Diabetes mellitus and cognitive functioning in a Serbian sample.

INTRODUCTION: Diabetes is associated with cognitive impairments, particularly in executive functioning and memory. AIM: The aim was to describe cognitive functioning in Type 1 (T1DM) and Type 2 (T2DM) diabetes compared to healthy controls in a Serbian sample. METHOD: We studied 15 patients with adult onset T1DM (age range 19-60 years), 37 patients with T2DM (age range 50-77 years), and 32 healthy controls (28-78 years). All participants underwent comprehensive neuropsychological assessment. RESULTS: T2DM subjects exhibited poorer performance than healthy controls in global cognitive performance, as well as verbal learning and memory. After correcting for multiple comparisons, follow-up examination of individual tests showed significantly poorer performance only on Trail Making Test Part B (TMT-B). Effect sizes for T2DM versus healthy controls ranged from medium to large for several cognitive variables, while comparisons between T1DM and the other two groups tended to yield much smaller effects. CONCLUSION: T2DM is associated with poorer cognition, particularly in executive functions, learning/memory, and global cognition. Lack of group differences may be due to use of an adult onset T1DM sample, relatively young age of our T2DM sample, or characteristics of healthy control subjects in our Serbian sample.

Significant impact of behavioral and cognitive impairment on quality of life in patients with myotonic dystrophy type 1.

OBJECTIVE: To assess an impact of cognitive and behavioral impairment on QoL in a larger cohort of patients with DM1. METHODS: Sixty six genetically confirmed DM1 patients (22 with juvenile (jDM1) and 44 with adult form (aDM1) of the disease) were recruited. Following behavioral tests were used: Hamilton scales for depression and anxiety (HamD and HamA), Daytime Sleepiness Scale (DSS), and Krupp's Fatigue Severity Scale (FSS). Patients also underwent detailed classic neuropsychological investigation and Cambridge Neuropsychological Test Automated Battery (CANTAB). Individualized Neuromuscular Quality of Life questionnaire (INQoL) was used as a measure of QoL. RESULTS: Patients with jDM1 scored lower than aDM1 patients regarding total INQoL score and all INQoL subdomains, except for myotonia. Significant predictors of total INQoL score in patients with jDM1 were severity of fatigue (ß=+0.60, p<0.01) and percentage of correct responses on Spatial Recognition Memory test from CANTAB that measures visuospatial abilities (ß=-0.38, p<0.05). The most important predictors of total INQoL score in patients with aDM1 were severity of fatigue (ß=+0.36, p<0.05) and level of education (ß=-0.29, p<0.05). CONCLUSION: Our results showed clear influence of different central manifestations on QoL in patients with both aDM1 and jDM1.

Cerebrospinal fluid biomarkers of neurodegeneration in patients with juvenile and classic myotonic dystrophy type 1.

BACKGROUND AND PURPOSE: The aim of the present study was to analyze cerebrospinal fluid (CSF) levels of total tau (T-tau), phosphorylated tau (P-tau) and the 42-amino-acid form of ß-amyloid (Aß42 ) in patients with myotonic dystrophy type 1 (DM1), and their possible correlations with cognitive and behavioral manifestations in these patients. METHODS: Lumbar puncture was performed in 74 patients with DM1 [27 with the childhood/juvenile form (jDM1) and 47 with the adult form (aDM1) of the disease] and 26 control subjects who were subjected to orthopedic surgery. Sandwich ELISA was used for measuring the levels of T-tau, P-tau and Aß42. RESULTS: The CSF level of Aß42 was at its lowest in patients with jDM1 and at its highest in controls (P < 0.05). A tendency of T-tau and P-tau to increase was greater in aDM1 patients than in jDM1 patients and controls (P > 0.05). In both jDM1 and aDM1 patients, significant correlations were found between Aß42 and T-tau (rho = 0.81 and rho = 0.67, respectively, P < 0.01), as well as between Aß42 and P-tau (rho = 0.87 and rho = 0.67, respectively, P < 0.01). The Aß42/P-tau ratio decreased with age in aDM1 patients (rho = -0.30, P < 0.05). Only the level of Aß42 in the CSF of jDM1 patients was correlated with the size of the CTG expansion (rho = -0.53, P < 0.05). Only a few correlations were observed between levels of biomarkers and neuropsychological testing. CONCLUSION: The CSF level of Aß42 was decreased in patients with jDM1, whilst the Aß42/P-tau ratio was decreased in aDM1 patients. Positive correlations between Aß42 , T-tau and P-tau were observed in both forms of disease. Further studies with larger cohorts of DM1 patients are necessary.

