Alcohol consumption in Dundee primigravidas and its effects on outcome of pregnancy

In a population based cohort study information on the consumption of alcohol was obtained from 95% of the 952 consecutive primigravidas who lived in the Dundee district and attended for antenatal care between May 1985 and April 1986. Before realising that they were pregnant more than 90% drank alcohol and 53% were cigarette smokers. During the first four months of pregnancy, however, the proportion of women drinking and smoking fell to 56% and 44%, respectively. Alcohol consumption of more than 120 g absolute alcohol/week (12 or more standard drinks) during pregnancy was related to shorter gestational age (-2·6 weeks), smaller head circumference (-18 mm), shorter (-21 mm) and lighter (-499 g) babies, and lower Apgar scores at five minutes (-0·4, all p<0·01). After adjustment for the effect of smoking, social class, mother''s size, and other confounding factors, however, an alcohol intake of more than 120 g/week was significantly related only to shorter gestational age (-2·0 weeks, p<0·001) and lower Apgar score at five minutes (-0·2, p<0·05). Alcohol intake in the region of 100-119 g/week was significantly related to smaller head circumference (-12 mm, p<0·05). Analysis by type of beverage consumed suggested that beer rather than wine or spirits was associated with a poorer outcome.As there was no detectable effect on pregnancy of alcohol consumption below 100 g/week, it is suggested that health education should be directed towards mothers who drink more than this amount.     

Raised plasma intact parathyroid hormone concentrations in young people with mildly raised blood pressure

To study the role of parathyroid gland activity in early primary hypertension plasma concentrations of intact parathyroid hormone were measured in 90 untreated young subjects, aged 16-29, with stable mildly raised blood pressure and in 40 normotensive control subjects selected from the same population in Zoetermeer, The Netherlands. Intact parathyroid hormone concentration was significantly higher in the hypertensive than the normotensive group (2.34 (SE 0.11) pmol/l v 1·47 (0·13)pmol/l, respectively; difference 0·87 pmol/l; 95% confidence interval 0·55 to 1·21; p<0·0001). Serum total calcium concentration was 2·36 (0·01) mmol/l in the hypertensive group and 2·42 (0·01) mmol/l in the normotensive group (difference 0·06 mmol/l; 95% confidence interval 0·02 to 0·09; p=0·02). Urinary calcium excretion over 24 hours did not differ significantly between the two groups (4·17 (0·28) mmol/24 h in the hypertensive group and 3·89 (0·39) mmol/24 h in the normotensive group; difference 0·28 mmol/24 h; 95% confidence interval -0·66 to 1·22). In the hypertensive group both systolic and diastolic blood pressures increased slightly though significantly with intact parathyroid hormone concentrations. No obvious associations between serum calcium concentration and blood pressure were observed.These findings support the view that enhanced activity of the parathyroid gland may play a part in the early stage of primary hypertension.     

Prolonged Delayed Graft Function Is Associated with Inferior Patient and Kidney Allograft Survivals

It is unclear if there is an association between the duration of delayed graft function (DGF) and kidney transplant (KT) outcomes. This study investigated the impact of prolonged DGF on patient and graft survivals, and renal function one year after KT. This single center retrospective analysis included all deceased donor KT performed between Jan/1998 and Dec/2008 (n = 1412). Patients were grouped in quartiles according to duration of DGF (1–5, 6–10, 11–15, and >15 days, designated as prolonged DGF). The overall incidence of DGF was 54.2%. Prolonged DGF was associated with retransplantation (OR 2.110, CI95% 1.064–4.184,p = 0.033) and more than 3 HLA mismatches (OR 1.819, CI95% 1.117–2.962,p = 0.016). The incidence of acute rejection was higher in patients with DGF compared with those without DGF (36.2% vs. 12.2%, p<0.001). Compared to patients without DGF, DGF(1–5), DGF(6–10), and DGF(11–15), patients with prolonged DGF showed inferior one year patient survival (95.2% vs. 95.4% vs. 95.5% vs. 93.4% vs. 88.86%, p = 0.003), graft survival (91% vs. 91.4% vs. 92% vs. 88.7% vs. 70.5%, p<0.001), death-censored graft survival (95.7% vs. 95.4% vs. 96.4% vs. 94% vs. 79.3%, p<0.001), and creatinine clearance (58.0±24.6 vs. 55.8±22.2 vs. 53.8±24.1 vs. 53.0±27.2 vs. 36.8±27.0 mL/min, p<0.001), respectively. Multivariable analysis showed that prolonged DGF was an independent risk factor for graft loss (OR 3.876, CI95% 2.270–6.618, p<0.001), death censored graft loss (OR 4.103, CI95% 2.055–8.193, p<0.001), and death (OR 3.065, CI95% 1.536–6.117, p = 0.001). Prolonged DGF, determined by retransplantation and higher HLA mismatches, was associated with inferior renal function, and patient and graft survivals at one year.     

