Effect of misspecification of gene frequency on the two-point LOD score.

In this study, we used computer simulation of simple and complex models to ask: (1) What is the penalty in evidence for linkage when the assumed gene frequency is far from the true gene frequency? (2) If the assumed model for gene frequency and inheritance are misspecified in the analysis, can this lead to a higher maximum LOD score than that obtained under the true parameters? Linkage data simulated under simple dominant, recessive, dominant and recessive with reduced penetrance, and additive models, were analysed assuming a single locus with both the correct and incorrect dominance model and assuming a range of different gene frequencies. We found that misspecifying the analysis gene frequency led to little penalty in maximum LOD score in all models examined, especially if the assumed gene frequency was lower than the generating one. Analysing linkage data assuming a gene frequency of the order of 0.01 for a dominant gene, and 0.1 for a recessive gene, appears to be a reasonable tactic in the majority of realistic situations because underestimating the gene frequency, even when the true gene frequency is high, leads to little penalty in the LOD score.     

Grading of complications and risk factor evaluation in laparoscopic colorectal surgery

Background

A grading system for postoperative complications is important for quality control and comparison among investigations. The objective of the current study was to evaluate complications associated with laparoscopic colorectal surgery according to a standardized grading system, and to examine risk factors associated with different complication grades.

Methods

Data of all patients who underwent elective laparoscopic colorectal surgery at two medical centers between September 2003 and January 2011 were collected prospectively. Complications were graded retrospectively into five categories based on a previously proposed grading system for colorectal operations. Age, gender, BMI, Charlson comorbidity score, indication for surgery, pathology site, conversion rate, learning curve, operative times, previous abdominal surgery, concurrent surgical procedures performed, and length of hospital stay were evaluated as risk factors and outcome measures for complications.

Results

A total of 501 patients were included in the study. Of them, 30.5 % suffered at least one complication and 6.5 % more than one. Complications that were mainly medical or surgical site infections requiring minor intervention (grades 1 and 2) occurred in 22.9 % of patients. Surgical complications requiring invasive interference (grades 3 and 4) occurred in 7.4 % of patients and mortality (grade 5) occurred in 0.2 % (1 patient). Length of hospital stay was directly related to complication grade. Average hospital stay was 6.8 ± 3.5, 10.5 ± 5.1, and 20.2 ± 12.3 days for patients with no complications, grade 1–2 complications, and grade 3–4 complications, respectively (p < 0.01). Minor complications (grades 1–2) were associated with conversion (p < 0.01), high Charlson score (p = 0.004), and additional surgical procedures (p = 0.04). Major complications (grades 3–4) were associated solely with conversion (p < 0.01) and rectal pathology (p < 0.01).

Conclusion

This study demonstrates the use of a uniform grading system for complications in laparoscopic colorectal surgery. Conversion was found to be associated with all grades of complications.     

Precipitation of fibrinogen, fibrinogen degradation products and fibrin monomer by histone H3

Incubation of histone H3 with normal citrated plasma resulted in the formation of insoluble aggregates, as determined by turbidity measurements. The precipitate was subjected to sodium dodecyl sulfate polyacrylamide gel electrophoresis, confirming that fibrinogen was a major component. Purified fibrinogen precipitated rapidly as determined with turbidity experiments and experiments with radioiodinated protein. The amount of fibrinogen precipitation was strongly dependent on H3 concentration. Variation of ionic strength (0.2-0.84) and pH (5.3-7.4), however, had little or no effect on the reaction. Fibrinogen subjected to gelatin-Sepharose chromatography or dialysis against 3.3M urea reacted equivalently with H3. Precipitation of 125I-fibrinogen by H3 was strongly favored by increasing temperature (4 degrees-45 degrees C). Precipitation of fibrinogen by protamine was maximized by decreasing the temperature. In addition, formation of insoluble fibrinogen-protamine aggregates was highly dependent on ionic strength and pH, suggesting that different types of protein-interaction are involved in the two studied precipitation reactions. Of the fibrinogen degradation products, only fragment X precipitated significantly when incubated with H3. Radioiodinated fibrin monomer also precipitated when incubated with H3 in solutions of sufficient ionic strength to prevent spontaneous polymerization. The extent of precipitation was equivalent for fibrin monomer and fibrinogen. Fragment D inhibited the precipitation of fibrinogen by H3 or protamine. These studies indicate that the proteins termed "paracoagulants" are not all equivalent and that the hydrophobic domain of H3 plays a critical role in fibrinogen precipitation.     