Prognostic factors for longer disease free survival and overall survival after surgical resection of isolated liver metastasis from breast cancer.

PURPOSE: Isolated liver metastases (LMs) from breast cancer (BC) occur in only 1-3% of the cases. Resection of isolated LMs improves survival. We examined the prognostic factors for time to LM development, disease free survival (DFS) and overall survival (OS) after BCLM resection. METHODS: From 2006 to 2009, 32 patients underwent LM resection. All of them had breast cancer surgery for their primary tumor and developed resectable LMs as the first and only site of disease progression. RESULTS: LMs developed after a median of 25 months. With a median follow up of 37 months (range 7-66) after metastases resection, median DFS and OS (with 95% CI) were 22.5 (12-40) and 37 (≥23) months, respectively. Tumor size ≥3 vs <3 cm and adjuvant chemotherapy vs no adjuvant chemotherapy correlated with shorter time to LM development (p<0.01 for both parameters). These parameters and BC negative estrogen (ER)/ progesterone receptors (PR) (ER?/PR? vs other) were related with shorter DFS. Positive (vs negative) axillary lymph nodes and BC negative ER/ PR (ER?/PR? vs other) status correlated with shorter OS (p<0.01 for both parameters). A period to metastases development ≥ 24 months (vs ≤24) and single (vs multiple) metastases were related with longer DFS and OS (p<0.01 for both conditions). CONCLUSION: Despite the relatively small number of patients in this study, we believe that positive ER/PR status for both BC and LMs, negative axillary lymph nodes, time to liver metastases development >24 months and single liver metastases predict longer DFS and OS after LM resection.

Specific binding of paraprotein to platelet receptors as a cause of platelet dysfunction in monoclonal gammopathies.

The study included 48 untreated patients with monoclonal gammopathies (MG). Paraprotein was isolated from the serum of 10 patients with decreased platelet aggregation. Platelet aggregation was measured before and after the addition of the isolated paraprotein to platelet-rich plasma (PRP) from 10 healthy donors, in vitro. Expression of platelet von Willebrand factor (vWF) receptor glycoprotein (GP)Ib and platelet collagen receptor GPVI was determined by flow cytometry in the PRP of healthy donors before and after the addition of isolated paraprotein using the monoclonal antibodies, CD42b (for GPIb) and CD36 (for GPVI). Flowcytometry showed that expression of CD42b and CD36 positive cells was reduced after the addition of isolated paraprotein to PRP from healthy donors (p < 0.001). These investigations demonstrated that paraprotein causes platelet dysfunction in patients with MG due to specific binding to the platelet vWF receptor GPIb and platelet collagen receptor GPVI.

Effects of IL-17 on erythroid progenitors growth: involvement of MAPKs and GATA transcription factors.

Interleukin-17 is Th17 cell cytokine implicated in regulation of hematopoiesis and inflammation. Besides promoting granulopoiesis, we have previously shown that IL-17 also affects erythropoiesis stimulating the development of early erythroid progenitors, BFU-E, but suppressing, at least partly via p38 MAPK, the growth of late stage erythroid progenitors, CFU-E. The aim of the present study was to investigate the involvement of other MAPKs, JNK and ERK1/2, as well as GATA transcription factors, in IL-17-mediated effects on murine bone marrow erythroid progenitors. Data obtained by use of specific MAPKs inhibitors indicated that MEK1/2-ERK1/2 MAPK signaling mediates IL-17-induced CFU-E inhibition, as well as that JNK and/or MEK1/2-ERK1/2 MAPKs activation underlies IL-17-induced stimulation of BFU-E growth. Furthermore, Western blot analyses demonstrated no effect on early hematopoiesis transcription factor, GATA-2, and enhanced expression level of erythroid-specific factor GATA-1 in murine bone marrow cells after IL-17 stimulation, which in light of previous reports that GATA-1 overexpression inhibits erythroid differentiation, could be related to IL-17-mediated inhibition of CFU-E growth. Although, no contribution for p38, JNK and ERK MAPKs in IL-17-induced GATA-1 expression was shown, data obtained using specific inhibitors pointed to the role of JNK and MEK1/2-ERK1/2 in GATA-1 downregulation. Overall, obtained data gave an insight into the mechanisms by which IL-17 exerts its effects on erythropoiesis, implying the involvement of JNK and ERK MAPKs, as well as GATA-1, in IL-17-regulated growth of erythroid progentors.

