Biomedical subjects
Publications and source records attributed to M Cremer.
Minocycline is widely prescribed for long-term treatment in acne. Major side effects are rare and include hepatitis and drug-related lupus. Hepatitis can be early and acute or late and chronic, whereas lupus presents as a tardive and insidious disease. We report a case of minocycline-induced lupus initially presenting as acute hepatitis, evolving to chronic cytolysis, in a young man treated for facial acne.
Free radicals have been suspected to play a role in the pathogenicity of alcohol-related chronic pancreatitis. The aim of this study was to determine the status of several antioxidant parameters in these patients and examine the factors that are likely to influence them. Thirty-five subjects (23 males and 12 females, mean age 48 +/- 8 years) with disease proven by endoscopic pancreatography and 14 healthy controls (6 males and 8 females, mean age 44 +/- 7 years) were included in the study. Biochemical antioxidant parameters included: selenium, zinc, and copper levels in plasma; glutathione peroxidase in plasma and erythrocytes; plasma malondialdehyde concentrations assessed by thiobarbituric acid reactants; and serum vitamin E and A levels. Selenium and vitamin E oral intake was assessed by a five-day diet analysis. Hemoglobin (130 +/- 16 vs 143 +/- 15 g/liter), vitamin E (8 +/- 5 vs 16 +/- 9 mg/liter), vitamin A (30 +/- 11 vs 49 +/- 12 micrograms/dl), selenium (54 +/- 20 vs 87 +/- 11 micrograms/liter), and plasma glutathione peroxidase (903 +/- 313 vs 1326 +/- 168 units/liter) were significantly lower in patients than in controls (P < 0.05). In contrast, white blood cell count, C-reactive protein, and plasma copper levels were significantly higher in patients than in controls. Cholesterol, triglycerides, iron, ferritin, total proteins, zinc, and malondialdehyde were not different. Vitamin E was lower in patients with steatorrhea, while vitamin A was lower in patients with concomitant diabetes mellitus. Dietary intakes were not different between patients and controls. In conclusion, patients with alcohol-related chronic pancreatitis have low blood levels in many antioxidant factors. Dietary intakes of some of them (selenium and vitamin E) are adequate, however. Such deficiencies are secondary to pancreatic insufficiency and probably to increased requirements related to enhanced oxidative stress.
Gastrointestinal angiodysplasias are the most common cause of obscure chronic digestive blood loss. Push-enteroscopy is likely to detect and to treat vascular lesions. Push-enteroscopy was performed in 83 patients (mean age 62 years) presenting with iron deficiency anemia of obscure origin. A nonrevealing preliminary evaluation included esophagogastroduodenoscopy, colonoscopy and, in 50% of the patients, small bowel barium studies. We employed a 240-cm Olympus push-enteroscope (XSIF-100), 11.3 mm in diameter. A potential bleeding lesion was observed in 49 patients (59%). Gastrointestinal angiodysplasias were the most common lesion (33 patients). Electrocoagulation (bicap) of angiodysplasias was performed when accessible and not diffuse (<20). If not contraindicated, hormonal treatment was proposed for patients who had at least five AD. Some patients had both treatments. Long-term follow-up (mean, 12.2 months) was obtained in 25 patients with small bowel angiodysplasias. A good outcome (neither recurrence of anemia nor blood transfusion requirements) was observed in 12 patients. The diagnostic efficacy of push-enteroscopy is high. Despite available and recommended therapeutic modalities, the long-term outcome was considered to be good in only 50% of the patients.
