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2.  A Technique for Estimating the Occlusion Effect for Frequencies Below 125 Hz 
Ear and hearing  2014;35(1):49-55.
The level of bone-conducted sound in the auditory meatus is increased at low frequencies by occlusion of the meatus, for example by the earmold of a hearing aid. Physical measures of this “occlusion effect” (OE) require vibration of the skull. In previous research, either self-voicing or audiometric bone-conduction vibrators have been used to produce this vibration, with the result that the OE could not be measured for frequencies below 125 Hz. However, frequencies below this can be important for music perception by hearing aid users. The objective was to develop and evaluate a method that gives a lower-bound estimate of the OE for frequencies below 125 Hz.
A low-noise amplifier with extended low-frequency response was used to record the output of a miniature microphone inserted into the meatus of participants. The signal came from sounds of the heartbeat and blood flow of the participant, transmitted via bone-conduction through the walls of the meatus. A simultaneous recording was made of the carotid pulse to permit time-locked averaging (and hence noise reduction) of the microphone signal. Recordings were made from seven otologically and audiometrically normal participants, using clinical probe tips to produce the occlusion. Recordings were also made from an overlapping group of nine participants, using fast-setting impression material to provide a more consistent degree of occlusion. The difference in level of the recorded signal for unoccluded and occluded conditions provided a lower bound for the magnitude of the OE.
The mean OE increased with decreasing frequency, reaching a plateau of about 40 dB for frequencies below 40 Hz. For some individual recordings, the OE reached 50 dB for frequencies below 20 Hz. With occlusion, the heartbeat became audible for most participants.
The OE can be very large at low frequencies. The use of hearing aids with closed fittings, which may be employed either to prevent acoustic feedback or to allow amplification of low frequencies, may lead to an unacceptable OE. We suggest reducing the OE by the use of a seal deep in the meatus, where the wall of the meatus is more rigid.
PMCID: PMC4197401  PMID: 24141593
Occlusion; earmold; hearing aid; bone conduction; heartbeat
3.  Impact of Mental Health Visits on Healthcare Cost in Patients with Diabetes and Comorbid Mental Health Disorders 
PLoS ONE  2014;9(8):e103804.
To assess the impact of mental health visits (MHV) on the cost of care for Veterans with diabetes and comorbid mental health conditions.
A national cohort of 120,852 Veterans with diabetes and at least one mental health diagnosis (i.e., substance abuse, depression or psychoses) in 2002 was followed through 2006. Outcomes were pharmacy, inpatient and outpatient costs in 2012 dollars.
Least-square covariate adjusted estimates from the joint model of total VA costs of the number of MHV using December 31, 2012 value dollars indicate that relative to those with fewer MHV, those with 3+ MHV had the lowest mean inpatient cost ($21,406), but the highest mean outpatient and pharmacy cost ($9,727 and $2,015, respectively). If all Veterans who received zero MHV actually received 3+ MHV, we estimate through simulated scenarios that between $32,272,329 and $181,460,247 in inpatient costs would be saved. However, these savings would be offset by additional expenditures of between $1,166,017,547 and $1,166,224,787 in outpatient costs and between $151,604,683 and $161,439,632 in pharmacy costs.
Among Veterans with diabetes and comorbid mental disorders having three or more mental health visits is associated with marginally decreased inpatient cost, but these potential savings seem to be offset by increased outpatient and pharmacy costs.
PMCID: PMC4118960  PMID: 25083903
4.  Longitudinal evaluation of quality of life in 288 patients with neurofibromatosis 2 
Journal of Neurology  2014;261(5):963-969.
Advances in molecular biology have resulted in novel therapy for neurofibromatosis 2-related (NF2) tumours, highlighting the need for robust outcome measures. The disease-focused NF2 impact on quality of life (NFTI-QOL) patient questionnaire was assessed as an outcome measure for treatment in a multi-centre study. NFTI-QOL was related to clinician-rated severity (ClinSev) and genetic severity (GenSev) over repeated visits. Data were evaluated for 288 NF2 patients (n = 464 visits) attending the English national NF2 clinics from 2010 to 2012. The male-to-female ratio was equal and the mean age was 42.2 (SD 17.8) years. The analysis included NFTI-QOL eight-item score, ClinSev graded as mild, moderate, or severe, and GenSev as a rank order of the number of NF2 mutations (graded as mild, moderate, severe). The mean (SD) 8.7 (5.4) score for NFTI-QOL for either a first visit or all visits 9.2 (5.4) was similar to the published norm of 9.4 (5.5), with no significant relationships with age or gender. NFTI-QOL internal reliability was good, with a Cronbach’s alpha score of 0.85 and test re-test reliability r = 0.84. NFTI related to ClinSev (r = 0.41, p < 0.001; r = 0.46 for all visits), but weakly to GenSev (r = 0.16, p < 0.05; r = 0.15 for all visits). ClinSev related to GenSev (r = 0.41, p < 0.001; r = 0.42 for all visits). NFTI-QOL showed a good reliability and ability to detect significant longitudinal changes in the QOL of individuals. The moderate relationships of NFTI-QOL with clinician- and genetic-rated severity suggest that NFTI-QOL taps into NF2 patient experiences that are not encompassed by ClinSev rating or genotype.
