Furosemide inhalation in dyspnea of mustard gas-exposed patients: a triple-blind randomized study

Dyspnea is the hallmark symptom of some respiratory diseases such as chronic obstructive pulmonary disease and bronchiolitis and is a major reason for which these patients seek medical attention. We performed a randomized triple-blind controlled crossover clinical trial in which we compared the efficacy of inhaled furosemide (4 ml equal to 40 mg in 10 min) with placebo (4 ml of 0.9% saline solution) in 41 mustard gas-exposed patients. Dyspnea index, visual analog scale (VAS), and pulmonary function test results were obtained before and 4 h after treatments. Results showed that both furosemide and placebo significantly decreased VAS and dyspnea index and increased FEV(1), FVC, and FEV(1)/FVC, while there was no difference between the two drugs in these effects (p values .23, .61, .81, .36, and .27, respectively). Our results failed to address the previously reported effects of inhaled furosemide on dyspnea. In fact, we suggest that patients with a previous exposure to sulfur mustard, in which chronic bronchitis and bronchiolitis are the most suggested underlying mechanisms, may not benefit from furosemide to alleviate their dyspnea.     

Inhaled corticosteroids and long-acting beta 2-agonists in treatment of patients with chronic bronchiolitis following exposure to sulfur mustard

We examined the role of two regimens of combination inhaler therapy on amount of reversibility of chronic lung complications in mustard gas exposed patients. In a phase III, prospective, randomized clinical trial, 105 participants received either combination form of fluticasone propionate and salmetrol, 500/100 microg daily (group 1; n = 52) or beclomethasone, 1000 microg daily, and salbutamol inhaler, 800 microg daily (group 2; n = 53) for 12 wk. Pulmonary function test (PFT) indices and respiratory symptoms (including dyspnea, night awakening due to dyspnea and cough) were assessed at baseline and in each visit. Thirty-six patients in group 1 and 30 patients in group 2 completed study course. Both medication regimes increased pretreatment forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC%, and peak expiratory force (PEF) by the end of 12 wk. It seems that these improvements are more constant in group 1 than in group 2. Reversibility, that is, 10% increase of FEV1 in the second month was seen for 27% of patients in the group 1 and for 7% in the group 2. VAS scores have decreased in two groups during treatment period (p = .003) and after follow-up period it remained sustained in group 1 alone. Inhaled corticosteroids and long-acting beta 2-agonists are effective in treatment of patients with chronic bronchiolitis following exposure to sulfur mustard. However, a medium dose of fluticasone/salmeterol has the same effect on the airways reversibility, rather than a very high dose of beclomethasone with only the short-acting beta-agonist.     

Acute and chronic effects of sulfur mustard on the skin: a comprehensive review

Sulfur mustard (2,2-dichlorodiethyl sulfide, SM) is one of the vesicant classes of chemical warfare agents that causes blistering in the skin and mucous membranes, where it can have lingering long-term effects for up to ten years (1). SM was employed extensively by the Iraqi army against not only Iranian soldiers but also civilians between 1983 and 1988, resulting in over 100,000 chemical casualties. Approximately 45,000 victims are still suffering from long-term effects of exposure (2,3). More than 90% of the patients exposed to SM exhibit various cutaneous lesions in the affected area. The human skin can absorb approximately 20% of the SM through exposure. Up to 70% of the chemical is concentrated in the epidermis and the remainder in the basement membrane and in the dermis (4).Sulfur mustard exists in different physical states. The liquid form of SM evaporates slowly in cold weather and can penetrate through the clothing, thereby increasing exposure. However, the gas form readily diffuses in the air and it can be inhaled, leading to systemic absorption. In addition, warm temperatures are ideal conditions that liquid SM present in the clothing of the exposed individual could be converted to gas form. SM-induced clinical cutaneous symptoms include itching and burning. Other clinical findings include erythema or painless sunburn, bulla, hypo- and hyper pigmentation in both exposed and unexposed areas (5,6) The mechanism and biochemical cascade of SM-induced cutaneous manifestations are not completely understood but several published pathways support many of the know facts. Our current understanding fails to explain the time interval between the acute chemical exposure and the late-onset and delayed tissue damage (7,8). The aim of this article is to review the acute and long-term cutaneous findings resulting from SM exposure. Also, cellular and molecular mechanism involved in SM-induced skin pathology have been discussed.     