To test whether the differentiation events that lead to the embryonal layers and their derived organs produce divergent X-chromosome activation ratios among the different tissues, the X-chromosome activation ratios in leucocytes and muscle (mesodermal origin), thyroid gland (endodermal origin) and medulla of the suprarenal glands (ectodermal origin) from ten deceased females were surveyed. Analysis of the degree of the methylation of the polymorphic alleles recognized by the probes M27beta and pSPT-PGK showed that the ratios for the medulla of the suprarenals correlated well with those of all other tissues except for leucocytes; the thyroid gland showed limited correlation with muscle, whereas leucocytes showed correlation only with muscle. The results of this preliminary study suggest that differentiation events result in considerable variation in the activation ratios in different tissues. As a consequence caution should be taken in extrapolating from the activation ratios observed in leucocytes or fibroblasts to tissues of endodermal or ectodermal origin.
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BACKGROUND: In severe chronic pancreatitis associated with intraductal stones, therapeutic endoscopy aims to reduce increased intraductal pressure by pancreatic sphincterotomy and stone clearance. METHODS: Results of treatment were evaluated in 70 new patients who underwent pancreatic sphincterotomy and attempted stone removal. Technical results and frequency of pain relief and recurrence are compared. RESULTS: Complete ductal clearance of calculi was obtained in 50% of cases. Immediate clinical improvement occurred in 95% of patients with painful attacks. No severe complications or mortality occurred. Fifty-four percent of all patients with painful chronic pancreatitis did not experience any pain recurrence within 2 years. Associations found to be statistically significant by multivariate analysis were ductal clearance and extracorporeal shock wave lithotripsy, pain disappearance and ductal clearance, pain recurrence and long evolution, and severe disease before treatment and presence of a ductal substenosis. CONCLUSIONS: In this subset of patients our results indicate that the pain of chronic pancreatitis is mainly related to increased intraductal pressure. Endoscopic management appears to be a safe, conservative, alternative to surgery. The best results are obtained when it is performed early in the course of calcifying chronic pancreatitis.
Mutations in distinct sites of epidermal keratins, in particular in the helix initiation and termination regions, cause human genodermatoses due to faulty intermediate filament formation. Extension of this observation to human hereditary hair and nail diseases includes population analyses of human hair keratin genes for natural sequence variations in the corresponding sites. Here we report on a large-scale genotyping of the short helix termination region (HTR) of the human type I cortical hair keratins hHa1, a3-I, and a3-II, and the cuticular hair keratin hHa2. We describe two polymorphic loci, P1 and P2, exclusively in the cuticular hHa2 gene, both creating dimorphic protein variants. P1 is due to a C to T mutation in a CpG element leading to a threonine to methionine substitution; P2 concerns a serine codon AGT that also occurs as an asparagine coding variant AAC. A third polymorphism, P3, is linked with a C to T point mutation located at the very beginning of intron 6. The three polymorphic sites are clustered in a 39-nucleotide sequence of the hHa2 gene. Both allelic frequency calculations in individuals of different races and pedigree studies indicate that the two-allelic hHa2 variants resulting from P1 and P2 occur ubiquitously in a ratio of about 1:1 (P1) and 2:1 (P2) respectively in our survey, and are clearly inherited as Mendelian traits. A genotype carrying both mutations simultaneously on one allele could not be detected in our sampling, and there was no association of a distinct allelic hHa2 variant with the known ethnic form variations of hairs. Sequence comparisons of the HTR of hHa2 with those of other type I hair keratins including the hHa2-ortholog from chimpanzee provide evidence that the P1- and P2-linked mutations must have occurred very early in human evolution and that the two P2-associated codon variants may be the result of two independent point mutations in an ancestral AGC serine codon. These data describe natural polymorphisms in the HTR of a member of the keratin multigene family.
