Which field test should be used to compare the functional exercise capacities of patients with type 2 diabetes mellitus with and without diabetic peripheral neuropathy? Cross-sectional study.

BACKGROUND: The 6-minute step test (6MST) has begun to be used as a simple and effective alternative for assessing functional exercise capacity. There is no study using 6MSTs to evaluate the exercise capacities of patients with type 2 diabetes mellitus (DM) with and without diabetic peripheral neuropathy (DPN). OBJECTIVE: To compare the cardiorespiratory responses of the 6-minute walk test (MWT) and the 6MST exercise tests and to analyze the usability of the 6MST in Type 2 DM patients with and without neuropathy. METHODS: 32 non-neuropathic Type 2 DM, 32 neuropathic Type 2 DM patients, and 30 healthy volunteers were included in this cross-sectional study. Functional exercise capacity was evaluated with the 6MWT and the 6MST. The 30-second sit-stand test (30s STS) was used to evaluate general lower extremity muscle strength and function. RESULTS: There was a significant difference in the results of 6MWT (m), 6MST (number of steps), and 30s STS of the three groups (p<0.05). The 6MST results of patients with neuropathic Type 2 DM were significantly lower than those of non-neuropathic diabetics and those who were healthy (number of steps; 114.07±25.57 vs. 133.48±33.57 vs. 160.35±28.52, respectively) (p=0.001). The change in cardiorespiratory response in systolic blood pressure, heart rate, perceived dyspnea, and leg fatigue severity was significantly higher at 6MST than 6MWT in the three groups (p<0.05). 6MST was correlated with 6MWT (r=0.679, p=0.001), and 30s STS (r=0.589, p=0.001) in patients with Type 2 DM. CONCLUSIONS: Cardiorespiratory responses increased more in 6MST compared to 6MWT. In patients with Type 2DM, 6MWT and 6MST were moderately correlated with each other. 6MST is an effective and safe assessment method that may better reveal the differences in functional exercise capacity between neuropathic and non-neuropathic individuals in clinics.

Machine learning analysis of adrenal lesions: preliminary study evaluating texture analysis in the differentiation of adrenal lesions

PURPOSE: This study aimed to determine the accuracy of texture analysis in differentiating adrenal lesions on unenhanced computed tomography (CT) images. METHODS: In this single-center retrospective study, 166 adrenal lesions in 140 patients (64 women, 76 men; mean age 56.58 ± 13.65 years) were evaluated between January 2015 and December 2019. The lesions consisted of 54 lipid-rich adrenal adenomas, 37 lipid-poor adrenal adenomas (LPAs), 56 adrenal metastases (ADM), and 19 adrenal pheochromocytomas (APhs). Each adrenal lesion was segmented by manually contouring the borders of the lesion on unenhanced CT images. A texture analysis of the CT images was performed using Local Image Feature Extraction software. First-order and second-order texture parameters were assessed, and 45 features were extracted from each lesion. One-Way analysis of variance with Bonferroni correction and the Mann-Whitney U test was performed to determine the relationships between the texture features and adrenal lesions. Receiver operating characteristic curves were performed for lesion discrimination based on the texture features. Logistic regression analysis was used to generate logistic models, including only the texture parameters with a high-class separation capacity (i.e., P < 0.050). SPSS software was used for all statistical analyses. RESULTS: First-order and second-order texture parameters were identified as significant factors capable of differentiating among the four lesion types (P < 0.050). The logistic models were evaluated to ascertain the relationships between LPA and ADM, LPA and APh, and ADM and APh. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of the first model (LPA vs. ADM) were 85.7%, 70.3%, 81.3%, 76.4%, and 79.5%, respectively. The sensitivity, specificity, PPV, NPV, and accuracy of the second model (LPA vs. APh) were all 100%. The sensitivity, specificity, PPV, NPV, and accuracy of the third model (ADM vs. APh) were 87.5%, 82%, 36.8%, 98.2%, and 82.7%, respectively. CONCLUSION: Texture features may help in the characterization of adrenal lesions on unenhanced CT images.

Clinical features of generalized lipodystrophy in Turkey: A cohort analysis.

