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Biomedical subjects

J D Wagner

Publications and source records attributed to J D Wagner.

At least 37 records · Page 2Linked to original sources
PubMed1999

Lymph node tumor volumes in patients undergoing sentinel lymph node biopsy for cutaneous melanoma.

BACKGROUND: Regional lymph node tumor volumes in patients undergoing sentinel lymph node (SN) biopsy (SNB) for treatment of cutaneous melanoma have not been described. The objectives of this study were to describe the lymph node tumor volumes typically seen in this population and to correlate tumor volumes with tumor thickness and positive SN characteristics. METHODS: Review of a consecutive series of patients with clinically localized cutaneous melanoma who underwent SNB of nonpalpable regional lymph node basins followed by complete lymphadenectomy (LND) was performed. Multiple lymph node sections from positive SNs and nonsentinel nodes (NSNs) in LND specimens were examined microscopically. Individual tumor deposit diameters were measured using an ocular micrometer. Aggregate tumor volumes were calculated for SN and LND specimens. Tumor volumes and SN and LND positivity rates were correlated with tumor thickness, the number of positive SNs, and the presence of multiple SN tumor deposits. RESULTS: SNB procedures were performed for 149 melanomas in 189 regional nodal basins. The mean tumor depth was 2.48 mm. The mean number of SNs/basin was 2.1. Thirty-two of 149 SNB procedures (21.5%) revealed a total of 34 nodal basins with at least one positive SN. The median tumor volume in positive SNs was 4.7 mm3 (range, 0.1-3618 mm3; mean, 209 mm3). The median aggregate tumor volume in positive LND specimens was 4.9 mm3 (range, 0.1-3618 mm3; mean, 224 mm3). Six basins (17.6%) contained at least one positive NSN. The regional node aggregate tumor volume correlated weakly with tumor thickness (Pearson's correlation coefficient = .302, P = .0934). NSN positivity was not predicted by tumor thickness, American Joint Committee on Cancer tumor stage, number of positive SNs, or number of metastatic deposits within SNs. CONCLUSIONS: Most melanoma-positive SNs contain minute tumor volumes. Tumor thickness and patterns of SN metastases may not be predictive of tumor burden or the presence of positive NSNs.

Biopsy↗
PubMed1999

Glycation of plasma low density lipoproteins increases interaction with arterial proteoglycans.

The increased susceptibility to atherosclerosis of diabetic individuals, may result from diabetes-associated modification in plasma low density lipoproteins (LDL) which enhance their interaction with arterial extracellular matrix proteoglycans. Using a nonhuman primate model for human diabetes, studies were conducted to examine diabetes-induced changes in LDL. Plasma LDL were isolated from control (n = 4) and streptozotocin-induced diabetic (n = 3) cynomolgus macaques by differential ultracentrifugation. An in vitro binding assay was used to measure LDL interaction with arterial proteoglycans. Significantly more diabetic LDL bound to proteoglycans than control LDL (12.9+/-0.7 microg LDL cholesterol/microg proteoglycan versus 8.9+/-0.5 microg LDL cholesterol/microg proteoglycan (mean +/- S.E.M.), P < 0.005). Glycation of LDL, determined by fructosamine content, was significantly enhanced in diabetic versus control animals (37+/-3.1 versus 20+/-1.5 micromol/l (mean +/- S.E.M.) P < 0.005). The correlation coefficient between fructosamine content of LDL and its binding to arterial proteoglycans was 0.95. No LDL compositional variables other than glycation correlated with proteoglycan binding. Removal of the glycated portion of LDL from diabetic animals returned LDL proteoglycan binding to normal. These data demonstrate that the diabetes induced glycation of LDL increases its proteoglycan binding properties: thus, a critical mechanism in atherosclerosis, enhanced LDL interaction with arterial proteoglycans, may be accelerated by the diabetic state.

Animals↗
PubMed1999

Intact dietary soy protein, but not adding an isoflavone-rich soy extract to casein, improves plasma lipids in ovariectomized cynomolgus monkeys.

