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Biomedical subjects

J Lindsey

Publications and source records attributed to J Lindsey.

At least 19 recordsLinked to original sources
PubMed2001

Population pharmacokinetics of dapsone in children with human immunodeficiency virus infection.

BACKGROUND: Previous studies of dapsone pharmacokinetics in children have been too small to allow assessment of the relationships between dapsone pharmacokinetic parameters and patient characteristics or markers of efficacy and toxicity. METHODS: We used population analysis to estimate dapsone pharmacokinetic parameters in children participating in a phase I/II study of daily and weekly dapsone in children with human immunodeficiency virus (HIV) infection. With use of the program NONMEM and a 1-compartment open model, the influence of demographic and clinical characteristics on oral clearance (CL/F) and oral volume of distribution (V/F) were examined. Measures of drug exposure (area under the concentration-time curve [AUC] and predicted concentrations just before and 2 hours after administration) were estimated for each patient and correlated with markers of efficacy and toxicity. RESULTS: Sixty children (median age, 3 years; age range, 2 months to 12 years) contributed 412 dapsone concentrations collected after 175 study doses. Final parameter estimates were 1.40 L/kg for V/F, 0.0283 L/kg/h for CL/F, and 2.66 for the absorption rate constant. Of the clinical characteristics evaluated, dapsone CL/F was significantly increased by 50% in children taking rifabutin, by 39% in black children, and by 38% in children younger than 2 years old. Although no significant correlations were found between any dapsone exposure parameter and markers of toxicity, increased AUC was associated with a decreased risk of Pneumocystis carinii pneumonia (PCP). CONCLUSION: Ethnicity, age, and concomitant rifabutin use were associated with dapsone CL/F, with more rapid clearance observed in black children, children younger than 2 years old, and children receiving rifabutin. Dapsone pharmacokinetic parameters were not associated with toxicity, but higher dapsone AUC was associated with decreased risk of PCP. Monitoring of serum dapsone levels may be needed for optimal management of dapsone for PCP prophylaxis in children.

AIDS-Related Opportunistic Infections↗
PubMed2000

Clinical and pathologic findings in hereditary spastic paraparesis with spastin mutation.

OBJECTIVE: To describe a family with chromosome 2p-linked hereditary spastic paraparesis (HSP) associated with dementia and illustrate the cerebral pathology associated with this disorder. BACKGROUND: HSP comprises a heterogeneous group of inherited disorders in which the main clinical feature is severe, progressive lower limb spasticity. Nongenetic classification relies on characteristics such as mode of inheritance, age at onset, and the presence or absence of additional neurologic features. Several loci have been identified for autosomal dominant pure HSP. The most common form, which links to chromosome 2p (SPG4), has recently been shown to be due to mutations in spastin, the gene encoding a novel AAA-containing protein. RESULTS: The authors report four generations of a British family with autosomal dominant HSP in whom haplotype analysis indicates linkage to chromosome 2p. In addition, a missense mutation has been identified in exon 10 of the spastin gene (A1395G). Dementia was documented clinically in one member of the family, two other affected family members were reported to have had late onset memory loss, and a younger affected individual showed evidence of memory disturbance and learning difficulties. Autopsy of the demented patient confirmed changes in the spinal cord typical of HSP and also demonstrated specific cortical pathology. There was neuronal depletion and tau-immunoreactive neurofibrillary tangles in the hippocampus and tau-immunoreactive balloon cells were seen in the limbic and neocortex. The substantia nigra showed Lewy body formation. The pathologic findings are not typical of known tauopathies. CONCLUSIONS: The authors confirm that chromosome 2p-linked HSP can be associated with dementia and that this phenotype may be associated with a specific and unusual cortical pathology.

Adenosine Triphosphatases↗
PubMed2000

Implementing a stroke risk assessment program in a community setting.

