Polymorphisms in the leptin receptor (LEPR)—putative association with obesity and T2DM

Leptin plays an important role in regulating adipose-tissue mass. Leptin controls energy balance and food intake through the leptin receptor in the hypothalamus of the brain, which suggests that some polymorphisms of the leptin receptor gene (LEPR) might contribute to obesity or obesity-related diseases. In an effort to identify genetic polymorphisms in a potential candidate gene for obesity and type 2 diabetes mellitus (T2DM) in the Korean population, we have sequenced the LEPR gene. Thirty-five sequence variants were identified (including 9 novel polymorphisms): 1 single nucleotide polymorphism (SNP) in the promoter region, 1 SNP in the 5 UTR, 8 SNPs in exons (3 non-synonymous SNPs), 23 SNPs in introns, 1 ins/del in the 3 UTR, and 1 SNP in the 3 downstream region. To investigate possible association of LEPR polymorphisms with body mass index (BMI) and the risk of T2DM, we genotyped for 11 polymorphisms in the Korean population (n=1,463). Using statistical analyses, no significant associations between the genetic polymorphisms in the LEPR gene and the risk of T2DM were detected. However, one non-synonymous SNP in exon 3, +5193G>A (Arg109Lys), showed marginal association with BMI (P=0.02) and gene dose-dependent genetic effects were observed. The present study provides information about additional genetic polymorphisms in LEPR and positive associations of those polymorphisms with BMI in the Korean population.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.Kyong Soo Park and Hyoung Doo Shin contributed equally to this work     

Immunoregulatory properties of cell-free DNA in plasma of celiac disease patients – A pilot study

The elevated plasma cell-free DNA (cfDNA) concentrations were repeatedly reported in association with the process of inflammation. The qualitative and quantitative characteristics of plasma cfDNA in active (newly diagnosed) celiac disease patients (CD) have not yet been studied despite the fact that cfDNA of healthy individuals is able to regulate immune response. We determined the total cfDNA concentration and relative content of telomeric sequences in plasma cfDNA in CD (n?=?10) and healthy age- and sex-matched controls (HC, n?=?10) by quantitative PCR. To obtain the evidence that the observed biological effects are caused solely by cfDNA molecules, we applied the treatment of paired plasma samples with DNase. Using paired samples of plasma (non-treated/native and treated by DNase), we analyzed the contribution of cfDNA to the activation of TLR9 and TNF-α mRNA expression in THP1 monocytic cell line. There were no significant differences in the quantities of plasma cfDNA and relative contents of telomeric sequences in their pools. When we compared the levels of TNF-α mRNA expression in THP1 cells achieved after stimulation with native CD and HC plasma samples, we found significantly (p?=?.031) higher expression after stimulation with CD samples. We documented also the ability of cfDNA contained in CD plasma samples to stimulate the production of TLR9 mRNA. The TLR9 mRNA expression levels were significantly (p?=?.014) lowered after cfDNA removal from CD plasma samples. The design of our experiments allowed us to study the effects of cfDNA without its isolation from plasma. cfDNA contained in CD plasma samples differs significantly in its immunoregulatory capacity from cfDNA in HC plasma. The differences are caused neither by different concentrations of cfDNA in plasma samples nor by different relative abundance of telomeric sequences. Further studies are needed to elucidate the role of plasma cfDNA in celiac disease pathogenesis.     

Relevance of 123I-BMIPP delayed scintigraphic imaging for patients with angina pectoris – a pilot study

Introduction

The study was designed to clarify the role of ¹²³I-β-methyl-iodophenylpentadecanoic acid (¹²³I-BMIPP) in the evaluation of myocardial fatty acid metabolism in patients with stable angina pectoris (AP) before and after percutaneous coronary intervention (PCI).

Material and methods

Ten controls (mean age: 70.4 ±10.5 years) and 12 patients with AP (mean age: 67.4 ±11.6 years) and single vessel coronary artery disease participated in the radionuclide cardiac study. Scintigraphic images were acquired at 30 min and at 4 h after ¹²³I-BMIPP injection to determine early and delayed BMIPP uptake, respectively. The heart-to-mediastinum (H/M) ratio and the washout rate (WR) were calculated from the planar images. All patients underwent scintigraphy one day before PCI and again 1 month after successful PCI.

