Identification of tyrosine brominated extracellular matrix proteins in normal and fibrotic lung tissues.

Peroxidasin (PXDN) is a secreted heme peroxidase that catalyzes the oxidative crosslinking of collagen IV within the extracellular matrix (ECM) via intermediate hypobromous acid (HOBr) synthesis from hydrogen peroxide and bromide, but recent findings have also suggested alternative ECM protein modifications by PXDN, including incorporation of bromide into tyrosine residues. In this work, we sought to identify the major target proteins for tyrosine bromination by HOBr or by PXDN-mediated oxidation in ECM from mouse teratocarcinoma PFHR9 cells. We detected 61 bromotyrosine (BrY)-containing peptides representing 23 proteins in HOBr-modified ECM from PFHR9 cells, among which laminins displayed the most prominent bromotyrosine incorporation. Moreover, we also found that laminin α1, laminin ß1, and tubulointerstitial nephritis antigen-like (TINAGL1) contained BrY in untreated PFHR9 cells, which depended on PXDN. We extended these analyses to lung tissues from both healthy mice and mice with experimental lung fibrosis, and in lung tissues obtained from human subjects. Analysis of ECM-enriched mouse lung tissue extracts showed that 83 ECM proteins were elevated in bleomycin-induced fibrosis, which included various collagens and laminins, and PXDN. Similarly, mRNA and protein expression of PXDN and laminin α/ß1 were enhanced in fibrotic mouse lung tissues, and also in mouse bone-marrow-derived macrophages or human fibroblasts stimulated with transforming growth factor ß1, a profibrotic growth factor. We identified 11 BrY-containing ECM proteins, including collagen IV α2, collagen VI α1, TINAGL1, and various laminins, in both healthy and mouse fibrotic lung tissues, although the relative extent of tyrosine bromination of laminins was not significantly increased during fibrosis. Finally, we also identified 7 BrY-containing ECM proteins in human lung tissues, again including collagen IV α2, collagen VI α1, and TINAGL1. Altogether, this work demonstrates the presence of several bromotyrosine-modified ECM proteins, likely involving PXDN, even in normal lung tissues, suggesting a potential biological function for these modifications.

Bromide toxicosis (bromism) secondary to a decreased chloride intake after dietary transition in a dog with idiopathic epilepsy: a case report.

BACKGROUND: Bromide is a halide ion of the element bromine usually administered in the form of potassium salt as monotherapy or add-on treatment in epileptic dogs. It is excreted unchanged in the urine and undergoes tubular reabsorption in competition with chloride. Thus, dietary chloride content affects serum bromide concentrations. This is the first published clinical report of bromide toxicosis secondary to a dietary modification of chloride content in an epileptic dog treated with potassium bromide. CASE PRESENTATION: A 3-year-old 55-kg neutered male Tibetan Mastiff was evaluated because of a 1-month history of progressive signs including ataxia, lethargy and behaviour changes. The dog was successfully treated for idiopathic epilepsy since the age of 1-year-old with phenobarbital and potassium bromide. Two months prior to presentation, the owners decided to change the dog's diet without veterinary advice. Physical examination was unremarkable. A 12-kg weight gain was recorded since last follow-up (8 months). Neurological examination revealed severe symmetric 4-limbs ataxia with altered vigilance and intermittent episodes of hyperactivity and aggressive behaviour without significant abnormality of cranial nerves. Serum bromide concentration was high and increased by 103 % since last follow-up. Nutritional evaluation revealed a 53 % decrease of chloride content in the diet before and after dietary transition. Bromide toxicosis was suspected, due to bromide reduced clearance secondary to the decreased dietary chloride content. Potassium bromide treatment was lowered by 15 % without further dietary changes. Neurologic signs progressively improved over the next month, without any seizure. After two months, the serum bromide concentration lowered to the same level measured before dietary modification. After four months, neurological examination was unremarkable. CONCLUSIONS: Dietary chloride content can directly influence serum bromide concentrations, therefore affecting seizure control or contributing to unexpected adverse effects. In the present case, a reduction in chloride intake markedly increased serum bromide concentrations causing bromism. Dietary changes should be avoided in dogs treated with potassium bromide to maintain stable serum bromide levels.

