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We are impressed with the magnitude and potential importance of the studies presented by Sigman and Ruskin in this monograph. The within-syndrome findings for the children with autism concerning relations between early joint attention and a range of cognitive abilities a full 9 years later provide the strongest evidence so far that early nonverbal communication skills play an important role in the later development of language, intelligence, and social relations with peers. The purpose of the monograph was not limited to within-syndrome research questions, however. Sigman and Ruskin state that a major goal of the research reported in the monograph was to identify specific, unique, and universal deficits for autism and Down syndrome. They base their method of identifying such syndrome characteristics on the group-matching procedure. Given that this procedure is fraught with difficulties, we are concerned that many of Sigman and Ruskin's cross-syndrome comparisons may be incorrect. We do not mean to single out Sigman and Ruskin. The group-matching method is frequently used in special populations research, with the null hypothesis of no differences on the control variable being accepted at dangerously low p values. Our concerns with the group-matching problem extend to much of the extant research that attempts to identify characteristics of individuals based on the performance of their syndrome group relative to a control group. The profiling procedure we outlined seems more fruitful and conceptually satisfying than the traditional matching method. When profiling is not possible, however, it is important to consider the impact of CA confounds and statistical decision procedures used to ensure matching on the control variable, when interpreting syndrome differences on variables of interest. [ABSTRACT FROM AUTHOR]

Expressive vocabulary data gathered during a systematic diary study of one male child's early language development are compared to data that would have resulted from longitudinal administration of the MacArthur Communicative Development Inventories spoken vocabulary checklist (CDI). Comparisons are made for (1) the number of words at monthly intervals (9; 10.15 to 2; 0.15), (2) proportion of words by lexical class (i.e. noun, predicate, closed class, 'other'), (3) growth curves. The CDI underestimates the number of words in the diary study, with the underestimation increasing as vocabulary size increases. The proportion of diary study words appearing on the CDI differed as a function of lexical class. Finally, despite the differences in vocabulary size, logistic curves proved to be the best fitting model to characterize vocabulary development as measured by both the diary study and the CDI. Implications for the longitudinal use of the CDI are discussed. [ABSTRACT FROM AUTHOR]

The forearm resistance vessels of men with primary hypertension respond to verapamil with a greater than normal dilatation relative to that induced by sodium nitroprusside. We have examined the effect on this functional abnormality of treatment with chlorthalidone (50 mg daily in 16 patients) and atenolol (100 mg daily in eight patients and 200 mg daily in two). The responsiveness of the forearm resistance vessels to local intra-arterial infusion of verapamil and sodium nitroprusside was assessed before treatment and again after a minimum of 1 month of drug therapy. Forearm blood flow was measured by venous occlusion plethysmography. Chlorthalidone induced significant reductions in calculated mean arterial pressure, which fell from 135 +/- 4 to 117 +/- 4 mm Hg, and the dilator response to verapamil at 5 micrograms/min, which was reduced from 2.4 +/- 0.2 to 1.5 +/- 0.2 ml min-1 100 ml-1 forearm; the response to sodium nitroprusside at 3.2 micrograms/min was not significantly changed. Atenolol induced significant reductions in mean arterial pressure, which fell from 134 +/- 6 to 123 +/- 6 mm Hg, heart rate which fell from 72 +/- 3 to 55 +/- 2 beats/min, and response to verapamil at 5 micrograms/min which fell from 2.7 +/- 0.2 to 2.1 +/- 0.2 ml min-1 100 ml-1 forearm; the response to sodium nitroprusside was not significantly changed. Both drugs caused reversion towards normal of the relative enhancement of responsiveness to verapamil that was present before treatment.(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

1 The effect of oral nifedipine has been examined in patients with hypertension in whom arterial pressure was not adequately controlled by the combination of a beta-adrenoceptor antagonist (or alpha-methyldopa) and a diuretic. 2 In 42 patients, nifedipine (10 mg capsules) was added to the existing therapy in a final dose of 20-60 mg daily. Six patients had to stop the drug on account of side-effects. In the 36 patients who continued treatment, arterial pressure fell by an average of 24/9 mmHg supine and 26/10 mmHg standing. 3 In 11 of these patients who subsequently completed a double-blind, cross-over, placebo controlled trial, nifedipine (30-60 mg daily) was found to reduce arterial pressure by an average of 19/11 mmHg supine and 21/12 mmHg standing. 4 In all 11 patients who were changed to a sustained release preparation of nifedipine, control of arterial pressure was at least as good as it had been when taking the capsules. [ABSTRACT FROM AUTHOR]