Results

No significant differences in the early or delayed H/M ratios were observed between the patients and the controls before PCI (early: 2.70 ±0.36 vs. 2.73 ±0.57; delayed: 2.26 ±0.33 vs. 2.40 ±0.43; p > 0.2 for both). The early and delayed H/M ratios remained unchanged with the comparison with before PCI (early: 2.72 ±0.27, delayed: 2.23 ±0.22; p > 0.2 for both). The global WR before PCI was significantly higher in the patients than in the control group (36.7 ±9.3%, vs. 28.1 ±8.2%, p = 0.02). However, the WR after PCI did not significantly differ between the patients and the controls (34.3 ±7.8% vs. 28.1 ±8.2%, p = 0.1).

Conclusions

These data may suggest that the WR of ¹²³I-BMIPP determined from the planar images enhances the presence of myocardial ischaemia.     

Patterns of association between PPARγ genetic variation and indices of adiposity and insulin action in African-Americans and whites: the CARDIA Study

We performed a combination of single-variant- and haplotype-based analyses to investigate the association of peroxisome-proliferator-activated receptor γ (PPARγ) gene sequence variation with indices of adiposity, including body mass index (BMI) and waist girth, as well as insulin action, including fasting blood glucose and insulin levels. Nine polymorphisms, selected based on race-specific pairwise linkage disequilibrium relations and/or potential functional relevance, were assayed in 3,875 African-American and white young adults from the Coronary Artery Risk Development in Young Adults Study. These polymorphisms were C25819G (C-681G), C65746G (Pro12Ala), G67222A, A69208G, G81556T, T95872C, T115432G, C127599T, and C148157T (C1431T). They defined seven and six common haplotypes in African-Americans and whites, respectively. Patterns of associations of PPARγ genetic variation with the metabolic traits differed between the two racial groups, with some exceptions. Haplotype CCGGCTCC was associated with a significant reduction in glucose levels in both racial groups (P<0.001 in each group), and the G69208 allele was associated with lower glucose levels in lean African-Americans and in whites (both P=0.02). Two haplotypes, relatively unique to whites, were associated with measures of adiposity and glucose levels. Two haplotypes, relatively unique to African-Americans, were associated with glucose levels. There were no significant effects of PPARγ haplotypes on measures of body size in this racial group, but a novel polymorphism, G67222A, significantly modulated the relation between BMI and glucose levels (P interaction, 0.003). This study provides evidence that variants, other than Pro12Ala, influence variation in body size and indices of insulin action. It underscores the role of genetic and environmental contexts in shaping the patterns of associations of PPARγ sequence variants with metabolic traits in human populations.     

Characteristics of platelet indices and their prognostic significance in selected medical condition – a systematic review

BackgroundPlatelets, also called thrombocytes, are produced in bone marrow and are the second most numerous blood cells which circulate in blood and play a pivotal role in hemostasis, wound healing, angiogenesis. There is a large body of evidence that platelets are likely to contribute to inflammation in multiple diseases. Also, recent studies revealed the association between platelet indices (PI) and inflammation.MethodsPubMed, Scopus and Google Scholar databases were searched and only papers published in the last 10 years were consequently analyzed.ResultsThe most frequently evaluated parameters are mean platelet volume (MPV), platelet diversity index (PDW), plateletcrit (PCT) and the presence of larger platelets (P-LCRs platelet larger cell ratio). The values of platelet indices (PI) were elevated in patients suffering from type 2 diabetes mellitus, myocardial infarction, cancers or acute surgical conditions, such as appendicitis. The measurement of PIs does not generate additional costs and can be performed during routine cell blood count, not requiring additional blood samples.ConclusionsPlatelet indices may have prognostic and predictive value in numerous conditions.     

