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1.  Mars Science Laboratory relative humidity observations: Initial results 
The Mars Science Laboratory (MSL) made a successful landing at Gale crater early August 2012. MSL has an environmental instrument package called the Rover Environmental Monitoring Station (REMS) as a part of its scientific payload. REMS comprises instrumentation for the observation of atmospheric pressure, temperature of the air, ground temperature, wind speed and direction, relative humidity (REMS-H), and UV measurements. We concentrate on describing the REMS-H measurement performance and initial observations during the first 100 MSL sols as well as constraining the REMS-H results by comparing them with earlier observations and modeling results. The REMS-H device is based on polymeric capacitive humidity sensors developed by Vaisala Inc., and it makes use of transducer electronics section placed in the vicinity of the three humidity sensor heads. The humidity device is mounted on the REMS boom providing ventilation with the ambient atmosphere through a filter protecting the device from airborne dust. The final relative humidity results appear to be convincing and are aligned with earlier indirect observations of the total atmospheric precipitable water content. The water mixing ratio in the atmospheric surface layer appears to vary between 30 and 75 ppm. When assuming uniform mixing, the precipitable water content of the atmosphere is ranging from a few to six precipitable micrometers.
Key Points
Atmospheric water mixing ratio at Gale crater varies from 30 to 140 ppmMSL relative humidity observation provides good dataHighest detected relative humidity reading during first MSL 100 sols is RH75%
PMCID: PMC4508910  PMID: 26213667
Mars; atmosphere; humidity; total water content; MSL; Gale
2.  Phenotypic Characterization of the KK/HlJ Inbred Mouse Strain 
Veterinary pathology  2013;51(4):846-857.
Detailed histopathological diagnoses of inbred mouse strains are important for interpreting research results and defining novel models of human diseases. The aim of this study was to histologically detect lesions affecting the KK/HlJ inbred strain. Mice were examined at 6, 12, and 20 months of age and near natural death (ie, moribund mice). Histopathological lesions were quantified by percentage of affected mice per age group and sex. Predominant lesions were mineralization, hyperplasia, and fibro-osseous lesions. Mineralization was most frequently found in the connective tissue dermal sheath of vibrissae, the heart, and the lung. Mineralization was also found in many other organs but to a lesser degree. Hyperplasia was found most commonly in the pancreatic islets, and fibro-osseous lesions were observed in several bones. The percentage of lesions increased with age until 20 months. This study shows that KK/HlJ mice demonstrate systemic aberrant mineralization, with greatest frequency in aged mice. The detailed information about histopathological lesions in the inbred strain KK/HlJ can help investigators to choose the right model and correctly interpret the experimental results.
PMCID: PMC4037397  PMID: 24009271
systemic mineralization; ectopic mineralization; PXE model; KK/HlJ mice; vibrissae dermal sheath
3.  Developing Objective Metrics for Unit Staffing (DOMUS) study 
BMJ Open  2014;4(9):e005398.
Safe midwifery staffing levels on delivery suites is a priority area for any maternity service. Escalation policies are tools that provide an operational response to emergency pressures. The aim of this study was to assess the feasibility of using a scoring system to contemporaneously assess the required staffing level based on demand and use this to determine delivery suite escalation level and utilise the information generated regarding clinical activity (Demand) and staffing levels (Capacity) to generate unit-specific calculation for the actual number of midwifery staff required.
A maternity unit of a university-affiliated tertiary referral hospital.
Over a 12-month period, specifically designed scoring sheets were completed by delivery suite shift co-ordinators four times a day (04:00, 10:00, 16:00 and 22:00). Based on the dependency score (Demand) and the number of midwifery staff available (Capacity), an escalation level was determined for each shift. The 80th centile of the demand was used to determine optimal capacity.
A total of 1160 scoring sheets were completed. Average staff number throughout the year on any shift was 7 (range 3–11). Average dependency score was 7 (range 1–14). The 80th centile for demand was calculated to be 11.
This study stresses the importance and usefulness of a simple tool that can be used to determine the level of escalation on delivery suite based on an objective scoring system and can also be used to determine the appropriate staffing on delivery suite.
