Lymphocyte interleukin 2 production and responsiveness are altered in patients with primary myelodysplastic syndrome

Immunoregulatory T and B cell functions in 15 patients with primary myelodysplastic syndrome (MDS) were studied by measuring the proliferative and the stimulatory capacity of T and B cells, respectively, in autologous (auto) and allogeneic (allo) mixed lymphocyte reaction (MLR). T cell proliferation in the auto MLR was 25% of the control (P less than .02), whereas proliferation in the allo MLR was normal. When control T cells were stimulated by MDS B cells, their proliferative response was only 57% of the control (P less than .01). The mechanism responsible for these abnormalities was studied by determining the capacity of MDS and normal T cells to produce interleukin 2 (IL 2) and to generate IL 2 receptors (IL 2R) following stimulation with control and MDS B cells. In the auto MLR of MDS patients, only 3% +/- 2% of T cells developed IL 2R positivity, whereas in control cultures 12% +/- 2% of T cells were positive, as determined by immunofluorescence, using a monoclonal antibody (MoAb) directed against the IL 2R, and FACS analysis. When MDS T cells were stimulated by control B cells, IL 2R generation and the production of IL 2 were within normal limits. In contrast, when control T cells were stimulated by MDS B cells or control B cells, the MDS B cells induced production of only 26% of IL 2 as compared with control B cells. In parallel experiments, IL 2R generation in control T cells stimulated by either MDS or control B cells was similar. We conclude that in the primary MDS, T and B cell interactions are impaired. Although MDS T cells develop normal quantities of IL 2R and produce normal amounts of IL 2 when stimulated by control B cells, they are markedly impaired when stimulated by self B cells. Similarly, MDS B cells can induce IL 2R generation in control T cells but not in MDS T cells. Myelodysplastic B cells are also defective in inducing IL 2 production by normal T cells in an allo MLR. These in vitro abnormalities strongly suggest that generation of lymphocytes with immunoregulatory functions is impaired in patients with MDS.     

Of sleep state and postnatal age on arousal responses induced by mild hypoxia in infants

STUDY OBJECTIVES: It has been suggested that mild hypoxia may not be a potent stimulus for arousal during sleep in infants because infants frequently fail to arouse from quiet sleep (QS). Our aim was to characterize arousal responses of sleeping infants in both active sleep (AS) and QS under normoxic and mildly hypoxic (15% O2) conditions over the first 6 months of life. PARTICIPANTS: Five healthy term and 6 healthy preterm infants were each studied at 2 to 5 weeks, 2 to 3 months, and 5 to 6 months postterm. All infants underwent daytime polysomnography during which nasal airflow was monitored using a purpose-built pneumotachograph. All infants were studied under both normoxic (21% O2) and hypoxic (15% O2, balance N2) conditions (presentation order randomized) in each sleep state at each study age. Tests were terminated at arousal, O2 saturation falling below 85%, or 5 minutes (failure to arouse). MEASUREMENTS: Probability of failure to arouse and mean arousal latency were compared between each experimental condition, with each infant serving as its own control. RESULTS: Infants aroused more frequently under hypoxic conditions than under normoxic conditions. Overall, arousal latencies were shorter during hypoxia compared to normoxia in both sleep states at each age. Arousal latencies were longer in QS compared to AS in both hypoxic and normoxic conditions. CONCLUSION: In sleeping infants, mild hypoxia serves as a stimulus for arousal in both AS and QS. Of particular significance is our finding that arousal from AS is readily elicited by mild hypoxia.     

Apolipoprotein epsilon4 allele frequency in young Africans of Ugandan descent versus African Americans

Through its role in lipid metabolism, Apolipoprotein epsilon4 (ApoE4) may affect "brain repair" in stroke, brain hemorrhage, Alzheimer's disease, and other brain injury syndromes for which African Americans may have greater morbidity and mortality. Cross-cultural evaluations of these and other genetic factors may provide insight on possible ethnic differences in risk of morbidity to acute central nervous system (CNS) injury and chronic neurodegenerative processes. As an initial step toward expanding knowledge of ApoE allele frequencies for persons of African descent, we compared ApoE genotype of a group of 70 young Ugandans to 59 (subset of a larger group of 342 African Americans of all ages) age-matched African Americans and to published frequencies for Caucasians and Asians. We found that the ApoE4 and epsilon2 alleles are more frequent in Ugandans (U) than Caucasians (C) or Asians (A) with corresponding alleles showing significant elevations of epsilon2 (U 15.71%, C 8.40%, A 4.20%) and 14 (U 25%, C 13.70%, A 8.90%) (p < .001). Comparing the differences between Ugandans and age-appropriate African Americans (AA) was not statically significant, but this outcome may be due to small sample size. These results provide the only published ApoE frequencies for Ugandans and the complete set of data provides the largest published community group of ApoE frequencies for African Americans.     

APOE is a potential modifier gene in an autosomal dominant form of frontotemporal dementia (IBMPFD).

