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Biomedical subjects

Mark E Williams

Publications and source records attributed to Mark E Williams.

At least 19 recordsLinked to original sources
PubMed2007

The ESRD uninsured matter.

Health-care insurance is the key to health-care access, yet the number of uninsured in the United States grows by a million persons per year and consists, in large part, of those who are financially unable to obtain medical coverage. Their unpaid medical bills add significantly to the cost of health insurance for those who do pay. Those without insurance receive care on a sporadic basis, and the risk of poor health-care outcomes is well established. The end-stage renal disease (ESRD) uninsured face unique problems related to chronicity of care and the system of chronic dialysis-care delivery. This article addresses the growing challenge of the ESRD uninsured in the United States and describes how the current system copes with the ESRD uninsured. More broadly, it discusses who the uninsured are (including undocumented immigrants), the health-care consequences of being without coverage, and how their care is currently financed. It also presents a health-care reform measure in Massachusetts designed to provide affordable insurance to those without coverage.

Compensation and Redress↗
PubMed2006

Internet organ solicitation, explained.

The growth of internet-based communications and the increasing demand for living organ donors are resulting in more use of Web sites for organ solicitation. Web resources have the capacity to improve public awareness about both organ donations and transplant outcomes. Rules for organ donation and fair allocation must follow legal principles regarding organ solicitation. Categories of internet recipient/donor matching services include "clearing house," "membership," and "individual" sites. All these raise ethical concerns related to the individual recipient/donor relationship and to the current system of organ allocation. However, a lack of rules and regulations regarding internet solicitation exists. Several pragmatic steps are proposed.

Health Knowledge, Attitudes, Practice↗
PubMed2006

New potential agents in treating diabetic kidney disease: the fourth act.

Despite the worldwide epidemic of chronic kidney disease complicating diabetes mellitus, current therapies directed against nephroprogression are limited to angiotensin conversion or receptor blockade. Nonetheless, additional therapeutic possibilities are slowly emerging. The diversity of therapies currently in development reflects the pathogenic complexity of diabetic nephropathy. The three most important candidate drugs currently in development include a glycosaminoglycan, a protein kinase C (PKC) inhibitor and an inhibitor of advanced glycation. In targeting primary mechanisms by which hyperglycaemia contributes to diabetic complications, these drugs could provide risk reduction complementary to the partial reduction proven for ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers). Glycosaminoglycans act to restore glycoproteins present in reduced amounts in the glomerular basement membrane and mesangium of diabetic animal models. Components of the drug sulodexide prevent pathological changes and proteinuria in diabetic rats. Reductions in albuminuria, a hallmark of early diabetic kidney disease, have been reported in initial human trials. In the US, a multicentre phase II study has been completed, with an interim analysis indicating reduction in urinary albumin losses. Pivotal phase II trials have begun in patients with type 2 diabetes. A second metabolic pathway of diabetic complications is overexpression of PKC. Several activators of this family of intracellular kinases have been identified and PKC activation may result in tissue damage through a variety of mechanisms. In animal models, the inhibitor ruboxistaurin reduces albuminuria, diabetic histological changes and kidney injury. Like sulodexide, drug development of ruboxistaurin has reached completion of a phase II evaluation with mixed results. The third metabolic target is the nonenzymatic formulation of advanced glycation end-products (AGEs) through well described biochemical pathways. Multiple pathways lead to AGE accumulation in tissues in diabetes and diverse AGE products are formed. AGE deposition has been implicated in animal models of diabetic nephropathy. The leading AGE inhibitor currently in development is pyridoxamine, which has multiple actions that inhibit glycation. Pyridoxamine is an efficient AGE inhibitor in experimental diabetes. A phase II study in diabetic patients with nephropathy reported mixed efficacy results and a favourable safety profile. Phase III evaluation of pyridoxamine has not begun. These three classes of potential therapies, if successfully developed, will confirm that diabetic kidney disease has entered the era of biochemical treatments.

