Correlation of cardiac autonomic neuropathy with small and large peripheral nerve function in type 2 diabetes mellitus.

AIMS: To analyse the correlation of cardiac autonomic neuropathy (CAN), sympathetic and parasympathetic dysfunction with the different diagnostic tools for large and small peripheral nerve fibres in type 2 diabetes mellitus (T2DM). METHODS: We included 153 T2DM subjects (92 men) with mean age of 64.4 years. CAN, as well as sympathetic and parasympathetic dysfunction were diagnosed by the Ewing's cardiovascular reflex tests. Vibration perception threshold (VPT), monofilament, Ipswich Touch test, automated sural nerve conduction study and neuropathy disability score (NDS) evaluated large and small peripheral nerve fibre function. RESULTS: CAN (adjusted odds ratio [aOR]: 44.57), parasympathetic (aOR: 18.40) and sympathetic dysfunction (aOR: 5.50) correlated with measures of small fibre function evaluated by pinprick sensation and temperature perception. Among tools for large nerve fibres, positive correlation was shown between: (1) CAN and abnormal VPT (aOR: 16.78), (2) parasympathetic dysfunction and abnormal VPT (aOR: 39.47). CONCLUSIONS: CAN and parasympathetic dysfunction correlate with peripheral neuropathy, especially when the latter is assessed through VPT and measures of small fibre function as evaluated by pinprick sensation and temperature perception. The latter additionally correlate with sympathetic nervous system impairment.

Prevalence of drug resistance among HIV-1 treatment-naive patients in Greece during 2003-2015: Transmitted drug resistance is due to onward transmissions.

BACKGROUND: The prevalence of HIV-1 drug resistance among treatment-naïve patients ranges between 8.3% and 15% in Europe and North America. Previous studies showed that subtypes A and B were the most prevalent in the Greek HIV-1 epidemic. Our aim was to estimate the prevalence of resistance among drug naïve patients in Greece and to investigate the levels of transmission networking among those carrying resistant strains. METHODS: HIV-1 sequences were determined from 3428 drug naïve HIV-1 patients, in Greece sampled during 01/01/2003-30/6/2015. Transmission clusters were estimated by means of phylogenetic analysis including as references sequences from patients failing antiretroviral treatment in Greece and sequences sampled globally. RESULTS: The proportion of sequences with SDRMs was 5.98% (n=205). The most prevalent SDRMs were found for NNRTIs (3.76%), followed by N(t)RTIs (2.28%) and PIs (1.02%). The resistance prevalence was 22.2% based on all mutations associated with resistance estimated using the HIVdb resistance interpretation algorithm. Resistance to NNRTIs was the most common (16.9%) followed by PIs (4.9%) and N(t)RTIs (2.8%). The most frequently observed NNRTI resistant mutations were E138A (7.7%), E138Q (4.0%), K103N (2.3%) and V179D (1.3%). The majority of subtype A sequences (89.7%; 245 out of 273) with the dominant NNRTI resistance mutations (E138A, K103N, E138Q, V179D) were found to belong to monophyletic clusters suggesting regional dispersal. For subtype B, 68.1% (139 out of 204) of resistant strains (E138A, K103N, E138Q V179D) belonged to clusters. For N(t)RTI-resistance, evidence for regional dispersal was found for 27.3% and 21.6% of subtype A and B sequences, respectively. CONCLUSIONS: The TDR rate based on the prevalence of SDRM is lower than the average rate in Europe. However, the prevalence of NNRTI resistance estimated using the HIVdb approach, is high in Greece and it is mostly due to onward transmissions among drug-naïve patients.

Family History of Type 2 Diabetes: Does Having a Diabetic Parent Increase the Risk?

