The transcriptional regulators, the immune system and the the circadian clock.

The immune system function oscillates with a 24-hour period driving circadian rhythmicity of immune responses. A circadian timing system comprising central and peripheral oscillators entrains body rhythmicity of physiology and behavior to environmental cues by means of humoral signals and autonomic neural outputs. In every single cell an oscillator goes ticking through a molecular clock operated by transcriptional/translational feedback loops driven by the rhythmic expression of circadian genes. This clock gene machinery steers daily oscillations in the regulation of immune cell activity, driving the periodicity in immune system function. The transcriptional networks that regulate temporal variation in gene expression in immunocompetent cells and tissues respond to diverse physiological clues, addressing well-timed adjustments of transcription and translation processes. Nuclear receptors comprise a unique class of transcriptional regulators that are capable of gauging hormones, metabolites, endobiotics and xenobiotics, linking ligand sensing to transcriptional responses in various cell types through switching between coactivator and corepressor recruitment. The expression of coregulators is highly responsive to physiological signals, and plays an important role in the control of rhythmic patterns of gene expression, optimizing the switch between nycthemeral patterns, and synchronizing circadian rhythmicity with changing physiological demands across the light-dark cycle. The nuclear receptors and transcription factors expressed in the immune components contribute to the cross-talk between the circadian timing system, the clock gene machinery and the immune system, influencing transcriptional activities and directing cell-type specific gene expression programs linked to innate and adaptive immune responses.

Glucocorticoid resistance in Crohn's disease and ulcerative colitis: an association study investigating GR and FKBP5 gene polymorphisms.

The aim of this study is to investigate the role of single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) and of the related co-chaperone FKBP5 genes in the development of glucocorticoid (GC) resistance in Crohn's disease (CD) and ulcerative colitis (UC) patients. We have developed a high-resolution DNA melting method that allows simultaneous identification of GR (BclI, N363S and ER22/23EK) and FKBP5 (rs3800373, rs1360780 and rs4713916) polymorphisms. Genotype frequencies were determined in 100 consecutive CD and 100 UC patients under GCs therapy (50 responders and 50 resisters). The variation of FKBP5 polymorphism rs4713916 (G/A), in the putative promoter region of FKBP5, is significantly associated with resistance to GC treatment in CD (responder=17% versus resister=35%; P=0.0043). No significant differences were found in UC patients. If these preliminary findings will be confirmed, the combination of GR and FKBP5 mutational analyses could help to identify subgroups of CD patients with higher chances to benefit from GC treatment.

Worse impact of second wave COVID-19 pandemic in adults but not in children with inflammatory bowel disease: an Italian single tertiary center experience.

OBJECTIVE: From September 2020, a second wave of COVID-19 pandemic started. We aimed at exploring the impact of SARS-CoV-2 infection in IBD patients during the two waves. PATIENTS AND METHODS: All IBD patients with a confirmed diagnosis of SARS-CoV-2 infection were enrolled. They were sorted into two groups (those infected before September 2020, and those from September 2020 to January 2021) and compared by demographic and clinical data. RESULTS: Twenty-five patients (out of about 600 with a follow-up visit) were infected with SARS-CoV-2 (4.1%). Sixteen were male and the mean age was 46.5 ± 14.3 years (range 24-74). Six were smokers and 11 had comorbidities; 2 were on steroids and 17 on immunosuppressants or biologics. Three patients (12%) needed hospitalization and other three patients were treated with azithromycin, steroids and LMWH, all of them during the second wave. No patient died or developed any sequelae. Two subjects were infected during the first wave (0.3 vs. 3.83, p<0.0001). Non-significant differences were found between the two groups. CONCLUSIONS: A higher number of IBD patients were infected during the second wave. No patient developed a severe form of pneumonia, even those treated with immunosuppressants or biologics. No risk factor for hospitalization was found.

The -A2518G polymorphism of monocyte chemoattractant protein-1 is associated with Crohn's disease.

