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Biomedical subjects

Mark Kester

Publications and source records attributed to Mark Kester.

15 recordsLinked to original sources
PubMed2007

Clinical experience using a minimally invasive surgical approach for total knee arthroplasty: early results of a prospective randomized study compared to a standard approach.

There has been recent attention concerning minimally invasive techniques for knee arthroplasty. It is not clear whether these complicated techniques can be reproduced across multiple centers and for all surgeons. This prospective, randomized, multicenter study was carried out to assess safety and efficacy of a minimally invasive total knee arthroplasty. The study consisted of 80 knees. There were no differences in blood loss, operative time for completion of surgery, infection, and ultimate wound healing. There were 4 knees with delayed wound healing in the minimally invasive surgical technique group versus 1 in the standard group, which did not affect outcome. Early clinical and radiographic results were also indistinguishable. At 12 weeks follow-up, there was no difference in mean Knee Society objective and functional scores. In summary, in this study, minimal incision total knee arthroplasty demonstrated no improvement over a standard approach.

Aged↗
PubMed2006

Minimally invasive revision total knee arthroplasty.

UNLABELLED: Exposure in revision total knee arthroplasty can be difficult. For example, eversion of the patella may require a number of procedures including vastus snips, V-Y turndowns, and tibial tubercle osteotomies. A minimally invasive approach further adds to exposure difficulties. We report a new approach for exposure during difficult revision total knee arthroplasties. A soft tissue envelope technique allows retraction of the patella and avoids eversion. This technique reduces the size of the incision, reduces quadriceps muscle damage, and enhances exposure. It is essential that appropriate instrumentation is used along with down sized femoral and tibial cutting blocks. We report all 17 revision knee arthroplasties using this technique including unicompartmental revisions, tibial component revisions, and femoral component revisions. Followup averaged 29 months (range, 24-39 months). We had one case of posterior retained cement after a full revision with no subsequent complications. One patient required an arthroscopic lateral release for patellar maltracking. Preliminary results are encouraging using improved instrumentation we find essential for enhanced exposure. We believe this a reasonable approach for selected total knee arthroplasty revisions. LEVEL OF EVIDENCE: Therapeutic study, level IV (retrospective case series). See the Guidelines for Authors for a complete description of levels of evidence.

Aged↗
PubMed2006

Use of an alumina-on-alumina bearing system in total hip arthroplasty for osteonecrosis of the hip.

BACKGROUND: The results of total hip arthroplasty in patients with osteonecrosis of the femoral head are not always optimal. The use of alumina-on-alumina interfaces in young and active patients may decrease wear and lower the rate of aseptic loosening of the implant and appears to be an attractive alternative to the use of conventional cobalt-chromium-on-polyethylene bearings. The purpose of this study was to evaluate the safety and efficacy of the alumina-on-alumina bearing in patients with osteonecrosis and to compare this group of patients to a group of similarly treated patients with osteoarthritis and a group of patients who received conventional cobalt-chromium-on-polyethylene bearings. METHODS: Patients were selected from a United States Investigational Device Exemption multicenter prospective randomized clinical study that was initiated in 1996. Seventy patients with osteonecrosis of the femoral head (seventy-nine hips) received a cementless alumina-on-alumina bearing system and were directly matched to seventy-six patients with osteoarthritis of the hip (seventy-nine hips) who were managed with the same implant. Both groups were compared with twenty-five patients (twenty-six hips) with osteonecrosis and twenty-five patients (twenty-six hips) with osteoarthritis who were managed with a cementless cobalt-chromium-on-polyethylene bearing system. All patients received a cementless hydroxyapatite-coated femoral stem and were followed both clinically and radiographically. RESULTS: The clinical outcomes for alumina-on-alumina bearings were similar for both osteonecrotic and osteoarthritic hips. The seven-year survival probability was 95.5% for the osteonecrotic hips and 89.4% for the osteoarthritic hips in the alumina-on-alumina bearing group and 92.3% for the osteonecrotic hips and 92.9% for the osteoarthritic hips in the cobalt-chromium-on-polyethylene bearing group. At the time of the most recent follow-up, the mean Harris hip score was 96 points for both the osteonecrotic and the osteoarthritic hips in the alumina-on-alumina group and 96 points for the osteonecrotic hips and 97 points for the osteoarthritic hips in the cobalt-chromium-on-polyethylene bearing group. CONCLUSIONS: The results of the use of alumina-on-alumina and cobalt-chromium-on-polyethylene bearings in cementless standard total hip implants in patients with osteonecrosis and osteoarthritis were comparable. The low revision rate for the alumina-on-alumina bearing is encouraging and offers a promising option for younger, more active patients who have this challenging disease. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions to Authors on jbjs.org for a complete description of levels of evidence.

