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[Sudden infant death. Epidemiological factors in unexplained, partially or insufficiently explained causes of death].

Epidemiologic investigations were carried out on 185 infants, who died suddenly and on whom autopsies were performed. 53 infants died a "true sudden infant death", for 90 infants death was partly, and for 42 death was adequately explained. The three groups of SID infants were concordant with regard to the following parameters: the peak of mortality was found at about three months of age; among the SID probands, first born were less, third and later born were more numerous than in the general population; mothers of first, second and third born SID probands were younger as compared to the general population; SID probands were born twice as often in October as in March. Differences between children of Swiss or foreign parentage respectively were of minor significance with relatively few illegitimate and relatively many foster children among the foreign SID probands. 185 diseased children who had died in hospital and on whom autopsies were performed served as one control group; a second control group consisted of 1020 unselected newborns of the city of Zurich. The test groups resembled one another in their deviation from the controls and thus seem to form an entity distinct from non-SID infants.

Adult↗

[A model of oligomeric enzymes explaining stepwise kinetic curves].

The complex kinetics of some oligomeric enzymes has been analysed. For interpreting such kinetics a theoretical model of an oligomeric enzyme is suggested, which is a modification of the "flip-flop" mechanism considered by Lazdunski et al. in 1971. Using our model, one can qualitatively interpret stepwise kinetic curves, i.e. the curves with few intermediate plateaus. Such curves are known from literature but have not exhaustively been explained. It is supposed that the enzyme kinetic curves can sometimes be of non-differential functions. The model used can also be applied to the kinetics of polyenzyme complexes.

Catalysis↗

Competitive nonspecific binding does not explain the potentiating effects of muscle relaxant combinations.

Combination of pancuronium (Pm) with d-tubocurarine (dTC) or metocurine (mTC) produces potentiation of neuromuscular effects. We tested the hypothesis that this effect is due to decreased plasma protein and/or nonspecific (noncholinergic) tissue binding by one or the other drug such that a greater than expected proportion of unbound drug reaches its neuromuscular site of activity. By varying the concentration of Pm, dTC, and mTC, competitive binding by Pm and dTC or Pm and mTC to plasma constituents was tested in vitro by equilibrium dialysis. Drug interaction and displacement from nonspecific binding sites in tissues was tested in vivo with Pm-mTC combinations. During recovery of mTC-induced neuromuscular paralysis, monitored by evoked twitch tension, 1 mg of Pm was administered intravenously. The twitch height and plasma mTC concentrations before and after Pm administration were noted. The in vitro plasma dTC or mTC binding was not significantly altered by the addition of Pm. Similarly, plasma mTC concentrations in vivo did not increase following the administration of Pm. Thus, there was no displacement of mTC from nonspecific tissue binding sites by Pm. Our in vitro and in vivo experiments both demonstrate that there is no interaction between Pm--dTC and Pm--mTC relative to plasma or tissue binding and thus cannot explain the potentiating effect of the drug combination.

Binding, Competitive↗

A mechanism to explain the antihypertensive action of propranolol.

The present experiments were designed to measure the direct effects of propranolol on carotid sinus pressoreceptor nerve activity in the semi-isolated, superfused sinus of the cat. Propranolol (5 microgram/ml) significantly enhanced carotid sinus nerve activity at perfusion pressures of 100, 150 and 250 mm Hg. The enhancement was due primarily to the recruitment of new fibers. In similar preparations, perfused at constant flow, propranolol increased sinus resistance in parallel with the increase in sinus discharge. These effects were rapidly dissipated by rinsing with drug-free perfusion solution. The evidence suggests that propranolol may produce a change in either the elastic or autoregulatory modalities of sinus smooth muscle. This may produce a functional "resetting" of the sinus and provide a mechanism to explain the antihypertensive effect of propranolol.

Action Potentials↗

[Relationships among the postnuclear band, chromatin and nuclear envelope of ram spermatids. Concept of a partial model to explain the displacements of the manchette].

After alkaline extraction, the postnuclear band appeared to be composed of two parts, the intranuclear part contiguous to the chromatin and the extranuclear part apposed to the external membrane of the nuclear envelope. This membrane was discontinuous inside the postnuclear band, revealing that the band might be a zone of nuclear envelope remodeling. A model is proposed to explain the pulling of the manchette by intranuclear forces and the formation of the redundant nuclear envelope during spermiogenesis.

Animals↗

The mathematics of repeat abortion: explaining the increase.

