Oral tacrolimus treatment of severe colitis in children

OBJECTIVE: To evaluate the efficacy of oral tacrolimus as an induction agent in steroid-refractory severe colitis. STUDY DESIGN: Open-label, multicenter trial of oral tacrolimus in patients with severe colitis. Patients not responding to conventional therapy received tacrolimus, 0.1 mg/kg/dose given twice a day, and the dosage was adjusted to achieve blood levels between 10 and 15 ng/mL. Response was defined as improvement in a number of clinical parameters (including abdominal pain, diarrhea, rectal bleeding, and cessation of transfusions). Patients who responded by 14 days continued to receive tacrolimus, and 6-mercaptopurine or azathioprine was added as a steroid-sparing agent 4 to 6 weeks after the tacrolimus was instituted. RESULTS: Fourteen patients were enrolled in the study. One patient elected to withdraw after 48 hours. Of the 13 remaining, 9 (69%) responded and were discharged. Tacrolimus was continued for 2 to 3 months in the responders, except for 1 patient who was given tacrolimus for 11 months. After 1 year of follow-up, only 5 (38%) patients were receiving maintenance therapy; the other 4 responders had undergone colectomy. CONCLUSION: Although tacrolimus is effective induction therapy for severe ulcerative or Crohn's colitis, fewer than 50% of patients treated will successfully achieve a long-term remission.     

Vaccinia virus mediated p53 gene therapy for bladder cancer in an orthotopic murine model

PURPOSE: We determined if vaccinia virus (VV) mediated delivery of human tumor suppressor p53 is safe and effective for bladder tumor therapy in an orthotopic murine model. MATERIALS AND METHODS: We used recombinant VV (rVV) vectors to express transgenes in murine bladder cancer MB-49 cells in culture and those growing orthotopically in syngeneic mice. Cultured MB-49 cells were infected with rVV expressing reporter genes (rVV-L15) or p53 (rVV-TK-53) to measure virus infection and apoptosis induction. Orthotopic MB-49 tumors in C57/Bl6 mice were treated with intravesical instillation of rVV, and the tumor incidence, survival and transgene expression were determined. RESULTS: Productive virus infection in vitro was observed in MB-49 cells, although at somewhat lower efficiency than in African Green Monkey kidney CV-1 cells (American Type Culture Collection, Manassas, Virginia). Expression of transgenes in vitro correlated with the virus dose. Cells infected with rVV underwent apoptosis with rVV-TK-53 inducing far greater cell death than rVV-L15. The rVV-L15 virus had no effect on tumor incidence but it increased mean survival compared with control. Instillation of rVV-TK-53 decreased the tumor incidence and 33% of mice survived treatment. At necropsy all nonsurviving mice had bladder tumor, whereas 2 survivors in the rVV-TK-53 treated group were tumor-free. Immunohistochemistry of tumors detected expression of the human p53 gene product in tumor cells. CONCLUSIONS: To our knowledge we report for the first time that recombinant vaccinia virus expressing human p53 can induce the death of MB-49 tumor cells in vivo, not only through the lytic effect of the virus, but also through expression of the death inducing p53 transgene. Further studies are needed to shed light on the mechanisms of rVV-TK-53 mediated tumor apoptosis and the antitumor immune response.     

Protective effect of sensory denervation in inflammatory arthritis (evidence of regulatory neuroimmune pathways in the arthritic joint)

OBJECTIVE: To investigate the direct effect of joint innervation on immune mediated joint inflammation in a patient with psoriatic arthritis (PsA).Case report: The patient developed arthritis mutilans in all digits of both hands with the exception of the left 4th finger, which had prior sensory denervation following traumatic nerve dissection. Plain radiography, ultrasonography and nerve conduction studies of the hands confirmed the absence of articular disease and sensory innervation in the left 4th digit. METHODS: This relationship between joint innervation and joint inflammation was investigated experimentally by prior surgical sensory denervation of the medial aspect of the knee in six Wistar rats in which carrageenan induced arthritis was subsequently induced. Prior sensory denervation--with preservation of muscle function--prevented the development of inflammatory arthritis in the denervated knee. DISCUSSION: Observations in human and animal inflammatory arthritis suggest that regulatory neuroimmune pathways in the joint are an important mechanism that modulates the clinical expression of inflammatory arthritis.     

