Cannabis Use as Risk or Protection for Type 2 Diabetes: A Longitudinal Study of 18 000 Swedish Men and Women.

Aims. Whether or not cannabis use may increase or decrease the risk of type 2 diabetes is not clear. We analyzed the association between cannabis and subsequent type 2 diabetes and if a potential positive or reverse association persisted after controlling for potential confounders. Methods. In this population-based cohort study, 17,967 Swedish men and women (aged 18-84 years), who answered an extensive questionnaire in 2002 (including questions on cannabis use), were followed up for new cases of type 2 diabetes (n = 608) by questionnaire (in 2010) and in health registers during 2003-2011. Odds ratios (ORs) with 95% CIs were estimated in a multiple logistic regression analysis. Potential confounders included age, sex, BMI, physical inactivity, smoking, alcohol use, and occupational position. Results. The crude association showed that cannabis users had a reduced risk of type 2 diabetes OR = 0.68 (95% CIs: 0.47-0.99). However, this inverse association attenuated to OR = 0.94 (95% CIs: 0.63-1.39) after adjusting for age. Conclusions. The present study suggests that there is no association between cannabis use and subsequent type 2 diabetes after controlling for age. To make more robust conclusions prospective studies, with longer periods of follow-up and more detailed information about cannabis use, are needed.

High dose ursodeoxycholic acid in primary sclerosing cholangitis does not prevent colorectal neoplasia.

BACKGROUND: Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) have a high risk of developing colorectal cancer and dysplasia. Ursodeoxycholic acid (UDCA) has been suggested to have chemopreventive effects on the development of colorectal cancer and dysplasia but long-term data and larger trials are lacking. AIM: To evaluate the effect of high dose (17-23 mg/kg/day) UDCA on colorectal neoplasia in a cohort of patients with PSC and IBD. METHODS: From our previous 5-year randomised controlled trial of UDCA vs. placebo in PSC, we performed a follow-up of 98 patients with concomitant IBD from entry of the trial 1996-1997 until 2009 for development of colorectal cancer or dysplasia. RESULTS: The total follow-up time was 760 person-years. Dysplasia/cancer-free survival was compared between placebo- (n = 50) and UDCA-treated (n = 48) patients. There was a similar frequency of dysplasia or cancer after 5 years between patients originally assigned to UDCA or placebo (13% vs. 16%) and no difference in dysplasia/cancer-free survival (P = 0.46, log rank test). At the end of 2009 no difference in cancer-free survival was detected, 30% of the placebo patients compared with 27% of UDCA patients had developed colorectal cancer or dysplasia. CONCLUSIONS: Long-term high dose ursodeoxycholic acid does not prevent colorectal cancer or dysplasia in patients with primary sclerosing cholangitis-associated inflammatory bowel disease.

Chronic colitis induces expression of ß-defensins in murine intestinal epithelial cells.

Anti-microbial peptides are important effectors in innate immunity. In the gut they defend against pathogens, shape the commensal microbiota and probably control intestinal homeostasis. Ulcerative colitis (UC), but not Crohn's disease, shows increased expression of inducible ß-defensins (hBD-2, hBD-3 and hBD-4) in colonic epithelial cells. Does inducible defensin production precede the chronic intestinal inflammation characteristic of UC, or is it a consequence of the T cell-driven chronic inflammation? The aim was to analyse defensin mRNA and protein expression in colonic epithelial cells in two colitis mouse models resembling UC, the interleukin (IL)-2(-/-) mouse and the dextran sulphate sodium (DSS)-induced colitis mouse. Defensin mRNA was assayed by in situ hybridization and quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR). Defensin peptide was assayed by immunohistochemistry. Mouse ß-defensin 3 (mBD-3, orthologue to hBD-2) was up-regulated strongly in colonic epithelium of 15-week-old IL-2(-/-) mice and DSS-induced colitis mice with chronic bowel inflammation, but not in apparently healthy IL-2(-/-) 5-week-old mice, IL-2(+/-) 15-week-old mice or in acute stage DSS mice. Up-regulation was seen both at the mRNA- and at the protein level (only mBD-3 investigated). IL-17, but not several other cytokines, including interferon (IFN)-γ, induced mBD-3 mRNA expression in mouse colon carcinoma cells. The mRNA expression level of the constitutively expressed α-defensin, cryptdin-4, was up-regulated marginally in acute stage DSS-colitis mice and in IL-2(-/-) mice before signs of colitis. Inducible ß-defensin expression in colonic epithelium is the consequence of the chronic bowel inflammation caused by activated T cells releasing cytokines including IL-17.