The dietary consumption of soy protein has been linked to a reduction in coronary heart disease and improvements in a number of related risk factors. Recent investigations have focused on isoflavone components of soy protein. The purpose of this study was to examine plasma lipids and lipoproteins, particularly LDL, with the intake of intact soy protein or casein-lactalbumin diets with and without a semipurified extract of soy, rich in isoflavones. Sixty ovariectomized cynomolgus monkeys were assigned to one of three groups fed diets containing the following: 1) casein-lactalbumin as the protein source (CAS; n = 20); 2) CAS plus a semipurified extract of soy, rich in isoflavones (ISO; n = 20); or 3) intact soy protein (SOY; n = 20) for 12 wk. Lipoproteins were fractionated by combined ultracentrifugation and HPLC. Isolated LDL particles were further subfractionated by dividing the LDL peak into three fractions for compositional analyses. The SOY group had significantly lower plasma total cholesterol, VLDL plus IDL cholesterol and LDL cholesterol, and significantly less HDL cholesterol than the CAS group. LDL particles from the SOY group had a significantly less cholesteryl ester than the CAS group. The semipurified extract of soy, rich in isoflavones, added to casein-lactalbumin protein did not have the same effects as intact soy protein on plasma lipids and lipoproteins. Other components of soy protein, either alone or in combination with isoflavones, may be involved in the effects seen in this study.

Animals↗
PubMed1999

Influence of caloric restriction on the development of atherosclerosis in nonhuman primates: progress to date.

Caloric restriction (CR) has been observed to retard aging processes and extend the maximum life span in rodents. In an effort to evaluate the effect of this nutritional intervention on physiologic variables in higher species, several nonhuman primate trials are ongoing. In particular, a study evaluating the independent effect of CR on the extent of atherosclerosis was initiated in 1993 in 32 adult cynomolgus monkeys. Therefore, the trial was designed to achieve identical cholesterol intake after animals were randomized to a control group or a calorie-restricted group (30% reduction from baseline caloric intake). The animals were routinely evaluated for glycated proteins, plasma insulin and glucose levels, insulin sensitivity, and specific measures for abdominal fat distribution by CT scans over a 4-year interval. The results from 4 years of intervention demonstrate that CR improves cardiovascular risk factors (such as visceral fat accumulation) and improves insulin sensitivity. In contrast to other primate studies with normolipidemic animals, CR had no independent effects on plasma lipid levels and composition in the presence of equivalent amounts of dietary cholesterol intake. Preliminary analysis of atherosclerotic lesion extent in the abdominal aorta has failed to demonstrate differences between control animals and CR animals. Follow-up studies are being conducted to determine the effect of CR on atherosclerosis extent in coronary and carotid arteries.

Aging↗
PubMed1999

Lymphoscintigraphy with sentinel lymph node biopsy in cutaneous Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare cutaneous malignancy characterized by an aggressive clinical behavior with high rates of locoregional and systemic recurrence. Regional disease and distant metastases are associated with poor prognosis. Despite a predisposition of MCC to spread via the lymphatics, prophylactic lymph node dissection in the absence of clinically apparent lymph node involvement is controversial. The value of lymphoscintigraphy in cutaneous melanoma is established in lesions with ambiguous lymphatic drainage patterns. When used with sentinel lymph node biopsy (SLNB), it can identify subjects with occult regional node metastasis. The authors present 2 patients with MCC who underwent regional node staging with lymphoscintigraphy-directed SLNB. Both patients had sentinel nodes that were positive for metastatic disease. In patients with MCC, minimally invasive regional node staging SLNB may be useful in limiting the sequelae of routine lymphadenectomies. Whether early identification and treatment of patients with occult regional node disease can influence survival in MCC is not known.

Aged↗
PubMed1999

Risk factors for predicting surgical salvage of sternal wound-healing complications.

