The weighted rank pairwise correlation statistic for linkage analysis: Simulation study and application to Alzheimer's disease

The weighted rank pairwise correlation (WRPC) statistic has been proposed as a robust test of genetic linkage, particularly adapted to the analysis of large and complex pedigrees and for age-dependent and heterogeneous diseases. In this paper a simulation study is presented. Validity and power of the WRPC test are studied and compared to the Haseman-Elston sibpair method for various types of problems. The power of the WRPC test is slightly lower than the Haseman-Elston method for analyzing a large number of small randomly chosen pedigrees. It is higher however in presence of genetic heterogeneity or for analyzing large individual pedigrees. Recently, evidence of linkage of Alzheimer's disease with a locus on chromosome 14, D14s43, has been obtained by the Lod-score method. We reanalyze these data using the WRPC test, essentially confirming the results of the Lod-score method. The WRPC test statistic is higher than the equivalent Lod-score statistic for the two pedigrees which show strong evidence of linkage with the two methods. The global WRPC test statistic is slightly lower than the Lod-score test statistic. The WRPC test, however, makes no hypothesis of a specific genetic transmission model and can be computed very quickly; in addition, an exact P-value can be computed by simulation for individual pedigrees. © 1994 Wiley-Liss, Inc.     

Effect of varying fibrinogen and hematocrit concentrations on magnetic resonance relaxation times of thrombus.

OBJECTIVES. The authors assessed the effects of varying one extracellular component (fibrinogen concentration) and one cellular component (hematocrit) on magnetic resonance (MR) T1 and T2 relaxation times of in vitro blood clots. METHODS. Blood from six male subjects was collected into sodium citrate anticoagulant (3.8%) and the whole blood was separated into platelet-rich plasma and packed erythrocytes. Subsequently, in vitro blood clots were made from varying concentrations of fibrinogen (1, 10, and 100 microM) in Tyrode's solution and washed, packed erythrocytes (hematocrit levels: 0%, 10%, 40%, and 80%). T1 and T2 measurements were completed at 20 MHz within 8 hours of initiating clotting. RESULTS. Significant shortening of MR relaxation times occurred with increasing fibrinogen concentration for hematocrit values of 0% and 10%. Extracellular fibrinogen concentration did not contribute significantly to variation in relaxation times at hematocrit values of 40% and 80%. For any given fibrinogen level, significant shortening occurred in T1 and T2 values for each successive increase in hematocrit values. CONCLUSIONS. Both extracellular (fibrinogen) and cellular (erythrocyte concentration) factors are significant determinants of thrombus T1 and T2 relaxation times.     

Cataract surgery takes longer in functionally monocular patients.

BACKGROUND AND OBJECTIVES: To determine differences in the amount of work involved in caring for functionally monocular patients who undergo cataract surgery compared with binocularly sighted patients. PATIENTS AND METHODS: This was a retrospective study that included 100 consecutive functionally monocular patients and 100 binocularly sighted control patients matched by age (+/-5 years) and date of surgery ( +/-1 year). Office records were reviewed to determine several measures of office and operating room work effort. RESULTS: There was no difference between groups in preoperative telephone calls (P = .136), postoperative telephone calls (P = .580), preoperative office visits (P = .875), postoperative office visits (P = .601), or the number of times surgery was scheduled (P = 1.00). Monocular patients required more time for surgery (37.4 minutes) than binocular patients (32.4 minutes) (P= .010). CONCLUSIONS: It takes longer to perform cataract surgery on functionally monocular patients than on binocularly sighted patients.     

Studies on the effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57BL/6 mice. Comparison with three other strains of mice

The effect of the parkinsonism-inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in C57BL/6 mice has been studied employing neuro- and histochemical techniques. The number of dopamine (DA) cell bodies in substantia nigra pars compacta (SNC) was reduced by 70% in MPTP-treated C57BL/6 mice, as demonstrated both by tyrosine hydroxylase (TH) immunohistochemistry and conventional histology (Cresyl violet staining) and an almost complete loss of DA fibers in striatum was also found. A detailed analysis of the effects of MPTP on endogenous catecholamine levels in various brain regions revealed that MPTP caused a severe reduction of endogenous DA in substantia nigra and striatum (35 and 5% of control) which was accompanied by an increase in the 3,4-dihydroxyphenylacetic acid (DOPAC)/DA ratio. There was also a decrease of DA in nucleus accumbens and the olfactory tubercle to 41 and 44% of control, respectively, without any significant change in the DOPAC/DA ratio and density of TH-positive fibers. Small but significant decreases of the noradrenaline (NA) levels in septum, entorhinal cortex and frontal cortex were seen, although the uptake of [3H]NA in frontal cortex was not significantly changed. Minor MPTP-induced decreases of the serotonin levels in frontal cortex, occipital cortex and spinal cord were also seen. The MPTP treatment also induced a 55% increase of adrenaline levels in hypothalamus, while no changes were seen in pons-medulla and spinal cord. Comparing this with 3 other strains of mice, the MPTP-induced reduction of endogenous DA in striatum was most pronounced in C57BL/6, less in N.M.R.I. and CBA/Ca mice, and least in Swiss-Webster. Concerning the effect of MPTP on cortical NA levels, the same relation was at hand except for C57BL/6, where, as mentioned, the effect was merely detectable. No reduction of DA perikarya in SNC was seen in Swiss-Webster mice. These findings show that in mice major differences exist in sensitivity of catecholamine neurons to MPTP between different strains. The data show that MPTP can produce an almost complete, permanent and relatively selective degeneration of the nigrostriatal DA neurons in C57BL/6 mice similar to that seen in primates. This strain may therefore serve as a useful model for studies on various aspects of MPTP-induced parkinsonism.     

