Detection of disability worsening in relapsing-remitting multiple sclerosis patients: a real-world roving Expanded Disability Status Scale reference analysis from the Italian Multiple Sclerosis Register.

BACKGROUND AND PURPOSE: In relapsing-remitting multiple sclerosis patients (RRMS) disability progressively accumulates over time. To compare the cumulative probability of 6-month confirmed disability-worsening events using a fixed baseline or a roving Expanded Disability Status Scale (EDSS) reference, in a real-world setting. METHODS: A cohort of 7964 RRMS patients followed for 2 or more years, with EDSS scores recorded every 6 months, was selected from the Italian Multiple Sclerosis Register. The overall probability of confirmed disability-worsening events and of confirmed disability-worsening events unrelated to relapse was evaluated using as reference a fixed baseline EDSS score or a roving EDSS score in which the increase had to be separated from the last EDSS assessment by at least 6 or 12 months. RESULTS: Using a fixed baseline EDSS reference, the cumulative probability of 6-year overall confirmed disability-worsening events was 33.2%, and that of events unrelated to relapse was 10.9% (33% of overall confirmed disability-worsening events). Using a roving EDSS, the proportions were respectively 35.2% and 21.3% (61% of overall confirmed disability-worsening events). CONCLUSIONS: In a real-world setting, roving EDSS reference scores appear to be more sensitive for detecting confirmed disability-worsening events unrelated to relapse in RRMS patients.

Fluctuations of MS births and UV-light exposure.

BACKGROUND: Patients with multiple sclerosis (MS) are more frequently born in spring when compared to autumn. Fluctuation of UV-light has been hypothesized to drive this phenomenon. AIM: To assess the correlation between fluctuation of sunlight and birth season in persons with MS. METHODS: For this record-linkage study, we collected from the international MSBase and the Italian MS iMed-web databases the dates of birth of 11,415 patients with MS from 36 centres from 15 countries worldwide and compared these to dates of live-births from national registries. From all participating sites, we collected data on UV-light fluctuation and assessed its correlation with seasonal fluctuation in MS births. RESULTS: Compared with the reference cohort, an increased proportion of persons with MS were born in spring and a decreased proportion in autumn (odds ratio (OR) to be born in spring versus autumn = 1.158, χ² = 36.347, P < 0.001). There was no significantly increased fluctuation of MS births with increased quartile of ambient UV-light fluctuation (Ptrend = 0.086). CONCLUSION: Seasonal fluctuation of MS births as found in this worldwide cohort of patients with MS did not correlate with variation in seasonal fluctuation of UV-light. Most likely, it results from a complex interplay between fluctuation of sunlight, behavioural factors, other environmental factors and (epi)genetic factors.

The burden of hospitalization related to diabetes mellitus: a population-based study.

BACKGROUND AND AIMS: To estimate the impact of diabetes and its complications, overall and in different age classes, on the likelihood of hospital admission for specific causes. METHODS AND RESULTS: We carried out a record-linkage analysis of administrative registers including data on 8,940,420 citizens in 21 Local Health Authorities in Italy. Individuals with pharmacologically treated diabetes (≥2 prescriptions of antidiabetic agents during the year 2008) were paired in a 1:1 proportion with those who did not receive such drugs (controls) based on propensity-score matching. Odds Ratios (ORs) of hospitalization for macro and microvascular conditions in individuals with diabetes as compared to controls were estimated. The system identified 498,825 individuals with diabetes pharmacologically treated (prevalence of 5.6%). Prevalence of diabetes in people aged <14 years, 14-39 years, 40-65 years, and ≥65 years was 0.1%, 0.6%, 6.4%, and 18.2%, respectively. Overall, 23.9% of subjects with diabetes and 11.5% of controls had had at least a hospital admission during 12 months for the causes considered. Diabetes increased the likelihood of hospitalization by two to six times for the different causes examined. In absolute terms, diabetes was responsible for an excess of over 12,000 hospital admissions per 100,000 individuals/year. CONCLUSION: Despite the availability of effective treatments to prevent or delay major complications, diabetes still places an enormous burden on both patients and the health care system. Given the continuous rise in diabetes prevalence both in middle-aged and elderly individuals, we can expect an additional, hardly sustainable increase in the demand for health care in the near future.

