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Jeffrey B Matthews

Publications and source records attributed to Jeffrey B Matthews.

At least 19 recordsLinked to original sources
PubMed2007

New reagents on the horizon for immune tolerance.

Recent advances in immunology and a growing arsenal of new drugs are bringing the focus of tolerance research from animal models into the clinical setting. The conceptual framework for therapeutic tolerance induction has shifted from a "sledgehammer" approach that relies solely on cellular depletion and cytokine targeting, to a strategy directed toward restoring a functional balance across the immune system, namely the different populations of naive cells, effector and memory cells, and regulatory cells. Unlocking the key to tolerance induction in the future will likely depend on our ability to harness the functions of T regulatory cells. Also, dendritic cells are strategically positioned at the interface between innate and adaptive immunity and may be subject to deliberate medical intervention in a way that can control a chronic inflammatory response. Many reagents with tolerance-inducing potential are currently undergoing clinical testing in transplantation, autoimmune diseases, and allergic diseases, and even more that are on the horizon promise to offer enormous benefits to human health.

Autoimmune Diseases↗
PubMed2005

Factors associated with insulin and narcotic independence after islet autotransplantation in patients with severe chronic pancreatitis.

BACKGROUND: For patients who suffer from severe chronic pancreatitis, total pancreatectomy can alleviate pain, and islet autotransplantation (IAT) might preserve endocrine function and circumvent the complications of diabetes. Factors that determine success after this operation have not been clearly defined. STUDY DESIGN: From 2000 to 2004, 45 total or subtotal pancreatectomies with IAT were performed. Patient characteristics, narcotic usage and insulin requirements were recorded at routine followup. Narcotic usage was standardized by conversion to morphine equivalents (MEs). Univariate and multivariate statistical analyses were performed to determine factors associated with insulin and narcotic independence. RESULTS: Forty-five patients (30 women, 15 men), with a mean age of 39 years (range 16 to 62 years) underwent total or completion (n=41) or subtotal (n=4) pancreatectomies with IAT. Forty percent of patients were insulin free after a mean followup of 18months (range 1 to 46months). Factors associated in univariate analyses with insulin independence included female gender (p=0.004), lower body weight (kg) (p=0.04), more islet equivalents per kg body weight (IEQ/kg) transfused (<0.05), lower mean insulin requirement for the first 24hours postoperation (p=0.002), and lower mean insulin requirement at discharge (p=0.0005). A multiple logistic regression using gender, body mass index, and IEQ/kg identified female gender as the only notable variable associated with insulin independence. There was a notable reduction (p < 0.0001) of postoperative MEs (mean 90 mg) compared with preoperative MEs (mean 206 mg) for the entire cohort; 58% of patients are narcotic independent. In the subset of patients with>5months followup (n=32), 23 (72%) are narcotic free, with a substantial decrease in ME usage (p=0.01). CONCLUSIONS: The likelihood of glycemic control after IAT is related to both patient characteristics and islet cell mass. Based on these data, more islet cells may be required for insulin independence than previously thought.

Adolescent↗
PubMed2005

Clinical significance of bacterial cultures from 28 autologous islet cell transplant solutions.

PURPOSE: Total pancreatectomy and autologous islet cell transplantation are being investigated as a novel surgical treatment for patients with chronic pancreatitis. Preliminary data has demonstrated the presence of enteric bacteria in solutions used to harvest islet cells. Subsequently, we started culturing autologous islet solutions to determine whether any concordance existed between these cultures and postoperative infectious complications. METHODS: A retrospective analysis evaluated microbiologic cultures between July 2000 and November 2003; 33 patients underwent total or completion pancreatectomy and islet cell transplantation. Five patients were excluded due to incomplete culture data. Aerobic, anaerobic and fungal cultures were performed on all islet preparation solutions. Patient charts were examined for postoperative infectious complications. Microbiologic data from these infections was compared to pretransplant islet cultures. Islet cells from each patient were tested in vitrofor both function and viability. RESULTS: Of the 28 patients, 25 (89.3%) had bacterial culture-positive media solutions. Only 4 patients (14.3%) had an infectious complication from which bacteria was isolated that corresponded to bacteria in their islet cell preparation. In vitro islet cell viability was greater than 95% in the pretransplant aliquots. CONCLUSION: These results suggest that transplantation of bacterial-positive islet cell solutions does not appear to increase the risk of postoperative infectious complications or impact islet cell viability. Therefore, prolonged antibiotic treatment against these specific bacteria beyond the perioperative period does not seem warranted.

