Biomedical subjects

D L Holmes

Publications and source records attributed to D L Holmes.

At least 19 recordsLinked to original sources

PubMed1996

Dissociation constants of water-insoluble carboxylic acids by 13C-NMR. pK(a)s of mesobiliverdin-XIII alpha and mesobilirubin-XIII alpha.

High-field 13C-NMR of 13C-enriched compounds in dilute aqueous d6-Me2-SO solutions provides a simple, accurate method for measuring pK(a)s of sparingly soluble carboxylic acids. Using this method, we found the pK(a)s of mesobilirubin-XIII alpha to be 4.2 and 4.9, much lower values than reported recently for bilirubin, and of mesobiliverdin-XIII alpha to be 3.9 and 5.3.

Bilirubin↗

PubMed1996

On the acid dissociation constants of bilirubin and biliverdin. pKa values from 13C NMR spectroscopy.

Biliverdin and bilirubin are naturally-occurring tetrapyrrolic bile pigments containing two propionic acid side chains. These side chains, and their propensity for ionization, are critical in the biological disposition of the pigments. Surprisingly, accurate dissociation constants for the propionic acid groups of biliverdin are unknown, and a wide range of values, extending over some 4 orders of magnitude, has been suggested for the Ka values of the propionic acid groups of bilirubin in aqueous solutions. Recently, pKa values of 6.7-9.3 have been reported for bilirubin--values much greater than the value of approximately 5 typical of propionic acid groups. These curiously high values, currently being used to explain the biological transport and metabolism of bilirubin and related compounds, have been attributed to intramolecular hydrogen bonding. We have determined the pKa values of 99% 13C-enriched (13CO2H) [8(3),12(3)-13C2]mesobilirubin-XIII, alpha, the corresponding biliverdin, and several monopropionic model compounds by 13C NMR spectroscopy. This technique allows direct observation and quantitative measurement of the carboxylic acid and carboxylate anion carbon signals. Analysis of the variation of carboxyl 13C NMR chemical shift with pH gave rubin pKa values of 4.2 and 4.9 and verdin pKa values of 3.9 and 5.3 in aqueous buffers containing only a very small quantity (0.086 mol fraction) of dimethyl sulfoxide. When extrapolated to water, the pKa values are essentially unchanged. The data provide the first experimentally-determined pKa values for a biliverdin. They indicate that intramolecular hydrogen bonding has little effect on the acid dissociation of bilirubin and suggest that the equilibrium acidity of the bilirubin carboxylic acid groups is not abnormally high but similar to the thermodynamic acidity found in other carboxylic acids, as originally suggested by Overbeek et al. (Overbeek, J. T. G., Vink, C. L. J., and Deenstra, H. (1955) Recl. Trav. Chim. Pays-Bas 74, 81-84).

Bilirubin↗

PubMed1996

Evaluating the impact of facilitated communication on the communicative competence of fourteen students with autism.

The purpose of this study was to evaluate facilitated communication (FC) as an augmentative or alternative communication system for 14 students attending the Eden Institute in Princeton, NJ. All participants had an independent diagnosis of autism and standardized testing revealed significant deficits in adaptive behavior across all developmental domains. A pretest-posttest design was utilized to (a) determine if any of the participants were immediately capable of communicating through FC (b) if necessary, instruct the participants in the use FC, and (c) determine if this instruction had any impact on their ability to use FC. At the end of 10 weeks of instruction, no participants were able to produce functional, typed communication. Findings are consistent with other quantitative studies that find no support for the cause-effect relationship proposed by FC proponents.

Adolescent↗

PubMed1995

Dialysis adequacy indices in high membrane transporters treated with short-dwell peritoneal dialysis.

