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PubMed1989

Causes of death in sheep exported live by sea.

Post-mortem examinations were conducted on 950 dead and terminally ill sheep during assembly for export and during transport by sea from Fremantle, Western Australia to various Middle East ports. Causes of death were grouped into 5 major categories; inanition (deaths associated with reduced feed intake, including hypocalcaemia and hypomagnesaemia), salmonellosis (enteric and septicaemic), trauma, diseases associated with excessive feed intake (lactic acidosis and enterotoxaemia) and miscellaneous diseases (mostly of farm origin). During assembly the causes of death were salmonellosis 53.4%, miscellaneous diseases 23.8%, trauma 12.6%, inanition 10.2%, acidosis 3.9%, enterotoxaemia 3.4% and no diagnosis was made in 3.4%. During shipping the causes of death in defined populations of sheep in 5 voyages were; inanition 43.4%, salmonellosis 20.2%, trauma 10.6%, miscellaneous diseases 5.9%, enterotoxaemia 1.0% and no diagnosis was made in 19.0%. The range of mortality rates per 10,000 sheep at risk for the first 11 days at sea in 5 voyages were inanition 52.6 to 76.7, salmonellosis 7.8 to 109.8, trauma 2.1 to 17.1, miscellaneous diseases 5.9 to 17.1 and enterotoxaemia nil to 10.3.

Animals↗
PubMed1995

Zidovudine compared with didanosine in patients with advanced HIV type 1 infection and little or no previous experience with zidovudine. AIDS Clinical Trials Group.

BACKGROUND: We conducted a trial to compare treatment with zidovudine or didanosine in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection who had received little or no previous therapy with zidovudine. METHODS: Six hundred seventeen patients with acquired immunodeficiency syndrome (AIDS), advanced AIDS-related complex (CD4 cell count, < or = 0.30 x 10(9)/L [300/microL]), or asymptomatic HIV (CD4 cell count, < or = 0.20 x 10(9)/L) received zidovudine, 500 mg/d of didanosine, or 750 mg/d of didanosine in a randomized, double-blind allocation, with cross-over to alternative medication after development of an end point or serious toxic effect. To be eligible, patients must have received either no or up to 16 weeks of zidovudine therapy before entry into the study. Primary end points were development of a new AIDS-defining event or death. Secondary clinical end points were new or recurrent AIDS-defining events, or death, and survival. RESULTS: In the study as a whole, there were no differences in the relative risks (RRs) of the development of end points between treatment groups. However, there was a strong interaction between the relative efficacies of zidovudine and didanosine and previous experience with zidovudine. Among 380 patients with no previous zidovudine therapy, zidovudine was more effective than 750 mg/d of didanosine (RR, 1.43; 90% confidence interval [CI], 1.02 to 2.00), with a similar trend for zidovudine compared with 500 mg/d of didanosine (RR, 1.21; 90% CI, 0.86 to 1.71). However, among 118 patients with more than 8 weeks but no more than 16 weeks of previous zidovudine therapy, 500 mg/d of didanosine was more effective than zidovudine (RR, 0.48; 90% CI, 0.27 to 0.86); there was a similar trend for increased effectiveness of 750 mg/d of didanosine compared with zidovudine (RR, 0.61; 90% CI, 0.36 to 1.03). Among 119 patients who had some but no more than 8 weeks of previous zidovudine therapy, there were no significant differences among the treatment arms. Similar findings were noted in the analysis of the two secondary clinical end points. No significant differences were found in efficacy between the groups receiving 500 and 750 mg/d of didanosine. The major toxic effect associated with zidovudine was hematopoietic (granulocytopenia) and that associated with didanosine was pancreatitis (dosage, 750 mg/d). CONCLUSIONS: In patients with advanced HIV disease, zidovudine appears to be more effective than didanosine as initial therapy; however, some patients with advanced HIV disease may benefit from a change to didanosine therapy after as little as 8 to 16 weeks of therapy with zidovudine.

AIDS-Related Opportunistic Infections↗
PubMed2005

Muscle-specific loss of apoptosis-inducing factor leads to mitochondrial dysfunction, skeletal muscle atrophy, and dilated cardiomyopathy.

