Pendred syndrome maps to chromosome 7q21-34 and is caused by an intrinsic defect in thyroid iodine organification.

Exactly 100 years ago, in 1896, Pendred first described the association of congenital deafness with thyroid goitre (MM#274600). The incidence of Pendred syndrome is estimated at 7.5-10/100,000, and may be responsible for as much as 10% of hereditary deafness. The cause of the congenital deafness in Pendred syndrome is obscure, although a Mondini type malformation of the cochlea exists in some patients. The reason for the association between the thyroid and cochlear defects is similarly obscure, leading some investigators to suggest that the two recessive defects may be occurring together by chance in highly consanguineous families. An in vivo defect in thyroid iodine organification in Pendred syndrome patients has been reported. However, the molecular basis of this defect is unknown and the presence of an intrinsic thyroidal defect has not been conclusively demonstrated. We have adopted a genetic linkage study as a first step towards identifying the gene. The availability of an inbred Pendred syndrome kindred allowed us to utilize an efficient DNA pooling strategy to perform a genome-wide linkage search for the disease locus. In this way, we have mapped the disease locus to an approximately 9-cM interval between GATA23F5 and D7S687 on chromosome 7. In addition, we demonstrate an intrinsic thyroid iodine organification defect in a patient's thyroid cells as the cause of the thyroid dysfunction.

Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).

Pendred syndrome is a recessively inherited disorder with the hallmark features of congenital deafness and thyroid goitre. By some estimates, the disorder may account for upwards of 10% of hereditary deafness. Previous genetic linkage studies localized the gene to a broad interval on human chromosome 7q22-31.1. Using a positional cloning strategy, we have identified the gene (PDS) mutated in Pendred syndrome and found three apparently deleterious mutations, each segregating with the disease in the respective families in which they occur. PDS produces a transcript of approximately 5 kb that was found to be expressed at significant levels only in the thyroid. The predicted protein, pendrin, is closely related to a number of known sulphate transporters. These studies provide compelling evidence that defects in pendrin cause Pendred syndrome thereby launching a new area of investigation into thyroid physiology, the pathogenesis of congenital deafness and the role of altered sulphate transport in human disease.

Incidence of Parkinson disease in North America.

Parkinson disease (PD) is the second most common age-related neurodegenerative condition diagnosed in North America. We recently demonstrated, using multiple epidemiological data sources, that the prevalence of PD diagnoses was greater than previously reported and currently used for clinical, research, and policy decision-making. Prior PD incidence estimates have varied, for unclear reasons. There is a need for improved estimates of PD incidence, not only for care delivery planning and future policy but also for increasing our understanding of disease risk. The objective of this study was thus to investigate the incidence of Parkinson disease across five epidemiological cohorts in North America in a common year, 2012. The cohorts contained data on 6.7 million person-years of adults ages 45 and older, and 9.3 million person-years of adults ages 65 and older. Our estimates of age-sex-adjusted incidence of PD ranged from 108 to 212 per 100,000 among persons ages 65 and older, and from 47 to 77 per 100,00 among persons ages 45 and older. PD incidence increased with age and was higher among males. We also found persistent spatial clustering of incident PD diagnoses in the U.S. PD incidence estimates varied across our data sources, in part due to case ascertainment and diagnosis methods, but also possibly due to the influence of population factors (prevalence of genetic risk factors or protective markers) and geographic location (exposure to environmental toxins). Understanding the source of these variations will be important for health care policy, research, and care planning.

Prevalence of Parkinson's disease across North America.