Acute aortic dissection in a patient with extremely low body mass index due to anorexia nervosa.

We report a case of successful surgical repair of an acute aortic dissection (Stanford Type A) in a severely malnourished 39-year old patient with anorexia nervosa (body mass index [BMI] 11.3 kg/m2) and essential hypertension. The case is of interest since 1) acute aortic dissection in patients with anorexia nervosa has not previously been described; 2) hypertension is extremely rare in patients with eating disorders; and 3) successful aortic repair in a patient with so low BMI has not been reported before. We conclude that extremely low BMI due to anorexia nervosa is not an absolute contraindication for major aortic surgery.

Real-life impact of early interferon beta therapy in relapsing multiple sclerosis.

OBJECTIVE: Recent findings support greater efficacy of early vs. delayed interferon beta (IFNbeta) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFNbeta treatment in definite relapsing-remitting MS (RRMS) and to assess the optimal time to initiate IFNbeta treatment with regard to the greatest benefits on disability progression. METHODS: A cohort of 2,570 IFNbeta-treated RRMS patients was prospectively followed for up to 7 years in 15 Italian MS Centers. A Cox proportional hazards regression model adjusted for propensity score (PS) quintiles was used to assess differences between groups of patients with early vs. delayed IFNbeta treatment on risk of reaching a 1-point progression in the Expanded Disability Status Scale (EDSS) score, and the EDSS 4.0 and 6.0 milestones. A set of PS-adjusted Cox hazards regression models were calculated according to different times of treatment initiation (within 1 year up to within 5 years from disease onset). A sensitivity analysis was performed to assess the robustness of findings. RESULTS: The lowest hazard ratios (HRs) for the three PS quintiles-adjusted models were obtained by a cutoff of treatment initiation within 1 year from disease onset. Early treatment significantly reduced the risk of reaching a 1-point progression in EDSS score (HR = 0.63; 95% CI = 0.48-0.85; p < 0.002), and the EDSS 4.0 milestone (HR = 0.56; 95% CI = 0.36-0.90; p = 0.015). Sensitivity analysis showed the bound of significance for unmeasured confounders. INTERPRETATION: Greater benefits on disability progression may be obtained by an early IFNbeta treatment in RRMS.

Post-marketing of disease modifying drugs in multiple sclerosis: an exploratory analysis of gender effect in interferon beta treatment.

BACKGROUND: There are a few and conflicting results from randomised controlled trials (RCTs) pertaining to the influence of gender in response to currently used disease modifying drugs in Multiple Sclerosis (MS). Observational studies may be especially valuable for answering effectiveness questions in subgroups not studied in RCTs. OBJECTIVE: To conduct a post-marketing analysis aimed to evaluate the gender effect on Interferon beta (IFNbeta) treatment response in a cohort of relapsing (RR) MS patients. METHODS: A cohort of 2570 IFNbeta-treated RRMS was prospectively followed for up to 7 years in 15 Italian MS Centers. Cox proportional hazards regression models were used to assess gender differences for risk of reaching 1st relapse and risk of progression by 1 point on Expanded Disability Status Scale (EDSS) score. Gender effects were also explored by a propensity score (PS) matching algorithm, and a tree-growing technique. RESULTS: The multivariate Cox Regression analyses showed that male patients had a significant (p=0.0097) lower risk for 1st relapse and a trend (p=0.0897) for a higher risk to reach 1 point EDSS progression than females. The PS matched multivariate Cox Regression confirmed these results. The RECPAM analysis showed that male sex conferred a significant reduction in the risk for 1st relapse (HR=0.86; 95% CI=0.76-0.98; p=0.0226) in the subgroup with a low pre-treatment number of bouts, and a significant increase in the risk for 1 point EDSS progression (HR=1.33; 95% CI: 1.00-1.76; p<0.05) in the subgroup with a delayed treatment, but a still young age at the start of treatment. CONCLUSION: The results of this exploratory analysis seem to suggest that male patients do not respond to IFNbeta treatment in the same way of females.

Analysis of survival and prognostic factors in amyotrophic lateral sclerosis: a population based study.

