PERINATAL MORTALITY: CHANGES IN THE DIAGNOSTIC PANORAMA 1974–1980

ABSTRACT. During the period 1974–1980, all late abortions (>19 completed gestational weeks) (LA), late fetal deaths (LFD) and early neonatal deaths (END) were surveyed in a cotninuous material of 17 813 births with an ascertained gestational age established by early ultrasound fetometry. There was no maternal death during the period. The total perinatal mortality (PM) was 0.98 % with an END rate of 0.51 %. In about 45 % of LFD no diagnosis was found. Intrapartum death was extremely rare as was END caused by asphyxia or infection. In END, death from immaturity constituted the major group in the beginning of the period, while after 1977 lethal malformations was the dominating diagnosis. There was a continuous decrease in Idiopathic Respiratory Distress Syndrome (IRDS) as a cause of END. The porportion of END in extremely premature children showed a constant decrease in the beginning of the period. No difference in sex was found in END except for lethal malformations where there was a significant male preponderance. As a consequence of a more active obstetrical care, some fetuses who would previously have been classified as LA were probably delivered liveborn, extremely premature and appeared as END. The question of where to set the limits for what should be included in PM is thus highly relevant.     

Physician-induced torsade de pointes--therapeutic implications

Torsade de pointes (TdP) is a clinico-electrocardiographic syndrome characterized by an abnormally prolonged QT interval and the occurrence of potentially life-threatening ventricular tachyarrhythmias. Two mayor causes can be distinguished: congenital and acquired long QT syndrome. Whereas the former has recently been identified as an ion channelopathy, the mechanisms underlying acquired long QT syndrome are far from being understood. It has been suggested that patients with the acquired form of the disease may suffer from a clinically hidden form of the congenital variant. However, recent studies have yielded only a small number of individual cases in whom genetic analyses revealed the presence of an ion channel gene mutation.Since acquired long QT syndrome is most often induced by drugs prolonging myocardial repolarization, it is largely an iatrogenic disease. In order to prevent unwitting exposure to risk, physicians prescribing agents that may prolong repolarization need to be aware of the typical clinico-electrocardiographic characteristics of drug-induced TdP, and its diagnosis and management. A clearer delineation of the risk factors predisposing to abnormal prolongation of repolarization, and a more precise quantification of the torsadogenic potency of individual drugs appear mandatory in order to prevent or at least minimize the occurrence of this potentially fatal adverse effect of certain drugs.     

Caspase-8 activation is necessary but not sufficient for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in the prostatic carcinoma cell line LNCaP

BACKGROUND: The differential sensitivity of tumor cells to TRAIL-induced apoptosis may be mediated by different intracellular inhibitors of apoptosis, and only a few reports have described the pathway(s) that are activated in response to TRAIL in prostate cells. METHODS: LNCaP was transfected with a dominant-negative form of FADD (FADD-DN) and cells were selected in the presence of hygromycin. Cell viability was estimated by calcein assay. Apoptosis was estimated by caspase activation using both fluorogenic substrates and Western blot analysis of activated caspases. To detect cytochrome c release, mitochondria-free cytosol was prepared and Western blot analysis was performed. RESULTS: LNCaP is resistant to TRAIL but TRAIL transiently induces DEVDase activity and activation of caspase-8; caspase-2, -3, -7, and -9 were not activated. Wortmannin, an inhibitor of the PI3K/Akt pathway, converted the phenotype of LNCaP from TRAIL-resistant to -sensitive. In the presence of wortmannin TRAIL induced activation of caspase-2, -3, -7, -8, and -9, as well as dissipation of mitochondrial transmembrane potential and release of cyto-chrome c from mitochondria into the cytosol. In addition, combined TRAIL and wortmannin treatment resulted in cleavage of several proteins: PARP, Akt, p21/WAF1, and MDM2 as well as dephosphorylation of Akt. The proteolysis of p21/WAFI and Akt, which are known survival factors, presumably amplify the apoptotic cascade in LNCaP. Transfection of FADD-DN in LNCaP resulted in inhibition of caspase activation as well as in resistance to combined treatment with TRAIL and wortmannin. CONCLUSIONS: These results suggest that caspase-8 activation is necessary but not sufficient for TRAIL-mediated apoptosis and is presumably blocked downstream of caspase-8 by the PI3K/Akt pathway.     