Cardiac and skeletal muscle critically depend on mitochondrial energy metabolism for their normal function. Recently, we showed that apoptosis-inducing factor (AIF), a mitochondrial protein implicated in programmed cell death, plays a role in mitochondrial respiration. However, the in vivo consequences of AIF-regulated mitochondrial respiration resulting from a loss-of-function mutation in Aif are not known. Here, we report tissue-specific deletion of Aif in the mouse. Mice in which Aif has been inactivated specifically in cardiac and skeletal muscle exhibit impaired activity and protein expression of respiratory chain complex I. Mutant animals develop severe dilated cardiomyopathy, heart failure, and skeletal muscle atrophy accompanied by lactic acidemia consistent with defects in the mitochondrial respiratory chain. Isolated hearts from mutant animals exhibit poor contractile performance in response to a respiratory chain-dependent energy substrate, but not in response to glucose, supporting the notion that impaired heart function in mutant animals results from defective mitochondrial energy metabolism. These data provide genetic proof that the previously defined cell death promoter AIF has a second essential function in mitochondrial respiration and aerobic energy metabolism required for normal heart function and skeletal muscle homeostasis.

Animals↗
PubMed2001

Expression of p21 and bcl-2 proteins and p53 mRNA in surgically resected preparations of non-small cell lung cancer (stage IIIA) after etoposide and cisplatin chemotherapy.

Apoptosis which is also a called programmed cell death plays an important role during development, homeostasis and in many diseases such as cancer. Apoptosis is a genetically encoded cell death program defined by characteristic morphological and biochemical features. It is well recognized as a distinct pathologic mechanism in tumours responding to anticancer therapies. Many genes play an important role in this process. We evaluated an expression of the tumour supressor gene p53 and proteins p21 and bcl-2 in non-small cell lung cancer. We examined resected tumour tissues from 30 patients who received neoadjuvant chemotherapy. As a control we assessed tissues from patients treated without chemotherapy. Histological slides of the resected tumours were evaluated by TUNEL, in situ hybridisation and with immunoperoxidase staining procedure. The results were documented by photography. We examined the level of extinction using cytophotometry. In conclusion, preoperative chemotherapy induces apoptosis in cancer cells. The level of p53 correlates with the acceleration of TUNEL reaction. The loss of bcl-2 expression correlated with an increased apoptotic cell death. There was an increased p21 protein expression in the examined cancer tissues after chemotherapy.

Antineoplastic Agents↗
PubMed2004

Symptoms as well as tumor size provide prognostic information on patients with localized renal tumors.

PURPOSE: T stage stratification of organ confined renal tumors is based only on tumor size. Currently T1a and T1b are defined as tumors less or greater than 4 cm. However, to our knowledge the validity of this stratification has not been determined. We determined whether symptoms could add additional prognostic information when integrated with tumor size into the TNM classification. MATERIALS AND METHODS: Patients with T1-T2N0M0 renal tumors at 6 academic centers in Europe and the United States were included in this study. T stage was defined according to the 2002 TNM classification. Age, gender, T stage, tumor size, symptoms at presentation, Fuhrman grade and cancer specific survival were determined in all cases. Survival estimates were compared using the Kaplan-Meier method and multivariate analysis of the data were performed with the Cox model. RESULTS: A total of 1,771 patients with pT1-T2N0M0 renal tumors were included in this study. There were 1,148 males and 623 females. Mean age was 59.6 years. Median tumor size was 5 cm. Of the tumors 781 (44.1%), 616 (34.8%) and 374 (21.1%) were stages T1a, T1b and T2, respectively. In 825 patients (46.6%) symptoms were related to renal cancer. T stage and symptoms strongly correlated, in that 67%, 51% and 29% of patients with T1a, T1b and T2 tumors, respectively, were asymptomatic. Symptoms increased the risk of cause specific death for each T stage level. On multivariate analysis Fuhrman grade (HR 1.46), T stage (HR 1.81) and symptoms (HR 2.98) were independent predictors of survival. Based on these results 4 groups resulting from combinations of 2002 TNM stage and symptoms with significantly different risks of death were defined, namely 1) T1a-4 cm or less without symptoms, 2) T1b-4 cm or less with symptoms and greater than 4 cm without symptoms, 3) T2a-greater than 4 cm and 7 cm or less with symptoms, and 4) T2b-greater than 7 cm with symptoms CONCLUSIONS: In this study we noted that a system combining tumor size and symptoms can accurately stratify patients for predicting survival in those with organ confined renal tumors. Our data support the idea that symptoms should be integrated in further modifications of the TNM system.

