Carcinogenic activity of pentabrominated diphenyl ether mixture (DE-71) in rats and mice.

Pentabrominated diphenyl ether (PBDE) flame retardants have been phased out in Europe and in the United States, but these lipid soluble chemicals persist in the environment and are found human and animal tissues. PBDEs have limited genotoxic activity. However, in a 2-year cancer study of a PBDE mixture (DE-71) (0, 3, 15, or 50 mg/kg (rats); 0, 3, 30, or 100 mg/kg (mice)) there were treatment-related liver tumors in male and female Wistar Han rats [Crl:WI(Han) after in utero/postnatal/adult exposure, and in male and female B6C3F1 mice, after adult exposure. In addition, there was evidence for a treatment-related carcinogenic effect in the thyroid and pituitary gland tumor in male rats, and in the uterus (stromal polyps/stromal sarcomas) in female rats. The treatment-related liver tumors in female rats were unrelated to the AhR genotype status, and occurred in animals with wild, mutant, or heterozygous Ah receptor. The liver tumors in rats and mice had treatment-related Hras and Ctnnb mutations, respectively. The PBDE carcinogenic activity could be related to oxidative damage, disruption of hormone homeostasis, and molecular and epigenetic changes in target tissue. Further work is needed to compare the PBDE toxic effects in rodents and humans.

Long noncoding RNA lincRNA-p21 is the major mediator of UVB-induced and p53-dependent apoptosis in keratinocytes.

LincRNA-p21 is a long noncoding RNA and a transcriptional target of p53 and HIF-1α. LincRNA-p21 regulates gene expression in cis and trans, mRNA translation, protein stability, the Warburg effect, and p53-dependent apoptosis and cell cycle arrest in doxorubicin-treated mouse embryo fibroblasts. p53 plays a key role in the response of skin keratinocytes to UVB-induced DNA damage by inducing cell cycle arrest and apoptosis. In skin cancer development, UVB-induced mutation of p53 allows keratinocytes upon successive UVB exposures to evade apoptosis and cell cycle arrest. We hypothesized that lincRNA-p21 has a key functional role in UVB-induced apoptosis and/or cell cycle arrest in keratinocytes and loss of lincRNA-p21 function results in the evasion of apoptosis and/or cell cycle arrest. We observed that lincRNA-p21 transcripts are highly inducible by UVB in mouse and human keratinocytes in culture and in mouse skin in vivo. LincRNA-p21 is regulated at the transcriptional level in response to UVB, and the UVB induction of lincRNA-p21 in keratinocytes and in vivo in mouse epidermis is primarily through a p53-dependent pathway. Knockdown of lincRNA-p21 blocked UVB-induced apoptosis in mouse and human keratinocytes, and lincRNA-p21 was responsible for the majority of UVB-induced and p53-mediated apoptosis in keratinocytes. Knockdown of lincRNA-p21 had no effect on cell proliferation in untreated or UVB-treated keratinocytes. An early event in skin cancer is the mutation of a single p53 allele. We observed that a mutant p53(+/R172H) allele expressed in mouse epidermis (K5Cre(+/tg);LSLp53(+/R172H)) showed a significant dominant-negative inhibitory effect on UVB-induced lincRNA-p21 transcription and apoptosis in epidermis. We conclude lincRNA-p21 is highly inducible by UVB and has a key role in triggering UVB-induced apoptotic death. We propose that the mutation of a single p53 allele provides a pro-oncogenic function early in skin cancer development through a dominant inhibitory effect on UVB-induced lincRNA-p21 expression and the subsequent evasion of UVB-induced apoptosis.

Controlled infection with a therapeutic virus defines the activation kinetics of human natural killer cells in vivo.

Human natural killer (NK) cells play an important role in anti-viral immunity. However, studying their activation kinetics during infection is highly problematic. A clinical trial of a therapeutic virus provided an opportunity to study human NK cell activation in vivo in a controlled manner. Ten colorectal cancer patients with liver metastases received between one and five doses of oncolytic reovirus prior to surgical resection of their tumour. NK cell surface expression of the interferon-inducible molecules CD69 and tetherin peaked 24-48 h post-infection, coincident with a peak of interferon-induced gene expression. The interferon response and NK cell activation were transient, declining by 96 h post-infection. Furthermore, neither NK cell activation nor the interferon response were sustained in patients undergoing multiple rounds of virus treatment. These results show that reovirus modulates human NK cell activity in vivo and suggest that this may contribute to any therapeutic effect of this oncolytic virus. Detection of a single, transient peak of activation, despite multiple treatment rounds, has implications for the design of reovirus-based therapy. Furthermore, our results suggest the existence of a post-infection refractory period when the interferon response and NK cell activation are blunted. This refractory period has been observed previously in animal models and may underlie the enhanced susceptibility to secondary infections that is seen following viral infection.