PMCID: PMC4163650  PMID: 25217367
4.  Structural changes in the temporal lobe and piriform cortex in frontal lobe epilepsy 
Epilepsy Research  2014;108(5):978-981.
•Voxelwise analysis of structural images is performed in a group of patients with FLE.•Structural abnormalities are found in piriform cortex and adjacent structures including amygdala.•These common areas of structural abnormality are seen independently of the side of seizure focus lateralisation.•This is concordant with previous findings in functional imaging analysis of patients with focal epilepsy.
Neuronal networks involved in seizure generation, maintenance and spread of epileptic activity comprise cortico-subcortical circuits. Although epileptic foci vary in location across focal epilepsy syndromes, there is evidence for common structures in the epileptogenic networks. We recently reported evidence from functional neuroimaging for a unique area in the piriform cortex, common to focal epilepsies in humans, which might play a role in modulating seizure activity.
In this study, we aimed to identify common areas of structural abnormalities in patients with frontal lobe epilepsy (FLE).
T1-weighted MRI scans of 43 FLE patients and 25 healthy controls were analysed using voxel based morphometry. Differences in regional grey matter volume were examined across the whole brain, and correlated with age at epilepsy onset, duration and frequency of seizures.
We detected areas of increased grey matter volume in the piriform cortex, amygdala and parahippocampal gyrus bilaterally, as well as left mid temporal gyrus of patients relative to controls, which did not correlate with any of the clinical variables tested. No common areas of atrophy were detected across the FLE group.
Structural abnormalities within the piriform cortex and adjacent structures of patients with FLE provide further evidence for the involvement of this area in the epileptogenic network of focal epilepsies. Lack of correlation with duration or age of onset of epilepsy suggests that this area of abnormality is not a consequence of seizure activity.
PMCID: PMC4037873  PMID: 24726451
Frontal lobe epilepsy; Piriform cortex; Voxel based morphometry; MRI
5.  Structural changes in the temporal lobe and piriform cortex in frontal lobe epilepsy 
Epilepsy research  2014;108(5):978-981.
Neuronal networks involved in seizure generation, maintenance and spread of epileptic activity comprise cortico-subcortical circuits. Although epileptic foci vary in location across focal epilepsy syndromes, there is evidence for common structures in the epileptogenic networks. We recently reported evidence from functional neuroimaging for a unique area in the piriform cortex, common to focal epilepsies in humans, which might play a role in modulating seizure activity.
In this study, we aimed to identify common areas of structural abnormalities in patients with frontal lobe epilepsy (FLE).
T1-weighted MRI scans of 43 FLE patients and 25 healthy controls were analysed using voxel based morphometry. Differences in regional grey matter volume were examined across the whole brain, and correlated with age at epilepsy onset, duration and frequency of seizures.
We detected areas of increased grey matter volume in the piriform cortex, amygdala and parahippocampal gyrus bilaterally, as well as left mid temporal gyrus of patients relative to controls, which did not correlate with any of the clinical variables tested. No common areas of atrophy were detected across the FLE group.
Structural abnormalities within the piriform cortex and adjacent structures of patients with FLE provide further evidence for the involvement of this area in the epileptogenic network of focal epilepsies. Lack of correlation with duration or age of onset of epilepsy suggests that this area of abnormality is not a consequence of seizure activity.
PMCID: PMC4037873  PMID: 24726451
Frontal lobe epilepsy; Piriform cortex; Voxel based morphometry; MRI
7.  Identification of novel nucleus pulposus markers 
Bone & Joint Research  2013;2(8):169-178.
Mesenchymal stem-cell based therapies have been proposed as novel treatments for intervertebral disc degeneration, a prevalent and disabling condition associated with back pain. The development of these treatment strategies, however, has been hindered by the incomplete understanding of the human nucleus pulposus phenotype and by an inaccurate interpretation and translation of animal to human research. This review summarises recent work characterising the nucleus pulposus phenotype in different animal models and in humans and integrates their findings with the anatomical and physiological differences between these species. Understanding this phenotype is paramount to guarantee that implanted cells restore the native functions of the intervertebral disc.
