The impact of CACNA1C gene, and its epistasis with ZNF804A, on white matter microstructure in health, schizophrenia and bipolar disorder1.

Genome-wide studies have identified allele A (adenine) of single nucleotide polymorphism (SNP) rs1006737 of the calcium-channel CACNA1C gene as a risk factor for both schizophrenia (SZ) and bipolar disorder (BD) as well as allele A for rs1344706 in the ZNF804A gene. These illnesses have also been associated with white matter abnormalities, reflected by reductions in fractional anisotropy (FA), measured using diffusion tensor imaging (DTI). We assessed the impact of the CACNA1C psychosis risk variant on FA in SZ, BD and health. 230 individuals (with existing ZNF804A rs1344706 genotype data) were genotyped for CACNA1C rs1006737 and underwent DTI. FA data was analysed with tract-based spatial statistics and threshold-free cluster enhancement significance correction (P < 0.05) to detect effects of CACNA1C genotype on FA, and its potential interaction with ZNF804A genotype and with diagnosis, on FA. There was no significant main effect of the CACNA1C genotype on FA, nor diagnosis by genotype(s) interactions. Nevertheless, when inspecting SZ in particular, risk allele carriers had significantly lower FA than the protective genotype individuals, in portions of the left middle occipital and parahippocampal gyri, right cerebellum, left optic radiation and left inferior and superior temporal gyri. Our data suggests a minor involvement of CACNA1C rs1006737 in psychosis via conferring susceptibility to white matter microstructural abnormalities in SZ. Put in perspective, ZNF804A rs1344706, not only had a significant main effect, but its SZ-specific effects were two orders of magnitude more widespread than that of CACNA1C rs1006737.

Chromogranin a levels in diagnosis, treatment and follow-up of 42 patients with non-functioning pancreatic endocrine tumours.

BACKGROUND/AIMS: Non-functioning pancreatic endocrine tumours (NFPET) constitute the largest component (35-50%) of pancreatic endocrine tumours. They are characterized by the absence of symptoms of hormone hypersecretion and frequently have clinical manifestations similar to the more common exocrine pancreatic adenocarcinoma. The present studyaims toevaluate the clinical features, diagnostic approach and, in particular, the significance of serum chromogranin A levels (CgA) in the management and outcome of 42 patients with NFPET (from a series of 121 patients with pancreatic endocrine tumours). METHODS: Twenty-five males and 17 females were included, and the mean age at diagnosis was 52.3 years (range: 26-68 years). The diagnosis for each patient was established by histopathological examination and immunohistochemistry. After the histopathological confirmation of diagnosis and during the follow-up period, patients were evaluated clinically and radiologically (including OctreoScan), whilst fasting gut hormones (including CgA) were also estimated. At diagnosis, all patients were checked for the presence of multiple endocrine neoplasia type I syndrome. The follow-up was complete and ranged from 12 to 86 months (mean: 49 months). RESULTS: Dyspepsia (66.5%) and weight loss (47.6%) were the most common symptoms at diagnosis, while in 21.4% of patients tumour lesions were revealed incidentally. Plasma CgA levels were significantly or moderately elevated in all patients with liver metastases at diagnosis (64.3%). The levels also reflected tumour progression or response to treatment during the follow-up period. OctreoScan showed avid uptake in 77.8% of patients with hepatic metastases. Moreover, in 2 patients OctreoScan revealed unexpected metastatic mesenteric deposits, which had not been found by the other studies. However, it was negative in 6 patients with liver metastases, in whom tumours were proved to be poorly differentiated (high-grade). CONCLUSIONS: (1) NFPET may present with clinical manifestations similar to those of an exocrine pancreatic tumour; (2) plasma CgA levels reflect tumour load, and also seem to correlate with tumour progression or response to treatment; (3) surgeryin patients with localized disease at presentation can be curative, while it can also reduce tumour burden in patients with metastases; (4) long-acting somatostatin analogues provide good quality of life and temporary disease stabilization in patients with low-grade tumours; (5) systemic chemotherapy or chemoembolization seem to be beneficial in high-grade and progressive tumours.

Comparison of T- and Z-score in identifying risk factors of osteoporosis in inflammatory bowel disease patients.

