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Andrew Roberts

Publications and source records attributed to Andrew Roberts.

16 recordsLinked to original sources
PubMed2007

An exploration of the function of the triceps surae during normal gait using functional electrical stimulation.

Gastrocnemius and soleus have a common tendon and both are active during stance phase, where they are thought to arrest and control tibial advance. Soleus is associated with the production of an extending moment at the knee. The two-joint gastrocnemius, which crosses the knee joint, will have an additional contribution to the knee flexors. Recent work using induced acceleration analysis (IAA) has demonstrated distinct differences between the actions of gastrocnemius and soleus. This study aims to use gait analysis to provide in vivo examination of these theoretical predictions. Functional electrical stimulation (FES) was chosen to provide a perturbation in muscle force, a close physical analogue to the theoretical predictions of IAA. Five adult male subjects, with no gait problems, participated. Each had gastrocnemius and soleus stimulated at three different timings during normal gait, while 3D gait data were collected. The order of testing was randomised and unstimulated trials were randomly interspersed to act as a control. The results show very different actions for soleus (ankle plantarflexing/knee extending) and gastrocnemius (ankle dorsiflexing/knee flexing) in stance phase. The counterintuitive nature of the action of gastrocnemius suggests that further clinical and biomechanical investigation into this muscle's function is required. The actions of both muscles at the knee confirm published IAA predictions. In vivo evidence such as this gives greater confidence when using model predictions. The approach adopted in this study could eventually be extended to other muscles and patient populations.

Adult↗
PubMed2006

Erythropoietic protoporphyria: a functional analysis of the leader sequence of human ferrochelatase.

Erythropoietic protoporphyria (EPP) results from an inherited partial deficiency of ferrochelatase, the terminal enzyme of haem biosynthesis. Excess protoporphyrin IX accumulates in erythrocytes, plasma, liver, and skin, which mediates a distinctive form of cutaneous photosensitivity that manifests during childhood. Ferrochelatase is synthesised on cytosolic ribosomes as a preprotein with a cleavable presequence at its amino-terminus. This leader sequence is thought to target ferrochelatase to mitochondria where it is cleaved to produce the active mature protein. In this study, we show that the 62 amino acid leader sequence is sufficient for targeting of a leader sequence-YFP fusion protein to mitochondria. A truncated fusion protein lacking the first 62 amino acids did not target to mitochondria, and formed punctate aggregates in the cytoplasm of cells. This suggests that all the information required for mitochondrial localisation resides within the first 62 amino acid presequence. A missense mutation, P62R, predicted to be located within the ferrochelatase presequence has been identified in a patient with EPP. We hypothesised that this mutation may exert its effect through defective targeting to mitochondria. Our data showed that this mutated full-length ferrochelatase successfully targeted to mitochondria. Interestingly, there was inhibited cleavage of YFP from wild-type and mutant leader sequence fusion proteins. Generation of leader sequence-YFP fusion proteins containing an additional 11 amino acids from the mature protein allowed proteolytic processing to occur. These data suggest that the first 62 amino acids allow targeting to mitochondria but do not contain sufficient information for efficient processing of the protein.

Amino Acid Sequence↗
PubMed2006

Subthalamic glutamic acid decarboxylase gene therapy: changes in motor function and cortical metabolism.

Parkinson's disease (PD) is associated with increased excitatory activity within the subthalamic nucleus (STN). We sought to inhibit STN output in hemiparkinsonian macaques by transfection with adeno-associated virus (AAV) containing the gene for glutamic acid decarboxylase (GAD). In total, 13 macaques were rendered hemiparkinsonian by right intracarotid 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. Seven animals were injected with AAV-GAD into the right STN, and six received an AAV gene for green fluorescent protein (GFP). Videotaped motor ratings were performed in a masked fashion on a weekly basis over a 55-week period. At 56 weeks, the animals were scanned with (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Histological examination was performed at the end of the study. No adverse events were observed after STN gene therapy. We found that the clinical rating scores for the two treatment groups had different patterns of change over time (group x time interaction, P<0.001). On FDG PET, the GAD animals exhibited an increase in glucose utilization in the right motor cortex relative to GFP controls (P<0.001). Metabolism in this region correlated with clinical ratings at end point (P<0.01). Histology confirmed GAD expression in treated animals. These findings suggest that STN AAV-GAD is well tolerated and potentially effective in a primate model of PD. The changes in motor cortical glucose utilization observed after gene therapy are consistent with the modulation of metabolic brain networks associated with this disorder.