BACKGROUND/AIM: The clinical presentation, pancreatographic findings, and outcome of patients with intraductal papillary mucinous tumours have not been reported in a large patient series in the English literature. This study reviewed 32 patients diagnosed between 1980 and 1994, with special attention to these features. PATIENTS/METHOD: Data on 24 operated and eight non-operated patients were abstracted from inpatient, outpatient, and procedure records. RESULTS: Acute pancreatitis was the most common presentation seen in 56% of patients. Relapses occurred during an average of 43 months before diagnosis. A patulous papilla was observed in 55% of the cases. Endoscopic pancreatography showed communicating cysts, a diffusely dilated main pancreatic duct, and amorphous defects in 42, 71, and 97% respectively. An invasive carcinoma was found in nine of 24 (37.5%) of operated patients: six of the patients (66%) died or developed metastases within three years after surgery. No mortality was related to the tumour in absence of invasive carcinoma. Benign recurrence on the remaining pancreas was unusual and occurred late after surgery. CONCLUSIONS: Intraductal papillary mucinous tumours must be considered in the differential diagnosis of relapsing pancreatitis. Despite slow growing, these tumours have an obvious malignant potential and a very poor prognosis when invasive carcinoma has developed. Early recognition and resection are the cornerstones of treatment.
OBJECTIVE: To compare the efficacy and safety of two enzyme-containing preparations, Pancrease HL (Cilag) containing 25,000 units of lipase per capsule and Creon (Triosol) with 8000 units of lipase per capsule, in patients with chronic pancreatitis and exocrine insufficiency. DESIGN: The study is a monocentric open crossover prospective study including 25 patients entered from March 1993 to May 1994. PATIENTS: Chronic pancreatitis was alcohol-related in 23 patients, previous surgery was performed in 9, 16 had diabetes and all had steatorrhoea (fat balance > 10g/24h). METHODS: Patients were investigated during four periods of 2 weeks, each one corresponding to a new treatment regimen: Pancrease HL, 3 capsules/day or Creon, 9 capsules/day, with or without omeprazole 20 mg/day. Stools were collected on the last 3 days at the end of each period when the patients were on a standard diet with a fixed daily intake of 100 g fat/day. RESULTS: Faecal fat, protein and energy excretion did not differ when both preparations were compared at roughly pharmaceutically equivalent doses. No significant improvement in fat and protein absorption was observed when omeprazole was taken with the pancreatic enzymes. However, omeprazole treatment was associated with a marked decrease in the fat-protein content ratio, suggesting an improvement in the fat digestive process but a decrease in the efficiency of protein digestion. Drug safety was comparable in the four groups of treatment. CONCLUSION: Pancrease HL with high lipase activity provides effective pancreatic enzyme replacement therapy in patients with chronic pancreatitis at an appreciably lower number of capsules per day than with standard preparations.
We report on a family with a severe form of X-linked dilated cardiomyopathy (DCM). Two brothers, the elder requiring heart transplantation, and a maternal cousin presented elevated creatine kinase levels, increased right ventricular diameters and electrocardiographic abnormalities. All complained of exertional cramping myalgia, but none had muscle weakness or a pathological electromyogram. Muscle biopsies of these individuals revealed a mild myopathic picture with atrophic type I and hypertrophic type II fibers. Immunofluorescence using N- and C-terminal antibodies (dys-2, dys-3) against the dystrophin protein showed preserved, but reduced intensity of staining of the sarcolemmal membranes. Using the same two antibodies, Western blot analyses revealed a dystrophin molecule of the expected molecular weight, which was quantitatively reduced by 80%. However, the dys-1 antibody, directed against the mid rod region of the dystrophin protein, did not react with dystrophin both on Western blot and immunofluorescence. Linkage analysis with polymorphic markers of the dystrophin gene revealed an identical haplotype at the 5' region in all affected individuals (two point lod score of 1.93, phi = 0). A deletion of exons 48, 45-53, 2-7 and 1 including the promoter region of the dystrophin gene, as described in rare cases with similar clinical signs could be excluded by multiplex PCR and Southern blot analyses of this DCM family. In addition, a major splice-mutation of dystrophin mRNA was excluded by RT-PCR of skeletal and heart muscle tissue. Therefore, we conclude that a novel mutation in the 5' region of the dystrophin gene phenotypically leads to this severe form of DCM. Extensive analyses of the dystrophin gene, in particular of the sequences coding for the antigenic determinants of the dys-1 antibody in the mid rod region, may identify the molecular cause of this monogenetic form of DCM.