Cite this article: Bone Joint Res 2013;2:169–78.
PMCID: PMC3747513  PMID: 23958792
Intervertebral disc; Disc degeneration; Nucleus pulposus; Phenotype; Cell-based therapies; Mesenchymal stem cells; Animal models
8.  All-Cause Mortality Risk of Metabolically Healthy Obese Individuals in NHANES III 
Journal of Obesity  2012;2012:460321.
Mortality risk across metabolic health-by-BMI categories in NHANES-III was examined. Metabolic health was defined as: (1) homeostasis model assessment-insulin resistance (HOMA-IR) <2.5; (2) ≤2 Adult Treatment Panel (ATP) III metabolic syndrome criteria; (3) combined definition using ≤1 of the following: HOMA-IR ≥1.95 (or diabetes medications), triglycerides ≥1.7 mmol/L, HDL-C <1.04 mmol/L (males) or <1.30 mmol/L (females), LDL-C ≥2.6 mmol/L, and total cholesterol ≥5.2 mmol/L (or cholesterol-lowering medications). Hazard ratios (HR) for all-cause mortality were estimated with Cox regression models. Nonpregnant women and men were included (n = 4373, mean ± SD, age 37.1 ± 10.9 years, BMI 27.3 ± 5.8 kg/m2, 49.4% female). Only 40 of 1160 obese individuals were identified as MHO by all definitions. MHO groups had superior levels of clinical risk factors compared to unhealthy individuals but inferior levels compared to healthy lean groups. There was increased risk of all-cause mortality in metabolically unhealthy obese participants regardless of definition (HOMA-IR HR 2.07 (CI 1.3–3.4), P < 0.01; ATP-III HR 1.98 (CI 1.4–2.9), P < 0.001; combined definition HR 2.19 (CI 1.3–3.8), P < 0.01). MHO participants were not significantly different from healthy lean individuals by any definition. While MHO individuals are not at significantly increased risk of all-cause mortality, their clinical risk profile is worse than that of metabolically healthy lean individuals.
PMCID: PMC3523154  PMID: 23304462
9.  Altered microstructural connectivity in juvenile myoclonic epilepsy 
Neurology  2012;78(20):1555-1559.
Juvenile myoclonic epilepsy (JME) is characterized by myoclonic jerks of the upper limbs, often triggered by cognitive stressors. Here we aim to reconcile this particular seizure phenotype with the known frontal lobe type neuropsychological profile, photosensitivity, hyperexcitable motor cortex, and recent advanced imaging studies that identified abnormal functional connectivity of the motor cortex and supplementary motor area (SMA).
We acquired fMRI and diffusion tensor imaging (DTI) in a cohort of 29 patients with JME and 28 healthy control subjects. We used fMRI to determine functional connectivity and DTI-based region parcellation and voxel-wise comparison of probabilistic tractography data to assess the structural connectivity profiles of the mesial frontal lobe.
Patients with JME showed alterations of mesial frontal connectivity with increased structural connectivity between the prefrontal cognitive cortex and motor cortex. We found a positive correlation between DTI and fMRI-based measures of structural and functional connectivity: the greater the structural connectivity between these 2 regions, the greater the observed functional connectivity of corresponding areas. Furthermore, connectivity was reduced between prefrontal and frontopolar regions and increased between the occipital cortex and the SMA.
The observed alterations in microstructural connectivity of the mesial frontal region may represent the anatomic basis for cognitive triggering of motor seizures in JME. Changes in the mesial frontal connectivity profile provide an explanatory framework for several other clinical observations in JME and may be the link between seizure semiology, neurophysiology, neuropsychology, and imaging findings in JME.