Animals↗
PubMed2006

Allogeneic stem cell transplantation with peripheral blood stem cells mobilized by pegylated G-CSF.

Mobilization of stem cells with pegylated granulocyte colony-stimulating factor (peg-G-CSF) modulates donor T- and natural killer T-cell (NKT-cell) functions, thus separating graft-versus-host from graft-versus-leukemia disease in animal models. We report a phase I/II study that analyzed the feasibility of mobilizing stem cells from normal donors with peg-G-CSF and the ability of these cells to restore hematopoiesis in allogeneic transplant recipients after myeloablative conditioning. Administration of 6 mg of peg-G-CSF resulted in suboptimal stem cell mobilization, with a peak peripheral blood CD34+ count of 29+/-5/microL. Apheresis 4 days after peg-G-CSF yielded 2.7+/-.4x10(6) CD34+ cells/kg recipient weight, and all donors required a second collection on day 5 to yield a total of 4.2+/-.5x10(6) CD34+ cells/kg recipient weight. After escalation of the dose to 12 mg, the peak CD34+ count was 99+/-11/microL and 12 of 13 donors collected sufficient stem cells for transplantation in a single apheresis (8.9+/-1.4x10(6) CD34+ cells/kg recipient weight). Late transient increases in serum hepatic transaminases were noted, but other side effects (predominantly bone pain) were otherwise similar to those seen in donors mobilized with standard G-CSF. Median neutrophil and platelet engraftments occurred on days 18 and 14, respectively, after transplantation and were identical to those seen with in recipients of grafts mobilized with standard G-CSF. With a median follow-up of 357 days, the incidence of grade II-IV acute graft-versus-host disease was 50% and there have been no relapses to date. Mobilization of stem cells with peg-G-CSF in normal donors is feasible and 12 mg results in mobilization characteristics similar to those of standard G-CSF.

Adult↗
PubMed2006

Dietary herbal supplements with phenylephrine for weight loss.

This study was designed to evaluate the efficacy and safety of a dietary herbal supplement containing citrus aurantium and phenylephrine in the treatment of obesity. Two pilot studies enrolled healthy subjects with body mass indexes 25-40 kg/m(2) to similar 8-week weight loss programs. Safety was assessed by physical examination and laboratory tests at screening and 8 weeks. The first pilot study randomized eight subjects to citrus aurantium (herbal phenylephrine) or placebo. Body composition by DEXA scan, waist circumference, and resting metabolic rate (RMR) were measured at baseline and 8 weeks. Food intake and appetite ratings were measured at baseline and week 2. The second pilot study randomized 20 subjects to two 2-hour RMR tests a week apart after phenylephrine (20 mg) or placebo followed by phenylephrine (20 mg) three times a day for 8 weeks. In the first pilot study, the citrus aurantium group gained 1.13 +/- 0.27 (mean +/- SEM) kg compared with 0.09 +/- 0.28 kg in the placebo group (P < .04). RMR at baseline rose more in the citrus aurantium group, 144.5 +/- 15.7 kcal/24 hours, than the placebo group, 23.8 +/- 28.3 kcal/24 hours (P < .002), but not at 8 weeks. DEXA, waist circumference, food intake, and hunger ratings were not different. In the second pilot study, the phenylephrine group lost 0.8 +/- 3.4 kg in 8 weeks (not significant), and RMR increased more in the phenylephrine group (111.5 +/- 32.6 vs. 37.4 +/- 22.7 kcal/24 hours, P = .02). There were no significant safety issues in either study. Although no toxicity was seen, these pilot studies suggest phenylephrine is not efficacious for weight loss.

Absorptiometry, Photon↗
PubMed2006

Globin digest: no evidence for a weight loss mechanism.

