Evaluation of 1,25-dihydroxyvitamin D3 pathway in patients with chronic urticaria.

BACKGROUND: Previous studies showed the role of vitamin D (Vit D) on the progression of chronic urticaria. To the best of our knowledge, there are no other results regarding the contribution of single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) and vitamin D binding protein (VDBP) genes in chronic urticaria (CU). AIM: In the present study, we investigated the Vit pathway and the association between VDR and VDBP gene polymorphisms and CU risk in Iranian population. METHODS: All participating individuals in the present study were evaluated for serum Vit D and VDBP concentration VDR rs1544410 and rs2228570 and VDBP rs7041using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The associations of studied analytes and three SNPs with clinical and laboratory outcomes were investigated in CU patients. RESULTS: Patients with CU showed lower Vit D compared to controls (19.26 ± 1.26 vs. 31.72 ± 7.14 ng/ml, P-value = 0.006). There was a significant correlation between Vit D levels and urticaria activity score. Serum VDBP was significantly higher in CU patients than controls (1317.3 ± 183.71 vs. 395.77 ± 12.96 µg/ml, P-value <0.0001) and had a positive correlation to progression of CU. The A allele of this polymorphism might be a potential risk factor for progression of CU [odds ratio 4.3434, 95% confidence interval (1.7331-10.8852), Z-statistic = 3.133, P-value = 0.0017]. CONCLUSION: In summary, this study demonstrated that change in Vit D pathway in the level of gene or protein may be a risk factor for progression of CU.

Penile Preservation for Male Urethral Cancer.

Tumors of the male urethra are rare, comprising <1% of urologic malignancies. This is a report of a 44-year-old man presented with a 4-month history of gross initial hematuria and dysuria. After examining the patient, we found a firm mass extending 1 cm within the proximal bulbar urethra and a pathologic report of moderately differentiated squamous cell carcinoma. He underwent excision of the involved urethra followed by end-to-end bulbar urethroplasty. External beam radiation was performed at the dose of 6000 Rad, in 33 courses. The patient was followed by surveillance protocol and, no evidence of urethral or bladder tumor was found in the 2-year follow-up with bi-annual cystoscopic examination.

Prevalence of type 2 diabetes mellitus in Iran and its relationship with gender, urbanisation, education, marital status and occupation.

INTRODUCTION: We investigated the prevalence of type 2 diabetes mellitus and its relationship between gender, urbanisation, education, marital status and occupation in the Iranian population. METHODS: A total of 3,778 men and women aged between 15 and 64 years were recruited by using a cluster-stratified sampling method from Khorasan province, northeast Iran. Using an interviewer-administrated questionnaire, demographical data including gender, urbanisation, education, marital status and occupation was collected. Anthropometrical and biochemical measurements were taken for each subject. Associations of type 2 diabetes mellitus and other variables were tested for significance. RESULTS: The prevalence of diabetes mellitus (defined as fasting blood sugar equal to or more than 126 mg/dL) was 5.5 percent, and the prevalence in men and women was 5.1 percent and 5.8 percent, respectively, with a significantly higher prevalence among urban dwellers (seven percent) compared to that of the rural subgroup (three percent, p-value is less than 0.001). Diabetes mellitus was found to be most prevalent among the older age group (age more than 60 years, 10.9 percent), those who were retired (14.4 percent), and illiterate (6.1 percent, p-value is less than 0.001). Marital status was not significantly related to diabetes mellitus (p-value equals 0.09). CONCLUSION: The prevalence of diabetes mellitus is related to some sociodemographical factors within the Iranian population. Thus the preventive strategies should be based on the affective factors. The urbanisation of the population with the migration of people from rural to urban areas may account in part for the increasing prevalence of type 2 diabetes mellitus in Iran.

A comparative study of long-term results of Buccal Mucosal Graft and Penile Skin Flap techniques in the management of diffuse anterior urethral strictures: first report in Iran.

