Mutations in the ligand-binding domain of the kit receptor: an uncommon site in human piebaldism

Heterozygous mutations in the gene for the Kit transmembrane receptor have been identified recently in human piebaldism and mouse "dominant spotting." Interestingly, all of the 14 known missense mutations that cause depigmentation in these species map to the tyrosine kinase domain of the receptor, whereas none have involved the extracellular ligand-binding domain. In an attempt to detect these uncommon mutations, we screened the nine exons encoding the extracellular portion of Kit for single-strand conformation polymorphisms (SSCP) in eight piebald subjects previously reported to be negative for kinase mutations. Four of these eight kindreds proved to carry novel mutations. The first mutation, found in two apparently unrelated probands with mild piebaldism and English ancestry, substitutes an arginine for a highly conserved cysteine at codon 136. This substitution disrupts a putative disulfide bond required for formation of the second Ig-like (D2) loop of the Kit ligand-binding domain. The second mutation, detected in a piebald kindred characterized by unusually limited depigmentation, substitutes a threonine for an alanine at codon 178, a site just proximal to conserved cysteines at codons 183 and 186. The third mutation, occurring in a kindred with more extensive depigmentation, is a novel four-base insertion in exon 2 that results in a proximal frameshift and premature termination. The data strongly suggest that piebaldism can result from missense mutations in the Kit ligand-binding domain, although the resulting phenotype may be milder than that observed for null or kinase mutations. The apparent clustering of these uncommon mutations at or near the conserved cysteines for the D2 Ig-like loop further suggests a critical role for this region in Kit receptor function.     

The hypolipidemic effect of SU-13,437 in rats with natural endogenous hypertriglyceridemia

The oral administration of 25 mg 2-methyl-2-[p-(1,2,3,4-tetrahydro-1-naphthyl)-phenoxy] propionic acid (SU-13,437) per kilogram body weight per day in two-month-old female rats with naturally occurring hypertriglyceridemia resulted in a 31% decrease (P<0.01) in the serum triglyceride concentration after 14 days of treatment, compared with littermate controls receiving diluent (Polyethylene glycol-300) only. Phospholipid, cholesterol, free fatty acid, glucose, red blood cell and white blood cell concentrations were similar in the blood of treated and control animals after 14 days of treatment. Liver total and relative weight was increased as a result of SU-13,437 treatment (P<0.01). The liver total lipid concentration per 10 gm liver decreased (P<0.05) due to a decrease in triglyceride (P<0.01), cholesterol (P<0.01), and free fatty acid (P<0.05) concentration following treatment. The relative liver glycogen concentration was elevated in treated rats at 7 (P<0.01) and 14 (P<0.05) days of treatment.     

Effects of age, system experience, and navigation technique on driving with an advanced traveler information system

This paper explores the effects of age, system experience, and navigation technique on driving, navigation performance, and safety for drivers who used TravTek, an Advanced Traveler Information System. The first two studies investigated various route guidance configurations on the road in a specially equipped instrumented vehicle with an experimenter present. The third was a naturalistic quasi-experimental field study that collected data unobtrusively from more than 1200 TravTek rental car drivers with no in-vehicle experimenter. The results suggest that with increased experience, drivers become familiar with the system and develop strategies for substantially more efficient and safer use. The results also showed that drivers over age 65 had difficulty driving and navigating concurrently. They compensated by driving slowly and more cautiously. Despite this increased caution, older drivers made more safety-related errors than did younger drivers. The results also showed that older drivers benefited substantially from a well-designed ATIS driver interface.     

Adenosine deaminase deficiency in adults

Adenosine deaminase (ADA) deficiency typically causes severe combined immunodeficiency (SCID) in infants. We report metabolic, immunologic, and genetic findings in two ADA-deficient adults with distinct phenotypes. Patient no. 1 (39 years of age) had combined immunodeficiency. She had frequent infections, lymphopenia, and recurrent hepatitis as a child but did relatively well in her second and third decades. Then she developed chronic sinopulmonary infections, including tuberculosis, and hepatobiliary disease; she died of viral leukoencephalopathy at 40 years of age. Patient no. 2, a healthy 28-year-old man with normal immune function, was identified after his niece died of SCID. Both patients lacked erythrocyte ADA activity but had only modestly elevated deoxyadenosine nucleotides. Both were heteroallelic for missense mutations: patient no. 1, G216R and P126Q (novel); patient no. 2, R101Q and A215T. Three of these mutations eliminated ADA activity, but A215T reduced activity by only 85%. Owing to a single nucleotide change in the middle of exon 7, A215T also appeared to induce exon 7 skipping. ADA deficiency is treatable and should be considered in older patients with unexplained lymphopenia and immune deficiency, who may also manifest autoimmunity or unexplained hepatobiliary disease. Metabolic status and genotype may help in assessing prognosis of more mildly affected patients.     

