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BRCA1 mutations and clinical outcome
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
death rates among women with BRCAI hereditary cancer. These results have implications for screening, prophylactic therapy and different treatments of hereditary breast cancer. JGM Klijn 16) Dr Daniel den Hoed Kliniek Rotterdam. The Netherlands (6)Lancet 199X: 3.51 : 316-21
Frameshift mutants: A new view on the etiology of Alzheimer’s disease Alzheimer’s disease (AD) is the most frequent form ot dementia. The cause of AD, however, has remained a mystery and its diagnosis is possible only after the patient has died. During the past decade much attention has t,cused Ion the inherited folms of AD, but this type only dccc’unts for a minority of the AD cases. Even though the discovery 01 these mutations \hed some light on the cause of Ihe disease, at least 60%~ of AD patients do not have a family history ot the discasc, and the cause ofthese ‘sporadic case<;’ remains unknown. Here a different, more general mechat lixm must be at work that ultimately leads to the ncuronal ,legenelation. WC surmise that wc have found evidence of such a mechanism. Normally, genetic information flows frown the genetic material. the DNA. via an intermediate message, InRNA. to functional proteins. The production of mRNA is thought to occur without errors. However, we have found .m exception: nerve cells of AD patients show mistakes in the mRNA. but not in the DNA of Tao genes that code for proteins that are closely associated with AD: \3-am!/loid precursor protein (PAPP) and ubiquitin B. The mistake is the loss of two building blocks, the so-called bases. in a subpopulation of the messenger molecules. The mechanism behind this loss of two bases is presently unknoun, but it results in the production of aberrant. or mutant, pl oteins. In all probability these mutant DAPP and ubiquitirl proteins then cease to function as they should. Ubiquitin i> involved in the degradation of misfolded proteins and the observed mutation probably leads to a total loss of this activity. The mutations in DAPP (messenger molecule) may result in misprocessinp of wild-type PAPP itself and result in the well known plaques. one of the characteristics of AD. We have seen that these mutant proteins accunulate in the nerve cells in all 21 brains of AD patients viith early (< 65 years) and late (> 65 years) onset. and 7 Down sq”drome patients we examined. as well as in 6 aged (> 72 years) non-demented controls. In contr;.st. these
mutant proteins were absent in the brains of young nondemented controls. Furthermore, the mutant proteins were present in exactly those structures (the so-called plaques and tangles) that are known as the neuropathological hallmarks of AD. which suggests a causal relationship. We suppose it is the accumulation of these mutant proteins and other as yet unknown ones that disturbs the normal functioning of the brain. Thus, during the process of aging as a result of a process called ‘molecular misreading’, neurons may generate and accumulate abnormal proteins that lead to cellular disturbances. thereby causing dementia. The novel type of mutation we have discovered in messenger RNA molecules may underlie AD, but also a number of other neurodegenerative and age-related diseases, such as cancer and cardiovascular diseases. FW van Leeuwen (7) Institute for Brain Research, Royal Netherlands Academy of Arts and Sciences. Amsterdam, The Netherlands (7) Science 1998 ; 779 : 242-7
Helping patients complete treatment for tuberculosis People with tuberculosis often do not complete treatment even when drugs are available, services are accessible and care is appropriate. A variety of strategies have been used to promote adherence to antituberculous therapy. We carried out a systematic review of randomised controlled trials that have assessed the effectiveness of these interventions. A comprehensive search identified only 5 trials that fulfilled the selection criteria for this review. Six different adherence-promoting strategies had been evaluated. Patient reminder cards, patient incentives (monetary), peer assistance through community health workers, and intensive staff supervision ail seemed to improve adherence. It is not clear from the current trials what the independent effect of patient education on adherence is. Furthermore. no conpleted trials of the most common intervention (directly observed therapy) used for improving adherence could be found, though two such trials are in progress and will be included in subsequent updates of this review. J Volmink (8) South African Cochrnne Centre Cape Town, South Africa (8)BrMedJ
