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1.  Tempting fate: control of communicable disease in England. 
BMJ : British Medical Journal  1993;306(6890):1461-1464.
Recent changes in the NHS have left many defects in the systems for the control of communicable diseases and infection and their surveillance and the management of outbreaks. Clear, explicit legislation is needed, placing the responsibilities on health authorities. New teams led by consultants need to be set up to investigate and manage outbreaks of communicable diseases of all types.
PMCID: PMC1677848  PMID: 8518646
2.  Identifying the seasonal origins of human campylobacteriosis 
Epidemiology and infection  2012;141(6):1267-1275.
Human campylobacteriosis exhibits a distinctive seasonality in temperate regions. This paper aims to identify the origins of this seasonality. Clinical isolates [typed by multi-locus sequence typing (MLST)] and epidemiological data were collected from Scotland. Young rural children were found to have an increased burden of disease in the late spring due to strains of non-chicken origin (e.g. ruminant and wild bird strains from environmental sources). In contrast the adult population had an extended summer peak associated with chicken strains. Travel abroad and UK mainland travel were associated with up to 17% and 18% of cases, respectively. International strains were associated with chicken, had a higher diversity than indigenous strains and a different spectrum of MLST types representative of these countries. Integrating empirical epidemiology and molecular subtyping can successfully elucidate the seasonal components of human campylobacteriosis. The findings will enable public health officials to focus strategies to reduce the disease burden.
PMCID: PMC4003528  PMID: 22989449
Bacterial typing; Campylobacter; foodborne zoonoses; modelling; molecular epidemiology
4.  Second-Trimester Diagnosis of Triploidy: A Series of Four Cases 
AJP Reports  2012;3(1):37-40.
Triploidy occurs in 2 to 3% of conceptuses and accounts for approximately 20% of chromosomally abnormal first-trimester miscarriages. As such, triploidy is estimated to occur in 1 of 3,500 pregnancies at 12 weeks', 1 in 30,000 at 16 weeks', and 1 in 250,000 at 20 weeks' gestation. We present a series of four cases of second-trimester triploidy diagnosed at our center within a 1-year timeframe. This is remarkable, as the delivery volume at our institution is roughly 2,500/y. All patients were at least 19 weeks' gestation, with multiple abnormalities identified on prenatal ultrasound at 18 to 20 weeks' gestation; all fetuses had lethal anomalies, but anomalies were not consistent between cases. All patients elected for induction of labor before 24 weeks' gestational age. Two of the four cases had amniocentesis and chromosome analysis prior to delivery, and two cases had chromosome analysis performed on fetal tissue after delivery. All fetuses were examined following delivery. This case series demonstrates that the diagnosis of triploidy may not be obvious based on ultrasound and physical examination findings and highlights the importance of routine chromosome analysis on all prenatal diagnoses of multiple congenital anomalies prior to consideration of more complex genetic testing.
PMCID: PMC3699153  PMID: 23943708
triploidy; ultrasound; phenotype; second trimester
5.  Molecular epidemiology of human Campylobacter jejuni shows association between seasonal and international patterns of disease 
Epidemiology and infection  2012;140(12):2247-2255.
We sought to explain seasonality and other aspects of Campylobacter jejuni epidemiology by integrating population genetic and epidemiological analysis in a large three-year longitudinal, two centre, population based study. Epidemiological information was collected for 1,505 isolates, which were multilocus sequence typed. Analyses compared pathogen population structure between areas, over time, and between clinical presentations. Pooled analysis was performed with published international datasets. Subtype association with virulence was not observed. UK sites had nearly identical C. jejuni populations. A clade formed by ST-45 and ST-283 clonal complexes showed a summer peak. This clade was common in a Finnish dataset but not in New Zealand and Australian collections, countries with less marked seasonality. The UK, New Zealand and Australian collections were otherwise similar. These findings map to known in-vitro differences of this clade. This identifies a target for studies to elucidate the drivers of the summer peak in human C. jejuni infection.
PMCID: PMC3487483  PMID: 22370165
6.  White Matter Hyperintensities in Mild Lewy Body Dementia 
The objective of this study was to explore the load of white matter hyperintensities (WMH) in patients with Lewy body dementia (LBD) and compare to Alzheimer's disease (AD) and normal controls (NC).
