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Biomedical subjects

M E Williams

Publications and source records attributed to M E Williams.

At least 19 recordsLinked to original sources
PubMed2006

Hemodialyzed type I and type II diabetic patients in the US: Characteristics, glycemic control, and survival.

Diabetes mellitus (DM) constitutes a major end-stage renal disease (ESRD) health problem. Glycemic control is fundamental to the management of diabetes and its complications, and relies on monitoring of hyperglycemia. We therefore performed a primary data analysis of glycemic control and survival on a large national ESRD database. Ninety-five percent of patients with DM had type II diabetes (N = 23,504), and five percent had type I diabetes (N = 1,371). For the combined population, the mean hemoglobin A1c (HgbA1c) was 6.77%, and the mean random blood glucose was 168 mg/dl. Mean HgbA1c values were >7.0% in 35% and >8.5% in 14%. Mean HgbA1c values were below 5% in 11.3% of patients. Type I study patients tended to have higher HgbA1c values. Most patients (75.8%) had three or more random blood glucose determinations within 90 days preceding the HgbA1c measurement. The HgbA1c showed only a weak correlation with mean random glucose values (R2 0.3716; s.e. = 1.36). The survival rates in the subsequent 12-month period ranged from 80 to 85% across different HgbA1c strata. Kaplan-Meier survival curves grouped by HgbA1c levels showed no correlation between HgbA1c and survival at 12 months. More studies are needed to refine recommendations for the role of HgbA1c and glycemic control in this patient population.

Adult↗
PubMed2002

Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by homozygous deletion in multiple myeloma cell lines: ectopic p18 expression inhibits growth and induces apoptosis.

Multiple myeloma (MM) is a clonal neoplasm of plasma cells which offers an excellent model to study multistep molecular oncogenesis. In 20-25% of primary tumors and cell lines examined, cyclin D1 is overexpressed due to the translocation t(11;14)(q13;q32). We have characterized cyclin-dependent kinase inhibitor p15 (CDKN2B), p16 (CDKN2A) and p18 (CDKN2C) deletions in cyclin D1-expressing and non-expressing MM cell lines. p18 was found to be frequently deleted (38%); in some cases p18 deletions coexisted with hemizygous p16 deletion. To examine the function of p18 as a putative tumor suppressor in myeloma cells, a zinc-inducible p18 construct was stably transfected into KMS12, a MM cell line with biallelic p18 and monoallelic p16 deletions as well as cyclin D1 overexpression. Ectopic expression of p18 caused 40-45% growth suppression as determined by trypan blue exclusion and MTS assays. p18 induction also resulted in apoptosis, suggesting that inhibition of the cyclin D1/CDK/pRb pathway in these tumor cells could be a crucial step toward the induction of tumor regression via apoptotic cell death. This cell cycle pathway is thus frequently mutated and provides a potentially novel target for gene therapeutic or pharmacologic approaches to human myeloma.

Apoptosis↗
PubMed2001

Expression of catecholaminergic mRNAs in the hyperactive mouse mutant coloboma.

The SNAP-25 deficient mouse mutant coloboma (Cm/+) is an animal model for investigating the biochemical basis of locomotor hyperactivity. The spontaneous hyperactivity exhibited by coloboma is three times greater than control mice and is a direct result of the SNAP-25 deletion. SNAP-25 is a presynaptic protein that regulates exocytotic neurotransmitter release; coloboma mice express only 50% of normal protein concentrations. Previous research has determined that there is an increase in the concentration of norepinephrine but a decrease in dopamine utilization in the striatum and nucleus accumbens of coloboma mice. In situ hybridization analysis revealed that there were corresponding increases in tyrosine hydroxylase (TH) mRNA expression in noradrenergic cell bodies of the locus coeruleus of Cm/+ mice. In contrast, TH mRNA expression in substantia nigra appeared normal in the mutant mouse. alpha(2)-Adrenergic receptors are important modulators of central noradrenergic function and dopamine release. In situ hybridization data revealed that alpha(2A)-adrenergic receptor mRNA expression is upregulated in Cm/+ mice. These results suggest an underlying abnormality in noradrenergic regulation in this hyperactive mouse mutant.

