Depressive symptoms and suicidal ideation during isotretinoin treatment: a 12-week follow-up study of male Finnish military conscripts.

OBJECTIVE: To investigate the putative association between isotretinoin treatment and depressive symptoms or suicidal ideation among Finnish male military conscripts. METHODS; Consecutive acne patients were enrolled into an uncontrolled, prospective 12-week follow-up study conducted at the Central Military Hospital, Helsinki, Finland. Of the 135 patients prescribed isotretinoin, 126 (93.3%) completed the follow-up. Depression and suicidal ideation were investigated with the Beck Depression Inventory (BDI) at baseline, weeks 4-6, and weeks 10-12. RESULTS: BDI mean score was low at baseline and declined further significantly (p < 0.001) during the follow-up from 3.0 (SD 3.948) to 1.8 (SD 3.783) among patients on isotretinoin. Moreover, the proportion of patients with clinically significant depressive symptoms (BDI > or= 10) declined non-significantly from 7.1 % to 3.2 %. Suicidal ideation was reported by 17 (13.5 %) patients at baseline and 9 (7.1%) patients at the end of the follow-up (NS). During the follow-up, one non-depressed patient attempted suicide while intoxicated by alcohol. CONCLUSION: On group level, isotretinoin seems not to be typically associated with treatment-emergent depression or suicidal ideation among young men. However, the possibility that individual patients may be susceptible for mood effects of isotretinoin as a rare idiosyncratic reaction can not be excluded.

Depressive symptoms, suicidal ideation and acne: a study of male Finnish conscripts.

OBJECTIVE: To investigate the association among acne, depressive symptoms and suicidal ideation in Finnish male military conscripts. METHODS: Consecutive 165 acne patients and 150 patients with mild knee symptoms for comparison were enrolled in the study conducted in the Central Military Hospital, Helsinki, Finland. They filled out the following questionnaires: General Health Questionnaire (GHQ-12), Beck Depression Inventory (BDI), Alcohol Use Disorders Identification Test and Rosenberg Self-Esteem Scale. The Leeds acne grading scale was used to estimate the severity of acne. RESULTS: Sixteen (9.7%) acne patients and 20 (13.3%) comparison patients had at least moderate level of depressive symptoms (BDI score 10; P > 0.05, between groups). Suicidal ideation (BDI suicidal item score 1) was reported by 24 (14.5%) acne patients and 16 (10.7%) comparison patients (P > 0.05, between groups). When comparing the mild facial acne patients (Leeds score 0-3) with those with moderate-severe facial acne (Leeds score 4), there were no statistical differences in depressive symptoms (9.5% vs. 10.0%) or suicidal ideation (13.7% vs. 15.7%). No linear relationship was observed between the BDI and facial Leeds scores (P > 0.05). Risk factors for suicidal ideation among the acne patients were depression and alcohol risk use. CONCLUSION: Young male patients with acne do not suffer more depressive symptoms or suicidal ideation than patients with mild knee symptoms, and the severity of acne is not associated with the presence of depressive symptoms. The risk factors for suicidal ideation among acne patients seem to be similar to those found in the general population.

Stromelysin-2 is upregulated during normal wound repair and is induced by cytokines.

Stromelysin-2 is a matrix metalloproteinase that degrades in vitro several protein components relevant to wound repair such as collagens III and IV, gelatin, nidogen, laminin-1, proteoglycans, and elastin. Furthermore, it can activate other matrix metalloproteinases, such as collagenase-1 (matrix metalloproteinase-1) and collagenase-2 (matrix metalloproteinase-8), as well as 92 kDa gelatinase. The aim of this study was to determine in a large variety of wounds (normally healing dermal and mucosal wounds, suction blisters, ex vivo cultures, diabetic, decubitus, rheumatic, and venous ulcers) and keratinocyte cultures, which factors contribute to stromelysin-2 expression and how it is induced in relation to other matrix metalloproteinases. Our results show that stromelysin-2 mRNA and protein are upregulated later (at 3 d) than matrix metalloproteinase-1 in normally healing wounds and ex vivo explants, in which stromelysin-2 is invariably expressed by keratinocytes migrating over dermal matrix. The number of keratinocytes expressing stromelysin-2 was greatest in chronic inflamed diabetic and venous ulcers compared with rheumatoid and decubitus ulcers, six of which had no signal. In keratinocyte cultures, tumor necrosis factor-alpha, epidermal growth factor, and transforming growth factor-beta1 induced stromelysin-2 expression as measured by quantitative reverse transcriptase-polymerase chain reaction, whereas different matrices did not upregulate the mRNA. Immunostaining demonstrated stromal transforming growth factor-beta1 in contact with the stromelysin-2-positive keratinocytes. Our results suggest that stromelysin-2 expression is important for the normal repair process and is upregulated by cytokines rather than cell-matrix interactions. Stromelysin-2 is most likely to participate in the remodeling of the newly formed basement membrane, and is not overexpressed in retarded wound healing.