A new 3.8-kb allele at the 5' region of the PGK 1 locus detected by the probe pSPT/PGK is reported. This variant was discovered in the Cabecar and Guaymi, two Chibchan Amerindian groups of Costa Rica. So far, a polymorphism that consists of an EcoRI/BglI (1.3-kb) variable site within an EcoRI/BglII (1.7-kb) fragment when DNA is simultaneously digested with EcoRI, BglI and BglII is known to occur in black and Caucasian populations. These two alleles were also found in the Amerindians tested. The newly described band is due to the lack of the BglII site situated 1.7 kb downstream from the EcoRI site and to the cleavage of another BglII site 2.1 kb downstream from the lacking one. This variant might be restricted to some Amerindian groups and perhaps also to Asiatic populations. Thus, it could be a useful marker in evolutive studies and for forensic applications. Moreover, the presence of a third allele in populations with Amerindian ancestry can increase the heterozygosity of the region disclosed by the pSPT/PGK probe, thus improving its application in issues dealing with X-chromosome activation ratios in females.
The X-chromosome activity states of 11 manifesting carriers of dystrophinopathies, all with normal karyotypes, were estimated by restriction fragment length polymorphism (RFLP)-methylation analysis with the probes M27 beta (DXS255), p2-19(DXS605) and pSPT/PGK (PGK1) to test the role of skewed X-inactivation ratios as the cause of their affected phenotypes. In eight cases preferential inactivation of the putative X chromosome carrying the normal dystrophin allele in > or = 90% of their peripheral lymphocytes was observed, two cases showed non-apparent deviant ratios (60:40 and 70:30) from the theoretically expected values around the mean of 50% and in one case the three markers employed yielded no information. The analysis of the X-inactivation ratio in six mother-daughter pairs, all non-manifesting Duchenne muscular dystrophy (DMD) carriers, and in the close female relatives of the patients showed: (a) neither of the two X chromosomes was preferentially inactivated with respect to their parental origin; (b) a high concordance among the activation ratios of mothers and daughters, a result difficult to explain just in terms of random X-chromosome inactivation.
Pantoprazole is a new substituted benzimidazole, which is a potent inhibitor of gastric acid secretion by its inhibition of H+,K(+)-ATPase. Pantoprazole, 40 mg, was compared with the H2-receptor antagonist ranitidine, 300 mg, in the healing of acute duodenal ulcer. Two hundred seventy-six patients with endoscopically diagnosed duodenal ulcer were studied in this multicenter double-blind study. Patients were reendoscopied after two weeks of treatment, and those patients whose ulcers remained unhealed were also endoscoped after an additional two weeks of treatment. The primary end point was the complete healing of the ulcer. Demographic characteristics were comparable in both treatment groups. After two weeks of treatment, 90/124 (73%) patients in the pantoprazole group had healed ulcers compared with 57/126 (45%) patients in the ranitidine group (P < 0.001, per-protocol analysis). After four weeks, the cumulative healing rates were 92% and 84% in the pantoprazole and ranitidine groups, respectively (P = 0.073). Symptoms were also improved at week 2, with 84% and 72% of patients in the pantoprazole and ranitidine groups, respectively, reporting no ulcer pain (P < 0.05, per-protocol analysis). Both treatments were well tolerated. This study has confirmed the superiority of pantoprazole compared with ranitidine in the healing of duodenal ulcers and pain relief after two weeks of treatment and has shown pantoprazole to be well tolerated in this indication.