OBJECTIVE: Most studies have shown contradictory results regarding predictive factors of osteoporosis in inflammatory bowel disease (IBD). Since in these studies either T- or Z-scores has been used, our aim was to compare T- and Z-score in identifying risk factors of osteoporosis in IBD patients. MATERIALS AND METHODS: Bone density was measured by dual X-ray absorptiometry (DXA) at L2-L4 of the spine and femoral neck in 122 patients. Twenty-two clinical parameters were recorded prior to DXA and evaluated by univariate and multivariate analysis. RESULTS: On multivariate analysis, cumulative steroid dose was a predictive factor of femoral neck T-score (p<0.001) and Z-score (p=0.001). Age was a predictive factor of femoral neck T-score (p<0.001). BMI was a predictive factor of femoral neck Z-score (p=0.03). None of the other 19 variables tested had any predictive value for bone density. Age >or=55 years was a risk factor of low femoral neck T-score (OR 5.08, 95% CI 1.90-13.57, p=0.001), as was cumulative dose of prednisolone >or=5 g (OR 3.41, 95% CI 1.50-7.73, p=0.004). CONCLUSIONS: There is a discordance of results depending on whether T- or Z-scores are used in analysis. Among 22 parameters, cumulative steroid dose and age proved to be the most important factors.

The Bcl-2/Bax system and apoptosis in ulcerative colitis.

BACKGROUND/AIMS: Ulcerative colitis (UC) constitutes a chronic inflammatory process of the colon of unknown etiology. Current data support a pivotal role of apoptosis in the evolution of pathogenesis of UC. We performed a prospective study in order to determine the role of Bcl-2, Bax and Bcl-x in the apoptotic pathway in UC. METHODOLOGY: We included 23 patients with UC and 11 controls. Histological severity of the disease was assessed according to the Sidney classification system. Patients in the UC group were divided in 2 groups according to histological severity of the disease. The TUNEL method was used for the in situ evaluation of apoptosis. Immunohistochemical staining was used for the detection of Bax, Bcl-2, Bcl-x. For the assessment of cellular proliferation we used the monoclonal antibody Ki67. Appropriate statistical methods were applied. RESULTS: Overall 77 specimens were assessed; 57 from UC patients and 20 from controls. Bcl-2, Bax and Bcl-x were upregulated in the group of patients with UC compared to controls. Nevertheless, Bax in epithelial cells and Bcl-x in lymphocytes were downregulated in patients with moderate/severe disease (p = 0.029 and 0.04 respectively). A weak correlation between epithelial apoptosis and Bcl-x expression in lymphocytes (r = 0.31, p = 0.02) was found. An even weaker correlation was also noticed between the epithelial component apoptosis and Bax in lymphocytes (r = 0.02, p = 0.07). CONCLUSIONS: Bcl-2/Bax system does not appear to be involved in the induction of apoptosis in UC. Activation of intraepithelial lymphocytes may be associated with epithelial apoptosis or simply represent epiphenomena related to the inflammatory process.

Photodynamic therapy in normal pig stomach: protective effect of octreotide.

BACKGROUND AND STUDY AIMS: Many factors, such as oxygen and vasculature, are involved in the cytotoxic effect of photodynamic therapy (PDT). It is known that somatostatin and its analog octreotide decrease the splanchnic blood flow and have multiple inhibitory effects in different functions of the peptic system. The aim of this experimental study was to assess the effect of octreotide administration on PDT outcome in normal pig stomach. METHODS: 28 healthy pigs, randomly assigned to two groups, A and B, were studied. Pigs in both groups were sensitized with 0.3 mg/kg intravenous meta-tetra (hydroxyphenyl) chlorin (m-THPC), and 48 hours later light of wavelength 650 nm was delivered from a 50-mW diode laser for 300 s (energy fluence 15 J/cm (2)) through a gastroscope to the gastric mucosa. Group A underwent PDT without octreotide and group B had PDT with administration of octreotide. At 72 h after light delivery, all the animals were sacrificed for macroscopic and histological evaluation of the irradiated site. RESULTS: The macroscopic images and the histology of the stomach PDT lesions (inflammation, ulceration, necrosis) showed significantly less severity in the group of animals with octreotide injection (group B). In this group, full-thickness necrosis was observed in 28.5 %, compared with over 71.4 % in group A; this was statistically significant ( P < 0.05). CONCLUSION: Octreotide may have a modulating effect on m-TPHC PDT in normal gastric tissue in pigs, probably due to alterations of hemodynamics in the stomach and to suppression of the inflammatory process.

