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S A Hawkins

Publications and source records attributed to S A Hawkins.

At least 19 recordsLinked to original sources
PubMed2006

Mapping candidate non-MHC susceptibility regions to multiple sclerosis.

Understanding the genetic basis of multiple sclerosis (MS) remains a major challenge, despite decades of intensive research. In order to identify candidate non-MHC susceptibility regions to MS, the results of whole genome screens for linkage or association and follow-up studies in 18 different populations were superimposed together in a combined genomic map. Analysis of this map led to the prediction of at least 38 potential susceptibility regions, each showing linkage and/or association in several populations. Among these, 17 regions were the most reproducibly reported in these studies, thus representing top predicted candidates for MS. This non-formal approach to meta-analysis demonstrated the ability to verify results and retrieve lost information in an association study. Assessment of the map in a Northern Irish refined screen (n=415 cases, n=490 controls) revealed association in 15 regions (P<0.05), including 10 promising candidates on chromosomes 1p13, 2p13, 2q14, 3p23, 7q21, 13q14, 15q13, 17p13, 18q21 and 20p12 (P<0.0025). Seven of these regions were previously overlooked in the Northern Irish whole genome association study. Collating results from numerous studies, this draft map represents a tool that should facilitate the analysis of the genetic backgrounds of MS in many populations.

Adult↗
PubMed2005

IFNG polymorphisms are associated with gender differences in susceptibility to multiple sclerosis.

Interferon-gamma (IFNgamma) treatment is deleterious in multiple sclerosis (MS). MS occurs twice as frequently in women as in men. IFNgamma expression varies by gender. We studied a population-based sample of US MS patients and ethnicity-matched controls and independent Northern Irish and Belgian hospital-based patients and controls for association with MS, stratified by gender, of an intron 1 microsatellite [I1(761)*CAn], a single nucleotide polymorphism 3' of IFNG [3'(325)*G --> A] and three flanking microsatellite markers spanning a 118 kb region around IFNG. Men carriers of the 3'(325)*A allele have increased susceptibility to MS compared to noncarriers in the USA (P=0.044; OR: 2.58, 95% CI: 0.97-8.08) and Northern Ireland (P=0.019; OR: 2.37, 95% CI: 1.10-5.13). There is a nonsignificant trend in the same direction in Belgian men (P=0.299; OR: 1.50, 95% CI: 0.71-3.26). Men carriers of I1(761)*CA13, which is in strong linkage disequilibrium with the 3'(325)*A, have increased susceptibility (P=0.050; OR: 2.22, 95% CI: 0.98-5.40), while men carriers of I1(761)*CA12 have decreased susceptibility (P=0.022; OR: 0.46, 95% CI: 0.23-0.90) to MS in the USA. Similar associations were reported in Sardinia between the I1(761)*CA12 allele and reduced risk of MS in men. Flanking markers were not associated with MS susceptibility. Polymorphisms of IFNG may contribute to differences in susceptibility to MS between men and women.

3' Flanking Region↗
PubMed2004

Latitudinal variation in the prevalence of multiple sclerosis in Ireland, an effect of genetic diversity.

BACKGROUND: Northern Ireland has a high and rising prevalence rate of multiple sclerosis (MS). The most recent survey in 1996 found a rate of 168.7/100 000. Recorded prevalence rates for the south of Ireland, including County Wexford, have been markedly lower and seemed to suggest the existence of a prevalence gradient within the island. OBJECTIVES: To compare the prevalence of multiple sclerosis in Co. Wexford in the south east of Ireland and Co. Donegal in the north west, and to establish whether a variation in prevalence of MS exists within Ireland. METHODS: Patients were referred from multiple sources. Review of clinical case records and/or patient examination confirmed the diagnosis. RESULTS: In Co. Wexford, 126 patients were found to have clinically definite or probable multiple sclerosis with a prevalence rate of 120.7/100 000 (95% confidence intervals (CI) 100.6 to 143.8), which is similar to other areas of similar latitude within the British Isles. In Co. Donegal, 240 people had clinically definite or probable MS with a prevalence rate of 184.6/100 000 (95% CI 162.0 to 209.5). The difference in prevalence rates is statistically significant (Z = 3.94, p = <0.001). CONCLUSION: There is a latitudinal variation in the prevalence rate of MS between the north and the south of Ireland. The increased prevalence of MS seen in Co. Wexford is likely to represent better case ascertainment and improved diagnostic accuracy rather than an actual increase in prevalence. The north/south variation in prevalence may represent a variation in the genetic predisposition to MS between the background populations of the two counties.