The epidemiology and clinical features of portal vein thrombosis: a multicentre study.

BACKGROUND: Reliable epidemiological data for portal vein thrombosis are lacking. AIMS: To investigate the incidence, prevalence and survival rates for patients with portal vein thrombosis. METHODS: Retrospective multicentre study of all patients registered with the diagnosis of portal vein thrombosis between 1995 and 2004. RESULTS: A total of 173 patients (median age 57 years, 93 men) with portal vein thrombosis were identified and followed up for a median of 2.5 years (range 0-9.7). The mean age-standardized incidence and prevalence rates were 0.7 per 100,000 per year and 3.7 per 100,000 inhabitants, respectively. Liver disease was present in 70 patients (40%), malignancy in 27%, thrombophilic factors in 22% and myeloproliferative disorders in 11%. Two or more risk factors were identified in 80 patients (46%). At diagnosis, 65% were put on anticoagulant therapy. Thrombolysis, TIPS, surgical shunting and liver transplantation were performed in 6, 3, 2 and 8 patients, respectively. The overall survival at 1 year and 5 years was 69% and 54%. In the absence of malignancy and cirrhosis, the survival was 92% and 76%, respectively. CONCLUSIONS: The incidence and prevalence rates of portal vein thrombosis were 0.7 per 100,000 inhabitants per year and 3.7 per 100,000 inhabitants, respectively. Concurrent prothrombotic risk factors are common. The prognosis is variable and highly dependent on underlying disease.

Tumor cure probability during alpha-RIT of ovarian cancer with different radiation sensitivity.

PURPOSE: To calculate the tumor cure probability (TCP) and metastatic cure probability (MCP) during alpha-radioimmunotherapy (alpha-RIT) of small ovarian cancer tumors with cells of different radiation sensitivity. MATERIALS AND METHODS: An in-house-developed biokinetic model and a Monte-Carlo program were used to calculate the cumulative activity on tumor cell surfaces and the specific energy to tumor cell nuclei, respectively. An in-house-developed computational model was used to calculate the TCP and MCP as a function of assumed radiation sensitivities, expressed as D(37), of the tumor cells. The calculations were performed using various assumptions regarding the activity distribution in measured tumors and used the alpha-particle energies emitted from astatine-211 ((211)At). Regarding the calculations of the cumulative activity on each cell surface, the number of antigenic sites expressed by NIH:OVCAR-3 cells for the mAb MX35 F(ab')2 was used. To illustrate the tumor growth at the peritoneum in nude mice, scanning electron microscopy images were used. RESULTS: In the case of a maximum diffusion depth of 30 mum for the activity in the tumors, the TCP was high for D(37) values not exceeding approximately 4.3, approximately 2.9, approximately 1.8, and approximately 0.8 Gy for 200, 100, 50, and 25 kBq (211)At-MX35 F(ab')2 four weeks after cell inoculation, respectively. In order to achieve complete remission of the metastatic disease in mice (i.e. MCP=1), the D(37) value should not exceed approximately 2.2, approximately 1.3, approximately 0.6, and approximately 0.3 Gy when injecting 200, 100, 50, or 25 kBq, respectively, assuming a maximum diffusion depth of 30 mum for the activity in the tumors. CONCLUSION: The radiation sensitivity, expressed as D(37), of tumor cells subjected to alpha-RIT could be decisive for therapeutic outcome, expressed as TCP or MCP, when treating small tumors of ovarian cancer.

An ex vivo loop system models the toxicity and efficacy of PEGylated and unmodified adenovirus serotype 5 in whole human blood.