1 The effect of nifedipine on peripheral blood vessels has been studied in man. 2 Nifedipine induced dilatation of the forearm resistance vessels when given either by local intra-arterial infusion or sublingually (10 mg). 3 Local infusion of the drug did not relax hand veins preconstricted by infusion of noradrenaline and neither local infusion nor sublingual administration prevented constriction mediated by the sympathetic nervous system. Nifedipine was, however, a potent inhibitor of hand vein contractions induced by high concentrations of potassium provided that the noradrenergic component of the response was suppressed by simultaneous infusion of phentolamine. 4 Sublingual nifedipine (10 mg) did not dilate the elbow collateral arteries. 5 The effects of nifedipine on peripheral blood vessels are similar, but not identical, to those of verapamil. The pattern of action, with dilatation of resistance vessels but not capacitance, resembles that of hydralazine rather than glyceryl trinitrate and this suggest that nifedipine may prove useful in the treatment of hypertension. [ABSTRACT FROM AUTHOR]

1 The effect on forearm blood flow of local intra-arterial infusion of hydrallazine has been studied in twelve patients with essential hypertension and six normal subjects. 2 When the patients with hypertension were not taking hydrallazine by mouth, they responded to intra-arterial infusions with a dose-dependent increase in forearm blood flow that was not significantly different from that in normal subjects. 3 When the patients were taking hydrallazine by mouth, the increase in forearm flow in response to intra-arterial infusions was reduced and forearm vascular resistance did not fall as low as it did in the control study (P less than 0.01). 4 In four patients, the response to intra-arterial hydrallazine was attenuated to a major extent, and in three of these, there was little or no response to oral treatment. In eight patients, the response to intra-arterial hydrallazine did not fall below one half of that in the control study and this minor reduction in sensitivity might be expected to impair, but not abolish, the response to oral treatment. 5 It is concluded that the resistance vessels commonly develop tolerance to the dilator action of hydrallazine during long-term oral therapy. In some patients a high degree of tolerance develops and this is an important cause of failure to respond to oral treatment. [ABSTRACT FROM AUTHOR]

Objective: American Indian and Alaska Native (AI/AN) persons are commonly misclassified in epidemiologic and administrative data sets. The race-corrected hepatitis C virus (HCV)-related mortality rate among AI/AN persons in the Northwest United States (Idaho, Oregon, and Washington State) is unknown. We quantified the disparity in HCV-related mortality between AI/AN persons and non-Hispanic white (NHW) persons in the Northwest during 2006-2012 after correcting misclassified AI/AN race., Methods: After conducting probabilistic record linkage between death records and the Northwest Tribal Registry, we calculated HCV-related mortality rates for AI/AN and NHW persons by using National Center for Health Statistics bridged-race estimates standardized to the US 2000 standard population., Results: The 2006-2012 aggregate age-adjusted HCV-related mortality rate per 100 000 population in the Northwest was 19.6 (95% confidence interval [CI], 17.3-22.2) for AI/AN persons and 5.9 (95% CI, 5.7-6.1) for NHW persons (rate ratio [RR] = 3.3; 95% CI, 3.0-3.8). The disparity was larger among females (RR = 4.6; 95% CI, 3.8-5.5) than among males (RR = 2.9; 95% CI, 2.5-3.4)., Conclusion: The disproportionate rate of HCV-related mortality among AI/AN persons in the Northwest highlights the need to expand HCV education, screening, and treatment among this population.

Objective: Limited English proficiency can be a barrier to asthma care and is associated with poor outcomes. This study examines whether pediatric patients in Ohio with limited English proficiency experience lower asthma care quality or higher morbidity., Methods: We used electronic health records for asthma patients aged 2-17 years from a regional, urban, children's hospital in Ohio during 2011-2015. Community-level demographics were included from U.S. Census data. By using chi-square and t-tests, patients with limited English proficiency and bilingual English-speaking patients were compared with English-only patients. Five asthma outcomes-two quality and three morbidity measures-were modeled using generalized estimating equations., Results: The study included 15 352 (84%) English-only patients, 1744 (10%) patients with limited English proficiency, and 1147 (6%) bilingual patients. Pulmonary function testing (quality measure) and multiple exacerbation visits (morbidity measure) did not differ by language group. Compared with English-only patients, bilingual patients had higher odds of ever having an exacerbation visit (morbidity measure) (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.2-1.6) but lower odds of admission to intensive care (morbidity measure) (aOR, 0.3; 95% CI, 0.2-0.7), while patients with limited English proficiency did not differ on either factor. Recommended follow-up after exacerbation (quality measure) was higher for limited English proficiency (aOR, 1.8; 95% CI, 1.4-2.3) and bilingual (aOR, 1.6; 95% CI, 1.3-2.1), compared with English-only patients., Conclusions: In this urban, pediatric population with reliable interpreter services, limited English proficiency was not associated with worse asthma care quality or morbidity.

