance imaging (MRI) and advanced sonographic techniques has led to a resurgence of interest in the role of imaging in the evaluation and management of spondyloarthritis. Radiography remains the cornerstone of diagnosis although MRI is more sensitive in early stages of the disease. Inflammatory changes in the sacroiliac joints and spine can now be reliably quantified and can also predict the subsequent development of radiographic changes in the corresponding locations. MRI-based scoring systems for inflammation are highly responsive, facilitating proof-of-concept studies of new therapies for spondyloarthritis. Assessment of chronic changes is much less reliable using MRI, while assessment using radiography lacks sensitivity to change. Assessment of disease modification therefore remains a principle challenge in the development of new therapies for ankylosing spondylitis. Ultrasound may be the preferred approach to the assessment of peripheral inflammation, especially enthesitis. Scintigraphy and computed tomography offer few advantages over MRI.     

血清GP73联合Dickkopf-1、AFP对肝细胞癌的诊断价值

目的:探讨血清高尔基体蛋白(GP73)联合Dickkopf-1、甲胎蛋白(AFP)对肝细胞癌的诊断价值。方法:收集2014年9月至2016年9月我院收治的117例肝细胞癌患者(肝细胞癌组)、80例乙型病毒性肝炎患者(肝炎组),以及随机选取的80例健康体检者(对照组)为研究对象,采用酶联免疫吸附法(ELISA)测定各组对象的血清GP73、Dickkopf-1、AFP水平,并分析其与临床病理特征之间的关系,分析GP73、Dickkopf-1、AFP联合对肝细胞癌的诊断价值。结果:肝细胞癌组血清GP73、Dickkopf-1、AFP水平高于肝炎组、对照组,且肝炎组血清AFP水平高于对照组,差异有统计学意义(P0.05)。Child Pugh分级中B~C级肝细胞癌患者GP73、Dickkopf-1、AFP水平高于A级,差异有统计学意义(P0.05),不同分化程度、肿瘤直径、肿瘤数目患者的GP73、Dickkopf-1、AFP水平差异无统计学意义(P0.05)。GP73+Dickkopf-1+AFP对肝细胞癌诊断的灵敏度、特异性、阳性预测值、阴性预测值、准确率均高于GP73、Dickkopf-1、AFP的诊断结果,差异有统计学意义(P0.05)。结论:血清GP73、Dickkopf-1、AFP在肝细胞癌中呈高表达水平,三者联合可明显提高对肝细胞癌的诊断价值,临床有重要的参考价值。     

Increase in the Prevalence of Obesity in Switzerland 1982–2007: Birth Cohort Analysis Puts Recent Slowdown into Perspective

Although the prevalence of obesity continues to increase in Switzerland, the latest figures suggest a slowdown in the rate of increase. In order to elucidate whether this could be the onset of a trend reversal, we analyzed cross‐sectional data by birth cohort. We assessed the prevalence of overweight+ (BMI ≥25 kg/m²) and obesity (BMI ≥30 kg/m²) in six population surveys with self‐reported height and weight values (Switzerland, N = 68,829, 1982–2007, men (45%) and women (55%), aged 20–84 years) by 10‐year birth cohorts (from the decade 1910–1919 through to 1970–1979). We found that increases in the prevalence of overweight+ and obesity occurred mainly in the cohort born 1930 to 1939, and again in the cohorts born 1960 to 1979. The accelerated increase in the prevalence of overweight+ in the youngest birth cohort and the lower prevalence in the oldest birth cohorts suggest that the current slowdown seen in Switzerland may not herald the onset of a trend reversal. As this example shows, simple comparisons of prevalence rates over time could provide a misleading picture of actual trends. Birth cohort analysis may offer a valuable alternative.     

