RBC improved survival due to recombinant human erythropoietin explains effectiveness of less frequent, low dose subcutaneous therapy.

Effectiveness of less frequent, once weekly, low dose subcutaneous recombinant human erythropoietin (rHuEPO) in maintaining 35% hematocrit in patients with chronic renal failure, predialysis and ESRD receiving dialysis, is dependent on rHuEPO induced prolonged RBC survival. One year of weekly rHuEPO doses to 7 patients originally part of the National Cooperative Protocol were evaluated for a total of 372 weeks for an average of 53 weeks per patient. The original 8 to 12 week dosage was directed by protocol for units per dose at 3 doses per week (4 IV, 3 subcutaneous). Thereafter, all doses were subcutaneous. Units/dose and doses/week were titrated to keep hematocrit at 35-38%. Dosage reduction of rHuEPO was determined by two investigators at the time of each examination. Statistical correlation was performed on effect of rHuEPO on 51Cr T1/2 RBC survival changes and changes of rHuEPO weekly doses. Patients evaluated at specific time points in the study were compared to themselves as their own controls by paired t-test analysis. The long-term increased RBC count correlated with prolonged RBC survival by 51Cr T1/2 rather than reticulocytosis. A relatively increased ease of sustaining the target hematocrit of 35% was demonstrated from the 8th week to 1 year. Thirty-two percent of the expanded RBC mass was older at 12 weeks and 22% was older at 1 year. rHuEPO dosage was reduced to 27% at weeks 8-12, to 21% at weeks 20-24, and to 38% at 1 year corresponding to prolonged RBC survival. 51Cr T1/2 increased from 21.6 days control to 28.6 days at 12 weeks and 26.3 days at 1 year.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of the mononuclear infiltrate involved in regression of halo nevi

Halo nevi are characterized by progressive degeneration of nevus cells surrounded by a mononuclear cell infiltrate. We studied the morphological features of the nevus cells and the composition of the mononuclear cell infiltrate in 15 cases of halo nevi using immunohistochemical techniques and a battery of antibodies to different subsets of lymphocytes and histiocytes. Regression could be divided into four more or less identifiable stages, associated with different subsets of lymphocytes and monocyte-macrophage lineage cells. Stage I (preregression): nests of unremarkable nevus cells were surrounded by a moderate number of T lymphocytes (relatively small percentage of helper/inducer T cells), occasional B cells and macrophages. Stage II (early regression): large number of T lymphocytes and FXIIIa-positive cells were in close contact with nevus cell clusters which showed ragged edges. Lysozymepositive cells and epidermal Langerhans cells were mildly increased. Stage III (late regression): single nevomelanocytes showing mild atypia were present. Numerous T lymphocytes and macrophages positive for lysozyme, KP1 and/or FXIIIa were interspersed between the nevus cells. Increased numbers of epidermal Langerhans cells were present. Stage IV (complete regression): no nevus cells were observed and moderate numbers of T lymphocytes only remained. These results suggest that T cells, especially T-suppressor cells, and different subsets of macrophages participate in the regression of the nevi.     

石杉碱甲类似物的研究II.N-甲基吡啶酮石杉碱甲类似物的合成

石杉碱甲(1)是从中草药石杉属植物千层塔(Lycopodium serratum Thunb.)中分得的一种高效可逆的乙酰胆碱酯酶抑制剂,临床试验证实它对早老性痴呆症有显著疗效。本文报道N-甲基吡啶酮石杉碱甲类似物2和3的合成。2-甲氧基-5-甲氧羰基-11-亚甲基-5,9-甲撑环辛-7-烯并吡啶(9)在乙腈中用三甲基氯硅烷和碘化钠选择性脱保护以定量的产率得吡啶酮10,再用甲醇钠和碘甲烷甲基化得N-甲基吡啶酮11,11经碱性水解,Curtius重排和氨基的脱保护得N-甲基吡啶酮石杉碱甲类似物2。通过类似的途径从中间体2-甲氧基-5-甲氧羰基-7-甲基-11-酮-5,9-甲撑环辛-7-烯并吡啶(14)合成了类似物3。类似物2和3的乙酰胆碱酯酶抑制活性均低于天然石杉碱甲。     

Pain in sciatica depresses lower limb nociceptive reflexes to sural nerve stimulation.

