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J H Wolfe

Publications and source records attributed to J H Wolfe.

At least 37 records · Page 2Linked to original sources
PubMed2000

Significantly increased expression of beta-glucuronidase in the central nervous system of mucopolysaccharidosis type VII mice from the latency-associated transcript promoter in a nonpathogenic herpes simplex virus type 1 vector.

Herpes simplex virus (HSV) has the ability to establish life-long latent infections in postmitotic neurons and to remain transcriptionally active, continuously expressing latency-associated transcripts (LAT) while producing minimal disease. These properties have made HSV an excellent candidate for neuronal gene transfer. Previously, we have shown that in mucopolysaccharidosis type VII mice (MPS VII, beta-glucuronidase deficiency) the LAT promoter is capable of expressing beta-glucuronidase (GUSB) in the trigeminal ganglion and the brainstem after latency is established. However, the number of neurons expressing GUSB is much lower than the number expressing 2-kb LAT following a wild-type virus infection. In this study, we have evaluated the effect of the position of the coding sequence relative to the LAT promoter on beta-glucuronidase gene expression in the central nervous system (CNS). Non-neurovirulent (ICP-34.5-deleted HSV-1) vectors were used, allowing direct intracranial injection. Significantly more GUSB activity was detected in brains of MPS VII mice inoculated with a recombinant virus (HSV-LAT-GUSB-JS) in which the GUSB cDNA was inserted near the LAT promoter, compared to viruses where it was inserted farther downstream in either the LAT exon 1 or overlapping exon 1 and the 2-kb LAT intron. This vector produced more than 100 times the number of positive cells than the other constructs. During acute infection, the distribution of viral replication differed from the distribution of GUSB enzyme expression. Viral antigen was predominately present in cells around the site of injection in the caudate putamen and in ependymal cells lining the ventricles. In contrast, GUSB expression was present mainly in cells of the thalamus and hypothalamus, which did not exhibit viral antigen, suggesting that GUSB enzyme activity was expressed from latently but not acutely infected neuronal cells. This vector design should be useful for high-level expression of various genes in the CNS.

Animals↗
PubMed2000

Gene transfer of low levels of beta-glucuronidase corrects hepatic lysosomal storage in a large animal model of mucopolysaccharidosis VII.

Gene therapy has been at least partially effective in several mouse disease models, but treatment of large mammals has been more difficult to achieve. One major limitation is that only low levels of expression of the corrective gene are often maintained in vivo. In a mouse model of the lysosomal storage disease mucopolysaccharidosis (MPS) type VII (Sly disease) with a null mutation in beta-glucuronidase, gene transfer experiments have shown that only 1-2% of normal beta-glucuronidase can correct the storage in some major organs. In contrast, MPS VII dogs, cats, and humans that have residual beta-glucuronidase activity levels in this range are affected. Thus, higher levels of transferred gene expression may be needed to achieve a therapeutic effect in large animals and humans. We tested this by examining liver pathology in MPS VII dogs after intraperitoneal transplantation of neo-organs containing retrovirus vector-corrected autologous fibroblasts that expressed low levels of beta-glucuronidase. The enzyme secreted from the neo-organs was taken up by the liver and significantly reduced the substrate content compared with untreated dogs. This suggests that small amounts of normal enzyme, when delivered to target tissues, may be therapeutically effective in human MPS VII patients.

Animals↗
PubMed2000

The surgical management of renovascular hypertension in children and young adults.

OBJECTIVES: To assess the outcome and durability of operative revascularisation in young patients with renovascular hypertension. DESIGN: Retrospective study. METHOD: The records of all young patients (under 25 years) operated on for renovascular hypertension at St Mary's Hospital 1988-1998 were reviewed. We assessed the aetiology of hypertension, operations performed, effect of treatment on blood pressure, renal function and requirement for antihypertensive medication during follow-up. RESULTS: Ten patients were identified who had been considered for surgery, of median age 16 years (22 months to 22 years). Fibromuscular dysplasia was present in five patients, mid-aortic syndrome (MAS) in four and neurofibromatosis in one. Operations performed were aortorenal bypass (three), aorto-aortic bypass+/-renal bypass (three), splenorenal bypass (one) and autotransplantation (one). Of the three patients treated by balloon angioplasty, only one had a successful result. One patient with MAS is currently awaiting surgery. Over a median follow-up of 24 months (8-144), seven patients are normotensive off all antihypertensive medication. Of two patients on reduced doses of medication, one (splenorenal bypass) required surgical repair of a late (9 years) coeliac stenosis. CONCLUSIONS: The surgical treatment of renovascular hypertension in carefully selected young patients gives durable results. Blood pressure is well controlled long-term, and the need for antihypertensive medication is removed altogether in the majority of patients.