Serum Neutralizing Activities from a Beijing Homosexual Male Cohort Infected with Different Subtypes of HIV-1 in China

Protective antibodies play a critical role in an effective HIV vaccine; however, eliciting antibodies to block infection by viruses from diverse genetic subtypes remains a major challenge. As the world’s most populous country, China has been under the threat of at least three major subtypes of circulating HIV-1 viruses. Understanding the cross reactivity and specificities of serum antibody responses that mediate broad neutralization of the virus in HIV-1 infected Chinese patients will provide valuable information for the design of vaccines to prevent HIV-1 transmission in China. Sera from a cohort of homosexual men, who have been managed by a major HIV clinical center in Beijing, China, were analyzed for cross-sectional neutralizing activities against pseudotyped viruses expressing Env antigens of the major subtype viruses (AE, BC and B subtypes) circulating in China. Neutralizing activities in infected patients’ blood were most capable of neutralizing viruses in the homologous subtype; however, a subset of blood samples was able to achieve broad neutralizing activities across different subtypes. Such cross neutralizing activity took 1–2 years to develop and CD4 binding site antibodies were critical components in these blood samples. Our study confirmed the presence of broadly neutralizing sera in China’s HIV-1 patient population. Understanding the specificity and breadth of these neutralizing activities can guide efforts for the development of HIV vaccines against major HIV-1 viruses in China.     

Possible Increase in Serum FABP4 Level Despite Adiposity Reduction by Canagliflozin,an SGLT2 Inhibitor

BackgroundFatty acid-binding protein 4 (FABP4/A-FABP/aP2) is secreted from adipocytes in association with catecholamine-induced lipolysis, and elevated serum FABP4 level is associated with obesity, insulin resistance and atherosclerosis. Secreted FABP4 as a novel adipokine leads to insulin resistance via increased hepatic glucose production (HGP). Sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease blood glucose level via increased urinary glucose excretion, though HGP is enhanced. Here we investigated whether canagliflozin, an SGLT2 inhibitor, modulates serum FABP4 level.MethodsCanagliflozin (100 mg/day) was administered to type 2 diabetic patients (n = 39) for 12 weeks. Serum FABP4 level was measured before and after treatment.ResultsAt baseline, serum FABP4 level was correlated with adiposity, renal dysfunction and noradrenaline level. Treatment with canagliflozin significantly decreased adiposity and levels of fasting glucose and HbA1c but increased average serum FABP4 level by 10.3% (18.0 ± 1.0 vs. 19.8 ± 1.2 ng/ml, P = 0.008), though elevation of FABP4 level after treatment was observed in 26 (66.7%) out of 39 patients. Change in FABP4 level was positively correlated with change in levels of fasting glucose (r = 0.329, P = 0.044), HbA1c (r = 0.329, P = 0.044) and noradrenaline (r = 0.329, P = 0.041) but was not significantly correlated with change in adiposity or other variables.ConclusionsCanagliflozin paradoxically increases serum FABP4 level in some diabetic patients despite amelioration of glucose metabolism and adiposity reduction, possibly via induction of catecholamine-induced lipolysis in adipocytes. Increased FABP4 level by canagliflozin may undermine the improvement of glucose metabolism and might be a possible mechanism of increased HGP by inhibition of SGLT2.

Trial Registration

UMIN-CTR Clinical Trial UMIN000018151     

Using the Whole Cohort in the Analysis of Case-Control Data

Standard analyses of data from case-control studies that are nested in a large cohort ignore information available for cohort members not sampled for the sub-study. This paper reviews several methods designed to increase estimation efficiency by using more of the data, treating the case-control sample as a two or three phase stratified sample. When applied to a study of coronary heart disease among women in the hormone trials of the Women’s Health Initiative, modest but increasing gains in precision of regression coefficients were observed depending on the amount of cohort information used in the analysis. The gains were particularly evident for pseudo- or maximum likelihood estimates whose validity depends on the assumed model being correct. Larger standard errors were obtained for coefficients estimated by inverse probability weighted methods that are more robust to model misspecification. Such misspecification may have been responsible for an important difference in one key regression coefficient estimated using the weighted compared with the more efficient methods.     

