The effect of recombinant GM-CSF on the recovery of monkeys transplanted with autologous bone marrow

The regulatory function of recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) on granulocyte production in vivo was evaluated in an autologous bone marrow transplantation model using rhesus monkeys. Monkeys were exposed to 9.0 Gy total body irradiation and then transplanted with 5.0 x 10(7) low-density bone marrow cells/kg. Alzet miniosmotic pumps were subcutaneously implanted to deliver rhGM-CSF at a rate of 50,400 U/kg/d. Minipumps, containing either rhGM-CSF or saline, were implanted between zero and five days after transplantation for seven days. Kinetic recoveries of peripheral blood cells after either saline or rhGM-CSF treatment were compared. Treatment with rhGM-CSF accelerated the recovery of neutrophils. Neutrophils in rhGM-CSF-treated animals recovered to 80% (3.4 x 10(3)/mm3) pre-irradiation control levels by day 20, in comparison with only 33% (0.9 x 10(3)/mm3) recovery for saline control monkeys. In addition, the recovery of neutrophils was enhanced over that of the controls, reaching 140% v 70% on day 30. Another prominent feature of rhGM-CSF-treated monkeys was the accelerated recovery of platelets, reaching near 50% normal levels by day 24 in comparison with 20% of normal levels for controls. The infusion of rhGM-CSF was shown to be an effective regulator of early hematopoietic regeneration, leading to the accelerated recovery of both neutrophils and platelets and then providing a consistent sustained increase of neutrophils even in the absence of rhGM-CSF.     

Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?

We identified 68 patients with clonal T-large granular lymphocyte (T- LGL) proliferations who were seen at the Mayo Clinic between 1984 and 1992. Nineteen (28%) were asymptomatic at diagnosis, while the rest experienced fatigue (60%), B-symptoms (12%), and recurrent infections (15%). Associated comorbid conditions included rheumatoid arthritis (RA) in 26%. Severe anemia (hemoglobin [Hb] < 8g/dL) and neutopenia (absolute neutrophil count [ANC] < 500/microL) were seen in 19% and 40% of patients, respectively. Immunophenotypic studies showed CD3+, CD8+ phenotype in the majority (72%). Twenty-one patients (31%) have required no therapy, and remain relatively stable with a median follow- up period of 50 months. Treatment was required at either diagnosis (36 patients) or at subsequent follow-up (11 patients). Initial response rates were similar in patients treated with cyclophosphamide (CTX) with or without prednisone (69%), or prednisone alone (73%). Overall, 61 patients (90%) are alive with a median follow-up of 44 months. Actuarial median survival of this entire cohort is 161 months. The presence of anemia or symptoms does not appear to correlate with the tumor burden. In patients requiring therapy, a lower ANC and the presence of B-symptoms/infection were independently associated with a significantly lower probability of achieving a molecular or hematologic complete remission (H-CR). Intermittent immunosuppressive therapy is effective in achieving durable responses in a number of patients. T-LGL proliferations are associated with a favorable prognosis and response to therapy. However, significant heterogeneity exists in clinical presentation and associated comorbid conditions. These disorders should be included in the differential diagnosis of patients with unexplained cytopenias, particularly in the setting of RA and other autoimmune disorders. Analogous to the situation with monoclonal gammopathies, a term such as T-cell clonopathy of undetermined significance (TCUS) may be more appropriate to describe these patients.     

The impact of chorionicity on umbilical cord acid–base values in twin gestations

Objective: To evaluate the impact of chorionicity on inter-twin differences in acid–base status at birth.

Methods: Records for twin pregnancies delivered at ??24 weeks' gestation from 1 January 1990 to 31 June 2000 were reviewed. Collected data included maternal demographics, gestational age, fetal presentation, anesthesia, delivery mode, inter-twin interval, umbilical artery (UA) and venous (UV) acid–base values, Apgar scores and birth weights. The influence of chorionicity on umbilical cord biochemistry was evaluated. (p?<?0.05 was considered significant.)

Results: Analysis was carried out in 87 twin pairs (29 monochorionic, MC; and 58 dichorionic, DC). MC and DC twins were similar in maternal age (25.5 vs. 28.2 years), estimated gestational age (33.7 vs. 33.6 weeks), Cesarean delivery (55.2 vs. 52.6%), delivery interval (10 v s.5?min) and respective birth weights (twin A,1882 vs. 1981; and twin B,1828 vs. 1872?g). MC first twins had a higher UA pH (7.31?±?0.05 vs. 7.26?±?0.08; p?=?0.0005) than DC first twins. MC first and second twins had higher UA and UV bicarbonate levels than their DC counterparts (ΔpH?=?21.7?±?5.1 vs. 18.5?±?3.1?mmol/l and 22.0?±?3.5 vs. 19.6?±?2.5?mmol/l, respectively; p?=?0.003). MC twins were more discordant in UA pH than DC twins (ΔpH?=?0.043?±?0.09 vs. 0.003?±?0.07; p?=?0.009). MC and DC twins had a similar venous pH (ΔpH?=?0.01?±?0.06 vs. 0.02?±?0.06; p?=?0.5).