PMCID: PMC3348847  PMID: 22551729
10.  Increased cavernosal relaxation by Phoneutria nigriventer toxin, PnTx2-6, via activation at NO/cGMP signaling 
Erectile dysfunction mechanisms in diabetic patients are multifactorial and often lead to resistance to current therapy. Animal toxins have been used as pharmacological tools to study penile erection. Human accidents involving the venom of Phoneutria nigriventer spider are characterized by priapism. We hypothesize that PnTx2-6 potentiates cavernosal relaxation in diabetic mice by increasing cGMP. This effect is nNOS dependent. Cavernosal strips were contracted with phenylephrine (10−5 M) and relaxed by electrical field stimulation (EFS, 20V, 1–32 Hz) in the presence or absence of PnTx2-6 (10−8 M).Cavernosal strips from nNOS and eNOS knocaut (KO) mice, besides nNOS inhibitor (10−5M), were used to evaluate the role of this enzyme in the potentiation effect evoked by PnTx2-6. Tissue cGMP levels were determined after stimulation with PnTx2-6 in presence or absence of L-NAME (10−4M) and ω-conotoxin GVIA (10−6M), an N-type calcium channel inhibitor. Results showed PnTx2-6 enhanced cavernosal relaxation in diabetic mice (65%) and eNOS KO mice, but not in nNOS KO mice. The toxin effect in the cavernosal relaxation was abolished by nNOS inhibitor. cGMP levels are increased by PnTx2-6, however L-NAME abolished this enhancement as well as ω-conotoxin GVIA. We conclude PnTx2-6 facilitates penile relaxation in diabetic mice through a mechanism dependent on nNOS, probably via increasing NO/cGMP production.
PMCID: PMC3253321  PMID: 21975567
Phoneutria nigriventer; erectile dysfunction; PnTx2-6 toxin; NO; cGMP
12.  Enzyme replacement therapy for mucopolysaccharidosis VI: long-term cardiac effects of galsulfase (Naglazyme®) therapy 
Characteristic cardiac valve abnormalities and left ventricular hypertrophy are present in untreated patients with mucopolysaccharidosis type VI (MPS VI). Cardiac ultrasound was performed to investigate these findings in subjects during long-term enzyme replacement therapy (ERT) with recombinant human arylsulfatase B (rhASB, rhN-acetylgalactosamine 4-sulfatase, galsulfase, Naglazyme®). Studies were conducted in 54 subjects before ERT was begun and at specific intervals for up to 96 weeks of weekly infusions of rhASB at 1 mg/kg during phase 1/2, phase 2, and phase 3 trials of rhASB. At baseline, mitral and aortic valve obstruction was present and was significantly greater in those ≥12 years of age. Mild mitral and trace aortic regurgitation were present, the former being significantly greater in those <12 years. Left ventricular hypertrophy, with averaged z-scores ranging from 1.6–1.9 SD greater than normal, was present for ages both <12 and ≥12 years. After 96 weeks of ERT, ventricular septal hypertrophy regressed in those <12 years. For those ≥12 years, septal hypertrophy was unchanged, and aortic regurgitation increased statistically but not physiologically. Obstructive gradients across mitral and aortic valves remained unchanged. The results suggest that long-term ERT is effective in reducing intraventricular septal hypertrophy and preventing progression of cardiac valve abnormalities when administered to those <12 years of age.
PMCID: PMC3590402  PMID: 22669363
13.  Converging PET and fMRI evidence for a common area involved in human focal epilepsies 
Neurology  2011;77(9):904-910.
Experiments in animal models have identified specific subcortical anatomic circuits, which are critically involved in the pathogenesis and control of seizure activity. However, whether such anatomic substrates also exist in human epilepsy is not known.
We studied 2 separate groups of patients with focal epilepsies arising from any cortical location using either simultaneous EEG-fMRI (n = 19 patients) or [11C]flumazenil PET (n = 18).
Time-locked with the interictal epileptiform discharges, we found significant hemodynamic increases common to all patients near the frontal piriform cortex ipsilateral to the presumed cortical focus. GABAA receptor binding in the same area was reduced in patients with more frequent seizures.
Our findings of cerebral blood flow and GABAergic changes, irrespective of where interictal or ictal activity occurs in the cortex, suggest that this area of the human primary olfactory cortex may be an attractive new target for epilepsy therapy, including neurosurgery, electrical stimulation, and focal drug delivery.