Relation between echinocytosis and erythrocyte calcium content in hemodialyzed uremic patients.

A rise in intracellular calcium concentration in erythrocytes has multiple effects on these cells. The purpose of this study was to determine the changes of calcium content in red blood cells (RBCs) and of echinocyte percentages in uremic patients during hemodialysis sessions. In 30 uremic patients under hemodialysis, the calcium content of RBCs and echinocyte percentages were determined in 3 blood samples collected at 0 min hemodialysis (prehemodialysis), 45 min hemodialysis, and 240 min hemodialysis (end hemodialysis) for a 4 h hemodialysis session. Calcium content of RBCs and echinocytes were also determined in 22 normal subjects (controls). The findings of the present study were that the mean values (+/-SD) of calcium content of RBCs in patients at 0 min hemodialysis, 45 min hemodialysis, and 240 min hemodialysis were 2.00 +/- 1.0, 2.66 +/- 0.87, and 1.62 +/- 0.66 microg/ml respectively and 0.65 +/- 0.07 microg/ml in controls. These values show that the calcium content of RBCs in uremic patients at 0 min hemodialysis, 45 min hemodialysis, and 240 hemodialysis was significantly higher than in controls (p < 0.0001), and that RBC calcium content at 45 min hemodialysis was significantly higher in comparison to that at 0 min hemodialysis (p < 0.001) and to that at 240 min hemodialysis (p < 0.0001), while that at 240 min hemodialysis was significantly lower than at 0 min hemodialysis (p < 0.05). The mean values (+/-SD) of echinocyte percentages in patients at 0 min hemodialysis, 45 min hemodialysis, and 240 hemodialysis were 11.93 +/- 6.18, 17.23 +/- 4.1, and 7.96 +/- 5.67% respectively, and in controls ranged from 0 to 1%. The values in uremic patients show a transient increase of echinocyte percentages at 45 min hemodialysis, which is significant in comparison to that at 0 min hemodialysis (p < 0.001) and to that at 240 min hemodialysis (p < 0.0001). Echinocyte percentages at 240 min hemodialysis were significantly lower to those at 0 min hemodialysis (p < 0.001). Correlation between calcium content of erythrocytes and echinocyte percentages shows a significantly positive relationship at 45 min hemodialysis (r = 0.368, p < 0.05) but no significant relationship at 0 min hemodialysis and 240 min hemodialysis. In conclusion, uremic patients under hemodialysis present with high calcium content in erythrocytes and abnormal erythrocytes like echinocytes. A rapid and transient increase of erythrocyte calcium is also accompanied by transient elevation of echinocytes in the first hour of hemodialysis (45 min hemodialysis), which returns after hemodialysis to lower than prehemodialysis levels.

Duodenal gangliocytic paraganglioma as a radiological moving defect.

BACKGROUND: Gangliocytic paraganglioma of the duodenum is a peculiar neuroendocrine tumor, often revealed as an incidental radiographic finding or as a result of gastrointestinal hemorrhage, due to frequent ulceration of the overlying mucosa. Most lesions are pedunculated and submucosal with distinctive histology, consisting of endocrine, ganglion and spindle-shaped Schwann cells. METHODS: A case of a duodenal gangliocytic paraganglioma is reported in a 50-year-old woman presenting with episodes of melena. Enteroclysis revealed a pedunculated tumor observed either in the second or third portion of the duodenum. Upper gastrointestinal endoscopy revealed a pedunculated ulcerated tumor which was subsequently confirmed by computed tomography. The tumor was simply excised through a duodenotomy. RESULTS: The size of the tumor was 4.5 x 3 x 1.5 cm. Immunohistochemical and ultrastructural features of the tumor classified it as a typical duodenal gangliocytic paraganglioma with positive cellular reaction for neuron-specific enolase, chromogranin, somatostatin, gastrin and S100. CONCLUSION: Forty-six months after surgery, the patient is well with no evidence of recurrence. The majority of the reported duodenal gangliocytic paragangliomas were of benign nature. However, the fact that in 4 isolated cases there was lymph node involvement indicates that thorough investigation for lymph node metastases is needed, as well as thorough postoperative follow-up.

