Citations

Background — The Multicenter Unsustained Tachycardia Trial (MUSTT) was designed to evaluate an antiarrhythmic treatment strategy, including drugs and implantable defibrillators (ICDs), guided by electrophysiological (EP) testing. We performed several statistical analyses to assess the contribution of defibrillators to the observed treatment benefit. Methods and Results — First, the effects of defibrillators were indirectly examined by comparing the randomized treatment arms (EP-guided therapy versus no antiarrhythmic therapy) within subgroups that varied according to ICD usage. Use of ICDs increased during the trial; hence, the randomized treatments were compared according to date of enrollment. There were also site-specific differences in ICD use; hence, the randomized arms were compared within groups of sites defined by level of ICD use. There was a distinct “dose response” in relation to ICD use. Where ICD use was high, EP-guided therapy produced significant reductions in arrhythmic death or cardiac arrest ( P <0.004). Where ICD use was low, there was no benefit of EP-guided therapy. Finally, outcomes of EP-guided therapy patients who received an ICD were directly compared with outcomes of other patients using the Cox proportional hazards model with receipt of an ICD as a time-dependent covariate. Adjusted for other prognostic factors, patients who received an ICD had risk reductions of >70% in arrhythmic death or cardiac arrest and >50% in total mortality ( P <0.001 for both end points). Conclusions — The benefit of EP-guided antiarrhythmic therapy observed in MUSTT was due to improved outcomes among patients who received an ICD but not among patients who received antiarrhythmic drugs.

Background — The TIMI myocardial perfusion grade (TMPG) and ST-segment resolution both reflect perfusion and are associated with mortality after thrombolysis for acute myocardial infarction. We hypothesized that these measures would also be associated with infarct size by single photon emission computed tomography (SPECT). Methods and Results — In the LIMIT AMI trial (Limitation of Myocardial Injury following Thrombolysis in Acute Myocardial Infarction) of lytic monotherapy versus lytic plus rhuMAb CD18, early 90-minute TMPG (n=221) and ST segment resolution (n=242) were compared with subsequent SPECT Technetium-99 m Sestamibi, measuring the percentage of the left ventricle with no Sestamibi uptake. Infarct sizes were larger with TMPG 0 or 1 (a closed or stained myocardium) than with TMPG 2 or 3 (open myocardium, median 13% versus 7%, P =0.004). Infarcts were also larger in patients with no ST segment resolution (median 15%) or incomplete resolution (11%) than in those with complete resolution (6%, overall P =0.0001). The difference in infarct size by TMPG persisted when stratified by category of ST resolution. Conclusions — There may be a pathophysiological link between early restoration of tissue-level perfusion and reduced subsequent infarct size that may partially explain why these early angiographic and electrocardiographic measures are associated with long-term survival.

PURPOSE: To evaluate the value of thymidylate synthase (TS), Ki-67, and p53 as prognostic markers in patients with Dukes’ B2 and C colon carcinoma. METHODS: We conducted a retrospective analysis to evaluate the prognostic value of TS, Ki-67, and p53 in 465 patients with Dukes’ B2 (220 patients) or Dukes’ C (245 patients) colon carcinoma. Patients represent a nonrandom subset obtained from five randomized phase III trials and were treated with either surgery alone (151 patients) or surgery plus fluorouracil-based chemotherapy (314 patients). All three markers were assayed using immunohistochemical techniques. RESULTS: With a minimum follow-up of 5 years, our retrospective analysis failed to demonstrate a consistent and significant association between TS, Ki-67, or p53 and either disease-free survival or overall survival. Exploratory analyses did not reveal a convincing explanation for these results that are in conflict with the published literature. Notable interactions were observed. In particular, high Ki-67 levels were associated with increased (decreased) survival in patients with low (high) TS intensity. Patients whose tumors stained positively for p53 seemed to benefit substantially from the use of adjuvant chemotherapy compared with those who were not treated (P = .05). CONCLUSION: This retrospective investigation failed to demonstrate a significant association between TS, Ki-67, or p53 staining and clinical outcome.