PMCID: PMC4008785  PMID: 24619350
Neurofibromatosis 2; NF2; NFTI-QOL; Vestibular schwannoma
5.  Medication Nonadherence in Diabetes 
Diabetes Care  2012;35(12):2533-2539.
To examine the longitudinal effects of medication nonadherence (MNA) on key costs and estimate potential savings from increased adherence using a novel methodology that accounts for shared correlation among cost categories.
Veterans with type 2 diabetes (740,195) were followed from January 2002 until death, loss to follow-up, or December 2006. A novel multivariate, generalized, linear, mixed modeling approach was used to assess the differential effect of MNA, defined as medication possession ratio (MPR) ≥0.8 on healthcare costs. A sensitivity analysis was performed to assess potential cost savings at different MNA levels using the Consumer Price Index to adjust estimates to 2012 dollar value.
Mean MPR for the full sample over 5 years was 0.78, with a mean of 0.93 for the adherent group and 0.58 for the MNA group. In fully adjusted models, all annual cost categories increased ∼3% per year (P = 0.001) during the 5-year study time period. MNA was associated with a 37% lower pharmacy cost, 7% lower outpatient cost, and 41% higher inpatient cost. Based on sensitivity analyses, improving adherence in the MNA group would result in annual estimated cost savings ranging from ∼$661 million (MPR <0.6 vs. ≥0.6) to ∼$1.16 billion (MPR <1 vs. 1). Maximal incremental annual savings would occur by raising MPR from <0.8 to ≥0.8 ($204,530,778) among MNA subjects.
Aggressive strategies and policies are needed to achieve optimal medication adherence in diabetes. Such approaches may further the so-called “triple aim” of achieving better health, better quality care, and lower cost.
PMCID: PMC3507586  PMID: 22912429
6.  Racial and Ethnic Differences in Longitudinal Blood Pressure Control in Veterans with Type 2 Diabetes Mellitus 
Journal of General Internal Medicine  2011;26(11):1278-1283.
Few studies have examined racial/ethnic differences in blood pressure (BP) control over time, especially in an equal access system. We examined racial/ethnic differences in longitudinal BP control in Veterans with type 2 diabetes.
We collected data on a retrospective cohort of 5,319 Veterans with type 2 diabetes and initially uncontrolled BP followed from 1996 to 2006 at a Veterans Administration (VA) facility in the southeastern United States. The mean blood pressure value for each subject for each year was used for the analysis with BP control defined as <140/<90 mmHg. The primary outcome measure was proportion with controlled BP. The main predictor variable was race/ethnicity categorized as non-Hispanic White (NHW), non-Hispanic Black (NHB), or Hispanic/Other (H/O). Other covariates included age, gender, employment, marital status, service connectedness, and ICD-9 coded medical and psychiatric comorbidities. Generalized linear mixed models were used to assess the relationship between race/ethnicity and BP control after adjusting for covariates.
Mean follow-up was 5.0 years. The sample was 46% NHW, 26% NHB, 19% H/O, and 9% unknown. The average age was 68 years. In the final model, after adjusting for covariates, NHB race (OR = 1.38, 95%CI: 1.2, 1.6) and H/O race (OR = 1.57, 95% CI: 1.3, 1.8) were associated with increased likelihood of poor BP control (>140/>90 mmHg) over time compared to NHW patients.
Ethnic minority Veterans with type 2 diabetes have significantly increased odds of poor BP control over ∼5 years of follow-up compared to their non-Hispanic White counterparts independent of sociodemographic factors and comorbidity patterns.
PMCID: PMC3208462  PMID: 21671132
blood pressure control; diabetes; epidemiology; race/ethnicity
7.  Vitamin D as a Mediator of Racial Differences in Blood Pressure 
Journal of General Internal Medicine  2011;26(10):1088-1089.
PMCID: PMC3181314  PMID: 21748433
8.  Uncontrolled and Apparent Treatment Resistant Hypertension in the U.S. 1988–2008 
Circulation  2011;124(9):1046-1058.
Despite progress, many hypertensive patients remain uncontrolled. Defining characteristics of uncontrolled hypertensives may facilitate efforts to improve blood pressure (BP) control.
