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PubMed1991

Prognostic modeling of clinical outcomes: an illustration with data from patients with membranous nephropathy.

Probabilities that a patient will occupy any of five clinically defined compartments at different future times are generated and graphed by a personal computer. The probabilities are functions of a patient's relevant baseline characteristics (treated or control group), clinical status, and follow-up time at which the prognosis is made. The illustrative prognostic model is based on a reanalysis of detailed individual records for 81 patients with idiopathic membranous nephropathy (42 treated with methylprednisolone and chlorambucil; 39 controls) in a randomized clinical trial. The compartments to and from which patients may pass are identified as (1) complete remission, (2) partial remission, (3) the nephrotic syndrome, (4) renal failure, and (5) death. Estimated risk functions for transitions between compartments involve baseline treatment, and intermediate and temporal variables, together with their relevant interactions. The model illustrates how, despite the overall advantage of treated over control patients, the comparative prognoses can change greatly and can even sometimes be reversed, depending on a variety of follow-up experiences.

Computer Simulation↗

PubMed1990

Serine proteinase requirement for the extra-cellular metabolism of pulmonary surfactant.

Pulmonary surfactant as lavaged from the alveoli exists in at least three structural subtypes, lamellar body-like, tubular myelin and vesicular forms that can be separated on the basis of their buoyant densities. Previous studies have suggested that surfactant is secreted in the lamellar body form and metabolized through the other subtypes in sequence. This metabolic sequence can be reproduced in vitro by cyclic expansion and contraction ('cycling') of the surface area of nascent surfactant at 38 degrees C. Cycling of nascent secretion, which is predominantly of lamellar body-like buoyant density, rapidly converted it to the buoyant density of tubular myelin and then to that of the vesicular subtype. We examined the role of proteinases in the conversion of nascent surfactant subtypes in vitro. Addition of metallo-, cysteine- and acid-proteinase inhibitors to the cycling mix did not inhibit the conversion of tubular myelin to vesicular subtype. However, a variety of serine proteinase inhibitors inhibited the formation of vesicular subtype. Their inhibitory effect was dose-related and most marked for alpha 1-antitrypsin where a concentration equal to that found in the alveolar fluid lining layer resulted in 50% inhibition of the generation of light subtype, suggesting physiological relevance. The enzyme(s) responsible for promoting the generation of light subtype was sedimentable and therefore presumably in particulate form. By differential centrifugation of lung secretions it was separable from alveolar macrophages and partially separable from surfactant itself. It has not been identified, nor has its substrate. We conclude that in vitro cycling provides a model for the study of alveolar surfactant metabolism and that the conversion of tubular myelin to vesicular forms of surfactant requires serine proteinase activity.

Animals↗

PubMed1979

A stochastic compartment model of stomach cancer with correlated waiting time distributions.

The incidence and growth rate of stomach cancer in the US population is modelled, for each sex, as a partially observed, discrete state stochastic process. Explicit evaluation of the transition rates between the states of the model is made possible by identifying them as specific functions of the time spent within each state. The functions used in the model were selected from the medical and epidemiological literature. With the model it was found possible to obtain fits to the age distribution of deaths due to stomach cancer for white males in 1975 and for selected age ranges for white females. These results suggested that the natural history of stomach cancer is different for females above and below age 65.

Adult↗

PubMed1991

Additive and multiplicative relative risk in the two-stage clonal expansion model of carcinogenesis.

The effects of exposure to two carcinogens are explored within the context of the two-stage clonal expansion model of carcinogenesis. This biologically based model provides a useful framework for the quantitative description of carcinogenesis, and for defining carcinogenic agents that act as initiators, promoters, and completers. This paper addresses the combined effects of simultaneous lifetime exposure to two carcinogens as well as nonoverlapping partial lifetime exposure to each agent. Whereas the age-specific relative risk for exposure to two initiators or two completers is additive, a multiplicative relative risk model holds for exposure to an initiator and a completer, or to a promoter and a completer. Exposure to two promoters yields supra-multiplicative relative risk. Exposure to an initiator and promoter leads to multiplicative and supra-multiplicative relative risks for simultaneous lifetime and nonoverlapping partial lifetime exposures, respectively. Although departures from the additive relative risk model may thus occur at moderate to high doses, conditions are identified under which additivity will provide a good approximation to the joint risk at low doses. The methods of analysis used in this paper can also be used to determine the joint effects of exposure to two carcinogens which may affect more than one stage (initiation, promotion, completion) of the process of carcinogenesis. In general, the joint effects of exposure to such agents depends on the relative magnitude of the effects on individual stages.

