The safety and efficacy of benzbromarone in gout in Aotearoa New Zealand.

BACKGROUND: Benzbromarone is a potent uricosuric but is not widely available due to concerns about hepatotoxicity. In Aotearoa New Zealand, benzbromarone has been available since April 2013, subject to funding restrictions, for patients with inadequate urate-lowering response or intolerance to allopurinol and probenecid. AIM: To assess the safety and efficacy of benzbromarone in a real-life setting. METHODS: All patients who received funding for benzbromarone from 1 April 2013 to 30 September 2014 were identified. Prescribers were sent a questionnaire for each individual. Information on demographics, efficacy of previous urate-lowering drugs and reasons for discontinuation were collected. Specific information about the dose, effect on serum urate, adverse effects and liver function tests after commencing benzbromarone was recorded. RESULTS: Completed questionnaires were returned for 123 of 164 (75%) patients. Mean (SD) serum urate prior to benzbromarone was 0.57 (0.12) mmol/L, and estimated glomerular filtration rate was 50.3 (22.8) mL/min/1.73 m(2) . The median dose of benzbromarone was 100 mg/day (25-200 mg/day). Six months after commencing benzbromarone, mean (SD) serum urate was 0.35 (0.12) mmol/L. Benzbromarone-related adverse events included rash (n = 4), diarrhoea (n = 9), nausea (n = 6) and urate stones (n = 3). Liver function test abnormalities were uncommon and tended to be mild. There were 14 patient deaths; none was considered related to benzbromarone. Allopurinol had been prescribed prior to benzbromarone in 117 of 123 patients; median maximum allopurinol dose was 200 mg/day (range 25-600 mg/day), and 19% patients received allopurinol >300 mg/day. CONCLUSION: Benzbromarone provides useful urate-lowering efficacy and does not appear unsafe in patients with gout. Urate-lowering therapy prescribing requires further optimisation.

Cloning and functional analysis of the Sry-related HMG box gene, Sox18.

The Sox gene family (Sry like HMG box gene) is characterised by a conserved DNA sequence encoding a domain of approximately 80 amino acids which is responsible for sequence specific DNA binding. We initially published the identification and partial cDNA sequence of murine Sox18, a new member of this gene family, isolated from a cardiac cDNA library. This sequence allowed us to classify Sox18 into the F sub-group of Sox proteins, along with Sox7 and Sox17. Recently, we demonstrated that mutations in the Sox18 activation domain underlie cardiovascular and hair follicle defects in the mouse mutation, ragged (Ra) (Pennisi et al., 2000. Mutations in Sox18 underlie cardiovascular and hair follicle defecs in ragged mice. Nat. Genet. 24, 434-437). Ra homozygotes lack vibrissae and coat hairs, have generalised oedema and an accumulation of chyle in the peritoneum. Here we have investigated the genomic sequences encoding Sox18. Screening of a mouse genomic phage library identified four overlapping clones, we sequenced a 3.25 kb XbaI fragment that defined the entire coding region and approximately 1.5 kb of 5' flanking sequences. This identified (i) an additional 91 amino acids upstream of the previously designated methionine start codon in the original cDNA, and (ii) an intron encoded within the HMG box/DNA binding domain in exactly the same position as that found in the Sox5, -13 and -17 genes. The Sox18 gene encodes a protein of 468 aa. We present evidence that suggests HAF-2, the human HMG-box activating factor -2 protein, is the orthologue of murine Sox18. HAF-2 has been implicated in the regulation of the Human IgH enhancer in a B cell context. Random mutagenesis coupled with GAL4 hybrid analysis in the activation domain between amino acids 252 and 346, of Sox18, implicated the phosphorylation motif, SARS, and the region between amino acid residues 313 and 346 as critical components of Sox18 mediated transactivation. Finally, we examined the expression of Sox18 in multiple adult mouse tissues using RT-PCR. Low-moderate expression was observed in spleen, stomach, kidney, intestine, skeletal muscle and heart. Very abundant expression was detected in lung tissue.

The human melanocortin-1 receptor locus: analysis of transcription unit, locus polymorphism and haplotype evolution.