Preclinical models have shown that transplantation of marrow mesenchymal cells has the potential to correct inherited disorders of bone, cartilage, and muscle. The report describes clinical responses of the first children to undergo allogeneic bone marrow transplantation (BMT) for severe osteogenesis imperfecta (OI), a genetic disorder characterized by defective type I collagen, osteopenia, bone fragility, severe bony deformities, and growth retardation. Five children with severe OI were enrolled in a study of BMT from human leukocyte antigen (HLA)–compatible sibling donors. Linear growth, bone mineralization, and fracture rate were taken as measures of treatment response. The 3 children with documented donor osteoblast engraftment had a median 7.5-cm increase in body length (range, 6.5-8.0 cm) 6 months after transplantation compared with 1.25 cm (range, 1.0-1.5 cm) for age-matched control patients. These patients gained 21.0 to 65.3 g total body bone mineral content by 3 months after treatment or 45% to 77% of their baseline values. With extended follow-up, the patients' growth rates either slowed or reached a plateau phase. Bone mineral content continued to increase at a rate similar to that for weight-matched healthy children, even as growth rates declined. These results suggest that BMT from HLA-compatible donors may benefit children with severe OI. Further studies are needed to determine the full potential of this strategy.

Pseudo-obstruction syndromes are increasingly recognized in clinical practice. They result from impairment of intrinsic neuromuscular or extrinsic control of gut motility. Typically, pseudo-obstruction syndromes result in features suggestive of mechanical obstruction and bowel dilatation in the absence of any demonstrable obstruction or mucosal disease. The syndrome may affect any region of the gut. Less severe variants without bowel dilatation are diagnosed by measurement of gastrointestinal transit and pressure profiles. The aims of treatment are restoration of nutrition and hydration, symptom relief, normalization of intestinal propulsion with prokinetics, and suppression of bacterial overgrowth. Surgery plays a limited role, adjunctive to medical treatment, facilitating enteral nutrition and decompression by means of jejunostomy. Infrequently, resection of localized disease or intestinal transplantation are indicated. The roles of intestinal pacemakers (interstitial cells of Cajal) and genetic mutations in the etiology of pseudo-obstruction, as well as the cost-benefit ratio of transplantation for pseudo-obstruction, will be clarified in the future.

▪ Abstract Genetic disorders of mitochondrial fatty acid β-oxidation have been recognized within the last 20 years as important causes of morbidity and mortality, highlighting the physiological significance of fatty acids as an energy source. Although the mammalian mitochondrial fatty acid-oxidizing system was recognized at the beginning of the last century, our understanding of its exact nature remains incomplete, and new components are being identified frequently. Originally described as a four-step enzymatic process located exclusively in the mitochondrial matrix, we now recognize that long-chain-specific enzymes are bound to the inner mitochondrial membrane, and some enzymes are expressed in a tissue-specific manner. Much of our new knowledge of fatty acid metabolism has come from the study of patients who were diagnosed with single-gene autosomal recessive defects, a situation that seems to be further evolving with the emergence of phenotypes determined by combinations of multiple genetic and environmental factors. This review addresses the normal process of mitochondrial fatty acid β-oxidation and discusses the clinical, metabolic, and molecular aspects of more than 20 known inherited diseases of this pathway that have been described to date.

▪ Abstract In vitro studies of adipocytes taken from different body fat regions suggest substantial differences in lipolysis between intra-abdominal, lower-body subcutaneous, and abdominal subcutaneous regions. Gender and obesity appear to influence these regional differences. In situ measurements of glycerol release from adipose tissue provided further evidence that regional heterogeneity of lipolysis occurs in humans. In vivo studies of regional free fatty acid (FFA) release have confirmed that adipose tissue lipolysis varies between upper- and lower-body fat. Release of FFA from lower-body adipose tissue is less than that from upper-body adipose tissue in both obese and non-obese men and women. In non-obese men and women, meal ingestion suppresses FFA release from all adipose tissue regions, and adrenergic stimulation activated FFA release from different sites in a gender-specific fashion. Significant regional and gender differences in adipose tissue lipolysis occur in humans, and this could contribute to differences in the health effects of adipose tissue and could theoretically influence body fat distribution.

