Risk of Alzheimer's disease is associated with a very low-density lipoprotein receptor genotype in Northern Ireland.

The epsilon-4 allele of apolipoprotein E (APOE) is associated with increased risk of Alzheimer's disease (AD), but the pathogenic mechanism is unknown. The 5-repeat allele of a CGG repeat polymorphism in the 5' untranslated region of the very low-density lipoprotein receptor (VLDL-R) gene, a receptor for apoE, has been found to be associated with increased risk of AD in a Japanese population. Other groups have been unable to replicate this in American Caucasian populations. A case-control study utilizing a clinically well-defined group of late-onset AD patients (n = 108) and age- and sex-matched control subjects (n = 108) from Northern Ireland was performed to test this association in a relatively homogeneous population. The 9,9 genotype of the VLDL-R was found to be significantly increased in patients compared to controls (P = 0.003; Pcorr = 0.035), leading to an increased risk of AD to subjects with this genotype (OR = 3.9; 95% CI, 1.52-11.25). In contrast to results from the Japanese study, the 5-repeat allele was found to be significantly reduced in the patient group when compared to controls (P = 0.008; Pcorr = 0.047). The results from this study suggest that individuals who have the 9,9 genotype of the VLDL-R gene are at increased risk of AD in Northern Ireland.

Common polymorphisms in LRP and A2M do not affect genetic risk for Alzheimer disease in Northern Ireland.

Genetic variation in one of the major APOE receptors in the brain has been associated with increased risk for Alzheimer disease (AD). A C/T polymorphism in exon 3 and a tetranucleotide repeat polymorphism in the 5' region of the low-density lipoprotein receptor-related protein gene have been reported to increase risk in some studies but these reports have not been universally replicated. In addition, genetic variation in another ligand of LRP, alpha-2 macroglobulin (A2M), has also been associated with increased AD risk. However, these reports also remain controversial. We have genotyped both LRP polymorphisms and two polymorphisms in the A2M gene in a large group of clinically well-defined AD cases and controls from the relatively genetically homogeneous Northern Ireland population. Comparison of genotype and allele frequencies for polymorphisms in LRP revealed no significant differences between cases and controls. Multiple logistic regression analysis performed to assess any possible interaction between LRP and APOE revealed little evidence for genetic interaction despite the obvious biological interaction. Genotype and allele comparisons between the groups for the A2M polymorphisms also gave no evidence that either polymorphism increased risk for disease. The results from this study indicate that polymorphisms in LRP and A2M are not associated with increased risk for AD in Northern Ireland.

Plasma chain-breaking antioxidants in Alzheimer's disease, vascular dementia and Parkinson's disease.

We studied the plasma chain-breaking antioxidants alpha carotene, beta carotene, lycopene, Vitamin A, Vitamin C, Vitamin E and a measure of total antioxidant capacity, TAC, in 79 patients with Alzheimer's disease (AD), 37 patients with vascular dementia (VaD), 18 patients with Parkinson's disease and dementia (PDem), and 58 matching controls, together with 41 patients with Parkinson's disease (PD) and 41 matching controls. Significant reductions in individual antioxidants were observed in all dementia groups. When compared to controls, the following were reduced: Vitamin A in AD (p < 0.01) and VaD (p < 0.001); Vitamin C in AD (p < 0.001), VaD (p < 0.001) and PDem (p < 0.01); Vitamin E in AD (p < 0.01) and VaD (p < 0.001); beta carotene in VaD (p = 0.01); lycopene in PDem (p < 0.001). Lycopene was also reduced in PDem compared to AD (p < 0.001) and VaD (p < 0.001). Antioxidant levels in PD were not depleted. No significant change in TAC was seen in any group. The reduction in plasma chain-breaking antioxidants in patients with dementia may reflect an increased free-radical activity, and a common role in cognitive impairment in these conditions. Increased free-radical activity in VaD and PDem could be associated with concomitant AD pathology. Individual antioxidant changes are not reflected in TAC.