Adult↗
PubMed2006

Diabetic retinopathy: seeing beyond glucose-induced microvascular disease.

Diabetic retinopathy remains a frightening prospect to patients and frustrates physicians. Destruction of damaged retina by photocoagulation remains the primary treatment nearly 50 years after its introduction. The diabetes pandemic requires new approaches to understand the pathophysiology and improve the detection, prevention, and treatment of retinopathy. This perspective considers how the unique anatomy and physiology of the retina may predispose it to the metabolic stresses of diabetes. The roles of neural retinal alterations and impaired retinal insulin action in the pathogenesis of early retinopathy and the mechanisms of vision loss are emphasized. Potential means to overcome limitations of current animal models and diagnostic testing are also presented with the goal of accelerating therapies to manage retinopathy in the face of ongoing diabetes.

Diabetic Retinopathy↗
PubMed2006

Diabetes alters sphingolipid metabolism in the retina: a potential mechanism of cell death in diabetic retinopathy.

Dysregulated sphingolipid metabolism causes neuronal cell death and is associated with insulin resistance and diseases. Thus, we hypothesized that diabetes-induced changes in retinal sphingolipid metabolism may contribute to neuronal pathologies in diabetic retinopathy. ESI-MS/MS was used to measure ceramide content and ceramide metabolites in whole retinas after 2, 4, and 8 weeks of streptozotocin-induced diabetes. After 4 and 8 weeks of diabetes, a approximately 30% decrease in total ceramide content was observed, concomitant with a significant approximately 30% increase in glucosylceramide levels in fed diabetic rats compared with their age-matched controls. Acute insulin therapy as well as a short-term lowering of glucose via fasting did not affect the increase in glucosylceramide composition. To assess the putative biological consequences of the increase in glucosylceramide composition, R28 retinal neurons were treated with glucosylceramide synthase inhibitors. Inhibiting glycosphingolipid metabolism increased insulin sensitivity in retinal neurons. Glycosphingolipid inhibitors augmented insulin-stimulated p70 S6kinase activity in the presence of inhibitory concentrations of high glucose or glucosamine. Inhibition of glycosphingolipid synthesis also suppressed glucosamine- and interleukin-1beta-induced death. Consistent with these inhibitor studies, pharmacological accumulation of glycosphingolipids increased activation of the endoplasmic reticulum stress response, a putative modulator of insulin resistance and neuronal apoptosis. It is speculated that an increase in glucosylceramide, and possibly higher-order glycosphingolipids, could contribute to the pathogenesis of diabetic retinopathy by contributing to local insulin resistance, resulting in neuronal cell death. Thus, dysfunctional glycosphingolipid metabolism may contribute to metabolic stress in diabetes, and therapeutic strategies to restore normal sphingolipid metabolism may be a viable approach for treatment of diabetic retinopathy.

Animals↗
PubMed2005

Paralemmin interacts with D3 dopamine receptors: implications for membrane localization and cAMP signaling.

Paralemmin is a novel lipid-anchored protein, which is highly expressed in neuronal plasma membranes. In this study, we demonstrate that paralemmin specifically interacts with the third intracellular loop of the D3 dopamine receptor. Utilizing co-immunoprecipitation and glutathione-S-transferase (GST) pulldown strategies, we demonstrate that paralemmin interacts exclusively with D3, but not D2 or D4 dopamine receptors or beta-adrenergic receptors. Immunocytochemistry demonstrated co-localization of paralemmin and D3 receptor in vivo in hippocampus and cerebellum and in vitro in glial and neuronal cultures. Deletion mutational analysis indicates that amino acids 154-230 of paralemmin strongly interacted with amino acids 211-227 and 281-330 of the third intracellular loop of D3 receptor. The consequences of these interactions were investigated by co-expression in HEK293 cells. Cell surface biotinylation experiments demonstrate that paralemmin decreased D3 receptor concentration at the plasma membrane. Consistent with this observation, paralemmin expression decreased dopamine-stimulated adenylate cyclase activity. However, paralemmin also decreased basal, isoproterenol and forskolin-stimulated adenylate cyclase activity, suggesting a more general cellular function for paralemmin. Taken together, paralemmin has been implicated as a potent modulator of cellular cAMP signaling within the brain.