Adolescent↗
PubMed2006

Spironolactone treatment and clinical outcomes in patients with systolic dysfunction and mild heart failure symptoms: a retrospective analysis.

BACKGROUND: The effect of spironolactone on clinical outcomes in patients with mild heart failure is unclear. METHODS AND RESULTS: We performed a retrospective analysis of 482 consecutive patients with left ventricular ejection fraction < or =40% and New York Heart Association I-II symptoms. Major cardiac event (MCE) was defined as death, left ventricular assist device implantation, or United Network of Organ Sharing 1 cardiac transplantation. Proportional hazards analysis was used to determine predictors of MCE and to derive an adjusted hazard for spironolactone therapy. Spironolactone was prescribed to 279 (58%) patients and mean follow-up was 1029 days. After controlling for predictors of clinical events, spironolactone treatment was associated with a trend for lower risk of MCE or heart failure rehospitalization (HR, 0.68; 95% CI, 0.43-1.07; P = .095). Exploration of interaction terms between medications revealed that treatment with the combination of spironolactone and thiazide diuretics was associated with lower risk of clinical events (HR, 0.32; 95% CI, 0.12-0.89; P = .029). CONCLUSION: In subjects with mild heart failure treated with a thiazide diuretic, the use of spironolactone is associated with reduced risk of MCE or heart failure rehospitalization. A randomized controlled trial is necessary to accurately define the clinical effects of spironolactone in patients with mild heart failure.

Adult↗
PubMed2004

Effect of improved endograft design on outcome of endovascular aneurysm repair.

OBJECTIVE: This study was undertaken to identify factors that lead to improvements in the results of endovascular aneurysm repair, with particular focus on new endograft design. METHODS: We analyzed data for patients enrolled in the European Collaborators on Stent Graft Techniques for Abdominal Aortic Aneurysm Repair (EUROSTAR) registry, and compared those for endografts now withdrawn from the market with those for endografts currently in use. Patients in whom a variety of endograft types were used in small numbers were excluded. Postoperative and long-term outcomes were initially compared with univariate analyses, and subsequently multivariate tests were used to adjust for baseline differences between the 2 groups. The main outcome measures were freedom from a variety of secondary interventions, aneurysm rupture, and death. RESULTS: Some 1224 patients received "withdrawn" endografts, and 2768 patients received "current" endografts. The 2 groups were generally similar, but patients with current devices were more often men, significantly older, more frequently unfit for open surgery, and had larger aneurysms with wider necks. Of no surprise, current endografts were also more often used by experienced (>60 previous cases) surgical teams (44% vs 20%; P <.0001). Thirty-day clinical outcomes were comparable in the 2 groups, although patients with withdrawn devices were less likely to have type II endoleak (9.2% vs 5.5%; P <.0001), and those with current devices had a shorter mean hospital stay (5.4 vs 6.8 days; P <.0001). At 3 years more patients with current devices were free from secondary transfemoral intervention (88.4% vs 76%; P <.0001) and conversion to open repair (95.4% vs 93.4%; P =.007). Aneurysm-related mortality at 3 years, defined as death due to aneurysm rupture or within 30 days of a secondary intervention, was also less frequent with current endografts (2.7% vs 4.4%; P =.02). Aneurysm rupture at 3 years was infrequent (0.8% vs 1.8%; P =.07). At multivariate analysis the use of current devices was a protective factor against late conversion to open repair (hazard ratio, 0.49; 95% confidence interval, 0.28-0.86; P =.014) and aneurysm-related death (hazard ratio, 0.51, 95% confidence interval, 0.34-0.75; P =.0008). Larger aneurysm or neck diameter and shorter neck length were also associated with late conversion to open repair; larger aneurysm diameter, older age, and unfitness for open surgery were predictive of aneurysm-related death. CONCLUSION: Modern endograft design has improved the results of endovascular aneurysm repair.

Aged↗
PubMed2001

[A proposal for a new definition of excess mortality associated with influenza-epidemics and its estimation].

