The Iberian legacy into a young genetic xeroderma pigmentosum cluster in central Brazil.

In central Brazil, in the municipality of Faina (state of Goiás), the small and isolated village of Araras comprises a genetic cluster of xeroderma pigmentosum (XP) patients. The high level of consanguinity and the geographical isolation gave rise to a high frequency of XP patients. Recently, two founder events were identified affecting that community, with two independent mutations at the POLH gene, c.764 + 1 G > A (intron 6) and c.907 C > T; p.Arg303* (exon 8). These deleterious mutations lead to the xeroderma pigmentosum variant syndrome (XP-V). Previous reports identified both mutations in other countries: the intron 6 mutation in six patients (four families) from Northern Spain (Basque Country and Cantabria) and the exon 8 mutation in two patients from different families in Europe, one of them from Kosovo. In order to investigate the ancestry of the XP patients and the age for these mutations at Araras, we generated genotyping information for 22 XP-V patients from Brazil (16), Spain (6) and Kosovo (1). The local genomic ancestry and the shared haplotype segments among the patients showed that the intron 6 mutation at Araras is associated with an Iberian genetic legacy. All patients from Goiás, homozygotes for intron 6 mutation, share with the Spanish patients identical-by-descent (IBD) genomic segments comprising the mutation. The entrance date for the Iberian haplotype at the village was calculated to be approximately 200 years old. This result is in agreement with the historical arrival of Iberian individuals at the Goiás state (BR). Patients from Goiás and the three families from Spain share 1.8 cM (family 14), 1.7 cM (family 15), and a more significant segment of 4.7 cM within family 13. On the other hand, the patients carrying the exon 8 mutation do not share any specific genetic segment, indicating an old genetic distance between them or even no common ancestry.

Comprehensive germline mutation analysis and clinical profile in a large cohort of Brazilian xeroderma pigmentosum patients.

BACKGROUND: Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system. OBJECTIVES: To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP. METHODS: Twenty-seven families were screened for germline variants in eight XP-related genes. RESULTS: All patients (N = 32) were diagnosed with bi-allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251-1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2/XPD, DDB2/XPE and ERCC5/XPG variants were found in a few patients. Aside from melanoma and non-melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma. CONCLUSIONS: We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP-related genes, unexpected non-skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described.

A genetic cluster of patients with variant xeroderma pigmentosum with two different founder mutations.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare human syndrome associated with hypersensitivity to sunlight and a high frequency of skin tumours at an early age. We identified a community in the state of Goias (central Brazil), a sunny and tropical region, with a high incidence of XP (17 patients among approximately 1000 inhabitants). OBJECTIVES: To identify gene mutations in the affected community and map the distribution of the affected alleles, correlating the mutations with clinical phenotypes. METHODS: Functional analyses of DNA repair capacity and cell-cycle responses after ultraviolet exposure were investigated in cells from local patients with XP, allowing the identification of the mutated gene, which was then sequenced to locate the mutations. A specific assay was designed for mapping the distribution of these mutations in the community. RESULTS: Skin primary fibroblasts showed normal DNA damage removal but abnormal DNA synthesis after ultraviolet irradiation and deficient expression of the Polη protein, which is encoded by POLH. We detected two different POLH mutations: one at the splice donor site of intron 6 (c.764 +1 G>A), and the other in exon 8 (c.907 C>T, p.Arg303X). The mutation at intron 6 is novel, whereas the mutation at exon 8 has been previously described in Europe. Thus, these mutations were likely brought to the community long ago, suggesting two founder effects for this rare disease. CONCLUSIONS: This work describes a genetic cluster involving POLH, and, particularly unexpected, with two independent founder mutations, including one that likely originated in Europe.

In vitro evaluation of dentifrice with low fluoride content supplemented with trimetaphosphate.

