The FOXC2 -512C>T variant is associated with hypertriglyceridaemia and increased serum C-peptide in Danish Caucasian glucose-tolerant subjects.

AIMS/HYPOTHESIS: The transcription factor FOXC2 plays a key role in adipocyte differentiation and the FOXC2 gene is a candidate gene for Type 2 diabetes, obesity and dyslipidaemia. We investigated whether the FOXC2 -512C>T promoter variant is associated with Type 2 diabetes or its intermediary phenotypes in glucose tolerant subjects. METHODS: The variant was genotyped using PCR-RFLP in 705 unrelated Type 2 diabetic patients, 505 unrelated glucose-tolerant control subjects and 219 glucose-tolerant offspring of Type 2 diabetic probands. RESULTS: The frequency of the T-allele was 58% (95% CI 56-61%) and 59% (56-62%) among the Type 2 diabetic patients and the unrelated glucose-tolerant control subjects, respectively ( p=0.6). Among the glucose-tolerant subjects, the T-allele carriers had higher fasting serum triglyceride ( p=0.03), fasting serum C-peptide concentrations ( p=0.009) and insulinogenic index ( p=0.04). Furthermore, in glucose-tolerant women, the waist-to-hip ratio was significantly higher in carriers of the T-allele. CONCLUSION/INTERPRETATION: Our data suggest that the FOXC2 -512C>T variant is not associated with Type 2 diabetes. However, among glucose-tolerant subjects the variant is associated with hypertriglyceridaemia and increased fasting serum C-peptide.

Dual versus triple therapy in eradication of Helicobacter pylori.

BACKGROUND/AIMS: Duodenal ulcers should be treated by eradication of Helicobacter pylori. This study compared the efficacy of a proton pump inhibitor together with one or two antibiotics in eradication therapy. METHODOLOGY: 177 patients who were H. pylori positive were randomized to receive 14 days of either: lansoprazole 30 mg bd and amoxicillin 1 g bd (LA), omeprazole 20 mg bd and amoxicillin 1 g bd (OA) or lansoprazole 30 mg bd, amoxicillin 1 g bd and clarithromycin 500 mg bd (LAC). The efficacy was assessed at four weeks and at six months after the end of treatment. Biopsies were taken for culture and bacterial sensitivity testing at inclusion and at four weeks after the end of treatment. RESULTS: 149 patients were evaluated for efficacy. The eradication rate was significantly higher in LAC (96%) compared to LA (51%) and OA (64%) treatments (P < 0.001). At baseline 17%, 21% and 19% of the patients in the LA, OA and LAC groups, respectively, were resistant to metronidazole and only one patient was resistant to clarithromycin. Post-treatment, four patients had acquired metronidazole resistance. CONCLUSIONS: LAC is more effective than LA and OA for eradication of H. pylori in duodenal ulcer disease.

FOXC2 is a winged helix gene that counteracts obesity, hypertriglyceridemia, and diet-induced insulin resistance.

Obesity, hyperlipidemia, and insulin resistance are common forerunners of type 2 diabetes mellitus. We have identified the human winged helix/forkhead transcription factor gene FOXC2 as a key regulator of adipocyte metabolism. Increased FOXC2 expression, in adipocytes, has a pleiotropic effect on gene expression, which leads to a lean and insulin sensitive phenotype. FOXC2 affects adipocyte metabolism by increasing the sensitivity of the beta-adrenergic-cAMP-protein kinase A (PKA) signaling pathway through alteration of adipocyte PKA holoenzyme composition. Increased FOXC2 levels, induced by high fat diet, seem to counteract most of the symptoms associated with obesity, including hypertriglyceridemia and diet-induced insulin resistance--a likely consequence hereof would be protection against type 2 diabetes.

Solution structure and dynamics of the DNA-binding domain of the adipocyte-transcription factor FREAC-11.

Transcription factors of the forkhead type share a highly conserved DNA-binding domain of about 100 amino acid residues. FREAC-11, expressed in adipocytes, belongs to this class. Here, we report on NMR studies that established the three-dimensional structure of the FREAC-11, DNA-binding domain. Although apparent similarities to the structures of other members within the forkhead family are observed, the structure also reveals some remarkable differences. Along with the complementary dynamics, the data provide insight into the fundamentals of sequence specificity within a highly conserved motif.

Piperacillin/tazobactam compared with cefuroxime/ metronidazole in the treatment of intra-abdominal infections.