AIM: To describe the Turkish generalized lipodystrophy (GL) cohort with the frequency of each complication and the death rate during the period of the follow-up. METHODS: This study reports on 72 patients with GL (47 families) registered at different centres in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ± 78 months. RESULTS: The Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16 years. Hyperglycaemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridaemia developed in 65 patients (90.3%). The Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridaemia was 14 years. Hypertriglyceridaemia was severe (≥ 500 mg/dl) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. The Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15 years. Liver disease progressed to cirrhosis in nine patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25 and 45 years, respectively. Females appeared to have a more severe metabolic disease, with an earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (because of recurrent intestinal perforations, coronavirus disease, diabetic foot infection and following coronary artery bypass graft surgery), myocardial infarction, heart failure because of dilated cardiomyopathy, stroke, liver complications and angiosarcoma. CONCLUSIONS: Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL.

Many Faces of Adrenal Lesions in a Large Patient Cohort: What Has Changed Over the Last Two Decades?

OBJECTIVE: To review the presentation characteristics, clinical and hormonal evaluations, and histopathological results of patients with adrenal lesions over a 21-year period and evaluate the changes across the two decades. METHODS: This single-center, retrospective study included 1003 patients with adrenal lesions who presented to our department between 2000 and 2021. Clinical, metabolic, hormonal, radiological, and pathological data of the patients were collected. RESULTS: Forty-seven percent of the lesions were non-functioning adrenal adenomas. Possible autonomous and autonomous cortisol secretion were detected in 22.2% of the patients. The percentages of the patients diagnosed with pheochromocytoma, primary hyperaldosteronism, adrenal Cushing syndrome, adrenocortical carcinoma, and adrenal metastasis were 7.4%, 4.8%, 4.7%, 0.9%, and 5.6%, respectively. Adrenalectomy was performed in 31.3% of the patients. Functional adrenal lesions were the leading cause of surgery (46.5%), followed by large size and/or suspicious imaging features (38.6%). Among the patients referred to surgery due to large size (≥6 cm), the diagnosis in 19% was metastasis, and in 12.1%, it was primary adrenocortical carcinoma. In patients with adrenal lesions with a size of 4-6 cm and suspicious imaging properties, the rates of metastasis and primary adrenocortical carcinoma were 44.4% and 4.8%, respectively. From the first to the second decade, major differences in presentation characteristics were increased detection of bilateral lesions and increased prevalence of possible autonomous and autonomous cortisol secretion. CONCLUSIONS: Adrenal lesions are common in the adult population, and while it is important to avoid overtreatment, hormone secretion, and malignancy should not be overlooked.

Pelvis Magnetic Resonance Imaging to Diagnose Familial Partial Lipodystrophy.

CONTEXT: The diagnosis of familial partial lipodystrophy (FPLD) is currently made based on clinical judgment. OBJECTIVE: There is a need for objective diagnostic tools that can diagnose FPLD accurately. METHODS: We have developed a new method that uses measurements from pelvic magnetic resonance imaging (MRI) at the pubis level. We evaluated measurements from a lipodystrophy cohort (n = 59; median age [25th-75th percentiles]: 32 [24-44]; 48 females and 11 males) and age- and sex-matched controls (n = 29). Another dataset included MRIs from 289 consecutive patients. RESULTS: Receiver operating characteristic curve analysis revealed a potential cut-point of ≤13 mm gluteal fat thickness for the diagnosis of FPLD. A combination of gluteal fat thickness ≤13 mm and pubic/gluteal fat ratio ≥2.5 (based on a receiver operating characteristic curve) provided 96.67% (95% CI, 82.78-99.92) sensitivity and 91.38% (95% CI, 81.02-97.14) specificity in the overall cohort and 100.00% (95% CI, 87.23-100.00) sensitivity and 90.00% (95% CI, 76.34-97.21) specificity in females for the diagnosis of FPLD. When this approach was tested in a larger dataset of random patients, FPLD was differentiated from subjects without lipodystrophy with 96.67% (95% CI, 82.78-99.92) sensitivity and 100.00% (95% CI, 98.73-100.00) specificity. When only women were analyzed, the sensitivity and the specificity was 100.00% (95% CI, 87.23-100.00 and 97.95-100.00, respectively). The performance of gluteal fat thickness and pubic/gluteal fat thickness ratio was comparable to readouts performed by radiologists with expertise in lipodystrophy. CONCLUSION: The combined use of gluteal fat thickness and pubic/gluteal fat ratio from pelvic MRI is a promising method to diagnose FPLD that can reliably identify FPLD in women. Our findings need to be tested in larger populations and prospectively.

Congenital generalized lipodystrophy type 4 due to a novel PTRF/CAVIN1 pathogenic variant in a child: effects of metreleptin substitution.