The complete sequence of the MC1R locus has been assembled, the coding region of the gene is intronless and placed within a 12 kb region flanked by the NULP1 and TUBB4 genes. The immediate promoter region has an E-box site with homology to the M-box consensus known to bind the microphthalmia transcription factor (MITF); however, promoter deletion analysis and transactivation studies have failed to show activation through this element by MITF. Polymorphism within the coding region, immediate 5' promoter region and a variable number tandem repeat (VNTR) minisatellite within the locus have been examined in a collection of Caucasian families and African individuals. Haplotype analysis shows linkage disequilibrium between the VNTR and MC1R coding region red hair variant alleles which can be used to estimate the age of these missense changes. Assuming a mean VNTR mutation rate of 1% and a star phylogeny, we estimate the Arg151Cys variant arose 7500 years before the present day, suggesting these variants may have arisen in the Caucasian population more recently than previously thought.

The effects of low doses of ranitidine on intragastric acidity in healthy men.

BACKGROUND: H2-receptor antagonists are becoming widely available as over-the-counter medications for the treatment of heartburn and excess gastric acidity. AIM: To determine the effects of single low doses of ranitidine on intragastric acidity. METHODS: Intragastric pH was measured for 9 h after lunch in five studies involving 24 healthy male volunteers. Antacid was given to all subjects on day 1. They then received single oral doses of a study drug 45 min after lunch on four separate occasions: placebo and either ranitidine 25 mg, 75 mg or 125 mg were given double-blind according to a predetermined randomization schedule. RESULTS: During both of the post-dosing time periods (0-5 h and 5-9 h) there were significant decreases in integrated intragastric acidity for each ranitidine dose compared with placebo (P < 0.0001). There was a significant linear relationship between dose and integrated intragastric acidity with a greater decrease in acidity with increasing ranitidine doses (P < 0.0001). Compared with placebo, time with pH > 3 was significantly greater for ranitidine 75 mg and 125 mg (P < 0.001), but not ranitidine 25 mg. Results with the antacid were similar to placebo. CONCLUSIONS: Using low doses of ranitidine (25, 75 or 125 mg) there was a dose-related decrease in intragastric acidity for 9 h after dosing. A single dose of antacid did not decrease intragastric acidity significantly.

Development of a new dyspepsia impact scale: the Nepean Dyspepsia Index.

BACKGROUND: There is not at present a suitable disease-specific health-related quality of life instrument for uninvestigated dyspepsia and functional (non-ulcer) dyspepsia. AIM: To develop a new multi-dimensional disease-specific instrument. METHODS: The Nepean Dyspepsia Index (NDI) was designed to measure impairment of a subject's ability to engage in relevant aspects of their life and also their enjoyment of these aspects; in addition, the individual importance of each aspect is assessed. A 42-item quality of life measure was developed and tested, both in out-patients presenting to general practice with upper gastrointestinal complaints (n = 113) and in a randomly chosen population-based sample (n = 347). RESULTS: Adequate face and content validity was documented by an expert panel. Factor analysis identified four clinically relevant subscales: interference with activities of daily living, work, enjoyment of life and emotional well-being; lack of knowledge and control over the illness; disturbance to eating or drinking; and disturbance to sleep because of dyspepsia. These scales had high internal consistency. Both symptoms and the quality of life scores discriminated dyspepsia from health. CONCLUSION: The Nepean Dyspepsia Index is a reliable and valid disease-specific index for dyspepsia, measuring symptoms and health-related quality of life.

The safety and efficacy of ranitidine bismuth citrate in combination with antibiotics for the eradication of Helicobacter pylori.

BACKGROUND: Ranitidine bismuth citrate is a novel salt of ranitidine and a bismuth citrate complex. It has intrinsic antisecretory and anti-Helicobacter pylori activity, but monotherapy rarely eradicates H. pylori infection in man. AIM: A pilot study to investigate rates of H. pylori eradication achieved by co-prescription of ranitidine bismuth citrate with antibiotics, and to identify several regimens which would merit further investigation. METHOD: One hundred dyspeptic patients infected with H. pylori were randomly allocated to treatment with ranitidine bismuth citrate 800 mg b.d. plus either amoxycillin, metronidazole, clarithromycin, cefuroxime axetil, tetracycline, tetracycline plus metronidazole or clarithromycin plus tetracycline for 14 days. Eradication of infection was assessed using the 13C-urea breath test 4 weeks after the end of treatment. RESULTS: In a per protocol analysis eradication of H. pylori ranged between 22 and 100%; the intention-to-treat eradication rates ranged between 15 and 92%. No adverse events were specifically attributed to ranitidine bismuth citrate. CONCLUSION: Co-prescription therapy, using ranitidine bismuth citrate and one or more antibiotics, is suitable for further investigation in large-scale clinical trials in patients infected with H. pylori.

