Chloroquine Is Grossly Under Dosed in Young Children with Malaria: Implications for Drug Resistance

Background

Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations.

Methods and Findings

Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m² were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10–14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662–988) and 758 (95% CI 640–876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10–14 taking 50 mg/kg and children aged 0–2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent.

Conclusions

CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10–14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa.     

Associations between Longer Habitual Day Napping and Non-Alcoholic Fatty Liver Disease in an Elderly Chinese Population

Context

Both longer habitual day napping and Non-Alcoholic Fatty Liver Disease (NAFLD) are associated with diabetes and inflammation, but the association between day napping and NAFLD remains unexplored.

Objective

To investigate the association between the duration of habitual day napping and NAFLD in an elderly Chinese population and to gain insight into the role of inflammatory cytokines in this association.

Design and Setting

We conducted a series of cross-sectional studies of the community population in Chongqing, China, from 2011 to 2012.

Participants

Among 6998 participants aged 40 to 75 years, 6438 eligible participants were included in the first study and analyzed to observe the association between day napping duration and NAFLD. In a separate study, 80 non-nappers and 90 nappers were selected to identify the role of inflammatory cytokines in this association. Logistic regression models were used to examine the odds ratios (ORs) of day nap duration with NAFLD.

Results

Day nappers had a significantly higher prevalence of NAFLD (P<0.001). Longer day napping duration was associated in a dose-dependent manner with NAFLD (P trend <0.001). After adjustment for potential confounders, the ORs were 1.67 (95% CI 1.13–2.46) for those reporting 0.5–1 h and 1.49 (95% CI 1.01–2.19) for those reporting >1 h of day napping compared with individuals who did not take day naps (all P<0.05). Longer-duration day nappers had higher levels of IL-6 and progranulin (PGRN) but lower levels of Secreted frizzled-related protein-5 (SFRP5, all P trend <0.001). After adjusting for IL-6, PGRN, and SFRP5, the association between day napping duration and NAFLD disappeared (all P>0.05).

Conclusion

Longer day napping duration is associated with a higher prevalence of NAFLD, and inflammatory cytokines may be an essential link between day napping and NAFLD.     

Relationship between HbA1c and Continuous Glucose Monitoring in Chinese Population: A Multicenter Study

Objective

Since there is a paucity of reference data in the literature to indicate the relationship between HbA1c, and 24 h mean blood glucose (MBG) from continuous glucose monitoring (CGM) in Chinese populations, we described the above relationship in adult Chinese subjects with different glucose tolerance status.

Methods

Seven-hundred-and-forty-two individuals without history of diabetes were included to the study at 11 hospitals in urban areas across China from 2007–2009 and data of 673 subjects were included into the final analysis. Oral glucose tolerance test (OGTT) classified the participants as nondiabetic subjects, including those with normal glucose regulation (NGR; n = 121) and impaired glucose regulation (IGR; n = 209), or newly diagnosed type 2 diabetes (n = 343). All participants completed testing for HbA1c levels and wore a CGM system for three consecutive days. The 24 h MBG levels were calculated. Spearman correlations and linear regression analyses were applied to quantify the relationship between glucose markers.

Results

The levels of HbA1c and 24 h MBG significantly increased with presence of glucose intolerance (NGR<IGR<type 2 diabetes; both, P<0.001). Analysis of the total population indicated that HbA1c was strongly correlated with 24 h MBG (r = 0.735). The correlation was also found to be significant for the subgroup of participants with newly diagnosed type 2 diabetes (r = 0.694, P<0.001). Linear regression analysis of the total study population yielded the following equation: 24 h MBG _mmol/L = 1.198×HbA1c–0.582 (24 h MBG _mg/dL = 21.564×HbA1c–10.476) (R² = 0.670, P<0.001). The model fit was not improved by application of exponential or quadratic modeling. When HbA1c was 6.5%, the calculated 24 h MBG was 7.2 (6.4–8.1) mmol/L (130 (115–146) mg/dL); and when HbA1c was 7.0%, the 24 h MBG was 7.8 (6.9–8.7) mmol/L (140 (124–157) mg/dL).