Strategies to implement a patient counseling and medication tickler system — A study of Maryland pharmacists and their hypertensive patients

The Maryland Pharmacy High Blood Pressure Program (MPHBPP) successfully enrolled over 100 pharmacies (approximately 200 pharmacists) in a program to educate, monitor and follow-up hypertensive patients to improve patient compliance with therapy regimen. Utilizing diffusion of innovation as a theoretical framework, strategies were developed to identify pharmacists willing to consider participation and implement a patient counseling and medication tickler system. Pharmacists who maintained patient profiles, had a private consultation area, provided verbal instruction and were members of one or more professional societies were over represented among the adopters and correlation (0.48, P = 0.00) and regression (r² = 0.18) analyses of these prior behaviors indicate that they were the best predictors of adopting the program. We conclude that added practice changes can be achieved if programs are tailored to be compatible with the practices of those who have already demonstrated the interest and capacity to change.     

How do patients with rheumatic disease experience their relationship with their doctors? A qualitative study of experiences of stress and support in the doctor-patient relationship

This study is evaluated what patients with rheumatic disease perceive as important in their medical encounters. We interviewed two groups of patients: one with a well-defined inflammatory condition (rheumatoid arthritis (RA) or ankylosing spondylitis) (n = 12) and one with non-inflammatory widespread chronic pain such as fibromyalgia (n = 14). Both groups focused on their relationship to their doctor. Two central themes emerged as of importance: 'to be seen' and 'to be believed'. However, these themes had different connotations for the two groups. For the patients with inflammatory conditions, 'to be seen' implied being seen as an individual and not as a mere diagnosis, and 'to be believed' as far as pain and suffering were concerned. For patients with non-inflammatory chronic pain 'to be seen' and 'to be believed' primarily implied being able to obtain a useful somatic diagnosis. Practical implications of these findings are discussed.     

Prognostic value of tissue factor in patients with abdominal aortic and iliac arterial aneurysms – preliminary study

Introduction

The decision on the time and choice of strategy of treatment of abdominal aortic aneurysm must be especially carefully balanced. The aim of the study was to evaluate the tissue factor (TF) plasma level as a potential factor useful in anticipation of abdominal aortic aneurysm and/or iliac arterial aneurysm via comparison of plasma TF level in patients with ruptured and non-ruptured aneurysms.

Material and methods

The study included 33 patients with aneurysm (17 operated on electively because of non-ruptured aneurysm and 16 operated on emergently due to ruptured aneurysm), 33 claudicant patients with atherosclerosis of the abdominal aorta and iliac arteries with normal diameter of arteries, and 30 healthy controls. Plasma TF level was assessed by ELISA method using the IMUBIND Tissue Factor ELISA Kit (American Diagnostica Inc.).

Results

The study showed an increased TF level in patients with aneurysm (134 ±54 pg/ml) and in patients with atherosclerosis without concomitant aneurysm (91 ±30 pg/ml) in comparison with the control group (62 ±20 pg/ml), respectively p < 0.001 and p = 0.008. A significantly higher TF plasma level was observed in patients with ruptured abdominal aortic aneurysms (160 ±57 pg/ml) as compared to patients with non-ruptured aortic aneurysms (109 ±39 pg/ml) or peripheral arterial occlusive disease (91 ±30 pg/ml), respectively p < 0.001 and p < 0.001. The difference in TF level between the group with non-ruptured aortic aneurysms (109 ±39 pg/ml) and the patients with atherosclerosis without aneurysm (91 ±30 pg/ml) was not statistically significant.

Conclusions

No difference in TF level between patients with non-ruptured AAA/IAA and patients with aortic and iliac atherosclerosis without aneurysm indicates that an increased TF plasma level is not specific for any of the above-mentioned vascular pathologies.     

Association between heart rate at rest and myocardial perfusion in patients with acute myocardial infarction undergoing cardiac rehabilitation – a pilot study

Introduction

This study was conducted to determine if there was a link among heart rate at rest (rHR), muscle volume changes, and single photon emission computed tomography (SPECT) parameters after 6-month cardiac rehabilitation in patients with acute myocardial infarction (AMI).