PURPOSE: To compare Buccal Mucosa Graft with Penile Skin Flap techniques in the management of anterior urethral diffuse strictures longer than 3 cm. MATERIALS AND METHODS: Thirty seven patients with a mean age of 28.5 (range 5 to 50) years had been treated by these two techniques using the ventral onlay patch from February 1997 to March 2002. Patients' follow-up included physical examination, history taking, retrograde urethrography, cystoscopy and uroflowmetry at the month six, at the end of the first and the second years, and then yearly if required. RESULTS: These techniques were applied for anterior urethral strictures (bulbar and penile) longer than 3 cm. Buccal mucosal graft (BMG) was used in 18 patients and penile skin flap (PSF) in 19. Mean follow-up was 27.5 (range 6 to 50) months. Mean age was 30.8+/-11.8 years for BMG group and 27.8+/-15.6 years for PSF group. Urethral stricture etiology, surgery history, and previous endoscopic surgery history were similar in both groups. The stricture site in BMG group was penile in 2 patients (11.1%), bulbar in 8 patients (44.4%), and penobulbar in 8 patients (44.4%). In PSF group the stricture site was penile in 11 patients (57.9%), bulbar in 5 patients (26.3%) and penobulbar in 3 patients (15.8%). Success rate in 6-month follow-up was 93.9% for BUG group and 83% for PSF. By performing dilatation and internal rethrotomy for mild strictures, the success rate with mean follow-up of 27.5 months was 13.8% for BMG group and 78.9% for PSF. Only one patient from BMG developed temporary impotence for about 12 months. CONCLUSION: BMG and PSF are considered as simple and proper techniques with good long term outcomes in the management of diffuse anterior urethral strictures. These 2 techniques could be applied in patients with history of several surgeries. The results of BMG were better than PSF, still, this difference was not statistically significant.

Alterations in spontaneous contractions in vitro after repeated inflammation of rat distal colon.

In inflammatory bowel disease, smooth muscle function reportedly varies with disease duration. The aim of these studies was to determine changes in the control of spontaneous contractions in a model of experimental colitis that included reinflammation of the healed area. The amplitude and frequency of spontaneous contractions in circular smooth muscle were determined after intrarectal administration of trinitrobenzenesulfonic acid in rat distal colon. With the use of a novel paradigm, rats were studied 4 h (acute) or 28 days (healed) after the initial inflammation. At 28 days, rats were studied 4 h after a second inflammation (reinflamed) of the colon. Colitis induced transient increases in the amplitude of spontaneous contractions coincident with a loss of nitric oxide synthase activity. The frequency of contractions was controlled by constitutive nitric oxide in controls. Frequency was increased in healed and reinflamed colon and was associated with a shift in the dominance of neural constitutive nitric oxide synthase control to that of inducible nitric oxide synthase (iNOS). The initial colitis induced a remodeling of the neural control of spontaneous contractions reflecting changes in their regulation by constitutive nitric oxide synthase and iNOS.

Progressive alterations in circular smooth muscle contractility in TNBS-induced colitis in rats.

The present study was designed to investigate inflammation-induced changes in smooth muscle responses to acetylcholine and the tachykinins that may contribute to the abnormal motility associated with inflammatory bowel disease. Colitis was induced in male Sprague-Dawley rats by intrarectal administration of trinitrobenzenesulphonic acid in ethanol. After either 4 h (acute) or 7 days (chronic) the distal colon was taken for in vitro measurement of smooth muscle tension and histological assessment. Acute colitis featured injury and neutrophilic infiltration confined to the mucosa while chronic inflammation showed marked injury, lymphocytic infiltration and muscle thickening. Acute inflammation increased responses to substance P and acetylcholine but decreased responses to neurokinin A. The enhanced response to substance P was dependent on nerves, while the decreased response to neurokinin A reflected a reduction in activity at the level of the smooth muscle. In the saline group, there was evidence of cholinergic interaction with substance P, but not neurokinin A. Substance P modulation of cholinergic nerves was absent in acute inflammation. Responses to all neurotransmitters were decreased in the chronic stage. These data demonstrate progressive changes in the smooth muscle function during acute and chronic colitis that may contribute to the abnormal motility associated with inflammatory bowel disease.

Ethnic differences in the frequency distribution of serum cholinesterase activity.