Treatment of high-membrane transporters with continuous ambulatory peritoneal dialysis (CAPD) is associated with ineffective ultrafiltration, increased dialysate protein loss, lower serum albumin levels, and lower protein catabolic rates, suggesting development of inadequate dialysis. The use of short-dwell nightly intermittent peritoneal dialysis (NIPD) and daytime ambulatory peritoneal dialysis (DAPD) has not been evaluated. Patients with inadequate ultrafiltration secondary to rapid membrane transport [peritoneal equilibration test (PET) confirmation] were managed with NIPD and DAPD (group A, n = 32) and compared to patients on CAPD and continuous cycling peritoneal dialysis (CCPD) (group B, n = 53) after at least 3 months of therapy. Groups A and B were similar in age, gender, diabetic status, prestudy months on peritoneal dialysis (PD), and residual renal function. No significant differences were observed between the groups with respect to serum albumin, daily protein loss, normalized protein catabolic rate (PCRN), or weekly KT/V urea indices. Diabetics demonstrated lower levels of serum albumin and PCRN than nondiabetics while maintaining equivalent KT/V urea indices. Reassessment of patients 6 months later also revealed no differences in outcome measures between group A (n = 20) and group B (n = 36). High transporters treated with NIPD and DAPD appear to have similar dialysate protein loss, adequacy, and nutrition indices when compared to patients on CAPD and CCPD. Future studies will determine if delivery of higher target small-solute clearances benefits patients on NIPD/DAPD as contrasted with continuous PD modalities (CAPD/CCPD), or diabetics compared to nondiabetics.

Biological Transport↗

PubMed1994

Oral contraceptives and renal and retinal complications in young women with insulin-dependent diabetes mellitus.

OBJECTIVE: To evaluate the effects of oral contraceptives (OCs) as a possible risk factor for early diabetic renal and/or retinal complications. DESIGN: A retrospective case-control study. SETTING: A university hospital diabetes clinic. PARTICIPANTS: Forty-three diabetic women who used OCs for 1 year or longer (mean, 3.4 years; range, 1.0 to 7.0 years) were compared with a computer-matched control group of 43 diabetic women who never used OCs. MAIN OUTCOME MEASURES: Hemoglobin A1c levels, albumin excretion rates, and mean retinopathy scores. RESULTS: The mean +/- SEM age and duration of diabetes were 22.7 +/- 0.5 years (range, 17.1 to 30.5 years) and 13.8 +/- 0.8 years, respectively, for the study group. The mean longitudinal hemoglobin A1c values were similar for study subjects and control subjects. The final mean albumin excretion rates, reflecting diabetic renal damage, and the mean eye grades were not significantly different between the groups. CONCLUSIONS: The use of OCs among young women with insulin-dependent diabetes mellitus does not pose an additional risk for the development of early diabetic retinopathy and/or nephropathy.

Adolescent↗

PubMed1994

Synthesis and structure-activity studies of N,N'-diarylguanidine derivatives. N-(1-naphthyl)-N'-(3-ethylphenyl)-N'-methylguanidine: a new, selective noncompetitive NMDA receptor antagonist.

Diarylguanidines, acting as NMDA receptor ion channel site ligands, represent a new class of potential neuroprotective drugs. Several diarylguanidines structurally related to N,N'-di-o-tolylguanidine (DTG), a known selective sigma receptor ligand, were synthesized and evaluated in in vitro radioligand displacement assays, with rat or guinea pig brain membrane homogenates, using the NMDA receptor ion channel site specific radioligand [3H]-(+)-5(S)-methyl-10(R),11-dihydro-5H-dibenzo[a,d]cyclohepten-5 ,10- imine (MK-801, 3), and the sigma receptor-specific radioligand [3H]-di-o-tolylguanidine (DTG, 5). This paper presents the structure-activity relationships leading to novel tri- and tetrasubstituted guanidines, which exhibit high selectivity for NMDA receptor ion channel sites and weak or negligible affinity for sigma receptors. The in vitro binding results from symmetrically substituted diphenylguanidines indicated that compounds having ortho or meta substituents (with respect to the position of the guanidine nitrogen) on the phenyl rings showed greater affinity for the NMDA receptor ion channel site compared with para-substituted derivatives. Among the group of ring substituents studied for symmetrical diarylguanidines, an isopropyl group was preferred at the ortho position and an ethyl group was preferred at the meta position. Several unsymmetrical guanidines containing a naphthalene ring on one nitrogen atom and an ortho- or a meta-substituted phenyl ring on the second nitrogen atom, e.g., N-1-naphthyl-N'-(3-ethylphenyl)guanidine (36), showed a 3-5-fold increase in affinity for the NMDA receptor ion channel site and no change in sigma receptor affinity compared to the respective symmetrical counterparts. Additional small substituents on the guanidine nitrogen atoms bearing the aryl rings resulted in tri- and tetrasubstituted guanidine derivatives which retained affinity for NMDA receptor ion channel sites but exhibited a significant reduction in their affinities for sigma receptors. For example, N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine (40) showed high affinity for the NMDA receptor ion channel site (IC50 = 36 nM vs [3H]-3) and low affinity for sigma receptors (IC50 = 2540 nM vs [3H]-5). Selectivity for the NMDA receptor ion channel sites over sigma receptors appears to be dependent upon the structure of the additional substituents on the guanidine nitrogen atoms bearing the aryl groups. Methyl and ethyl substituents are most preferred in the tri- and tetrasubstituted diarylguanidines. The trisubstituted guanidine, N-1-naphthyl-N'-(3-ethylphenyl)-N'-methylguanidine (40) and its close analogues showed good in vivo neuroprotection and are potential neuroprotective drug candidates for the treatment of stroke and other neurodegenerative disorders.