Stroke, one of the most catastrophic medical events to befall an individual, is also one of the most preventable. Stroke risk assessment screenings (SRAS) provide an ideal means of lowering the risk by identifying high-risk individuals and educating the community about recognition and prevention of stroke. To facilitate public awareness in a northwestern Pennsylvania county, a multifocal media campaign was initiated approximately 2 months before the screening program. From April 1 to June 30, 1998, screenings were offered free-of-charge at 61 public sites. The screenings were staffed by volunteer nurses. A brief health history was taken and risk factor assessments (blood pressure, pulse, and carotid bruit screening) were performed. Individualized action plans were developed and discussed with the participants. The signs and symptoms of stroke were reviewed and educational material provided. Utilizing American Heart Association (AHA) guidelines, the nurses recommended medical follow-up as appropriate. With 3,116 individuals evaluated, this program represented the largest coordinated effort by any county in Pennsylvania. This program was thought to be instrumental in increasing community awareness of stroke.

Community Health Services↗
PubMed1999

Toxicity and efficacy of daily vs. weekly dapsone for prevention of Pneumocystis carinii pneumonia in children infected with human immunodeficiency virus. ACTG 179 Study Team. AIDS Clinical Trials Group.

BACKGROUND: Dapsone is an alternative drug for Pneumocystis carinii pneumonia (PCP) prophylaxis in individuals intolerant to trimethoprim-sulfamethoxazole (T/S). There are, however, few data on the pharmacokinetics, toxicity or efficacy of dapsone in children. Design. Randomized, multicenter trial comparing daily (1 or 2 mg/kg) with weekly (4 mg/kg) dapsone regimens in 94 HIV-infected children intolerant to T/S. METHODS: Hematologic and hepatic toxicity was monitored, as well as the occurrence of skin rash, PCP or death. RESULTS: Initial pharmacokinetic data indicated that adequate serum dapsone concentrations were not achieved with the daily 1-mg/kg regimen; the daily dose was then increased to 2 mg/kg. Both short and long term hematologic toxicities were marginally greater in children receiving the daily 2 mg/kg compared with the weekly regimen. Allergic skin rashes were similar in children receiving the daily and weekly regimens (17% in both) and were not associated with prior history of rash with T/S. PCP occurred most frequently with the daily 1-mg/kg regimen (22.0 cases/100 patient years), least frequently with the daily 2-mg/kg regimen (0 case/100 patient years) and at intermediate frequency with the weekly regimen (9.5 cases/100 patient years). More deaths were observed in patients receiving the daily than the weekly regimen (8 vs. 2, respectively), although the deaths were not directly attributable to dapsone treatment. CONCLUSION: Although a weekly dapsone regimen of 4 mg/kg produced less hematologic toxicity than a daily regimen of 2 mg/kg, this advantage was offset by a trend toward higher breakthrough rates of PCP.

AIDS-Related Opportunistic Infections↗
PubMed1999

Results of complete soft tissue clubfoot release combined with calcaneocuboid fusion in the 4-year to 8-year age group following failed clubfoot release.

A subset of postoperative recurrent clubfeet was isolated in a group of patients 4 to 8 years old. Twenty-seven consecutive patients who underwent redo surgery consisting of complete soft tissue clubfoot release combined with a calcaneocuboid fusion were reviewed for this study. Twenty-six feet of 27 feet in 20 patients had a long-term good result, suggesting that this procedure is the one of choice for this age group.

Algorithms↗
PubMed1999

Pharmacokinetics of dapsone administered daily and weekly in human immunodeficiency virus-infected children.

Although dapsone is a commonly used alternative agent for prophylaxis against Pneumocystis carinii pneumonia in children intolerant to trimethoprim-sulfamethoxazole, there are few data that describe dapsone pharmacokinetics in children. We studied dapsone pharmacokinetics in 30 children (median age, 2.8 years; age range, 0. 3 to 12 years) receiving a new proprietary liquid preparation by three dosing regimens (1 mg/kg of body weight daily, 2 mg/kg daily, or 4 mg/kg weekly). Dosing of children with 2 mg/kg daily or 4 mg/kg weekly resulted in peak concentrations equivalent to those reached in adults receiving 100-mg tablets daily. For the entire population, the median half-life was 22.2 h (range, 7.1 to 40.3 h), the median oral clearance was 0.0365 liter/kg/h (range, 0.0104 to 0.1021 liter/kg/h), and the median oral apparent volume of distribution was 1.13 liters/kg (range, 0.50 to 2.32 liters/kg). The median dapsone oral clearance was significantly increased in those infants less than 2 years of age compared to the oral clearance in those over 2 years of age (0.0484 versus 0.0278 liter/kg/h; P = 0.011). These data suggest that absorption of this liquid preparation is adequate and that the concentrations in the sera of children receiving 2 mg/kg daily or 4 mg/kg weekly are equivalent to those seen in adults receiving standard dapsone dosing. Dapsone oral clearance appears to be increased in children under 2 years of age.

