Real-World Outcomes of Patients Starting Intravenous and Transitioning to Subcutaneous Vedolizumab in Inflammatory Bowel Disease.

BACKGROUND: Real-world data on starting intravenous (IV) vedolizumab (VDZ) and transitioning to subcutaneous (SC) treatment in inflammatory bowel disease (IBD) are scarce. AIMS: To assess treatment outcomes of patients with IBD starting IV VDZ and switching to SC VDZ in routine clinical care. METHODS: Adult patients with IBD switching from IV to SC VDZ treatment between 1 March 2020 and 31 December 2021 were identified from the Swedish IBD quality register. The primary outcome was SC VDZ persistence. Secondary outcomes included clinical remission, changes in quality of life (QoL) according to EuroQual 5-Dimensions 5-Levels (EQ-5D-5L) and the Short-Health Scale (SHS) and inflammatory markers, including faecal Calprotectin (FCP). RESULTS: Altogether, 406 patients with IBD (Crohn's disease, n = 181; ulcerative colitis, n = 225) were identified. After a median follow-up of 30 months from starting IV VDZ treatment, the persistence rates were 98%(178/181) in Crohn's disease and 94% (211/225) in ulcerative colitis. Most patients (84%) transitioned during maintenance therapy, and the median follow-up from switch to SC VDZ was 10 months. Compared to baseline, statistically significant improvements were observed in all domains of the SHS, EQ-5D index value and visual analogue scale. Median (interquartile range) FCP concentrations (µg/g) decreased from 459 (185-1001) to 65 (26-227) in Crohn's disease (n = 45; p < 0.001) and from 646 (152-1450) to 49 (20-275) in ulcerative colitis (n = 58; p < 0.001). CONCLUSION: Initiating IV VDZ and switching to SC treatment was associated with high persistence rates and improvements in measures of QoL and FCP. These findings are reassuring for patients who start IV VDZ and switch to SC VDZ.

Anti-Saccharomyces cerevisiae Antibodies Are Only Modestly More Common in Subjects Later Developing Crohn's Disease.

BACKGROUND: The pathogenic processes in the preclinical phase of inflammatory bowel disease (IBD) are mainly unknown. AIMS: To study typical antibodies for IBD in the preclinical phase in a cohort of Northern Sweden. METHODS: Antibodies typical for IBD (ASCA, pANCA, lactoferrin-ANCA, antibodies to goblet cells, and pancreas antigen) were analyzed in 123 subjects with preclinical ulcerative colitis (UC), 54 subjects with preclinical Crohn's disease (CD) and in 390 sex- and age-matched controls. In addition, in a subset of subjects, inflammatory markers (CRP, albumin, calprotectin and ferritin) were measured in plasma. RESULTS: The mean years between blood samples and IBD diagnosis were for UC 5.1 (SD 3.5) years and CD 5.6 (SD 3.5) years. There was no difference in the proportion of overall positive antibodies between subjects who later developed IBD compared to controls (16.9% vs. 12.3%; p = 0.137). The subjects who later developed CD had a significantly higher proportion of positive ASCA compared to controls (9.3% vs 2.8%; p = 0.034), but for all other antibodies, there were no differences compared to control subjects. Subjects with preclinical IBD and elevated antibodies showed significantly higher plasma calprotectin levels compared to subjects without antibodies (980 µg/L vs 756 µg/L; p = 0.042), but there was no difference in the levels of CRP, albumin and ferritin. CONCLUSIONS: We found no significant increase in antibodies typical for IBD years before diagnosis except for ASCA, which was slightly more common in subjects who later developed CD. Very few subjects had detectable antibodies to goblet cells and pancreas antigen.

L-Cysteine Containing Vitamin Supplement Which Prevents or Alleviates Alcohol-related Hangover Symptoms: Nausea, Headache, Stress and Anxiety.