Adenylyl Cyclases↗
PubMed2005

Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma.

In vitro tumor cell culture models have illuminated the potential therapeutic utility of elevating the intracellular concentration of the antimitogenic and proapoptotic sphingolipid, ceramide. However, although cell-permeable, short-chain ceramide is an effective apoptotic agent in vitro, its use as an in vivo, systemically delivered therapeutic is limited by its inherent lipid hydrophobicity and physicochemical properties. Here, we report that the systemic i.v. delivery of C6-ceramide (C6) in a pegylated liposomal formulation significantly limited the growth of solid tumors in a syngeneic BALB/c mouse tumor model of breast adenocarcinoma. Over a 3-week treatment period, a well-tolerated dose of 36 mg/kg liposomal-C6 elicited a >6-fold reduction in tumor size compared with empty ghost liposomes. Histologic analyses of solid tumors from liposomal-C6-treated mice showed a marked increase in the presence of apoptotic cells, with a coincident decrease in cellular proliferation and in the development of a microvessel network. Liposomal-C6 accumulated within caveolae and mitochondria, suggesting putative mechanisms by which ceramide induces selective cancer cell cytotoxicity. A pharmacokinetic analysis of systemic liposomal-C6 delivery showed that the pegylated liposomal formulation follows first-order kinetics in the blood and achieves a steady-state concentration in tumor tissue. Confirming the therapeutic utility of i.v. liposomal-C6 administration, we also shown diminution of solid tumor growth in a human xenograft model of breast cancer. Together, these results indicate that bioactive ceramide analogues can be incorporated into pegylated liposomal vehicles for improved solubility, drug delivery, and antineoplastic efficacy.

Adenocarcinoma↗
PubMed2004

Deregulated Akt3 activity promotes development of malignant melanoma.

Malignant melanoma is the skin cancer with the most significant impact on man, carrying the highest risk of death from metastasis. Both incidence and mortality rates continue to rise each year, with no effective long-term treatment on the horizon. In part, this reflects lack of identification of critical genes involved and specific therapies targeted to correct these defects. We report that selective activation of the Akt3 protein promotes cell survival and tumor development in 43 to 60% of nonfamilial melanomas. The predominant Akt isoform active in melanomas was identified by showing that small interfering RNA (siRNA) against only Akt3, and not Akt1 or Akt2, lowered the amount of phosphorylated (active) Akt in melanoma cells. The amount of active Akt3 increased progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Mechanisms of Akt3 deregulation occurred through a combination of overexpression of Akt3 accompanying copy number increases of the gene and decreased PTEN protein function occurring through loss or haploinsufficiency of the PTEN gene. Targeted reduction of Akt3 activity with siRNA or by expressing active PTEN protein stimulated apoptotic signaling, which reduced cell survival by increasing apoptosis rates thereby inhibiting melanoma tumor development. Identifying Akt3 as a selective target in melanoma cells provides new therapeutic opportunities for patients in the advanced stages of this disease.

Animals↗
PubMed2004

Minimally invasive total knee arthroplasty.