Impact of Renal Sympathetic Denervation on Left Ventricular Structure and Function at 1-Year Follow-Up

Background

Catheter-based sympathetic renal denervation (RDN) is a recent therapeutic option for patients with resistant hypertension. However, the impact of RDN in left ventricular (LV) mass and function is not completely established. Our aim was to evaluate the effects of RDN on LV structure and function (systolic and diastolic) in patients with resistant hypertension (HTN).

Methods and Results

From a single centre prospective registry including 65 consecutive patients with resistant HTN submitted to RDN between July-2011 and April-2015, 31 patients with baseline and 1-year follow-up echocardiogram were included in this analysis. Mean age was 65±7 years, 48% were males, 71% had type 2 diabetes. Most had hypertension lasting for more than 10 years (90%), and were being treated with a median number of 6 anti-hypertensive drugs, including 74% on spironolactone. At 1-year, there was a significant decrease both on office SBP (176±24 to 149±13mmHg, p<0.001) and DBP (90±14 to 79±11mmHg, p<0.001), and also in 24h ABPM SBP (150±20 to 132±14mmhg, p<0.001) and DBP (83±10 to 74±9mmHg, p<0.001). There was also a significant decrease in LV mass from 152±32 to 136±34g/m² (p<0.001), an increase in LV end diastolic volume (93±18 to 111±27 mL, p = 0.004), an increase in LV ejection fraction (65±9 to 68±9%, p = 0.001) and mitral valve E deceleration time (225±49 to 247±51ms, p = 0.015) at 1-year follow up. There were no significant changes in left atrium volume index or in the distribution of patients among the different left ventricle geometric patterns and diastolic function subgroups.

Conclusions

In this single centre registry of patients with resistant hypertension, renal denervation was associated with significant reduction in both office and ABPM blood pressure and a significant decrease in left ventricle mass evaluated by transthoracic echocardiogram at 1 year follow-up.     

Depressive Symptoms are the Main Predictor for Subjective Sleep Quality in Patients with Mild Cognitive Impairment—A Controlled Study

Objective

Controlled data on predictors of subjective sleep quality in patients with memory complaints are sparse. To improve the amount of comprehensive data on this topic, we assessed factors associated with subjective sleep quality in patients from our memory clinic and healthy individuals.

Methods

Between February 2012 and August 2014 patients with mild cognitive impairment (MCI) and subjective cognitive decline (SCD) from our memory clinic and healthy controls were recruited. Apart from a detailed neuropsychological assessment, the subjective sleep quality, daytime sleepiness and depressive symptoms were assessed using the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS) and the Beck Depression Inventory (BDI-II).

Results

One hundred fifty eight consecutive patients (132 (84%) MCI patients and 26 (16%) SCD patients) and 75 healthy controls were included in the study. Pairwise comparison of PSQI scores showed that non-amnestic MCI (naMCI) patients (5.4±3.5) had significantly higher PSQI scores than controls (4.3±2.8, p = .003) Pairwise comparison of PSQI subscores showed that naMCI patients (1.1±0.4) had significantly more “sleep disturbances” than controls (0.9±0.5, p=.003). Amnestic MCI (aMCI) (0.8±1.2, p = .006) and naMCI patients (0.7±1.2, p = .002) used “sleep medication” significantly more often than controls (0.1±0.6) Both, aMCI (11.5±8.6, p<.001) and naMCI (11.5±8.6, p<.001) patients showed significantly higher BDI-II scores than healthy controls (6.1±5.3). Linear regression analysis showed that the subjective sleep quality was predicted by depressive symptoms in aMCI (p<.0001) and naMCI (p<.0001) patients as well as controls (p<.0001). This means, that more depressive symptoms worsened subjective sleep quality. In aMCI patients we also found a significant interaction between depressive symptoms and global cognitive function (p = .002)

Discussion

Depressive symptoms were the main predictor of subjective sleep quality in MCI patients and controls, but not in SCD patients. Better global cognitive function ameliorated the negative effect of depressive symptoms on the subjective sleep quality in aMCI patients.     

Association of Right Ventricular Pressure and Volume Overload with Non-Ischemic Septal Fibrosis on Cardiac Magnetic Resonance

Background

Non-ischemic fibrosis (NIF) on cardiac magnetic resonance (CMR) has been linked to poor prognosis, but its association with adverse right ventricular (RV) remodeling is unknown. This study examined a broad cohort of patients with RV dysfunction, so as to identify relationships between NIF and RV remodeling indices, including RV pressure load, volume and wall stress.

