Matrix Metalloproteinase-2 (MMP-2) and-9 (MMP-9) Gene Variants and Microvascular Complications in Type 2 Diabetes Patients.

Vascular complications are the leading cause of increased morbidity and mortality of diabetic patients. It has been postulated that matrix metalloproteinases MMP-2 and MMP-9, zinc-dependent endopeptidases through remodeling of the extracellular matrix, can contribute to the onset and progression of diabetic vascular complications. The aim of our study was to assess whether there is a major difference in single nucleotide polymorphisms in the MMP-2 (at position -1306C˃T) and MMP-9 (at position -1562C˃T) gene in type 2 diabetic patients and healthy controls and to determine whether there is an association of these gene variants with the presence of microvascular complications in diabetic patients. Our study included 102 type 2 diabetes patients and a control group which was comprised of 56 healthy controls. All diabetic patients were screened for microvascular diabetes complications. Genotypes were detected by polymerase chain reactions followed by restriction analyses with specific endonucleases and their frequencies were determined. The MMP-2 variant -1306C>T showed a negative correlation with type 2 diabetes (p=0.028). It was also shown that the presence of the -1306C allele increases the probability of developing type 2 diabetes. This was a 2.2 fold increase and that the -1306 T allele has a protective role in regards to type 2 diabetes. The MMP-2 variant -1306T showed a negative correlation with diabetic polyneuropathy (p=0.017), meaning that allele-1306T has a protective role in regards to diabetic polyneuropathy while the presence of allele -1306C increases the probability of developing diabetic polyneuropathy by 3.4 fold. Our study showed that the MMP-2 gene variant (-1306C) doubles the risk of developing type 2 diabetes, and for the first time an association of this gene variant and the presence of diabetic polyneuropathy was shown.

ADRB2 Gene Polymorphisms and Salbutamol Responsiveness in Serbian Children with Asthma.

Inhaled ß2 adrenergic receptor (ß2-AR) agonists are the mainstay of asthma therapy. The ß2-AR protein is encoded by the ADRB2 gene and variants within this gene can have significant consequences for modulating the response to asthma therapy. This cross-sectional study performed at the University Children's Hospital in Belgrade, included 54 children with asthma. The subjects were genotyped for ADRB2 +46A>G (Arg16Gly, rs1042713) and +79C>G (Gln27Glu, rs 1042714) polymorphisms and the association with asthma severity and response to inhaled salbutamol was examined. In Serbian asthmatic children, allele +46A was detected with a frequency of 41.7% and allele +79G was detected with a frequency of 23.1%. Allele +46G was found to be associated with a better response to inhaled salbutamol (p <0.05) and with mild form of asthma (p <0.05). Polymorphism ADRB2 +46A>G may be a determinant of asthma severity and response to salbutamol in children with asthma. We did not find any association of +79C>G polymorphisms with the asthma severity and bronchodilator response to inhaled salbutamol. The results of this study can be potentially useful for personalization of asthma treatment.

A critical re-evaluation of the specificity of action of perivagal capsaicin.

Perivagal application of capsaicin (1% solution) is considered to cause a selective degeneration of vagal afferent C fibres and has been used extensively to examine the site of action of many gastrointestinal (GI) neuropeptides. The actions of both capsaicin and GI neuropeptides may not be restricted to vagal afferent fibres, however, as other non-sensory neurones have displayed sensitivity to capsaicin and brainstem microinjections of these neuropeptides induce GI effects similar to those obtained upon systemic application. The aim of the present study was to test the hypothesis that perivagal capsaicin induces degeneration of vagal efferents controlling GI functions. Experiments were conducted 7-14 days after 30 min unilateral perivagal application of 0.1-1% capsaicin. Immunohistochemical analyses demonstrated that, as following vagotomy, capsaicin induced dendritic degeneration, decreased choline acetyltransferase but increased nitric oxide synthase immunoreactivity in rat dorsal motor nucleus of the vagus (DMV) neurones. Electrophysiological recordings showed a decreased DMV input resistance and excitability due, in part, to the expression of a large conductance calcium-dependent potassium current and the opening of a transient outward potassium window current at resting potential. Furthermore, the number of DMV neurones excited by thyrotrophin-releasing hormone and the gastric motility response to DMV microinjections of TRH were decreased significantly. Our data indicate that perivagal application of capsaicin induced DMV neuronal degeneration and decreased vagal motor responses. Treatment with perivagal capsaicin cannot therefore be considered selective for vagal afferent C fibres and, consequently, care is needed when using perivagal capsaicin to assess the mechanism of action of GI neuropeptides.

