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Biomedical subjects

Mark Baker

Publications and source records attributed to Mark Baker.

14 recordsLinked to original sources
PubMed2022

Genetic structure correlates with ethnolinguistic diversity in eastern and southern Africa.

African populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multi-generational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within Africa as well as how within-Africa variation can be informative for broader variant interpretation; many variants that are rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity across Africa.

Africa, Southern↗
PubMed2006

Prediction of plasma protein binding displacement and its implications for quantitative assessment of metabolic drug-drug interactions from in vitro data.

Although displacement from plasma protein binding (dPB) is usually of little clinical significance, it should be taken into account when interpreting changes in total plasma concentrations of drugs subject to metabolically based drug-drug interactions (mDDI). The aim of this study was to develop an approach to predict changes in the free fractions (fu) of pairs of drugs that compete for plasma binding, knowing their binding affinity constants, and to consider the implications of associated concentration- and time-dependence of such changes with respect to drug exposure. Experimental fu values of valproic acid and phenytoin in the presence of ibuprofen, diflunisal, or naproxen were predicted successfully (within 0.99- to 1.36-fold) by the model. In addition, the simulation of time-dependent changes in fu of valproic acid following administration of ibuprofen indicated different extents of dPB during 'first-pass' through the liver after oral absorption and on systemic recirculation. To understand the impact of the time-dependent change in fu, a full physiologically based pharmacokinetic model, that accounts for concentration-time profile of displacee and displacer and their mutual effect on each other, is required. The approach developed in this study is a first step towards the development of such a model.

Drug Interactions↗
PubMed2005

Bolus transit patterns in healthy subjects: a study using simultaneous impedance monitoring, videoesophagram, and esophageal manometry.

Impedance monitoring (Imp) measures bolus transit. Combining Imp with manometry (EM) allows the effect of contractile patterns on transit to be assessed. The objective of this study is to identify bolus transit patterns in normal subjects, correlate Imp findings with the gold standard barium esophagram (Ba), and compare bolus transit with concomitant EM findings. Simultaneous Ba-Imp-EM was performed for 2 min in 15 normal volunteers (women, 11; age, 43 yr). Combined impedance-pressure sites were 5, 10, 15, 20 cm above the lower esophageal sphincter (LES). Boluses (10 ml) of 45% barium mixed with 0.9% NaCl were swallowed at > or = 20-s intervals (5-6 swallows/subject). Imp and Ba showed three bolus transit patterns, and the two methods were in agreement on the pattern type in 97% (83/86) of swallows. Normal bolus transit was found in 73% (61/83), and each had normal peristalsis and contraction amplitude. Stasis in the proximal esophagus occurred in 7 of 83 swallows despite normal manometric parameters in 4 of 7 swallows. Retrograde escape of a residue of incompletely cleared bolus from just above the LES to the site 5 cm above occurred in 14 of 83 swallows. Retrograde escape was triggered by the next swallow, occurred despite normal manometric parameters, and did not occur if the swallow interval was >30 s. In 55% (47/86) of swallows, air accumulated in the distal esophagus and persisted there for a mean of 3.6 s until cleared into the stomach. We conclude that impedance monitoring is a valid transit test and describe bolus transit patterns in normal subjects for comparison with patients with esophageal motility disorders.

Adult↗
PubMed2003

Hepatic abscess after liver transplantation: 1990-2000.