Disseminated vegetating infantile bromoderma: A dramatic response to systemic steroids.

Bromoderma is a rare hypersensitivity reaction caused by bromide intake. It was relatively frequent in the early years of the previous century because of the common use of bromide-containing solutions in pediatrics due to their antispasmodic, expectorant, sedative, and anticonvulsant effects. Although recently prohibited in many countries, bromides are still used as an adjuvant anticonvulsant drug and still present in some over the counter antispasmodics and analgesics. Bromoderma usually present with pustular and vegetating lesions that may represent a diagnostic challenge for dermatologists. We describe a severe case of vegetating bromoderma that showed an excellent response to the withdrawal of the bromide-containing medication associated with systemic steroid administration.

Potassium Bromide in the Treatment of Pediatric Refractory Epilepsy.

OBJECTIVE: We evaluated potassium bromide's (KBr's) efficacy and tolerability for pediatric refractory epilepsy. METHODS: We retrospectively reviewed the records of 42 patients treated with KBr in our hospital between 2008 and 2016 (age: 4 months to 19 years; mean: 6.2 years). Thirteen of them had 2 seizure types. The treatment durations ranged from 1 month to 6 years (mean: 15.0 months). RESULTS: KBr had an excellent effect (seizure-free status) in 3 patients (7.1%), a moderate effect (>50% reduction in seizure frequency from the pretreatment baseline) in 21 patients (50.0%), and no effect (<50% reduction in seizure frequency from the pretreatment baseline) in 18 patients (42.9%). The effective daily doses ranged from 20 to 80 mg/kg (mean: 50.0 mg/kg). KBr was effective in 59.1% patients with generalized epilepsy (n = 22), 55.6% patients with focal epilepsy (n = 18), and both patients with Dravet syndrome. An excellent or moderate effect was found in 72.2% patients with tonic seizures (n = 18), 66.6% patients with generalized tonic-clonic seizures (n = 6), 75.0% patients with secondary generalized seizures (n = 4), 46.2% patients with focal seizures (n = 13), and 20% patients with infantile spasms (n = 10) but no patients with myoclonic seizures (n = 2). Adverse effects including drowsiness, excitement, and rashes were reported in 13 patients (31.0%). CONCLUSIONS: These findings suggest that KBr is particularly effective for tonic seizures, generalized tonic-clonic seizures, and secondary generalized seizures. Although the adverse effects need further attention, KBr should be considered for pediatric refractory epilepsy.

Environmental exposure of humans to bromide in the Dead Sea area: Measurement of genotoxicy and apoptosis biomarkers.

Bromide (Br-) is a bromine atom with a negative charge which is released mainly in the production of pesticides and flame retardants. It is also found naturally in seawater. Br¯ has been associated with many detrimental effects such as respiratory problems, gastric hemorrhages, and dermal burns. The aim of the study was to monitor serum bromide in humans and to correlate its level with genotoxicity and apoptosis in human. The study utilized comet assay, to measure DNA damage in peripheral leukocytes (i.e. T%DNA), enzyme-linked immunosorbent assay were used to determine fortilin level as an apoptosis marker, and spectrophotometry to measure serum Br¯ in two populations at the Dead Sea area, which are located close to and far from a local bromine factory: Ghor As-safi and Deir Alla, respectively. The biomarkers were compared with the correlating serum Br¯. A total of 397 individuals were involved in the study. The serum Br- and the genotoxicity biomarker were significantly higher (p < 0.001) in Ghor As-safi than in Deir Alla. In contrast, serum fortilin did not differ significantly between the two regions (p > 0.05). T%DNA was significantly correlated (r = 0.867, p < 0.01) to serum Br¯. In conclusion, residing near a bromide source site is increasing the bromide body burden, and enhancing genotoxicity with no detectible apoptosis. Furthermore, the selected biomarkers could serve as tools to assess the toxicity of bromide as a consequence of environmental exposure.