Animals↗

PubMed1993

Factors influencing the onset and progression of diabetic retinopathy in subjects with insulin-dependent diabetes mellitus.

BACKGROUND: The etiology of diabetic retinopathy is poorly understood. In the current study, factor associated with the onset and the progression or regression of retinopathy are evaluated. METHODS: Two hundred seventy-seven subjects with insulin-dependent (type I) diabetes mellitus (IDDM) were evaluated longitudinally for retinal changes over a mean of 2.7 years. The multistate Markov model was used to analyze the influences of the duration of diabetes, a family history of hypertension, age, sex, cigarette smoking, systolic blood pressure, diastolic blood pressure, cholesterol levels, and longitudinal glycohemoglobin (GHb) values on the development and the progression or regression of retinopathy. RESULTS: Univariate analysis confirmed that four factors were significantly associated with the etiology and the progression or regression of diabetic retinopathy: age, duration of diabetes, mean longitudinal GHb levels (all at P < 0.01), and diastolic blood pressure (P < 0.04). However, age was no longer significant when controlled by duration of diabetes. Cigarette smoking was only associated significantly with background retinopathy (stages 2 and 3). Systolic blood pressure, sex, a family history of hypertension, and cholesterol levels were not significantly associated with retinopathy. CONCLUSIONS: The onset of diabetic retinopathy is associated with the duration of diabetes, mean longitudinal GHb levels, smoking, and diastolic blood pressure. A longer duration of diabetes, higher GHb values, and higher diastolic blood pressure levels are associated with an increased risk of progression and a decreased chance of regression of diabetic retinopathy.

Adolescent↗

PubMed1993

Hypertonic saline compresses: therapy for complicated exit-site infections.

We review our experience with hypertonic saline compress therapy in 17 patients with complicated peritoneal dialysis catheter exit-site infections (ESIs). Compresses consisted of exit-site application of 4-5 gauze pads soaked with warm 3% saline for 5-10 minutes, three times daily, for 2-4 weeks, followed by once-daily use thereafter. The mechanism of action involves inhibition of bacterial growth by a hypertonic medium. Eleven patients with cultures positive for Staphylococcus aureus or Pseudomonas were treated with local exist-site measures (cleansers, antiseptics, antibiotic ointments). Therapy, which included multiple courses of systemic antibiotics, failed in 8 patients; in 3 patients, who were intolerant to antibiotics, ESI remained unresolved after local care only. Six patients with culture-negative ESIs received no systemic antibiotics and were unimproved following local therapy. Factors associated with therapy failure included malnutrition, diabetes, obesity, and dermal sensitization and injury associated with prolonged topical agent use. Following hypertonic saline compress therapy, we observed resolution of ESI in all patients without recurrence for follow-up intervals of 3-12 months (mean 6.5 months). Advantages of this therapy include excellent patient acceptance, ease of use, lack of adverse effects on exit site, adjacent skin, catheter or systemic reaction, and minimal expense. Future potential applications include routine daily use for infection prophylaxis and as therapy combined with antibiotics for established ESIs.

Administration, Topical↗

PubMed1993

Short-dwell peritoneal dialysis: increased use and impact on clinical outcome.