BACKGROUND: It is well established that there is an important genetic predisposition for type 2 diabetes mellitus (T2DM). OBJECTIVE: To summarise available epidemiological data regarding T2DM transmission in various populations. METHOD: Narrative review. RESULTS: The estimated risk for the diagnosis of T2DM increases approximately by 2-4 times, when father, mother or both have this condition. Conversely, many T2DM patients have family members with DM. Studies have suggested that the likelihood of T2DM in the next generation is higher in the event of a diabetic mother than father. Both genetic factors, such as mitochondrial DNA mutations, and environmental components, such as intra-uterine environment, have been implicated in the higher maternal transmission of T2DM. Despite the above findings, some studies in populations with high frequency of T2DM have not corroborated the predominantly maternal transmission. Such works have shown either an excess paternal or an equal transmission of T2DM. CONCLUSION: It appears that potential biases in reporting family history data, especially between the various racial groups, have contributed to the controversy over the existence of excess maternal transmission of DM.

The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes.

INTRODUCTION: There is now an abundance of anti-diabetic agents. However, only few patients achieve glycemic targets. Moreover, current glucose-lowering agents mainly depend upon insulin secretion or function. Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion. AREAS COVERED: In this review, the authors discuss the key efficacy and safety data from phase II clinical trials in type 2 diabetes mellitus (T2DM) of the main SGLT2 inhibitors approved or currently in development, and provide a rationale for their use in T2DM. EXPERT OPINION: Despite the very promising characteristics of this new therapeutic class, a number of issues await consideration. One important question is what to expect from head-to-head comparison data. We also need to know if dual inhibition of SGLT1/SGLT2 is more efficacious in reducing HbA1c and how this therapy affects metabolic and cardiovascular parameters. Additionally, several SGLT2 agents that have not yet come to market have hitherto been evaluated in Asian populations, whereas approved SGLT2 inhibitors have been frequently studied in other populations, including Caucasian subjects. Thus, we need more information on the potential role of ethnicity on their efficacy and safety.

Retinol Binding Protein-4 and Adiponectin Levels in Thyroid Overt and Subclinical Dysfunction.

Thyroid dysfunction is accompanied by numerous changes in intermediary metabolism. Retinol binding protein-4 (RBP-4) and adiponectin are 2 adipocytokines that have multiple metabolic functions. The aim of our study was to examine serum RBP4 and adiponectin levels in clinical (before and after therapy) and subclinical hyperthyroid and hypothyroid subjects as compared to controls.150 patients with thyroid dysfunction were recruited (65 hyperthyroid and 85 hypothyroid) while 28 euthyroid subjects served as a control group. We measured anthropometric, biochemical and hormonal (free T4, free T3, TSH, insulin) parameters in all participants. RBP-4 and adiponectin were measured using commercial ELISA kits.Mean baseline levels of RBP-4 were higher in patients with clinical hypothyroidism (29.0±10.2 ng/ml, 25.1±12.6 ng/ml, 38.8±16.5 ng/ml, 31.9±13.2 ng/ml, 20.4±8.2 ng/ml in patients with hyperthyroidism, subclinical hyperthryrodism, hypothyroidism, subclinical hypothyroidism and controls respectively, F=4.86, P<0.001) and decreased significantly in patients with clinical hyperthyroidism and hypothyroidism after normalization of thyroid hormones' levels (from 29.0±10.2 to 24.9±8.4 ng/ml, p=0.003 and from 38.8±16.5 to 29.0±10.8 ng/ml, p=0.001 respectively). We did not observe analogous changes in adiponectin levels in any of the studied groups.RBP-4 levels are higher in patients with clinical hypothyroidism and exhibit a marked decrease after normalization of thyroid function in both hyper and hypothyroid patients. We suggest that RBP-4 may play a role in the metabolic disturbances which accompany thyroid dysfunction.

The indicator test Neuropad in the assessment of small and overall nerve fibre dysfunction in patients with type 2 diabetes: a large multicentre study.