PMCID: PMC3162638  PMID: 21849655
14.  Weekend hospitalization and additional risk of death: An analysis of inpatient data 
To assess whether weekend admissions to hospital and/or already being an inpatient on weekend days were associated with any additional mortality risk.
Retrospective observational survivorship study. We analysed all admissions to the English National Health Service (NHS) during the financial year 2009/10, following up all patients for 30 days after admission and accounting for risk of death associated with diagnosis, co-morbidities, admission history, age, sex, ethnicity, deprivation, seasonality, day of admission and hospital trust, including day of death as a time dependent covariate. The principal analysis was based on time to in-hospital death.
National Health Service Hospitals in England.
Main Outcome Measures
30 day mortality (in or out of hospital).
There were 14,217,640 admissions included in the principal analysis, with 187,337 in-hospital deaths reported within 30 days of admission. Admission on weekend days was associated with a considerable increase in risk of subsequent death compared with admission on weekdays, hazard ratio for Sunday versus Wednesday 1.16 (95% CI 1.14 to 1.18; P < .0001), and for Saturday versus Wednesday 1.11 (95% CI 1.09 to 1.13; P < .0001). Hospital stays on weekend days were associated with a lower risk of death than midweek days, hazard ratio for being in hospital on Sunday versus Wednesday 0.92 (95% CI 0.91 to 0.94; P < .0001), and for Saturday versus Wednesday 0.95 (95% CI 0.93 to 0.96; P < .0001). Similar findings were observed on a smaller US data set.
Admission at the weekend is associated with increased risk of subsequent death within 30 days of admission. The likelihood of death actually occurring is less on a weekend day than on a mid-week day.
PMCID: PMC3284293  PMID: 22307037
15.  Fistula after pyloroplasty – A novel approach to the management of a leak following oesophagectomy 
Management of upper gastrointestinal anastomotic leaks is an inter-disciplinary challenge. We present a case of late pyloroplasty leak following 3-stage oesophagectomy. We describe a novel, combined endoscopic and fluroscopic procedure to introduce a T-tube into the anastomotic leak proving an ideal plug at the site of leak which enabled the patient to consume a normal diet and return home safely.
PMCID: PMC3649494  PMID: 24960785
16.  Differential Protein Expression during Aging in Ventricular Myocardium of Fischer 344 X Brown Norway Hybrid Rats 
Experimental Gerontology  2008;43(10):909-918.
The aging heart undergoes well characterized structural changes associated with functional decline, though the underlying mechanisms are not understood. The aim of this study was to determine to what extent ventricular myocardial protein expression was altered with age and which proteins underwent protein nitration. Fischer 344 X Brown Norway F1 hybrid (FBN) rats of four age groups were used, 4, 12, 24, and 34 months. Differential protein expression was determined by 2-DE and proteins were identified by peptide mass fingerprinting. Altered protein nitration with age was assessed by immunoblotting. Over 1,000 protein spots per sample were detected, and 255 were found to be differentially expressed when all aged groups were compared to young rats (4 months) (p ≤ 0.05). A strong positive correlation between differential protein expression and increasing age (p=0.03, R2=0.997) indicated a progressive, rather than abrupt, change with age. Of 46 differentially expressed proteins identified, 17 have roles in apoptosis, 10 in hypertrophy, 7 in fibrosis, and 3 in diastolic dysfunction, aging-associated processes previously reported in both human and FBN rat heart. Protein expression alterations detected here could have beneficial effects on cardiac function; thus, our data indicate a largely adaptive change in protein expression during aging. In contrast, differential protein nitration increased abruptly, rather than progressively, at 24 months of age. Altogether, the results suggest that differential myocardial protein expression occurs in a progressive manner during aging, and that a proteomic-based approach is an effective method for the identification of potential therapeutic targets to mitigate aging-related myocardial dysfunction.