Adolescent↗
PubMed1999

Localization of cannabinoid CB1 receptors in the human anterior eye and retina.

PURPOSE: To determine the presence and distribution of CB1 cannabinoid receptors within the human eye. METHODS: A subtype-specific affinity-purified polyclonal antibody to the cannabinoid CB1 receptor was used to determine CB1 localization. Postmortem human eyes were fixed in methacarn and embedded in paraffin. Sagittal sections were mounted on slides and immunostained using antibodies to the CB1 receptor. Antibody binding was detected either by using peroxidase conjugated secondary antibodies and developing with diaminobenzidine or by using fluorescent secondary antibodies. RESULTS: Strong CB1 receptor labeling was detected in the ciliary epithelium, the corneal epithelium, and endothelium of the anterior human eye. Strong-to-moderate levels of CB1 staining were found in the trabecular meshwork and Schlemm's canal. Moderate labeling was detected in the ciliary muscle and in the blood vessels of the ciliary body. Moderate-to-light labeling also was detected in the sphincter papillae of the anterior human eye. Staining for CB1 receptors also was detected in human retina. The two synaptic layers of the retina and the inner and outer plexiform layers, were both moderately stained for CB1. In addition, moderate labeling was detected in the inner nuclear layer, and the ganglion cell layer. Strong labeling was detected in the outer segments of photoreceptors. No staining was observed in the corneal stroma or in the choroid. CONCLUSIONS: The wide distribution of cannabinoid CB1 receptors in both the anterior eye and the retina of humans suggests that cannabinoids influence several different physiological functions in the human eye.

Adult↗
PubMed1998

Attempting to enhance the enrollment of adolescents into AIDS clinical trials: the design of ACTG Protocol 220.

The epidemic of HIV infection continues to grow in adolescents and young adults. Unfortunately, because treatment regimens have been developed based on data derived from clinical trials, little data are available on adolescents because they are infrequently included in these trials. In an effort to facilitate the enrollment of more adolescents into AIDS Clinical Trials Group (ACTG) clinical trials, we designed a nontreatment protocol to familiarize adolescents with clinical trials requirements. Two hundred fifty-six adolescents (150 females, 106 males) between the ages of 13 and 21 years were enrolled at 43 different clinical trials sites throughout the United States. The majority of patients (50%) were enrolled at sites that had specific programs for adolescents. Most of the young women (85%) had acquired their infection via heterosexual transmission, whereas the largest transmission categories in men were blood or factor transfusions (43%) or same-sex contact (34%). Admission CD4 counts were lower in males (mean = 396 cells/mm3) than in females (mean = 513 cells/mm3) (p = 0.01). Psychosocial profiles revealed a variety of ongoing risk behaviors in HIV-infected adolescents. Two years into the study, 223 patients are still being observed. We conclude that adolescents can be enrolled in an observational protocol. The success of this trial will be determined by how many ACTG Protocol 220 participants are ultimately enrolled in therapeutic trials.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Transient neurologic deficit after spinal anesthesia: local anesthetic maldistribution with pencil point needles?