One way to reduce dental fluorosis is by reducing the fluoride (F) concentration in dentifrice, but low-F dentifrice should be as effective as a standard dentifrice. This study evaluated in vitro whether the supplementation with sodium trimetaphosphate (TMP) of a dentifrice with low F content (500 microg/g) would provide a similar effect to that of a standard dentifrice. Bovine enamel blocks were submitted to a pH cycling regime incorporating daily exposures to a slurry of dentifrice: a low-F dentifrice with or without 0.1-3.0% TMP; an F-free, phosphate-free dentifrice (negative control), or a dentifrice with 1,100 microg/g F (positive control). The addition of TMP to dentifrice with or without F was associated with higher surface hardness and decreased loss of integrated subsurface hardness after pH cycling. The combination of 1% TMP and 500 microg F/g had a greater effect than the positive control dentifrice. It is concluded that the addition of TMP to the 500-microg F/g dentifrice allowed a similar or larger effect as compared with a standard dentifrice in this in vitro model.

Once-daily, low-cost, highly effective Helicobacter pylori treatment to family members of gastric cancer patients.

BACKGROUND: Helicobacter pylori eradication in family members of gastric cancer patients is now widely accepted, although problems related to costs and compliance persist. AIM: To compare the efficacy, tolerability and long-term re-infection rates of two once-daily regimens for the eradication of H. pylori in family members of gastric cancer patients. METHODS: 106 first-degree family members of gastric cancer patients were recruited and submitted to the 13C-urea breath test (UBT) to detect H. pylori. If positive, they were randomly allocated to receive a combination of lanzoprazole 30 mg, clarithromycin OD (extended-release formulation) 500 mg and furazolidone 400 mg, once daily, in the morning, for 7 days (Group A) or the same regimen with only 200 mg furazolidone (Group B). Eradication was confirmed by urea breath test performed 6 weeks after treatment. 13C-urea breath test was repeated at 944 (784-1258) days after treatment in successfully treated participants to look for re-infection. RESULTS: Twenty-five participants were H. pylori negative and two H. pylori-positive individuals refused to sign the informed consent and were excluded. Therefore, 79 participants were studied. Forty participants were allocated to Group A and 39 to Group B. All participants completed treatment. Adverse effects, mostly mild, were observed in 18% of Group A and 18% of Group B (N.S.). The intention-to-treat eradication rate was 87.5% in Group A and 61.5% in Group B (P = 0.006). The mean annual re-infection rate was 3%. CONCLUSIONS: The combination of lanzoprazole 30 mg, one tablet of clarithromycin OD (extended release formulation) 500 mg and furazolidone 400 mg, once daily for 7 days, constitutes an inexpensive, safe and effective alternative for anti-H. pylori therapy in family members of gastric cancer patients.

Azithromycin, furazolidone and omeprazole: a promising low-dose, short-term, anti-H. pylori triple therapy

Aim: Tocompare four anti-H. pylori regimes using omeprazole and azithromycin associated to different antimicrobials in peptic ulcer H. pylori positive patients. Patients and methodos: afterinformed consent, 136 endoscopically proven peptic ulcer patients(74 male, 62 female) were randomly assigned to one of thefollowing therapy groups: Group 1: Om 20mg mane for 7 ays + Az 500mgmane for 3 days + tinidazole (Ti) 500mg bid for 7 ays. Group 2: Om 20 mg mane for 7 days + Az 500mane for 3 days + amoxycilin (Am) 500mg tid for 7 days. Group 3 Om 20 mg mane for 7 days + Az 500mg mane for 3 days + furazolidone (F) 200 mg tid for 7 days. Group 4: Om 20 mg mane for 7 days +Az 500mg mane for 3 days + colloidal bismuth subcitrate (CBS) 120 mg tid ( double dose at bedtime) for7 days. The H. Pylori status was assessed before treatment and 94 (63-214) days post treatment using urease test, and 14C-urea breath test. Statistical analysis was performed by Kruskal-Wallis test, chi-square test, Fisher's exact test, and Lancaster & Irvin method. Results: The four groups had similar demographic and clinical characteristics. 120/136 patients completed the study. One patient discontinued treatment due to side effects and 15 were lost to follow-up.32/136 (23.5por cento) hed side effect during treatment, mainly nause. H.pylori eradication in group 3 was statistically different from the other groups ( p=0.000). Group 3 & 4 (statistically non-different) presented significantly more side effects than group 1 and 2 (p=0.002). Conclusion: 1)Om + Associated to F (the cheapest ant- H.Pylori drug) for one week represents an efficient reasonaaable well-tolerates alternatiaaaaaave to H.pylori eradication. 2) Future studies testing F with other macrolides or Az during 7 days can enhance H. Pylori eradication rates

