Monoclonal antibodies against human granulocytes and myeloid differentiation antigens

Monoclonal antibodies (MCA) were obtained by immunizing BALB/c mice with 99% pure granulocytes from normal donors or with a whole leukocyte suspension obtained from a chronic myelogenous leukemia (CML) patient, and then fusing the mouse spleen cells with a 315–43 myeloma cell clone. Four MCA were selected and studied using ELISA, immunofluorescence, cytotoxicity assays, and FACS analysis. Antibodies 80H.1. 80H.3. and 80H.5 (from normals) and 81H.1 (from CML) detected antigens expressed on neutrophils. Antibodies 80H.1 and 80H.3 (lgG) also reacted with monocytes but not with other blood cell subsets. Antibodies 80H.5 and 81H.1 (lgM) were cytotoxic and reacted strongly with most of the cells of the neutrophil maturation sequence. i.e., myeloblasts, promyelocytes, myelocytes, and mature granulocytes. Antibodies 80H.5 and 81H.1 also inhibited BFU-GM and CFU-E. Antigens recognized by 80H.3. 80H.5, and 81H.1 were expressed both on a proportion of cells from HL.60, KG.1, ML.1, and K562 myeloid cell lines, and on a proportion of blast cells isolated from patients with acute myelogenous leukemia. They were not found on lymphoid cell lines or lymphoid leukemia cells. These MCA recognize either late differentiation antigens expressed on mature neutrophils and monocytes (80H.1 and 80H.3) or early differentiation antigens (80H.5 and 81H.1) specific to the granulocytic lineage. They may be useful for a better definition of those antigens specific to hematopoietic stem cells and their relationship with normal or neoplastic hematopoiesis.     

Effect of propentofylline on cerebral blood flow in a gerbil focal cerebral ischemia

BACKGROUND AND PURPOSE: Neuroprotection and improvement of cerebral blood flow are two basic principles of pharmacological intervention in acute stroke. Propentofylline, an adenosine uptake and phosphodiesterase inhibitor, has been shown to be neuroprotective in various models of cerebral ischemia. However, its effect on cerebral circulation in ischemic conditions is not yet fully elucidated. Present experiments were designed to investigate the effect of propentofylline on regional cerebral blood flow (rCBF) in the gerbil permanent focal cerebral ischemia model. METHODS: Focal cerebral ischemia in gerbils was produced by clipping one common carotid artery and contralateral external carotid artery. rCBF was measured in both parietal cortices concurrently by the hydrogen clearance. RESULTS: Propentofylline at 10 mg/kg administered intraperitoneally 30 min after induction of cerebral ischemia significantly increased rCBF in ischemic regions (increase of 94.6%). Effects were dose dependent. Higher dosage (30 mg/kg) induced reductions of ischemic rCBF, which were associated with significant decreases of mean arterial blood pressure. Lower dosage (5 mg/kg) was without significant effect. CONCLUSIONS: Results suggest that propentofylline at suitable dosage improves rCBF in ischemic brain areas. Taking into account neuroprotective potentials of propentofylline, results offer additional rationale for clinical trials investigating efficacy of propentofylline in treatment of acute stroke.     

Simplifying antiretroviral therapy

The substantial benefits conferred by HAART require strict patient adherence. Many of the initial HAART regimens consisted of a number of large pills that needed to be taken several times daily, sometimes with meal restrictions. The development of once-daily antiretroviral agents has eased some of the burden associated with the intense, difficult schedules of early HAART regimens.. The majority of regimens currently used in treatment-naive HIV-positive patients contain a mixture of agents that are taken on a once- and twice-daily basis. Although this is an improvement over past regimens, the asynchronous administration of pills throughout the day still presents a scheduling challenge for most patients. The newest advance in simplifying antiretroviral therapy is the use of regimens in which all pills are taken at the same time once a day. Choosing drugs for a fully once-daily regimen requires awareness of a number of factors, including pharmacokinetics, potency, durability of response, resistance and safety. At this time, there are a limited number of combinations that can be used as a fully once-daily regimen and few clinical trials evaluating such combinations. Results from initial clinical trials using simplified, once-daily regimens in treatment-naive patients have been promising. Additional studies should add to this experience and provide guidance on the role and timing of such regimens in the management of patients with HIV disease.     