Methods and Results
Subjects included 13,375 hypertensive adults from National Health and Nutrition Examination Surveys (NHANES) subdivided into 1988–1994, 1999–2004, 2005–2008. Uncontrolled hypertension was defined as BP ≥140/≥90 mmHg and apparent treatment resistant (aTRH) when subjects reported taking ≥3 antihypertensive medications. Framingham 10-year coronary risk (FCR) was calculated. Multivariable logistic regression was used to identify clinical characteristics associated with untreated, treated uncontrolled on 1–2 BP medications, and aTRH across all three survey periods. More than half of uncontrolled hypertensives were untreated across surveys including 52.5% in 2005–2008. Clinical factors linked with untreated hypertension included male sex, infrequent healthcare visits (0–1/yr), body mass index <25 kg/m2, absence of chronic kidney disease (CKD), and FCR <10% (p<0.01). Most treated, uncontrolled patients reported taking 1–2 BP medications, a proxy for therapeutic inertia. This group was older, had higher FCR than patients controlled on 1–2 medications (p<0.01), and comprised 34.4% of all uncontrolled and 72.0% of treated uncontrolled patients in 2005–2008. Apparent TRH increased from 15.9% (1998–2004) to 28.0% (2005–2008) of treated patients, p<0.001. Clinical characteristics associated with aTRH included ≥4 visits/yr, obesity, CKD and FCR >20% (p<0.01).
Untreated, under-treated, and aTRH patients have consistent characteristics that could inform strategies to improve BP control by decreasing untreated hypertension, reducing therapeutic inertia in under-treated patients, and enhancing therapeutic efficiency in aTRH.
PMCID: PMC3210066  PMID: 21824920
Hypertension; high blood pressure; hypertension control; antihypertensive medications; treatment resistant hypertension; demographic differences
9.  A case of severe staphylococcal septicaemia: septic arthritis and a mediastinal abscess following leflunamide therapy for rheumatoid arthritis 
BMJ Case Reports  2010;2010:bcr0720092082.
This highly unusual case illustrates how a potentially life-threatening complication may develop insidiously in the context of immunosuppression.
A 46-year-old woman presented with increasing malaise and a marked inflammatory response in the context of immunosuppressive therapy for rhueumatoid arthritis. On the basis of microbiological findings, the patient was treated for systemic staphylococcal infection with a prolonged antibiotic course. In addition, incision and drainage procedures were performed on associated, non-resolving abscesses at various sites. One particular lesion in the breast was slow to heal and was monitored with ultrasound imaging. Subsequent cross-sectional imaging revealed that this was, in fact, a large mediastinal abscess, eroding the manubrium and lying within close proximity of the aorta. The patient was eventually referred to a cardiothoracic unit for complete evacuation of this lesion. Following a prolonged illness and treatment period, the patient recovered well and successfully resumed employment.
PMCID: PMC3029350  PMID: 22766573
10.  Regional, Geographic, and Racial/Ethnic Variation in Glycemic Control in a National Sample of Veterans With Diabetes 
Diabetes Care  2011;34(4):938-943.
We performed a retrospective analysis of a national cohort of veterans with diabetes to better understand regional, geographic, and racial/ethnic variation in diabetes control as measured by HbA1c.
A retrospective cohort study was conducted in a national cohort of 690,968 veterans with diabetes receiving prescriptions for insulin or oral hypoglycemic agents in 2002 that were followed over a 5-year period. The main outcome measures were HbA1c levels (as continuous and dichotomized at ≥8.0%).
Relative to non-Hispanic whites (NHWs), HbA1c levels remained 0.25% higher in non-Hispanic blacks (NHBs), 0.31% higher in Hispanics, and 0.14% higher in individuals with other/unknown/missing racial/ethnic group after controlling for demographics, type of medication used, medication adherence, and comorbidities. Small but statistically significant geographic differences were also noted with HbA1c being lowest in the South and highest in the Mid-Atlantic. Rural/urban location of residence was not associated with HbA1c levels. For the dichotomous outcome poor control, results were similar with race/ethnic group being strongly associated with poor control (i.e., odds ratios of 1.33 [95% CI 1.31–1.35] and 1.57 [1.54–1.61] for NHBs and Hispanics vs. NHWs, respectively), geographic region being weakly associated with poor control, and rural/urban residence being negligibly associated with poor control.
In a national longitudinal cohort of veterans with diabetes, we found racial/ethnic disparities in HbA1c levels and HbA1c control; however, these disparities were largely, but not completely, explained by adjustment for demographic characteristics, medication adherence, type of medication used to treat diabetes, and comorbidities.
PMCID: PMC3064054  PMID: 21335370
11.  Clinical Outcome of Acute Upper Gastrointestinal Hemorrhage among Patients Admitted to a Government Hospital in Egypt 
Acute upper gastrointestinal hemorrhage (AUGIH) is a life-threatening emergency that results in high morbidity and mortality. The mortality rate varies between 4% and 14%. The aim of the study was to determine the clinical outcome of AUGIH among patients admitted to a government hospital in Egypt.