Plasma somatostatin and gastrointestinal peptides in Alzheimer's disease and vascular dementia.

Few markers distinguish between different dementia types. As dementia affects many body systems outside the central nervous system, we investigated gastrointestinal regulatory peptides as possible disease markers in Alzheimer's Disease (AD) and vascular dementia (VaD). Subjects with mild-to-moderate dementia were diagnosed as probable AD and VaD according to defined criteria. Gastrointestinal peptides were stimulated using a standardized meal test, administered after an overnight fast to 58 dementia patients (40 AD, 18 VaD) and 47 controls matched for age and sex. Blood samples were taken at designated time intervals, and basal and stimulated plasma concentrations of eleven peptides were determined by radio-immunoassay. Results were analysed using the Kruskal-Wallis one-way analysis of variance; the Mann-Whitney U test was used in post hoc analysis where appropriate. There were significant differences in somatostatin levels but in none of the other peptides. Basal somatostatin was significantly increased in VaD compared to controls (p<0.05), and AD (p<0.005). Maximum stimulated levels were significantly elevated in VaD compared to AD (p<0.01). Median basal and stimulated levels of somatostatin were increased in VaD compared to AD, but the overlap in individual values between the groups makes it unlikely to be useful in distinguishing the two types of dementia.

Cathepsin D gene exon 2 polymorphism and sporadic Alzheimer's disease.

It has recently been reported that a genetic polymorphism in exon 2 of the cathepsin D gene conferred increased risk for development of Alzheimer's disease (AD). Because of the potential importance of this report we tested this association in a clinically well-defined group of AD patients and age and sex matched control subjects from the relatively genetically homogeneous Northern Ireland population. This study failed to confirm the reported association between the cathepsin D exon 2 polymorphism and AD. We conclude that if an association exists between this polymorphism and AD it is likely to be small.

An audit of thyroid surgery in a general surgical unit.

A total of 143 patients undergoing thyroid surgery in a general surgical unit over an 8-year period were reviewed. In only two patients did thoracic inlet views or thyroid function tests alter clinical management. Fine-needle aspiration failed to detect one well-differentiated follicular carcinoma (false-negative rate 1.1%). The sensitivity for malignancy of fine-needle aspiration, ultrasound and radioisotope scan were 94%, 53% and 24%, respectively. The corresponding specificity was 59%, 72% and 58% and accuracy 65%, 70% and 49%, respectively. The specificity of fine-needle cytology for detecting neoplastic disease (adenoma or carcinoma) was 86% and accuracy 91%. Combinations of fine-needle cytology, ultrasound and radioisotope scanning increased the sensitivity for malignancy, so that fewer tumours were missed, but at the cost of reduced specificity, positive predictive value and accuracy. Hence, ultrasound was only recommended when fine-needle aspiration was inconclusive. Overall perioperative morbidity was 6.3% (one case of postoperative bleeding, two wound infections, four cases of prolonged hypocalcaemia). There were two proven cases of transient, but no permanent, recurrent laryngeal nerve injuries as a result of surgery. Thyroid surgery may be performed satisfactorily by general surgeons with an interest in thyroid disease. Fine-needle cytology is the most informative preoperative investigation. Although aspiration cytology, ultrasound, and scintigraphy all have appropriate indications and limitations, there is no single test or group of tests that can substitute for careful clinical assessment and follow-up.

A retrorectal abscess due to Crohn's disease of the terminal ileum.

A case of retrorectal abscess due to Crohn's disease is reported. This is a rare complication, of which only one previous report in the literature has been found.

Digital imaging: a valuable technique for the postoperative assessment of cochlear implantation.