Objectives: Shigella species are the third most common cause of bacterial gastroenteritis in the United States. During a Shigella sonnei outbreak in Oregon from July 2015 through June 2016, Shigella cases spread among homeless persons with onset of the wettest rainy season on record., Methods: We conducted time series analyses using Poisson regression to determine if a temporal association between precipitation and shigellosis incidence existed. Models were stratified by housing status., Results: Among 105 infections identified, 45 (43%) occurred in homeless persons. With increasing precipitation, cases increased among homeless persons (relative risk [RR] = 1.36 per inch of precipitation during the exposure period; 95% confidence interval [CI] = 1.17-1.59), but not among housed persons (RR = 1.04; 95% CI 0.86-1.25)., Conclusions: Heavy precipitation likely contributed to shigellosis transmission among homeless persons during this outbreak. When heavy precipitation is forecast, organizations working with homeless persons could consider taking proactive measures to mitigate spread of enteric infections., (Published by Elsevier Ltd.)

OBJECTIVE To investigate an outbreak of Pseudomonas aeruginosa infections and colonization in a neonatal intensive care unit. DESIGN Infection control assessment, environmental evaluation, and case-control study. SETTING Newly built community-based hospital, 28-bed neonatal intensive care unit. PATIENTS Neonatal intensive care unit patients receiving care between June 1, 2013, and September 30, 2014. METHODS Case finding was performed through microbiology record review. Infection control observations, interviews, and environmental assessment were performed. A matched case-control study was conducted to identify risk factors for P. aeruginosa infection. Patient and environmental isolates were collected for pulsed-field gel electrophoresis to determine strain relatedness. RESULTS In total, 31 cases were identified. Case clusters were temporally associated with absence of point-of-use filters on faucets in patient rooms. After adjusting for gestational age, case patients were more likely to have been in a room without a point-of-use filter (odds ratio [OR], 37.55; 95% confidence interval [CI], 7.16-∞). Case patients had higher odds of exposure to peripherally inserted central catheters (OR, 7.20; 95% CI, 1.75-37.30) and invasive ventilation (OR, 5.79; 95% CI, 1.39-30.62). Of 42 environmental samples, 28 (67%) grew P. aeruginosa. Isolates from the 2 most recent case patients were indistinguishable by pulsed-field gel electrophoresis from water-related samples obtained from these case-patient rooms. CONCLUSIONS This outbreak was attributed to contaminated water. Interruption of the outbreak with point-of-use filters provided a short-term solution; however, eradication of P. aeruginosa in water and fixtures was necessary to protect patients. This outbreak highlights the importance of understanding the risks of stagnant water in healthcare facilities. Infect Control Hosp Epidemiol 2017;38:801-808.

Background: In 2012, Oregon observed its highest numbers of reported pertussis cases since 1953. The greatest morbidity occurred among infants <6 months of age, with higher rates among Hispanics than non-Hispanics. To explain this disparity, we analyzed pertussis surveillance data., Methods: An analysis was conducted among infants <6 months of age in the Portland metropolitan area during 2010-2012. Characteristics examined were ethnicity (Hispanic or non-Hispanic), household size (>4 or ≤4 persons), pertussis vaccination status (upto-date or not up-to-date for age), child care center attendance (yes or no), infant birth weight (<2500 or ≥2500 g) and maternal age (<20 or ≥20 years)., Results: Eighty-two infants <6 months of age with pertussis were identified. Twenty-eight case-infants (34%) were Hispanic, and 54 (66%) were non-Hispanic. By ethnicity, infants with pertussis were similar in illness confirmation method, sex, age, hospitalization status, vaccination status, child care center attendance, infant birth weight and maternal age. Hispanic infants were more likely than non-Hispanic infants to live in households with >4 persons. Univariate analysis showed Hispanic infants had approximately 2.3 times the risk for pertussis, compared with non-Hispanic infants, and infants living in households >4 persons had approximately 2.4 times the risk for illness, compared with those in households with <4 persons; stratified risk ratios did not differ between Hispanic (2.4; confidence interval: 1.0-5.7]) and non-Hispanic infants (2.0; confidence interval: 1.2-3.5)., Conclusions: A household size of >4 persons is a potential risk factor for pertussis; the magnitude of this risk is similar for Hispanic and non-Hispanic infants.