A high-performance,ad hoc,fuzzy query processing system

Database queries involving imprecise or fuzzy predicates are currently an evolving area of academic and industrial research (Buckles and Perty 1987; Bosc et al. 1988; Bosc and Pivert 1991; Kacprzyk et al. 1989; Prade and Testemale, 1987; Tahani, 1977; Umano, 1983; Zemankova and Kandel, 1985). Such queries place severe stress on the indexing and I/O subsystems of conventional database systems since they frequently involve the search of large numbers of records. The Datacycle (Datacycle is a trademark of Bellcore.) architecture and research prototype is a database processing system that uses filtering technology to perform an efficient, exhaustive search of an entire database. It has been modified to include fuzzy predicates in its query processing. The approach obviates the need for complex index structures, provides high-performance query throughput, permits the use of ad hoc fuzzy membership functions and provides deterministic response time largely independent of query complexity and load. This paper describes the Datacycle prototype implementation of fuzzy queries and some recent performance results.     

Lipid metabolism following triglyceride ingestion in intact and adrenalectomized rats

Although both adrenalectomized and intact Long Evans rats absorbed the same amount of fat over a 24 hr period, the livers of the intact rats accumulated triglyceride while the livers of the adrenalectomized rats failed to do so. Of the glycerides excreted in the feces, the adrenalectomized rat excreted a significantly higher proportion of triglycerides while the intact rats excreted primarily monoglycerides. Fecal excretion of bile acids and phospholipids was significantly lower in the adrenalectomized rats compared to intact rats. Thus adrenal hormones appear to influence intestinal lipolysis. Serum and liver phospholipids appeared to be significantly lower in response to a fat load in adrenalectomized rats compared to intact rats. The phospholipid content of the small intestinal wall was five-fold higher in the intact rats than in the adrenalectomized rats. The adrenal gland appears to control phospholipid synthesis during triglyceride assimilation.     

Differential effects of aging and Alzheimer's disease on conceptual implicit and explicit memory.

The effects of aging and Alzheimer's disease (AD) on conceptual explicit and implicit memory were examined. Three groups of participants patients with AD; age-matched, older control participants; and younger control participants made deep (semantic) or shallow (nonsemantic) judgments about low-dominant category exemplars. Explicit memory was measured by category cued recall and implicit memory was measured by priming on a category-exemplar generation task. Younger participants had enhanced cued recall and priming following deep, relative to shallow, encoding; this indicated that both memory measures were conceptually driven. Aging reduced explicit, but not implicit, test performance, and it did not reduce conceptually driven processes for either test. In contrast, AD reduced explicit and implicit test performance, and it impaired conceptually driven memory processes for both tests. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impact of Alzheimer's-type dementia and information source on the assessment of depression.

Assessment of depression in patients with Alzheimer's disease (AD) is complicated by uncertainty regarding the accuracy of information supplied by the patient and collateral informants. Agreement between these two sources in completing the Hamilton Rating Scale for Depression (HRSD; M. Hamilton, 1960) was compared in patients with AD (n?=?185) and two groups of nondemented outpatients: patients with Parkinson's disease (n?=?57) and geriatric referrals (n?=?54). The correlation between HRSD scores generated from structured interviews with patients and collateral sources was attenuated in AD (r?=?.29) in comparison with Parkinson's disease (r?=?.92) and geriatric outpatients (r?=?.85). Differences in scores between interview methods in AD reflected a generally low rate of symptom endorsement by patients. These findings highlight the potential insensitivity of patient report in AD and support the use of collateral informants as an alternative source of clinical information in persons with significant cognitive impairment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)