One-week triple therapy with omeprazole plus azithromycin and secnidazole is ineffective in eradicating "helicobacter pylori"

Background: There is not yet consensus on the most effective treatment for the helicobacter pylori infection, particularly in most developing countries. Azithromycin is a new macrolide and relatively novel agent for H. pylori eradication with an in vitro MIC90 lower than 1 mg/ml.Secnidazole, a nitromidazole that causes fewer side effects than metronidazole, was recenty reported to be used, for the firt time, in the treatment of H. pylori infection. Aim: To evaluate, in a prospective, randomized, single-center study, the association of twodifferent doses of omeprazole, azithromycin and secnidazole in H. pylori eradication. Patients and methods: After informed consent, 55 patients (36m,19F) with duodenal ulcer associated with H. pylori infection were randomized to receive omeprazole 20mg uid (Group A) or 20mg bid (Group B) for sevem days plus azithromycin 500mg uid for six days and secnidazole 2,000mg uid in the first, fourth and seventh day. The H. pylori status was assessed before and 60-90 days posttreatment using urease test, histology and 13C-urea breath test. Statistical analysis was performed by X² test. Results: The two groups had similar demographic characteristics. Fifty-five patients (36M, 19F) were enrolled. Six patients did not show-up for the second visit posttreatment. So, of the 49 evaluable patients, 25por cento (6/24) in Group A and 44por cento(11/25) in Group B wereeradicated, in a per protocol (PP) analysis. Intetion-to-treat (ITT) eradication rates were 21,4por cento (6/28) in Group A and 40.7por cento (11/27) im Group B. The differences betweem ITT and PP analysis from the two groups were not statistically significant. Conclusions: This study shows a very low eradication rate with the two regimens comprising of omeprazole, azithromycin and secnidazole and therefore, should not be recommended for thetreatment of H. pylori infection

Application of isotope-selective non-dispersive infrared spectrometry for the evaluation of the 13C-urea breath test: comparison with three concordant methods

The aim of this work was to compare the performance of isotope-selective non-dispersive infrared spectrometry (IRIS) for the 13C-urea breath test with the combination of the 14C-urea breath test (14C-UBT), urease test and histologic examination for the diagnosis of H. pylori (HP) infection. Fifty-three duodenal ulcer patients were studied. All patients were submitted to gastroscopy to detect HP by the urease test, histologic examination and 14C-UBT. To be included in the study the results of the 3 tests had to be concordant. Within one month after admission to the study the patients were submitted to IRIS with breath samples collected before and 30 min after the ingestion of 75 mg 13C-urea dissolved in 200 ml of orange juice. The samples were mailed and analyzed 11.5 (4-21) days after collection. Data were analyzed statistically by the chi-square and Mann-Whitney test and by the Spearman correlation coefficient. Twenty-six patients were HP positive and 27 negative. There was 100 per cent agreement between the IRIS results and the HP status determined by the other three methods. Using a cutoff value of delta-over-baseline (DOB) above 4.0 the IRIS showed a mean value of 19.38 (minimum = 4.2, maximum = 41.3, SD = 10.9) for HP-positive patients and a mean value of 0.88 (minimum = 0.10, maximum = 2.5, SD = 0.71) for negative patients. Using a cutoff value corresponding to 0.800 per cent CO2/weight (kg), the 14C-UBT showed a mean value of 2.78 (minimum = 0.89, maximum = 5.22, SD = 1.18) in HP-positive patients. HP-negative patients showed a mean value of 0.37 (minimum = 0.13, maximum = 0.77, SD = 0.17). IRIS is a low-cost, easy to manage, highly sensitive and specific test for H. pylori detection. Storing and mailing the samples did not interfere with the performance of the test.

[Association of thymoma and severe intestinal strongyloidiasis]. / Associação timoma e estrongiloidíase intestinal grave.

A 59-years-old man with thymoma and severe intestinal strongyloidiasis is reported. The authors pointed out a possible influence of immunological response related with thymoma in the development of hyperinfection by Strongyloides stercoralis.

