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PubMed1996

A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. AIDS Clinical Trials Group Study 175 Study Team.

BACKGROUND: This double-blind study evaluated treatment with either a single nucleoside or two nucleosides in adults infected with human immunodeficiency virus type 1 (HIV-1) whose CD4 cell counts were from 200 to 500 per cubic millimeter. METHODS: We randomly assigned 2467 HIV-1--infected patients (43 percent without prior antiretroviral treatment) to one of four daily regimens: 600 mg of zidovudine; 600 mg of zidovudine plus 400 mg of didanosine; 600 mg of zidovudine plus 2.25 mg of zalcitabine; or 400 mg of didanosine. The primary end point was a > or = 50 percent decline in the CD4 cell count, development of the acquired immunodeficiency syndrome (AIDS), or death. RESULTS: Progression to the primary end point was more frequent with zidovudine alone (32 percent) than with zidovudine plus didanosine (18 percent; relative hazard ratio, 0.50; P<0.001), zidovudine plus zalcitabine (20 percent; relative hazard ratio, 0.54; P<0.001), or didanosine alone (22 percent; relative hazard ratio, 0.61; P<0.001). The relative hazard ratios for progression to an AIDS-defining event or death were 0.64 (P=0.005) for zidovudine plus didanosine, as compared with zidovudine alone, 0.77 (P=0.085) for zidovudine plus zalcitabine, and 0.69 (P=0.019) for didanosine alone. The relative hazard ratios for death were 0.55 (P=0.008), 0.71 (P=0.10), and 0.51 (P=0.003), respectively. For zidovudine plus zalcitabine, the benefits were limited to those without previous treatment. CONCLUSIONS: Treatment with zidovudine plus didanosine, zidovudine plus zalcitabine, or didanosine alone slows the progression of HIV disease and is superior to treatment with zidovudine alone. Antiretroviral therapy can improve survival in patients with 200 to 500 CD4 cells per cubic millimeter.

Acquired Immunodeficiency Syndrome↗

PubMed2002

Long-term survival following radiofrequency catheter ablation of atrioventricular junction for atrial fibrillation: clinical and ablation determinants of mortality.

BACKGROUND: For patients with drug-refractory atrial fibrillation, radiofrequency catheter ablation of the atrioventricular junction and pacemaker implantation is a nonpharmacologic option routinely used nowadays. Few data are available on the long-term survival following the procedure or on evaluation of the risk factors for death in a large study cohort. METHODS: The patient population included 359 subjects undergoing atrioventricular junction ablation and pacemaker insertion. Fourteen clinical and 9 ablation variables were collected at baseline. During a mean following-up of 40.8 +/- 25.6 months, 46 patients died. Survival probability was estimated by the Kaplan-Meier methods. Multivariate Cox proportional hazards regression analysis was applied to define predictors of death. RESULTS: Mean age was 64.6 +/- 10.6 years with 203 male (57.7%). Actuarial survival probability for the total patients was 0.953 and 0.827 at 1 and 5 year. Four clinical variables, but no ablation variables, were found to be independent predictors of death: age > or =65 year (hazard ratio [HR], 1.92; 95% confidence interval [CI], 1.00-3.69), the presence of heart failure (HR, 3.83; 95% CI, 1.87-7.86), coexisting diabetes (HR, 2.91; 95% CI, 1.47-5.77), and the value of fractional shortening < or =20% (HR, 5.79, 95% CI, 3.00-11.18). There were 20 deaths in 28 patients with > or =3 risk factors and 4 deaths in 115 patients with no risk factor. CONCLUSION: The risk of death in patients undergoing ablation and pacing can be identified by readily available clinical variables. Patients with multiple risk factors are associated with an increasing mortality.

Adult↗

PubMed2005

Discretionary death: conditions, dilemmas, and normative regulation.

The author examines a major shift in the conceptualization and practices relating to death and dying in Western and other societies with advanced medicine. This shift is the result of socio-technical and cultural developments characterized by but not limited to the routine widespread application of life support technologies in the hospital together with notions of increased patient rights. It has resulted in a class of end-of-life situations, which the author defines as "discretionary death." The concept of discretionary death underscores the role of contextual and discretionary factors in end-of-life decision-making. The author identifies and discusses the necessary and complex process of norm formation that informs and regulates end-of-life medical practice and establishes societal consensus across society with respect to legitimizing "discretionary death."