The mathematical analysis of the heart rate and blood lactate curves during incremental exercise testing.

This paper describes a new mathematical approach for the analysis of HR (heart rate) and BL (blood lactate) curves during incremental exercise testing using a HR/BL curve and its derivatives, taking into account the native shape of all curves, without any linear approximation. Using this approach the results indicate the appearance of three characteristic points (A, B and C) on the HR/BL curve. The point A on the HR/BL curve which is the value that corresponds to the load (12.73 ± 0.46 km h-1) at which BL starts to increase above the resting levels (0.9 ± 0.06 mM), and is analogous to Lactate Turn Point 1 (LTP1). The point C on the HR/BL curve which corresponds to a BL of approximately 4mM, and is analogous to LTP2. The point B on the HR/BL curve, which corresponds to the load (16.32 ± 0.49 km h-1) at which the moderate increase turns into a more pronounced increase in BL. This point has not been previously recognized in literature. We speculate this point represents attenuation of left ventricular ejection fraction (LVEF) increase, accompanied by the decrease in diastolic time duration during incremental exercise testing. Proposed mathematical approach allows precise determination of lactate turnpoints during incremental exercise testing.

[Alternative arterial cannulation site in acute aortic dissections].

INTRODUCTION: Acute aortic dissection is an urgent surgical disease. Often, due to hemodynamic instability, that is an indication for emergent surgical intervention. Majority of surgeons uses Femoral or Axillary artery as arterial inflow site forextracorporal circulation. Both approaches have disadvantages that potentially may cause devastating complications. Some of them have been described in literature such as inadequate flow on heart-lung machine, retrograde dissection and malperfusion syndrome. AIM OF STUDY: Aim of study is to show, that by using transventricular cannulation we are eliminating all technical problems and lowering peroperative morbidity and mortality. METHOD: Between 1996-2006 at Institute for Cardiovascular Disease "Dedinje" 107 patients were operated for acute ascending aortic dissection Femoral artery was used for arterial cannulation in 91 patients. Last 16 patients were operated by using transventricular approach to establish extracorporeal circulation. We used retrograde cerebral perfusion in 21 cases at the beginning of our experience. RESULTS: In group of patients where transapical cannulation was used, no neurological incidents were noticed. We didn't have any other problems related to extracorporeal circulation or placement of arterial cannula. Is this series we had only one death case. Patient passed away on eight postoperative day due to multiorgan insufficiency. CONCLUSION: Transapical cannulation is very simple and safe method for quick establishment of extracorporeal circulation. It always gives patient sufficient antegrade, physiological flow on heart-lung machine. This is the way to minimize possibility of malperfusion syndrome and to significantly diminish risk of neurological complication. By using this method all negative effects of other cannulation sites will be avoided.

A biased Gm haplotype and Gm paraprotein allotype in multiple myeloma suggests a role for the Gm system in myeloma development.