Conclusions

Our study provided the reference data of the relationship between HbA1c and CGM in Chinese subjects.     

The Monoamine Re-Uptake Inhibitor UWA-101 Improves Motor Fluctuations in the MPTP-Lesioned Common Marmoset

Background

The wearing-OFF phenomenon is a common motor complication of chronic L-3,4-dihydroxyphenylalanine (L-DOPA) therapy for Parkinson’s disease. We recently described the discovery of UWA-101, a dual serotonin (SERT) and dopamine (DAT) transporter inhibitor, which increases the duration of “good quality” ON-time provided by L-DOPA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned primate. Here, we further characterise the effects of UWA-101 on this extension of ON-time in terms of L-DOPA-induced side-effects in the MPTP-lesioned common marmoset.

Methods

Marmosets were rendered parkinsonian by MPTP injection and “primed” by repeated L-DOPA administration, to exhibit dyskinesia and psychosis-like behaviours. Animals were then administered acute challenges of L-DOPA in combination with UWA-101 (1, 3, 6 and 10 mg/kg) or vehicle.

Results

In combination with L-DOPA, UWA-101 (3, 6 and 10 mg/kg) significantly increased duration of ON-time (by 28%, 28%, and 33%, respectively; all P<0.05). UWA-101 (10 mg/kg) significantly extended duration of ON-time without disabling dyskinesia (by 62%, P<0.01). UWA-101 did not exacerbate the severity of dyskinesia (P>0.05). However, at the highest doses (6 and 10 mg/kg), UWA-101 increased the severity of psychosis-like behaviours (P<0.05).

Conclusions

Our results demonstrate that dual SERT/ DAT inhibitors can effectively enhance L-DOPA anti-parkinsonian action, without exacerbating dyskinesia and, as such, represent a promising new therapeutic class for wearing-OFF. However, at higher doses, dual SERT/ DAT inhibitors may exacerbate dopaminergic psychosis.     

Spleen Dynamic Contrast-Enhanced Magnetic Resonance Imaging as a New Method for Staging Liver Fibrosis in a Piglet Model

Objective

To explore spleen hemodynamic alteration in liver fibrosis with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and to determine how to stage liver fibrosis with spleen DCE-MRI parameters.

Materials and Methods

Sixteen piglets were prospectively used to model liver fibrosis staged by liver biopsy, and underwent spleen DCE-MRI on 0, 5th, 9th, 16th and 21st weekend after modeling this disease. DCE-MRI parameters including time to peak (TTP), positive enhancement integral (PEI), maximum slope of increase (MSI) and maximum slope of decrease (MSD) of spleen were measured, and statistically analyzed to stage this disease.

Results

Spearman''s rank correlation tests showed that TTP tended to increase with increasing stages of liver fibrosis (r = 0.647, P<0.001), and that PEI tended to decrease from stage 0 to 4 (r = −0.709, P<0.001). MSD increased slightly from stage 0 to 2 (P>0.05), and decreased from stage 2 to 4 (P<0.05). MSI increased from stage 0 to 1, and decreased from stage 1 to 4 (all P>0.05). Mann-Whitney tests demonstrated that TTP and PEI could classify fibrosis between stage 0 and 1–4, between 0–1 and 2–4, between 0–2 and 3–4, or between 0–3 and 4 (all P<0.01). MSD could discriminate between 0–2 and 3–4 (P = 0.006), or between 0–3 and 4 (P = 0.012). MSI could not differentiate between any two stages. Receiver operating characteristic analysis illustrated that area under receiver operating characteristic curve (AUC) of TTP was larger than of PEI for classifying stage ≥1 and ≥2 (AUC = 0.851 and 0.783, respectively). PEI could best classify stage ≥3 and 4 (AUC = 0.903 and 0.96, respectively).

Conclusion

Spleen DCE-MRI has potential to monitor spleen hemodynamic alteration and classify liver fibrosis stages.     