Attitude to Death↗

PubMed1998

Escape from Premature Death Due to Nuclear Mutations in Podospora anserina: Repeal versus Respite.

Premature death has been defined as a growth stoppage linked to the accumulation of specific deletions of the mitochondrial genome (mtDNA) in Podospora anserina. This occurs only in strains carrying the AS1-4 mutation which lies in a gene encoding a cytosolic ribosomal protein. Here we describe the isolation and genetic characterization of 10 nuclear mutations which either delay the appearance of this syndrome (respite from premature death) or cause a switch to the classical senescence process (repeal of premature death). These mutations lie in at least six genes. Some cause defects at the levels of ascospore germination, growth rates, and/or sensitivity toward inhibitors of protein syntheses. All modify the onset of senescence in wild-type (AS1+) strains. The role played by these genes is discussed with respect to the control of diseases due to mtDNA rearrangements in filamentous fungi. Copyright 1998 Academic Press.

Journal Article↗

PubMed2000

Suicide by antidepressant intoxication identified at autopsy in Vienna from 1991-1997: the favourable consequences of the increasing use of SSRIs.

In the area of Vienna, any person dying under questionable circumstances is examined at the Institute of Forensic Medicine, where the cause of death is determined by means of autopsy and chemical analysis. Our study on fatal intoxications was performed in the period between 1991 and 1997, when selective serotonin reuptake inhibitors (SSRIs) were establishing themselves on the market, reaching the top of prescription statistics. Tricyclic antidepressants (TCAs) were involved in 30 single- and 127 multiple-substance intoxications, with amitriptyline and doxepin being the most frequently used drugs. SSRIs were involved in five multiple-substance intoxications. The f-value, which refers to the number of deaths per million defined daily doses prescribed, was found to be significantly (P</=0.001) higher in TCAs than in SSRIs. The f-value for the total group of all antidepressants declined significantly (P</=0.05) during the observation period of 7 years. In conclusion, SSRIs turned out to be less toxic than TCAs, and the increasing use of new antidepressants did not coincide with an increased number of deaths caused by these drugs.

Antidepressive Agents↗

PubMed1994

Quantification of HIV-1 virus load under zidovudine therapy in patients with symptomatic HIV infection: relation to disease progression.

OBJECTIVE: To measure changes in HIV-1 virus load following zidovudine therapy, and to investigate the relationship between these changes and clinical progression. DESIGN: Prospective study of 18 symptomatic, zidovudine-naive patients, with CD4 count < 350 x 10(6)/l. METHODS: The following parameters were measured at each visit, before zidovudine therapy, after 1 month of therapy, and every 3 months thereafter. HIV-1 virus load in peripheral blood was determined by serum immune complex-dissociated HIV-1 p24 antigen (ICD-p24 Ag), quantitative plasma and cellular viraemia. A virologic response under zidovudine was defined as > 50% decrease in ICD-p24 Ag levels or > 1 log10 decrease in plasma or cellular viraemia titres from baseline values. CD4 and CD8 cell counts, and beta 2-microglobulin levels were also measured. Disease progression was defined as the time to a new AIDS-defining event or death. RESULTS: At enrolment, 13 out of 18 (72%) patients had positive ICD-p24 Ag and positive plasma viraemia, with a mean of 44 median tissue culture infective dose (TCID50) per ml; all patients had positive cellular viraemia with a mean TCID50 of 230 per 10(6)/l cells. Median CD4 cell count was 43 x 10(6)/l. Ten patients developed a new AIDS-defining event and eight died during a median follow-up of 15 months on zidovudine. Baseline prognostic markers for development of a new AIDS-defining event included ICD-p24 Ag, CD4 and CD8 cell counts, but only CD4 cell count remained predictive on multivariate analysis (P = 0.003). When each laboratory marker was analysed as a time-dependent covariate, only CD4 (P = 0.002) and CD8 (P = 0.001) cell counts predicted the occurrence of a new AIDS-defining event. Eight out of 13 (61.5%) patients had an ICD-p24 Ag response, and seven out of 13 (54%) a plasma viraemia response, but only cellular viraemia responders (five out of 18; 28%) had a 5.6-fold decrease in their risk of developing an AIDS-defining event (90% confidence interval, 1-33; P = 0.05). None of these markers correlated with survival. CONCLUSIONS: Plasma viraemia and ICD-p24 Ag, while providing useful short-term markers of zidovudine antiviral activity in vivo, do not correlate with disease progression in patients with advanced HIV infection. CD4 cell count remained the best initial and time-dependent predictor for development of new AIDS-defining events. Interestingly, a high CD8 cell count and a decrease in cellular viraemia titres also appear to be predictive of improved clinical outcome in this population.