Endoscopic drainage of acute obstructive cholecystitis in patients with increased operative risk.

Emergency biliary surgery for acute obstructive cholecystitis in the elderly is associated with an increased hospital mortality. We therefore attempted to drain the obstructed gallbladder via the transpapillary route in 18 patients (mean age: 67 years) who had cystic duct obstruction on ERC and who were at an increased surgical risk. A cholecystonasal catheter was successfully introduced after a small EPT in sixteen of them (89%). This resulted in effective bile drainage, obviating the need for emergency surgery in all patients. No procedure-associated morbidity or mortality was found. Following clinical remission, elective treatment consisted of ESWL/direct stone dissolution (n = 10) or elective surgery (n = 3). Three patients received no further therapy. Our results show that endoscopic gallbladder drainage may be a valuable alternative to emergency surgery in high risk patients with acute obstructive cholecystitis.

Sucralfate and ranitidine twice daily in the treatment of gastric ulcer. A multicenter randomized double-blind study.

Sucralfate and ranitidine were compared in the treatment of gastric ulcer (GU) in this multicenter randomized double-blind study. Sixty-four patients with endoscopically diagnosed GU initially included in the trial were randomly assigned to treatment with sucralfate, 2 g b.i.d. (morning and evening on an empty stomach), or ranitidine, 150 mg b.i.d. Nine patients were subsequently excluded for various reasons. The remaining 55 were examined endoscopically after 4 and, if unhealed, 8 weeks. At 4 weeks, 54.2% (13 of 24) of the sucralfate group had a healed ulcer, in comparison to 45.2% (14 of 31) of the ranitidine group (NS). At 8 weeks, cumulative healing rates were 87.5% (21 of 24) and 84% (26 of 31), respectively (NS). No differences were found in the healing effects of the drugs on smokers and nonsmokers or in side effects. These results suggest that both drugs are equally effective in the short-term treatment of GU.

Comparison of sucralfate and ranitidine twice daily in duodenal ulcer treatment: a multicenter randomized double-blind study.

Sucralfate and ranitidine were compared in the treatment of duodenal ulcer in this multicenter, randomized, double-blind study. A total of 165 patients with endoscopically proven duodenal ulceration were included in the trial and randomized to treatment with sucralfate, 2 g b.i.d. (morning and evening with an empty stomach), or ranitidine, 150 mg twice daily. All patients were endoscopically examined after 4 and, if unhealed, 8 weeks. Of the patients considered suitable for analysis at 4 weeks, 73.5% (61 of 83) of the sucralfate group demonstrated healing of the ulcer in comparison with 63.3% (50 of 79) of the ranitidine group. At 8 weeks cumulative healing rates were 89% (74 of 83) and 84.8% (67 of 79), respectively. When smokers were considered separately, healing rates at 4 weeks were 69.2% (36 of 52) for sucralfate and 53.3% (24 of 45) for ranitidine. At 8 weeks cumulative healing rates were 92.3% (48 of 52) and 77.7% (35 of 45), respectively (p less than 0.05). Overall, there was no difference in the two groups regarding symptom relief and side effects. These results suggest that these drugs are equally effective in the short-term treatment of duodenal ulcer, although in smokers sucralfate appears to be more effective than ranitidine.

Crohn's disease: course, treatment and long term prognosis.

The course, treatment and outcome of Crohn's disease affecting 174 patients diagnosed more than 20 years ago and followed for 20 to 45 years are reported. Fifty patients died, 23 related to Crohn's disease, against an expected 33, giving an increased mortality risk of 1.5 for the series. Fistulae of varying type occurring in 38 per cent of patients were successfully treated usually by excision and had no significant adverse effect upon the long term prognosis. The incidence of suicide and dementia appeared to be increased. Amyloid disease, obstructive uropathy and osteomalacia were other important complications. Definitive surgical operations averaged 2.5 per patient and after the first five years following diagnosis varied between 5 and 7 per cent of those at risk each year for the next 20 years. Recurrence rates were similar after any of the first five operations on a patient for the first 10 years after any operation. There was no evidence that the chance of operation was increased or made to recur more frequently by the performance of such an operation. All but two of the 121 living patients (three lost to follow-up) with a mean duration since diagnosis of 28 years were leading a normal life free from physical restrictions from Crohn's disease though three were mentally handicapped, 21 had radiological abnormality (recurrence), mostly longstanding, and 16 had less than 200 cm small intestine remaining. Specific therapy (corticosteroids 58 patients, sulphasalazine 11 patients and azathioprine four patients) was used at some time in only one third of the series so that such treatment did not appear necessary to produce good results in the majority. It is concluded that the indications for corticosteroid therapy are limited and that at present the joint efforts of physician and surgeon with adequate supportive therapy and well timed surgical resection produce the best results. An optimistic attitude to the eventual outcome is justified.

