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1H-NMR studies on partially and fully reduced 2(4Fe-4S) ferredoxin from Clostridium pasteurianum.

The ferredoxin from Clostridium pasteurianum, containing two Fe4S4 clusters, has been investigated through 1H-NMR spectroscopy in the reduced and partially oxidized states. The 1H-NMR spectrum of fully reduced ferredoxin, obtained by addition of stoichiometric amounts of dithionite, has been characterized. One- and two-dimensional NMR saturation transfer experiments on partially reduced samples have allowed the isotropically shifted signals of the reduced form to be correlated to those of the oxidized form, for which the complete assignment of the beta-CH2 cysteinyl residues is available. In addition, observation of the 1H-NMR signals of the intermediate species with characteristic chemical shift values for each cluster allowed us to assign all the Cys beta-CH2 signals to cluster I or cluster II and to calculate the difference in redox potential between them. Starting from these results, reanalysis of the 1H-NMR features of the two clusters in the oxidized form showed that they are strikingly similar, supporting the idea of a high degree of internal symmetry between them, in agreement with crystallographic results on an homologous ferredoxin. On the other hand, the 1H-NMR properties of the two clusters in the reduced form deviate considerably from each other, suggesting that reduction of the clusters brings about different structural changes and loss of internal symmetry. A theoretical approach is reported to account for the isotropic shifts and the temperature dependence of the NMR signals of the reduced protein.

Clostridium↗

The development of the sense of self in adolescence.

This study attempts to clarify the sense of self that may underlie the adolescent's subjective experience of identity. The initial orientation was provided by descriptions of three different modes of experiencing identity derived from a reanalysis of Loevinger, Wessler, and Redmore's (1970) ego development categories. Our goal was to replicate by a more direct method the Loevinger-derived descriptions. Specifically, we looked at whether the various aspects of the pre-identity mode ("Social Role Identity") and of the early identity mode ("Identity Observed") would in fact form different clusters and whether these clusters would differentiate early and middle adolescent groups. Participants were 24 sixth graders and 24 high-school seniors, equally divided by sex. In individual interviews they were asked questions concerning the main characteristics of the Identity Observed Mode. Six self scales were constructed from subjects' responses. Our two major hypotheses were strongly supported: (a) The two age groups differed dramatically on each of the self scales; and (b) the six self scales highly correlated with each other. Moreover, clusters of responses could be constructed that model the a priori descriptions of identity modes and that sharply separate the two grades.

Adolescent↗

Perspectives on the recent decline in disability at older ages.

A decline has been found in the prevalence of disability among the older U.S. population during the 1980s and 1990s. One source of evidence for this decline is data from the National Long-Term Care Survey (NLTCS). This article investigates possible ambiguities in measuring disability using large-scale household surveys, illustrating the consequences of such problems with new analyses of NLTCS data. The reanalysis suggests a more gradual decline in disability than that found in prior research. The article also discusses three societal trends in areas other than health or functioning that might contribute to declines in disability levels: a reduced supply of informal care, changes in the technology of self-care, and changes in the definition and perception of both "ability" and "disability."

Aged↗

The identical-twin transfusion syndrome: a source of error in estimating IQ resemblance and heritability.

Published studies show that among identical twins, lower birthweight is associated with lower adult intelligence. However, no such relation between birthweight and adult IQ exists among fraternal twins. A likely explanation for the association between birthweight and intelligence among identical twins is the identical twin transfusion syndrome which occurs only between some monochorionic identical twin pairs. The IQ scores from separated identical twins were reanalysed to explore the consequences of identical twin transfusion syndrome for IQ resemblance and heritability. Among 129 published cases of identical twin pairs reared apart, 76 pairs contained some birthweight information. The 76 pairs were separated into three classes: 23 pairs in which there was clear evidence of a substantial birthweight differences (indicating the probable existence of the identical twin transfusion syndrome), 27 pairs in which the information on birthweight was ambiguous (?), and 26 pairs in which there was clear evidence that the twins were similar in birthweight. The reanalyses showed: (1) birthweight differences are positively associated with IQ differences in the total sample of separated identical twins; (2) within the group of 23 twin pairs who showed large birthweight differences, there was a positive relation between birthweight differences and IQ differences; (3) when heritability of IQ is estimated for those twins who do not suffer large birthweight differences, the resemblance (and thus, h2/b) of the separated identical twins' IG is 0-95. Given that the average reliability of the individual IQ test is around 0-95, these data suggest that genetic factors and errors of measurement cause the individual differences in IQ among human beings. Because of the identical twin transfusion syndrome, previous studies of MZ twins have underestimated the effect of genetic factors on IQ. An analysis of the IQs for heavier and lighter birthweight twins suggests that the main effect of the identical twin transfusion syndrome is to lower the IQ of the lighter birthweight twin, rather than to raise the IQ of the more fortunate partner or to influence the IQ of both members. This reanalysis suggests that postnatal cultural and social environment produce little of the total phenotypic variation in IQ found in the normal population. In the future, investigators who use twin studies to estimated heritability must ascertain whether their identical twin pairs suffered from the identical twin transfusion syndrome. Accurate estimates of heritability can only be obtained using identical twins who do not suffer from placental circulation problems. Most likely, the identical twin transfusion syndrome produces anoxia and brain damage during early prenatal development in the smaller identical twin. The anoxia is caused by a lowering of the haemoglobin content of the smaller twin by 35% or more.