OBJECTIVE: To measure survivorship and predictors of prognosis of amyotrophic lateral sclerosis (ALS). METHODS: Incident cases, diagnosed in the 1998-1999 period and classified according to the El Escorial criteria, were enrolled from a prospective population based registry established in Puglia, Southern Italy, with a reference population of 4,025,329. Cases were followed up until death or 30 June 2004. RESULTS: We identified 130 incident cases of ALS while four were lost to follow-up. Median survival was 28 months from first symptoms and 16 months from diagnosis, while cumulative survivorship at 4 years was approximately 30%. Advanced age (>75 years: hazard ratio (HR) 7.5; 95% CI 1.9 to 29.6; p = 0.004) and bulbar or generalised (HR 1.8; 95% CI 1.1 to 3.0; p = 0.01) onset of symptoms were independent predictors of adverse survival. After stratifying patients according to site of first symptoms, age was a predictor of death among spinal (HR for patients aged >75 years compared with patients aged 45 years or less: HR 11; 95% CI 1.5 to 78.5; p = 0.01) but not among bulbar ALS (HR 4.5; 95% CI 0.4 to 46.5; p = 0.2). Among spinal onset cases, cases with predominant upper motoneuronal (UMN) involvement presented with a borderline significant better survivorship (HR 0.5; 95% CI 0.2 to 1.3; p = 0.1) CONCLUSIONS: Bulbar signs and advanced age among subjects with spinal onset were indicators of poor prognosis while El Escorial category at entry did not predict survival. Among subjects with spinal onset of the disease, a trend for a better survivorship of subjects with UMN signs was noted.

Riluzole and amyotrophic lateral sclerosis survival: a population-based study in southern Italy.

Riluzole is to date the only treatment that prolongs amyotrophic lateral sclerosis (ALS) survival. However, results on the efficacy of riluzole in observational population-based studies with a longer follow-up are conflicting and it is still unclear if the effect of the drug is limited to an early stage of the disease and to some specific subgroups of patients. The objective is: (i) to evaluate the effect of riluzole on ALS survival in a cohort of incident cases; (ii) to examine whether bulbar-ALS benefits from the medication to a greater extent and (iii) to assess the efficacy of the drug in elderly patients. Source of the study was a prospective population-based registry of ALS established in Puglia, Southern Italy. We examined survival of 126/130 incident ALS cases diagnosed during the period 1998-1999. Seventy-three patients were prescribed riluzole and the remaining 53 were not. Riluzole therapy increased survival rates at 12 months by approximately 10% and prolonged survival by 6 months (18.2 months vs. 12.4; peto-test: 2.78; P = 0.09). This beneficial effect was present amongst bulbar-onset ALS (peto-test: 4.11; P = 0.042), but not in subjects with limb-onset (peto-test: 0.48; P = 0.4). In patients aged >70 years riluzole treatment was associated with an 8 months longer median survival time [15.4 months vs. 7.1] and a reduction in mortality rate at 12 months by 27%, regardless of site of symptoms onset. In multivariate analysis, riluzole use was an independent predictor of survival at 12 months from the diagnosis with borderline significance (P = 0.06). Riluzole was effective amongst cases with bulbar-onset ALS (P = 0.04), whereas in subjects with limb-onset there was no effect on survival at 12 months (P = 0.5). In each model riluzole did not influence survival at 24 months. Conversely, riluzole use was associated with an improvement in survival amongst elderly patients both at 12 (P = 0.07), at 24 months (P = 0.03) and in the entire follow-up period (P < 0.04). In this population-based series, we found that riluzole therapy improves ALS survival. The efficacy of the drug was present amongst bulbar-onset ALS and older patients, but not in subjects with limb-onset. The favourable effect of the drug was transient, as it was lost in prolonged follow-up. Our observations support the use of riluzole at an early stage of ALS in bulbar and elderly patients. However, the appropriate duration of riluzole treatment remains to be established.

Italian Multiple Sclerosis Database Network.

