- Email: [email protected]
IFNa-2b alone or in combination with ribavirin for treatment of chronic HCV infection
Biomed
& Pharmacother
1999 ; 53 : 106-X 0 Elsevier,
Paris
Notes
Is mefloquine an effective antimalarial?
HIV infection of endothelial cells promotes the development of AIDS-associated B cell lymphomas AIDS patients are at significantly greater risk for developing aggressive B cell non-Hodgkin’s lymphoma (AIDS-NHL) than immunocompetent individuals. Since neoplasia correlates strongly with duration of HIV infection, this life-threatening condition will persis: as a significant clinical problem even as patients survive longer with more effective anti-retroviral therapies. Thus, an understanding of the etiology of AIDS-NHL to allow development of novel and effective therapeutic interventions becomes an increasing priority. AIDS-‘VHL frequently develop at extranodal sites, particularly the gut. liver, bone marrow and CNS. While neoplastic B cells are not directly infected with HIV, the virus may promote lymphomagenesis via infection of accessory cells interacting with the lymphoma ceils. We have demonstrated that HIV infects rnicrovascular endothelial cells (MVEC) in the brain and bone marrow a.nd propose that HIV-infected MVEC contribute t’, homing and growth of malignant B cells at these e:ttranodal sites. In this report we demonstrate that infection of bone marrow MVEC derived from patients with Nl-IL allows the in vitro outgrowth and survival of autologous lymphoma cells and that HIV-infected brai- MVEC support enhanced attachment and growth of tnalignant B cells. Our studies show that HIV infection of MVEC increases expression of CD40 which. when simulated by its ligand CD40L on malignant B cells. induces expression of the B cell adhesion and signaling molecule VCAM-I on the infected MVEC. We propose that HIV contributes to the development of B cell NHL in AIDS patients by infecting MVEC and inducing a phenotype that promotes lymphoma cell attachment and growth. Full clarification of the function of the microenvironment in regulating lymphomagenesis should permit the rational design 01’ preventive strategies. AV Moses
(1)
Oregon Health Sciences University Portland, Oregon, USA (I ) Nature Medicine I997 ; 3 : 1242.7
Mefloquine (LariamO) has been used for malaria prophylaxis since 1986, and has been prescribed to over 12 million travellers. There is much anecdotal evidence that the drug is poorly tolerated in general travellers, and that it can cause neuropsychiatric and other severe side effects. This review (1) was carried out as part of the international research activity of the Cochrane Collaboration, and was supported in part by the European Commission Directorate General XII, Belgium. The authors carried out a systematic search of all randomised controlled trials of mefloquine prophylaxis. and synthesised the results from ten of these trials. There has been no randomised controlled trial of mefloquine prophylaxis in general travellers. Clinical toxicity studies carried out in non-travelling volunteer confirm that withdrawals from mefloquine are higher than withdrawals from placebo. Five field trials have been carried out in soldiers, and these trials suggest that in general travellers withdrawals from mefloquine will be high, impairing the drug’s effectiveness. A Croft (2) Headquarters Defence Secondary Care Agency London, LJK (2)BrMedJ
1997;315:
1412%
IFNa-2b alone or in combination with ribavirin for treatment of chronic HCV infection A Swedish research team recently published their results of a randomised double-blind, placebo-controlled study on single treatment with IFN alfa-2b vs. combination treatment with IFN alfa-2b + ribavirin for patients with chronic hepatitis C virus (HCV) infection. One hundred patients were recruited and treated for 6 months whereafter a 6 months follow-up ensued. Sustained virological eradication which clearance of HCV RNA from serum at the end of follow-up was achieved in significantly more combination treated patients with baseline high viral loads (HCV RNA levels above 3 million genome equivalents per mL serum as measured by branched DNA technology) 40% vs. 4% whereas no significant difference in response was seen in patients with lower viral loads. This improves treatment
options for patients with chronic HCV infection and suggest that all patients with high viral loads should be offered combination treatment to ensure optimal treatment for this slowly evolving disease with feared late consequences of cirrhosis and hepatocellular carcinoma. 0 Weiland (3) Huddinge University Hospital Huddinge. Sweden (3) Lancet 1998 ; 51 : 83-7
Mechanical ventilation with conventional volumes and pressuresare not associatedwith increased air leaks or increased mortality We analyzed data from a prospective trial of aerosolired synthetic surfactant in 725 patients with acute respiratory distress syndrome induced by sepsis. We compared. the ventilatory pressures and volumes in the patients without any air leaks with the pressures and volumes in those with pneumothorax or with any air leaks. 6.9% had pneumothorax and 10.6% had pneumothorax or other air leaks. There were no significant differences, with or without air leaks in any pressure or volume. Overall mortality at 30 days was 40.0% (95% Cl 36.443.6), with pneumothorax it was 46.0% (95% Cl 32.2-59.8), without pneumothorax it was 39.3% (95% Cl 35.643.0). Mortality was 45.5% with any air leaks and 39.0% (95% Cl 35.3-42.8) without air leaks 0, = 0.2X). Mechanical ventilation with conventional pressures and volumes had no signihcant correlations with pneumothorax or other air leaks. and they were not associated with a significantly increased mortality rate. JG Weg (4) University of Michigan Medical Center Ann Arbor, MI, USA