A retrospective study was performed to determine whether clinical factors can predict which complicated poststernotomy wounds can be managed successfully by debridement and reclosure, and which wounds require a muscle flap for healing. Between January 1990 and December 1996, 3,435 median sternotomies were performed at Indiana University Medical Center and affiliated hospitals. A total of 91 patients (2.6%) were reoperated for sternal wound-healing complications. Seventy-six patients (83.5%) underwent debridement and rewiring, and 15 patients (16.5%) underwent primary flap coverage. Of the 76 patients who underwent initial rewiring, 45 (59%) healed and 31 (41%) required additional operative procedures. Of the 31 rewiring failures, 26 patients (84%) were healed with muscle flaps and 4 patients (13%) were managed with a second successful rewiring. The following clinical factors were correlated with operative procedure and outcome: history of smoking, chronic obstructive pulmonary disease, steroid use, previous sternotomy, age, diabetes, harvest of the left or right internal mammary artery (IMA), emergency operation, operation time, pump time, cross-clamp time, ischemic time, coronary artery bypass grafting alone versus combined with a valve replacement, positive wound cultures, positive blood cultures, elevated white blood cell count, and fever. When comparing patients with successful rewiring with those who had a failed rewiring, positive wound and blood cultures were significant risk factors (p < 0.05) on univariate analysis. Presence of a positive wound culture was significant on multivariate analysis. When comparing risk factors in patients who were rewired successfully versus all patients who had muscle flap coverage, the presence of a positive blood culture was significant on both univariate and multivariate analyses. We conclude patients most likely to fail rewiring and to require muscle flap closure are those with infected wounds, positive blood cultures, and possibly left IMA bypasses.

Adult↗
PubMed1999

Prospective study of fluorodeoxyglucose-positron emission tomography imaging of lymph node basins in melanoma patients undergoing sentinel node biopsy.

PURPOSE: To prospectively compare positron emission tomography (PET) imaging of regional lymph node basins to sentinel node biopsy (SNB) in patients with American Joint Committee on Cancer (AJCC) stage I, II, and III melanoma localized to the skin. METHODS: Patients with cutaneous melanoma with Breslow's depth greater than 1 mm (AJCC T2-4N0M0) or localized regional cutaneous recurrence (TxN2bM0) underwent whole-body imaging of glucose metabolism with fluorodeoxyglucose (FDG) PET followed by SNB. PET scans were interpreted in a blinded fashion and compared with histologic analyses of SNB specimens and clinical follow-up examination. Nodal tumor volumes were estimated. RESULTS: Eighty-nine lymph node basins were evaluated by FDG-PET and SNB in 70 assessable patients. Eighteen patients (25.7%) had lymph node metastases at the time of FDG-PET imaging: 17 proved by SNB (24.3%) and one by follow-up examination (1.4%). Median tumor volume in positive sentinel node basins was 4.3 mm3 (range, 0.07 to 523 mm3). Sensitivity of SNB for detection of occult regional lymph node metastases was 94.4%, specificity was 100%, positive predictive value (PPV) was 100%, and negative predictive value (NPV) was 98.6%. Sensitivity of FDG-PET was 16.7%, specificity was 95.8%, PPV was 50%, and NPV was 81.9%. At a median follow-up duration of 16.6 months, seven patients (10%) developed recurrent disease. PET predicted one recurrence (14.3%) in a node basin missed by SNB. CONCLUSION: FDG-PET is an insensitive indicator of occult regional lymph node metastases in patients with melanoma because of the minute tumor volumes in this population. FDG-PET does not have a primary role for staging regional nodes in patients with clinically localized melanoma.

Adult↗
PubMed1999

Breast cancer in Poland syndrome.

A 33-year-old African-American woman with a severe manifestation of Poland syndrome developed breast cancer in the ipsilateral breast. She had a severely hypoplastic upper extremity, including symbrachydactyly, and a hypoplastic forearm and upper arm. In addition, she lacked the sternal origin of the pectoralis muscle. She had a very small nipple-areola complex and no axillary hair. This is the first case report of breast cancer developing in the ipsilateral breast of a patient with Poland syndrome.

Adult↗
PubMed1999

In vitro lipid peroxidation of LDL from postmenopausal cynomolgus macaques treated with female hormones.