Ballistic fractures during the 2003 Gulf conflict--early prognosis and high complication rate.

BACKGROUND: Ballistic fractures are devastating injuries often necessitating extensive reconstructive surgery or amputation, particularly if associated with high-energy transfer wounds. Infective complications are common, particularly in the austere environment encountered in war. We present the management and early outcome of these injuries with reference to the mechanism of injury and bony injury. METHOD: Data on ballistic fractures was collected prospectively during the 'war-fighting' phase of the 2003 Gulf Conflict, between 19th March and 20th May. Fractures were scored using the Red Cross Fracture classification and early outcome analysed. RESULTS: Thirty-nine patients, with 50 ballistic fractures, were treated by British military surgeons. Patients were predominantly Iraqi (90%) and 50 per cent of ballistic fractures were caused by bullets. Seventeen upper limb fractures and 33 lower limb fractures were sustained. There were seven traumatic amputations, and a further 2 limbs were amputated primarily. Methods of primary stabilisation for the remaining 41 fractures were: external fixation (22%), POP (14.5%), K-wires (14.5%) traction (10%), and no stabilisation (39%). Seven individuals were evacuated early after primary surgery, hence 43 ballistic fractures were available for follow-up. 13/43 (30%) of wounds became infected, 5/43 (11.5%) were deep infections necessitating surgical drainage. There were 4 late amputations (9.5%), 3 of which had initially been managed by external fixation. Infection occurred significantly more often in gunshot fractures (10/21, 48%), wounds closed primarily against the principles of war surgery (415, 80%) and intra-articular fractures (3/3, 100%) (p=0.022, 0.024 and 0.023 respectively). Differing methods of stabilisation had no bearing on the rate of postoperative infection. CONCLUSION: Ballistic fractures remain a challenge for trauma surgeons in times of war and still have a poor prognosis. Further work is required to determine the optimal treatment of these injuries during conflicts. In addition, there still seems to be a continued need to re-learn the principles of war surgery in order to minimise complications and optimise functional recovery.

Early failure of external fixation in the management of war injuries.

OBJECTIVE: To review external fixation in the management of war injuries. METHOD: We prospectively followed up 15 external fixators (14 patients) applied in the management of war injuries. All these patients were treated at 202 Field Hospital during the 2003 Gulf Conflict. RESULTS: Of the 15 fixators, 13 (86.7%) required early revision or removal due to complications of the injury or the fixator. Instability was a problem with 10 fixators (67%), pin loosening was noted with 5 fixators (33%) involving twelve pins, and a significant pin track infection developed at 14 pin sites (3 fixators - 20%), which failed to resolve despite intravenous antibiotics. CONCLUSIONS: This study demonstrates a very high early complication rate of external fixation in the management of military injuries and cautions against its universal acceptance. If used, consideration must be given to the optimum time of frame application, whether at the time of initial debridement or at a later operation, and the optimal frame design, which will depend on the specific bone and fracture pattern. Pin site care must also be considered, particularly with the restrictions imposed by the military environment.

Development of water-based liquid chromatography at the critical condition.

Liquid chromatography at the critical condition (LCCC) is a chromatographic technique that allows for the isolation of one area of the polymer matrix so that other areas of the polymer may be probed with size-exclusion or adsorptive chromatographic modes. This technique has been successfully applied to the analysis of functionality distributions in functionalized oligomers and to polymer distributions within copolymers. Herein, the critical conditions of two polar polymers, poly(acrylic acid) and polystyrene sulfonate, are determined. These conditions were identified by varying buffer concentration, organic modifier within the mobile phase, or both. At the critical condition of poly(acrylic acid), the retention characteristics of a copolymer of acrylic acid and vinyl pyrrolidinone were determined. This extension to water-based mobile phase conditions will substantially broaden the possible applications of LCCC.