PURPOSE: As methods for estimating excess mortality associated with influenza-epidemic, the Serfling's cyclical regression model and the Kawai and Fukutomi model with seasonal indices have been proposed. Excess mortality under the old definition (i.e., the number of deaths actually recorded in excess of the number expected on the basis of past seasonal experience) covers the random error for that portion of variation regarded as due to chance. In addition, it disregards the range of random variation of mortality with the season. In this paper, we propose a new definition of excess mortality associated with influenza-epidemics and a new estimation method, considering these questions with the Kawai and Fukutomi method. RESULTS: The new definition of excess mortality and a novel method for its estimation were generated as follows. Factors bringing about variation in mortality in months with influenza-epidemics may be divided into two groups: 1. Influenza itself, 2. others (practically random variation). The range of variation of mortality due to the latter (normal range) can be estimated from the range for months in the absence of influenza-epidemics. Excess mortality is defined as death over the normal range. CONCLUSION: A new definition of excess mortality associated with influenza-epidemics and an estimation method are proposed. The new method considers variation in mortality in months in the absence of influenza-epidemics. Consequently, it provides reasonable estimates of excess mortality by separating the portion of random variation. Further, it is a characteristic that the proposed estimate can be used as a criterion of statistical significance test.

Epidemiologic Methods↗
PubMed1994

Ionizing radiation-induced cell death.

Selected aspects of radiation-induced cell death, connected with signal transduction pathways are reviewed. Cell death is defined as insufficiency of the cellular signal transducing system to maintain the cell's physiological functions. The insufficiency may be due to impaired signal reception and/or transduction, lack or erroneous transcription activation, and eventual cellular 'misexpression' of the signal. The molecular basis of this insufficiency would be damage to genomic (but also other cellular) structures and closing of specific signalling pathways or opening of others (like those leading to apoptosis). I describe experimental data that suggest an important role of RAS/NF1 and p53/p105 Rb proteins in cell cycle control-coupled responses to DNA damage.

Animals↗
PubMed2000

Acute humoral xenograft rejection: destruction of the microvascular capillary endothelium in pig-to-nonhuman primate renal grafts.

The major cause of xenograft loss beyond hyperacute rejection is a form of injury, traditionally termed delayed xenograft rejection (DXR), whose pathogenesis is unknown. Here we analyze the immunologic and morphologic features of DXR that develops in pig kidney xenografts transplanted into nonhuman primates. Kidneys from miniature swine were transplanted into cynomolgus monkeys (n = 14) or baboons (n = 11) that received regimens aimed to induce mixed chimerism and tolerance. No kidney was rejected hyperacutely. Morphologic and immunohistochemical studies were performed on serial biopsies, and an effort was made to quantify the pathologic features seen. The early phase of DXR (Days 0-12) was characterized by focal deposition of IgM, IgG, C3, and scanty neutrophil and macrophage infiltrates. The first abnormality recognized was glomerular and peritubular capillary endothelial cell death as defined by in situ DNA nick-end labeling (TUNEL). Damaged endothelial cells underwent apoptosis and, later, frank necrosis. The progressive phase developed around Day 6 and was characterized by progressive deposition of IgM, IgG, C3, and prominent infiltration of cytotoxic T cells and macrophages, with a small number of NK cells. Thrombotic microangiopathy developed in the glomeruli and peritubular capillaries with TUNEL+ endothelial cells, platelet aggregation, and destruction of the capillary network. Only rare damaged arterial endothelial cells and tubular epithelial cells were observed, with rare endothelialitis and tubulitis. In the advanced phase of DXR, interstitial hemorrhage and infarction occurred. During the development of DXR, the number of TUNEL+ cells increased, and this correlated with progressive deposition of antibody. The degree of platelet aggregation correlated with the number of TUNEL+ damaged endothelial cells. We conclude that peritubular and glomerular capillary endothelia are the primary targets of renal DXR rather than tubular epithelial cells or arterial endothelium and that the earliest detectable change is endothelial cell death. DXR was characterized by progressive destruction of the microvasculature (glomeruli and peritubular capillaries) and formation of fibrin-platelet thrombi. Both cytotoxic cells and antibodies potentially mediate the endothelial damage in DXR; however, in this model, DXR is largely humorally mediated and is better termed "acute humoral xenograft rejection."

Acute Disease↗
PubMed1999

Post mortem molecularly defined familial hypercholesterolemia and sudden cardiac death of young men.