OBJECTIVE: To assess the effect of piperacillin/tazobactam compared with cefuroxime/metronidazole in the treatment of patients with intra-abdominal infections. DESIGN: Randomised open study. SETTING: 16 Swedish and 6 Norwegian hospitals. SUBJECTS: 269 patients with intra-abdominal infections were randomised and treated with at least one dose of each study drug. 205 patients, 105 treated with piperacillin/tazobactam and 100 with cefuroxime, were clinically evaluable for follow up (had been given the full course of treatment). INTERVENTION: Patients were given piperacillin 4g/tazobactam 0.5 g every 8 hours or cefuroxime 1.5 g every 8 hours plus metronidazole 1.5 g every 24 hours. Each patient was to be treated for a minimum of 3 days and not more than 10 days. MAIN OUTCOME MEASURES: Clinical evaluation of infection at the end of and 4-6 weeks after treatment. Evaluation of safety and tolerance to the drugs and bacteriological susceptibility to the treatment drugs. RESULTS: In the intention to treat analysis treatment was equally successful for piperacillin/ tazobactam (103/140, 74%) and the cefuroxime/metronidazole groups (90/129, 70%) (p = 0.6). Corresponding figures for the clinically evaluable group were 102/105 (97%) and 94/100 (94%) for piperacillin/tazobactam and cefuroxime/metronidazole groups, respectively, at the end of treatment. At late follow up, 92/105 (88%) and 83/100 (83%) in the two groups, respectively, remained free of infection. The side effects of the treatment were mild and evenly distributed between the two groups. Most pathogens were susceptible to the drugs in both treatment groups. CONCLUSION: Both piperacillin/tazobactam and cefuroxime/metronidazole are well suited to the treatment of patients with intra-abdominal infections, and we found no significant difference between the two. The drugs were safe and well tolerated in the regimens used.

The kidney-expressed winged helix transcription factor FREAC-4 is regulated by Ets-1. A possible role in kidney development.

In this paper we show that the kidney-expressed winged helix transcription factor FREAC-4 is regulated by Ets-1, another kidney-expressed transcription factor. Through transfection experiments three Ets-1 cis-elements are identified within the first 152 nucleotides upstream of the transcription start in the freac-4 promoter. These sites are confirmed in a DNase I in vitro protection assay using recombinant Ets-1 protein. In cotransfection experiments using an Ets-1 expression vector, the induction of freac-4 reporter gene activity is attenuated approximately 6-fold when the three Ets-1 binding sites are mutated. Furthermore, we demonstrate that overexpression of Ets-1 in the human embryonic kidney cell line 293 is sufficient to increase freac-4 mRNA levels. These results are compatible with the hypothesis that Ets-1 acts as an upstream regulator of FREAC-4 expression during kidney development.

Metronidazole prophylaxis to prevent infections after total abdominal hysterectomy.

METHODS: In a randomized double-blind study, 134 patients were given 500 mg metronidazole as an intravenous infusion immediately before operation for abdominal total hysterectomy and again 8 hours later and 124 patients received placebo. RESULTS: There was more wound infection, postoperative hospitalization was longer and the sedimentation rate on the sixth postoperative day was significantly higher in the placebo group. There was no difference in postoperative temperature. Postoperative wound infections occurred in 12% in the placebo group and 6% in the metronidazole group. Eight percent in the total material had urinary tract infections, the diagnosis was based on urine cultures. CONCLUSIONS: Prophylaxis with intravenous infusion of metronidazole is recommended in total hysterectomies.

Cloning and characterization of freac-9 (FKHL17), a novel kidney-expressed human forkhead gene that maps to chromosome 1p32-p34.

We describe the cloning of a near full-length cDNA of 4258 nucleotides encoding freac-9 (HGMW-approved symbol FKHL17), a novel human forkhead gene. The 5' untranslated region is unusual since it is very long, 2127 nucleotides, and contains 15 upstream AUG codons. Hybridization to a panel consisting of RNA derived from 50 different tissues showed that freac-9 is transcribed exclusively in the kidney. The kidney-derived cell lines COS-7 and 293 are shown to express freac-9. A combination of fluorescence in situ hybridization and somatic cell hybrids localizes freac-9 to the chromosomal region of 1p32-p34. The conceptual translation product predicts a protein of 372 amino acids with an N-terminal domain rich in acidic amino acids and with a high likelihood of forming an amphipatic helix, a DNA binding forkhead domain, and a C-terminal region that has a high probability of forming an amphipatic beta-sheet. The amino acid sequence of the DNA binding forkhead motif of FREAC-9 is identical to that of another forkhead protein, FREAC-4, whereas 12 substitutions are present at the nucleotide level. There are no similarities in regions outside of the DNA binding domains of FREAC-9 and FREAC-4 and since freac-4 maps to a different chromosome (5q12-q13) it is likely that an evolutionary selection has acted to maintain identical DNA binding domains between these two kidney expressed transcription factors.