The association between a particular Gm haplotype and susceptibility to multiple myeloma (MM) is not clear. The reason is probably because no investigations have so far been carried out on the relationship between the Gm haplotype, which represents the inherited combination of IgG Gm allotypes, and the Gm allotype expressed at the IgG paraprotein (M-component), which reflects the enhanced gene expression within the haplotype in MM. We studied the incidence of Gm allotypic markers present in IgG subclasses in the serum from 52 patients with MM and in parallel with the isolated IgG paraproteins. The results showed that 84.6% of the patients were heterozygous for haplotypes Gm(a; z; n-; g;)/Gm(f; n+/n-; b1; b0; b5) and 15.3% were homozygous for Gm(f; n/n-; b1; b0; b5), while no homozygous Gm(a; z; n-; g) individuals were found among the studied patients. The incidence of these combinations in the healthy population in Serbia is 34%, 66% and < 1%, respectively. Subjects with Gm(a; z; n-; g)/Gm(f; n+/n-; b1; b0; b5) combination are over 10 times [odds ratio (OR) = 10.69; 95% confidence interval 1.67-68] as likely to be affected by the disease as the subjects with homozygous Gm(f; n+/n-; b1; b0; b5) combination (OR = 0.35, 95% confidence interval 0.06-2.23). However, despite the Gm heterozygosity, most of the Gm(a; z; n-; g;)/Gm(f; n+/n-; b1; b0; b5) positive patients with MM (86.3%) had IgG paraprotein with the allotypic marker from the Gm(f; n+/n-; b1; b0; b5) haplotype. Together with patients homozygous for this haplotype, the relative number of patients with serum IgG paraprotein carrying allotypic marker from the Gm(f; n/n-; b1; b0; b5) haplotype was 88.5%. These results suggest that the development of an M-component could be related to a disturbance on chromosome 14q32 carrying the Gm (f; n+/n-; b1; b0; b5) set of genes.

Substituting dietary saturated fat with polyunsaturated fat changes abdominal fat distribution and improves insulin sensitivity.

AIMS/HYPOTHESIS: British dietary recommendations are to decrease total fat intake to less than 30 % of daily energy intake and saturated fat to less than 10 %. In practice, it is difficult for people to make these changes. It may be easier to encourage people to switch from a diet rich in saturated fatty acids to one rich in polyunsaturated fatty acids. METHODS: A total of 17 subjects - six people with Type II (non-insulin-dependent) diabetes mellitus, six non-obese and five obese people without diabetes - were randomised to spend two 5-week periods on a diet rich in saturated or in polyunsaturated fatty acids, in a crossover design. At the start of the study and after each dietary period, we assessed abdominal fat distribution using magnetic resonance imaging, insulin sensitivity using hyperinsulinaemic-euglycaemic clamps and fasting lipid parameters. RESULTS: Dietary compliance, assessed by weekly 3-day dietary records and measurement of biochemical markers, was good. Energy and fat intake appeared to be reduced on the diet rich in polyunsaturated fatty acids although body weights did not change. Insulin sensitivity and plasma low density lipoprotein cholesterol concentrations improved with the diet rich in polyunsaturated fatty acids compared with the diet rich in saturated fatty acids. There was also a decrease in abdominal subcutaneous fat area. CONCLUSION/INTERPRETATION: If this result is confirmed in longer-term studies, this dietary manipulation would be more readily achieved by the general population than the current recommendations and could result in considerable improvement in insulin sensitivity, reducing the risk of developing Type II diabetes.

Monitoring adipose tissue blood flow in man: a comparison between the (133)xenon washout method and microdialysis.

INTRODUCTION: Adipose tissue blood flow (ATBF) increases after meal intake and a failure to regulate ATBF in the postprandial period seems to be a feature of insulin resistance and obesity. ATBF can be measured quantitatively by the (133)Xe washout technique, but the microdialysis ethanol escape method has also been employed to detect relative changes in ATBF. METHODS: We compared (133)Xe washout and the recovery of exogenous ethanol and endogenous urea by microdialysis in abdominal subcutaneous adipose tissue, after physiological stimulation of ATBF by ingestion of oral glucose (75 g) in eight healthy people (age 23-52 y, body mass index (BMI) 19.4-29.6 kg/m(2)). RESULTS: The ATBF response was heterogeneous. In subjects responding vigorously to the stimulus as measured by (133)Xe washout, the microdialysis ethanol escape was increased (indicating an increase in ATBF). An increased recovery of urea was observed, also indicating an increase in ATBF. The recovery of both small molecules was delayed compared with increased blood flow and failed to return to baseline in response to a rapid decline in ATBF. CONCLUSION: We conclude that the (133)Xe washout technique is more responsive to physiological change in ATBF than ethanol escape or urea recovery by microdialysis.

[Assisted circulation II--systems for intermediate and long-term mechanical circulatory support]. / Asistirana cirkulacija II--sistemi za intermedijarnu i dugotrajnu mehanicku potporu cirkulacije.