This study was designed to document the mechanism through which globin digest, a dietary herbal supplement, might cause weight loss by exploring possible fat malabsorption, calorie malabsorption, energy expenditure, and fat oxidation. Six healthy subjects were placed on an outpatient diet for 14 days and given a meal containing 40.9 g of fat on days 5 and 11, and stools were collected for 72 hours after each meal for analysis of fecal fat content. Four grams of globin digest was given with one meal and placebo with the other. In another separate study, six subjects were placed on a 100-g fat, weight-maintaining diet for 14 days. All food was prepared by the Pennington Center (Baton Rouge, LA) metabolic kitchen. Globin digest (2 g) or placebo was given with each of three meals per day, and stool was collected for calorie determinations during the last 72 hours of each week. Subjects received globin digest during one of the 2 weeks and placebo during the other. Resting metabolic rate and respiratory quotient were measured on the last day of each 1-week period. There was no increase in 72-hour fecal fat or fecal calories by bomb calorimetry during either of the studies. There was no difference in the respiratory quotient. Globin digest did result in an increase in resting metabolic rate. However, this increase was not statistically significant. Globin digest, if effective, does not cause weight loss or fat loss through fat malabsorption or a relative increase in fat oxidation. Future studies are needed to document the efficacy of globin digest for weight loss in humans before further mechanistic investigation is attempted.

Adolescent↗
PubMed2005

Aerosol delivery of mammalian cells for tissue engineering.

We developed a two fluid atomizer to spray mammalian cells suspended in phosphate buffered saline (PBS)-Pluronic F-127 polymer solutions. We used the device to spray suspensions of bovine articular chondrocytes and porcine tracheal epithelial cells, in either PBS or the polymer solutions, and studied their viability and growth kinetics. Under the operating conditions examined in this study, the cells had better than 70% viability after spraying, the growth rates were comparable to cells that were not sprayed, and the appearance of the cells at confluence was normal.

Aerosols↗
PubMed2005

A multicenter phase II trial of thalidomide and celecoxib for patients with relapsed and refractory multiple myeloma.

Preclinical data indicates that cyclooxygenase-2 (COX-2) inhibition impairs plasma cell growth and potentially synergizes with thalidomide. We performed a trial in previously treated patients with myeloma using thalidomide up to a maximum dose of 800 mg/d with celecoxib (400 mg bid). Outcomes were compared with a prior trial of thalidomide. Sixty-six patients with median age of 67 (range, 43-85) received a median dose of thalidomide and celecoxib of 400 and 800 mg/d, respectively, with median durations of treatment of 27 and 13 weeks, respectively. The most common toxicities associated with premature discontinuation of celecoxib (n = 30 of 53, 57%) were fluid retention and deterioration of renal function. Overall response rate (RR) was 42% and with 20 months median follow-up; the actuarial median progression-free survival and overall survival were 6.8 and 21.4 months, respectively. Unlike our prior study, age >65 years was not predictive of inferior RR due to improvement in RR in older patients with the combination (37% versus 15%, P = 0.08). The RR was superior in patients who received a total dose of celecoxib exceeding 40 g in the first 8 weeks of therapy (62% versus 30%, P = 0.021). Progression-free survival and overall survival were also improved. Other predictors for inferior progression-free survival were age >65 years (P = 0.016) and elevated beta(2)-microglobulin (P = 0.017). This study provides evidence that the addition of high-dose celecoxib adds to the antimyeloma activity of thalidomide but this comes with unacceptable toxicity. Future studies should use newer COX-2 inhibitors with thalidomide, or their respective derivatives.

Adult↗
PubMed2004

Estimation of hamstring length at initial contact based on kinematic gait data.

This study proposes a simple estimate of hamstring length at initial contact (LEST) for use when musculoskeletal modelling is not available. The estimate is calculated by using the kinematic curves to measure the excessive flexion (above normal) at the hip and knee at initial contact. The excessive hip flexion is then multiplied by a scaling factor (k) and the excessive knee flexion subtracted from the result. Validation of this estimate was carried out using kinematic gait data from 25 children with cerebral palsy (50 limbs) by comparing the results of the estimate with an equivalent measure derived from musculoskeletal modelling (LTRUE). Very high agreement was found when LTRUE and LEST were compared for the three biarticular hamstring muscles, demonstrated by correlation coefficients of over 0.9. Different k values were tested with a value of 3 giving the best results overall. The estimate is acceptable as a simple 'rule of thumb' for use in clinical practice. It can provide useful additional information to complement the clinical examination and gait assessment results.