Animals↗

PubMed1994

Premature strand transfer by the HIV-1 reverse transcriptase during strong-stop DNA synthesis.

Reverse transcription of retroviral genomes starts near the 5' end of the viral RNA by use of an associated tRNA primer. According to the current model of reverse transcription, the initial cDNA product, termed minus-strand strong-stop DNA, 'jumps' to a repeated sequence (R region) at the 3' end of the RNA template. The human retroviruses have relatively long R regions (97-247 nucleotides) when compared to murine and avian viruses (16-68 nucleotides). This suggests that the full complement of the R region is not required for strand transfer and that partial cDNA copies of the 5' R can prematurely jump to the 3' R. To test this hypothesis, we generated mutants of the human immunodeficiency virus with R region changes and analyzed whether 5' or 3' R sequences were inherited by the progeny. We found that in most cases, 5' R-encoded sequences are dominant, which is consistent with the model of reverse transcription. Using a selection protocol, however, we were also able to identify progeny viruses with R sequences derived from the original 3' R element. These results suggest that partial strong stop cDNAs can be transferred with R region homologies much shorter than 97 nucleotides.

Base Sequence↗

PubMed1983

Identification of a trans-acting regulatory factor involved in the control of the pyrimidine pathway in E. coli.

A pyrimidine auxotroph of Escherichia coli was isolated which contained a defect in its ability to synthesize both oroate phosphoribosyl transferase, the product of the gene pyrE, and orotidine monophosphate decarboxylase, product of the gene pyrF. A single location on the E. coli linkage map was found to be responsible for the loss of both enzyme activities. This gene was located near cysE at 80.55 min by a combination of Hfr crosses and P1 transductions. The pyrimidine requirement was also corrected by episome F'140 which was found not to carry any pyrimidine structural genes. These data confirm the existence of a new gene, pyrS, unlinked to any previously mapped pyrimidine structural gene, responsible for partial control of pyrimidine biosynthesis. A spontaneous revertant of the mutant strain was also identified which displayed constitutive levels of aspartate transcarbamylase, dihydroorotase, dihydroorotate dehydrogenase, orotidine monophosphate decarboxylase, and limited levels of orotate phosphoribosyl transferase. A model is proposed in which the pyrS gene product is an activator protein, necessary for the transcription of the pyrE and pyrF genes. This activator protein is nonfunctional in the original mutant strain, and partially functional in the revertant strain. The data presented here cannot rule out an alternative mechanism involving a repressor.

Escherichia coli↗

PubMed1996

Identification of symptomatologic patterns common to major psychoses: proposal for a phenotype definition.

Our study was designed to identify the underlying symptomatologic structure common to major psychoses as a preliminary step for a phenotype definition. We investigated 1,004 inpatients affected by mood disorders or the schizophrenia spectrum (DSM-III-R) using the OPCRIT checklist (operational criteria checklist for psychotic illness). Symptomatologic structure was extracted by factor analytic techniques and factor scores were first obtained on 500 subjects. A CFA (confirmatory factor analysis) was then conducted on the remaining 504 subjects to evaluate fitness of the model. We identified four factors: excitement, depression, disorganization, and delusion. These factors accounted for 54.6% of the total variance of the OPCRIT checklist symptomatologic subset of 38 items. CFA indices showed a good fit for the model. We identified symptomatologic structures common to major psychoses. The factors identified were confirmed in an independent sample. Two of these symptomatologic structures are partially overlapping with categorical diagnoses (excitement and depression), and two constitute independent psychopathologic traits (delusion and disorganization). The use of "factor-derived scores" in genetic research may add a dimensional definition to the diagnostic subdivision of major psychoses.

