Biomedical subjects

Paula K Shireman

Publications and source records attributed to Paula K Shireman.

14 recordsLinked to original sources

PubMed2006

MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration.

We examined the role of MCP-1, a potent chemotactic and activating factor for macrophages, in perfusion, inflammation, and skeletal muscle regeneration post-ischemic injury. MCP-1-/- or C57Bl/6J control mice [wild-type (WT)] underwent femoral artery excision (FAE). Muscles were collected for histology, assessment of tissue chemokines, and activity measurements of lactate dehydrogenase (LDH) and myeloperoxidase. In MCP-1-/- mice, restoration of perfusion was delayed, and LDH and fiber size, indicators of muscle regeneration, were decreased. Altered inflammation was observed with increased neutrophil accumulation in MCP-1-/- versus WT mice at Days 1 and 3 (P< or =0.003), whereas fewer macrophages were present in MCP-1-/- mice at Day 3. As necrotic tissue was removed in WT mice, macrophages decreased (Day 7). In contrast, macrophage accumulation in MCP-1-/- was increased in association with residual necrotic tissue and impaired muscle regeneration. Consistent with altered inflammation, neutrophil chemotactic factors (keratinocyte-derived chemokine and macrophage inflammatory protein-2) were increased at Day 1 post-FAE. The macrophage chemotactic factor MCP-5 was increased significantly in WT mice at Day 3 compared with MCP-1-/- mice. However, at post-FAE Day 7, MCP-5 was significantly elevated in MCP-1-/- mice versus WT mice. Addition of exogenous MCP-1 did not induce proliferation in murine myoblasts (C2C12 cells) in vitro. MCP-1 is essential for reperfusion and the successful completion of normal skeletal muscle regeneration after ischemic tissue injury. Impaired muscle regeneration in MCP-1-/- mice suggests an important role for macrophages and MCP-1 in tissue reparative processes.

Animals↗

PubMed2006

Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2-/- mice following ischemic injury.

Chemokines recruit inflammatory cells to sites of injury, but the role of the CC chemokine receptor 2 (CCR2) during regenerative processes following ischemia is poorly understood. We studied injury, inflammation, perfusion, capillary formation, monocyte chemotactic protein-1 (MCP-1) levels, muscle regeneration, fat accumulation, and transcription factor activation in hindlimb muscles of CCR2-/- and wild-type (WT) mice following femoral artery excision (FAE). In both groups, muscle injury and restoration of vascular perfusion were similar. Nevertheless, edema and neutrophil accumulation were significantly elevated in CCR2-/- compared with WT mice at day 1 post-FAE and fewer macrophages were present at day 3. MCP-1 levels in post-ischemic calf muscle of CCR2-/- animals were significantly elevated over baseline through 14 days post-FAE and were higher than WT mice at days 1, 7, and 14. In addition, CCR2-/- mice exhibited impaired muscle regeneration, decreased muscle fiber size, and increased intermuscular adipocytes with similar capillaries/mm(2) postinjury. Finally, the transcription factors, MyoD and signal transducers of and activators of transcription-3 (STAT3), were significantly increased above baseline but did not differ significantly between groups at any time point post-FAE. These findings suggest that increases in MCP-1, and possibly, MyoD and STAT3, may modulate molecular signaling in CCR2-/- mice during inflammatory and regenerative events. Furthermore, alterations in neutrophil and macrophage recruitment in CCR2-/- mice may critically alter the normal progression of downstream regenerative events in injured skeletal muscle and may direct myogenic precursor cells in the regenerating milieu toward an adipogenic phenotype.

Adipocytes↗

PubMed2006

Glutathione-peroxidase-1 null muscle progenitor cells are globally defective.