Patients and Methods:
This was a cross-sectional hospital-based study performed in 1000 patients presenting with AUGIH over a 7-year period between January 2004 and January 2011.
One thousand patients were analyzed. Fifty-four percent were male. Mean age was 52 ± 17 years. Eighty-eight percent were emergency admissions and 12% were inpatients at the time of bleeding. At presentation 68% had major comorbidity and 50% had liver disease. Seven hundred and twenty-four patients (72%) underwent endoscopy. Bleeding varices accounted for 31% of AUGIH and peptic ulcer 28%. Two hundred and thirty-two patients had endoscopically diagnosed bleeding varices or peptic ulcer with a visible vessel or active bleeding. These received endoscopic therapy. Initial hemostasis was achieved in 207 (89%). Thirteen patients (6%) had therapy at a subsequent endoscopy for further bleeding. Surgery was performed on 9 patients (0.9%) with AUGIH. Complications were reported in 70 patients (7%) mainly liver failure (4%). Six hundred and eighty-four patients (68%) were discharged improved, 162 (16%) left hospital without a diagnosis and 4 (0.4%) were referred to another facility. The overall mortality was 15%. Mortality was 24% in patients ≥60 years, 37% among inpatients, and 21% in those who had a major comorbidity. Mortality was 22% in patients who had liver disease and 9% in variceal bleeding.
The most common cause of AUGIH was variceal in origin. Endoscopic therapy was successful in most cases. Mortality after AUGIH was particularly high among elderly patients, inpatients, and patients who had a major comorbidity, liver disease, and variceal bleeding.
PMCID: PMC3271692  PMID: 22249090
Egypt; gastrointestinal hemorrhage; outcome
12.  Prevalence of Microscopic Colitis in Patients with Chronic Diarrhea in Egypt: A Single-center Study 
Microscopic colitis (MC) is diagnosed when a patient with chronic watery non-bloody diarrhea (CWND) has an endoscopically normal colon, but colonic biopsies show unique inflammatory changes characteristic of lymphocytic or collagenous colitis. MC is a disorder of unknown etiology. Studies comparing the prevalence of the disease in developing countries as compared to developed countries may shed more light on the possibility of a post-infectious etiology. Most data on the incidence and prevalence of MC are from developed countries where it accounts for 4-13% of cases of CWND. There are only a few reports from developing countries. Two studies from Peru and Tunis, with high prevalence of infectious gastroenteritis, revealed MC in 40% and 29.3% of cases of CWND, respectively. The aim of this study was to investigate the prevalence of MC in patients presenting with CWND in Egypt.
Materials and Methods:
A total of 44 patients with CWND of unexplained etiology who had undergone full colonoscopy with no macroscopic abnormalities between January 2000 and January 2010 were assessed retrospectively.
The histological appearance of MC was identified in 22 (50%) patients. Twelve (55%) patients were male and 10 (45%) female. Mean age was 40 years (range: 20-65 years). Twenty (91%) of MC cases had lymphocytic colitis and 2 (9%) had collagenous colitis.
The prevalence of MC in Egyptian patients with CWND is high when compared to that in developed countries. MC mainly affects young and middle-aged patients and it is more commonly of the lymphocytic type.
PMCID: PMC3221111  PMID: 22064335
Chronic diarrhea; colitis; microscopic
13.  Antihypertensive Medication Prescribing Patterns in a University Teaching Hospital 
Treatment of hypertension among hospitalized patients represents an opportunity to improve blood pressure recognition and treatment. To address this issue, we examined patterns of antihypertensive medication prescribing among 5,668 hypertensive inpatients. Outcomes were treatment with any antihypertensive medication and treatment with first line therapy, defined as ACE inhibitor, beta blocker, thiazide diuretic, or calcium channel blocker. Logistic regression models adjusting for age, sex, race, length of stay (LOS), service line, and co-morbidity were used for all comparisons. The multivariate-adjusted odds ratios for treatment were higher for men (1.4, p<0.001), older patients (2.5 for age >80 vs. 1.0 for age < 40, p<0.001), non-white race (1.2 vs. 1.0 for white race, p<0.004), and generalist service line (1.4 vs. 1.0 for all other services, p<0.001). Multivariate-adjusted odds ratios for receiving first-line agents were higher for older patients and generalist service line. Among surgical patients, receipt of medical consultation was only marginally associated with higher odds of antihypertensive or first-line treatment after adjustment for relevant clinical variables. Demographic factors and service line appear to play a major role in determining the likelihood of inpatients hypertension treatment. Understanding and addressing these disparities has the potential to incrementally improve hypertension control rates in the population.
