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1.
JPRAS Open ; 39: 127-131, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38235265

ABSTRACT

There has been a growing body of evidence indicative of the effectiveness of headache surgery in treating patients with refractory headache disorders. The American Society of Plastic Surgeons issued a Policy Statement in 2018 stating that peripheral nerve decompression surgery for the treatment of refractory chronic headache disorders in select patients is considered a standard of care treatment. This endorsement sparked the interest of numerous plastic surgeons into initiating their own headache surgery practices. However, establishing a headache surgery clinic introduces challenges and considerations. This report outlines the key pillars for launching a successful headache surgery practice in academic and private practice environments.

2.
J West Afr Coll Surg ; 8(3): 45-58, 2018.
Article in English | MEDLINE | ID: mdl-32754456

ABSTRACT

BACKGROUND: Limb amputation is reported to be a major but preventable public health problem that is associated with profound economic, social and psychological effects on the patient and family especially in developing countries where prosthetic services are unavailable, inaccessible or unaffordable. AIM: The purpose of this study was to determine the patterns of and indications for limb amputations. METHODOLOGY: A retrospective study, covering a 4-year period, involving 126 patients who underwent amputation at a teaching hospital was carried out. Data on patients including indication for amputation were obtained from theatre record books and folders and analyzed using SPSS and MS Excel. Data was presented in frequencies and percentages. Chi square tests were used to compare categorical variables and differences were considered significant if p<0.05. RESULTS: The mean age of the 126 patients was 60.92(SD19.03) years with a median of 67years. There were 68 females and 58 males giving a female to male ratio of 1.2:1. Lower limb amputations were performed in 114(90.48%) and upper limb amputations in 12(9.52%) patients. The commonest indication for amputation was diabetic foot gangrene accounting for 54(42.86%) patients, followed by peripheral vascular disease 43(34.13%) and trauma 12(9.52%). Twenty-one of the patients who had amputations for indications other than diabetic foot gangrene also had diabetes mellitus. Below knee amputation was the commonest procedure performed (43.65%). One hundred and twenty (95.2%) were unilateral and 116 (92.1% ) were performed in a single-stage procedure. CONCLUSION: Most of the amputations in the Cape Coast Teaching Hospital were performed in elderly patients, with a slight preponderance of women over men. Lower limb amputations were far more common than upper limb ones. The commonest indication for amputations was diabetic foot gangrene, with below knee amputation being the commonest type. There is an urgent need for public education on diabetes and its complications and on diabetic foot care. The establishment of a multidisciplinary diabetic foot care clinic is advocated if the incidence of limb amputations is to be reduced in the Cape Coast Teaching Hospital.

3.
Transfus Med ; 27 Suppl 5: 369-374, 2017 Oct.
Article in English | MEDLINE | ID: mdl-28393455

ABSTRACT

BACKGROUND: HLAMatchmaker has been used in the Irish Blood Transfusion Service (IBTS) to select platelets for HLA-alloimmunised, platelet refractory thrombocytopaenic patients since 2006. Although available since 2002, only three studies have been published supporting the programme's effectiveness for this indication. OBJECTIVES: We sought to examine increments to HLA-matched platelets (HMPs) at various matchmaker scores and to examine the impact of transfusing older platelets and ABO-mismatched platelets to this patient group. METHODS/MATERIALS: A total of 20 consecutive HLA-alloimmunised thrombocytopaenic patients were retrospectively studied. Data collected included: pre- and post-transfusion platelet count, indication for transfusion, HLAMatchmaker score, age of unit and degree of ABO mismatch. Data were also collected on the last 3 U of (RDPs). The Mann-Whitney U-test was used to compare increments between transfusion episodes of random donor platelets (RDPs) vs HMPs with matchmaker scores <3, 4-7 or >8. RESULTS: Increments at <2 h were available for 63 transfusion episodes. Increments at 2-24 h were available for 93 transfusion episodes. Increments were higher when transfusing HMPs than when transfusing RDPs. Increments for HMPs that were ABO mismatched were no different than for ABO-identical units, with the exception of late increments post-transfusing HMPs with a major ABO mismatch. Age of platelets did not influence increments. CONCLUSION: The use of HLAMatchmaker to select platelet units for thrombocytopaenic HLA-alloimmunised patients produced satisfactory platelet increments. When providing HLAMatchmaker-selected HMPs, ABO mismatch and the use of platelet units that are up to 7 days old should be permissible.