Response of the skin in dermatitis herpetiformis to a gluten free diet, with reference to jejunal morphology.

Twenty-one patients with dermatitis herpetiformis have been on a gluten free diet regularly followed up for at least one year (mean four years). Eighteen patients had a 'flat' mucosal appearance (grade III), one patient had moderately severe mucosal abnormality (grade II), one patient had mild mucosal abnormality (grade I), and one patient had a normal mucosal appearance (grade O). On the diet, 10 patients had no skin rash and took no dapsone, seven patients controlled the skin rash on a lower dose of dapsone, and four noticed no improvement. There was no correlation between pre-diet jejunal morphology and response of the skin. A repeat jejunal biopsy, on the gluten free diet, was possible in 15 patients. While all those with skin improvement showed some improvement in jejunal morphology, there was no association between the degree of skin improvement and the degree of recovery of the jejunal mucosa.

IgA class reticulin antibodies in relatives of patients with coeliac disease.

IgA class reticulin antibodies were not found in patients with Crohn's disease, ulcerative colitis, and hiatus hernia despite a significant incidence of IgG class reticulin antibodies. None of 56 normal healthy subjects was positive. In contrast, 13 (76%) of the sera from 17 patients with coeliac disease on normal diet were positive for IgA class antibodies as were 19 (20%) of 93 first degree relatives. Seventy-three relatives underwent jejunal biopsy. Grade III (flat) histology was found in 13 and, of these patients, 10 (77%) showed IgA class reticulin antibody in their serum. It is suggested that determination of IgA class reticulin antibodies was a useful test to determine which relative must be biopsied.

Histocompatibility antigens in inflammatory bowel disease. Their clinical significance and their association with arthropathy with special reference to HLA-B27 (W27).

Histocompatibility (HLA) antigen phenotypes have been studied in 100 patients with ulcerative colitis, 100 with Crohn's disease, and 283 normal controls. In addition the incidence of ankylosing spondylitis, sacroiliitis, and "enteropathic" peripheral arthropathy was determined in the patients with inflammatory bowel disease (IBD). There was no significant difference in antigen frequency between patients and controls. However, the incidence of HLA-B27 was increased in the patients complicated by ankylosing spondylitis and/or sacroiliitis in both ulcerative colitis and Crohn's disease. In contrast, none of the 29 IBD patients with "enteropathic" peripheral arthropathy had B27 antigen. Furthermore, ankylosing spondylitis was found more frequently in ulcerative colitis bearing HLA-B27 compared with non-B27 patients (P less than 0-01). The same was found in Crohn's disease, although this difference was not statistically significant. In addition, 12 of 14 ulcerative colitis patients and five out of six Crohn's patients with HLA-B27 had total colitis, compared with the frequency of total colitis in non-B27 patients (P less than 0-024 and less than 0-03 respectively). The data suggest that B27 histocompatibility antigen could be a pathogenetic discriminator between the arthropathies in IBD and may be of prognostic significance with respect to extension and severity of the disease.

Serum lysozyme in inflammatory bowel and coeliac disease.

Serum lysozyme levels were determined by a turbidometric method using egg white lysozyme as standard in 100 patients with Crohn's disease, 86 with ulcerative colitis, 31 with coeliac disease, and in 38 normal control subjects. Though the levels in Crohn's disease were significantly higher than those in ulcerative colitis and in coeliac disease, there was marked overlap between the disorders and control subjects, and so they were of no value in differential diagnosis. There was some evidence that serum lysozyme levels reflected disease activity in Crohn's disease but not in ulcerative colitis.