Peripheral neuropathy after chronic endoneurial ischemia

We have developed a method for producing chronic regional nerve ischemia in rats by creating proximal limb arteriovenous shunts. This procedure results in a 50 to 75% reduction in endoneurial blood flow within the distal sciatic nerve as measured by the iodoantipyrine method. Nerve conduction velocities in sciatic nerves ipsilateral to the shunt fell by 25 to 30% within 2 weeks after creation of the shunt and did not recover for up to 10 months after the procedure. Morphological studies of the ischemic nerves showed structural abnormalities at nodes of Ranvier and mild axonal atrophy. Neither segmental demyelination nor axonal degeneration were evident. These results indicate that reduced endoneurial blood flow, insufficient to cause infarction, may result in measurable functional and morphological abnormalities in peripheral nerves.     

FMRFamide-related peptides,partial serotonin depletion,and osmoregulation in Helisoma duryi (mollusca: pulmonata)

Serotonergic neurons were studied by specific histological methods, and neurons containing Phe-Met-Arg-Phe-NH₂ (FMRFamide)-related heptapeptides were identified with an antiserum specific for these substances in the central nervous system of the freshwater snail Helisoma duryi. Serotonergic neurons and their axons are present in all of the ganglia (paired buccal, cerebral, pedal, pleural, parietal, and single visceral) and major nerves of the central nervous system. Large neurons containing FMRFamide-related peptide immunoreactivity are located in the left parietal and visceral ganglia, whereas a few small neurons are located in the cerebral and pedal ganglia. Both serotonergic and FMRFamide-related peptide-immunoreactive dendrites and varicosities were observed in the kidney. A second antiserum with high affinity for FMRFamide-related heptapeptides was used to measure the levels of the immunoreactive material in various tissues, and such material was found in every tissue analyzed. When snails were exposed to a medium isosmotic to their hemolymph, the levels of immunoreactive FMRFamide-related peptides increased in the hemolymph, central nervous system, mantle, and kidney. Injection of dihydroxytryptamine, which is known to deplete serotonin content in the snail, also reduced the levels of FMRFamide-related-immunoreactive material in the above tissues. Therefore, serotonin may influence the levels of FMRFamide-related peptides in tissues by regulating the rate of their synthesis, axonal transport, or release. Both serotonin and FMRFamide-related peptides could be involved in osmoregulation. J. Comp. Neurol. 393:25–33, 1998. © 1998 Wiley-Liss, Inc.     

Regional flow-metabolism couple following middle cerebral artery occlusion in cats

The regional flow-metabolism couple was studied during the recovery period after 1 h of left middle cerebral artery (MCA) occlusion in cats. Local CBF (LCBF) was assessed at the end of ischemia as well as at the end of 4 h of recirculation by the microsphere technique. Local CMRgl (LCMRgl) was measured at the end of the recirculation period with [14C]2-deoxyglucose. Histology was evaluated by light microscopy from coronal brain blocks adjacent to those used for the determination of LCBF and LCMRgl. When LCBF in the central and peripheral MCA territories during the recovery period was between 40 and 115% of the value in sham occlusion studies, LCMRgl was greater than the control level found in the sham studies, and was accompanied by slight histological damage. This finding suggests that anaerobic glycolysis may persist after transient ischemia in spite of the recovery of LCBF to a level that is normally greater than the threshold for the activation of anaerobic glycolysis (less than 40% of the control). Persistent anaerobic glycolysis in the reperfusion period following an ischemic insult may be a sign of early tissue damage. Some of the regions in the peripheral MCA territory with LCBF between 40 and 110% of the levels during the recovery period in the sham studies showed a mild to moderate depression in LCMRgl so that the flow-metabolism ratio remained normal. These regions did not exhibit histological damage. This possible protective mechanism of the tissue in response to ischemia is discussed from the standpoint of the relationship between flow and metabolism.     