Methods and Results

The population comprised patients with RV dysfunction (EF<50%) undergoing CMR and transthoracic echo within a 14 day (5±3) interval. Cardiac structure, function, and NIF were assessed on CMR. Pulmonary artery systolic pressure (PASP) was measured on echo. 118 patients with RV dysfunction were studied, among whom 47% had NIF. Patients with NIF had lower RVEF (34±10 vs. 39±9%; p = 0.01) but similar LVEF (40±21 vs. 39±18%; p = 0.7) and LV volumes (p = NS). RV wall stress was higher with NIF (17±7 vs. 12±6 kPa; p<0.001) corresponding to increased RV end-systolic volume (143±79 vs. 110±36 ml; p = 0.006), myocardial mass (60±21 vs. 53±17 gm; p = 0.04), and PASP (52±18 vs. 41±18 mmHg; p = 0.001). NIF was associated with increased wall stress among subgroups with isolated RV (p = 0.005) and both RV and LV dysfunction (p = 0.003). In multivariable analysis, NIF was independently associated with RV volume (OR = 1.17 per 10 ml, [CI 1.04–1.32]; p = 0.01) and PASP (OR = 1.43 per 10 mmHg, [1.14–1.81]; p = 0.002) but not RV mass (OR = 0.91 per 10 gm, [0.69–1.20]; p = 0.5) [model χ² = 21; p<0.001]. NIF prevalence was higher in relation to PA pressure and RV dilation and was > 6-fold more common in the highest, vs. the lowest, common tertile of PASP and RV size (p<0.001).

Conclusion

Among wall stress components, NIF was independently associated with RV chamber dilation and afterload, supporting the concept that NIF is linked to adverse RV chamber remodeling.     

Circulating microRNAs have a sex-specific association with metabolic syndrome

Background

The microRNAs let-7 g and miR-221 have been demonstrated to be related to the glucose metabolism. This study assessed the serum levels of these two microRNAs in subjects with and without metabolic syndrome (MetS).

Results

The serum microRNA levels were detected in 102 subjects aged 40 to 80 years who were recruited from the general population. The status of MetS was defined by the Adult Treatment Panel III (ATP III) criteria modified for Asians. Subjects with histories of cardiovascular diseases or who were receiving treatment with hypoglycemic or lipid-lowering agents were excluded. The levels of both circulating microRNAs (let-7 g and miR-221) were higher in subjects with MetS (p = 0.004 and p = 0.01, respectively). The sex-specific analysis showed that the difference was more prominent in women (for both miRNAs, p < 0.05 in women and p > 0.1 in men). In the female subjects, increased expression of both microRNAs was associated with an increased number of MetS risk components (p = 0.002 for let-7 g and p = 0.022 for miR-221). Moreover, the elevation of serum let-7 g was significantly associated with a low level of high-density lipoprotein cholesterol (p = 0.022) and high blood pressure (p = 0.023). In contrast, the miR-221 level was not associated with any individual MetS risk component.

Conclusions

The circulating levels of let-7 g and miR-221 displayed a female-specific elevation in individuals with metabolic syndrome.     

Irisin and the Metabolic Phenotype of Adults with Prader-Willi Syndrome

Context

Hyperphagia, low resting energy expenditure, and abnormal body composition contribute to severe obesity in Prader Willi syndrome (PWS). Irisin, a circulating myokine, stimulates “browning” of white adipose tissue resulting in increased energy expenditure and improved insulin sensitivity. Irisin has not been previously studied in PWS.

Objectives

Compare plasma and salivary irisin in PWS adults and normal controls. Examine the relationship of irisin to insulin sensitivity and plasma lipids.

Design and Study Participants

A fasting blood sample for glucose, lipids, insulin, leptin, adinopectin, and irisin was obtained from 22 PWS adults and 54 healthy BMI-matched volunteers. Saliva was collected for irisin assay in PWS and controls.

Results

Fasting glucose (77±9 vs 83±7mg/dl, p = 0.004), insulin (4.1±2.0 vs 7.9±4.7μU/ml, p<0.001), and triglycerides (74±34 vs 109±71mg/dl, p = 0.007) were lower in PWS than in controls. Insulin resistance (HOMA-IR) was lower (0.79±0.041 vs 1.63±1.02, p<0.001) and insulin sensitivity (QUICKI) was higher (0.41±0.04 vs 0.36±0.03, p<0.001) in PWS. Plasma irisin was similar in both groups, but salivary irisin (64.5±52.0 vs 33.0±12.1ng/ml), plasma leptin (33.5±24.2 vs 19.7±19.3ng/ml) and plasma adinopectin (13.0±10.8 vs 7.6±4.5μg/ml) were significantly greater in PWS (p<0.001). In PWS, plasma irisin showed positive Pearson correlations with total cholesterol (r = 0.58, p = 0.005), LDL-cholesterol (r = 0.59, p = 0.004), and leptin (r = 0.43, p = 0.045). Salivary irisin correlated negatively with HDL-cholesterol (r = -0.50, p = 0.043) and positively with LDL-cholesterol (r = 0.51, p = 0.037) and triglycerides (r = 0.50, p = 0.041).