Age- and Sex-Based Hematological and Biochemical Parameters for Macaca fascicularis

Background

The cynomolgus monkey (Macaca fascicularis) has been increasingly used in biomedical research, making knowledge of its blood-based parameters essential to support the selection of healthy subjects and its use in preclinical research. As age and sex affect these blood-based parameters, it is important to establish baseline indices for these parameters on an age and sex basis and determine the effects of age and sex on these indices.

Methods

A total of 917 cynomolgus monkeys (374 males and 543 females) were selected and segregated by age (five groups) and sex. A total of 30 hematological and 22 biochemical parameters were measured, and the effects of age and sex were analyzed.

Results

Baseline indices for hematological and biochemical parameters were separately established by age and sex. Significant effects by age, sex, and age-sex interaction were observed in a number of blood parameters. In the 49–60 months and 61–72 months age groups, red blood cell count, hemoglobulin, and hematocrit showed significantly lower values (P<0.01) in females than males. Serum alkaline phosphatase varied with age in both sexes (P<0.01) and was significantly higher in females than males (P<0.05) in the groups aged 13–24 months and 25–36 months; however, in the three groups aged over 25–36 months, serum alkaline phosphatase was significantly lower in females than males (P<0.01). Creatinine concentration increased with age (P<0.01) in all age groups; specifically in the groups aged 49–60 months and 61–72 months, creatinine was significantly higher (P<0.01) in males than females. Total protein and globulin both increased with age (P<0.01).

Conclusion

The baseline values of hematological and biochemical parameters reported herein establish reference indices of blood-based parameters in the cynomolgus monkey by age and sex, thereby aiding researchers in selecting healthy subjects and evaluating preclinical studies using this species.     

Association between Kidney Function and Framingham Global Cardiovascular Disease Risk Score: A Chinese Longitudinal Study

Background

Chronic kidney disease (CKD) is generally considered an independent risk factor for cardiovascular disease (CVD) development, but rates in individuals with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m² are uncertain. The Framingham global CVD risk score (FRS) equation is a widely accepted tool used to predict CVD risk in the general population. The purpose of the present study was to examine whether an association exists between eGFR and FRS in a Chinese population with no CKD or CVD.

Methods

A total of 333 participants were divided into three groups based on FRS. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and CKD-EPI equation for Asians (CKD-EPI-ASIA) were used to measure eGFR.

Results

A significant inverse association between eGFR and FRS was confirmed with Pearson correlation coefficients of –0.669, –0.698 (eGFR_CKD-EPI, P<0.01) and –0.658, –0.690 (eGFR_CKD-EPI-ASIA, P<0.01). This association gradually diminished with progression from the low- to high-risk groups (eGFR_CKD-EPI, r = –0.615, –0.282, –0.197, P<0.01, P<0.01, P>0.05; similar results according to the CKD-EPI-ASIA equation). In the low- or moderate-risk new-groups, this association became stronger with increased FRS (eGFR_CKD-EPI-ASIA, r = –0557, –0.622 or –0.326, –0.329, P<0.01). In contrast to the results from 2008, eGFR was independently associated with FRS following adjustment for traditional cardiovascular risk factors (P<0.05).

Conclusion

Renal function has multiple influences on predicting CVD risk in various populations. With increasing FRS and decreasing eGFR, it is also independently associated with CVD, even in individuals with eGFR >60 ml/min/1.73 m².     

Intraoperative Blood Loss Independently Predicts Survival and Recurrence after Resection of Colorectal Cancer Liver Metastasis

Background

Although numerous prognostic factors have been reported for colorectal cancer liver metastasis (CRLM), few studies have reported intraoperative blood loss (IBL) effects on clinical outcome after CRLM resection.

Methods

We retrospectively evaluated the clinical and histopathological characteristics of 139 patients who underwent liver resection for CRLM. The IBL cutoff volume was calculated using receiver operating characteristic curves. Overall survival (OS) and recurrence free survival (RFS) were assessed using the Kaplan–Meier and Cox regression methods.

