Cyclooxygenase-2 derived thromboxane A2 and reactive oxygen species mediate flow-induced constrictions of venules in hyperhomocysteinemia

ObjectiveHyperhomocysteinemia (HHcy) has been shown to impair the endothelial function of arterial vessels and promote thrombosis. There are no studies, however, assessing the effects of HHcy on the vasomotor function of venules. We hypothesized that HHcy activates pathophysiological mechanisms impairing flow/shear stress-dependent responses of venules.Methods and resultsChanges in diameter of isolated gracilis muscle venules (diameter: ～250 μm at 10 mmHg) of control and HHcy rats (induced by methionine diet for 5 weeks) to increases in intraluminal flow were measured. Increases in flow elicited dilations in control (at max.: 14 ± 1%), but induced constrictions in HHcy venules (at max.: ?24 ± 4%). Flow-induced constrictions in HHcy venules were converted to dilations in the presence of the thromboxane A₂ (TxA₂) receptor (TP) antagonist SQ 29,548, which were then abolished by the simultaneous administration of nitric oxide (NO) synthase inhibitor, L-NAME and non-selective cyclooxygenase (COX) blocker, indomethacin. In addition, the selective COX-2 inhibitor NS 398 reversed flow-induced constrictions to dilations, which were significantly decreased by additional COX-1 inhibitor, SC 560. Also, as compared to controls, a SOD/CAT sensitive increased ethidium bromide fluorescence was detected in HHcy small veins, indicating substantial production of reactive oxygen species (ROS) in HHcy. Correspondingly, SOD/CAT diminished flow-induced constrictions in venules of HHcy rats.ConclusionsIn hyperhomocysteinemia increases in flow/shear stress increases the production of COX-2-derived TxA₂, and reactive oxygen species – that overcome the dilator effects of NO and prostaglandins – eliciting constrictions in skeletal muscle venules; changes which can increase vascular resistance and favor thrombus formation in the venular circulation.     

Towards a non-invasive interictal application of hypothermia for treating seizures: a feasibility and pilot study

Objectives – To evaluate the feasibility and safety of head‐neck cooling in conscious normal volunteers (10) and patients with medically refractory epilepsy (5) without causing shivering. Patients and methods – We used a non‐invasive head‐neck cooling system (CoolSystems Inc., Lincoln, CA, USA). The tympanic temperature (TT) and intestinal temperature (IT) were measured as two measurements of ‘core temperature’ (CT), and multi‐site external temperatures, several physiologic variables and EEG were monitored. Seizure counts over 4‐week precooling, treatment and follow‐up phases were compared. Results – All 15 participants completed all the cooling sessions without significant complaints. At the end of 60 min of cooling, scalp temperature fell on average by 12.2°C (P < 0.001), TT by 1.67°C (P < 0.001), and IT by 0.12°C (P = NS). Average weekly seizure frequency decreased from 2.7 to 1.7 events per patient per week (MANOVA: P < 0.05). Conclusions – Non‐invasive head‐neck cooling is safe and well‐tolerated. Initial pilot data in patients suggest that additional therapeutic studies are warranted.     

Clinical course of the non-operated hand in patients with bilateral idiopathic carpal tunnel syndrome

PURPOSE: Patients with bilateral carpal tunnel syndrome (CTS) who had unilateral carpal tunnel surgery usually ask about the prognosis for the non-operated, opposite hand. In this study, we investigated the effects of unilateral carpal tunnel surgery on the clinical course of the non-operated, opposite hand in bilateral idiopathic CTS. METHODS: In this prospective study, only patients who had bilateral idiopathic CTS but had unilateral carpal tunnel surgery were included. Sixty-six patients were included in the study. All patients were women with the mean age 47 years and mean duration of symptoms 4 years. Forty-six surgeries were performed on right hands, and 20 surgeries performed on left hands. Forty-eight (73%) patients were housewives. Their non-operated, opposite hands were evaluated before and 6 months after unilateral surgery. The evaluations consisted of subjective symptoms and objective findings. Paired t-test and chi-square test were used for statistical analysis. RESULTS: There were no statistically significant differences between the means of symptom severity score, functional status score, power and pinch grip strength before and 6 months after unilateral surgery in the non-operated, opposite hands. There was no statistically significant differences among the percentages of the Tinel's sign, Phalen test, and electrophysiological changes before and 6 months after unilateral surgery on the non-operated, opposite hands. During the study period, 57 (86%) patients had surgery or intended to have surgery for their opposite hands. CONCLUSIONS: It seems that unilateral surgery for bilateral idiopathic CTS does not affect the clinical course of the non-operated, opposite hand. We recommend that each hand of patients with bilateral CTS be managed separately, based on their symptoms.     

Dose-related effects of 1,25-dihydroxyvitamin D3 on growth, modeling, and morphology of fetal mouse metatarsals cultured in serum-free medium.