Adult↗

PubMed2004

Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death.

BACKGROUND: Endothelial dysfunction of coronary and peripheral arteries has been demonstrated in patients with chronic heart failure (CHF) and appears to be associated with functional implications. However, it is unknown whether endothelial dysfunction in CHF is independently associated with impaired outcome or progression of the disease. METHODS AND RESULTS: We assessed the follow-up of 67 consecutive patients with CHF [New York Heart Association (NYHA) functional class II-III] in which flow-dependent, endothelium-mediated vasodilation (FDD) of the radial artery was assessed by high resolution ultrasound. The primary endpoint was defined by cardiac death, hospitalization due to worsening of heart failure (NYHA class IV, pulmonary oedema), or heart transplantation. Cox regression analysis was used to determine whether FDD was associated with these heart failure-related events. During a median follow-up of 45.7 months 24 patients had an event: 18 patients were hospitalized due to worsening of heart failure or heart transplantation, six patients died for cardiac reasons. Cox regression analysis demonstrated that FDD (P<0.01), diabetes mellitus (P<0.01), and ejection fraction (P<0.01) were independent predictive factors for the occurrence of the primary endpoint. The Kaplan-Meier survival curve revealed a significantly better clinical outcome in patients with FDD above the median (6.2%) compared with those with FDD below the median (P<0.013). CONCLUSION: These observations suggest that endothelium-mediated vasodilation represents an independent predictor of cardiac death and hospitalization in patients with CHF, consistent with the notion that endothelium-derived nitric oxide may play a protective role in heart failure.

Chronic Disease↗

PubMed2005

Bloodstream infections due to Candida species in the intensive care unit: identifying especially high-risk patients to determine prevention strategies.

Nosocomial bloodstream infections due to Candida species are associated with a 40% crude (total) mortality rate in the United States. The attributable mortality rate defines the number of deaths due directly to the infection and represents the proportion of the total number of deaths influenced by the use of anti-infectives. We used 4 defined risk factors to create a conditional logistic regression model of individual patients' risk of candidemia and then examined the possibility of using a calculated risk threshold to begin treatment with anti-Candida antibiotics. We subsequently examined the number needed to treat (NNT) to prevent a single death related to bloodstream infection due to Candida species. By use of our model and assuming a 33% threshold for treating with an antibiotic, which is assumed to prevent 65% of candidal bloodstream infections, we show that the NNT would be 7 patients. Use of defined risk factors to select patients who are at high risk for candidemia and treatment with effective antibiotics would be an efficient way to reduce infection-related deaths.

Anti-Infective Agents↗

PubMed1979

Intravenous prophylhexedrine (Benzedrex®) abuse and sudden death.

Propylhexedrine was implicated in 15 deaths investigated by the Dallas County Medical Examiner since 1973. Twelve of the deaths were attributable to intravenous abuse of the contents of the Benzedrex® inhaler. Each death could be defined as sudden. Pulmonary edema, foreign body granulomas, fibrosis and evidence of pulmonary hypertension were frequent postmortem findings. Right ventricular hypertrophy was present in nine of the 12 subjects who died of intravenous propylhexedrine abuse. Two homicides and one suicide were propylhexedrine-related. Intravenous propylhexedrine abuse should be considered in the differential diagnosis of right ventricular hypertrophy and/or pulmonary hypertension, and it should be suspected in cases of sudden death involving young adults displaying evidence of intravenous drug abuse.

Adult↗

PubMed2005

[Medical and legal problems of death certificates].