Temporal variation in community composition, pigmentation, and F(v)/F(m) of desert cyanobacterial soil crusts.

Summers on the Colorado Plateau (USA) are typified by harsh conditions such as high temperatures, brief soil hydration periods, and high UV and visible radiation. We investigated whether community composition, physiological status, and pigmentation might vary in biological soil crusts as a result of such conditions. Representative surface cores were sampled at the ENE, WSW, and top microaspects of 20 individual soil crust pedicels at a single site in Canyonlands National Park, Utah, in spring and fall of 1999. Frequency of cyanobacterial taxa, pigment concentrations, and dark adapted quantum yield [F(v)/F(m)] were measured for each core. The frequency of major cyanobacterial taxa was lower in the fall compared to spring. The less-pigmented cyanobacterium Microcoleus vaginatus showed significant mortality when not in the presence of Nostoc spp. and Scytonema myochrous (Dillw.) Agardh. (both synthesizers of UV radiation-linked pigments) but had little or no mortality when these species were abundant. We hypothesize that the sunscreen pigments produced by Nostoc and Scytonema in the surface of crusts protect other, less-pigmented taxa. When fall and spring samples were compared, overall cyanobacterial frequency was lower in fall, while sunscreen pigment concentrations, chlorophyll a concentration, and F(v)/F(m) were higher in fall. The ratio of cyanobacterial frequency/chlorophyll a concentrations was 2-3 times lower in fall than spring. Because chlorophyll a is commonly used as a surrogate measure of soil cyanobacterial biomass, these results indicate that seasonality needs to be taken into consideration. In the fall sample, most pigments associated with UV radiation protection or repair were at their highest concentrations on pedicel tops and WSW microaspects, and at their lowest concentrations on ENE microaspects. We suggest that differential pigment concentrations between microaspects are induced by varying UV radiation dosage at the soil surface on these different microaspects.

Overexpression of manganese superoxide dismutase suppresses increases in collagen accumulation induced by culture of mesangial cells in high-media glucose.

Superoxide has been implicated in the cellular signalling pathways, which regulate growth of mesangial cells (MC) and vascular smooth muscle cells. Manganese (Mn)(2+)-dependent superoxide dismutase (SOD-2) is primarily responsible for metabolism of superoxide produced in mitochondria by respiratory chain activity during aerobic metabolism of glucose and other substrates. In the current studies, we examined the role of superoxide in the stimulation of collagen accumulation induced in MC by culture in media containing a high concentration of glucose. Aconitase, an iron sulfur enzyme whose activity is inhibited by superoxide, was used as an index of cellular superoxide production and action. SV-40-transformed mouse MC were cultured in media containing 100 (low) or 500 (high) mg/dL D-glucose and infected with a recombinant adenoviral (Ad) vector encoding either human mitochondrial Mn(2+) SOD-2 or green fluorescent protein (GFP). In cells infected with SOD-2 (SOD-2-Ad) and cultured in low glucose, SOD-2 activity was 5-fold higher than in cells infected with GFP (GFP-Ad), whereas Cu(2+)/Zn(2+) cytoplasmic SOD (SOD-1) did not differ; culture in high-glucose media did not alter SOD-2 or SOD-1 activity in either GFD-Ad or SOD-2-Ad. In GFP-Ad, high glucose suppressed aconitase activity and increased collagen accumulation compared with corresponding values in low glucose. In SOD-2-Ad, high glucose failed to suppress aconitase activity or increase collagen accumulation. Addition of exogenous (presumably extracellular) SOD to GFP-Ad had no effect on the stimulation of collagen accumulation by high glucose. Analogous to the effects of SOD-2-Ad, diphenylene iodonium (DPI), a nonspecific inhibitor of the production of superoxide by mitochondrial respiration and other nicotinamide adenine dinucleotide (phosphate) (NAD)(P)H oxidase activities, reduced collagen accumulation in GFP-Ad cultured in low glucose and blocked stimulation of collagen accumulation induced by culture in high glucose. These results support a role for increased cellular superoxide production derived from NAD(P)H oxidase activity in the stimulation of collagen accumulation induced in MC by high glucose and demonstrate that an increase in mitochondrial SOD-2 activity suppresses this response.

Overexpression of Cu2+/Zn2+ superoxide dismutase protects against early diabetic glomerular injury in transgenic mice.