Familial hypercholesterolemia (FH) is among the most common single-gene diseases and is due to mutations of the low-density lipoprotein (LDL) receptor gene. In heterozygous FH, serum LDL-cholesterol level is elevated two- to threefold compared to unaffected individuals, men in particular are prone to premature atherosclerosis and early cardiac deaths. However, very little data are available concerning the incidence of premature deaths in FH patients. In Finland two LDL receptor founder mutations cover two-thirds of FH cases, offering a unique possibility to study the potential role of FH in unexpected early cardiac deaths. We studied a total of 149 deceased who had suffered early (< or = 50 years) unexpected cardiac death due to coronary heart disease (CHD). Three individuals (2%) had molecularly defined heterozygous FH, and heterozygous FH was present in two (3%) of the 67 subjects who had demonstrable acute myocardial infarction (AMI). Considering that the two FH mutations cover two-thirds of FH cases in Finland, the overall prevalence of FH underlying early cardiac deaths caused by AMI may be estimated to be in the range 3 to 5%.

Adult↗
PubMed2000

Computerized video time-lapse analysis of apoptosis of REC:Myc cells X-irradiated in different phases of the cell cycle.

Asynchronous rat embryo cells expressing Myc were followed in 50 fields by computerized video time lapse (CVTL) for three to four cycles before irradiation (4 Gy) and then for 6-7 days thereafter. Pedigrees were constructed for single cells that had been irradiated in different parts of the cycle, i.e. at different times after they were born. Over 95% of the cell death occurred by postmitotic apoptosis after the cells and their progeny had divided from one to six times. The duration of the process of apoptosis once it was initiated was independent of the phase in which the cell was irradiated. Cell death was defined as cessation of movement, typically 20-60 min after the cell rounded with membrane blebbing, but membrane rupture did not occur until 5 to 40 h later. The times to apoptosis and the number of divisions after irradiation were less for cells irradiated late in the cycle. Cells irradiated in G(1) phase divided one to six times and survived 40-120 h before undergoing apoptosis compared to only one to two times and 5-40 h for cells irradiated in G(2) phase. The only cells that died without dividing after irradiation were irradiated in mid to late S phase. Essentially the same results were observed for a dose of 9.5 Gy, although the progeny died sooner and after fewer divisions than after 4 Gy. Regardless of the phase in which they were irradiated, the cells underwent apoptosis from 2 to 150 h after their last division. Therefore, the postmitotic apoptosis did not occur in a predictable or programmed manner, although apoptosis was associated with lengthening of both the generation time and the duration of mitosis immediately prior to the death of the daughter cells. After the non-clonogenic cells divided and yielded progeny entering the first generation after irradiation with 4 Gy, 60% of the progeny either had micronuclei or were sisters of cells that had micronuclei, compared to none of the progeny of clonogenic cells having micronuclei in generation 1. However, another 20% of the non-clonogenic cells had progeny with micronuclei appearing first in generation 2 or 3. As a result, 80% of the non-clonogenic cells had progeny with micronuclei. Furthermore, cells with micronuclei were more likely to die during the generation in which the micronuclei were observed than cells not having micronuclei. Also, micronuclei were occasionally observed in the progeny from clonogenic cells in later generations at about the same time that lethal sectoring was observed. Thus cell death was associated with formation of micronuclei. Most importantly, cells irradiated in late S or G(2) phase were more radiosensitive than cells irradiated in G(1) phase for both loss of clonogenic survival and the time of death and number of divisions completed after irradiation. Finally, the cumulative percentage of apoptosis scored in whole populations of asynchronous or synchronous populations, without distinguishing between the progeny of individually irradiated cells, underestimates the true amount of apoptosis that occurs in cells that undergo postmitotic apoptosis after irradiation. Scoring cell death in whole populations of cells gives erroneous results since both clonogenic and non-clonogenic cells are dividing as non-clonogenic cells are undergoing apoptosis over a period of many days.

Animals↗
PubMed1997

Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group.