OBJECTIVES: The -A2518G variation in monocyte chemoattractant protein (MCP)-1 gene promoter has been associated with autoimmune diseases. Our aim was to investigate the gene polymorphism and MCP-1 plasma levels in patients with inflammatory bowel disease (IBD). METHODS: Family-based and case-control association analyses of the -A2518G polymorphism (rs1024611) were performed in 1,936 subjects (770 patients with Crohn's disease (CD), 316 patients with ulcerative colitis (UC), 302 healthy relatives (151 CD trios), and 548 healthy controls (HCs)). Extensive gene sequencing was also undertaken, and a further six single-nucleotide polymorphisms (SNPs) were genotyped in 435 CD patients and 189 HCs. MCP-1 protein plasma levels in 234 CD patients, 117 UC patients, and 108 HCs were assessed by an immunosorbent assay. RESULTS: Five SNPs in strong linkage disequilibrium (D'>0.85) were associated with CD, with the strongest signal found at the -A2518G SNP. The frequency of the G allele was significantly lower in CD patients (22.1%), compared with HCs (29.8%), both at case-control (P=6 x 10(-6)) and at transmission disequilibrium test analyses (T/U 41/88; P=4 x 10(-4)). No difference in alleles (26.1%) and genotype frequencies were found in UC patients. MCP-1 plasma levels in CD and UC patients were similar to those in HCs (P=0.38), irrespective of disease activity, or MCP-1 genotypes. However, 30 CD (13%) and 20 UC patients (17%) with extensive colonic involvement had plasma levels significantly higher than HCs (P=0.02). CONCLUSIONS: The -A2518G polymorphism seems to be associated with CD but does not influence MCP-1 plasma levels, which in contrast are increased in UC and CD with extensive colonic involvement.

Genetic variants in the region harbouring IL2/IL21 associated with ulcerative colitis.

OBJECTIVES: Genetic susceptibility is known to play a large part in the predisposition to the inflammatory bowel diseases (IBDs) known as Crohn's disease (CD) and ulcerative colitis (UC). The IL2/IL21 locus on 4q27 is known to be a common risk locus for inflammatory disease (shown in coeliac disease, type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus and psoriasis), while the roles that interleukin 2 (IL2) and IL21 play in the immune response also make them attractive candidates for IBD. The objective of this study was to test for association between the IL2/IL21 locus and the IBDs. METHODS: The four single nucleotide polymorphisms (SNPs) in the IL2/IL21 locus most associated with coeliac disease were genotyped in 1590 subjects with IBD and 929 controls from The Netherlands, and then replicated in a North American cohort (2387 cases and 1266 controls) and an Italian cohort (805 cases and 421 controls), yielding a total of 4782 cases (3194 UC, 1588 CD) and 2616 controls. Allelic association testing and a pooled analysis using a Cochran-Mantel-Haenszel test were performed. RESULTS: All four SNPs were strongly associated with UC in all three cohorts and reached genome-wide significance in the pooled analysis (rs13151961 p = 1.35 x 10(-10), rs13119723 p = 8.60 x 10(-8), rs6840978 p = 3.0 7x 10(-8), rs6822844 p = 2.77 x 10(-9)). A moderate association with CD was also found in the pooled analysis (p value range 0.0016-9.86 x 10(-5)). CONCLUSIONS: A strong association for the IL2/IL21 locus with UC was found, which also confirms it as a general susceptibility locus for inflammatory disease.

Polymorphism of the IRGM gene might predispose to fistulizing behavior in Crohn's disease.