Mice lacking glutathione peroxidase-1 (Gpx1) have decreased resistance to systemically administered oxidants as well as infections, and sustain increased damage after ischemia-reperfusion injuries. However, stem or progenitor cell function in these animals has not been studied. We characterized patterns of proliferation, apoptosis, and differentiation of primary muscle progenitor cells (myoblasts) from Gpx1(-/-) mice. Myoblasts are the transit amplifying compartment of skeletal muscle. All aspects of myoblast biology are negatively affected by deletion of Gpx1. In particular, passaged, proliferating Gpx1(-/-) myoblasts, when induced to differentiate into fused multinucleated myotubes, show significant impairment, and form only a few immature myotubes. This defect occurs despite increased expression of the core regulators of muscle differentiation, the myogenic basic helix-loop-helix (bHLH) transcription factors, in the Gpx1(-/-) myoblasts. Furthermore, Gpx1(-/-) myoblasts exhibited decreased proliferation and increased apoptosis compared to wild-type cells. In vivo, muscle fiber areas are decreased in Gpx1(-/-) vs wild-type mice. These data suggest that Gpx1 is important for adult muscle progenitor cell function at many levels, is necessary for integrity of muscle differentiation, and that quiescent resident stem cell populations may be particularly vulnerable to peroxide-mediated damage.

Animals↗

PubMed2006

MCP-1 parallels inflammatory and regenerative responses in ischemic muscle.

BACKGROUND: Monocyte chemotactic protein-1 (MCP-1) is important in macrophage recruitment and activation. However, the magnitude and temporal sequence of MCP-1 expression in relation to tissue injury and regeneration following ischemic injury remains unknown. MATERIALS AND METHODS: Hind limb ischemia was induced by femoral artery excision (FAE) in C57Bl/6J mice; a sham surgery was performed on the contralateral leg. Muscle lysates were used to measure MCP-1 and activities of creatine kinase, lactate dehydrogenase, and myeloperoxidase. Histology and immunohistochemistry were used to localize inflammation and MCP-1. RESULTS: FAE resulted in a prolonged period of ischemia and the administration of MCP-1 did not alter the restoration of perfusion. One day after femoral artery excision, extensive muscle necrosis and neutrophils were prevalent throughout the musculature of the lower leg. By 3 days, a mononuclear cell infiltrate predominated in association with robust muscle regeneration as indicated by myoD expression. Concomitantly, myeloperoxidase was maximally increased. Muscle enzymes (creatine kinase and lactate dehydrogenase) were maximally decreased within 3 days and returned to baseline levels by day 14, a time course consistent with injury and regeneration observed by histology. In parallel with these inflammatory and regenerative events, MCP-1 in muscle was maximally increased at day 3. By immunohistochemistry, MCP-1 was within vascular endothelial cells and infiltrating macrophages in areas of ischemic injury. CONCLUSIONS: The transient increases and selective tissue distribution of MCP-1 during early inflammation and muscle regeneration support the hypothesis that this cytokine participates in the early reparative events preceding the restoration of vascular perfusion following ischemic injury.

Animals↗

PubMed2005

Differential necrosis despite similar perfusion in mouse strains after ischemia.

BACKGROUND: Numerous mouse models have been used to study the tissue response to ischemia, but multiple technical differences make comparisons difficult. We have comprehensively characterized the mouse hind limb ischemia model and determined how different genetic backgrounds of mice affect recovery. MATERIALS AND METHODS: Severity of tissue necrosis and restoration of perfusion after femoral artery excision or femoral artery transection, using five different surgical procedures, were evaluated using laser Doppler imaging in a mouse model of hind limb ischemia. Severity of necrosis was concurrently measured using a five-point scale. RESULTS: Significant differences were observed depending upon the surgical procedure used to initiate ischemia as well as the strain of mouse used. First, a progressively delayed and incomplete recovery of vascular perfusion occurred in relation to the anatomical position and extent of the arterial defect. Second, among mouse strains, the severity of tissue necrosis varied despite similar restoration of perfusion. Thus, DBA/1J mice had significantly increased severity and incidence of tissue loss as compared with either C57Bl/6J (P = 0.01) or BALB/c (P = 0.01) mice. Finally, contrary to previous reports, T-cell-mediated immune events did not modify ischemia-induced hind limb perfusion and necrosis as responses in nude mice were not different than controls on either BALB/c or C57Bl/6J backgrounds. CONCLUSIONS: Surgical approach, mouse strain, and measures of hind limb perfusion and tissue injury are crucial considerations in the study of ischemia. Understanding how different genetic backgrounds in mice can affect necrosis may provide insights into the diverse healing responses observed in humans.