Chromosome localization, sequence analysis, and expression pattern identify FKHL 18 as a novel human forkhead gene.

The forkhead gene family of transcription factors belongs to the "winged helix" class of DNA-binding proteins. Today over 40 members of this gene family have been identified. Forkhead genes have been shown to be involved in embryonic development, tumorigenesis, and direction of tissue specificity of gene expression. Here we describe a new human forkhead gene called freac-10 (HGMW-approved symbol FKHL 18). A combination of fluorescence in situ hybridization and somatic cell hybrids localizes freac-10 to the chromosomal region of 20q11.1-q11.2. Hybridization to a panel consisting of RNA derived from 50 different tissues shows that freac-10 is transcribed predominantly in the aorta, thus having a unique expression pattern compared with other forkhead genes. Sequence comparison reveals a striking similarity, over the conserved DNA binding region, to a murine forkhead gene-fkh-3. We propose, based on sequence differences in the N- and C-terminal regions of the forkhead domain and a clear difference in expression pattern between freac-10 and fkh-3, that freac-10 represents a novel member of this gene family.

Characterization of the human forkhead gene FREAC-4. Evidence for regulation by Wilms' tumor suppressor gene (WT-1) and p53.

We describe the cloning and sequence analysis of a nearly full-length cDNA as well as a corresponding 5.2-kilobase pair genomic fragment encoding FREAC-4, a member of the forkhead family of transcription factors. The cDNA is collinear with respect to the coding region of the intronless genomic clone. The conceptual translation product predicts a protein of 465 amino acids with a hyperacidic amino-terminal end, a DNA binding forkhead domain and a carboxyl-terminal part that is rich in homopolymeric runs of prolines and alanines. The transcription start is identified using an RNase protection assay. A 2.7-kilobase pair genomic DNA fragment, located immediately upstream of the translation start, was fused to a luciferase reporter gene. Significant levels of luciferase activity were detected when this construct was transfected into two kidney-derived cell lines, 293 and COS-7 cells, whereas only background reporter gene expression was observed in a cell line of nonkidney origin. Cotransfections with plasmids expressing WT-1, WTAR (a mutated form of WT-1), p53, and a mutated form of p53 revealed a complex pattern of regulation with a 3-fold induction with WT-1, a 7-fold induction with mutated p53, and a 4-fold repression with wild-type p53. A 5'-promoter deletion series delimits a DNA fragment necessary for WT-1 inducibility in cotransfection experiments. This fragment is shown to contain at least one cis-element that is capable of interacting with recombinant WT-1.

Truncal gunshot wounds in Finland, 1985 to 1989.

A nationwide survey of truncal gunshot wounds identified 119 patients managed in 34 institutions. The wounds resulted from low-velocity bullets in 69%, high-velocity bullets in 6%, and shotgun pellets in 25%. The thoracic or abdominal cavity was penetrated in 62%, and the mean Injury Severity Score was 16 (range, 1 to 57). The wounding capacity of close-range shotgun pellets equaled that of high-velocity bullets, whereas long-range (>10 meters) shotgun injuries resembled air rifle injuries in their poor ability to penetrate deeper structures and cause internal injuries. A thoracotomy or sternotomy was required in 31% of the penetrating thoracic injuries. Of 57 laparotomies, 9% were negative. In four cases (7% of all laparotomies), a significant abdominal organ injury was overlooked at the initial operation, emphasizing the importance of meticulous exploration of all abdominal organs, and especially the diaphragm and the retroperitoneal structures.

Penetration of clarithromycin and its 14-hydroxy metabolite into middle ear effusion in children with secretory otitis media.