PMCID: PMC3255083  PMID: 18682286
aging; F344 X BN hybrid; heart; MALDI-TOF; nitrosylation; peptide mass fingerprinting; proteomics; two-dimensional electrophoresis
17.  Dose-Response Effects of Insulin Glargine in Type 2 Diabetes 
Diabetes Care  2010;33(7):1555-1560.
To determine the pharmacokinetic and pharmacodynamic dose-response effects of insulin glargine administered subcutaneously in individuals with type 2 diabetes.
Twenty obese type 2 diabetic individuals (10 male and 10 female, aged 50 ± 3 years, with BMI 36 ± 2 kg/m2 and A1C 8.3 ± 0.6%) were studied in this single-center, placebo-controlled, randomized, double-blind study. Five subcutaneous doses of insulin glargine (0, 0.5, 1.0, 1.5, and 2.0 units/kg) were investigated on separate occasions using the 24-h euglycemic clamp technique.
Glargine duration of action to reduce glucose, nonessential fatty acid (NEFA), and β-hydroxybutyrate levels was close to or >24 h for all four doses. Increases in glucose flux revealed no discernible peak and were modest with maximal glucose infusion rates of 9.4, 6.6, 5.5, and 2.8 μmol/kg/min for the 2.0, 1.5, 1.0, and 0.5 units/kg doses, respectively. Glargine exhibited a relatively hepatospecific action with greater suppression (P < 0.05) of endogenous glucose production (EGP) compared with little or no increases in glucose disposal.
A single subcutaneous injection of glargine at a dose of ≥0.5 units/kg can acutely reduce glucose, NEFA, and ketone body levels for 24 h in obese insulin-resistant type 2 diabetic individuals. Glargine lowers blood glucose by mainly inhibiting EGP with limited effects on stimulating glucose disposal. Large doses of glargine have minimal effects on glucose flux and retain a relatively hepatospecific action in type 2 diabetes.
PMCID: PMC2890358  PMID: 20357371
18.  Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy 
Neurology  2011;76(1):34-40.
The aim of this study was to determine if there were focal cortical abnormalities in juvenile myoclonic epilepsy (JME) using neuropsychological investigations and MRI.
Twenty-eight patients with JME and a large sample of healthy controls were assessed using a series of neuropsychological tests as well as structural and diffusion tensor MRI (DTI). DTI measures assessed fractional anisotropy (FA) within a white matter skeleton.
Neuropsychological testing indicated subtle dysfunctions in verbal fluency, comprehension, and expression, as well as nonverbal memory and mental flexibility. Utilizing whole-brain voxel-based morphometry for gray matter MRI data and tract-based spatial statistics for white matter diffusion MRI data, we found reductions in gray matter volume (GMV) in the supplementary motor area and posterior cingulate cortex and reductions in FA in underlying white matter of the corpus callosum. Supplementary motor area FA predicted scores in word naming tasks and expression scores. Posterior cingulate cortex GMV and FA predicted cognitive inhibition scores on the mental flexibility task.
The neuropsychological, structural, and tractography results implicate mesial frontal cortex, especially the supplementary motor area, and posterior cingulate cortex in JME.
PMCID: PMC3030222  PMID: 21205693
19.  Tx2-6 toxin of the Phoneutria nigriventer spider potentiates rat erectile function☆ 
The venom of the spider Phoneutria nigriventer contains several toxins that have bioactivity in mammals and insects. Accidents involving humans are characterized by various symptoms including penile erection. Here we investigated the action of Tx2-6, a toxin purified from the P. nigriventer spider venom that causes priapism in rats and mice. Erectile function was evaluated through changes in intracavernosal pressure/mean arterial pressure ratio (ICP/MAP) during electrical stimulation of the major pelvic ganglion (MPG) of normotensive and deoxycorticosterone-acetate (DOCA)-salt hypertensive rats. Nitric oxide (NO) release was detected in cavernosum slices with fluorescent dye (DAF-FM) and confocal microscopy. The effect of Tx2-6 was also characterized after intracavernosal injection of a non-selective nitric oxide synthase (NOS) inhibitor, L-NAME. Subcutaneous or intravenous injection of Tx2-6 potentiated the elevation of ICP/MAP induced by ganglionic stimulation. L-NAME inhibited penile erection and treatment with Tx2-6 was unable to reverse this inhibition. Tx2-6 treatment induced a significant increase of NO release in cavernosum tissue. Attenuated erectile function of DOCA-salt hypertensive rats was fully restored after toxin injection. Tx2-6 enhanced erectile function in normotensive and DOCA-salt hypertensive rats, via the NO pathway. Our studies suggest that Tx2-6 could be important for development of new pharmacological agents for treatment of erectile dysfunction.