We studied the activity of the enzyme pseudocholinesterase (serum cholinesterase) and its sensitivity to inhibition by dibucaine and fluoride in 400 (200 Iranian and 200 Irish) healthy subjects. The results show Irish subjects have significantly higher serum cholinesterase activity than Iranian subjects (7.82 +/- 0.14 vs 5.22 +/- 0.09 u/ml, mean +/- SEM, p < 0.01). Furthermore, the percent of inhibition of enzyme activity by dibucaine (82.19 +/- 0.68 vs 69.29 +/- 0.68) and fluoride (79.90 +/- 70.13 +/- 0.62) was also significantly higher (p < 0.001) in Irish than in Iranian subjects. One subject (Iranian) with very low pseudocholinesterase activity and a dibucaine number below 20 (atypical) had a history of apnoea following succinylcholine (suxamethonium). These data indicate that the frequency of atypical and heterozygote genes for cholinesterase activity leading to prolonged apnoea is much higher in Iranian than Irish populations. This study emphasises the importance of ethnic pharmacology.

Role of endotoxemia in cardiovascular dysfunction and lethality: virulent and nonvirulent Escherichia coli challenges in a canine model of septic shock.

We investigated whether the severity of septic shock is determined by virulence factors associated with or the levels of endotoxemia produced by two Escherichia coli strains. Canines were challenged intraperitoneally with an E. coli strain (O6:H1:K2) that has virulence factors associated with human disease or with an equal dose of a nonvirulent strain (O86:H8) that lacks these factors. Both strains were administered in viable, heat-killed, and purified endotoxin forms. Median survival times with the virulent strain compared with the nonvirulent strain were shorter with viable bacteria (5 x 10(10) CFU/kg) (144 h versus > 672 h; Wilcoxon, P = 0.03), longer with heat-killed bacteria (5 x 10(9) CFU/kg) ( > 676 h versus 26 h; P = 0.03), and similar with purified endotoxin (15 mg/kg) (28 h versus 48 h; P = 0.71). However, whether the challenge contained viable bacteria, heat-killed bacteria, or purified endotoxin, the virulent strain produced less endotoxemia (P = 0.001). Hence, the changing outcomes with differing forms of the two strains cannot be attributed solely to endotoxin levels. The viable virulent strain caused less endotoxemia but more harm, and this does not appear to be explained by a more potent endotoxin or other heat-stable component. This study suggests that circulating endotoxin levels per se are less important in the outcome of septic shock than virulence factors associated with E. coli strains. Furthermore, the data call into question the significance of the endotoxin concentration in the blood in predicting the severity of shock and the lethality of gram-negative infections.

Differential hemodynamic effects of L-NMMA in endotoxemic and normal dogs.

We studied the differential hemodynamic effects of N omega-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide (NO) synthesis, in normal and endotoxemic dogs and examined its activity across the venous, pulmonary, and systemic circulations. Survival was used to determine therapeutic efficacy. In both normal and endotoxemic animals, L-NMMA similarly increased systemic (P = 0.01) and pulmonary (P = 0.047) vascular resistance, marginally increased mean arterial pressure (P = 0.07), and decreased oxygen delivery (P = 0.01) compared with normal saline. In contrast, the effect of L-NMMA on mean pulmonary arterial pressure, central venous pressure, and pulmonary capillary wedge pressure was different in endotoxemic than in normal animals (P < 0.05), but this differential effect occurred > 6 h after endotoxin challenge. L-NMMA (1-10 mg.kg-1.h-1) did not significantly increase survival rates or times in endotoxemic animals, but the highest dose decreased survival times (P < 0.05). Thus the effect of L-NMMA was similar on the systemic arterial circulation in endotoxemic dogs compared with normal dogs but was increased in the venous and pulmonary vascular beds after endotoxin, suggesting that the induction of NO production was greater in low-resistance vessels. We were unable to show that nonselective inhibition of NO production was beneficial in endotoxemic dogs.

Therapeutic trial of reconstituted human high-density lipoprotein in a canine model of gram-negative septic shock.