Ex vivo and in vitro observations implicate superoxide as a mediator of cell injury in diabetes, but in vivo evidence is lacking. In the current studies, parameters of glomerular injury were examined in hemizygous nondiabetic transgenic mice (SOD) and streptozotocin-diabetic (D) transgenic mice (D-SOD), which overexpress human cytoplasmic Cu2+/Zn2+ superoxide dismutase (SOD-1), and in corresponding wild-type littermates (WT, D-WT) after 4 months of diabetes. In both SOD and D-SOD mice, renal cortical SOD-1 activity was twofold higher than values in the WT mice; blood glucose and glycosylated hemoglobin (GHb) levels did not differ in the two diabetic groups. Urinary albumin excretion, fractional albumin clearance, urinary transforming growth factor-beta (TGF-beta) excretion, glomerular volume, glomerular content of immunoreactive TGF-beta, and collagen alpha1 (IV) and renal cortical malondialdehyde (MDA) levels were significantly higher in D-WT mice compared with corresponding values in D-SOD mice. Glomerular volume, glomerular content of TGF-beta and collagen IV, renal cortical MDA, and urinary excretion of TGF-beta in D-SOD mice did not differ significantly from corresponding values in either the nondiabetic SOD or WT mice. In separate groups of mice studied after 8 months of diabetes, mesangial matrix area, calculated as a fraction of total glomerular tuft area, and plasma creatinine were significantly higher in D-WT but not in D-SOD mice, compared with corresponding values in the nondiabetic mice. In vitro infection of mesangial cells (MC) with a recombinant adenovirus encoding human SOD-1 increased SOD-1 activity threefold over control cells and prevented the reduction of aconitase activity, an index of cellular superoxide, and the increase in collagen synthesis that otherwise occurred in control MC in response to culture with 300 or 500 mg/dl glucose. Thus, increases in cellular SOD-1 activity attenuate diabetic renal injury in vivo and also prevent stimulation of MC matrix protein synthesis induced in vitro by high glucose.

Frequency and temporal resolution in elderly listeners with good and poor word recognition.

There is a subgroup of elderly listeners with hearing loss who can be characterized by exceptionally poor speech understanding. This study examined the hypothesis that the poor speech-understanding performance of some elderly listeners is associated with disproportionate deficits in temporal resolution and frequency resolution, especially for complex signals. Temporal resolution, as measured by gap detection, and frequency resolution, as measured by the critical ratio, were examined in older listeners with normal hearing, older listeners with hearing loss and good speech-recognition performance, and older listeners with hearing loss and poor speech-recognition performance. Listener performance was evaluated for simple and complex stimuli and for tasks of added complexity. In addition, syllable recognition was assessed in quiet and noise. The principal findings were that older listeners with hearing loss and poor word-recognition performance did not perform differently from older listeners with hearing loss and good word recognition on the temporal resolution measures nor on the spectral resolution measures for relatively simple stimuli. However, frequency resolution was compromised for listeners with poor word-recognition abilities when targets were presented in the context of complex signals. Group differences observed for syllable recognition in quiet were eliminated in the noise condition. Taken together, the findings support the hypothesis that unusual deficits in word-recognition performance among elderly listeners were associated with poor spectral resolution for complex signals.

Regulation of the laminin C1 promoter in cultured mesangial cells.

