A host gene regulates the structure of the transmembrane envelope protein of murine leukemia viruses.

Heterogeneity in the structure of the envelope proteins has been observed in many human and animal retroviruses and may influence pathogenicity. However, the biological significance of this heterogeneity and the mechanisms by which it is generated are poorly understood. We have studied a mouse model in which the envelope gene structure of lymphoma-associated viruses appears to be controlled by a single host gene. The inoculation of HRS and CWD mice with a leukemogenic murine leukemia virus (MuLV) results in recombination between the injected virus and envelope gene sequences of endogenous retroviruses. The genomes of HRS (class I) env recombinants and CWD (class II) env recombinants differ in the sequences encoding the NH2-terminal portion of the transmembrane envelope protein (TM). We have shown that an HRS gene linked to the MHC on chromosome 17 mediates a dominant selection for recombinant retroviruses with the class I envelope gene structure. CBA mice, which share the H-2k haplotype with HRS, also carry the dominant allele at this locus. This system provides a useful model for studies of host factors involved in the selection of specific variants of pathogenic retroviruses.

Expression of leukemogenic recombinant viruses associated with a recessive gene in HRS/J mice.

HRS/J inbred mice carry a mutant autosomal recessive gene (hr), which in homozygotes coincides with susceptibility to spontaneous thymic leukemia. Unlike their heterozygote (hr/+) littermates, hr/hr homozygotes express high levels of xenotropic virus during the preleukemic period, and viruses with a broadened host range (termed polytropic viruses) can be isolated from their preleukemic and leukemic tissues. Because hr/hr and hr/+ mice are otherwise genetically identical, the virological differences between them support the role of polytropic viruses in the generation of thymic leukemia. In the present report we show that the HRS/J polytropic viruses are env gene recombinants with unique oligonucleotide and peptide maps. These polytropic viruses appear to arise by recombination between ecotropic virus and an unidentified genome related, but not identical to, the endogenous xenotropic viruses. Moreover, polytropic viruses not only accelerate leukemogenesis in HRS/J mice, but also induce thymic leukemia in the low leukemia strain CBA/J. By contrast, cloned ecotropic and xenotropic viruses have no leukemogenic action.

Stem cells: a primer.

Having great therapeutic and biotechnological potential, stem cells are extending the frontier in medicine. Not only replace dysfunctional or damaged cells, the so-called regenerative medicine, stem cells may also offer us new perspectives regarding the nature of aging and cancer. This review will cover some basics of stem cells, their current development, and possible applications in medicine. Meanwhile, important remaining challenges of stem cell research are discussed as well.

Ventilation and exercise performance after phrenic nerve and multiple intercostal nerve transfers for avulsed brachial plexus injury.

BACKGROUND: Diaphragmatic excursion, lung function, exercise performance, and clinical symptoms have not been previously described in patients after phrenic nerve transfer (PNT) and/or multiple intercostal nerve transfer (MIT) for the repair of avulsed brachial plexus injury (ABPI) to prevent functional musculoskeletal impairment in the shoulder. SETTING: A university-based hospital. METHODS: Dyspnea scores, chest ultrasonography to assess diaphragmatic excursion, and pulmonary function testing were performed to assess ventilation in patients sustaining trauma to their brachial plexus. In addition, cardiopulmonary exercise testing was also performed. These studies were obtained prior to surgical intervention, and were repeated postoperatively at 6, 12, 18, 24, and 36 months. The results obtained preoperatively were compared to those obtained throughout the postoperative monitoring period. RESULTS: This study demonstrates that the PNT-MIT procedure results in permanent ipsilateral diaphragmatic paralysis accompanied by an approximately 8% decrease in inspiratory capacity, FVC, and total lung capacity. There was also an 11% increase in diffusing capacity noted during the period between 6 months and 3 years after PNT-MIT procedure. Despite these measurable changes in lung function, the patients reported amelioration of their dyspnea complaint within 6 months of undergoing this procedure, which was due mainly to an improvement in their cardiovascular exercise performance related to increased daily activity. CONCLUSIONS: This study demonstrates that the PNT-MIT procedure is a safe method for the restoration of drop shoulder incurred by ABPI. This surgery has an impact on measurable diaphragmatic and lung function but with minimal impact in terms of postoperative clinical symptoms and exercise performance.

