The Danish HD Registry-a nationwide family registry of HD families in Denmark.

The Danish Huntington's Disease Registry (DHR) is a nationwide family registry comprising 14 245 individuals from 445 Huntington's disease (HD) families of which the largest family includes 845 individuals in 8 generations. 1136 DNA and/or blood samples and 18 fibroblast cultures are stored in a local biobank. The birthplace of the oldest HD carrier in each of the 261 families of Danish origin was unevenly distributed across Denmark with a high number of families in the middle part of the peninsula Jutland and in Copenhagen, the capital. The prevalence of HD in Denmark was calculated to be 5-8:100 000. 1451 individuals in the DHR had the size of the HTT CAG repeat determined of which 975 had 36 CAG repeats or more (mean ± SD: 43,5 ± 4,8). Two unrelated individuals were compound heterozygous for alleles ≥36 CAGs, and 60 individuals from 34 independent families carried an intermediate allele.

Psychiatric and cognitive symptoms in Huntington's disease are modified by polymorphisms in catecholamine regulating enzyme genes.

Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disorder characterized by motor, psychiatric, and cognitive manifestations. HD is caused by a CAG repeat expansion in the Huntingtin (HTT) gene but the exact pathogenesis remains unknown. Dopamine imbalance has previously been shown in HD, and furthermore dopamine is thought to be implicated in cognition, behavioral and motor disturbances. A substantiated inverse correlation between motor onset and the elongated CAG repeat in the HTT has been established. This relation does not account for the full variability of the motor onset, and efforts have been put into finding genetic modifiers of motor onset, however, mostly with unsuccessful outcome. In this study, we took an alternative approach focusing on symptom complexes and searched for modifiers of cognitive impairment and psychiatric symptoms in a well-described cohort of Danish HD gene-expansion carriers. We show that cognitive impairment and psychiatric symptoms in HD are modified by polymorphisms in the monoamine oxidase A (MAOA) and catechol-O-methyltransferase (COMT) genes and by the 4p16.3 B haplotype. These results support the theory of dopamine imbalance in HD, and point toward more personalized treatment modalities of HD in the future.

Ubiquitin: a potential cerebrospinal fluid progression marker in Huntington's disease.

BACKGROUND: Finding early and dynamic biomarkers in Huntington's disease is a key to understanding the early pathology of Huntington's disease and potentially to tracking disease progression. This would benefit the future evaluation of potential neuroprotective and disease-modifying therapies, as well as aid in identifying an optimal time point for initiating a potential therapeutic intervention. METHODS: This explorative proteomics study evaluated cerebrospinal fluid from 94 Huntington's disease gene-expansion carriers (39 premanifest and 55 manifest) and 27 Huntington's disease gene-expansion negative individuals using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry. Differences in peak intensity from SELDI-TOF spectra were evaluated. RESULTS: Levels of 10 peaks were statistically significantly different between manifest gene-expansion carriers and controls. One of them identified as ubiquitin was shown to be dependent on the Unified Huntington Disease Rating Scale Total Functional Capacity, a pseudo-measure of disease severity (P = 0.001), and the Symbol Digit Modalities Test (0.04) in manifest and CAG-age product score (P = 0.019) in all gene-expansion carriers. CONCLUSIONS AND RELEVANCE: Multiple studies have shown that the ubiquitin-proteasome system is involved in Huntington's disease pathogenesis and understanding of this involvement may have therapeutic potential in humans. This is the first study on cerebrospinal fluid to confirm the involvement of the ubiquitin-proteasome system in Huntington's disease. Furthermore it is shown that ubiquitin increases with disease progression and CAG-age product score and therefore may have the potential as a Huntington's disease progression marker, also prior to motor onset.

NIPA1 mutation in complex hereditary spastic paraplegia with epilepsy.