Results

All patients underwent curative resection. The median follow up period was 25.0 months (range, 2.1–88.8). Body mass index (BMI) and CRLM number and tumor size were associated with increased IBL. BMI (P=0.01; 95% CI = 1.3–8.5) and IBL (P<0.01; 95% CI = 1.6–12.5) were independent OSOs predictors. Five factors, including IBL (P=0.02; 95% CI = 1.1–4.1), were significantly related to RFS via multivariate Cox regression analysis. In addition, OSOs and RFS significantly decreased with increasing IBL volumes. The 5-year OSOs of patients with IBL≤250, 250–500, and >500mL were 71%, 33%, and 0%, respectively (P<0.01). RFS of patients within three IBL volumes at the end of the first year were 67%, 38%, and 18%, respectively (P<0.01).

Conclusions

IBL during CRLM resection is an independent predictor of long term survival and tumor recurrence, and its prognostic value was confirmed by a dose–response relationship.     

Assessment of pharmacological activities of two medicinal plant of Bangladesh: Launaea sarmentosa and Aegialitis rotundifolia roxb in the management of pain,pyrexia and inflammation

Background

The current study aims at evaluating the analgesic, anti-pyretic and anti-inflammatory properties of methanolic extract of the stem, bark and leaves of Launaea sarmentosa and Aegialitis rotundifolia roxb.

Results

The AELS and AEAR extract presented a significant (***p < 0.001) dose dependent increase in reaction time in writhing method and showed inhibition of 63.1% and 57.1% respectively at the doses of 400 mg/kg body weight while standard drug showed (P < 0.001) inhibition of 69.23%. In tail immersion method, AELS and AEAR showed maximum time of tail retention at 30 min in hot water i.e. 6.93 sec and 6.54 sec respectively at highest doses of 400 mg/kg body weight than lower dose while standard pentazocine showed reaction time of 7.62 sec. The AELS and AEAR extract also exhibited promising anti-inflammatory effect as demonstrated by statistically significant inhibition of paw volume by 32.48% and 26.75% respectively at the dose of 400 mg/kg body weight while the value at the dose of 200 mg/kg body weight were linear to higher dose at the 3^rd hour of study. On the other hand, Standard indomethacin inhibited 40.13% of inflammation (***P < 0.001). In Cotton-pellet granuloma method, AELS and AEAR extract at the dose of 400 mg/kg body weight exhibited inhibition of inflammation of 34.7% and 29.1% respectively while standard drug showed (P < 0.001) inhibition of 63.22%. Intraperitoneal administration of AELS and AEAR showed dose dependent decrease in body temperature in brewer’s yeast induced hyperthermia in rats at both doses. However, AELS significantly decreased body temperature (***p < 0.001) at 400 mg/kg compared to control.

Conclusions

Present work propose that the methanolic extract of Launaea sarmentosa and Aegialitis rotundifolia roxb possesses dose dependent pharmacological action which supports its therapeutic use in folk medicine possibly mediated through the inhibition or blocking of release of prostaglandin and/or actions of vasoactive substances such as histamine, serotonin and kinins.     

Inflammatory and Haematological Markers in the Maternal,Umbilical Cord and Infant Circulation in Histological Chorioamnionitis

Background

The relationship between histological chorioamnionitis and haematological and biochemical markers in mothers and infants at delivery, and in infants postnatally, is incompletely characterised. These markers are widely used in the diagnosis of maternal and neonatal infection. Our objective was to investigate the effects of histological chorioamnionitis (HCA) on haematological and biochemical inflammatory markers in mothers and infants at delivery, and in infants post-delivery.

Methods

Two hundred and forty seven mothers, delivering 325 infants, were recruited at the only tertiary perinatal centre in Western Australia. Placentae were assessed for evidence of HCA using a semi-quantitative scoring system. Maternal high sensitivity C-reactive protein (hsCRP), procalcitonin, and umbilical cord hsCRP, procalcitonin, white cell count and absolute neutrophil count were measured at delivery. In infants where sepsis was clinically suspected, postnatal CRP, white cell count and absolute neutrophil count were measured up to 48 hours of age. The effect of HCA on maternal, cord and neonatal markers was evaluated by multivariable regression analysis.