Expression of the genes encoding several matrix proteins, including the laminin gamma1 and beta1 subunits, is increased in glomeruli or renal cortex from diabetic animals or in mesangial cells cultured in high concentrations of glucose. Transforming growth factor (TGF)-beta1 and IGF-1 have been implicated as mediators of this response. In the present study, we assessed the influence of high glucose concentrations and the roles of TGF-beta1 and IGF-1 in the regulation of laminin C1 gene expression in cultured mesangial cells. Culture of normal rat mesangial cells (RMC) or SV40-transformed mouse mesangial (MES-13) cells in 500 mg/dl D-glucose for 2 days to 3 weeks significantly increased laminin C1 mRNA abundance compared with cells cultured in 100 mg/dl D-glucose. IGF-1 also increased laminin C1 mRNA abundance in RMC or MES-13 cells, whereas TGF-beta1 was without effect. The influence of raising the medium glucose concentration on laminin C1 promoter activity was further studied in MES-13 cells that had been stably transfected with a reporter gene containing the promoter linked to luciferase. Culture in 500 mg/dl D-glucose for 4 h to at least 1 week increased laminin C1 promoter activity compared with cells maintained in 100 mg/dl glucose. In contrast, culture of cells in medium that contained 400 mg/dl mannitol or 400 mg/dl L-glucose in addition to 100 mg/dl D-glucose did not increase laminin C1 promoter activity. The ability of high glucose to increase laminin C1 promoter activity was absolutely dependent on the presence of serum. Consistent with results obtained with mRNA, TGF-beta1 had no influence on promoter activity in stable integrants. Whereas IGF-1 transiently increased promoter activity in stable integrants, the increase was not sustained (6 h). Moreover, neutralizing antibody to TGF-beta or to IGF-1 receptor did not suppress increases in laminin C1 promoter activity induced by culture of stable integrants in high glucose. Several inhibitors of protein kinase C, including bisindolylmaleimide (GFX), myristoylated PKC inhibitor peptide, and LY333531, were also without effect on increases in laminin C1 promoter activity induced by culture in high glucose. Exposure to the NO donor (+/-)-s-nitroso-n-acetylpenicillamine (SNAP) blocked increases in laminin C1 promoter activity induced by serum and by culture in high glucose without influencing promoter activity in cells cultured in the absence of serum and in 100 mg/dl glucose. The ability of high glucose concentrations and IGF-1 to increase laminin C1 promoter activity in cultured mesangial cells, and the suppression of glucose actions by the NO donor SNAP, provide potential mechanisms whereby the synthesis of the laminin gamma1 chain may be regulated in the glomerulus in diabetes. Of note, the mechanism by which high glucose increases laminin C1 promoter activity appears to differ from mechanisms previously described for some other glucose actions on matrix protein synthesis. In this regard, TGF-beta and protein kinase C were not implicated as mediators of the effect of high glucose on laminin C1 promoter activity.

Sexual offending and antisocial sexual behavior among patients with schizophrenia.

BACKGROUND: A number of studies have indicated excessive offending behavior among people with schizophrenia; however, sexual offending has not been widely described. METHOD: This study reports on a subgroup of 15 men with schizophrenia, diagnosed according to ICD-10 guidelines, in a secure hospital who had committed sexual offenses or shown antisocial sexual behavior. A comparison group comprised 55 male patients with schizophrenia and a history of violent behavior who were being treated in the same hospitals as the study group. RESULTS: In 12 of the 15 cases, the sexual offending/behavior postdated illness onset and occurred in the context of psychotic symptoms. Although 12 of the offenders were known to psychiatric services, contact was erratic and only 4 were taking medication. At assessment, those with sexual offenses or antisocial sexual behavior were twice as likely as the larger study sample to report unimpaired sexual interest. This may be of particular relevance in that the group also reported difficulty in forming close personal relationships. CONCLUSION: Illness-related factors appear to make an important contribution to sexual offending by this group of patients, highlighting the need for comprehensive and vigorous treatment.

Clinical disorders of potassium homeostasis. Hyperkalemia and hypokalemia.

Potassium plays an important role in cell metabolism and membrane excitability. Disorders of potassium balance can have profound clinical effects, particularly on the cardiovascular and neuromuscular systems. Chronic hyperkalemia invariably results from impaired renal potassium excretion. Hyperkalemia can be a potentially life-threatening disturbance requiring emergency intervention. Treatment is usually directed at correcting the defect in potassium excretion. Hypokalemia has become closely linked with in cats. Clinical signs include muscle weakness and renal dysfunction, which usually respond well to oral potassium supplementation.

Outcomes comparison of solo-practitioner and group practice models.

A solo-practitioner care delivery model is utilized in the predoctoral teaching clinics at the University of Washington School of Dentistry. This model requires students to independently manage their practices using central resources. The model is perceived as cumbersome for patients and students and as failing to achieve optimum educational and productivity outcomes. During the 1995-96 academic year, a group practice model of patient care delivery was pilot tested to assess whether productivity, educational, and care delivery outcomes could be enhanced in comparison to the solo-practitioner model. This group practice model combined third- and fourth-year students for purposes of sharing resources and collaborating in patient care delivery. Resources dedicated to each group practice included a practice advisor, shared patient care coordinator, dental assistant, and shared clinic receptionist. Two group practices and twenty-five student solo practitioners participated in the study. Based upon an analysis of productivity, participant, and patient data, the group practice participants had greater billing volume, better attendance, enhanced satisfaction with the staff/faculty support and their ability to fill appointments, and generally comparable patient satisfaction ratings. These results suggest that the group practice model, through the dedication of resources and collaboration of providers, could enhance the outcomes of the clinical education program.