Subject(s)
Blood Donors , Blood Platelets/immunology , Histocompatibility Testing , Platelet Transfusion , Thrombocytopenia , ABO Blood-Group System/immunology , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Platelet Transfusion/adverse effects , Platelet Transfusion/methods , Retrospective Studies , Thrombocytopenia/etiology , Thrombocytopenia/immunology , Thrombocytopenia/therapy
4.
Sci Rep ; 7: 39662, 2017 01 03.
Article in English | MEDLINE | ID: mdl-28045073

ABSTRACT

Pain places a devastating burden on patients and society and current pain therapeutics exhibit limitations in efficacy, unwanted side effects and the potential for drug abuse and diversion. Although genetic evidence has clearly demonstrated that the voltage-gated sodium channel, Nav1.7, is critical to pain sensation in mammals, pharmacological inhibitors of Nav1.7 have not yet fully recapitulated the dramatic analgesia observed in Nav1.7-null subjects. Using the tarantula venom-peptide ProTX-II as a scaffold, we engineered a library of over 1500 venom-derived peptides and identified JNJ63955918 as a potent, highly selective, closed-state Nav1.7 blocking peptide. Here we show that JNJ63955918 induces a pharmacological insensitivity to pain that closely recapitulates key features of the Nav1.7-null phenotype seen in mice and humans. Our findings demonstrate that a high degree of selectivity, coupled with a closed-state dependent mechanism of action is required for strong efficacy and indicate that peptides such as JNJ63955918 and other suitably optimized Nav1.7 inhibitors may represent viable non-opioid alternatives for the pharmacological treatment of severe pain.


Subject(s)
NAV1.7 Voltage-Gated Sodium Channel/metabolism , Pain/metabolism , Spider Venoms/pharmacology , Voltage-Gated Sodium Channel Blockers/pharmacology , Animals , Cell Line , Ganglia, Spinal/drug effects , Ganglia, Spinal/metabolism , Humans , Male , Pain/prevention & control , Rats, Sprague-Dawley , Spider Venoms/chemistry , Voltage-Gated Sodium Channel Blockers/chemistry
5.
Acta Crystallogr D Biol Crystallogr ; 71(Pt 3): 615-31, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25760610

ABSTRACT

The protein calexcitin was originally identified in molluscan photoreceptor neurons as a 20 kDa molecule which was up-regulated and phosphorylated following a Pavlovian conditioning protocol. Subsequent studies showed that calexcitin regulates the voltage-dependent potassium channel and the calcium-dependent potassium channel as well as causing the release of calcium ions from the endoplasmic reticulum (ER) by binding to the ryanodine receptor. A crystal structure of calexcitin from the squid Loligo pealei showed that the fold is similar to that of another signalling protein, calmodulin, the N- and C-terminal domains of which are known to separate upon calcium binding, allowing interactions with the target protein. Phosphorylation of calexcitin causes it to translocate to the cell membrane, where its effects on membrane excitability are exerted and, accordingly, L. pealei calexcitin contains two protein kinase C phosphorylation sites (Thr61 and Thr188). Thr-to-Asp mutations which mimic phosphorylation of the protein were introduced and crystal structures of the corresponding single and double mutants were determined, which suggest that the C-terminal phosphorylation site (Thr188) exerts the greatest effects on the protein structure. Extensive NMR studies were also conducted, which demonstrate that the wild-type protein predominantly adopts a more open conformation in solution than the crystallographic studies have indicated and, accordingly, normal-mode dynamic simulations suggest that it has considerably greater capacity for flexible motion than the X-ray studies had suggested. Like calmodulin, calexcitin consists of four EF-hand motifs, although only the first three EF-hands of calexcitin are involved in binding calcium ions; the C-terminal EF-hand lacks the appropriate amino acids. Hence, calexcitin possesses two functional EF-hands in close proximity in its N-terminal domain and one functional calcium site in its C-terminal domain. There is evidence that the protein has two markedly different affinities for calcium ions, the weaker of which is most likely to be associated with binding of calcium ions to the protein during neuronal excitation. In the current study, site-directed mutagenesis has been used to abolish each of the three calcium-binding sites of calexcitin, and these experiments suggest that it is the single calcium-binding site in the C-terminal domain of the protein which is likely to have a sensory role in the neuron.