Molecular diagnosis of inheritable neuromuscular disorders. Part I: Genetic determinants of inherited disease and their laboratory detection

Understanding of the genetic basis of inheritable neuromuscular disorders has grown rapidly over the last decade, resulting in improved classification and understanding of their pathogenesis. A consequence of these advances has been the development of genetic tests of blood specimens for the diagnosis of many of these diseases. For many patients, these blood tests have eliminated the need for other more invasive diagnostic tests such as muscle or nerve biopsy, and for some patients, reduced exposure to immunosuppressive medication and its complications. The first part of this review focuses on the nature of genetic disorders, the laboratory methods used in the performance of genetic tests, and general practical aspects of their use and interpretation. The second part discusses the applicability of these tests to the range of neuromuscular disorders.     

First trimester exposure to cefuroxime: a prospective cohort study

AIMS: There are no published studies on the safety of cefuroxime use during pregnancy. We therefore investigated prospectively the possible teratogenic effect of intrauterine exposure to cefuroxime. METHODS: One hundred and six women who received cefuroxime during the first trimester of pregnancy were recruited from three teratogen information centres in Israel. Exposed women were paired for age, smoking habits and alcohol consumption with references being exposed to nonteratogenic antibiotics administered for the same indications. RESULTS: Maternal history, birthweight, gestational age at delivery, rates of live births, spontaneous abortions and fetal distress were comparable among the two groups. Rates of major malformations in the cefuroxime group (3.2%) did not differ from references (2%) (P = 0. 61, relative risk = 1.56, 95% confidence interval 0.27-9.15). There was a significantly higher rate of induced abortions among the cefuroxime exposed women as compared to the references (P = 0.04, relative risk = 3.33, 95% confidence interval 0.94-11.77). CONCLUSIONS: Our data may suggest that exposure to cefuroxime during the first trimester is probably not associated with an increased risk for malformations or spontaneous abortions; however, in light of the small sample size and the broad confidence limits, larger studies are needed to confirm these findings.     

Change in neurocognitive functioning after treatment with cranial radiation in childhood.

PURPOSE: To evaluate the pattern of stability and change over time across multiple domains of neurocognitive function in radiated survivors of posterior fossa (PF) tumors. PATIENTS AND METHODS: Thirty-four children (25 males) treated for malignant PF tumors were observed with serial clinical neuropsychologic assessments. Thirty patients were treated for medulloblastoma and four patients were treated for ependymoma. Twelve patients were treated with reduced-dose and 21 patients were treated with standard-dose cranial radiation. All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized neuropsychologic tests were administered at different times after diagnosis for each child. The rate of change in scores was determined using a mixed model regression. RESULTS: Results showed a 2- to 4-point decline per year in intelligence scores. For our relatively young sample, intellectual function declined quickly in the first few years after treatment, and then more gradually. Significant declines in visual-motor integration, visual memory, verbal fluency, and executive functioning were also documented. No decline was evident for verbal memory and receptive vocabulary. CONCLUSION: Cranial radiation is associated with a decline in multiple neurocognitive domains, with a few notable exceptions. Our results must be interpreted in the context of common limitations of clinical research, including patient variability, changes in test versions, small sample size, and clinical referral bias.     

Mapping of the gene for cleidocranial dysplasia in the historical Cape Town (Arnold) kindred and evidence for locus homogeneity.

Cleidocranial dysplasia (CCD) is an autosomal dominant disorder, features of which include a patient anterior fontanelle, a bulging calvarium, hypoplasia or aplasia of the clavicles, a wide public symphysis, dental anomalies, vertebral malformation, and short stature. The Cape Town kindred which is under our genetic management was originally described more than four decades ago and now consists of more than 1000 people. Following reports of rearrangements on chromosomes 6 and 8 in people with CCD, we have carried out linkage analyses between highly information microsatellite dinucleotide repeat markers in the rearranged regions and the disorder in a branch of this South African CCD kindred, consisting of 38 subjects, 18 of whom are affected. Maximum lod scores (at theta = 0.00) of 7.14 (for marker D6S459), 4.32 (TCTE), 4.99 (D6S452), 5.97 (D6S269), and 3.95 (D6S465) confirm linkage of the disorder to the short arm of chromosome 6. Our data indicate that the CCD gene is located within a minimal region of approximately 10 cM flanked by the marker D6S451 distally and D6S466 proximally. This information is vital towards isolating and characterising the gene for CCD, and is being used to construct a physical map of 6p21.1-6p21.3. More importantly, mapping of the locus in the South African kindred of mixed ancestry, in which the "founder" of the disorder was of Chinese origin, suggests that a single locus is responsible for classic CCD.