Defining vitamin D status using multi-metabolite mathematical modelling: A pregnancy perspective.

Vitamin D deficiency is linked to adverse pregnancy outcomes such as pre-eclampsia (PET) but remains defined by serum measurement of 25-hydroxyvitamin D3 (25(OH)D3) alone. To identify broader changes in vitamin D metabolism during normal and PET pregnancies we developed a relatively simple but fully parametrised mathematical model of the vitamin D metabolic pathway. The data used for parametrisation were serum vitamin D metabolites analysed for a cross-sectional group of women (n = 88); including normal pregnant women at 1 st (NP1, n = 25) and 3rd trimester (NP3, n = 21) and pregnant women with PET (n = 22), as well as non-pregnant female controls (n = 20). To account for the effects various metabolites have upon each other, data were analysed using an ordinary differential equation model of the vitamin D reaction network. Information obtained from the model was then also applied to serum vitamin D metabolome data (n = 50) obtained from a 2nd trimester pregnancy cohort, of which 25 prospectively developed PET. Statistical analysis of the data alone showed no significant difference between NP3 and PET for serum 25(OH)D3 and 24,25(OH)2D3 concentrations. Conversely, a statistical analysis informed by the reaction network model revealed that a better indicator of PET is the ratios of vitamin D metabolites in late pregnancy. Assessing the potential predicative value, no significant difference between NP3 and PET cases at 15 weeks gestation was found. Mathematical modelling offers a novel strategy for defining the impact of vitamin D metabolism on human health. This is particularly relevant within the context of pregnancy, where major changes in vitamin D metabolism occur across gestation, and dysregulated metabolism is evidenced in women with established PET.

Prospective and descriptive study of adult dengue cases in an emergency department, in Martinique.

OBJECTIVE: Knowing about the clinical aspects of dengue in endemic zones is essential to implementation of appropriate case management protocols and public health interventions. PATIENTS AND METHODS: The authors made a 4-year prospective, observational study of dengue-infected patients admitted to the emergency department of the Fort-de-France University Hospital. RESULTS: Two hundred and sixty-three male and 297 female patients were included. The median age was 37 years (range: 14-91). The diagnosis was based on a positive RT-PCR (463 patients) or on the presence of specific IgM (97 patients). Two hundred and seventy-seven patients (49.5%) presented with dengue fever without complications. According to WHO criteria, 95 patients (17%) developed plasma leakage, including 39 patients (7%) diagnosed with DHF, and 10 (1.8%) diagnosed with DSS. Among the other patients without plasma leakage, 84 (15%) had isolated thrombocytopenia, 14 (2.5%) had internal bleeding, and 90 (16%) had unusual manifestations. Seven patients died (1.3%): fulminant hepatitis (two), myocarditis (one), encephalitis (one), acute respiratory failure (one), gangrenous cholecystitis (one), and post-traumatic intracranial hemorrhage (one). The other patients recovered. Seven patients were pregnant (1.3%) from 6 to 27 weeks of amenorrhea and carried their pregnancy to term without complications. CONCLUSION: With this experience, we were able to develop appropriate case management protocols for patients during dengue epidemics.

[Indications for brain scan in patients presenting benign cranial injury]. / Indications du scanner cérébral chez les patients présentant un traumatisme crânien bénin.