AIMS: Alcohol-related hangover symptoms: nausea, headache, stress and anxiety cause globally considerable amount of health problems and economic losses. Many of these harmful effects are produced by alcohol and its metabolite, acetaldehyde, which also is a common ingredient in alcohol beverages. The aim of the present study is to investigate the effect of the amino acid L-cysteine on the alcohol/acetaldehyde related aftereffects. METHODS: Voluntary healthy participants were recruited through advertisements. Volunteers had to have experience of hangover and/or headache. The hangover study was randomized, double-blind and placebo-controlled. Nineteen males randomly swallowed placebo and L-cysteine tablets. The alcohol dose was 1.5 g/kg, which was consumed during 3 h. RESULTS: The primary results based on correlational analysis showed that L-cysteine prevents or alleviates hangover, nausea, headache, stress and anxiety. For hangover, nausea and headache the results were apparent with the L-cysteine dose of 1200 mg and for stress and anxiety already with the dose of 600 mg. CONCLUSIONS: L-cysteine would reduce the need of drinking the next day with no or less hangover symptoms: nausea, headache, stress and anxiety. Altogether, these effects of L-cysteine are unique and seem to have a future in preventing or alleviating these harmful symptoms as well as reducing the risk of alcohol addiction.

Concentrations of infliximab and anti-drug antibodies in relation to clinical response in patients with rheumatoid arthritis.

OBJECTIVE: The efficacy of anti-tumour necrosis factor-α (anti-TNF-α) treatment with infliximab (IFX) may be reduced by the development of anti-drug antibodies (ADAs). This study evaluated drug concentration and the presence of ADAs, relative to response, in rheumatoid arthritis (RA) patients treated with IFX. METHOD: Ninety-four RA patients were consecutively included and assessed for disease activity at baseline, and after 14, and 30 or 52 weeks. Serum IFX concentration and ADAs were analysed using in-house enzyme-linked immunosorbent assays. ADA analysis was based on binding to TNF-α-coated plates, with the lower detection limit set at mean + 2 sd of controls. RESULTS: At 14 and 52 weeks, 74.5% of the patients had moderate to good response. Good responders had significantly higher IFX concentrations than moderate and poor responders at 52 weeks (6.6 ± 1.4 µg/mL vs 3.6 ± 1.3 µg/mL and 2.6 ± 1.6 µg/mL, respectively). An IFX concentration ≥4.66 µg/mL at 14 weeks yielded a moderate to good response at 30/52 weeks, with 91.3% specificity and 39.3% sensitivity. Eleven patients dropped out owing to lack of efficacy and eight owing to side effects; three with IFX concentration ≤ 0.5 µg/mL were ADA positive. At an IFX concentration ≤ 0.5 µg/mL, 43.8% and 30.1% at 14 and 52 weeks, respectively, were ADA positive. None of the good responders had ADAs. CONCLUSION: One-quarter of patients had an IFX concentration ≤ 0.5 µg/mL but only 11.7% had ADAs. High IFX concentration was related to a good response, suggesting that the lack of response could be due to a lack of IFX, rather than to the presence of ADAs.

Genetic-epidemiological evidence for the role of acetaldehyde in cancers related to alcohol drinking.

Alcohol drinking increases the risk for a number of cancers. Currently, the highest risk (Group 1) concerns oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast, as assessed by the International Agency for Research on Cancer (IARC). Alcohol and other beverage constituents, their metabolic effects, and alcohol-related unhealthy lifestyles have been suggested as etiological factors. The aim of the present survey is to evaluate the carcinogenic role of acetaldehyde in alcohol-related cancers, with special emphasis on the genetic-epidemiological evidence. Acetaldehyde, as a constituent of alcoholic beverages, and microbial and endogenous alcohol oxidation well explain why alcohol-related cancers primarily occur in the digestive tracts and other tissues with active alcohol and acetaldehyde metabolism. Genetic-epidemiological research has brought compelling evidence for the causality of acetaldehyde in alcohol-related cancers. Thus, IARC recently categorized alcohol-drinking-related acetaldehyde to Group 1 for head and neck and esophageal cancers. This is probably just the tip of the iceberg, since more recent epidemiological studies have also shown significant positive associations between the aldehyde dehydrogenase ALDH2 (rs671)*2 allele (encoding inactive enzyme causing high acetaldehyde elevations) and gastric, colorectal, lung, and hepatocellular cancers. However, a number of the current studies lack the appropriate matching or stratification of alcohol drinking in the case-control comparisons, which has led to erroneous interpretations of the data. Future studies should consider these aspects more thoroughly. The polymorphism phenotypes (flushing and nausea) may provide valuable tools for future successful health education in the prevention of alcohol-drinking-related cancers.