Is quality of life in non-demented Parkinson's disease patients related to cognitive performance? A clinic-based cross-sectional study.

Whilst the association between dementia and poorer health-related quality of life (Hr-QoL) in Parkinson's disease (PD) has been well established, we aimed to explore the relationship between cognitive performance and Hr-QoL in PD without dementia. Consecutive PD patients (n = 124, 54% men, age 60.4 +/- 10.3 years) judged as non-demented based on DSM-IV criteria and Mini Mental State Examination, free of other neurodegenerative diseases or psychotic difficulties and antipsychotic/antidepressive/anxyolitic treatment were assessed in a battery of neuropsychological tests. We used Parkinson's disease questionnaire (PDQ-39) to asses Hr-QoL and Beck's Depression Inventory (BDI) to quantify depression. In the univariate analysis, better performance in each of the tests evaluating visual attention/memory or visuospatial and executive functions was associated with better Hr-QoL. In multivariate analysis [adjustment for BDI score, PD severity and duration, l-dopa dose, age, sex, education, employment status and early PD onset (<50 years of age)] in which these tests were either represented by a common variable identified in a principal components analysis or were considered individually, better cognitive performance was independently associated with better Hr-QoL. The association was conditional on the level of depression, i.e., apparent only in patients with low(er) BDI scores. Cognitive performance appears associated with Hr-QoL even in non-demented PD patients.

Oxidative stress parameters in plasma of Huntington's disease patients, asymptomatic Huntington's disease gene carriers and healthy subjects : a cross-sectional study.

BACKGROUND: Animal data and postmortem studies suggest a role of oxidative stress in the Huntington's disease (HD), but in vivo human studies have been scarce. AIM: To assess the presence of oxidative stress in HD patients and its occurrence relative to clinical symptoms. METHODS: Oxidative stress markers were determined in plasma of HD patients (n = 19), asymptomatic HD gene carriers (with > 38 CAG repeats) (n = 11) and their respective sex and agematched healthy controls (n = 47 and n = 22) in a cross-sectional study. RESULTS: With adjustment for age and sex, HD patients had higher plasma lipid peroxidation (LP) levels (ratio 1.20, 95% CI 1.09 to 1.32, p < 0.001) and lower reduced glutathione (GSH) levels (ratio 0.72, CI 0.55 to 0.94, p = 0.011) than their age and sex-matched controls. Although considerably younger, HD gene carriers did not differ from HD patients regarding LP and GSH levels, and had higher plasma LP (ratio 1.16, CI 1.02 to 1.32, p = 0.016) and lower GSH than their matched controls (ratio 0.73, CI 0.5 to 1.05). They had higher LP (ratio 1.18, CI 1.02 to 1.34, p = 0.019) and lower GSH (ratio 0.75, CI 0.51 to 1.11) than the healthy subjects matched to HD patients. CONCLUSIONS: Oxidative stress is more pronounced in HD patients and asymptomatic HD gene carriers than in healthy subjects. Differences in plasma LP and GSH are in line with the brain findings in animal models of HD. Data suggest that oxidative stress occurs before the onset of the HD symptoms.

Association of rural life setting and poorer quality of life in Parkinson's disease patients: a cross-sectional study in Croatia.

Assessment of quality of life (QoL) has become an important measure in Parkinson's disease (PD) healthcare as a part of the efforts to evaluate the 'total burden' of the illness, and not only the motor disabilities. By analogy with some other diseases, we aimed to investigate potential urban-rural disparities in QoL in PD patients. A total of 111 consecutive PD patients were assessed for QoL using a specific 39-item version of PD quality of life questionnaire (PDQ-39) in a cross-sectional study involving two centers in Croatia. Rural life setting (adjustment for center, age, sex, levodopa dose, disease duration and severity, education, employment status and number of household co-members) was an independent negative predictor of QoL: rural patients had significantly (P < 0.05) worse PDQ-39 Summary Index Score and most of the PDQ-39 subscale scores (cognition, social support, stigma, emotional wellbeing and mobility score, and communication and activity of daily living scores with borderline significance) than their urban counterparts. Socioeconomic background should be considered in attempts to achieve the best management of PD patients' needs.

Could hybrid minimally invasive esophagectomy improve the treatment results of esophageal cancer?