The objectives of this article are to clarify the concepts of violent death, suspicious death and natural death, and to define the situations which need to be reported to the coroner's office, while referring to the recommendations of the National Order of the Doctors and to the European recommendation n degrees R (99) 3 about the harmonisation of the rules in the field of forensic autopsy. In practice, the indications for forensic autopsy are as follows: homicide or suspicion of homicide, suicide or suspicion of suicide, violation of human rights, death in custody or potentially associated actions of police or army, death engaging a possible responsibility, death bringing into play a particular legislation, collective catastrophe, unexpected sudden death, not identified bodies or skeletal remainders. A guiding principle is that an unexpected death remains non natural until forensic proof of the opposite!

Death Certificates↗

PubMed1997

Cumulative risk of bypass, amputation or death following percutaneous transluminal angioplasty.

OBJECTIVE: To define cumulative risk of reconstruction, amputation or death following percutaneous transluminal angioplasty (PTA). DESIGN: Non-randomised observational study. PATIENTS AND METHODS: Two hundred and thirty-four PTAs in 212 patients. Minimum follow-up 6 months. Examination of data collected prospectively on manual card index. Examination of radiology and theatre ledgers over 2.5-year period. District Information System (Dis Data). Life-table analysis. RESULTS: The cumulative risks of reconstruction at 12 months were 14.9% and 6.7%, respectively, following angioplasties below and above the inguinal ligament. Major and minor amputations were more common if the original lesions were below the inguinal ligament (relative risk (RR) 3.32, confidence interval (CI) CI 0.42-26.26 and RR 4.24, CI 0.055-32.9, respectively). They were also more likely in diabetic compared with non-diabetic patients (RR 9.95, CI 2.85-34.47 and RR 3.66, CI 1.28-10.44, respectively). No patient who presented with claudication underwent amputation. Death was more common in patients originally presenting with rest pain or gangrene than claudication (RR 3.94, CI 1.51-10.31). CONCLUSION: This study confirms the poor outlook of diabetic patients with peripheral vascular disease or those presenting with rest pain, ulceration or gangrene. Percutaneous transluminal angioplasty was associated with approximately 80% limb salvage rate in those patients during the duration of the study.

Adult↗

PubMed1998

The activity of differentiation factors induces apoptosis in polyomavirus large T-expressing myoblasts.

It is commonly accepted that pathways that regulate proliferation/differentiation processes, if altered in their normal interplay, can lead to the induction of programmed cell death. In a previous work we reported that Polyoma virus Large Tumor antigen (PyLT) interferes with in vitro terminal differentiation of skeletal myoblasts by binding and inactivating the retinoblastoma antioncogene product. This inhibition occurs after the activation of some early steps of the myogenic program. In the present work we report that myoblasts expressing wild-type PyLT, when subjected to differentiation stimuli, undergo cell death and that this cell death can be defined as apoptosis. Apoptosis in PyLT-expressing myoblasts starts after growth factors removal, is promoted by cell confluence, and is temporally correlated with the expression of early markers of myogenic differentiation. The block of the initial events of myogenesis by transforming growth factor beta or basic fibroblast growth factor prevents PyLT-induced apoptosis, while the acceleration of this process by the overexpression of the muscle-regulatory factor MyoD further increases cell death in this system. MyoD can induce PyLT-expressing myoblasts to accumulate RB, p21, and muscle- specific genes but is unable to induce G0(0) arrest. Several markers of different phases of the cell cycle, such as cyclin A, cdk-2, and cdc-2, fail to be down-regulated, indicating the occurrence of cell cycle progression. It has been frequently suggested that apoptosis can result from an unbalanced cell cycle progression in the presence of a contrasting signal, such as growth factor deprivation. Our data involve differentiation pathways, as a further contrasting signal, in the generation of this conflict during myoblast cell apoptosis.

Animals↗

PubMed1985

Why do patients with postsurgical acute tubular necrosis die?