Cloning and characterization of cyclooxygenase-1b (putative cyclooxygenase-3) in rat

A splice variant of cyclooxygenase-1 (COX-1), COX-1b (previously termed as COX-3), has been identified in canine tissues as an acetaminophen-sensitive isoform, but the sequence of COX-1b mRNA and the encoded protein are not known in rats. We cloned and sequenced rat COX-1b mRNA from cerebral endothelial cells. Sequence analysis indicated that the 98-base pair intron-1 of COX-1 gene remains unprocessed in the COX-1b mRNA, causing a frameshift mutation and a 127-amino acid open reading frame with no sequence similarity with known cyclooxygenases. Transient and permanent transfection of COS-7 cells with a vector containing the rat COX-1b cDNA resulted in synthesis of a protein of the expected size. We generated an affinity-purified polyclonal antibody against the rat COX-1b protein. Western blot analysis of rat tissues using this antibody demonstrated the likely existence of rat COX-1b protein in vivo with the highest expression in heart, kidney, and neuronal tissues. Our results on both stable and on transiently transfected COS-7 cells suggest that rat COX-1b does not have cyclooxygenase activity and does not have any effect on the inhibition of prostaglandin production by acetaminophen. Because this protein has a completely different amino acid sequence than COX-1 and COX-2 and it does not have cyclooxygenase activity, we suggest a name cyclooxygenase variant protein to distinguish it from the known prostaglandin-synthesizing cyclooxygenase isoforms.     

Child and adolescent suicides in Virginia: 1987 to 2003

OBJECTIVES: The aim of this study was to better understand suicides in children and adolescents using records from the Office of the Medical Examiner of Virginia from 1987 to 2003. MAIN FINDINGS, KEY DATA, AND STATISTICS: Suicide accounted for 16.8% of unnatural deaths. Suicide rates were highest for Caucasians. Guns were the most common method of death for suicides, followed by hanging and poisoning. Poisoning other than carbon monoxide accounted for 7.8% of suicides, with tricyclic antidepressants (TCAs) the most identifiable poison. Female youths were 10 times more likely to die from TCAs than male youths, after adjusting for race and age. CONCLUSIONS: Guns and hanging were the principal methods of suicide. Among the antidepressants, TCAs have been the most common poisons used in suicide. Increasing age was a powerful determinant of suicide. Some patients may have stockpiled their TCAs for a while before their TCA overdose. Other suicide victims may have used TCA supplies from family members. Hence, some of the suicide victims may not have taken TCAs on a regular basis before committing suicide. Further exploration of TCA-induced suicidal thoughts is needed. Conclusions cannot be made at the time about the precise role that TCAs played in TCA-induced suicide reported in our study.     

Body mass index (BMI) in newly admitted child and adolescent psychiatric inpatients

INTRODUCTION: Obesity is a major problem among children and adolescents suffering from chronic mental illness. State-of-the-art measures such as body mass index (BMI) and growth-related weight charts are now readily available to clinicians and investigators interested in psychotropic drug-associated weight gain in the pediatric population. However, no reports that utilize such measures in large series of children and adolescents with psychiatric disorders are available. METHODS: The authors employed the Nutstat module of the Centers for Disease Control and Prevention (CDC) Epi Info software to assess BMI in a psychiatry inpatient child and adolescent population in Central Virginia. The authors also developed a scoring system to relate psychotropic administration to BMI. RESULTS: Children and adolescents with chronic mental illness had greater BMI measurements than the general pediatric population. Our scoring system found a relationship between antipsychotic drug administration and increased BMI that almost reached a level of significance (p=0.062). CONCLUSIONS: The present methodology using absolute weight to assess psychotropic drug-associated increase in body weight for children and adolescents is unsatisfactory. The authors offer a new and convenient methodology to correct this problem.     

Responding to the threat of chronic diseases in India

At the present stage of India's health transition, chronic diseases contribute to an estimated 53% of deaths and 44% of disability-adjusted life-years lost. Cardiovascular diseases and diabetes are highly prevalent in urban areas. Tobacco-related cancers account for a large proportion of all cancers. Tobacco consumption, in diverse smoked and smokeless forms, is common, especially among the poor and rural population segments. Hypertension and dyslipidaemia, although common, are inadequately detected and treated. Demographic and socioeconomic factors are hastening the health transition, with sharp escalation of chronic disease burdens expected over the next 20 years. A national cancer control programme, initiated in 1975, has established 13 registries and increased the capacity for treatment. A comprehensive law for tobacco control was enacted in 2003. An integrated national programme for the prevention and control of cardiovascular diseases and diabetes is under development. There is a need to increase resource allocation, coordinate multisectoral policy interventions, and enhance the engagement of the health system in activities related to chronic disease prevention and control.