AIM: To assess the effectiveness of hybrid minimally invasive esophagectomy (hMIE) in comparison with open esophagectomy (OE) in esophageal cancer treatment. METHODS: The single center prospective nonrandom cohort study included a total of 88 patients in convenience sample, who underwent the Ivor-Lewis procedure with a curative intention for the middle- and lower-third esophageal cancer between January 2009 and February 2015. All patients were operated by the one surgical team. Out of 88 patients, 44 underwent OE and 44 hMIE laparoscopic approach (laparoscopic gastric mobilization). Primary endpoints were significant early postoperative complications, including major postoperative pulmonary complications (MPPCs). Secondary endpoints were perioperative characteristics, 30-day mortality and oncological outcomes. RESULTS: The total number of complications was 21 in the OE group vs. 13 in the hMIE group (p > 0.05). Higher prevalence of major postoperative pulmonary complications (MPPCs) was observed in the OE group compared to the hMIE group. Mean intensive care unit (ICU) stay was 3.8 (1-21) days; there was a statistically significant difference in favor of the hMIE group. Mean number of harvested lymph nodes was 26.3 in the OE group compared to 31.9 in the hMIE group (p < 0.05). There was no statistically significant difference regarding 30-day mortality between the groups. Overall median survival rate was 807 days; 824 days in the OE group vs. 778 days in the hMIE group (p > 0.05). CONCLUSION: Perioperative and oncologic results after hMIE are not inferior but are even better in some aspects of treatment when compared to OE.

Effect of earthworm (G-90) extract on formation and lysis of clots originated from venous blood of dogs with cardiopathies and with malignant tumors.

The stability of homeostasis is important to keep a balance between coagulation and fibrinolysis. A disorder of homeostasis leads to different physiological changes and causes different diseases such as cardiopathies and malignant tumors. Cardiopathies is characterized by a hypercoagulation. In the malignant tumors, besides the hypercoagulation due to plasminogen activators (PA) formed inside the tumor, a disorder of homeostasis leads also to acceleration of the fibrinolysis. The variety of internal and external factors in both cases determine the deviation of time for the clots formation, as well as the lyses of blood and fibrin clots. In this study the venous blood as well as the blood and the fibrin clots, derived from healthy dogs, the dogs with cardiopathies and with malignant tumors, were examined for the time of coagulation and fibrinolysis by adding different substances. In these experiments we used a glycolipoprotein extract from earthworm tissue homogenate (G-90) and the proteolytic enzymes P I and P II, isolated from G-90. The efficacy of the tested substances was comparable with the clinically administered anticoagulants. The most significant differences in clotting time among the three tested groups of dogs were obtained by application of the original G-90. The results suggest a possibility that G-90, along with the fibrinolytic enzymes and other biologically active factors, also contains a factor that decelerates the formation of clot in a specific medium, such as the blood from the dogs with malignant tumors.

Feline high-rise syndrome: 119 cases (1998-2001).

High-rise syndrome was diagnosed in 119 cats over a 4-year period. 59.6% of cats were younger than one year, and the average height of the fall was four stories. High-rise syndrome was more frequent during the warmer period of the year. 96.5% of the presented cats, survived after the fall. 46.2% of cats had fractured limbs; 38.5% of fractures were of the forelimb, 61.5% of the hindlimb. The tibia was fractured most often (36.4%), followed by the femur (23.6%). 78.6% of femoral fractures were distal. The mean age of patients with femoral fractures was 9.1 months, and with tibial fractures 29.2 months. Thoracic trauma was diagnosed in 33.6% of cats. Pneumothorax was diagnosed in 20% of cats, and pulmonary contusions in 13.4%. Falls from the seventh or higher stories, are associated with more severe injuries and with a higher incidence of thoracic trauma.

[Hepatocerebral degeneration]. / Hepatocerebralna degeneracija.

Hepatocerebral degeneration is a hereditary copper metabolic disorder caused by yet unknown pathological process in the 13th chromosome. The disease is more frequent than is usually believed and has systemic characteristics, although the central nervous system and liver are most often affected. The authors describe 35 patients with neurological form of the disease (mean age 29.3 +/- 1.9 years; mean duration of the disease 3.8 +/- 1.7 years). The most frequent symptoms of these patients are dysarthria (88.6%), tremor (85.7%) and rigidity (80%), while elevated liver copper concentration (97.1%) presents the most frequent biochemical disorder of the copper metabolism. Contrary to common opinion about the pathognomy of Kayser-Fleischer ring, its existence is confirmed in only 60% of the patients. On the basis of the author's own results, along with the reference to already described data from literature, the authors give a survey of current knowledge about hepatocerebral degeneration.

Glucose-dependent trafficking of 5-HT3 receptors in rat gastrointestinal vagal afferent neurons.