Iatrogenic renal disease

We studied iatrogenic problems in nephrology by classifying all patients for nephrology consultation into nine presenting syndromes and seven etiologic groups. One hundred (2.2%) of all admissions were seen in nephrology consultation. Acute renal failure was the most common presenting syndrome, accounting for 59% of the consultations. Forty-one of the 100 consultations (1% of all admissions) had a renewal syndrome of iatrogenic origin. Of these 41 patients, 38 had acute renal failure and three had fluid and electrolyte problems. Twenty of the 41 patients had drug-induced problems. Eighteen of these patients were dehydrated, and in three patients, acute renal failure occurred after surgery. Of the 20 patients with iatrogenic renal problems caused by drugs, seven problems were antibiotic related, five were due to diuretics, four were due to nonsteroidal anti-inflammatory drugs, three were due to angiotensin-converting enzyme inhibitors, and one was from the use of contrast medium. The 41 patients with iatrogenic-related renal disease were older than the other 59 patients (61.8 vs 49.3 years). Iatrogenic renal disease developed in 1% of all patients admitted to a tertiary care hospital, and 12% of these patients died. The most common renal syndrome is acute renal failure, most often caused by nephrotoxic drugs. The incidence can probably be decreased by better monitoring of body weight and fluid balance to prevent dehydration and by the avoidance of nephrotoxic drugs.     

Perfluorochemicals as US contrast agents for tumor imaging and hepatosplenography: preliminary clinical results

In animals, perfluorochemicals (PFCs) are effective ultrasound (US) contrast agents that produce hepatic, splenic, and tumor enhancement. The use of Fluosol-DA 20%, an emulsion of perfluorodecalin and perfluorotripropylamine, was studied in nine non-critically ill patients with cancer who had liver lesions. US studies without Fluosol were compared with studies obtained 24, 48, and 72 hours after Fluosol infusion. Vital signs and extensive laboratory analyses are performed before and after Fluosol infusion. Liver metastases from colonic, pancreatic, and gastric carcinoma exhibited rim or diffuse enhancement after a Fluosol dose of 1.6 g/kg or greater. Fluosol produced echogenic enhancement of the liver and spleen relative to kidney at a dose of 2.4 g/kg, allowing the detection of nonenhancing lesions. In addition, Fluosol at a dose of 1.6 g/kg or greater allowed detection of lesions not seen before contrast medium was administered in three of the seven patients studied. There was a mild increase in the level of serum glutamic oxaloacetic transaminase in two patients, one given 2.4 and the other 3.2 g/kg of Fluosol. Mild and transient allergic reactions without change in vital signs were experienced by two patients.     

Innervation of crab-eating monkey trachealis muscle determined in vitro

Strips of smooth muscle from the cervical tracheae of six adult male crab-eating monkeys (Macaca fascicularis) were studied in jacketed 25 ml organ baths filled with Krebs-bicarbonate solution maintained at 37 degrees C and gassed with 5% CO2 in oxygen. Isometric tissue tension increased in response to electrical field stimulation (18 V, 25 Hz, 0.5 msec), norepinephrine in the presence of propranolol, acetylcholine and histamine. Atropine abolished the contractile response to electrical stimulation. Tissues that were contracted with acetylcholine or pretreated with atropine then contracted with histamine relaxed when stimulated electrically. The relaxation was unaffected by propranolol but was abolished by tetrodotoxin. Isoproterenol relaxed tissues that were contracted with histamine, but failed to relax histamine-contracted tissues that had been pretreated with propranolol. Norepinephrine did not change isometric tension in untreated tissues or tissues pretreated with phentolamine. These results demonstrate the presence of excitatory and inhibitory nerves and noninnervated beta-adrenergic receptors in macaque trachealis. The excitatory nerves appear to be cholinergic. The inhibitory response to electrical stimulation is not mediated through muscarinic cholinergic or beta-adrenergic receptors. The inhibitory response to electrical field stimulation was likely mediated through nonadrenergic noncholinergic nerves.