Angiography↗

PubMed2005

Healing of transmetatarsal amputation in the diabetic patient: is angiography predictive?

Transmetatarsal amputation (TMA) is a durable reconstruction in the diabetic patient with limited forefoot gangrene. However, predicting TMA healing remains difficult. Our goals were to (1) determine the success rate of TMA and (2) identify factors predictive of TMA healing, in particular arterial foot anatomy. A retrospective review of all diabetic patients undergoing TMA was done. Blood supply to the foot was classified as mostly anterior (anterior tibial and/or dorsalis pedis artery), mostly posterior (posterior tibial or plantar arteries), or equally distributed (both systems patent or peroneal runoff). Foot vessels were assigned runoff scores from 0 to 3 according to Society for Vascular Surgery/International Society for Cardiovascular Surgery (SVS/ISCVS) criteria. Forty-four TMAs in 29 men and 12 women were reviewed. Revascularization was done in 35 cases. In nine cases (20%), no bypass was deemed necessary (n = 7) or feasible (n = 2). Blood flow to the foot was deemed mostly anterior in 16 cases, mostly posterior in 17 cases, and equally distributed in 11. The TMA was left open in 19 cases and closed with staples or sutures in the rest. Limb salvage was achieved in 30 cases (68%) at a median follow-up of 48 weeks. Three of the four patients on dialysis required leg amputation (75%) vs. 11 of the 40 (27%) nondialysis patients (p = 0.05). When the TMA was left open, leg amputation was more likely (58%) than when closed primarily (12%) (p < 0.01). No angiographic factors were predictive of limb salvage. The need for revascularization was not associated with limb loss, although both patients with no feasible bypass option required below-knee amputation. TMA healing can be expected in a majority of diabetic patients after adequate revascularization but cannot be predicted by angiographic findings. Efforts should be made to achieve primary wound closure.

Aged↗

PubMed2003

Outcomes following distal bypass graft occlusion in diabetics.

The objectives of this study were to define clinical outcomes following distal bypass graft occlusion in diabetic patients and identify factors predictive of limb loss. A retrospective review was conducted of all distal graft occlusions over a 5-year period in diabetic patients. Popliteal grafts, perioperative (30 days) failures, and redo distal bypasses were excluded. Eighty grafts were studied (43 cases done for ulcers, 31 for gangrene, and 6 for rest pain). Time to occlusion averaged 13 +/- 17 months post-bypass (median 6 months). Interventions following graft occlusion (lysis, thrombectomy, revision, or new bypass) were carried out in only 26 cases, leading to limb salvage in 11 cases (42%). This compares to a limb salvage rate of 54% in the 54 cases where no intervention was done ( p = NS). The overall amputation rate was 50% (14 AKAs and 26 BKAs). The interval between graft occlusion and amputation averaged 2 +/- 2 months. Limbs saved were followed an average of 14 +/- 11 months after graft occlusion. The presence of a foot wound (new or old) was associated with a higher likelihood of amputation (67% vs. 32% for cases with no foot wounds at the time of bypass failure; p < 0.005). In cases requiring an amputation, the toebrachial index averaged 0 +/- 0 post-bypass failure vs. 0.2 +/- 0.2 in cases where limbs were saved ( p < 0.05). Patients with congestive heart failure or who were nonambulatory at the time of graft occlusion were more likely to end up with an amputation ( p < 0.05). Limb loss was also more likely when gangrene had been the initial operative indication. No other factors were predictive of limb loss, including vein configuration, inflow or outflow level, prior bypass revision, known graft stenosis, time to occlusion, age, gender, other medical conditions, pre- or post-bypass ABI or TBI, graft velocities, or use of anticoagulants. Limb loss following primary distal bypass failure in diabetics is high. Repeat interventions have limited success. The findings justify aggressive programs of graft maintenance, and vigorous attempts at early closure of foot wounds.