A serum-free, fetal bone organ culture model that permits the simultaneous determination of modeling and growth parameters was used to examine the effects of a near physiologic and a pharmacologic dose of 1,25-dihydroxycholecalciferol [1,25-(OH)2D3]. The fetuses of pregnant mice were removed on day 17 of gestation, and three medial metatarsal rudiments were cleaned and after preculturing were cultured as pair-matched groups for 4 days in MEM supplemented with 0.2% BSA. 1,25-(OH)2D3 was added to the cultures at concentrations of 10(-12) or 10(-6) M. Cultures treated with the carrier and devitalized bones served as controls. For resorption studies, pregnant mice were given 45Ca on day 17 of pregnancy and fetal metatarsals harvested 24 h later. Resorption was determined by the amount of 45Ca released into the media. DNA synthesis was estimated by determining the incorporation of [3H]thymidine, collagen synthesis by measuring the incorporation of [3H]proline, mineralization by the incorporation of 45Ca, and proteoglycan synthesis by the incorporation of 35S. The amount of radiolabel was detected in media, as well as in noncultured, dead, and cultured rudiments. The total length of the rudiments and length of the calcified diaphyses were measured daily. In addition, rudiments from all experimental groups were prepared for light and electron microscopy. The high dose (10(-6) M) of 1,25-(OH)2D3 suppressed total rudiment growth but not the growth of the calcified diaphysis, 1,25-(OH)2D3 also decreased DNA, collagen, and proteoglycan synthesis, reduced calcification, and increased bone resorption in a dose-related manner. There were morphologic and ultrastructural changes in the osseous tissues and cells, particularly with the high dose of vitamin D, that supported the biochemical findings of suppressed activity of the osteogenic and chondrogenic cells. However, the suppression of collagen production and bone cell proliferation observed with the pharmacologic dose of vitamin D may be partially attributable to the decrease in bone mass (from increased resorption), thus resulting in less osseous tissue surface for these events to occur as endochondral osteogenesis progressed. The lower dose of vitamin D, however, had effects on 35S and 45Ca incorporation that could not be attributed to a decreased osseous tissue mass. This study emphasizes the importance of measuring specialized activities of the various cell populations in bone rudiment culture models to more fully understand the changes in tissue metabolism that result in changes in rudiment growth and modeling.     

Epigenetic involvement in etiopathogenesis and implications in treatment of systemic lupus erythematous

Background

Recent researches in the field of genetics have extended our knowledge through the discovery of genetic factors associated with autoimmune diseases (AID). Genetics by itself, however, cannot elucidate all the uncertainties encountered in the etiopathology of AID. On the other hand, incomplete harmony in the prevalence of AID in identical twins suggests that non-genetic factors may play an important role in determining the disease susceptibility. Besides, epigenetics, which is defined by changes in gene expression without a corresponding change in the DNA sequences, has come in to provide new awareness in the disease etiopathology by bridging the genetic and epigenetic factors. The recent advances in the field of epigenetics provide a new insight into the understanding of the disease mechanisms, development, diagnostic and prognostic approaches, as well as the various treatment methods.

Purpose

This review paper aims to present an overview of epigenetic modifications involved in the pathogenesis of systemic lupus erythematosus (SLE) and discuss their important roles in clinical and pharmacological settings, including novel and recent therapeutic applications.

Results

Nowadays, it is believed that autoimmune diseases, such as SLE, begin when genetically susceptible factors associate with environmental triggers. The current therapeutic approaches for SLE treatment have been based on treatments with immunosuppressive drugs, which are linked to various side effects. It is difficult to develop highly effective treatments for SLE patients with minimal or no side effects, mainly due to the disease complexity. The breakthrough of pharmacoepigenetics provides a new approach to solve this problem. Epigenetic modifications can influence the efficacy of drugs by changing the gene expression through modifying chromatin remodeling. In this regard, epigenetic studies in SLE are expected to reveal novel disease biomarkers and therapeutic targets.

Conclusions

Accumulating evidence disclosed that epigenetic dysregulations are engaged in SLE pathogenesis and may be exerted as biomarkers to diagnose and as tools to treat these patients.

     

Opium and opioid abuse in orthopedic inpatients: a cross sectional study in Urmia University of Medical Sciences

During a cross-sectional study, patients who were admitted to the orthopedic department of the Urmia University of Medical Sciences were asked about opium/opioid abuse. Demographic characteristics, the pattern of consumption, the substance, the duration of the use, the duration of hospital stay and the cause of their injuries were recorded. Among 2,867 patients, 74 (2.5%) patients (71 men and 3 women) with the mean age of 38 were opium/opioid users. Most of the patients used opium through inhalation. The mean duration of the substance use was 7.4 years. The mean duration of hospital stay between the regular orthopedic patients and the opium/opioid abuser orthopedic patients was statistically significant. (P=000). Among four Hepatitis C Virus (HCV) infected patients, three subjects were injection users and Human Immunodeficiency Virus (HIV) also infected two of them. Road traffic accidents (37.8%), and work related injuries (17.5%) were the two most common reasons for the patient's injuries.     

Hepatocyte growth factor in saliva of patients with renal failure and periodontal disease

Background: Hepatocyte growth factor (HGF), endogenous cytokine with pleiotropic repairing and regeneration properties in relation to most tissues and organs, contributes to the progression of periodontal disease (PD). Furthermore, PD is a significant health problem in patients with chronic renal failure (CRF). The role of HGF in the development of PD in this specific population was not a subject of research so far. Material and methods: The following groups were enrolled in the study: (1) 26 chronic hemodialysis (HD) subjects, (2) 26 patients treated by continuous ambulatory peritoneal dialysis (CAPD), (3) 28 predialysis CRF patients, (4) 26 subjects with advanced PD (without coexisting diseases), and (5) 20 healthy subjects without PDs. HGF level in saliva was measured using the immunoenzymatic method. Gingival index, papillary bleeding index, plaque index, and the loss of clinical attachment level were evaluated. Results: The HGF level in saliva of HD patients was twice higher than in that of subjects with healthy periodontium. Direct relationships between proper HGF level in saliva and the indices GI, PBI, and PI in CAPD-treated patients and with more severe PD were shown. It was found that PD is most advanced in HD patients, moderately in CAPD-treated patients and to the smallest extent in predialysis CRF patients. Conclusions: The HGF level in mixed saliva is the index of PD progression in subjects without renal failure and in CAPD-treated patients. PD is common in renal failure patients and is a significant problem concerning general health status.