Estimates of the prevalence of Parkinson's disease in North America have varied widely and many estimates are based on small numbers of cases and from small regional subpopulations. We sought to estimate the prevalence of Parkinson's disease in North America by combining data from a multi-study sampling strategy in diverse geographic regions and/or data sources. Five separate cohort studies in California (2), Minnesota (1), Hawaii USA (1), and Ontario, Canada (1) estimated the prevalence of PD from health-care records (3), active ascertainment through facilities, large group, and neurology practices (1), and longitudinal follow-up of a population cohort (1). US Medicare program data provided complementary estimates for the corresponding regions. Using our age- and sex-specific meta-estimates from California, Minnesota, and Ontario and the US population structure from 2010, we estimate the overall prevalence of PD among those aged ≥45 years to be 572 per 100,000 (95% confidence interval 537-614) that there were 680,000 individuals in the US aged ≥45 years with PD in 2010 and that that number will rise to approximately 930,000 in 2020 and 1,238,000 in 2030 based on the US Census Bureau population projections. Regional variations in prevalence were also observed in both the project results and the Medicare-based calculations with which they were compared. The estimates generated by the Hawaiian study were lower across age categories. These estimates can guide health-care planning but should be considered minimum estimates. Some heterogeneity exists that remains to be understood.

Characterization of the fetal glucose transporter in rabbit kidney. Comparison with the adult brush border electrogenic Na+-glucose symporter.

Glucose transport was characterized in rabbit renal brush border membrane vesicles (BBMV) of the fetus late in gestation. Highly purified, osmotically reactive fetal BBMV contained a glucose transporter that was qualitatively indistinguishable from that in the adult: both are concentrative, Na+ dependent, electrogenic, stereospecific, and sensitive to phlorizin. Although the apparent Km for glucose is similar in the fetus and adult, the Vmax is significantly higher in the adult. When the membrane potential was clamped with a protonophore, this difference diminished; however, Vmax remained significantly higher in adult BBMV. This postnatal increase in Vmax was paralleled by a similar increase in the number of phlorizin binding sites. These findings indicate that the maturational increase in glucose transport is, in part, consequent to a more favorable electrical potential for Na+-dependent glucose transport and, in part, the result of the insertion of new transporters. The homogenate activity of several brush border enzymes also demonstrated significant maturational increases. The magnitude of these changes was variable and enzyme dependent. These combined observations suggest that mature expression of membrane proteins (transporters and enzymes) occurs at different stages of development of renal proximal tubule cells.

Ontogeny of Na/H antiporter activity in rabbit renal brush border membrane vesicles.

The development of the Na/H antiporter was studied in renal brush border membrane vesicles (BBMV) from fetal and adult rabbits using isotopic and fluorescent techniques. The kinetics of the antiporter studied by 22Na+ uptake revealed that the Vmax was only 25% of that in the adult; however, the Km's for Na+ were not significantly different. These data were confirmed by a fluorescent assay using the pH-sensitive probe, acridine orange: the Vmax was significantly lower in the fetal BBMV. Conductive Na+ movement was estimated from amiloride-insensitive 22Na+ uptake and the rate of alkalinization induced by K+, an ion whose relative conductance was found to be similar to that of Na+. Although relative Na+ conductance was significantly greater in fetal BBMV, the lower Vmax in fetal vesicles could not be ascribed to this factor. Maternal administration of betamethasone (50 micrograms/kg intramuscularly) for 2 d before delivery significantly increased the Vmax of the antiporter to levels observed in the adult; Km was unaffected. Na/K ATPase activity increased fourfold after betamethasone, but the specific activities of four brush border marker enzymes and the kinetics of Na(+)-glucose cotransport were unchanged. These data indicate that there is a developmental increase in brush border Na/H exchange which is the result of an increase in the number and/or the turnover number of the carriers. Further, these data suggest that the postnatal increase in antiporter activity may be related to the surge in glucocorticoid concentration that occurs perinatally.

Effects of secretin, pancreozymin, or gastrin on the response of the endocrine pancreas to administration of glucose or arginine in man.

Intravenous administration of porcine secretin or pancreozymin or synthetic human gastrin II resulted in raised increments in serum immunoreactive insulin during intravenous infusion of glucose in normal man. Enhancement of serum immunoreactive insulin by each hormone was associated with accelerated disposal of glucose. In response to prolonged intravenous infusion of arginine with pancreozymin there was a maintained rise in immunoreactive insulin and glucagon-like immunoreactivity in the blood. These effects of pancreozymin and arginine were not reproduced with secretin and arginine, and may have been due to the stimulation of glucagon secretion together with insulin by pancreozymin. Enteric infusion of hydrochloric acid, or stimulation of gastric acid secretion by betazole, presumed to cause release of endogenous secretin, led to enhancement of insulin secretion during intravenous infusion of glucose. Enteric infusion of arginine, presumed to cause release of endogenous pancreozymin, led to a rise in serum immunoreactive insulin not attributable to effects of circulating glucose and amino acids. It is concluded that secretin and pancreozymin released in response to physiological stimuli contribute to stimulation of the endocrine pancreas after ingestion of food.