In any given population, an increase in the proportion of repeat abortions, and a repeat-abortion rate that is substantially higher than the first-abortion rate, can be anticipated to occur over a number of years after abortion has been legalized. These are the findings of an analysis of repeat abortion for a population of women aged 15--44, using simple mathematical models based on the assumptions that the risk of abortion is constant over time and independent of prior abortion experience. The data generated by the models explain both the rapidly increasing percentage and the high rate of repeat abortion following legalization and refute assertions that making abortion widely available discourages the practice of contraception.

Abortion, Induced↗

[Decrease in coronary heart disease mortality in 1974-1992 largely explainable by changes in cholesterol and smoking risk factors].

OBJECTIVE: To ascertain to what extent the dramatic decrease in coronary heart disease (CHD) mortality from 1972 to the present can be attributed to a change in risk factors. DESIGN: Descriptive study based on literature data. SETTING: The Netherlands. METHODS: Changes in four risk factors were assessed: a survey on trends in average systolic and diastolic blood pressure and serum cholesterol from three national screening projects, conducted 1974-1980, among 30,000 men and women aged 37-43 years, 1981-1986 among 80,000 men aged 33-37 years, and 1987-1992 among 42,000 men and women aged 20-59 years, and the percentage of smokers observed by the Foundation on Public Health and Smoking in yearly surveys among 20,000 people from the age of 15. Using a preventable proportion calculation, the effect on mortality was estimated of the observed changes in these risk factors, applying published relative risks and regression coefficients for these risk factors for men. The estimated curves were compared with the coronary mortality curves observed by the Netherlands Central Bureau of Statistics. RESULTS: From 1974 to 1992 a substantial decrease in the percentage of smokers and in men a moderate decrease in average serum cholesterol level were observed. Serum cholesterol decreased little in women. Changes in blood pressure were not consistent. The calculations predicted a 33% decrease in CHD mortality; the decrease actually observed was 48% for men aged 20-69 and 42% for women. CONCLUSION: It appears that by far the largest proportion of the decrease in CHD mortality can be explained by a decrease in the values of relevant risk factors (cholesterol and smoking) and only a small part by improved therapy.

Adolescent↗

Does the time course of bubble evolution explain decompression sickness risk?

A probabilistic model of decompression sickness (DCS) risk based on linear-exponential (LE) kinetics has given the best fit of the human air and nitrox DCS database. To test the hypothesis that its success may be due to the formation of a gas phase during decompression, we developed a physiologically based bubble evolution model using a numerical solution of a partial differential equation system. Because of the computational intensity of this method, it could not be used to fully explore our hypothesis. Consequently, we compared the solution with that of a computationally simpler approximation that was previously published by Van Liew and found the two approaches gave similar results. Using the simpler model, assuming bubble densities of 1 and 1,000 bubbles/cm3, we found a tissue time constant of at least 80 min (equivalent to perfusion of 1/80 ml.g-1.min-1) was required to achieve a delay in bubble dissolution comparable to the prolonged risk of DCS predicted by the LE model. We suggest that the persistence of single bubbles in a uniformly perfused homogeneous tissue alone is unlikely to explain persistent DCS risk.

Blood Flow Velocity↗

Allelic differences in the VHOx-1 gene explain the absence of a B cell clonal dominance in the primary response of C57BL/6 mice to phthalate.

A highly conserved Id (CRIXmp-1) associated with the murine (BALB/c) humoral immune response to the hapten phthalate (Xmp) is conspicuously absent in C57BL/6 mice. The absence of this Id in C57BL/6 mice is shown here to be due to the absence of the appropriate VH gene (VHOx-1) usage in the Xmp response. To determine whether the failure to utilize this VH was due to an active suppression or to the lack of the requisite VH gene in the available repertoire, VHOx-1 gene-specific primers were used to amplify the germ-line VHOx-1 gene from genomic DNA from BALB/c and C57BL/6 mice. The germ-line coding sequence of the C57BL/6 allele of the VHOx-1 gene is 99% similar to the germ-line coding sequence of the BALB/c allele. Amplification of cDNA made from splenic RNA from C57BL/6 mice confirmed that this gene is expressed. There are four nucleotide differences that lead to three amino acid changes in the predicted protein sequence. Each change is either in or immediately adjacent to a complementarity-determining region (CDR). Two of these changes are unique to the C57BL/6 allele and are not shared with CRIXmp-1-expressing strains. These two changes are predicted to alter the Xmp binding capabilities of the C57BL/6 allelic form of this VH gene, thereby explaining the absence of the Xmp-1 clonotype, which is dominant in the primary Xmp immune response of most other strains of mice.

Alleles↗

Theories explaining racial differences in the utilization of diagnostic and therapeutic procedures for cerebrovascular disease.