The Multiple Sclerosis Database Network (MSDN) is the first Italian multiple sclerosis (MS) registry. The preliminary results on the MSDN cohort demonstrated that the risk of disability progression, in a sample of 2090 MS patients, was reduced by about four- to five-fold in patients exposed to IFNbeta for more than 4 years compared with patients exposed for up to 2 years. More recent results showed, in a subset of 1170 relapsing-remitting MS patients, of whom 918 were treated with IFNbeta and 252 were untreated, that IFNbeta-treated patients had a differential reduction in EDSS score change of -0.055 for each year of follow-up in comparison with the untreated group. These results provide significant information on the effectiveness of IFNbeta treatment on long-term disability progression in MS.

Signs and symptoms at diagnosis of amyotrophic lateral sclerosis: a population-based study in southern Italy.

Amyotrophic lateral sclerosis (ALS) diagnostic criteria are used to select patients for clinical trials based on different levels of diagnostic certainty, according to the spread of upper (UMN) and lower motoneuron (LMN) signs in different anatomic regions. However, the clinical presentation of ALS patients is extremely variable and this can delay the time to diagnosis and decrease the likelihood for trial entry. The aims of the study were to describe the signs and symptoms of diagnosis in a population-based incident cohort of ALS cases, using the El Escorial (EEC) and the Revised Airlie Diagnostic Criteria (AHC). The source of the study was a prospective population-based registry established in Puglia, southern Italy, in 1997. The diagnosis and the classification of the cases were based on EEC and AHC. All incident ALS cases during the period 1998-1999 were enrolled and followed up. During the surveillance period, we identified 130 ALS incident cases, and bulbar-ALS represented 20% of our cohort. The highest risk for bulbar onset was among subjects aged >75 years [RR: 20.1, 95% confidence interval (CI) 3.4-118.0] compared with subjects aged <55 years and among females compared with males (Relative risk (RR): 2.75, 95% CI: 1-7.3). The vast majority of patients (72%) referred progressive muscle weakness in the limbs as the presenting symptom. Eighty percent of cases presented contemporary bulbar or spinal involvement; UMN signs in the bulbar region were present in 24% of cases and any motoneuronal sign in thoracic region in only 15% of the cases. In this population-based series, progressive muscle weakness was the most common presenting sign; bulbar onset was associated with advanced age and female sex. UMN signs in the bulbar region and any motoneuronal sign in the thoracic region were observed in 20% of our case series. This may represent the main limitation to show the spread of signs during diagnostic assessment for inclusion in epidemiological studies and clinical trials.

Incidence of amyotrophic lateral sclerosis in southern Italy: a population based study.

BACKGROUND: While the incidence of amyotrophic lateral sclerosis (ALS) is similar across the world (range, 1.0 to 2.5/100,000), a latitude gradient from north to south has been observed. OBJECTIVE: To determine the incidence of ALS in Puglia, a region of south eastern Italy, and to test the latitude gradient hypothesis comparing the present study with findings in studies conducted with the same design in a northern latitude. METHODS: Puglia (4,086,613 residents in 2001) is the site of a multicentre-multisource prospective population based registry established in 1997. All incident ALS cases during the period 1998-99 were enrolled and followed up. Cases were classified using the first and the revised El Escorial criteria. RESULTS: During the study period 130 cases were enrolled. The annual crude incidence for ALS in Puglia for the two year period 1998-99 was 1.6/100,000 (95% confidence interval, 1.3 to 1.9). The incidence was higher for men (incidence rate (IR) = 2.1 (1.7 to 2.7) than for women (IR = 1.2 (0.9 to 1.5)) in all age groups, with a male to female ratio of 1.6. For both men and women, the incidence increased through age 75 and declined rapidly afterwards. The mean annual incidence adjusted by age and sex to the 2001 Italian population was 1.7/100,000 (1.4 to 2.0). CONCLUSIONS: ALS incidence is within a narrow range across countries, with a peak between 65 and 75 years and a higher incidence in men. A north to south latitude gradient of ALS incidence is not supported by the results of cohort studies.

Treatment of descending thoracic aneurysms by endovascular stent grafting.