(4)N Engl J Med 1998 ; 338 : 34 I -6
Loss of neutral endopeptidase in androgenindependent prostate cancer Cell-surface peptidases play a key role in the control of growth and differentiation by modulating the activity of neuropeptides and regulating their access to adjacent cells. Recent data suggest that growth of prostate cancer (PC) following withdrawal of androgen is mediated in part by neuropeptides such as neurotensin. bombesin and
endothelin-1. These peptides are substrates for the cellsurface peptidase neutral endopeptidase 24.11 (NEP), suggesting that an alteration in NEP expression or function occurs when cells become androgen-independent. As shown in this paper, NEP is expressed by normal prostate epithehal cells, and by PC cells which are still dependent on androgen for growth, but decreased in metastatic PCs which continue to proliferate despite androgen withdrawal. This occurs in part because the expression of the NEP gene is activated by androgen and repressed by androgen withdrawal. Consequently, PC cells which survive androgenwithdrawal may emerge with reduced levels of NEP. To demonstrate the biological significance of NEP, the investigators showed that the introduction of a vector construct containing the NEP gene into androgen-independent PC cells resulting in overexpression of NEP or incubation with recombinant NEP protein inhibited PC cell growth. These studies suggest that decreased NEP expression, common in androgen-independent PCs, is facilitated by androgen withdrawal, and that NEP loss plays an important role in the development of androgen-independent PC by allowing PC cells to use neuropeptides as an alternate source to androgen to stimulate growth. DM Nanus (5) The New York Hospital - Cornell Medical Center New York, NY, USA (5 ) Nature Medicine 1998 ; 4 : 50
BRCAl mutations and clinical outcome Hereditary breast cancer has been associated with mutations in the BReast CAncer genes BRCAI and BRCA2. However till recently it was not known whether patients with BRCA I associated primary breast cancer had a different prognosis in comparison with patients with sporadic turnours. The results of the present study show that 49 breast-cancer cases from 20 Dutch families with proven specific germ-line BRCAI mutations differed from a control set of 196 sporadic tumours (matched for patient age and year of diagnosis) in various clinical variables. The most important findings were the significantly increased occurrence of steroid-receptor-negative and bilateral tumours in patients with BRCAI associated breast cancers. Despite these differences and other reported tumour characteristics, disease-free and overall survival, and local failure rate, did not significantly differ from those in patients with sporadic breast cancer, A stage-corrected analysis revealed slightly (but no significantly) higher
& Pharmacother
1999 ; 53 : 106-X 0 Elsevier,
Paris
Notes
Is mefloquine an effective antimalarial?
HIV infection of endothelial cells promotes the development of AIDS-associated B cell lymphomas AIDS patients are at significantly greater risk for developing aggressive B cell non-Hodgkin’s lymphoma (AIDS-NHL) than immunocompetent individuals. Since neoplasia correlates strongly with duration of HIV infection, this life-threatening condition will persis: as a significant clinical problem even as patients survive longer with more effective anti-retroviral therapies. Thus, an understanding of the etiology of AIDS-NHL to allow development of novel and effective therapeutic interventions becomes an increasing priority. AIDS-‘VHL frequently develop at extranodal sites, particularly the gut. liver, bone marrow and CNS. While neoplastic B cells are not directly infected with HIV, the virus may promote lymphomagenesis via infection of accessory cells interacting with the lymphoma ceils. We have demonstrated that HIV infects rnicrovascular endothelial cells (MVEC) in the brain and bone marrow a.nd propose that HIV-infected MVEC contribute t’, homing and growth of malignant B cells at these e:ttranodal sites. In this report we demonstrate that infection of bone marrow MVEC derived from patients with Nl-IL allows the in vitro outgrowth and survival of autologous lymphoma cells and that HIV-infected brai- MVEC support enhanced attachment and growth of tnalignant B cells. Our studies show that HIV infection of MVEC increases expression of CD40 which. when simulated by its ligand CD40L on malignant B cells. induces expression of the B cell adhesion and signaling molecule VCAM-I on the infected MVEC. We propose that HIV contributes to the development of B cell NHL in AIDS patients by infecting MVEC and inducing a phenotype that promotes lymphoma cell attachment and growth. Full clarification of the function of the microenvironment in regulating lymphomagenesis should permit the rational design 01’ preventive strategies. AV Moses
(1)
Oregon Health Sciences University Portland, Oregon, USA (I ) Nature Medicine I997 ; 3 : 1242.7
Mefloquine (LariamO) has been used for malaria prophylaxis since 1986, and has been prescribed to over 12 million travellers. There is much anecdotal evidence that the drug is poorly tolerated in general travellers, and that it can cause neuropsychiatric and other severe side effects. This review (1) was carried out as part of the international research activity of the Cochrane Collaboration, and was supported in part by the European Commission Directorate General XII, Belgium. The authors carried out a systematic search of all randomised controlled trials of mefloquine prophylaxis. and synthesised the results from ten of these trials. There has been no randomised controlled trial of mefloquine prophylaxis in general travellers. Clinical toxicity studies carried out in non-travelling volunteer confirm that withdrawals from mefloquine are higher than withdrawals from placebo. Five field trials have been carried out in soldiers, and these trials suggest that in general travellers withdrawals from mefloquine will be high, impairing the drug’s effectiveness. A Croft (2) Headquarters Defence Secondary Care Agency London, LJK (2)BrMedJ
