Increased Urinary Albumin Excretion, Insulin Resistance, and Related Cardiovascular Risk Factors in Patients With Type 2 Diabetes

OBJECTIVE—While the relevant role of insulin resistance in the pathogenesis of increased urinary albumin excretion (UAE) is well established in type 1 diabetes, its contribution in type 2 diabetes is controversial. Our aim was to investigate whether insulin resistance was associated with increased UAE in a large cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS— A total of 363 men and 349 women, aged 61 ± 9 years, with a disease duration of 11 ± 9 years and HbA1c levels of 8.6 ± 2.0% were included. Insulin resistance was derived from the homeostasis model assessment of insulin resistance (HOMAIR), and UAE was derived from the albumin-to-creatinine ratio (ACR) defined as increased if the value was ≥2.5 mg/mmol in men and ≥3.5 mg/mmol in women. ACR was correlated with HOMAIR (r = 0.15, P = 0.0001), independently of age, disease duration, blood pressure, HbA1c, triglycerides, waist circumference, and smoking. RESULTS—When the two sexes were investigated separately, a significant correlation between ACR and HOMAIR was reached in men (n = 363; r = 0.21, P = 0.0001) but not women (n = 349; r = 0.08, P = 0.14), suggesting that insulin resistance and sex may interact (P for interaction = 0.04) in determining UAE. When men were subgrouped into quartiles of HOMAIR, those of the third and fourth quartile (i.e., the most insulin resistant) were at higher risk to have increased ACR than patients of the first quartile (third quartile: odds ratio 2.2 [95% CI 1.2–4.2], P = 0.01) (fourth quartile: 4.1 [2.2–7.9], P = 0.00002). Finally, ACR was significantly higher in men with two or more insulin resistance–related cardiovascular risk factors (i.e., abdominal obesity, dyslipidemia, and arterial hypertension) than in men with fewer than two insulin resistance–related cardiovascular risk factors (0.90 [0.2–115.1] vs. 1.56 [0.1–1367.6], respectively, P = 0.005). CONCLUSIONS—In type 2 diabetic patients, increased UAE is strongly associated with insulin resistance and related cardiovascular risk factors. This association seems to be stronger in men than in women

Model Numerikal Reservoir Sistem Panasbumi Pada Daerah Topografi Relatif Datar Untuk Mencari Kondisi Natural State Dan Menganalisa Sensitivitas Panas Pada Reservoir Menggunakan Software Tough2

Telah dilakukan pemodelan reservoir menggunakan software Tough2 dengan data sintetik, berupa data permeabilitas dan pororsitas. Dimana terdiri dari 4 lapisan, yaitu lapisan overburden, lapisan clay caps, lapisan recharge area + lapisan reservoir (berada pada lapisan yang sama), dan lapisan basement dengan tujuan untuk menganalisa sensitivitas panas, serta untuk mencari kondisi natural state (natural state merupakan kondisi setimbang, yaitu dimana kondisi tekanan, temperatur dan kondisi reservoirnya tidak berubah terhadap waktu).Dari hasil pemodelan reservoir oleh Tough2 didapat bahwa kondisi natural state selama 2,20857E+4 tahun, dimana terjadi penurunan suhu dari kondisi natural state tanpa sumur produksi berbanding kondisi natural state dengan sumur produksi, dimana suhu pada saat kondisi natural state tanpa sumur produksi sebesar 245OC dan suhu pada saat kondisi natural state dengan sumur produksi sebesar 235OC pada kedalaman 1350 m. Sedangkan untuk penggunaan rate 20 kg/s, 25 kg/s, 30 kg/s dan 35 kg/s untuk melihat sensitivitas heat nya, didapatkan bahwa semakin besar nilai rate yang dipakai dalam suatu sumur produksi, maka akan menurunnya nilai temperatur di sumur produksi tersebut

Electrical Remodeling of Ventricular Repolarization Abnormality after Treatment in Pheochromocytoma: U Wave Finding in a Retrospective Analysis

