Showing papers by "University of Maryland, Baltimore published in 2001"

Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression.

Abstract: Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines.

An emerging ground-based aerosol climatology: Aerosol optical depth from AERONET

Abstract: Long-term measurements by the AERONET program of spectral aerosol optical depth, precipitable water, and derived Angstrom exponent were analyzed and compiled into an aerosol optical properties climatology. Quality assured monthly means are presented and described for 9 primary sites and 21 additional multiyear sites with distinct aerosol regimes representing tropical biomass burning, boreal forests, midlatitude humid climates, midlatitude dry climates, oceanic sites, desert sites, and background sites. Seasonal trends for each of these nine sites are discussed and climatic averages presented.

Determinants of Viral Clearance and Persistence during Acute Hepatitis C Virus Infection

Abstract: The virological and immunological features of hepatitis C virus (HCV) infection were studied weekly for 6 months after accidental needlestick exposure in five health care workers, four of whom developed acute hepatitis that progressed to chronicity while one subject cleared the virus. In all subjects, viremia was first detectable within 1–2 weeks of inoculation, 1 month or more before the appearance of virus-specific T cells. The subject who cleared the virus experienced a prolonged episode of acute hepatitis that coincided with a CD38+ IFN-γ− CD8+ T cell response to HCV and a small reduction in viremia. Subsequently, a strong CD4+ T cell response emerged and the CD8+ T cells became CD38− and started producing IFN-γ in response to HCV, coinciding with a rapid 100,000-fold decrease in viremia that occurred without a corresponding surge of disease activity. Chronic infection developed in two subjects who failed to produce a significant T cell response and in two other subjects who initially mounted strong CD4+ T cell responses that ultimately waned. In all subjects, viremia was higher at the peak of acute hepatitis than it was when the disease began, and the disease improved during the viremia. These results provide the first insight into the host–virus relationship in humans during the incubation phase of acute HCV infection, and they provide the only insight to date into the virological and immunological characteristics of clinically asymptomatic acute HCV infection, the commonest manifestation of this disease. In addition, the results suggest that the vigor and quality of the antiviral T cell response determines the outcome of acute HCV infection, that the ability of HCV to outpace the T cell response may contribute to its tendency to persist; that the onset of hepatitis coincides with the onset of the CD8+T cell response, that disease pathogenesis and viral clearance are mediated by different CD8+ T cell populations that control HCV by both cytolytic and noncytolytic mechanisms, and that there are different pathways to viral persistence in asymptomatic and symptomatic acute HCV infection.

A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport

Abstract: The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the alpha (NR1C1) and gamma (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the delta (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPARdelta agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Our results suggest that PPARdelta agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

A molecular marker for chloroquine-resistant falciparum malaria.

Abstract: Background Chloroquine-resistant Plasmodium falciparum malaria is a major health problem, particularly in sub-Saharan Africa. Chloroquine resistance has been associated in vitro with point mutations in two genes, pfcrt and pfmdr 1, which encode the P. falciparum digestive-vacuole transmembrane proteins PfCRT and Pgh1, respectively. Methods To assess the value of these mutations as markers for clinical chloroquine resistance, we measured the association between the mutations and the response to chloroquine treatment in patients with uncomplicated falciparum malaria in Mali. The frequencies of the mutations in patients before and after treatment were compared for evidence of selection of resistance factors as a result of exposure to chloroquine. Results The pfcrt mutation resulting in the substitution of threonine (T76) for lysine at position 76 was present in all 60 samples from patients with chloroquine-resistant infections (those that persisted or recurred after treatment), as compared with a base-line p...

The Brain Metabolite Kynurenic Acid Inhibits α7 Nicotinic Receptor Activity and Increases Non-α7 Nicotinic Receptor Expression: Physiopathological Implications

Abstract: The tryptophan metabolite kynurenic acid (KYNA) has long been recognized as an NMDA receptor antagonist. Here, interactions between KYNA and the nicotinic system in the brain were investigated using the patch-clamp technique and HPLC. In the electrophysiological studies, agonists were delivered via a U-shaped tube, and KYNA was applied in admixture with agonists and via the background perfusion. Exposure (≥4 min) of cultured hippocampal neurons to KYNA (≥100 nm) inhibited activation of somatodendritic α7 nAChRs; the IC50 for KYNA was ∼7 μm. The inhibition of α7 nAChRs was noncompetitive with respect to the agonist and voltage independent. The slow onset of this effect could not be accounted for by an intracellular action because KYNA (1 mm) in the pipette solution had no effect on α7 nAChR activity. KYNA also blocked the activity of preterminal/presynaptic α7 nAChRs in hippocampal neurons in cultures and in slices. NMDA receptors were less sensitive than α7 nAChRs to KYNA. The IC50 values for KYNA-induced blockade of NMDA receptors in the absence and presence of glycine (10 μm) were ∼15 and 235 μm, respectively. Prolonged (3 d) exposure of cultured hippocampal neurons to KYNA increased their nicotinic sensitivity, apparently by enhancing α4β2 nAChR expression. Furthermore, as determined by HPLC with fluorescence detection, repeated systemic treatment of rats with nicotine caused a transient reduction followed by an increase in brain KYNA levels. These results demonstrate that nAChRs are targets for KYNA and suggest a functionally significant cross talk between the nicotinic cholinergic system and the kynurenine pathway in the brain.

