The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland.

The neuronal ceroid lipofuscinoses (NCLs) are the commonest neurodegenerative disorders of children. The aims of this study were to determine the incidence of NCL in Newfoundland, identify the causative genes, and analyze the relationship between phenotype and genotype. Patients with NCL diagnosed between 1960 and 2005 were ascertained through the provincial genetics and pediatric neurology clinics. Fifty-two patients from 34 families were identified. DNA was obtained from 28/34 (82%) families; 18 families had mutations in the CLN2 gene, comprising five different mutations of which two were novel. One family had a CLN3 mutation, another had a novel mutation in CLN5, and five families shared the same mutation in CLN6. One family was misdiagnosed, and in two, molecular testing was inconclusive. Disease from CLN2 mutations had an earlier presentation (p = 0.003) and seizure onset (p < 0.001) compared with CLN6 mutation. There was a slower clinical course for those with CLN5 mutation compared with CLN2 mutation. NCL in Newfoundland has a high incidence, 1 in 7353 live births, and shows extensive genetic heterogeneity. The incidence of late infantile NCL, 9.0 per 100,000 (or 1 in 11,161) live births, is the highest reported in the world.

Sequence and task analysis of instrument use in common laparoscopic procedures.

BACKGROUND: In the area of instrument evaluation, one aspect that still requires objective assessment is the dynamics of instrument maneuver and exchange. If we could gain a better understanding of these phenomena, we could improve the design of the instruments themselves. METHODS: A total of 29 laparoscopic procedures were videotaped and reviewed using time motion analysis. Instrument multifunctionality was determined using a standardized list of laparoscopic maneuvers. State transition diagrams were utilized to document the sequence of instrument exchanges. RESULTS: The curved dissector, atraumatic grasper, and cautery scissors were identified as the most multifunctional instruments; each was able to perform five distinct maneuvers. Instrument sequences were found to consist of a three-part dissect --> clip --> cut cycle and a two-part dissect --> suction cycle of instrument exchange. CONCLUSION: This study demonstrated that laparoscopic instruments are often used to perform a variety of maneuvers in addition to their primary function. Furthermore, there are common patterns in instrument exchange that provide a potential source of design parameters for improved surgical efficiency.

Design of multifunctional compliant mechanisms for minimally invasive surgery.

Compliant mechanisms that can perform multiple unique functions have great potential for use in minimally invasive therapy. A fully compliant mechanism may be thought of as a monolithic mechanism without hinge joints which uses elastic deformation to achieve force and motion transmission. Incorporating multifunctional compliant mechanisms into minimally invasive surgical tools has many possible advantages, including reduced instrument exchanges and additional dexterity at the surgical site. Compliant mechanisms also offer the advantage of single-piece construction and ease of manufacture over their rigid-link counterparts, eliminating the need for complex millimeter-scale assembly and cleaning in hinge areas. A multicriteria topology optimization procedure for the design of multifunctional compliant mechanisms is illustrated through the design of a combination tool that will perform forceps and scissor function. A working solid model of the combination forceps/scissors has been generated based on the optimal topology. Results of detailed finite element modeling are discussed along with implications for practical manufacture and implementation.

Nutritional patterns of mothers of children with neural tube defects in Newfoundland.

In an exploratory study of the genetic epidemiology of neural tube defects in Newfoundland, we studied mothers who had given birth to a child with a neural tube defect (NTD) with respect to their nutrition, as well as various other factors. The frequency of NTD in the area studied was 3.5/1,000 births and has not decreased recently, as it has in some other parts of the world. Twenty-five mothers of children with NTD and a comparison group (CG), matched for age and neighbourhood, completed 3 day dietary records. The NTD group consisted of all mothers who had given birth to an NTD child within the previous 3.5 years in the chosen area. The CG mothers were ascertained through the local public health nurse who chose the nearest unaffected child born in the same time period as the NTD probands. NTD mothers were younger, heavier, and of lower socioeconomic status than were CG mothers. CG group women consumed more vitamin supplements during the periconceptional period (P < 0.05) and consumed more dairy and cereal products, fruits and vegetables (other than potatoes), and fewer sweets than did NTD mothers. Sixty-four percent of NTD mothers had folacin intakes below the recommended level (168 mg) compared to 27% of CG mothers (P < 0.01). These findings support previous evidence that poor maternal nutrition, and low dietary folate in particular, increase the chance of having a child with an NTD, and emphasize the need for supplementary folate in the diet of women of childbearing age in areas where the frequency of NTDs is high.

Immunological associations in familial and non-familial Alzheimer patients and their families.