Changes in chemokines and their receptors in blood during treatment with the TNF inhibitor infliximab in patients with rheumatoid arthritis.

OBJECTIVES: Chemokines are involved in leucocyte recruitment into inflammatory sites. The release of certain chemokines is augmented by tumour necrosis factor (TNF). Infliximab, a monoclonal antibody that blocks the effects of TNF, is used for treatment of rheumatoid arthritis (RA). The effect of TNF blockage on chemokines is not fully understood. The aim of this study was to analyse the effects on chemokines and their receptors on peripheral mononuclear cells of anti-TNF treatment in RA patients. METHOD: Twelve patients with established RA who started treatment with infliximab and nine patients with early RA treated with other anti-rheumatic drugs were followed clinically for 30 weeks and chemokine levels in blood samples were analysed along with chemokine receptor expression on the surface of T cells and monocytes. Nine healthy subjects were included as a control group. RESULTS: The chemokine CXCL10/IP-10 was significantly higher in RA patients than in healthy controls (p = 0.012). Two weeks after infliximab infusion, CXCL10/IP-10, CCL2/MCP-1, and CCL4/MIP-1ß had decreased significantly (p = 0.005, 0.037, and 0.028, respectively), and after 30 weeks of treatment, soluble CD26 was significantly increased (p = 0.050). Several chemokine receptors on T cells were elevated in RA patients at inclusion. The expression of CCR2 and CXCR1 on T cells decreased significantly after infliximab treatment. CONCLUSIONS: The chemokines CXCL10/IP-10, CCL2/MCP-1, and CCL4/MIP-1ß, mainly targeting the T-helper (Th)1 immune response, decreased after treatment with anti-TNF, suggesting a more pronounced effect on Th1 activity than on Th2-mediated response. Several chemokine receptors on blood T cells were elevated in RA patients, suggesting that they may be involved in the recruitment of T lymphocytes from the blood to affected tissues.

Decreased prevalence of left-handedness among females with male co-twins: evidence suggesting prenatal testosterone transfer in humans?

Studies of singletons suggest that right-handed individuals may have higher levels of testosterone than do left-handed individuals. Prenatal testosterone levels are hypothesised to be especially related to handedness formation. In humans, female members from opposite-sex twin pairs may experience elevated level of prenatal exposure to testosterone in their intrauterine environment shared with a male. We tested for differences in rates of left-handedness/right-handedness in female twins from same-sex and opposite-sex twin pairs. Our sample consisted of 4736 subjects, about 70% of all Finnish twins born in 1983-1987, with information on measured pregnancy and birth related factors. Circulating testosterone and estradiol levels at age 14 were available on 771 and 744 of these twins, respectively. We found significantly (p=.006) lower prevalence of left-handedness in females from opposite-sex pairs (5.3%) compared to females from same-sex pairs (8.6%). The circulating levels of neither testosterone nor estradiol related to handedness in either females or males. Nor were there differences in circulating testosterone or estradiol levels between females from opposite-sex and same-sex twin pairs. Birth and pregnancy related factors for which we had information were unrelated to handedness. Our results are difficult to fully explain by postnatal factors, but they offer support to theory that relates testosterone to formation of handedness, and in a population-based sample, are suggestive of effects of prenatal testosterone transfer.

Interleukin-6 and soluble interleukin-2 receptor alpha-markers of inflammation in patients with psoriatic arthritis?