Clarithromycin suspension was given at a dosage of 7.5 mg/kg bd for 7 days to 31 children with secretory otitis media, scheduled for insertion of grommets. The fifth dose was given approximately 2.5 h before myringotomy and aspiration of the middle ear effusion at which time a blood sample also was taken. In addition, in 16 children blood samples were taken at 1, 1.5 and 4 h after the fifth dose. The concentrations of clarithromycin and its active 14-hydroxylated metabolite, in middle ear effusion and serum, were determined by HPLC. Before therapy, at surgery on day 3 and after completion of treatment, nasopharyngeal samples were taken for culture and susceptibility testing. In the middle ear effusions mean concentrations of clarithromycin (2.5 mg/L) and metabolite (1.3 mg/L) were considerably higher than the serum concentrations (1.7 and 0.8 mg/L, respectively). The mean concentrations in middle ear effusion exceeded the MICs for most respiratory pathogens. Complete eradication of Streptococcus pneumoniae, Moraxella catarrhalis and Streptococcus pyogenes from the nasopharynx was achieved after three days of therapy. Approximately 50% of the isolates of Haemophilus influenzae were eradicated from approximately 50% of the patients and the growth of the persisting strains was decreased from abundant or moderate to sparse. Adverse events were mild and transient and were experienced by only two of the 31 children.

Prevalence of genital Chlamydia trachomatis infection among women in a Swedish primary health care area.

The objective of this study was to estimate the prevalence of genital chlamydial infection in an unselected population of young women by offering a screening investigation to all women between the ages of 15 and 34 in a primary health care area. Specimens were taken from both the urethra and the cervix in all participating women, and data regarding the participants' symptoms, sexual habits, contraceptive use and socioeconomic factors were also collected. The specimens were analyzed with a primary enzyme immunoassay (Syva MikroTrak) and a confirmatory direct immunofluorescence test (Syva MikroTrak). A total of 543 women were invited to the study and 374 women (68.9%) participated. 10/374 women (2.7%) were chlamydia positive and only 2 of these 10 chlamydia infected women were less than 25 years of age. The chlamydia infected women had positive tests either from the urethra (4 women) or from the cervix (6 women), and in no case the tests were positive from both locations. No statistically significant differences between the chlamydia positive and negative women were found concerning any clinical or anamnestic factor.

Young onset peptic ulcer disease and non-ulcer dyspepsia are separate entities.

The characteristics of peptic ulcer and non-ulcer dyspepsia in young men were studied in 202 consecutive conscripts who attended Central Military Hospital in Helsinki because of long-standing upper abdominal complaints. Active peptic ulceration (APU) was found in 48 patients, inactive peptic ulcer disease (IPU) was diagnosed in 77 patients, non-ulcer dyspepsia (NUD) was diagnosed in 52 patients. In 25 cases the reason for symptoms was another disease, and these patients were excluded from the study. A control series (CON) consisted of 30 symptomless healthy young male volunteers. The likelihood of discriminating between peptic ulcer disease and non-ulcer dyspepsia in a young male patient with dyspepsia are indicated by odds ratios (OR) and its 95% confidence limits (CL 95). Active peptic ulcer disease differs from NUD, e.g., by 1) presence of antrum gastritis, OR 41.5 (CL 95: 10.1-171), 2) Helicobacter pylori in the gastric mucosa, OR 31.0 (7.4-130), 3) Lewisa+ phenotype, OR 8.9 (1.7-45.4), 4) serum pepsinogen I (S-PGI) greater than 100 micrograms/l, OR 4.6 (1.7-12.4), 5) non-secretor status, OR 4.3 (1.6-11.6), and 6) O-blood group, OR 3.0 (1.2-7.7). In conclusion, the status of gastroduodenal mucosa, gastric secretion pattern and distribution of some genetic markers in patient series indicate that young onset peptic ulcer and non-ulcer dyspepsia are two separate entities. Helicobacter-positive antrum gastritis is the best determinant of ulcer risk, but also high S-PGI, Lewisa+ phenotype, non-secretor status and O-blood group are signs of increased risk of peptic ulcer.

Ultrasonography of jumper's knee.

The aim of the study was to evaluate the role of ultrasonography (US) in the management of jumper's knees. Sixty-two cases of clinically suggested jumper's knees, 52 asymptomatic contralateral knees and 100 asymptomatic knees of healthy middle aged men were examined. In the symptomatic group US was normal in 25 cases, all recovered with conservative therapy. In 31 symptomatic knees the findings were consistent with jumper's knee as a hypoechoic lesion located in the upper insertion of the patellar tendon in 23 cases and in the distal insertion in one case. In 7 cases the lesion was situated in the insertion of the quadriceps tendon. Surgery was performed on 20 knees and in all of them there was a lesion matching the lesion detected by US. In 6 cases US findings were pathologic, but different from jumper's knee. US findings consistent with jumper's knee could not be detected in the asymptomatic group.