Conclusions

Salivary irisin was markedly elevated in PWS although plasma irisin was similar to levels in controls. Significant associations with plasma lipids suggest that irisin may contribute to the metabolic phenotype of PWS.     

Effect of a High Intake of Conjugated Linoleic Acid on Lipoprotein Levels in Healthy Human Subjects

Background

Trans fatty acids are produced either by industrial hydrogenation or by biohydrogenation in the rumens of cows and sheep. Industrial trans fatty acids lower high-density lipoprotein (HDL) cholesterol, raise low-density lipoprotein (LDL) cholesterol, and increase the risk of coronary heart disease. The effects of trans fatty acids from ruminants are less clear. We investigated the effect on blood lipids of cis-9, trans-11 conjugated linoleic acid (CLA), a trans fatty acid largely restricted to ruminant fats.

Methodology/Principal Findings

Sixty-one healthy women and men were sequentially fed each of three diets for three weeks, in random order, for a total of nine weeks. Diets were identical except for 7% of energy (approximately 20 g/day), which was provided either by oleic acid, by industrial trans fatty acids, or by a mixture of 80% cis-9, trans-11 and 20% trans-10, cis-12 CLA. After the oleic acid diet, mean (± SD) serum LDL cholesterol was 2.68±0.62 mmol/L compared to 3.00±0.66 mmol/L after industrial trans fatty acids (p<0.001), and 2.92±0.70 mmol/L after CLA (p<0.001). Compared to oleic acid, HDL-cholesterol was 0.05±0.12 mmol/L lower after industrial trans fatty acids (p = 0.001) and 0.06±0.10 mmol/L lower after CLA (p<0.001). The total-to–HDL cholesterol ratio was 11.6% higher after industrial trans fatty acids (p<0.001) and 10.0% higher after CLA (p<0.001) relative to the oleic acid diet.

Conclusions/Significance

High intakes of an 80∶20 mixture of cis-9, trans-11 and trans-10, cis-12 CLA raise the total to HDL cholesterol ratio in healthy volunteers. The effect of CLA may be somewhat less than that of industrial trans fatty acids.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00529828","term_id":"NCT00529828"}}NCT00529828     

Early Vascular Aging in Young and Middle-Aged Ischemic Stroke Patients: The Norwegian Stroke in the Young Study

Background

Ischemic stroke survivors have high risk of cardiovascular morbidity and mortality even at young age, suggesting that early arterial aging is common among such patients.

Methods

We measured aortic stiffness by carotid-femoral pulse wave velocity (PWV) in 205 patients (69% men) aged 15–60 years with acute ischemic stroke in the prospective Norwegian Stroke in the Young Study. High for age carotid-femoral PWV was identified in the reference normogram.

Results

Patients were on average 49±10 years old, 34% had a history of hypertension and 37% had metabolic syndrome (MetS). In the total study population, higher PWV was associated with history of hypertension (β = 0.18), higher age (β = 0.34), systolic blood pressure (BP) (β = 0.28) and serum creatinine (β = 0.18) and lower high-density lipoprotein (HDL) cholesterol (β = –0.10, all p<0.01) in multivariate linear regression analysis (multiple R² = 0.42, p<0.001). High for age PWV was found in 18% of patients. In univariate analyses, known hypertension was associated with a 6-fold, MetS with a 4-fold and presence of carotid plaque with a 3.7-fold higher risk for high for age PWV (all p<0.01). In multiple logistic regression analysis higher systolic BP (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.02–1.06; p<0.01), history of hypertension (OR 3.59; 95% CI 1.52–8.51; p<0.01), low HDL cholesterol (OR 3.03; 95% CI 1.00–9.09; p = 0.05) and higher serum creatinine (OR 1.04; 95% CI 1.01–1.06; p<0.01) were associated with high for age PWV.

Conclusions

Higher PWV is common in younger and middle-aged ischemic stroke patients and associated with a clustering of classical cardiovascular risk factors.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01597453","term_id":"NCT01597453"}}NCT01597453     

Association of Dyslipidemia with Renal Cell Carcinoma: A 1∶2 Matched Case-Control Study

Abnormal serum lipid profiles are associated with the risk of some cancers, but the direction and magnitude of the association with renal cell carcinoma is unclear. We explore the relationship between serum lipids and renal cell carcinoma via a matched case-control study. A 1∶2-matched case-control study design was applied, where one renal cell carcinoma patient was matched to two non-renal-cell-carcinoma residents with respect to age (±0 year) and gender. Cases (n = 248) were inpatients with a primary diagnosis of renal cell carcinoma, confirmed by pathology after operations. Controls were sampled from a community survey database matched on age and gender with cases, 2 controls for each case. Stratified Cox proportional hazard regression analysis was used to obtain hazard ratios and corresponding 95% confidence intervals of lipids level and dyslipidemia for the risk of renal cell carcinoma. Elevated serum cholesterol (p<0.001), LDL cholesterol (p<0.001), and HDL cholesterol (p = 0.003) are associated with decreased hazard of renal cell carcinoma, adjusting for obesity, smoke, hypertension and diabetes. However, risk caused by hTG showed no statistical significance (p = 0.263). This study indicates that abnormal lipid profile influences the risk of renal cell carcinoma.     