During July to November 2012, two botulism outbreaks (12 cases total) occurred in one all-male prison; both were associated with illicitly brewed alcohol (pruno) consumption. Inmate surveys were conducted to evaluate and develop prevention and education strategies. Qualitative surveys with open-ended questions were performed among inmates from rooms where outbreaks occurred to learn about pruno consumption. Quantitative surveys assessed knowledge gained after the outbreaks and preferred information sources. For the quantitative surveys, 250 inmates were randomly selected by bed from across the correctional facility and 164 inmates were interviewed. Only 24% of inmates reported any botulism knowledge before the outbreaks and education outreach, whereas 73% reported knowledge after the outbreaks (p < .01). Preferred information sources included handouts/fliers (52%) and the prison television channel (32%)., (© The Author(s) 2015.)

Risk factors for illness during a serogroup C meningococcal disease outbreak among men who have sex with men in New York City, New York, USA, in 2012-2013 included methamphetamine and cocaine use and sexually transmitted infections. Outbreak investigations should consider routinely capturing information regarding drug use and sex-related risk factors.

Objective: Short-term exposure to ground-level ozone has been linked to adverse respiratory and other health effects; previous studies typically have focused on summer ground-level ozone in urban areas. During 2008-2011, Sublette County, Wyoming (population: ~10,000 persons), experienced periods of elevated ground-level ozone concentrations during the winter. This study sought to evaluate the association of daily ground-level ozone concentrations and health clinic visits for respiratory disease in this rural county., Methods: Clinic visits for respiratory disease were ascertained from electronic billing records of the two clinics in Sublette County for January 1, 2008-December 31, 2011. A time-stratified case-crossover design, adjusted for temperature and humidity, was used to investigate associations between ground-level ozone concentrations measured at one station and clinic visits for a respiratory health concern by using an unconstrained distributed lag of 0-3 days and single-day lags of 0 day, 1 day, 2 days, and 3 days., Results: The data set included 12,742 case-days and 43,285 selected control-days. The mean ground-level ozone observed was 47 ± 8 ppb. The unconstrained distributed lag of 0-3 days was consistent with a null association (adjusted odds ratio [aOR]: 1.001; 95% confidence interval [CI]: 0.990-1.012); results for lags 0, 2, and 3 days were consistent with the null. However, the results for lag 1 were indicative of a positive association; for every 10-ppb increase in the 8-h maximum average ground-level ozone, a 3.0% increase in respiratory clinic visits the following day was observed (aOR: 1.031; 95% CI: 0.994-1.069). Season modified the adverse respiratory effects: ground-level ozone was significantly associated with respiratory clinic visits during the winter months. The patterns of results from all sensitivity analyzes were consistent with the a priori model., Conclusions: The results demonstrate an association of increasing ground-level ozone with an increase in clinic visits for adverse respiratory-related effects in the following day (lag day 1) in Sublette County; the magnitude was strongest during the winter months; this association during the winter months in a rural location warrants further investigation., (Published by Elsevier Inc.)

Fungal endophthalmitis is a rare but serious infection. In March 2012, several cases of probable and laboratory-confirmed fungal endophthalmitis occurring after invasive ocular procedures were reported nationwide. We identified 47 cases in 9 states: 21 patients had been exposed to the intraocular dye Brilliant Blue G (BBG) during retinal surgery, and the other 26 had received an intravitreal injection containing triamcinolone acetonide. Both drugs were produced by Franck's Compounding Lab (Ocala, FL, USA). Fusarium incarnatum-equiseti species complex mold was identified in specimens from BBG-exposed case-patients and an unopened BBG vial. Bipolaris hawaiiensis mold was identified in specimens from triamcinolone-exposed case-patients. Exposure to either product was the only factor associated with case status. Of 40 case-patients for whom data were available, 39 (98%) lost vision. These concurrent outbreaks, associated with 1 compounding pharmacy, resulted in a product recall. Ensuring safety and integrity of compounded medications is critical for preventing further outbreaks associated with compounded products.

