Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy

BACKGROUND: Invasive aspergillosis (IA) is an important cause of morbidity and mortality among immunocompromised patients. Echinocandins are novel antifungal molecules with in vitro and in vivo activity against Aspergillus species. METHODS: We investigated the efficacy and safety of caspofungin in the treatment of IA. Ninety patients with IA who were refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B, or triazoles were enrolled to receive caspofungin. RESULTS: Efficacy was assessed for 83 patients who had infection consistent with definitions of IA and who received >or=1 dose of study drug. Common underlying conditions included hematologic malignancy (48% of patients), allogeneic blood and marrow transplantation (25% of patients), and solid-organ transplantation (11% of patients). Seventy-one patients (86%) were refractory to and 12 patients (14%) were intolerant of previous therapy. A favorable response to caspofungin therapy was observed in 37 (45%) of 83 patients, including 32 (50%) of 64 with pulmonary aspergillosis and 3 (23%) of 13 with disseminated aspergillosis. Two patients discontinued caspofungin therapy because of drug-related adverse events. Drug-related nephrotoxicity and hepatotoxicity occurred infrequently. CONCLUSION: Caspofungin demonstrated usefulness in the salvage treatment of IA.     

Leukopenic chronic T cell leukemia mimicking hairy cell leukemia: association with human retroviruses

We report two cases of a T cell lymphoproliferative disease not previously described, with cytologic and clinical features similar to those associated with Galton's "prolymphocytic" leukemia (PL). Our patients, like those with Galton's PL, had massive splenomegaly and minimal or absent hepatomegaly and lymphadenopathy. In contrast, however, our patients had leukopenia, as well as low percentages of leukemic cells in the peripheral blood and in the bone marrow. In splenic imprints, the nuclear chromatin pattern of most of the leukemic cells was intermediate between those of mature lymphocytes and those of lymphoblasts, and the nuclei contained single, centrally located, conspicuous nucleoli. In sections of the spleen, the leukemic cells diffusely infiltrated the red pulp in a pattern strikingly similar to that of hairy cell leukemia; however, when the leukemic cells were studied cytochemically, the cytoplasmic acid phosphatase positivity was punctate and tartrate-sensitive. The leukemic cells were sheep erythrocyte rosette-positive and expressed T cell-associated antigens. Initially, both patients responded well to therapeutic splenectomy. One patient received combination chemotherapy after splenectomy and is alive and well 24 months after diagnosis. The other patient was in complete clinical remission for one year after splenectomy and received chemotherapy at relapse. He died, however, 23 months after splenectomy, with disseminated disease. IgG antibody titers against human T lymphotropic virus type I (HTLV-I) were detected in one patient and against HTLV-II in the other. The leukemia in these patients represents a distinct clinicopathologic entity within the spectrum of peripheral T cell lymphoproliferative diseases that includes Galton's PL of T cell derivation, T cell chronic lymphocytic leukemia, T cell hairy cell leukemia, and adult T cell leukemia/lymphoma.     

Human T-lymphocyte products stimulate human hemopoietic progenitor cell proliferation in diffusion chambers in vivo

Human myeloid colony formation in diffusion chambers in mice (CFU-DG) was enhanced following administration of a human T-cell-line-derived conditioned medium (Mo). The Mo cell line also elaborates activities stimulating human myeloid colony formation in vitro in agar (CSF) and potentiating erythroid colony formation in vitro in methylcellulose (EPA). Depletion of CSF from Mo conditioned medium by heat inactivation or gel exclusion chromatography did not affect CFU-DG formation. EPA and CFU-DG stimulating activities are heat stable and have approximately the same molecular weight. Culture of human bone marrow cells in diffusion chambers in mice for 4 days under the influence of Mo conditioned medium resulted in significant increment of BFU-E and CFU-DG as judged by subculture of diffusion chamber contents. No effect on CFU-C could be detected.     