Adult↗

PubMed1996

The experiential facilitation of memory development in the home environment.

Relationships among young children's home experiences, their memory knowledge, and their memory-task performance were examined. The participants were 78 children in 2nd and 3rd grades and their families. The children were administered 2 study-recall memory tasks and a memory-knowledge questionnaire. Home experiences were assessed with data gathered during a home visit and from a parents' self-report questionnaire. Specific home experiences that relate to the development of memory knowledge and memory-task performance were identified. Regression analyses supported a hypothesized theoretical model in which the influence of home experiences on memory-task performance is, at least partially, a function of the relationship between parents' requirements for self-regulation and self-responsibility and the development of children's knowledge about memory requirements and memory strategies.

Child↗

PubMed1987

Operating characteristics of the male hypothalamo-pituitary-gonadal axis: pulsatile release of testosterone and follicle-stimulating hormone and their temporal coupling with luteinizing hormone.

To appraise the physiological pattern(s) of episodic testosterone and FSH release in man, we withdrew blood samples at 10-min intervals for 24-36 h in a total of 15 normal men. We subjected the resulting FSH (15 men) and testosterone (5 men) time series to 3 statistically based and mathematically independent procedures for detecting hormone pulsatility, viz. Cluster analysis, the Detect program, and Fourier transformation. The Cluster technique disclosed discrete testosterone and FSH peaks occurring at mean (+/- SEM) interpulse intervals of 112 +/- 14 and 85 +/- 3.4 min, respectively. These values were not significantly different from the mean LH interpulse interval of 95 +/- 11 min. The average durations of the testosterone and FSH pulsations were 90 +/- 11 and 59 +/- 3 min, respectively. The mean testosterone pulse amplitude reached a maximal value of 910 +/- 92 ng/dL (31.5 +/- 3.2 nmol/L), which represented a mean increase of 242 +/- 26 ng/dL (8.4 +/- 0.9 nmol/L) above the preceding nadir. FSH pulses had a maximum of 7.2 +/- 0.3 IU/L, and an incremental amplitude of 1.3 +/- 0.1 IU/L. An independent pulse detection procedure. Detect, yielded a testosterone pulse frequency of 12.3 +/- 0.8 pulses/day [P = NS vs. Cluster program (13 +/- 1.9 pulses/day)]. The Cluster and Detect estimates of FSH pulse frequency were also similar, viz. 16 +/- 1.9 and 16 +/- 0.6 pulses/day. Further analysis by Fourier transformation revealed significant circadian periodicities for serum testosterone, FSH, and LH, which had mean nyctohemeral amplitudes of 185 ng/dL (6.4 nmol/L), 0.38 IU/L, and 1.3 IU/L, respectively. Cross-correlation analyses disclosed significantly positive uncorrected cross-correlations between LH and testosterone that were maximal at a testosterone lag of 60 min (range, 50-70 min). To eliminate high intrinsic autocorrelations within the testosterone and LH time series, stepwise autoregressive fitting was employed. The resulting partial cross-correlation matrices indicated that LH concentrations at any given instant were significantly positively correlated to testosterone concentrations lagged by 10 and 20 min. Similarly, contemporaneous LH and FSH concentrations were significantly positively correlated (r = 0.40-0.89; P less than 0.001). Moreover, autoregressive modeling disclosed significantly positive partial cross-correlations between LH and FSH at a FSH lag of 10 min. In summary, we have identified significant pulsatile as well as circadian (24-h) patterns of testosterone and FSH release in normal men.(ABSTRACT TRUNCATED AT 400 WORDS)

Activity Cycles↗

PubMed1985

Rate sensitivity of blood pressure to hypoxia.

A biochemical kinetic model is used to describe changes in mean arterial blood pressure in dogs to three different rates of fall of arterial partial pressure of oxygen. The model is a linear loop with one variable rate coefficient (parametric control) which has been previously shown to characterize the rate sensitivity to presented stimuli. A three component model was identified under a least squares criterion and it showed that a unique (stimulation independent) representation can be obtained which can serve as a conceptual framework for the study of this phenomenon.