Subject(s)
Calcium-Binding Proteins/chemistry , Decapodiformes/chemistry , Molecular Dynamics Simulation , Nerve Tissue Proteins/chemistry , Amino Acid Substitution , Animals , Calcium-Binding Proteins/genetics , Calcium-Binding Proteins/metabolism , Crystallography, X-Ray , Decapodiformes/genetics , Decapodiformes/metabolism , Mutation, Missense , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Protein Structure, Tertiary , Structure-Activity Relationship
6.
Eye (Lond) ; 28(9): 1136-42, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24993321

ABSTRACT

PURPOSE: To demonstrate the use of the multifocal electroretinogram (mfERG) in addition to the full-field electroretinogram (ERG) in defining varying clinical pictures in children within a family with Bardet-Biedl syndrome (BBS). METHODS: All members from a family generation underwent a detailed history and examination before proceeding to a detailed ERG in accordance with the International Society of Clinical Electrophysiology for Vision protocol and a rapid, low-resolution mfERG. Of the sibling pair, the 13-year-old boy showed reduced vision and atypical maculopathy and the 10-year-old sister showed normal vision and atrophic maculopathy. Parents had normal ocular examination. RESULTS: The male sibling had reduced rod and cone full-field ERG responses with a relatively spared central response from the mfERG suggesting central macular sparing. In contrast, for the female sibling, the ERG was normal for the cone pathway although reduced for rod pathway, with mfERG showing central involvement. The mother had rod responses at the lower end of normal range, a normal cone pathway, and a normal mfERG. The father showed a normal ERG and mfERG. CONCLUSION: The mfERG is a useful adjunct to full-field ERG in the paediatric population and in family studies.


Subject(s)
Bardet-Biedl Syndrome/diagnosis , Electroretinography , Photoreceptor Cells, Vertebrate/physiology , Retinal Dystrophies/diagnosis , Adolescent , Bardet-Biedl Syndrome/genetics , Bardet-Biedl Syndrome/physiopathology , Child , DNA Mutational Analysis , Female , Humans , Male , Microtubule-Associated Proteins/genetics , Mutation , Pedigree , Photic Stimulation , Retinal Dystrophies/genetics , Retinal Dystrophies/physiopathology , Siblings , Visual Acuity
7.
Clin Exp Dermatol ; 39(4): 519-24, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24758522

ABSTRACT

BACKGROUND: Anti-tumour necrosis factor (TNF)-α therapies have revolutionized the treatment of psoriasis; however, up to 50% of patients do not respond satisfactorily. Identification of pharmacogenetic markers of treatment response is an important stop in the development of individually tailored treatment. The objective of this study was to assess the association of human leucocyte antigen (HLA)-C, killer immunoglobulin receptor (KIR) and vitamin D receptor (VDR) genotypes with response to treatment by etanercept and adalimumab. METHODS: This was a study of 138 patients with severe chronic plaque psoriasis who were treated with etanercept and/or adalimumab. Patients were classified as responders if they achieved a 75% reduction in PASI (PASI75) or were almost clear of psoriasis after 24 weeks of therapy. The frequencies of HLA-C and KIR haplotypes and VDR polymorphisms were compared in responders and nonresponders. The frequency of all HLA-C and KIR genotypes were compared between the 138 patients with psoriasis and 247 healthy donors. RESULTS: The number of patients classified as responders was 46 of 94 (49%) in the etanercept group and 50 of 76 (66%) in the adalimumab group. None of the HLA-C, KIR or VDR genotypes examined was predictive of treatment response. Compared with healthy controls, patients with psoriasis were more likely to have the HLA-C*06 genotype (P < 0.001) and less likely to have the HLA-C*07 genotype (P < 0.001), whereas there was no significant difference in frequencies of any KIR subtype. CONCLUSIONS: Using the candidate gene approach to identify biomarkers of treatment response in psoriasis may have limited utility. This was a small study with limited power. Future larger studies are needed to further examine these findings and to explore alternative approaches to identify predictors of treatment response to biological agents.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Immunoglobulin G/therapeutic use , Immunosuppressive Agents/therapeutic use , Psoriasis/drug therapy , Receptors, Tumor Necrosis Factor/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adalimumab , Adult , Chronic Disease , Etanercept , Female , Genetic Markers , Genotype , HLA-C Antigens/genetics , Humans , Male , Middle Aged , Predictive Value of Tests , Psoriasis/genetics , Receptors, Calcitriol/genetics , Receptors, KIR/genetics
8.
BJOG ; 120(9): 1051-60, 2013 Aug.
Article in English | MEDLINE | ID: mdl-23639083