Spurious Hyperchloremia in the Presence of Elevated Plasma Salicylate: A Cohort Study.

BACKGROUND: Acute metabolic acidosis is rarely associated with a reduced or negative anion gap (AG), but several case reports have described such an abnormality occurring in the setting of acute salicylate intoxication. The underlying cause of this phenomenon is unclear. METHODS: In this retrospective cohort study, we reviewed our institutional database to identify all patients admitted for salicylate intoxication at Mayo Clinic (Rochester, MN, USA) from January 2010 through December 2012. Serum chloride was measured with the Cobas INTEGRA 400 plus electrode (expedited laboratory test) or Cobas 6000 (routine laboratory test). We compared blood chloride levels measured by the 2 devices in the presence of positive blood salicylate level. RESULTS: Twelve adult patients with salicylate levels >20 mg/dL had markedly elevated chloride concentrations. The median (interquartile range) chloride level at admission was 120 (107-145) mmol/L on their initial laboratory studies, resulting in reduced or even negative AGs. None of the patients had bromide toxicity, nor did they have any other identifiable cause of hyperchloremia or decreased AG. Further testing of the same blood samples with an alternative measurement system (Roche Cobas 6000) yielded normal chloride values, indicating that falsely elevated chloride values with the initial testing led to the diminished or negative AG values. CONCLUSION: Circulating levels of salicylate can interfere with chloride measured by using routine techniques, resulting in spurious hyperchloremia outcomes and erroneous AG values. In patients with acute metabolic acidosis and abnormally reduced or negative AG, salicylate interference with chloride measurement should be suspected.

Bromide supplementation exacerbated the renal dysfunction, injury and fibrosis in a mouse model of Alport syndrome.

A seminal study recently demonstrated that bromide (Br-) has a critical function in the assembly of type IV collagen in basement membrane (BM), and suggested that Br- supplementation has therapeutic potential for BM diseases. Because salts of bromide (KBr and NaBr) have been used as antiepileptic drugs for several decades, repositioning of Br- for BM diseases is probable. However, the effects of Br- on glomerular basement membrane (GBM) disease such as Alport syndrome (AS) and its impact on the kidney are still unknown. In this study, we administered daily for 16 weeks 75 mg/kg or 250 mg/kg (within clinical dosage) NaBr or NaCl (control) via drinking water to 6-week-old AS mice (mouse model of X-linked AS). Treatment with 75 mg/kg NaBr had no effect on AS progression. Surprisingly, compared with 250 mg/kg NaCl, 250 mg/kg NaBr exacerbated the progressive proteinuria and increased the serum creatinine and blood urea nitrogen in AS mice. Histological analysis revealed that glomerular injury, renal inflammation and fibrosis were exacerbated in mice treated with 250 mg/kg NaBr compared with NaCl. The expressions of renal injury markers (Lcn2, Lysozyme), matrix metalloproteinase (Mmp-12), pro-inflammatory cytokines (Il-6, Il-8, Tnf-α, Il-1ß) and pro-fibrotic genes (Tgf-ß, Col1a1, α-Sma) were also exacerbated by 250 mg/kg NaBr treatment. Notably, the exacerbating effects of Br- were not observed in wild-type mice. These findings suggest that Br- supplementation needs to be carefully evaluated for real positive health benefits and for the absence of adverse side effects especially in GBM diseases such as AS.

Umeclidinium bromide versus placebo for people with chronic obstructive pulmonary disease (COPD).