BACKGROUND: Infections following solid-organ transplants are a major cause of morbidity and mortality. Few studies have reported the complications of hepatic abscesses. METHODS: This investigation consisted of a retrospective chart review of all solid-organ transplant recipients from 1990 to 2000. Criteria for diagnosis included parenchymal hepatic lesions, positive cultures from liver aspirates or blood cultures, or both, and a compatible clinical presentation. RESULTS: Of 2,175 recipients of all organ transplants (heart, lung, kidney, liver, pancreas), we identified 12 patients who had experienced 14 episodes of hepatic abscess, all in liver transplant recipients. Median time from transplant to hepatic abscess was 386 days (range 25-4,198). The most common predisposing factor was hepatic artery thrombosis (HAT), which occurred in eight patients, and was diagnosed at an average of 249 days (range 33-3,215) after transplantation. Clinical presentation of hepatic abscess was similar to that described in non-immunosuppressed patients. All but one patient showed hypoalbuminemia (<3.5 g/dL); those with HAT also had significantly elevated lactate dehydrogenase. Liver aspirates grew gram-positive aerobic bacteria (50% of isolates), gram-negative aerobic bacteria (30%), and anaerobes and yeasts (10% each). Patients received an average of 6 weeks of intravenous antibiotic therapy. Catheter drainage was successful in 70% of cases; and five patients required retransplantation. Altogether, five of the patients died, yielding a mortality rate of 42%. CONCLUSIONS: Hepatic abscess, a rare complication after liver transplantation, was frequently associated with hepatic artery thrombosis. Mortality was higher than in patients who had not undergone transplantation. Prolonged antibiotic therapy, drainage, and even retransplantation may be required to improve the outcome in these patients.

Adult↗
PubMed2003

New functions of an old protein: the eukaryotic porin or voltage dependent anion selective channel (VDAC).

Mitochondrial porin or VDAC (Voltage Dependent Anion selective Channels) was identified for the first time in 1976, on the basis of the evolutionary similarity between the gram negative and mitochondrial outer membranes. Since this achievement VDAC has been extensively investigated: its functional features have been sharply defined upon reconstitution in artificial membranes and its sequence has been determined in many genomes. Unfortunately the tertiary structure has not yet been solved, mainly because it proved to be very difficult to get suitable crystals. Despite this established knowledge, in the last few years this protein has attracted renewed interest. There are two main reasons for this interest: the discovery, in most eukaryotes, of a family of genes encoding VDAC isoforms and the claims of VDAC involvement in the intrinsic pathway of apoptosis and in particular in the mechanism of cytochrome c release from mitochondria. We can affirm that nowadays the eukaryotic porin (or VDAC) is studied in a more general cellular contest, looking at the interactions and integration with other molecules, since VDAC is in a crucial position in the cell, forming the main interface between the mitochondrial and the cellular metabolisms. In this minireview we will briefly focus our attention onto the following topics: 1) recent advances about the structure of VDAC; 2) the VDAC-related multigene families; 3) the presence, targeting and function of VDAC in various cell membranes.

Animals↗
PubMed2003

Arthroscopic rotator cuff tear repair.

Rotator cuff injuries or disease can be particularly troubling to patients by causing them pain, weakness, and dysfunction of the shoulder. Surgery of the shoulder and, in particular, of the rotator cuff, has evolved over the years from open surgery to include arthroscopic treatment for many conditions. Although technically demanding, arthroscopic repair of full- and partial-thickness rotator cuff tears has been shown to produce satisfactory results. Along with the advantages of the arthroscopic technique, smaller skin incisions, access to the glenohumeral joint for inspection and treatment of intra-articular lesions, no detachment of the deltoid, and less soft-tissue dissection, patients' results are comparable with those obtained with the open method of repair. The three phases of shoulder rehabilitation for patients who have undergone surgical treatment of rotator cuff disease are described: Phase 1, the immediate postoperative, or protective, phase; phase 2, the progressive strengthening phase; and phase 3, the advanced conditioning and return-to-sport phase. The postoperative rehabilitation programs for the arthroscopic and mini-open rotator cuff repair are essentially the same.

Arthroscopy↗
PubMed2002

Nanoporous zeolite film electrodes.

Nanoporous and oriented zeolite A films have been synthesized on tin oxide substrates. The films can be modified to reject or pass molecular oxygen to an underlying electrode; films such as these show great promise for template-assisted growth of nanostructures.

Journal Article↗
PubMed2002

Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer.