Adolescent↗
PubMed2004

Influence of CCR5 delta32 polymorphism on multiple sclerosis susceptibility and disease course.

The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). We carried out an allelic association study using a deletion polymorphism in the coding region of the CCR5 gene in 331 relapsing-remitting (RR) and secondary progressive (SP) MS patients, 108 primary progressive (PP) MS patients and 230 healthy controls. Of the 331 RR and SPMS patients, 172 were recruited from specialist clinics and 159 from a population survey. Disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS) and used to calculate a progression index for each patient (defined as EDSS divided by duration of disease). No significant difference in distribution of the CCR5 delta32 allele was observed between the 331 RR/SPMS patients and controls, between the 108 PPMS patients and controls or between the PPMS and RR/SPMS groups. Furthermore, no differences in rate of disease progression were detected between carriers and noncarriers of the delta32 allele. In the population-based group of RR/SPMS patients, carriage of the CCR5 delta32 polymorphism was associated with a lower age at disease onset (mean age 26.562 versus 31.065 years, P = 0.003). However, no significant differences in age of onset were present in the PPMS group or in a second RRMS population. These results suggest that the CCR5 delta32 polymorphism is not a major determinant of susceptibility to develop MS in the population under study, and conflict with a previously reported association between CCR5 delta32 carriage and a better prognosis.

Adult↗
PubMed2002

Expression of the bilateral deficit during reflexively evoked contractions.

During maximal contractions, the sum of forces exerted by homonymous muscles unilaterally is typically larger than the sum of forces exerted by the same muscles bilaterally. This phenomenon is known as the bilateral deficit (BLD), and it is suggested that this deficit is due to neural inhibition. It remains unclear, however, whether such inhibition is mediated by supraspinal mechanisms or by reflex pathways at the level of spinal cord. To further study the origin of likely neural influences, we tested for the presence of BLD under the condition of reflexive force generation. Force output and integrated electromyogram (iEMG) (quadriceps femoris) were measured in 17 male participants after initiation of the myotatic patellar reflex under unilateral and bilateral conditions. A significant BLD of 9.26 +/- 1.19 (P = 0.004) and 16.76 +/- 4.69% (P = 0.001) was found for force and iEMG, respectively. However, because similar findings were not evident during maximal isometric knee extensions, it is difficult to predict the contribution of a spinal mechanism to the BLD under the condition of maximal voluntary activation.

Adult↗
PubMed2002

Primary progressive multiple sclerosis: increasing clarity but many unanswered questions.

Heterogeneity in the clinical course of multiple sclerosis (MS) is well recognised and patients following a primary progressive course, 10-15% of the MS population, have a distinct clinical and paraclinical phenotype. This review examines recent advances in our understanding of this subgroup of patients and examines the new criteria to be applied in diagnosis. It also highlights developments in genetic, immunological, magnetic resonance and pathological aspects of the disease, whilst also outlining the results of recent therapeutic trials.

Controlled Clinical Trials as Topic↗
PubMed2001

Rapid test for the preclinical postmortem diagnosis of BSE in central nervous system tissue.

The efficacy of a rapid test for detecting PrP(Sc) in central nervous system tissue was evaluated for the postmortem diagnosis of BSE at different times during the course of the disease. One hundred and six samples of brain, at the level of the medulla oblongata, and spinal cord, derived from the experimental study of the pathogenesis of BSE carried out in Great Britain between 1991 and 1995, were examined. PrP(Sc) was detected in the samples from most of the exposed animals killed 32 months or more after they had been exposed to the agent, and before the onset of clinical signs which were first recorded at 35 months. Comparisons with the results of histology, fibril detection, PrP immunohistochemistry and mouse bioassay indicated that the rapid test is at least as sensitive as these conventional confirmatory diagnostic methods and its result can be obtained more quickly.

Animals↗
PubMed2001

Serum and cerebrospinal fluid soluble Fas levels in clinical subgroups of multiple sclerosis.

Elevated sFas levels have been described in multiple sclerosis (MS) patients with active disease. The aim of this study was to assess the diagnostic potential of serum and cerebrospinal fluid (CSF) sFas measurements in differentiating clinically defined MS patient subgroups. Levels of sFas and sFas indices were determined in patients with stable relapsing-remitting MS (RRMS), active RRMS, primary progressive MS (PPMS), secondary progressive MS (SPMS) and patients with inflammatory (IND) and noninflammatory neurological diseases (NIND). Serum sFas modulation over 32 weeks IFN-beta1a therapy was also investigated. Serum and CSF sFas levels and sFas indices were elevated in MS compared to NIND and IND patients. Within the MS group, serum and CSF sFas levels were highest in PPMS, with active RRMS patients demonstrating the highest sFas indices. This may reflect an ongoing disease process which is occurring acutely (active disease) or incessantly (progressive disease). IFN-beta1a induced a transient increase in circulating sFas following initiation of therapy. Whilst evidence was provided for variable sFas expression in clinical subgroups of MS, there was insufficient definition between the respective groups to advocate sFas measurements as a diagnostic marker of clinical subgroups of MS.