ABSTRACT

OBJECTIVE: To characterise changing risk factors of preterm birth in Western Australia between 1984 and 2006. DESIGN: Population-based study. SETTING: Western Australia. POPULATION: All non-Aboriginal women giving birth to live singleton infants between 1984 and 2006. METHODS: Multinomial, multivariable regression models were used to assess antecedent profiles by preterm status and labour onset types (spontaneous, medically indicated, prelabour rupture of membranes [PROM]). Population attributable fraction (PAF) estimates characterized the contribution of individual antecedents as well as the overall contribution of two antecedent groups: pre-existing medical conditions (including previous obstetric history) and pregnancy complications. MAIN OUTCOME MEASURE: Antecedent relationships with preterm birth, stratified by labour onset type. RESULTS: Marked increases in maternal age and primiparous births were observed. A four-fold increase in the rates of pre-existing medical complications over time was observed. Rates of pregnancy complications remained stable. Multinomial regression showed differences in antecedent profiles across labour onset types. PAF estimates indicated that 50% of medically indicated preterm deliveries could be eliminated after removing six antecedents from the population; estimates for PROM and spontaneous preterm reduction were between 10 and 20%. Variables pertaining to previous and current obstetric complications (previous preterm birth, previous caesarean section, pre-eclampsia and antepartum haemorrhage) were the most influential predictors of preterm birth and adverse labour onset (PROM and medically indicated). CONCLUSIONS: Preterm antecedent profiles have changed markedly over the 23 years studied. Some changes may be attributable to true change, others to advances in surveillance and detection. Still others may signify change in clinical practice.


Subject(s)
Asthma/epidemiology , Herpes Genitalis/epidemiology , Hypertension/epidemiology , Obstetric Labor, Premature/epidemiology , Pre-Eclampsia/epidemiology , Pregnancy, High-Risk , Premature Birth/epidemiology , Adult , Asthma/complications , Cesarean Section, Repeat/adverse effects , Female , Fetal Membranes, Premature Rupture/epidemiology , Herpes Genitalis/complications , Humans , Hypertension/complications , Infant, Newborn , Maternal Age , Parity , Predictive Value of Tests , Pregnancy , Premature Birth/etiology , Premature Birth/prevention & control , Regression Analysis , Risk Factors , Socioeconomic Factors , Western Australia/epidemiology
10.
J Neurol Neurosurg Psychiatry ; 82(3): 317-22, 2011 Mar.
Article in English | MEDLINE | ID: mdl-21248317

ABSTRACT

BACKGROUND: The relationship between prevalence of multiple sclerosis (MS) and latitude may be due to both genetic and environmental factors. The hypothesis that, in Ireland, MS prevalence is increasing and that north-south differences relate to variation in serum 25-hydroxyvitamin D (25(OH)D) levels was tested in this study. PATIENTS AND METHODS: Patients and matched control subjects were identified in counties Donegal, Wexford and South Dublin through multiple sources. Prevalence was determined. Blood samples were taken for serum 25(OH)D and serum intact parathyroid hormone measurement, and DNA was extracted. RESULTS: Prevalence in 2007 was significantly greater in Donegal (northwest) (290.3/105, 95% CI 262.3 to 321.7) compared with 2001 (184.6/105; 162 to 209.5). In Wexford (southeast), there was a non-significant increase in prevalence in 2007 compared with 2001. Prevalence was significantly higher in Donegal than in Wexford (144.8/105; 126.7 to 167.8, p<0.0001) and South Dublin (127.8/105; 111.3 to 148.2, p<0.0001). Overall, mean 25(OH)D levels were low and did not differ between patients (38.6 nmol/l) and controls (36.4 nmol/l) However, significantly more patients than controls had 25(OH)D levels <25 nmol/l (deficiency) (p=0.004). Levels of 25(OH)D (mean 50.74 nmol/l) were significantly higher in South Dublin (area with lowest prevalence) (p<0.0001) than in Donegal or Wexford. HLA DRB1*15 occurred most frequently in Donegal (greatest MS prevalence) and least frequently in South Dublin. CONCLUSION: Vitamin D deficiency is common in Ireland. Latitudinal variation in MS probably relates to an interaction between genetic factors and environment (25(OH)D levels), and MS risk may be modified by vitamin D in genetically susceptible individuals.