Increase in Dickkopf-1 Serum Level in Recent Spondyloarthritis. Data from the DESIR Cohort

Objectives

To investigate DKK-1 and SOST serum levels among patients with recent inflammatory back pain (IBP) fulfilling ASAS criteria for SpA and associated factors.

Methods

The DESIR cohort is a prospective, multicenter French cohort of 708 patients with early IBP (duration >3 months and <3 years) suggestive of AxSpA. DKK-1 and SOST serum levels were assessed at baseline and were compared between the subgroup of patients fulfilling ASAS criteria for SpA (n = 486; 68.6%) and 80 healthy controls.

Results

Mean SOST serum levels were lower in ASAS+ patients than healthy controls (49.21 ± 25.9 vs. 87.8 ± 26 pmol/L; p<0.0001). In multivariate analysis, age (p = 5.4 10⁻⁹), CRP level (p<0.0001) and serum DKK-1 level (p = 0.001) were associated with SOST level. Mean DKK-1 serum levels were higher in axial SpA patients than controls (30.03 ± 15.5 vs. 11.6 ± 4.2 pmol/L; p<0.0001). In multivariate analysis, DKK-1 serum levels were associated with male gender (p = 0.03), CRP level (p = 0.006), SOST serum level (p = 0.002) and presence of sacroiliitis on radiography (p = 0.05). Genetic association testing of 10 SNPs encompassing the DKK-1 locus failed to demonstrate a significant contribution of genetics to control of DKK-1 serum levels.

Conclusions

DKK-1 serum levels were increased and SOST levels were decreased among a large cohort of patients with early axial SpA compared to healthy controls. DKK-1 serum levels were mostly associated with biological inflammation and SOST serum levels.     

Elevated serum squalene and cholesterol synthesis markers in pregnant obese women with gestational diabetes mellitus

We examined serum cholesterol synthesis and absorption markers and their association with neonatal birth weight in obese pregnancies affected by gestational diabetes mellitus (GDM). Pregnant women at risk for GDM (BMI >30 kg/m²) were enrolled from maternity clinics in Finland. GDM was determined from the results of an oral glucose tolerance test. Serum samples were collected at six time-points, one in each trimester of pregnancy, and at 6 weeks, 6 months, and 12 months postpartum. Analysis of serum squalene and noncholesterol sterols by gas-liquid chromatography revealed that in subjects with GDM (n = 22), the serum Δ8-cholestenol concentration and lathosterol/sitosterol ratio were higher (P < 0.05) than in the controls (n = 30) in the first trimester, reflecting increased cholesterol synthesis. Also, subjects with GDM had an increased ratio of squalene to cholesterol (100 × μmol/mmol of cholesterol) in the second (11.5 ± 0.5 vs. 9.1 ± 0.5, P < 0.01) and third (12.1 ± 0.8 vs. 10.0 ± 0.7, P < 0.05) trimester. In GDM, the second trimester maternal serum squalene concentration correlated with neonatal birth weight (r = 0.70, P < 0.001). In conclusion, in obesity, GDM associated with elevated serum markers of cholesterol synthesis. Correlation of maternal serum squalene with neonatal birth weight suggests a potential contribution of maternal cholesterol synthesis to newborn weight in GDM.     

Increased Circulating ANG II and TNF-α Represents Important Risk Factors in Obese Saudi Adults with Hypertension Irrespective of Diabetic Status and BMI

Central adiposity is a significant determinant of obesity-related hypertension risk, which may arise due to the pathogenic inflammatory nature of the abdominal fat depot. However, the influence of pro-inflammatory adipokines on blood pressure in the obese hypertensive phenotype has not been well established in Saudi subjects. As such, our study investigated whether inflammatory factors may represent useful biomarkers to delineate hypertension risk in a Saudi cohort with and without hypertension and/or diabetes mellitus type 2 (DMT2). Subjects were subdivided into four groups: healthy lean controls (age: 47.9±5.1 yr; BMI: 22.9±2.1 Kg/m²), non-hypertensive obese (age: 46.1±5.0 yr; BMI: 33.7±4.2 Kg/m²), hypertensive obese (age: 48.6±6.1 yr; BMI: 36.5±7.7 Kg/m²) and hypertensive obese with DMT2 (age: 50.8±6.0 yr; BMI: 35.3±6.7 Kg/m²). Anthropometric data were collected from all subjects and fasting blood samples were utilized for biochemical analysis. Serum angiotensin II (ANG II) levels were elevated in hypertensive obese (p<0.05) and hypertensive obese with DMT2 (p<0.001) compared with normotensive controls. Systolic blood pressure was positively associated with BMI (p<0.001), glucose (p<0.001), insulin (p<0.05), HOMA-IR (p<0.001), leptin (p<0.01), TNF-α (p<0.001) and ANG II (p<0.05). Associations between ANG II and TNF-α with systolic blood pressure remained significant after controlling for BMI. Additionally CRP (p<0.05), leptin (p<0.001) and leptin/adiponectin ratio (p<0.001) were also significantly associated with the hypertension phenotype. In conclusion our data suggests that circulating pro-inflammatory adipokines, particularly ANG II and, TNF-α, represent important factors associated with a hypertension phenotype and may directly contribute to predicting and exacerbating hypertension risk.     