Microelectromechanical system (MEMS) development has become an active area for research in over the last decade. This area has advanced rapidly in recent years due to the potential ability of MEMS devices to perform complex functions in a smaller area. There is also the prospect to develop devices that can (1) be easily manufactured, (2) offer low power consumption, and (3) reduce waste. Especially in the BioMEMS area these advantages are important in terms of applied devices for biosensing, clinical diagnostics, physiological sensing, flow cytometry, and other lab-on-a-chip applications. However, one major obstacle that has been overlooked is the interface of these microdevices with the macroworld. This is critical to enable applications and development of the technology, as currently testing and analysis of data from these devices is mostly limited to generic microprobe stations. New advancements in BioMEMS have to occur in concert with the development of data acquisition systems and signal preprocessors to fully appreciate and test these developing technologies. In this work, we present the development of a cost effective, high throughput data acquisition system (Bio-HD DAQ) and a signal preprocessor for a MEMS-based cell electrophysiology lab-on-a-Chip (CEL-C) device. The signal preprocessor consists of a printed circuit board mounted with the CEL-C device and a 64-channel filter/amplifier circuit array. The data acquisition system includes a high-density crosspoint switching matrix that connects the signal preprocessor to a 16-channel, 18 bit, and 625 kSs DAQ card. Multimodule custom software designed on LABVIEW 7.0 is used to control the DAQ system. While this version of the Bio-HD DAQ system and accompanying software are designed keeping in view the specific requirements of the CEL-C device, it is highly adaptable and, with minor modifications, can become a generic data acquisition system for MEMS development, testing, and application.

The roles of verbal short-term and working memory were examined in a sample of children with Williams syndrome (mean chronological age 10 years, 2 months) and a sample of grammar-matched children who are developing normally. Forward digit span, nonword repetition, and backward span were all found to be correlated with receptive grammatical ability in the sample of children with Williams syndrome, but not in the sample of children who are developing normally. The relation between working memory, as measured by backward digit span, and grammatical ability was found to be significantly stronger in children with Williams syndrome than in the control group. This finding highlights the possibility that children with Williams syndrome may rely on their working memory to a greater extent than children who are developing normally to learn grammar. Hierarchical regression analyses indicated receptive vocabulary may mediate the relations among forward digit span, backward digit span, and grammatical ability for the children with Williams syndrome. Phonological short-term memory, however, contributed independently to grammatical ability even after receptive vocabulary was taken into account.

Asthma is a complex disease, with an etiology that includes both genetic and environmental influences that may interact. The moderate heritability of asthma has led researchers to investigate its molecular genetic basis using both exploratory investigations of linkage via genome scans, as well as targeted studies of specific candidate genes. Promising candidate genes include the cytokine genes on chromosome 5q23-31. Both genome scans and association studies of these candidate genes/genomic regions have yielded mixed findings, which raise the possibilities of a true relation that emerges more strongly in certain samples simply due to sampling variability, as well as of genetic heterogeneity. Meta-analytic approaches that combine data across samples and examine how findings may vary as a function of effect modifiers can address both of these possibilities. In this study, we used a meta-analytic approach to examine linkage between the interleukin-9 gene (IL9), one of the cytokine genes located on chromosome 5q31, and asthma diagnoses and serum IgE levels in four samples. We analyzed IBD allele sharing for affected, unaffected, and discordant sib pairs, and as a function of sibling differences in IgE levels. We used a recently developed logistic regression-based method that allows for the inclusion of covariates and/or effect modifiers in the analysis of allele sharing in sib-pairs [Rice et al., Genet Epidemiol 17(Suppl. 1):S691-5, 1999]. Sex of the siblings and transmitting parent were considered both as covariates and effect modifiers in analyses. The results provided little evidence for linkage, or for heterogeneity therein due to sex or transmitting parent, either within or across samples.

Williams syndrome is a rare neurodevelopmental disorder caused by a hemizygous deletion of approximately 1.5 megabases on chromosome 7q11.23. In this article, we outline a Williams Syndrome Cognitive Profile (WSCP) that operationalizes the cognitive characteristics of the syndrome using measures of absolute and relative performance on subtests of the Differential Abilities Scales (Elliot, 1990a). Testing confirmed excellent sensitivity and specificity scores for the WSCP. Seventy-four of 84 individuals with Williams syndrome fit the WSCP while only 4 participants in a contrast group met all of the WSCP criteria. It was also found that the WSCP does not vary greatly with chronological age or overall level of cognitive ability for individuals with Williams syndrome. Possible applications for the WSCP include psychoeducational evaluation and empirical research such as the search for genotype/phenotype relations in this genetically based syndrome., (Copyright 2000 Academic Press.)

