A Case of Mody 2 - Associated Hyperglycemia Diagnosed as Gestational Diabetes.

Maturity-onset diabetes of the young (MODY) is the most common monogenic form of diabetes, accounting for 1-2% of all diabetes cases. At least 14 different MODY subtypes have been identified the most common of which is MODY 2 caused by mutations in the glucokinase (GSK) gene. The mild hyperglycemia of MODY 2 is often first detected during pregnancy. Patients with MODY are usually misdiagnosed as either idiopathic type 1 or type 2 diabetes. The recognition of MODY 2 during pregnancy has important clinical implications as the management of hyperglycemia may differ from the established algorithm in gestational diabetes. Fetus development could be seriously affected in case it has inherited the GSK mutation and maternal hyperglycemia is insulin treated to the pregnancy adopted glycemic targets. The case report describes the stepwise diagnostic approach to a 43-year-old woman with a history of gestational diabetes and persistent prediabetes who was found to be a carrier of a heterozygous pathogenic variant in GSK (c.184G>A) and discusses the possible genotype of her two children according to their birth weight.

Genetic, Genomic and Epigenomic Studies of Balkan Endemic Nephropathy (Ben).

BEN is a primary, chronic tubulointerstitial nephritis characterized with chronic anemia, absence of edema, xantoderma, normal blood pressure and normal findings on the fundus oculi. The disease is distributed in restricted areas in Bulgaria, Romania, Croatia, Bosnia, Former Yugoslavia. Despite numerous studies on genetic and environmental factors and their possible involvement in BEN, its etiopathogenesis still remains elusive. Our recent study aim to elucidate the possible epigenetic component in BEN development. Whole genome DNA array methylation analysis was applied to compare the methylation profiles of male and female BEN patients from endemic regions in Bulgaria and Serbia and healthy controls. All three most prominent candidate genes with aberrations in the epigenetic profile discovered with this study are involved in the inflammatory/immune processes and oncogenesis. These data are in concordance with the reported pathological alterations in BEN. This research supports the role of epigenetic changes in BEN pathology. Exome sequencing of 22.000 genes with Illumina Nextera Exome Enrichment Kit revealed three mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients which encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.

NGS nominated CELA1, HSPG2, and KCNK5 as candidate genes for predisposition to Balkan endemic nephropathy.

Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression leading to terminal renal failure. The results of molecular biological investigations propose that BEN is a multifactorial disease with genetic predisposition to environmental risk agents. Exome sequencing of 22 000 genes with Illumina Nextera Exome Enrichment Kit was performed on 22 DNA samples (11 Bulgarian patients and 11 Serbian patients). Software analysis was performed via NextGene, Provean, and PolyPhen. The frequency of all annotated genetic variants with deleterious/damaging effect was compared with those of European populations. Then we focused on nonannotated variants (with no data available about them and not found in healthy Bulgarian controls). There is no statistically significant difference between annotated variants in BEN patients and European populations. From nonannotated variants with more than 40% frequency in both patients' groups, we nominated 3 genes with possible deleterious/damaging variants--CELA1, HSPG2, and KCNK5. Mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.

[The characteristics of glucose tolerance in obesity]. / Osobenosti na gliukozniia tolerans pri zatlustiavane.

In 151 obese patients an oral glucose tolerance test was carried out. In 118 patients (mean relative body mass 161.5 +/- 39%) the test was normal. In 33 patients (mean relative body mass 167 +/- 32.1%) the glucose tolerance was decreased. In these patients the mean duration of the pathologic overmass was 15.2 +/- 4.8 years. 4 basic types of curves of pathologic tolerance are described. Obesity in men is significantly more frequently complicated with pathologic glucose tolerance than in women (42.2% vs 15.5%). The great variety of glucose tolerance curves in the obese patient is probably related to various types of response of the insulin secretion and the contrainsular mechanisms.

[The Stein-Leventhal syndrome with obesity]. / Prouchvaniia vurkhu sindroma na Stein-Leventhal sus zatlustiavane.

The authors carried out studies on 28 women with the syndrome of Stein-Leventhal with obesity. It was established that patients with hypothalamic genuine obesity of III degree predominated. The number of patients with liver steatosis was the largest among accompanying metabolic disturbances, followed by those with arterial hypertension and asymptomatic hyperuricemia. Menarche occurred on time, but it was succeeded by various menstrual disturbances. There was increased level of testosterone in sera of 12 out of 20 examined women patients, of LH-in 17, of 17-ketosteroids-in 8, of estrogens-in 6, of prolactin-in 8 patients. These data in parallelism between menstrual disturbances and hirsutism were interpreted by the authors as an expression of primary disturbances in hypothalamic-hypophysial-gonadal interrelationships with secondary changes in the ovaries. The role of fatty tissue in the metabolism of steroid hormones is discussed as well as the possibility for participation of genetic factors in the development of the syndrome of Stein-Leventhal and obesity.