In a controlled, randomized trial, the authors investigated the effects of reconstituted human high-density lipoprotein (R-HDL) on survival, endotoxemia, cytokine production and pathophysiologic and metabolic events in an animal model of gram-negative septic shock. At 0.5, 8 and 16 hr after implantation of a clot infected with Escherichia coli, canines received intravenous R-HDL (n = 13), control lipid (n = 7) or human serum albumin (HSA, n = 7) divided into three doses (0.3, 0.1 and 0.1 g/kg, respectively) at an hourly rate of 0.1 g/kg. All animals were treated with antibiotics and fluids. Animals treated with R-HDL had lower levels of circulating endotoxin and tumor necrosis factor and a smaller decrease in white blood cell counts than did animals treated with lipids and HSA (all P < .05). The survival times of lipid- and HSA-treated animals were similar (P = .3) and were significantly greater than those of R-HDL-treated animals (P = .02). During the first 6 hr after clot implantation, R-HDL-treated animals had significantly greater abnormalities in liver function test findings compared with lipid- and HSA-treated animals (all P < .05). For the first 24 hr, R-HDL-treated animals had significant increases in HDL levels; however, there were no significant relationships between these levels and the constituents of HDL (apolipoprotein AI and phosphatidylcholine) or liver function abnormalities and survival times (all r < .2, P > .3). In normal animals, administration of R-HDL (in similar doses) caused transient elevation of liver enzymes; in animals given sterile clot i.p., R-HDL caused seizures.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of dextroamphetamine and methylphenidate on calcium and magnesium concentration in hyperactive boys.

Levels of calcium in plasma, red blood cells, and mononuclear blood cells, levels of calcium in plasma, and the plasma calcium-to-magnesium ratio were measured at baseline and after 3 weeks of each drug phase of a double-blind, placebo-controlled study of methylphenidate and dextroamphetamine in hyperactive boys. Levels of magnesium in plasma were significantly higher after 3 weeks of dextroamphetamine treatment, and the calcium-to-magnesium ratio was significantly lower after 3 weeks of either drug compared with the baseline or placebo condition. There was no change in magnesium levels in red blood cells or mononuclear blood cells. These measures were obtained 30 minutes before the morning dose and at 9 a.m., 9:30 a.m., 10:30 a.m., 11:00 a.m., and noon on the last day of each 3-week phase. Analysis of variance revealed a drug effect on plasma magnesium and on the calcium-to-magnesium ratio but no drug x time interaction. Although these changes were not correlated with the time course of acute symptomatic response to stimulant therapy, the decrease in the ratio may be relevant to side effects and treatment resistance associated with stimulant use.

Erythrocyte and mononuclear blood cell magnesium concentrations are normal in hypomagnesemic patients with chronic renal magnesium wasting.

OBJECTIVE: The purpose of this study was to determine the plasma, erythrocyte, and mononuclear blood cell (MBC) magnesium concentrations in patients with chronic, severe hypomagnesemia due to a chronic magnesium-wasting tubulopathy. METHODOLOGY: Six patients with Bartter's syndrome and five patients with magnesium-wasting tubulopathy were compared with normal subjects. We determined magnesium in plasma, erythrocytes, and MBCs. RESULTS: Patients with chronic magnesium-wasting tubulopathy had a significantly lower plasma magnesium concentration than controls, but erythrocyte magnesium concentration and MBC magnesium concentration and content did not differ significantly between patients and controls. CONCLUSION: Two disorders with chronic magnesium-wasting tubulopathies are associated with a low plasma magnesium concentration but normal erythrocyte and MBC magnesium.

Endotoxemia in sudden infant death syndrome.

Endotoxemia has been proposed as a significant cause of Sudden Infant Death Syndrome (SIDS). We examined postmortem sera from left and right heart samples of 21 SIDS cases (1989 definition) and 23 controls. The controls were < 1 year of age and had died suddenly and unexpectedly of infection, abuse, suffocation, blunt injury, or fire and smoke inhalation. Endotoxin was measured without knowledge of the clinical status by using a kinetic modification of the chromogenic limulus amoebocyte lysate assay. The SIDS cases had insignificant concentrations of endotoxin in serum, whereas some of the controls who experienced blunt injury, abuse, or severe infection exhibited moderately elevated concentrations. Postmortem interval and postmortem blood culture results did not materially affect endotoxin concentrations. Thus, we conclude that endotoxemia is not a substantial pathophysiologic event in SIDS.

Magnesium measures across the menstrual cycle in premenstrual syndrome.