A case of zinc chloride ingestion.

Zinc chloride is a powerful corrosive agent. Reports of zinc chloride ingestion are uncommon, and there is little information about its toxicity and management. The authors report the clinical course of a 10-year-old girl who accidentally ingested an acid soldering flux solution (pH, 3.0; zinc chloride, 30% to < 60%). Systemic effects after the ingestion were unremarkable except for lethargy. Thus, chelation therapy was not considered. Severe gastric corrosion was caused by local caustic action. An antral stricture of the stomach approximately 3 weeks after the ingestion developed, and she underwent a modified Heineke-Mikulicz antropyloroplasty. Postoperatively, she made an uneventful recovery. On follow-up, although she was tolerating a normal diet, results of a barium meal showed her stomach to be totally aperistaltic. Results of a nuclear medicine study showed moderately delayed gastric emptying. Careful long-term follow-up is necessary, because there is potential risk for malignancy in the damaged stomach.

Prevalence, severity and associated features of gastro-oesophageal reflux and dyspepsia: a population-based study.

AIMS: To describe the prevalence and severity of dyspepsia and gastro-oesophageal reflux in the community, to investigate their association with lifestyle factors and to evaluate the consultation pattern for these conditions. METHOD: A previously validated questionnaire was posted to 1000 adults randomly selected from the electoral rolls of the greater Wellington region. It investigated symptoms of dyspepsia, reflux, lifestyle and consultation pattern over the previous twelve months. RESULTS: Response rate was 81.7%. Prevalence of dyspepsia was 34.2%. Prevalence of reflux was 30%. The overall prevalence of both symptom groups combined was 45.2%. Most subjects had multiple symptoms. Results indicated 63% of subjects with reflux also had symptoms of dyspepsia and 56% of subjects with dyspepsia showed symptoms of reflux. Although 69% of subjects with heartburn used over-the-counter medications, only 17% consulted medical practitioners. Current and ex-smokers had a higher prevalence of reflux. Dyspeptic symptoms were not associated with alcohol intake or aspirin use. Prevalence of dyspeptic symptoms did not change with increasing age. CONCLUSIONS: Dyspepsia is very common in the community. Significant overlap among the subgroups of dyspepsia makes a classification, based on symptoms alone, of questionable value. Frequency and severity of symptoms should be incorporated in the definition to exclude those subjects with trivial symptoms.

Klebsiella pneumoniae producing KPC carbapenemase in a district general hospital in the UK.

We report two patients with multidrug-resistant KPC-carbapenemase-producing Klebsiella pneumoniae urinary tract infections. A bla(KPC-2) gene was detected in both of the isolates by polymerase chain reaction and sequencing. The isolates had identical pulsed-field gel electrophoresis patterns and belonged to sequence type ST11. The index patient probably acquired the KPC-producing strain while in hospital in Curaçao, with subsequent nosocomial transmission to the second patient occurring in our hospital. We describe the interventions that were taken to prevent its further spread within the acute Trust and the community.

Stable free-radical forms of plasma proteins or simpler related structures which induce brain excitatory effects.

Stable free radicals have been prepared from purified plasma proteins, pituitary peptides, and simpler related structures like 5-OH tryptophan and melatonin by oxidation with the free-radical nitrosyl disulfonate in alkaline solution under controlled conditions. The presence of tyrosine or trytophan amino acid residues in the protein was found essential for free-radical formation. These red-colored, stable free radicals showed electron spin resonance spectra in aqueous solutions at room temperature and maintained this characteristic for weeks when stored at 5 degrees C. Illumination, by visible light, of the free-radical proteins and peptides separated from excess nitrosyl disulfonate by salt fractionation or chromatography enhanced the free-radical concentration in the light. The increased signal decayed in the dark. Intravenous administration of the free-radical proteins or peptides into rabbits equipped with chronic cranial electrodes and sedated with a small dose of pentobarbital caused a sudden EEG arousal accompanied by behavioral changes indicative of brain excitation. Illumination of the free-radical compounds prior to administration enhanced the effects. Untreated control proteins or peptides had no effects. The observations are interpreted to suggest the involvement of free-radical structures in the transfer of energy in nervous tissue.