BACKGROUND: People with chronic obstructive pulmonary disease (COPD) have poor quality of life, reduced survival, and accelerated decline in lung function, especially associated with acute exacerbations, leading to high healthcare costs. Long-acting bronchodilators are the mainstay of treatment for symptomatic improvement, and umeclidinium is one of the new long-acting muscarinic antagonists approved for treatment of patients with stable COPD. OBJECTIVES: To assess the efficacy and safety of umeclidinium bromide versus placebo for people with stable COPD. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register (CAGR), ClinicalTrials.gov, the World Health Organization (WHO) trials portal, and the GlaxoSmithKline (GSK) Clinical Study Register, using prespecified terms, as well as the reference lists of all identified studies. Searches are current to April 2017. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of parallel design comparing umeclidinium bromide versus placebo in people with COPD, for at least 12 weeks. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. If we noted significant heterogeneity in the meta-analyses, we subgrouped studies by umeclidinium dose. MAIN RESULTS: We included four studies of 12 to 52 weeks' duration, involving 3798 participants with COPD. Mean age of participants ranged from 60.1 to 64.6 years; most were males with baseline mean smoking pack-years of 39.2 to 52.3. They had moderate to severe COPD and baseline mean post-bronchodilator forced expiratory volume in one second (FEV1) ranging from 44.5% to 55.1% of predicted normal. As all studies were systematically conducted according to prespecified protocols, we assessed risk of selection, performance, detection, attrition, and reporting biases as low.Compared with those given placebo, participants in the umeclidinium group had a lesser likelihood of developing moderate exacerbations requiring a short course of steroids, antibiotics, or both (odds ratio (OR) 0.61, 95% confidence interval (CI) 0.46 to 0.80; four studies, N = 1922; GRADE: high), but not specifically requiring hospitalisations due to severe exacerbations (OR 0.86, 95% CI 0.25 to 2.92; four studies, N = 1922, GRADE: low). The number needed to treat for an additional beneficial outcome (NNTB) to prevent an acute exacerbation requiring steroids, antibiotics, or both was 18 (95% CI 13 to 37). Quality of life was better in the umeclidinium group (mean difference (MD) -4.79, 95% CI -8.84 to -0.75; three studies, N = 1119), and these participants had a significantly higher chance of achieving a minimal clinically important difference of at least four units in St George's Respiratory Questionnaire (SGRQ) total score compared with those in the placebo group (OR 1.45, 95% CI 1.16 to 1.82; three studies, N = 1397; GRADE: moderate). The NNTB to achieve one person with a clinically meaningful improvement was 11 (95% CI 7 to 29). The likelihood of all-cause mortality, non-fatal serious adverse events (OR 1.33; 95% CI 0.89 to 2.00; four studies, N = 1922, GRADE: moderate), and adverse events (OR 1.06, 95% CI 0.85 to 1.31; four studies, N = 1922; GRADE: moderate) did not differ between umeclidinium and placebo groups. The umeclidinium group demonstrated significantly greater improvement in change from baseline in trough FEV1 compared with the placebo group (MD 0.14, 95% CI 0.12 to 0.17; four studies, N = 1381; GRADE: high). Symptomatic improvement was more likely in the umeclidinium group than in the placebo group, as determined by Transitional Dyspnoea Index (TDI) focal score (MD 0.76, 95% CI 0.43 to 1.09; three studies, N = 1193), and the chance of achieving a minimal clinically important difference of at least one unit improvement was significantly higher with umeclidinium than with placebo (OR 1.71, 95% CI 1.37 to 2.15; three studies, N = 1141; GRADE: high). The NNTB to attain one person with clinically important symptomatic improvement was 8 (95% CI 5 to 14). The likelihood of rescue medication usage (change from baseline in the number of puffs per day) was significantly less for the umeclidinium group than for the placebo group (MD -0.45, 95% CI -0.76 to -0.14; four studies, N = 1531). AUTHORS' CONCLUSIONS: Umeclidinium reduced acute exacerbations requiring steroids, antibiotics, or both, although no evidence suggests that it decreased the risk of hospital admission due to exacerbations. Moreover, umeclidinium demonstrated significant improvement in quality of life, lung function, and symptoms, along with lesser use of rescue medications. Studies reported no differences in adverse events, non-fatal serious adverse events, or mortality between umeclidinium and placebo groups; however, larger studies would yield a more precise estimate for these outcomes.