A number of autoimmune diseases and immune-related conditions were investigated in a series of 100 Alzheimer patients and their families. The group was divided into those who had familial dementia of the Alzheimer type and non-familial dementia of the Alzheimer type. HLA DR3 was associated with the familial dementia of the Alzheimer type patients. Adult exposure to tuberculosis appeared to be a risk factor for familial dementia of the Alzheimer type patients. Autoimmune diseases clustered among the non-familial dementia of the Alzheimer type patients, and also among their relatives. Asthma and infertility were also significantly increased among non-familial dementia of the Alzheimer type relatives. The analysis showed that (1) autoimmunity may be important in the sporadic form of Alzheimer disease; (2) it may be possible to confer a decreased risk for Alzheimer disease among relatives when many autoimmune diseases occur in the family; (3) it may be important to assess environmental risk factors for Alzheimer disease separately in patients with familial and sporadic disease; and (4) the efficacy of drug therapies may be dependent on whether the patients have a familial or sporadic form of Alzheimer disease.

Dementia in Newfoundland: identification of a geographical isolate?

STUDY OBJECTIVE: The aims were (1) to identify from death certificates regions with an increased incidence of dementia mortality; and (2) to determine whether a previously observed excess of patients with Alzheimer disease originating from a small area could be confirmed in a survey of death certificates. DESIGN: The study identified all individuals dying with dementia, recorded on death certificates as an immediate, antecedent, underlying, or contributing cause of death. Rather than the usual residence, the birthplace of these individuals was used to determine regional differences in dementia mortality. A comparison was made of two areas to test the significance of a geographical isolate of persons. To test for a possible genetic component of the excess, an analysis was made of the frequencies of family names. To test for a possible environmental component an analysis was made of standard measurements of drinking water quality. SETTING: The survey data were derived from all 1985 and 1986 deaths in the province of Newfoundland. MEASUREMENTS AND MAIN RESULTS: Based on the current census population, the prevalence of dementia at death for 1985 and 1986 was 34 and 37/100,000. For both years there was a significant excess of persons originating from a small area (95% CI, 1.1-20.7%, and 2.5-20.4%). This excess could not be explained by differences in age, sex, ethnic origin, or by variation in mobility patterns. The study area has a high concentration of aluminium in the drinking water. An analysis of the family names gave inconclusive evidence of a clustering among the dementia cases. CONCLUSIONS: If all contributing causes of death are recorded and the birthplace of individuals is noted, mortality statistics can reveal regional differences in dementia rates. This shows the need to examine areas smaller than census districts to identify subpopulation variation in the prevalence of dementia. Environmental influences can vary substantially in areas relatively close together, as evidenced in measurements of drinking water chemistry. Genetic influences are more likely to be revealed from the birthplace of individuals, which may indicate a common ancestry.

Association between Alzheimer disease and amyotrophic lateral sclerosis?

We report two cases of Alzheimer disease (AD)--one of them familial--in which the patient also had amyotrophic lateral sclerosis (ALS), and one patient with familial AD who had a son with ALS. Three further cases of probable ALS were found in pedigrees of AD reported from the literature. It is proposed that this association is not coincidental, but may suggest an etiological factor in common.

Major histocompatibility complex (MHC) factors predisposing to and protecting against Graves' eye disease.

We investigated the influence of gene mapping within the major histocompatibility complex on the susceptibility to Graves' eye disease. We studied 133 randomly selected patients with Graves' disease, many of whom had eye disease. HLA B8 and DR3 carried the greatest risk for disease but the difference between the two patient groups was not statistically significant. An earlier finding that Hungarian patients with a subset of B8, (B8 + DR7 +) had a greatly enhanced risk for eye disease was confirmed in Newfoundland patients. HLA B8 and DR7 are probably carried on different homologous chromosomes and their interaction enhances eye disease. HLA-DR4 was negatively correlated with eye disease. In particular, a subset of DR4 (B35 + DR4 +) appears to protect against eye disease. We have also derived the haplotypes of 22 probands, half of whom had eye disease. The haplotype data emphasized the high frequency of HLA A1 B8 DR3 C4A*QO and C4B*1 in both patient groups, 15% of the haplotypes in the group with eye disease and 25% in that without eye disease. Forty-one percent of haplotypes in the eye disease group and 32% in the no eye disease group were either C4A*QO or C4B*QO. In one proband with eye disease B8 and DR7 were carried on separate chromosomes. The phenotype DR4, C4A*3 C4B*1 was found in 3/20 haplotypes of patients without eye disease but in 0/20 of patients with eye disease. This finding is in keeping with the increased frequency of the DR4 C4A*3 C4B*1 in the patient group with no eye disease when 94 patients were phenotyped.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidemiological studies of neural tube defects in Newfoundland.

A 9-year survey of neural tube defects in Newfoundland showed (1) evidence for secular variation, with a peak in 1980, but no general downward trend as seen in some other populations; (2) significant geographic variation which did not correlate with hardness or nitrate content of the lake water; (3) a tendency for the proportion of females among anencephalic births to increase with increasing frequency of anencephaly among geographic regions. This supports previous evidence for a female-specific contribution to the causes of increased liability to neural tube defect.

Genetic factors in Graves' ophthalmopathy.