PURPOSE: Endovascular stent-graft treatment for true aneurysms of the descending thoracic aorta is a valid and effective alternative to conventional surgery. A review of our experience with 21 consecutive patients is reported and technical considerations are discussed. METHODS: Twenty-one patients (mean age 73 years) with true aneurysms of the descending thoracic aorta (n = 14) or contained rupture (n = 7) were treated between October 1999 and July 2001. Seven patients (33%) underwent emergency endovascular procedure. Postoperatively, the patients were followed with CT scans at 1, 3, 6, and 12 months. Follow-up, which averaged 17 months, was 100% complete. THIRTY-DAY RESULTS: No conversions to open repair were necessary. Two patients died (10%), one of acute intestinal ischemia and the other because of multiorgan failure. Four patients showed endoleaks immediately after stenting. Two patients required new endovascular stentgrafts, while the remaining two were treated conservatively. Besides endoleaks, eight major complications occurred in six patients (two stroke, two paraplegia, two respiratory insufficiency, and one renal failure). MID-TERM RESULTS: Three more patients died during the follow-up period. One patient died of heart failure after a complicated postoperative course, 91 days after stenting. The second patient died because of aortic rupture, 139 days after stenting. The third patient died of heart failure, 15 months after the endovascular procedure. The remaining 16 patients are alive and have been regularly controlled by CT scans. No late migration or endoleaks have been detected. In all the survivors, the size of the aneurysm was unchanged or diminished. CONCLUSIONS: Treatment of descending thoracic aortic aneurysms by endovascular stentgraft devices has good early and mid-term results. More accurate selection of patients may further reduce mortality and morbidity.

Course and prognosis in early-onset MS: comparison with adult-onset forms.

OBJECTIVES: To establish the prognostic role of clinical and demographic factors in a hospital-based cohort of MS patients categorized by age at clinical onset and clinical course. METHODS: Eighty-three patients with MS had a clinical onset of the disease in childhood (age <16 years; early-onset MS [EOMS]) and 710 in adult age (between 16 and 65 years; adult-onset MS [AOMS]). Patients were followed for a mean period of observation of 5 years. Univariate and multivariate analyses of clinical and demographic predictors for rapid progression and disability were performed using a stepwise Cox regression model with time-dependent covariates. RESULTS: In EOMS, the Expanded Disability Status Scale (EDSS) evaluated at last clinical examination was lower than in AOMS, despite a longer disease duration. The probability to reach growth disability and progression was significantly lower in EOMS than in AOMS. Median times to reach EDSS score of 4 and secondary progression were longer in EOMS than in AOMS, but the age at both endpoints was significantly lower in EOMS. In EOMS and AOMS, an irreversible disability was related to a secondary progressive course, a sphincteric system involvement at onset, and an older age at onset (in EOMS only for the group >14 years); in AOMS, other unfavorable factors were a pyramidal involvement at onset and a high relapse frequency in the first 2 years. The risk of entering secondary progression was significantly influenced by a high number of relapses in EOMS and by a higher age at onset and a short interattack interval in AOMS. CONCLUSION: A slower rate of progression of disease characterized EOMS patients, suggesting more plasticity to recover in developing CNS, but the early clinical manifestation cannot be considered a positive prognostic factor.

[Chorea in hemodialysis: Is chorea just a neurological syndrome or is it related to uremia or dialysis?]. / Corea in emodializzato: sindrome strettamente neurologica o correlata all'uremia e alla dialisi?

Chronic renal failure and haemodialysis patients are prone to develop encephalopathy. The causes of encephalopathy are often unclear. Clinical signs of encephalopathy in the uraemic patient often overlap with several other affections causing neurological disorders. Whenever basal ganglia are anatomically involved, movement disorders arise, including chorea. Some acute and chronic neurological syndromes associated with chronic uraemia have consistently been reported (uraemic encephalopathy, dialysis disequilibrium syndrome, dialysis dementia, nephroangiosclerosis neuropathy and ageing neuropathy). Other clinical conditions in which neurological involvement exists are not so frequent in both haemodialysis patients and in the general population (Wernicke's encefalopathy, Creutzfeldt-Jacob disease). Because of the non specific symptoms and the very heterogeneous aetiology, a careful physical examination should be performed in haemodialysis patients with clinical signs of encephalopathy and the main metabolic alterations should be sought; moreover, central nervous system imaging examination is often appropriate. In case of basal ganglia anatomical involvement, supported by findings of imaging techniques, it is necessary to evaluate individual causes of encephalopathy by means of more accurate tests including analysis of cerebro-spinal fluid, measurement of plasma levels of vitamin B components and laboratory tests searching for more uncommon diseases such as Huntington's chorea and Wilson's disease.