Adolescent↗
PubMed2000

Optimum intermittent pneumatic compression stimulus for lower-limb venous emptying.

OBJECTIVE: intermittent pneumatic compression (IPC) of the foot (IPC(foot)), calf (IPC(calf)) or both (IPC(foot+calf)) augments calf inflow, and improves the walking ability and peripheral haemodynamics of claudicants (IPC(foot), IPC(foot+calf)), largely due to venous outflow enhancement. This cohort study, using direct pressure measurements in healthy limbs, determines the optimal combination of frequency (2-4 impulses/minute), applied pressure (60-140 mmHg), mode (IPC(foot)-IPC(calf)-IPC(foot+calf)) and delay time of calf-to-foot impulse (0 s-0.5 s-1 s) that enables IPC to generate an almost complete and sustained decrease in venous pressure. RESULTS: (a) IPC(foot)at 120 and 80 mmHg generated lower venous pressure than that with 100 and 60 mmHg (p=0.036) respectively, for 2-4 impulses/minute; venous pressure differences between applied pressures of 140 and 120 mmHg or between 80 and 100 mmHg were insignificant. (b) Venous pressure with IPC(calf)at 80 mmHg was lower than that with 60 mmHg (p=0.036) (2-4 cycles/minute); differences in venous pressure between applied pressures of 140 and 100 mmHg or between 120 and 80 mmHg were insignificant. (c) At applied pressures 60-140 mmHg, IPC(foot+calf)with one-second delay generated lower venous pressure than that with half-second delay (p=0.036), the latter being more efficient than zero delay; increasing applied pressures produced lower venous pressure, but differences were small. Venous pressure decreased with increasing IPC frequency (from 2 to 3-4/minute), at applied pressures 60-140 mmHg. CONCLUSIONS: IPC(foot+calf)at applied 120-140 mmHg, a frequency of 3-4 impulses/minute and one-second delay, provided the optimum intermittent pneumatic stimulus.

Adult↗
PubMed2000

Myocardial injury in major aortic surgery.

PURPOSE: The purpose of this study was to examine the effects of major aortic surgery and its associated oxidative stress and injury on the myocardium. METHODS: Plasma from 27 patients who underwent thoracoabdominal aortic aneurysm (TAAA) repair and 17 patients who underwent infrarenal aortic aneurysm (AAA) repair was collected at incision, aortic crossclamping, and reperfusion and 1, 8, and 24 hours thereafter. Samples were assayed for the myocardial specific protein troponin-T, total antioxidant status, and lipid hydroperoxides. RESULTS: Ten patients experienced cardiac dysfunction in the first 24 hours after surgery (eight patients in the TAAA group and two patients in the AAA group). Immediately after reperfusion, total antioxidant status levels dropped in all patients with TAAA and with AAA; this was more marked in patients with TAAA, leading to a significant difference between the two groups at this time point and for up to 1 hour thereafter (P <.01). Patients with TAAA showed a sharp rise in lipid hydroperoxide levels immediately after reperfusion, and levels were significantly higher than in patients with AAA (P =.0007). In patients with AAA, no significant change in troponin-T was observed throughout the study period; whereas in patients with TAAA, levels were significantly elevated at 8 and 24 hours after reperfusion (P <.01). Troponin-T levels significantly correlated with total antioxidant status (r = -0.5) and lipid hydroperoxides (r = 0.78) but not with systolic blood pressure. CONCLUSION: Supracoeliac aortic crossclamping is associated with a significant release of the myocardial injury marker troponin-T. This seems to correlate with the severity of oxidative rather than hemodynamic stresses. Ameliorating oxidative injury during TAAA surgery may therefore have a cardioprotective effect.