Diagnosis of LBD and AD was made according to consensus criteria and cognitive tests were administered. MRI scans for 77 (61 AD and 16 LBD) patients and 37 healthy elderly control subjects were available for analysis. We segmented WMH from FLAIR images using an automatic thresholding technique and calculated the volume of WMH in several regions of the brain, using non-parametric tests to compare groups. Multivariate regression was applied.
There were no significant differences in WMH between AD and LBD. We found a significant correlation between total and frontal WMH and Mini-Mental State Examination (MMSE) and verbal fluency scores in the AD group, but not in the LBD group.
The WMH load in LBD was similar to that of AD. A correlation between WMH load and cognition was found in the AD group, but not in the LBD group, suggesting that vascular disease contributes to cognitive impairment in AD but not LBD.
PMCID: PMC3507264  PMID: 23189084
Cerebrovascular diseases; Cognition; Alzheimer's dementia; Lewy body dementia; Parkinson's disease; Magnetic resonance imaging; White matter hyperintensities
7.  Vaginal progesterone reduces the rate of preterm birth in women with a sonographic short cervix: a multicenter, randomized, double-blind, placebo-controlled trial 
Women with a sonographic short cervix in the mid-trimester are at increased risk for preterm delivery. This study was undertaken to determine the ef cacy and safety of using micronized vaginal progesterone gel to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix.
This was a multicenter, randomized, double-blind, placebo-controlled trial that enrolled asymptomatic women with a singleton pregnancy and a sonographic short cervix (10–20 mm) at 19 + 0to23 + 6 weeks of gestation. Women were allocated randomly to receive vaginal progesterone gel or placebo daily starting from 20 to 23 + 6 weeks until 36 + 6 weeks, rupture of membranes or delivery, whichever occurred rst. Randomization sequence was strati ed by center and history of a previous preterm birth. The primary endpoint was preterm birth before 33 weeks of gestation. Analysis was by intention to treat.
Of 465 women randomized, seven were lost to follow-up and 458 (vaginal progesterone gel, n = 235; placebo, n = 223) were included in the analysis. Women allocated to receive vaginal progesterone had a lower rate of preterm birth before 33 weeks than did those allocated to placebo (8.9% (n = 21) vs 16.1% (n = 36); relative risk (RR), 0.55; 95% CI, 0.33–0.92; P = 0.02). The effect remained signi cant after adjustment for covariables (adjusted RR, 0.52; 95% CI, 0.31–0.91; P = 0.02). Vaginal progesterone was also associated with a signi cant reduction in the rate of preterm birth before 28 weeks(5.1%vs10.3%; RR, 0.50;95%CI, 0.25–0.97; P = 0.04) and 35 weeks (14.5% vs 23.3%; RR, 0.62; 95% CI, 0.42–0.92; P = 0.02), respiratory distress syndrome (3.0% vs 7.6%; RR, 0.39; 95% CI, 0.17–0.92; P = 0.03), any neonatal morbidity or mortality event (7.7% vs 13.5%; RR, 0.57; 95% CI, 0.33–0.99; P = 0.04) and birth weight < 1500 g (6.4% (15/234) vs 13.6% (30/220); RR, 0.47; 95% CI, 0.26–0.85; P = 0.01). There were no differences in the incidence of treatment-related adverse events between the groups.
The administration of vaginal progesterone gel to women with a sonographic short cervix in the mid-trimester is associated with a 45% reduction in the rate of preterm birth before 33 weeks of gestation and with improved neonatal outcome.
PMCID: PMC3482512  PMID: 21472815
pregnancy; preterm delivery; preterm labor; progestins; progestogens; respiratory distress syndrome; transvaginal ultrasound; uterine cervix; vaginal administration
8.  Novel setting for addressing tobacco-related disparities: a survey of community welfare organization smoking policies, practices and attitudes 
Health Education Research  2012;28(1):46-57.