OBJECTIVES: Recently, genome-wide association analyses have identified single nucleotide polymorphisms in the IRGM gene (rs1000113 and rs4958847) as strong candidate susceptibility factors for Crohn's disease (CD). The aim of our study was to test whether these variants are associated with inflammatory bowel disease (IBD) in adult- and childhood-onset Italian patients. METHODS: Allele and genotype frequencies of rs1000113 and rs4958847 were determined in 823 CD (265 younger than 19 years at diagnosis), 353 ulcerative colitis (UC) (130 younger than 19 years at diagnosis), and 578 controls. Genotype distributions were examined both within IBD clinical sub-phenotypes and CARD15 genotypes. RESULTS: rs1000113 and rs4958847 were both associated with adult-onset (P=2 x 10(-4); P=2.5 x 10(-3), respectively) and childhood-onset (P=4 x 10(-4); P=8 x 10(-3), respectively) CD cohorts. Similarly, the genotype frequencies remained significantly different for both variants (adult rs1000113, P=1 x 10(-4); rs4958847, P=1 x 10(-3); pediatric rs1000113, P=2.3 x 10(-4); rs4958847, P=9.6 x 10(-3)). At logistic regression, the rs4958847 polymorphism was associated with fistulizing behavior (P=0.037, OR=1.54, CI=1.02-2.31) and perianal fistulas (P=0.045, OR=1.55, CI=1.01-2.38). Conversely, no association with UC and sub-phenotypes was shown. CONCLUSIONS: We replicated the previously reported associations between CD and rs1000113 and rs4958847, confirming that IRGM is a susceptibility locus only for CD, either adult- or early-onset in the Italian population; furthermore, we have also shown its influence on specific clinical features (fistulizing disease).

Gender-stratified analysis of DLG5 R30Q in 4707 patients with Crohn disease and 4973 controls from 12 Caucasian cohorts.

BACKGROUND: DLG5 p.R30Q has been reported to be associated with Crohn disease (CD), but this association has not been replicated in most studies. A recent analysis of gender-stratified data from two case-control studies and two population cohorts found an association of DLG5 30Q with increased risk of CD in men but not in women and found differences between 30Q population frequencies for males and females. Male-female differences in population allele frequencies and male-specific risk could explain the difficulty in replicating the association with CD. METHODS: DLG5 R30Q genotype data were collected for patients with CD and controls from 11 studies that did not include gender-stratified allele counts in their published reports and tested for male-female frequency differences in controls and for case-control frequency differences in men and in women. RESULTS: The data showed no male-female allele frequency differences in controls. An exact conditional test gave marginal evidence that 30Q is associated with decreased risk of CD in women (p = 0.049, OR = 0.87, 95% CI 0.77 to 1.00). There was also a trend towards reduced 30Q frequencies in male patients with CD compared with male controls, but this was not significant at the 0.05 level (p = 0.058, OR = 0.87, 95% CI 0.74 to 1.01). When data from this study were combined with previously published, gender-stratified data, the 30Q allele was found to be associated with decreased risk of CD in women (p = 0.010, OR = 0.86, 95% CI 0.76 to 0.97), but not in men. CONCLUSION: DLG5 30Q is associated with a small reduction in risk of CD in women.

Mediterranean lifestyle: nutritional education on-line.

Our goal is to spread on-line the Italian Weekly Pyramid, a tool designed to convey both portion size and frequency of food intake. The Pyramid is referring to the "Well-being Index" (WI) as a unit for an adequate lifestyle. The user can verify his weekly lifestyle by participating to a "game" based on food/beverages consumption and time assigned to physical activity. The site has been visited by 15920 individuals, of whom 4033 completed the game. Self-selected sample, not representative of the Italian population. The data collected included WI consumption by gender for each food group compared to WI suggested. Statistical data evaluation has been performed with the SPSS inc.13 program, without applying any statistical significance to the results. The sample showed a varied eating pattern; all the food groups were consumed almost daily, albeit in much lower quantities with regards to the suggested WI. Fruit and vegetable consumption was higher in women, while men showed a higher intake of meat and cut meats. The percentage of the participants consuming more WI with respect to the recommended amounts was very low for fruit, vegetable, pasta and bread, while was much higher as regards energy dense food.

[Pulmonary cryptosporidiosis in AIDS patients]. / Criptosporidiosis broncopulmonar en pacientes infectados por el virus de la inmunodeficiencia humana.