BACKGROUND AND PURPOSE: Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterized in the 'pure' phenotype by progressive spasticity and weakness of the lower limbs. In the 'complex' phenotype, additional neurologic symptoms or signs are found. Mutations in the NIPA1 gene have been reported to cause spastic paraplegia type 6 (SPG6) in 10 families. SPG6 is a rare form of autosomal dominantly inherited HSP associated with a pure phenotype; however, in one complex SPG6 family, idiopathic generalized epilepsy (IGE) has been described and in addition, recurrent microdeletions at 15q11.2 including NIPA1 have been identified in patients with IGE. The purpose was to identify NIPA1 mutations in patients with pure and complex HSP. METHODS: Fifty-two patients with HSP were screened for mutations in NIPA1. RESULTS: One previously reported missense mutation c.316G>A, p.Gly106Arg, was identified in a complex HSP patient with spastic dysarthria, facial dystonia, atrophy of the small hand muscles, upper limb spasticity, and presumably IGE. The epilepsy co-segregated with HSP in the family. CONCLUSION: NIPA1 mutations were rare in our population of patients with HSP, but can be found in patients with complex HSP. Epilepsy might be more common in SPG6 than in other forms of HSP because of a genetic risk factor closely linked to NIPA1.

Surveillance in von Hippel-Lindau disease (vHL).

von Hippel-Lindau disease (vHL) is a hereditary multisystem cancer syndrome requiring lifelong prophylactic surveillance. Current surveillance recommendations rely on best medical judgement and no evidence of effect exists. We aimed to evaluate the capability of surveillance in manifestation detection, before these turn symptomatic, in order to prevent disabling or even fatal outcomes. We focus on surveillance of central nervous system (CNS) hemangioblastomas, retinal hemangiomas and renal cell carcinoma (RCC) as these have the most severe consequences. On the basis of full medical records from 54 living vHL-mutation carriers, risks of intercurrent manifestations in-between surveillance examinations were determined and clinical consequences of surveillance findings evaluated. Current recommendations of annual ophthalmic and abdominal examinations corresponded to acceptably low intercurrent manifestation risks (1.7% and 1.2%, respectively), whereas recommendations of biennial CNS imaging corresponded to a risk of 7.2%. Annual CNS examinations, however, significantly reduces this risk to 2.7%. Furthermore, most CNS manifestations found due to surveillance (71%, 106 of 150) had clinical consequence for the patient. Also, pre-symptomatic surveillance increased cumulative incidence of clinical vHL diagnosis from 46% to 72% and from 89% to 94% by age 30 and 50 years, respectively. The present results promote optimization of surveillance, expectantly improving clinical vHL outcomes.

4p16.3 haplotype modifying age at onset of Huntington disease.

Huntington disease (HD) is caused by an expanded CAG repeat sequence in the HD gene. Although the age at onset is correlated to the CAG repeat length, this correlation only explains approximately half of the variation in onset age. Less variation between siblings indicates that the variation is, in part, explained by genetic modifiers. We analyzed polymorphic loci within or close to the HD gene on the HD chromosome in Danish HD patients. We found one specific haplotype segregating with later age at onset, compared with patients with similar CAG repeat length and another haplotype. The nine Danish families in the study carrying this haplotype most likely have a common founder. Several of the polymorphic loci displayed alleles that may be specific to the late-onset haplotype, implicating that from this study we cannot determine which of the loci tested (or other polymorphic loci in this chromosomal area) do in fact contain genetic modifiers of age at onset.

Neuroticism modulates mood responses to pharmacological sex hormone manipulation in healthy women.