Research in the United States and Australia acknowledges the potential of non-government social and community service organizations (SCSOs) for reaching socially disadvantaged smokers. This study aimed to describe SCSO smoking policies and practices, and attitudes of senior staff towards smoking and cessation. It also investigated factors associated with positive tobacco control attitudes. In 2009, a cross-sectional telephone survey was undertaken of senior staff in Australian SCSOs, 149 respondents representing 93 organizations completed the survey (response rate = 65%; 93/142). Most service clients (60%) remained in programs for 6 months plus, and 77% attended at least weekly. Although 93% of respondents indicated they had an organizational smoking policy, it often did not include the provision of smoking cessation support. Most respondents indicated that client smoking status was not recorded on case notes (78%). Attitudes were mostly positive towards tobacco control in SCSOs, with a mean (standard deviation) score of 8.3 (2.9) of a possible 13. The practice of assessing clients’ interest in quitting was the only statistically significant factor associated with high tobacco control attitude scores. The results suggest that SCSOs are appropriate settings for reaching socially disadvantaged smokers with cessation support. Although generally receptive to tobacco control, organizations require further support to integrate smoking cessation support into usual care. In particular, education, training and support for staff to enable them to help their clients quit smoking is important.
PMCID: PMC3549586  PMID: 22798564
9.  What Goes Down Must Come Up: Role of the Posteromedial Cortices in Encoding and Retrieval 
Cerebral Cortex (New York, NY)  2010;21(1):22-34.
The hypothesis that the neural network supporting successful episodic memory retrieval overlaps with the regions involved in episodic encoding has garnered much interest; however, the role of the posteromedial regions remains to be fully elucidated. Functional magnetic resonance imaging (fMRI) studies during successful encoding typically demonstrate deactivation of posteromedial cortices, whereas successful retrieval of previously encoded information has been associated with activation of these regions. Here, we performed an event-related fMRI experiment during an associative face–name encoding and retrieval task to investigate the topography and functional relationship of the brain regions involved in successful memory processes. A conjunction analysis of novel encoding and subsequent successful retrieval of names revealed an anatomical overlap in bilateral posteromedial cortices. In this region, a significant negative correlation was found: Greater deactivation during encoding was related to greater activation during successful retrieval. In contrast, the hippocampus and prefrontal cortex demonstrated positive activation during both encoding and retrieval. Our results provide further evidence that posteromedial regions constitute critical nodes in the large-scale cortical network subserving episodic memory. These results are discussed in relation to the default mode hypothesis, the involvement of posteromedial cortices in successful memory formation and retention, as well as potential implications for aging and neurodegenerative disease.
PMCID: PMC3000562  PMID: 20363808
cued recall; default mode network; episodic memory; fMRI; posterior cingulate
10.  Cerebral blood flow by arterial spin labeling in poststroke dementia 
Neurology  2011;76(17):1478-1484.
To investigate the relationship between cerebral blood flow and dementia in older stroke survivors and subjects with Alzheimer disease (AD).
This cohort study used arterial spin labeling MRI at 3 T to examine cerebral blood flow (CBF). We scanned 39 patients 6 years after stroke. They were older than 75 years at the time of stroke and free of dementia 3 months poststroke, with 8 subsequently developing dementia. We also scanned 17 subjects with AD and 29 healthy control subjects. We determined the perfusion in regions of interest (ROIs). Hippocampal volume was also measured using a previously validated automated procedure.
The gray matter/white matter CBF ratio was reduced globally in the poststroke dementia (PSD) group (1.55 SD = 0.12) relative to control subjects (1.78 SD = 0.18; p = 0.03). The CBF ratio in a parietal ROI was reduced in the AD (1.34 SD = 0.31; p = 0.003), PSD (1.32 SD = 0.22; p = 0.041), and poststroke no-dementia (PSND) (1.44 SD = 0.34; p = 0.014) groups relative to that of control subjects (1.70 SD = 0.32). In subjects without stroke, the best predictor of dementia was hippocampus volume, whereas in the stroke group, it was the global CBF gray matter/white matter ratio. Hippocampus volume was not significantly different between the AD and PSD groups, and both had reduced hippocampi relative to those of control subjects and the PSND group.
We found evidence for both vascular and AD pathology in PSD, suggesting that both the direct impact of the stroke and subsequent development of AD-type changes play a role in the etiology of PSD.
PMCID: PMC3087466  PMID: 21518997
11.  Longitudinal fMRI in elderly reveals loss of hippocampal activation with clinical decline(e–Pub ahead of print) 
Neurology  2010;74(24):1969-1976.