Pulmonary cryptosporidiosis is a rare complication of intestinal cryptosporidiosis in AIDS patients. We report the epidemiological, clinical, radiological, microbiological and immunological findings in 5 AIDS patients with pulmonary cryptosporidiosis. Diagnosis was based on the detection of acid-fast oocysts in sputum or aspirated bronchial material using the Kinyoun technique. Microbiology laboratories should be alert to the possibility of Cryptosporidium spp oocysts presence in respiratory specimens from patients with advanced HIV/AIDS disease and pulmonary involvement.

[Study by multiplex PCR of Listeria monocytogenes serotypes isolated in Argentine]. / Estudio mediante PCR múltiple de serotipos de Listeria monocytogenes aislados en Argentina.

A multiplex PCR assay, recently validated to characterize the serotypes of Listeria monocytogenes was evaluated in comparison to conventional serotyping. Three hundred forty two L. monocytogenes strains isolated from human, food, animal and environmental sources during the 1992-2005 period were assayed. The concordance between the two methods for serotypes 1/2a, 1/2b and 1/2c was 100%, whereas for serotype 4b it was 98%. Serotyping is a useful tool for first line strain differentiation during epidemiological surveillance and outbreaks. The multiplex PCR assay offers a fast and low-cost alternative, which is easily adaptable to clinical bacteriology and bromatology laboratories.

Sequential evaluation of thiopurine methyltransferase, inosine triphosphate pyrophosphatase, and HPRT1 genes polymorphisms to explain thiopurines' toxicity and efficacy.

AIM: To evaluate the polymorphisms of several genes involved in the azathioprine and mercaptopurine metabolism, in an attempt to explain their toxicity and efficacy in Crohn's disease and ulcerative colitis. METHODS: In 422 consecutive patients (250 with Crohn's disease and 172 with ulcerative colitis) and 245 healthy controls, single nucleotide polymorphisms of thiopurine methyltransferase, inosine triphosphate pyrophosphatase and hypoxanthine phosphoribosyl transferase (HPRT1) genes were related to the occurrence of adverse drug reactions (ADRs) and efficacy of therapy. RESULTS: Seventy-three patients reported 81 episodes of ADRs; 45 patients did not respond to therapy. Frequency of thiopurine methyltransferase risk haplotypes was significantly increased in patients with leucopenia (26% vs. 5.7% in patients without ADRs, and 4% of controls) (P < 0.001); no correlation with other ADRs and efficacy of therapy was found. Conversely, the frequency of inosine triphosphate pyrophosphatase and HPRT1 risk genotypes was not significantly different in patients with ADRs (included leucopenia). Non-responders had an increased frequency of inosine triphosphate pyrophosphatase risk genotypes (P = 0.03). CONCLUSIONS: The majority of azathioprine/mercaptopurine-induced ADRs and efficacy of therapy are not explained by the investigated gene polymorphisms. The combined evaluation of all three genes enhanced the correlation with leucopenia (43.5% vs. 23% in controls) (P = 0.008), at the expense of a reduced accuracy (60%).

Role of CARD15, DLG5 and OCTN genes polymorphisms in children with inflammatory bowel diseases.

AIM: To investigate the contribution of variants of CARD15, OCTN1/2 and DLG5 genes in disease predisposition and phenotypes in a large Italian cohort of pediatric patients with inflammatory bowel diseases (IBD). METHODS: Two hundred patients with Crohn's disease (CD), 186 ulcerative colitis (UC) patients, 434 parents (217 trios), and 347 healthy controls (HC) were studied. Polymorphisms of the three major variants of CARD15, 1672C/T and -207G/C SNPs for OCTN genes, IGR2096a_1 and IGR2198a_1 SNPs for the IBD5 locus, and 113G/A variant of the DLG5 gene were evaluated. Potential correlations with clinical sub-phenotypes were investigated. RESULTS: Polymorphisms of CARD15 were significantly associated with CD, and at least one variant was found in 38% of patients (15% in HC, OR = 2.7, P < 0.001). Homozygosis for both OCTN1/2 variants was more common in CD patients (1672TT 24%, -207CC 29%) than in HC (16% and 21%, respectively; P = 0.03), with an increased frequency of the TC haplotype (44.8% vs 38.3% in HC, P = 0.04). No association with the DLG5 variant was found. CD carriers of OCTN1/2 and DLG5 variants more frequently had penetrating disease (P = 0.04 and P = 0.01), while carriers of CARD15 more frequently had ileal localization (P = 0.03). No gene-gene interaction was found. In UC patients, the TC haplotype was more frequent (45.4%, P = 0.03), but no genotype/phenotype correlation was observed. CONCLUSION: Polymorphisms of CARD15 and OCTN genes, but not DLG5 are associated with pediatric onset of CD. Polymorphisms of CARD15, OCTN, and DLG5 genes exert a weak influence on CD phenotype.