Animals↗
PubMed2001

The routine use of diagnostic laparoscopy in the intensive care unit.

BACKGROUND: Delay in the diagnosis of intraabdominal pathology is a major contributor to the morbidity and mortality of intensive care unit (ICU) patients. Laparoscopy is a valuable diagnostic tool that can be used safely and efficiently in the evaluation of intraabdominal processes that may be difficult to diagnose with conventional methods. Our goal was to show that laparoscopy performed at the bedside in the ICU could be used as a routine diagnostic tool in the evaluation of critically ill patients, just as computed tomography (CT), ultrasonography (US), and radiography are. METHODS: We present 11 patients who underwent 12 bedside examinations in the ICU of a community teaching hospital. Several different surgeons with varying degrees of laparoscopic experience performed these procedures over a 1-year period. RESULTS: Four patients had previously undergone recent abdominal operations. Nontherapeutic laparotomy was avoided in six patients because of diagnostic laparoscopy. One patient also underwent a therapeutic maneuver at the time of diagnostic laparoscopy. None of the patients required general anesthesia, although local anesthetics and sedation with midazolam or propofol were used. One patient underwent the procedure without endotracheal intubation. There were no complications or mortalities directly related to the procedure. CONCLUSION: We conclude that bedside laparoscopy in the ICU under local anesthesia is a diagnostic and potentially therapeutic tool that can be used safely in the work-up of potential abdominal pathology in critically ill patients.

Abdomen↗
PubMed2001

Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats.

Peripheral nerve injury can lead to a persistent neuropathic pain state in which innocuous tactile stimulation elicits pain behavior (tactile allodynia). Spinal administration of the anticonvulsant gabapentin suppresses allodynia by an unknown mechanism. In vitro studies indicate that gabapentin binds to the alpha(2)delta-1 (hereafter referred to as alpha(2)delta) subunit of voltage-gated calcium channels. We hypothesized that nerve injury may result in altered alpha(2)delta subunit expression in spinal cord and dorsal root ganglia (DRGs) and that this change may play a role in neuropathic pain processing. Using a rat neuropathic pain model in which gabapentin-sensitive tactile allodynia develops after tight ligation of the left fifth and sixth lumbar spinal nerves, we found a >17-fold, time-dependent increase in alpha(2)delta subunit expression in DRGs ipsilateral to the nerve injury. Marked alpha(2)delta subunit upregulation was also evident in rats with unilateral sciatic nerve crush, but not dorsal rhizotomy, indicating a peripheral origin of the expression regulation. The increased alpha(2)delta subunit expression preceded the allodynia onset and diminished in rats recovering from tactile allodynia. RNase protection experiments indicated that the DRG alpha(2)delta regulation was at the mRNA level. In contrast, calcium channel alpha(1B) and beta(3) subunit expression was not co-upregulated with the alpha(2)delta subunit after nerve injury. These data suggest that DRG alpha(2)delta regulation may play an unique role in neuroplasticity after peripheral nerve injury that may contribute to allodynia development.

Animals↗
PubMed2001

An ionic liquid form of DNA: redox-active molten salts of nucleic acids.

Ionic liquids are described that contain duplex DNA as the anion and polyether-decorated transition metal complexes based on M(MePEG-bpy)(3)(2+) as the cation (M = Fe, Co; MePEG-bpy = 4,4'-(CH(3)(OCH(2)CH(2))(7)OCO)(2)-2,2'-bipyridine). When the undiluted liquid DNA-or molten salt-is interrogated electrochemically by a microelectrode, the molten salts exhibit cyclic voltammograms due to the physical diffusion (D(PHYS)) of the polyether-transition metal complex. When M = Co(II), the cyclic voltammogram of the melt shows an oxidative wave due to the Co(III/II) couple at E(1/2) = 0.40 V (versus Ag/AgCl) and a D(PHYS) of 6 x 10(-12) cm(2)/s, which is significantly lower than that for Co(MePEG-bpy)(3)(ClO(4))(2) (D(PHYS) = 2.6 x 10(-10) cm(2)/s) due to greater viscosity provoked by the DNA polymer. When a 1:1 mixture is made of the Co(MePEG-bpy)(3).DNA and Fe(MePEG-bpy)(3)(ClO(4))(2) melts, two redox waves are observed. The first is due to the Co(III/II) couple, and the second is a catalytic wave due to oxidation of guanine in DNA by electrogenerated Fe(III) in the undiluted melt. Independent experiments show that the Fe(III) form of the complex selectively oxidizes guanine in duplex DNA. These DNA molten salts constitute a new class of materials whose properties can be controlled by nucleic acid sequence and that can be interrogated in undiluted form on microelectrode arrays.