We reviewed 216 patients on peritoneal dialysis over a 3-year period to assess the effects on patient outcome of short-dwell dialysis (SDD), defined as dwell time below 4 hours with a daily dry (empty peritoneum) interval. Forty-nine patients (23%) required SDD for improved management of ultrafiltration failure (82%), effective blood pressure control (8%), abdominal wall hernia (4%), hydrothorax (4%), and patient convenience (2%). Ultrafiltration failure was recognized as the inability to achieve resolution of clinical overhydration, confirmed by the peritoneal equilibration test (PET), demonstrating high membrane glucose transport (absorption) and observed retention of dialysate volume. Daytime ambulatory peritoneal dialysis (DAPD) was used by 69% of patients and nightly peritoneal dialysis (NPD) with cyclers by 31%. Only one patient (hydrothorax) transferred to hemodialysis. Observations include sustained hydration and blood pressure control in all patients with maintenance of biochemical dialysis adequacy, less reliance on very hypertonic solutions, an increase in dry weight in 25% of patients, decreased use of antihypertensive agents, effective management of hernia and hydrothorax in 3 of 4 patients, and satisfactory patient tolerance of DAPD and NPD regimens, and daily dry intervals. Factors promoting SDD include improved understanding of PET studies, use of disconnect systems, and improvement in cycler design. We anticipate increasing use of SDD as recognition of its usefulness and application techniques expands.

Adolescent↗

PubMed1993

Angiotensin-converting enzyme inhibitor treatment for young normotensive diabetic subjects: a two-year trial.

Microangiopathy characterizes both diabetic retinopathy and nephropathy. It is currently unclear which diabetic subjects should be treated with angiotensin-converting enzyme (ACE) inhibitors. A double-blind, placebo-controlled protocol was implemented using captopril to treat subjects with Type I diabetes, early diabetic nephropathy (albumin excretion rates, 20-200 micrograms/min), and normal blood pressures. After two years, the final eye grades were improved in two treated subjects but not in any of the controls. Three control and one treated subject showed worsening of their eye grade after two years (P < .001, by chi-square test). Significant differences in renal albumin excretion were not seen between the two groups. The distribution of changes in retinal grades in the treatment group compared with the placebo group was improved after two years. Studies of larger numbers of patients will be necessary to determine if ACE inhibitors should be used routinely in subjects with diabetic retinopathy and to determine which subjects are most likely to respond.

Adolescent↗

PubMed1992

Expression of growth factor mRNA in rabbit PVR model systems.

Proliferative vitreoretinopathy (PVR) involves the formation of intravitreal fibrocellular membranes which may lead to traction retinal detachment and blindness. The cellular component of epiretinal membranes originates from the proliferation and migration of cells within the eye. Several growth factors and other cytokines are plausible candidates for directing the processes leading to membrane formation. A reproducible animal model is needed for experimental studies of cytokine expression during PVR induction or treatment. We found that intravitreal injection of > 10(6) mixed mononuclear leukocytes or adherent monocytes along with a trans-scleral incision through the pars plana leads to the development of PVR-like disease in rabbit eyes. The severity of the disease was related to the number of monocytes injected. Typically, organized membranes extending from the incision toward the optic nerve formed within one week. Progression to extensive traction retinal detachment required 1 to 4 weeks. Injection of up to 5 x 10(6) lymphocytes or freeze-thaw killed monocytes was ineffective, and coinjecting 100 micrograms endotoxin with the monocytes did not result in enhanced disease. The histological appearance of the epiretinal membranes was similar to human PVR membranes. Macrophage, cytokeratin-positive (epithelial), and fibroblast-like cells were present. Northern blot analysis of RNA extracted from the rabbit membranes revealed the presence of mRNA for acidic fibroblast growth factor (aFGF). Acidic FGF mRNA was not expressed by the injected monocytes. A comparable level of aFGF mRNA and also mRNAs for basic FGF, platelet-derived growth factor-B, and transforming growth factor beta were found in epiretinal membranes induced by a scleral incision in association with cryopexy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Angiotensin-converting enzyme inhibitor therapy and diabetic retinopathy.