OBJECTIVE: Validate the clinical criteria, which, when absent, would make it safe to bypass CT scan examination in mild cranial injuries. MATERIAL: and methods. Prospective study including 285 patients with mild cranial injury with a Glasgow score of 15, a normal clinical examination but transitory loss of consciousness or suspected transitory loss of consciousness. The following clinical parameters were systematically reviewed: history of stroke; post-injury headache; post-injury vomiting; alcohol, medication, or drug intoxication; clinical signs of cervico-cranio-facial injury; post-injury convulsions; or coagulation impairment. Systematic CT exploration looked for cranial, encephalic, and facial lesions and individualized the lesions requiring neurosurgical or maxillofacial treatment. RESULTS: Of the patients studied, 7% presented a cranioencephalic lesion and 7% a facial bone lesion. Neurosurgical intervention was necessary in 0.4% of the patients and maxillofacial surgery in 2.5%. Patients with a positive CT all had at least one clinical risk factor and patients with cranioencephalic lesions had at least two risk factors present. Had patients with no risk factors not been scanned, 15% of the patients would not have had the CT procedure. CONCLUSION: Selecting CT indications in cases of mild cranial injury with loss of consciousness using a simple and validated evaluation can save 15% of CT procedures without missing any cranial, encephalic, or facial lesions.

DNA dinucleotide evolution in humans: fitting theory to facts.

We examine length distributions of approximately 6000 human dinucleotide microsatellite loci, representing chromosomes 1-22, from the GDB database. Under the stepwise mutation model, results from theory and simulation are compared with the empirical data. In both constant and expanding population scenarios, a simple single-step model with parameters chosen to account for the observed variance of microsatellite lengths produces results inconsistent with the observed heterozygosity and the dispersion of length skewness. Complicating the model by allowing a variable mutation rate accounts for the homozygosity, and introducing a small probability of a large mutation step accounts for the dispersion in skewnesses. We discuss these results in light of the long-term evolution of microsatellites.

A power analysis of microsatellite-based statistics for inferring past population growth.

We present results concerning the power to detect past population growth using three microsatellite-based statistics available in the current literature: (1) that based on between-locus variability, (2) that based on the shape of allele size distribution, and (3) that based on the imbalance between variance and heterozygosity at a locus. The analysis is based on the single-step stepwise mutation model. The power of the statistics is evaluated for constant, as well as variable, mutation rates across loci. The latter case is important, since it is a standard procedure to pool data collected at a number of loci, and mutation rates at microsatellite loci are known to be different. Our analysis indicates that the statistic based on the imbalance between allele size variance and heterozygosity at a locus has the highest power for detection of population growth, particularly when mutation rates vary across loci.

Signatures of population expansion in microsatellite repeat data.

To examine the signature of population expansion on genetic variability at microsatellite loci, we consider a population that evolves according to the time-continuous Moran model, with growing population size and mutations that follow a general asymmetric stepwise mutation model. We present calculations of expected allele-size variance and homozygosity at a locus in such a model for several variants of growth, including stepwise, exponential, and logistic growth. These calculations in particular prove that population bottleneck followed by growth in size causes an imbalance between allele size variance and heterozygosity, characterized by the variance being transiently higher than expected under equilibrium conditions. This effect is, in a sense, analogous to that demonstrated before for the infinite allele model, where the number of alleles transiently increases after a stepwise growth of population. We analyze a set of data on tetranucleotide repeats that reveals the imbalance expected under the assumption of bottleneck followed by population growth in two out of three major racial groups. The imbalance is strongest in Asians, intermediate in Europeans, and absent in Africans. This finding is consistent with previous findings by others concerning the population expansion of modern humans, with the bottleneck event being most ancient in Africans, most recent in Asians, and intermediate in Europeans. Nevertheless, the imbalance index alone cannot reliably estimate the time of initiation of population expansion.

Legal issues affecting IPA formation.

Independent practice associations (IPAs) and similar organizations are forming more rapidly as the healthcare industry evolves. The formation of IPAs, however, raises a number of legal issues that must be addressed and resolved, issues related to licensure and choice of entity, antitrust, self-referral, insurance regulations, and liability.

Evolution of SACRED (staff authority credentialing): an automated credentialing system.

Over a period of 5 years, the medical record department (MRD) at the Warren G. Magnuson Clinical Center of the National Institutes of Health developed and refined a customized medical staff credentialing system. The result is SACRED, an automated credentialing system that supports the changing requirements of the credentialing process and continues to meet the needs of its customers. Using a reiterative approach to development and application of the concept of controlled manageable growth, the system can be maintained by the MRD and is adaptable to change without requiring reinvention or replacement of its basic structure, process, or equipment.