Conjunctival microbial florae in patients with seriously sulfur mustard induced eye injuries

Introduction: Ocular surface disorders and infections in sulfur mustard (SM) exposed patients are of particular clinical importance. The aim of the present study is to detect the conjunctival bacterial florae in patients with seriously SM induced eye injuries.

Materials and methods: Conjunctival bacterial florae of 143 seriously eye injured subjects as the study group was detected. The results were compared with 26 normal participants. Both groups were matched in age and sex. The samples were taken by sterile swab from interior fornixes of conjunctiva in both groups and were transported to microbiology laboratory by Stuart’s Transport Medium. All samples were inoculated onto Blood agar, Mac Conkey agar and Chocolate agar and isolated microorganisms were identified by biochemical tests. The data were analyzed by SPSS and Man Whitney tests.

Results: Nineteen cases (13.39%) and none of the controls (0%) had positive culture results (p = .043). Isolated microorganisms from patients included coagulase-negative staphylococci 10 cases (52.6%), Staphylococcus aureus 5 cases (26.3%), non enterobacteriaceae gram negative bacilli 2 cases (10.5%), Penicillium spp. 2 cases (10.5%), Citrobacter sp. 1 case (5.2%), non-spore forming Gram positive bacillus 1 case (5.2%) and α hemolytic streptococcus 1 case (5.2%). Two patients had mixed microorganisms and other patients had just one microorganism. Most of the S. aureus isolates were sensitive to usual antibiotics.

Conclusions: The results of this study showed that the prevalence rate of conjunctival bacterial isolates in patients with seriously SM induced ocular injuries are higher and potentially more dangerous than normal controls.     

Amelioration of sulfur mustard skin injury following a topical treatment with a mixture of a steroid and a NSAID

The ability to ameliorate sulfur mustard (HD)-induced oedema by treatment with anti-inflammatory drugs was reported previously after screening four steroids and four non-steroidal anti-inflammatory drugs (NSAIDs) using the mouse ear vesicant model. Following the screening study, one steroid and one NSAID (Adexone and Voltaren) were selected as the most effective, and a mixture of the two was chosen for the present more extensive research. The effect of the combined treatment on clinical, biochemical and histopathological parameters following HD insult was studied. Mice ears were exposed to 0.2 micro l of HD for 10 min to produce a moderate skin injury. Oedema development peaked ca. 48 h following exposure, as determined by weighing ear biopsies. Histological observations at that time exhibited damage to the epidermis and dermis. An increase in prostaglandin E (PGE) was measured in skin homogenates, starting 8 h following exposure and lasting at least up to 48 h post-exposure. A topical treatment using the above anti-inflammatory mixture significantly reduced inflammatory parameters when applied up to 4 h following exposure. These parameters included extent of oedema, levels of PGE, area of clinical damage and extent of cytotoxic injury (vesications and damaged epithelial cells). Thus, a combination of a steroid and NSAID was found to be effective in reducing the intensity of HD skin injury and possibly shortening the time to full recovery. The treatment, however, did not prevent completely the ensuing cytotoxic processes in the epithelial layer.     

Exposure to hookworms in patients with Crohn's disease: a case-control study

Aliment Pharmacol Ther 2011; 34: 923–930

Summary

Background Helminths have been used to inhibit intestinal inflammation in patients with Crohn’s disease. Aim This study was undertaken to determine if there is a protective association of prior hookworm infection with Crohn’s disease, in a region where there is epidemiological transition from parasitic and infectious diseases to increased auto‐inflammatory diseases. Methods Hookworm exposure was assessed by peripheral blood mononuclear cell (PBMC) activation by hookworm antigens in 78 patients with Crohn’s disease and 75 healthy control participants. The change in proportion of T cells exhibiting CD69 after exposure to crude hookworm antigens was measured. Interferon‐γ ELISPOT response to a panel of six recombinant hookworm antigens was analysed. Results Patients with Crohn’s disease were more often from an urban background (P = 0.005) compared to controls, while their socioeconomic status was not significantly different. T cell activation (increase in CD3⁺CD69⁺ population) by hookworm antigen was significantly higher in controls compared to Crohn’s disease patients (P = 0.017), while activation by the nonspecific mitogen phytohemagglutinin was similar in both groups. Circulating T memory cells (CD3⁺CD45RO⁺) after exposure to hookworm antigens were not significantly different between the two groups. Mirroring these changes, interferon‐γ ELISPOT responses to hookworm antigens were seen in 36 of 75 controls compared to 20 of 78 Crohn’s disease patients (Fisher’s exact P = 0.005). Multivariate analysis indicated that CD3CD69 shifts (P = 0.019), ELISPOT reactivity (P = 0.039) and place of residence (P = 0.024) were all independently associated with Crohn’s disease. Conclusion The inverse association between Crohn’s disease and hookworm antigen reactivity is consistent with the hygiene hypothesis, but requires further exploration.     