We examined the diagnostic utility of the indicator test Neuropad in the assessment of overall and small fibre dysfunction in 1,010 patients with type 2 diabetes mellitus (T2DM) (608 men, mean age 63.9 ± 10.3 years) from 5 diabetes clinics. Sudomotor function was diagnosed by the Neuropad® test. Overall and small nerve fibre dysfunction was diagnosed through clinical examination and symptoms. Patients were divided into Groups A (441 patients with sudomotor dysfunction) and B (569 patients without sudomotor dysfunction). The former were older (p<0.05) and had longer T2DM duration (p<0.05) than the latter. For overall nerve fibre dysfunction, abnormal Neuropad defined as patchy/blue had 94.9% sensitivity, 70.2% specificity and 98.1% negative predictive value (NPV), while for small fibre dysfunction the corresponding values were 85.6%, 71.2% and 93.3%. For overall nerve fibre dysfunction, abnormal Neuropad defined as blue had 64% sensitivity, 96% specificity and 91% NPV, while for small fibre dysfunction the corresponding values were 52%, 96% and 85%. The odds ratios (ORs) of Neuropad patchy/blue for overall and for small fibre dysfunction were 43.7 and 14.7, respectively. The ORs of Neuropad blue for overall and for small fibre dysfunction were 45.7 and 24.9, respectively. In conclusion, Neuropad patchy/blue response exhibited better diagnostic performance both for overall and small nerve fibre dysfunction. Its very high NPV renders it an excellent screening tool primarily to exclude neuropathy in T2DM.

Olfactory dysfunction in type 2 diabetes mellitus: an additional manifestation of microvascular disease?

We evaluated olfactory dysfunction in 154 adults (74 men, mean age 60.9±11.9 years), of whom 119 had type 2 diabetes mellitus (T2DM). Olfactory function was assessed with "Sniffin' Sticks." A total Threshold-Discrimination-Identification (TDI) score was calculated. Type 2 diabetes mellitus, hypertension, and hyperlipidemia were associated with lower olfactory scores (all TDI scores<0.001). Age was negatively associated with odor threshold, odor identification, and TDI score (P=.009, <.001, and <.001, respectively). After adjusting for age, gender, body mass index, smoking, alcohol, diabetes, hypertension, hyperlipidemia, and cardiovascular disease, only T2DM and hypertension were associated with TDI score (R square=0.281). Diabetic complications were associated with olfactory dysfunction (P=.006): TDI scores were lower in the presence of diabetic peripheral neuropathy (P=.017) and retinopathy (P=.047). In conclusion, T2DM and hypertension are independently associated with olfactory dysfunction while diabetic peripheral neuropathy and retinopathy are significantly associated with lower olfactory scores. The clinical relevance of these findings needs to be further examined.

Alpha1-microglobulin as an early biomarker of sepsis-associated acute kidney injury: a prospective cohort study.

BACKGROUND: Sepsis emerges as the leading risk factor for acute kidney injury (AKI) development in critically ill patients. Much effort has been invested so far on early diagnosis of AKI using promising biomarkers. This study aimed to determine whether urine alpha1-microglobulin (α1m), a lipocaline member previously used as an indicator of proximal tubular dysfunction, can early predict the development of sepsis-associated AKI (SAAKI) in critically ill patients. METHODS: A prospective, observational study was conducted in a single center Intensive Care Unit (ICU). Patients with normal renal function admitted to the ICU followed for sepsis and AKI development. Urine α1m levels were analyzed in pooled samples from 24-hour urine collections on sepsis onset and at various time points thereafter. The diagnostic performance of urine α1m was assessed using thenonparametriccalculation of the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: Among 286 critically ill patients admitted to our ICU in a year, 45 patients with sepsis met the inclusion criteria. SAAKI developed in 16 septic patients (35.6%). Urine α1m levels were significantly elevated in all septic patients (average value of all samples on the day of sepsis: 46.02 ± 7.17 mg/l) and showed a trend to increase in patients who finally developed SAAKI. The AUC for SAAKI prediction according to α1m urine levels 24-hours before SAAKI onset was 0.739 (sensitivity 87.5%, specificity 62.07%, cutoff level 47.9 mg/l). Urine α1m 24-hours before SAAKI, serum creatinine on sepsis onset and Acute Physiology and Chronic Health Evaluation II (APACHE II) score on sepsis onset emerged as the most powerful independent predictors of SAAKI. The combination of these three parameters improved the AUC for SAAKI prediction to 0.944. CONCLUSION: Urine α1m levels might help in the early prediction of SAAKI development and may prove useful biomarker. The pathogenetic implications of α1m in sepsis and SAAKI need further investigation. Hippokratia 2014; 18 (3): 262-268.