Amputation, Surgical↗

PubMed2003

Duplex screening for asymptomatic carotid artery disease in Hispanic diabetic patients undergoing lower extremity revascularization: is it a worthwhile endeavor?

Screening for carotid artery disease in patients with systemic manifestations of atherosclerosis (e.g., peripheral vascular disease or coronary artery disease) has been recommended. We have been anecdotally impressed by what appears to be a unique atherosclerotic disease pattern in the Hispanic patient population of South Texas. To determine the prevalence of significant carotid artery disease in Hispanic patients with diabetes presenting with limb-threatening ischemia and to identify factors predictive of occurrence, we conducted a year-long prospective study of 92 consecutive patients undergoing infrainguinal bypass for limb salvage at The University of Texas Health Science Center in San Antonio. Peak systolic and end diastolic velocities in both internal carotid arteries were recorded by perioperative color duplex scanning. We found that the presence of a carotid artery stenosis did not correlate with any variables other than advanced age and presence of a bruit. Only 2 patients had a greater than 80% stenosis. We concluded that screening for carotid artery disease in diabetic Hispanics with critical lower extremity ischemia cannot be justified in younger patients. Even in patients older than 60 years, the presence of high-grade stenosis and, therefore, the need for carotid endarterectomy, is unlikely. However, screening in older patients is recommended to identify persons with moderate stenosis (peak systolic velocity greater than 175 cm/sec) whose disease is more likely to progress.

Adult↗

PubMed2002

Early duplex-derived hemodynamic parameters after lower extremity bypass in diabetics: implications for mid-term outcomes.

Early postoperative changes in the hemodynamic parameters of infrainguinal bypass grafts in diabetics have not been well defined. We undertook this study to better define such changes in duplex-derived velocities and waveforms, and correlate any observed changes with intermediate-term outcomes. A prospective study of 68 primary vein bypasses for limb salvage was carried out, with scans obtained intraoperatively, daily until discharge, and at 8- to 12-weeks intervals. During follow-up (12 +/- 6 months), 20 grafts developed stenoses, 17 occluded, and 8 limbs were amputated. Most grafts show a variant of a biphasic waveform intraoperatively at the mid-graft (MG) and distal graft (DG) levels (54% and 57%); 65% of waveforms remain unchanged during the first week, and 54% remain unchanged at 3 months. No duplex-derived factors were predictive of the development of stenoses. A number of parameters were predictive of ultimate graft thrombosis. Intraoperative MG velocity was higher in grafts that eventually remained patent (83 +/- 36 vs. 60 +/- 29 cm/sec; p <0.025). Grafts that remained patent also had a much lower decline in DG and distal native (DN) velocities from immediately postoperative to 8-12 weeks later, than grafts that eventually thrombosed (-3 +/- 35 vs. -44 +/- 43 cm/sec for DG, p <0.001; and -17 +/- 66 vs. -76 +/- 53 cm/sec for DN, p <0.04 respectively). In terms of limb salvage, when the MG or DG waveform worsened (from postoperation to 12 weeks later), amputation was more likely than when it remained unchanged or improved (MG 67% vs. 9% limb loss, p <0.04; DG 43% vs. 8% limb loss, p <0.04). We conclude that intensive graft duplex surveillance does not identify grafts likely to develop stenoses. However, a number of features allow the prediction of ultimate graft failure or limb loss.

Aged↗

PubMed2002

Does lower limb revascularization result in an improvement in sensory perception thresholds?