Animals↗
PubMed2005

Differential distribution of voltage-gated calcium channel alpha-2 delta (alpha2delta) subunit mRNA-containing cells in the rat central nervous system and the dorsal root ganglia.

Voltage-gated calcium channels (VGCCs) play an essential role in controlling neurotransmitter release, neuronal excitability, and gene expression in the nervous system. The distribution of cells that contain mRNAs encoding the auxiliary alpha2delta-1, alpha2delta-2, and alpha2delta-3 subunits of the VGCCs in the central nervous system (CNS) and the dorsal root ganglia (DRG) was examined in rats by using in situ hybridization. Specific labeling of alpha2delta-1, alpha2delta-2, and alpha2delta-3 mRNAs appeared to be largely confined to neurons and was widely, although differentially, distributed in the brain, the spinal cord, and the DRG. Importantly, alpha2delta-2 mRNA was found to be expressed in interneurons in the cortex, the hippocampus, the striatum, and in regions that contain dense cholinergic neurons. Our results suggest that different alpha2delta subunits may exert distinctive functions in the CNS. The alpha2delta-1 subunit mRNA is localized in brain regions known to be involved in cortical processing, learning and memory, defensive behavior, neuroendocrine secretion, autonomic activation, primary sensory transmission, and general arousal. The alpha2delta-2 subunit mRNA is present in brain regions known to modulate the overall activities of the cortex, the hippocampus, and the thalamus. The alpha2delta-2 subunit is also found in brain regions known to be involved in olfaction, somatic motor control, fluid homeostasis, ingestive and defensive behaviors, neuroendocrine functions, and circadian rhythm. In addition to being localized in brain regions that express alpha2delta-1 and alpha2delta-2 subunit mRNAs, alpha2delta-3 subunit mRNA is highly expressed in regions involved in auditory information processing and somatic movement.

Animals↗
PubMed2005

Diabetic nephropathy: the proteinuria hypothesis.

BACKGROUND/AIMS: Proteinuria, nearly a universal finding in progressive kidney disease, has been the subject of frequent recent analyses in the renal literature. Proteinuria is a hallmark of diabetic nephropathy: microalbuminuria is the principal early predictor for progression of diabetic glomerulopathy, and proteinuria may be viewed as a measure of the severity and promoter of progression of nephropathy. METHODS: This article critically reviews for the first time the full scope of diabetic proteinuria--complex molecular mechanisms, natural history, and analysis of treatment trials--in order to address the validity of 'the proteinuria hypothesis', i.e., that diabetic proteinuria is a modifiable determinant of renal progression. This hypothesis is analyzed in detail, including recent studies on the primary therapy of diabetic nephropathy, renin-angiotensin blockade. RESULTS: As fully developed, this hypothesis consists of three postulates: that higher amounts of proteinuria predict progressive loss of function, that proteinuria reduction correlates with slowing progression, and that proteinuria is a surrogate endpoint for clinical trials. The latter postulate has not before been adequately linked to growing information about the first two postulates as they apply to diabetic kidney disease. CONCLUSION: While diabetic nephropathy is a disease model for the potential use of proteinuria as a surrogate marker for renal progression, this shift in perspective will require prospective data from additional clinical trials, particularly of non-renin-angiotensin blocking drugs, to be complete.

Diabetic Nephropathies↗
PubMed2005

The next generation of diabetic nephropathy therapies: an update.