The concept of artificial circulatory support has been established almost 200 years ago. It has only been within the last four decades that physicians and engineers have developed mechanical assist devices that can temporarily support the circulation until the native heart recovers from a reversible injury. In patients who do not regain native heart function, long-term circulatory support or permanent replace (biologically--heart transplant or permanent mechanical circulatory support) is indicated. In this paper we describe the devices (ABIOMED BSV 5000, Thoratec, HeartMate, Novacor and CardioWest TAH), that are in current clinical use for intermediate and long-term mechanical circulatory support.

[Detection of B-lymphocyte clonality in samples of salivary gland tissue in patients with primary Sjogren syndrome]. / Detekcija klonalnosti B limfocita u uzorcima tkiva pljuvacnih zlezda bolesnika sa primarnim Sjegrenovim sindromom.

Intensive lymphoplasmocytic infiltration with atrophy of glandular tissue structures is the dominant patohistological feature found in exocrine glands of patients with Sjögren syndrome (SS). The infiltrates consist of T and B lymphocyte clusters that make the structures resembling germinal centers, and numerous plasmocytes that are secreting imunoglobulines locally, including autoantibodies. By applying the polymerase chain reaction (PCR) in our study we have shown the existence of dominant B cell clone in salivary glands samples of 4 out of 6 patients with SS, in the absence of clinical, routine laboratory, and patohistological signs of the lymphoma. B lymphocyte clones were detected upon the amplification of gene segment that encoded variable heavy chain immunoglobulin CDR3 region. Finding of single, dominant B lymphocyte clone could be of predictive significance, because these patients are predisposed to non-Hodgkin lymphoma (NHL) for which there is an assumption that it originates out of salivary glands from one of the clusters of proliferating B lymphocytes.

[Detection of K-ras and p-53 oncogene mutations in a patient with acute lymphoblastic leukemia before and after bone marrow transplantation]. / Detekcija mutacija u K-ras i p-53 onkogenima kod obolelog od akutne limfoblastne leukemije pre i posle transplanticije kostine srzi.

We present a case of 22 years old male patient, who was submitted to singenic transplantation of hematopoietic cells originating from the bone marrow in the remission phase of the diagnosed acute lymphoblastic leukemia (ALL). The bone marrow sample was donated by his healthy twin brother. The pretransplantation and transplantation phases were regular. We analyzed the presence of K-ras and p-53 point mutations in our patient with ALL and for the first time we had the opportunity to analyze the samples from two monozygotic twins. DNA was isolated from the peripheral blood mononuclear cells (PBMNC) by the standard procedure, of the patient with ALL before and after bone marrow (BM) transplantation and of his clinically healthy twin brother. Samples were subjected to PCR amplification of K-ras exons 1 and 2 and p-53 exons 5, 6, 7 and 8. In PBMNC of the patient with ALL before BM transplantation, mutations were observed in exon 1 of K-ras and exon 8 of p-53 gene. These mutations were found neither in PBMNC sample of his twin brother, nor in PBMNC of the patient with ALL after BM transplantation. In the p-53 exons 5, 6 and 7 and exon 2 of K-ras, there were no mutations in any analyzed samples. Detected mutations in K-ras and p-53 genes could be a part of larger genetic abnormalities and the obtained results had shown the possibility of using DNA mutational changes in the follow-up of the success of BM transplantation. The molecular disease marker that was found by this method was also significant for the detection of minimal residual disease at the molecular level.

Uptake of individual fatty acids into adipose tissue in relation to their presence in the diet.