Beneficial effects of tempol, a membrane-permeable radical scavenger, on the multiple organ failure induced by zymosan in the rat.

BACKGROUND AND METHODS: We investigated the effects of tempol, a membrane-permeable radical scavenger, on the multiple organ failure (MOF) caused by zymosan in the rat. Zymosan (500 mg/kg, suspended in saline solution, ip) enhances formation of reactive oxygen species, which contribute to the pathophysiology of MOF. After zymosan or saline administration, animals were monitored for 12 days. RESULTS: Treatment of rats with tempol (10, 30, or 100 mg/kg ip, 1 and 6 hrs after zymosan) attenuated the peritoneal exudation and the migration of polymorphonuclear cells caused by zymosan in a dose-dependent fashion. Tempol also attenuated the lung, liver, and intestinal injury (histology) as well as the increase in the concentrations of myeloperoxidase and malondialdehyde caused by zymosan in the lung, liver, and intestine. Immunohistochemical analysis for nitrotyrosine and for poly(adenosine 5'-diphosphate-ribose)synthetase demonstrated a positive staining in lung, liver, and intestine from zymosan-treated rats. The degree of staining for nitrotyrosine and for poly(adenosine 5'-diphosphate-ribose) synthetase was markedly reduced in tissue sections obtained from zymosan-treated rats that had received tempol (100 mg/kg ip). Furthermore, treatment of rats with tempol significantly reduced the following: a) the formation of peroxynitrite, b) the DNA damage, c) the impairment in mitochondrial respiration, and d) the decrease in the cellular concentration of oxidized nicotinamide adenine dinucleotide observed in macrophages harvested from the peritoneal cavity of rats treated with zymosan. CONCLUSION: This study provides the first evidence that tempol, a small molecule that permeates biological membranes and scavenges reactive oxygen species, attenuates the degree of MOF associated with zymosan-induced peritonitis in the rat.

Aortic surgery in patients with marfan syndrome: long-term survival, morbidity and function.

BACKGROUND AND AIM OF THE STUDY: The natural history of patients with Marfan syndrome is depressing, but surgical intervention on the aorta can improve the prognosis. Study results were analyzed with reference to long-term survival, morbidity and function. METHODS: Seventy-four Marfan patients (51 males, 23 females; mean age 41+/-14 years), underwent first-time aortic surgery between 1977 and 1998. Follow up information regarding mortality, morbidity and functional status was obtained from patient records and by questionnaire. The mean follow up was 5 years (range: 0-19 years). Forty-seven patients (64%) had a dissection, 27 (36%) an aneurysm, and 45 (61%) patients underwent emergency operations (<4 h from arrival at hospital). In 72 patients (97%) the disease affected the ascending aorta, and implantation of a composite graft was the most frequent operation. RESULTS: Overall 30-day mortality was 12% (3% in elective cases, 18% in emergency cases, p <0.05). Emergency operations and surgery extended to the aortic arch were risk factors for early mortality. Overall actuarial survival was 63.4+/-8% at 10 years. Age was the only risk factor for late mortality. Seventeen patients were reoperated on due to pathologies of the remaining aorta (n = 12), pseudoaneurysms (n = 4) and aortic valve endocarditis (n = 1). A total of five patients had endocarditis; one patient with a homograft required surgery, and medical treatment was successful in the other four patients. Five patients had neurological thromboembolic episodes without permanent damage, and six had minor bleeding complications. Freedom from early and late mortality, reoperation on the aorta and major cardiovascular events (endocarditis episodes, thromboembolic/hemorrhagic strokes and other major bleeding/embolic episodes) was 33.3 +/- 8.1% at 10 years. At follow up, 98% of patients were in NYHA functional class I or II, and 80% were working. CONCLUSION: Elective aortic surgery in Marfan patients can be performed with good results. Close follow up of patients undergoing surgery is important. The long-term functional status of surviving patients is satisfactory.