We investigated the distribution of HLA and immunoglobulin G heavy chain markers (Gm) in 117 patients with Graves' disease, 62 with ophthalmopathy and 55 without. With Graves' disease per se, there is a closer association with HLA-DR3 than with B8. The opposite was true for Graves' patients with ophthalmopathy (odds ratio for ophthalmopathy associated with B8 was 12.4 and with DR3 was 7.7, both with P less than 0.0005). HLA-DR7 interacts with B8 in modifying the risk for eye disease; using the phenotype B8- DR7- as reference, the odds ratios were 16.7 for B8+ DR7+, 8.7 for B8+ DR7- and 0.26 for B8- DR7+. Thus, DR7 enhanced the risk for ophthalmopathy in the presence of B8+ but had a protective influence in its absence. Although Gm showed no association with eye disease, it modified the risk for ophthalmopathy associated with HLA-B8; the odds ratios were 20.9 for B8+ Gmfb homozygozity (fb+), 15.3 for B8+ fb- and 1.7 for B8- fb+ (B8- fb- = 1.00). We conclude that the genetic factors contributing to Graves' ophthalmopathy are different from those related to liability for Graves' hyperthyroidism.

Seasonal variation of neural tube defects in Newfoundland and elsewhere.

In Newfoundland, babies with anencephaly are conceived most often in January, and those with spina bifida in August. These and previous observations suggest that (1) seasonal fluctuations are greatest when the population frequency is neither very high nor very low, and that (2) the peak season for conception of anencephalic babies may occur in any season except August-November in various populations, whereas for spina bifida seasonal peaks are confined almost exclusively to May-August.

Heterogeneity by cluster analysis techniques of Graves' patients typed for HLA DR and IgG heavy chain markers.

In a previous study we were able to separate, using cluster analysis, 196 patients with Graves' disease evaluated for a large number of clinical and laboratory characteristics, including HLA-A and HLA-B typing into one subset with recurring disease and a high prevalence of ophthalmopathy and another subset with mild disease and little ophthalmopathy. Prevalence of HLA-B8 was much higher in the first as compared to the second group. The present study was undertaken in 117 new patients with Graves' disease, typed for HLA-A, HLA-B, HLA-C and DR antigens and IgG heavy chain markers, to determine whether these characteristics could be used to segregate patients into clinically relevant subsets. There was a greater proportion of Gm fb homozygotes among patients than among controls (chi2 = 4.71, p less than 0.05) as well as individuals with HLA-B8 and DR3, previously documented for this disease. Two patient clusters were identified. In one (C1), there is a high incidence of exophthalmos, recurrence of hyperthyroidism after drug treatment, high titres of anti-thyroglobulin antibody, and an association with other autoimmune (including thyroid) diseases, a tendency for the disease to be familial and the presence of larger goitres. The incidence of HLA-B8 was greater in C1, while HLA-B12 was more frequent in the mild cluster, C2. HLA-DR3 was found to be associated with patients in the severe cluster and HLA-DR2 with patients in the mild cluster.(ABSTRACT TRUNCATED AT 250 WORDS)

A prognostic score for Graves' disease.

We have reanalysed the clinical and laboratory data on 196 individuals with Graves' disease. The consensus of two clustering techniques and a new method of allocating patients to a cluster resulted in two groups of patients, those with a severe and others with a mild disease. The severe disorder is characterized by a high frequency of HLA-B8 and -Al, a low complement level, high titres of circulating immune complex and anti-thyroglobulin antibody, a high lymphocyte transformation index and serum T3 level, a low level of active E-rosettes, large goitres and a high value for the Crooks test. The mild disorder shows a higher frequency of HLA-B12 and an abnormally low absolute lymphocyte number. A weight was calculated for each character according to the relative frequency in the two clusters. A total score could then be calculated for each patient based on their clinical and laboratory findings. There were two distinct distributions of scores corresponding to the two subgroups. This suggests different aetiological factors which may be more easily studied in these more homogeneous groups. Prognostic predictions can be made using the score. The risk of recurrence and the frequency and severity of ophthalmopathy increases dramatically as the score increases. The use of the score in making therapeutic decisions needs to be tested.

Confirmation of regional assignment of nucleoside phosphorylase (NP) on chromosome 14 by gene dosage studies.

Gene dosage studies yielded results consistent with assignment of the locus for nucleoside phosphorylase to band 14q13. The red blood cells from a patient with the karyotype 47,XX,+der(14),t(8;14)(8qter leads to 8q24::14q21 leads to 14pter)pat had enzyme activity 50% higher than red cells from 47 normal controls, two trisomies involving chromosomes other than 14, and five balanced translocations involving chromosome 14. On the other hand, the red cells of a case with a karyotype 45,XX,-14,-22+der(22),t(14;22)(14qter leads to 14q11 or 14q12::22p11 leads to 22qter)mat and a case with a a karyotype 47,XX,+der(14),t(14;16)(14pter leads to 14q11::16q24 leads to 16qter)mat had normal activity