This pilot project suggested that angiotensin-converting enzyme (ACE) inhibitors may have an effect on delaying or reversing diabetic retinopathy. One patient who had Grade 5 (preproliferative) retinopathy improved to Grade 2 (microaneurysms only) after two years of treatment. Of the 450 patients followed in our eye and kidney clinic, no other patient showed a similar reversal from Grade 5 retinopathy without treatment. Improvement by one or more grades was seen in three other patients with variable grades of retinopathy after a mean of 3.3 years of treatment. Improvement was not related consistently to a decrease in blood pressure (0 of 4), better glycemic control (2 of 4), or reduction in albumin excretion rate (0 of 4). Proper double-blind controlled studies are needed to prove the effect of ACE inhibitors on diabetic microangiopathy of the eye.

Adolescent↗

PubMed1991

Estimation of polyacrylamide gel pore size from Ferguson plots of normal and anomalously migrating DNA fragments. I. Gels containing 3% N,N'-methylenebisacrylamide.

The mobilities of normal and anomalously migrating DNA fragments were determined in polyacrylamide gels of different acrylamide concentrations, polymerized with 3% N,N'-methylenebisacrylamide as the crosslinker. The DNA samples were a commercially available 123-bp ladder and two molecular weight ladders containing multiple copies of two 147-base pair (bp) restriction fragments, obtained from the MspI digestion of plasmid pBR322. One of the 147 bp fragments is known to migrate anomalously slowly in polyacrylamide gels. Ferguson plots were constructed for all multimer ladders, using both absolute mobilities and relative mobilities with respect to the smallest DNA molecule in each data set. If the retardation coefficients were calculated from the relative mobilities, and the rms radius of gyration was used as the measure of DNA size, the Ogston equations were obeyed and the gel fiber parameters could be calculated. The effective pore sizes of the gels were estimated from the gel concentration at which the mobility of a given DNA molecule was reduced to one-half its mobility at zero gel concentration. The estimated pore radii ranged from approximately 130 nm for 3.5% gels to approximately 70 nm for 10.5% gels. These values are much larger than the pore sizes previously determined for the polyacrylamide matrix.

Acrylamides↗

PubMed1991

Estimation of polyacrylamide gel pore size from Ferguson plots of linear DNA fragments. II. Comparison of gels with different crosslinker concentrations, added agarose and added linear polyacrylamide.

The mobilities of various DNA fragments in two normally migrating molecular weight ladders were studied in polyacrylamide gels containing different concentrations of the crosslinker N,N'-methylenebisacrylamide (Bis). The acrylamide concentration ranged from 2.5-10.5%T (w/v); the Bis concentration ranged from 0.5-10%C (w/w), with respect to total acrylamide. Ferguson plots were constructed for each of the DNA fragments in gels of each composition. The Ferguson plots of the different multimers in each molecular weight ladder were nearly parallel in gels containing 0.5-3%C, converged close to a common intercept at zero gel concentration in gels containing 4%C, and crossed at approximately 1.5%T in gels containing 5 and 10%C. If the mobilities observed for the different DNA fragments at zero gel concentration were also extrapolated to zero DNA molecular weight, a common limiting mobility was observed in gels of all crosslinker concentrations. This limiting mobility was approximately equal to the free solution mobility of DNA. The effective pore radius of each gel was estimated from Ferguson plots based on relative mobilities, using the mobility of the smallest DNA fragment in each molecular weight ladder as the reference mobility. The calculated gel pore radii ranged from 142 nm to 19 nm, respectively, for gels containing 4.6%T, 1.5%C, and 10.5%T, 5 or 10%C. These pore radii are an order of magnitude larger than previously accepted values, but are consistent with scanning electron microscope measurements (Rüchel, R., et al., J. Chromatogr. 1978, 42, 77-90).(ABSTRACT TRUNCATED AT 250 WORDS)

Acrylamides↗

PubMed1991

Social policy on the use of aversive interventions: empirical, ethical, and legal considerations.

In an effort to address the controversy regarding the use of aversive interventions in the treatment of individuals with developmental disabilities, this paper presents a review of the literature on the efficacy of such interventions, along with brief reviews of the ethical and legal issues involved. In general, there appears to be empirical, ethical, and legal support for the continued availability of aversive interventions as treatment options, but only if sufficient safeguards are in place.

Autistic Disorder↗

PubMed1991

Pre-spiking dialysate bags: improved peritonitis prevention in patients on CAPD.