Previous cross-sectional fMRI studies in subjects with prodromal Alzheimer disease (AD) have reported variable results, ranging from hypoactivation, similar to patients with AD, to paradoxically increased activation or hyperactivation compared to cognitively normal older individuals. We have hypothesized that subjects in early phases of prodromal AD may experience a period of hippocampal hyperactivation, followed by loss of hippocampal activation as the disease progresses.
We studied 51 older individuals without dementia (Clinical Dementia Rating [CDR] at baseline of 0, n = 21, and 0.5, n = 30) with longitudinal clinical and neuropsychological assessments, as well as fMRI during a face-name associative memory paradigm. Whole brain and region-of-interest analyses were applied to the longitudinal fMRI data.
Subjects classified as CDR 0 at baseline showed no difference in fMRI activity over 2 years, whereas those who were CDR 0.5 at baseline demonstrated a decrease in fMRI activity in the right hippocampus (p < 0.001). Dividing the subjects on the basis of their clinical and neuropsychological change over the 2 years, we found that subjects with more rapid decline demonstrated both the highest hippocampal activation at baseline, and the greatest loss of hippocampal activation. These findings remained significant after accounting for age, hippocampal volume, and APOE ε4 carrier status.
Clinical decline is associated with loss of hippocampal activation in older subjects. Longitudinal fMRI provides a reliable indicator of brain activation over time, and may prove useful in identifying functional brain changes associated with cognitive decline on the trajectory toward clinical Alzheimer disease.
= Alzheimer disease;
= analysis of variance;
= blood oxygen level dependent;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= California Verbal Learning Test;
= echoplanar imaging;
= mild cognitive impairment;
= medial temporal lobe;
= novel vs repeated;
= Rey Auditory Verbal Learning Test;
= region of interest;
= statistical parametric mapping.
PMCID: PMC2905893  PMID: 20463288
12.  Ictal SPECT statistical parametric mapping in temporal lobe epilepsy surgery 
Neurology  2010;74(1):70-76.
Objective: Although subtraction ictal SPECT coregistered to MRI (SISCOM) is clinically useful in epilepsy surgery evaluation, it does not determine whether the ictal–interictal subtraction difference is statistically different from the expected random variation between 2 SPECT studies. We developed a statistical parametric mapping and MRI voxel-based method of analyzing ictal–interictal SPECT difference data (statistical ictal SPECT coregistered to MRI [STATISCOM]) and compared it with SISCOM.
Methods: Two serial SPECT studies were performed in 11 healthy volunteers without epilepsy (control subjects) to measure random variation between serial studies from individuals. STATISCOM and SISCOM images from 87 consecutive patients who had ictal SPECT studies and subsequent temporal lobectomy were assessed by reviewers blinded to clinical data and outcome.
Results: Interobserver agreement between blinded reviewers was higher for STATISCOM images than for SISCOM images (κ = 0.81 vs κ = 0.36). STATISCOM identified a hyperperfusion focus in 84% of patients, SISCOM in 66% (p < 0.05). STATISCOM correctly localized the temporal lobe epilepsy (TLE) subtypes (mesial vs lateral neocortical) in 68% of patients compared with 24% by SISCOM (p = 0.02); subgroup analysis of patients without lesions (as determined by MRI) showed superiority of STATISCOM (80% vs 47%; p = 0.04). Moreover, the probability of seizure-free outcome was higher when STATISCOM correctly localized the TLE subtype than when it was indeterminate (81% vs 53%; p = 0.03).
Conclusion: Statistical ictal SPECT coregistered to MRI (STATISCOM) was superior to subtraction ictal SPECT coregistered to MRI for seizure localization before temporal lobe epilepsy (TLE) surgery. STATISCOM localization to the correct TLE subtype was prognostically important for postsurgical seizure freedom.
PMCID: PMC3462472  PMID: 20038775
Neurology  2009;73(22):1928-1930.
PMCID: PMC2881860  PMID: 19949041
14.  α4β2 nicotinic receptor status in Alzheimer's disease using 123I‐5IA‐85380 single‐photon‐emission computed tomography 
Loss of the α4β2 nicotinic receptor subtype is found at autopsy in Alzheimer's disease.
To investigate in vivo changes in this receptor using single‐photon‐emission CT (SPECT) with 123I‐5‐iodo‐3‐[2(S)‐2‐azetidinylmethoxy] pyridine (5IA‐85380), a novel nicotinic acetylcholine receptor ligand which binds predominantly to the α4β2 receptor.
