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1.  Family history of premature coronary heart disease and risk prediction in the EPIC-Norfolk prospective population study 
Heart (British Cardiac Society)  2010;96(24):1985-1989.
Objective
The value of a family history for coronary heart disease (CHD) in addition to established cardiovascular risk factors in predicting an individual’s risk of CHD is unclear. In the EPIC-Norfolk cohort, we tested whether adding family history of premature CHD in first degree relatives improves risk prediction compared to the Framingham risk score (FRS) alone.
Methods and Results
This study comprised 10,288 men and 12,553 women aged 40 to 79 years participating in the EPIC-Norfolk cohort who where followed for an average of 10.9 ± 2.1 years (mean ± SD). We computed the Framingham risk score as well as a modified score taking into account family history of premature CHD. A family history of CHD was indeed associated with an increased risk of future CHD, independent of established risk factors (FRS-adjusted hazard ratio of 1.74 (95%CI 1.56-1.95) for family history of premature CHD). However, adding family history of CHD to the Framingham risk score resulted in a negative net reclassification of 2%. In the subgroup of individuals estimated to be at intermediate risk, family history of premature CHD resulted in an increase in net reclassification of 2%. The sensitivity increased with 0.4 % and the specificity decreased 0.8%.
Conclusion
Although family history of CHD was an independent risk factor of future CHD, its use did not improve classification of individuals into clinically relevant risk categories based on the FRS. Among study participants at intermediate risk of CHD, adding family history of premature CHD resulted in, at best, a modest improvement in reclassification of individuals into a more accurate risk category.
doi:10.1136/hrt.2010.210740
PMCID: PMC3773915  PMID: 20962344
2.  Isolated protein S deficiency presenting as catastrophic systemic arterial and subsequently venous thrombosis 
The Australasian Medical Journal  2012;5(8):424-428.
Isolated protein S deficiency is an inherited condition having proven association with venous thromboembolism. There is controversy regarding clear association between protein S deficiency and arterial thrombosis. It is therefore necessary to bring focus to this uncommon clinical condition and highlight the probable association with arterial thrombosis facilitating timely diagnosis of this condition. We describe a 48-year-old male with stroke and pulmonary thromboembolism with chronic deep vein thrombosis secondary to isolated protein S deficiency, managed with thrombolysis and long-term anticoagulation.
doi:10.4066/AMJ.2012.1309
PMCID: PMC3442186  PMID: 23024716
Isolated protein S deficiency; Stroke in young; Pulmonary Thromboembolism; Deep Venous Thrombosis; Thrombolysis
3.  Respiratory recovery following high cervical hemisection 
In this paper we review respiratory recovery following C2 spinal cord hemisection (C2HS) and introduce evidence for ipsilateral (IL) and contralateral (CL) phrenic motor neuron (PhrMN) synchrony post-C2HS. Rats have rapid, shallow breathing after C2HS but ventilation (Ṿe) is maintained. Ṿe deficits occur during hypercapnic challenge reflecting reduced tidal volume (Vt), but modest recovery occurs by 12 wks post-injury. IL PhrMN activity recovers in a time-dependent manner after C2HS, and neuroanatomical evidence suggests that this may involve both mono- and polysynaptic pathways. Accordingly, we used cross-correlation to examine IL and CL PhrMN synchrony after C2HS. Uninjured rats showed correlogram peaks consistent with synchronous activity and common synaptic input. Correlogram peaks were absent at 2 wks post-C2HS, but by 12 wks 50% of rats showed peaks occurring with a 1.1±0.19 ms lag from zero on the abscissa. These data are consistent with prolonged conduction time to IL (vs. CL) PhrMNs and the possibility of polysynaptic inputs to IL PhrMNs after chronic C2HS.
doi:10.1016/j.resp.2009.06.014
PMCID: PMC2783827  PMID: 19560562
spinal cord injury; breathing; phrenic; plasticity
4.  Replication of the association between variants in the WFS1 gene and risk of type 2 diabetes in European populations 
Diabetologia  2007;51(3):458-463.