Colloidal bismuth subcitrate and omeprazole inhibit alcohol dehydrogenase mediated acetaldehyde production by Helicobacter pylori.

We have recently shown that Helicobacter pylori possesses marked alcohol dehydrogenase (ADH) activity and is capable--when incubated with an ethanol containing solution in vitro--of producing large amounts of acetaldehyde. In the present study we report that some drugs commonly used for the eradication of H. pylori and for the treatment of gastroduodenal diseases are potent ADH inhibitors and, consequently, effectively prevent bacterial oxidation of ethanol to acetaldehyde. Colloidal bismuth subcitrate (CBS), already at a concentration of 0.01 mM, inhibited H. pylori ADH by 93% at 0.5 M ethanol and decreased oxidation of 22 mM ethanol to acetaldehyde to 82% of control. At concentrations above 5 mM, CBS almost totally inhibited acetaldehyde formation. Omeprazole, a drug also known to suppress growth of H. pylori, also inhibited H. pylori ADH and suppressed bacterial acetaldehyde formation significantly to 69% of control at a drug concentration of 0.1 mM. By contrast, the H2-receptor antagonists ranitidine and famotidine showed only modest effect on bacterial ADH and acetaldehyde production. We suggest that inhibition of bacterial ADH and a consequent suppression of acetaldehyde production from endogenous or exogenous ethanol may be a novel mechanism by which CBS and omeprazole exert their effect both on the growth of H. pylori as well as on H. pylori associated gastric injury.

Alcohol dehydrogenase mediated acetaldehyde production by Helicobacter pylori--a possible mechanism behind gastric injury.

Two standard Helicobacter pylori strains showed significant cytosolic alcohol dehydrogenase activity and produced considerable amounts of acetaldehyde when incubated with an ethanol containing solution in vitro. The alcohol dehydrogenase activity of the Helicobacter pylori strains was almost as high as that found in Klebsiella pneumoniae and far greater than that in Escherichia coli or Campylobacter jejuni. The amount of acetaldehyde produced by cytosol prepared from Helicobacter pylori exceeded that by any of the other bacteria studied. The bacterial production of acetaldehyde--a highly toxic and reactive substance--could be an important factor in the pathogenesis of Helicobacter pylori associated gastric injury and increased risk of gastric cancer.

Effect of alcohol consumption on the risk of Helicobacter pylori infection.

To investigate the effect of alcohol consumption on the risk of Helicobacter pylori infection, standardized questionnaires on drinking habits were used to interview 451 patients, whose H. pylori status was determined both by culture and serology. Reported alcohol consumption did not increase the risk of H. pylori infection (a 1.0 odds ratio, CI95 0.6-1.6). However, when the patients were divided into two age-groups, those under 35 years who reported to use alcohol seemed to have a slightly higher risk of H. pylori infection (a 3.3 odds ratio CI95 0.9-12.2) compared to those over 35 years (a 1.0 odds ratio, CI95 0.5-2.2). This phenomenon did not reach statistical significance. The type of alcohol consumed did not affect the age-adjusted risk of H. pylori infection. If pathologically defined chronic gastritis was found, the risk for H. pylori was high (a 26.7 odds ratio, CI95 12.1-59.0, for those under 35 years, and a 12.8 odds ratio, CI95 6.7-24.3, for those over 35 years of age.

Effect of ABO blood group and secretor status on the frequency of Helicobacter pylori antibodies.