Chloroquine-Resistant Malaria

Abstract: The development of chloroquine as an antimalarial drug and the subsequent evolution of drug-resistant Plasmodium strains had major impacts on global public health in the 20th century. In P. falciparum, the cause of the most lethal human malaria, chloroquine resistance is linked to multiple mutations in PfCRT, a protein that likely functions as a transporter in the parasite's digestive vacuole membrane. Rapid diagnostic assays for PfCRT mutations are already employed as surveillance tools for drug resistance. Here, we review recent field studies that support the central role of PfCRT mutations in chloroquine resistance. These studies suggest chloroquine resistance arose in > or = 4 distinct geographic foci and substantiate an important role of immunity in the outcomes of resistant infections after chloroquine treatment. P. vivax, which also causes human malaria, appears to differ from P. falciparum in its mechanism of chloroquine resistance. Investigation of the resistance mechanisms and of the role of immunity in therapeutic outcomes will support new approaches to drugs that can take the place of chloroquine or augment its efficiency.

Spatial and temporal independent component analysis of functional MRI data containing a pair of task-related waveforms.

Abstract: r r Abstract: Independent component analysis (ICA) is a technique that attempts to separate data into maximally independent groups. Achieving maximal independence in space or time yields two varieties of ICA mean- ingful for functional MRI (fMRI) applications: spatial ICA (SICA) and temporal ICA (TICA). SICA has so far dominated the application of ICA to fMRI. The objective of these experiments was to study ICA with two predictable components present and evaluate the importance of the underlying independence assumption in the application of ICA. Four novel visual activation paradigms were designed, each consisting of two spatiotemporal components that were either spatially dependent, temporally dependent, both spatially and temporally dependent, or spatially and temporally uncorrelated, respectively. Simulated data were generated and fMRI data from six subjects were acquired using these paradigms. Data from each paradigm were analyzed with regression analysis in order to determine if the signal was occurring as expected. Spatial and temporal ICA were then applied to these data, with the general result that ICA found components only where expected, e.g., S(T)ICA "failed" (i.e., yielded independent components unrelated to the "self-evident" com- ponents) for paradigms that were spatially (temporally) dependent, and "worked" otherwise. Regression analysis proved a useful "check" for these data, however strong hypotheses will not always be available, and a strength of ICA is that it can characterize data without making specific modeling assumptions. We report a careful examination of some of the assumptions behind ICA methodologies, provide examples of when applying ICA would provide difficult-to-interpret results, and offer suggestions for applying ICA to fMRI data especially when more than one task-related component is present in the data. Hum. Brain Mapping 13:43-53, 2001. © 2001 Wiley-Liss, Inc.

Functional annotation of a full-length mouse cDNA collection

Abstract: The RIKEN Mouse Gene Encyclopaedia Project, a systematic approach to determining the full coding potential of the mouse genome, involves collection and sequencing of full-length complementary DNAs and physical mapping of the corresponding genes to the mouse genome. We organized an international functional annotation meeting (FANTOM) to annotate the first 21,076 cDNAs to be analysed in this project. Here we describe the first RIKEN clone collection, which is one of the largest described for any organism. Analysis of these cDNAs extends known gene families and identifies new ones.

Obesity and health-related quality of life.