School-aged children and adults with Williams syndrome have repeatedly been found to evidence an expressive vocabulary advantage relative to same-aged individuals with Down syndrome. However, Singer Harris, Bellugi, Bates, Jones, and Rossen (1997) argued that this advantage is reversed during the initial period of language acquisition; during this time, children with Down syndrome have larger expressive vocabularies than children with Williams syndrome. This result may have been due to methodological problems, however. This study uses a different design to reconsider the question of whether toddlers with Williams syndrome show an expressive vocabulary advantage over same-aged toddlers with Down syndrome. Parents of twenty-four 2-year-olds with Williams syndrome and twenty-eight 2-year-olds with Down syndrome completed the vocabulary checklist from the MacArthur Communicative Development Inventory: Words and Sentences. The 2 groups were carefully matched for chronological age (CA). Results indicated that the toddlers with Williams syndrome had substantially and significantly larger expressive vocabulary sizes than did the CA-matched children with Down syndrome. Additional analyses of children for whom data were available between the ages of 2 years 0 months and 2 years 3 months indicated that the expressive vocabulary advantage for children with Williams syndrome was present even at this very young age when none of the children had begun to produce word combinations. The Discussion section that follows addresses the discrepancy between these findings and those of Singer Harris et al. and considers the variability present within both the Williams syndrome and Down syndrome samples. Also discussed is the continuity across the lifespan in both the expressive vocabulary advantage shown by individuals with Williams syndrome relative to same-aged individuals with Down syndrome and the expressive vocabulary variability within each syndrome.

The transmission disequilibrium test (TDT), designed as a test of linkage in the presence of association (i.e. linkage disequilibrium), has received considerable attention in the recent statistical genetics literature due to its advantages over other within-family analytic methods. One limitation of the conventional TDT is its application solely to linkage disequilibrium between a genetic marker and a single categorical trait (e.g. presence or absence of a disease). In this paper, we present an extension of the TDT using logistic regression to examine the relation between a candidate gene or genetic marker and one or more continuous or categorical explanatory variables. This logistic regression extension of the TDT possesses all of the desirable features of the conventional TDT, as well as many advantages associated with traditional regression analysis. We describe the model and its properties, as well as a number of its possible applications, and apply it to examine linkage disequilibrium between the dopamine receptor D2 gene (DRD2) and symptoms of childhood attention deficit hyperactivity disorder (ADHD). We also briefly compare the logistic regression TDT to other quantitative TDTs that have been proposed in the literature, and highlight the advantages of a regression-based approach for examining the relation between a candidate gene and one or more continuous or categorical traits. Given its features, we regard the logistic regression extension of the TDT as a flexible new data analytic method with extensive potential applications to problems in medical, psychiatric, and behavioral genetics.

The transmission disequilibrium test (TDT) recently has become a popular method of testing for linkage in the presence of association due to its simplicity and advantages over other within-family analytic methods. In this paper, we describe a logistic regression extension to the TDT that can be used to test for differences in linkage disequilibrium as a function of one or more continuous and/or categorical explanatory variables. We highlight important features of this method and demonstrate some of its possible uses. We applied these analyses to test for linkage disequilibrium between the dopamine receptor D2 (DRD2) and alcohol dehydrogenase 3 (ADH3) genes and both diagnostic and quantitative indices of alcoholism. Using data from the Collaborative Study on the Genetics of Alcoholism data set, we found evidence suggesting linkage disequilibrium between DRD2 and ADH3 and quantitative indices of alcoholism and correlated phenotypes corresponding to smoking and personality. None of the evidence for linkage disequilibrium varied by sex or age.

The early lexical and grammatical development of 1 male child is examined with growth curves and dynamic-systems modeling procedures. Lexical-development described a pattern of logistic growth (R2 = .98). Lexical and plural development shared the following characteristics: Plural growth began only after a threshold was reached in vocabulary size; lexical growth slowed as plural growth increased. As plural use reached full mastery, lexical growth began again to increase. It was hypothesized that a precursor model (P. van Geert, 1991) would fit these data. Subsequent testing indicated that the precursor model, modified to incorporate brief yet intensive plural growth, provided a suitable fit. The value of the modified precursor model for the explication of processes implicated in language development is discussed.

Since its introduction into the statistical genetics literature, the transmission disequilibrium test (TDT) has seen widespread use in analyses of linkage and association due not only to its simplicity but also to its desirable properties relative to other within-family analytic methods. In this paper, we describe an extension to the TDT useful for examining genetic heterogeneity. This extension uses contingency table analyses such as log-linear analysis to test for differences in linkage disequilibrium across levels of one or more moderator variables. We applied these analyses to test for linkage disequilibrium between the dopamine transporter gene (DAT1) and bipolar disorder, as well as for genetic heterogeneity due to sex, diagnostic breadth, and study site. Using data from two studies (the UCSD/UBC and Cardiff data sets), we found evidence suggesting linkage disequilibrium between DAT1 and bipolar disorder, as well as heterogeneity due to diagnostic breadth and study site.