Antibiotic Prophylaxis↗
PubMed2005

Apical ammonium inhibition of cAMP-stimulated secretion in T84 cells is bicarbonate dependent.

Normal human colonic luminal (NH(4)(+)) concentration ([NH(4)(+)]) ranges from approximately 10 to 100 mM. However, the nature of the effects of NH(4)(+) on transport, as well as NH(4)(+) transport itself, in colonic epithelium is poorly understood. We elucidate here the effects of apical NH(4)(+) on cAMP-stimulated Cl(-) secretion in colonic T84 cells. In HEPES-buffered solutions, 10 mM apical NH(4)(+) had no significant effect on cAMP-stimulated current. In contrast, 10 mM apical NH(4)(+) reduced current within 5 min to 61 +/- 4% in the presence of 25 mM HCO(3)(-). Current inhibition was not simply due to an increase in extracellular K(+)-like cations, in that the current magnitude was 95 +/- 5% with 10 mM apical K(+) and 46 +/- 3% with 10 mM apical NH(4)(+) relative to that with 5 mM apical K(+). We previously demonstrated that inhibition of Cl(-) secretion by basolateral NH(4)(+) occurs in HCO(3)(-)-free conditions and exhibits anomalous mole fraction behavior. In contrast, apical NH(4)(+) inhibition of current in HCO(3)(-) buffer did not show anomalous mole fraction behavior and followed the absolute [NH(4)(+)] in K(+)-NH(4)(+) mixtures, where K(+) concentration + [NH(4)(+)] = 10 mM. The apical NH(4)(+) inhibitory effect was not prevented by 100 microM methazolamide, suggesting no role for apical carbonic anhydrase. However, apical NH(4)(+) inhibition of current was prevented by 10 min of pretreatment of the apical surface with 500 microM DIDS, 100 microM 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS), or 25 microM niflumic acid, suggesting a role for NH(4)(+) action through an apical anion exchanger. mRNA and protein for the apical anion exchangers SLC26A3 [downregulated in adenoma (DRA)] and SLC26A6 [putative anion transporter (PAT1)] were detected in T84 cells by RT-PCR and Northern and Western blots. DRA and PAT1 appear to associate with CFTR in the apical membrane. We conclude that the HCO(3)(-) dependence of apical NH(4)(+) inhibition of secretion is due to the action of NH(4)(+) on an apical anion exchanger.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2005

Dynamic regulation of Na(+)-K(+)-2Cl(-) cotransporter surface expression by PKC-{epsilon} in Cl(-)--secretory epithelia.

In secretory epithelia, activation of PKC by phorbol ester and carbachol negatively regulates Cl(-) secretion, the transport event of secretory diarrhea. Previous studies have implicated the basolateral Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) as a target of PKC-dependent inhibition of Cl(-) secretion. In the present study, we examined the regulation of surface expression of NKCC1 in response to the activation of PKC. Treatment of confluent T84 intestinal epithelial cells with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (PMA) reduced the amount of NKCC1 accessible to basolateral surface biotinylation. Loss of cell surface NKCC1 was due to internalization as shown by 1) the resistance of biotinylated NKCC1 to surface biotin stripping after incubation with PMA and 2) indirect immunofluorescent labeling. PMA-induced internalization of NKCC1 is dependent on the epsilon-isoform of PKC as determined on the basis of sensitivity to a panel of PKC inhibitors. The effect of PMA on surface expression of NKCC1 was specific because PMA did not significantly alter the amount of Na(+)-K(+)-ATPase or E-cadherin available for surface biotinylation. After extended PMA exposure (>2 h), NKCC1 became degraded in a proteasome-dependent fashion. Like PMA, carbachol reduced the amount of NKCC1 accessible to basolateral surface biotinylation in a PKC-epsilon-dependent manner. However, long-term exposure to carbachol did not result in degradation of NKCC1; rather, NKCC1 that was internalized after exposure to carbachol was recycled back to the cell membrane. PKC-epsilon-dependent alteration of NKCC1 surface expression represents a novel mechanism for regulating Cl(-) secretion.

