Short-term memory deficits in carrier females with KDM5C mutations.

We present the cognitive abilities of females from five families who carry a mutation in a gene (KDM5C, formerly JARIDIC or SMCX) in Xp 11.2 that encodes a transcriptional regulator with histone demethylase activity that is specific for dimethylated and trimethylated H3K4. In this report, the cognitive abilities of females who carry KDMSC mutations are compared to females who carry mutations in other genes known to cause X-linked intellectual and developmental disability (XLIDD) conditions. The KDM5C mutation carriers had higher mean scores on the abstract/visual and quantitative sections of the Stanford-Binet Intelligence Scale: Fourth Edition and lower mean short term memory scores. Implications for counseling are presented.

Nitrous oxide and laparoscopic bariatric surgery.

BACKGROUND: Nitrous oxide (N2O) is frequently used to supplement more potent anesthetic agents. One side-effect of N2O is its ability to expand an air-containing space. We investigated if N2O adversely affected operating conditions by distending normal bowel during laparoscopic bariatric procedures. METHODS: 50 morbidly obese patients were divided into 2 study groups. Group 1 patients were ventilated with a halogenated anesthetic/oxygen/air mixture, while Group 2 received a halogenated anesthetic/oxygen/N2O mixture. At 30, 60, and 90 min intervals during the operation, the surgeon was asked if N2O was being used. RESULTS: The surgeons responded correctly only 42% (30 min), 50% (60 min), and 48% (90 min) of the time. In Group 2 (N2O) patients, they incorrectly answered that N2O was not being used 88% (30 min), 68% (60 min), and 68% (90 min); and in Group 1 (air) patients, they incorrectly answered that N2O was being used 28% (30 min), 32% (60 min), and 36% (90 min) of the time. CONCLUSION: We found that using N2O did not cause noticeable bowel distention during laparoscopic bariatric procedures of relatively short duration.

Can one written word mean many things? Prereaders' assumptions about the stability of written words' meanings.

Results of three experiments confirmed previous findings that in a moving word task, prereaders 3 to 5 years of age judge as if the meaning of a written word changes when it moves from a matching to a nonmatching toy (e.g., when the word "dog" moves from a dog to a boat). We explore under what circumstances children make such errors, we identify new conditions under which children were more likely correctly to treat written words' meanings as stable: when the word was placed alongside a nonmatching toy without having been alongside a matching toy previously, when two words were moved from a matching toy to a nonmatching toy, and when children were asked to change what the print said. Under these conditions, children more frequently assumed that physical forms had stable meanings as they do with other forms of external representation.

Differences in the diagnostic yield of upper gastrointestinal endoscopy in dyspeptic patients receiving proton-pump inhibitors and H2-receptor antagonists.

BACKGROUND AND STUDY AIMS: Patients attending for diagnostic oesophagogastroduodenoscopy (OGD) for dyspeptic symptoms are often receiving acid-suppression therapy that has not been discontinued prior to endoscopy, and this may reduce the diagnostic yield of endoscopy. The aim of this study was to compare the diagnostic yield of OGD in uncomplicated dyspepsia in patients receiving no medication, those receiving acid-suppression therapy, and those receiving nonsteroidal anti-inflammatory drugs (NSAIDs) at the time of endoscopy. PATIENTS AND METHODS: A total of 6825 diagnostic OGDs performed in our unit between 1993 and 2001 were analysed. Patients were excluded if they had sinister symptoms, were receiving NSAIDs, or were undergoing repeat or surveillance endoscopy. RESULTS: A total of 4233 OGDs (62 %) fulfilled the criteria for uncomplicated dyspepsia. Of the patients examined in these procedures, 1367 (32 %) were receiving acid-suppression therapy. A total of 724 patients (53 % of those on therapy) were receiving proton-pump inhibitors (PPIs), 393 of whom (54 %) had positive endoscopic findings (oesophagitis 31 %, gastritis 16 %, duodenal ulcer/duodenitis 16 %). A total of 643 (47 % of the patients on therapy) were receiving H 2 -receptor antagonists, 443 of whom (69 % of this group) had positive endoscopic findings (oesophagitis 30 %, gastritis 21 %, duodenal ulcer/duodenitis 31 %). A total of 2866 patients were not receiving acid-suppression therapy, 1805 of whom (63 %) had endoscopic findings (oesophagitis 37 %, gastritis 14 %, duodenal ulcer/duodenitis 24 %). The endoscopic yield was significantly lowest in the PPI group, except for the diagnosis of oesophagitis. Overall, 17 carcinomas were detected in patients referred with simple dyspepsia, and in five of these cases the patients were receiving acid suppression. CONCLUSIONS: The widespread use of acid suppression in the treatment of simple dyspepsia prior to endoscopy leads to a reduction in the endoscopic recognition of mucosal lesions caused by acid-peptic disease, but not to a high healing rate for these lesions, and it may mask malignancy.