32 non‐smoking subjects (16 with Alzheimer's disease and 16 normal elderly controls) underwent 123I‐5IA‐85380 and perfusion (99mTc‐hexamethylenepropyleneamine oxime (HMPAO)) SPECT scanning. Region of interest analysis was performed with cerebellar normalisation.
Significant bilateral reductions in nicotinic receptor binding were identified in frontal (left, p = 0.004; right, p = 0.002), striatal (left, p = 0.004; right, p = 0.003), right medial temporal (p = 0.04) and pons (p<0.001) in patients with AD compared to controls. There were no significant correlations with clinical or cognitive measures. The pattern of nicotinic binding significantly differed from that of perfusion in both patients with AD and controls. Both 123I‐5IA‐85380 and 99mTc‐HMPAO SPECT imaging demonstrated similar diagnostic performance in correctly classifying controls and patients with AD.
Using 123I‐5IA‐85380 SPECT we found changes consistent with significant reductions in the nicotinic α4β2 receptor in cortical and striatal brain regions. This method could facilitate diagnosis and may be useful for monitoring progression of the disease and response to treatment in patients with AD and related diseases.
PMCID: PMC2077777  PMID: 17135460
15.  Effect of levodopa on cognitive function in Parkinson's disease with and without dementia and dementia with Lewy bodies 
Levodopa (L‐dopa) is the gold standard treatment for Parkinson's disease, but a lack of clear efficacy combined with a perceived liability to neuropsychiatric side effects has limited L‐dopa use in patients with parkinsonism and dementia. Therefore, the effect of L‐dopa on the cognitive profile of dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unclear.
To ascertain the acute and long‐term effects of L‐dopa on aspects of attention and cognition in patients with DLB and PDD, and to compare these with the effects in Parkinson's disease.
Baseline cognitive and motor function was assessed off L‐dopa in patients with Parkinson's disease (n = 22), PDD (n = 27) and DLB (n = 11) using standard “bedside” measures and a computerised programme detecting reaction times and accuracy. All patients then underwent an acute L‐dopa challenge with subsequent subjective and objective analysis of alertness, verbal recall, reaction times and accuracy. The same parameters were measured after 3 months on L‐dopa to assess the prolonged effect.
Acute L‐dopa challenge considerably improved motor function and subjective alertness in all patients without compromising either reaction times or accuracy, but increased fluctuations were noted in both groups with dementia. Neuropsychiatric scores improved in patients with Parkinson's disease both with and without dementia on L‐dopa at 3 months. Although patients with Parkinson's disease also had better mean global cognitive function at this time, mean verbal attention and memory deteriorated, and patients with PDD had slower reaction times in some tests. No patient had a marked deterioration over this time. Patients with DLB did not experience any adverse cognitive or neuropsychiatric effects after 3 months of L‐dopa treatment.
The use of L‐dopa in patients with parkinsonism with dementia does not adversely affect cognitive function.
PMCID: PMC2077405  PMID: 16952917
16.  Peroxisome Proliferator-Activated Receptor γ and Retinoid X Receptor transcription factors are released from activated human platelets and shed in microparticles 
Thrombosis and haemostasis  2008;99(1):86-95.
Peroxisome proliferator-activated receptor γ (PPARγ) and its ligands are important regulators of lipid metabolism, inflammation, and diabetes. We previously demonstrated that anucleate human platelets express the transcription factor PPARγ and that PPARγ ligands blunt platelet activation. To further understand the nature of PPARγ in platelets, we determined the platelet PPARγ isoform(s) and investigated the fate of PPARγ following platelet activation. Our studies demonstrated that human platelets contain only the PPARγ1 isoform and after activation with thrombin, TRAP, ADP or collagen PPARγ is released from internal stores. PPARγ release was blocked by a cytoskeleton inhibitor, Latrunculin A. Platelet-released PPARγ was complexed with the retinoid X receptor (RXR) and retained its ability to bind DNA. Interestingly, the released PPARγ and RXR were microparticle associated and the released PPARγ/RXR complex retained DNA-binding ability. Additionally, a monocytic cell line, THP-1, is capable of internalizing PMPs. Further investigation following treatment of these cells with the PPARγ agonist, rosiglitazone and PMPs revealed a possible transcellular mechanism to attenuate THP-1 activation. These new findings are the first demonstrating transcription factor release from platelets, revealing the complex spectrum of proteins expressed and expelled from platelets, and suggest that platelet PPARγ has an undiscovered role in human biology.