Recent reports of transient neurologic deficits have raised concern about the potential toxicity of single-dose spinal 5% lidocaine in 7.5% dextrose. Two cases of volunteers who experienced minor local sensory deficits after slow (60 s) injections of 2 mL 5% lidocaine via Whitacre needles are described. One case was a result of a double injection because of a "failed" block. It seemed possible that the neurologic deficit in these cases resulted from neurotoxicity associated with maldistribution of local anesthetic. Using an in vitro spinal model, we investigated drug distribution resulting from injections through side-port spinal needles to determine whether the use of these needles could result in high local concentrations of hyperbaric solutions. A spinal canal model was fabricated using human magnetic resonance measurements. The model was placed in a surgical supine position and filled with lactated Ringer's solution to simulate the specific gravity of cerebral spinal fluid at 22 degrees C. A hyperbaric solution of phthalocyanine blue dye and dextrose (SG 1.042), simulating the anesthetic, was injected through three different needles (27-gauge 4 11/16-in. Whitacre, 25-gauge 3 1/2-in. Whitacre, 25-gauge 3 1/2-in. Quincke). Triplicate injections were done at rapid (2 mL/10 s) and slow (2 mL/60 s) rates, with needle side ports oriented in a sacral and cephalad direction. At slow rates of injection, using 27- or 25-gauge sacrally directed Whitacre needles, injections showed evidence of maldistribution with extrapolated peak sacral lidocaine concentrations reaching 2.0%. In contrast, distribution after slow injection through sacrally directed Quincke needles was uniform.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

A new locus for autosomal dominant retinitis pigmentosa on chromosome 7p.

Autosomal dominant retinitis pigmentosa (adRP) is known to result from mutations in two different retinal genes--rhodopsin and peripherin--while a third locus has been implicated by linkage data. However, families have been reported in which all three known loci have been excluded. We report linkage of adRP in one such family to two microsatellite markers on chromosome 7p. D7S435 has previously been localized to 7p13-15.1; D7S460, previously only localized to chromosome 7, maps to within 2 cM of D7S435 with a lod score of 12.15. Two point linkage analysis between these markers and adRP gave lod scores of 5.65 (theta = 0) and 4.19 (theta = 0.046) for D7S460 and D7S435, respectively. Multipoint analysis gave a maximum lod score of 8.22. These data strongly suggest a new adRP locus on chromosome 7p.

Base Sequence↗
PubMed1993

Etiology of symptomatic recurrent interdigital neuromas.

Morton's neuroma is a common disease entity of the foot that is often treated with surgical resection. A complication of neuroma resection is recurrence of symptoms as a result of the formation of an amputation neuroma. The authors offer an anatomical and biomechanical explanation for the location of symptomatic amputation neuromas. The neuromas are found on the plantar surface proximal to the condyles of the metatarsal and medial to the interspace where the nerve is resected. The theory is based on intraoperative observations during surgery for recurrent neuromas and on cadaver dissections and offers a method based on this theory to reduce the number of recurrences.

Amputation Stumps↗
PubMed1993

Rheumatoid arthritic foot. Two manifestations with case studies.

The authors review rheumatoid arthritis with focus on two pedal manifestations, rheumatoid nodules and digital deformities. The prevalence, presentation, and diagnostic features concerning these entities are discussed, and three case studies are presented.

Aged↗
PubMed1992

Exclusion of chromosome 6 and 8 locations in nonrhodopsin autosomal dominant retinitis pigmentosa families: further locus heterogeneity in adRP.

Genetic studies have revealed that 25 to 30% of autosomal dominant retinitis pigmentosa (adRP) families have mutations in the rhodopsin gene, while the remainder do not. More recently linkage data and mutation detection have demonstrated two further loci implicated in adRP, at an as yet unidentified gene on chromosome 8p and at the human gene homologue of the mouse Rds (Retinal Degeneration Slow) gene on chromosome 6p. We have previously reported exclusion of adRP from the rhodopsin locus on 3q in two large adRP families. We now report exclusion data for both families, on chromosomes 6 and 8, demonstrating that the adRP phenotype results from mutations in at least four locations.

Chromosome Mapping↗
PubMed1992

Thawing fresh frozen plasma in a microwave oven. A comparison with thawing in a 37 degrees C waterbath.