Successful colonoscopy; completion rates and reasons for incompletion.

Factors such as poor bowel preparation or obstructing colonic disease may confound the reporting of colonoscopy completion rates, as these factors are outside of the control of the endoscopist performing the procedure. By adjusting for these factors when calculating a colonoscopy completion rate, it may be possible to make a more accurate assessment of a unit's or individuals' competence. Details of two thousand two hundred and sixteen colonoscopies performed by four consultants and their trainees between 1993-2000 were analysed retrospectively from a prospective endoscopy database. Crude (all cases) and adjusted (excluding poor bowel preparation and disease as causes of incompletion) rates were recorded for each sex, and by age according to cause. Overall crude and adjusted completion rates were 77.9% and 85.0% respectively. There was a significant difference between male and female completion rates due to a difference in the incidence of excess looping and intolerance of the procedure (adjusted rate 88.9% in males vs. 81.6% in females, p<0.05). There was a non-significant trend to lower completion rates in patients over 75 years of age compared to younger patients. Completion rates were significantly higher following bowel resection (adjusted rates 93.5% vs. 82.8%, p<0.05). There was no significant difference between completion rates for inpatient and outpatient referrals (P=0.36). Reporting colonoscopy completion rates by adjusting for factors such as poor bowel preparation and obstructing colonic disease allows for direct comparisons of completion rates reported by different units. Reporting completion rates in this way also highlights the effect of inadequate bowel preparation on successful colonoscopy.

Cognitive function in Coffin-Lowry syndrome.

Coffin-Lowry syndrome (CLS) is an X-linked disorder associated with mental retardation, distinctive facies and hands, hypotonia, and skeletal abnormalities. The syndrome results from mutations in the RSK2 gene located in Xp22.2. Although the syndrome has been elucidated clinically, few, if any, studies have focused on the cognitive deficits of the affected males or carrier females. The subjects of the present study were selected from two African-American families who have the same missense mutation (C340T) in RSK2. The subjects included six affected males, seven carrier females, three normal males and three non-carrier (normal) females. Normal family members served as contrast/comparison cohorts to control for socio-economic, sociocultural and genetic variables which would impinge on intellectual abilities. Analysis of cognitive function, as measured by the Stanford-Binet Intelligence Scale, 4th edn, demonstrated a distinct hierarchy of abilities from normal to carrier to affected patients. The mean composite IQs of the cohorts were 90.8, 65.0 and 43.2 for normal, carrier and affected individuals, respectively. These findings lend support to the clinical concept of negative intellectual effects in carriers of certain X-linked mental retardation conditions. X-inactivation studies showed that carrier females had mild to significant skewing. Normal females in the family did not demonstrate skewing. The correlation coefficient between IQ and X-inactivation status among carriers was not significant.

Does prophylactic endoscopic sphincterotomy prevent recurrent biliary problems in patients with gallstones and a normal cholangiogram?

BACKGROUND: Endoscopic sphincterotomy (ES) is indicated in patients with confirmed bile duct stones at endoscopic retrograde cholangiopancreatography (ERCP). The role of ES in patients with suspected bile duct stones but a normal cholangiogram, in the prevention of recurrent biliary symptoms, when cholecystectomy is not planned, is unclear. AIM: To determine if prophylactic ES prevents further biliary problems in such patients. METHODS: Patients were identified with gallbladder stones presenting with jaundice, abnormal liver function tests (LFTs) or dilated bile ducts on ultrasound, in whom cholecystectomy was not planned and who had a normal cholangiogram at ERCP. Patients were followed-up to determine the frequency of recurrent biliary problems or repeat investigations. RESULTS: Forty-one patients were included, of whom 20 had an ES. The frequency of pre-ERCP features did not differ between the two groups. Median follow-up was 32 months (range 15-66). Post-ERCP recurrent abdominal pain (5 vs 3; p=0.39), jaundice (3 vs 1; p=0.28), pancreatitis (0 vs 1; p=0.32), and repeat ultrasound (2 vs 1; p=0.52), ERCP (1 vs 1; p=0.97) or cholecystectomy (2 vs 3, p=0.82) did not differ between the two groups. CONCLUSIONS: Patients with gallstones, suspected common bile duct (CBD) stones and a normal cholangiogram need not have a prophylactic sphincterotomy since there is no reduction in recurrent biliary problems and this potentially increases the morbidity.