Polyethylene glycol coating (PEGylation) of adenovirus serotype 5 (Ad5) has been shown to effectively reduce immunogenicity and increase circulation time of intravenously administered virus in mouse models. Herein, we monitored clot formation, complement activation, cytokine release and blood cell association upon addition of uncoated or PEGylated Ad5 to human whole blood. We used a novel blood loop model where human blood from healthy donors was mixed with virus and incubated in heparin-coated PVC tubing while rotating at 37 degrees C for up to 8 h. Production of the complement components C3a and C5a and the cytokines IL-8, RANTES and MCP-1 was significantly lower with 20K-PEGylated Ad5 than with uncoated Ad5. PEGylation prevented clotting and reduced Ad5 binding to blood cells in blood with low ability to neutralize Ad5. The effect was particularly pronounced in monocytes, granulocytes, B-cells and T-cells, but could also be observed in erythrocytes and platelets. In conclusion, PEGylation of Ad5 can reduce the immune response mounted in human blood, although the protective effects are rather modest in contrast to published mouse data. Our findings underline the importance of developing reliable models and we propose the use of human whole blood models in pre-clinical screening of gene therapy vectors.

Clinical trial: the safety and short-term efficacy of recombinant cholera toxin B subunit in the treatment of active Crohn's disease.

BACKGROUND: The cholera toxin B subunit ameliorates experimentally induced colitis in mice. In humans, cholera toxin B subunit has never been tested in the treatment of Crohn's disease (CD). AIM: To evaluate the safety and efficacy of treatment with recombinant cholera toxin B subunit of patients with CD. METHODS: An open-label, multicentre, nonrandomized trial including 15 patients with mild/moderate CD. Patients received an oral solution of 5 mg recombinant cholera toxin B subunit three times weekly for 2 weeks. Reduction in CD Activity Index (CDAI) with >100 between baseline and days 15, 29, 42 and 70 defined clinical response. Patients with CDAI score < or = 150 were defined as being in remission. RESULTS: A significant decrease in CDAI score was observed. Response rates were 40% in the full analysis set and 42% in the per protocol analysis. Two patients receiving adjuvant treatment after day 29 were excluded, after which 40% were in remission at 4 weeks and 30% at 8 weeks post-treatment. Mild side effects (arthralgia, headache and pruritus) were seen in 33% of patients. CONCLUSIONS: Treatment with recombinant cholera toxin B subunit was safe. Approximately 40% of patients with active CD responded to treatment. Randomized studies are needed to establish the clinical efficacy of recombinant cholera toxin B subunit.

Basal lymphoid aggregates in ulcerative colitis colon: a site for regulatory T cell action.

Regulatory T cells seem to play a central role in maintaining immune tolerance in the gut mucosa. Previously we have shown that interleukin (IL)-10 is produced at high levels in the inflamed colonic tissue of ulcerative colitis (UC) patients. The cellular source was CD4+ T cells, suggesting local activation of regulatory T cells. The present study was performed to determine whether the frequency of regulatory T cells is increased in UC colon and whether they are present in the basal lymphoid aggregates, the prominent microanatomical structure in UC colon. Colonic tissue specimens from UC and control patients were analysed for frequencies of lamina propria lymphocytes expressing the regulatory T cell markers forkhead box protein 3 (FoxP3), CD25 and glucocorticoid-induced tumour necrosis factor receptor family-related gene (GITR) as well as CD28, CD4 and CD3 by using marker specific reagents in immunomorphometry. Two-colour immunohistochemistry was used for detection of CD25/IL-10, FoxP3/IL-10 and CD25/FoxP3 double-positive cells. GITR+ and FoxP3+ cells were present in normal colon mucosa, although at a relatively low frequency, and were located preferentially within the solitary follicles. UC was associated with significantly increased frequencies of CD25+, GITR+ and FoxP3+ lamina propria lymphocytes both within the basal lymphoid aggregates and in the lamina propria outside. Many of the CD25+ cells co-expressed FoxP3 as well as IL-10, suggesting that these are indeed IL-10 secreting regulatory T cells, activated in an attempt to counteract the inflammation. Increased frequency of regulatory T cell subtypes seems insufficient to control the disease activity in UC.

Increased therapeutic efficacy of the prostate-specific oncolytic adenovirus Ad[I/PPT-E1A] by reduction of the insulator size and introduction of the full-length E3 region.