Despite a higher risk of stroke, blacks are less likely than whites to receive the invasive procedures that are used to diagnose and treat cerebrovascular disease, particularly carotid endarterectomy. Explanations for the lower rate of procedural use include racial bias, racial differences in pathophysiology of cerebrovascular disease, affordability, and racial variation in patient decisions regarding care. Studies consistently indicate that blacks are less likely to have severe atherosclerotic lesions of the carotid arteries, reducing their likelihood of being appropriate candidates for carotid endarterectomy. Although ability to pay does not explain the observed variation in use of carotid endarterectomy, it may influence the evaluation process prior to hospitalization. A racial difference in patients' decisions about health care for cerebrovascular disease has never been investigated; it should be a topic of future studies.

Black or African American↗

New urodynamic model to explain micturition disorders in benign prostatic hyperplasia patients. Pressure-flow relationships in collapsable tubes, hydraulic analysis of the urethra and evaluation of urethral resistance.

How can the hydrodynamic disorders caused by benign prostatic hyperplasia (BPH) be explained? And how can they be measured in order to assess the efficiency of treatment? To answer these questions, a model based on the results of experiments performed in collapsable tubes and on a hydraulic analysis of the urethra is elaborated. A BPH combining hypertonia and/or hypertrophy, essentially leads to a rise in the opening pressure which increases bladder work before micturition, as well as a reduction in the functional caliber of the prostatic urethra. Whatever its origin, this reduction in caliber is the only explanation for the importance of the urethral resistance increase noticed in cases of BPH. Instantaneous resistance calculation, based on the pressure/maximum flow rate relationship, measured when the flow is steady (for a few seconds), would be a good experimental physical parameter. However, on a clinical basis, an exact calculation is impossible, which makes its precision and reliability not as good as they should be. In order to calculate the resistance to micturition as a whole, particularly taking into account the difficulty in urethral opening, it was suggested to include the opening pressure in the pressure/flow study. But this fits neither with fluid mechanics data nor with the results of experiments carried out in collapsable tubes. Eventually, considering that no evaluation method of the resistance to urinary flow is acknowledged to be accurate on a hydraulic basis or urodynamically applicable, one wonders whether placing more confidence in simple data obtained in a noninvasive way, and used without mathematical tricks, is not preferable.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗

Explaining trends in health insurance coverage between 1988 and 1991.

This paper uses regression-based decompositions to examine the downward trend in insurance coverage between 1988 and 1991. I find that falling family incomes account for much of the decline in overall insurance coverage, while a secular decline in insurance coverage across all industries, firm sizes, employment statuses, income levels, and demographic groups accounts for most of the decline in employer-sponsored insurance among workers. Rising unemployment and changing patterns of industrial employment explain little of the decline in coverage across the entire population. Taken together, these results suggest that fewer employers are offering health coverage, workers are finding it difficult to pay their share of the premiums, and those without access to employer-sponsored plans are finding it harder to purchase nongroup insurance. Thus, it appears that the rising cost of health insurance coupled with falling incomes and profits during the recession account for the fall in health insurance coverage between 1988 and 1991.

Family↗

Coordinated hydrolysis explains the mechanical behavior of kinesin.

The two-headed motor protein kinesin hydrolyzes nucleotide to move unidirectionally along its microtubule track at speeds up to 1000 nm/s (Saxton et al., 1988) and develops forces in excess of 5 pN (Hunt et al., 1994; Svoboda et al., 1994a). Individual kinesin molecules have been studied recently in vitro, and their behavior has been characterized in terms of force-velocity curves and variance measurements (Svoboda and Block, 1994a; Svoboda et al., 1994b). We present a model for force generation in kinesin in which the ATP hydrolysis reactions are coordinated with the relative positions of the two heads. The model explains the experimental data and permits us to study the relative roles of Brownian motion and elastic deformation in the motor mechanism of kinesin.

Animals↗

Favorable prognosis of hyperdiploid common acute lymphoblastic leukemia may be explained by sensitivity to antimetabolites and other drugs: results of an in vitro study.