[Late complications in patients having undergone a gastric resection]. / K voprosu o pozdnikh oslozhneniiakh u bol'nykh, perenesshikh rezektsiiu zheludka.

A total of 37 patients who had undergone partial gastrectomy for duodenal or gastric ulcers, were investigated. The postoperative periods ranged from 5 to 28 years. All the patients were subjected to comprehensive clinical and neurologic examinations. The content of vitamin B12 and folic acid in the blood serum was studied by radioimmunoassay in 29 gastrectomized patients, hematological parameters (hemoglobin, serum iron, red blood cell morphology, proteinogram) were estimated in 19 patients. The mean content of vitamin B12 in the blood serum of patients was lower than in normal subjects. The mean level of folic acid in the blood of patients was also lower than in the control, however, this difference was insignificant. Nine patients had subnormal content of vitamin B12, eight of them showed manifest neurologic complications, such as myelopathy and polyneuropathy. Only 3 patients had subnormal content of folic acid in the blood serum. Weakly pronounced anemic syndrome was detected only in 2 out of 19 patients. The role of vitamin B12 deficiency in the development of neurologic symptoms has been considered.

[Indications for and the therapeutic action of hypolipidemic agents in patients with hyperlipoproteinemias]. / Pokazaniia i lechebno vuzdeistvie na niakoi khipolipidemichni sredstva pri bolni s khiperlipoproteinemii.

Seventy three patients with hyperlipoproteinemia (HLP) type II and IV were divided into three groups and treated with different pharmaceuticals. The first group was treated with 300 mg Radecol daily, the second--with 750 mg Probucol and the third--with 600 mg Bezalip. Best results in the patients with HLP, type II A, as regards the effect on total cholesterol were obtained in those treated with Probucol, in type II B the results from the treatment with Radecol and Probucol are similar. In type IV HLP the reduction of triglycerides is best manifested in those treated with Bezalip. The tolerance and indications for the treatment of the patients with the three preparations are evaluated with a view to individualization of the medicamentous treatment.

[Clinical research on the hypolipidemic action of a probucol preparation]. / Klinichni prouchvaniia vurkhu khipolipidmichnoto deistvie na preparata probukol.

Probucol is a drug with hypolipidemic effect from the group of diphenols. The preparation has been administered to 33 patients with hyperlipoproteinemia--15 with type IIA, 17--with IIB and 1--with type III, in a dose of 750 mg for 28 days. The following serum indices were studied: total cholesterol (TCh), cholesterol in lipoproteins with high density (Ch-HDL), triglycerides (Tg), percentage of free cholesterol FCh) and ester cholesterol (ECh) in HDL and lipid-acid composition of ECh in HDL and lipoproteins with low density (LDL). The preparation has a good tolerance. By the end of the treatment, TCh was significantly reduced in the patients with type IIA--with 28.4% (p less than 0.001) and in IIB--with 23.3% (p less than 0.001). Ch-HDL was reduced with 19% on the average in type II ChLD (p less than 0.001). An essential reduction of serum Tg was established--with 32.2%. Significant reduction of lipid acids in the composition of ECh and HDL was established in type IIA ChLD.

[Treatment of patients with the Pickwickian syndrome by reduction of body weight]. / Lechenie na bolni sus sindroma na Pikuik chrez reduktsiia na telesnata masa.

The characteristic signs of Pickwickian syndrome are the high degree of obesity and cardiovascular and respiratory insufficiency, to various degrees. Forty five patients with Pickwickian syndrome were treated at the Clinic of Metabolic Diseases. They represent 3.4 per cent of the total number of patients with obesity of various degrees, observed and treated. The majority of the affected were established to be males (34), mainly III and IV degree of obesity. The average age of the patients was 51 years. Somnolence, lassitude, enhanced appetite, cyanosis and dyspnea with unrestful sleep, with sloring were observed in all patients. The moderate motive regiment applied and the hypoenergy diet under clinical condicions with an average stay of 26 days at the clinic led to considerable reduction of body mass (with 11,7 kg on the average), resulting into an improvement of the functional respiratory parameters and ECG. The elevated values of blood pressure were normalized in the majority of the patients after the treatment. In all patients, the unpleasant subjective complaints, somnolence including, disappeared and respiratory indices were improved. The significant disorders in lipid, carbohydrate and purine metabolism were favourably influenced by the therapeutic regiment applied.

Weight-reducing diets.