We review experience with 238 patients over 5.5 years to determine the impact of techniques of spiking dialysis bags in advance of their use (pre-spiking) on peritonitis incidence. Our two units provide peritoneal dialysis therapies only with liberal patient acceptance policies. The Y-set was used almost exclusively over the last 4 years (192/238 patients), peritonitis rate 1:31.5 patient-months (99 episodes/3,122 months). Nineteen patients spiked each exchange, 23 episodes/282 months, 1:12.3; 173 pre-spiked 1-14 days in advance using Y-set and compact exchange device (CXD), 76 episodes/2,840 months, 1:37.4. Peritonitis rates did not worsen with increased pre-spiking intervals: 1 day, 1:16.2; 2-6 days, 1:47.9; 7 days, 1:62.2; 8-14 days, 1:34.3. Similarly, pre-spiking in CCPD patients at 10 day intervals (4 patients) yielded a peritonitis rate of 1:19. We conclude that pre-spiking dialysis bags using the Y-set and CXD promotes significant peritonitis prevention. By spiking at less frequent intervals, technical performance improves, exchanges are simplified and done under more flexible circumstances. Participation by patient-assistants is facilitated. Transfer from CAPD to CCPD is decreased. Low peritonitis rates contribute to excellent patient acceptance and retention. The potential CAPD-eligible population is broadened.

Adolescent↗

PubMed1990

The electric field dependence of DNA mobilities in agarose gels: a reinvestigation.

The electric field dependence of the electrophoretic mobility of linear DNA fragments in agarose gels was reinvestigated in order to correct the observed mobilities for the different temperatures actually present in the gel during electrophoresis in different electric field gradients. When corrected to a common temperature, the electrophoretic mobilities of DNA fragments less than or equal to 1 kilobase pairs (kbp) in size were independent of electric field strength at all field strengths from 0.6 to 4.6 V/cm if the gels contained less than or equal to 1.4% agarose. The mobilities of larger DNA fragments increased approximately linearly with electric field strength. If the agarose concentration was higher than 2%, the mobilities of all DNA fragments increased with increasing electric field strength. The electric field dependence of the mobility was larger in gels cast and run in Tris-borate buffer (TBE) than in gels cast and run in Tris-acetate buffer (TAE), and was more pronounced in gels without ethidium bromide incorporated in the matrix. Ferguson plots were constructed for the various DNA fragments, both with and without extrapolating the temperature-corrected mobilities to zero electric field strength. Linear Ferguson plots were obtained for all fragments less than or equal to 12 kbp in size in agarose gels less than or equal to 1.4% in concentration if the mobilities were first extrapolated to zero electric field strength. Concave upward curvature of the Ferguson plots was observed for DNA fragments greater than or equal to 2 kbp in size at finite electric field strengths. Convex downward curvature of the Ferguson plots was observed for DNA fragments greater than or equal to 1 kbp in size in agarose gels greater than or equal to 2% in concentration. The mobilities of the various DNA fragments, extrapolated to zero agarose concentration and zero electric field strength, decreased with increasing DNA molecular weight; extrapolating to zero molecular weight gave an "intrinsic" DNA mobility of 2.7 x 10(-4) cm2/Vs at 20 degrees C. The pore sizes of LE agarose gels cast and run in TAE and TBE buffers were estimated from the mobility of the DNA fragments.(ABSTRACT TRUNCATED AT 400 WORDS)

Boric Acids↗

PubMed1990

Resolution of a paradox in the electrophoresis of DNA in agarose gels.

A paradox was observed in a previous study of the electrophoresis of linear DNA fragments in agarose gels (D. L. Holmes and N. C. Stellwagen, Electrophoresis 1990, 11, 5-15). The pore size of the agarose matrix was more accurately determined if the root-mean-square radius of gyration was used to measure DNA macromolecular size. However, the Ogston equations were obeyed and other gel parameters such as the apparent fiber radius and fiber volume appeared to be better described if the geometric mean radius was used to measure DNA size. This paradox can be resolved if relative mobilities (with respect to the smallest DNA molecule in the data set) are used to construct the Ferguson plots, instead of absolute mobilities. Using relative mobilities and the root-mean-square radius of gyration, the Ogston equations are obeyed and the pore size of the matrix is consistent with values determined by other methods.

DNA↗