Melatonin reduces dinitrobenzene sulfonic acid-induced colitis.

Inflammatory bowel disease (IBD) is characterized by oxidative and nitrosative stress, leukocyte infiltration, and up-regulation of intercellular adhesion molecule 1 (ICAM-1) expression in the colon. The aim of this study was to examine the effects of the pineal secretory product melatonin in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced bloody diarrhea and a significant loss of body weight. Four days after DNBS administration, the colon damage was characterized by areas of mucosal necrosis. Neutrophil infiltration (indicated by myeloperoxidase [MPO] activity in the mucosa) was associated with up-regulation of ICAM-1, expression of P-selectin, and high levels of malondialdehyde (MDA). Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) synthetase (PARS) showed an intense staining in the inflamed colon. Staining of colon tissue sections obtained from DNBS-treated rats with an anti-cycloxygenase-2 (COX-2) antibody showed a diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthase (iNOS) was found mainly in the macrophages of the inflamed colons from DNBS-treated rats. Treatment with melatonin (15 mg/kg daily, intraperitoneally) significantly reduced the appearance of diarrhea and the loss of body weight. This was associated with a remarkable amelioration of the disruption of the colonic architecture, as well as a significant reduction of colonic MPO activity and MDA levels. Melatonin also reduced the appearance of nitrotyrosine and PARS immunoreactivity in the colon, as well as reducing the up-regulation of ICAM-1 and the expression of P-selectin. The intensity and degree of the stainings for COX-2 and iNOS were markedly reduced in tissue sections obtained from melatonin-treated rats. The results of the this study suggest that the administration of melatonin might be beneficial for the treatment of IBD.

Ectopic metaplastic ossification after sternotomy.

Ectopic ossification is a rare complication after a major operation. We report a case of cutaneous infection and metaplastic ossification in an 80-year-old man who underwent coronary artery bypass grafting 4 years earlier. Computed tomographic scan demonstrated a partial pseudarthrosis of the corpus sterni. The infected part of the sternal scar was excised and sternal wires were removed. Eight months later, the wound has healed without complications and the cutaneous ossification is unaltered.

The tyrosine kinase inhibitor tyrphostin AG 126 reduced the development of colitis in the rat.

Inflammatory bowel disease is characterized by oxidative and nitrosative stress, leukocyte infiltration, up-regulation of the expression of intercellular adhesion molecule-1 (ICAM-1), and up-regulation of P-selectin in the colon. Here we investigate the effects of the tyrosine kinase inhibitor, Tyrphostin AG 126, in rats subjected to experimental colitis. Colitis was induced in rats by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Rats experienced hemorrhagic diarrhea and weight loss. Four days after administration of DNBS, the mucosa of the colon exhibited large areas of necrosis. Neutrophil infiltration (determined by histology as well as an increase in myeloperoxidase activity in the mucosa) was associated with up-regulation of ICAM-1 and P-selectin, as well as high tissue levels of malondialdehyde. Immunohistochemistry for nitrotyrosine and poly(ADP-ribose) polymerase showed an intense staining in the inflamed colon. Staining with an anti-COX-2 antibody of sections of colon obtained from DNBS-treated rats showed a diffuse staining of the inflamed tissue. Furthermore, expression of inducible nitric oxide synthase was found mainly in macrophages located within the inflamed colon of DNBS-treated rats. Tyrphostin AG 126 (5 mg/kg daily ip) significantly reduced the degree of hemorrhagic diarrhea and weight loss caused by administration of DNBS. Tyrphostin AG 126 also caused a substantial reduction of (1) the phosphorylation of tyrosine residues of proteins (immunoblots of inflamed colon), (2) the degree of colonic injury, (3) the rise in myeloperoxidase activity (mucosa), (4) the increase in the tissue levels of malondialdehyde, (5) the increase in staining (immunohistochemistry) for nitrotyrosine and poly(ADP-ribose) polymerase, as well as (6) the up-regulation of ICAM-1 and P-selectin caused by DNBS in the colon. Thus, we provide the first evidence that the tyrosine kinase inhibitor Tyrphostin AG126 reduces the degree of colitis caused by DNBS.