OBJECTIVES: Congenital generalized lipodystrophies (CGLs) are a heterogeneous group of rare autosomal recessive disorders characterized by near/total absence of body fat. Pathogenic variants in polymerase-I and transcript release factor gene (PTRF), or CAVIN1, is responsible for CGL4. In addition to generalized fat loss, patients with CGL4 were reported to suffer from myopathy, malignant cardiac arrhythmias, gastrointestinal disorders, and skeletal abnormalities. Here we describe the phenotype of a child with CGL4 due to a rare, novel pathogenic variant in the PTRF/CAVIN1 gene and the long-term effects of metreleptin substitution on comorbidities. CASE PRESENTATION: We describe a now 20-year-old female patient. At the age of 14-years, she was referred to the University Clinic because of uncontrolled diabetes with an HbA1c of 9.3%, requiring 2.4 IU insulin/kg total-body-weight to normalize blood glucose, hepatomegaly, and hypertriglyceridemia of 515 mg/dL. Additionally, she was suffering from malignant cardiac arrhythmia, myopathy, and hyperCKemia. In light of these clinical findings, she was diagnosed with CGL due to a rare, novel variant in the PTRF gene, and was started on metreleptin, a synthetic analog of human leptin. After the initiation of metreleptin treatment, insulin therapy could be stopped and improvement of sonographically assessed liver size was observed, even though serum liver function test stayed mildly elevated. Furthermore, a noticeable improvement of the serum triglyceride levels was also seen. Medical care and regular follow-up visits are being carried out by a multi-disciplinary team. CONCLUSIONS: Although CGL4 is rare, due to its life-threatening comorbidities and the opportunity for an early intervention, it is important that the clinicians should recognise these patients.

Invasive Heart Rate Control as a Salvage Therapy in Amiodarone-induced Thyroid Storm.

Atrial fibrillation (AF) is the most common arrhythmia, and amiodarone is one of the most commonly used drugs for medical cardioversion of AF, which should be used carefully due to its toxic effects. Amiodarone-induced thyrotoxicosis (AIT) may develop in amiodarone-treated patients. In contrast, the most common rhythm disturbance accompanying a thyroid storm is AF. This association may put both AF and thyrotoxicosis treatment into a vicious circle, leading to AI cardiomyopathy. Herein, we aimed to present atrioventricular node ablation as a salvage therapy in a patient with AIT who had AF-causing hemodynamic impairment, resistance to medical therapy, and cardioversion.

Cardiac phenotype in familial partial lipodystrophy.

OBJECTIVES: LMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations. STUDY DESIGN: Retrospective cohort study. METHODS: Clinical data from 122 patients (age range: 13-77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with an LMNA variant were studied as proof-of-concept for future studies. RESULTS: Subjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45-9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04-32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34-9.27). Non-codon 482 LMNA variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41-15.98 for arrhythmia; OR: 17.67, 95% CI: 2.45-127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37-23.76 for conduction disease). LMNA mutant hiPSC-CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC-CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure. CONCLUSIONS: Our results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. In addition, hiPSC-CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations.

Intra-operative parathyroid hormone evaluation is superior to frozen section analysis in parathyroid surgery.

BACKGROUND: Surgery is currently the only treatment option for patients with primary hyperparathyroidism (PHPT). Recently, minimally invasive parathyroidectomy (MIP) has begun to replace traditional bilateral neck exploration (BNE). OBJECTIVE: The aim of this study is to compare the results of parathyroidectomies performed in our hospital over the past decade that were guided by intra-operative parathyroid hormone (IOPTH) sampling or frozen section (FS) analysis. MATERIAL AND METHODS: Data on 697 patients who underwent parathyroidectomies in the Department of Endocrine Surgery, Dokuz Eylul University between January 2005 and 2018 were included in this study. Patients with malignancies other than thyroid papillary microcarcinoma and parathyroid cancer were excluded from the study. RESULTS: The concomitant use of neck ultrasound (US) and technetium 99m Sestamibi (99mTc MIBI) scintigraphy successfully localized the hyperfunctioning parathyroid glands in nearly 96% of cases. As compared with the IOPTH group, the operation time was longer in the FS group (p < 0.001), and the need for postoperative calcium (Ca) supplementation was higher (p < 0.001). The duration of hospitalization (days) was significantly higher in the FS group (4.2 ± 3.4 vs. 2.6 ± 1.9) as compared with that in the IOPTH group (p < 0.001). In addition, the recurrence rate in the FS group was significantly higher than that in the IPOTH group (p = 0.002). CONCLUSION: IOPTH sampling is a safe and effective method when performed by experienced surgeons and with appropriate preoperative screening. This study emphasizes that IOPTH sampling. We believe that the success in parathyroid surgery is due to three factors: correct indication, accurate localization and experienced surgeon.