Although treatments for diabetic kidney disease are available, many patients still have progressive disease. More effective therapies are urgently needed. Novel agents currently under evaluation in clinical trials are described in this review. Sulodexide, a mixture of three glycosaminoglycans, appears to prevent diabetic nephropathy in experimental models by ameliorating abnormalities in the glomerular basement membrane and mesangial matrix. Pyridoxamine is an inhibitor of advanced glycation end-product (AGE) formation derived from vitamin B(6). Alagebrium is an AGE cross-link breaker. AGEs injure the kidneys and other vascular targets by mechanisms such as oxidative stress, inflammation, and protein cross-linking, among others. By inhibiting AGE formation or breaking AGE cross-links, experimental models have demonstrated kidney protection. Ruboxistaurin is an inhibitor of protein kinase C beta (PKC-beta), a mediator of signal transduction that leads to cell growth, fibrosis, and tissue injury. In diabetes, PKC-beta is up-regulated and activated in the kidney. Ruboxistaurin prevents diabetic kidney disease in animal models. These agents have appeared promising (by reduction of albuminuria and preservation of kidney function) in phase II studies. To determine whether clinical outcomes (mortality, renal, and cardiovascular events) are improved beyond the current standard of care, phase III trials are planned.

Animals↗
PubMed2004

Ric-3 promotes functional expression of the nicotinic acetylcholine receptor alpha7 subunit in mammalian cells.

Expression of functional, recombinant alpha7 nicotinic acetylcholine receptors in several mammalian cell types, including HEK293 cells, has been problematic. We have isolated the recently described human ric-3 cDNA and co-expressed it in Xenopus oocytes and HEK293 cells with the human nicotinic acetylcholine receptor alpha7 subunit. In addition to confirming the previously reported effect on alpha7 receptor expression in Xenopus oocytes we demonstrate that ric-3 promotes the formation of functional alpha7 receptors in mammalian cells, as determined by whole cell patch clamp recording and surface alpha-bungarotoxin binding. Upon application of 1 mm nicotine, currents were undetectable in HEK293 cells expressing only the alpha7 subunit. In contrast, co-expression of alpha7 and ric-3 cDNAs resulted in currents that averaged 42 pA/pF with kinetics similar to those observed in cells expressing endogenous alpha7 receptors. Immunoprecipitation studies demonstrate that alpha7 and ric-3 proteins co-associate. Additionally, cell surface labeling with biotin revealed the presence of alpha7 protein on the plasma membrane of cells lacking ric-3, but surface alpha-bungarotoxin staining was only observed in cells co-expressing ric-3. Thus, ric-3 appears to be necessary for proper folding and/or assembly of alpha7 receptors in HEK293 cells.

Animals↗
PubMed2004

Clinical studies of advanced glycation end product inhibitors and diabetic kidney disease.

Current treatment of the nephropathy complication of diabetes mellitus is suboptimal in halting the progression of the complex disease. Among the irreversible effects of sustained hyperglycemia is the heightened formation of advanced glycation end products (AGEs). The role of AGEs in diabetic nephropathy has been established by years of basic research. This article reports progression through human studies of the few AGE inhibitors that have reached clinical development, including pimagedine, pyridoxamine, and alagebrium.

Diabetic Nephropathies↗
PubMed2004

Doxercalciferol safely suppresses PTH levels in patients with secondary hyperparathyroidism associated with chronic kidney disease stages 3 and 4.

BACKGROUND: Calcitriol lowers parathyroid hormone (PTH) levels in patients with chronic kidney disease (CKD) stages 3 and 4, but its use is limited by a low therapeutic index and concerns regarding hypercalcemia and acceleration of kidney disease. We evaluated doxercalciferol (1alpha-hydroxyvitamin D2) as an alternative therapy in a randomized, double-blinded, placebo-controlled, multicenter trial. METHODS: Fifty-five adults with stage 3 or 4 CKD and an intact PTH (iPTH) level greater than 85 pg/mL (ng/L) completed 8 baseline weeks, followed by 24 weeks of oral therapy with doxercalciferol or placebo. Pretreatment demographics and biochemical features did not differ between groups. Dosages were increased gradually if iPTH level was not decreased by 30% or greater and serum calcium and phosphorus levels were stable. Regular monitoring included plasma iPTH, serum calcium and phosphorus, urinary calcium, bone-specific serum markers, and serum lalpha,25-dihydroxyvitamin D levels. Glomerular filtration rate (GFR) was measured before and after treatment. RESULTS: Mean plasma iPTH level decreased by 46% from baseline after 24 weeks of doxercalciferol treatment (P <0.001), but was unchanged with placebo. After 6 weeks, iPTH level reductions with doxercalciferol treatment exceeded those with placebo at all subsequent intervals (P <0.001). No clinically significant differences in mean serum calcium or phosphorus or urinary calcium levels or incidence of hypercalcemia, hyperphosphatemia, or hypercalciuria were noted between groups. Serum C- and N-telopeptide and bone-specific alkaline phosphatase levels decreased with doxercalciferol treatment relative to both baseline and placebo (P <0.01). Adverse-event rates and changes in GFR did not differ between groups. CONCLUSION: Doxercalciferol is safe and effective in controlling secondary hyperparathyroidism of patients with CKD stages 3 and 4.