PMCID: PMC2754860  PMID: 18217139
Microparticles; Peroxisome Proliferator-Activated Receptor γ(PPARγ); Platelets; Retinoic X Receptor (RXR); transcription factors
17.  Motor subtype and cognitive decline in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies 
A previous cross sectional study found over‐representation of a postural instability gait difficulty (PIGD) motor subtype in Parkinson's disease patients with dementia (PDD) and dementia with Lewy bodies (DLB), compared with Parkinson's disease (PD).
(1) To examine rates of cognitive and motor decline over two years in PD (n = 40), PDD (n = 42) and DLB (n = 41) subjects, compared with age matched controls (n = 41), (2) to record whether motor phenotypes of PD, PDD, and DLB subjects changed during the study, (3) to find out if cognitive and motor decline in PD was associated with baseline motor subtype, and (4) to report the incidence of dementia in PD patients in relation to baseline motor subtype.
Most of PDD and DLB participants were PIGD subtype at baseline assessment. In the non‐demented PD group, tremor dominant (TD) and PIGD subtypes were more evenly represented. Cognitive decline over two years was greater in PDD and DLB groups (mean decline in MMSE −4.5 and −3.9, respectively), compared with PD (−0.2) and controls (−0.3). There was an association between PIGD subtype and increased rate of cognitive decline within the PD group. Of 40 PD patients, 25% of the 16 PIGD subtype developed dementia over two years, compared with none of the 18 TD or six indeterminate phenotype cases (χ2 = 6.7, Fisher's exact test p<0.05).
A PIGD motor subtype is associated with a faster rate of cognitive decline in PD and may be considered a risk factor for incident dementia in PD.
PMCID: PMC2117449  PMID: 16614017
Lewy body disease; dementia; parkinsonism; motor subtype; progression
18.  Choriocarcinoma metastatic to the choroid 
PMCID: PMC1857042  PMID: 16622101
choriocarcinoma; choroid
19.  Longitudinal change in 99mTcHMPAO cerebral perfusion SPECT in Parkinson's disease over one year 
Objective: To carry out a longitudinal study of perfusion in patients with Parkinson's disease and controls to find areas showing a reduction in perfusion over one year.
Methods: Two HMPAO cerebral perfusion scans were acquired one year apart in 30 subjects with Parkinson's disease (mean (SD) age, 76 (5) years) and 34 healthy comparison subjects (76 (7) years). Scans were normalised to the mean intensity in the cerebellum.
Results: Using SPM99 within groups to investigate regions that showed a decrease in perfusion between scans, it was found that in Parkinson's disease subjects but not controls there was a significant cluster in the frontal lobe (Brodmann area 10) where perfusion decreased over the year.
Conclusions: The progressive frontal perfusion deficits in Parkinson's disease are consistent with results from previous structural and neuropsychological studies suggesting frontal lobe involvement and executive dysfunction even in early Parkinson's disease.
PMCID: PMC1739344  PMID: 16170094
20.  The role of levodopa in the management of dementia with Lewy bodies 
Background: One of the core clinical features of dementia with Lewy bodies (DLB) is extrapyramidal syndrome (EPS). Levodopa is currently the gold standard oral therapy for Parkinson's disease (PD), but its use in DLB has been tempered by concerns of exacerbating neuropsychiatric symptoms.
Aim: To assess the efficacy and tolerability of L-dopa in managing EPS in DLB and to compare the motor response with that seen in PD and PD with dementia (PDD).
Method: EPS assessment consisted of the Unified Parkinson's Disease Rating Scale, motor subsection (UPDRS III), and finger tapping and walking tests. Patients with DLB were commenced on L-dopa. After 6 months, patients were examined in the "off" state, given L-dopa and assessed for motor responses. Identical assessments were performed in patients with PD and PDD also receiving L-dopa.