Variants of OCTN1-2 cation transporter genes are associated with both Crohn's disease and ulcerative colitis.

BACKGROUND: Two variants in the organic cation transporter gene cluster have been recently reported to confer susceptibility to Crohn's disease (CD). AIM: To investigate these variants in CD and ulcerative colitis (UC), and their interaction with CARD15 gene and correlation to clinical subphenotypes. METHODS: Case-control association analysis was performed in 899 patients (444 CD and 455 UC) and 611 controls. The organic cation transporter gene cluster single nucleotide polymorphisms G207G-->C and 1672C-->T, the IGR2198a_1 single nucleotide polymorphism in the IBD5 locus, and the R702W, G908R and L1007finsC variants of CARD15 gene were genotyped by ABI-7700, restriction fragment length polymorphic analysis and multiplex pyrosequencing, respectively. RESULTS: The 1672TT and -207CC genotype frequencies were increased in both CD (OR = 1.5, P = 0.011; OR = 1.6, P = 0.002), and UC (OR = 1.5, P = 0.017; OR = 1.4, P = 0.033), respectively. Compared with controls, the TC haplotype frequency was increased in both CD (36% vs. 44%, P < or = 0.01) and UC (36% vs. 45%, P < or = 0.01). The frequency of the TC haplotype was 43% in CARD15-positive and 44% in CARD15-negative CD, respectively. Similar results were found in UC. In CD a significant association of the TC haplotype was found with presence of perianal fistulae (P = 0.007) and steno-fistulizing behaviour (P = 0.037). In UC, the TC haplotype was more frequent in patients with more extensive disease (P = 0.015), and those on immunosuppressives (P = 0.004). CONCLUSIONS: Organic cation transporter gene cluster variants may confer susceptibility to both CD and UC, and the TC haplotype may influence some clinical features of IBD, but does not interact with CARD15 variants.

HLA and enteric antineuronal antibodies in patients with achalasia.

The aetiopathogenesis of primary achalasia is largely unknown, although an immunogenetic predisposition is suspected. To establish whether a correlation exists among possible aetiological factors, including class II human leucocyte antigen (HLA) alleles and autoantibodies to enteric neurones, and clinical features of patients with achalasia, a total of 60 patients and 200 healthy subjects were typed by high-resolution HLA-DQ and HLA-DR alleles. Circulating antineuronal antibodies were investigated by using indirect immunofluorescence on enteric neurones of rat ileum and colon and immunoblotting assay in a subset of achalasic patients and in all controls. The DQB1*0502 and DQB1*0601 alleles were significantly increased in patients with achalasia compared with controls (P < 0.03, P < 0.001, respectively). Moreover a negative correlation with the DQB1*0201 allele was found (P = 0.016). As a whole, 14 of 60 (23.3%) achalasia patients were carriers of HLA risk alleles, and 10 of 41 (24.4%) presented antineuronal antibodies. No significant correlation among HLA risk alleles, antineuronal antibodies and clinical features was found. In achalasia, no correlation exists among HLA alleles, antineuronal antibodies and clinical features. However, given the association between achalasia and HLA-DQ1, further research is needed to clarify the role of HLA antigens and antineuronal antibodies in this disease.