The inhibitory effects of acute pain produced by the Lasègue's manoeuvre on the lower limb nociceptive flexion reflexes induced by electrical sural nerve stimulation were explored in patients complaining of sciatica as a result of an identified unilateral disc protrusion. Lassègue's manoeuvre on the affected side produced a typical radicular pain and resulted in a powerful depression of nociceptive reflexes elicited either in the normal or in the affected lower limb. Simultaneously, patients reported relief of the electrically-induced pain. In contrast, painless Lasègue's manoeuvre on the normal side had no effect on these parameters.     

Renal cell carcinoma in patients with tuberous sclerosis

An adolescent with anemia and weight loss was found to have bilateral renal cell carcinoma (hypernephroma). Further investigation revealed an underlying tuberous sclerosis that had escaped previous clinical detection. Several reports of this association were subsequently found when the world's literature was reviewed. Physicians treating patients with tuberous sclerosis should be aware of the possible development of these renal malignancies in their patients.     

Human small intestine facilitative fructose/glucose transporter (GLUT5) is also present in insulin-responsive tissues and brain. Investigation of biochemical characteristics and translocation.

A recent study by C.F. Burant et al. (13) demonstrates that GLUT5 is a high-affinity fructose transporter with a much lower capacity to transport glucose. To characterize the potential role of GLUT5 in fructose and glucose transport in insulin-sensitive tissues, we investigated the distribution and insulin-stimulated translocation of the GLUT5 protein in human tissues by immunoblotting with an antibody to the COOH-terminus of the human GLUT5 sequence. GLUT5 was detected in postnuclear membranes from the small intestine, kidney, heart, four different skeletal muscle groups, and the brain, and in plasma membranes from adipocytes. Cytochalasin-B photolabeled a 53,000-M(r) protein in small intestine membranes that was immunoprecipitated by the GLUT5 antibody; labeling was inhibited by D- but not L-glucose. N-glycanase treatment resulted in a band of 45,000 M(r) in all tissues. Plasma membranes were prepared from isolated adipocytes from 5 nonobese and 4 obese subjects. Incubation of adipocytes from either group with 7 nM insulin did not recruit GLUT5 to the plasma membrane, in spite of a 54% insulin-stimulated increase in GLUT4 in nonobese subjects. Thus, GLUT5 appears to be a constitutive sugar transporter that is expressed in many tissues. Further studies are needed to define its overall contribution to fructose and glucose transport in insulin-responsive tissues and brain.     

Retrovirus-mediated enzymatic correction of Tay-Sachs defect in transduced and non-transduced cells

Tay-Sachs disease is a severe neurodegenerative disorder due to mutations in the HEXA gene coding for the alpha-chain of the alpha-beta heterodimeric lysosomal enzyme beta-hexosaminidase A (HexA). Because no treatment is available for this disease, we have investigated the possibility of enzymatic correction of HexA-deficient cells by HEXA gene transfer. Human HEXA cDNA was subcloned into a retroviral plasmid generating to G.HEXA vector. The best Psi-CRIP producer clone of G.HEXA retroviral particles was isolated, and murine HexA-deficient fibroblasts derived from hexa -/- mice were transduced with the G.HEXA vector. Transduced cells overexpressed the alpha-chain, resulting in the synthesis of interspecific HexA (human alpha-chain/murine beta- chain) and in a total correction of HexA deficiency. The alpha-chain was secreted in the culture medium and taken up by HexA-deficient cells via mannose-6-phosphate receptor binding, allowing for the restoration of intracellular HexA activity in non-transduced cells.