慢性咳嗽82例的病因程序分析

目的探讨胸片正常的慢性咳嗽患者的病因分布及诊断。方法选择2006年5月-2007年4月，82例持续咳嗽8周以上到我院呼吸科就诊的病人，采用Irwin的慢性咳嗽解剖学诊断程序进行病因初步诊断，并通过针对性治疗予以证实。结果82例慢性咳嗽患者中确诊76例，确诊率92．6％。其中咳嗽变异型哮喘31例，占40．7％；鼻后滴漏综合征22例，占28．9％；胃食管反流性疾病14例，占18.4％；嗜酸性粒细胞支气管炎3例，占3．9％；病因未明6例，占7．8％；结论Irwin的慢性咳嗽解剖诊断程序是诊断慢性咳嗽的重要手段。上述是慢性咳嗽的常见病因，针对咳嗽病因的特异性治疗有效，是确诊病因的重要环节。     

Low serum HBV DNA levels and development of hepatocellular carcinoma in patients with chronic hepatitis B: a case-control study

AIM: To investigate the level of hepatitis B virus (HBV) DNA in Chinese chronic hepatitis B (CHB) patients below which hepatocellular carcinoma (HCC) is unlikely to occur. METHODS: A total of 92 CHB patients diagnosed with HCC were recruited; 184 CHB patients without HCC, matched for age, sex and HBeAg status were included as controls. HBV DNA levels were performed at the time of HCC development and at the same age time points for control group. RESULTS: The median HBV DNA level in HCC patients was 1.7 x 10(6) copies/mL compared with 2.2 x 10(5) copies/mL in controls (P = 0.006). In HCC patients, 21 (22.8%) were HBeAg(+), with no significant difference in HBV DNA levels compared with controls. Seventy-one (77%) HCC patients were HBeAg(-) with median HBV DNA level of 3.2 x 10(5) copies/mL, compared with 6.0 x 10(4) copies/mL in controls (P = 0.006). In HBeAg(-) patients, the control group had significantly greater proportion of patients having HBV DNA levels <10(5) and <10(4) copies/mL compared with HCC patients. Fifteen per cent of all HCC patients had HBV DNA levels <10(3) copies/mL. CONCLUSIONS: In HBeAg(+) patients, HBV DNA levels were high in both HCC and control patients. In HBeAg(-) patients, HCC was more likely to develop in patients with HBV DNA level >10(4) copies/mL. However, 15% of the patients with HCC had HBV DNA levels <10(3) copies/mL.     

Role of oxidative stress and antioxidant therapy in acute and chronic phases of sulfur mustard injuries: a review

Sulfur mustard (SM) is a chemical compound that preferentially targets ocular, cutaneous and pulmonary tissues. Although pathologic effect of SM has been extensively considered, molecular and cellular mechanism of its toxicity, especially at the chronic phase of injury is not well-understood. Excessive production of reactive oxygen species (ROS) and oxidative stress (OS) appears to be involved in SM-induced injuries. SM may trigger several molecular and cellular pathways linked to OS and inflammation that can subsequently result in cell death and apoptosis. At the acute phase of injury, SM can enhance ROS production and OS by reducing the activity of antioxidants, depletion of intercellular glutathione (GSH), decreasing the productivity of GSH-dependent antioxidants, mitochondrial deficiency, accumulation of leukocytes and pro-inflammatory cytokines. Overexpression of ROS producing enzymes and down-regulation of antioxidant enzymes are probably the major events by which SM leads to OS at the chronic phase of injury. Therefore, antioxidant therapy with potent antioxidants such as N-acetylcysteine and curcumin may be helpful to mitigate SM-induced OS damages. This review aims to discuss the proposed cellular and molecular mechanisms of acute and delayed SM toxicity, the importance of OS and mechanisms by which SM increases OS either at the acute or chronic phases of injuries along with research on antioxidant therapy as a suitable antidote.     

Efficacy of Aloe vera/olive oil cream versus betamethasone cream for chronic skin lesions following sulfur mustard exposure: a randomized double-blind clinical trial

Background: Chronic pruritic skin lesions are among the common late complications of sulfur mustard intoxication. In the present randomized double-blind clinical trial, therapeutic efficacy of Aloe vera/olive oil combination cream in the alleviation of these lesions was evaluated and compared to that of betamethasone 0.1% cream.