APACHE↗
PubMed2000

Improving walking ability and ankle brachial pressure indices in symptomatic peripheral vascular disease with intermittent pneumatic foot compression: a prospective controlled study with one-year follow-up.

PURPOSE: Intermittent pneumatic foot compression (IPC(foot)) augments arterial leg inflow. It has been suggested that prolonged use of impulse leg compression at home might ameliorate claudication caused by peripheral vascular disease by improving collateral circulation. The purpose of this study was to determine the effect of IPC(foot) treatment on claudication distance and arterial hemodynamics in patients with intermittent claudication caused by peripheral vascular disease. METHODS: Thirty-seven patients with stable intermittent claudication were admitted to this prospective controlled study. Of these, 25 patients received IPC(foot) (>4 hr/d) for 4.5 months (group 1), and the other 12 patients acted as control patients (group 2). Both groups were advised to exercise unsupervised for a minimum of 1 hour daily and received aspirin (75 mg/d). Groups were matched for age, sex, risk factors, claudication distances, and ankle pressures at baseline. In each patient, initial claudication distance (ICD), absolute claudication distance (ACD), resting ankle brachial index (r-ABI), ankle brachial pressure index after exercise (p-eABI), and popliteal artery volume flow were measured at day 0, 2 weeks, and 1, 2, 3, and 4.5 months. On completion of the treatment period (4.5 months), both groups continued with aspirin (75 mg/d) and unsupervised exercise and were re-examined after 12 months. Data analysis is based on nonparametric statistics, the Wilcoxon signed ranks test, and the Mann-Whitney test for intragroup and intergroup comparisons, respectively. Results are expressed as median and interquartile ranges. RESULTS: Over the 4.5 months of active treatment, (1) median ICD in group 1 increased by 146% (P <.001), from 78 m (interquartile range, 65-102 m) at baseline to 191.5 m (interquartile range, 127-254 m); ICD did not significantly increase in group 2; (2) median ACD in group 1 improved by 106% (P <.001), from 124 m (interquartile range, 100-160 m) to 255 m (interquartile range, 149-398 m); no significant changes were documented in group 2; (3) median r-ABI in group 1 rose by 18% (P <.001), from 0.57 (interquartile range, 0.48-0.62) to 0.67 (interquartile range, 0.64-0.70); no improvement was noted in group 2; (4) median p-eABI in group 1 rose by 110% (P <.001), from 0.21 (interquartile range, 0.07-0.27) to 0.44 (interquartile range, 0. 36-0.52); no changes were noted in group 2; and (5) median popliteal artery volume flow in group 1 improved by 36% (P <.001), from 100 mL/min (interquartile range, 59-163 mL/min) to 136 mL/min (interquartile range, 99.5-173.4 mL/min); no significant changes were found in group 2. At 4.5 months, ICD, ACD, r-ABI, and p-eABI in group 1 were all significantly better than those in group 2 (P <.01). Twelve months' posttreatment, walking ability and ABIs in group 1 were not statistically different from those at 4.5 months and remained significantly better than those of control subjects. CONCLUSION: Intermittent pneumatic foot compression used at home for 4.5 months increases claudication distance by over 100%. Associated increases in r-ABI by 18%, p-eABI by 110%, and arterial calf inflow by 36% suggest an improved collateral circulation. Maximum benefit seems to be offered over the initial 3 months. Treatment benefits are maintained 1 year after treatment. A multicenter study is indicated to quantify actual benefits and to demonstrate cost effectiveness.

Aged↗
PubMed2000

Visceral aneurysms in Ehlers-Danlos syndrome: case report and review of the literature.

A patient with Ehlers-Danlos syndrome type IV had a celiac artery aneurysm. There are only nine previously published cases of visceral artery aneurysms in this condition, and surgical management was used in only four of them. This is, we believe, the first published report of a successfully treated celiac artery aneurysm in this condition in which the hazards of treatment and our rationale are explained. The literature of this rare problem is also reviewed.

Adult↗
PubMed2000

Mucopolysaccharidosis type VII in the developing mouse fetus.