Aged↗
PubMed2004

Modal gating of human CaV2.1 (P/Q-type) calcium channels: I. The slow and the fast gating modes and their modulation by beta subunits.

The single channel gating properties of human CaV2.1 (P/Q-type) calcium channels and their modulation by the auxiliary beta1b, beta2e, beta3a, and beta4a subunits were investigated with cell-attached patch-clamp recordings on HEK293 cells stably expressing human CaV2.1 channels. These calcium channels showed a complex modal gating, which is described in this and the following paper (Fellin, T., S. Luvisetto, M. Spagnolo, and D. Pietrobon. 2004. J. Gen. Physiol. 124:463-474). Here, we report the characterization of two modes of gating of human CaV2.1 channels, the slow mode and the fast mode. A channel in the two gating modes differs in mean closed times and latency to first opening (both longer in the slow mode), in voltage dependence of the open probability (larger depolarizations are necessary to open the channel in the slow mode), in kinetics of inactivation (slower in the slow mode), and voltage dependence of steady-state inactivation (occurring at less negative voltages in the slow mode). CaV2.1 channels containing any of the four beta subtypes can gate in either the slow or the fast mode, with only minor differences in the rate constants of the transitions between closed and open states within each mode. In both modes, CaV2.1 channels display different rates of inactivation and different steady-state inactivation depending on the beta subtype. The type of beta subunit also modulates the relative occurrence of the slow and the fast gating mode of CaV2.1 channels; beta3a promotes the fast mode, whereas beta4a promotes the slow mode. The prevailing mode of gating of CaV2.1 channels lacking a beta subunit is a gating mode in which the channel shows shorter mean open times, longer mean closed times, longer first latency, a much larger fraction of nulls, and activates at more positive voltages than in either the fast or slow mode.

Calcium Channels, N-Type↗
PubMed2004

The short-term effect of interdisciplinary medication review on function and cost in ambulatory elderly people.

OBJECTIVES: To determine whether a medication review by a specialized team would promote regimen changes in elders taking multiple medications and to measure the effect of regimen changes on monthly cost and functioning. DESIGN: A randomized-controlled trial. SETTING: Health center ambulatory clinic. PARTICIPANTS: Community-dwelling older adults taking five or more medications were assessed at baseline and 6 weeks. A medication-change intervention group of 57 elders was compared with a control group of 76 elder adults. INTERVENTION: The primary intervention was a comprehensive review and recommended modification of a patient's medication regimen. Changes were endorsed by each patient's primary physician and discussed with each patient. MEASUREMENTS: Measures were the Timed Manual Performance Test, Physical Performance Test, Functional Reach Assessment, subtests from the Wechsler Adult Intelligence Scale, a modified Randt Memory Test, the Center for Epidemiological Studies-Depression Scale, the Self-Rating Anxiety Scale, and the Rand 36-item Health Survey 1.0. Comorbidity was determined using the International Classification of Diseases, Ninth Revision, Clinical Modification. Medication usage was determined using brown bag review. RESULTS: Intervention subjects decreased their medications by an average of 1.5 drugs. No differences in functioning were observed between groups. Intervention subjects saved an average $26.92 per month in wholesale medication costs; control subjects saved $6.75 per month (P<.006). CONCLUSION: Although the intervention significantly reduced the medications taken and monthly cost, most patients were resistant to reducing medications to the recommended level. Further study is needed to understand patient resistance to reducing adverse polypharmacy and to devise better strategies for addressing this important problem in geriatric health. Greater focus on prescriber behavior is recommended.