PMCID: PMC3019117  PMID: 18397797
Phoneutria nigriventer; Tx2-6 toxin; Nitric oxide; Erectile function
20.  Order Parameter Dynamics of Body-scaled Hysteresis and Mode Transitions in Grasping Behavior 
Journal of Biological Physics  2009;35(2):127-147.
Several experimental studies have shown that human grasping behavior exhibits a transition from one-handed to two-handed grasping when to-be-grasped objects become larger and larger. The transition point depends on the relative size of objects measured in terms of human body-scales. Most strikingly, the transitions between the two different behavioral ‘modes’ of grasping exhibit hysteresis. That is, one-to-two hand transitions and two-to-one hand transitions occur at different relative object sizes when objects are scaled up or down in size. In our study we approach body-scaled hysteresis and mode transitions in grasping by exploiting the notion that human behavior in general results from self-organization and satisfies appropriately-defined order parameter equations. To this end, grasping transitions and grasping hysteresis are discussed from a theoretical perspective in analogy to cognitive processes defined by Haken’s neural network model for pattern recognition. In doing so, issues such as the exclusivity of grasping modes, biomechanical constraints, mode-mode interactions, single subject behavior and population behavior are explored.
PMCID: PMC2669118  PMID: 19669557
Order parameters; Hysteresis; Grasping
21.  Non‐response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS‐3) in patients with chronic hepatitis C, viral genotype 1 
Gut  2006;55(4):529-535.
Interferon α (IFN‐α) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown.
To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN‐α therapy and to determine hepatic expression of factors inhibiting IFN‐α signalling in obese and non‐obese subjects with chronic HCV.
A total of 145 subjects were analysed to determine host factors associated with non‐response to antiviral therapy. Treatment comprised IFN‐α or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time‐polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS‐3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment.
Non‐response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p<0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index ⩾ 30 kg/m2 (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS‐3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS‐3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS‐3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non‐responders compared with responders (p = 0.014).
In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN‐α.
PMCID: PMC1856185  PMID: 16299039
insulin resistance; tumour necrosis factor; phosphoenolpyruvate carboxy kinase; suppressor of cytokine signalling; obesity; antiviral therapy; hepatitis C
22.  The apolipoprotein E ε4 allele selectively increases the risk of frontotemporal lobar degeneration in males 
To determine whether polymorphic variations in the apolipoprotein E gene (APOE) are associated with increased risk of frontotemporal lobar degeneration (FTLD) when mutation in tau gene is absent.
The APOE gene was genotyped by polymerase chain reaction from DNA routinely extracted from blood or brain tissues. The APOE ε4 allele frequency in 198 patients with FTLD not associated with mutations in tau gene was compared with that of a control group of 756 normal individuals drawn from the same geographical region. Analyses were done according to clinical subtype or sex.
The APOE ε4 allele frequency (19.4%) was increased (p = 0.01) in FTLD v the whole control group (14.1%), while the APOE ε2 allele frequency in FTLD (6.5%) was slightly lower than in controls (8.0%) (NS). The APOE ε4 allele frequency in men with FTLD (22.3%) was greater (p = 0.002) than in male controls (12.3%); the frequency in women (16.3%) was similar to that in female controls (14.8%) (NS). The APOE ε2 allele frequency in men with FTLD was 4.9% while in male controls it was 9.5% (p = 0.06), but there was no difference in women (7.5% v 7.9%, NS). Neither the APOE ε2 nor APOE ε4 allele frequency varied significantly between any of the clinical subtypes.