Carbachol↗
PubMed2005

Missense mutations in Na+:HCO3- cotransporter NBC1 show abnormal trafficking in polarized kidney cells: a basis of proximal renal tubular acidosis.

The kidney Na(+):HCO(3)(-) cotransporter NBC1 is located exclusively on the basolateral membrane of kidney proximal tubule cells and is responsible for the reabsorption of majority of filtered bicarbonate. Two well-described missense mutations in NBC1, R510H and S427L, are associated with renal tubular acidosis (RTA). However, the exact relationship between these mutations and NBC1 dysregulation remains largely unknown. To address this question, cDNAs for wild-type kidney NBC1 and its mutants R510H and S427L were generated, fused in frame with NH(2) terminally tagged GFP, and transiently expressed in Madin-Darby canine kidney cells. In parallel studies, oocytes were injected with the wild-type and mutant NBC1 cRNAs and studied for membrane expression and activity. In monolayer cells grown to polarity, the wild-type GFP-NBC1 was exclusively localized on the basolateral membrane domain. However, GFP-NBC1 mutant R510H was detected predominantly in the cytoplasm. GFP-NBC1 mutant S427L, on the other hand, was detected predominantly on the apical membrane with residual cytoplasmic retention and basolateral membrane labeling. In oocytes injected with the wild-type or mutant GFP-NBC1 cRNAs, Western blot analysis showed that wild-type NBC1 is predominantly localized in the membrane fraction, whereas NBC1-R510H mutant was predominantly expressed in the cytoplasm. NBC1-S427L mutant was mostly expressed in the membrane fraction. Functional analysis of NBC1 activity in oocytes by membrane potential recording demonstrated that compared with wild-type GFP-NBC1, the GFP-NBC1 mutants H510R and S427L exhibited significant reduction in activity. These findings suggest that the permanent isolated proximal RTA in patients with H510R or S427L mutation resulted from a combination of inactivation and mistargeting of kidney NBC1, with H510R mutant predominantly retained in the cytoplasm, whereas S427L mutant is mistargeted to the apical membrane.

Acidosis, Renal Tubular↗
PubMed2005

Bile salt diarrhea.

Alterations in bile acid metabolism and in the enterohepatic circulation are often associated with chronic diarrhea and should be considered when more common causes of chronic diarrhea have been excluded. Bile acid diarrhea most often occurs in disease or resection of the terminal ileum, in which there is increased exposure of the colonic mucosa to bile salts with consequent activation of fluid and electrolyte secretion. Congenital or acquired defects in the enterohepatic circulation of bile acids also may lead to diarrhea. Although multiple diagnostic tests may be considered to confirm abnormal fecal bile acid losses, the most critical elements of the clinical evaluation of suspected bile acid diarrhea are a careful history to exclude more common causes of chronic diarrhea and a diagnostic trial of bile acid-binding resins.

Bile Acids and Salts↗
PubMed2005

Role of protein kinase C in intestinal ischemic preconditioning.