Evaluation of Chemotherapy Response with Serum Squamous Cell Carcinoma Antigen Level in Cervical Cancer Patients: A Prospective Cohort Study

MRI does not always reflect tumor response after chemotherapy. Therefore, it is necessary to explore additional parameters to more accurately evaluate tumor response for the subsequent clinical determination about radiotherapy or radical surgery. A training cohort and an external validation cohort were used to examine the predictive performance of SCC-ag to evaluate tumor response from teaching hospital of Harbin Medical University. The study included 397 women with SCC (age: 28–73 years). Patients consecutively enrolled between August 2008 and January 2010 (n = 205) were used as training cohort. Patients consecutively enrolled between February 2010 and May 2011 (n = 192) were used as validation cohort. A multivariate regression analysis of the data from the training cohort indicated that serum SCC-ag level is an independent factor for neo-adjuvant chemotherapy (NACT) response. Analysis of the data from the validation cohort suggested that chemotherapy response could be more accurately predicted by SCC-ag than by magnetic resonance imaging (MRI) (sensitivity (Se): 0.944 vs. 0.794; specificity (Sp): 0.727 vs. 0.636; positive predictive value (PPV): 0.869 vs. 0.806; negative predictive value (NPV): 0.873 vs. 0.618; the area under ROC curve (AUC): 0.898 vs. 0.734). Combining SCC-ag with MRI was more powerful than MRI alone (Se: 0.952 vs. 0.794; Sp: 0.833 vs. 0.636; PPV: 0.916 vs. 0.806; NPV: 0.902 vs. 0.618; AUC: 0.950 vs. 0.734). Our study indicates that serum SCC-ag level is a sensitive and reliable measure to evaluate cervical cancer response to chemotherapy. Using SCC-ag in combination with MRI findings further improves the predictive power.     

Cobas Ampliprep/Cobas TaqMan HIV-1 v2.0 Assay: Consequences at the Cohort Level

Background

High-sensitive real-time PCR assays are routinely used to monitor HIV-1 infected subjects. Inter-assay discrepancies have been described at the low viral load (VL) end, where clinical decisions regarding possible virological rebound are based.

Methods

A retrospective study was performed to analyze frequencies of viral blips after transition to the COBAS Ampliprep/COBAS TaqMan v2.0 HIV-1 assay (Taqman v2.0) in patients with prior undetectable VLs as measured with the Roche Cobas Ampliprep Amplicor HIV-1 Monitor Test, v1.5 (Amplicor) and was evaluated in comparison to a group of patients monitored with the Abbott Real-time HIV-1 assay (Abbott RT) during the same period of time.

Results

85 of 373 patients with VLs below the limit of quantification with Amplicor had VLs >50 copies/mL after transition to the TaqMan v2.0 assay. Among these 74.1% had VLs ranging from 50–499 copies/mL, 22.9% had VLs >500 copies/mL. From 22 patients with initial Taqman v2.0 based VLs exceeding 500 copies/mL, 6 patients had VLs <20 copies/mL after novel VL measurement on a next visit. In our control group with VL quantification using the Abbott RT assay, only 1 patient became detectable and showed a VL of <40 copies/mL after new measurement.

Conclusions

Transition to the Taqman v2.0 assay was accompanied by an increase of quantifiable HIV-1 VLs in patients with long term viral suppression under antiretroviral therapy that might be attributed to technical shortcomings of the Taqman v2.0 assay. A high test variability at the low VL end but also beyond was observed, making meaningful clinical interpretation of viral blips derived from different assays difficult.     

Induction of the Wnt antagonist Dickkopf-1 is involved in stress-induced hippocampal damage

The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein Dickkopf-1 (Dkk-1), an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of β-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway. In adrenalectomized mice, Dkk-1 was induced by corticosterone injection, but not by exposure to stress. Corticosterone also induced Dkk-1 in mouse organotypic hippocampal cultures and primary cultures of hippocampal neurons and, at least in the latter model, the action of corticosterone was reversed by the type-2 glucocorticoid receptor antagonist mifepristone. To examine whether induction of Dkk-1 was causally related to stress-induced hippocampal damage, we used doubleridge mice, which are characterized by a defective induction of Dkk-1. As compared to control mice, doubleridge mice showed a paradoxical increase in basal hippocampal Dkk-1 levels, but no Dkk-1 induction in response to stress. In contrast, stress reduced Dkk-1 levels in doubleridge mice. In control mice, chronic stress induced a reduction in hippocampal volume associated with neuronal loss and dendritic atrophy in the CA1 region, and a reduced neurogenesis in the dentate gyrus. Doubleridge mice were resistant to the detrimental effect of chronic stress and, instead, responded to stress with increases in dendritic arborisation and neurogenesis. Thus, the outcome of chronic stress was tightly related to changes in Dkk-1 expression in the hippocampus. These data indicate that induction of Dkk-1 is causally related to stress-induced hippocampal damage and provide the first evidence that Dkk-1 expression is regulated by corticosteroids in the central nervous system. Drugs that rescue the canonical Wnt pathway may attenuate hippocampal damage in major depression and other stress-related disorders.     