Transduction of hematopoietic cells by foamy virus vectors

Foamy viruses are retroviruses of the spumavirus family that are often isolated from primary cultures of primate cells. We previously constructed vectors based on human foamy virus (HFV) and found that they were able to transduce a wide variety of vertebrate cells by integration of the vector genome. Here we show that several types of hematopoietic cells are efficiently transduced by an HFV vector that encodes alkaline phosphatase (AP). These cell types include transformed cell lines and primary hematopoietic progenitors from mice, baboons, and humans. The transduction rates of HFV vectors compare favorably with those obtained by murine leukemia virus vectors, which suggests that HFV vectors may be effective in the treatment of hematologic diseases by gene therapy.     

Identification and characterization of a high-affinity granulocyte- macrophage colony-stimulating factor receptor on primary rat oligodendrocytes

We previously showed the presence of receptors for granulocyte- macrophage colony-stimulating factor (GM-CSF) on tumor tissues and tumor cell lines that are derived from the neural crest. To determine whether normal neural cells express functional GM-CSF receptors, we isolated and analyzed primary rat brain cells, including microglia, astrocytes, and oligodendrocytes. Scatchard analysis of equilibrium binding of 125I-GM-CSF to primary rat oligodendrocytes showed an average of 1,110 GM-CSF binding sites per cell, with a kd of 20 pmol/L. In six separate experiments, no specific binding was detectable on the astrocyte population. Microglia were used in competitive binding experiments with oligodendrocytes, and addition of microglia did not increase the specific binding of labeled ligand to oligodendrocytes. In dose-response assays, we measured 3H-thymidine uptake in rat oligodendrocytes, microglia and control murine 32D cells stimulated with various concentrations of GM-CSF. Over concentration ranges of 0.025 to 1000 pmol/L, cell proliferation and peak 3H-thymidine incorporation was observed at approximately 30 pmol/L for both the control cells and the oligodendrocytes. However, the microglial cells did not proliferate in response to GM-CSF. These data indicate the presence of a functional receptor for GM-CSF on primary rat oligodendrocytes, and suggest that hematopoietic growth factors such as GM-CSF may play a role in nerve cell development, function, or response to injury.     

Identification of CRKL as the constitutively phosphorylated 39-kD tyrosine phosphoprotein in chronic myelogenous leukemia cells

Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia (Ph) chromosome in clonally derived hematopoietic precursors and their progeny. The Ph chromosome arises from a translocation that deregulates the c-ABL protein tyrosine kinase, giving it transforming potential and increased kinase activity. We observed a unique 39-kD tyrosine phosphoprotein (pp39), previously reported in blastic CML cell lines, in neutrophils from 50 cases of chronic phase CML. This protein was prominently and constitutively tyrosine-phosphorylated in CML neutrophils and was not phosphorylated in normal neutrophils. Stimulation of normal neutrophils with cytokines and agonists did not induce tyrosine phosphorylation of proteins migrating in the region of pp39, and the phosphorylation state of pp39 in CML neutrophils was not affected by kinase inhibitors known to downregulate the ABL kinase. The pp39 was not phosphorylated in hematopoietic cells from healthy donors or from patients with Ph chromosome-negative myeloproliferative disorders. Using micro amino acid sequencing of purified preparations of pp39, we identified pp39 as CRKL protein, which is consistent with recent immunologic studies in the blastic K562 cell line. Immunoblotting with anti-CRKL antibodies showed the presence of CRKL protein in CML cells and cell lines as well as in antiphosphotyrosine immunoprecipitates from CML cells. Our results suggest that pp39 CRKL in CML neutrophils may be stably tyrosine-phosphorylated by the BCR/ABL kinase at an early stage of myeloid differentiation when the ABL kinase is active. CRK, CRKL, and other SH2 (SRC homology domain)/SH3-containing proteins function as adaptor molecules in nonreceptor tyrosine kinase signalling pathways. Although the CRKL protein is present in normal neutrophils, it is not tyrosine-phosphorylated, and the inability to induce such phosphorylation in normal neutrophils suggests a special role of this phosphoprotein in the pathogenesis of CML. Constitutive phosphorylation of CRKL is unique to CML, indicating that it may be a useful target for therapeutic intervention.     