Conditionally replicating adenoviruses are developing as a complement to traditional cancer therapies. Ad[I/PPT-E1A] is an E1B/E3-deleted virus that replicates exclusively in prostate cells, since the expression of E1A is controlled by the recombinant 1.4 kb prostate-specific PPT promoter. The transcriptional integrity of PPT is maintained by the 3.0 kb mouse H19 insulator that was introduced directly upstream of the PPT sequence. In order to increase the cloning capacity to be able to reintroduce E3 sequences in the 35.7 kb Ad[I/PPT-E1A] genome, various shorter insulators were examined in a luciferase reporter gene assay. It was found that the 1.6 kb core H19 insulator (i) improves the activity of PPT, compared to the 3.0 kb full-length insulator, while still maintaining prostate cell specificity and releasing 1.4 kb of space for insertion of additional sequences. To improve the ability of the virus to efficiently lyse infected cells and persist in vivo, we inserted the adenovirus death protein (ADP) or the full-length adenovirus E3 region. The oncolytic activity of PPT-E1A-based viruses was studied using MTS, crystal violet and replication assays. The virus with the reintroduced full-length E3-region (Ad[i/PPT-E1A, E3]) showed the highest cytopathic effects in vitro. Furthermore, this virus suppressed the growth of aggressively growing prostate tumors in vivo. Therefore, we conclude that Ad[i/PPT-E1A, E3] is a prostate-specific oncolytic adenovirus with a high potential for treating localized prostate cancer.

Cystatin C reduces the in vitro formation of soluble Abeta1-42 oligomers and protofibrils.

There are an increasing number of genetic and neuropathological observations to suggest that cystatin C, an extracellular protein produced by all nucleated cells, might play a role in the pathophysiology of sporadic Alzheimer's disease (AD). Recent observations indicate that small and large soluble oligomers of the beta-amyloid protein (Abeta) impair synaptic plasticity and induce neurotoxicity in AD. The objective of the present study was to investigate the influence of cystatin C on the production of such oligomers in vitro. Co-incubation of cystatin C with monomeric Abeta1-42 significantly attenuated the in vitro formation of Abeta oligomers and protofibrils, as determined using electron microscopy (EM), dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting, thioflavin T (ThT) spectrofluorimetry and gel chromatography. However, cystatin C did not dissolve preformed Abeta oligomers. Direct binding of cystatin C to Abeta was demonstrated with the formation of an initial 1:1 molar high-affinity complex. These observations suggest that cystatin C might be a regulating element in the transformation of monomeric Abeta to larger and perhaps more toxic molecular species in vivo.

The biological effect of pentoxifylline on the survival of human head and neck cancer cells treated with continuous low and high dose-rate irradiation.

AIM: The aim of this study was to compare the radiosensitivity effect of the G2/M arrest-abrogating substance, pentoxifylline (PTX), with high dose-rate irradiation (HDRI) and low dose-rate irradiation (LDRI), during which DNA repair and cell proliferation occur. METHODS: Three squamous cell carcinoma cell lines, FaDu, RPMI 2650 and SCC-61, with differences in genomic imbalance and intrinsic radiosensitivity, were irradiated with 140 cGy/min (HDRI) and 0.7 cGy/min (LDRI) in the presence and absence of 2.0 mM PTX. The surviving fraction at 2.0 Gy (SF2) and cell-cycle phase distribution were assessed by DNA flow cytometry analysis and bromodeoxyuridine incorporation. RESULTS: With HDRI and LDRI the SF2 of FaDu cells decreased by 38.5% and 27.6%, respectively, while the corresponding figures for RPMI 2650 were 28.5% and 48.5%, and for SCC-61 were 44.2% and 28.6%. Increases in G2 populations were evident after both HDRI and LDRI of all cell lines. CONCLUSIONS: The enhancement in the cytotoxic effect of PTX was statistically significant after HDRI as well as after LDRI in all three cell lines. We therefore conclude that PTX in combination with LDRI is worth further study, both in vitro, for disclosing underlying mechanisms, and in vivo, to confirm the findings.

beta-Defensin-3 and -4 in intestinal epithelial cells display increased mRNA expression in ulcerative colitis.