Abstract: Although it is well documented that obesity is strongly associated with morbidity and mortality, less is known about the impact of obesity on functional status and health-related quality of life (HRQL). However, in recent years research has been conducted to estimate the impact of obesity on HRQL, and to determine the effects of weight reduction on HRQL. The majority of published studies indicate that obesity impairs HRQL, and that higher degrees of obesity are associated with greater impairment. Obesity-associated decrements on HRQL tend to be most pronounced on physical domains of functioning. Studies of the effect of obesity surgery among morbidly obese patients indicate that this procedure produces significant and sustained improvements in the majority of HRQL indices; among mild-to-moderately obese persons, modest weight reduction derived from lifestyle modification also appears to improve HRQL, at least in the short term. Additional research is needed to (1) further characterize the effect that obesity has on HRQL; (2) estimate the short- and long-term effects of various methods of weight reduction (e.g. surgery, lifestyle modification) on HRQL; (3) improve both the conceptualization and measurement of HRQL to incorporate the personal preferences and values of the patient; and (4) develop ways to enhance and sustain positive changes in HRQL, even if weight maintenance is elusive.

Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality.

Abstract: Background: Non‐high-density lipoprotein cholesterol (non‐HDL-C) contains all known and potential atherogenic lipid particles. Therefore, non‐HDL-C level may be as good a potential predictor of risk for cardiovascular disease (CVD) as low-density lipoprotein cholesterol (LDL-C). Objectives: Todeterminewhethernon‐HDL-Clevelcould be useful in predicting CVD mortality and to compare the predictive value of non‐HDL-C and LDL-C levels. Methods: Data are from the Lipid Research Clinics Program Follow-up Study, a mortality study with baseline data gathered from 1972 through 1976, and mortality ascertained through 1995. A total of 2406 men and 2056 women aged 40 to 64 years at entry were observed for an average of 19 years, with CVD death as the main outcome measure. Results: A total of 234 CVD deaths in men and 113 CVD deaths in women occurred during follow-up. Levels of HDL-C and non‐HDL-C at baseline were significant and strong predictors of CVD death in both sexes. In contrast, LDL-C level was a somewhat weaker predictor of CVD death in both. Differences of 0.78 mmol/L (30 mg/ dL) in non‐HDL-C and LDL-C levels corresponded to increases in CVD risk of 19% and 15%, respectively, in men. In women, differences of 0.78 mmol/L (30 mg/dL) in non‐HDL-C and LDL-C levels corresponded to increases in CVD risk of 11% and 8%, respectively. Conclusions: Non‐HDL-C level is a somewhat better predictor of CVD mortality than LDL-C level. Screening for non‐HDL-C level may be useful for CVD risk assessment.

Complex HLA-DR and -DQ Interactions Confer Risk of Narcolepsy-Cataplexy in Three Ethnic Groups

Abstract: Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB1*0602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA1*0102 and -DQB1*0602. A strong predisposing effect was observed in DQB1*0602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB1*0602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB1*0602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Three alleles—DQB1*0601, DQB1*0501, and DQA1*01 (non-DQA1*0102)—were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of λ statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.

Usher Syndrome 1D and Nonsyndromic Autosomal Recessive Deafness DFNB12 Are Caused by Allelic Mutations of the Novel Cadherin-Like Gene CDH23

Abstract: Genes causing nonsyndromic autosomal recessive deafness (DFNB12) and deafness associated with retinitis pigmentosa and vestibular dysfunction (USH1D) were previously mapped to overlapping regions of chromosome 10q21-q22. Seven highly consanguineous families segregating nonsyndromic autosomal recessive deafness were analyzed to refine the DFNB12 locus. In a single family, a critical region was defined between D10S1694 and D10S1737, ∼0.55 cM apart. Eighteen candidate genes in the region were sequenced. Mutations in a novel cadherin-like gene, CDH23, were found both in families with DFNB12 and in families with USH1D. Six missense mutations were found in five families with DFNB12, and two nonsense and two frameshift mutations were found in four families with USH1D. A northern blot analysis of CDH23 showed a 9.5-kb transcript expressed primarily in the retina. CDH23 is also expressed in the cochlea, as is demonstrated by polymerase chain reaction amplification from cochlear cDNA.

The biomechanics of vertebroplasty. The effect of cement volume on mechanical behavior.

Abstract: Study Design. Ex vivo biomechanical study using osreoporotic cadavetic vertebral bodies. Objective. To determine the association between the volume of compent injected during percutaneous vertebroplasty and the restoration of strength and stiffness in osteoporotic vertebral bodies, two investigational cements were studied: Orthocomp (Orthovita, Malvern, PA) and Simplex 20 (Simplex P with 20% by weight barium sulfate content: Stryker-Howmedica-Osteonics, Rutherford, NJ). Summary of Background Data. Previous biomechanical studies have shown that injections of 8-10 mL of cement during vertebroplasty restore or increase vertebral body strength and stiffness; however, the doseresponse association between cement volume and restoration of strength and stiffness is unknown. Methods. Compression fractures were experimentally created in 144 vertebral bodies (T6-L5) obtained from 12 osteoporotic spines harvested from female cadavers. After initial strength and stiffness were determined, the vertebral bodies were stabilized using bipedicular injections of cement totaling 2, 4, 6, or 8 mL and recompressed, after which post-treatment strength and stiffness were measured. Strength and stiffness were considered restored when post-treatment values were not significantly different from initial values. Results. Strength was restored for all regions when 2 mL of either cement was injected. To restore stiffness with Orthocomp, the thoracic and thoracolumbar regions required 4 mL, but the lumbar region required 6 mL. To restore stiffness with Simplex 20, the thoracic and lumbar regions required 4 mL, but the thoracolumbar region required 8 mL. Conclusion. These data provide guidance on the cement volumes needed to restore biomechanical integrity to compressed osteoporotic vertebral bodies.