Subject(s)
HLA Antigens/genetics , Multiple Sclerosis/epidemiology , Vitamin D/blood , Vitamins/blood , Adult , Aged , Aged, 80 and over , Female , Genotype , Geography , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Humans , Ireland/epidemiology , Male , Middle Aged , Multiple Sclerosis/etiology , Multiple Sclerosis/genetics , Parathyroid Hormone/blood , Prevalence , Vitamin D Deficiency/complications , Young Adult
11.
Med Sci Sports Exerc ; 43(1): 146-56, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20473227

ABSTRACT

UNLABELLED: Resistance exercise has been used as a means to prevent the musculoskeletal losses associated with spaceflight. Therefore, the National Aeronautics and Space Administration designed the Advanced Resistive Exercise Device (ARED) to replace the initial device flown on the International Space Station. The ARED uses vacuum cylinders and inertial flywheels to simulate, in the absence of gravity, the constant mass and inertia, respectively, of free weight (FW) exercise. PURPOSE: To compare the musculoskeletal effects of resistance exercise training using the ARED with the effects of training with FW. METHODS: Previously untrained, ambulatory subjects exercised using one of two modalities: FW (6 men and 3 women) or ARED (8 men and 3 women). Subjects performed squat, heel raise, and dead lift exercises 3 d·wk(-1) for 16 wk. Squat, heel raise, and dead lift strength (one-repetition maximum; using FW and ARED), bone mineral density (via dual-energy x-ray absorptiometry), and vertical jump were assessed before, during, and after training. Muscle mass (via magnetic resonance imaging) and bone morphology (via quantitative computed tomography) were measured before and after training. Bone biomarkers and circulating hormones were measured before training and after 4, 8, and 16 wk. RESULTS: Muscle strength, muscle volume, vertical jump height, and lumbar spine bone mineral density (via dual-energy x-ray absorptiometry and quantitative computed tomography) significantly increased (P ≤ 0.05) in both groups. There were no significant differences between groups in any of the dependent variables at any time. CONCLUSIONS: After 16 wk of training, ARED exercise resulted in musculoskeletal effects that were not significantly different from the effects of training with FW. Because FW training mitigates bed rest-induced deconditioning, the ARED may be an effective countermeasure for spaceflight-induced deconditioning and should be validated during spaceflight.


Subject(s)
Adaptation, Physiological , Bone and Bones/physiology , Muscle, Skeletal/physiology , Resistance Training/instrumentation , Space Flight , Absorptiometry, Photon , Adult , Bone Density , Exercise/physiology , Female , Femur/diagnostic imaging , Femur/physiology , Hip/diagnostic imaging , Hip/physiology , Humans , Lumbar Vertebrae/diagnostic imaging , Lumbar Vertebrae/physiology , Magnetic Resonance Imaging , Male , Muscle Strength , Muscle, Skeletal/metabolism , Resistance Training/methods , Thigh , Tomography, X-Ray Computed , United States , United States National Aeronautics and Space Administration , Weightlessness
12.
J Strength Cond Res ; 24(5): 1414-20, 2010 May.
Article in English | MEDLINE | ID: mdl-20386484

ABSTRACT

The purpose of this investigation was to determine the effect of different lifting cadences on the ground reaction force (GRF) during the squat exercise. Squats performed with greater acceleration will produce greater inertial forces; however, it is not well understood how different squat cadences affect GRF. The hypotheses were that faster squat cadences would result in greater peak GRF and that the contributions of the body and barbell, both of equivalent mass, to total system inertial force would not be different. Six experienced male subjects (31 +/- 4 years, 180 +/- 9 cm, 88.8 +/- 13.3 kg) performed 3 sets of 3 squats using 3 different cadences (fast cadence [FC] = 1-second descent/1-second ascent; medium cadence [MC] = 3-second descent/1-second ascent; and slow cadence [SC] = 4-second descent/2-second ascent) while lifting a barbell mass equal to their body mass. Ground reaction force and velocity sensor data were used to calculate inertial force contributions of both the body and barbell to total inertial force. Peak GRF were significantly higher in FC squats compared to MC (p = 0.0002) and SC (p = 0.0002). Ranges of GRF were also significantly higher in FC compared to MC (p < 0.05) and higher in MC compared to SC (p < 0.05). The inertial forces associated with the body were larger than those associated with the barbell, regardless of cadence. Faster squat cadences result in significantly greater peak GRF as a result of the inertia of the system. This study demonstrates that GRF was more dependent on descent cadence than on ascent cadence and that researchers should not use a single point on the body to approximate the location of the center of mass during squat exercise analysis.