DNA↗
PubMed2001

Abnormal presynaptic catecholamine regulation in a hyperactive SNAP-25-deficient mouse mutant.

The consequences of a reduction in the presynaptic protein, SNAP-25, were investigated to determine the neurochemical basis of the marked hyperlocomotor activity in coloboma (Cm/+) mice. SNAP-25 is part of the minimal presynaptic machinery necessary for exocytotic neurotransmitter release. Reserpine treatment was used to deplete vesicular stores of catecholamines. Coloboma mice were more sensitive to the effects of reserpine than control mice. However, presynaptic regulation of dopamine (DA) release, as assessed by low-dose apomorphine challenge, was intact. There were region-specific reductions in in vivo tyrosine hydroxylation and the DA metabolites homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens of Cm/+ mice. While hyperactivity is often associated with changes in DA concentration, norepinephrine (NE) concentration was significantly increased in the striatum and nucleus accumbens of the hyperactive mutant. The increase in NE may regulate the hyperactivity in these mice, as suggested by current hypotheses of the mechanisms underlying attention-deficit hyperactivity disorder (ADHD) and Tourette's syndrome.

Animals↗
PubMed2000

Mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin's lymphoma that is incurable with current chemotherapeutic approaches. Despite response rates of 50% to 70% to many regimens, all patients have disease progression after chemotherapy, and median survival is approximately 3 years. There is no clear standard of care for MCL, which increases the importance of enrolling patients in clinical trials. Off protocol, chemotherapy with chlorambucil or combination regimens can be used in patients who are not candidates for high-dose therapy. Autologous stem cell transplant as initial therapy has high response rates and prolongs time to progression but has not been shown to improve survival. For young patients with matched donors, allogeneic transplant appears promising in the limited numbers of patients treated to date. Other agents, including rituximab, fludarabine, and cladribine, have demonstrated activity but do not appear to offer survival advantages over combination chemotherapy.

Antibodies, Monoclonal↗
PubMed2000

Optical coherence microscopy. A technology for rapid, in vivo, non-destructive visualization of plants and plant cells.

We describe the development and utilization of a new imaging technology for plant biology, optical coherence microscopy (OCM), which allows true in vivo visualization of plants and plant cells. This novel technology allows the direct, in situ (e.g. plants in soil), three-dimensional visualization of cells and events in shoot tissues without causing damage. With OCM we can image cells or groups of cells that are up to 1 mm deep in living tissues, resolving structures less than 5 microm in size, with a typical collection time of 5 to 6 min. OCM measures the inherent light-scattering properties of biological tissues and cells. These optical properties vary and provide endogenous developmental markers. Singly scattered photons from small (e.g. 5 x 5 x 10 microm) volume elements (voxels) are collected, assembled, and quantitatively false-colored to form a three-dimensional image. These images can be cropped or sliced in any plane. Adjusting the colors and opacities assigned to voxels allows us to enhance different features within the tissues and cells. We show that light-scattering properties are the greatest in regions of the Arabidopsis shoot undergoing developmental processes. In large cells, high light scattering is produced from nuclei, intermediate light scatter is produced from cytoplasm, and little if any light scattering originates from the vacuole and cell wall. OCM allows the rapid, repetitive, non-destructive collection of quantitative data about inherent properties of cells, so it provides a means of continuously monitoring plants and plant cells during development and in response to exogenous stimuli.

Microscopy↗
PubMed2000

Combination immunotherapy of relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma with rituximab and interferon-alpha-2a.