Material and methods

Twenty-nine consecutive AMI patients (mean age: 63.0 ±9.1 years) who received appropriate percutaneous coronary intervention on admission were enrolled. ^99mTc-Sestamibi myocardial SPECT images were obtained at the early (30 min) and delayed (4 h) phases after tracer injection at 2 weeks (0M) and 6 months (6M) after the onset of AMI. Within a few days of SPECT, all patients underwent cardiopulmonary exercise test for evaluation of cardiac rehabilitation effects. Before the initiation of exercise test, leg muscle volume was measured. All patients were stratified into the ≥ 70 beats per minute (bpm) (n = 15) or < 70 bpm (n = 14) group based on rHR at 6M.

Results

There were no significant differences in the recanalization time, peak cardiac enzyme, or initial left ventricular ejection fraction between the two groups. After the 6-month training, the muscle volume changes in the lower limbs (< 70 bpm, 0.23 ±0.22; ≥ 70 bpm, –0.07 ±0.26, p < 0.05) were significantly greater in the < 70 bpm group than the ≥ 70 bpm group. The decreased rate of rHR had a significant correlation with the improved global severity (r = 0.62, p = 0.001) and extent (r = 0.48, p = 0.017) of left ventricle evaluated by ^99mTc-Sestamibi myocardial SPECT delayed phase.

Conclusions

The result of this preliminary study demonstrated that improved myocardial perfusion was closely related to decreased rHR after cardiac rehabilitation.     

Correlation between insulin resistance and breast elasticity heterogeneity measured by shear wave elastography in premenopausal women – a pilot study

Introduction

Recent studies have demonstrated a strong correlation between obesity, insulin resistance, increased insulin and insulin-like growth factor levels and the risk of breast cancer. Our study was aimed at exploring correlations between glucose, insulin, insulin resistance, obesity and quantitatively estimated breast elasticity in healthy women.

Material and methods

The pilot study included 37 premenopausal women aged 22-45 years who underwent B-mode sonography and real-time shear wave elastography. Blood was collected for fasting insulin and glucose, and HOMA insulin resistance index was calculated.

Results

The mean elasticity of glandular and fatty tissue measured in both breasts was 12.5 ±3.5 kPa and 10.9 ±3.7 kPa respectively. Insulin levels did not correlate with glandular tissue elasticity (Rs=–0.23, p=0.15), but nearly correlated with fat tissue elasticity (Rs=–0.30, p=0.06), in outer quadrants significantly (Rs=–0.38, p=0.02). Interestingly, a strong correlation of insulin and insulin resistance with elasticity heterogeneity was found in fatty tissue (Rs=–0.59, p<0.001 and Rs=–0.60, p<0.001 respectively). The heterogeneity of fatty tissue but not glandular elasticity also correlated with body mass index.

Conclusions

Insulin levels and insulin resistance correlate with breast fat tissue heterogeneity, but their role in breast pathology remains unclear.     

Significance of BRCA1 expression in breast and ovarian cancer patients with brain metastasis – A multicentre study

PurposeCerebral metastases develop in 10–30% of patients with breast cancer (BC) and in around 3.3 to 4% of patients with ovarian cancer (OC). The aim of the multicenter study is to investigate the correlation between the expression of estrogen alpha receptors (ERα), progesterone receptors (PR), human epidermal growth factor receptor 2 (HER2), stromal cell-derived factor 1 (SDF1) and its receptor C-X-C chemokine receptor type 4 (CXCR4), breast cancer metastasis suppressor 1 (BRMS1), astrocyte elevated gene 1 (AEG1), depending on the status of BRCA1 protein, in patients suffering from OC and BC with brain metastases.Patients and methodsThe analysis included 51 patients: 29 with BC and 22 with OC, in whom brain metastases were disclosed.ResultsIn most patients (65.5% of BC patients and 68.2% of patients with OC tumors) BRCA1 protein loss was found. No correlation was disclosed between the levels of ERα, PR receptors, HER2, SDF1, CXCR4, AEG1, BRMS1 and BRCA1 status, patient age, stage of disease advancement, grade of histological maturity of the cells, presence of metastases to lymph nodes. A statistically significant correlation was disclosed between the negative expression of PR receptors and a high expression of CXCR4 in patients with BC. High values of the AEG1 protein (linked to metastases) were detected alongside a high expression of BRMS1 (a suppressor of metastases).ConclusionsPatients with BC and OC and brain metastases have a frequent loss of BRCA1 expression. The role of ERα, PR, HER2, SDF1, CXCR4, AEG1, BRMS1 in metastatic process needs further studies.     