Adjunctive Treatment with Rhodiola Crenulata in Patients with Chronic Obstructive Pulmonary Disease--A Randomized Placebo Controlled Double Blind Clinical Trial.

UNLABELLED: Chronic obstructive pulmonary disease (COPD) is a low grade systemic inflammatory disease characterized by dyspnea and exercise intolerance even under standard therapy. Rhodiola crenulata (RC) has been shown to exert anti-inflammatory effects and to enhance exercise endurance, thereby having the potential to treat COPD. In this 12-week, randomized, double-blind, placebo-controlled clinical trial, 57 patients with stable moderate-to-severe COPD aged 70±8.8 years were given RC (250 mg twice/day) (n=38) or a placebo (250 mg twice/day) (n=19) in addition to their standard regimen. There were no significant differences in anthropometrics, quality of life, lung function, six-minute walk and incremental exercise tests between the two groups at enrollment. Over the 12 weeks, RC was well tolerated, significantly reduced triceps skin thickness (Δ=-1 mm, p=.04), change of FEV1 (4.5%, p=.03), and improved workload (Δ=10%, p=.01); although there were no significant differences in these factors between the two groups. However, there were significant between-group differences in tidal volume and ventilation-CO2-output ratio at peak exercise (both p=.05), which were significantly related to peak work rate (both p<.0001). RC tended to protect against acute exacerbation of COPD (p=.1) but not other measurements. RC did not improve the six-minute walk test distance but significantly improved tidal breathing and ventilation efficiency, most likely through improvements in work rate. Further studies with a larger patient population are needed in order to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02242461.

Candida prosthetic arthritis: report of a case treated with fluconazole and review of the literature.

Prosthetic arthritis due to Candida species is uncommon, with only 15 cases reported in the literature. We recently cared for a human immunodeficiency virus-infected patient who developed Candida parapsilosis prosthetic arthritis unresponsive to resection arthroplasty, intravenous amphotericin B, and suppressive ketoconazole therapy. Treatment with fluconazole led to mycologic cure and symptom improvement, although he subsequently underwent above-the-knee amputation due to continued joint instability. Fluconazole may be useful follow-up therapy after a course of amphotericin B combined with resection arthroplasty or when removal of the prosthesis cannot be accomplished.

Shifts of T4/T8 T lymphocytes from BAL fluid and peripheral blood by clinical grade in patients with pulmonary tuberculosis.

OBJECTIVES: We investigated the shifts of T4/T8 lymphocytes from BAL fluid (BALF) and peripheral blood by the clinical grade of pulmonary tuberculosis (TB), which is determined by factors such as extent of pulmonary involvement, fever, and loss of body weight. MATERIALS AND METHODS: In order to explore these questions, BALF was collected from 45 patients presenting with active pulmonary TB and 14 healthy control subjects. The percentages for T-lymphocyte subpopulations, including CD4(+), CD8(+), and CD3(+) T cells, were measured using two-color flow cytometry. RESULTS: A higher percentage of CD3(+)CD4(+) T lymphocytes, with a relatively lower percentage of CD3(+)CD8(+) T lymphocytes, was revealed for the patients with a higher grade of pulmonary TB, compared to patients with a lower grade of pulmonary TB, resulting in an increased BALF C4(+)/CD8(+) ratio. By contrast, a higher percentage of CD3(+)CD8(+) T lymphocytes with a relatively low percentage of CD3(+)CD4(+) T lymphocytes was demonstrated for these patients with a higher grade of pulmonary TB, resulting in a decreased peripheral blood CD4(+)/CD8(+) ratio. CONCLUSIONS: Our findings suggest that compartmentalization of the CD4(+) T lymphocytes in the infected lungs may occur for patients with higher grades of pulmonary TB.