BACKGROUND: Women show increased risk of depressive symptoms during hormonal transition phases. The risk mechanisms may include changes in mood in response to fluctuating ovarian hormones moderated by predisposing risk factors for mood disorders, such as personality trait Neuroticism. METHODS: A pooled sample of 92 mentally healthy women (28.3 ± 7.1, mean age ± SD) from two independent cohorts run in our lab, using gonadotropin-releasing hormone agonist (GnRHa) experimentally (n = 28) compared to placebo (n = 27) and as part in vitro fertilization (n = 37), were extracted from the Center for Integrated Molecular Brain Imaging database. All women filled in questionnaires of trait Neuroticism from the NEO personality Inventory-Revised (NEO PI-R) at baseline and self-reported levels of mood disturbances with the Profile of Mood States (POMS) daily during 14 days of GnRHa intervention or placebo. Effects of intervention by trait Neuroticism on serial daily reports of mood disturbances were examined using mixed model analyses. RESULTS: Personality trait Neuroticism significantly modulated daily mood responses to GnRHa, but not placebo. Women with high and low scores on trait Neuroticism at baseline experienced more pronounced changes in mood when exposed to GnRHa, whereas women with medium trait Neuroticism scores remained relatively stable. CONCLUSIONS: The susceptibility to hormone-triggered mood changes appears to depend upon women's general tendency to experience distress and destabilization of mood, as captured by personality trait Neuroticism. This could aid clinicians evaluate hormone-related vulnerability for mood disorders in women and may guide targeted prevention in reproductive care.

Predictors of ovarian response in intrauterine insemination patients and development of a dosage nomogram.

The objective of this prospective study was to identify predictors of ovarian response in ovulatory patients treated with low-dose recombinant FSH (rFSH), gonadotrophin-releasing hormone antagonist and intrauterine insemination (IUI), and to develop an rFSH dosage nomogram based on the findings. Patients (n = 159) were stimulated with a starting dose of 75 IU rFSH/day. Ten parameters were investigated as possible predictors of the number of mature follicles >or=15 mm: age, spontaneous cycle length, body weight, body mass index, smoking status, total ovarian volume, total number of antral follicles, total Doppler score of the ovarian stromal blood flow, baseline FSH and oestradiol. Simple and multiple linear regressions were used for the statistical analysis. Appropriate ovarian response was defined as two to three mature follicles. Body weight (P = 0.001) and the number of antral follicles (P = 0.004) were the strongest independent predictive factors of the number of mature follicles. In conclusion, body weight and antral follicle count may be used to achieve appropriate ovarian response for IUI in ovulatory patients. Based on this, a simple rFSH dosage nomogram was developed for individual ovarian stimulation prior to IUI.

Sex hormone manipulation slows reaction time and increases labile mood in healthy women.

BACKGROUND: Women show increased risk of depressive symptoms in life phases where ovarian steroid hormone levels fluctuate or decline rapidly. The risk mechanisms may include changes in mental state and affective cognition possibly mediated by serotonergic neurotransmission. METHODS: In a randomized controlled double-blinded trial, 61 healthy women (mean age 24.3±4.9 years) were tested with measures of affective verbal memory, reaction time, mental distress, and serotonin transporter binding at baseline and at follow-up after receiving gonadotropin-releasing hormone agonist (GnRHa) or placebo intervention. Women also reported daily mood profiles during intervention. We tested direct effects of intervention and indirect effects through changes in serotonin transporter binding on verbal affective memory, simple reaction time and self-reported measures of mental distress, and further effects of GnRHa on daily mood. RESULTS: GnRHa induced an increase in simple reaction time (p=0.03) and more pronounced fluctuations in daily self-reported mood in a manner dependent on baseline mood (p=0.003). Verbal affective memory recall, overall self-perceived mental distress, and serotonin transporter binding were not affected. CONCLUSIONS: In healthy women transient sex-steroid hormone fluctuations decrease speed of information processing and further produce more labile mood only in women with elevated levels of mood disturbances at baseline.

Nutrition and oral health.

Reduced chewing function in community-dwelling older people with adequate general health is linked to having fewer than 20 teeth present or to wearing removable dentures. By chewing for longer periods of time or swallowing larger food particles they are normally able to compensate for the impaired function. The masticatory function can be restored by adequate prosthetic therapy, which results in increased activity of the masticatory muscles during chewing and reduces the chewing time and the number of chewing strokes until swallowing. In frail or dependent elderly people undernutrition is prevalent because of health problems, reduced appetite and poor quality of life. Poor oral health and xerostomia are often associated with a reduced body mass index and serum albumin level and the avoidance of difficult-to-chew foods. Maintenance or re-establishment of masticatory function is an integral part of the medical health care of these patients, with the aim of improving their nutritional status and quality of life.