Adolescent↗
PubMed2004

Class III obesity continues to rise in African-American women.

BACKGROUND: The Behavior Risk Factor Surveillance System (BRFSS) survey, a random telephone survey of the United States, found a rising prevalence of Class III obesity, body mass index (BMI) >40 kg/m(2). African-American women were largely responsible for this increase. The prevalence of Class III obesity in African-American women in the BRFSS during the year 2000 was 6%, identical to the Pennington Biomedical Research Center (PBRC) database during the same year. The PBRC Database might predict the trend in class III obesity in the years 2000-2002. METHODS: The PBRC is an academic research center in Baton Rouge, that maintains a database with information collected by telephone regarding BMI and race, for subjects responding to solicitations to participate in clinical trials. This database contains 7787 subjects entered from 1995 through 2002, of which 1820 were African-American women and 3006 were Caucasian women. The prevalence of Class III obesity was plotted for women of these 2 racial groups and compared with the year 2000 prevalence in the BRFSS. RESULTS: The prevalence of Class III obesity in African-American women increased from 0.5% in 1995 to 6% in 2000 (identical to the BRFSS) and to 7.5% in 2002. The prevalence of Class III obesity in Caucasian women remained about 3%. CONCLUSION: The prevalence of Class III obesity continues to rise in African-American women, a group with greater need and less access to obesity surgery, the only effective treatment, than Caucasian women, an inequality deserving of public policy attention.

Black or African American↗
PubMed2003

Blunt traumatic aortic transection: the endovascular experience.

BACKGROUND: Thoracic aortic transection resulting from blunt trauma is usually fatal. It is almost always associated with multiple, complex, nonaortic injuries that could be adversely affected by standard surgical repair of the aorta. Endovascular stenting techniques offer these patients a less physiologically disruptive treatment option. We studied the feasibility and safety of endovascular stent graft placement for treatment of acute traumatic aortic transection. METHODS: Between 1994 and 2001, 9 patients were treated emergently for aortic transections with stent graft placement. The first patient had a custom-made prototype, and the other 8 patients had the Cook-Zenith thoracic stent graft implanted. All were polyester-covered Z-stent construction and deployed through a femoral 20- to 24-F delivery sheath. RESULTS: Stent graft placement successfully sealed the aorta in all patients. One patient died as a result of a cerebrovascular accident. One patient required a brachial thrombectomy to relieve arm ischemia. The remaining eight patients were alive and without complications during the follow-up period (mean 21 months). CONCLUSIONS: Endovascular repair for acute aortic transection is a safe, effective, and timely treatment option. It may be the treatment of choice in patients with extensive associated injuries.

Adult↗
PubMed2002

Discovery and optimization of a series of carbazole ureas as NPY5 antagonists for the treatment of obesity.

The hypothesis that antagonists of the neuropeptide Y5 receptor would provide safe and effective appetite suppressants for the treatment of obesity has prompted vigorous research to identify suitable compounds. We discovered a series of acylated aminocarbazole derivatives (e.g., 3a) that are potent and selective Y5 antagonists, representing interesting starting points but suffering from poor bioavailability and concerns about potential toxicity as a consequence of the embedded aminocarbazole fragment. It proved relatively easy to improve the drug metabolism and pharmacokinetic (DMPK) properties by variation of the side chain (as in 4a) but difficult to eliminate the aminocarbazole fragment. For compounds in this series to have the potential to be drugs, we believed that both the compound itself and the component aniline must be free of mutagenic activity. Parallel structure-activity relationship studies looking at the effects of ring substitution have proved that it is possible by incorporation of a 4-methyl substituent to produce carbazole ureas with potent Y5 activity, comprised of carbazole anilines that in themselves are devoid of mutagenic activity in the Ames test. Compound 4o (also known as NPY5RA-972) is highly selective with respect to Y1, Y2, and Y4 receptors (and also to a diverse range of unrelated receptors and enzymes), with an excellent DMPK profile including central nervous system penetration. NPY5RA-972 (4o) is a highly potent Y5 antagonist in vivo but does not block neuropeptide Y-induced feeding nor does it reduce feeding in rats, suggesting that the Y5 receptor alone has no significant role in feeding in these models.