Characterization of melanocyte stimulating hormone receptor variant alleles in twins with red hair.

The association between MSHR coding region variation and hair colour in humans has been examined by genotyping 25 red haired and 62 non-red Caucasians, all of whom were 12 years of age and members of a twin pair study. Twelve amino acid substitutions were seen at 11 different sites, nine of these being newly described MSHR variants. The previously reported Val92Met allele shows no association with hair colour, but the three alleles Arg151Cys, Arg160Trp and Asp294His were associated with red hair and one Val60Leu variant was most frequent in fair/blonde and light brown hair colours. Variant MSHR genotypes are associated with lighter skin types and red hair (P < 0.001). However, comparison of the MSHR genotypes in dizygotic twin pairs discordant for red hair colour indicates that the MSHR gene cannot be solely responsible for the red hair phenotype, since five of 13 pairs tested had both haplotypes identical by state (with three of the five having both identical by descent). Rather, it is likely that additional modifier genes exist, making variance in the MSHR gene necessary but not always sufficient, for red hair production.

Ranitidine bismuth citrate with clarithromycin for the eradication of Helicobacter pylori and for ulcer healing.

BACKGROUND: In a pilot study, ranitidine bismuth citrate (RBC; Pylorid, Tritec) in coprescription with clarithromycin achieved a Helicobacter pylori eradication rate (based on 13C urea breath test alone) of 83%. The aim of the current study was to validate this finding by using three diagnostic tests and a larger group of H. pylori-positive patients with active duodenal ulcer. METHODS: In a blinded study, 95 patients were given either 4 weeks of treatment with RBC, 400 mg bid, alone (RBC400, n = 31) or RBC, 400 mg bid or 800 mg bid, in coprescription with clarithromycin, 250 mg qid for 14 days, followed by 14 days of RBC, 400 mg bid, alone (RBC400 + CLAR and RBC800 + CLAR, respectively; n = 32 for each). Rates of ulcer healing at week 4 and of H. pylori eradication (assessed by antral and corpus urease tests and histology and by 13C urea breath test) at week 8 were compared, together with the incidence of adverse events. RESULTS: All three regimens were effective at duodenal ulcer healing and were tolerated well. The coprescription regimens gave significantly higher observed H. pylori eradication rates (82% and 74% for RBC400 + CLAR and RBC800 + CLAR) compared with RBC400 (0%; p < .001). CONCLUSIONS: RBC in dual therapy with clarithromycin provides excellent H. pylori eradication therapy and is an effective duodenal ulcer healing drug.

Identification and eradication of Helicobacter pylori infection in haemophilic patients.

The aim of this study was to identify and eradicate H. pylori infection in patients with haemophilia. Patients were screened for IgG antibodies against H. pylori; active infection was determined using a (13) C-urea breath test and infected patients were given combination therapy with antibiotics to eradicate infection. Seventy-eight of 219 (36%) patients with haemophilia were found to have an elevated serum antibody titre against H. pylori; of 36 antibody-positive patients with confirmatory testing, 14 were found to have active H. pylori infection. H. pylori infection was successfully eradicated in every infectedpatient using acombination of ranitidine plus two antibiotics (usually amoxycillin and metronidazole). It is concluded that eradication of H. pylori infection is likely to be a cost-effective screening strategy in patients with haemophilia, to prevent complications of peptic ulcer disease.

Complete sequence and polymorphism study of the human TYRP1 gene encoding tyrosinase-related protein 1.

The complete 24,667 nucleotide sequence spanning the human TYRP1 gene has been determined from the inserts of two overlapping lambda clones. A LINE-1 repeat element is immediately adjacent to and may demarcate the immediate 5' promoter region of the gene. A search for polymorphism within the seven TYRP1 coding exons has been performed by an RNase mismatch detection procedure. Analysis of the TYRP1 gene in 100 Caucasian individuals of varying hair color has found no amino acid sequence variation nor revealed any hemizygous mutant allele in the hypopigmented phenotype of two 9p- syndrome patients.