Results

The median gestational age was 34 weeks and HCA was present in 26 of 247 (10.5%) placentae. Mothers whose pregnancies were complicated by HCA had higher hsCRP (median 26 (range 2–107) versus 5.6 (0–108) mg/L; P<0.001). Histological chorioamnionitis was associated with higher umbilical cord hsCRP (75^th percentile 2.91 mg/L (range 0–63.9) versus 75^th percentile 0 mg/L (0–45.6); P<0.001) and procalcitonin (median 0.293 (range 0.05–27.37) versus median 0.064 (range 0.01–5.24) ug/L; P<0.001), with a sustained increase in neonatal absolute neutrophil count (median 4.5 (0.1–26.4)×10⁹/L versus 3.0 (0.1–17.8)×10⁹/L), and CRP up to 48 hours post-partum (median 10 versus 6.5 mg/L) (P<0.05 for each).

Conclusion

Histological chorioamnionitis is associated with modest systemic inflammation in maternal and cord blood. These systemic changes may increase postnatally, potentially undermining their utility in the diagnosis of early-onset neonatal infection.     

Discordance between Liver Biopsy and FibroTest in Assessing Liver Fibrosis in Chronic Hepatitis B

Background and Aims

The FibroTest (FT) demonstrated excellent diagnostic performance in the prediction of liver fibrosis in patients with chronic hepatitis B (CHB). Here, we aimed to identify predictors of discordance between FT and liver biopsy (LB) in Asian patients with CHB.

Methods

Consecutive patients with CHB who underwent both LB and FT on the same day between 2007 and 2010 were recruited from three medical institutes. Laboratory evaluations including specific parameters for calculating FT score, such as α2-macroglobulin, apolipoprotein A1, haptoglobin, γ-glutamyl transpeptidase, and total bilirubin levels, were obtained. The Batts and Ludwig scoring system was used for histological analysis.

Results

A total of 330 patients (200 male and 130 female) were analyzed. Discordances of at least two fibrosis stages between FT and LB were observed in 30 (9.1%) patients; using FT, fibrosis was underestimated in 25 patients and overestimated in 5 patients with reference to LB. Patients with discordance had a higher proportion of F3–4 (P<0.001) and F4 (P = 0.012) compared with those with nondiscordance. The discordance rate was significantly higher in those with F3–4 than those with F1–2 (15.4% vs. 3.0%, P<0.001). Multivariate analysis demonstrated F3–4 at LB as the only independent factor for discordance (P<0.001; odds ratio 5.95). After adjusting fibrosis stages, neither necroinflammatory activity on histology nor serum ALT level influenced FT values independently.

Conclusion

Advanced fibrosis stage (F3–4) is the sole factor of discordance between FT and LB in Asian patients with CHB.     

Plasma MicroRNAs as Potential Noninvasive Biomarkers for In-Stent Restenosis

Objective

To investigate whether microRNAs (miRs) can serve as novel biomarkers for in-stent restenosis (ISR).

Methods

This retrospective, observational single-centre study was conducted at the cardiovascular department of a tertiary hospital centre in the north of China. Follow-up coronary angiography at 6 to 12 months was performed in 181 consecutive patients implanted with drug-eluting stents. Fifty-two healthy volunteers served as the control group. The plasma miRs levels were analyzed by quantitative real-time PCR. Receiver-operating characteristic curve (ROC) analysis was performed to investigate the characters of these miRs as potential biomarkers of ISR.

Results

MiR-21 levels in ISR patients were significantly higher than those in non-ISR patients and healthy controls (P<0.05), while miR-100 (P<0.05), miR-143 (P<0.001) and miR-145 (P<0.0001) levels were significantly decreased in ISR patients. Further analysis showed that miR-21 levels were remarkably increased (P = 0.045), while miR-100 (P = 0.041), miR-143 (P = 0.029) and miR-145 (P<0.01) levels were dramatically decreased in patients with diffuse ISR compared to those with focal ISR. ROC analysis demonstrated that the area under curve of miR-145, miR-143, miR-100 and miR-21 were 0.880 (95% confidence interval; CI = 0.791–0.987, P<0.001), 0.818 (95% confidence interval; CI = 0.755–0.963, P<0.001), 0.608 (95% confidence interval; CI = 0.372–0.757, P<0.05) and 0.568 (95% confidence interval; CI = 0.372–0.757, P<0.05), with specificity of 83.1%, 80.1%, 68.9% and 68.6%, and sensitivity of 88.7%, 82.1%, 60.2% and 50.1%, respectively.