Should patients with challenging anatomy be offered endovascular aneurysm repair?

OBJECTIVES: Treatment of abdominal aortic aneurysm is controversial in patients at high physiologic risk for open repair and high anatomic risk for endovascular repair. We compared outcome in patients at high risk because of anatomy (short or angulated neck), severe occlusive disease, or bilateral iliac aneurysms (group A) with outcome in patients at low risk (group B). MATERIAL AND METHODS: Patients at high anatomic risk who underwent treatment between October 1998 and March 2002 with the Zenith endovascular graft (group A) were compared with patients at low anatomic risk enrolled in a prospective multicenter trial (group B). Variables compared included overall mortality, need for secondary interventions, development of endoleak, and change in aneurysm sac diameter. The chi(2) test, Student t test, and proportions analysis were used to assess the data. RESULTS: Data for 493 patients (group A, 141; group B, 352) were evaluated. Mean follow-up was 9 months (range, 1-24 months). Perioperative mortality was similar for groups A and B (0.7% vs 1%). Frequency of endoleak was higher in patients with high-risk anatomy (25% vs 11%), but not significantly so (P >.06). The rate of aneurysm shrinkage, even in the absence of endoleak, was slower in group A (P <.05). CONCLUSIONS: In physiologically challenged patients at higher anatomic risk for endovascular aneurysm repair, initial mortality rate is similar to that in patients at lower risk. Short-term technical results are acceptable. Decreased long-term survival (largely unrelated to the procedure), slightly higher frequency of endoleak, and a lower rate of sac shrinkage may temper enthusiasm for endovascular repair in this subgroup. Risks of repairing aneurysms in this patient population must be viewed in the context of expected results of intervention or medical observation.     

Prevalence and determinants of impaired glucose metabolism in frail elderly patients: the Belgian Elderly Diabetes Survey (BEDS)

BACKGROUND: Although diabetes in elderly persons is generally type 2, the metabolic abnormalities associated with aging suggest that elderly persons may differ from younger persons with type 2 diabetes. In addition, nonobese elderly persons with type 2 diabetes show a marked impairment in insulin release accompanied by mild insulin resistance, whereas obese elderly persons have marked insulin resistance in the presence of "adequate" levels of insulin. Other factors that could adversely affect glucose tolerance in aging include drug use, associated disease, and other stressful conditions commonly encountered in geriatric inpatients units. The authors' objectives in this study were 1) to prospectively assess the prevalence of glucose homeostasis abnormalities among elderly hospitalized patients and the degree to which it reflects abnormalities in insulin secretion or insulin sensitivity using homeostasis model assessment of fasting glucose, insulin, and C-peptide; and 2) to define the social, functional, pathologic, and nutritional characteristics of persons with impaired glucose tolerance or diabetes. METHODS: Ninety-eight patients underwent a comprehensive geriatric assessment. Determinants of glucose homeostasis were assessed using the homeostasis model assessment, which provides estimates of beta-cell function (%B) and insulin sensitivity (%S). RESULTS: Twelve patients (12%) had fasting glucose concentrations greater than 110 mg/dl. Four patients had impaired fasting glucose levels greater than 110 mg/dl but less than 126 mg/dl (IFG group), and 8 patients had levels greater than 126 mg/dl (type 2 diabetes group). Except for a higher proportion of women in the IFG-diabetes group, the latter did not exhibit significant differences in functional, morbidity, or nutritional characteristics compared with the normal glucose tolerance group. The entire cohort (n=98) presented with a mean (+/-SD) %B of 71%+/-47% and a mean %S of 208%+/-198%. Compared with the normal glucose tolerance group, the IFG-diabetes group had a fasting glycemia level of 142+/-24 mg/dl (vs 92+/-9 mg/dl), a %B of 43%+/-21% (vs 74%+/-45%), and a mean %S of 126%+/-113% (vs 219%+/-205%). CONCLUSIONS: These data confirm the high prevalence of impaired glucose metabolism among elderly people, although the usual risk factors were not significantly increased. Marked beta secretory defects seem to be the rule, whereas a significant degree of insulin resistance is unusual.     