Conclusions: There is a significant association between placental chorionicity and umbilical cord biochemistry in twins. Although it is possible that the mechanism of this finding is related to placental angioarchitecture, it is unlikely to be a result of simple mixing of blood volumes between twins. The physiology of underlying processes requires further study.     

Receptor localization, native tissue binding and ex vivo occupancy for centrally penetrant P2X7 antagonists in the rat

BACKGROUND AND PURPOSE

The P2X7 receptor is implicated in inflammation and pain and is therefore a potential target for therapeutic intervention. Here, the development of a native tissue radioligand binding, localization and ex vivo occupancy assay for centrally penetrant P2X7 receptor antagonists is described.

EXPERIMENTAL APPROACH

Autoradiography studies using the P2X7 antagonist radioligand [³H]-A-804598 were carried out in rat brain and spinal cord. Subsequent in vitro binding and ex vivo occupancy assays were performed using rat cortex homogenate.

KEY RESULTS

P2X7 expression was shown to be widespread throughout the rat brain, and in the grey matter of the spinal cord. In binding assays in rat cortex homogenate, ∼60% specific binding was achieved at equilibrium. In kinetic binding assays, k_on and k_off values of 0.0021·min⁻¹·nM⁻¹ and 0.0070·min⁻¹ were determined, and the K_d derived from kinetic measurements was consistent with that derived from saturation analysis. Novel P2X7 antagonists inhibited the binding of [³H]-A-804598 to rat cortex P2X7 receptors with K_i values of <40 nM. In an ex vivo occupancy assay, a P2X7 antagonist dosed orally to rats caused a concentration-dependent inhibition of the specific binding of [³H]-A-804598 to rat cortex.

CONCLUSIONS AND IMPLICATIONS

The present study describes the development of an assay that allows localization of P2X7 receptors, the measurement of the binding affinity of P2X7 receptor antagonists in native tissue, and provides a means of determining central P2X7 receptor occupancy. These assays could form an important part of a P2X7 drug discovery programme.     

Antimycobacterial Evaluation of Fifteen Medicinal Plants in South Africa

Fifteen plant species were collected from the Nelspruit Botanical Garden based on a list of plants provided by Phytomedicine Programme at the University of Pretoria and their ethnopharmacological information. Hexane, dichloromethane (DCM), acetone and methanolic extracts were screened for antimycobacterial activity against Mycobacterium smegmatis. The acetone extract of Milletia stulhimannii was the most active, showing activity against Mycobacterium smegmatis with minimum inhibitory concentration (MIC) value of 0.13 mg/ml. Acetone extracts for all plants had lower MIC values ranging between 0.11–1.25 mg/ml against M. smegmatis. Milletia stulhimannii, Albizia gummifera, Xanthocercis zambesiaca and Barringtonia racemosa have shown great potential as anti-tuberculosis agents. They were active against M. smegmatis with average MIC values of acetone extracts of 0.13 mg/ml.     

The importance of being there: perspectives of social support by adolescents with cancer.

Adolescents with cancer are confronted with many challenges. The extent to which they are able to deal with such challenges appears to be partly contingent on a positive strong social support system. In this article, the author describes findings specific to the sources of social support that 15 adolescents with cancer found to be most important in getting them through the cancer experience. Data were collected as part of a longitudinal qualitative interpretive study and involved individual interviews, focus group interviews, and participant observation as the main sources of data. The relationships that adolescents maintained with their nuclear families, health care team members, and special friends were the 3 main supportive relationships in the adolescents'lives. The act of others "being there" was seen by the adolescents as the key element of a supportive relationship and involved 6 main behaviors. Although the 3 key supportive relationships were essential in helping adolescents get through cancer, these relationships were at times a source of stress for adolescents.     

5-取代-1-正丁基-3-吡唑烷酮类化合物的合成及抗惊作用的构效关系

1-正癸基-3-吡唑烷酮是一种新的抗惊活性物质。杜明慧、雷小平等相继合成了一系列3-吡唑烷酮类化合物,结果,1-正丙基-5-对氟苯基-3-吡唑烷酮的抗惊作用最强(EP_(50)=14.7 mg/kg)。为了继续研究1位和5位取代基对抗惊活性的影响,我们将前人合成的35个化合物(表1中化合物1～35)进行了Hansch分析得到以下方程:     

石斛类叶鞘的显微鉴定研究

商品石斛的植物来源复杂,规格繁多,外形鉴定较困难。为了准确鉴定石斛的品种,对常作为药用的16种石斛属(Dendrobium Sw)植物的叶鞘进行了显微观察,发现其表皮细胞的形状,大小,所含草酸钙结晶的形状、大小、分布等种间区别较明显,可作为鉴别石斛种类的科学依据之一。本文对金钗石斛D.nobile Lindl。等16种石斛的叶鞘表面特征加以描述,并附主要特征图和检索表。