Duodenal ulcer is associated with such genetic characteristics as blood group O and secretor status. Since Helicobacter pylori has been proved to be an important factor in the pathogenesis of duodenal ulcer, we wanted to study whether the frequency of H. pylori antibodies would vary in individuals with different blood group antigens. Antibodies against H. pylori were determined in 271 blood donors. Acid glycine extract from an H. pylori strain was used as antigen in enzyme immunoassay. Our results suggested no significant association of increased level of H. pylori antibodies with ABO blood group and secretor status, which implies that H. pylori infection is not associated with the ABO group and secretor status. Thus H. pylori and blood group antigens seem to be independently linked to duodenal ulcer.

Is Helicobacter pylori infection associated with chronic urticaria?

There have been controversial reports of an elevated prevalence rate of Helicobacter pylori infection in chronic urticaria patients. Furthermore, in some studies remission of chronic urticaria has been reported after eradication of H. pylori. The aim of this investigation was to evaluate the prevalence of H. pylori infection among chronic urticaria patients and to study the effect of eradication therapy on urticaria symptoms. Chronic urticaria patients (n=235) were enrolled and H. pylori status was determined serologically. Thirty-five patients received antimicrobial triple therapy. 25% of the patients were positive for H. pylori. The prevalence of H. pylori infection was not significantly higher among urticaria patients compared with the normal Finnish population in any of the age groups studied. Of the successfully treated patients, 27% showed remission of urticaria. Our data suggest that the prevalence of H. pylori infection is not elevated among chronic urticaria patients and that H. pylori eradication does not appear to influence the course of chronic urticaria.

Effect of bismuth and nitecapone on acetaldehyde production by Helicobacter pylori.

BACKGROUND: We have recently shown that colloidal bismuth subcitrate inhibits cytosolic alcohol dehydrogenase of Helicobacter pylori as well as acetaldehyde production from excess ethanol. We now extend our studies to bismuth subsalicylate and nitecapone, a novel antiulcer agent. METHODS: Cytosol of H. pylori was incubated with 0.1% or 1% ethanol in the presence of different drug concentrations for 2 h, whereafter acetaldehyde formed was analyzed by head space gas chromatography. In addition, we incubated a culture solution containing intact bacteria with the drugs at 1% ethanol. RESULTS: Bismuth subsalicylate and nitecapone inhibit acetaldehyde formation from 0.1% ethanol by H. pylori cytosol at drug concentrations theoretically achievable in the stomach after intake of therapeutic doses of these drugs. Furthermore, colloidal bismuth subcitrate, bismuth subsalicylate, and nitecapone also inhibit acetaldehyde production by intact H. pylori, although rather high drug concentrations are required for this to occur. CONCLUSIONS: Inhibition of H. pylori acetaldehyde formation may be one of the mechanisms by which bismuth and nitecapone exert their effect in the treatment of H. pylori-related disorders.

Acetaldehyde and ethanol production by Helicobacter pylori.

By virtue of possessing alcohol dehydrogenase activity, cytosol prepared from Helicobacter pylori produces toxic acetaldehyde from ethanol in vitro. To approach the in vivo situation in the stomach, we have now investigation whether intact H. pylori--without addition of exogenous nicotinamide adenine dinucleotide--also forms acetaldehyde. Furthermore, to assess the energy metabolism of H. pylori, we determined whether the alcohol dehydrogenase-catalyzed reaction can run in the opposite direction with ethanol as the end-product and thereby yield energy for the organism. Intact H. pylori formed acetaldehyde already at low ethanol concentrations (at 0.5% ethanol, acetaldehyde, 64 +/- 21 and 75 +/- 9 mumol/l (mean +/- SEM) for strains NCTC 11637 and NCTC 11638, respectively). H. pylori produced ethanol in concentrations that can be significant for the energy metabolism of the organism. Acetaldehyde production by H. pylori may be an important factor in the pathogenesis of gastroduodenal diseases associated with the organism. The primary function of H. pylori alcohol dehydrogenase may, however, be alcoholic fermentation and consequent energy production under microaerobic conditions.

Antigenic characterization of Helicobacter pylori strains from different parts of the world.