Benchmark dose calculations of methylmercury-associated neurobehavioural deficits.

Prenatal methylmercury exposure is associated with neuropsychological deficits in Faroese children at age 7 years. Lower confidence bounds of benchmark doses (BMDLs) have now been calculated. With the cord-blood mercury concentration as the dose parameter, a logarithmic dose-response model tended to show a better fit than a linear dose model for the attention, language and verbal memory tests. The lowest BMDLs averaged approximately 5 microgram/l cord blood, which corresponds to a maternal hair concentration of approximately 1 microgram/g. However, most BMDLs for hair mercury concentrations were higher. Thus, the results of the benchmark calculations depend on the assumed dose-response model.

Evoked potentials in Faroese children prenatally exposed to methylmercury.

A study of 7-year-old children from a fishing village on Madeira has suggested that latencies of evoked potentials may be delayed because of increased exposures to methylmercury during development. Data from a previously published prospective study in the Faroe Islands have therefore been reexamined. Because of changes in instrumentation, results obtained during the second year of examination were excluded. After this restriction, the results show significant mercury-associated delays of the peak III latency and the I-III interpeak latency of the auditory brainstem evoked potentials. Mercury concentrations in both maternal hair at parturition and in cord blood indicated this association, whereas no such relationship was apparent with the child's current hair-mercury concentration. Thus, in agreement with the findings from Madeira, a delay of the peak III latency of the brainstem auditory evoked potentials appears to serve as a marker of prenatal methylmercury toxicity from contaminated seafood.

Neurobehavioral deficits associated with PCB in 7-year-old children prenatally exposed to seafood neurotoxicants.

Prenatal exposure to polychlorinated biphenyls (PCBs) was examined by analysis of cord tissue from 435 children from a Faroese birth cohort. Analysis of 50 paired cord blood samples showed excellent correlation with the cord tissue concentration (r=.90). Among 17 neuropsychological outcomes determined at age 7 years, the cord PCB concentration was associated with deficits on the Boston Naming Test (without cues, two-tailed P=.09 not adjusted for mercury; with cues, P=.03), the Continuous Performance Test reaction time (P=.03), and, possibly, on long-term recall on the California Verbal Learning Test (P=.15). The association between cord PCB and cord-blood mercury (r=.42) suggested possible confounding. While no PCB effects were apparent in children with low mercury exposure, PCB-associated deficits within the highest tertile of mercury exposure indicated a possible interaction between the two neurotoxicants. PCB-associated increased thresholds were seen at two of eight frequencies on audiometry, but only on the left side, and no deficits occurred on evoked potentials or contrast sensitivity. The limited PCB-related neurotoxicity in this cohort appears to be affected by concomitant methylmercury exposure.

Periodontal conditions following treatment with distally extending cantilever bridges or removable partial dentures in elderly patients. A 5-year study.

The aim of the present study was to evaluate the periodontal conditions following treatment with distally extending cantilever bridges or removable partial dentures (RPDs) in elderly patients. All participants had a complete denture in the maxilla and moderate-to-advanced bone loss around the teeth present in the mandible. After undergoing periodontal treatment, 27 patients were treated with distally extending cantilever bridges and 25 patients with a RPD. During the first 2 years following prosthetic treatment, the patients were recalled twice a year and during the last 3 years once a year for oral prophylaxis and assessment of the periodontal status. The patients treated with a RPD showed higher mean Plaque and Gingival Indexes than the patients treated with cantilever bridges. No change in probing pocket depths was observed in either group, and only a small decrease in radiographic alveolar bone height was revealed. In conclusion, only minor changes in the periodontal conditions were recorded during the 5 years of observation after treatment with cantilever bridges or RPDs.