Conclusions

Circulating miR-143 and miR-145 levels are associated with the occurrence of ISR and can serve as novel noninvasive biomarkers for ISR.     

Positive Relationship between Serum Low-Density Lipoprotein Cholesterol Levels and Visceral Fat in a Chinese Nondiabetic Population

Background

It has been reported that obesity and serum low-density lipoprotein cholesterol (LDL-c) are important risk factors of cardiovascular disease (CVD). It is recognized that regionalized adiposity has different cardiovascular risk, visceral versus subcutaneous, is a better predictor of CVD. However, the relationship between regionalized adiposity and LDL-c is unclear. The present study was designed to investigate the relationship between visceral fat accumulation and serum LDL-c levels in a Chinese cohort.

Methods

A total of 1 538 subjects (539 men, 999 women; 20–75 years old) with normal glucose tolerance and blood pressure were recruited. All subjects underwent magnetic resonance imaging to quantify visceral fat area (VFA) and subcutaneous fat area. Serum LDL-c levels were detected by direct assay method.

Results

Overweight/obese subjects (body mass index (BMI) ≥25 kg/m²) had significantly higher serum LDL-c levels than the lean subjects (BMI <25 kg/m²) (P<0.01). An increasing trend in serum LDL-c levels was found to accompany the increase in VFA (P for trend <0.01). Within the same BMI category, subjects with abdominal obesity (VFA ≥80 cm²) had significantly higher LDL-c levels than those without abdominal obesity (VFA <80 cm²) (P<0.05). Multiple stepwise regression analysis showed that increased VFA was an independent risk factor for elevated LDL-c levels, not only in the entire study population (Standard β = 0.138; P<0.01), but also when the study population was subdivided into men, premenopausal and postmenopausal women (Standard β = 0.117, 0.145, 0.090 respectively for men, premenopausal women, postmenopausal women; all P<0.01).

Conclusions

VFA was positively correlated with serum LDL-c levels in a nondiabetic Chinese population with normal blood pressure.     

Among Patients with Sustained Viral Suppression in a Resource-Limited Setting,CD4 Gains Are Continuous Although Gender-Based Differences Occur

Introduction

There is conflicting data on long-term CD4 immune recovery after combination antiretroviral therapy (ART) in resource-limited settings. Virologic suppression is rarely documented in cohorts from sub-Saharan Africa so objective evidence of adherence is biologically unsubstantiated. We sought to investigate long-term patterns of immune recovery in Ugandan patients on ART with sustained viral suppression.

Methods

A prospective cohort of patients starting ART between April, 2004 and April, 2005 at the Infectious Diseases Institute with sustained viral suppression (viral load ≤400 copies/ml at month 6 and 12) while on first-line ART. Propensity scores were used to adjust for treatment allocation (nevirapine or efavirenz) at ART initiation. Data were analyzed using Kaplan Meier methods and cross-sectional time series regression.

Results

Three hundred and fifty-six patients were included in the analysis.71.6% were female, 87% in WHO stage 3 or 4, median age was 37 years, (IQR:32–43), and median CD4 count was 108 cells/µL, (IQR:35–174) at ART start. At multivariable analysis, lower immune recovery (measured by change in CD4 from ART start at each time interval) was associated with male-gender (-59, 95% CI: 90, -28, P<0.001), baseline CD4 count of 101–200 cells/µL (-35, 95% CI: 62, -9, P=0.009) and >200 (-64, 95% CI: 101, -26, P=0.001), and use of AZT at baseline (-47, 95% CI: -74, -20, P=0.001). Median time to reach >400 cells/µL was longer in males (197.4 weeks, IQR:119.9–312.0), compared to females (144.7 weeks, IQR:96.6–219.7, P<0.001). The cumulative probability of attaining CD4 >400 cells/µL over 7 years was higher in females compared to males (P<0.001).