Leukocyte ABCA1 Remains Atheroprotective in Splenectomized LDL Receptor Knockout Mice

Aim

ATP-binding cassette transporter A1 (ABCA1) is an important mediator of macrophage cholesterol efflux. It mediates the efflux of cellular cholesterol to lipid-poor apolipoprotein A-I. LDL receptor (LDLr) knockout (KO) mice deficient for leukocyte ABCA1 (ABCA1 KO→LDLr KO) show increased atherosclerosis and splenic lipid accumulation despite largely attenuated serum cholesterol levels. In the present study, we aimed to explore the importance of the spleen for the atheroprotective effects of leukocyte ABCA1.

Methods

LDLr KO mice were transplanted with bone marrow from ABCA1 KO mice or wild-type (WT) controls. After 8 weeks recovery, mice were either splenectomized (SP-x) or underwent a sham operation, and were subsequently challenged with a Western-type diet (WTD).

Results

In agreement with previous studies, the atherosclerotic lesion area in ABCA1 KO→LDLr KO sham animals (655±82×10³ µm²) was 1.4-fold (p = 0.03) larger compared to sham WT→LDLr KO mice (459±33×10³ µm²) after 8 weeks WTD feeding, despite 1.7-fold (p<0.001) lower serum cholesterol levels. Interestingly, deletion of ABCA1 in leukocytes led to 1.6-fold higher neutrophil content in the spleen in absence of differences in circulating neutrophils. Levels of KC, an important chemoattractant for neutrophils, in serum, however, were increased 2.9-fold (p = 0.07) in ABCA1 KO→LDLr KO mice. SP-x induced blood neutrophilia as compared to WT→LDLr KO mice (1.9-fold; p<0.05), but did not evoke differences in serum cholesterol and anti-oxLDL antibody levels. Atherosclerotic lesion development, however, was 1.3-fold induced both in the presence and absence of leukocyte ABCA1 (WT: 614±106×10³ µm², ABCA1 KO: 786±44×10³ µm²). Two-way ANOVA revealed independent effects on atherosclerosis for both leukocyte ABCA1 deficiency and SP-x (p<0.05).

Conclusions

The observed splenic alterations induced by leukocyte ABCA1 deficiency do not play a significant role in the anti-atherogenic effects of leukocyte ABCA1 on lesion development.     

Identifying Adult Dengue Patients at Low Risk for Clinically Significant Bleeding

Background

Clinically significant bleeding is important for subsequent optimal case management in dengue patients, but most studies have focused on dengue severity as an outcome. Our study objective was to identify differences in admission parameters between patients who developed clinically significant bleeding and those that did not. We sought to develop a model for discriminating between these patients.

Methods

We conducted a retrospective study of 4,383 adults aged >18 years who were hospitalized with dengue infection at Tan Tock Seng Hospital, Singapore from 2005 to 2008. Patients were divided into those with clinically significant bleeding (n = 188), and those without (n = 4,195). Demographic, clinical, and laboratory variables on admission were compared between groups to determine factors associated with clinically significant bleeding during hospitalization.

Results

On admission, female gender (p<0.001); temperature >38°C (p<0.001); nausea/vomiting (p = 0.009) and abdominal pain/tenderness (p = 0.005); lower systolic blood pressure (p<0.001); higher pulse rate (p<0.001); increased absolute neutrophil count (ANC; p<0.001); reduced absolute lymphocyte count (ALC; p<0.001), haematocrit percentage (p<0.001) and platelet count (p = 0.04), and increased prothrombin time (p = 0.003) were significantly associated with clinically significant bleeding on univariate analysis. Multivariate analysis showed that independent variables in the final model were female gender (aOR 2.85; 95% CI: 1.9–4.33); temperature >38°C (aOR 1.81; 95% CI: 1.27–2.61), nausea/vomiting (aOR 1.39; 95% CI: 0.94–2.12), ANC (aOR 1.3; 95% CI: 1.15–1.46), ALC (aOR 0.4; 95% CI: 0.25–0.64), hematocrit percentage (aOR 0.96; 95% CI: 0.92–1.002) and platelet count (aOR 0.993; 95% CI: 0.988–0.998). At the cutoff of -3.919, the model achieved an AUC of 0.758 (sensitivity:0.87, specificity: 0.38, PPV: 0.06, NPV: 0.98).