ABSTRACT A 300-bp plasmid fragment of the hemagglutinin gene was used as target DNA to develop a rapid real-time LightCycler (Roche Applied Science, Indianapolis, Ind.) PCR assay for laboratory detection of smallpox virus. PCR primers and probes were designed specifically for detection of smallpox virus DNA, but all viruses of the genus Orthopoxvirus tested could be detected by use of the hemagglutinin gene target sequence. Base pair mismatches in the 204-bp amplicon allowed discrimination of cowpox virus (melting temperature [ T m ], 56.40°C), monkeypox virus ( T m , 56.24°C), and vaccinia virus ( T m , 56.72°C), including the Dryvax vaccine strain, from smallpox virus ( T m , 62.45°C) by melting curve analysis. The analytical sensitivity was 5 to 10 copies of target DNA per sample. The assay was specific for members of the genus Orthopoxvirus ; the DNAs of herpes simplex virus and varicella-zoster virus were not detected by the smallpox virus LightCycler PCR.

ABSTRACTElderly individuals are at high risk for morbidity and mortality when infected with influenza virus. Vaccinations with inactivated virus are less effective in the elderly due to the declining competency of the aging immune system. We have explored whether immunological parameters predict poor anti-influenza virus vaccine responses and can be used as biological markers of immunosenescence. One hundred fifty-three residents of community-based retirement facilities aged 65 to 98 years received a trivalent influenza vaccine. Vaccine-induced antibody responses were determined by comparing hemagglutination inhibition titers before and 28 days after immunization. The composition of the T-cell compartment was analyzed by flow cytometry and the sizes of three T-cell subsets, CD4+CD45RO+cells, CD4+CD28nullcells, and CD8+CD28nullcells, were determined. Only 17% of the vaccine recipients were able to generate an increase in titers of antibody to all three vaccine components, and 46% of the immunized individuals failed to respond to any of the three hemagglutinins. The likelihood of successful vaccination declined with age and was independently correlated with the expansion of a particular T-cell subset, CD8+CD28nullT cells. The sizes of the CD4+CD45RO+memory T-cell and CD4+CD28nullT-cell subsets had no effect on the ability to mount anti-influenza virus antibody responses. Frequencies of CD8+CD28nullT cells are useful biological markers of compromised immunocompetence, identifying individuals at risk for insufficient antibody responses.

ABSTRACT The dissemination of the Edmonston measles virus (Ed-MV) vaccine strain was studied with genetically modified mice defective for the alpha/beta interferon receptor and expressing human CD46 with human-like tissue specificity and efficiency. A few days after intranasal infection, macrophages expressing Ed-MV RNA were detected in the lungs, in draining lymph nodes, and in the thymus. In lymph nodes, large syncytia which stained positive for viral RNA and for macrophage surface marker proteins were found and apoptotic cell death was monitored. In the thymus, smaller syncytia which stained positive for macrophage and dendritic cell markers were detected. Thus, macrophages appear to be the main vectors for dissemination of MV infection in these mice; human macrophages may have a similar function in the natural host. We then compared the pathogenicities of two recombinant viruses lacking the C or V nonstructural proteins to that of the parental strain, Ed-MV. These viruses were less effective in spreading through the lymphatic system and, unlike Ed-MV, were not detected in the liver. After intracerebral inoculation the recombinant viruses caused lethal disease less often than Ed-MV and induced distinctive patterns of gliosis and inflammation. Ed-MV was reisolated from brain tissue, but its derivatives were not. C- and V-defective viruses should be considered as more-attenuated MV vaccine candidates.