Adolescent↗
PubMed2001

Interferon-beta1a administration results in a transient increase of serum amyloid A protein and C-reactive protein: comparison with other markers of inflammation.

Putative markers of inflammation such as serum beta2-microglobulin and neopterin have been shown to be transiently upregulated following interferon-beta (IFN-beta) administration to multiple sclerosis (MS) patients. However, to date the role of the important inflammatory mediators serum amyloid A protein (SAA) and C-reactive protein (CRP) have not been described. Here we show that SAA but not CRP is elevated in relapsing-remitting MS patients compared to normal healthy individuals, and furthermore that both are transiently upregulated following intramuscular injection with IFN-beta1a (Avonex). This pattern of expression was found to parallel that of beta2-microglobulin and neopterin following injection and was mirrored by a selective activation of peripheral monocytes with respect to upregulation of receptors known to be involved in the inflammatory response (HLA-DR, CD16 and CD86). Injection of saline solution intramuscularly to six healthy control individuals did not produce a similar upregulation of any of the inflammatory markers investigated. Following IFN-beta1a injection, all inflammatory responses were attenuated at week 12 of therapy in comparison to those following the initial injection in a group of follow-up patients. In addition, IFN-beta1a injected on a weekly basis did not produce a sustained modulation of any of the markers investigated in patients treated for 32 weeks.

Adult↗
PubMed2001

Traumatic Brown-Séquard-plus syndrome.

BACKGROUND: In the 1840s Brown-Séquard described the motor and sensory effects of sectioning half of the spinal cord. Penetrating injuries can cause Brown-Séquard or, more frequently, Brown-Séquard-plus syndromes. OBJECTIVE: To report the case of a 25-year-old man who developed left-sided Brown-Séquard syndrome at the C8 level and left-sided Horner syndrome plus urinary retention and bilateral extensor responses following a stab wound in the right side of the neck. RESULTS: Magnetic resonance imaging demonstrated a low cervical lesion and somatosensory evoked potentials confirmed the clinical finding of left-side dorsal column disturbance. At follow-up, the patient's mobility and bladder function had returned to normal. CONCLUSION: This patient recovered well after a penetrating neck injury that disturbed function in more than half the lower cervical spinal cord (Brown-Séquard-plus syndrome).

Adult↗
PubMed2001

Influence of weight training exercise and modification of hormonal response on skeletal muscle growth.

To investigate the influence of carbohydrate (CHO) consumption on the acute hormonal response, and chronic adaptation to weight lifting exercise, two studies were conducted. Following a four-hour fast, seven young men (21.3 +/- 3.5 y) performed (on two occasions) a nine-station weight lifting protocol, completing 3 sets of 10 repetitions at 75% of 1RM (series 1). Randomly assigned, one session included the ingestion of a non-caloric placebo, and the other, a 6% CHO solution. For series 2, two groups of young men (21.3 +/- 1.5 y) participated in 12 weeks of progressive resistance weight training. Training for one group included the ingestion of a non-caloric placebo, and the other, a 6% CHO solution. In series 1, weight lifting exercise with CHO ingestion significantly (p < 0.05) elevated blood glucose and plasma insulin levels above baseline, as well as that occurring with the placebo. This resulted in a significant blunting of the cortisol response (7% with CHO compared to 99% with placebo). These findings indicate that CHO consumption during weight lifting exercise can modify the acute hormonal response to exercise. With series 2, CHO consumption continued to blunt the cortisol response to exercise during the twelve weeks of training. This is in contrast to significantly elevated cortisol levels observed for the placebo control group. Corresponding with the modified response patterns were differences in muscle growth. Weight training exercise with CHO ingestion resulted in significantly greater gains in both type I (19.1%) and type II (22.5%) muscle fibre area than weight training exercise alone. The difference in the cortisol response accounted for 74% of the variance (r = 0.8579, p = 0.006) of change in type I muscle fibre area, and 52.3% of the variance (r = 0.7231, p = 0.043) of change in type II muscle fibre area. These findings suggest that the modification of the cortisol response associated with CHO ingestion can positively impact the skeletal muscle hypertrophic adaptation to weigh training.