BACKGROUND: Intestinal glucose induces gastric relaxation via vagally mediated sensory-motor reflexes. Glucose can alter the activity of gastrointestinal (GI) vagal afferent (sensory) neurons directly, via closure of ATP-sensitive potassium channels, and indirectly, via the release of 5-hydroxytryptamine (5-HT) from mucosal enteroendocrine cells. We hypothesized that glucose may also be able to modulate the ability of GI vagal afferent neurons to respond to the released 5-HT, via regulation of neuronal 5-HT(3) receptors. METHODS: Whole-cell patch clamp recordings were made from acutely dissociated GI-projecting vagal afferent neurons exposed to equiosmolar Krebs' solution containing different concentrations of d-glucose (1.25-20 mmol L(-1)) and the response to picospritz application of 5-HT assessed. The distribution of 5-HT(3) receptors in neurons exposed to different glucose concentrations was also assessed immunohistochemically. KEY RESULTS: Increasing or decreasing extracellular d-glucose concentration increased or decreased, respectively, the 5-HT-induced inward current and the proportion of 5-HT(3) receptors associated with the neuronal membrane. These responses were blocked by the Golgi-disrupting agent Brefeldin-A (5 µmol L(-1)) suggesting involvement of a protein-trafficking pathway. Furthermore, l-glucose did not mimic the response of d-glucose implying that metabolic events downstream of neuronal glucose uptake are required to observe the modulation of 5-HT(3) receptor mediated responses. CONCLUSIONS & INFERENCES: These results suggest that, in addition to inducing the release of 5-HT from enterochromaffin cells, glucose may also increase the ability of GI vagal sensory neurons to respond to the released 5-HT, providing a means by which the vagal afferent signal can be amplified or prolonged.

A 12-month, randomized, placebo-controlled trial of propentofylline (HWA 285) in patients with dementia according to DSM III-R. The European Propentofylline Study Group.

Alzheimer's disease (AD) and vascular dementia (VaD) share several features such as overactivation of microglial cells, damage induced by free radicals, glutamate and calcium overload. Propentofylline (HWA 285) has shown beneficial effects on all of these common elements, thus favouring its use in both subtypes of dementia. In a multinational, randomized, 12-month, double-blind, parallel-group study 260 out-patients with mild to moderate AD or VaD received 300 mg propentofylline (n = 129) or placebo (n = 131) three times daily 1 h before meals. The efficacy was tested at four independent rater levels (physician, psychologist, relative and patient) with assessments covering three major domains of dementia (global function, cognitive function and activities of daily living). After 12 months, the total patient population showed statistically significant treatment differences in favour of propentofylline for the global measures of dementia (Gottfries-Bråne-Steen scale, GBS, p = 0.001; Clinical Global Impressions, CGI, item I: p = 0.004, item II: p = 0.072) as well as for the cognitive measures (Syndrome Short Test, SKT, p = 0.002) and Mini-Mental State Examination (p = 0.001). The activities of daily living also showed a significant treatment difference in favour of propentofylline (p = 0.002). No significant treatment differences were found for rating scales performed by the patients. At month 12, VaD patients showed treatment differences in favour of propentofylline for the GBS total score (p = 0.006), CGI item I (p = 0.004), GGI item II (p = 0.044) and SKT (p = 0.028). Treatment differences for AD patients were all in favour of propentofylline and reached statistical significance for the SKT (p = 0.018). Propentofylline showed a good safety profile with respect to adverse events, vital signs, ECG and laboratory changes.

Molecular analysis and electromyoneurographic abnormalities in Croatian children with proximal spinal muscular atrophies.

Childhood onset proximal spinal muscular atrophy presents with considerable clinical variability. This study included 14 Croatian children aged 11 days to 8 years with spinal muscular atrophy types I-III verified clinically and electromyoneurographically. DNA of affected children was screened for deletions of exons 7 and 8 of the survival motor neuron gene and for deletion of exon 5 of the neuronal apoptosis inhibitor protein gene. Motor nerve conduction velocity and compound muscle action potential amplitude were decreased in children with spinal muscular atrophy type I and II. Deletions of exons 7 and 8 of the survival motor neuron gene and of exon 5 of the neuronal apoptosis inhibitor protein gene in children with spinal muscular atrophy type I-II suggested existence of more genetic abnormalities as compared to type III. A decrease in compound muscle action potential amplitude and motor nerve conduction velocity in children with spinal muscular atrophy correlated with the disease severity, probably as a result of axonal degeneration. Phenotypic severity in children onset spinal muscular atrophy is directly correlated with the extent of survival motor neuron and neuronal apoptosis inhibitor protein exon deletions.