OBJECTIVE: To evaluate a possible systemic effect of joint inflammation in contrast to skin disease only, by measuring IL-6 and IL-2sRalpha. METHODS: Two hundred and nineteen patients (111 male / 108 female, age 50.4+/-14.5 yrs (mean+/-SD)) with psoriasis were clinically and laboratory examined. 134 patients had inflammatory joint manifestations defined as peripheral arthritis and/or axial disease, of whom 37 had measurable inflammation, defined as ESR >25 mm/h and/or CRP >15 mg/L. RESULTS: Interleukin-6 was significantly higher in patients with joint disease and measurable inflammation ((median, Q1-Q3) 4.07, 0.92-14.60), and in patients without measured inflammation (1.22, 0.70-3.46), compared to patients with skin disease only (0.70, 0.70-1.73, p<0.001 and p=0.002 respectively). The difference between the two groups of patients with inflammatory joint manifestations was significant (p=0.001). The levels of IL-6 correlated with the actual number of joints affected with arthritis (p<0.001; rs=0.248), ESR (p<0.001; rs=0.459), CRP (p<0.001; rs=0.314) and IL-2sRalpha (p=0.002; rs=0.210). The levels of IL-2sRalpha. did not differ between the 3 groups. CONCLUSION: In this study, IL-6 was significantly higher in patients with psoriasis and inflammatory joint disease with or without routine measurable inflammatory activity compared with patients having psoriasis of the skin. We found that patients with psoriasis and joint inflammation may have systemic effects that could be captured by serum measurements of IL-6. Soluble IL-2Ralpha was not a marker of inflammation in this study.

Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury.

BACKGROUND & AIMS: The transcription factor nuclear factor-eythroid 2-related factor 2 (Nrf2(-/-)) is essential for protecting cells against xenobiotic and oxidative stress. Increased oxidative stress has been implicated in the pathophysiology of many diseases including ethanol-induced liver disease. Therefore, the role of Nrf2(-/-) in ethanol-induced liver injury was investigated. METHODS: Wild-type and Nrf2(-/-) mice were fed with the ethanol diet, followed by examination of liver pathology, mortality, and ethanol metabolism. RESULTS: Nrf2(-/-) mice displayed a dramatically increased mortality associated with liver failure when fed doses of ethanol that were tolerated by WT mice. Nrf2(-/-) mice showed a significantly reduced ability to detoxify acetaldehyde, leading to an accumulation of the toxic metabolite. Loss of Nrf2(-/-) caused a marked steatosis in livers of ethanol-fed mice, and Srebp1 was identified as a candidate transcription factor responsible for lipogenic enzyme induction. Furthermore, ethanol consumption led to a progressive depletion of total and mitochondrial reduced glutathione, which was associated with more pronounced structural and functional changes to mitochondria of Nrf2(-/-) mice. In addition, ethanol feeding elicited an aggravated inflammatory response mediated by Kupffer cells in Nrf2(-/-) mice as shown by an increased tumor necrosis factor-alpha secretion and activation of the interleukin-6/Stat-3 pathway. Together these changes lead to a vicious cycle of accumulating hepatocellular damage, ultimately leading to liver failure and death of Nrf2(-/-) mice. CONCLUSIONS: Our data establish a central role for Nrf2(-/-) in the protection against ethanol-induced liver injury.

The role of aldehyde dehydrogenase-1 (ALDH1A1) polymorphisms in harmful alcohol consumption in a Finnish population.