Currently, minimally invasive total knee arthroplasty is defined as an incision length of < 14 cm. However, the length of the incision is not the primary influence on potential postoperative benefits to the patient and should not be the only characteristic of the minimally invasive approach for knee arthroplasty. Some other factors that should also be included in this definition are: 1. The amount of soft-tissue dissection (including muscle, ligament, and capsular damage). 2. Patellar retraction or eversion. 3. Tibiofemoral dislocation. Minimally invasive surgery should not be considered to be a cosmetic procedure but rather one that addresses patients' concerns with regard to postoperative pain and slow rehabilitation. Standard total knee arthroplasties provide pain relief, but returning to activities of daily living remains a challenge for some individuals, who may take several weeks to recover. Several studies have demonstrated long-term success (at more than ten years) of standard total knee arthroplasties. However, many patients remain unsatisfied with the results of the surgery. In a study of functional limitations of patients with a Knee Society score of > or = 90 points after total knee arthroplasty, only 35% of patients stated that they had no limitations. This finding was highlighted in a study by Dickstein et al., in which one-third of the elderly patients who underwent knee replacement were unhappy with the outcome at six and twelve months postoperatively. Although many surgeons utilize objective functional scoring systems to evaluate outcome, it is likely that the criteria for a successful result of total knee arthroplasty differ between the patient and the surgeon. This was evident in a report by Bullens et al., who concluded that surgeons are more satisfied with the results of total knee arthroplasty than are their patients. Trousdale et al. showed that, in addition to concerns about long-term functional outcome, patients' major concerns were postoperative pain and the time required for recovery. Patients undergoing total knee arthroplasty have specific functional goals, such as climbing stairs, squatting, kneeling, and returning to some level of low-impact sports after surgery. Our clinical investigations demonstrated that the minimally invasive surgical approach reduces hospital stays, decreases postoperative pain, and decreases rehabilitation needs as well as enables patients to return to normal function more quickly. It is important for surgeons to take an evolutionary, rather than a revolutionary, approach when performing minimally invasive total knee arthroplasty. The surgeon should downsize incisions progressively to prevent severe damage to the quadriceps mechanism. Extensive open exposure, prolonged patellar eversion, and dislocation of the tibiofemoral joint should evolve into a vastus medialis muscle split with patellar subluxation, retraction but not dislocation of the patella, and avoidance of gross dislocation of the tibiofemoral joint. Developing the techniques of minimally invasive total knee arthroplasty may be difficult and time-consuming, but patient benefits and satisfaction should outweigh the extra effort required. These changes require well-designed clinical studies to further document their effectiveness.

Arthroplasty, Replacement, Knee↗
PubMed2003

Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells.

It is therapeutically desirable to effectively deliver ceramide, an antimitogenic and proapoptotic lipid second messenger, to transformed cell types. However, the targeted delivery of cell-permeable ceramide analogs, including C6-ceramide, to cells may be impeded by the hydrophobicity of these bioactive lipids, resulting in reduced efficacy. The objective of this study is to develop and optimize liposomal vehicles to augment ceramide delivery to a breast adenocarcinoma cell line. We designed conventional, cationic, and pegylated drug release vesicles to efficaciously deliver ceramide to MDA-MB-231 breast adenocarcinoma cells. In vitro pharmacokinetic analysis demonstrated that liposomal ceramide delivery resulted in significantly greater accumulation of ceramide in MDA-MB-231 cells. Ceramide-formulated liposomes significantly inhibited MDA-MB-231 cell proliferation as compared with nonliposomal administration of ceramide. Ceramide-induced apoptosis correlated with the pharmacokinetic profile and the diminished proliferation in this highly aggressive, metastatic cell line. Liposomal ceramide formulations inhibited phosphorylated Akt levels and stimulated caspase-3/7 activity more effectively than nonliposomal ceramide, events consistent with apoptosis. Together, these results indicate that bioactive ceramide analogs can be incorporated into conventional, cationic, or pegylated liposomal vehicles for improved drug delivery and release.

Apoptosis↗
PubMed2003

Characterization of insulin signaling in rat retina in vivo and ex vivo.

Insulin receptor (IR) signaling cascades have been studied in many tissues, but retinal insulin action has received little attention. Retinal IR signaling and activity were investigated in vivo in rats that were freely fed, fasted, or injected with insulin by phosphotyrosine immunoblotting and by measuring kinase activity. A retina explant system was utilized to investigate the IR signaling cascade, and immunohistochemistry was used to determine which retinal cell layers respond to insulin. Basal IR activity in the retina was equivalent to that in brain and significantly greater than that of liver, and it remained constant between freely fed and fasted rats. Furthermore, IR signaling increased in the retina after portal vein administration of supraphysiological doses of insulin. Ex vivo retinas responded to 10 nM insulin with IR beta-subunit (IRbeta) and IR substrate-2 (IRS-2) tyrosine phosphorylation and AktSer473 phosphorylation. The retina expresses mRNA for all three Akt isoforms as determined by in situ hybridization, and insulin specifically increases Akt-1 kinase activity. Phospho-AktSer473 immunoreactivity increases in retinal nuclear cell layers with insulin treatment. These results demonstrate that the retinal IR signaling cascade to Akt-1 possesses constitutive activity, and that exogenous insulin further stimulates this prosurvival pathway. These findings may have implications in understanding normal and dysfunctional retinal physiology.

Animals↗
PubMed2003

Sphingolipids as therapeutics.