Adolescent↗

The misplace of litigation in medical practice.

Medical decision-making is based upon mathematical probability in determining the significance of variables involved. Truth is often not absolute and medical decisions often require reconsideration of information, reanalysis and possible change. Litigation based upon error negates the ordinary practice of medicine. Error is intrinsic to all human behaviour and contributed to by uncertainty concerning precision in diagnosis and treatment of some diseases, mood change affecting ability to process cognitive and analytic function, and adverse work environment. Error is an important process in learning and providing it is recognized and fully admitted is a creative process providing opportunity for improving medical practice. Litigation is based on proof of negligence. Negligence is defined as carelessness, which is a rare cause of human and medical errors. The law confuses error with negligence; error should not be the basis for litigation. Litigation based on error is counter-productive to the best practice and improvement of clinical medicine. The assessment of errors and negligence is limited by the method of choice of medical experts, the adversarial system often ignoring the intermediate position in favour of a yes-no answer, the selection of experts to favour the desired result rather than the real situation, the method of questioning of witnesses which discourages explanation and creative solution of disagreement, and the hierarchical system which does not allow exploration of the issues and creative solutions. The basis for financial compensation for ill health is relevant when this assists the sufferer to cope with the ill health. The ethical basis for compensation when ill health results from error by health care workers is not more valid than ill health resulting from biological or environmental factors. Human error is common normal behaviour, while biological and environmental causes of ill health are common errors of human biology and the environment. Unintentional human error should not be the basis of financial remuneration or punishment. This latter principle has been applied to all services between the customer and service supplier, which may lead to unnecessary mistrust, anxiety and alienation in modern society. Incapacity from injury or disablement is covered by damages payment in only a small percentage of permanent disability cases (1.5% in the U.K.). Universal insurance by government or private agencies e.g. as in motor accident insurance to include the 98% of the permanently disabled who are receiving no payment at present would be both preferable and fairer. The protection of barristers from litigation for negligence in court is based upon arguments that could apply to most other occupations, and are equally, if not more relevant to medicine. The legal system of settling claims for negligence by doctors needs to be replaced by an investigative system which seeks to explain the basis and cause of error, which would benefit the patient and the doctor, and improve medical practice. A creative process needs to replace a judgmental, rigid and punitive system. A committee involving specialist groups in selecting expert witnesses, a health counsellor and a patient representative may be most suitable. Criminal acts, where error is performed deliberately, assault or sexual misdemeanors, would still be subject to the common law.

Australia↗

Cusums to measure chronic daily headache.

OBJECTIVE: To investigate whether cumulated summed differences (cusums) can be used as a method for detecting effective interventions in chronic daily headache (CDH). If so, then can such interventions be detected sooner than 28 days? BACKGROUND: CDH probably represents the greatest current challenge in the field of headache treatment. Clinical trial methodologies for its study are not standardized but usually use fixed 28-day observation periods. Similarly, 28-day observation periods are common review intervals for stepped-care patient management strategies. METHODS: A theoretical patient was modeled, with daily headache scores that had maximal variation for 28 consecutive daily measures. The cusums for this "norm" or control data set were plotted and correlated with time using a simple spreadsheet. Departure of a postintervention cusum from the 95% confidence interval of the control data set was chosen as an indicator of sensitivity to various model perturbations that had clinical correlates. RESULTS: When 1 to 17 randomly distributed headache-free days were used to perturb the 28-day model, cusums consistently diverged from the norm. If at least 3 headache-free days occurred, then the cusum detected the intervention in less than 28 days of observation. Reanalysis of a previously published study of magnesium oxide suggests that its negative conclusions should be reconsidered. CONCLUSION: Cusums can be useful tools for detecting change in CDH, whether at the level of the clinical trial or when managing patients using stepped-care treatment algorithms.