Serum immunoglobulin levels and the risk of bladder cancer in the AMORIS Cohort

BackgroundThe anti-tumour T-cell response in bladder cancer has been shown to correlate with response to treatment and prognosis. However, little is known about the role of humoral immunity in this highly immunogenic human cancer, which is characterised by a high mutation-associated neoantigen load and a strong response to immunotherapy. In the present study, we interrogated the Swedish Apolipoprotein Mortality Risk Study (AMORIS) to explore the relationship between pre-diagnostic serum immunoglobulin levels and the risk of developing bladder cancer.MethodsOur analysis included all AMORIS participants aged 20 years or older, who had all three major serum immunoglobulins (IgA, IgM, IgG) recorded at the same baseline measurement (n = 29,876). All participants were free from bladder cancer at the time of measurement. Samples were obtained between 1985–1996, with follow-up information until 2011. Multivariate Cox proportional hazards regression was used to investigate the association between bladder cancer risk and different levels of pre-diagnostic serum immunoglobulins.ResultsDuring a mean follow-up period of 15.31 years, 163 (0.5%) individuals were diagnosed with bladder cancer. Multivariate Cox regression showed an inverse association between pre-diagnostic serum IgM levels ≥ 1.4 g/L and bladder cancer risk compared to serum IgM levels < 1.4 g/L [HR: 0.68 (95% CI 0.45–1.03)]. Corresponding associations could not be established for serum IgA or IgG.ConclusionOur findings implicate serum IgM in the pathogenesis of bladder cancer and suggest that the concept of humoral immune surveillance against cancer warrants further mechanistic investigation.     

Change of Cyclic AMP Level in Synaptosomes from Cerebral Cortex; Increase by Adenosine Derivatives

The endogenous level of cyclic AMP in incubated synaptosomes from cerebral cortex of guinea pigs was investigated after the addition of various agents to the incubation medium. It appeared that the synaptosomal suspension already contained exogenous adenosine. Preincubation with theophylline or with adenosine deaminase (ADase) decreased both the exogenous level of adenosine and the intrasynaptosomal level of cyclic AMP. The level of cyclic AMP was reincreased by the addition of adenosine agonists, especially 2-chloroadenosine. This increase was antagonized by deoxyadenosine and was not inhibited by dipyridamole. These results suggest that the adenosine derivatives in the synaptic cleft regulate the level of cyclic AMP in nerve terminals through adenosine receptor on the presynaptic membrane. ADP, ATP, dopamine, and histamine also stimulate the formation of cyclic AMP in the ADase-treated synaptosomes.     

血清Dickkopf1蛋白水平对原发性肝癌的诊断价值

目的:探索血清Dickkopf1(DKK1)水平对原发性肝癌(PLC)的诊断价值。方法:将我院收治的50例PLC患者、60例良性肝病患者、50例健康体检者及50例其它恶性肿瘤患者分别组成PLC组、良性肝病组、健康对照组及其他肿瘤组,采用ELISA定量检测各组血清DKK1蛋白的浓度,分析和比较其与α-fetoprotein(AFP)单独或联合诊断PLC的效能。结果:PLC组血清DKK1水平(838.96±104.14 ng/L)明显高于良性肝病组(322.61±25.44 ng/L)及健康对照组(213.03±25.70 ng/L),差异有统计学意义(P0.05)。AFP、DKK1单独鉴别诊断PLC和良性肝病的灵敏度分别为66%、46%,特异度分别为81.7%、96.7%,一致率分别为71.8%、73.6%;两者联合诊断的灵敏度、特异度及一致率分别为84%、78.3%、80.9%。AFP、DKK1联合诊断PLC的灵敏度和一致率均明显高于AFP、DKK1单独诊断。结论:血清DKK1在原发性肝癌中高表达,与原发性肝癌的发生密切相关,对PLC的早期诊断有一定参考价值,与AFP联合诊断可有效提高PLC的诊断效能。     