Aged↗
PubMed2003

Randomized trial of an inhibitor of formation of advanced glycation end products in diabetic nephropathy.

BACKGROUND/AIMS: Pimagedine inhibits the formation of advanced glycation end products and slows the progression of diabetic complications in experimental models. This study was undertaken to determine if pimagedine ameliorates nephropathy in type 1 (insulin-dependent) diabetes mellitus. METHODS: This was a randomized, double-masked, placebo-controlled study performed in 690 patients with type 1 diabetes mellitus, nephropathy, and retinopathy. The patients received twice daily dosing with placebo, pimagedine 150 mg, or pimagedine 300 mg for 2-4 years. The primary end point was the time to doubling of serum creatinine; the secondary end points included evaluations of proteinuria, kidney function, and retinopathy. RESULTS: Serum creatinine doubled in 26% (61/236) of the placebo-treated patients and in 20% (91/454) of those who received pimagedine (p = 0.099). The estimated glomerular filtration rate decreased more slowly in the pimagedine-treated patients with a 36-month decrease from baseline of 6.26 ml/min/1.73 m(2) as compared with 9.80 ml/min/1.73 m(2) in the placebo-treated patients (p = 0.05), and pimagedine reduced the 24-hour total urinary proteinuria. (The mean reduction from baseline at month 36 was 732 mg/24 h at the low dose and 329 mg/24 h at the high dose as compared with 35 mg/24 h in the placebo group; p </= 0.001.) Fewer pimagedine-treated patients with baseline and end point evaluations (31/324; 10%) as compared with those receiving placebo (16%; 28/179) experienced a three-step or greater progression of the retinopathy (Early Treatment of Diabetic Retinopathy Study) score (p = 0.030). Three patients receiving high-dose pimagedine but none receiving low-dose treatment developed glomerulonephritis. CONCLUSIONS: While this study did not demonstrate a statistically significant beneficial effect of pimagedine on the progression of overt nephropathy resulting from type 1 diabetes, it is noteworthy in providing the first clinical proof of the concept that inhibiting advanced glycation end product formation can result in a clinically important attenuation of the serious complications of type 1 diabetes mellitus.

Adult↗
PubMed2003

New therapies for advanced glycation end product nephrotoxicity: current challenges.

BACKGROUND: The role of advanced glycation end products (AGEs) in diabetic nephropathy has been developed during several years of research and increasingly complex AGE biochemistry. However, the structural diversity of AGE chemistry has created new challenges in the search for AGE-based inhibition therapies. RESULTS: The challenges include the need to standardize measurements of serum and tissue AGE levels, identifying nephrotoxic AGE compounds, understanding the cell biological state of AGEs in the diabetic kidney, determining the mechanism of action of selective inhibition of the glycation cascade, and forming complementary therapies. CONCLUSION: Current challenges in the development of new therapies for AGE nephrotoxicity are reviewed.

Animals↗
PubMed2003

A new approach to assessing function in elderly people.

Current functional assessment methods and measures of elderly people are limited in their ability to detect small decrements in function or in discriminating between different patterns of functional loss. Nor do they directly assess function in the patient's usual environment. Recent technological advances have led to the development of small, wearable microelectronic devices that detect motion, velocity and acceleration. These devices can be used to develop new tools for more precise monitoring, assessment, and prediction of function by characterizing the 'electronic signatures' of successful or unsuccessful task-specific performance, and to allow for continuous assessment in a home environment. This presentation will summarize current efforts to translate new technologies into a clinical and research tool for improved assessment, monitoring, and prediction of function among older individuals.

Acceleration↗