PURPOSE: We wished to critically examine the level of activity of weekly paclitaxel in a patient population with well-characterized platinum/paclitaxel-resistant (3-week schedule) ovarian cancer. PATIENTS AND METHODS: Eligibility criteria for this phase II trial included the following: ovarian and fallopian tube cancers or primary carcinoma of the peritoneum; prior initial therapy with platinum/paclitaxel; and failure to respond to treatment (progression or stable disease as best response), or a response duration of less than 3 months, or if the response was more than 3 months, retreatment with both agents required and failure to respond a second time or the response duration was less than 3 months. Measurable or assessable disease (CA-125 response criteria) was required. Patients received weekly paclitaxel (80 mg/m(2)) until disease progression, unacceptable toxicity developed, or they elected to discontinue treatment. RESULTS: Fifty-three patients (52 assessable for toxicity and 51 for response) were entered onto this multi-institution trial. Of 248 total cycles (887 doses), only 13 (1%) were modified (dose reduction or treatment delay) because of side effects. Therapy was discontinued in five patients because of toxicity (four because of peripheral neuropathy, and one because of painful fingernail beds). Thirteen patients (25%; 95% confidence interval, 13.5% to 37.5%) achieved an objective response (four by CA-125 criteria, and nine by > or = 50% reduction of measurable disease). CONCLUSION: Weekly paclitaxel (80 mg/m(2)) is generally well tolerated and is an active second-line regimen against ovarian cancer that has demonstrated resistance to platinum/paclitaxel delivered on an every-3-week schedule.

Adult↗
PubMed2002

Association between alphavbeta6 integrin expression, elevated p42/44 kDa MAPK, and plasminogen-dependent matrix degradation in ovarian cancer.

Altered expression of alphav integrins plays a critical role in tumor growth, invasion, and metastasis. In this study, we show that normal human epithelial ovarian cell line, HOSE, and ovarian cancer cell lines, OVCA 429, OVCA 433, and OVHS-1, expressed alphav integrin and associated beta1, beta3, and beta5 subunits, but only ovarian cancer cell lines OVCA 429 and OVCA 433 expressed alphavbeta6 integrin. The expression of alphavbeta6 in OVCA 429 and OVCA 433 was far higher than alphavbeta3 and alphavbeta5 integrin and correlated with high p42/p44 mitogen activated protein kinase (MAPK) activity and high secretion of high molecular weight urokinase plasminogen activator (HMW-uPA), pro-metalloproteinase 2 and 9 (pro-MMP-9 and pro-MMP-2). In contrast to HOSE and OVHS 1, OVCA 433 and OVCA 429 exhibited approximately 2-fold more plasminogen-dependent [3H]-collagen type IV degradation. Plasminogen-dependent [3H]-collagen IV degradation was inhibited by inhibitor of uPA (amiloride) and MMP (phenanthroline) and by antibodies against uPA or MMP-9 or alphavbeta6 integrin, indicating the involvement of alphavbeta6 integrin, uPA and MMP-9 in the process. The alphavbeta6 correlated increase in HMW-uPA and pro-MMP secretion could be inhibited by tyrosine kinase inhibitor genistein or the MEK 1 inhibitor U0126, consistent with a role of active p42/44 MAPK in the elevation of uPA, MMP-9, and MMP-2 secretion. Under similar conditions, genistein and U0126 inhibited plasminogen-dependent [3H]-collagen type IV degradation. These data suggest that sustained elevation of p42/44 MAPK activity may be required for the co-expression of alphavbeta6 integrin, which in turn may regulate the malignant potential of ovarian cancer cells via proteolytic mechanisms.

Antigens, Neoplasm↗
PubMed2002

In vitro and in vivo characterization of XR11576, a novel, orally active, dual inhibitor of topoisomerase I and II.