Although Helicobacter pylori is considered to be relatively homogeneous at the phenotypic level, our aim was to describe its antigenic heterogeneity and to examine differences in host response. Whole-cell lysates of H. pylori strains originally isolated from persons from Africa, the People's Republic of China, Japan, Peru, Thailand, or the United States or from monkeys were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Immunoblots were performed by using sera from H. pylori-infected persons from different areas of the world and rabbit immune sera against H. pylori antigens. Specific H. pylori antibody responses in persons from the United States and the People's Republic of China were analyzed by enzyme-linked immunosorbent assay with antigens prepared from U.S. or Chinese strains. Despite diverse origins, the strains showed conserved major bands of 84, 60, 56, 31, and 25 kDa. Although there were clear differences in minor bands, there was no obvious geographic pattern. The anti-CagA serum recognized 120- to 140-kDa bands in cagA+ strains from around the world. Although antigenic preparations from individual U.S. or Chinese strains were not optimally sensitive for serologic detection of infection in the heterologous country, use of pools of strains largely overcame this phenomenon. We conclude that conserved H. pylori antigens exist and are recognized by sera from persons from many parts of the world. The heterogeneity of H. pylori antigens and the serological responses of infected hosts is not fully explained by geographic differences. Use of pools may allow development of antigens for serologic testing in any country.

Increase of allergen-specific immunoglobulin E antibodies from 1973 to 1994 in a Finnish population and a possible relationship to Helicobacter pylori infections.

BACKGROUND: The prevalence of atopic diseases--hayfever, asthma and eczema--has increased over the past decades. The increase may be associated with decreased rates of infections such as measles, hepatitis A, tuberculosis, toxoplasmosis, and, as recently suggested, Helicobacter pylori gastritis. OBJECTIVE: Since the increase of atopy has been mainly based on clinical studies, we wanted to study the prevalence of allergen-specific Immunoglobulin (Ig)E antibodies in two cross-sectional, adult population-based serum samples two decades apart. Since the sera had been tested for H. pylori antibodies, we also had a chance to look for a possible relationship between these two findings. METHODS: We determined the prevalence rate of allergen-specific serum IgE antibodies against birch and timothy pollen, and cat and dog epithelium allergens by the radioallergosorbent test in a 15-54-years-old Finnish population using 326 sera collected in 1973 and 319 sera collected in 1994 from randomly selected subjects. RESULTS: From 1973 to 1994 allergen-specific IgE prevalence rates and IgE antibody levels rose. In 1994, the prevalence rate of positive findings in 15-24-year-old population had increased from 11 to 38% (3.5-fold increase, P = 0.0001, OR 5.12, CI 95% 2.32-11.3). In older 10-year age groups similar trends did not reach significance, but the overall change was significant with all three cut-off levels of allergen-specific IgE analysed. The percentage of IgE-positive persons rose mainly in the subgroup with no H. pylori antibodies. In 1994 21% of the H. pylori-negative subjects had IgE antibodies compared with 5% of the H. pylori-positive subjects (in 1973 11% in both subgroups). CONCLUSIONS: IgE-based evidence for an increase in IgE-mediated allergy was uncovered. The increase occurred mainly in the subgroup with no antibodies to H. pylori, which support the hypothesis that H. pylori could be one of the microbes counteracting atopy.

Flavodoxin-dependent pyruvate oxidation, acetate production and metronidazole reduction by Helicobacter pylori.

Helicobacter pylori flavodoxin was purified to homogeneity from cell extracts of strain NCTC 11637. The molecular weight of the protein was estimated by gel electrophoresis to be 18 kDa. Oxidized flavodoxin showed an absorption spectrum with maxima at 378 nm and 453 nm, and it was reduced to a neutral form of flavin semiquinone by the electrons generated in the oxidation of pyruvate. This coenzyme A dependent pyruvate:flavodoxin oxidoreductase activity of H. pylori was also detected as a reduction of methyl viologen or cytochrome c by bacterial extracts. The apparent Km of pyruvate was 310 microM. Anaerobically incubated bacteria (10[9]) of strain NCTC 11637 produced acetate (96 +/- 16 nmol/h) from pyruvate concomitantly reducing metronidazole (17 +/- 5 nmol/h). In anaerobic conditions both sensitive and resistant H. pylori strains reduced metronidazole, and there was a significant positive correlation between acetate production and metronidazole activation (r = 0.77, P < 0.01, n = 11). In the presence of atmospheric oxygen, H. pylori excreted twice as much acetate but metronidazole was not activated. These results suggest that the pyruvate:flavodoxin oxidoreductase complex catalyses pyruvate oxidation in H. pylori. Electrons generated in this reaction are transferred to flavodoxin and under anaerobic conditions further to metronidazole (imidazoles) thus reducing the drug to its bactericidal form.