BACKGROUND: The fatty acid composition of adipose tissue triacylglycerol reflects, but is not identical to, the fatty acid composition of the habitual diet. OBJECTIVE: We investigated whether the fatty acid composition of adipose tissue is explained by differences between fatty acids in early storage in adipose tissue after a meal. DESIGN: Nine healthy men ate a meal containing several fatty acids. Blood samples were taken for 6 h after the meal from an arterialized hand vein and a vein draining the anterior abdominal subcutaneous adipose tissue. RESULTS: Net storage of fatty acids in adipose tissue occurred between 1 and 4 h after the meal. In relation to the amount fed, storage of fatty acids differed (P < 0. 01) between classes (n-3 polyunsaturated < saturated < n-6 polyunsaturated < monounsaturated); oleic acid was stored in the greatest amounts. These differences agreed closely with published data, except for n-3 polyunsaturated fatty acids. The only individual metabolic step at which significant differences between fatty acids was shown was incorporation of fatty acids into chylomicron triacylglycerol. Differences between fatty acids in rate of extraction from chylomicron triacylglycerol and net uptake into adipose tissue in the postprandial period were significant (P < 0. 01), but not when expressed in relation to proportions in chylomicron triacylglycerol. CONCLUSIONS: The characteristic fatty acid pattern of adipose tissue may predominantly reflect the early metabolic handling of different fatty acids. Adipose tissue uptake of n-3 polyunsaturated fatty acids is slow in relation to that of other fatty acids.

Use of structured triacylglycerols containing predominantly stearic and oleic acids to probe early events in metabolic processing of dietary fat.

Early events in the metabolic processing of dietary triacylglycerol may have an important impact on subsequent development of risk factors for coronary heart disease. We have used structured triacylglycerols containing predominantly stearic or oleic acids at the sn -2 position to probe aspects of the processing of dietary fatty acids presented to adipose tissue in chylomicron-triacylglycerol. Studies were conducted on 14 healthy women who were given meals containing 85 g carbohydrate and 60 g of either of the two structured triacylglycerols in random order. Systemic concentrations and arterio-venous differences across adipose tissue for plasma triacylglycerol and non-esterified fatty acids were measured, together with analysis of the fatty acid composition of the relevant fractions. The stereo-specific structure of the ingested triacylglycerol was largely preserved in chylomicron-triacylglycerol. Systemic concentrations of total and individual non-esterified fatty acids were not significantly different after ingestion of the two fats, nor were their rates of release across adipose tissue. The composition of non-esterified fatty acids released from adipose tissue changed after the meal to reflect more closely the composition of the triacylglycerol ingested, but again no significant differences were observed between the two test meals. There was no detectable release of monoacylglycerol from adipose tissue after either test meal. We conclude that the environment for lipoprotein lipase action in adipose tissue in vivo is likely to be highly organized, such that there is no release of monoacylglycerol, nor preferential uptake or release of fatty acids from chylomicron-triacylglycerol according to the nature or the position within triacylglycerol of the fatty acid.

Development of glycinergic transmission in organotypic cultures from auditory brain stem.

We investigated whether glycinergic transmission develops organotypically in auditory brain stem cultures. Slices of the medial nucleus of the trapezoid body and the lateral superior olive were incubated in medium with a raised extracellular K+ concentration. As in vivo, glycine receptor alpha1 subunit immunoreactivity increased and became clustered on somata and proximal dendrites. Together with organotypic expression of glycine transporter GLYT2, this indicates that molecular components of glycinergic synapses form properly. In contrast, glycinergic synaptic currents did not develop as in vivo: after 7 days in vitro they were still similar to those at the time of culture preparation. We suggest that for organotypic development of glycine receptors and transporters, Ca2+ influx due to elevated K+ is sufficient. The development of functional synaptic transmission, however, may require patterned electrical activity.

Adipose tissue metabolism in the postprandial period: microdialysis and arteriovenous techniques compared.

We investigated whether two different methods of studying metabolism in adipose tissue, microdialysis and the arteriovenous technique, produced comparable results during the postprandial period. Interstitial glycerol concentrations measured by microdialysis are usually used as an index of intracellular lipolysis, and it is not known whether they also reflect the intravascular action of lipoprotein lipase in the postprandial period. The two techniques were compared in 10 healthy subjects fed mixed meals. Interstitial glycerol concentrations reflected those measured in adipose tissue venous plasma. However, the calculation of the rate of glycerol release from adipose tissue using the microdialysis data differed systematically from that using arteriovenous difference measurement. The former method gave, on average, 40% lower values than the latter one. The difference is probably due to the assumptions that had to be made for the calculation of glycerol release. The two techniques have complementary places in the study of postprandial adipose tissue metabolism, with microdialysis reflecting intracellular hormone-sensitive lipase action rather than intravascular lipoprotein lipase.