Conclusions

There was long-term, continuous, immunologic recovery up to 7 years after ART initiation in an urban Ugandan cohort. Virologically suppressed women had better sustained immune recovery than men. Men take longer to immune reconstitute and have a lower probability of reaching a CD4 cell count >400 cells/µL. The biologic mechanisms of these gender differences need further exploration.     

Poor Prognosis of Phosphatase of Regenerating Liver 3 Expression in Gastric Cancer: A Meta-Analysis

Background

Overexpression of phosphatase of regenerating liver 3 (PRL-3) has been implicated in gastric cancer (GC) metastasis. Epidemiological studies have evaluated the relationship between PRL-3 expression and prognosis in GC. However, results still remains controversial. In this study, a meta-analysis was performed to evaluate the association of PRL-3 expression with overall survival (OS) and clinicopathological characteristics.

Methods

Literature databases were searched to identify eligible studies dated until April 2013. Summary hazard ratios (HRs) or odds ratios (ORs) with 95% confidence interval (95% CI) were calculated to estimate the association.

Results

A total of 1380 GC patients from six studies were included in the meta-analysis. Overall, the combined HR estimate for OS in a random-effect model was 1.89 (95% CI = 1.38–2.60; P<0.001). Results showed that PRL-3 overexpression was significantly associated with OS, indicating that it may be a biomarker for poor prognosis of GC. Both subgroup and sensitivity analyses further identified the prognostic role of PRL-3 expression in GC patients. Moreover, PRL-3 overexpression was significantly associated with tumor stage (OR = 2.25; 95% CI = 1.63–3.12; P<0.001), depth of invasion (OR = 2.03; 95% CI = 1.38–2.98; P<0.001), vascular invasion (OR = 2.52; 95% CI = 1.79–3.56; P<0.001), lymphatic invasion (OR = 3.74; 95% CI = 2.49–5.63; P<0.001), and lymph node metastasis (OR = 4.56; 95% CI = 2.37–8.76; P<0.001). However, when age, sex, tumor size, and tumor differentiation were considered, no obvious association was observed.

Conclusions

This meta-analysis reveals significant association of PRL-3 overexpression with OS and some clinicopathological features in GC. PRL-3 may be a predicative factor of poor prognosis and aggressive tumor behavior in GC patients.     

Self-Management Behavior in Patients with Type 2 Diabetes: A Cross-Sectional Survey in Western Urban China

Purpose

To investigate the current status of diabetic self-management behavior and the factors influencing this behavior in Chengdu, a typical city in western China.

Methods

We performed stratified sampling in 6 urban districts of Chengdu. We used questionnaires concerning self-management knowledge, self-management beliefs, self-management efficacy, social support, and self-management behavior to investigate patients with T2DM from August to November 2011. All of the data were analyzed using the SPSS 17.0 statistical package.

Results

We enrolled a total of 364 patients in the present study. The median score of self-management behavior was 111.00, the interquartile range was 100.00–119.00, and the index score was 77.77. Self-management was described as “good” in 46%, “fair” in 45%, and “poor” in 6% of patients. A multiple-factor analysis identified age (OR, 0.43; 95% CI, 0.20–0.91; P = 0.026), education in “foot care” (OR, 0.42; 95% CI, 0.18–0.99; P = 0.048), self-management knowledge (OR, 0.86; 95% CI, 0.80–0.92; P<0.001), self-management belief (OR, 0.92; 95% CI, 0.87–0.97; P = 0.002), self-efficacy (OR, 0.93; 95% CI, 0.90–0.96; P<0.001), and social support (OR, 0.62; 95% CI, 0.41–0.94; P = 0.023) as positive factors. Negative factors included diabetes duration (5–9 years: OR, 14.82; 95% CI, 1.64–133.73; P = 0.016; and ≥10 years: OR, 10.28; 95% CI, 1.06–99.79; P = 0.045) and hospitalization experience (OR, 2.96; 95% CI, 1.64–5.36; P<0.001).