Conclusion

Clinical risk factors associated with clinically significant bleeding were identified. This model may be useful to complement clinical judgement in triaging adult dengue patients given the dynamic nature of acute dengue, particularly in pre-identifying those less likely to develop clinically significant bleeding.     

Corneal Sensitivity and Dry Eye Symptoms in Patients with Keratoconus

Purpose

To investigate corneal sensitivity to selective mechanical, chemical, and thermal stimulation and to evaluate their relation to dry eye symptoms in patients with keratoconus.

Methods

Corneal sensitivity to mechanical, chemical, and thermal thresholds were determined using a gas esthesiometer in 19 patients with keratoconus (KC group) and in 20 age-matched healthy subjects (control group). Tear film dynamics was assessed by Schirmer I test and by the non-invasive tear film breakup time (NI-BUT). All eyes were examined with a rotating Scheimpflug camera to assess keratoconus severity.

Results

KC patients had significatly decreased tear secretion and significantly higher ocular surface disease index (OSDI) scores compared to controls (5.3±2.2 vs. 13.2±2.0 mm and 26.8±15.8 vs. 8.1±2.3; p<0.001). There was no significant difference in NI-BUT between the two groups (KC: 9.8±4.8 vs. control: 10.7±3.8; p>0.05). The mean threshold for selective mechanical (KC: 139.2±25.8 vs. control: 109.1±24.0 ml/min), chemical (KC: 39.4±3.9 vs. control: 35.2±1.9%CO₂), heat (KC: 0.91±0.32 vs. control: 0.54±0.26 Δ°C) and cold (KC: 1.28±0.27 vs. control: 0.98±0.25 Δ°C) stimulation in the KC patients were significantly higher than in the control subjects (p<0.001, for all parameters). No correlation was found between age and mechanical, chemical, heat or cold thresholds in the patients with KC (p>0.05), whereas in the control subjects both mechanical (r = 0.52, p = 0.02), chemical (r = 0.47, p = 0.04), heat (r = 0.26, p = 0.04) and cold threshold (r = 0.40, p = 0.03) increased with age. In the KC group, neither corneal thickness nor tear flow, NI-BUT or OSDI correlated significantly with mechanical, chemical, heat or cold thresholds (p>0.05 for all variables).

Conclusions

Corneal sensitivity to different types of stimuli is decreased in patients with keratoconus independently of age and disease severity. The reduction of the sensory input from corneal nerves may contribute to the onset of unpleasant sensations in these patients and might lead to the impaired tear film dynamics.     

Pre-Existing Hypoxia Is Associated with Greater EEG Suppression and Early Onset of Evolving Seizure Activity during Brief Repeated Asphyxia in Near-Term Fetal Sheep

Spontaneous antenatal hypoxia is associated with high risk of adverse outcomes, however, there is little information on neural adaptation to labor-like insults. Chronically instrumented near-term sheep fetuses (125 ± 3 days, mean ± SEM) with baseline PaO₂ < 17 mmHg (hypoxic group: n = 8) or > 17 mmHg (normoxic group: n = 8) received 1-minute umbilical cord occlusions repeated every 5 minutes for a total of 4 hours, or until mean arterial blood pressure (MAP) fell below 20 mmHg for two successive occlusions. 5/8 fetuses with pre-existing hypoxia were unable to complete the full series of occlusions (vs. 0/8 normoxic fetuses). Pre-existing hypoxia was associated with progressive metabolic acidosis (nadir: pH 7.08 ± 0.04 vs. 7.33 ± 0.02, p<0.01), hypotension during occlusions (nadir: 24.7 ± 1.8 vs. 51.4 ± 3.2 mmHg, p<0.01), lower carotid blood flow during occlusions (23.6 ± 6.1 vs. 63.0 ± 4.8 mL/min, p<0.01), greater suppression of EEG activity during, between, and after occlusions (p<0.01) and slower resolution of cortical impedance, an index of cytotoxic edema. No normoxic fetuses, but 4/8 hypoxic fetuses developed seizures 148 ± 45 minutes after the start of occlusions, with a seizure burden of 26 ± 6 sec during the inter-occlusion period, and 15.1 ± 3.4 min/h in the first 6 hours of recovery. In conclusion, in fetuses with pre-existing hypoxia, repeated brief asphyxia at a rate consistent with early labor is associated with hypotension, cephalic hypoperfusion, greater EEG suppression, inter-occlusion seizures, and more sustained cytotoxic edema, consistent with early onset of neural injury.     