Adaptation, Physiological↗
PubMed2001

Monocyte-derived dendritic cells: a potential target for therapy in multiple sclerosis (MS).

Monocytes can differentiate into dendritic cells (DC), cells with a pivotal role in both protective immunity and tolerance. Defects in the maturation or function of DC may be important in the development of autoimmune disease. We sought to establish if there were differences in the cytokine (granulocyte-macrophage colony-stimulating factor and IL-4)-driven maturation of monocytes to DC in patients with MS and whether drugs used to treat MS affected this process in vitro. We have demonstrated that there is no defect in the ability of magnetic activated cell sorting (MACS)-purified monocytes from patients with MS to differentiate to DC, but equally they show no tendency to acquire a DC phenotype without exogenous cytokines. Interferon-beta1a prevents the acquisition of a full DC phenotype as determined by light and electron microscopy and by flow cytometry. Methylprednisolone not only prevents the development of monocyte-derived DC but totally redirects monocyte differentiation towards a macrophage phenotype. Evidence is evolving for a role for DC in central nervous system immunity, either within the brain or in cervical lymph nodes. The demonstrated effect of both drugs on monocyte differentiation may represent an important site for immune therapy in MS.

Adult↗
PubMed2001

Oral inoculation of sheep with the agent of bovine spongiform encephalopathy (BSE). 1. Onset and distribution of disease-specific PrP accumulation in brain and viscera.

Sixty-three Romney sheep aged 6 months, consisting of three groups (PrP(ARQ/ARQ), PrP(ARQ/ARR), and PrP(ARR/ARR)genotypes) of 21 animals, were infected orally with brain tissue from BSE-infected cattle. Sub-groups of the 21 PrP(ARQ/ARQ) animals were killed, together with uninfected controls 4, 10, 16, 22 or 24-28 (after the development of full clinical disease) months post-inoculation (mpi). One sheep from each of the two groups of four killed at 4 or 10 mpi were shown by immunohistochemical examination to possess disease-specific PrP accumulations in single lymph nodes. At 16 mpi, such accumulations were detected in two of four infected sheep in some viscera and in the spinal cord and brain. At 22 mpi, three of five infected sheep had widespread disease-specific PrP accumulations in all tissues examined, but the remaining two animals gave positive results only in the central nervous system. Clinical disease appeared at 20-28 mpi. Three sheep killed with advanced clinical signs showed widespread PrP accumulation in brain, spinal cord and peripheral tissues. These results confirmed that PrP(ARQ/ARQ) Romney sheep are susceptible to experimental infection with the BSE agent. The different sites at which initial PrP accumulations were detected suggested that the point of entry of infection varied. Once established, however, infection appeared to spread rapidly throughout the lymphoreticular system. The results suggested that in some BSE-infected sheep neuroinvasion occurred in the absence of detectable PrP accumulations in the viscera or peripheral nervous system. In contrast to cattle with BSE, however, most sheep showed disease-specific PrP accumulations in the lymphoreticular system. In this respect, BSE-infected resembled scrapie-infected sheep; it is possible, however, that future research will reveal differences in respect of targeting of cell types within the lymphoreticular and peripheral nervous systems. The PrP(ARQ/ARR)and PrP(ARR/ARR)sheep were also killed in sub-groups at intervals after inoculation. Up to 24 mpi, however, none of these animals showed disease-specific PrP accumulations. Further results will be reported later.

Administration, Oral↗
PubMed2001

Relationship between physiological loss, performance decrement, and age in master athletes.

BACKGROUND: The use of master athletes to describe an idealized rate of physiological loss associated with aging is quite common. The results of such studies suggest that older athletes may be able to reduce the rate of decline in functional loss. The findings of such studies have been questioned due to their limited sample size and the age range and gender of their subjects. METHODS: We examined a group of 146 male and 82 female master athletes over the age of 40 years. Physiological parameters included maximal oxygen uptake (VO2max), body composition, muscle strength, bone density, and blood chemistries. Medical histories and training records were obtained via questionnaire. RESULTS: Results demonstrated gender differences in body composition, blood chemistries, blood pressure, VO2max, muscle strength, bone density, and performance (p <.05). All metabolic parameters for men and most for women demonstrated significant losses across the age range (p <.05). In addition, strength and performance for men and women and bone density for women declined significantly with age (p <.05). The demonstrated loss rates did not differ by gender. CONCLUSIONS: Although limited by the lack of a sedentary comparison group, these data suggest that age-related losses in VO2max may not be different from data previously reported for older sedentary adults and that loss in muscle strength and performance with aging is not linear.