Synthesis of chloroplast membrane lipids and chlorophyll in synchronous cultures of Chlamydomonas reinhardi.

Chloroplast membrane lipid synthesis has been studied in synchronously growing cultures of Chlamydomonas reinhardi. The synthesis of sulfolipid and phospholipid were measured by incorporation of 35SO4(2-) and 32PO4(3-) during a 1-h pulse. Galactolipid synthesis was measured by H14CO3- incorporation into lipid fractions separated by thin layer chromatography. Lipid synthesis occurs principally during the light portion of the synchronous cycle. Phosphatidylglycerol is synthesized between 3-4 h in the light and sulfolipid is labeled between 7-9 h in the light. Galactolipid synthesis appears to reach maximal rates shortly after the lights go on and again at 7 h. Chlorophyll reaches maximal rates of synthesis after 7 h. These lipids are made and inserted into the chloroplast membrane prior to major increases in photosynthetic capacity. Our results also show that chloroplast membrane lipids are synthesized in a sequential or multistep process.

A prospective, multicenter study of patients' refusal of antipsychotic medication.

Refusal of treatment with antipsychotic medication was studied prospectively in a sample of 1434 psychiatric patients admitted to four acute inpatient units in state-operated mental health facilities in Massachusetts during a 6-month period. Compared with a control group of patients who accepted prescribed antipsychotic treatment, the 103 patients who refused were older, of a higher social class, and less likely to have been prescribed antiparkinsonian medications. On admission, prior to refusal of medication, patients who refused were found to have significantly higher Brief Psychiatric Rating Scale scores than compliant patients and more negative attitudes regarding their hospitalization and past, present, and future treatment. Treatment refusal had negative effects on the hospital milieu and on the patient; refusers were more likely to require seclusion or restraint and had longer hospitalizations than treatment acceptors. Most refusal episodes ended with voluntary acceptance of treatment. In 23% of cases medications were discontinued. Only 18% of the sample reached formal, judicial review, and in every case that did, involuntary treatment was ordered. The policy implications of these findings are discussed.

Alcohol-related problems in older persons. Determinants, consequences, and screening.

Demographic trends reveal the elderly to be the fastest growing segment of the population. Physicians can therefore anticipate encountering increasing numbers of older patients with alcohol-related problems. These problems include liver disease, dementia, confusion (masquerading as dementia), peripheral neuropathy, insomnia, late-onset seizure disorder, poor nutrition, incontinence, diarrhea, myopathy, inadequate self-care, macrocytosis, depression, fractures, and adverse reactions to medications. Despite the prevalence of alcohol use in older people, their risks and problems are often unrecognized. We reviewed published literature on the determinants and consequences of alcohol-related problems in persons aged 65 years and older and the usefulness of available screening measures. Thirteen of 25 eligible studies on determinants and consequences met quality criteria and were reviewed. Nine additional studies on screening tests were also evaluated. Determinants include history of alcohol use and abuse, social isolation, and reduced mobility; consequences consist of risks of hip fracture from falls, neoplasms, and psychiatric illness. Currently accessible screening tests focus on high levels of alcoholic beverage use and abuse and dependence. They are not useful in screening for hazardous consumption that may result from relatively low levels of alcohol use alone or in combination with medications, medical illness, or preexisting diminished physical, emotional, or social function. Research is needed on the consequences of lower levels of alcohol consumption on the physical and psychosocial health of older individuals and on methods for distinguishing alcohol-related from age-related problems. Existing screening tests should be expanded or new screening methods developed in anticipation of a growing public health problem.

Explicit criteria for determining inappropriate medication use in nursing home residents. UCLA Division of Geriatric Medicine.