INTRODUCTION: Tissue protection by ischemic preconditioning (IPC) has been previously characterized in organs such as the heart and involves at least in part PKC activation. It is not yet clear whether such preconditioning against ischemia/reperfusion (I/R) injury operates in the intestine, and, if so, whether IPC involves protein kinase C (PKC). MATERIALS AND METHODS: IPC of the small intestine in male Sprague Dawley rats was induced by 10-min superior mesenteric artery (SMA) clamp followed by 120-min reperfusion. Sham-operated control or IPC rats were then rechallenged with 20-min SMA clamp. Histological injury to jejunal mucosa was assessed by microscopic examination and Parks' injury score (Grade 0-4; 0 = no damage). PKC activity was determined by immunoprecipitation of specific isoforms followed by in vitro kinase assay using mucosal scrapings of the harvested jejunum. Data were expressed as mean +/- SEM and analyzed by one-way ANOVA with multiple comparison tests. RESULTS: Ten-minute SMA clamp led to epithelial damage that was fully reversed by 120-min reperfusion. Activity of several PKC isoforms (PKCalpha, -delta, -epsilon) increased after 10-min ischemia. Epithelial injury associated with 20-min SMA clamp was attenuated by prior IPC. The protective effect of IPC on intestinal mucosa was prevented when animals were pretreated with the conventional (c) and novel (n) PKC inhibitor Go6850, but not with Go6976 (selective cPKC inhibitor), rottlerin (selective PKCdelta inhibitor), or saline control. CONCLUSIONS: Brief mesenteric ischemia induces a reversible epithelial injury in rats associated with activation of several PKC isoforms. Injury induced by mesenteric ischemia is reduced by brief ischemic preconditioning, an effect that is abolished by nonselective PKC inhibition but not by a selective inhibitor of cPKC or PKCdelta. The results suggest that activation of nPKC isoform(s), especially PKCepsilon during and following ischemic insults (IPC), may play an important role in protection against I/R injury in the intestine.

Animals↗
PubMed2005

Surgery for pancreatic cancer: recent controversies and current practice.

Pancreatic duct carcinoma remains a common disease with a poor prognosis. More than 30,000 Americans will die of the disease in 2004, making it the fourth leading cause of cancer death. Despite significant advances in the treatment of many other human tumors, the 5-year survival rate for persons diagnosed with pancreatic cancer has not changed in decades and remains <5%. This is due both to the inherently aggressive biology of the disease and to its late diagnosis in most cases. Surgical resection of localized disease remains the only hope for cure of pancreatic cancer. Over the past 2 decades, significant advances in diagnostic imaging, staging, surgical technique, and perioperative care have led to marked improvement in the surgical management of pancreatic cancer patients. Operative mortality rates for pancreaticoduodenectomy are now <5% at major centers, and the average length of hospital stay has been reduced to <2 weeks. Improvements in patient outcome after pancreatic cancer surgery have made possible, for the first time, the design and conduct of large adjuvant therapy studies in pancreatic cancer. Such clinical trials are critical for improving outcomes for pancreatic cancer patients.

Carcinoma, Pancreatic Ductal↗
PubMed2005

The cost effectiveness of laparoscopic versus open gastric bypass surgery.

BACKGROUND: Over the last decade, laparoscopic gastric bypass (LGBP) has been proven to be a safe and well-tolerated approach to the Roux-en-Y gastric bypass, despite its increased cost when compared to the open approach (OGBP). This increased expense has led many to question whether LGBP is a cost effective alternative to OGBP. The aim of this study is to determine which approach is most cost effective, considering costs associated with the operation itself, perioperative complications, and income lost during convalescence. METHODS: A PubMed search of the National Library of Medicine online journal database was conducted. Studies that met predetermined criteria for selection were included in the analyses of patient demographics, perioperative complications, length of hospital stay, excess weight loss, and time to recovery. Data on 6,425 OGBP and 5,867 LGBP patients were used to compare the outcomes associated with each approach. RESULTS: Significant differences were found in the perioperative complication profiles, time to recovery, and overall expense of the two approaches. OGBP was associated with an increased incidence of major perioperative complications, especially extraintestinal complications, and greater perioperative mortality. LGBP was associated with shorter hospital stays, increased incidence of intestinal complications, and a 2.25% incidence of conversion to OGBP. Patient demographics and percent excess weight loss (%EWL) at 3 years follow-up were found to be similar with both OGBP and LGBP. CONCLUSION: LGBP is a cost effective alternative to OGBP for surgical weight loss. Despite the increased cost of LGBP, patients suffer fewer expensive and lifethreatening perioperative complications.