PMCID: PMC2997726  PMID: 20433545
14.  Pitch Comparisons between Electrical Stimulation of a Cochlear Implant and Acoustic Stimuli Presented to a Normal-hearing Contralateral Ear 
Four cochlear implant users, having normal hearing in the unimplanted ear, compared the pitches of electrical and acoustic stimuli presented to the two ears. Comparisons were between 1,031-pps pulse trains and pure tones or between 12 and 25-pps electric pulse trains and bandpass-filtered acoustic pulse trains of the same rate. Three methods—pitch adjustment, constant stimuli, and interleaved adaptive procedures—were used. For all methods, we showed that the results can be strongly influenced by non-sensory biases arising from the range of acoustic stimuli presented, and proposed a series of checks that should be made to alert the experimenter to those biases. We then showed that the results of comparisons that survived these checks do not deviate consistently from the predictions of a widely-used cochlear frequency-to-place formula or of a computational cochlear model. We also demonstrate that substantial range effects occur with other widely used experimental methods, even for normal-hearing listeners.
PMCID: PMC2975889  PMID: 20526727
cochlear implants; pitch
15.  Pitch Comparisons between Electrical Stimulation of a Cochlear Implant and Acoustic Stimuli Presented to a Normal-hearing Contralateral Ear 
Four cochlear implant users, having normal hearing in the unimplanted ear, compared the pitches of electrical and acoustic stimuli presented to the two ears. Comparisons were between 1,031-pps pulse trains and pure tones or between 12 and 25-pps electric pulse trains and bandpass-filtered acoustic pulse trains of the same rate. Three methods—pitch adjustment, constant stimuli, and interleaved adaptive procedures—were used. For all methods, we showed that the results can be strongly influenced by non-sensory biases arising from the range of acoustic stimuli presented, and proposed a series of checks that should be made to alert the experimenter to those biases. We then showed that the results of comparisons that survived these checks do not deviate consistently from the predictions of a widely-used cochlear frequency-to-place formula or of a computational cochlear model. We also demonstrate that substantial range effects occur with other widely used experimental methods, even for normal-hearing listeners.
PMCID: PMC2975889  PMID: 20526727
cochlear implants; pitch
16.  The PXR is a drug target for chronic inflammatory liver disease☆ 
PXR activators are used to treat pruritus in chronic inflammatory liver diseases such as primary biliary cirrhosis (PBC). The aims of this study were to determine whether PXR activators could have an additional benefit of inhibiting inflammation in the liver, and determine whether cyclosporin A – which more effectively prevents PBC recurrence in transplanted patients than FK506 – is a PXR activator. In SJL/J mice (which have constitutively high levels of hepatic portal tract inflammatory cell recruitment), feeding a PXR activator inhibited inflammation, TNFα and Il-1α mRNA expression in SJL/J-PXR+/+, but not SJL/J-PXR−/−. Monocytic cells – a major source of inflammatory mediators such as TNFα – expressed the PXR and PXR activators inhibited endotoxin-induced NF-κB activation and TNFα expression. PXR activation also inhibited endotoxin-stimulated TNFα secretion from liver monocytes/macrophages isolated from PXR+/+ mice, but not from cells isolated from PXR−/− mice. To confirm that PXR activation inhibits NF-κB in vivo, 3x-κB-luc fibrotic mice (which express a luciferase gene regulated by NF-κB) were imaged after treatment with the hepatotoxin CCl4. PXR activator inhibited the induction of hepatic NF-κB activity without affecting CCl4 toxicity/hepatic damage. Using a PXR reporter gene assay, cyclosporin A – but not FK506 – was shown to be a direct PXR activator, and also to induce expression of the classic PXR-regulated CYP3A4 gene in human hepatocytes and in a cell line null for the FXR, a nuclear receptor with similar properties to the PXR. Conclusion: PXR activation is anti-inflammatory in the liver and the effects of cyclosporin A in PBC disease recurrence may be mediated in part via the PXR. Since PXR activation promotes hepatocyte growth and is also anti-fibrogenic, the PXR may be an excellent drug target for the treatment of chronic inflammatory liver disease.
PMCID: PMC2937210  PMID: 20416375
ALT, alanine aminotransferase; CsA, cyclosporin A; GT, gliotoxin; GAPDH, glyceradehyde 3 phosphate dehydrogenase; HYP, hyperforin; IKK2-In, IκB kinase 2 inhibitor; LPS, lipopolysaccharide; METYR, metyrapone; MTS, ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt; PBC, primary biliary cirrhosis; PCN, pregnenolone 16α carbonitrile; PTI, portal tract inflammation; PPARγ, peroxiome proliferator activated receptor γ; PXR, pregnane X receptor; RIF, rifampicin; SULF, sulfasalazine; TLR4, toll-like receptor 4; TNFα, tumour necrosis factor-α; Pregnane X receptor; SXR; NF-κB; Rifampicin; Hyperforin; TNFα
17.  Initial poor quality of life and new onset of dyspepsia: results from a longitudinal 10‐year follow‐up study 
Gut  2006;56(3):321-327.