Clinical Trials as Topic↗

Racial response to angiotensin-converting enzyme therapy in systolic heart failure.

The treatment of heart failure with angiotensin-converting enzyme inhibitors has resulted in substantial improvements in morbidity and mortality due to heart failure. Varying reports in the literature have suggested that African Americans respond less well to angiotensin-converting enzyme inhibitors, but careful reanalysis of major clinical trials in heart failure, especially the Studies of Left Ventricular Dysfunction (SOLVD), demonstrates a similar mortality benefit for African Americans as for whites. Morbidity, measured as hospitalizations, may not be as favorably impacted. African Americans do respond to angiotensin-converting enzyme inhibitors as a preemptive strategy to prevent heart failure, but the incidence of heart failure is still higher in this population. Mechanisms for these potential nuances in the response to angiotensin-converting enzyme inhibitors are not yet clear. The exaggerated benefit of nitrates and hydralazine implicates alterations in nitric oxide homeostasis. Race is an inadequate model to explain the observed differences. Careful translational research focusing on genetic patterns of disease may help resolve these outstanding questions.

Black or African American↗

Validation and clinical utility of a simple in-home testing tool for sleep-disordered breathing and arrhythmias in heart failure: results of the Sleep Events, Arrhythmias, and Respiratory Analysis in Congestive Heart Failure (SEARCH) study.

Fifty patients with New York Heart Association class III systolic heart failure were enrolled in this prospective multicenter study that compared the diagnostic accuracy of a home-based cardiorespiratory testing system with standard attended polysomnography. Patients underwent at least 2 nights of evaluation and were scored by blinded observers. At diagnostic cutoff points of > or =5, > or =10, and > or =15 events per hour for respiratory disturbance severity, polysomnography demonstrated a sleep-disordered breathing prevalence of 69%, 59%, and 49%, respectively. Compared with polysomnography, the cardiorespiratory testing system demonstrated predictive accuracies of 73%, 73%, and 75%, which improved to 87%, 87%, and 83%, respectively, when analysis of covariance suggested reanalysis omitting one site's data. The system accurately identified both suspected and unsuspected arrhythmias. The device was judged by 80% of patients to be easy or very easy to use, and 74% of patients expressed a preference for the in-home system. Therefore, this system represents a reasonable home testing device in these patients.

Adult↗

Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human teratogenesis associated with maternal epilepsy.

PURPOSE: To quantify the risks of intrauterine antiepileptic drug (AED) exposure in monotherapy and polytherapy. METHODS: Data from five prospective European studies totaling 1,379 children were pooled and reanalyzed. Data were available for 1,221 children exposed to AED during pregnancy and for 158 children of unexposed control pregnancies. RESULTS: Overall, when comparing a subgroup of 192 children exposed to AED with 158 children of matched nonepileptic controls, there was an increased risk of major congenital malformations (MCA) in children exposed to AED during gestation [relative risk (RR) 2.3; 95% confidence interval (CI): 1.2-4.7]. A significant increase in risk was found for children exposed to valproate (VPA) (RR 4.9; 95% CI: 1.6-15.0) or carbamazepine (CBZ) (RR 4.9; 95% CI: 1.3-18.0) in monotherapy. When comparing different AED regimens during all 1,221 pregnancies, risks of MCA were significantly increased for the combination of phenobarbital (PB) and ethosuximide (RR 9.8; 95% CI: 1.4-67.3) and the combination of phenytoin, PB, CBZ, and VPA (RR 11.0; 95% CI: 2.1-57.6). Offspring of mothers using > 1,000 mg VPA/day were at a significantly increased risk of MCA, especially neural tube defects, compared to offspring exposed < or =600 mg VPA/day (RR 6.8; 95% CI: 1.4-32.7). No difference in risk of MCA was found between the offspring exposed to 601-1,000 mg/day and < or =600 mg/day. CONCLUSIONS: This reanalysis shows that VPA is consistently associated with an increased risk of MCA in babies born to mothers with epilepsy. Significant associations were also observed with CBZ. Larger prospective population-based studies are needed to evaluate the risks of many other less frequently prescribed treatment regimens, including newly marketed AEDs.

