Citations

AbstractSummary: We report identification of short‐chain acyl‐CoA dehydrogenase (SCAD) deficiency in a 12‐year‐old boy who suffered from recurrent attacks of vomiting once or twice a year from infancy. Growth and development were normal and there were no muscular symptoms. Metabolic screening was performed during a hospitalization at 8 years of age and revealed an increased excretion of ethylmalonic acid (EMA; 45–80 mmol/mol creatinine, normal 0.2–6.6), suggesting a degradation defect of short‐chain fatty acids. An increased n‐butyrylcarnitine was found in freshly collected serum (0.9 µmol/L; normal <0.4) but not in dry blood spots. Neither of the frequent SCAD gene variants 625G>A and 511C>T was present, but direct sequencing of the promoter and coding regions of the SCAD gene revealed that the patient had mutations on both alleles: 417G>C (Trp115Cys) and 1095G>T (Gln341His). Neither mutation has been described before in compound heterozygosity or homozygosity. Enzymatic investigations subsequently confirmed a defect of SCAD in both fibroblasts and muscle extracts. Furthermore, expression studies of both mutations demonstrated impaired enzyme function or structure. To our knowledge, this case is the first description of a patient with proven SCAD deficiency presenting with recurrent emesis but without other symptoms, and emphasizes the wide clinical phenotype of this disorder.

Background and Purpose— Mortality after cerebral infarction (CI) has remained unchanged during the past 20 years, despite advances in neurologic care. Key factors affecting survival may be underrecognized. The purpose of this study was to determine the rate and cause of mortality after first CI. Methods— In this case-control, population-based study, all available medical records were reviewed for Rochester (Minnesota) residents with a first CI between 1985 and 1989 to identify morbidities and cause of death. Predictors for mortality were analyzed. Results— First CI was recorded for 444 patients. Survival was 83% at 1 month, 71% at 1 year, and 46% at 5 years. The most frequent causes of death were cardiovascular events (22%), respiratory infection (21%), and initial stroke complications (14%). Recurrent stroke and cancer accounted for 9% and 7.5% of deaths, respectively. In the first month after CI, 51% of deaths were attributed to the initial CI, 22% to respiratory infections, and 12% to cardiovascular events. During the first year, 26% of deaths resulted from respiratory infections and 28% from cardiovascular disease. Mortality was higher among patients than controls for at least 2 years after CI. Age, cardiac comorbid conditions, CI severity, stroke recurrence, seizures, and respiratory and cardiovascular morbidities were independent predictors of death. Conclusions— In the first month after CI, mortality resulted predominantly from neurologic complications. Later mortality remained high because of respiratory and cardiovascular causes. To improve long-term survival after CI, aggressive management of pulmonary and cardiac disease is as important as secondary stroke prevention.

B7-H1 and B7-DC are ligands for PD-1, a receptor implicated in negative regulation of T and B cell functions. These ligands, however, also costimulate T cell responses. It remains elusive whether or not costimulation is mediated through PD-1. By comparative molecular modeling and site-directed mutagenesis, we found that nonconserved residues between these ligands on the A′GFCC′C′′ face mediate interaction with PD-1. This indicates significant structural heterogeneity of the interactions between PD-1 and its ligands. Importantly, ligand mutants with abolished PD-1 binding capacity could still costimulate proliferation and cytokine production of T cells from normal and PD-1–deficient mice. Our results reveal unique binding characteristics of B7-H1 and B7-DC and provide direct evidence for an independent costimulatory receptor other than PD-1.

OBJECTIVESCD62L was evaluated as a determinant of human pre‐effector T cells.STUDY DESIGN AND SETTINGPhenotype and cytokine secretion profiles of CD62L cells were determined based on activation status.RESULTSCD62LLow T cells demonstrated significantly higher secretion of interleukin (IL)‐10 and interferon (IFN)‐Γ than did CD62LHigh T cells. After activation, the majority of cells expressed high levels of the CD62L surface marker. Postactivation levels of IL‐10 production remained elevated or unchanged. In a murine B16 melanoma model, freshly isolated CD62LLow tumor draining lymph nodes (TDLN) T cells showed increased secretion of IL‐2 and IL‐4 but not of IL‐10 or IFN‐γ. The surface expression of CD62L and cytokine secretion patterns were maintained after activation with concomitant increases in IL‐10.CONCLUSIONOur results provide evidence that CD62LLow T cells in TDLNs of progressively growing squamous cell carcinoma of the head and neck differ phenotypically and functionally from those of mouse origin.SIGNIFICANCECharacterization of this human CD62LLow T cell population provides initial insight regarding novel surface markers in TDLN T cells that might correlate with antitumor reactivity.

B7-H1 is a recently described B7-like molecule that costimulates T-cell growth and cytokine secretion without binding to CD28, cytotoxic T-lymphocyte antigen-4 (CTLA-4), and inducible costimulator (ICOS). In this report, a mouse homologue of human B7-H1 is identified, and its immunologic functions are studied in vitro and in vivo. Mouse B7-H1 shares 69% amino acid homology to the human counterpart. Similar to human B7-H1, mouse B7-H1 can be induced to express on macrophages, T cells, and B cells and to enhance T-cell proliferation and secretion of interleukin-10 (IL-10), interferon-γ, and granulocyte-macrophage colony-stimulating factor but not IL-2 and IL-4. Furthermore, B7-H1 preferentially costimulates CD4+ T cells independently of CD28 and enhances mixed lymphocyte responses to allogeneic antigens. In contrast to B7-1, expression of B7-H1 on murine P815 tumor cells by transfection fails to increase allogeneic and syngeneic cytolytic T-cell responses in vitro and in vivo. Administration of B7-H1Ig fusion protein, however, enhances keyhole limpet hemocyanin– specific T-cell proliferation and 2,4,6-trinitrophenyl–specific immunoglobulin G2a antibody production. The study thus identifies a unique costimulatory pathway that preferentially affects T-helper cell functions.

Abnormalities of fatty acid metabolism are recognized to play a significant role in human disease, but the mechanisms remain poorly understood. Long-chain acyl-CoA dehydrogenase (LCAD) catalyzes the initial step in mitochondrial fatty acid oxidation (FAO). We produced a mouse model of LCAD deficiency with severely impaired FAO. Matings between LCAD +/− mice yielded an abnormally low number of LCAD +/− and −/− offspring, indicating frequent gestational loss. LCAD −/− mice that reached birth appeared normal, but had severely reduced fasting tolerance with hepatic and cardiac lipidosis, hypoglycemia, elevated serum free fatty acids, and nonketotic dicarboxylic aciduria. Approximately 10% of adult LCAD −/− males developed cardiomyopathy, and sudden death was observed in 4 of 75 LCAD −/− mice. These results demonstrate the crucial roles of mitochondrial FAO and LCAD in vivo .