We compared early (less than 70 days) cumulative survival, cause of death, and morbidity (defined as the number of organ system failures and reoperations) of 236 patients who needed dialysis for acute tubular necrosis (ATN) after transplantation with that of a control group of 215 transplant patients who had immediate renal function after transplantation. The patients were matched for age, number of transplants, time of transplantation, diabetic status, living-related vs cadaveric donor, and number of HLA matches. There were no differences in cumulative survival after transplantation, causes of death, organ system failure, or surgical complications as evident from the number of reoperations. The ATN patients' overall clinical course was similar to that described for other postsurgical patients with ATN in their native kidneys. We conclude that the poor survival and the surgical complications in patients with postoperative ATN are due to the basic disease and not to acute renal failure or to dialysis. To improve survival, research should be focused on the basic disease and the surgical procedures rather than on dialysis technique.

Acute Kidney Injury↗

PubMed2003

Time-updated CD4+ T lymphocyte count and HIV RNA as major markers of disease progression in naive HIV-1-infected patients treated with a highly active antiretroviral therapy: the Aquitaine cohort, 1996-2001.

In naive HIV-1 infected patients who start a highly active antiretroviral therapy (HAART), the relationship between time-updated CD4+ cell count, HIV RNA, and clinical progression (new AIDS-defining event or death) is incompletely understood. A 2-step statistical approach was adopted: first, modeling the evolution of the 2 markers taking into account left-censoring of HIV RNA and, second, studying their respective effect on clinical progression. The study sample consisted in 551 previously untreated patients of the Aquitaine Cohort who started their first HAART regimen between 1996 and 2000. During a median follow-up of 33 months, 46 patients experienced a new AIDS-defining diagnosis and 23 died. In multivariate survival analysis, time-updated CD4+ cell count (hazard ratio [HR] = 1.92 for 100 cells/mm3 lower, P < 10(-4) and HIV RNA (HR = 1.30 for 1 log(10) copies/mL higher, P = 0.04) on continuous scale were associated with clinical progression. When analyzing the effect of updated biomarkers using usual thresholds, the association with clinical progression was weaker for CD4+ but still significant (P = 0.007) whereas it remained only significant for updated HIV RNA above 4 log(10) copies/mL (P = 0.01). The prognostic information of updated HIV RNA adjusted on updated CD4+ is significant but depends on how the markers are taken into account. Clinical decisions and interpretation of clinical trial results must weigh the signification of each of these 2 biomarkers.

Adult↗

PubMed2004

Myelofibrosis with myeloid metaplasia: new developments in pathogenesis and treatment.

Myeloid metaplasia with myelofibrosis (MMM) is a chronic myeloproliferative disorder (CMPD) characterized by progressive anemia, massive splenomegaly, both hepatosplenic and non-hepatosplenic extramedullary hematopoiesis (EMH), a leukoerythroblastic blood smear, circulating progenitor cells, and marked bone marrow stromal reaction including collagen fibrosis, osteosclerosis and angiogenesis. The overall median survival is 5 years although it might range from 2 to 15 years depending on the presence or absence of clinically defined prognostic factors. Death is often due to leukemic transformation, portal hypertension or infection. In addition to shortened survival, quality of life is often affected by frequent red blood cell transfusions, profound constitutional symptoms, and cachexia. Drug therapy and autologous hematopoietic stem cell transplantation (HSCT) are of only palliative value and have not been shown to improve survival. The role of allogeneic HSCT, both myeloablative and non-myeloablative, is actively being investigated. Both splenectomy and radiation therapy have defined therapeutic roles to control EMH-associated symptoms. Analysis of the molecular biology of the disease is underway with the aid of animal models leading to the identification of novel therapeutic targets. Among the novel agents tested, thalidomide seems the most promising although newer agents are on the horizon.

Aged↗

PubMed2002

Impact of age and sex on sudden cardiovascular death following myocardial infarction.