PURPOSE: Inclusion-body myopathy, Paget's disease of bone and frontotemporal dementia is an adult-onset autosomal dominant illness (IBMPFD) caused by mutations in the valosin-containing protein (VCP) on chromosome 9p21.1-p12. The penetrance of the gene is 82% for myopathy, 49% for Paget's disease, but may be as low as 30% for frontotemporal dementia. Modifier genes could account for decreased frontotemporal dementia penetrance. In this study apolipoprotein-E (APOE) was evaluated for this role in IBMPFD families based on its known modifier effect in Alzheimer's disease. METHODS: From a database of 231 members of 15 families, 174 had APOE genotype available for analysis. Logistic regressions on APOE genotype and frontotemporal dementia were performed, using appropriate covariates. RESULTS AND CONCLUSION: FTD was associated with APOE 4 genotype (P=0.0002), myopathy (P=0.0006), and age (P=0.01), but not microtubule associated protein tau (MAPT) H2 haplotype (P=0.5) or gender (0.09) after adjustment for membership in pedigrees with at least one APOE 4 genotype. These data suggest a potential link between APOE 4 genotype and the specific form of frontotemporal dementia found in IBMPFD. The molecular basis of this link bears further investigation. We did not observe an association of frontotemporal dementia and H2 MAPT haplotype.     

Left ventricular outflow tract obstruction associated with chronic ventricular assist device support

Favorable long-term patient outcome after insertion of a left ventricular assist device (LVAD) as a bridge to recovery or destination therapy for the treatment of end-stage cardiomyopathy is adversely affected by pathophysiologic changes affecting the heart. Alterations in the native aortic valve apparatus, specifically aortic valve cusp fusion, is an example of such a phenomenon and may especially affect patients in cases of bridge to recovery, a rare but reported event. A retrospective review of the last 33 LVAD placements at our institution was conducted, including reviews of operative reports and pathologic examinations of the native hearts. Seven hearts were found to have varying degrees of aortic valve cusp fusion after chronic LVAD support (63-1, 339 days). Five of these patients had native aortic valves, and two had bioprosthetic valves. The left ventricular outflow tracts in two patients were surgically occluded at the time of LVAD insertion. Aortic valve cusp fusion occurs in roughly 25% of patients on chronic LVAD support. This phenomenon may prove to be clinically significant by creating a potential source of emboli and infection. In addition, in the case of myocardial recovery, left ventricular outflow tract obstruction could limit parallel flow and produce suprasystemic ventricular pressures that in turn would elevate left ventricular end diastolic pressures. The latter may contribute to further myocardial injury, ultimately limiting the ability of an otherwise recovered heart to be weaned from LVAD support.     

Pulmonary reaction to long and short asbestos fibers is independent of fibroblast growth factor production by alveolar macrophages.

The role of alveolar macrophage (AM)-derived secretory products in fibroblast stimulation after the instillation of long and short asbestos to rat lungs is now investigated. A pure sample of 1 mg long crocidolite (greater than 2.5 mu) induced pulmonary fibrosis in 8 weeks, but secretions of lavaged AM from these lungs did not enhance growth or collagen synthesis in cultured rat lung fibroblasts. In contrast, the same dose of short fibers did not produce pulmonary fibrosis, although AM lavaged from these lungs were increased in number, had more phagocytized fibers, and when incubated, secreted factors that stimulated fibroblasts in culture. When normal AM were exposed to these fiber samples for 24 hours in vitro, greater phagocytosis of particles occurred and each asbestos fiber sample induced secretion of an AM-derived growth factor for cultured fibroblasts. The results indicate that both long and short fibers are capable of inducing AM to secrete fibrogenic factors in vitro, but in vivo, cytokine secretion by AM into the alveolar spaces in response to short fibers is not associated with stimulation of the interstitial fibroblast. In contrast, pulmonary fibrosis after long fiber administration appears unrelated to an AM secretion and is probably caused by fiber penetration into the peribronchiolar tissue, where interstitial macrophage activation may occur over several weeks.     

Effect of improved glycemic control by continuous subcutaneous insulin infusion on hormonal responses to insulin-induced hypoglycemia in type 1 diabetics

Glucose counter-regulatory capacity and the hormonal responses to insulin-induced hypoglycemia were studied in eight type 1 diabetics before and after improvement of metabolic control by continuous subcutaneous insulin infusion (CSII). The intensified treatment resulted in a decrease in mean glycosylated hemoglobin from 11.6 +/- 0.5 to 9.3 +/- 0.4% within a mean period of 14 weeks. During a constant rate infusion of insulin (2.4 U/h), steady state levels of glucose appeared in all subjects. The steady state glucose level was identical before and after CSII. The counter-regulatory hormonal responses showed significantly higher epinephrine levels, while glucagon, growth hormone, and cortisol were not influenced. In parallel with the heightened epinephrine response the pulse rate response was significantly enhanced. The restitution of blood glucose after insulin hypoglycemia was not modified. It is concluded that a more vigorous catecholaminergic response to hypoglycemia is achieved after improved metabolic control by CSII.