Aims/hypothesis:
Mutations at the Wolframin encoding gene, WFS1, cause Wolfram syndrome, a rare neurological condition. Associations between single nucleotide polymorphisms (SNPs) at WFS1 and type 2 diabetes have recently been reported. In the present study, we sought to replicate those associations in a northern Swedish case-control study for type 2 diabetes. We also meta-analyzed published and previously unpublished data from Sweden, Finland and France to obtain updated summary effect estimates.
Methods:
Four WFS1 SNPs (rs10010131, rs6446482, rs752854, rs734312 [R611H]) were genotyped in a type 2 diabetes case-control study (N=1,296/1,412) of Swedish adults. Logistic regression was used to assess the association between each WFS1 SNP and type 2 diabetes, following adjustment for age, sex, and body mass index. We then performed a meta-analysis of 11 studies of type 2 diabetes, comprising up to 14,139 cases and 16,109 controls, to obtain a summary effect estimate for the WFS1 variants.
Results:
In the northern Swedish study, the minor allele at rs752854 was associated with reduced type 2 diabetes risk (OR=0.85; 95% CI=0.75-0.96; p=0.010). Borderline statistical associations were observed for the remaining SNPs. The meta-analysis of the four independent replication studies for SNP rs10010131, or its proxy variants, showed evidence for statistical association (OR=0.87; 95% CI=0.82-0.93; p=4.5×10−5). In an updated meta-analysis of all 11 studies, comprising 14,139 cases and 16,109 controls, strong evidence for statistical association was also observed (OR=0.89; 95% CI=0.86-0.92; p=4.9×10−11).
Conclusion:
In this study of WFS1 gene variants and type 2 diabetes risk, we have replicated the previously reported associations between SNPs at this locus and risk of type 2 diabetes.
doi:10.1007/s00125-007-0887-6
PMCID: PMC2670195  PMID: 18040659
Wolfram Syndrome; WFS1; Genetic; Replication; Type 2 diabetes; Association study; Swedish; Meta-analysis
5.  Modest spontaneous recovery of ventilation following chronic high cervical hemisection in rats 
Experimental neurology  2008;211(1):97-106.
Following C2 spinal hemisection (C2HS) in adult rats, ipsilateral phrenic motoneuron (PhMN) recovery occurs through a time-dependent activation of latent, crossed-spinal collaterals (i.e., spontaneous crossed phrenic phenomenon; sCPP) from contralateral bulbospinal axons. Ventilation is maintained during quiet breathing after C2HS, but the ability to increase ventilation during a respiratory stimulation (e.g. hypercapnia) is impaired. We hypothesized that long-term expression of the sCPP would correspond to a progressive normalization in ventilatory patterns during respiratory challenge. Breathing was assessed via plethsymography in unanesthetized animals and phrenic motor output was measured in urethane-anesthetized, paralyzed and vagotomized rats. At 2-week post-C2HS, minute ventilation (VE) was maintained during baseline (room air) conditions as expected but was substantially blunted during hypercapnic challenge (68±3% of VE in uninjured, weight-matched rats). However, by 12 weeks the spinal-lesioned rats achieved a hypercapnic VE response that was 85±7% of control (p = 0.017 vs. 2 wks). These rats also exhibited augmented breaths (AB's) or “sighs” more frequently (p<0.05) than controls; however, total AB volume was significantly less than control at 2- and 12-week post-injury (69±4% and 80±5%, p<0.05, respectively). We also noted that phrenic neurograms demonstrated a consistent delay in onset of the ipsilateral vs. contralateral inspiratory phrenic burst at 2-12-week post-injury. Finally, the ipsilateral phrenic response to respiratory challenge (hypoxia) was greater, though not normalized, at 4-12- vs. 2-week post-injury. We conclude that recovery of ventilation deficits occurs over 2-12-week post-C2HS; however, intrinsic neuroplasticity remains insufficient to concurrently restore a normal level of ipsilateral phrenic output.