Rituximab and IFN have each demonstrated single-agent activity in patients with low-grade non-Hodgkin's lymphoma (NHL). A single-arm, multicenter, Phase II trial was conducted to assess the safety and efficacy of combination therapy with rituximab and IFN-alpha-2a in 38 patients with relapsed or refractory, low-grade or follicular, B-cell NHL. IFN-alpha-2a [2.5 or 5 million units (MIU)] was administered s.c., three times weekly for 12 weeks. Starting on the fifth week of treatment, rituximab was administered by i.v. infusion (375 mg/m2) weekly for 4 doses. All 38 patients received four complete infusions of rituximab and were evaluable for efficacy, although 11 patients (29%) did not-receive all 36 injections of IFN. The mean number of IFN-alpha-2a injections was 31 doses; the mean total units received were 141 MIU (maximum, 180 MIU). The study treatment was reasonably well tolerated with no unexpected toxicities stemming from the combination therapy. No grade 4 events were reported. Frequent adverse events during the treatment period included asthenia (35 of 38 patients), chills (31 of 38), fever (30 of 38), headache (28 of 38), nausea (23 of 38), and myalgia (22 of 38). The overall response rate was 45% (17 of 38 patients); 11% had a complete response, and 34% had a partial response. The Kaplan-Meier estimates for the median response duration and the median time to progression in responders are 22.3 and 25.2 months, respectively. Further follow-up is needed to determine whether this treatment combination leads to a significantly longer time to progression than single-agent treatment with rituximab.

Adult↗
PubMed1999

Functional consequences of mutations in the human alpha1A calcium channel subunit linked to familial hemiplegic migraine.

Mutations in alpha1A, the pore-forming subunit of P/Q-type calcium channels, are linked to several human diseases, including familial hemiplegic migraine (FHM). We introduced the four missense mutations linked to FHM into human alpha1A-2 subunits and investigated their functional consequences after expression in human embryonic kidney 293 cells. By combining single-channel and whole-cell patch-clamp recordings, we show that all four mutations affect both the biophysical properties and the density of functional channels. Mutation R192Q in the S4 segment of domain I increased the density of functional P/Q-type channels and their open probability. Mutation T666M in the pore loop of domain II decreased both the density of functional channels and their unitary conductance (from 20 to 11 pS). Mutations V714A and I1815L in the S6 segments of domains II and IV shifted the voltage range of activation toward more negative voltages, increased both the open probability and the rate of recovery from inactivation, and decreased the density of functional channels. Mutation V714A decreased the single-channel conductance to 16 pS. Strikingly, the reduction in single-channel conductance induced by mutations T666M and V714A was not observed in some patches or periods of activity, suggesting that the abnormal channel may switch on and off, perhaps depending on some unknown factor. Our data show that the FHM mutations can lead to both gain- and loss-of-function of human P/Q-type calcium channels.

Amino Acid Substitution↗
PubMed1999

Structural elements in domain IV that influence biophysical and pharmacological properties of human alpha1A-containing high-voltage-activated calcium channels.

We have cloned two splice variants of the human homolog of the alpha1A subunit of voltage-gated Ca2+ channels. The sequences of human alpha1A-1 and alpha1A-2 code for proteins of 2510 and 2662 amino acids, respectively. Human alpha1A-2alpha2bdeltabeta1b Ca2+ channels expressed in HEK293 cells activate rapidly (tau+10mV = 2.2 ms), deactivate rapidly (tau-90mV = 148 micros), inactivate slowly (tau+10mV = 690 ms), and have peak currents at a potential of +10 mV with 15 mM Ba2+ as charge carrier. In HEK293 cells transient expression of Ca2+ channels containing alpha1A/B(f), an alpha1A subunit containing a 112 amino acid segment of alpha1B-1 sequence in the IVS3-IVSS1 region, resulted in Ba2+ currents that were 30-fold larger compared to wild-type (wt) alpha1A-2-containing Ca2+ channels, and had inactivation kinetics similar to those of alpha1B-1-containing Ca2+ channels. Cells transiently transfected with alpha1A/B(f)alpha2bdeltabeta1b expressed higher levels of the alpha1, alpha2bdelta, and beta1b subunit polypeptides as detected by immunoblot analysis. By mutation analysis we identified two locations in domain IV within the extracellular loops S3-S4 (N1655P1656) and S5-SS1 (E1740) that influence the biophysical properties of alpha1A. alpha1AE1740R resulted in a threefold increase in current magnitude, a -10 mV shift in steady-state inactivation, and an altered Ba2+ current inactivation, but did not affect ion selectivity. The deletion mutant alpha1ADeltaNP shifted steady-state inactivation by -20 mV and increased the fast component of current inactivation twofold. The potency and rate of block by omega-Aga IVA was increased with alpha1ADeltaNP. These results demonstrate that the IVS3-S4 and IVS5-SS1 linkers play an essential role in determining multiple biophysical and pharmacological properties of alpha1A-containing Ca2+ channels.