Cochlear implantation with a multi-channel electrode array which provides stimulation via the auditory nerve has become a standard treatment for profound deafness. Postoperative radiography demonstrates electrode position and enables confirmation of satisfactory intra-cochlear electrode placement. The number of active electrodes which have been inserted can be determined and possible complications such as electrode kinking or slippage can be assessed. We evaluated digital radiography with confirmation of electrode position by intermittent fluoroscopy and assessed the relative radiation dose of the digital technique, conventional radiography and CT scanning. Radiation dose for this method usually ranges between 40 microGy and 440 microGy compared with a single exposure on the skull stand which produces a dose to the region of the cochlea of 470 microGy and a CT exposure of 950 microGy. The digital technique is comfortable for the patient, easily reproducible and provides images of high diagnostic quality enabling each electrode to be identified, which is especially valuable in association with postoperative electrode mapping. It also involves a lower radiation dose than conventional radiography. We now use digital radiography for all postoperative cochlear implant assessment.

Hyperglycaemia and mortality from acute stroke.

Hyperglycaemia has been observed after acute stroke, and is associated with a poor prognosis. It is not known whether this is due to the stress response of the acute illness or whether hyperglycaemia is, in itself, harmful to ischaemic nervous tissue. Seventy-one patients admitted to hospital with acute stroke and no history of diabetes or other acute illness were recruited, and fasting blood sampling was carried out within 24 h of symptom onset, for plasma glucose and stress hormones and levels of haemoglobin A1c (HbA1c). Computerized tomography of the brain was carried out on 77% of the subjects. The subjects were followed up for 3 months or until death. Glucose levels were higher in subjects who died during the course of the study (p = 0.025), but this relationship became non-significant after age (p < 0.001) and cortisol (p = 0.001) levels were taken into account with multivariate analysis. The correlation between serum cortisol and the volume of the lesion on CT scan was also stronger than the relation of glucose with volume. Haemoglobin A1c had no relationship with either mortality or lesion volume. These findings suggest that the hyperglycaemia seen after an acute stroke is secondary to a stress response and they do not support the theory of hyperglycaemia being harmful to ischaemic nervous tissue. These findings have implications for the treatment of acute stroke with hypoglycaemic agents.

Herniography for occult hernia and groin pain.

In a prospective 3-year study herniography was used to assess patients with unexplained groin pain in whom clinical signs were inconclusive. Fifty-two patients were studied. No serious complications were observed. Twenty-two hernias were identified in 18 patients. The positive herniographic findings were confirmed at operation in 12 patients. Of 34 patients with a negative herniogram, none has developed a hernia. Pain settled spontaneously in 29 patients and five were referred to a pain clinic for further management.

Butyrylcholinesterase K variant is genetically associated with late onset Alzheimer's disease in Northern Ireland.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that has been associated, sometimes controversially, with polymorphisms in a number of genes. Recently the butyrylcholinesterase K variant (BCHE K) allele has been shown to act in synergy with the apolipoprotein E epsilon4 (APOE epsilon4) allele to promote risk for AD. Most subsequent replicative studies have been unable to confirm these findings. We have conducted a case-control association study using a clinically well defined group of late onset AD patients (n=175) and age and sex matched control subjects (n=187) from the relatively genetically homogeneous Northern Ireland population to test this association. The BCHE genotypes of patients were found to be significantly different from controls (chi(2)=23.68, df=2, p<<0.001). The frequency of the K variant allele was also found to differ significantly in cases compared to controls (chi(2)=16.39, df=1, p<<0.001) leading to an increased risk of AD in subjects with this allele (OR=3.50, 95% CI 2. 20-6.07). This risk increased in subjects 75 years and older (OR=5. 50, 95% CI 2.56-11.87). At the same time the APOE epsilon4 associated risk was found to decrease from 6.70 (95% CI 2.40-19.04) in 65-74 year olds to 3.05 (95% CI 1.34-6.95) in those subjects 75 years and older. However, we detected no evidence of synergy between BCHE K and APOE epsilon4. The results from this study suggest that possession of the BCHE K allele constitutes a significant risk for AD in the Northern Ireland population and, furthermore, this risk increases with increasing age.