To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition.

The word-learning ability of 12 school-age subjects with moderate or severe mental retardation was assessed. Subjects had little or no functional speech and used the System for Augmenting Language with visual-graphic symbols for communication. Their ability to fast map novel symbols revealed whether they possessed the novel name-nameless category (N3C) lexical operating principle. On first exposure, 7 subjects were able to map symbol meanings for novel objects. Follow-up assessments indicated that mappers retained comprehension of some of the novel words for up to delays of 15 days and generalized their knowledge to production. Ability to fast map reliably was related to symbol achievement status. Implications for understanding vocabulary acquisition by youth with mental retardation were discussed.

The cholesterol:phospholipid ratio was measured in platelet plasma membrane, red blood cell (RBC) membranes, low density lipoprotein (LDL) and whole plasma in patients with primary hypertension and in matched normal controls. The cholesterol:phospholipid ratio was raised in the platelet membrane from hypertensive patients compared with that from normal controls (0.65 +/- 0.03 vs 0.53 +/- 0.02: mean +/- SEM; P less than 0.01). The ratio observed in RBC membranes, LDL and whole blood was similar in the two groups. If this abnormality in the lipid composition of platelet plasma membrane is present in other cells it could account for some of the changes in cell membrane function that have been described in hypertension.

Vascular smooth muscle is activated through 2 major systems. One, which can be inhibited by calcium-entry blocking agents, involves the influx of calcium through potential-sensitive channels. The other, which can be inhibited by sodium nitroprusside, involves the entry of calcium through agonist-controlled channels and probably its mobilization from within the cell as well. Human veins, muscular arteries and resistance vessels show differing patterns of response to agents that selectively inhibit the 2 activation systems. The responses indicate that physiologic contractions of cutaneous veins and muscular arteries depend on the agonist-controlled system; contractions of veins induced by high concentrations of potassium depend on the potential-sensitive system as, probably, does local spasm in arteries. The tone of resistance vessels depends on a balance between the potential-sensitive and agonist-controlled systems. The forearm resistance vessels of men with primary hypertension respond to verapamil with larger-than-normal dilatation compared with that induced by nitroprusside. This is interpreted as showing an increased contribution to resistance vessel tone from the potential-sensitive system. This functional abnormality does not depend on the inhibition of sodium pump activity that is known to occur in hypertension, because it cannot be reproduced by local infusion of ouabain. It probably results from a primary disorder of calcium handling by the cell membrane.

1. Major differences in physiological and pharmacological responsiveness may be observed between blood vessels that differ either in anatomical type or in that they serve different organs or tissues. 2. The intrinsic properties of the vascular smooth muscle appears to differ little between species. No important differences in noradrenergic innervation have been observed, but major differences may exist in neural dilator systems. A few differences have been demonstrated that can be attributed to variations in the receptor population. No clear differences in local humoral mechanisms are known. There is, however, an insufficient number of strictly comparable studies in different species and it is likely that more differences will be found as our knowledge of vascular responsiveness is extended.

Calcium-entry blocking agents resemble established dilators such as diazoxide, minoxidil and hydralazine in that they act predominantly on the arterial resistance vessels and have little or no effect upon the veins. They have therefore been evaluated in the treatment of hypertension. Controlled studies have shown that verapamil and nifedipine are effective in decreasing blood pressure when given as sole agents. The antihypertensive effect of nifedipine is additive with that of a beta blocker, and nifedipine is also effective when given as a "third step" agent in combination with a beta blocker (or alpha methyldopa) and a diuretic. In contrast to other directly acting dilators, nifedipine causes, at most, only moderate stimulation of renin secretion and verapamil does not increase renin release at all; neither drug induces sodium retention. Both verapamil and nifedipine produce a moderate incidence of unwanted effects; these are mostly subjective in nature, but verapamil may cause constipation that is occasionally severe and nifedipine sometimes causes ankle swelling. Calcium-entry blockers should be considered as initial therapy when some contraindication exists to the use of other standard drugs. Nifedipine appears preferable to hydralazine for use in combination with a beta blocker and a diuretic: it is at least as effective as hydralazine and has a lower incidence of serious adverse effects.

Verapamil and nifedipine are calcium-blocking agents that have a selective dilator effect on resistance vessels. Both drugs have been shown to lower arterial pressure when given in long-term therapy under conditions of a double-blind controlled trial. Both agents may be effective as sole therapy or when given in combination with a diuretic; nifedipine has been used successfully in conjunction with beta-adrenoceptor antagonist/diuretic combinations. Calcium-blocking agents do not evoke tolerance in long-term treatment; in contrast to other directly acting dilator drugs, they do not consistently lead to a rise in plasma renin activity and they induce little or no sodium retention. Calcium-blocking agents do not all share the same mechanism of action, and they vary considerably in their effect on the heart. These differences may be important in determining which compound is best suited for use in particular clinical situations.