Investigation of association of 13 polymorphisms in eight genes in southeastern African American Alzheimer disease patients as compared to age-matched controls.

Alzheimer disease (AD) is an emotionally devastating and exceptionally costly disease. Apolipoprotein E (APOE) is a major risk factor gene for AD regardless of age of onset or family history. However, this association may not be as strong or consistent in ethnic groups such as African Americans, raising the possibility of other modifier gene(s). In a group of African American AD patients, a significantly increased risk of AD was associated with two E4 alleles (OR = 5.6; 95% CI = 1.5-21.0) or one E4 allele (OR = 2.5; 95% CI = 1.3-5.0) when compared to E3/E3 genotype, and there was a significant lowering of age of onset for affecteds with E4/E4 genotype as compared to one E2 allele (P = 0.02) or all others (P = 0.03). We also found a significant increase in age of onset with the -308 #2 (A) allele of TNF when compared to AD cases with no #2 allele. A significant increase in age was also demonstrated with the #2 allele (99 base pairs) of the microsatellite TNFa, located approximately 10.5 kb upstream of TNF. When these two alleles were combined with the TNF -238G (#1) allele to give a haplotype, the significant increase in age was still demonstrated. Polymorphisms in the APOE promoter and six other candidate genes did not appear to demonstrate any significant association with our African American AD patients. Our results confirm the established association of APOE4 to AD observed in several ethnic groups, including African Americans. In addition, TNF appears to have some modifying effect in AD, primarily on age of onset, or it could be in linkage disequilibrium with a modifier locus nearby.

Flexible sigmoidoscopy and the changing distribution of colorectal cancer: implications for screening.

BACKGROUND AND AIMS: There has been a significant proximal shift in the distribution of colorectal cancer (CRC) in Northern Ireland over recent decades. The aim of this study was to investigate the potential implications of this proximal shift in CRC distribution on the efficacy of flexible sigmoidoscopy (FS) as a screening tool. PATIENTS AND METHODS: The site distribution of 5153 CRCs was available from the Northern Ireland Colorectal Cancer Register for the period 1990-1997. Similar data on 1241 CRCs between 1976 and 1978 were available from a previous study. Data on the site reached by FS were obtained from a prospectively collected endoscopy database at one of Northern Ireland's main teaching hospitals for the period 1993-1998. RESULTS: There was a significant proximal shift in CRC distribution between the two periods (23.5% proximal to the splenic flexure between 1976 and 1978 v 36.7% between 1990 and 1997; p<0.001). The descending colon was visualised during 74.4% of FS examinations. By combining the observed extent of FS examination with CRC site distribution, it was calculated that FS could have visualised 68.8% of CRCs between 1976 and 1978 but only 56.0% between 1990 and 1997. Extrapolating these data to a Northern Ireland screening programme involving FS and faecal occult blood testing suggests that significantly more CRCs could have been detected between 1976 and 1978 than between 1990 and 1997 (51.7% v 48.2%, respectively; p=0.03). CONCLUSIONS: This study confirms the previously documented left to right shift in CRC distribution in Northern Ireland and demonstrates that if this shift continues, FS will become less successful as a screening tool than is currently predicted.

The role of TNF and its receptors in Alzheimer's disease.

Tumor necrosis factor (TNF) is an important proinflammatory cytokine that is upregulated in Alzheimer disease (AD) patients and involved with AD genes. Several TNF promoter polymorphisms that increase expression are associated with inflammatory and infectious diseases. We previously reported results that detected a AD associated region near the TNF gene. Using family-based association tests we also reported an association between AD and a TNF haplotype in sibling-pair families, and a significant increase in the mean age of onset for a group of African-American AD patients carrying this same haplotype. Previous reports have shown that that the chromosome 1p and chromosome 12p regions are linked to late-onset AD. These two regions harbor TNF receptors (TNFR) 2 and 1, respectively, and binding to them mediates biological effects of TNF. We found a significant asssociation of a TNFR2 exon 6 polymorphism with late-onset AD in families with no individuals possessing the APOE E4E4 genotype under a dominant model. We found no significant association of three polymorphisms in the TNFR1 gene to AD. These results provide further evidence for the involvement of TNF in the pathogenesis of AD.

Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative.

Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

General practitioners' habits and knowledge in relation to the management of H. pylori-associated dyspepsia and their views about a locally available 13-carbon urea breath test.