Premenopausal women and postmenopausal women given estrogen are protected from cardiovascular diseases compared with men. Previous studies investigated whether estrogen treatment protects low density lipoprotein (LDL) from in vitro oxidation as a potential mechanistic explanation for the beneficial effect of estrogen. Results of these studies are mixed, and very few studies considered aspects of LDL that influence LDL oxidation. This study investigated whether treating postmenopausal female cynomolgus macaques with conjugated equine estrogens (CEE), medroxyprogesterone acetate (MPA), CEE + MPA, or tamoxifen, a mixed estrogen receptor agonist/antagonist, would protect LDL from in vitro oxidation. LDL was isolated from monkeys fed an atherogenic diet for 12 weeks or the same diet with CEE, MPA, CEE + MPA, or tamoxifen added at levels equivalent (on a caloric basis) to those given to women. LDL was subjected to Cu(2+) (3 micromol/L) or 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH, 1 mmol/L) and LDL oxidation was determined by the lag time before rapid formation of conjugated dienes and by the maximal rate of conjugated diene formation (propagation rate). Lag times and propagation rates were not affected by treatment. Lag times for Cu(2+) oxidation were related to LDL tocopherol while lag times for AAPH oxidation were related to high density lipoprotein (HDL) cholesterol and to LDL molecular weight. Multivariate analysis showed that LDL alpha- and gamma-tocopherol together could explain 27% of the variation in Cu(2+) mediated lag time (P < 0.005) among animals while HDL cholesterol, LDL gamma-tocopherol, and LDL molecular weight combined could explain 40% of the variation in AAPH- mediated lag time (P = 0.0006) among animals. After adjustment for these predictors, LDL lag times were not affected by treatment. In conclusion, in monkeys treated with female hormones, multiple factors influence in vitro low density lipoprotein (LDL) oxidation; future work will be needed to determine whether estrogen alters oxidation of LDL in the artery.-Schwenke, D. C., J. D. Wagner, and M. R. Adams. In vitro lipid peroxidation of LDL from postmenopausal cynomolgus macaques treated with female hormones.

Alkenes↗
PubMed1998

The DEAH-box protein PRP22 is an ATPase that mediates ATP-dependent mRNA release from the spliceosome and unwinds RNA duplexes.

Of the proteins required for pre-mRNA splicing, at least four, the DEAH-box proteins, are closely related due to the presence of a central 'RNA helicase-like' region, and extended homology through a large portion of the protein. A major unresolved question is the function of these proteins. Indirect evidence suggests that several of these proteins are catalysts for important structural rearrangements in the spliceosome. However, the mechanism for the proposed alterations is presently unknown. We present evidence that PRP22, a DEAH-box protein required for mRNA release from the spliceosome, unwinds RNA duplexes in a concentration- and ATP-dependent manner. This demonstrates that PRP22 can modify RNA structure directly. We also show that the PRP22-dependent release of mRNA from the spliceosome is an ATP-dependent process and that recombinant PRP22 is an ATPase. Non-hydrolyzable ATP analogs did not substitute for ATP in the RNA-unwinding reaction, suggesting that ATP hydrolysis is required for this reaction. Specific mutation of a putative ATP phosphate-binding motif in the recombinant protein eliminated the ATPase and RNA-unwinding capacity. Significantly, these data suggest that the DEAH-box proteins act directly on RNA substrates within the spliceosome.

Adenosine Triphosphatases↗
PubMed1998

The DEAH-box splicing factor Prp16 unwinds RNA duplexes in vitro.

BACKGROUND: During pre-mRNA splicing, dynamic rearrangement of RNA secondary structure within the spliceosome is crucial for intron recognition and formation of the catalytic core. Splicing factors belonging to the DExD/DExH-box family of RNA-dependent ATPases are thought to have a central role in directing these rearrangements by unwinding RNA helices. Proof of this hypothesis has, however, been conspicuously lacking. RESULTS: Prp16 is a DEAH-box protein that functions in the second step of splicing in vitro. Using various RNA duplexes as substrate, we have shown that Prp16 has an ATP-dependent RNA unwinding activity. This activity is independent of sequence in either the single-stranded or duplexed regions of the RNA substrate. A mutation (prp16-1) near the ATP-binding motif of Prp16 inhibits both the RNA-dependent ATPase activity and the ATP-dependent RNA unwinding activity. CONCLUSIONS: Our findings provide strong biochemical evidence that Prp16 can disrupt a duplexed RNA structure on the spliceosome. Because the purified protein lacks sequence specificity in unwinding RNA duplexes, targeting of the unwinding activity of Prp16 in the spliceosome is likely to be determined by other interacting protein factors. The demonstration of unwinding activity will also help our understanding of how the fidelity of branchpoint recognition is controlled by Prp16.