mRNA expression of two recently described human beta-defensins (hBD-3 and hBD-4) in epithelial cells of normal small and large intestine and the impact of chronic intestinal inflammation on their expression levels was investigated. Intestinal specimens from patients with ulcerative colitis (UC), Crohn's disease (CD) and controls with no history of inflammatory bowel disease were studied. hBD-3 and hBD-4 mRNAs were determined in freshly isolated epithelial cells by real-time quantitative reverse transcription-polymerase chain reaction (QRT-PCR) and by in situ hybridization. The effect of proinflammatory cytokines on hBD-3 and hBD-4 mRNA expression in colon carcinoma cells was also investigated. Purified epithelial cells of normal small and large intestine expressed both hBD-3 and hBD-4 mRNA, with higher expression levels of hBD-3 mRNA. In situ hybridization revealed higher levels of mRNA expression in the crypt- compared to the villus/luminal-compartment. Interferon (IFN)-gamma, but not tumour necrosis factor (TNF)-alpha or IL-1beta, augmented hBD-3 mRNA expression. None of these agents stimulated hBD-4 expression. Colonic epithelial cells from patients with UC displayed a significant increase in hBD-3 and hBD-4 mRNA compared to epithelial cells of controls. In contrast, small intestinal epithelial cells from CD patients did not show increased expression levels compared to the corresponding control cells. Moreover, Crohn's colitis did not show increased expression of hBD-4 mRNA, while the data are inconclusive for hBD-3 mRNA. We conclude that the chronic inflammatory reaction induced in the colon of UC patients enhances hBD-3 and hBD-4 mRNA expression in the epithelium, whereas in CD this is less evident.

Cytolytic capabilities of lamina propria and intraepithelial lymphocytes in normal and chronically inflamed human intestine.

Cell-mediated lymphocyte cytotoxicity in ileum and colon of patients with ulcerative colitis (UC), Crohn's disease (CD) and controls was investigated. Frequencies of cells expressing perforin and Fas-ligand (FasL) were determined by immunomorphometry. mRNA expression of perforin, granzyme B and FasL in T cells and subsets was assayed by reverse transcriptase-polymerase chain reaction. Cytotoxicity of intraepithelial and lamina propria lymphocytes was analysed without ex vivo activation in three functional assays: (1) anti-CD3-dependent T-cell receptor (TCR)-/CD3-mediated redirected cytotoxicity, (2) Fas-/FasL-mediated TCR-/CD3-independent cytotoxicity and (3) natural killer (NK) cell cytotoxicity. Inflammation in ileum of CD patients caused increased frequency of perforin-expressing cells and enhanced perforin-dependent TCR-/CD3-mediated cytotoxicity. In contrast, lymphocytes in the inflamed colon of UC or Crohn's colitis patients did not display this cytotoxicity nor did lymphocytes of normal colon. Normal colon lymphocytes showed spontaneous Fas-/FasL-mediated cytotoxicity. This activity was retained but not enhanced in inflamed UC colon. In contrast, a significant increase of FasL-expressing cells was seen in situ. Inflammation did not induce NK cell activity in colonic lymphocytes. Intestinal lymphocytes comprise effectors active in two different cytolytic processes. 'Classical' cytotoxic T lymphocytes in small intestine and lymphocytes executing TCR-/CD3-independent FasL-/Fas-mediated killing of unknown biological role present throughout the intestinal mucosa. Ongoing normal cytolytic processes seem to be enhanced by chronic inflammation.

Over-expression of interleukin 10 in mucosal T cells of patients with active ulcerative colitis.

Ulcerative colitis (UC), a chronic inflammatory bowel disease, exhibits pronounced increase of T lymphocytes in the inflamed mucosa. To understand the role of intestinal T lymphocytes in the pathogenesis of UC their cytokine production in the mucosa was analysed. Intestinal T lymphocytes of UC, Crohn's disease and control patients were analysed for cytokine mRNA levels by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) directly after isolation without in vitro stimulation. Frequencies of cytokine positive cells were determined in UC and control colon by immunomorphometry. T lymphocytes in normal colon expressed interleukin (IL)-2, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and transforming growth factor (TGF)-beta1, but not IL-4, IL-5 or IL-10. In UC, a highly significant increase in IL-10 mRNA levels in T lymphocytes and an increased frequency of IL-10 positive cells was seen in colon. IL-10 mRNA levels were also elevated in T lymphocytes of the non-inflamed ileum and correlated with disease activity at both locations. CD4+ T lymphocytes were the major source of IL-10 mRNA. IL-2, IFN-gamma and TNF-alpha mRNA levels were decreased in colonic T lymphocytes, and virtually no IL-2, IFN-gamma, TNF-alpha or TGF-beta positive cells were detected in basal lymphoid aggregates. However, scattered IL-10 positive cells were found here. Lamina propria outside the aggregates contained IL-10-, IFN-gamma, TNF-alpha and TGF-beta but not IL-2 positive cells. T cells of UC patients did not express IL-4 or IL-5. Taken, together the data suggest a generalized activation of IL-10 producing CD4+ T cells along the intestine of UC patients. The local environment seems to determine the biological consequences of elevated IL-10.