The Helicobacter felis mouse model in assessing anti-Helicobacter therapies and gastric mucosal prostaglandin E2 levels.

BACKGROUND: The aims of the present study were to assess the usefulness of the Helicobacter felis mouse model in the evaluation of antimicrobial therapies and the effect of Helicobacter infection on gastric mucosal prostaglandin E2 release. METHODS: Barrier-maintained BALB/c mice were infected with H. felis and treated with different antibacterial therapies. H. felis status was determined by bacterial culture, urease test, and bacterial and histologic stainings. Release of prostaglandin E2 from the gastric mucosa was measured by radioimmunoassay. RESULTS: All triple-treated mice were cleared of bacteria both 24 h and 1 month after treatment. However, tinidazole alone also resulted in 100% eradication. Monotherapies with erythromycin acistrate, tetracycline, colloidal bismuth subcitrate, and nitecapone failed to eradicate the bacteria. The release of gastric prostaglandin E2 was doubled in the infected mice (554 +/- 39, mean +/- SE) compared with the noninfected mice (270 +/- 35) (p < 0.01). CONCLUSIONS: The H. felis mouse model proved satisfactory for assessing both anti-Helicobacter therapies and the prostaglandin E2 release. The reliability of this method was improved when several methods to assess the H. felis status were used in parallel.

Association of alcohol consumption and Helicobacter pylori infection in young adulthood and early middle age among patients with gastric complaints. A case-control study on Finnish conscripts, officers and other military personnel.

There is growing evidence that Helicobacter pylori is responsible for a variety of gastric and duodenal changes which can eventually lead to stomach cancer. Little is known about risk factors for H. pylori infection. We re-analyzed the association of alcohol with H. pylori positivity in 451 conscripts, officers and other military personnel endoscoped due to gastric complaints in the Central Military Hospital of Finland in 1987 and 1988. Serology and culture were done in all patients. Alcohol consumption histories were obtained by use of a self-administered questionnaire. We observed a high odds ratio (OR) of H. pylori infection among young adults who were heavy alcohol consumers compared to non-drinkers (OR 5.32, 95% confidence interval: 1.09-25.95). There was evidence of a dose response when heavy and moderate drinkers were compared to non-drinkers (Mantel-Haenszel chi 2 for trend, p = 0.02) in young adulthood. A subgroup of young respondents who reported drinking all classes of alcohol (including hard liquor) showed an even stronger association and more significant dose-response. Multivariate techniques revealed a qualitative interaction of alcohol with H. pylori positivity in different age groups and among old people an inverse association of H. pylori and alcohol consumption was observed. These findings, if confirmed independently, might have implications for preventing a variety of gastric and duodenal lesions, since they allow identification of high risk groups.

DNA sequence conservation and diversity in transposable element IS605 of Helicobacter pylori.

BACKGROUND: IS605, a transposable element-like sequence identified in the virulence-associated cag region of Helicobacter pylori reference strain NCTC11638, is unusual in containing two oppositely-oriented open reading frames whose products are homologues of the single transposases of the unrelated elements, IS200 and IS1341. METHODS: One hundred independent H. pylori isolates from different parts of the world were screened by PCR and dot blot hybridization to determine the presence of IS605. For some positive isolates, southern hybridizations and sequence analyses were done. RESULTS: Of the 100 isolates, 31 were found to contain sequences related to each ORF with orientation and spacing matching those in canonical IS605-hybridizing sequences. No isolate containing just one ORF and not the other was found. The frequencies of IS605 carriage were independent of geographical origin (U.S. vs. non-U.S.), and of the probable virulence of the isolate (cag status, toxin production or vacA alleles, patient symptoms). Southern blot hybridization of six IS605-containing strains revealed one to nine IS605 copies per genome. Two types of DNA sequence diversity were found: first, a specific 100 bp deletion in two isolates; second, base substitution divergence of 0.4% to 7.5% in pairwise comparisons among the eight isolates characterized, a level of divergence similar to that seen in other H. pylori chromosomal genes. CONCLUSIONS: Based on these findings, we speculate that IS605 is a relatively ancient component of the H. pylori gene pool that has proliferated in this species by horizontal gene transfer, homologous recombination, and transposition.