OBJECTIVE: To evaluate and compare the risk of sudden cardiovascular death (SCD) and non-SCD after myocardial infarction (MI) associated with age and sex. DESIGN: Cohort study of patients admitted with an enzyme verified acute MI and discharged alive. Patients were followed up for up to four years. PATIENTS: 5983 consecutive hospital survivors of acute MI were enrolled in the TRACE (trandolapril cardiac evaluation) registry from 1990-92. Four age groups were prespecified: < 56, 56-65, 66-75, and > or = 76 years. MAIN OUTCOME MEASURES: SCD was defined as cardiovascular death within one hour of onset of symptoms. RESULTS: There were 536 SCD and 725 non-SCD. SCD mortality was 4.8% in the youngest and 15.7% in the oldest age groups. Non-SCD mortality was 3.5% and 25%, respectively. The ratio of SCD to non-SCD mortality varied from 1.44 in the youngest (< 56 years) to 0.55 in the oldest patients (> or = 76 years). Age significantly increased both SCD and non-SCD risk (p < 0.0001), but the increase in non-SCD risk was 40% higher (p < 0.0001). Male sex was associated with increased risk of SCD independently of age (risk ratio 1.34, p < 0.005). However, the absolute three year probability of SCD among women older than 66 years exceeded 10%. CONCLUSIONS: Compared with non-SCD the risk of SCD is relatively highest in the younger age groups, but the absolute risk of SCD is much higher among the upper age groups than the younger. The risk of SCD was slightly lower in women but not enough to warrant a different treatment strategy.

Adult↗

PubMed1995

Effect of donor age and sex on the outcome of liver transplantation.

We correlated donor and recipient factors with graft outcome in 436 adult patients who underwent 462 liver transplants. Donor variables analyzed were age, gender, ABO blood group, cause of death, length of stay in the intensive care unit, use of pressors or pitressin, need for cardiopulmonary resuscitation, terminal serum transaminases, and ischemia time. Recipient variables analyzed were age, gender, primary diagnosis, history of previous liver transplant, ABO blood group, cytotoxic antibody crossmatch, United Network for Organ Sharing (UNOS) status, and waiting time (except for the cross-match results, they were all known at the time of the operation). The endpoint of the analysis was graft failure, defined as patient death or retransplantation. Using multivariate analysis, graft failure was significantly associated with donor age, donor gender, previous liver transplantation, and UNOS 4 status of the recipient. The effect of donor age became evident only when they were older than 45 years. Livers from female donors yielded significantly poorer results, with 2-year graft survival of female to male 55% (95% CI, 45% to 67%); female to female, 64% (95% CI, 54% to 77%); male to male, 72% (95% CI, 66% to 78%); and male to female, 78% (95% CI, 70% to 88%). The only donors identified as questionable for liver procurement were old (> or = 60 years) women in whom the adverse age and gender factors were at least additive. However, rather than discard even these livers, in the face of an organ shortage crisis, their individualized use is suggested with case reporting in a special category.

Adult↗

PubMed1994

Early death or retransplantation in adults after orthotopic liver transplantation. Can outcome be predicted?

Early, reliable outcome prediction after a liver transplant would help improve organ use by minimizing unnecessary retransplantations. At the same time, early intervention in those cases destined to fail may ameliorate the high morbidity and mortality associated with retransplantation. The purpose of this study was to analyze several parameters that have been identified in the past as being associated with patient and graft outcome, and to try to develop a model that would allow us to make predictions based on data available in the early postoperative period. A total of 148 patients were followed in a prospective, observational study. Graft failure was defined as patient death or retransplantation within 3 months of surgery. Preoperative variables studied included patient demographics, need for life support, presence of ascites, serum bilirubin, serum albumin, prothrombin time, serum creatinine, and the results of the cytotoxic crossmatch. During the first 5 postoperative days, standard measurements included serum transaminases, serum bilirubin, ketone body ratio, prothrombin time, factor V, and serum lactate. Oxygen consumption was measured shortly after surgery, once the patients had rewarmed to 36 degrees C. There were 131 successful transplants (88.5%) and 17 failures (11.5%). Most of the variables studied were found to be associated with outcome (by univariate analysis) at different points in the early postoperative period. However, receiver operating characteristic curve analysis showed that the predictive ability of even the best parameter was not adequate to make decisions on individual patients. Multivariate analysis, using stepwise logistic regression, yielded a model with an overall accuracy of 92.7%. Again, receiver operating characteristic curve analysis suggested that this model did not achieve the discriminating power needed for routine clinical use. We are still not able to accurately predict outcome in the early posttransplant period. We must be very careful when evaluating parameters, or scoring systems, that are said to accomplish this. It is especially important in this era of cost containment, with its renewed pressures to guide therapy based on our perceived understanding of a patient's future clinical course.

Bilirubin↗