Abnormalities, Drug-Induced↗

Alcohol sensitivity and smoking history in men and women.

Many studies have found genetic effects to contribute to alcoholism risk in both men and women. Based on preliminary evidence for shared genetic risk between smoking and drinking problems, a reanalysis of alcohol challenge data on 412 Australian twins was performed to explore the possibility that smoking may diminish or moderate the intoxicating effects of alcohol. We found history of smoking to be strongly associated with self-reported intoxication after alcohol challenge in women (women: r = -0.44 +/- 0.08; men: r = -0.21 +/- 0.08), comparable with self-reported average weekly consumption of alcohol, which was more strongly associated in men (women: r = -0.37 +/- 0.07; men: r = -0.54 +/- 0.06). Structural equation model-fitting indicated a strong association between heavy drinking and smoking, but the association between smoking and postalcohol intoxication remained even when the effects of heavy drinking were controlled for. These results prompt the question of whether smoking cigarettes directly influences the transition from moderate to excessive use of alcohol by diminishing feelings of alcohol intoxication.

Adolescent↗

Pharmacological treatment for antisocial personality disorder alcoholics: a preliminary study.

A short time ago, we reported that a subgroup of hospitalized alcoholic men with comorbid antisocial personality disorder (ASP) seemed to benefit significantly from antidepressant medication at the end of a 6-month period in a double-blind, random assignment, placebo-controlled study. In a reanalysis of those data, we divided the ASP alcoholic group (n = 29) into those who did (n = 15) and who did not (n = 14) also satisfy DSM-III-R criteria for an additional current mood and/or anxiety disorder and then compared the 6-month outcomes of these two smaller subgroups. Despite the small ns, the results for most drinking outcome measures indicated: (1) that ASP alcoholics with a current mood/anxiety disorder improved significantly more with pharmacological treatment, relative to placebo; and (2) that ASP alcoholics with no current mood/anxiety disorder failed to respond differentially to pharmacological treatment over the 6-month period. These findings suggest a possibly useful and inexpensive approach to the long-term management of a very difficult-to-treat subgroup of men substance abusers.

Adult↗

Influence of diagnostic classification on outcomes and charges in geriatric assessment and rehabilitation.

OBJECTIVE: To determine if diagnostic classification is associated with different outcomes from treatment on a geriatric assessment unit (GAU) compared with usual care for elderly patients with acute illnesses. STUDY DESIGN: Reanalysis after post-hoc diagnostic classification of a randomized clinical trial with one year follow up. SETTING: Community hospital with rehabilitation facility. SUBJECTS: A total of 155 subjects, mean age 78 years and 78% female, of whom 58 subjects had a rehabilitation classification of their diagnoses and 97 had a medical or surgical classification. OUTCOME MEASURES: Mortality, nursing home use, activities of daily living, and charges for subsequent medical services. RESULTS: Mortality was decreased in persons with a rehabilitation classification who had received the GAU intervention. The GAU increased point-prevalence residence in the community for persons with a rehabilitation classification. For persons with a medical-surgical classification, the GAU intervention was associated with decreased cumulative use of nursing homes. However, GAU intervention was also associated with trends for increased charges in both diagnostic classification groups, even when adjusted for differential survival. CONCLUSION: Greater benefit from the GAU intervention on mortality and maintenance of residence in the community was observed in a group with a rehabilitation classification when compared with a group with a medical-surgical classification. These improved outcomes in the rehabilitation group were not accompanied by decreased charges for later medical services that could compensate for initial rehabilitation charges.

Activities of Daily Living↗

Interspecific scaling of toxicity data.

This paper reexamines the scaling approaches used in cancer risk assessment and proposes a more precise body weight scaling factor. Two approaches are conventionally used in scaling exposure and dose from experimental animals to man: body weight scaling (used by FDA) and surface area scaling (BW0.67--used by EPA). This paper reanalyzes the Freireich et al. (1966) study of the maximum tolerated dose (MTD) of 14 anticancer agents in mice, rats, dogs, monkeys, and humans, the dataset most commonly cited as justification for surface area extrapolation. This examination was augmented with an analysis of a similar dataset by Schein et al. (1970) of the MTD of 13 additional chemotherapy agents. The reanalysis shows that BW0.75 is a more appropriate scaling factor for the 27 direct-acting compounds in this dataset.