Regulation by oxygen of photoreceptor death in the developing and adult C57BL/6J mouse

We have examined the role of tissue oxygen in the regulation of photoreceptor death in the C57BL/6J mouse. Litters of C57BL/6J mice were raised in dim cyclic (12 hr dark, 12 hr 50 lx) light. Adults or litters aged P7 or P8 were placed with their mothers in plexiglass chambers in which oxygen levels were set at 21% (normoxic), 10 or 11% (hypoxic) or 70% (hyperoxic) for up to 22 days. At intervals after introduction to these chambers, retinas were examined for cell death, using the TUNEL technique. Hypoxia accelerated cell death up to five-fold during a critical developmental period from approximately P12 to 18. Thereafter hypoxia-induced cell death declined rapidly. Hyperoxia slowed photoreceptor death over the same period, to approximately half control levels. At the anterior edge of the developing retina the effects of hypoxia and hyperoxia differed markedly from the rest of the retina. In the adult, hypoxia accelerated photoreceptor death, but the acceleration was an order of magnitude weaker than during the critical period of developing retina. Hypoxia-induced photoreceptor death remained above control levels after 20 days exposure. Results suggest that the naturally occurring wave of photoreceptor death seen in developing mouse retina during their development (P12-P20) is regulated by a physiological episode of hypoxia. After P20, photoreceptor vulnerability to hypoxia falls to a low but significant level. The edge of the retina appears subject to chronic hyperoxic stress from P14 into adulthood. Tissue oxygen levels are important determinants of photoreceptor death and survival in both developing and adult retina.     

Differing Postneonatal Mortality Rates of African-American and White Infants in Chicago: An Ecologic Study

Objectives: This study sought to determine whether neighborhood impoverishment explains the racial disparity in urban postneonatal mortality rates. Methods: Stratified and multivariate logistic regression analyses were performed on the vital records of all African-Americans and whites born in Chicago by means of a linked 1992–1995 computerized birth–death file with appended 1990 U.S. census income and 1995 Chicago Department of Public Health data. Four community-level variables (low median family income, high rates of unemployment, homicide, and lead poisoning) were analyzed. Communities with one or more ecologic risk factors were classified as impoverished. Results: The postneonatal mortality rate of African-Americans (N = 104,656) was 7.5/1000 compared to 2.7/1000 for whites (N = 52,954); relative risk (95% confidence interval) equaled 2.8 (2.3–3.3). Seventy-nine percent of African-American infants compared to 9% of white infants resided in impoverished neighborhoods; p < 0.01. In impoverished neighborhoods, the adjusted odds ratio (controlling for infant and maternal individual-level risk factors) of postneonatal mortality for African-American infants equaled 1.5 (0.5–4.2). In nonimpoverished neighborhoods, the adjusted odds ratio of postneonatal mortality for African-American infants equaled 1.8 (1.1–2.9). Conclusions: We conclude that urban African-American infants who reside in nonimpoverished neighborhoods are at high risk for postneonatal mortality.     

The selective p38 inhibitor SB-239063 protects primary neurons from mild to moderate excitotoxic injury

Inhibition of the p38 mitogen-activated protein kinase (MAP Kinase) pathway reduces acute ischemic injury in vivo, suggesting a direct role for this signaling pathway in a number of neurodegenerative processes. The present study was designed to evaluate further the role of p38 MAP Kinase in acute excitotoxic neuronal injury using the selective p38 inhibitor SB-239063 (trans-1-(4hydroxycyclohexyl)-4-(fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl) imidazole). Unlike the widely used p38 inhibitor, SB-203580 (4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole), this second generation p38 inhibitor more selectively inhibits p38 MAP Kinase without affecting the activity of other MAP Kinase signaling pathways and provides a more accurate means to selectively assess the role of p38 in excitotoxicity that has not been previously possible. SB-239063 provided substantial protection against cell death induced by either oxygen glucose deprivation (OGD) or magnesium deprivation in cultured neurons. The ability of this compound to block excitotoxicity was not due to direct inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated currents as SB-239063 did not alter NMDA electrophysiological responses. SB-239063 did not protect against a severe excitotoxic insult induced by 60-min exposure to NMDA. However, when tested against a less severe, brief (5 min) NMDA exposure, p38 inhibition provided substantial protection. These data demonstrate that inhibition of p38 MAP Kinase can confer neuroprotection in vitro against mild but not severe excitotoxic exposure, and suggests that other additional pathways/mechanism(s) may be involved in severe excitotoxic cell death.     