Increasing attention is being paid to inappropriate medication use in nursing homes. However, criteria defining the appropriate or inappropriate use of medication in this setting are not readily available and are not uniform. We used a two-round survey, based on Delphi methods, with 13 nationally recognized experts to reach consensus on explicit criteria defining the inappropriate use of medications in a nursing home population. The criteria were designed to use pharmacy data with minimal additional clinical data so that they could be applied to chart review or computerized data sets. The 30 factors agreed on by this method identify inappropriate use of such commonly used categories of medications as sedative-hypnotics, antidepressants, antipsychotics, antihypertensives, nonsteroidal anti-inflammatory agents, oral hypoglycemics, analgesics, dementia treatments, platelet inhibitors, histamine2 blockers, antibiotics, decongestants, iron supplements, muscle relaxants, gastrointestinal antispasmodics, and antiemetics. These criteria may be useful for quality assurance review, health services research, and clinical practice guidelines. The method used to establish these criteria can be used to update and expand the guidelines in the future.

Inappropriate medication use in community-residing older persons.

BACKGROUND: Elderly patients taking inappropriate drugs are at increased risk for adverse outcomes. We investigated the prevalence of inappropriate drug use and its predisposing factors in community-residing older persons. METHODS: We conducted in-home interviews with 414 subjects aged 75 years and older living in the community of Santa Monica, Calif. Inappropriate medication use was evaluated using explicit criteria developed through a modified Delphi consensus process. These criteria identified drugs that should generally be avoided in elderly community-residing subjects regardless of dosage, duration of therapy, or clinical circumstances. RESULTS: Based on these conservative criteria, 14.0% of the subjects were using at least one inappropriate drug. The most common examples were long-acting benzodiazepines, persantine, amitriptyline, and chlorpropamide. Subjects using three or more prescription drugs, compared with one or two, were more likely to be taking an inappropriate medication (odds ratio, 3.9; 95% confidence interval, 1.9 to 7.9). Furthermore, subjects with depressive symptoms had a higher risk of receiving inappropriate medications than nondepressive subjects (odds ratio, 2.2; 95% confidence interval, 1.1 to 4.1). CONCLUSIONS: Inappropriate drug use is a common problem in community-residing older persons. The risk of inappropriate drug use is increased in patients taking multiple medications and in patients with depressive symptoms.

A randomized trial of in-home visits for disability prevention in community-dwelling older people at low and high risk for nursing home admission.

BACKGROUND: In-home preventive visits with multidimensional geriatric assessments can delay the onset of disabilities in older people. METHODS: This was a stratified randomized trial. There were 791 participants, community-dwelling people in Bern, Switzerland, older than 75 years. The participants' risk status was based on 6 baseline predictors of functional deterioration. The intervention consisted of annual multidimensional assessments and quarterly follow-up in-home visits by 3 public health nurses (nurses A, B, and C), who, in collaboration with geriatricians, evaluated problems, gave recommendations, facilitated adherence with recommendations, and provided health education. Each nurse was responsible for conducting the home visits in 1 ZIP code area. RESULTS: After 3 years, surviving participants at low baseline risk in the intervention group were less dependent in instrumental activities of daily living (ADL) compared with controls (odds ratio, 0.6; 95% confidence interval, 0.3-1.0; P = .04). Among subjects at high baseline risk, there were no favorable intervention effects on ADL and an unfavorable increase in nursing home admissions (P= .02). Despite the similar health status of subjects, nurse C identified fewer problems in the subjects who were visited compared with those assessed by nurses A and B. Subgroup analysis revealed that among low-risk subjects visited by nurses A and B, the intervention had favorable effects on instrumental ADL (P = .005) and basic ADL (P = .009), reduced nursing home admissions (P = .004), and resulted in net cost savings in the third year (US $1403 per person per year). Among low-risk subjects visited by nurse C, the intervention had no favorable effects. CONCLUSIONS: These data suggest that this intervention can reduce disabilities among elderly people at low risk but not among those at high risk for functional impairment, and that these effects are likely related to the home visitor's performance in conducting the visits.

Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping.

Approximately 10% of newborns with congenital hypothyroidism are unable to convert iodide into organic iodine. This iodide organification defect has a prevalence of 1 in 40,000 newborns and may be caused by defects in the thyroid peroxidase enzyme (TPO), the hydrogen peroxide-generating system, the TPO substrate thyroglobulin, or inhibitors of TPO. We identified a high incidence of severe hypothyroidism due to a complete iodide organification defect in the youngest generation of five nuclear families belonging to an inbred Amish kindred. Genealogical records permitted us to trace their origin to an ancestral couple 7-8 generations back and to identify an autosomal recessive pattern of inheritance. Initial studies of homozygosity by descent using two polymorphic markers within the TPO gene showed no linkage to the phenotype. In fact, 4 of 15 affected siblings from 2 of the nuclear families were heterozygous, resulting in homozygosity values of 73% and 53% in affected and unaffected family members, respectively. A genome-wide homozygosity screen using DNA pools from affected and unaffected family members localized the defect to a locus close to the TPO gene. Linkage analysis using 4 additional polymorphic markers within the TPO gene reduced the number of homozygous unaffected siblings to zero without altering the percent homozygosity initially found in the affected. Sequencing of the TPO gene revealed 2 missense mutations, E799K and R648Q. TPO 779K was found in both alleles of the 11 affected homozygotes, both mutations were present in each of the 3 affected compound heterozygotes, and there were no TPO mutations in 1 subject with hypothyroidism of different etiology. These results demonstrate the power of the DNA pooling strategy in the localization of a defective gene and the pitfalls of linkage analysis when 2 relatively rare mutations coexist in an inbred population.

Emergency psychiatric assessment of violence.

OBJECTIVE: The purpose of the study was to 1) ascertain whether there are clinical and demographic characteristics that distinguish dangerous from nondangerous patients evaluated in a psychiatric emergency service and 2) identify variables that distinguish dangerous patients who are hospitalized form those who are not. METHOD: The authors conducted a case comparison study of 99 psychiatric emergency patients whom staff identified as dangerous to others, that is, violent or potentially violent. Clinical staff were interviewed and records reviewed. These data were contrasted with record review data for 95 nondangerous patients. RESULTS: Log linear analysis showed that 1) variables relating to violence in community samples--age, sex, and past history of violence--related minimally or not at all to violence in this sample and 2) disposition to hospital versus community was associated with psychotic mental status and restraint in the psychiatric emergency service. Patients requiring restraint were more likely to have recently committed assault or battery and to have been brought in by the police. CONCLUSIONS: Enduring personal characteristics of patients relate neither to psychiatric emergency service assessments of current dangerousness nor to the decision to hospitalize. These determinations appear to be related to assessments of current patient state and immediate past behavior.

Reports of childhood incest and current behavior of chronically hospitalized psychotic women.

Of the female patients (N = 26) on a state hospital unit who remained chronically institutionalized and actively psychotic despite psychopharmacologic and psychosocial treatment, 12 (46%) reported histories of childhood incest. These 12 patients were more likely than the others to engage socially with ward staff. A higher proportion had sexual delusions, affective symptoms, substance abuse, suspected organicity, and major mental problems, and they spent more time in seclusion than other patients. The authors acknowledge the difficulty of assessing the accuracy of reports of incest. They discuss the implications of a possible relationship between incest and severe, intractable psychotic disorder.

Training in geriatric psychiatry: will the supply meet the demand?

The number of geriatric patients with major psychiatric disorders is expected to grow along with the rising proportion of people age 65 and older. Despite recognition of this growth and increases in the training of geropsychiatrists, the supply of specialists is unlikely to keep up with the demand. The authors argue for greater resource expenditure in fellowship programs and a focus on training academic leaders to serve as role models for general psychiatrists and other primary care givers.

Immunocytochemical localization of pedal peptide in the central nervous system of the gastropod mollusc Tritonia diomedea.