Subject(s)
Musculoskeletal Physiological Phenomena , Resistance Training/methods , Acceleration , Adult , Biomechanical Phenomena , Humans , Male , Weight-Bearing
13.
Doc Ophthalmol ; 120(2): 159-64, 2010 Apr.
Article in English | MEDLINE | ID: mdl-19949833

ABSTRACT

The mfERG has proven to be a useful tool in determining central retinal and macular function. It is, however, reliant on good subject co-operation and fixation. This cannot always be guaranteed due to visual impairment or poor co-operation. Whilst a change in fixation is easy to identify with camera monitoring of the subject, a small eccentric fixation can be difficult to notice or quantify. Whilst the problem of fixation can be obviated by stimulating the retina directly with SLO (Scanning Laser Ophthalmoscope), this is expensive and a certain amount of expertize in optics is required to properly stimulate the retina. In this study, peak latency of response was investigated to see whether it changed across the retina and whether this measure could be used to help assess fixation. Eighteen normal eyes were stimulated using a 60 Hz CRT monitor with only 2 hexagons, one central and one peripheral. These hexagons were presented at three stimulation rates, fast (no filler frames between steps of the m-sequence) and slow (4 and 7 black filler frames between each step of the m-sequence), under all conditions significantly increased central hexagon latencies were noted. In a smaller experiment with 19 hexagons and only 4 subjects, it was noted a significant delay in latency was observed in ring 1 compared to ring 2 and 3 with central fixation, but not when the subjects fixed mid-peripheral and in the periphery to slow stimulation, showing that the central hexagon response was only delayed in the central hexagon when there was adequate fixation. This study suggests that latency could provide a clue to fixation particular at slow rates thereby improving the quality and confidence of recordings made clinically.


Subject(s)
Electroretinography/methods , Fixation, Ocular , Reaction Time , Humans , Macula Lutea/physiology , Photic Stimulation/methods , Time Factors , Vision, Ocular
14.
J Strength Cond Res ; 23(3): 883-90, 2009 May.
Article in English | MEDLINE | ID: mdl-19387389

ABSTRACT

Treadmill exercise is commonly used for aerobic and anaerobic conditioning. During nonmotorized treadmill exercise, the subject must provide the power necessary to drive the treadmill belt. The purpose of this study was to determine what factors affected the time to fatigue on a pair of nonmotorized treadmills. Twenty subjects (10 men/10 women) attempted to complete 5 minutes of locomotion during separate trials at 3.22, 4.83, 6.44, 8.05, 9.66, and 11.27 kmxh. Total exercise time (

Subject(s)
Exercise Test/instrumentation , Muscle Fatigue/physiology , Anthropometry , Female , Humans , Male , Military Personnel , Oxygen Consumption/physiology , Proportional Hazards Models , Time Factors
15.
Br J Pharmacol ; 156(2): 316-27, 2009 Jan.
Article in English | MEDLINE | ID: mdl-19154437

ABSTRACT

BACKGROUND AND PURPOSE: Prostanoid EP(4) receptor antagonists may have therapeutic utility in the treatment of migraine since EP(4) receptors have been shown to be involved in prostaglandin (PG)E(2)-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP(4) receptor antagonist. EXPERIMENTAL APPROACH: BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP(4) receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo. KEY RESULTS: BGC20-1531 exhibited high affinity at recombinant human EP(4) receptors expressed in cell lines (pK(B) 7.6) and native EP(4) receptors in human cerebral and meningeal artery (pK(B) 7.6-7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE(2)-induced vasodilatation of human middle cerebral (pK(B) 7.8) and meningeal (pK(B) 7.6) arteries in vitro, but had no effect on responses induced by PGE(2) on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1-10 mg.kg(-1) i.v.) caused a dose-dependent antagonism of the PGE(2)-induced increase in canine carotid blood flow in vivo. CONCLUSIONS AND IMPLICATIONS: BGC20-1531 is a potent and selective antagonist at EP(4) receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.