Serological confirmation of human T-lymphotropic virus type I infection in healthy blood and plasma donors

We wished to develop criteria for serological confirmation of human T- lymphotropic virus type I (HTLV-I) infection in healthy donors. Selected serum or plasma samples reactive by HTLV-I enzyme immunosorbent assay or gel-agglutination assays with at least one viral- specific band on Western immunoblot (WIB) were tested in six laboratories by four WIBs and four radioimmunoprecipitation assays (RIPAs) for antibodies to HTLV-I proteins encoded by gag (p19 and p24), env (gp46 and/or gp61), and tax (p40x) genes. One hundred forty-two donor sera were obtained from 38 Japanese, 69 American, and 35 Caribbean blood or plasma donors. Among these samples, WIB assays appeared more sensitive to p24 antibodies, whereas RIPAs were significantly more sensitive to gp61 antibodies. All sera (137) with gp61 antibodies had p24 antibodies. Of the 137 sera positive for p24 and gp61 antibodies, p19 antibodies were detected in 129 sera, and p40x antibodies were detected in 108. In sera with p19 antibodies and antibodies to env- or tax-encoded proteins, p24 antibodies were always present. Antibodies to p40x were not found in the absence of gp61 antibodies. Virological evidence of infection was found in seven American donors by lymphocyte coculture (one HTLV-I, one HTLV-II) or by polymerase chain reaction (three HTLV-I, two HTLV-II). Sera from all seven donors showed p24 and gp46 and/or gp61 antibodies. We suggest that seroreactivity to both p24 and gp46 and/or gp61 by WIB or RIPA or both are suitable criteria to confirm but not to distinguish HTLV-I and HTLV-II infections.     

CLIMACTERIC SYMPTOMS IN HEALTHY MIDDLE-AGED WOMEN

SUMMARY The incidence of climacteric symptoms was determined in 247 healthy premenopausal women in a community setting. These volunteers had been recruited to a longitudinal study of bone density. Of these subjects, 46 ceased to menstruate during the study, and in this subgroup symptoms were compared before and after cessation of menstruation. Only hot flushes increased after cessation of menstruation in the longitudinal study and showed age correlation in the cross-sectional study. Hot flushes thus emerged as a true menopausal symptom. Although evidence for this is weaker, cold sweats and suffocation seem likely to be genuinely menopausal. Breast discomfort and the four mood symptoms of irritability, excitability, depression and poor concentration improved after cessation of menstruation, and this study gives no support for their being part of the menopausal syndrome; it suggests that these symptoms are more likely to be related to menstruation than to the menopause.     

新型输送型球囊扩张导管在颅内动脉狭窄治疗中的临床应用研究

目的：探讨新型输送型球囊扩张导管(Fastunnel)在颅内动脉粥样硬化狭窄介入治疗中的应用效果。方法：2021年11月至2022年2月,我们使用新型输送型球囊扩张导管对10例颅内动脉粥样硬化狭窄的患者进行了球囊扩张+支架成形术。收集并分析了患者的基线情况、影像学特点、治疗情况及围手术期情况。结果：男6例,女性4例,平均年龄(62.7±6.7)岁。10例患者均成功接受手术治疗,手术时长为16~65(37.3±18.2)min,治疗过程所受辐射剂量为1381~4901(2643.7±1131.7)mGy,剂量面积乘积(DAP)值为5707~38112(17526.8±10809.5)μGym₂^。围手术期无出血及缺血相关并发症。结论：输送型球囊扩张导管具有较好的安全性,能有效地简化手术步骤、缩短手术时间,对减少患者及医生所受射线剂量。