Suppression of cytotoxin-induced cell death in isolated hepatocytes by tea catechins

To elucidate the hepatoprotective effects of green tea catechins, the following experiments were conducted utilizing (−)-epigallocatechin-3-gallate (EGCG), the major component of green tea catechin, together with other catechins. The protective effects of catechins against hepatotoxins, bromobenzene or rubratoxin B, were examined in primary cultures of rat hepatocytes. Bromobenzene and rubratoxin B are known to induce necrosis and apoptosis of cells, respectively. After 24-h treatment with toxin, EGCG and (−)-epigallocatechin-3-(3″-O-methyl)gallate (EGCg-3″-OMe) suppressed the bromobenzene-induced morphological change and dose-dependently prevented bromobenzene-induced cell death. Both catechins also prevented apoptotic cell death caused by rubratoxin B. In rubratoxin B-treated cells, both catechins were found to suppress the activation of caspase-3 by rubratoxin B. The results in the present study suggest that EGCG and EGCg-3″-OMe are potent hepatoprotective agents. This report is the first to show that catechins suppress cytotoxin-induced cell death.     

Patterns of mortality in patients with motor neurone disease

OBJECTIVE: Motor neurone disease (MND) is a rapidly fatal condition with survival of less than 4 years. Patients can deteriorate quickly in the preterminal stages resulting in inappropriate resuscitation or admission to intensive care units (ICU) or accident and emergency (A & E). MATERIAL AND METHODS: We looked at patterns of mortality with emphasis on the place of death. A retrospective study was performed of all patients attending an MND clinic, who had died within a 10-year period. RESULTS: Of 179 patients (63 female), 81 patients (45%) died at home, in a hospice or in a nursing home. Sixty-five patients (36%) died in hospital (11 in ICU or A & E). Nine of the latter were previously known to have MND and six admissions were probably avoidable. Most ward patients died of respiratory causes and were treated conservatively. CONCLUSION: The proportion of patients dying in A & E or ICU was small but could have been reduced further. A number of those who died on the wards could probably have been managed conservatively at home. Older patients and those with bulbar disease had a poorer prognosis.     

Involvement of 5-hydroxytryptamine4 receptor in the exacerbation of neuronal loss by psychological stress in the hippocampus of SHRSP with a transient ischemia

A transient forebrain ischemia produced a delayed neuronal death of the hippocampus pyramidal cells in stroke-prone spontaneously hypertensive rats (SHRSP). Long term exposure of rats to stress has been reported to induce deleterious effects on the brain including morphological neuronal degeneration in the hippocampus. The present study was designed to examine the effects of psychological and physical stress on the ischemia-related neuronal death and the effects of 5-hydroxytryptamine(4) (5-HT(4)) receptor antagonist. SHRSP were exposed to the psychological or physical stress for 60 min in the communication box once or repeatedly for 3 days and occluded. SB204070, a 5-HT(4) receptor antagonist was injected before the occlusion. Seven days after the occlusion, the number of the neurons damaged morphologically was examined. A transient bilateral carotid occlusion produced a neuronal death of the CA1 subfield of the hippocampus in a time-dependent manner between 3 and 10 min. A 4 min occlusion induced very little morphological damage and a 5 min one produced a significant neuronal death. Exposure of rats to the psychological stress during 60 min for 3 days before the ischemic insults damaged the pyramidal cells by 4 min ischemia much more than without stress. Physical stress daily for 3 times also increased the damaged neurons. Pretreatment of SB204070 0.1 mg/kg after the stress exposure for 3 days significantly decreased the neuronal damage exacerbated by the stress exposure; however, it did not alter the damage induced by 4 or 10 min occlusion without stress. These results suggest that the repeated exposure of animals to the stress dramatically exacerbates the neuronal death by a transient ischemia and the 5-HT(4) receptor may be involved in the stress-induced exacerbating mechanism of the neuronal damage.     

Dynamic expression of p38beta MAPK in neurons and astrocytes after transient focal ischemia

Here we report the dynamically regulated expression of p38beta MAPK isoform in specific subsets of cells in postischemic brain. The activity of p38beta MAPK in the postischemic brain revealed biphasic induction at 30 min and 4 days after 1 h MCAO. During the early surge period, p38beta MAPK was preferentially localized in the nucleus and dendrites of neurons in the future infarction area, while during the delayed surge p38beta MAPK was heavily induced in reactive astrocytes in penumbra. The temporally and spatially regulated pattern of p38beta MAPK expression in the postischemic brain suggests distinct roles of p38beta MAPK in neuronal death and in the astrocyte activation.