Alterations in the phenotype of hairy cells during culture in the presence of PHA: requirement for T cells

Culture studies of peripheral blood mononuclear cells from 7 entirely typical cases of hairy cell leukemia showed that after culture in the presence of PHA for 2--5 days, the predominant cell type changed from E- SIg+ CIg+ gamma FcR+ muFcR+ hairy cells to an E+ SIg- CIg- gamma FcR- muFcR- population of transformed cells derived from hairy cells. Depletion and readdition experiments demonstrated that cell-to-cell contact with T cells was necessary for the phenotypic change, while several observations indicated that the E+ population was not derived from T cells present before culture. The E positivity of the cultured cells was shown to be due to the possession of E receptor not acquired from the culture fluid, but the cells differed from true T cells in lacking both mature and immature T-cell antigens. The relevance of these in vitro observations to the continuing controversy concerning the nature of the hairy cell and to the in vivo fluctuations in immunologic phenotype not infrequently observed in hairy cell leukemia is briefly discussed.     

THY-1 induction is associated with up-regulation of fibronectin and thrombospondin-1 in human ovarian cancer

We recently identified THY-1 as a putative tumor suppressor gene for human ovarian cancer. To understand the carcinogenic role of THY-1, and its downstream effects on cancer cells, a THY-1 inducible system was established in the human ovarian cancer cell line SKOV-3 based on the tetracycline (tet) regulating system. To establish an inducible system for Thy-1 expression, two plasmids, pUHD172-1neo and pTEP4mThy-1, which are neomycin and hygromycin resistant were co-transfected into the ovarian carcinoma cell line, SKOV-3. The inducibility of Thy-1 expression in the SKOV-3 cell line by doxycycline (dox) was determined by northern blot analysis, immunocytochemistry, and flow cytometry. A time course study revealed that Thy-1 expression is induced 3 hours post dox exposure. Expression was reversible such that 12 hours post the removal of dox almost no Thy-1 could be detected. Furthermore, 2 genes, Fibronectin (FN) and Thrombospondin (TSP-1) involved in cellular differentiation and the regulation of tumor angiogenesis, respectively, were found to be up-regulated upon THY-1 induction. In contrast, the gene SPARC was found to be independent of Thy-1 expression. This study supports the hypothesis that THY-1 plays a critical role in regulating downstream genes associated with the regulation of ovarian tumor growth and cellular differentiation.     

Carotid endarterectomy in nonagenarians

HYPOTHESIS: The North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial demonstrated that a greater benefit from carotid endarterectomy (CEA) was seen in elderly compared with younger patients. However, no patients older than 89 years were included in either study. We hypothesized that CEA is safe and effective in patients 89 years and older. DESIGN AND SETTING: This is a retrospective review of 3 neurosurgeons' CEA experience with nonagenarian patients. PARTICIPANTS AND INTERVENTIONS: Of our 1800 patients who underwent CEA, 26 were 89 years or older. Twenty-three patients had had cerebral ischemic symptoms (unilateral hemispheric symptoms in 21 and 2 dizzy spells associated with bilateral high-grade stenosis). Cerebral angiography was performed in 3 patients. Twenty-three patients underwent noninvasive imaging. Four patients had bilateral high-grade stenosis and underwent staged bilateral CEA. All procedures were performed after the induction of general anesthesia with electroencephalographic (and, more recently, transcranial Doppler) monitoring and etomidate-induced burst suppression for cerebral protection during cross-clamping. RESULTS: Unusual technical difficulties were frequently noted, including high bifurcations, looping rotated internal carotid arteries, and marked adherence of surrounding soft tissues. In 3 of the 30 procedures, a shunt was used. There were no perioperative cerebral ischemic or cardiac events. The mean hospital stay was 2 days. One patient had a transient vocal cord paresis. Twenty-two patients were alive and well 24 months following the procedure. Four patients died of non-stroke-related causes. CONCLUSIONS: Carotid endarterectomy was successfully performed without perioperative cerebral or cardiac complications in our series of 26 patients 89 years and older undergoing 30 CEAs. Extrapolating from reported results from the North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial, we believe CEA should be considered in nonagenarian patients with high-grade symptomatic carotid stenosis who are otherwise well medically. Our recommendations are less certain in the case of asymptomatic disease.     