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a deficiency of beta-glucuronidase (1). MPS VII is a fatal, progressive degenerative disorder, and a number of patients die of hydrops fetalis. Thus an approach to treating this disease may be by transplantation or gene therapy in utero. A mouse model of MPS VII has been studied extensively but the disease in affected fetal mice has not been characterized, which is essential for evaluation of therapeutic efficacy. Fetal and newborn mice affected with MPS VII were examined for lysosomal enzyme activities and for the presence of typical storage lesions in comparison to normal and carrier littermates. No beta-glucuronidase enzymatic activity was detected in any of the tissues of affected mice, indicating that transplacental transfer of beta-glucuronidase from the dam did not occur. Lesions were not detected in affected fetuses of 13.5 d gestational age on light or electron microscopy. Vacuolation in cells, typical of lysosomal accumulation of substrate, was first seen in a small number of cells of the reticulo-endothelial system in 15.5 d gestational age livers and in 18.5 d gestational age brains. Storage lesions were not seen consistently in endothelial and Kupffer cells of fetal livers until 18.5 d gestational age and in brains until birth. The results suggest that treatment of affected mice performed at 13.5 d gestational age may be effective in forestalling disease manifestations.

Animals↗
PubMed2000

Endotoxemia during supraceliac aortic crossclamping is associated with suppression of the monocyte CD14 mechanism: possible role of transforming growth factor-beta1.

PURPOSE: Monocyte CD14 and its soluble form (sCD14) mediate the proinflammatory response to endotoxemia. The aim of this study was to measure the changes to these factors after major aortic surgery and the possible inhibitory role of transforming growth factor-beta(1) (TGF-beta(1)) during these procedures. METHODS: Twenty-four patients with supraceliac aortic crossclamping during thoracoabdominal aortic aneurysm (TAAA) repair and 12 patients with infrarenal aortic crossclamping as part of infrarenal aneurysm repair (AAA) were studied. Blood was collected at incision, aortic clamping, and reperfusion and at 1, 8, and 24 hours after reperfusion. Samples were assayed for endotoxin, peripheral blood monocyte CD14 expression, sCD14, tumor necrosis factor-alpha, and TGF-beta(1). RESULTS: Although there was significant endotoxemia on reperfusion in both groups of patients, peak plasma endotoxin levels were significantly higher in patients with TAAA (P =.001). Monocyte CD14 and plasma sCD14 were significantly decreased in patients with TAAA at reperfusion and 1 hour after reperfusion (P <.01, both points). In patients with AAA, a significant upregulation of CD14 was observed at 24 hours after reperfusion (P <.01), but no significant changes in sCD14 were observed. TNF-alpha showed no significant changes during the study period in both groups. In patients with TAAA, TGF-beta(1) showed significant elevation at all time points (P <.01); whereas in patients with AAA, TGF-beta(1) showed no significant changes. CONCLUSION: Splanchnic ischemia reperfusion in patients who undergo supraceliac aortic clamping is associated with peripheral blood monocyte CD14 suppression and significant elevation of TGF-beta(1). TGF-beta(1) may play an important role in modulating the immune response to endotoxemia during major aortic aneurysm surgery.

Aged↗
PubMed2000

Venous boot construction for a distal prosthetic bypass.

Autologous vein should be used at all costs for infrainguinal grafting. There is, nevertheless, a need for other materials in tertiary referral centres whose practice is becoming more complex. Polytetrafluoroethylene (PTFE) has been the prosthesis of choice for most surgeons, but results were poor for grafts to crural arteries. The use of a venous boot, cuff, or collar appeared to improve these results, but only one randomized trial has been performed. This article describes the St Mary's venous boot, which purports to combine the advantages of the other techniques.

Anastomosis, Surgical↗
PubMed1999

Molecular basis of feline beta-glucuronidase deficiency: an animal model of mucopolysaccharidosis VII.