Adult↗
PubMed2004

Differential subcellular targeting of PKC-epsilon in response to pharmacological or ischemic stimuli in intestinal epithelia.

Ischemia is the central pathogenic factor underlying a spectrum of intestinal disorders. The study of the cellular signaling responses to ischemic stress in nonepithelial cells has progressed substantially in the previous several years, but little is known about the response in epithelial cells. Unique features of the epithelial response to ischemic stress suggest differential regulation with regards to signaling. The PKC family of proteins has been implicated in ischemic stress in nonepithelial systems. The role of PKC isoforms in chemical ischemia in intestinal epithelial cells is evaluated in this study. Additionally, the phosphorylation of the F-actin cross-linking protein myristoylated alanine-rich C kinase substrate (MARCKS) is also studied. Chemical ischemia resulted in the transient activation of only the isoform PKC-epsilon as detected by translocation employing the subcellular fractionation technique. The pharmacological agonists phorbol 12-myristate 13-acetate and carbachol also led to the translocation of PKC-epsilon. By immunofluoresence, MARCKS is noted to be located at the lateral membrane under control conditions. In response to carbachol, MARCKS translocates to the cytosol, indicating its phosphorylation, which is additionally confirmed biochemically. Consistent with this observation, carbachol induces the translocation of PKC-epsilon to proximity with MARCKS at the lateral membrane. In response to chemical ischemia, MARCKS fails to translocate and phosphorylation does not increase. Additionally, the translocation of PKC-epsilon is not to the lateral membrane but rather basally. The data suggest that the differential translocation of PKC-epsilon in response to pharmacological agonists versus ischemic stress may lead to different effects on downstream targets.

Carbachol↗
PubMed2004

Identification of a carboxyl-terminal motif essential for the targeting of Na+-HCO-3 cotransporter NBC1 to the basolateral membrane.

The Na+-HCO3- cotransporter NBC1 is located exclusively on the basolateral membrane and mediates vectorial transport of bicarbonate in a number of epithelia, including kidney and pancreas. To identify the motifs that direct the targeting of kidney NBC1 to basolateral membrane, wild type and various carboxyl-terminally truncated kidney NBC1 mutants were generated, fused translationally in-frame to GFP, and transiently expressed in kidney epithelial cells. GFP was linked to the NH2 terminus of NBC1, and labeling was examined by confocal microscopy. Full-length (1035 aa) and mutants with the deletion of 3 or 20 amino acids from the COOH-terminal end of NBC1 (lengths 1032 and 1015 aa, respectively) showed strong and exclusive targeting on the basolateral membrane. However, the deletion of 26 amino acid residues from the COOH-terminal end (length 1010 aa) resulted in retargeting of NBC1 to the apical membrane. Expression studies in oocytes demonstrated that the NBC1 mutant with the deletion of 26 amino acid residues from the COOH-terminal end is functional. Additionally, the deletion of the last 23 amino acids or mutation in the conserved residue Phe at position 1013 on the COOH-terminal end demonstrated retargeting to the apical membrane. We propose that a carboxyl-terminal motif with the sequence QQPFLS, which spans amino acid residues 1010-1015, and specifically the amino acid residue Phe (position 1013) are essential for the exclusive targeting of NBC1 to the basolateral membrane.

Amino Acid Motifs↗
PubMed2004

Salmonella typhimurium SipA-induced neutrophil transepithelial migration: involvement of a PKC-alpha-dependent signal transduction pathway.