Multidrug resistance 1 gene in inflammatory bowel disease: a meta-analysis.

The MDR1 gene is an attractive candidate gene for the pathogenesis of inflammatory bowel disease (IBD) and perhaps response to therapy, with evidences at both functional and genetic levels. Its product, the P-glycoprotein (P-gp) functions as a transmembrane efflux pump thus influencing disposition and response of many drugs, some of whom (i.e. glucocorticoids) central to IBD therapy. In addition P-gp is highly expressed in many epithelial surfaces, included gastrointestinal tract (G-I) with a putative role in decreasing the absorption of endogenous or exogenous toxins, and perhaps host-bacteria interaction. Many genetic variations of MDR1 gene has been described and in some instances evidences for different P-gp expression as well drugs metabolism have been provided. However data are often conflicting due to genetic heterogeneity and different methodologies employed. Perhaps the greatest piece of evidence of the physiological importance of P-gp in the G-I tract has come from the description of the mdr1 knock-out mice model, which develops a spontaneous colitis in a specific pathogen-free environment. Studies investigating MDR1 gene polymorphism and predisposition to IBD have also shown conflicting results, owing to the known difficulties in complex diseases, especially when the supposed genetic contribution is weak. In this study we have undertaken a meta-analysis of the available findings obtained with two SNPs polymorphism (C3435T and G2677T/A) in IBD; a significant association of 3435T allele and 3435TT genotype has been found with UC (OR = 1.17, P = 0.003 and OR = 1.36, P = 0.017, respectively). In contrast no association with CD and the G2677T/A polymorphism could be demonstrated.

NOD2/CARD15 in healthy relatives of IBD patients.

BACKGROUND: Crohn's disease (CD) and Ulcerative Colitis (UC) are related chronic inflammatory disorders of the intestine (IBD) caused by a combination of genetic and environmental factors. Three polymorphisms within the NOD2/CARD15 gene are highly associated with CD, increasing the risk from 2 up to 44-fold, depending on the presence of one or two risk alleles. Aim of this study was to investigate the presence of two risk alleles on healthy relatives of IBD patients and prospectively follow them for possible development of IBD. MATERIALS AND METHODS: Healthy relatives of familial IBD patients were recruited in our Institution and across Italy in a multicenter study of the IG-IBD. One hundred and twenty one IBD families were identified and blood samples were obtained from 415 first-degree healthy relatives. Single nucleotide polymorphisms (SNPs) R702W, G908R, and L1007finsC of the CARD15 gene were investigated by multiplex pyrosequencing technique. Data obtained in 205 healthy controls (HC) were compared by chi-square or Fisher's test. RESULTS: Ninety eight (28.7%) healthy relatives had one risk allele (HC 14.6%; p = 0.002, OR 2, C.I. 1-4), while 8 had two risk alleles (vs 0.5% of healthy controls; p = 0.01). All subjects were asymptomatic at the time of blood sample and record collections (between 1996 and 1999) and were further investigated with abdominal ultrasonography, blood chemistry and haemoccult test, after 5-8 years of follow-up. All were still asymptomatic with negative findings. CONCLUSIONS: Our study once again supports the importance of gene-gene and gene-environment interactions for the final development of the disease.

Multidrug resistance 1 gene polymorphisms are not associated with inflammatory bowel disease and response to therapy in Italian patients.