Hereditary transthyretin amyloidosis from a Scandinavian perspective.

Hereditary transthyretin (TTR) amyloidosis is a rare often fatal form of systemic amyloidosis, that until recently was considered intractable, with the patients dying from the disease 5-15 years after onset. The phenotype of the disease varies according to the type of mutation, but generally the heart and/or the nervous system is affected. Liver and in some cases heart transplantation has now been shown to stop the progress of the disease, but the outcome depends on the patients' status at the time of operation, as no substantial improvement of the patients' symptoms has been noted after the procedure. Thus an early diagnosis is of importance for the outcome. In the following, we summarize our knowledge of the amyloidogenic TTR mutations found in the Scandinavian countries, their symptoms, how to settle the diagnosis and the outcome of transplantation. Besides, the problems arising from our capability to genetically test asymptomatic members of affected families for the trait will be discussed.

Increased expression of antimicrobial peptides and lysozyme in colonic epithelial cells of patients with ulcerative colitis.

The impact of chronic inflammation on the expression of human alpha-defensins 5 and 6 (HD-5, HD-6), beta-defensins 1 and 2 (hBD-1, hBD-2) and lysozyme in epithelial cells of small and large intestine was investigated. Intestinal specimens from 16 patients with ulcerative colitis (UC), 14 patients with Crohn's disease (CD) and 40 controls with no history of inflammatory bowel disease were studied. mRNA expression levels of the five defence molecules were determined in freshly isolated epithelial cells by real-time quantitative RT-PCR. Specific copy standards were used allowing comparison between the expression levels of the different defensins. HD-5 and lysozyme protein expression was also studied by immunohistochemistry. Colonic epithelial cells from patients with UC displayed a significant increase of hBD-2, HD-5, HD-6 and lysozyme mRNA as compared to epithelial cells in controls. Lysozyme mRNA was expressed at very high average copy numbers followed by HD-5, HD-6, hBD-1 and hBD-2 mRNA. HD-5 and lysozyme protein was demonstrated in metaplastic Paneth-like cells in UC colon. There was no correlation between hBD-2 mRNA levels and HD-5 or HD-6 mRNA levels in colon epithelial cells of UC patients. Colonic epithelial cells of Crohn's colitis patients showed increased mRNA levels of HD-5 and lysozyme mRNA whereas ileal epithelial cells of Crohn's patients with ileo-caecal inflammation did not. Chronic inflammation in colon results in induction of hBD-2 and alpha-defensins and increased lysozyme expression. hBD-1 expression levels in colon remain unchanged in colitis. The high antimicrobial activity of epithelial cells in chronic colitis may be a consequence of changes in the epithelial lining, permitting adherence of both pathogenic bacteria and commensals directly to the epithelial cell surface.

Differential expression of vasoactive intestinal polypeptide receptor 1 and 2 mRNA in murine intestinal T lymphocyte subtypes.