1997;315:
1403.6
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
death rates among women with BRCAI hereditary cancer. These results have implications for screening, prophylactic therapy and different treatments of hereditary breast cancer. JGM Klijn 16) Dr Daniel den Hoed Kliniek Rotterdam. The Netherlands (6)Lancet 199X: 3.51 : 316-21
Frameshift mutants: A new view on the etiology of Alzheimer’s disease Alzheimer’s disease (AD) is the most frequent form ot dementia. The cause of AD, however, has remained a mystery and its diagnosis is possible only after the patient has died. During the past decade much attention has t,cused Ion the inherited folms of AD, but this type only dccc’unts for a minority of the AD cases. Even though the discovery 01 these mutations \hed some light on the cause of Ihe disease, at least 60%~ of AD patients do not have a family history ot the discasc, and the cause ofthese ‘sporadic case<;’ remains unknown. Here a different, more general mechat lixm must be at work that ultimately leads to the ncuronal ,legenelation. WC surmise that wc have found evidence of such a mechanism. Normally, genetic information flows frown the genetic material. the DNA. via an intermediate message, InRNA. to functional proteins. The production of mRNA is thought to occur without errors. However, we have found .m exception: nerve cells of AD patients show mistakes in the mRNA. but not in the DNA of Tao genes that code for proteins that are closely associated with AD: \3-am!/loid precursor protein (PAPP) and ubiquitin B. The mistake is the loss of two building blocks, the so-called bases. in a subpopulation of the messenger molecules. The mechanism behind this loss of two bases is presently unknoun, but it results in the production of aberrant. or mutant, pl oteins. In all probability these mutant DAPP and ubiquitirl proteins then cease to function as they should. Ubiquitin i> involved in the degradation of misfolded proteins and the observed mutation probably leads to a total loss of this activity. The mutations in DAPP (messenger molecule) may result in misprocessinp of wild-type PAPP itself and result in the well known plaques. one of the characteristics of AD. We have seen that these mutant proteins accunulate in the nerve cells in all 21 brains of AD patients viith early (< 65 years) and late (> 65 years) onset. and 7 Down sq”drome patients we examined. as well as in 6 aged (> 72 years) non-demented controls. In contr;.st. these
mutant proteins were absent in the brains of young nondemented controls. Furthermore, the mutant proteins were present in exactly those structures (the so-called plaques and tangles) that are known as the neuropathological hallmarks of AD. which suggests a causal relationship. We suppose it is the accumulation of these mutant proteins and other as yet unknown ones that disturbs the normal functioning of the brain. Thus, during the process of aging as a result of a process called ‘molecular misreading’, neurons may generate and accumulate abnormal proteins that lead to cellular disturbances. thereby causing dementia. The novel type of mutation we have discovered in messenger RNA molecules may underlie AD, but also a number of other neurodegenerative and age-related diseases, such as cancer and cardiovascular diseases. FW van Leeuwen (7) Institute for Brain Research, Royal Netherlands Academy of Arts and Sciences. Amsterdam, The Netherlands (7) Science 1998 ; 779 : 242-7
Helping patients complete treatment for tuberculosis People with tuberculosis often do not complete treatment even when drugs are available, services are accessible and care is appropriate. A variety of strategies have been used to promote adherence to antituberculous therapy. We carried out a systematic review of randomised controlled trials that have assessed the effectiveness of these interventions. A comprehensive search identified only 5 trials that fulfilled the selection criteria for this review. Six different adherence-promoting strategies had been evaluated. Patient reminder cards, patient incentives (monetary), peer assistance through community health workers, and intensive staff supervision ail seemed to improve adherence. It is not clear from the current trials what the independent effect of patient education on adherence is. Furthermore. no conpleted trials of the most common intervention (directly observed therapy) used for improving adherence could be found, though two such trials are in progress and will be included in subsequent updates of this review. J Volmink (8) South African Cochrnne Centre Cape Town, South Africa (8)BrMedJ
1997;315:
1403.6