Adenosine Triphosphatases↗
PubMed1998

Extracellular matrix modulates mesangial cell apoptosis and mRNA expression of cathepsin-B and tissue transglutaminase.

Mesangial matrix is a dynamic structure which modulates mesangial cell function. Since accumulation of matrix precedes the development of focal glomerulosclerosis, we studied the effect of different matrices on mesangial cell (MC) apoptosis. Suspended mesangial cells became apoptotic in a time dependent manner. Collagen type III did not modulate MC apoptosis when compared to cells grown on plastic. MCs grown on Matrigel, collagen type I and IV showed an increased number of apoptotic cells when compared to MCs grown on plastic. DNA end-labeling further confirmed these observations. MCs grown on Matrigel showed enhanced (P < 0.05) mRNA expression for tissue transglutaminase (TTG) and cathepsin-B. Mesangial cells grown on Matrigel also showed enhanced expression of superoxide dismutase (SOD). We conclude that mesangial cells require attachment to the matrix for their survival and alteration of the quality of matrix modulates mesangial cell apoptosis.

Animals↗
PubMed1998

Predictive factors for functional recovery after free tissue transfer oromandibular reconstruction.

BACKGROUND: Recovery of upper aerodigestive tract function after reconstruction of segmental oromandiblectomy defects is frequently incomplete. The purpose of this study was to quantitate postreconstruction function and define variables that predict functional outcome in this population. METHODS: A prospective study of 21 patients who underwent microvascular free tissue transfer reconstruction of segmental oromandibular defects was performed. Measures of swallowing, speech, bite, and oral intake were performed preoperatively and at 1, 3, 6, and 12 months postoperatively or until plateau. Preoperative versus maximal postoperative measures were compared and correlated with nine potentially predictive variables. Univariate and multivariate analyses were performed to determine the most significant predictive factors. RESULTS: Baseline function in the study population was abnormal. Postoperative bite force improved, but swallowing, speech, and oral intake were worse than preoperative. Significant (univariate) predictors of outcome included diagnosis of cancer, tongue resection, pharynx resection, and flap skin paddle area. Only tongue resection remained significant in multivariate analysis. CONCLUSIONS: Increasing need for oropharyngeal lining replacement, especially after tongue resection, is the most important predictor of functional outcome in reconstruction of segmental mandible defects.

Adult↗
PubMed1998

Sex steroids increase cholesterol 7alpha-hydroxylase mRNA in nonhuman primates.

One mechanism that may account for our prior observation that oral contraceptives decrease the hepatic cholesterol concentration independently of the low-density lipoprotein (LDL) receptor in sexually intact nonhuman primates is that sex hormones increase biliary cholesterol secretion by increasing hepatic mRNA abundance for cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in the conversion of cholesterol into bile acids. To examine the independent effect of estrogen, progestin, and combined estrogen and progestin on the hepatic cholesterol concentration and cholesterol 7alpha-hydroxylase mRNA abundance, 34 ovariectomized adult female cynomolgus monkeys were fed a moderately atherogenic diet for 12 weeks with either oral conjugated equine estrogen ([CEE] n = 8), medroxyprogesterone acetate ([MPA] n = 9), or combined CEE + MPA (n = 9) and compared with a control group (n = 8) that did not receive exogenous sex hormones. After 12 weeks, hepatic cholesterol was significantly lower in CEE-treated (6.2 +/- 1.2 mg/g liver) and CEE + MPA-treated (6.4 +/- 0.9 mg/g liver) animals compared with the control (12.6 +/- 1.9 mg/g liver) and MPA-treated (14.6 +/- 1.6 mg/g liver) groups. Hepatic cholesterol 7alpha-hydroxylase mRNA abundance was significantly increased in CEE-treated (0.553 +/- 0.08 pg/microg RNA), MPA-treated (0.734 +/- 0.12 pg/microg RNA), and CEE + MPA-treated (0.487 +/- 0.07 pg/microg RNA) animals compared with the controls (0.318 +/- 0.03 pg/microg RNA). There was no significant difference in the plasma LDL cholesterol concentration and hepatic LDL receptor mRNA abundance between the groups. These data support but do not prove the hypothesis that low-dose oral estrogen induces an increase in cholesterol 7alpha-hydroxylase mRNA abundance, which is correlated with biliary cholesterol secretion and may result in depletion of hepatic cholesterol.