The purpose of this study was to evaluate blood magnesium (Mg) measures across the menstrual cycle in women with premenstrual syndrome (PMS) and control women. Longitudinal determinations of plasma, red blood cell (RBC) and mononuclear blood cell (MBC) Mg were made in 26 women with prospectively confirmed PMS and in a control group of 19 women. Data were analyzed using analysis of variance with repeated measures and Spearman rank correlations. Significant diagnostic group effects were observed for RBC and MBC Mg concentrations (p < 0.05). These effects reflected lower Mg concentrations in PMS patients at each sampling time. No significant effects were observed for either plasma Mg or MBC Mg content, nor were there significant time by diagnosis effects for any of the measures. Consistent with earlier studies, we found decreased RBC Mg concentrations and additionally observed decreased MBC Mg concentrations in women with PMS. However, neither of these relative deficits were confined to the luteal phase.

A controlled trial of HA-1A in a canine model of gram-negative septic shock.

OBJECTIVE: To investigate the therapeutic efficacy and microbiological and physiological effects of a human IgM monoclonal antibody (HA-1A) directed against the lipid A component of endotoxin in a canine model of sepsis that simulates the cardiovascular abnormalities of human septic shock. DESIGN: Blinded, placebo-controlled 28-day trial. INTERVENTIONS: Purpose-bred beagles were implanted with an intraperitoneal clot infected with Escherichia coli O111:B4. At clot placement, animals received HA-1A (10 mg.kg-1), control human IgM antibody (10 mg.kg-1), or control human serum albumin intravenously. All animals were given antibiotic and fluid therapy. MEASURES: Survival and microbiological and physiological events. RESULTS: Only two (15%) of 13 animals in the HA-1A group, compared with eight (57%) of 14 control animals (combined control human IgM antibody and control human serum albumin groups) (P = .05), survived 28 days. At 24 hours, the HA-1A group had lower mean arterial pressure (P = .04) and cardiac index (P = .004) and higher lactate levels (P = .05) compared with the combined-controls group. In addition, these parameters in the HA-1A group were significantly more predictive of death. The HA-1A and combined-controls groups had similar significant increases in the level of endotoxemia and bacteremia. Studies of toxic effects showed no harmful effects of control human IgM antibody in infected animals or HA-1A in non-infected animals. CONCLUSION: In a canine model of E coli sepsis, HA-1A did not alter levels of bacteremia or endotoxemia and actually decreased survival. If these data are relevant to human septic shock, HA-1A therapy should be limited until the conditions under which this monoclonal antibody has beneficial or deleterious effects are more completely defined.

N omega-amino-L-arginine, an inhibitor of nitric oxide synthase, raises vascular resistance but increases mortality rates in awake canines challenged with endotoxin.

Inhibitors of nitric oxide synthase (NOS) have been reported to increase mean arterial pressure in animal models of sepsis and recently have been given to patients in septic shock. However, controlled studies to determine the effects of these agents on cardiovascular function and survival in awake animal models of sepsis have not been reported. To examine the therapeutic potential of NOS inhibition in septic shock, we challenged canines with endotoxin (2 or 4 mg/kg i.v.) and treated them with either normal saline or N omega-amino-L-arginine (10 or 1 mg/kg/h), the most specific inhibitor available for the isoform of NOS implicated in septic shock. Endotoxemic animals treated with N omega-amino-L-arginine (n = 11) had higher systemic and pulmonary vascular resistance indices (SVRI and PVRI, p less than or equal to 0.033) and decreased heart rates (p = 0.009), cardiac indices (CI, p = 0.01), oxygen delivery indices (p = 0.027), and oxygen consumption indices (p = 0.046) compared with controls (n = 6). Moreover, N omega-amino-L-arginine increased mortality rates after endotoxin challenge (10 of 11 vs. 1 of 6 controls, p = 0.005). Administration of L-arginine did not improve survival or alter the cardiopulmonary effects of N omega-amino-L-arginine, which suggests that inhibition of NOS may not have been competitive. In normal animals, N omega-amino-L-arginine alone (n = 3) increased SVRI (p = 0.0008) and mean arterial pressure (p = 0.016), and decreased CI (p = 0.01) compared with saline-treated controls (n = 3), but, at the high dose, also produced neuromuscular rigidity and seizure-like activity that was not apparent in the endotoxemic model. Thus, the mortality rate from endotoxemia increased either because of NOS inhibition per se or because of properties unique to N omega-amino-L-arginine, or both.