Background. Pheochromocytoma is a rare neuroendocrine tumor, clinically characterized by high blood pressure, palpitations, and headache. It is often associated with abnormalities of the ventricular repolarization phase; the dispersion of ventricular repolarization is the basis for ventricular arrhythmias (torsion de point, ventricular tachycardia or ventricular fibrillation). Objectives. Analysis of abnormal ventricular repolarization focused on the presence and amount of U wave in patients affected by pheochromocytoma and its modification after surgery. Materials and Methods. We reviewed pathology records of 722 patients admitted for adrenal nodule or suspected chromaffin-cell tumor and identified 39 patients affected by pheochromocytoma. Metanephrine, normetanephrine, and 3-methoxytyramine have been assessed by determining concentrations in 24-hour urine collection. Standard 12-lead electrocardiogram records have been reviewed with analysis of heart rate, P wave, PR interval, QRS duration, QTc, and U wave. Then we selected and compared 22 patients of 39 affected by pheochromocytoma, with both clinical and electrocardiographic data before and after surgery. Results. In our cohort of 39 patients affected by pheochromocytoma, we found U wave in ECG, before treatment, in 82.8 percent of patients, while only 37.0 percent after treatment (p<0.001) and we observed a statistically significant correlation between this wave and the urinary metanephrine. After surgery, in the selected 22 patients, we observed a clear significant reduction in systemic blood pressure, fasting glucose, metanephrine, normetanephrine, and 3-methoxytyramine. We found a significant reduction of U wave presence and leads involved in these patients after surgery (90.9% versus 9%). We observed a linear correlation between the amount of U waves in 12-lead electrocardiogram and metanephrine (r2=0.333, p=0.015), 3-methoxytyramine levels (r2=0.458, p=0.006), and tumor size (r2=0.429, p=0.003). Conclusions. In our retrospective analysis, patients affected by pheochromocytoma presented U wave in electrocardiogram. The presence and amount of U wave were associated with the metanephrine levels and the tumor size with significant reduction after surgical removal

Comparison of Clinical Features and Mortality Rate of Adult Patients with Multigenerational Diabetes and of Patients with Type 2 Diabetes Mellitus

Clinical experience teaches us that some adult patients who are diagnosed as having type 2 diabetes (T2D) are, instead, components of families with a multigenerational form of diabetes. We investigated clinical features and mortality rate of such patients as compared to those with T2D. From 2,583 consecutive Italian patients who had been routinely defined as affected by T2D, we looked for those belonging to families with diabetes in 3 or more consecutive generations. After excluding patients carrying known MODY gene mutations (n=22), clinical features of those affected by what we propose to define as “familial diabetes of the adulthood” (FDA; n=134) were compared to those of 1,208 T2D patients, not belonging to multigenerational (>2) pedigrees, who have been previously characterized for studying risk factors of all-cause mortality. In an age-adjusted model, age at diagnosis (p<0.001), waist circumference (p=0.03) and proportion of hypertension (p=0.001) were lower in FDA than in T2D. The two groups were similar for BMI, HbA1c, anti-hyperglycemic treatment, albuminuria and the proportion of dyslipidemia. In 121 FDA and 837 T2D patients, age-adjusted incidence rate of all-cause mortality was similar: 1.92 vs. 1.90 event per 100 person-years. In conclusion, this is the first report on clinical characteristics of adult patients from families with a multigenerational form of diabetes, we propose to define as FDA. FDA patients are characterized by a younger age at diagnosis, a lower waist circumference and a reduced proportion of hypertension, as compared to T2D patients. Though all-cause mortality rate is superimposable, it remains to be investigated whether such differences shape a different cardiovascular risk in these two groups of patients

Identification and clinical characterization of adult patients with multigenerational diabetes mellitus

Background. Some patients diagnosed as having type 2 diabetes mellitus (T2DM) are, instead, affected by multigenerational diabetes whose clinical characteristics are mostly undefined. Objective. 1. To identify among patients who had been previously defined as affected by T2DM those, in fact, affected by multigenerational diabetes; 2. After excluding patients carrying the most common MODY genes and mitochondrial mutations, we compared clinical features of remaining patients with those of patients with T2DM. Methods. Among 2,583 consecutive adult patients who had been defined as affected by T2DM, we looked for those with diabetes in ≥3 consecutive generations. All probands were screened for mutations in six MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B and NeuroD1) and for the A3243G mitochondrial mutation. After excluding patients with mutations in one of such genes, we compared clinical features of the remaining 67 patients (2.6% of the whole initial sample) affected by multigenerational “familial diabetes of the adulthood” (FDA) and of their diabetic relatives (n=63) to those with T2DM (n=1,028) by generalized hierarchical linear models followed by pairwise comparisons. Results. Age, age at diagnosis, proportion of hypertension (all p<0.001), and waist circumference (p<0.05) were lower in FDA than T2DM. Nonetheless, the two groups had similar age-adjusted incidence rate of all-cause mortality. Conclusions. Beside younger age at diagnosis, FDA patients show lower waist circumference and reduced proportion of hypertension as compared to those with T2DM; despite such reduced potential cardiovascular risk factors, FDA patients did not show a reduced mortality risk than patients with T2DM

Phenotypic variability of a pathogenic PKP2 mutation in an Italian family affected by arrhythmogenic cardiomyopathy and juvenile sudden death : considerations from molecular autopsy to sport restriction

Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic disorder with an estimated prevalence between 1:2,000 and 1:5,000 and is characterized by the fibrofatty replacement of cardiomyocytes that predisposes to malignant arrhythmias, heart failure, and sudden cardiac death. The diagnosis is based on the 2010 Task Force Criteria including family history, electrocardiographic traits and arrhythmogenic pattern, specific gene mutations, and structural and/or histological abnormalities. Most ACMs display an autosomal dominant mode of inheritance often with incomplete penetrance and variable expressivity. Genetic screening of patients with ACM identifies pathogenic or likely pathogenic variants, prevalently in genes encoding the cardiac desmosome (PKP2, DSP, DSC2, DSG2, and JUP) or less frequently in non-desmosomal genes (CTNNA3, PLN, TMEM43, RYR2, SCN5A, CDH2, and DES). Methods: In the present study, we performed molecular autopsy in a boy who died suddenly during physical exertion. In addition to post-mortem examination, a DNA sample was analyzed with next-generation sequencing (NGS). Results: The genetic analysis revealed the presence of pathogenic heterozygous c.314del (p.Pro105Leufs(*)7) frameshift variant in the PKP2 gene. Cascade screening of family members allowed us to identify 12 mutation carriers and to intervene on subjects at risk, many of whom were athletes. Conclusions: Molecular autopsy can establish cardiogenetic diagnosis and allow appropriate preventative measures in high-risk relatives

Pharmacogenomics of Pediatric Cardiac Arrest: Cisplatin Treatment Worsened by a Ryanodine Receptor 2 Gene Mutation

In thelast few decades, the roles of cardio-oncology and cardiovascular geneticsgained more and more attention in research and daily clinical practice, shaping a new clinical approach and management of patients affected by cancer and cardiovascular disease. Genetic characterization of patients undergoing cancer treatment can support a better cardiovascular risk stratification beyond the typical risk factors, suchas contractile function and QT interval duration, uncovering a possible patient’s concealed predisposition to heart failure, life threatening arrhythmias and sudden death. Specifically, an integrated cardiogenetic approach in daily oncological clinical practice can ensure the best patient-centered healthcare model, suggesting, also the adequate cardiac monitoring timing and alternative cancer treatments, reducing drug-related complications. We report the case of a 14-month-old girl affected by neuroblastoma, treated by cisplatin, complicated by cardiac arrest. We described the genetic characterization of a Ryanodine receptor 2 (RYR2) gene mutation and subsequent pharmacogenomic approach to better shape the cancer treatment

Coexistence of multiple endocrine neoplasia type 1 and type 2 in a large Italian family

To describe the coexistence of mutations of both the multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) genes in a large Italian family and evaluate if it could be associated with more aggressive clinical manifestations of the two syndromes. Blood samples were obtained for genetic and biochemical analyses. The RET gene exons (8, 10, 11, 13, 14, 15, 16, 18) and the MEN1 coding regions, including the exon-intron boundaries, were amplified by PCR and directly sequenced. We identified two germline mutations in the proband: the first one, K666M, located at the exon 11 of RET proto-oncogene and the second one, IVS4+1G > T, located in the MEN1 gene. The functional characterization of IVS4+1G > T variation, located in the splicing donor site of exon 4 of MEN1 gene, caused the in-frame junction of exon 3 to exon 5, thus obtaining a shorter protein. The same proband's germline mutations were found in 16 relatives out of 21 screened subjects: 8 carried IVS4+1G > T, 4 RET K666M, and 4 both the mutations. This is the second report in literature of coexistence in the same family of germline mutations of both RET proto-oncogene and MEN1 gene. The simultaneous presence of the two mutations was not apparently associated with more aggressive diseases, since at last follow-up all patients appeared to be disease-free or well compensated by medical therapy; finally, no one exhibited metastatic diseases

Pharmacogenomics of Pediatric Cardiac Arrest: Cisplatin Treatment Worsened by a Ryanodine Receptor 2 Gene Mutation

In thelast few decades, the roles of cardio-oncology and cardiovascular geneticsgained more and more attention in research and daily clinical practice, shaping a new clinical approach and management of patients affected by cancer and cardiovascular disease. Genetic characterization of patients undergoing cancer treatment can support a better cardiovascular risk stratification beyond the typical risk factors, suchas contractile function and QT interval duration, uncovering a possible patient&rsquo;s concealed predisposition to heart failure, life threatening arrhythmias and sudden death. Specifically, an integrated cardiogenetic approach in daily oncological clinical practice can ensure the best patient-centered healthcare model, suggesting, also the adequate cardiac monitoring timing and alternative cancer treatments, reducing drug-related complications. We report the case of a 14-month-old girl affected by neuroblastoma, treated by cisplatin, complicated by cardiac arrest. We described the genetic characterization of a Ryanodine receptor 2 (RYR2) gene mutation and subsequent pharmacogenomic approach to better shape the cancer treatment