In FTLD not associated with mutations in tau gene, possession of APOE ε4 allele in men roughly doubles the chances of developing disease, whereas this has no impact upon disease risk in women.
PMCID: PMC2077587  PMID: 16421115
frontotemporal lobar degeneration; apolipoprotein E gene; dementia; genetic risk; gender
23.  A combination of genetic polymorphisms increases the risk of progressive disease in chronic hepatitis C 
Journal of Medical Genetics  2005;42(7):e45.
Background: There is increasing interest in the influence of host genetic factors on hepatic fibrosis, and whether genetic markers can reliably identify subjects at risk of developing severe disease. We hypothesised that hepatitis C virus (HCV) infected subjects with progressive fibrosis, classified using strict criteria based on histology at biopsy in addition to disease duration would be more likely to inherit several genetic polymorphisms associated with disease progression compared with subjects with a low rate of disease progression.
Methods: We examined polymorphisms in eight genes that have been reported to have an association with hepatic fibrosis.
Results: Associations between polymorphisms in six genes and more rapidly progressing fibrosis were observed, with individual adjusted odds ratios ranging from 2.1 to 4.5. The relationship between rapidly progressing fibrosis and possession of ⩾3, ⩾4, or ⩾5 progression associated alleles was determined and the adjusted odds ratios increased with increasing number of progression associated alleles (9.1, 15.5, and 24.1, respectively). Using logistic regression analysis, a predictive equation was developed and tested using a second cohort of patients with rapidly progressing fibrosis. The predictive equation correctly classified 80% of patients in this second cohort.
Conclusions: This approach may allow determination of a genetic profile predictive of rapid disease progression in HCV and identify patients warranting more aggressive therapeutic management.
PMCID: PMC1736103  PMID: 15994870
24.  Preoperative fMRI predicts memory decline following anterior temporal lobe resection 
Anterior temporal lobe resection (ATLR) benefits many patients with refractory temporal lobe epilepsy (TLE) but may be complicated by material specific memory impairments, typically of verbal memory following left ATLR, and non-verbal memory following right ATLR. Preoperative memory functional MRI (fMRI) may help in the prediction of these deficits.
To assess the value of preoperative fMRI in the prediction of material specific memory deficits following both left- and right-sided ATLR.
We report 15 patients with unilateral TLE undergoing ATLR; eight underwent dominant hemisphere ATLR and seven non-dominant ATLR. Patients performed an fMRI memory paradigm which examined the encoding of words, pictures and faces.
Individual patients with relatively greater ipsilateral compared with contralateral medial temporal lobe activation had greater memory decline following ATLR. This was the case for both verbal memory decline following dominant ATLR and for non-verbal memory decline following non-dominant ATLR. For verbal memory decline, activation within the dominant hippocampus was predictive of postoperative memory change whereas activation in the non-dominant hippocampus was not.
These findings suggest that preoperative memory fMRI may be a useful non-invasive predictor of postoperative memory change following ATLR and provide support for the functional adequacy theory of hippocampal function. They also suggest that fMRI may provide additional information, over that provided by neuropsychology, for use in the prediction of postoperative memory decline.
PMCID: PMC2564863  PMID: 17898035
25.  Measurement of amygdala T2 relaxation time in temporal lobe epilepsy 
Methods: 20 healthy subjects and 25 patients with known hippocampal sclerosis (HS) were studied using a dual echo CSE sequence on a 1.5T MRI GE scanner. The T2 relaxation time of the amygdala was calculated and measured using a previously validated method.
Results: The mean control AT2 was 88.1 ms (SD 2 ms). The coefficient of reliability was good at 6.3% test-retest and 7.4% inter-rater. The upper limit of normal AT2 was 92 ms. AT2 was abnormal ipsilaterally in six, and bilaterally in three, of 20 patients with unilateral HS. Two of five patients with bilateral HS had unilateral abnormal AT2.
Conclusion: Reliable T2 measurements can be obtained in the amygdala, and may be useful in the detection of amygdala abnormality.
PMCID: PMC1757376  PMID: 12438484

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