A family of domestic cats was found that exhibited clinical and biochemical abnormalities consistent with mucopolysaccharidosis VII, an autosomal recessive lysosomal storage disorder caused by beta-glucuronidase deficiency. beta-Glucuronidase activity was undetectable in affected cat fibroblasts and restored by retroviral gene transfer of rat beta-glucuronidase cDNA. beta-Glucuronidase mRNA was normal in affected cat testis by Northern blot analysis. Normal feline beta-glucuronidase cDNA was cloned and characterized, and amplified from affected cat fibroblasts by reverse transcription coupled polymerase chain reaction. There was a G-to-A transition in the affected cat cDNA that predicted an E351K substitution, destroyed a BssSI site, and eliminated GUSB enzymatic activity in expression studies. Multiple species comparison and the crystal structure of human beta-glucuronidase indicated that E351 is a highly conserved residue most likely essential in maintenance of the enzyme's conformation. BssSI digestion of polymerase chain reaction products amplified from genomic DNA indicated that affected cats were homozygous and cats with half-normal beta-glucuronidase activity were heterozygous for the missense mutation. Carriers identified in this manner produced affected kittens in prospective breedings, and a feline MPS VII breeding colony has been established.

Amino Acid Sequence↗
PubMed1999

Retrovirus vector-mediated correction and cross-correction of lysosomal alpha-mannosidase deficiency in human and feline fibroblasts.

Lysosomal alpha-mannosidase (EC 3.2.1.24) is an exoglycosidase in the glycoprotein degradation pathway. A deficiency of this enzyme causes the lysosomal storage disease alpha-mannosidosis. Retrovirus vector transfer of a new human alpha-mannosidase cDNA resulted in high-level expression of alpha-mannosidase enzymatic activity in deficient human and feline fibroblasts. The expressed alpha-mannosidase had the same biochemical properties (thermal stability, pH profile, inhibitor/activator sensitivity) as the native enzyme expressed in normal cells. The transferred enzyme colocalized with a control lysosomal hydrolase in cell fractionation experiments. The vector-encoded enzyme also was released at high levels from the corrected cells, and was taken up by untreated mutant cells via the mannose 6-phosphate receptor-mediated endocytic pathway (cross-correction). It is envisioned that genetic correction of a subset of cells (e.g., hematopoietic stem cells) in patients will provide a source of corrective enzyme for other affected tissues in this multisystem disease. Development of a vector expressing high levels of alpha-mannosidase that cross-corrects mutant cells will enable somatic gene transfer experiments in the cat model of human alpha-mannosidosis.

Animals↗
PubMed1999

Single cell analysis and selection of living retrovirus vector-corrected mucopolysaccharidosis VII cells using a fluorescence-activated cell sorting-based assay for mammalian beta-glucuronidase enzymatic activity.

Mutations in the acid beta-glucuronidase gene lead to systemic accumulation of undegraded glycosaminoglycans in lysosomes and ultimately to clinical manifestations of mucopolysaccharidosis VII (Sly disease). Gene transfer by retrovirus vectors into murine mucopolysaccharidosis VII hematopoietic stem cells or fibroblasts ameliorates glycosaminoglycan accumulation in some affected tissues. The efficacy of gene therapy for mucopolysaccharidosis VII depends on the levels of beta-glucuronidase secreted by gene-corrected cells; therefore, enrichment of transduced cells expressing high levels of enzyme prior to transplantation is desirable. We describe the development of a fluorescence-activated cell sorter-based assay for the quantitative analysis of beta-glucuronidase activity in viable cells. Murine mucopolysaccharidosis VII cells transduced with a beta-glucuronidase retroviral vector can be isolated by cell sorting on the basis of beta-glucuronidase activity and cultured for further use. In vitro analysis revealed that sorted cells have elevated levels of beta-glucuronidase activity and secrete higher levels of cross-correcting enzyme than the population from which they were sorted. Transduced fibroblasts stably expressing beta-glucuronidase after subcutaneous passage in the mucopolysaccharidosis VII mouse can be isolated by cell sorting and expanded ex vivo. A relatively high percentage of these cells maintain stable expression after secondary transplantation, yielding significantly higher levels of enzymatic activity than that generated in the primary transplant.

Animals↗
PubMed1999

Sustained production of beta-glucuronidase from localized sites after AAV vector gene transfer results in widespread distribution of enzyme and reversal of lysosomal storage lesions in a large volume of brain in mucopolysaccharidosis VII mice.