Tritonia pedal ganglion peptides (TPeps) are a trio of pentadecapeptides isolated from the brain of the nudibranch Tritonia diomedea. TPeps have been shown both to increase the beating rate of ciliated cells of Tritonia and to accelerate heart contractions in the mollusc Clione limacina. Here we examine the immunocytochemical distribution of TPeps in the Tritonia central nervous system. We found the brain and buccal ganglia to be rich sources of TPep immunoreactivity. Specific cells in both structures, some of them previously identified, were immunoreactive. Moreover, immunoreactive fibers were seen connecting ganglia and exiting almost all the major nerves. In the brain, we found that the paired, ciliated statocysts apparently receive TPep innervation. In addition, we observed unstained cell bodies in each buccal ganglion with extensive TPep immunoreactive projections surrounding their somata and primary neurites. Similar projections were not observed in the brain. We also compared the TPep immunoreactivity with that of SCP(b) in the buccal ganglia. We observed many neurons and processes that were immunoreactive to both peptides. One neuron that contains both TPep- and SCP(b)-like peptides (B12) has an identified role in the Tritonia feeding network. Together, these findings suggest that TPeps may play an active role in the central nervous system of Tritonia as neurotransmitters modulating orientation, swimming, and feeding.

Collection of genomic DNA from adults in epidemiological studies by buccal cytobrush and mouthwash.

Blood samples are an excellent source of large amounts of genomic DNA. However, alternative sources are often needed in epidemiological studies because of difficulties in obtaining blood samples. This report evaluates the buccal cytobrush and alcohol-containing mouthwash protocols for collecting DNA by mail. Several DNA extraction techniques are also evaluated. The study was conducted in two phases. In phase 1, we compared cytobrush and mouthwash samples collected by mail in two different epidemiological studies: (a) cytobrush samples (n = 120) from a United States case-control study of breast cancer; and (b) mouthwash samples (n = 40) from a prospective cohort of male United States farmers. Findings from phase 1 were confirmed in phase 2, where we randomized cytobrush (n = 28) and mouthwash (n = 25) samples among participants in the breast cancer study to directly compare both collection methods. The median human DNA yield determined by hybridization with a human DNA probe from phenol-chloroform extracts was 1.0 and 1.6 microg/2 brushes for phases 1 and 2, respectively, and 27.5 and 16.6 microg/mouthwash sample for phases 1 and 2, respectively. Most (94-100%) mouthwash extracts contained high molecular weight DNA (>23 kb), in contrast to 55-61% of the brush extracts. PCR success rates for amplification of beta-globin gene fragments (268, 536, and 989 bp) were similar for cytobrush and mouthwash phenol-chloroform extracts (range, 94.4-100%). Also, we obtained high success rates in determining the number of CAG repeats in the androgen receptor gene, characterizing tetranucleotide microsatellites in six gene loci, and screening for mutations in the BRCA1/2 genes in a subset of phenol-chloroform DNA extracts. Relative to DNA extracted by phenol-chloroform from cytobrush samples, DNA extracted by NaOH had lower molecular weight, decreased PCR success rates for most assays performed, and unreliably high spectrophotometer readings for DNA yields. In conclusion, although DNA isolated from either mouthwash or cytobrush samples collected by mail from adults is adequate for a wide range of PCR-based assays, a single mouthwash sample provides substantially larger amounts and higher molecular weight DNA than two cytobrush samples.

cDNA expressed sequence tags of Trypanosoma brucei rhodesiense provide new insights into the biology of the parasite.

A total of 518 expressed sequence tags (ESTs) have been generated from clones randomly selected from a cDNA library and a spliced leader sub-library of a Trypanosoma brucei rhodesiense bloodstream clone. 205 (39%) of the clones were identified based on matches to 113 unique genes in the public databases. Of these, 71 cDNAs display significant similarities to genes in unrelated organisms encoding metabolic enzymes, signal transduction proteins, transcription factors, ribosomal proteins, histones, a proliferation-associated protein and thimet oligopeptidase, among others. 313 of the cDNAs are not related to any other sequences in the databases. These cDNA ESTs provide new avenues of research for exploring both the novel trypanosome-specific genes and the genome organization of this parasite, as well as a resource for identifying trypanosome homologs to genes expressed in other organisms.