Absorptiometry, Photon↗
PubMed2001

A longitudinal assessment of change in VO2max and maximal heart rate in master athletes.

PURPOSE: The purpose of this study was to determine the longitudinal change in VO2max and HRmax in male and female master endurance runners and to compare these changes based upon gender, age, and change in training volume. METHODS: Eighty-six male (53.9 +/- 1.1 yr) and 49 female (49.1 +/- 1.2 yr) master endurance runners were tested an average of 8.5 yr apart. Subjects were grouped by age at first visit, change in VO2max, and change in training volume. Measurements included body composition by hydrostatic weighing, maximal exercise testing on a treadmill, and training history by questionnaire. Data were analyzed by ANOVA and multiple regression. RESULTS: VO2max and HRmax declined significantly regardless of gender or age group (P < 0.05). The rate of change in VO2max by age group ranged from -1% to -4.6% per year for men and -0.5% to 2.4% per year for women. Men with the greatest loss in VO2max had the greatest loss in LBM (-2.8 +/- 0.7 kg), whereas women with the greatest loss in VO2max demonstrated the greatest change in training volume (-24.1 +/- 3.0 km.wk-1). Additionally, women with the greatest loss in VO2max (-9.6 +/- 2.6 mL.kg-1.min-1) did not replace estrogen after menopause independent of age. HRmax change did not differ by VO2max change or training volume change in either gender. CONCLUSIONS: In conclusion, these data suggest that VO2max declines in male and female master athletes at a rate similar to or greater than that expected in sedentary older adults. Additionally, these data suggest that maintenance of LBM and VO2max were associated in men, whereas in women, estrogen replacement and maintenance of training volume were associated with maintained VO2max.

Age Factors↗
PubMed2001

An assessment of the spectrum of disability and handicap in multiple sclerosis: a population-based study.

OBJECTIVES: To establish the spectrum of disability and handicap in a population based sample of multiple sclerosis (MS) patients. BACKGROUND: Much knowledge exists about the epidemiology of MS but, despite its importance for health and social service planning, there remains relatively little data on the extent and nature of disability and handicap in this population. METHODS: In a prevalence study in the north-east of N. Ireland, 288 patients (Poser criteria) were identified. Disability and handicap were assessed using the Incapacity Status Scale and Environmental Status Scale of the Minimal Record of Disability for MS. RESULTS: Both scales were completed for 248 (86%) of patients. Just 71 (29%) are fully independent in all basic ADL's of bathing, dressing, grooming and feeding. Fifty-seven (23%) are unable to climb a flight of stairs and 102 (42%) acknowledge problems with sexual function. Sixty-one (25%) were working essentially full-time and 53 (21%) had no external financial support. Forty-five (18%) had changed residence due to MS, 12 (5%) were institutionalised and 86 (35%) required assistance for at least 1 h/day with ADL's. Eighty-one (33%) were unable to drive a car or use public transport. Forty-two (17%) access community services for at least 1 h/day on average. CONCLUSIONS: This data gives a clear indication of the considerable range of basic health and social issues in a typical MS community. Further work is required to establish patient perceptions of the adequacy of care provision and whether standards of care for MS patients are being met.

Activities of Daily Living↗
PubMed2000

An evaluation of interleukin genes fails to identify clear susceptibility loci for multiple sclerosis.

Differential expression of interleukins may influence susceptibility to inflammatory diseases such as MS. IL-1a production is increased in MS patients during acute relapse, IL-2 receptor (IL-2R) secretion correlates with disease activity in several inflammatory disorders and is variable in MS. Both IL-4 and IL-10 expression vary significantly with relapse/remission in MS and IL-9 is postulated to inhibit steroid-induced apoptosis. To examine the influence of interleukin (IL) genes on MS susceptibility and clinical course, gene association studies using separate polymorphic microsatellite markers for il-1 alpha, il-2, il-2r beta, il-4 il-9 and il-10 were performed, incorporating 150-177 relapsing-remitting or secondary progressive MS (RR/SPMS) patients, 100-110 primary progressive (PPMS) patients and 152-210 controls. No significant differences existed in allele frequencies between either MS group and controls for any of the interleukin microsatellite markers studied, nor were statistically significant differences observed in PPMS vs. RR/SPMS for any marker. These data indicate that the IL-1 alpha, IL-2, IL-2R beta, IL-4, IL-9 and IL-10 genes are unlikely to be susceptibility loci for MS in this population.

Alleles↗