Liver cystolic aldehyde dehydrogenase 1 (ALDH1A1) has been previously associated with both alcohol dependence and alcohol consumption behaviour, and has been implicated in alcohol-induced flushing and alcohol sensitivity in Caucasians. The present study tested for association between ALDH1A1 and alcohol consumption behaviour and susceptibility to problem drinking or alcohol dependence in Finnish cohorts of unrelated male subjects recruited from alcoholism clinical treatment facilities ( n = 104) and from the general population ( n = 201). All participants completed the Alcohol Use Disorder Identification Test (AUDIT) and were genotyped for eight single nucleotide polymorphisms (SNPs) within or flanking ALDH1A1 . To test for association between alcohol consumption behaviour and these polymorphisms, we used generalised linear models and haplotypic analysis. Three SNPs were nominally associated (rs348449, p = 0.043; rs610529, p = 0.013; rs348479, p = 0.025) with the quantitative AUDIT score, which evaluates alcohol consumption behaviour. Two-locus (rs610529-rs2288087) haplotype analysis increased the strength of association with AUDIT score ( p = 0.0015). Additionally, rs348449 is highly associated with problem drinking (allelic odds ratio [OR] 7.87, 95 per cent confidence interval [CI] 1.67-37.01) but due to the low minor allele frequency (0.01 and 0.07 in controls and problem drinkers, respectively), more samples are required to validate this observation. Conversely, rs348479 ( p = 0.019) and rs610529 (allelic OR 0.65, 95 per cent CI 0.43-0.98; genotypic OR 0.32, 95 per cent CI 0.12-0.84) are implicated in alcohol dependence status. This study provides further evidence for a role for ALDH1A1 in alcohol consumption behaviour, including problem drinking and possibly alcohol dependence, in our Finnish population.

A well-being programme in severe mental illness. Baseline findings in a UK cohort.

INTRODUCTION: Patients with severe mental illness (SMI) have higher rates of cardiovascular disease (CVD) morbidity and mortality than the general population. In the UK, data were limited regarding the known prevalence of physical health screening of SMI patients. AIMS: A total of 966 patients with SMI from seven geographically varied regions in the UK agreed to participate in a 2-year nurse-led intervention (Well-being Support Programme), designed to improve their overall physical health by providing basic physical health checks, health promotion advice, weight management and physical activity groups in secondary care. RESULTS: At baseline, only 31% of participants had undergone a recent physical health check. There were high rates of obesity (BMI > 30 in 49%), glucose abnormalities (12.4%), hypertension/prehypertension (50%), hyperlipidaemia (71%), poor diet (32%), low exercise levels (37.4%) and smoking (50%). CONCLUSIONS: Patients with SMI where healthcare professionals have concerns regarding their physical health, have potentially modifiable risk factors for CVD, which remain undiagnosed. Programmes designed to address the physical health problems in SMI need to be implemented and evaluated in this already marginalised group of people.

Effect of moderate alcohol consumption on plasma dehydroepiandrosterone sulfate, testosterone, and estradiol levels in middle-aged men and postmenopausal women: a diet-controlled intervention study.

BACKGROUND: Moderate alcohol consumption is inversely associated with cardiovascular diseases. Changes in hormone levels might in part help explain the positive health effect. This study was performed to examine the effect of moderate alcohol consumption on plasma dehydroepiandrosterone sulfate (DHEAS), testosterone, and estradiol levels. METHODS: In a randomized, diet-controlled, crossover study, 10 middle-aged men and 9 postmenopausal women, all apparently healthy, nonsmoking, and moderate alcohol drinkers, consumed beer or no-alcohol beer with dinner during two successive periods of 3 weeks. During the beer period, alcohol intake equaled 40 and 30 g per day for men and women, respectively. The total diet was supplied and had essentially the same composition during these 6 weeks. Before each treatment there was a 1 week washout period, in which the subjects were not allowed to drink alcoholic beverages. At the end of each of the two experimental periods, fasting blood samples were collected in the morning. RESULTS: Moderate alcohol consumption increased plasma DHEAS level by 16.5% (95% confidence interval, 8.0-24.9), with similar changes for men and women. Plasma testosterone level decreased in men by 6.8% (95% confidence interval, -1.0- -12.5), but no effect was found in women. Plasma estradiol level was not affected. Serum high-density lipoprotein cholesterol level increased by 11.7% (95% confidence interval, 7.3-16.0), with similar changes for men and women. The overall alcohol-induced relative changes in DHEAS, testosterone, and estradiol correlated positively with the relative increase in high-density lipoprotein cholesterol (adjusted for the relative change in body weight); however, findings were only borderline significant for DHEAS and estradiol (r = 0.44, p = 0.08; r = 0.32, p = 0.21; and r = 0.46, p = 0.06, respectively). CONCLUSIONS: A protective effect of moderate alcohol consumption for cardiovascular disease risk may in part be explained by increased plasma DHEAS level.