Magnetic resonance spectroscopy to assess hepatic steatosis in patients with lipodystrophy.

BACKGROUND/AIMS: Lipodystrophy is a rare metabolic disorder characterized by near total or partial lack of subcutaneous adipose tissue and associated with insulin resistance. We aimed to evaluate the efficacy of magnetic resonance spectroscopy imaging (MRS) to explore the fat content of the liver in patients with lipodystrophy and to determine the relationship between the liver fat accumulation and clinical presentations of lipodystrophy. MATERIALS AND METHODS: Between July 2014 and February 2016, 34 patients with lipodystrophy were assessed by MRS for quantification of hepatic steatosis. All patients had metabolic abnormalities associated with insulin resistance. Metabolic parameters and the MRS findings were analyzed to identify potential correlations between the liver fat content and disease severity. RESULTS: The MRS fat ratios (MRS-FR) were markedly higher, indicating severe hepatic steatosis in lipodystrophy. Patients with generalized and partial lipodystrophy had comparable levels of MRS-FRs, although patients with generalized lipodystrophy were significantly younger. Patients with genetically based lipodystrophy had elevated MRS-FR compared to those with acquired lipodystrophy (p=0.042). The MRS-FR was positively correlated with liver enzyme alanine aminotransferase (p=0.028) and serum adiponectin (p=0.043). CONCLUSION: Our data suggest that MRS might be an effective, noninvasive imaging method to quantify hepatic fat content in patients with lipodystrophy. Further studies are needed to validate the technique and threshold values which would allow accurate comparison of data acquired by different machines and centers.

Homozygous LMNA p.R582H pathogenic variant reveals increasing effect on the severity of fat loss in lipodystrophy.

BACKGROUND: Classical heterozygous pathogenic variants of the lamin A/C (LMNA) gene cause autosomal dominant familial partial lipodystrophy type 2 (FPLD2). However, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants, and a few patients have been associated with generalized fat loss. CASE PRESENTATION: Here, we report a patient with a lamin A specific pathogenic variant in exon 11, denoted LMNA (c.1745G > A; p.R582H), present in the homozygous state. Fat distribution was compared radiographically to an unrelated heterozygote LMNA p.R582H patient from another pedigree, a healthy female control, a series of adult female subjects with congenital generalized lipodystrophy type 1 (CGL1, n = 9), and typical FPLD2 (n = 8). The whole-body MRI of the index case confirmed near-total loss of subcutaneous adipose tissue with well-preserved fat in the retroorbital area, palms and soles, mons pubis, and external genital region. This pattern resembled the fat loss pattern observed in CGL1 with only one difference: strikingly more fat was observed around mons pubis and the genital region. Also, the p.R582H LMNA variant in homozygous fashion was associated with lower leptin level and earlier onset of metabolic abnormalities compared to heterozygous p.R582H variant and typical FPLD2 cases. On the other hand, the heterozygous LMNA p.R582H variant was associated with partial fat loss which was similar to typical FPLD2 but less severe than the patients with the hot-spot variants at position 482. CONCLUSIONS: Our observations and radiological comparisons demonstrate an additive effect of LMNA pathogenic variants on the severity of fat loss and add to the body of evidence that there may be complex genotype-phenotype relationships in this interesting disease known as FPLD2. Although the pathological basis for fat loss is not well understood in patients harboring pathogenic variants in the LMNA gene, our observation suggests that genetic factors modulate the extent of fat loss in LMNA associated lipodystrophy.

UNUSUAL PRESENTATIONS OF LMNA-ASSOCIATED LIPODYSTROPHY WITH COMPLEX PHENOTYPES AND GENERALIZED FAT LOSS: WHEN THE GENETIC DIAGNOSIS UNCOVERS NOVEL FEATURES.