Predominant cultivable microflora of plaque on removable dentures in patients with healthy oral mucosa.

Plaque from the fitting surface of upper full dentures in eight patients with healthy palatal mucosa was studied. To characterize the predominant cultivable flora, 916 isolates (100-128 from each sample) were subcultured from anaerobic roll-tubes. Streptococci constituted 0-81 per cent (median, 41 per cent) of the isolates with varying proportions of Streptococcus milleri, Streptoccus mutans, Streptococcus salivarius, Streptococcus mitior and Streptococcus sanguis. Staphylococcus aureus made up 0-13 per cent (median, 6 per cent). Gram-positive rods constituted 1-74 per cent (median, 33 per cent). Among these, Actinomyces israelii, Actinomyces naeslundii, Actinomyces viscosus and Actinomyces odontolyticus were the most common species, whereas lactobacilli were isolated only from two samples, constituting 21 and 48 per cent. Among Gram-negative bacteria, only Veillonella parvula was common, constituting 3-20 per cent (median, 10 per cent). Gram-negative rods were isolated only from three samples in small proportions making up 0-6 per cent (median, 0 per cent) of the flora. Forty-seven isolates (5 per cent) were lost. Cultures for yeasts on Sabouraud agar were positive for five samples and the yeast counts corresponded to 0-0.45 per cent (median, 0.002 per cent) of the total viable counts. The microflora of denture plaque is highly variable and is to a large extent similar to that of some forms of dental plaque.

Prognosis of overdenture abutments in the aged: effect of denture wearing habits.

The effect of denture wearing habits was studied in 35 overdenture wearers (20 day-and-night wearers, 15 day-wearers) during a period of 3 yr with controlled oral hygiene. Prior to prosthetic treatment intensive instruction and motivation in oral hygiene were carried out and the patients were recalled 2-4 times yearly during the study period. Before treatment mean Plaque Index (PlI) and Gingival Index (GI) were 1.5 and 1.6, respectively, in both groups of patients. At day 0, 1 yr, 2 yr and 3 yr mean PlI and GI were 0.3-0.5 and 0.6-0.8, respectively, in the group of day-wearers and 0.5-1.0 and 1.0-1.2, respectively, in the group of day-and-night wearers. This difference was statistically significant. Furthermore, during the study period 16% of the abutment tooth surfaces showed attachment loss (1-4 mm) in the group of day-and-night wearers against 7% of the tooth surfaces in the group of day-wearers. This difference was statistically significant. During the 3 yr 36 carious lesions developed in the group of day-and-night wearers, but none in the group of day-wearers. The results of this study have shown that day-and-night wearing of dentures is a major periodontitis and caries risk factor in complete overdenture wearers with controlled oral hygiene.

An epidemiologic study of yeasts in elderly denture wearers.

The purpose of this study has been to assess the prevalence of denture stomatitis and candida infection in an elderly Danish population. Ten percent of the population above the age of 65 in a Danish community was selected randomly. The study group consisted of 465 persons wearing a removable maxillary denture, who were examined in their homes. Yeasts were isolated by oral swabs for cultivation and by mucosal and denture scrapings for microscopy. The prevalence of denture stomatitis was 65%. Yeasts, especially C. albicans, were cultivated in most denture wearers with denture stomatitis (Group 1) or with clinically normal palatal mucosa (Group 2). However, large accumulations of hyphae were present in 77% of the patients in Group 1 compared with 47% in Group 2; both hyphae and inflammatory cells were seen in smears in 65% of Group 1 but only in 14% of Group 2. On the other hand, bacterial contamination of the smears was more pronounced in Group 2 than in Group 1. The study has revealed that candida infection and poor denture cleanliness are very common in elderly denture wearers.

Effects of an oral health program on the occurrence of oral candidosis in a long-term care facility.