We show in this report that fresh frozen plasma (FFP) can be thawed faster using a specifically designed microwave oven (MWO) (WesLabs Plasma Defroster, Westmorland Laboratories, Inc., New Brunswick, Canada) than using 37 degrees C water bath (WB) and that the thawed product was equivalent to FFP thawed by WB. Paired plasma bags (200 mL/bag) from plasma pools were frozen, stored at -35 degrees C, and thawed in parallel, one bag in MWO, the other in WB. Mean thaw time (mean + SD) by MWO was 6.99 + 1.3 minutes; by WB the time was 17.6 + 1.7 minutes (n = 24; P less than 0.005). Rapid calorimetry of thawed plasma showed that MWO-thawed FFP temperature was 20.4 + 2.5 degrees C, whereas WB-thawed FFP was 15.4 + 3.3 degrees C (n = 24; P less than 0.005). Except for thrombin time (MWO = 20.1 seconds; WB = 19.8 seconds; n = 24; P = 0.023), no significant differences were observed in the 23 other coagulation parameters and plasma proteins studied. Faster thawing and freedom from risk of contamination may make MWO the method of choice for emergency thawing of FFP.

Blood Coagulation↗
PubMed1992

Developmental changes in sequential activation of laryngeal abductor muscle and diaphragm in infants.

In animals and human adults, upper airway muscle activity usually precedes inspiratory diaphragm activity. We examined the interaction of the posterior cricoarytenoid muscle (PCA), which abducts the larynx, and the diaphragm (DIA) in the control of airflow in newborn infants to assess the effect of maturation on respiratory muscle sequence. We recorded tidal volume, airflow, and DIA and PCA electromyograms (EMG) in 12 full-term, 14 premature, and 10 premature infants with apnea treated with aminophylline. In most breaths, onset of PCA EMG activity preceded onset of DIA EMG activity (lead breaths). In all subjects, we also observed breaths (range 6-61%) in which PCA EMG onset followed DIA EMG onset (lag breaths). DIA neural inspiratory duration and the neuromechanical delay between DIA EMG onset and inspiratory flow were longer in lag than in lead breaths (P < 0.05 and P < 0.01, respectively). The frequency of lag breaths was greater in the premature infants [33 +/- 4% (SE)] than in either the full-term infants (21 +/- 3%, P < 0.03) or the premature infants with apnea treated with aminophylline (16 +/- 2%, P < 0.01). We conclude that the expected sequence of onset of PCA and DIA EMG activity is frequently disrupted in newborn infants. Both maturation and respiratory stimulation with aminophylline improve the coordination of the PCA and DIA.

Apnea↗
PubMed1992

Recombination between rhodopsin and locus D3S47 (C17) in rhodopsin retinitis pigmentosa families.

Autosomal dominant retinitis pigmentosa (adRP) has shown linkage to the chromosome 3q marker C17 (D3S47) in two large adRP pedigrees known as TCDM1 and adRP3. On the basis of this evidence the rhodopsin gene, which also maps to 3q, was screened for mutations which segregated with the disease in adRP patients, and several have now been identified. However, we report that, as yet, no rhodopsin mutation has been found in the families first linked to C17. Since no highly informative marker system is available in the rhodopsin gene, it has not been possible to measure the genetic distance between rhodopsin and D3S47 accurately. We now present a linkage analysis between D3S47 and the rhodopsin locus (RHO) in five proven rhodopsin-retinitis pigmentosa (rhodopsin-RP) families, using the causative mutations as highly informative polymorphic markers. The distance, between RHO and D3S47, obtained by this analysis is theta = .12, with a lod score of 4.5. This contrast with peak lod scores between D3S47 and adRP of 6.1 at theta = .05 and 16.5 at theta = 0 in families adRP3 and TCDM1, respectively. These data would be consistent with the hypothesis that TCDM1 and ADRP3 represent a second adRP locus on chromosome 3q, closer to D3S47 than is the rhodopsin locus. This result shows that care must be taken when interpreting adRP exclusion data generated with probe C17 and that it is probably not a suitable marker for predictive genetic testing in all chromosome 3q-linked adRP families.

Chromosome Mapping↗