Low-Dose ATG/GCSF in Established Type 1 Diabetes: A Five-Year Follow-up Report

Previously, we demonstrated low-dose antithymocyte globulin (ATG) and granulocyte colony-stimulating factor (GCSF) immunotherapy preserved C-peptide for 2 years in a pilot study of patients with established type 1 diabetes (n = 25). Here, we evaluated the long-term outcomes of ATG/GCSF in study participants with 5 years of available follow-up data (n = 15). The primary end point was area under the curve (AUC) C-peptide during a 2-h mixed-meal tolerance test. After 5 years, there were no statistically significant differences in AUC C-peptide when comparing those who received ATG/GCSF versus placebo (P = 0.41). A modeling framework based on mean trajectories in C-peptide AUC over 5 years, accounting for differing trends between groups, was applied to recategorize responders (n = 9) and nonresponders (n = 7). ATG/GCSF reponders demonstrated nearly unchanged HbA_1c over 5 years (mean [95% CI] adjusted change 0.29% [–0.69%, 1.27%]), but the study was not powered for comparisons against nonresponders 1.75% (–0.57%, 4.06%) or placebo recipients 1.44% (0.21%, 2.66%). These data underscore the importance of long-term follow-up in previous and ongoing phase 2 trials of low-dose ATG in recent-onset type 1 diabetes.     

Changes in newspaper coverage of cardiovascular health issues in conjunction with a community-based intervention

Numerous community-based prevention projects, with significant media components, have been conducted over the past decade. Multiple evaluation strategies have been used to document the effectiveness of these interventions, including intermediate measures of community impact such as assessment of media coverage. As part of the evaluation of a community-based intervention (the Bootheel Heart Health Project), dissemination of information on cardiovascular disease (CVD) was measured through a media content analysis of newspapers. Data were analyzed from 23 newspapers in six rural counties in southeastern Missouri for the period October 1988 through August 1993. An increase was observed in CVD-related coverage in the pre-intervention period (mean articles per month = 31.5) compared with the post-intervention period (mean articles per month = 50.7) (F = 10.2; P = 0.003). In supporting data from a separate randomized risk factor survey of 1510 residents in the same area, respondents reported hearing of heart health coalitions primarily through local newspapers. The current study documents increasing print media coverage of cardiovascular health issues in a high-risk, rural area and shows that media content analysis can be a useful evaluation tool in community-based interventions.     

Synovial sarcoma of the neck associated with previous head and neck radiation therapy.

Synovial sarcoma is a rare neoplasm that uncommonly arises in the neck. Fourteen years after facial and neck radiation therapy for acne, synovial sarcoma of the neck developed in a young man. Possible radiation-induced benign and malignant neoplasms that arise in the head and neck region, either of thyroid or extrathyroid origin, remain a continuing medical problem.     

The epidemiology of endometrial cancer in young women

A case-control study was conducted in Los Angeles County, California, of 127 endometrial cancer cases aged 45 years or less at diagnosis, to investigate the role of fertility, obesity and exogenous oestrogens in the development of the disease in young women. Use of sequential oral contraceptive (SOCs) or oestrogen replacement therapy (ERT) for greater than or equal to 2 years was strongly associated with increased risk of endometrial cancer. After excluding these cases, since the SOC or ERT use was probably the cause of their disease, we were left with 110 case-control pairs for further study. Among these remaining case-control pairs increasing parity was strongly associated with decreased risk (relative risk of 0.12 for women of parity 3 compared to nulliparous women, P less than 0.001). Current weight was associated with increased risk (relative risk of 17.7 for women weighing greater than or equal to 190 lbs compared to women weighing less than 130 lbs, P less than 0.001). Combination oral contraceptive (COC) use was associated with a decreased risk, which decreased with duration of COC use (relative risk of approximately 0.28 at 5 years of use, P less than 0.001), but the estimate of the protective effect was reduced and became statistically non-significant when allowance was made for weight and parity. The protective effect of COC use was only clearly evident in women who had less than 3 live-births and weighed less than 170 lbs. These results provide further support for the "unopposed" oestrogen hypothesis of the aetiology of endometrial cancer.     

Neuropathologic substrates of ischemic vascular dementia

Ischemic vascular dementia (IVD) is a relatively uncommon entity, in the course of which multiple ischemic brain lesions result in progressive cognitive and memory impairment. Ischemic brain lesions may also aggravate the neuropsychologic deficit of Alzheimer disease (AD). In this review we summarize our experience based upon autopsy examination of the central nervous system in 20 patients (age range 68-92 years) enrolled in a longitudinal investigation of structural, neurochemical, functional neuroimaging, and neuropsychologic components of IVD, especially dementia associated with cerebral microvascular disease. While cystic infarcts were present in the CNS of 5 patients, the most commonly observed neuropathologic abnormalities were lacunar infarcts and microinfarcts--both types of lesion were encountered in over half of patients' brains. Evidence of (remote) hippocampal injury was found in 11/20 patients. Severe atherosclerosis and arterio/ arteriolosclerosis were both associated with the occurrence of multiple lacunar infarcts. Pronounced cerebral amyloid angiopathy (CAA) was noted in a single patient, who also showed other microscopic changes of severe AD. While fairly unusual as a nosologic entity, IVD appears to correlate with widespread small ischemic lesions distributed throughout the CNS. We furthermore propose an approach to quantifying the burden of ischemic vascular and parenchymal disease that may be associated with a dementia syndrome. A brief review of neuropathologic features of vascular dementia (both familial and sporadic) is presented.     