The sphingolipid field has made significant strides over the past 10 years: from identifying metabolites of the sphingomyelin pathway as second messengers to discerning the molecular biology and biophysics of these lipid-derived second messengers. Building upon this vast basic science literature, scientists from multiple disciplines have begun to translate manipulations of endogenous sphingolipid metabolites and targets into therapeutic initiatives. Multiple publications have reviewed the biochemistry [Biochemistry 40 (16) (2001) 4893 [1]; Environ. Health Perspect. 109 (Suppl. 2) (2001) 283 ], biophysics [J. Cell Physiol. 184 (3) (2000) 285; Trends Cell Biol. 10 (10) (2000) 408 ], molecular biology [Biochim. Biophys. Acta 1426 (2) (1999) 347 ], and physiology [J. Biol. Chem. 277 (29) (2002) 25851; J. Biol. Chem. 277 (29) (2002) 25847 ] of sphingolipid metabolites. The present review serves to document the emerging concept of sphingolipid metabolites as therapeutics with clear clinical potential.

Animals↗
PubMed2002

Regulatory role of sphingomyelin metabolites in hypoxia-induced vascular smooth muscle cell proliferation.

Vascular cell adaptive response to hypoxic stress includes enhanced production of sphingomyelin metabolites that regulate cell growth. Here, we examined the vascular smooth muscle (VSM) cell adaptive response to hypoxia (2 and 5% O(2)) and demonstrated that acute (</=16h) hypoxic stress significantly stimulated VSM cell growth compared to cells grown under normoxic (21% O(2)) conditions. This stimulatory effect of hypoxia on VSM cell growth was significantly inhibited by pretreatment of cells with D-erythro-N,N-dimethylsphingosine, an inhibitor of sphingosine kinase. These results suggest a mechanism by which sphingosine 1-phosphate (S-1-P), a promitogenic sphingolipid-derived second messenger, may play a key role in hypoxia-induced VSM cell growth. Supporting this, S-1-P formation was significantly increased in VSM cells subjected to hypoxia. The hypoxia-induced increase in S-1-P level correlated with the decrease in total cellular ceramide content, a sphingolipid metabolite associated with inhibition of cell growth. The activity of sphingomyelinase was also significantly inhibited in hypoxia-treated VSM cells, likely further contributing to a decrease in total intracellular content of ceramide. As a decrease in ceramide content may play a role in hypoxia-induced VSM growth, we next examined the effects of ceramide in VSM cell growth. Elevating intracellular ceramide content through exogenous (C(6)-ceramide) or endogenous (ceramidase inhibition) manipulations led to a decrease in hypoxia-induced VSM cell growth. In contrast, hypoxia-induced VSM cell growth was further enhanced by S-1-P treatment. Together, our study indicates that hypoxia-induced VSM cell growth may be modulated by sphingomyelin metabolism that results in reduction of total intracellular ceramide level with concomitant increase in S-1-P formation.

Animals↗
PubMed2001

Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest.

We recently demonstrated that ceramide-coated balloon catheters limit vascular smooth muscle cell (VSMC) growth after stretch injury in vivo. In that study, inhibition of VSMC growth was correlated with a decrease in phosphorylation of the cell survival kinase Akt (protein kinase B). Utilizing cultured A7r5 VSMCs, we have now examined the mechanism by which ceramide inhibits Akt phosphorylation/activation. Our initial studies showed that ceramide-induced inhibition of Akt phosphorylation was not mediated through diminution in phosphoinositide 3-kinase activity. As we have previously demonstrated that protein kinase Czeta (PKCzeta) is a target of ceramide, we proposed an alternative signaling mechanism by which ceramide induces inhibition of Akt through activation of PKCzeta. We demonstrate that C(6)-ceramide (but not the inactive analog dihydro-C(6)-ceramide) induced PKCzeta activity and also caused a selective increase in the association between Akt and PKCzeta, without affecting PKCepsilon, in A7r5 cells. In addition, the ability of ceramide to significantly decrease platelet-derived growth factor-induced Akt phosphorylation or cell proliferation was abrogated in A7r5 cells overexpressing a dominant-negative mutant of PKCzeta. Taken together, these data suggest that ceramide-mediated activation of PKCzeta leads to diminished Akt activation and consequent growth arrest in VSMCs. The therapeutic potential for ceramide to limit dysregulated VSMC growth has direct applicability to vascular diseases such as restenosis and atherosclerosis.

Animals↗