OBJECTIVES: The aim was to evaluate the effectiveness of a preventive oral health program on the prevalence of oral candidosis in 237 frail or dependent residents in a long-term care facility. Half of the residents were included in an experimental group which benefited from a preventive oral hygiene program including instruction of the carers and implementation of a recall program for professional oral hygiene care. METHODS: Intraoral examinations and yeast cultures from the oral mucosa and the fitting denture surface were carried out at baseline and 18 months later. The outgrowth of yeast was estimated on Oricult-N dip slides using the scale: no growth; 1-20 colonies; 21-100 colonies; >100 colonies. RESULTS: At baseline (n = 237) and at 18 months (n = 159) the experimental and the control groups were similar with regard to the residents' distribution by age, sex, dental and prosthetic status and prevalence of denture stomatitis. The 78 residents lost had the same baseline characteristics as the survivors, except for being older. In the experimental group the severity of the inflammation of the palate decreased (P = 0.005) as well as the prevalence of glossitis (P = 0.005). At baseline high yeast scores from the mucosa (>20) were observed in about 50% of the residents in the experimental as well as the control group. At 18 months this figure was 23.4% for the experimental and 48.7% for the control group (P = 0.001). There was also a reduction of the number of residents with positive cultures and the denture yeast scores at 18 months in the experimental group (P = 0.05). CONCLUSIONS: This study has shown that the preventive program was effective in reducing the colonization of the oral mucosa and dentures by Candida and thereby improving the health of the oral mucosa.

Restoration of the partially edentulous mouth--a comparison of overdentures, removable partial dentures, fixed partial dentures and implant treatment.

OBJECTIVES: Loss of posterior teeth may result in the loss of neuromuscular stability of the mandible, reduced masticatory efficiency, loss of vertical dimension of occlusion and poor aesthetics. Prosthetic rehabilitation should aim at restoring the vertical dimension and increasing the occlusal contact area in the premolar/molar region. Overdentures are particularly indicated in patients with a severe loss of periodontal attachment, uncertain periodontal prognosis and complicated functional or aesthetic conditions. Removable partial dentures are particularly indicated in Kennedy Class I cases when there is need for a simple and economic solution. Placement of a removable partial denture with occlusal overlays is a simple way to restore occlusal face height. Cross-arch cantilevered fixed partial dentures are primarily indicated for stabilization of periodontally weakened abutments. Short unilateral or bilateral bridges are a solution in patients who refuse removable appliances and who cannot afford more extensive rehabilitation with fixed prosthodontics. Rehabilitation with a fixed partial denture supported by means of osseointegrated implants is the optimal solution in Kennedy Class II cases provided that the bone conditions are appropriate. For any prosthetic treatment, a definite recall system should be established depending on the patient's degree of cooperation, caries susceptibility, periodontal status and the rate of residual ridge resorption. This is essential in order to obtain a satisfactory prognosis. In a patient with poor oral hygiene, the best solution, with regard to the prognosis of the remaining teeth, is to abstain from any prosthetic treatment. METHODS: This manuscript reviews the current literature to identify treatment options for the Kennedy Class I and II partially edentulous patient.

Successful aging--the case for prosthetic therapy.

Reduced chewing ability in community-dwelling older people is linked to the presence of removable dentures and having fewer than 20 natural teeth present. Compensation is provided by chewing longer and swallowing larger food particles. Replacement of posterior tooth loss by fixed or removable prostheses increases the activity of the masticatory muscles, and reduces chewing time and the number of chewing strokes until swallowing. In residents of nursing homes and long-term care facilities undernutrition is prevalent because of general medical problems, reduced appetite, and poor quality of life. Poor oral health and xerostomia are often present and may have a negative effect on masticatory function and nutrition, precipitating avoidance of difficult-to-chew foods. There is no evidence that the provision of prosthetic therapies can markedly improve dietary intakes; however, it might improve oral comfort and quality of life and avoid enteral alimentation.