Aniline Compounds↗
PubMed2002

Dok-related protein negatively regulates T cell development via its RasGTPase-activating protein and Nck docking sites.

Downstream of kinase (Dok)-related protein (DokR, also known as p56(dok)/FRIP/Dok-R) is implicated in cytokine and immunoreceptor signaling in myeloid and T cells. Tyrosine phosphorylation induces DokR to bind the signal relay molecules, RasGTPase-activating protein (RasGAP) and Nck. Here, we have examined the function of DokR during hematopoietic development and the requirement for RasGAP and Nck binding sites in its biological function. Retroviral-mediated expression of DokR in bone marrow cells dramatically inhibited their capacity to form colonies in vitro in response to the cytokines macrophage colony-stimulating factor and stem cell factor, whereas responses to interleukin-3 and granulocyte macrophage colony-stimulating factor were only weakly affected. When introduced into lethally irradiated mice, hematopoietic cells expressing DokR showed a drastically reduced capacity to repopulate lymphoid tissues. Most notably, DokR dramatically reduced repopulation of the thymus, in part by reducing the number of T cell precursors seeding in the thymus, but equally, through inhibiting the transition of CD4(-)CD8(-) to CD4(+)CD8(+) T cells. Consequently, the number of mature peripheral T cells was markedly reduced. In contrast, a minimal effect on B cell and myeloid lineage development was observed. Importantly, functional RasGAP and Nck binding sites were found to be essential for the biological effects of DokR in vitro and in vivo.

Adaptor Proteins, Signal Transducing↗
PubMed2002

A comparison of the biomechanical effects of opening and closing wedge varus osteotomies in Perthes' disease.

Varus femoral osteotomy is a commonly employed surgical method of effecting containment in the management of Perthes' disease. This can be achieved by performing either an opening lateral wedge or a closing medial wedge osteotomy. The effects of these two techniques on the biomechanical interrelationships about the involved hip were compared using a three-dimensional computer simulation. Both procedures lead to femoral shortening and reduce the moment capacity of the hip abductors. The shortening effect and consequent leg length discrepancy are greater for the closing wedge osteotomy than for the opening wedge procedure. Pelvic obliquity compensation, likely to be greater for a closing wedge osteotomy, provides a beneficial increase in femoral head coverage but at the cost of a further reduction in the hip abductor moment capacity.

Biomechanical Phenomena↗
PubMedDate not supplied

Association of carotid artery intima-media thickness with complex aortic atherosclerosis in patients with recent stroke.

This study was undertaken to determine whether carotid intima-media thickness can predict complex aortic atherosclerosis. A retrospective review was conducted of 64 consecutive patients who underwent transesophageal echocardiography and carotid ultrasonography for evaluation of recent ischemic stroke at MCP Hahnemann University, Medical College of Pennsylvania Hospital between January 1, 1999, and December 31, 1999. The mean age was 65+/-14 years and 59% of the patients were women. Thirty-nine patients (61%) had carotid atherosclerosis (defined as an intima-media thickness > or =1 mm) and seven patients (11%) had complex aortic atherosclerosis (defined as the presence of protruding atheroma > or =4 mm thick, mobile atherosclerotic debris, or plaque ulceration in any aortic segment by transesophageal echocardiography). Compared to patients without complex aortic atherosclerosis, patients with complex aortic atherosclerosis were more likely to have hypercholesterolemia (19% vs 57%, p = 0.05) and a carotid intima-media thickness of 2 mm or greater (35% vs 86%, p = 0.02). A carotid intima-media thickness of 2 mm or more had 86% sensitivity, 65% specificity, 23% positive predictive value, 97% negative predictive value, 2.5 positive likelihood ratio, and 0.22 negative likelihood ratio for the diagnosis of complex aortic atherosclerosis. Carotid intimamedia thickness measurement can be used to noninvasively estimate the probability of complex aortic atherosclerosis. A carotid intima-media thickness less than 2 mm makes complex aortic atherosclerosis very unlikely.

Aged↗