Patients with peripheral vascular disease are susceptible to neuropathy from chronic hypoxia. We wished to determine whether revascularization of chronically ischemic limbs results in any clinical changes in peripheral sensory thresholds. We prospectively measured quantitative vibration perception thresholds (VPT) using a Horwell neurothesiometer (in volts) in patients undergoing infrainguinal bypass, preoperatively and up to 6 month postoperatively. The bypassed limbs' preoperative VPT values were higher (lesser sensory perception) than the contralateral control limbs' preoperative values (mean score differences: 6 +/- 2 and 4 +/- 10 at toe and foot levels respectively; p ? 0.004). Preoperative VPT values were not different from the 6-month postoperative values for the revascularized legs at toe and foot levels for all 55 patients (mean score change of ?0.84 and ?1.32, p > 0.5). The contralateral limbs' VPT values did not change significantly over the 6-month period (mean change scores of 2.9, p > 0.15, and 2, p > 0.30, for toe and foot, respectively). A comparison of preoperative values between limbs that were eventually amputated and saved revealed no statistically significant differences. This study suggests that revascularization does not result in a clinically detectable improvement in sensory neuropathy. It may, however, prevent further degradation. The degree of preoperative neuropathy does not affect outcome in terms of limb salvage.

Aged↗

PubMed2002

Angiographic scoring of vascular occlusive disease in the diabetic foot: relevance to bypass graft patency and limb salvage.

OBJECTIVE: We graded the severity of occlusive disease in foot vessels of patients with diabetes and correlated the scoring obtained with graft patency and limb salvage. METHODS: In this retrospective review of 199 limbs studied by means of angiography in 117 patients with diabetes mellitus, 124 limbs underwent bypass grafting. Each dorsalis pedis (DP), lateral plantar (LP), and medial plantar (MP) artery was assigned a score according to the reporting standards of the Joint Vascular Societies Council (0, no stenosis > 20%; 1, 21%-49% stenosis; 2, 50%-99% stenosis; 2.5, < half the vessel length occluded; 3, > half the vessel length occluded.) A foot score (DP + MP + LP + 1) was calculated for each foot (1 to 10). The mean follow-up period was 14 months. RESULTS: For all 199 limbs and for the 124 limbs that underwent bypass grafting, the mean scores were similar for the DP, MP, and LP (1.8 +/- 1.0, 1.9 +/- 1.0, 1.9 +/- 1.0, respectively; P >.4). Only the MP and LP correlated with each other (r = 0.57; P <.0001). There were no scoring differences between limbs with symptoms and limbs that did not undergo bypass grafting. Bypass graft patency correlated with both the foot score and the MP score for tibial and inframalleolar grafts (P <.04). Patency correlated with the LP score only for inframalleolar bypass grafting procedures. The DP score alone did not differ between bypass grafts that remained patent and bypass grafts that failed. Bypass grafts in limbs with a foot score less than 7 and an MP score less than 2 had only a 2% failure rate. A foot score greater or equal to 7 was associated with a 30% failure rate for all bypass grafts (41% for inframalleolar grafts). Bypass grafts with low foot scores that failed did so much later than bypass grafts with high foot scores that failed (17 +/- 11 months vs 6 +/- 8 months; P <.02), possibly reflecting different etiologies for the failure. The limb salvage rate correlated with foot score (P <.05). The limbs that were saved had an average foot score of 6.4 +/- 2.0, versus 7.2 +/- 1.4 for limbs that required amputation. CONCLUSION: In patients with diabetes mellitus, the foot score is a useful tool for predicting the likelihood of graft patency and limb salvage for infrapopliteal revascularization. However, the relatively high bypass success rate (70%) in the presence of a high foot score (>or= 7) does not allow its use in identifying the subgroup of patients who are unlikely to benefit from bypass grafting surgery. It cannot be used as a means of selecting patients for primary amputation.

Arterial Occlusive Diseases↗

PubMed2002

Major lower-extremity amputation: contemporary experience in a single Veterans Affairs institution.