XR11576, a novel phenazine, was developed as an inhibitor of both topoisomerase I and II. This study characterized the ability of XR11576 to inhibit both enzymes, and determined its in vitro and in vivo antitumor efficacy against a number of murine and human tumor models. XR11576 was a potent inhibitor of purified topoisomerase I and IIalpha, and exhibited similar potency for both enzymes. The compound stabilized enzyme-DNA cleavable complexes indicating that it acted as a topoisomerase poison. The DNA cleavage patterns obtained with XR11576 were different from those induced by camptothecin and etoposide, which are topoisomerase I and II poisons, respectively. XR11576 demonstrated potent cytotoxic activity against a variety of human and murine tumor cell lines (IC50=6-47 nM). Its activity profile was comparable to or better than that of many widely used anticancer drugs. Moreover, XR11576 was unaffected by multidrug resistance (MDR) mediated by overexpression of either P-glycoprotein or MDR-associated protein, or by down-regulation of topoisomerase II. The latter property supports the dual inhibitory mechanism of action of the compound. XR11576 exhibited a similar pharmacokinetic profile in mice and rats after either i.v. or p.o. administration. In vivo XR11576 showed marked efficacy against a number of tumors including sensitive (H69/P) and multidrug-resistant (H69/LX4) small cell lung cancer and the relatively refractory MC26 and HT29 colon carcinomas following i.v. and p.o. administration. The efficacy of XR11576 was at least comparable to that of TAS-103, originally proposed as a dual inhibitor of topoisomerase I and II. These results suggest that XR11576 is a promising new antitumor agent with oral and i.v. activity, and warrants further development.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Sodium channels in primary sensory neurons: relationship to pain states.

Electrophysiological studies of dorsal root ganglion (DRG) neurons, and the results of PCR, Northern blot and in situ hybridization analyses have demonstrated the molecular diversity of Na+ channels that operate in sensory neurons. Several subtypes of alpha-subunit have been detected in DRG neurons and transcripts encoding all three beta-subunits are also present. Interestingly, one alpha subunit, Na(v)1.8, is selectively expressed in C-fibre and Adelta fibre associated sensory neurons that are predominantly involved in damage sensing. Another channel, Na(v).3, is selectively up regulated in a variety of models of neuropathic pain. In this review we focus on Na+ channels that are selectively expressed in DRG neurons as potential analgesic drug targets. In the absence of subtype specific inhibitors, the production of null mutant mice provides useful information on the specialized functions of particular Na+ channels. A refinement of this approach is to delete Na+ channel genes flanked by lox-P sites in the sensory ganglia of adult animals, using viruses to deliver the bacteriophage Cre recombinase enzyme.

Animals↗
PubMedDate not supplied

Cancer of the penis.

BACKGROUND: Cancer of the penis is an uncommon malignancy in developed countries, but the incidence is as high as 17% of all male cancers in some undeveloped countries. The surgical management of this disease has improved due to better knowledge of risk for metastasis and newer imaging technologies to assess the regional lymph nodes. METHODS: We review the literature on incidence, etiology, pathology, clinical presentation, staging, and management of penile cancer. We present our institutional experience with 160 patients who underwent extended ilioinguinal lymph node dissection, as well as with 7 patients who underwent a modified lymph node dissection. RESULTS: Better understanding of pathologic features allow for stratification of patients into low, intermediate, or high risk for lymph node involvement. Lymphatic mapping to this stratification improves selection of patients who might benefit from lymph node dissection after excision of the primary lesion. Our experience with lymph node dissection yielded a high incidence of positive lymph nodes when lymphadenopathy was present. The recent use of a modified lymph node dissection has minimized morbidity. Current chemotherapy agents are ineffective in this disease. CONCLUSIONS: Pathologic features of the primary lesion and the incorporation of lymphatic mapping have improved the selection of patients who might benefit from lymph node dissection. The use of a modified lymph node dissection in selected patients has decreased morbidity. Effective chemotherapy agents are needed in the management of advanced penile cancer.

Adult↗
PubMedDate not supplied

Optimizing shade match using all-ceramic and composite materials.

Aesthetic management of the anterior dentition often requires the restorative team to use materials of varying color properties. The utilization of shade-selection devices to assist in color interpretation along with dental photography can improve communication between dentist and technician. Additionally, a shade guide system that addresses the four components of color in both ceramics and composites can have a profound impact on the predictability of matching different restorative materials. This article addresses several key elements that should be considered when utilizing different restorative media.

Color↗