Lipid Peroxidation and Total Cholesterol in HAART-Na?ve Patients Infected with Circulating Recombinant Forms of Human Immunodeficiency Virus Type-1 in Cameroon

Background

HIV infection has commonly been found to affect lipid profile and antioxidant defense.

Objectives

To determine the effects of Human Immunodeficiency Virus (HIV) infection and viral subtype on patient’s cholesterol and oxidative stress markers, and determine whether in the absence of Highly Active Antiretroviral Therapy (HAART), these biochemical parameters could be useful in patient’s management and monitoring disease progression in Cameroon. For this purpose, we measured total cholesterol (TC), LDL cholesterol (LDLC), HDL cholesterol (HDLC), total antioxidant ability (TAA), lipid peroxidation indices (LPI), and malondialdehyde (MDA) in HIV negative persons and HIV positive HAART-naïve patients infected with HIV-1 group M subtypes.

Methods

We measured serum TC, LDLC, HDLC, plasma MDA, and TAA concentrations, and calculated LPI indices in 151 HIV-positive HAART-naïve patients and 134 seronegative controls. We also performed gene sequence analysis on samples from 30 patients to determine the effect of viral genotypes on these biochemical parameters. We also determined the correlation between CD4 cell count and the above biochemical parameters.

Results

We obtained the following controls/patients values for TC (1.96±0.54/1. 12±0. 48 g/l), LDLC (0. 67±0. 46/0. 43±0. 36 g/l), HDLC (105. 51±28. 10/46. 54±23. 36 mg/dl) TAA (0. 63±0. 17/0. 16±0. 16 mM), MDA (0. 20±0. 07/0. 41±0. 10 µM) and LPI (0. 34±0. 14/26. 02±74. 40). In each case, the difference between the controls and patients was statistically significant (p<0.05). There was a positive and statistically significant Pearson correlation between CD4 cell count and HDLC (r = +0.272; p<0.01), TAA (r = +0.199; p<0.05) and a negative and statistically significant Pearson correlation between CD4 cell count and LPI (r = −0.166; p<0.05). Pearson correlation between CD4 cell count and TC, CD4cell count and LDLC was positive but not statistically significant while it was negative but not statistically significant with MDA. The different subtypes obtained after sequencing were CRF02_AG (43.3%), CRF01_AE (20%), A1 (23.3%), H (6.7%), and G (6.7%). None of the HIV-1 subtypes significantly influenced the levels of the biochemical parameters, but by grouping them as pure subtypes and circulating recombinant forms (CRFs), the CRF significantly influenced TC levels. TC was significantly lower in patients infected with CRF (0.87±0.27 g/l) compared to patients infected with pure HIV-1 subtypes (1.32±0.68 g/l) (p<0.017). MDA levels were also significantly higher in patients infected with HIV-1CRF01_AE (0.50±0.10 µM), compared to patients infected with CRF02_AG (0. 38±0. 08 µM) (p<0.018).

Conclusion

These results show that HIV infection in Cameroon is associated with significant decrease in TAA, LDLC, HDLC and TC, and increased MDA concentration and LPI indices which seem to be linked to the severity of HIV infection as assessed by CD4 cell count. The data suggests increased oxidative stress and lipid peroxidation in HIV-infected patients in Cameroon, and an influence of CRFs on TC and MDA levels.     

Weight loss in obese subjects on a restricted diet given BRL 26830A,a new atypical β adrenoceptor agonist

A double blind placebo controlled study was carried out in 40 subjects newly referred for treatment for obesity to determine the effects of the new thermogenic β adrenoceptor agonist BRL 26830A. The subjects were randomised to receive either BRL 26830A, 200 mg daily for two weeks then 400 mg daily, or placebo for 18 weeks, and all were instructed to follow a 3·35 MJ diet that was low in fat and high in fibre. Weight loss was 15·4 (SD 6·6) kg in subjects given BRL 26830A compared with 10·0 (5·9) kg in those given placebo (p=0·02). The relative weight loss was 0·93 (0·39)% a week with BRL 26830A and 0·61 (0·38)% with placebo (p=0·02). Urinary excretion of nitrogen was similar in both groups, whereas measurements of skinfold thickness indicated a 4·1 kg difference in the amount of fat lost, suggesting that weight loss with BRL 26830A was mainly from adipose and not lean tissue. BRL 26830A had no effect on resting pulse rate or pressor effects on either diastolic or systolic blood pressure. No significant differences were found between the two groups in serum cholesterol concentration, percentage of high density lipoprotein cholesterol, plasma concentrations of glucose and insulin, the ratio of glucose to insulin, serum concentrations of triiodothyronine and thyroxine, and creatinine clearance. Short term administration of BRL 26830A to six subjects who had taken the drug for 18 weeks showed that the expenditure of energy increased by 11·6% during the second hour after administration, which suggests that BRL 26830A may enhance weight loss thermogenically.BRL 26830A may be a useful drug in the treatment of obesity.