No single diet exists for the treatment of obesity. On the contrary, a variety of diet regimes should be taken in consideration in this disease. Even a normoenergic diet can produce the desired reduction of overweight if it is combined with physical exercise. A moderately reducing diet has a number of advantages over the very low-energic ones, as it leads to the preservation of the lean body mass, especially when the diet is accompanied by a regime of high physical activity. In obesity and other metabolic disorders, it is convenient to include in the diet low-energy foods rich in fiber with a possibly specific hypolipidemic effect, such as soy dishes, pectin-enriched dishes, fruit purees and juices, skimmed milk yogurt, wheat bran bisquits, and others.

[High-density lipoprotein cholesterol and the atherogenic index in patients with different types of hyperlipoproteinemias]. / Kholesterolut vuv visokoplutnostnite lipoproteini i aterogenniiat indeks pri bolni s razlichni tipove khiperlipoproteinemii.

A total of 180 subjects (82 males and 98 females), aged from 20 to 60 were examined. Sixty four of them (29 males and 35 females) were regular blood donors (control group) and 116 subjects (53 males and 63 females) - with huperlipoproteinemias: type IIa - 50 subjects (17 males and 33 females), type IIb - 37 (23 males and 14 females) and type IV - 29 (13 males and 16 females). Triglycerides, total cholesterol and cholesterol in lipoproteins with high density (Ch-HDLP) were also determined. The percentage of Ch-HDLP was calculated from total cholesterol (TCh) as well as the atherogenic index [(TCh-Ch-HDLP): Ch-KDLP)] A drop down of Ch-HDLP (p less than 0,01) was found only in hyperlipoproteinemia type IV, as compared with the control group. Ch-HDLP percentage was diminished (p less than 0,001) whereas the atherogenic index was increased (p less than 0,001) in hyperlipoproteinemias from the three types. Both sexes were affected by the changes decrided.

[Serum lipid studies of hyperlipoproteinemia patients during diet therapy with pectin preparations]. / Prouchvanniia na serumnite lipidi u bolni s khiperlipoproteinemiia po vreme na dietolechenie s pektinovi preparati.

Seventy one patients with nutritional-metabolic obesity (II--IV degree) were examined, with or without hyperlipoproteinemia, treated in hospitals or sanatoria for 25 days. The effect of the hypoenergy diet regimen (5,94 kJ = 1460 cal) was studied, that was combined with an average daily import of 11 g esterified, apple pectin (in fruit pastes and drinks) upon the level of 6 serum lipid indices. A decrease (less than 0,05) of total cholesterol, triglycerides and some other lipid indices was established both in the patients with hyperlipoproteinemia type II (IIa and IIb) and type IV, in those without hyperlipoproteinemia syndrome as well. Due to the hypolipidemic effect established the newly produced articles with high esterified apple pectin are recommended in the complex treatment of the patients with obesity (with or without secondary hyperlipoproteinemeia.

[Biochemical characteristic of arteriosclerosis and obesity in the industrial and agricultural complex of Burgas]. / Biokhimichna kharkteristika na aterosklerozata i zatlustiavaneto v PAK--Burgas.

The following indices were determined in 444 subjects (healthy, patients with various forms of atherosclerosis and obese subjects) with the study of a representative population group from IAC--Burgas: total cholesterol, cholesterol in beta-lipoproteins, lecithin, cholesterol-lecithin index, total fats, beta-lipoproteins, esterified fatty acids and uric acid. The biochemical syndrome of atherosclerosis is characterized by moderate (and not ebigatorily in each case) increase of lipid indices and uric acid in serum. The hyperlipidmic syndrome is more frequent and better manisfested in the patients with obesity. That syndrome in the patients with body overweight could be considered to increase the risk of early atherosclerotic complications.

[Diet with maximum restriction of caloric intake in diabetes mellitus and obesity]. / Rezhim na maksimalno ogranichivane na kalorazha pri zakharen diabet i zatlustvane.

To a group of 40 diabetic patients and obesity, a treatment was conducted by dietetic regimen of maximum restriction of the daily calories, from 3352 to 5028 kilojoules (800 to 1200 kilocal) according to obesity degree. Prior to treatment, only 10 per cent of the patients were with compensated diabetes. The treatment in 10 per cent of them was only a diet and in 5 per cent--insulin and in 85 per cent--peroral drugs. Completely compensated were 90 per cent of the patients subjected only to a diet, and in 10 per cent the inclusion of 5-10 mg maninil daily was necessitated. Body weight reduction with 3650 g was obtained within an average of 24 hospital days. All parameters of lipid metabolism, followed up at the beginning and at the end of the treatment were diminished: total fats (not significantly), cholesterol (significantly in females), triglycerides (significantly in males), betlipoproteins (significantly in females) and ketobodies (significantly for both sexes). In 20 patients with hyperlipoproteinuria, type IV, symptomatic anomaly in lipid metabolism was admitted, because after the treatment, only eight remained with such type of deviations. The dietetic regimen of maximum restriction of the calories applied by the authors, is admitted to be effective, with no risk of ketoacidosis, easy to apply and is recommended for the practice.