Cellular pharmacodynamic effects of Pycnogenol® in patients with severe osteoarthritis: a randomized controlled pilot study

Background

The standardized maritime pine bark extract (Pycnogenol®) has previously shown symptom alleviating effects in patients suffering from moderate forms of knee osteoarthritis (OA). The cellular mechanisms for this positive impact are so far unknown. The purpose of the present randomized pilot controlled study was to span the knowledge gap between the reported clinical effects of Pycnogenol® and its in vivo mechanism of action in OA patients.

Methods

Thirty three patients with severe OA scheduled for a knee arthroplasty either received 100 mg of Pycnogenol® twice daily or no treatment (control group) three weeks before surgery. Cartilage, synovial fluid and serum samples were collected during surgical intervention. Relative gene expression of cartilage homeostasis markers were analyzed in the patients’ chondrocytes. Inflammatory and cartilage metabolism mediators were investigated in serum and synovial fluid samples.

Results

The oral intake of Pycnogenol® downregulated the gene expression of various cartilage degradation markers in the patients’ chondrocytes, the decrease of MMP3, MMP13 and the pro-inflammatory cytokine IL1B were statistically significant (p ≤?0.05). Additionally, protein concentrations of ADAMTS-5 in serum were reduced significantly (p?≤?0.05) after three weeks intake of the pine bark extract.

Conclusions

This is the first report about positive cellular effects of a dietary supplement on key catabolic and inflammatory markers in patients with severe OA. The results provide a rational basis for understanding previously reported clinical effects of Pycnogenol® on symptom scores of patients suffering from OA.

Trial registration

ISRCTN10754119. Retrospectively registered 08/10/2015.

     

Ultrasound point shear wave elastography of the pancreas: comparison of patients with type 1 diabetes and healthy volunteers – results from a pilot study

Background

The aims of this study were to establish shear wave elastography of the pancreas by comparing measurements in patients with type 1 diabetes (T1D) and healthy volunteers and to consider whether this method could contribute to the screening or prevention of T1D.

Methods

This pilot study included 15 patients with T1D (10 men, 5 women) and 15 healthy volunteers (10 men, 5 women) as controls. Measurements were performed with a Siemens Acuson S3000 (Siemens Healthcare, Erlangen, Germany) using a 6C1 convex transducer and the Virtual Touch? tissue quantification (VTQ) method.

Results

The mean shear wave velocity of the head of the pancreas was 1.0?±?0.2?m/s (median: 1.1?m/s) for the study group and likewise 1.0?±?0.2?m/s (median: 0.9?m/s) for the control group. Velocities of 1.2?±?0.2?m/s (median: 1.2?m/s) were measured in the body of the pancreas in both groups. There was a significant difference between the values obtained in the tail of the pancreas: patients 1.1?±?0.1?m/s (median: 1.0?m/s) versus controls 0.9?±?0.1?m/s (median: 0.8?m/s) (p?=?0.0474). The mean value in the whole pancreas of the study group was not significantly above that of the control group: 1.1?±?0.1?m/s (median: 1.0?m/s) versus 1.0?±?0.1?m/s (median: 1.0?m/s) (p?=?0.2453).

Conclusions

Sonoelastography of the pancreas revealed no overall difference between patients with T1D and healthy volunteers. Patients with T1D showed higher values only in the tail segment. Future studies need to determine whether specific regional differences can be found in a larger study population.

     

Atopic dermatitis in adolescents and adults – the evaluation of association with other allergic diseases and parameters

There is a lack of reports focusing on the course of atopic dermatitis (AD) with respect to its evolution and association with other allergic diseases and parameters. This study gives the review of results concerning the evaluation of different parameters in patients suffering from AD older than 14 years of age. This study evaluates the occurrence of food allergy, food intolerance, inhalant allergy, occurrence of asthma bronchiale, allergic rhinitis, peripheral blood eosinophilia, family history of atopy, onset of AD and the severity of AD according to the SCORAD index.