Numerous studies examining the prevalence and natural history of dyspepsia in the general population have been conducted. However, few have reported the effect of quality of life on the development of dyspepsia. A 10‐year longitudinal follow‐up study examining the effect of quality of life on subsequent dyspepsia was performed.
Individuals originally enrolled in a population‐screening programme for Helicobacter pylori were contacted through a validated postal dyspepsia questionnaire. Baseline demographic data, quality of life at original study entry, and dyspepsia and irritable bowel syndrome (IBS) symptom data were already on file. Consent to examine primary‐care records was sought, and data regarding non‐steroidal anti‐inflammatory drugs (NSAID) and aspirin use were obtained from these.
Of 8407 individuals originally involved, 3912 (46.5%) provided symptom data at baseline and 10‐year follow‐up. Of 2550 (65%) individuals asymptomatic at study entry, 717 (28%) developed new‐onset dyspepsia at 10 years, an incidence of 2.8% per year. After multivariate logistic regression, lower quality of life at study entry (OR 2.63; 99% CI 1.86 to 3.71), higher body mass index (OR per unit 1.05; 99% CI 1.02 to 1.08), presence of IBS at study entry (OR 3.1; 99% CI 1.51 to 6.37) and use of NSAIDs and/or aspirin (OR 1.32; 99% CI 0.99 to 1.75) were significant risk factors for new‐onset dyspepsia.
The incidence of new‐onset dyspepsia was almost 3% per year. Low quality of life at baseline exerted a strong effect on the likelihood of developing dyspepsia at 10 years.
PMCID: PMC1856829  PMID: 16908511
18.  Why does Japan have a high incidence of gastric cancer? Comparison of gastritis between UK and Japanese patients 
Gut  2006;55(11):1545-1552.
Background and aims
The incidence of gastric cancer in Japan is four times higher than in the UK. It usually arises in a stomach with corpus predominant or pangastritis that has undergone extensive atrophy and intestinal metaplasia. We hypothesised that a Japanese population would have a more severe gastritis with a corpus predominant or pangastritis pattern and a greater degree of atrophy and intestinal metaplasia than that found in the UK. To test this we designed a comparative trial.
A total of 252 age matched consecutive patients were recruited from the endoscopy services in Leeds and Tokyo. In each centre, 21 patients were prospectively selected from each decennial, between the ages of 20–80 years. All had epigastric discomfort as their predominant symptom. Patients with peptic ulcer, cancer, and oesophagitis were excluded. Five gastric biopsies were examined by two histopathologists using the updated Sydney system. Helicobacter pylori infection was assessed by histology and culture of biopsies and enzyme linked immunosorbent assay and immunoblot of plasma.
Gastritis was found by both pathologists in 59 (47%) UK and 76 (60%) Japanese patients (χ2 test, p = 0.04). In those patients with gastritis, corpus predominant or pangastritis was commoner in the Japanese (63% Japan v 36% in the UK (χ2 test, p = 0.003) Atrophy and intestinal metaplasia were more extensive and severe (Mann‐Whitney U test, p<0.001) and chronic inflammation and polymorph activity were also greater, especially in the corpus (Mann‐Whitney U test, p<0.001). Fifty three of 59 UK gastritis patients (90%) and 67/76 (88%) (χ2 test, p = 1) Japanese gastritis patients were positive for H pylori. Using a previously described “gastric cancer risk index” among H pylori positive patients, there were significantly more Japanese than UK subjects with a “high risk” score.
In Japanese as opposed to English patients, gastritis is more prevalent and severe with more corpus predominant atrophy and intestinal metaplasia. These differences may partially explain the higher incidence of gastric cancer in Japan.
PMCID: PMC1860129  PMID: 16603635
gastritis;  Helicobacter pylori ; population comparison; gastric cancer risk
19.  Behavioral and physiological correlates of temporal pitch perception in electric and acoustic hearing 
In the “4-6” condition of experiment 1, normal-hearing (NH) listeners compared the pitch of a bandpass-filtered pulse train, whose inter-pulse intervals (IPIs) alternated between 4 and 6 ms, to that of isochronous pulse trains. Consistent with previous results obtained at a lower signal level, the pitch of the 4-6 stimulus corresponded to that of an isochronous pulse train having a period of 5.7 ms – longer than the mean IPI of 5 ms. In other conditions the IPI alternated between 3.5-5.5 ms and 4.5-6.5 ms. Experiment 2 was similar but presented electric pulse trains to one channel of a CI. In both cases, as overall IPI increased, the pitch of the alternating-interval stimulus approached that of an isochronous train having a period equal to the mean IPI. Experiment 3 measured compound action potentials (CAPs) to alternating-interval stimuli in guinea pigs and in NH listeners. The CAPs to pulses occurring after 4-ms intervals were smaller than responses to pulses occurring after 6-ms intervals, resulting in a modulated pattern that was independent of overall level. The results are compared to the predictions of a simple model incorporating auditory-nerve (AN) refractoriness, and where pitch is estimated from 1st-order intervals in the AN response.