Our objective is to describe our current experience with major lower-extremity amputation secondary to vascular disease. We conducted a retrospective review of sequential amputations over a 3-year period at one Veterans Affairs institution. One hundred thirteen amputations were performed in 99 men (age 70 +/- 11 years). Seventy-five per cent were diabetic and 23 per cent were on dialysis. Fifty-six per cent were primary amputations. The final AKA/BKA (above-knee to below-knee amputation) ratio was 3:2 and was not related to prior bypass, ethnicity, or dialysis status (P > 0.5). Forty-three per cent of amputations were BKAs in diabetics versus 26 per cent in nondiabetics (P = 0.08). The in-hospital and 30-day mortality rates were 2.6 and 8 per cent and were not related to amputation level (P = 0.76). Forty per cent experienced postoperative complications that were most frequently wound related (22%). Wound complications were more frequent with BKA than AKA (P = 0.04). At an average follow-up of 10 +/- 8 months only 65 per cent were alive. Although 51 per cent were discharged to rehabilitation units only 26 per cent regularly wore a prosthesis with 23 per cent ambulating. BKA patients were more likely to ambulate than AKA (34% vs 9%; P = 0.001), and dialysis patients were less likely to ambulate than nondialysis patients (5% vs 25%; P < 0.02). During follow-up 17 per cent of patients discharged with an intact contralateral limb required amputation of that limb and 7 per cent had bypass surgery on that limb. Complication rates were higher in African Americans and Hispanics than in whites (59%, 45%, and 23%, respectively; P < 0.001), although mortality and ambulation rates were similar. Despite an acceptable perioperative mortality complication rates remain high especially in nonwhites. One-year mortality is high. Low rehabilitation rates especially in dialysis patients mandate further efforts in this regard. Vigilant follow-up of the contralateral limb is essential.

Aged↗

PubMedDate not supplied

Does the efficacy of dorsalis pedis artery bypasses vary among diabetic patients of different ethnic backgrounds?

Hispanic patients suffer from a high rate of leg amputations, far beyond what would be expected from the high prevalence of diabetes in this population. This raises questions about the efficacy of bypass operations across ethnic lines. We focused this review on dorsalis pedis bypasses, as these are frequently performed in diabetic patients. We compared outcomes between Hispanics and non-Hispanics and sought to identify factors predictive of failure or complications. The authors conducted a retrospective review of 144 dorsalis pedis bypasses in 106 men and 29 women with a mean age of 62 years. Eighty-two percent were Hispanic; 96% of cases were done for tissue loss, and 4% for rest pain. Twenty-five percent of patients experienced perioperative complications; these were more frequent in non-Hispanics than Hispanics (40% vs 22%, p = 0.05). The most frequent complications were wound related (11%). The 30-day mortality was 1.5% and 30-day graft thrombosis was 5%. Follow-up ranged from 1 to 62 months and averaged 12 months. Eighty-one percent of the limbs at risk were saved, although 36% of cases required minor foot amputations. Estimated primary graft patency was 68% at 30 months. The 30-month Kaplan-Meier curves for primary patency, assisted patency, and limb salvage were not statistically different between Hispanics and non-Hispanics (p > 0.4). Grafts that remained patent had higher duplex-derived intraoperative flow velocities in the dorsalis pedis artery than grafts that eventually failed (121 +/-69 vs 74 +/-26 cm/sec, p = 0.02). In grafts that remained patent, dorsalis pedis velocity decreased from the perioperative period to the 8 to 12 weeks time point, whereas no change was seen in grafts that eventually failed (mean decline of 48 +/-76 vs 1 +/-58 cm/sec, p = 0.02). No other factors were predictive of graft failure. The results of dorsalis pedis bypass in Hispanic patients compare favorably to those seen in other ethnic groups. This suggests that other factors must account for the high amputation rates seen in Hispanics, such as a frequent occurrence of nonreconstructible disease or unaccounted for cardiovascular risk factors. The usefulness of duplex-derived flow velocities in the dorsalis pedis to predict long-term graft patency warrants further investigation.

Adult↗

PubMedDate not supplied

Current concepts in diabetic microvascular dysfunction.

Microvascular dysfunction is an important component of the pathologic processes that occur in diabetic foot disease. The endothelial abnormalities observed in patients with diabetes mellitus are poorly understood, and evidence suggests that endothelial dysfunction could be involved in the pathogenesis of diabetic macroangiopathy and microangiopathy. With the advent of insulin replacement in the early 1900s and increased efforts toward metabolic control of diabetes, long-term complications of this disease have become apparent. These late-term complications are primarily disorders of the vascular system. This article reviews the process of microvascular dysfunction and how it may relate to the pathogenesis of diabetic foot problems.

Diabetic Angiopathies↗