doi:10.1016/j.expneurol.2008.01.013
PMCID: PMC2613014  PMID: 18308305
Plasticity; Crossed phrenic phenomenon; Phrenic; Motoneurons
6.  Ventilation and phrenic output following high cervical spinal hemisection in male vs. female rats 
Female sex hormones influence the neural control of breathing and may impact neurologic recovery from spinal cord injury. We hypothesized that respiratory recovery after C2 spinal hemisection (C2HS) differs between males and females and is blunted by prior ovariectomy (OVX) in females. Inspiratory tidal volume (VT), frequency (fR), and ventilation (VE) were quantified during quiet breathing (baseline) and 7% CO2 challenge before and after C2HS in unanesthetized adult rats via plethysmography. Baseline breathing was similarly altered in all rats (reduced VT, elevated fR) but during hypercapnia females had relatively higher VT (i.e. compared to pre-injury) than male or OVX rats (p < 0.05). Phrenic neurograms recorded in anesthetized rats indicated that normalized burst amplitude recorded ipsilateral to C2HS (i.e. the crossed phrenic phenomenon) is greater in females during respiratory challenge (p < 0.05 vs. male and OVX). We conclude that sex differences in recovery of VT and phrenic output are present at 2 weeks post-C2HS. These differences are consistent with the hypothesis that ovarian sex hormones influence respiratory recovery after cervical spinal cord injury.
doi:10.1016/j.resp.2008.06.005
PMCID: PMC2605649  PMID: 18586119
Plasticity; Spinal cord injury; Sex; Ovariectomy; Phrenic; Gender
7.  Somatotrophs and lactotrophs: an immunohistochemical study of Gallus domesticus pituitary gland at different stages of induced moult 
The objective of this study was to determine the distribution of somatotrophs and lactotrophs and conduct a morphometrical analysis of immunoreactive somatotrophs and lactotrophs in the pituitary glands of White Leghorn Hens (Gallus domesticus) during the period of induced moult. We divided the periods of induced moulting into three phases viz. 7, 14 and 21 days. The labeled alkalinephsphatase method with anti-GH (growth hormone) and anti-PRL (prolactin) as a primary antibody was used to detect somatotrophs and lactotrophs, in the midsagital sections of chicken adenohypophysis. Immunohistochemistry showed that somatotrophs are not only confined to the cephalo-caudal axis but can also be found in the caudal lobe; while lactotrophs were distributed in both lobes of the anterior pituitary gland at all stages of moulting (7, 14 and 21 days). Lactotrophs were of different shapes but somatotrophs were oval to round in morphology. At the given stages of induced moulting, some hypertrophied lactotrophs were also present after 7 days of induced moult in the anterior pituitary gland. However, there were moulting-related changes: from 7 to 21 days of induced moulting the immunoreactive-PRL cell population decreased, while the mean lactotroph size was more than that of somatotrophs. Basic quantitative and morphological information relating to somatotrophs and lactotrophs during the period of induced moult in laying hens is reported here and the changes brought about by induced moulting are restricted to PRL positive cells rather than GH positive cells.
doi:10.4081/ejh.2010.e25
PMCID: PMC3167303  PMID: 20558346
Moult; pituitary gland; somatotrophs; lactotrophs; chicken.
8.  Graded unilateral cervical spinal cord injury and respiratory motor recovery 
Respiratory physiology & neurobiology  2008;165(2-3):245-253.
We examined the potential contribution of ventromedial (VM) tissue sparing to respiratory recovery following chronic (1 mo) unilateral C2 spinal cord injury (SCI) in rats. Preserved white matter ipsilateral to the injury was quantitatively expressed relative to contralateral white matter. The ipsilateral-to-contralateral white matter ratio was 0 after complete C2 hemisection (C2HS) and 0.23±0.04 with minimal VM sparing. Inspiratory (breath•min−1) and phrenic frequency (burst•min−1), measured by plethysmography (conscious rats) and phrenic neurograms (anesthetized rats) respectively, were both lower with minimal VM sparing (p<0.05 vs. C2HS). Tidal volume also was greater in minimal VM sparing rats during a hypercapnic challenge (p<0.05 vs. C2HS). In other C2 hemilesioned rats with more extensive VM matter sparing (ipsilateral-to-contralateral white matter ratio = 0.55±0.05), respiratory deficits were indicated at 1 mo post-injury by reduced ventilation during hypercapnic challenge (p<0.05 vs. uninjured). Anterograde (ventral respiratory column-to-spinal cord) neuroanatomical tracing studies showed that descending respiratory projections from the brainstem are present in VM tissue. We conclude that even relatively minimal sparing of VM tissue after C2 hemilesion can alter respiratory outcomes. In addition, respiratory deficits can emerge in the adult rat after high cervical SCI even when relatively extensive VM sparing occurs.