PMCID: PMC2279014  PMID: 18247900
20.  Inhibiting TGF-β signaling restores immune surveillance in the SMA-560 glioma model 
Neuro-Oncology  2007;9(3):259-270.
Transforming growth factor-β (TGF-β) is a proinvasive and immunosuppressive cytokine that plays a major role in the malignant phenotype of gliomas. One novel strategy of disabling TGF-β activity in gliomas is to disrupt the signaling cascade at the level of the TGF-β receptor I (TGF-βRI) kinase, thus abrogating TGF-β–mediated invasiveness and immune suppression. SX-007, an orally active, small-molecule TGF-βRI kinase inhibitor, was evaluated for its therapeutic potential in cell culture and in an in vivo glioma model. The syngeneic, orthotopic glioma model SMA-560 was used to evaluate the efficacy of SX-007. Cells were implanted into the striatum of VM/ Dk mice. Dosing began three days after implantation and continued until the end of the study. Efficacy was established by assessing survival benefit. SX-007 dosed at 20 mg/kg p.o. once daily (q.d.) modulated TGF-β signaling in the tumor and improved the median survival. Strikingly, approximately 25% of the treated animals were disease-free at the end of the study. Increasing the dose to 40 mg/kg q.d. or 20 mg/kg twice daily did not further improve efficacy. The data suggest that SX-007 can exert a therapeutic effect by reducing TGF-β–mediated invasion and reversing immune suppression. SX-007 modulates the TGF-β signaling pathway and is associated with improved survival in this glioma model. Survival benefit is due to reduced tumor invasion and reversal of TGF-β–mediated immune suppression, allowing for rejection of the tumor. Together, these results suggest that treatment with a TGF-βRI inhibitor may be useful in the treatment of glioblastoma.
PMCID: PMC1907409  PMID: 17522330
kinases; neuroimmunology; tumor immunity
21.  Preoperative Audiovestibular Handicap in Patients with Vestibular Schwannoma 
Skull Base  2006;16(4):193-199.
Objectives: To evaluate preoperative hearing, dizziness, and tinnitus handicap in patients with unilateral vestibular schwannoma (VS). Design: Prospective administration of the Hearing Handicap Inventory (HHI), Dizziness Handicap Inventory (DHI), and Tinnitus Handicap Inventory (THI), prior to surgical intervention. Setting: A tertiary referral neuro-otology clinic. Participants: A total of 145 consecutive patients who were admitted for excision of their vestibular schwannomas between May 1998 and July 2002. Main Outcome Measures: HHI, THI, and DHI scores. Results: HHI, THI, and DHI scores were all found to be significantly correlated. There was no significant association between tumor size and any of the questionnaire scores. When data were categorized to give a measure of handicap severity, 68% had mild to significant hearing handicap, 30% had mild to severe tinnitus handicap, and 75% had mild to severe dizziness handicap. Eighty-eight percent of patients had some handicap in at least one domain, and 23% had some handicap in all three domains. Seven percent of patients had severe or significant handicap in all three domains. Conclusions: A considerable proportion of patients with unilateral VS have hearing, tinnitus, and dizziness handicap. These patients should optimally be offered appropriate rehabilitation, something that is especially important as conservative management by “watch, wait, and rescan” becomes more common.
PMCID: PMC1766462  PMID: 17471318
Vestibular schwannoma; acoustic neuroma; hearing handicap; tinnitus handicap; dizziness handicap; conservative management
22.  The Clinical Characteristics of Tinnitus in Patients with Vestibular Schwannoma 
Skull Base  2006;16(2):49-58.