Post-exercise ankle-brachial index is not an indispensable tool for the detection of peripheral arterial disease in an epidemiological survey. A post-hoc analysis of the Athens Study.

AIM: Previous studies have estimated the sensitivity, specificity and predictive value of non-invasive methods for the detection of peripheral arterial disease (PAD). The aim of our study was to evaluate the performance of non-invasive diagnostic tools and more specifically ankle-brachial index (ABI) at rest and after exercise for the detection of PAD in an epidemiological survey conducted in Greece. METHODS: Overall, a representative sample of 2089 adults (911 men and 1178 women), 18-90 years old (mean age 46.88+14.98 years) living in the greater Athens area, participated in the study. For the detection of intermittent claudication, the Rose questionnaire (RQ) was used. Moreover, physical examination (PE) of the lower extremities was performed, ABI both at rest and after exercise was measured. RESULTS: Thirty subjects were diagnosed with PAD, corresponding to a prevalence of 1.43%. Sensitivity and specificity of RQ, PE, ABI at rest and one minute after stress test were 53.33%, 66.67%, 100%, 64.71% and 98.79%, 97.77%, 99.81%, 94.94%, respectively. The combination of RQ with PE and ABI at rest yielded a 41.18% sensitivity, but a very high specificity (100%) and positive predictive value (100%). CONCLUSION: ABI at rest detected PAD in the epidemiological setting, and its combination with RQ and PE attained a very high specificity. Intermittent claudication and physical examination, while easier to evaluate, were considerably less sensitive. Finally, inclusion of postexercise ABI did not increase sensitivity which leads to the conclusion that this diagnostic tool is not needed for the detection of PAD in large epidemiological surveys.

Determinants of microbial load in infected diabetic foot ulcers: a pilot study.

We examined the determinants of microbial load in infected diabetic foot ulcers in 62 patients (38 men and 24 women, mean age: 65.63 ± 12.71 years) with clinically infected diabetic foot ulcers. Tissue cultures were taken from ulcers by 4 mm punches. Ulcer grade (University of Texas classification), neuropathy disability score (NDS), neuropathy symptom score (NSS), ankle-brachial index (ABI), perfusion, extent, depth, infection, and sensation (PEDIS) grade of diabetic foot infection, and laboratory parameters were evaluated in all patients. Total microbial load was positively correlated with the number of isolates on tissue cultures (r s = 0.544, P < 0.001), white blood cell count (WBC) (r s = 0.273, P = 0.032), and platelet count (PLT) (r s = 0.306, P = 0.015). It also exhibited a borderline insignificant positive correlation with PEDIS infection grade (r s = 0.246, P = 0.053). In stepwise linear regression analysis, the number of isolates on tissue cultures and WBC were identified as the only two significant parameters accounting for 38% of the variation in the log of total microbial load (adjusted R (2) = 0.380, P < 0.001). In conclusion, patients with infected diabetic foot ulcer exhibit a positive correlation of total microbial load with the number of isolates on tissue cultures, WBC and PLT.

Monocyte chemoattractant protein 1 is correlated with glycemic control and peripheral arterial disease in type 2 diabetic patients with metabolic syndrome.

We evaluated the serum levels of monocyte chemoattractant protein 1 (MCP-1) and their association with peripheral arterial disease (PAD) in 199 patients with type 2 diabetes mellitus (T2DM) and metabolic syndrome ([MetS], group A) in comparison with 109 healthy controls (group B). In group A, MCP-1 levels were significantly (P < .001) higher than group B and exhibited a positive correlation with HbA1c (P < .001) and a negative correlation with ankle-brachial index (P < .001). In the same group, patients with PAD had significantly higher MCP-1 levels compared with those without PAD (P < .001). In conclusion, T2DM patients with MetS exhibit higher serum MCP-1 levels. The latter is associated with worse glycemic control and PAD. These results suggest a potential contributory role for MCP-1 in the pathogenesis of PAD in the presence of hyperglycemia and MetS in T2DM.