Oestradiol and human male alcohol-related aggression.

AIMS: In comparison to androgens, almost nothing is known about the role of endogenous oestrogens in human aggressive behaviour. This new aspect was studied in the present investigation involving men with a history of alcohol-related aggression (AGG+) and in an age-matched male control population (AGG-). METHODS: Male AGG+ volunteers were recruited through advertisements and the controls were drawn from the Finnish Population Register. Alcohol misuse and interpersonal partner violence were estimated by questionnaires. Endogenous hormone levels were measured from morning plasma samples. RESULTS: A positive association emerged between plasma oestradiol and emotional negotiation during interpersonal conflict situations. Furthermore, a negative association was observed between oestradiol and testosterone-related physical, violent, aggression in the AGG+ men. In addition, oestradiol, rather than testosterone, was positively associated with psychological aggression in both groups of men. CONCLUSION: It is suggested that endogenous female sex hormones may be related to empathic behaviour and could, thus, represent a counter-balancing factor in alcohol-related male aggressive behaviour. Altogether, oestrogen may represent a multifactor ingredient in the complex interactions of partner conflicts.

Abnormal expression of chemokine receptors on T-cells from patients with systemic lupus erythematosus.

The expression of chemokine receptors on T-cells and chemokine levels in the blood was studied in 23 patients with SLE (ACR criteria), seven patients with rheumatoid arthritis (RA) and in 15 healthy controls using flow cytometry, RT-PCR and ELISA. The cell surface expression of the chemokine receptors CXCR5 and CCR6 was decreased in SLE patients compared with controls (P = 0.051 and P = 0.002, respectively). The decrease of CXCR5 was confined to SLE patients with inactive disease (SLEDAI < 6) compared with active disease (SLEDAI > 6) and controls. CXCR2 and CCR1 were increased in patients with active SLE compared with patients with inactive disease (P = 0.001 and P = 0.01, respectively) and with controls (P = 0.02 and P = 0.053, respectively). The levels of the chemokines MIP-1alpha MCP-1, SDF-1alpha, IP-10 and RANTES were significantly elevated in SLE patients compared with controls. Patients with renal involvement had increased surface expression of CXCR3 and CCR3 (P = 0.04 in both) and a lower level of soluble IP-10 compared with patients without renal disease (P = 0.025) and compared with controls (P = 0.001). The ratio between CCR5 and CCR3 was significantly increased in RA patients compared with SLE patients and controls supporting a Th1 overweight in RA. In conclusion, patients with SLE showed abnormal T-cell expression of several chemokine receptors and levels of soluble chemokines in their plasma/serum.

Protection by glutathione of neutrophils against the toxic effects of peritoneal dialysis fluid.

The possibility of reducing the cytotoxic effect of heat-sterilized peritoneal dialysis (PD) fluid by addition of antioxidants/scavengers during incubation of titanium-adhering cells was investigated. Capillary blood from healthy donors was placed in drops on commercially available titanium pieces and incubated in a humidified chamber at 37 degrees C for 60min. After incubation the adherent polymorphonuclear leukocytes were immersed for 1-4h in PD-fluid, pH 7.4, containing 2.5% glucose with glutathione (GSH), superoxide dismutase, catalase or dithiothreitol (DTT). Luminol- or isoluminol-amplified chemiluminescence was used to measure the zymosan- and phorbol myristate acetate (PMA)-stimulated respiratory burst activity, as an indicator of the cytotoxicity of the PD-fluids. Heat sterilized PD-fluid had inhibitory effect on zymosan-induced respiratory burst and impaired both the extracellular and intracellular PMA-induced respiratory burst. Addition of GSH to the PD-fluid resulted in reduction of cytotoxical effects on the zymosan-induced and extracellular PMA-induced respiratory burst. The intracellular respiratory burst was not affected. The present results show that GSH and DTT have the ability to protect polymorphonuclear leukocytes against the cytotoxic effects of the PD-fluid by keeping the cell membrane in a reduced state.