Subject(s)
Migraine Disorders/drug therapy , Pyridines/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Sulfonamides/pharmacology , Vasodilator Agents/pharmacology , Adult , Aged , Animals , Carotid Artery, Common/drug effects , Carotid Artery, Common/physiology , Cell Line , Cerebral Arteries/drug effects , Cerebral Arteries/physiology , Dinoprostone/pharmacology , Dogs , Dose-Response Relationship, Drug , Female , Humans , In Vitro Techniques , Male , Meningeal Arteries/drug effects , Meningeal Arteries/physiology , Middle Aged , Muscle, Smooth, Vascular/drug effects , Muscle, Smooth, Vascular/physiology , Pyridines/adverse effects , Pyridines/therapeutic use , Radioligand Assay , Receptors, Prostaglandin E, EP4 Subtype , Recombinant Proteins/antagonists & inhibitors , Sulfonamides/adverse effects , Sulfonamides/therapeutic use , Vasoconstriction/drug effects , Vasodilator Agents/adverse effects , Vasodilator Agents/therapeutic use , Young Adult
16.
BMJ Case Rep ; 20092009.
Article in English | MEDLINE | ID: mdl-21686418

ABSTRACT

A 35-year-old man presented with keratoconus; his best corrected visual acuities were -18.00/+10.00 ×180 (6/60) oculus dexter and -10.00/+8.00 ×5 (6/36) oculus sinister. Bilateral steep central corneal thinning, paracentral ectasia and Vogts striae were present. Normal fundi. Corneal topography disclosed 7.4 dioptres of irregular astigmatism in the central 3 mm with thinning (335 µm). Electroretinography (ERG) showed no response. There were no medical or environmental influences for his keratoconus. Occurrence of keratoconus and congenital stationary night blindness (CSNB) in the patient may represent a chance association, but keratoconus has not been previously linked with CSNB1 either as a chance or true association though both show genetic predisposition.

17.
Int J Immunogenet ; 35(4-5): 295-302, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18976432

ABSTRACT

The frequencies of human leucocyte antigen (HLA) class I and II alleles and haplotypes of 250 Irish unrelated bone marrow donors were determined by high resolution polymerase chain reaction (PCR), using a combination of reverse line blot hybridization and PCR with sequence-specific primers. Phylogenetic analyses indicate that this Irish population is closely related to British, North-western European, American and Australian Caucasian populations. These observations are consistent with recognized historical, geographical, cultural, ethnic and linguistic relationships between these populations and suggest that Irish haematopoietic stem cell transplant recipients have a greater likelihood of finding a phenotypically matched donor within registries based on these populations. HLA-A, B, Cw, DRB1, DQB1 and DPB1 analysis confirms that this young homogenous population is characterized by features of a North-western European anthropological type with limited influence of additional ethnic haplotypes.


Subject(s)
Genetics, Population , HLA Antigens/genetics , Haplotypes/genetics , Bone Marrow/immunology , Cluster Analysis , Gene Frequency , HLA-A Antigens/genetics , HLA-B Antigens/genetics , HLA-C Antigens/genetics , HLA-DP Antigens/genetics , HLA-DQ Antigens/genetics , HLA-DQ beta-Chains , HLA-DR Antigens/genetics , HLA-DRB1 Chains , Histocompatibility Testing , Humans , Ireland/ethnology
18.
J Exp Biol ; 211(Pt 7): 1087-92, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18344482

ABSTRACT

The addition of inertia to exercising astronauts could increase ground reaction forces and potentially provide a greater health benefit. However, conflicting results have been reported regarding the adaptations to additional mass (inertia) without additional net weight (gravitational force) during locomotion. We examined the effect of increasing inertia while maintaining net gravitational force on vertical ground reaction forces and temporal kinematics during walking and running. Vertical ground reaction force was measured for 10 healthy adults (five male/five female) during walking (1.34 m s(-1)) and running (3.13 m s(-1)) using a force-measuring treadmill. Subjects completed locomotion at normal weight and mass and at 10, 20, 30 and 40% of added inertial force. The added gravitational force was relieved with overhead suspension, so that the net force between the subject and treadmill at rest remained equal to 100% body weight. Ground reaction forces were affected by the added inertial force, but not to the magnitude predicted by the increase in mass, suggesting that adaptations in motion occurred. Vertical ground reaction force production and adaptations in gait temporal kinematics were different between walking and running. Peak vertical impact forces and loading rates increased with increased inertia during walking, and decreased during running. As inertia increased, peak vertical propulsive forces decreased during walking and did not change during running. Stride time increased during walking and running, and contact time increased during running. The increased inertial forces were utilized independently from gravitational forces by the motor control system when determining coordination strategies.