We report the results of general practitioners' views on Helicobacter pylori-associated dyspepsia and use of screening tests in the community. The use of office serology tests in screening is of concern as independent validation in specialist units has been disappointing.

Microsatellite analysis provides evidence of neoplastic transformation in long-segment, but not in short-segment, Barrett's oesophagus.

It has been suggested that the high prevalence of short segments of specialised intestinal metaplasia (SIM) at the gastro-oesophageal junction is associated with the rising incidence of oesophageal adenocarcinoma. Our aims were to document the prevalence of short segments of SIM at the gastro-oesophageal junction in patients attending for routine endoscopy and to determine if there was molecular evidence of neoplastic transformation in those with SIM. Patients (n = 101) were recruited from randomly selected upper gastro-intestinal endoscopy lists. Biopsy specimens were taken at the squamo-columnar junction to assess the prevalence of SIM. Frozen sections were assessed for molecular evidence of neoplastic transformation using microsatellite analysis. Squamo-columnar biopsies were suitable for analysis in 95 patients, of whom 20 (21%) had oesophagitis and 2 (2%) had Barrett's oesophagus (>3 cm of endoscopically apparent columnar-lined oesophagus). Twenty patients had SIM at the gastro-oesophageal junction, including 2 with Barrett's oesophagus and 18 with short segments of SIM, one of whom had an associated intramucosal adenocarcinoma detected incidentally by histology. Three of the 20 cases with SIM exhibited novel microsatellite alleles, 2 with Barrett's oesophagus and 1 with short segment SIM and an associated adenocarcinoma. The 18 patients with short segments of SIM at the gastro-oesophageal junction were significantly older than those without SIM.

A prospective randomised trial of a "test and treat" policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic.

BACKGROUND: Management of dyspepsia remains a controversial area. Although the European Helicobacter pylori study group has advised empirical eradication therapy without oesophagogastroduodenoscopy (OGD) in young H pylori positive dyspeptic patients who do not exhibit alarm symptoms, this strategy has not been subjected to clinical trial. AIMS: To compare a "test and treat" eradication policy against management by OGD. PATIENTS: Consecutive subjects were prospectively recruited from open access OGD and outpatient referrals. METHODS: H pylori status was assessed using the carbon-13 urea breath test. H pylori positive patients were randomised to either empirical eradication or OGD. Symptoms and quality of life scores were assessed at baseline and subsequent reviews over a 12 month period. RESULTS: A total of 104 H pylori positive patients aged under 45 years were recruited. Fifty two were randomised to receive empirical eradication therapy and 52 to OGD. Results were analysed using an intention to treat policy. Dyspepsia scores significantly improved in both groups over 12 months compared with baseline; however, dyspepsia scores were significantly better in the empirical eradication group. Quality of life showed significant improvements in both groups at 12 months; however, physical role functioning was significantly improved in the empirical eradication group. Fourteen (27%) in the empirical eradication group subsequently proceeded to OGD because of no improvement in dyspepsia. CONCLUSIONS: This randomised study strongly supports the use of empirical H pylori eradication in patients referred to secondary practice; it is estimated that 73% of OGDs in this group would have been avoided with no detriment to clinical outcome.

Effect of Helicobacter pylori eradication on antral somatostatin cell density in humans.

OBJECTIVE: As Helicobacter pylori infection is associated with an elevation in plasma gastrin with normal antral gastrin cell counts, an abnormality in antral somatostatin cells may be associated with the infection. We evaluated the effect of eradication of H. pylori on antral somatostatin cell density in the light of antral gastrin cell density and plasma gastrin levels. DESIGN: Prospective study. METHODS: Of 25 dyspeptic patients with H. pylori infection, nine had H. pylori successfully eradicated and the rest remained infected. Antral biopsies were immunostained for somatostatin cells and plasma gastrin measured before and 4 weeks after H. pylori eradication therapy. Ten other dyspeptic patients without H. pylori infection had their somatostatin cell density evaluated as controls. RESULTS: Somatostatin cell density in the patients without H. pylori infection at the outset was significantly higher than that in the patients with H. pylori infection at the outset (median 57 [18-83] vs. 37 [6-80] cells/mm) respectively (P <0.05). Somatostatin cell density increased after H. pylori eradication (before treatment, median 50 [15-72]; after treatment 71 [39-107] cells/mm) (P < 0.05) but was unchanged with persistent H. pylori infection. Plasma gastrin decreased after H. pylori eradication (before treatment, median 70 [45-100]; after treatment 30 [10-100] ng/l) (P < 0.05) but was unchanged with persistent H. pylori infection. CONCLUSIONS: Following eradication of H. pylori, there is an increase in somatostatin cell density with a fall in plasma gastrin. This supports the theory that H. pylori infection results in a decrease in somatostatin cell density and, as the latter is an inhibitor of gastrin cells, this results in an increased plasma gastrin.