Associação timoma e estrongiloidíase intestinal grave / Association of thymoma and severe intestinal strongyloidiasis

A 59-years-old man with thymoma and severe intestinal strongyloidiasis is reported. The authors pointed out a possible influence of immunological response related with thymoma in the development of hyperinfection by Strongyloides stercoralis.

Os autores relatam o caso de um homem de 59 anos de idade com timoma e estrongiloidíase intestinal grave. São revistos aspectos da resposta imunitária relacionados ao tumor e, possivelmente, implicados no desenvolvimento da hiperinfecção pelo Strongyloides stercoralis.

Primary hepatic non-Hodgkin's lymphoma in children: a case report and review of the literature.

Non-Hodgkin's lymphomas presenting exclusively in the liver are rather uncommon in adults and extremely rare in children. We describe a six-year-old white boy with jaundice, abdominal pain, and weight loss of two weeks duration. Physical examination disclosed asthenia, jaundice, abdominal swelling, large hepatomegaly, and ascitis. Aminotransferases bilirubin, and alkaline phosphatase were significantly elevated. Bone marrow aspiration, cerebrospinal fluid, chest x-ray, renal function tests, and uric acid were normal. Abdominal ultrasound showed liver enlargement with irregular regular borders, many parenchymal nodules in both liver lobes, a large hypoechogenic mass in the inferior segment of the liver, normal biliary ducts and two pancreatic nodules resembling those in the liver. Liver needle biopsy disclosed diffuse lymphomatous infiltration. Blast cells were positive for leukocyte common antigen (CD 45). Immunohistochemistry study for T or B cell lineage differentiation was not done. The child showed an excellent response to chemotherapy based on the BFM-83 protocol for B cell non-Hodgkin's lymphomas. The patient had his therapy discontinued in June 1995 and remains in first complete remission as of May 20th, 1996.

Histology of the mucosa of gastric antrum and body before and after eradication of Helicobacter pylori

1. Helicobacter pylori status and the histology of the antral and oxyntic mucosa were evaluated in 25 patients with duodenal ulcer treated with a triple schedule of furazolidone, metronidazole and amoxicillin, and in 16 patients treated only with cimetidine. 2. Before treatment, H. pylori was detected in all patients. One month after treatment with the antimicrobial agents, H. pylori was not found in 18 (72.0 per cent ) of 25 patients treated with the triple schedule. In the patients treated with cimetidine (N = 16) the H. pylori tests continued to be positive after treatment. 3. Inflammatory activity and intensity of gastritis were significantly reduced in patients treated with the antimicrobial agents but not in cimetidine-treated patients. Three patients who had negative cultures and improvement of gastritis 1 month after treatment became H. pylori positive again within 2 months, with concomitant reappearance of gastritis. 4. This study provides additional evidence that histological gastritis observed in H. pylori-positive patients with duodenal ulcer is due to the presence of the microorganism

Effect of Helicobacter pylori eradication on antral gastrin- and somatostatin-immunoreactive cell density and gastrin and somatostatin concentrations.

The density of antral gastrin (G)- and somatostatin (D)-immunoreactive cells and the contents of antral gastrin and somatostatin were investigated in endoscopic antral biopsy specimens from patients with duodenal ulcer before and after eradication of Helicobacter pylori. After H. pylori eradication both antral somatostatin concentration (p = 0.0002) and antral D-cell density (p = 0.01) increased significantly. Conversely, although the number of G-cells was unchanged, antral (p = 0.0002) and serum (p = 0.001) gastrin contents decreased significantly. The number of oxyntic D-cells did not change significantly. These results strongly suggest that the hypergastrinaemia observed in H. pylori-positive patients may be due to a deficiency in antral somatostatin, which normally inhibits the synthesis and release of gastrin.

The effect of chronic ingestion of ethanol on modulation of granulomatous inflammation in experimental schistosomiasis in mice

We studied the role of ethanol on the modulation of liver granulomata around Schistosoma mansoni eggs in mice. Albino mice, receiving 7 ethanol as the sole drinking liquid, at 60 and 90 days post-infection, presented smaller granulomata than controls did, when sacrificed at 120 days post-infection. No differences in diameters could be observed, when ethanol was given 4 months before up to 120 days after infection. The results suggested that modulation of schistosome granulomata by ethanol ingestion varies with time and duration of drug consumption.