Conclusion

We observed good self-management behavior in patients with T2DM in Chengdu. When self-management education is provided, age, education, knowledge, belief, self-efficacy, and social support should be considered to offer more appropriate intervention and to improve patients'' behavior.     

Optimal Proteinuria Target for Renoprotection in Patients with IgA Nephropathy

Background

Proteinuria is a target for renoprotection in kidney diseases. However, optimal level of proteinuria reduction in IgA nephropathy (IgAN) is unknown.

Methods

We conducted a retrospective observational study in 500 patients with biopsy-proven IgAN. Time-averaged proteinuria (TA-P) was calculated as the mean of every 6 month period of measurements of spot urine protein-to-creatinine ratio. The study endpoints were a 50% decline in estimated glomerular filtration rate (eGFR), onset of end-stage renal disease (ESRD), and slope of eGFR.

Results

During a median follow-up duration of 65 (12–154) months, a 50% decline in eGFR occurred in 1 (0.8%) patient with TA-P of <0.3 g/g compared to 6 (2.7%) patients with TA-P of 0.3–0.99 g/g (hazard ratio, 2.82; P = 0.35). Risk of reaching a 50% decline in eGFR markedly increased in patients with TA-P of 1.0–2.99 g/g (P = 0.002) and those with TA-P≥3.0 g/g (P<0.001). ESRD did not occur in patients with TA-P<1.0 g/g compared to 26 (20.0%) and 8 (57.1%) patients with TA-P of 1.0–2.99 and ≥3.0 g/g, respectively. Kidney function of these two groups deteriorated faster than those with TA-P<1.0 g/g (P<0.001). However, patients with TA-P of 0.3–0.99 g/g had a greater decline of eGFR than patients with TA-P<0.3 g/g (−0.41±1.68 vs. −0.73±2.82 ml/min/1.73 m²/year, P = 0.03).

Conclusion

In this study, patients with TA-P<1.0 g/g show favorable outcomes. However, given the faster eGFR decline in patients with TA-P of 0.3–0.99 g/g than in patients with TA-P<0.3 g/g, the ultimate optimal goal of proteinuria reduction can be lowered in the management of IgAN.     

Lower Cerebrospinal Fluid/Plasma Fibroblast Growth Factor 21 (FGF21) Ratios and Placental FGF21 Production in Gestational Diabetes

Objectives

Circulating Fibroblast Growth Factor 21 (FGF21) levels are increased in insulin resistant states such as obesity, type 2 diabetes mellitus and gestational diabetes mellitus (GDM). In addition, GDM is associated with serious maternal and fetal complications. We sought to study human cerebrospinal fluid (CSF) and corresponding circulating FGF21 levels in women with gestational diabetes mellitus (GDM) and in age and BMI matched control subjects. We also assessed FGF21 secretion from GDM and control human placental explants.

Design

CSF and corresponding plasma FGF21 levels of 24 women were measured by ELISA [12 GDM (age: 26–47 years, BMI: 24.3–36.3 kg/m²) and 12 controls (age: 22–40 years, BMI: 30.1–37.0 kg/m²)]. FGF21 levels in conditioned media were secretion from GDM and control human placental explants were also measured by ELISA.

Results

Glucose, HOMA-IR and circulating NEFA levels were significantly higher in women with GDM compared to control subjects. Plasma FGF21 levels were significantly higher in women with GDM compared to control subjects [234.3 (150.2–352.7) vs. 115.5 (60.5–188.7) pg/ml; P<0.05]. However, there was no significant difference in CSF FGF21 levels in women with GDM compared to control subjects. Interestingly, CSF/Plasma FGF21 ratio was significantly lower in women with GDM compared to control subjects [0.4 (0.3–0.6) vs. 0.8 (0.5–1.6); P<0.05]. FGF21 secretion into conditioned media was significantly lower in human placental explants from women with GDM compared to control subjects (P<0.05).

Conclusions

The central actions of FGF21 in GDM subjects maybe pivotal in the pathogenesis of insulin resistance in GDM subjects. The significance of FGF21 produced by the placenta remains uncharted and maybe crucial in our understanding of the patho-physiology of GDM and its associated maternal and fetal complications. Future research should seek to elucidate these points.