BACKGROUND/AIMS: Transforming growth factor beta 1 (TGF-beta 1) is thought to be the mediator of fibrosis in liver, glomerular, and pulmonary fibrosis. This study investigated the expression of TGF-beta 1 precursor (beta 1 latency-associated peptide), latent TGF-beta 1-binding protein (LTBP), and TGF-beta 1 messenger RNA (mRNA) in chronic pancreatitis. METHODS: Beta 1 latency-associated peptide and LTBP expression were studied by immunohistochemistry, and TGF-beta 1 mRNA expression was studied by reverse-transcription polymerase chain reaction analysis in normal pancreatic parenchyma and in tissues from patients with chronic pancreatitis of different etiologies. RESULTS: In normal specimens, TGF-beta 1 precursor was present in islet cells and in a few ductal and acinar cells but not in periductal connective tissue. No immunoreactivity for LTBP was detected. In chronic pancreatitis, TGF-beta 1 precursor was detected mainly in mononuclear cells located in the fibrotic areas and also in ducts damaged by fibrosis, more frequently in calcifying chronic pancreatitis. LTBP was present predominantly in mononuclear cells and in the extracellular matrix around them. TGF-beta 1 mRNA was either not expressed or was faintly expressed in normal tissue, whereas intense signals were detected in chronic pancreatitis. CONCLUSIONS: The findings suggest the involvement of TGF-beta 1 in the development of fibrosis in chronic pancreatitis and the important role of inflammatory cells.
Partial deletions of the dystrophin gene are the predominant genetic lesions in Duchenne (DMD) and Becker (BMD) muscular dystrophies. According to the reading frame hypothesis [1], any deletion disrupting the translational reading frame of the mRNA cannot result in expression of the dystrophin molecule and should lead to severe phenotypes of DMD. In contrast, deletions which maintain the reading frame across the deleted exons may give rise to truncated, semifunctional proteins and milder courses of the disease (i.e. BMD). Among the notable exceptions of this hypothesis are very large "in-frame" deletions by which functionally indispensable domains of the dystrophin molecule have been removed. Here, we report on two DMD patients with large intragenic in-frame deletions. Grossly truncated, but stable dystrophin molecules with preserved C-terminal domains were detected at the sarcolemma on cryosections in both patients. However, dystrophin organization on single-teased muscle fibers revealed disarrangement of the costameric pattern, if compared to normal skeletal muscle fibers. Compared to dystrophin-deficient DMD muscle, expression of chromosome-6-encoded dystrophin-related protein (DRP) was greatly diminished in skeletal muscle of both patients. We show, that loss of more than 50% of dystrophin seems to be deleterious for the protein's function and therefore, the extent of the deletions may have an impact on construction of dystrophin mini genes. Moreover, these findings shed new light on the functional significance of the C-terminal domain of dystrophin. They also suggest a negative correlation between sarcolemmal expression of the dystrophin C-terminus and DRP expression at the sarcolemma.
BACKGROUND: We report our current experience using endoscopic retrograde cholangiography in the management of post-transplantation biliary tract complications. METHODS: Twenty-three patients among 109 adult liver transplant recipients underwent retrograde cholangiography because of cholestasis (18 patients) or bile leaks (5 patients). RESULTS: Eleven of 18 patients developed anastomotic strictures, all successfully dilated by plastic stents; one patient required Roux-en-Y revision due to recurrent cholangitis while stented. Three had biliary calculi extracted following sphincterotomy. Two developed intrahepatic ductal strictures secondary to severe rejection. One patient had hepatic artery thrombosis with a hilar stricture. One cholangiogram was normal. Three patients developed bile peritonitis following T-tube removal, all treated by sphincterotomy and nasobiliary drainage. Choledochal perforation resulting from an impacted T-tube limb was detected in two patients, both treated with sphincterotomy and nasobiliary drainage. CONCLUSIONS: Strictures within 3 months of surgery required 3 months of stenting; those occurring later required longer periods of time to respond. Bile leaks responded uniformly and rapidly to drainage. Endoscopic retrograde cholangiography is a useful diagnostic and therapeutic intervention for post-transplantation biliary tract complications.