Methods: Sixty-seven Iranian chemical warfare-injured veterans were randomized to apply A. vera/olive oil (n?=?34, completers?=?31) or betamethasone 0.1% (n?=?33, completers?=?32) cream twice daily for 6 weeks. Evaluation of pruritus severity was performed using a pruritic score questionnaire and visual analogue scale (VAS).

Results: Both treatments were associated with significant reductions in the frequency of pruritus (p?<?0.05), burning sensation (p?<?0.01 and p?<?0.001 in A. vera/olive oil and betamethasone group, respectively), scaling (p?<?0.01 and p?<?0.05) and dry skin (p?<?0.001) at the end of trial. Fissure and excoriation were only reduced in the A. vera group (p?<?0.05). The change in the frequency of hyper- and hypopigmentation lesions, blisters, erythema and lichenification did not reach statistical significance in any of the groups (p?>?0.05). Mean pruritus (p?<?0.05) and VAS scores (p?<?0.01 and p?<?0.05) were significantly decreased by the end of trial in both groups. The rate of improvement in the pruritus severity [defined as being classified in a less severe category (mild, moderate and severe)] was found to be comparable between the groups (p?>?0.05).

Conclusion: A. vera/olive oil cream was at least as effective as betamethasone 0.1% in the treatment of sulfur mustard-induced chronic skin complications and might serve as a promising therapeutic option for the alleviation of symptoms in mustard gas-exposed patients.     

Endothelial cell damage following sulfur mustard exposure in rabbits and its association with the delayed-onset ocular lesions

Objective: Ocular injuries following exposure to the toxic agent sulfur mustard (SM) are characterized by acute corneal erosions and inflammation of the anterior segment that may be followed by delayed corneal injuries, expressed clinically by neovascularization and epithelial defects. The present study aimed to investigate the effects of SM on corneal endothelium (CE) during the acute and delayed phase in relation to the development of the long-term pathology.

Methods: Rabbit eyes were exposed to SM vapor. A clinical follow-up including pachymetry for measurement of corneal thickness were conducted up to 3 months following exposure. In vivo analysis of corneal endothelium in the central and peripheral cornea was carried out, using a contact specular microscopy. orphometric analysis of cell area and number of cells was performed, to include the acute and delayed phases. Eyes were taken for histology at different time points following exposure (1?h to 3 months). TUNEL staining (Terminal deoxynucleotidyl transferase dUTP nick end labeling) was conducted for detection of apoptosis during the acute phase.

Results: SM induced acute corneal erosions and prolonged anterior segment inflammation. Corneal thickness increased within hours, declined after few days but remained higher compared to baseline value for months after the exposure, indicating a chronic edema. Apoptotic alterations were first observed at 6?h resulting in a significant decline in the number of endothelial cells at 24–48?h following exposure. Healing of the endothelium was relatively fast and at one week the Descemet’s membrane was resurfaced, yet, the density and morphology of the cells was often abnormal. Moreover, histological evaluation revealed deformation and enlargement of many cells (polymegathism and pleomorphism), thickening and double layered Descemet’s membrane. These changes were more pronounced in corneas displaying delayed pathology.

Discussion and conclusions: SM induced apoptotic cell death of endothelial cells that was accompanied by corneal edema. The impaired healing of the endothelium, including the decrease in endothelial cell density was associated with the delayed-onset injuries. Since human corneal endothelium is almost amitotic, endothelium toxicity should be taken into consideration when testing potential treatments against ocular injuries following SM exposure.     

Improved diagnosis of gastro-oesophageal reflux in patients with unexplained chronic cough

BACKGROUND: Symptoms, oesophageal pHmetry and proton pump inhibitor treatment are used for diagnosing gastro-oesophageal reflux-related cough. Weakly acidic reflux is now increasingly associated with reflux symptoms such as regurgitation or chest pain. AIM: To study the association between weakly acidic reflux and cough in a selected, large group of patients with unexplained chronic cough. METHODS: A total of 100 patients with chronic cough (77 'off' and 23 'on' a proton pump inhibitor) were studied using impedance-pHmetry for reflux detection and manometry for objective cough monitoring. Symptom Association Probability (SAP) Analysis characterized the reflux-cough association. RESULTS: Acid reflux could be a potential mechanism for cough in 45 patients (with either heartburn, high acid exposure or +SAP for acid reflux). Weakly acidic reflux could be a potential mechanism for cough in 24 patients (with either increased oesophageal volume exposure, increased number of weakly acidic reflux or +SAP for weakly acidic reflux). Reflux could not be identified as a potential mechanism for cough in 31 patients. CONCLUSION: A positive association between cough and weakly acidic reflux was found in a significant subgroup of patients with unexplained chronic cough. Impedance-pH-manometry identified patients in whom cough can be related to reflux that would have been disregarded using the standard diagnostic criteria for acid reflux.     