The effect of treating reflux oesophagitis with omeprazole on quality of life.

BACKGROUND/AIMS: Despite the commonplace nature of heartburn and reflux oesophagitis, little is known of their impact on patients' quality of life. The aim of this study was to assess quality of life in oesophagitis patients before and after medical therapy and compare the results with a sample of the general population. METHODS: Consecutive attenders with frequent heartburn and grade II-III oesophagitis on endoscopy were recruited from one of two centres and treated with omeprazole 20 mg BD for 8-14 weeks. A symptomatic questionnaire, including the Short Form-36 (SF-36) quality of life questionnaire, was completed before and at the end of treatment. Actual quality of life scores were compared with 'expected' scores derived from a sample (n = 3015) of the Northern Ireland population. RESULTS: Seventy two (83%) of the 87 patients recruited were healed after 14 weeks therapy and 77 completed the SF-36 before and after therapy. Three quality of life parameters (bodily pain, vitality and social function) were significantly lower before treatment than the 'expected' scores. Seven of the quality of life parameters measured by the SF-36 showed a significant improvement after treatment and the eighth (mental health) just failed to achieve a significant improvement (P = 0.06). Comparison of the improvements in SF-36 scores for those who were healed with scores for those who were not healed showed no significant difference. CONCLUSIONS: Patients with grade II-III oesophagitis and frequent heartburn have lower quality of life scores for some parameters than would be expected in the general population. Treatment of the oesophagitis with omeprazole 20 mg BD causes a significant improvement not just in reflux symptoms but in several physical and mental aspects of quality of life regardless of whether or not the oesophagitis is healed.

Nested primers improve sensitivity in the detection of Helicobacter pylori by the polymerase chain reaction.

To investigate potential routes of spread of infection by the polymerase chain reaction (PCR) it is important that the technique is effective in the types of specimen to be investigated. To establish the limits of detection of Helicobacter pylori by PCR in clinical material from the gastric mucosa, faeces, dental plaque and oral rinses, samples were seeded with known numbers of bacteria. DNA extraction was followed by amplification with primers from the urease C gene. Nested primers were used to amplify the PCR product which was detected using a digoxigenin-labelled probe. Faeces or plaque inhibited the single reaction 10(2)-10(6) fold. A second amplification using nested primers and probing increased the sensitivity to a level similar to that obtained with pure culture. This method is potentially useful with less likelihood of false negative results when trying to detect H. pylori by PCR in highly contaminated, clinical material.

Three- to 4.5-year prospective study of prognostic indicators in gastro-oesophageal reflux disease.

BACKGROUND: Data on the long-term natural history of gastro-oesophageal reflux disease (GORD) are sparse. This prospective study was designed to determine the clinical outcome on the basis of therapeutic requirements 3 to 4.5 years after initial diagnosis of GORD and to identify specific prognostic indicators of a poor outcome. METHODS: One hundred and one GORD patients were followed up by symptomatic questionnaire 3 to 4.5 years after diagnosis and offered repeat investigation with endoscopy and oesophageal pH monitoring if symptoms persisted. RESULTS: Seventy-seven (76%) patients responded (mean follow-up period, 39 months; range, 32-54 months); of these, 28 had grade-II or -III oesophagitis at initial endoscopy, 17 had normal endoscopy but abnormal pH monitoring, and 32 had normal investigations but frequent heartburn. At follow-up 32 (42%) were taking acid suppression therapy, and a further 15 patients started acid suppression therapy after repeat investigation indicated a need to do so, giving a total of 47 (61%) patients receiving acid suppression. The following factors predicted a need for acid suppression at follow-up: oesophagitis on initial endoscopy (P = 0.009), abnormal pH monitoring (P = 0.0005), increased age (P < 0.0005), and increased body mass index (BMI) (P = 0.001). Gender, smoking status, alcohol intake, and lower oesophageal sphincter pressure had no prognostic value. Regression analysis confirmed that age (P = 0.0007), BMI (P = 0.04), and endoscopy result (P = 0.04) all independently affected outcome. CONCLUSIONS: Most GORD patients still require acid suppression therapy 3 to 4.5 years after initial diagnosis. Age, BMI, and presence of oesophagitis at initial endoscopy all independently predict those who will require long-term acid suppression therapy.