Expression of constitutively active Notch4 (Int-3) modulates myeloid proliferation and differentiation and promotes expansion of hematopoietic progenitors.

The Notch family of transmembrane receptors has been implicated in the regulation of many developmental processes. In this study, we evaluated the role of Notch4 in immature hematopoietic progenitors by inducing, with retroviral transduction, enforced expression of Int-3, the oncogenic and constitutively active form of mouse Notch4. Int-3-transduced human myeloid leukemia (HL-60) cells demonstrated significantly delayed expression of differentiation markers following retinoic acid and 12-0-tetradecanoylphorbol 13-acetate treatment. Furthermore, HL-60 cells expressing Int-3 displayed a slower growth rate than cells infected with void virus, and accumulation in the G0/G1 phases of cell cycle. Transduction with deletion mutants of Int-3 defined the importance of individual domains of the protein (in particular, the ANK domain and the C-terminal domain) in the inhibition of differentiation and growth arrest of HL-60 cells. When mouse bone marrow enriched for stem cells (5-fluorouracil-resistant, lineage negative) was transduced and cultured for two weeks, the Int-3-transduced population displayed a lower expression of differentiation markers and a three- to five-fold higher frequency of colony-forming cells (CFU-GM/BFU-E) than control cultures. These results strongly support the notion that Notch signaling inhibits differentiation and promotes expansion of hematopoietic stem/progenitor cells.     

Tongue reconstruction with a combined brachioradialis-radial forearm flap

Total glossectomy adversely affects speech and swallowing, and subsequent reconstruction results in limited functional return. The radial forearm flap has been reliably used to resurface glossectomy defects, but has limited bulk with which to aid in palatoglossal contact for speech. The authors have modified the forearm flap by incorporating a segment of brachioradialis muscle, to increase bulk posteriorly and to aid in speech. Sufficient muscle perforators arise from the proximal brachial artery and enter the brachioradialis to permit transfer of the muscle with the fasciocutaneous forearm flap as a single free-flap unit. The muscle is folded onto itself and enclosed within the forearm flap skin to create a neotongue. Coaptation of the antebrachial cutaneous nerves can provide a senate flap. Successful transfer of the combined brachioradialis/forearm flap in a patient who had undergone total glossectomy resulted in a neotongue good shape. Speech was rated good by a speech pathologist, and palatoglossal contact was observed on cineoradiograph. No functional loss at the donor site occurred. Inclusion of the brachioradialis muscle with the radial forearm flap as a combined unit results in a neotongue with good form and increased bulk posteriorly at the base, compared to a standard fasciocutaneous flap alone. This is a useful variation of the forearm flap. Sensory return is possible if the medial and/or lateral antebrachial cutaneous nerves of the flap are coapted to the lingual nerve.     

舌诊指导临床辨证论治初探

望舌能够测知体质禀赋强弱；察舌能够准确地进行临床辨证；舌诊可帮助鉴别诊断；望舌能够预测疾病的进退预后；舌诊还能够指导临床定治则、遣方药。如能将舌诊和其他诊法有机地结合起来，将进一步提高临床诊断准确率和治愈好转率。     

浅论企业药品召回管理规范的制定

结合中美史克公司召回康泰克的经验,浅谈企业药品召回管理规范的制定.     

十八甲基炔诺酮透皮控释传递系统在人体不同部位皮肤的药物动力学

6名健康妇女分别于上臂、臀部和腹部三部位经皮给予合LNG的透皮控释传递系统（TCDS）后，用放射免疫法测定LNG血清浓度，计算其主要药物动力学参数。结果表明：在TCDS用药期间，三部位的C（max）、T（max）及AUC（0～168h）基本接近，部位间无显著性差异（P＞0．05）；TCDS揭除后，AUC（168～204h）及消除相半衰期T（1／2）（Ke）均以腹部最大，臀部次之，上臂最小，在腹部与上臂间有显著性差异（P＜0．05）。上述结果可归因于TCDS对LNG的控释和人体皮下脂肪的“贮库效应”。     

Morphologic and electrophysiologic maturation in developing dentate gyrus granule cells

Dentate gyrus granule cells from immature (7-28 days) Sprague-Dawley rats were examined with whole cell patch clamp recordings and biocytin filling in in vitro hippocampal slice preparations. Although recordings were confined to the middle third of the suprapyramidal limb of the dentate, the granule cells exhibited marked variability in their physiologic properties: input resistance (IR) ranged from 250 MOmega to 3 GOmega, and resting membrane potential (RMP) from -82 to -41 mV. Both IR and RMP were inversely correlated with dendritic length, a morphometric indicator of cell maturity. Thus the highest IR cells were the youngest, and maturation was characterized by a progressive decrease in IR, hyperpolarization of RMP, and elongation of the dendritic arbor. When cells were grouped by IR, significant intergroup differences were found in RMP, dendritic length, and number of dendritic terminal branches. Although cells of all IR categories were examined throughout the age spectrum under study, none of the inter-IR group differences was age-dependent. These data suggest that IR provides a reasonable estimate of granule cell maturity and that maturation entails predictable changes in cell properties and morphology. These aspects of maturation correlate with each other, are independent of animal age, and most likely proceed according to a program related to cell birth.     

Physiology and pharmacology of native glycine receptors in developing rat ventral tegmental area neurons

Properties of whole-cell glycine-activated currents (I(Gly)) of neurons freshly isolated from ventral tegmental area of rats between postnatal day (P) 0 and 40 (P0-P40) were examined using the gramicidin-perforated patch technique. I(Gly) was present throughout the period of investigation and displayed age-related alternations in its kinetics, reversal potentials (E(Gly)) and sensitivity to antagonists. During development, the time constant for desensitization of I(Gly) decreased about two-fold, and the E(Gly) shifted to more negative potentials. Specifically, E(Gly) was -29 mV in neonatal (P0-P7) and decreased to -50 mV in adult (P24-P40) neurons. While the neonatal glycine receptors (GlyRs) are resistant to strychnine, the adult GlyRs are sensitive to STR. The values for 50% inhibition (IC(50)) of I(Gly) was 110 and 12 nM in P0-P3 and P24-P40 neurons, respectively. Picrotoxin, on the other hand, was more effective in blocking neonatal neurons. The IC(50) values were 17 and 231 microM for the neonatal and adult neurons, respectively. These observations are discussed in terms of developmental changes of subunit composition of GlyRs and of intracellular Cl(-) concentrations.