Serum CEACAM1 Level Is Associated with Diagnosis and Prognosis in Patients with Osteosarcoma

Carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1) is a trans-membrane multifunctional cell adhesion molecule associated with tumor cell proliferation, apoptosis, angiogenesis, invasion, and migration during tumor development. In the present study, we evaluated serum CEACAM1 level in osteosarcoma patients to explore its diagnostic and prognostic value for this particular malignancy. Sera from 113 patients with primary osteosarcoma, 98 patients with benign bone tumors and 126 healthy controls were obtained. Serum CEACAM1 level was measured with ELISA and correlation with clinicopathological characteristics was further analyzed. Receiver operating curves (ROC), Kaplan-Meier curves, and log-rank analyses as well as Cox proportional hazard models were used to evaluate diagnostic and prognostic significance. The results revealed that serum CEACAM1 level was significantly higher in osteosarcoma patients compared to benign bone tumors and healthy controls (455.2 ± 179.9 vs 287.4 ± 103.2, 260.8 ± 109.7 pg/ml, respectively). Osteosarcoma patients with larger tumors, later-tumor stages, low tumor grades, and distant metastases had much higher CEACAM1 compared to those with smaller tumors, earlier tumor stages, high tumor grades and non-distant metastases (P < 0.05 for all). Multivariate logistic regression analysis confirmed that high serum CEACAM1 level was an independent risk factor for distant metastases (OR = 3.02, 95%CI 1.65–4.17). To distinguish osteosarcoma patients from those with benign bone tumor and healthy controls, ROC/AUC analysis indicated an AUC of 0.81 (sensitivity 0.61; specificity 0.89) and an AUC of 0.77 (sensitivity 0.57; specificity 0.92), respectively. Osteosarcoma patients with higher CEACAM1 had relatively lower survival compared to those with low CEACAM1 (P < 0.01), and multivariate analyses for overall survival revealed that high serum CEACAM1 level was an independent prognostic factor for osteosarcoma (HR = 1.56, 95%CI 1.23–3.28). The present study suggested that elevated serum CEACAM1 level might be a novel diagnostic and prognostic biomarker for osteosarcoma patients.     

Mechanisms of Topoisomerase I (TOP1) Gene Copy Number Increase in a Stage III Colorectal Cancer Patient Cohort

Background

Topoisomerase I (Top1) is the target of Top1 inhibitor chemotherapy. The TOP1 gene, located at 20q12-q13.1, is frequently detected at elevated copy numbers in colorectal cancer (CRC). The present study explores the mechanism, frequency and prognostic impact of TOP1 gene aberrations in stage III CRC and how these can be detected by fluorescent in situ hybridization (FISH).

Methods

Nine CRC cell line metaphase spreads were analyzed by FISH with a TOP1 probe in combination with a reference probe covering either the centromeric region of chromosome 20 (CEN-20) or chromosome 2 (CEN-2). Tissue sections from 154 chemonaive stage III CRC patients, previously studied with TOP1/CEN-20, were analyzed with TOP1/CEN-2. Relationships between biomarker status and overall survival (OS), time to recurrence (TTR) in CRC and time to local recurrence (LR; rectal cancer only) were determined.

Results

TOP1 aberrations were observed in four cell line metaphases. In all cell lines CEN-2 was found to reflect chromosomal ploidy levels and therefore the TOP1/CEN-2 probe combination was selected to identify TOP1 gene gains (TOP1/CEN-2≥1.5). One hundred and three patients (68.2%) had TOP1 gain, of which 15 patients (14.6%) harbored an amplification (TOP1/CEN-20≥2.0). TOP1 gene gain did not have any association with clinical endpoints, whereas TOP1 amplification showed a non-significant trend towards longer TTR (multivariate HR: 0.50, p = 0.08). Once amplified cases were segregated from other cases of gene gain, non-amplified gene increases (TOP1/CEN-2≥1.5 and TOP1/CEN-20<2.0) showed a trend towards shorter TTR (univariate HR: 1.57, p = 0.07).