The lysosomal storage disorders are a large group of inherited diseases that involve central nervous system degeneration. The disease in the brain has generally been refractory to treatment, which will require long-term correction of lesions dispersed throughout the central nervous system to be effective. A promising approach is somatic gene therapy but the methods have so far been inadequate because they have only achieved short-term or localized improvements. A potential approach to overcome these limitations is to obtain sustained high level expression and secretion of the missing normal enzyme from a small group of cells for export to neighboring diseased cells, which might allow the therapeutic protein to reach distal sites. We tested this in a mouse model of mucopolysaccharidosis VII (Sly disease) using an adeno-associated virus vector. After a single treatment the vector continuously produced the normal enzyme from infected cells at the injection sites. The secreted enzyme was disseminated along most of the neuraxis, resulting in widespread reversal of the hallmark pathology. An extensive sphere of correction surrounding the transduction sites was created, suggesting that a limited number of appropriately spaced sites of gene transfer may provide overlapping spheres of enzyme diffusion to cover a large volume of brain tissue.

Animals↗
PubMed1999

Improved management of infrainguinal bypass graft infection with methicillin-resistant Staphylococcus aureus.

BACKGROUND: There is considerable debate over the management of infected infrainguinal grafts. This report describes recent experience in this field and documents the change in clinical practice needed to deal with methicillin-resistant Staphylococcus aureus (MRSA). METHODS: All infected infrainguinal grafts between January 1991 and July 1997 were reviewed. In the light of the findings, clinical practice was modified considerably. A further 1 year was audited prospectively up to August 1998. RESULTS: Twenty-six patients were treated for 27 infrainguinal graft infections (25 prosthetic, two vein). Twenty were treated by complete graft excision as the initial therapy; graft preservation was attempted in six patients. Before 1995, the infecting organisms were predominantly Pseudomonas aeruginosa or methicillin-sensitive staphylococci. Subsequently all 14 patients treated up to 1997 had infection with MRSA. The overall amputation rate was 17 of 26; ten amputations were in patients with MRSA. Four patients died, all with MRSA sepsis. As a result of this experience a policy of complete isolation was adopted for all patients infected with MRSA. In the 12 months since this policy was introduced, 77 infrainguinal grafts (61 vein, 16 prosthetic) have been inserted. Two grafts (3 per cent) have become infected, necessitating graft excision and amputation. CONCLUSION: MRSA infection of an infrainguinal graft is a serious complication with high associated amputation and mortality rates. Isolation and barrier nursing appeared to contain the problem.

Adult↗
PubMed1999

Repair of ruptured thoracoabdominal aortic aneurysm is worthwhile in selected cases.

INTRODUCTION: The risks and benefits of operating on patients with ruptured thoracoabdominal aortic aneurysm (TAAA) have not been defined. The aim of the present study is to report this unit's experience with operations performed for ruptured TAAA over a 10-year period. METHODS: Interrogation of a prospectively gathered computerised database. PATIENTS: Between 1 January 1983 and 30 June 1996, 188 consecutive patients with TAAA were operated on, of whom 23 (12%) were operated for rupture. RESULTS: There were nine survivors (40%). Patients whose preoperative systolic blood pressure remained above 100 mmHg were significantly more likely to survive (4/8 vs. 13/15, p = 0.03 by Fisher's exact test). Survival was also related to Crawford type: type I (two of three survived); II (none of six); III (two of six); and IV (five of eight). All non-type II, non-shocked patients survived operation. Survivors spent a median of 28 (range 10-66) postoperative days in hospital, of which a median of 6 (range 2-24) days were spent in the intensive care unit. Survivor morbidity comprised prolonged ventilation (> 5 days) (n = 3); tracheostomy (n = 1); and temporary haemofiltration (n = 2). No survivor developed paraplegia or required permanent dialysis. CONCLUSIONS: Patients in shock with a Crawford type II aneurysm have such a poor prognosis that intervention has to be questioned except in the most favourable of circumstances. However, patients with types I, III and IV who are not shocked on presentation can be salvaged and, where possible, should be transferred to a unit where appropriate expertise and facilities are available.

Aged↗