Risk factors in patients with herpes zoster infections: case-control study

The aim of this study was to determine the prevalence of chronic disease and the risk factors for herpes zoster infection. In this case-control study medical records were collected from 55 patients who presented with herpes zoster and 54 patients in a control group who presented with gastroenterocolitis. Both groups were treated at the Clinic for Infectious Diseases, University Clinical Hospital Mostar from January, 2005 to December, 2010. When we compared the herpes zoster group with the control group, we did not demonstrate any significant difference in the overall prevalence of chronic diseases. However, the prevalence of diabetes and cancer was statistically higher when compared to the control group. A statistically significant difference in the number of cigarette smokers was not observed, whereas the number who consumed alcohol in the herpes zoster group was significantly higher compared to the control group. The correlation between alcohol and herpes zoster could help in solving the reactivation mechanism of VZV.     

Differential cholinergic regulation in Alzheimer's patients compared to controls following chronic blockade with scopolamine: a SPECT study

The effects of low-dose chronic scopolamine on measures of cerebral perfusion and muscarinic receptors were tested in eight Alzheimer's disease (AD) subjects and eight elderly controls. Single photon emission computed tomography (SPECT) scans using technetium-labelled hexamethypropylene amine oxide (^99mTc-HMPAO) to measure cerebral perfusion before and after chronic scopolamine revealed a significant 12% increase in the normal controls (P<0.01) while the AD subjects showed no significant change. In contrast, the controls showed decreased muscarinic binding as evidenced by¹²³I-quinuclidinyl-4-iodobenzilate (¹²³I-QNB) labelling after chronic drug (–10%,P<0.01) whereas the AD subjects showed increased¹²³I-QNB labelling (+8%,P<0.05). The difference between AD and control subjects was even more marked when the ratio of I-QNB to HMPAO uptake was compared, pointing to a double dissociation in the SPECT results. These data cannot be explained by group differences in cerebral perfusion alone and suggest a differential sensitivity between AD and elderly controls to chronic cholinergic blockade.     

非瓣膜性心房颤动患者血管性痴呆危险因素的病例对照研究

目的 探讨非瓣膜性心房颤动（房颤）患者血管性痴呆的危险因素,评估不同抗凝药物与心房颤动患者发生血管性痴呆的关系。方法 采用病例对照研究,选取血管性痴呆的非瓣膜性房颤患者66例（病例组）。对照组为未患血管性痴呆的非瓣膜性房颤患者132例。比较2组患者年龄、性别、体质量指数（BMI）、教育水平、吸烟等一般情况以及糖尿病、高...     

Reactions of sulfides with S-330, a potential decontaminant of sulfur mustard in formulations

Because the vesicant sulfur mustard (HD) remains a major chemical threat from either domestic terrorists or countries in conflict, topical preparations are being evaluated as protectants from HD exposure. The objective of this study was to evaluate the effectiveness of chloroamide S-330 as a potential reactive component in topical formulations. Therefore, the rate, mechanism and by-products of the oxidation reactions of sulfides by S-330 in solvent media or specific formulation vehicles were investigated. Using NMR, LC, LC-MS and GC-MS, the reactions of S-330 with HD, dibutyl sulfide (DBS) and methyl phenyl sulfide (MPS) were studied in acetonitrile, chloroform and perfluoropolyether (PFPE) oil. The oxidation of the three sulfides with S-330 was very rapid and completed in <4 min in acetonitrile-water or PFPE oil, but the rates of reaction in chloroform were significantly slower. In a large excess of S-330, the major products resulted from chlorination of the side chains. At a high HD/S-330 ratio, the major product was HD sulfoxide. Under both conditions, only a trace of HD sulfone, also a blistering agent, was observed. Reactions with DBS and MPS primarily gave sulfoxides and sulfones, with less side-chain chlorination. The chloroamide S-330 appeared to be a rapid and effective decontaminant of HD in either polar media or in a PFPE oil. The two alkyl and aryl sulfides are suitable simulants of HD for the initial screening and evaluation of S-330 or other similar oxidizing agents.