BACKGROUND: There is no satisfactory medical therapy for patients with primary sclerosing cholangitis. Ursodiol (ursodeoxycholic acid) benefits patients with primary biliary cirrhosis, another cholestatic liver disease. METHODS: From May 1989 to July 1995, we enrolled 105 patients with well-documented primary sclerosing cholangitis in a randomized, double-blind study comparing ursodiol (13 to 15 mg per kilogram of body weight per day in divided doses) with placebo. The primary outcome was the time to treatment failure, defined as death; liver transplantation; histologic progression by two stages (of four) or progression to cirrhosis; the development of varices, ascites, or encephalopathy; sustained quadrupling of the serum bilirubin concentration; marked worsening of fatigue or pruritus; inability to tolerate the drug; or voluntary withdrawal from the study. RESULTS: We analyzed data on the 51 patients in each group with at least 3 months of follow-up; the median follow-up was 2.2 years. There was no significant difference between the groups in time to treatment failure (relative risk of treatment failure in the ursodiol group, 1.01; 95 percent confidence interval, 0.6 to 1.7). During the first two years of follow-up, treatment was unsuccessful in 17 of 32 patients (53 percent) in the placebo group and 16 of 31 (52 percent) in the ursodiol group. There were also no differences in time to treatment failure for patients with early-stage disease or in time to liver transplantation. Ursodiol, but not placebo, was associated with improvement in serum alkaline phosphatase, aspartate aminotransferase, bilirubin, and albumin levels at one and two years. CONCLUSIONS: In a group of patients with well-defined primary sclerosing cholangitis, ursodiol provided no clinical benefit.

Adult↗
PubMed2003

Detection limit in low-amplitude EEG measurement.

Electrocerebral inactivity for the determination of cerebral death is defined as no findings of EEG greater than the amplifier's inherent internal noise level when recording at increased sensitivity. A surface biopotential electrode contains two interfaces composed of skin gel (electrolyte) and gel electrode (metal), each forming a noise source. The power spectral density, S(f), of extremely low noise signals was obtained by means of autocorrelation and fast Fourier transformation. Interelectrode resistance, R(f), was measured with synchronous rectification. The formula of equivalent noise resistance R(n) = S(f)/4kT, where k is the Boltzmann constant and T is room temperature in Kelvin, gives a resistance that generates the thermal noise corresponding to the measured S(f). Rn/R is a parameter derived from normalization by R. When Rn/R = 1, measured noise contains thermal noise only. Meanwhile, Rn/R > 1 indicates presence of excess noise, such as 1/f, and tissue noise in addition to the thermal noise. Mean square root (Rn/R) of the scalp noise was 10.8 at 10 Hz, showing existence of excess noise. The study results suggest that it is necessary to take excess noise into consideration in the measurement of low-amplitude EEG for the determination of cerebral death.

Adult↗
PubMed1993

Smoking and the incidence of coronary heart disease in an Australian population.

OBJECTIVE: To estimate the impact of smoking on the incidence of coronary heart disease in Australia. Data collected for the WHO MONICA Project were used. DESIGN: Combined data from a community-based register of all suspected coronary events and a survey of risk factor prevalence in a random sample of the same population. SETTING AND PARTICIPANTS: All residents of the Hunter Region of New South Wales aged 35-69 years who had a first acute myocardial infarction or fatal heart attack (without a history of coronary heart disease) between 1 January 1986 and 31 December 1990. MAIN OUTCOME MEASURES: Acute myocardial infarction or coronary death, as defined by the WHO MONICA Project. RESULTS: Men who are current smokers are 2.9 times (95% CI, 2.7-3.1) more likely than non-smokers to have a first myocardial infarction or fatal heart attack, and for women the equivalent figure is 3.5 times (95% CI, 3.2-3.8), after adjusting for age. Current male smokers with a history of hypertension are 4.5 times more likely to have a coronary event (7.9 times in women) than are non-smokers without a history of hypertension. The age-adjusted excess rate was 566 per 100,000 per year in men and 373 per 100,000 per year in women. Smoking is a stronger predictor of coronary heart disease incidence than a history of hypertension (relative risk [RR] = 1.6 for men and 1.9 for women) or a known history of hypercholesterolaemia (RR not significantly different from 1). CONCLUSIONS: Cigarette smoking plays a more important role in the causation of a first myocardial infarction or fatal heart attack and appears to have more influence on the incidence of coronary heart disease in Australia than hypertension.

Adult↗
PubMed2005

The role of macrophages in the in vitro generation of extracellular DNA from apoptotic and necrotic cells.