Conclusions

TOP1 gene copy number increase occurs frequently in stage III CRC in a mechanism that often includes CEN-20. Using CEN-2 as a measurement for tumor ploidy levels, we were able to discriminate between different mechanisms of gene gain, which appeared to differ in prognostic impact. TOP1 FISH guidelines have been updated.     

Dietary Protein-induced Changes of the Erythropoietin Level in Rat Serum

Erythropoietin, a glycoprotein, is the primary regulator of erythropoiesis. The most convenient and sensitive assay for active erythropoietin is to measure its stimulatory effect on in vitro ³H-thymidine incorporation into DNA of erythropoietin-responsive cells. An attempt with this method to estimate the erythropoietin level in rat serum, however, was unsuccesful because of the presence of inhibitory substance(s) and non-erythropoietic factor(s) stimulating ³H-thymidine incorporation. Pretreatment of the serum by heating, extraction of erythropoietin from denatured-protein aggregates, and subsequent concentration of erythropoietin in the extract with alcohol precipitation made it possible to measure the serum erythropoietin levels. Rabbit anti-erythropoietin antibody was used for a quantitative estimation of erythropoietin in the concentrated extracts. Erythropoietin levels in sera of rats fed on varied amounts of casein for 7 days were measured with these procedures to find if the impairment of erythropoiesis upon protein deprivation was due to changes in the erythropoietin level. We found that the level in protein-deprived rats was less than 1/8 that of 20% casein-fed rats, a level undetectable by the present assay, and that the serum erythropoietin increased as the protein content in the diet was increased up to 20%, then leveled off. The erythropoietin in serum decreased rapidly after protein deprivation; the level at 12hr after deprivation began was about 1/5 that in 20% casein-fed rats. Thus, the depression of erythropoiesis upon protein deprivation is primarily caused by the lowered level of erythropoietin.     

Effects of Taxifolin on the Serum Cholesterol Level in Rats

Four new polyacetylenic glucosides isolated from the leaf of Jerusalem artichoke (Helianthus tuberosus L.) were characterized as methyl β-D-glucopyranosyl helianthenate C (5), D (6), E (7), and F (8). The absolute stereochemistry of the glucosyloxymethine was also determined to be of R configuration by preparing the relative compounds with Sharpless asymmetric epoxidation as the key step and source of optical activity.     

Proportional Hazards Regression for the Analysis of Clustered Survival Data from Case–Cohort Studies

Summary Case–cohort sampling is a commonly used and efficient method for studying large cohorts. Most existing methods of analysis for case–cohort data have concerned the analysis of univariate failure time data. However, clustered failure time data are commonly encountered in public health studies. For example, patients treated at the same center are unlikely to be independent. In this article, we consider methods based on estimating equations for case–cohort designs for clustered failure time data. We assume a marginal hazards model, with a common baseline hazard and common regression coefficient across clusters. The proposed estimators of the regression parameter and cumulative baseline hazard are shown to be consistent and asymptotically normal, and consistent estimators of the asymptotic covariance matrices are derived. The regression parameter estimator is easily computed using any standard Cox regression software that allows for offset terms. The proposed estimators are investigated in simulation studies, and demonstrated empirically to have increased efficiency relative to some existing methods. The proposed methods are applied to a study of mortality among Canadian dialysis patients.     

Maternal Serum and Breast Milk Vitamin D Levels: Findings from the Universiti Sains Malaysia Pregnancy Cohort Study

Background

Vitamin D deficiency has become a global health issue in pregnant women. This study aimed to assess the adequacy of maternal vitamin D status by measuring maternal serum and breast milk 25-hydroxyvitamin D [25(OH)D] levels and to determine the association between maternal serum and milk 25(OH)D levels.

Methods

Data was obtained from the Universiti Sains Malaysia Pregnancy Cohort Study. This study was conducted from April 2010 to December 2012 in the state of Kelantan, Malaysia. Blood samples from pregnant women aged 19 to 40 years were drawn in the second and third trimesters of pregnancy, while breast milk samples at delivery, 2, 6 and 12 months postpartum were collected to analyze for 25(OH)D levels. A total of 102 pregnant women were included in the analysis.