The comprehensive microbial resource

Abstract: The Comprehensive Microbial Resource or CMR (http://cmr.jcvi.org) provides a web-based central resource for the display, search and analysis of the sequence and annotation for complete and publicly available bacterial and archaeal genomes. In addition to displaying the original annotation from GenBank, the CMR makes available secondary automated structural and functional annotation across all genomes to provide consistent data types necessary for effective mining of genomic data. Precomputed homology searches are stored to allow meaningful genome comparisons. The CMR supplies users with over 50 different tools to utilize the sequence and annotation data across one or more of the 571 currently available genomes. At the gene level users can view the gene annotation and underlying evidence. Genome level information includes whole genome graphical displays, biochemical pathway maps and genome summary data. Comparative tools display analysis between genomes with homology and genome alignment tools, and searches across the accessions, annotation, and evidence assigned to all genes/genomes are available. The data and tools on the CMR aid genomic research and analysis, and the CMR is included in over 200 scientific publications. The code underlying the CMR website and the CMR database are freely available for download with no license restrictions.

From the archives of the AFIP. Imaging of giant cell tumor and giant cell reparative granuloma of bone: Radiologie-pathologic correlation

Abstract: The radiologic features of giant cell tumor (GCT) and giant cell reparative granuloma (GCRG) of bone often strongly suggest the diagnosis and reflect their pathologic appearance. At radiography, GCT often demonstrates a metaepiphyseal location with extension to subchondral bone. GCRG has a similar appearance but most commonly affects the mandible, maxilla, hands, or feet. Computed tomography and magnetic resonance (MR) imaging are helpful in staging lesions, particularly in delineating soft-tissue extension. Cystic (secondary aneurysmal bone cyst) components are reported in 14% of GCTs. However, biopsy must be directed at the solid regions, which harbor diagnostic tissue. These solid components demonstrate low to intermediate signal intensity at T2-weighted MR imaging, a feature that can be helpful in diagnosis. Multiple GCTs, although rare, do occur and may be associated with Paget disease. Malignant GCT accounts for 5%–10% of all GCTs and is usually secondary to previous irradiation of benign GCT. Treat...

Virulence Functions of Autotransporter Proteins

Abstract: Bacterial pathogens must execute a prodigious array of complex functions in order to survive, multiply, and disseminate within mammalian hosts. Virulence determinants are usually proteinaceous in nature and are often either secreted to the bacterial cell surface or released into the external

Evidence-based practices for services to families of people with psychiatric disabilities.

Abstract: Family psychoeducation is an evidence-based practice that has been shown to reduce relapse rates and facilitate recovery of persons who have mental illness. A core set of characteristics of effective family psychoeducation programs has been developed, including the provision of emotional support, education, resources during periods of crisis, and problem-solving skills. Unfortunately, the use of family psychoeducation in routine practice has been limited. Barriers at the level of the consumer and his or her family members, the clinician and the administrator, and the mental health authority reflect the existence of attitudinal, knowledge-based, practical, and systemic obstacles to implementation. Family psychoeducation dissemination efforts that have been successful to date have built consensus at all levels, including among consumers and their family members; have provided ample training, technical assistance, and supervision to clinical staff; and have maintained a long-term perspective.