Cell death is a ubiquitous process that occurs by apoptosis or necrosis depending on the triggering event. While apoptotic and necrotic cells differ biochemically, both are cleared by macrophages for elimination. The process is very efficient, although DNA can appear in the blood in various clinical conditions associated with cell death. To define the role of macrophages in the generation of extracellular DNA, in vitro experiments were performed, assessing the release of DNA into the media of apoptotic or necrotic Jurkat cells cultured with RAW264.7 or J774 macrophage cell lines. DNA was measured by a fluorimetric assay using the dye PicoGreen. In these experiments, while necrotic cells alone did not release DNA, in the presence of macrophages, significant amounts of DNA appeared in the medium. This DNA contained sequences from the Jurkat cells and had reduced molecular weight in comparison to cellular DNA. Furthermore, coculture of macrophages with enucleated necrotic Jurkat cells did not release DNA, suggesting that the DNA came from the dead cell. In contrast, Jurkat cells made apoptotic by treatment with either staurosporine or etoposide spontaneously released DNA, while coculture with macrophages caused a decrease in the DNA released. With apoptotic cells, the DNA in the medium showed low molecular weight and laddering whether or not macrophages were present. Together, these results indicate that macrophages play an important role in the generation of extracellular DNA from dead and dying cells, with the effect dependent on how the cell died.

Animals↗
PubMed1996

Your child is brain dead.

One to two per cent of admissions to Paediatric Intensive Care Units eventually fulfil the criteria for brain death, implying the need for very difficult decisions. Brain death is defined as irreversible loss of function of the whole brain. The diagnostic criteria caused a great deal of anxiety but are now the subject of a consensus approach. When the situation can be anticipated it is of immense value for the professional staff to develop a good working relationship with the parents to help and support them through the phase of impending disaster and facing the issue when the time actually comes. However, it is vital to help parents to make their own decision regarding continuation or otherwise of life support and they should be supported in whichever decision they take. They must be absolutely convinced that the child is brain dead and this territory may have to be covered again and again in discussion, questions must be answered factually, and time allowed for reflection. Stage management of the process of 'switching off' is vital and the parents' wishes may vary widely from one family to another. They must be warned what is likely to happen and provided with appropriate privacy and support for expression of their grief. The question of asking for post-mortem permission has to be handled sensitively and long-term support for the parents must be offered. Education of undergraduate and postgraduate doctors in this area is now receiving more attention with skills being increased by video teaching and role play. It should not be overlooked that the professional staff attending such patients sometimes require counselling and support themselves.

Brain Death↗
PubMed2006

Postasphyxial hypoxic-ischemic encephalopathy in neonates: outcome prediction rule within 4 hours of birth.

OBJECTIVES: To construct and validate a model and derive a simple rule that is usable in any birth location for the prediction of outcome of term infants with severe asphyxia. DESIGN: Retrospective cohort study. SETTING: Regional outborn neonatal intensive care unit. PARTICIPANTS: Infants with postintrapartum asphyxial hypoxic-ischemic encephalopathy (n = 375). MAIN EXPOSURES: Clinical and laboratory predictors available at age 4 hours. MAIN OUTCOME MEASURES: A logistic regression model was developed and internally validated (with random sampling and based on the year of birth) for severe adverse outcome, which was defined as death or severe disability (severe cerebral palsy, severe developmental delay, sensorineural deafness, or cortical blindness singly or in combination). A simple prediction rule was derived from 3 variables. RESULTS: Complete data were available for 302 (92%) of the 345 infants with known outcomes (204 infants with severe adverse outcome). Six independent predictors of outcomes were identified. Using the 3 most significant predictors (chest compressions, age at onset of respiration, and base deficit), severe adverse outcome rates were 46% (95% confidence interval, 33%-58%) with none of the 3 predictors, 64% (95% confidence interval, 54%-73%) with any 1 predictor, 76% (95% confidence interval, 66%-85%) with any 2 predictors, and 93% (95% confidence interval, 81%-99%) with all of the 3 predictors present. The internal validations revealed a robust model. CONCLUSIONS: This predictive model for neonatal hypoxic-ischemic encephalopathy provides a sliding scale of probabilities that could be used for prognostication and to design eligibility criteria for decision making including neuroprotective therapy.

Age Factors↗