Animals↗

PubMed1996

Peroxidase-catalyzed generation of catechin oligomers that inhibit glucosyltransferase from Streptococcus sobrinus.

Oolong tea extract (OTE) and the purified polymeric polyphenols from OTE have been found to inhibit glucosyltransferase (GTase) of mutans streptococci. In view of the partial fermentation characteristic of oolong tea, we describe here an in vitro model reaction system to produce partially fermented products of D-(+)-catechin or green tea extract (GTE) using horseradish peroxidase. A dimeric catechin molecule was identified as dehydro-dicatechin A by instrumental analyses. The molecular size of some oligomeric catechins was estimated by the elution profile with HPLC. These catechin oligomers markedly inhibited GTase from Streptococcus sobrinus 6715. As the degree of polymerization of catechin or GTE increased, GTase was inhibited more effectively. These results suggest that polymeric polyphenols found in OTE are synthesized by partial fermentation due to oxidases/peroxidases present in tea leaves.

Bacterial Adhesion↗

PubMed1989

A dynamic model for the structure of acyl carrier protein in solution.

The determination of solution structures of proteins using two-dimensional NMR data is commonly based on the assumption that the structure can be represented by a single rigid conformer. We present here a procedure whereby this assumption can be relaxed and illustrate its application to acyl carrier protein from Escherichia coli, a small negatively charged protein with no internal disulfide bonds. The methodology rests on a model having two distinct conformers in dynamic equilibrium. Use of this two-state model results in a dramatic improvement in fit to cross-relaxation-derived distance constraints and a substantial lowering of molecular mechanics energies for individual conformers of acyl carrier protein. The two-state model retains the three-helix motif previously identified on the basis of a one-state structure, but substantial motion of loop regions and the C-terminal peptide, as well as partial disruption of the second helix, is suggested to occur. Support for the existence of these motions can be found in amide exchange rate and spin relaxation time data.

Acyl Carrier Protein↗

PubMed1978

Autoimmunity in multiple slcerosis: do we have an experimental model?

Experimental autoimmunity of the CNS has been well characterized--the antigen has been identified, effector cell specificity has been defined, and the relationship between cellular sensitization and antibody production has been partially clarified. In the guinea pig, experimental allergic encephalomyelitis (EAE) is induced by one injection of myelin basic protein in complete Freund's adjuvant (BP/CFA). If BP/CFA is preceded by repeated injections of basic protein in incomplete Freund's adjuvant (BP/IFA), EAE is not induced; the guinea pigs survive and ultimately produce antibody. Induction and prevention of EAE as well as antibody induction by this schedule are dependent on the presence of the intact encephalitogenic (T-cell) site in the polypeptide used for sensitization and preimmunization. In contrast, B cell sites (those peptide sequences which bind antibody) are independent of the T-cell site. At least 5 specific antigenic regions (B-cell sites) have been demonstrated in the BP molecule. High mycobacteria levels bypass the specificity requirement of helper T-cells but cannot bypass the specificity requirement of effector T-cells. In spite of the sophisticated immunologic techniques available, our knowledge of humoral and cellular sensitivity in multiple sclerosis (MS) patients is very limited. The experimental demonstration of an analogy between EAE and MS is weak: a) Demonstration of BP-sensitized cells or BP-specific antibodies in peripheral blood of MS patients has not been successful. b) Anti-myelin serum factors reported to be associated with both disease states (experimental autoimmunity and MS) are clearly not identical. Nevertheless, successful treatment of EAE in animals by BP/IFA injections has encouraged consideration of clinical trials to test the therapeutic value of BP injections in MS patients. If successful, the question will be answered: if unsuccessful, the dilemma still remains.

Adjuvants, Immunologic↗

PubMed1991

Patient intensity for nursing index: the measurement model.