Bromoderma in an infant

Abstract Bromoderma is a cutaneous eruption caused by the absorption of bromide. Clinical manifestations include acneiform and vegetative lesions. We report the case of an infant with bromoderma caused by the use of syrup for abdominal colic containing calcium bromide. The lesions regressed after discontinuation of the drug.

Bromoderma in an infant.

Bromoderma is a cutaneous eruption caused by the absorption of bromide. Clinical manifestations include acneiform and vegetative lesions. We report the case of an infant with bromoderma caused by the use of syrup for abdominal colic containing calcium bromide. The lesions regressed after discontinuation of the drug.

Efficacy of antiepileptic drugs for the treatment of Dravet syndrome with different genotypes.

OBJECTIVE: Evaluation of the efficacy of antiepileptic drugs (AEDs) used in the treatment of Dravet syndrome (DS) with different genotypes. METHODS: Patients with DS were recruited from different tertiary hospitals. Using a direct sequencing method and Multiplex Ligation-Dependent Probe Amplification (MLPA), genetic abnormalities were assessed within the exons and flanking introns of SCN1A gene, which encodes the α1 subunit of neuronal sodium channels. Patients were divided into SCN1A-positive and SCN1A-negative groups according to the results of genetic tests. Medical records, including detailed treatment information, were surveyed to compare the effect of different AEDs on clonic or tonic-clonic seizures (GTCS). Efficacy variable was responder rate with regard to seizure reduction. RESULTS: One hundred and sixty of 276 (57.97%) patients had mutation in SCN1A gene (only 128 of them had provided detailed medical records). Among the 116 patients without SCN1A mutations, 87 had provided detailed medical records. Both older AEDs (valproate, phenobarbital, bromide, carbamazepine, clonazepam, and clobazam) and newer AEDs such as zonisamide were used in these patients. Valproate was the most frequently used AED (86.72% in the SCN1A-positive group, 78.16% in the SCN1A-negative group), with 52.25% and 41.18% responder rates in SCN1A-positive and SCN1A-negative patients, respectively (P=0.15). Bromide was used in 40.63% of the SCN1A-positive patients and 20.69% of the SCN1A-negative patients, and its responder rates were 71.15% and 94.44% in SCN1A-positive and SCN1A-negative patients, respectively (P=0.05). Efficacy rates of clonazepam, clobazam, phenobarbital, and zonisamide ranged from 30% to 50%, and these rates were not correlated with different genotypes (P>0.05). Carbamazepine had either no effect or aggravated seizures in all SCN1A-positive patients. SIGNIFICANCE: Bromide is most effective and is a well-tolerated drug among DS patients, especially among SCN1A-negative patients. Carbamazepine should be avoided in patients with SCN1A mutations.

Bromoderma mimicking pyoderma gangrenosum caused by commercial sedatives.

Bromoderma is a rare skin disorder caused by bromide intake. It presents as single or multiple papillomatous nodules or plaques, and ulcers studded with small pustules on the face or limbs. The clinical features of bromoderma are similar to those of pyoderma gangrenosum. A 41-year-old Japanese woman was diagnosed with pyoderma gangrenosum 11 years prior to presentation. Pyoderma had repeatedly appeared over her entire body despite treatment. She also frequently complained of syncopal episodes. She was admitted to our hospital after loss of consciousness and an episode of generalized convulsion. Laboratory tests revealed a negative serum anion gap and hyperchloremia. Her serum bromide level was significantly elevated, suggesting bromide intoxication. The patient had a 10-year history of high serum bromide levels. After the intake of bromide-containing sedatives was stopped, there was no recurrence of pyoderma in the absence of treatment. In conclusion, this case was diagnosed as bromoderma with commercial sedative-induced bromide intoxication. Although the US Food and Drug Administration have banned the use of bromides, over-the-counter (OTC) treatments containing bromides are still used in Japan and other countries. Long-term use of OTC medicines containing bromvalerylurea may result in the development of bromoderma. If unclarified neurological or psychiatric symptoms are associated with pyoderma, we propose measurement of the patient's serum chloride concentration. Determination of hyperchloremia is helpful for the diagnosis of chronic intoxication with bromides.