Desferrioxamine inhibits production of cytotoxic heme to protein cross-linked myoglobin: a mechanism to protect against oxidative stress without iron chelation

The heme group of myoglobin can form a covalent bond to the protein when met (ferric) myoglobin is reacted with peroxides under acidic conditions. This heme to protein cross-linked species is highly pro-oxidant and found in the urine of patients with rhabdomyolytic-associated acute renal failure. Desferrioxamine, an iron-chelating agent used in the treatment of iron overload, is reported to be partially effective at preventing kidney failure following rhabdomyolysis. In this article, we show that in addition to its capacity as an iron chelator, desferroxamine can inhibit the peroxide-induced formation of heme to protein cross-linked myoglobin and decreases the pro-oxidant activity of both native and heme to protein cross-linked myoglobin. The mechanism of peroxidation and of heme to protein cross-linking involves the formation of ferryl intermediate (Fe(4+)=O(2-)), and it is by the reduction of this intermediate to the ferric form that desferrioxamine can exert inhibitory effects. The concentrations at which desferrioxamine inhibits the formation of heme to protein cross-linked myoglobin and prevents the pro-oxidant activity of native and oxidatively modified myoglobins are comparable to the concentrations used for in vivo studies of iron-related oxidative stress. Thus, the ameliorative effects of treatment of posthemolytic events by desferrioxamine cannot be exclusively assigned to its ability to chelate free iron.     

Iliopsoas muscles: MR study of normal anatomy and disease

Magnetic resonance (MR) imaging was performed on 15 healthy subjects to define the appearance of the iliopsoas muscle and on 15 patients with iliopsoas disease. Seven patients had tumorous involvement of the muscles, five had inflammatory disease, one had retroperitoneal hemorrhage, one had iliopsoas bursitis, and one had bilateral hypertrophy. MR imaging permitted delineation of the muscles and depiction of the disease condition. Transverse MR images alone almost always provided the necessary data to determine the origin and extent of disease. Sagittal images were occasionally useful in defining the extension of disease into the spine. T1-weighted images provided optimal contrast between the muscles and adjacent tissues, while T2-weighted images were more useful for depicting disease within the muscles themselves.     

Malaria control in Papua New Guinea results in complex epidemiological changes

With a renewed interest in large-scale malaria interventions, knowledge about the possible long-term effects of such interventions on the nature of malaria transmission is essential. We document complex changes in malaria epidemiology over the last 40 years associated with changing malaria control activities in Karimui, an isolated area in Papua New Guinea. An initially equal distribution of Plasmodium falciparum, P. vivax and P. malariae changed to currently 68% P. falciparum, after passing through a phase of transitory P. vivax dominance, when control started to fail. Initial drops in malaria prevalence proved difficult to sustain and present post-control levels are significantly higher than pre-control levels. The example of Karimui indicates that unsustained control can lead to changes in malaria patterns that may leave a population worse off.     

The evolutionary distribution and structural organization of the homeobox-containing repeat D4Z4 indicates a functional role for the ancestral copy in the FSHD region [published erratum appears in Hum Mol Genet 1997 Mar;6(3):502]

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disease that has been linked to deletions within a tandem array of 3.2 kb repeats adjacent to the telomere of 4q. These repeats are also present in other locations in the human genome, including the short arms of all the acrocentric chromosomes. Here, we examine two models for the role of this repeat in FSHD. First, because of the extensive similarity between the 3.2 kb repeats on 4q and those adjacent to rDNA on the acrocentric chromosomes, we investigated whether the FSHD region on 4q is involved in sub-nuclear localization, specifically to the nucleolus. The results likely exclude any involvement of nucleolar localization in the development of FSHD. Second, we investigated a model that suggests that a functional gene may be buried within the tandem array of 3.2 kb repeats. Toward this end, we evaluated the evolutionary conservation of the repeat and a double homeodomain sequence within the repeat in a variety of primate species. The genomic organization of the 3.2 kb repeat in humans, great apes and lower primates identified the FSHD-associated repeat on chromosome 4q as the likely ancestral copy. The sequence of the rhesus monkey double homeodomain reveals significant sequence identity with the human 4q sequence. These results strongly suggest a functional role for a component of the FSHD-associated repeat.