One part of the psychometric evaluation of the Patient Intensity for Nursing Index (PINI), a new measure of nursing intensity, is reported. The PINI has four interrelated components: (a) severity of illness, (b) dependency, (c) complexity of care, and (d) time. Taken together, the 10 items that make up these four components comprise the multidimensional construct of nursing intensity. Using the factor analytic approach and a model specification search, the measurement model for the Patient Intensity for Nursing Index was identified. The structure consists of Dependency, Severity, and Complexity with time (hours of nursing care) loading on each factor. When results were cross-validated using data from four other hospitals, support emerged for a consistent pattern of factor loadings. The loadings themselves, however, are only partially invariant. Further examination of the relationship between severity and time is suggested and areas for future research are identified.

Dependency, Psychological↗

PubMed2026

PLayer-FL: A Principled Approach to Personalized Layer-wise Cross-Silo Federated Learning.

Non-identically distributed data is a major challenge in Federated Learning (FL). Personalized FL tackles this by balancing local model adaptation with global model consistency. One variant, partial FL, leverages the observation that early layers learn more transferable features by federating only early layers. However, current partial FL approaches use predetermined, architecture-specific rules to select layers, limiting their applicability. We introduce Principled Layer-wise-FL (PLayer-FL), which uses a novel federation sensitivity metric to identify layers that benefit from federation. This metric, inspired by model pruning, quantifies each layer's contribution to cross-client generalization after the first training epoch, identifying a transition point in the network where the benefits of federation diminish. We first demonstrate that our federation sensitivity metric shows strong correlation with established generalization measures across diverse architectures. Next, we show that PLayer-FL outperforms existing FL algorithms on a range of tasks, also achieving more uniform performance improvements across clients.

Journal Article↗

PubMed1991

An outcomes model of medical decision making.

In the traditional 'fix-it' model of medical decision making, the identified problem is typically characterized by a diagnosis that indicates a deviation from normalcy. When a medical problem is multifaceted and the available interventions are only partially effective, a broader vision of the health care endeavor is needed. What matters to the patient, and what should matter to the practitioner, is the patient's future possibilities. More specifically, what is important is the character of the alternative futures that the patient could have and choosing among them so as to achieve the best future possible, with the ranking of outcomes determined by the patient's preferences. This paper describes the fix-it model, presents and defends the outcomes-based model, and demonstrates that the latter is useful in developing normative conceptions of informed consent and decision making and in establishing a basis for societal involvement in the decision making process. Finally, several shortcomings of the model will be acknowledged.

Attitude of Health Personnel↗

PubMed1994

Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma.

BACKGROUND: This report presents the results of a prospective multi-institutional study of intrapleural treatment with gamma-interferon in patients with Butchart's Stages I and II epithelial or mixed malignant pleural mesothelioma. METHODS: Interferon was administered at a dose of 40 million units twice a week for 8 weeks intrapleurally via a catheter or an implantable port. Thoracoscopic or surgical biopsy was performed if computed tomography scan 2 weeks after the end of treatment demonstrated a reduction in tumor size. Survival was calculated after a follow-up of at least 18 months. Prognostic factors were identified by univariate and multivariate analyses (Cox model). RESULTS: Eighty-nine patients were included over 46 months. Eight histologically confirmed complete responses and nine partial responses with at least a 50% reduction in tumor size were obtained. The overall response rate was 20%. Most responses were achieved in patients with early stage disease. The response rate for patients with Stage I disease was 45%. Tolerance of interferon was good. Treatment was performed on an outpatient basis. The main side effects were hyperthermia, liver toxicity, neutropenia, and catheter-related infection. CONCLUSIONS: Gamma-interferon is effective mainly in Stage I mesothelioma, especially if the tumor is confined to the parietal or diaphragmatic pleura (Stage IA).

Aged↗

PubMed1989

Characterisation and partial purification of a novel prohormone processing enzyme from ovine adrenal medulla.

An enzymatic activity has been identified which is capable of generating a product chromatographically identical with adrenorphin from the model substrate BAM12P. This enzyme was purified by gel filtration and ion-exchange chromatography and characterised as having a molecular mass between 30 and 45 kDa and an acidic pI. The enzyme is active at the acid pH expected in the secretory vesicle interior and is inhibited by EDTA, suggesting that it is a metalloprotease. This activity could not be mimicked by incubation with lysosomal fractions and it meets the criteria to be considered as a possible prohormone processing enzyme.

Adrenal Medulla↗