DNA hyperdiploidy is a favorable prognostic factor in childhood acute lymphoblastic leukemia (ALL). The explanation for this prognostic significance is largely unknown. We have studied whether DNA ploidy was related to cellular resistance to 12 drugs, assessed with the methyl-thiazol-tetrazolium assay, in samples of 74 children with common (CD10+ precursor B-cell) ALL. Sixteen patients had hyperdiploid ALL cells and 58 patients had nonhyperdiploid ALL cells. Hyperdiploid ALL cells were more sensitive to mercaptopurine (median, 9.0-fold; P = .000003), to thioguanine (1.4-fold; P = .023), to cytarabine (1.8-fold; P = .016), and to I-asparaginase (19.5-fold; P = .022) than were nonhyperdiploid ALL cells. In contrast, these two ploidy groups did not differ significantly in resistance to prednisolone, dexamethasone, vincristine, vindesine, daunorubicin, doxorubicin, mitoxantrone, and teniposide. The percentage of S-phase cells was higher (P = .05) in the hyperdiploid ALL samples (median, 8.5%) than in the nonhyperdiploid ALL samples (median, 5.7%). However, the percentage of cells in S-phase was not significantly related to in vitro drug resistance. We conclude that the favorable prognosis associated with DNA hyperdiploidy in childhood common ALL may be explained by a relative sensitivity of hyperdiploid common ALL cells to antimetabolites, especially to mercaptopurine and to I-asparaginase.

Adolescent↗

[Does intake of antihypertensive agents and sedatives explain the increasing incidence of colonic neoplasms?].

Not much attention has been given to drug use and risk of colorectal cancer. We investigated the issue in an 18-year prospective cohort study of 5249 Copenhagen males aged 40-59 years. Potential confounders included were tobacco smoking, alcohol consumption, coffee drinking, physical activity, and social class. Colon cancer was diagnosed in 51 men, rectal cancer in 42 (all adenocarcinomas). Estimated from a Cox proportional hazards regression equation, use of antihypertensive medicine was highly significantly associated with risk of colon cancer, relative risk (95% confidence limits) was 3.5 (1.6-7.5), p = 0.001. Frequent use of minor tranquillizers or sleeping pills was also associated with a highly significantly increased risk of colon cancer, relative risk was 3.2 (1.6-6.6), p = 0.002. By contrast, there was no such association with rectum cancer. We suggest that use of antihypertensive medicine and use of minor tranquillizers or sleeping pills may be strong risk factors for colon cancer, and that their use may contribute substantially to explaining the increased incidence of colon cancer since 1945.

Adenocarcinoma↗

Location of CD4 dimerization site explains critical role of CDR3-like region in HIV-1 infection and T-cell activation and implies a model for complex of coreceptor-MHC.

CD4 cross-linking by antibodies or its natural ligands triggers a tyrosine kinase activity that is one of the necessary steps in the mechanism of human immunodeficiency virus type 1 (HIV-1)-induced syncytium formation and full Th-cell activation. In this study we mapped a part of the dimerization site of human CD4 to amino acids 87-98 using a bivalent CD4 immunoadhesin and a series of overlapping 12-mer peptides of the D1 domain. The dimerization site we found is part of the complementary determining region (CDR) 3-like region of CD4. Using the three-dimensional structure of other immunoglobulin dimers as a basis, a molecular modeling study was performed to dimerize the D1 domains of CD4. Both the peptide binding studies and molecular modeling studies independently led to the conclusion that the CDR3-like region is part of the CD4 dimerization site. The suggested dimerization of CD4 through its CDR3-like region explains the important role that has been ascribed to this region in Th-cell activation and HIV-1-mediated fusion. Based on this model of the CD4 dimer and published results of different mutational analysis studies, a model was proposed for the complex of the CD4 dimer with two MHC-II molecules. The CD4 dimer allows tight binding to a large surface of MHC-II and the complex of CD4 and MHC-II reconciles mutational analysis studies that were previously incompatible. Moreover, the complex suggests how CD4 can dimerize through ligand binding.

Amino Acid Sequence↗

A new consistent model explaining structure (conformation)-activity relationships of opiates with mu-selectivity.

Several different classes of opiates such as PET (7-alpha-(1-Hydroxy-1-methyl-3-phenylpropyl)-6,14-endo-ethenotetra - hydronorthebaine), phenazocine, fentanyl, carfentanil, ohmefentanyl, prodine derivatives, methadone and etonitazene have been investigated using the molecular modelling program package SYBYL and the TRIPOS empirical force field. Comparison of the energetically optimized structures and their corresponding molecular electrostatic potentials was used for the development of a new model of conformation-activity relationships of mu-selective opiates. We considered six important spatial positions of these molecules which were assumed to be directly implicated in the interaction with the opiate receptor. We found that these opiates may bind to the receptor with their protonated nitrogen atom assuming one or the other of two different orientations. The obtained results offer new insights into important receptor interactions and the diverse opiate activities of all the compounds examined can be explained in a unified manner. For example, the most active ohmefentanyl stereo-isomer was predicted on the basis of the proposed model.

Analgesics↗