Treatment with cisplatin and etoposide in patients with neuroendocrine tumors.

BACKGROUND: Patients with malignant endocrine pancreatic tumors (EPTs) are responsive to combinations of chemotherapy with streptozotocin and 5-fluorouracil/doxorubicin, whereas patients with malignant carcinoids are not. For both categories of patients, alpha-interferon and/or somatostatin analogs can produce long-lasting responses. Cisplatin in combination with etoposide has been suggested to be effective in patients with malignant neuroendocrine carcinomas. The authors used this therapy as second-line or third-line treatment in patients with poorly differentiated and/or rapidly progressing disease. METHODS: Thirty-six patients with histopathologically verified malignant neuroendocrine tumors were included: Eighteen tumors were of foregut origin, of which 5 were atypical, and 15 tumors were EPTs, of which 4 were poorly differentiated endocrine carcinomas. Three tumors were of midgut origin. The median patient age was 47.5 years. The median duration of disease from the time of diagnosis was 12 months. All patients had metastatic disease. Thirty of 36 patients had received previous treatment. Etoposide was given at a dose of 100 mg/m(2) per day for 3 days, and cisplatin was given at a dose of 45 mg/m(2) on Days 2 and 3 as a continuous intravenous infusion that was repeated every 4 weeks. RESULTS: Ten of 18 patients with foregut carcinoids (56%) responded radiologically and/or biochemically, with a median duration of 9 months; and 7 of 14 patients with EPTs (50%) responded radiologically and/or biochemically, with a median duration of 9 months. No difference in response was seen between patients with atypical or typical foregut carcinoids or between patients with well differentiated or poorly differentiated endocrine pancreatic carcinoma. Nineteen of 36 patients (53%) experienced World Health Organization (WHO) Grade 1-2 nephrotoxicity, and 23 patients (64%) suffered from WHO Grade 3-4 neutropenia. CONCLUSIONS: The combination of cisplatin and etoposide can produce significant responses in patients with heavily pretreated and poorly differentiated/rapidly progressing neuroendocrine tumors. The toxicity is considerable, and nephrotoxicity is the dose limiting factor.

The role of acetaldehyde in the actions of alcohol (update 2000).

BACKGROUND: Recent advances in the field of acetaldehyde (AcH) research have raised the need for a comprehensive review on the role of AcH in the actions of alcohol. This update is an attempt to summarize the available AcH research. METHODS: The descriptive part of this article covers not only recent research but also the development of the field. Special emphasis is placed on mechanistic analyses, new hypotheses, and conclusions. RESULTS: Elevated AcH during alcohol intoxication causes alcohol sensitivity, which involves vasodilation associated with increased skin temperature, subjective feelings of hotness and facial flushing, increased heart and respiration rate, lowered blood pressure, sensation of dry mouth or throat associated with bronchoconstriction and allergy reactions, nausea and headache, and also reinforcing reactions like euphoria. These effects seem to involve catecholamine, opiate peptide, prostaglandin, histamine, and/or kinin mechanisms. The contribution of AcH to the pathological consequences of chronic alcohol intake is well established for different forms of cancer in the digestive tract and the upper airways. AcH seems to play a role in the etiology of liver cirrhosis. AcH may have a role in other pathological developments, which include brain damage, cardiomyopathy, pancreatitis, and fetal alcohol syndrome. AcH creates both unpleasant aversive reactions that protect against excessive alcohol drinking and euphoric sensations that may reinforce alcohol drinking. The protective effect of AcH may be used in future treatments that involve gene therapy with or without liver transplantation. CONCLUSIONS: AcH plays a role in most of the actions of alcohol. The individual variability in these AcH-mediated actions will depend on the genetic polymorphism, not only for the alcohol and AcH-metabolizing enzymes but also for the target sites for AcH actions. The subtle balance between aversive and reinforcing, protecting and promoting factors will determine the overall behavioral and pathological developments.