Amino Acid Sequence↗
PubMed1999

Recurrent Epstein-Barr virus-associated post-transplant lymphoproliferative disorder: report of a patient with histologically similar but clonally distinct metachronous abdominal and brain lesions.

A liver transplant patient developed a single central nervous system (CNS) intraparenchymal lesion 5 months after the diagnosis of an intraabdominal diffuse large B-cell post-transplant lymphoproliferative disorder (PTLD). Biopsy of the new CNS lesion showed a diffuse large B-cell PTLD morphologically and immunohistochemically indistinguishable from the abdominal lesion. In addition, both lesions were positive for Epstein-Barr virus (EBV) DNA by polymerase chain reaction (PCR) and for EBV-encoded RNA by in situ hybridization. Although these results were consistent with a metastatic origin for the CNS lesion, the finding of an intraparenchymal lesion without leptomeningeal or dural spread was suggestive of a new primary CNS lymphoma. Proof that the brain lesion was a second primary and not a metastasis was obtained by immunoglobulin gene rearrangement studies and assessment of EBV clonality. Multiple primary lymphoid neoplasms arise at higher frequency in the setting of immunosuppression, and molecular investigations of tumor clonality can provide clinically relevant staging and prognostic information.

Abdominal Neoplasms↗
PubMed1999

Structure and functional characterization of a novel human low-voltage activated calcium channel.

We have isolated and characterized overlapping cDNAs encoding a novel, voltage-gated Ca2+ channel alpha1 subunit, alpha1H, from a human medullary thyroid carcinoma cell line. The alpha1H subunit is structurally similar to previously described alpha1 subunits. Northern blot analysis indicates that alpha1H mRNA is expressed throughout the brain, primarily in the amygdala, caudate nucleus, and putamen, as well as in several nonneuronal tissues, with relatively high levels in the liver, kidney, and heart. Ba2+ currents recorded from human embryonic kidney 293 cells transiently expressing alpha1H activated at relatively hyperpolarized potentials (-50 mV), rapidly inactivated (tau = 17 ms), and slowly deactivated. Similar results were observed in Xenopus oocytes expressing alpha1H. Single-channel measurements in human embryonic kidney 293 cells revealed a single-channel conductance of approximately 9 pS. These channels are blocked by Ni2+ (IC50 = 6.6 microM) and the T-type channel antagonists mibefradil (approximately 50% block at 1 microM) and amiloride (IC50 = 167 microM). Thus, alpha1H-containing channels exhibit biophysical and pharmacological properties characteristic of low voltage-activated, or T-type, Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Distance learning for hospital managers.

Telemedicine technology enabled this class to meet. The Chapel Hill instructor could not have traveled to Scotland Neck for the classes, and the class members could not have taken time away from their jobs to travel to Chapel Hill. The technology allowed the participants to fit the classes into their schedules. For the group of managers at this small, isolated hospital, the experience of participating in a management class with an expert was a positive one. They were introduced to standard management practices, learned new skills, and formed a support group/team onsite. The students felt close to the leader, yet the physical distance made her an outsider in a way that encouraged frankness. The technology seemed to foster the best of both worlds--intimacy, yet physical distance and, thus, safety. These new managers were able to take part in a course that taught tangible skills for improving their job performance and, more important, afforded access to resources outside of Halifax County. They were able to step away from their daily routine and interact with outsiders and each other in new ways, without the stress and expense of travel. The results of this pilot study indicate that distance learning is feasible for courses of this kind. Staff burnout and turnover are chronic problems in rural facilities, with isolation contributing to job dissatisfaction. Distance learning offers exciting possibilities for addressing these problems in healthcare settings across the country.

Attitude of Health Personnel↗