Estimating Potential Increased Bladder Cancer Risk Due to Increased Bromide Concentrations in Sources of Disinfected Drinking Waters.

Public water systems are increasingly facing higher bromide levels in their source waters from anthropogenic contamination through coal-fired power plants, conventional oil and gas extraction, textile mills, and hydraulic fracturing. Climate change is likely to exacerbate this in coming years. We estimate bladder cancer risk from potential increased bromide levels in source waters of disinfecting public drinking water systems in the United States. Bladder cancer is the health end point used by the United States Environmental Protection Agency (EPA) in its benefits analysis for regulating disinfection byproducts in drinking water. We use estimated increases in the mass of the four regulated trihalomethanes (THM4) concentrations (due to increased bromide incorporation) as the surrogate disinfection byproduct (DBP) occurrence metric for informing potential bladder cancer risk. We estimate potential increased excess lifetime bladder cancer risk as a function of increased source water bromide levels. Results based on data from 201 drinking water treatment plants indicate that a bromide increase of 50 µg/L could result in a potential increase of between 10(-3) and 10(-4) excess lifetime bladder cancer risk in populations served by roughly 90% of these plants.

Canine Pancreas-Specific Lipase and C-reactive Protein in Dogs Treated With Anticonvulsants (Phenobarbital and Potassium Bromide).

Animals treated with anticonvulsant drugs may have increased canine pancreas-specific lipase (cPLI) values. Inflammatory conditions and specifically acute pancreatitis are of major concern in these animals. Elevation in C-reactive protein is being associated with inflammatory status in dogs and it has been correlated with the clinical severity of pancreatitis. In the present study, we investigated if there is a correlation between the cPLI increase, changes in C-reactive protein and hepatic enzymes, as well as the incidence of severe acute pancreatitis (AP) in dogs with anticonvulsant treatment (phenobarbital, or potassium bromide or both). Increased values of pancreas-specific lipase were found in 6.8% of the animals in treatment with anticonvulsants, and this increase is correlated with the increase in triglycerides, alkaline phosphatase, and alanine aminotransferase but not with C-reactive protein levels, which suggests a possible induction or release phenomenon rather than a clear severe AP. C-reactive protein levels did not affect cPLI values on the population studied. Only 2 animals had clinical and analytical data suggestive of AP, indicating a low prevalence (0.6%). In conclusion, cPLI may be increased in a low percentage of animals with anticonvulsants treatment and its increase may not be associated with severe AP. It may be induced by the anticonvulsants drugs; however, further studies are advised to rule out other possible causes that increased cPLI.

The effects of CaCl2 and CaBr2 on the reproduction of Daphnia magna Straus.

Concentrated CaCl2 and CaBr2 salt solutions of densities up to 2.3 kg L-1 are regularly used to control hydrostatic pressure in oil wells during special operations in the exploration and production of natural gas and crude oil. Various concentrations of high density salts are frequently left in mud pits near the drilling site as waste, polluting fresh and ground waters by spillage and drainage. The toxic effects of these salts have already been observed. This study investigated the effects of CaCl2 and CaBr2 on water flea Daphnia magna Straus in a 21-day reproduction test. The three tested concentrations of CaCl2 (240, 481, and 1925 mg L-1) caused a significant dose-response decrease of reproduction (p<0.001). With CaBr2 (533 and 1066 mg L-1), only aborted eggs were produced, demonstrating the embryotoxicity of the substance. The results suggest that high concentrations of the tested chemicals are harmful to Daphnia's reproduction and could reduce its abundance.