doi:10.1016/j.resp.2008.12.010
PMCID: PMC2646795  PMID: 19150658
plasticity; spinal cord injury; crossed phrenic; breathing; respiratory
9.  The PARL Leu262Val is not associated with fasting insulin levels in UK populations 
Diabetologia  2006;49(11):2649-2652.
Aims/hypothesis:
PARL (encoding presenilins-associated rhomboid-like protein) maps to chromosome 3q27 within a quantitative trait locus (QTL) that influences components of the metabolic syndrome. Recently, an amino acid substitution (Leu262Val, rs3732581) in PARL was associated with fasting plasma insulin levels in a US white population (N = 1031). This variant was also found to modify the positive association between age and fasting insulin. The aim of this study was to test the replication of these findings in two UK population-based cohorts.
Methods:
Participants from the MRC Ely and Hertfordshire cohort studies were genotyped for this variant using a SNaPshot primer extension assay and Taqman assay respectively. Full phenotypic and genotypic data were available for 3666 study participants.
Results:
Based on a dominant model, we found no association between the Leu262Val polymorphism and fasting insulin levels (p=0.79) or BMI (p=0.98). Nor did we observe the previously reported interaction between age and genotype on fasting insulin (p=0.14).
Conclusions/interpretation:
Despite having greater statistical power, our data do not support the previously reported association between PARL Leu262Val and fasting plasma insulin levels, a measure of insulin resistance. Our findings indicate that this variant is unlikely to importantly contribute to insulin resistance in UK populations.
doi:10.1007/s00125-006-0443-9
PMCID: PMC2672784  PMID: 17019603
association study; fasting insulin; insulin resistance; polymorphism; PARL
10.  Testing of diabetes-associated WFS1 polymorphisms in the Diabetes Prevention Program 
Diabetologia  2007;51(3):451-457.
Aims/hypothesis
Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is caused by mutations in the WFS1 gene. Recently, single nucleotide polymorphisms (SNPs) in WFS1 have been reproducibly associated with type 2 diabetes. We therefore examined the effects of these variants on diabetes incidence and response to interventions in the Diabetes Prevention Program (DPP), in which a lifestyle intervention or metformin treatment was compared with placebo.
Methods
We genotyped the WFS1 SNPs rs10010131, rs752 854 and rs734312 (H611R) in 3,548 DPP participants and performed Cox regression analysis using genotype, intervention and their interactions as predictors of diabetes incidence. We also evaluated the effect of these SNPs on insulin resistance and beta cell function at 1 year.
Results
Although none of the three SNPs was associated with diabetes incidence in the overall cohort, white homozygotes for the previously reported protective alleles appeared less likely to develop diabetes in the lifestyle arm. Examination of the publicly available Diabetes Genetics Initiative genome-wide association dataset revealed that rs10012946, which is in strong linkage disequilibrium with the three WFS1 SNPs (r2=0.88–1.0), was associated with type 2 diabetes (allelic odds ratio 0.85, 95% CI 0.75–0.97, p=0.026). In the DPP, we noted a trend towards increased insulin secretion in carriers of the protective variants, although for most SNPs this was seen as compensatory for the diminished insulin sensitivity.
Conclusions/interpretation
The previously reported protective effect of select WFS1 alleles may be magnified by a lifestyle intervention. These variants appear to confer an improvement in beta cell function.
doi:10.1007/s00125-007-0891-x
PMCID: PMC2483955  PMID: 18060660
Beta cell function; Diabetes prevention; Genetic association study; Single nucleotide polymorphism; Type 2 diabetes; Wolfram syndrome
11.  Diabetes mellitus, family history, and colorectal cancer 
doi:10.1136/jech.56.6.479
PMCID: PMC1732183  PMID: 12011210

Results 1-12 (12)