Phase II study of paclitaxel (Genaxol) and cisplatin combination in treating Chinese patients with advanced non-small cell lung cancer (NSCLC).

PURPOSE: To assess the efficacy of 3-h paclitaxel infusion (Genaxol) combined with cisplatin as the first line chemotherapy for patients with advanced/metastatic non-small cell lung cancer (NSCLC). The aim of the present study is to evaluate the efficacy, safety, and quality of life of the combination of paclitaxel (Genaxol) and cisplatin on Chinese patients. METHODS: Forty-five patients with histology confirmed NSCLC, who met the selection criteria were enrolled in this study between June 1999 and May 2000. They were all at an advanced stage, i.e. stage IIIB with pleural effusion, or stage IV. Paclitaxel (Genaxol) at a dose of 175 mg/m(2) and cisplatin at a dose of 75 mg/m(2) were administered every 3 weeks. RESULTS: Of the 45 eligible patients, one had a CR and 19 achieved a PR. The overall response was 44.4% (95% CI: 29.3-59.5%). Eleven (24.4%) patients were in stable disease. The median time to disease progression for all patients was 5.5 months (95% CI: 4.0-7.0 months). The median survival was 11.1 months (95% CI: 6.6-15.6 months), the 1-year survival probability was 46.5%. Major non-hematology toxicities were asthenia, paresthesias, nausea, and vomiting. Hematological toxicity results showed 18 (40%) patients experienced grade 3/4 neutropenia but there was no febrile neutropenia, three (6.6%) patients experienced Grade 3 anemia, and one (2.2%) patient experienced Grade 3 thrombocytopenia. CONCLUSIONS: The combined paclitaxel and cisplatin regimen is safe and effective in the treatment of NSCLC but the quality of life is disappointed.

Immunoglobulin gene rearrangement in abnormal lymph node hyperplasia.

The histologic designation "abnormal lymphoid hyperplasia" is applied to lymph nodes demonstrating varying degrees of architectural effacement and/or cytologic atypia. Although some of these cases may be suggestive of non-Hodgkin's lymphoma, a definitive diagnosis is not possible despite careful morphologic and immunophenotypic studies. Because the demonstration of immunoglobulin and T-cell receptor gene rearrangements by Southern blot analysis provides a sensitive marker of lineage and clonality in lymphoid malignant conditions, the frequency with which such gene rearrangements could be identified in abnormal hyperplasia and their significance were studied. DNA samples from lymph node biopsy samples of 11 patients with abnormal lymphoid hyperplasia were analyzed for rearrangements of immunoglobulin and T-cell receptor genes by Southern blot hybridization. Six of these patients had monoclonal B-cell populations identified by immunoglobulin gene rearrangements; all were found subsequently to have non-Hodgkin's lymphoma by repeated biopsy from 8 days to 46 months later. Two patients with negative Southern blot studies also developed lymphoma, one a T-cell non-Hodgkin's lymphoma and one a cutaneous B-cell non-Hodgkin's lymphoma. Three patients without detectable gene rearrangements showed no evidence of malignant lymphoma at 36-, 45-, and 60-month follow-up evaluations. Southern blot analysis thus identified monoclonal B-cell lymphoid populations in a subset of patients with abnormal lymphoid hyperplasia; the presence of clonal immunoglobulin gene rearrangement predicted progression to overt non-Hodgkin's lymphoma.

Toward the survival of private healthcare delivery.

PREMISE: a major cause of the rising real cost of healthcare is the lack of coordinated management. The task of the delivery of care falls onto three autonomous systems: hospitals, physicians, and insurers. If all these entities were interdependent subsystems within an encompassing task system, the redundancies and duplications, which impair progress and efficiency, could be modified or eliminated. The establishment of internal and external feedback mechanisms, seriously lacking at present, would improve function and allow adaptation to the present accelerating changes in the healthcare environment.

Response to hypercapnic challenge is associated with successful weaning from prolonged mechanical ventilation due to brain stem lesions.