Salmonella typhimurium elicits an intense proinflammatory response characterized by movement of polymorphonuclear neutrophils (PMN) across the epithelial barrier to the intestinal lumen. We previously showed that S. typhimurium, via the type III secretion system effector protein SipA, initiates an ADP-ribosylation factor-6- and phospholipase D-dependent lipid-signaling cascade that directs activation of protein kinase C (PKC) and subsequent transepithelial movement of PMN. Here we sought to determine the specific PKC isoforms that are induced by the S. typhimurium effector SipA in model intestinal epithelia and to link the functional consequences of these isoforms in the promotion of PMN transepithelial migration. In vitro kinase PKC activation assays performed on polarized monolayers of T84 cells revealed that S. typhimurium and recombinant SipA induced activation of PKC-alpha, -delta, and -epsilon. To elucidate which of these isoforms play a key role in mediating epithelial cell responses that lead to the observed PMN transepithelial migration, we used a variety of PKC inhibitors with different isoform selectivity profiles. Inhibitors selective for PKC-alpha (Gö-6976 and 2,2',3,3',4,4'-hexahydroxyl-1,1'-biphenyl-6,6'-dimethanoldimethyl ether) markedly reduced S. typhimurium- and recombinant SipA-induced PMN transepithelial migration, whereas inhibitors to PKC-delta (rottlerin) or PKC-epsilon (V1-2) failed to exhibit a significant decrease in transepithelial movement of PMN. These results were confirmed biochemically and by immunofluorescence coupled to confocal microscopy. Our results are the first to show that the S. typhimurium effector protein SipA can activate multiple PKC isoforms, but only PKC-alpha is involved in the signal transduction cascade leading to PMN transepithelial migration.

ADP-Ribosylation Factor 6↗
PubMed2004

An algorithm for the accurate identification of benign liver lesions.

BACKGROUND: Benign liver lesions may be difficult to characterize preoperatively. In most instances, determination of the etiology of a hepatic mass makes its management decisions clear-cut. We present our experience using an algorithm for the management of liver masses of suspected benign or uncertain pathology and highlight this approach along with our surgical experience in benign liver lesions. METHODS: Seventy-one patients underwent hepatectomy with a preoperative diagnosis of benign disease or unknown etiology from December 1992 to February 2002. Patients were preoperatively assessed with computed tomography, along with other imaging studies, as indicated. Final pathology was reviewed to confirm the preoperative diagnosis. RESULTS: Ninety-two percent (65 of 71) were correctly characterized preoperatively. Diagnosis was inaccurate in 6 patients. Of these patients, final pathology revealed focal nodular hyperplasia in 4 patients. The remaining 2 patients, who had adenoma, were found to harbor malignancy within the surgical specimens. CONCLUSIONS: An algorithm to manage liver lesions resulted in a high diagnostic accuracy of a preoperative evaluation. Hepatic resection for benign disease can be performed with low morbidity and mortality and is highly successful in achieving relief for symptomatic patients.

Adult↗
PubMed2003

Regulation of MDCK cell-substratum adhesion by RhoA and myosin light chain kinase after ATP depletion.

The attachment of epithelial cells to the extracellular matrix substratum is essential for their differentiation and polarization. Despite this, the precise adhesion mechanism and its regulation are poorly understood. In the kidney, an ischemic insult causes renal tubular epithelial cells to detach from the basement membrane, even though they remain viable. To understand this phenomenon, and to probe the regulation of epithelial cell attachment, we used a model system consisting of newly adherent Madin-Darby canine kidney (MDCK) cells subjected to ATP depletion to mimic ischemic injury. We found that MDCK cells detach from collagen I after 60 min of ATP depletion but reattach when resupplied with glucose. Detachment is not caused by degradation or endocytosis of beta(1)-integrins, which mediate attachment to collagen I. Basal actin filaments and paxillin-containing adhesion complexes are disrupted by ATP depletion and quickly reform on glucose repletion. However, partial preservation of basal actin by overexpression of constitutively active RhoA does not significantly affect cell detachment. Furthermore, Y-27632, an inhibitor of the RhoA effector Rho-kinase, does not prevent reattachment of cells on glucose addition, even though reformation of central stress fibers and large adhesion complexes is blocked. In contrast, reattachment of ATP-depleted cells and detachment of cells not previously subjected to ATP depletion are prevented by ML-7, an inhibitor of myosin light chain kinase (MLCK). We conclude that initial adherence of MDCK cells to a collagen I substratum is mediated by peripheral actin filaments and adhesion complexes regulated by MLCK but not by stress fibers and adhesion complexes controlled by RhoA.

Adenosine Triphosphate↗