The effect of chronic ingestion of ethanol on modulation of granulomatous inflammation in experimental schistosomiasis in mice.

We studied the role of ethanol on the modulation of liver granulomata around Schistosoma mansoni eggs in mice. Albino mice, receiving 7% ethanol as the sole drinking liquid, at 60 and 90 days post-infection, presented smaller granulomata than controls did, when sacrificed at 120 days post-infection. No differences in diameters could be observed, when ethanol was given 4 months before up to 120 days after infection. The results suggested that modulation of schistosome granulomata by ethanol ingestion varies with time and duration of drug consumption.

Antiácido de alta potência versus cimetidina no tratamento da úlcera duodenal: comodidade posológica / High potency antacid versus cometidine in the treatment of duodenal ulcer: commodus psosology

Foram estudados 98 pacientes com úlcera péptica duodenal distribuídos de forma randômica em dois grupos. Um grupo recebeu antiácido liquido de alta potência (282,4mEq/dia) dividido em 4 tomadas durante 4 semanas e outro recebeu cimetidina (800 mg/dia) dividida em 2 tomadas por igual período. A potência antiácida da associaçäo líquida utilizada é de 7,06 mEq/ml. Todos os pacientes foram avaliados clinicamente no pré-tratamento e duas e quatro semanas após, com exames endoscópicos realizados na admissäo e após quatro semanas. A eficácia, considerada como cicatrizaçäo da úlcera duodenal associada a melhora da sintomatologia foi equivalente para ambos os tratamentos, näo havendo diferença estatisticamente significante. A tolerabilidade de ambas as drogas foi considerada boa

Comparison of the urease test and of direct smear examination in the control of treatment of Helicobacter pylori-induced infection

The sensitivity and specificity of the preformed urease test and of carbolfuchsin-stained smears for the diagnosis of the presence of Helicobacter pylori in gastric mucosa were evaluated before and after antimicrobial treatment. The results obtained by culture were used as the reference point. We studied 41 patients with endoscopically diagnosed duodenal ulcer. Twenty-five of these were treated with furazolidone (100 mg t.i.d.), amoxicillin (500 mg t.i.d.) and metronidazole (250 mg t.i.d.) for 5 days and then with only furazolidone (100 mg t.i.d.) for an additional 25 days. The 16 control patients were treated with cimetidine (800 mg, 4 times a day). The sensitivity of the urease test and of direct smear examination was 100 per cent before treatment and 84.6 per cent and 92.3 per cent , respectively, after treatment. We conclude that the urease test and carbolfuchsin-stained smears, which are highly sensitive for H. pylori diagnosis, present reduced sensitivity when they are employed for the follow-up of patients treated with antimicrobials

Duodenal ulcer and eradication of Helicobacter pylori in a developing country. An 18-month follow-up study.

Forty-eight patients with endoscopically proven duodenal ulcer (DU) and Helicobacter pylori infection detected by 14C-urea breath test (BT) were assigned to 5 days of treatment with furazolidone, metronidazole, and amoxicillin in addition to eventual classical anti-ulcer agents if necessary. Clinical evaluation and BT were repeated at 2, 6, and 18 months after therapy to determine H. pylori eradication or reinfection. Endoscopy was also repeated at 6 and 18 months after treatment to detect DU relapse. In 29 (60%) patients H. pylori had been eradicated at 2 months after therapy, and in 19 (40%) infection persisted. After successful eradication, 6 of 29 (20.7%) were reinfected. All 24 patients who were negative at the 18-month evaluation were asymptomatic, free of anti-ulcer drugs, and with healed ulcers, whereas among the 19 positive patients followed up, 11 (57%) continued to be symptomatic and still using anti-ulcer agents (p less than 0.010), and 10 (53%) showed active ulcers at endoscopy (p less than 0.010). H. pylori eradication is clearly followed by long-term remission of DU. Reinfection may be an additional problem in treating DU patients in developing countries.