Quorum Sensing Is a Global Regulatory Mechanism in Enterohemorrhagic Escherichia coli O157:H7

Abstract: Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is responsible for outbreaks of bloody diarrhea and hemolytic-uremic syndrome in many countries. EHEC virulence mechanisms include the production of Shiga toxins (Stx) and formation of attaching and effacing (AE) lesions on intestinal epithelial cells. We recently reported that genes involved in the formation of the AE lesion were regulated by quorum sensing through autoinducer-2, which is synthesized by the product of the luxS gene. In this study we hybridized an E. coli gene array with cDNA synthesized from RNA that was extracted from EHEC strain 86-24 and its isogenic luxS mutant. We observed that 404 genes were regulated by luxS at least fivefold, which comprises approximately 10% of the array genes; 235 of these genes were up-regulated and 169 were down-regulated in the wild-type strain compared to in the luxS mutant. Down-regulated genes included several involved in cell division, as well as ribosomal and tRNA genes. Consistent with this pattern of gene expression, the luxS mutant grows faster than the wild-type strain (generation times of 37.5 and 60 min, respectively, in Dulbecco modified Eagle medium). Up-regulated genes included several involved in the expression and assembly of flagella, motility, and chemotaxis. Using operon::lacZ fusions to class I, II, and III flagellar genes, we were able to confirm this transcriptional regulation. We also observed fewer flagella by Western blotting and electron microscopy and decreased motility halos in semisolid agar in the luxS mutant. The average swimming speeds for the wild-type strain and the luxS mutant are 12.5 and 6.6 μm/s, respectively. We also observed an increase in the production of Stx due to quorum sensing. Genes encoding Stx, which are transcribed along with λ-like phage genes, are induced by an SOS response, and genes involved in the SOS response were also regulated by quorum sensing. These results indicate that quorum sensing is a global regulatory mechanism for basic physiological functions of E. coli as well as for virulence factors.

CNS Region-Specific Oxytocin Receptor Expression: Importance in Regulation of Anxiety and Sex Behavior

Abstract: The oxytocin receptor (OTR) is differentially expressed in the CNS. Because there are multiple mechanisms by which the OTR can be transcriptionally induced, we hypothesized that differences in OTR expression may be explained by activation of distinct signal transduction pathways and may be critical for the control of anxiety and sex behaviors. To determine the regulation and functional significance of this expression, we infused female rats with modifiers of protein kinases before assaying for behavior and oxytocin receptor binding. In the ventromedial nucleus of the hypothalamus (VMH), estrogen-dependent induction of oxytocin receptors required protein kinase C activation, and oxytocin infused here promoted female sex behavior but had no effect on anxiety. In contrast, dopamine controlled tonic oxytocin receptor expression in the central nucleus of the amygdala (cAmyg) through activation of protein kinase A, and oxytocin infused here was anxiolytic but had no effect on female sex behavior. Therefore, we have identified brain region-specific regulation of the OTR in the VMH and cAmyg. Distinct signal transduction pathways regulating receptor expression and binding in each brain region may mediate in part the ability of oxytocin to exert these differential behavioral effects.

Comorbidity of the nonmotor symptoms of Parkinson's disease

Abstract: Many patients with Parkinson's disease (PD) have clinically significant anxiety, depression, fatigue, sleep disturbance, or sensory symptoms. The comorbidity of these nonmotor symptoms and their relationship to PD severity has not been extensively evaluated. Ninety- nine nondemented PD patients were evaluated with the following battery of tests: Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), Fatigue Severity Scale (FSS), Pittsburgh Sleep Quality Index (PSQI), a sensory symptom questionnaire, Unified Parkinson's Disease Rating Scale (UPDRS), Hoehn & Yahr (H/Y) Stage, and the Schwab & England ADL scale (S/E). The comorbidity of the nonmotor symptoms and their relationship to PD severity was analyzed. Thirty-six percent of the study population had depression (BDI ≥10), 33% had anxiety (BAI ≥10), 40% had fatigue (FSS > 4), 47% had sleep disturbance (PSQI > 5), and 63% reported sensory symptoms. Only 12% of the sample had no nonmotor symptoms. Fifty-nine percent of the patients had two or more nonmotor symptoms, and nearly 25% had four or more. Increased comorbidity was associated with greater PD severity (P < 001). This study reveals that the nonmotor symptoms of PD frequently occur together in the same patients. Increased comorbidity of the five nonmotor symptoms was associated with greater PD severity. These results suggest that recognition of these diverse nonmotor symptoms may be enhanced by looking for others when one nonmotor symptom has been identified. © 2001 Movement Disorder Society.

Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F.

Abstract: Human chromosome 10q21-22 harbors USH1F in a region of conserved synteny to mouse chromosome 10. This region of mouse chromosome 10 contains Pcdh15, encoding a protocadherin gene that is mutated in ames waltzer and causes deafness and vestibular dysfunction. Here we report two mutations of protocadherin 15 (PCDH15) found in two families segregating Usher syndrome type 1F. A Northern blot probed with the PCDH15 cytoplasmic domain showed expression in the retina, consistent with its pathogenetic role in the retinitis pigmentosa associated with USH1F.