Local infusion of verapamil induced a significantly greater dilatation in the forearm resistance vessels of men with primary hypertension than that observed in a control group of men with normal arterial pressure; the response to sodium nitroprusside, however, was reduced. These findings indicate an abnormality in the mechanisms by which resistance vessel tone is maintained in patients with raised arterial pressure and they suggest that calcium channel blockers may be particularly suited for use as arteriolar dilators in hypertension. In an open trial in patients with hypertension that was inadequately controlled by the combination of a beta-adrenoceptor antagonist and a diuretic, nifedipine was shown to be effective in causing a further fall in arterial pressure; this finding was confirmed in a subsequent double-blind, placebo controlled study.

The effect on the forearm resistance vessels of small increases in the local plasma concentration of calcium and magnesium has been examined in 20 men with primary hypertension. Studies were carried out by a standard plethysmographic method with infusion of drugs into the brachial artery. Infusion of calcium at 10 mumol/min into the forearm caused basal blood flow to fall by 9% (n = 17;0.1 greater than P greater than 0.05) and the dilator response to verapamil to fall by 28% (P less than 0.005). Infusion of magnesium at the same rate caused basal blood flow to rise by 22% (n = 12; P less than 0.05), but the dilator response to verapamil was not significantly changed. The response of the resistance vessels to verapamil is known to be enhanced in patients with hypertension, and the results show that this response is attenuated by a small increase in the local calcium concentration. The findings are consistent with the view that altered handling of calcium by the cell membrane contributes to the functional abnormality of the hypertensive resistance vessel.

The effect of beta-blockers in improving exercise tolerance in angina pectoris can be accounted for by the reduction in heart rate and arterial pressure than they produce. The failure of a few patients to respond despite reduction in heart rate and the failure of those who do respond to obtain the full expected benefit suggests that beta-blockade has some action that offsets in while or in part the advantage gained from reduction in heart rate and pressure. This action might include an increase in left ventricular size with consequent increase in work, or an increase in left ventricular diastolic pressure with resultant impairment of blood flow to the inner layers of the myocardium.

1. The response of the forearm resistance vessels to local intra-arterial infusion of verapamil and sodium nitroprusside has been assessed by a plethysmographic method in 23 men with normal arterial pressure and 35 men with primary hypertension. 2. In the 20 patients with hypertension for whom full dose-response curves were determined, the dilator response to verapamil was significantly greater than that in the normal controls, whereas the response to sodium nitroprusside was reduced. 3. Comparison of responses to the two dilators in individual subjects enabled the scattering effect of variables common to both drugs to be reduced. Analysis of the results in this way showed a highly significant difference between the hypertensive men as a whole and the normotensive controls (P less than 0.00001); 24 out of the 35 hypertensive men showed responses that were outside the normal range. 4. The abnormal pattern of response observed in the hypertensive group cannot be accounted for by structural changes in the vessels and strongly suggests a functional abnormality of the vascular smooth muscle.

Differences in the activation systems by which contraction is maintained in blood vessels of different types are an important cause of selectivity in the action of dilator agents. The sympathetic nervous system is the main stimulus for contraction in the limb veins whereas intrinsic (or myogenic) tone makes an important contribution to the contraction of resistance vessels. Drugs that inhibit the effect of the sympathetic nervous system are therefore selective dilators of the veins and drugs that prevent membrane depolarization or block calcium channels are strongly selective for resistance vessels. Substances such as the nitrovasodilators that increase intracellular concentrations of cyclic (c)GMP act preferentially on the veins. Those that act by increasing the concentrations of cyclic (c)AMP show little selectivity unless, as with the beta-adrenoceptor agonists, they act through receptors whose distribution varies between vessels. Differences in the distribution of receptors may also be important in the action of some other vasoactive substances such as the prostaglandins.

Using polarization measurements, the reflectance factor R(theta(i),phi(i),theta(r),phi(r)) of two wheat canopies is divided into components due to specularly and diffusely reflected light. The data show that two key angles may be predicted, the angle of the polarizer for minimum flux and the angle of incidence of sunlight specularly reflected by a leaf to a sensor. The results show that specular reflection is a key aspect to radiation transfer by two canopies. Results suggest that the advent of heading in wheat may be remotely sensed from polarization measurements of the canopy reflectance.