The role of medications in geriatric failure to thrive.

Geriatric failure to thrive (GFTT) is a syndrome associated with functional decline, depression and malnutrition. Adverse drug reactions are cited as one of the most common causes of GFTT. Two distinct drug-related issues should be considered. Firstly, failure to provide appropriate treatment for conditions such as anaemia, depression, nutritional deficiencies and pain may precipitate GFTT. Secondly, drug-induced functional decline and decreased nutrient intake may cause or contribute to the syndrome. Pharmacological intervention may include discontinuing potentially offending agents for a trial period, or drug treatment of anorexia and depression.

A population pharmacokinetic model for docetaxel (Taxotere): model building and validation.

A sparse sampling strategy (3 samples per patient, 521 patients) was implemented in 22 Phase 2 studies of docetaxel (Taxotere) at the first treatment cycle for a prospective population pharmacokinetic evaluation. In addition to the 521 Phase 2 patients, 26 (data rich) patients from Phase I studies were included in the analysis. NONMEM analysis of an index set of 280 patients demonstrated that docetaxel clearance (CL) is related to alpha 1-acid glycoprotein (AAG) level, hepatic function (HEP), age (AGE), and body surface area (BSA). The index set population model prediction of CL was compared to that of a naive predictor (NP) using a validation set of 267 patients. Qualitatively, the dependence of CL on AAG, AGE, BSA, and HEP seen in the index set population model was supported in the validation set. Quantitatively, for the validation set patients overall, the performance (bias, precision) of the model was good (7 and 21%, respectively), although not better than that of the NP. However, in all the subpopulations with decreased CL, the model performed better than the NP; the more the CL differed from the population average, the better the performance. For example, in the subpopulation of patients with AAG levels > 2.27 g/L (n = 26), bias and precision of model predictions were 24 and 32% vs. 53 and 53%, respectively, for the NP. The prediction of CL using the model was better (than that of the NP) in 73% of the patients. The population model was redetermined using the whole population of 547 patients and a new covariate, albumin plasma level, was found to be a significant predictor in addition to those found previously. In the final model, HEP, AAG, and BSA are the main predictors of docetaxel CL.

Positive elements in the laminin gamma 1 gene synergize to activate high level transcription during cellular differentiation.

Transcription of the murine laminin gamma 1 gene is activated during retinoic acid/cAMP induced differentiation of F9 embryonal carcinoma cells. Positive transcription control elements associated with two DNase I hypersensitive regions in the large first intron of the gene have been identified which confer a differentiation response on the laminin gamma 1 promoter. However, the kinetics of transcriptional activation suggest each DNA region interacts with transcription factors appearing at different times during differentiation. Synergy between the two regions in cis causes high level activation.

Genetic epidemiologic study of hearing loss in an adult population.

Previous population studies of hearing loss have been limited to children with moderate to profound impairment, and have reported that heritability accounts for at least 50% of congenital or early-onset cases. The present study was designed to assess genetic factors associated with late-onset hearing impairment in an adult population. A brief family history and audiologic questionnaire was sent to approximately 11,200 members of the consumer organization, Self Help for the Hard of Hearing, Inc., and 4,039 questionnaires were returned. All respondents reported having at least one previous audiologic exam. Reported data were verified against audiograms when available. Regardless of the reported causes, 49% of early-onset cases (< or = 20 years of age) had one or two parent(s) with some form of hearing loss compared with 62% in later-onset cases. As expected, mean age at onset was substantially younger for cases with positive family histories than cases with negative family histories. Results from nuclear segregation analysis showed that fully recessive and dominant models failed to explain the early- or late-onset hearing loss data. In this nationwide survey, the large proportion of cases with positive family histories clearly indicates the importance of genetic factors in adult-onset forms of hearing loss. Comparison with younger-onset cases will permit further delineation of differences in inheritance patterns. This study should identify more homogeneous groups of adult-onset families for further genetic study, and provide empiric information for use in genetic counselling.