OBJECTIVE: Lipodystrophy represents a group of rare diseases characterized by loss of body fat. While patients with generalized lipodystrophy exhibit near-total lack of fat, partial lipodystrophy is associated with selective fat loss affecting certain parts of the body. Although classical familial partial lipodystrophy (FPLD) is a well-described entity, recent reports indicate phenotypic heterogeneity among carriers of LMNA pathogenic variants. METHODS: We have encountered 2 unique cases with complex phenotypes, generalized fat loss, and very low leptin levels that made the distinction between generalized versus partial lipodystrophy quite challenging. RESULTS: We present a 61-year-old female with generalized fat loss, harboring the heterozygous pathogenic variant p.R541P (c.1622G>C) on the LMNA gene. The discovery of the pathogenic variant led to correct clinical diagnosis of her muscle disease, identification of significant heart disease, and a recommendation for the implantation of a defibrillator. She was able to start metreleptin based on her generalized fat loss pattern and demonstration of the genetic variant. Secondly, we report a 40-year-old Turkish female with generalized fat loss associated with a novel heterozygous LMNA pathogenic variant p.K486E (c.1456A>G), who developed systemic B cell follicular lymphoma. CONCLUSION: Clinicians need to recognize that the presence of an LMNA variant does not universally lead to FPLD type 2, but may lead to a phenotype that is more complex and may resemble more closely generalized lipo-dystrophy. Additionally, providers should recognize the multisystem features of laminopathies and should screen for these features in affected patients, especially if the variant is not at the known hotspot for FPLD type 2.

Validity and reliability of the Turkish version of the Michigan Neuropathy Screening Instrument

Background/aim: The aim of this study was to demonstrate the validity and reliability of the Turkish version of the Michigan Neuropathy Screening Instrument (MNSI-TR). Materials and methods: The study included 127 patients aged 45­76 years who were previously diagnosed with type 1 or 2 diabetes. Stability of the instrument was assessed by intraclass correlation coefficient. Reliability of the MNSI-TR was assessed using the Kuder­ Richardson formula 20 test, item-total correlations, and floor/ceiling effect. Validity was evaluated with receiver operating characteristic curve analysis. A logistic regression model was used to determine to what degree the MNSI-TR explain nerve conduction study (NCS) results in the prediction of neuropathy. Results: With a cut-off value of 3.5 for the questionnaire, sensitivity and specificity of the MNSI-TR were 75.5% and 68.1%, respectively. A cut-off of 2.75 for the physical assessment part of the scale resulted in 87.5% sensitivity and 93.6% specificity. The scale was able to diagnose neuropathy in the rate of 71.5% of the patients diagnosed with neuropathy by NCS. Conclusion: The MNSI-TR is a valid and reliable method for evaluating diabetic peripheral neuropathy in Turkish speaking societies. It must be obtained a minimum of 4 points from the questionnaire part and a minimum of 2.5 points from the physical assessment part for the diagnosis of neuropathy

The Role of Adiponectin in Maintaining Metabolic Homeostasis.

BACKGROUND: Adiponectin is an adipocyte-derived cytokine closely associated with obesity, altered body adipose tissue distribution, insulin resistance, and cardiovascular diseases. INTRODUCTION: Evidence from animal and human studies demonstrate that adiponectin plays an important role in the regulation of glucose and lipid metabolism. Adiponectin increases insulin sensitivity and improves systemic lipid metabolism. Although research efforts on adiponectin mostly aim towards its endocrine functions, this adipocyte-derived molecule also has profound autocrine and paracrine functions. CONCLUSION: In this review, our aim is to discuss the role of adiponectin in maintaining metabolic homeostasis and its association with cardiovascular health. The proper identification of these roles is of great importance, which has the potential to identify a wealth of novel targets for the treatment of diabetes and related cardio-metabolic diseases.

Prognostic Factors in Elderly Patients with Diffuse Large B-Cell Lymphoma and Their Treatment Results

Objective: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL). The treatment of older NHL patients has always been a struggle; however, treatment statistics have begun showing favorable results similar to those of younger DLBCL patients thanks to newer treatment protocols. Here, we analyze the progress of our own elderly DLBCL patients who were followed between 2000 and 2016 in our center. Materials and Methods: Eighty-seven DLBCL patients, who were diagnosed and treated in the Dokuz Eylül University Department of Hematology between 2000 and 2016, were included in this study. Median age was 72 (65-89) years and 13 (14.9%) patients were older than 80 years. Results: Median follow-up time was 19 months and 45 patients (51.7%) died during the follow-up period. Median overall survival (OS) was 55 months and median progression-free survival was calculated as 27 months. Sixty-three patients (72.4%) received standard R-CHOP therapy. Complete response was seen in 46 (52.9%) patients. The median survival time for patients who had complete response was 136 months (p<0.001); however, OS was not statistically different between older (>80 years) and younger patients (p=0.236). Conclusion: According to our findings, we think that being able to complete standard R-CHOP therapy is vital for the survival rate of elderly DLBCL patients.