Results

Vitamin D deficiency [25(OH)D <50 nmol/L] was detected in 60% and 37% of women in the second and third trimesters of pregnancy, respectively. There were 6% and 23% of women who reached normal level of vitamin D status in the second trimester and the third trimester, respectively. Multivitamin intakes during pregnancy were significantly associated with higher serum 25(OH)D levels in the second trimester (β = 9.16, p = 0.005) and the third trimester (β = 13.65, p = 0.003). 25(OH)D levels in breast milk during the first year of lactation ranged from 1.01 to 1.26 nmol/L. Higher maternal serum 25(OH)D level in the second trimester of pregnancy was associated with an elevated level of 25(OH)D in breast milk at delivery (β = 0.002, p = 0.026).

Conclusions

This study shows that high proportions of Malay pregnant women are at risk of vitamin D deficiency. Maternal vitamin D status in the second trimester of pregnancy was found to influence vitamin D level in breast milk at delivery.     

Is the clinical course of HIV-1 changing? Cohort study.

OBJECTIVE: To assess whether the clinical course of HIV infection has changed from 1985 to 1995. DESIGN: Cohort Study. SETTING: Infectious disease clinic. SUBJECTS: 285 patients recruited from September 1985 to January 1995 with < or = 12 months between the dates of their last seronegative and first seropositive test result and with first follow up visit in the six months after seroconversion and at least 12 months'' follow up. Patients were grouped according to the date of seroconversion. MAIN OUTCOME MEASURES: Time to CD4 cell count of < 500, 400, and 200 x 10(6) cells/l, and clinical outcome defining AIDS; variation in cell count per day between consecutive visits, and ratio between this variation and time from estimated date of seroconversion at each visit. RESULTS: The groups were similar in age, number with acute primary HIV infection, CD4 cell count at intake, and cell count at the beginning of antiretroviral treatment; they differed in sex ratio, risk factors for HIV, probability of CD4 cell decline to < 500, 400, and 200 x 10(6) cells/l. and risk of developing AIDS. Acute infection, seroconversion after December 1989, and serum beta 2 microglobulin > 296 nmol/l were independent predictors of poor clinical course. The speed of CD4 cell decline, expressed as cell variation divided by the number of days between consecutive visits, increased with more recent seroconversion (P = 0.02). Ratio between the speed of CD4 cell decline and time from estimated date of seroconversion at each visit was also higher in the patients who seroconverted after December 1989. CONCLUSIONS: The faster disease progression and the higher speed of CD4 cell decline at early stages in the patients with recently acquired HIV infection suggest changes in the clinical course of HIV infection.     

A Proteasome Inhibitor-stimulated Nrf1 Protein-dependent Compensatory Increase in Proteasome Subunit Gene Expression Reduces Polycomb Group Protein Level

The polycomb group (PcG) proteins, Bmi-1 and Ezh2, are important epigenetic regulators that enhance skin cancer cell survival. We recently showed that Bmi-1 and Ezh2 protein level is reduced by treatment with the dietary chemopreventive agents, sulforaphane and green tea polyphenol, and that this reduction involves ubiquitination of Bmi-1 and Ezh2, suggesting a key role of the proteasome. In the present study, we observe a surprising outcome that Bmi-1 and Ezh2 levels are reduced by treatment with the proteasome inhibitor, MG132. We show that this is associated with a compensatory increase in the level of mRNA encoding proteasome protein subunits in response to MG132 treatment and an increase in proteasome activity. The increase in proteasome subunit level is associated with increased Nrf1 and Nrf2 level. Moreover, knockdown of Nrf1 attenuates the MG132-dependent increase in proteasome subunit expression and restores Bmi-1 and Ezh2 expression. The MG132-dependent loss of Bmi-1 and Ezh2 is associated with reduced cell proliferation, accumulation of cells in G₂, and increased apoptosis. These effects are attenuated by forced expression of Bmi-1, suggesting that PcG proteins, consistent with a prosurvival action, may antagonize the action of MG132. These studies describe a compensatory Nrf1-dependent, and to a lesser extent Nrf2-dependent, increase in proteasome subunit level in proteasome inhibitor-treated cells and confirm that PcG protein levels are regulated by proteasome activity.