Animals↗

Lognormal distributions for skin area as a function of body weight.

This paper reanalyzes the dataset cited by the U.S. Environmental Protection Agency in its Exposure Factors Handbook that contains measurements of skin area, height, and body weight for 401 people spanning all stages of development. The reanalysis shows that a univariate model for total skin area as a function of body weight gives useful and practical results with little or no loss of reliability as compared to the Agency's bivariate model. This new result leads to a new method to develop Lognormal distributions for total skin area as a function of body weight alone.

Body Surface Area↗

The bases of differences between American and Canadian cities.

The author presents a reanalysis of multivariate data used in a 1986 study by Goldberg and Mercer entitled "The myth of the North American city: continentalism challenged", which examined differences between U.S. and Canadian cities. He concludes that "if one factors out that part of the variance in these 34 variables associated with metropolitan population, racial composition, and variations in the boundaries delimiting central municipalities, and in the criteria used to delimit metropolitan areas in the two countries, then the apparent national urban differences they find are considerably muted."

Americas↗

Behavioral marriage therapy. IV. Take two aspirin and call us in the morning.

The Jacobson-Weiss critique of the Gurman-Knudson and Gurman-Kniskern discussions of behavioral marriage therapy (BMT), while scholarly, derives from such a narrow conceptual set that, with only minor exceptions, Jacobson and Weiss have failed basically to comprehend the essence of our theoretical and logical criticisms of BMT. Moreover, a careful reanalysis of the research cited by our critics as evidence for the efficacy of BMT reveals the strength of the empirical foundation of this approach to have been greatly exaggerated. While few of our concerns about a preominantly behavioral approach to marriage therapy have been ameliorated by Jacobson and Weiss' commentary, some success seems to have been achieved in terms of our original purpose: to stimulate critical thinking about the premises and process of marital therapy.

Behavior Therapy↗

Oral ultrastructure and oral development of the misaligned undulating membrane mutant of Tetrahymena thermophila.

The misaligned undulating membrane (mum) mutant of Tetrahymena thermophila is a non-conditional, single gene recessive mutation. The major effect of the mum mutation is the production of multiple undulating membrane (UM) fragments in the oral apparatus (OA). The ultrastructure of the UM fragments of mum OAs is identical to that of the single UM of wild-type OAs. Analysis of OA development at midbody using a combination of light microscopy of protargol-stained cells and SEM of demembranated whole cells showed that the phenotypic effect of the mum mutation first becomes evident during mid to late stage 4 and is fully manifested in early stage 5. The effect of the mutation involves a proliferation of excess basal bodies in the UM field. Subsequent events in the development of the mum OA from mid to late stage 5 are identical to those in wild-type OAs. This study suggests that the mum mutation establishes conditions that allow the production of multiple UMs and thus reveals that the UM field is competent for the complete and coordinated development of several adjacent UMs. This level of regional control is not clearly evident when a single UM is present. The comparison of development of wild-type and mum OAs required an extensive reanalysis of stages 4 and 5 of normal oral development. On the basis of current and previous observations, we propose a new and more subdivided staging system for oral development in Tetrahymena.

Animals↗

Fatal mephenesin intoxication.

This report describes a death related to the abuse of and intoxication by mephenesin. To the best of our knowledge, this is the first report case of lethal intoxication involving solely mephenesin and reporting mephenesin blood concentrations. The victim was a 48-year-old woman found unconscious at home. Resuscitation was unsuccessful. Toxicological analysis was performed on a blood sample collected during resuscitation. The results being negative, the body was exhumed for an autopsy, which revealed bronchial inhalation syndrome. Analysis in a second laboratory has revealed the presence of mephenesin in samples collected during autopsy. No other drug/toxin was found, and alcohol was negative. Reanalysis of the peripheral blood collected during resuscitation found a mephenesin concentration of 15.81 microg/mL (15-fold greater that the maximum concentration that would result from a single intake of a 500 mg formulation). The pathologist has concluded on a bronchial inhalation syndrome consecutive to a mephenesin overdose as the cause of death. The manner of this death is discussed in the light of the toxicological hair analysis and the medical past of the victim.

Bronchial Diseases↗