Animals↗
PubMed1998

Chronic hyperglycemia increases arterial low-density lipoprotein metabolism and atherosclerosis in cynomolgus monkeys.

Diabetes mellitus confers a threefold to fivefold increased risk of mortality from vascular disease. The primary cause of this increased incidence of vascular disease is atherosclerosis, but the mechanisms accounting for the increase are unclear. Chronic hyperglycemia is a common feature of all forms of diabetes mellitus and may contribute greatly to the increased incidence of atherosclerosis, via promotion of both lipoprotein and tissue glycation, which may have atherogenic effects. The present study investigated the effect of chronic hyperglycemia on measures of low-density lipoprotein (LDL) metabolism and atherosclerosis in streptozotocin-induced diabetic (STZ-DM) and control cynomolgus monkeys after 6 months of study. Consistent with a chronic hyperglycemic state, diabetic monkeys had significant increases in glycated hemoglobin (GHb) and glycated plasma LDL concentrations, but had minimal changes in total plasma cholesterol (TPC) or triglyceride (TG) concentrations during the study. Forty-eight hours before necropsy, control and in vitro-glycated LDL were differentially radiolabeled and coinjected into diabetic and control monkeys. There was a significant increase in arterial LDL accumulation in femoral arteries from diabetic monkeys compared with controls, with similar trends in other arterial sites. The effect of LDL glycation on arterial LDL accumulation was minimal in both groups. Arterial segments from diabetic monkeys also had greater amounts of arterial cholesterol content compared with controls. Histomorphometric analyses showed that diabetic monkeys had significantly greater intimal areas in the femoral artery and abdominal aorta compared with controls. Diabetic monkeys also had reduced arterial remodeling, or compensation, in the femoral artery and abdominal aorta. However, there was no difference in advanced glycation end products (AGE) in arterial collagen between groups. In conclusion, experimentally induced diabetes mellitus increases arterial LDL accumulation and atherosclerosis extent in cynomolgus monkeys before changes in AGE formation. The increased atherogenesis may be due to changes in lipoproteins or direct effects of hyperglycemia on the artery wall.

Animals↗
PubMed1998

Metastatic melanoma to retropharyngeal lymph nodes causing pharyngeal obstruction.

The finding of melanoma that has metastasized to regional lymph nodes is prognostically unfavorable. Occasionally, lymph nodes beyond the regional lymph node basin are the site of distant melanoma metastases. We present the case of a patient with melanoma who developed nonregional lymph node metastases to retropharyngeal/parapharyngeal lymph nodes, resulting in symptoms of upper aerodigestive tract obstruction. Physical examination of the head and neck, fiberoptic examination, and CT scan were abnormal. The patient underwent unilateral transcervical lymphadenectomy and resection of the obstructing retropharyngeal tumor mass. A sternocleidomastoid muscle flap was used to augment the posterior pharyngeal wall closure. The patient was able to resume full oral intake without need for a tracheostomy. Surgical intervention can play an important role in the palliation of selected patients with nonregional metastatic melanoma to the head and neck.

Adult↗
PubMed1998

Odontogenic keratocyst of the mandible: an unusual cause of a parotid mass.

Odontogenic keratocyst (OKC) of the mandible refers to an uncommon benign lesion of the jaw that originates from dental primordia. Clinically an OKC is characterized by aggressive, local growth. The likelihood of local recurrence following initial treatment is high. The diagnosis of a mandibular OKC may be suspected based on physical examination and plain film radiographic findings. However, histopathological confirmation is required to make the diagnosis with certainty. Complete surgical removal is the preferred treatment. In the current report, we describe the management of a patient with a large mandibular OKC that produced an apparent mass in the parotid gland. In addition, the diagnosis, management, and long-term results of treatment of mandibular OKCs are reviewed.

Adult↗