1997;315:
1412%
IFNa-2b alone or in combination with ribavirin for treatment of chronic HCV infection A Swedish research team recently published their results of a randomised double-blind, placebo-controlled study on single treatment with IFN alfa-2b vs. combination treatment with IFN alfa-2b + ribavirin for patients with chronic hepatitis C virus (HCV) infection. One hundred patients were recruited and treated for 6 months whereafter a 6 months follow-up ensued. Sustained virological eradication which clearance of HCV RNA from serum at the end of follow-up was achieved in significantly more combination treated patients with baseline high viral loads (HCV RNA levels above 3 million genome equivalents per mL serum as measured by branched DNA technology) 40% vs. 4% whereas no significant difference in response was seen in patients with lower viral loads. This improves treatment
options for patients with chronic HCV infection and suggest that all patients with high viral loads should be offered combination treatment to ensure optimal treatment for this slowly evolving disease with feared late consequences of cirrhosis and hepatocellular carcinoma. 0 Weiland (3) Huddinge University Hospital Huddinge. Sweden (3) Lancet 1998 ; 51 : 83-7
Mechanical ventilation with conventional volumes and pressuresare not associatedwith increased air leaks or increased mortality We analyzed data from a prospective trial of aerosolired synthetic surfactant in 725 patients with acute respiratory distress syndrome induced by sepsis. We compared. the ventilatory pressures and volumes in the patients without any air leaks with the pressures and volumes in those with pneumothorax or with any air leaks. 6.9% had pneumothorax and 10.6% had pneumothorax or other air leaks. There were no significant differences, with or without air leaks in any pressure or volume. Overall mortality at 30 days was 40.0% (95% Cl 36.443.6), with pneumothorax it was 46.0% (95% Cl 32.2-59.8), without pneumothorax it was 39.3% (95% Cl 35.643.0). Mortality was 45.5% with any air leaks and 39.0% (95% Cl 35.3-42.8) without air leaks 0, = 0.2X). Mechanical ventilation with conventional pressures and volumes had no signihcant correlations with pneumothorax or other air leaks. and they were not associated with a significantly increased mortality rate. JG Weg (4) University of Michigan Medical Center Ann Arbor, MI, USA
(4)N Engl J Med 1998 ; 338 : 34 I -6
Loss of neutral endopeptidase in androgenindependent prostate cancer Cell-surface peptidases play a key role in the control of growth and differentiation by modulating the activity of neuropeptides and regulating their access to adjacent cells. Recent data suggest that growth of prostate cancer (PC) following withdrawal of androgen is mediated in part by neuropeptides such as neurotensin. bombesin and
endothelin-1. These peptides are substrates for the cellsurface peptidase neutral endopeptidase 24.11 (NEP), suggesting that an alteration in NEP expression or function occurs when cells become androgen-independent. As shown in this paper, NEP is expressed by normal prostate epithehal cells, and by PC cells which are still dependent on androgen for growth, but decreased in metastatic PCs which continue to proliferate despite androgen withdrawal. This occurs in part because the expression of the NEP gene is activated by androgen and repressed by androgen withdrawal. Consequently, PC cells which survive androgenwithdrawal may emerge with reduced levels of NEP. To demonstrate the biological significance of NEP, the investigators showed that the introduction of a vector construct containing the NEP gene into androgen-independent PC cells resulting in overexpression of NEP or incubation with recombinant NEP protein inhibited PC cell growth. These studies suggest that decreased NEP expression, common in androgen-independent PCs, is facilitated by androgen withdrawal, and that NEP loss plays an important role in the development of androgen-independent PC by allowing PC cells to use neuropeptides as an alternate source to androgen to stimulate growth. DM Nanus (5) The New York Hospital - Cornell Medical Center New York, NY, USA (5 ) Nature Medicine 1998 ; 4 : 50
BRCAl mutations and clinical outcome Hereditary breast cancer has been associated with mutations in the BReast CAncer genes BRCAI and BRCA2. However till recently it was not known whether patients with BRCA I associated primary breast cancer had a different prognosis in comparison with patients with sporadic turnours. The results of the present study show that 49 breast-cancer cases from 20 Dutch families with proven specific germ-line BRCAI mutations differed from a control set of 196 sporadic tumours (matched for patient age and year of diagnosis) in various clinical variables. The most important findings were the significantly increased occurrence of steroid-receptor-negative and bilateral tumours in patients with BRCAI associated breast cancers. Despite these differences and other reported tumour characteristics, disease-free and overall survival, and local failure rate, did not significantly differ from those in patients with sporadic breast cancer, A stage-corrected analysis revealed slightly (but no significantly) higher