Are blood platelets involved in the pathogenesis of ischemic brain edema in gerbils?

Edema formation following severe permanent or temporary cerebral ischemia in gerbils with an artificially reduced platelet count was investigated. Acute focal cerebral ischemia was produced by extracranial carotid ligation, and the local cerebral blood flow was estimated using the hydrogen clearance method. Brain tissue water and sodium and potassium contents were taken as indexes of brain edema. The platelet count was reduced in some gerbils by intravenous injection of neuraminidase. After 60 minutes of ischemia, a marked increase in tissue water and sodium contents accompanied by a decrease in potassium content was observed in untreated gerbils. However, gerbils with a reduced platelet count revealed similar but significantly smaller changes in all the measured parameters. Restoration of blood flow after 60 minutes of ischemia resulted in further accumulation of water and sodium and in depletion of potassium in both groups. These changes were significantly smaller in the gerbils with a reduced platelet count. It is concluded that platelets, activated by cerebral ischemia, may be involved in the development of ischemic brain edema in gerbils.     

Skin involvement in Susac's syndrome

Susac's syndrome (SS) is a rare microangiopathy affecting the precapillary arterioles of the brain, retina and inner ear, presumably resulting from an autoimmune endotheliopathy. We report the first case of SS with histologically proven skin involvement, in a 24-year-old male who presented a subacute encephalopathy, branch retinal artery occlusions and bilateral hearing loss, two weeks after the onset of a livedo racemosa of the flanks and feet. Skin biopsies revealed a thrombus in several dermal arterioles, endothelial cells swelling and a mild perivascular lymphocytic infiltrate, which correspond to the same histological findings as previously observed in brain but also in muscle biopsies of patients with SS. A complete recovery was achieved in 4 months with corticosteroids. Follow-up MRI showed centro-callosal "holes". Skin involvement in SS has pathological plausibility since serum antibodies directly binding to central nervous system but also to generic endothelium cells have been reported. Our report supports that SS is a systemic disease that could affect other organs in addition to the brain, retina and inner ear. We suggest careful skin examination should be considered in patients with a suspicion of SS.     

Structure of the supernumerary ring and giant rod chromosomes in adipose tissue tumors

Supernumerary ring or giant rod marker chromosomes are a characteristic of well‐differentiated liposarcomas (WDLPS) and atypical lipomas (ALP) and are often observed as the sole cytogenetic abnormality, but are rare in lipomas. Using a combination of different methods, we extensively investigated the structure and composition of rings and giant rods in a series of 17 WDLPS‐ALP samples and three intra‐ or intermuscular lipomas (IMLP), revealing a unique combination of particular features strikingly related to these tumors. Although the rings and rods displayed in vitro and in vivo stability, the presence of alpha‐satellites could not be detected on these supernumerary structures. Comparative genomic hybridization analysis, in combination with fluorescence in situ hybridization, identified the chromosomal regions contributing to the formation of these chromosomes: in WDLPS‐ALP, all carried amplifications of 12q14–15 and the MDM2 gene, with variable other noncontiguous regions. In the three IMLP, the rings consistently carried amplifications of 12q15–21 and 1q21, but increased copies of MDM2 were found in only one case. Other genes located more proximal in 12q14–15 were amplified in several WDLPS‐ALP, but showed a normal copy number in IMLP. Furthermore, the immunohistochemical expression of the MDM2 protein was detected in most (12/14) WDLPS‐ALP, in 1–30% of the cells, but never in IMLP. These supernumerary chromosomes represent a peculiar kind of amplification structure, midway between double minute chromosomes and homogeneously staining regions, but the mechanisms underlying the formation of these structures remain obscure. Genes Chromosomes Cancer 24:30–41, 1999. © 1999 Wiley‐Liss, Inc.