Results: Acute L-dopa challenge in 14 DLB patients yielded a mean 13.8% (p = 0.02) improvement in UPDRS III score, compared with 20.5% in PD (n = 28, p<0.0001) and 23% in PDD (n = 30, p<0.0001) respectively. Finger tapping scores increased (12.3% v 20% and 23%), while walking test scores decreased (32% v 41% and 67%). Of the DLB patients, 36% were classified as "responders" on L-dopa challenge, compared with 70% of the PDD and 57% of the PD patients. Nineteen DLB patients were treated for 6 months with L-dopa (mean daily dose 323 mg). Two withdrew prematurely with gastrointestinal symptoms and two with worsening confusion.
Conclusion: L-dopa was generally well tolerated in DLB but produced a significant motor response in only about one third of patients. Younger DLB cases were more likely to respond to dopaminergic treatment.
PMCID: PMC1739807  PMID: 16107351
21.  Effects of celecoxib in human retinoblastoma cell lines and in a transgenic murine model of retinoblastoma 
The British Journal of Ophthalmology  2005;89(9):1217-1220.
Background/aim: Celecoxib, a cyclooxygenase-2 inhibitor and antiangiogenic agent, has demonstrated potent anticancer effects in preclinical studies and in human clinical trials. To evaluate the potential utility of this agent in the treatment of retinoblastoma, the authors investigated the effects of celecoxib in retinoblastoma cell lines and in a murine model of this disease.
Methods: Growth inhibitory effects of celecoxib were evaluated in Y79 and Weri-RB1 human retinoblastoma cell lines by WST-1 cell proliferation assay. For animal study, two groups of 24, 8 week old LHβ-TAg transgenic mice were treated with celecoxib (250 mg/kg, orally once a day) or vehicle control, 5 days/week for 6 weeks. Mice were sacrificed on day 43. Enucleated eyes were serially sectioned and ocular tumour burden was quantified by histopathological analysis.
Results: Celecoxib did not inhibit proliferation of Y79 or Weri-RB1 cells, even at concentrations far exceeding clinically achievable levels. No significant difference in ocular tumour burden between celecoxib treated and control mice (p = 0.73) was found.
Conclusion: Celecoxib was ineffective at inhibiting proliferation of retinoblastoma cells in vitro and was ineffective at controlling retinoblastoma tumour growth in a murine model of this disease. On the basis of these findings, oral celecoxib therapy is unlikely to have clinical utility in the treatment of retinoblastoma.
PMCID: PMC1772840  PMID: 16113385
celecoxib; cell lines; drug evaluation; mice; retinoblastoma
22.  Ultrasound biomicroscopy: role in diagnosis and management in 130 consecutive patients evaluated for anterior segment tumours 
Background/aim: Ultrasound biomicroscopy (UBM) is an important tool for assessing anterior segment pathology. This study sought to evaluate UBM in the management of anterior segment tumours.
Methods: Retrospective analysis of medical records of consecutive patients referred to the ocular oncology unit, University of California San Francisco (UCSF), for suspected anterior segment tumours from 1999 to 2004.
Results: 132 eyes from 130 patients were evaluated, including 55 uveal melanomas (UM), 21 iris naevi, 30 iris cysts, and 26 remaining lesions. Of the melanomas, 45 were also evaluated with conventional A/B-scan. There was 29% correspondence between the anatomical structures invaded by melanoma as identified by B-scan v disease extent defined by UBM. Ciliary body and peripheral iris involvement by melanomas was significantly more frequently observed by UBM than B-scan. Seven of 30 benign cysts were diagnosed as cystic before UBM evaluation. In three cases, neuroepithelial cysts were associated with intercurrent pathology including iris naevus (n = 2) and ciliary body melanoma (n = 1). Two ciliary body melanomas showed cavitation, including one patient with a pseudocyst. Histopathological correlation was possible in six cases.
Conclusion: UBM is an indispensable tool for the management of anterior segment tumours. This study demonstrates the superiority of UBM v conventional B-scan for the precise localisation of uveal melanoma, especially involving the ciliary body and peripheral iris.