BACKGROUND: Host genetic factors may be important in determining not only disease susceptibility, but also disease behaviour and response to therapy in inflammatory bowel disease. Two polymorphisms (C3435T and G2677T/A) of the multidrug resistance 1 gene have been correlated with the altered P-glycoprotein expression and function in humans, and associated with predisposition to ulcerative colitis and Crohn's disease. AIM: To investigate the contribution of these polymorphisms to disease susceptibility and response to medical therapy. METHODS: A total of 946 inflammatory bowel disease patients (478 Crohn's disease, 272 males, mean age 43 +/- 14 years and 468 ulcerative colitis, 290 males, mean age 48 +/- 15 years) and 450 healthy controls were genotyped for the single nucleotide polymorphisms C3435T and G2677T/A. Patients were also classified on the basis of response to medical therapy (mesalazine, steroids, immunosuppressives and infliximab). RESULTS: Both single nucleotide polymorphisms were in Hardy-Weinberg equilibrium and significant linkage disequilibrium. No significant difference in the allele, genotype, and haplotype frequencies was found in both Crohn's disease and ulcerative colitis patients compared with the controls. No correlation with clinical features was found, except for a reduced frequency of extra-intestinal manifestations in Crohn's disease patients with the G2677T genotype (40%) compared with GG2677 and 2677TT genotypes (54% and 58%, respectively) (P = <0.02). No significant difference was also found after stratifying the patients on the basis of their response to medical therapy. CONCLUSION: The investigated polymorphisms of the multidrug resistance 1 gene have no significant role in disease susceptibility and response to medical therapy in our Italian population of inflammatory bowel disease patients.

Re-treatment of patients with anti-HBe-positive chronic hepatitis B who relapsed after an initial course of lamivudine.

AIM: To evaluate the efficacy of a long-term course of lamivudine monotherapy in patients with anti-HBe-positive chronic hepatitis B who relapsed after the first course of either lamivudine/interferon (n = 16; Group 1) or lamivudine (n = 20; Group 2). METHODS: Biochemical and virological tests were performed every 3 months. At baseline and breakthrough, the region coding for the YMDD amino acid motif was sequenced. RESULTS: The length of re-treatment averaged 24 months. The virological response peaked at 6 months (94.4%), and declined to 66.7% and 50% at 12 and 24 months, respectively. The rates of breakthrough were 2.9%, 31.4% and 48.6% at 6, 12 and 24 months, respectively. By the second year, responders amounted to 62.5% and 40% in Groups 1 and 2, respectively (P = 0.10). The 18 responders at month 24 are still on therapy after 25-51 months of treatment: 14 still maintain a response, nine from Group 1 and five from Group 2. CONCLUSIONS: Re-treatment with lamivudine can control viral replication. This effect is maintained for the initial 12 months in two-thirds of patients, but afterwards the duration of response lessens due to the development of viral resistance.

Frequency of NOD2/CARD15 variants in both sporadic and familial cases of Crohn's disease across Italy. An Italian Group for Inflammatory Bowel Disease Study.

BACKGROUND: Three variants of the NOD2/CARD15 gene are strongly associated with susceptibility to Crohn's disease; however, striking racial and geographic differences of their frequency have been described. AIMS: We have compared the allele frequencies of familial cases of Crohn's disease recruited in a multicentre study across Italy, in order to disclose possible geographic heterogeneity. Moreover, we also compared the allele frequencies in sporadic cases of Crohn's disease and healthy controls from Southern Italy with those reported in other two populations from Central and Northern Italy. SUBJECTS AND METHODS: A total of 731 subjects were genotyped for the polymorphism of three main variants (R702W, G908R and 1007 fs): 152 patients were familial cases of Crohn's disease, 183 were healthy first-degree relatives, 180 were sporadic cases of Crohn's disease, and 216 were unrelated healthy subjects. RESULTS: The frequency of the frameshift mutation (1007 fs) was significantly higher in both familial and sporadic cases of Crohn's disease (P = 0.000001), and healthy first-degree relatives (P = 0.0001) compared to controls. At least one risk allele was found in 44% of familial Crohn's disease patients, compared to 7% of healthy controls (OR = 4; CI = 2-6.5). Two risk alleles were found in 14% of familial Crohn's disease, compared to less than 1% of controls (OR = 26: CI = 4-129). CONCLUSIONS: Our data confirm the strong correlation between the 1007 fs variant and Crohn's disease, in both familial and sporadic cases. Moreover, no significant difference of allele frequencies was detected in familial cases, sporadic cases and healthy controls among different geographic areas of Italy.