Neuropeptides may exert a variety of effects on the immune cells at both systemic and mucosal immune sites. The immunoregulatory properties refer to the ability of physiological signals and pathways to influence various immune functions. Vasoactive intestinal polypeptide (VIP), a neuropeptide present in high concentration in gut, was studied for its production and receptor expression in intraepithelial and lamina propria T lymphocytes of mouse intestine. Using reverse transcription-polymerase chain reaction (RT-PCR) analysis, it was demonstrated that VIP receptor 1 (VIPR1) was constantly expressed in intraepithelial and lamina propria T lymphocytes from both small and large intestine. In contrast, VIPR2 was identified only in T cells from small intestine. Further studies on purified subpopulations of T lymphocytes indicated the existence of VIPR2 in CD8(+) T cells, but not CD4(+) and CD4CD8 double negative T cells, although all these three subpopulations displayed VIPR1. In addition, VIPR1 mRNA was detected in splenic T lymphocytes, but no signal was obtained for VIPR2 mRNA, even after stimulation of the cells with anti-CD3(epsilon)-chain mAb, phorbol 12-myristate 13-acetate (PMA) and/or VIP. The presence of VIP receptor(s) on intestinal T lymphocytes was supported by the detection of VIP on the cell surface using dual colour immunoflowcytometry. In-vitro treatment with VIP resulted in a tendency towards an increased size of the VIP immunoreactive T cell population and significantly enhanced the average immunofluorescence intensity of the surface labelling. This indicates that the receptors are partially occupied by locally produced VIP in vivo and that more peptide molecules can be bound on the lymphocytes when needed, released and accumulated in higher concentration at the action sites. We failed to detect the expression of VIP mRNA in T lymphocytes, from either intestine or spleen. These observations support that VIP may be an important immune modulator in gut acting through specific receptors on T lymphocytes. The differential mRNA expression of VIP receptor subtypes in cells with different phenotypes and in different immune compartments may suggest diverse regulatory roles of the neuropeptide in immune responses.

Health-related quality of life in patients with adolescent idiopathic scoliosis: a matched follow-up at least 20 years after treatment with brace or surgery.

No results on long-term outcome in terms of health-related quality of life (HRQL) have previously been presented for patients treated for adolescent idiopathic scoliosis. A consecutive series of patients with adolescent idiopathic scoliosis, treated between 1968 and 1977 before the age of 21, either with distraction and fusion using Harrington rods [surgical treatment group (ST), n=156; 145 females and 11 males] or with a brace [brace treatment group (BT), n=127; 122 females and 5 males] were followed at least 20 years after completion of the treatment. Ninety-four percent of ST and 91% of BT patients filled in a questionnaire comprising the SF-36, Psychological General Well-Being Index (PGWB), Oswestry Disability Back Pain Questionnaire, parts of SRS/MODEM'S questionnaire and study-specific questions concerning the treatment, as a part of an unbiased personal follow-up examination including radiography and clinical examination. An age- and sex-matched control group of 100 persons was randomly selected and subjected to the same examinations. The results showed no differences in terms of sociodemographic data between the groups. Both ST and BT patients had a slightly, but significantly, reduced physical function using the SF-36 subscales, SF-36/Physical Component Summary (PCS) score as well as the Oswestry Disability Back Pain Questionnaire compared to the controls. Neither the mental subscales and the Mental Component Summary (MCS) score of SF-36 nor the PGWB index showed any significant difference between the groups. Forty-nine percent of ST, 34% of BT and 15% of controls admitted limitation of social activities due to their back [P<0.001 ST vs controls, P=0.0010 BT vs controls, and n.s. (P=0.024) ST vs BT], mostly due to difficulties with physical participation in activities or self-consciousness about appearance. Pain was a minor reason for limitation. No correlation was found between the outcome scores and curve size after treatment, curve type, total treatment time or age at completed treatment. Patients treated for adolescent idiopathic scoliosis were found to have approximately the same HRQL as the general population. A minority of the patients (4%) had a severely decreased psychological well-being, and a few (1.5%) were severely physically disabled due to the back.

Familial occurrence of microscopic colitis: a report on five families.

BACKGROUND: The etiology and pathogenesis of microscopic colitis is unknown. Whether genetic predisposition is of importance, as in many other gastrointestinal diseases, is unknown. Familial occurrence of collagenous colitis has earlier been reported only in two families. METHODS: Familial occurrence of microscopic colitis was searched for in a Swedish national microscopic colitis register. RESULTS: Familial occurrence of microscopic colitis was identified in five families. In all families a sister-sister relationship was found. Two sisters with collagenous colitis had been living apart in different Nordic countries for many years before developing the disease. In one pair, the smoking sister had collagenous colitis and the never smoking sister had lymphocytic colitis. CONCLUSIONS: Considering the relative rarity of microscopic colitis, these findings indicate that a genetic predisposition may be of importance.