Campylobacter pylori is associated with chronic gastritis but not with active peptic ulcer disease.

Campylobacter pylori is supposed to be involved in the pathogenesis of gastroduodenal peptic ulcer diseases and chronic gastritis. In order to study whether the Campylobacter pylori in the stomach of peptic ulcer patients is related to ulcer itself or to a co-existing chronic gastritis, we examined the frequency of the bacteria in Giemsa stained histological sections of biopsy specimens from a series of patients with active peptic ulcer and from series of non-ulcer control subjects. We found no difference in the frequency of Campylobacter- positive cases between ulcer patients and non-ulcer controls when the comparison was done within the same category of chronic gastritis; e.g., within the category of chronic superficial gastritis 74% and 78% of cases showed the bacteria in antral biopsies from ulcer patients and from non-ulcer controls, respectively. In both ulcer patients and control subjects, in similar way in both antral and body mucosa, the Campylobacter pylori was strongly associated with chronic superficial gastritis but was more weakly associated with chronic atrophic gastritis, and the bacteria were only occasionally seen in normal mucosa. We conclude that Campylobacter pylori is associated with chronic gastritis in peptic ulcer patients but is not related to active ulcer.

Intrafamilial spreading of Escherichia coli resistant to trimethoprim.

Bacterial resistance to trimethoprim has mainly been considered a problem confined to hospitals. The present investigation was undertaken to check for any possible spread of trimethoprim resistance borne by uropathogenic Escherichia coli among families of outpatients. Family members, living in the same household as outpatients with urinary tract infections caused by a trimethoprim-resistant E. coli strain, were asked to deliver faecal specimens. Of a total number of 51 family members 16 were found to be carrying trimethoprim-resistant E. coli in their faecal flora. A comparison of serotypes showed 8 of the 16 family members to have the same E. coli strain in their faeces as originally isolated in the urine of the index patient from the same family. The results indicate that resistance to trimethoprim not only spreads in hospitals with intensive use of antibiotics, but also among the families of trimethoprim-treated outpatients.

The effect of cefaclor on the nasopharyngeal flora in children with chronic OME.

About 80% of children with chronic OME carry respiratory pathogens in the nasopharynx, with a remarkably stable spectrum and frequency. In a randomized clinical trial the nasopharyngeal flora was determined in 45 untreated cases and in 32 cases treated with cefaclor (Kefolor), 20 mg/kg body weight b.i.d. for 10 days. Compared to the untreated children, the treated group showed a significantly decreased frequency of Streptococcus pneumoniae and Branhamella catarrhalis, and a reduced number of cultures with mixed pathogens. An approximate quantitative survey showed a decreased growth of Haemophilus influenzae, but the frequency of isolation was unchanged. The results are put in relation to the penetration of cefaclor to adenoid tissue and middle ear effusion in chronic OME.

The effect of erythromycin on the nasopharyngeal pathogens in children with secretory otitis media.

Seventy-five children not older than 11 years, with secretory otitis media of more than 3 months' duration were randomly divided into two groups prior to myringotomy. One group remained untreated, whereas the other received erythromycin ethylsuccinate (Abboticin) in standard dosage for the last 10 days before surgery. Nasopharyngeal cultures were taken under general anaesthesia, which ensured an uniform mode of sampling. In the erythromycin-treated group the occurrence of Streptococcus pneumoniae (3%) and Branhamella catarrhalis (0%) was significantly lower than in the control group (35% and 32%, respectively); and the frequency of cultures with no pathogen was significantly higher in the treated group. The occurrence of Haemophilus influenzae remained essentially unchanged.

Comparison of metronidazole with doxycycline prophylaxis in elective colorectal surgery. A prospective, randomized multicentre study.

In a series of 157 patients undergoing elective colorectal surgery, metronidazole or doxycycline was given to prevent infectious complications. The prophylaxis was started just before the operation and was administered for a total of three days. Excluding mild, negligible infections, 39 (25%) of the 157 patients had infectious complications, 23 from the metronidazole group (28%) and 16 from the doxycycline group (21%). The type of infection varied according to the medication. In four cases of the metronidazole group and 16 of the doxycycline group, anaerobic bacteria were found. The corresponding figures for aerobes were 36 and 20. Doxycycline thus was significantly more effective in preventing complications in general, but metronidazole gave superior protection against anaerobes.