Subject(s)
Locomotion/physiology , Adult , Biomechanical Phenomena , Female , Humans , Male , Running/physiology , Time Factors , Walking/physiology , Weight-Bearing/physiology
19.
J Appl Physiol (1985) ; 104(3): 837-44, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18096753

ABSTRACT

The intensity of exercise above which oxygen uptake (Vo2) does not account for all of the required energy to perform work has been associated with lactate accumulation in the blood (lactate threshold, LT) and elevated carbon dioxide output (gas exchange threshold). An increase in hydrogen ion concentration ([H+]) is approximately concurrent with elevation of blood lactate and CO2 output during exercise. Near-infrared spectra (NIRS) and invasive interstitial fluid pH (pHm) were measured in the flexor digitorum profundus during handgrip exercise to produce a mathematical model relating the two measures with an estimated error of 0.035 pH units. This NIRS pHm model was subsequently applied to spectra collected from the vastus lateralis of 10 subjects performing an incremental-intensity cycle protocol. Muscle oxygen saturation (SmO2) was also calculated from spectra. We hypothesized that a H+ threshold could be identified for these subjects and that it would be different from but correlated with the LT. Lactate, gas exchange, SmO2, and H+ thresholds were determined as a function of Vo2 using bilinear regression. LT was significantly different from both the gas exchange threshold (Delta = 0.27 +/- 0.29 l/min) and H+ threshold (Delta = 0.29 +/- 0.23 l/min), but the gas exchange threshold was not significantly different from the H+ threshold (Delta = 0.00 +/- 0.38 l/min). The H+ threshold was strongly correlated with LT (R2 = 0.95) and the gas exchange threshold (R2 = 0.85). This initial study demonstrates the feasibility of noninvasive pHm estimations, the determination of H+ threshold, and the relationship between H+ and classical metabolic thresholds during incremental exercise.


Subject(s)
Exercise/physiology , Extracellular Fluid/metabolism , Hand Strength , Muscle Contraction , Muscle, Skeletal/metabolism , Spectroscopy, Near-Infrared , Adult , Anaerobic Threshold , Feasibility Studies , Female , Humans , Hydrogen-Ion Concentration , Lactic Acid/metabolism , Male , Models, Biological , Oxygen Consumption , Pulmonary Gas Exchange , Quadriceps Muscle/metabolism , United States
20.
Physiol Meas ; 28(6): 639-49, 2007 Jun.
Article in English | MEDLINE | ID: mdl-17664618

ABSTRACT

Oxygen and acid-base status during exercise is well established for the lungs, large arteries and veins. However, values for these parameters in exercising muscle are less frequently reported. In this study we examined the relationship between intramuscular PO(2), pH, PCO(2) and the comparable venous values during rhythmic isometric handgrip exercise at target levels of 15%, 30% and 45% of maximum voluntary contraction (MVC). A small fiber optic sensor was inserted into the flexor digitorum profundus (FDP) muscle for continuous measurement of intramuscular (IM) PO(2), pH and PCO(2). Venous blood samples were taken from the forearm every minute during each exercise bout. IM pH and PCO(2) were similar to their venous counterparts at baseline, but the difference between IM and venous values increased when exercise exceeded 30% MVC. During exercise at 15% MVC and greater, venous PO(2) declined from 40 to 21 Torr (approximately 5.3 to 2.8 kPa). IM PO(2) declined from 24 to 8 Torr with 15% MVC, and approached 0 Torr at 30% MVC and 45% MVC. IM pH declined rapidly when IM PO(2) reached 10 Torr and continued to decrease with increasing exertion, despite an IM PO(2) near 0 Torr.


Subject(s)
Carbon Dioxide/metabolism , Exercise/physiology , Hand Strength/physiology , Muscle, Skeletal/physiology , Oxygen/metabolism , Veins/metabolism , Adult , Carbon Dioxide/blood , Female , Humans , Hydrogen-Ion Concentration , Lactic Acid/blood , Male , Oxygen/blood , Partial Pressure , Temperature , Time Factors
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