Association of serum AACT levels and AACT signal polymorphism with late-onset Alzheimer's disease in Northern Ireland.

alpha1-antichymotrypsin (AACT) is a serine protease inhibitor that has been associated with amyloid plaques in the brains of patients with Alzheimer's disease (AD). It has been reported that AACT serum levels are higher in AD patients than in age and sex matched controls. In addition, polymorphisms in the signal peptide and 5' of the AACT gene have been reported to increase the risk of developing AD. Serum AACT has also been suggested to be associated with cognitive decline in elderly subjects. Our objective was to investigate whether a relationship existed between serum AACT levels, AACT genotypes and risk for AD in a case control association study using 108 clinically well defined late onset AD cases and 108 age and sex matched controls from Northern Ireland. We also wished to determine whether higher serum AACT affected levels of cognition as had been previously reported. Serum AACT levels were found to be significantly raised in cases compared to controls (t=3.8, df=209, p<0.001). However, we detected no relationship between serum AACT levels and cognitive decline. We report allelic association of the AACT signal polymorphism with AD (chi(2)=3.70, df=1, p=0.04) but we failed to show any correlation between AACT serum levels and genotype.

Evaluation and outcome of patients with chronic non-productive cough using a comprehensive diagnostic protocol.

BACKGROUND: Asthma, post-nasal drip syndrome (PNDS), and gastro-oesophageal reflux (GOR) account for many cases of chronic non-productive cough (CNPC). Each may simultaneously contribute to cough even when clinically silent, and failure to recognise their contribution may lead to unsuccessful treatment. METHODS: Patients (all lifetime non-smokers with normal chest radiographs and spirometric measurements) referred with CNPC persisting for more than three weeks as their sole respiratory symptom underwent histamine challenge, home peak flow measurements, ear, nose and throat (ENT) examination, sinus CT scanning, and 24 hour oesophageal pH monitoring. Treatment was prescribed on the basis of diagnoses informed by investigation results. RESULTS: Forty three patients (29 women) of mean age 47.5 years (range 18-77) and mean cough duration 67 months (range 2-240) were evaluated. On the basis of a successful response to treatment, a cause for the cough was identified in 35 patients (82%) as follows: cough variant asthma (CVA) (10 cases), PNDS (9 cases), GOR (8 cases), and dual aetiologies (8 cases). Histamine challenge correctly predicted CVA in 15 of 17 (88%) positive tests. ENT examination and sinus CT scans each had low positive predictive values for PNDS (10 of 16 (63%) and 12 of 18 (67%) positive cases, respectively), suggesting that upper airways disease frequently co-exists but does not always contribute to cough. When negative, histamine challenge and 24 hour oesophageal pH monitoring effectively ruled out CVA and GOR, respectively, as a cause for cough. CONCLUSION: This comprehensive approach aids the accurate direction of treatment and, while CVA, PNDS and GOR remain the most important causes of CNPC to consider, a group with no identifiable aetiology remains.

Serum neurone-specific enolase as an indicator of stroke volume.

Serum neurone-specific enolase (NSE) and computerized tomography (CT) stroke volume were compared in patients admitted within 24 h of an acute stroke. Serum samples were obtained on admission and daily for the next 4 days. Of 163 patients, CT scans revealed 25 with intracerebral haemorrhages, one haemorrhagic infarct and 83 measurable acute infarcts. The serum NSE levels of those with infarcts was significantly higher than in those with haemorrhages at 48 (P = 0.0003) and 72 h (P = 0.04). The maximum serum NSE value tended to occur later in those with large infarcts (P = 0.0035). There was a significant correlation between infarct volume and serum NSE at 48 h (r = 0.27, P = 0.015) and 96 h (r = 0.27, P = 0.015) and with the maximum serum NSE over the 4 days (r = 0.36, P = 0.001). There was no significant correlation between haemorrhage volume and NSE. In conclusion, serum NSE may be a useful marker of infarct volume in studies of therapy in acute stroke. Sampling for NSE should continue, at least in those with large infarcts, for longer than 4 days. Serum NSE cannot be used to distinguish between haemorrhage and infarction in patients with an acute stroke.