PMCID: PMC1772796  PMID: 16024841
ultrasound biomicroscopy; uvea; iris; ciliary body; melanoma
23.  Connexin35 Mediates Electrical Transmission at Mixed Synapses on Mauthner Cells 
Auditory afferents terminating as “large myelinated club endings” on goldfish Mauthner cells are identifiable “mixed” (electrical and chemical) synaptic terminals that offer the unique opportunity to correlate physiological properties with biochemical composition and specific ultrastructural features of individual synapses. By combining confocal microscopy and freeze-fracture replica immunogold labeling (FRIL), we demonstrate that gap junctions at these synapses contain connexin35 (Cx35). This connexin is the fish ortholog of the neuron-specific human and mouse connexin36 that is reported to be widely distributed in mammalian brain and to be responsible for electrical coupling between many types of neurons. Similarly, connexin35 was found at gap junctions between neurons in other brain regions, suggesting that connexin35-mediated electrical transmission is common in goldfish brain. Conductance of gap junction channels at large myelinated club endings is known to be dynamically modulated by the activity of their colocalized glutamatergic synapses. We show evidence by confocal microscopy for the presence of the NR1 subunit of the NMDA glutamate receptor subtype, proposed to be a key regulatory element, at these large endings. Furthermore, we also show evidence by FRIL double-immunogold labeling that the NR1 subunit of the NMDA glutamate receptor is present at postsynaptic densities closely associated with gap junction plaques containing Cx35 at mixed synapses across the goldfish hindbrain. Given the widespread distribution of electrical synapses and glutamate receptors, our results suggest that the plastic properties observed at these identifiable junctions may apply to other electrical synapses, including those in mammalian brain.
PMCID: PMC1805790  PMID: 12930787
gap junction; connexin36; electrical synapse; NMDA; synaptic plasticity; electrical coupling; auditory
24.  Short-Range Functional Interaction Between Connexin35 and Neighboring Chemical Synapses 
Cell communication & adhesion  2003;10(4-6):419-423.
Auditory afferents terminating as mixed, electrical, and chemical, synapses on the goldfish Mauthner cells constitute an ideal experimental model to study the properties of gap junctions in the nervous system as well as to explore possible functional interactions with the other major form of interneuronal communication—chemically mediated synapses. By combining confocal microscopy and freeze-fracture replica immunogold labeling (FRIL), we found that gap junctions at these synapses contain connexin35 (Cx35), the fish ortholog of the neuron-specific human and mouse connexin36 (Cx36). Conductance of gap junction channels at these endings is known to be dynamically modulated by the activity of their co-localized chemically mediated glutamatergic synapses. By using simultaneous pre- and postsynaptic recordings at these single terminals, we demonstrate that such functional interaction takes place in the same ending, within a few micrometers. Accordingly, we also found evidence by confocal and FRIL double-immunogold labeling that the NR1 subunit of the NMDA glutamate receptor, proposed to be a key regulatory element, is present at postsynaptic densities closely associated with gap junction plaques containing Cx35. Given the widespread distribution of Cx35- and Cx36-mediated electrical synapses and glutamatergic synapses, our data suggest that the local functional interactions observed at these identifiable junctions may also apply to other electrical synapses, including those in mammalian brain.
PMCID: PMC1803252  PMID: 14681051
Auditory; connexin36; electrical coupling; electrical synapse; gap junction; NMDA; synaptic plasticity
25.  The PPAR-Platelet Connection: Modulators of Inflammation and Potential Cardiovascular Effects 
PPAR Research  2007;2008:328172.
Historically, platelets were viewed as simple anucleate cells responsible for initiating thrombosis and maintaining hemostasis, but clearly they are also key mediators of inflammation and immune cell activation. An emerging body of evidence links platelet function and thrombosis to vascular inflammation. peroxisome proliferator-activated receptors (PPARs) play a major role in modulating inflammation and, interestingly, PPARs (PPARβ/δ and PPARγ) were recently identified in platelets. Additionally, PPAR agonists attenuate platelet activation; an important discovery for two reasons. First, activated platelets are formidable antagonists that initiate and prolong a cascade of events that contribute to cardiovascular disease (CVD) progression. Dampening platelet release of proinflammatory mediators, including CD40 ligand (CD40L, CD154), is essential to hinder this cascade. Second, understanding the biologic importance of platelet PPARs and the mechanism(s) by which PPARs regulate platelet activation will be imperative in designing therapeutic strategies lacking the deleterious or unwanted side effects of current treatment options.
PMCID: PMC2233896  PMID: 18288284

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