A novel semiautomated method for the estimation of free fatty acid in serum or plasma.

A modification of the semiautomated assay method of Antonis (1965. J. Lipid Res. 6:307-312) for free fatty acid is presented. Free fatty acids are extracted from serum or plasma into di-n-butyl ether-2-methoxyethanol; the extract is almost free from phospholipids. The acids are analyzed in a portion of extract by a copper soap method using diphenylcarbazide. The extractant, being less dense than water, is easily separated from an aqueous phase both in the extraction of samples and in the assay of copper soaps. The assay is comparable in accuracy with well-tried titrimetric methods and is quicker and easier to operate.

Methods for the rapid separation and estimation of the major lipids of arteries and other tissues by thin-layer chromatography on small plates followed by microchemical assays.

Methods are described for the rapid separation of the major individual phospholipids and neutral lipids of tissues by thin-layer chromatography on small glass plates (75 X 75 mm), and for the specific microchemical estimation of separated lipids and for determination of fatty acid composition and radioactivity. The overall method, involving tissues extraction, thin-layer chromatographic separation and assay has been evaluated using pure standards and biological samples and gives good reproducibility and almost complete recovery of lipids.

Carcinoembryonic antigen in management of colorectal carcinoma.

Carcinoembryonic antigen (C.E.A.) estimation has been used in the preoperative assessment of colorectal carcinoma patients and has been shown to give a useful guide to the presence of metastatic disease and ultimately to a poor prognosis if the serum concentration is 100 ng/ml or more. C.E.A. has been shown to be a more reliable index of tumour spread than either clinical examination or serum alkaline phosphatase estimation. Raised C.E.A. levels of less than 100 ng/ml do not, however, necessarily imply a poor prognosis. Routine C.E.A. estimation may have a valuable role in the assessment of the colorectal cancer patient by identifying those likely to benefit from postoperative chemotherapy.The test has also been assessed in a group of patients attending cancer follow-up clinics after radical resection of a colorectal tumour. Raised C.E.A. occurred in most of those developing recurrent disease, and in several patients a rising C.E.A. level preceded clinical or biochemical evidence of recurrence. C.E.A. estimation is a superior guide and of clinical importance when applied to the follow-up of the colorectal cancer patient.

The effect of serum protein concentrations on the specificity of the radioimmunoassay of carcinoembryonic antigen in malignant neoplasia and non-neoplastic disease.

Carcinoembryonic antigen (CEA) has been measured in parallel with seven serum proteins and seromucoids in the sera of patients with malignant neoplasia and non-neoplastic disease. In the total group significant correlations were found between CEA and seromucoids and between CEA and several serum proteins. However, with two exceptions, when the individual disease groups were examined no correlation was seen. It is concluded that abnormal concentrations of the specific proteins measured do not consistently interfere in the CEA radioimmunoassay and do not explain the high CEA levels in patients with non-neoplastic diseases.

Serum carcinoembryonic antigen in clinical disorders.

Carcinoembryonic antigen (CEA) levels have been measured in the serum of 490 patients and 93 normal controls using the double antibody radioimmunoassay technique. Levels were elevated in 71 of patients with carcinomata of the gastrointestinal tract and in 42% with other types of malignancy. In patients with non-neoplastic disease of the gastrointestinal tract and liver, elevated levels were found in 14 and 66% respectively. In general the CEA level tends to be higher in cancer patients with haematogenous dissemination. Following complete surgical removal of a tumour, levels fall to normal within 14 days in the majority of patients. Of 33 patients studied during follow up, elevated levels were found in 12, 10 of whom had evidence of recurrence. The significance of these findings and the possible application of CEA assay in clinical practice are discussed.