The Internet and clinical practice of child neurology

The Internet has great potential for aiding patient care. Concerns regarding patient confidentiality, provider liability, and efficient and fair use of these new resources have triggered specific recommendations for integration of the Internet into our practices.     

Tirapazamine plus carboplatin and paclitaxel in advanced malignant solid tumors: a california cancer consortium phase I and molecular correlative study.

PURPOSE: Tumor hypoxia confers chemotherapy resistance. Tirapazamine is a cytotoxin that selectively targets hypoxic cells and has supra-additive toxicity with platinums and taxanes in preclinical studies. We conducted a Phase I study of tirapazamine, carboplatin, and paclitaxel and assessed potential plasma markers of hypoxia as surrogates for response. EXPERIMENTAL DESIGN: Forty-two patients with advanced solid tumors were treated at four dose levels; parallel dose escalations were carried out in chemotherapy-naive and previously treated subjects. Pre and post-therapy plasma levels of the hypoxia-induced proteins plasminogen activator inhibitor-1 and vascular endothelial growth factor were measured. RESULTS: Three of four chemotherapy-na?ve patients developed dose-limiting toxicities at dose level 4 (grade 3 stomatitis/infection, grade 3 emesis, and grade 4 febrile neutropenia). Four of seven previously treated patients developed dose-limiting toxicities at dose level 3, including one death [grade 3 myalgia, grade 3 infection/grade 4 neutropenia, grade 3 infection/grade 4 neutropenia, and grade 5 infection (death)/grade 4 neutropenia]. Of 38 patients assessable for response, 3 had a complete response, 1 a partial response, 1 an unconfirmed partial response, and 23 had stable disease in at least one evaluation; 10 quickly progressed. One complete responder had normalization of vascular endothelial growth factor and plasminogen activator inhibitor-1 levels. CONCLUSION: Dose levels 3 (carboplatin AUC of 6, 225 mg/m(2) paclitaxel, and 330 mg/m(2) tirapazamine) and 2 (carboplatin AUC 6, 225 mg/m(2) paclitaxel, and 260 mg/m(2) tirapazamine) are the maximum tolerated doses for chemotherapy naive and patients treated previously, respectively. Dose level 3 is the experimental arm of a Phase III Southwest Oncology Group trial (S0003) in advanced non-small cell lung cancer. Potential markers of tumor hypoxia may be useful correlates in studies of hypoxic cytotoxins and are being prospectively investigated in S0003.     

Screening for complement deficiency in bacterial meningitis

Seventy-seven children with bacterial meningitis were screened for complement deficiency. Both the classical and the alternate pathways were normal in 75 patients. Transiently reduced total haemolytic activity of the classical pathway was documented in a boy with meningococcal meningitis. Total haemolytic activity of both the classical and the alternate pathways were reduced in another patient with pneumococcal meningitis: individual complement components determination indicated predominant activation of the alternate pathway.     

Identification of differentially expressed genes in aflatoxin B1- treated cultured primary rat hepatocytes and Fischer 344 rats

Aflatoxin B1 (AFB1), a mutagen and hepatocarcinogen in rats and humans, is a contaminant of the human food supply, particularly in parts of Africa and Asia. AFB1-induced changes in gene expression may play a part in the development of the toxic, immunosuppressive and carcinogenic properties of this fungal metabolite. An understanding of the-role of AFB1 in modulating gene regulation should provide insight regarding mechanisms of AFB1-induced carcinogenesis. We used three PCR- based subtractive techniques to identify AFB1-responsive genes in cultured primary rat hepatocyte RNA: differential display PCR (DD-PCR), representational difference analysis (RDA) and suppression subtractive hybridization (SSH). Each of the three techniques identified AFB1- responsive genes, although no individual cDNA was isolated by more than one technique. Nine cDNAs isolated using DD-PCR, RDA or SSH were found to represent eight genes that are differentially expressed as a result of AFB1 exposure. Genes whose mRNA levels were increased in cultured primary rat hepatocytes after AFB1 treatment were corticosteroid binding globulin (CBG), cytochrome P450 4F1 (CYP4F1), alpha-2 microglobulin, C4b-binding protein (C4BP), serum amyloid A-2 and glutathione S-transferase Yb2 (GST). Transferrin and a small CYP3A-like cDNA had reduced mRNA levels after AFB1 exposure. Full-length CYP3A mRNA levels were increased. When liver RNA from AFB1-treated male F344 rats was evaluated for transferrin, CBG, GST, CYP3A and CYP4F1 expression, a decrease in transferrin mRNA and an increase in CBG, GST, CYP3A and CYP4F1 mRNA levels was also seen. Analysis of the potential function of these genes in maintaining cellular homeostasis suggests that their differential expression could contribute to the toxicity associated with AFB1 exposure.