Characteristics of Helicobacter pylori alcohol dehydrogenase.

BACKGROUND: Helicobacter pylori shows alcohol dehydrogenase activity, which in the presence of ethanol leads to in vitro production of acetaldehyde, a toxic and highly reactive substance. The present study was undertaken to further define H. pylori-related ethanol and acetaldehyde metabolism by characterizing H. pylori alcohol dehydrogenase and by determining whether the organism possesses aldehyde dehydrogenase. METHODS: Cytosolic alcohol and aldehyde dehydrogenase activities were determined spectrophotometrically. Acetaldehyde produced by cytosol during incubation with ethanol was measured by head space gas chromatography. Isoenzyme pattern was studied using isoelectric focusing. RESULTS: Significant alcohol dehydrogenase activity was observed at a neutral pH known to occur in gastric mucus. The Km for ethanol oxidation was approximately 100 mmol/L for the two strains tested. Acetaldehyde was formed already from a low ethanol concentration known to prevail in the stomach endogenously. Isoelectric focusing of the enzyme showed activity bands with pI at 7.1-7.3, a pattern different from that of gastric mucosal alcohol dehydrogenase. 4-methylpyrazole inhibited enzyme activity in a competitive manner and suppressed the growth of the organism during culture. Neither Helicobacter strain studied showed aldehyde dehydrogenase activity and can thus not remove acetaldehyde by that pathway. CONCLUSIONS: Acetaldehyde production by H. pylori from exogenous or endogenous ethanol may be a pathogenetic mechanism behind mucosal injury associated with the organism.

Phenotypic diversity in Lewis expression of Helicobacter pylori isolates from the same host.

Populations of Helicobacter pylori cells show a stable expression of Lewis surface antigens, although phase variation may occur among individual organisms grown in vitro. We searched for variation in Lewis phenotypes among H. pylori cells of minimally in vitro-passaged isolates. Lewis expression in 180 clonal H. pylori populations from the primary culture of 20 gastric biopsy samples from 12 patients, and that in 160 isolates from primary cultures from 16 experimentally infected rodents, were examined by enzyme immunoassays. Substantial differences in Lewis expression were found among the isolates from 9 (75%) of 12 patients. These differences were unrelated to overall genetic diversity as determined by polymerase chain reactions for random amplified polymorphic DNA or cagA status, and they persisted during subsequent in vitro passage. In contrast, Lewis expression was highly uniform in H. pylori isolates from different rodents infected for up to 20 weeks. Variation in H. pylori Lewis expression in genetically closely related organisms in human subjects may provide a pool of bacterial phenotypes for the continuous selection of optimally host-adapted populations suitable for persistence.

Helicobacter infection and gastric ethanol metabolism.

The organism frequently colonizing the stomach of patients suffering from chronic active gastritis and peptic ulcer disease--Helicobacter pylori--possesses marked alcohol dehydrogenase (ADH) activity. Consequently, Helicobacter infection may contribute to the capacity of the stomach to metabolize ethanol and lead to increased acetaldehyde production. To study this hypothesis, we first determined ADH activity in a variety of H. pylori strains originally isolated from human gastric mucosal biopsies. ADH activity was also measured in endoscopic gastric mucosal specimens obtained from H. pylori-positive and -negative patients. Furthermore, we used a mouse model of Helicobacter infection to determine whether infected animals exhibit more gastric ethanol metabolism than noninfected controls. Most of the 32 H. pylori strains studied possessed clear ADH activity and produced acetaldehyde. In humans, gastric ADH activity of corpus mucosa did not differ between H. pylori-positive and -negative subjects, whereas in antral biopsies ADH activity was significantly lower in infected patients. In mice, gastric ADH activity was similar or even lower in infected animals than in controls, depending on the duration of infection, despite the fact that the infectious agent used--Helicobacter felis--showed ADH activity in vitro. In accordance with this, Helicobacter infection tended to decrease rather than increase gastric ethanol metabolism in mice. In humans, it remains to be established whether the observed decrease in antral ADH activity associated with H. pylori infection can lead to reduced gastric first-pass metabolism of ethanol.