Objectives: To review the symptoms, signs, and clinical findings in a large series of patients diagnosed with unilateral sporadic vestibular schwannoma (VS) to describe the clinical characteristics of tinnitus in this population. Further, to ascertain which of the proposed mechanisms of tinnitus generation in VS was supported. Design: Retrospective case note and database review. Setting: Tertiary university teaching hospital departments of audiology and neuro-otology. Participants: Nine hundred forty-one patients with unilateral sporadic VS, diagnosed during the period 1986 to 2002. Twenty-three additional patients were excluded due to missing clinical data. Main outcome measures: The presence or absence of tinnitus, and its rated subjective severity were analyzed in conjunction with data regarding patient demographics, symptoms, signs, and diagnostic audiovestibular test findings. Results: No statistical association at the 5% level was found between tinnitus presence/absence and patient age, gender, 2- to 4-kHz audiometric thresholds, ipsilateral auditory brainstem response abnormality, length of history, tumor side, nor caloric test abnormality. Statistically significant associations were found between tinnitus presence/absence and tumor size (p = 0.012) and type of hearing loss (progressive, sudden, fluctuant, nil) with a tendency for patients without hearing loss to be less likely to experience tinnitus. Statistically significant associations were identified between classification of tinnitus severity and age at diagnosis (p < 0.001) (greater age being associated with greater tinnitus severity), abnormal findings on caloric testing (p = 0.01) (abnormal calorics being associated with greater tinnitus severity), and tinnitus as a principal presenting symptom (p < 0.001) (this being associated with greater tinnitus severity). Conclusions: The analysis does not identify any single one of the proposed mechanisms for tinnitus as being the obvious culprit. In fact, even in a homogeneous group of patients such as this, there is evidence of multiple mechanisms that are not mutually exclusive. The association between increased tinnitus severity in older patients, patients with canal pareses on caloric testing, and with tinnitus as a principal presenting symptom should be borne in mind by the clinician.
PMCID: PMC1502033  PMID: 17077869
Vestibular schwannoma; tinnitus; mechanisms
23.  Ten year follow up of ulcerative colitis patients with and without low grade dysplasia 
Gut  2003;52(8):1127-1132.
Background and aims: Low grade dysplasia (LGD) is believed to predispose to colorectal cancer (CRC), and proctocolectomy has been advocated when this is identified. Between 1978 and 1990, 160 patients with longstanding extensive ulcerative colitis (UC) were recruited for annual colonoscopic surveillance and 40 developed LGD at some stage. We report the outcome of this cohort 10 years after the original study ended.
Methods: Retrospective cohort study and histopathological review of the original diagnoses of LGD. The outcome of 158/160 (98.8%) patients was established in 2000.
Results: Of the 128 patients still alive and with an intact colon at the end of 1990, two were not traceable, 29 had LGD, and 97 had no dysplasia (controls). After 10 years, high grade dysplasia (HGD) or CRC developed in 3/29 LGD (10%) and in 4/97 controls (4.0%). Kaplan-Meier analysis from 1991 to death or colectomy did not show a statistically significant difference between the two groups (log rank test p=0.63). Histopathological review demonstrated the unreliability of LGD diagnosis. Agreement between pathologists was uniformly poor: kappa <0.4 for all comparisons.
Conclusion: LGD diagnosis is not sufficiently reliable to justify prophylactic colectomy. Conservative management of established LGD cases should not be ruled out.
PMCID: PMC1773763  PMID: 12865270
ulcerative colitis; low grade dysplasia; high grade dysplasia; colorectal cancer; colectomy; surveillance
24.  Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss 
Journal of Medical Genetics  2002;39(11):796-803.
Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal α-intercalated cell's apical H+-ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively.
We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity.
In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases.
The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.
PMCID: PMC1735017  PMID: 12414817
25.  Bile reflux gastritis and intestinal metaplasia at the cardia 
Gut  2002;51(3):351-355.
Background and aims: Intestinal metaplasia (IM) at the cardia is likely to be a precursor of cardia cancer. Previous work has shown that it is associated with chronic inflammation attributable to either gastro-oesophageal reflux disease (GORD) or Helicobacter pylori infection. An alternative aetiological factor is bile reflux. Duodenogastric reflux brings about histological changes in the gastric mucosa that can be graded and used to calculate a bile reflux index (BRI). We used the BRI to assess whether reflux of bile plays a part in the development of cardia IM.
Methods: Histological changes in simultaneous gastric antrum and cardia biopsies from 267 dyspeptic patients were independently graded by two pathologists. The association between cardia IM and age, sex, clinical group, H pylori status, increased BRI (>14), and inflammation at the cardia were evaluated using logistic regression.
Results: A total of 226 patients had adequate cardia and antral biopsies; 149 had GORD and 77 had non-ulcer dyspepsia. Cardia IM was present in 66 (29%) patients, of whom 28 (42%) had complete IM. Increasing age, male sex, chronic inflammation, and a high BRI emerged as significant independent associations with cardia IM. Clinical group and H pylori status were not independent risk factors.
Conclusions: Histological evidence of bile reflux into the stomach is associated with cardia IM. This could have an important bearing on carcinogenesis at this site.
PMCID: PMC1773352  PMID: 12171955
bile reflux; intestinal metaplasia; gastric cardia

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