OBJECTIVE: We propose that higher airway occlusion pressure (P0.1) responses to hypercapnic challenge (HC) indicate less severe injury. The study aim was to determine whether P0.1 responses to HC were associated with successful weaning after prolonged mechanical ventilation (PMV) in patients with brainstem lesions and to determine a reference value for clinical use. DESIGN AND SETTING: Forty-two patients with brainstem lesions on PMV were recruited. Breathing parameters and P0.1 were measured before HC. Three-minute HC challenges with increasing CO(2) concentrations were initiated and P0.1, respiratory rate, minute ventilation (V (e)), tidal volume (V (t)) and end tidal CO(2) were measured. MEASUREMENTS AND RESULTS: Patients were classified into high (group I) and low (group II) response groups on the basis of P0.1 responses to HC. Increases in V (e) and V (t) after HC were significantly greater in group I patients (12.22 +/- 8.22 vs. 3.08 +/- 4.84 L/min, P < 0.001 and 399.11 +/- 278.18 vs. 110.54 +/- 18.275 ml, P < 0.001). P0.1 levels were significantly higher in group I compared to group II before HC (2.69 +/- 1.81 vs. 1.28 +/- 1.04 cmH(2)O, P = 0.003). The increase in P0.1 following HC was significantly greater in group I compared to group II patients (11.05 +/- 4.06 vs. 2.90 +/- 2.53 cmH(2)O, P < 0.001). Weaning success was significantly higher in group I compared to group II patients (72.2% vs. 33.3%, P = 0.02). A P0.1 increase of >6 cmH(2)O following HC was significantly associated with successful weaning. CONCLUSIONS: Assessing the P.01 response to serial increases in the level of HC may be a safe means to ascertain whether patients with brainstem lesions are ready for ventilator weaning.

Phase II study of epirubicin in combination with weekly docetaxel for patients with advanced NSCLC who have failed or relapsed after the frontline platinum-based chemotherapy.

BACKGROUND: We conducted a phase II study to evaluate the efficacy and toxicity of weekly docetaxel combined with epirubicin on D15 as second-line chemotherapy in Taiwanese patients with advanced non small cell lung cancer (NSCLC) who failed or relapsed after the frontline platinum-based chemotherapy. PATIENTS AND METHODS: Patients with histologically confirmed advanced NSCLC (Stage IIIB-IV) were entered into this Phase II trial. Eastern Cooperative Oncology Group performance status was 0 to 2 and adequate organ function was required. Docetaxel, 30 mg/m, was given intravenously on days 1, 8, and 15 for 30 minutes and epirubicin, 60 mg/m, was given intravenously on day 15, then following one week of rest. Treatment was repeated every 4 weeks for a maximal total of 6 cycles. RESULTS: Of the 43 eligible patients, 39 patients were evaluated for response, and all were evaluated for toxicity. The overall response rate was 11.6% [95% confidence interval (CI), 1.6-21.6%]. The median time to disease progression for all patients was 2.8 months (95% CI 1.3-4.3%). The median survival time for all patients was 7.7 months (95% CI 5.5-9.9%). The 1-year survival was 32.6% (95% CI 25.4%-39.7%). The major hematologic toxicities were neutropenia, 8/43 (19%) with grade 3-4 neutropenia, as well as anemia, 6/43 (14%) with grade 3-4 anemia. Nonhematological toxicities were modest. Fatigue was common, 77.8% in all, but only 3 (7%) patients with grade 3-4 toxicities. Diarrhea was also common but not severe, 7/43 (16%) with grade 1-2 episodes, and 1/43 (2%) with grade 3-4 episodes. Nail changes, peripheral edema, lacrimation, and alopecia were mild. Hepatic and renal impairment was also only mild. CONCLUSION: Combining weekly doses of docetaxel 30 mg/m with epirubicin 60 mg/m on D15 was not shown to improve both efficacy and tolerability for advanced NSCLC patients who have relapsed disease after frontline platinum-based chemotherapy.