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Biomedical subjects

M Shelton

Publications and source records attributed to M Shelton.

At least 19 recordsLinked to original sources
PubMed2001

Impact of chronic hepatitis B and interferon-alpha therapy on growth of children.

Interferon-alpha (IFN) has been approved as treatment for children with chronic hepatitis B (CHB). The aims of this study were to assess the impact on children's growth of the disease itself and of IFN treatment. The growth of 142 children with CHB (70 IFN-treated, 72 untreated) was monitored for a minimum of one year. Regression analysis models were used to determine which of the variables most affected children's growth. After adjusting for racial differences, the population of 142 children with CHB had a mean baseline height for age percentile of 39 and a mean baseline weight for age percentile of 38, which were significantly different (P < 0.0001) from the 50th percentiles of their respective reference populations. The height for age Z score of untreated children was inversely correlated with serum hepatitis B virus DNA and aspartate aminotransferase levels, and the weight for age Z score was inversely correlated with serum hepatitis B virus DNA levels. While undergoing IFN therapy, children displayed a "U-shaped" growth pattern, such that height for age and weight for age Z scores at 3 or 6 months were lower than scores at baseline or 12 months. In this study the average child with CHB showed compromised growth even in the absence of IFN therapy. During IFN therapy, children's growth was temporarily disrupted.

Adolescent↗
PubMed2001

Regulatory responses to an oral D-glutamate load: formation of D-pyrrolidone carboxylic acid in humans.

Previously published studies have shown D-glutamate to be the most potent natural inhibitor of glutathione synthesis known, yet how D-glutamate is handled in humans is unknown. Therefore, we administered an oral D-glutamate load to four healthy volunteers and monitored the plasma D-glutamate concentration and excretion over a 3-h postload period. Compared with time controls, the plasma D-glutamate concentration increased 10-fold in the 1st h and then reached a plateau over the remaining time course. In contrast, plasma D-pyrrolidone carboxylic acid increased progressively throughout the 3-h time course to a level 10-fold higher than the D-glutamate plasma concentration. Excretion of D-glutamate progressively increased despite a constant filtered D-glutamate load rising from only 5 to 95% of the filtered amount. Excretion of D-pyrrolidone carboxylic acid increased with the rise in filtered load without significant reabsorption. The amount of D-pyrrolidone carboxylic acid excreted over the 3-h time course was 10 times the amount excreted as D-glutamate and accounted for almost 20% of the administered D-glutamate. These findings indicate that plasma D-glutamate concentration is tightly regulated through two mechanisms: 1) the transport into cells and metabolic conversion to D-pyrrolidone carboxylic acid and excretion, and 2) the enhancement of D-glutamate clearance by the kidneys.

Absorption↗
PubMed2001

Natural history of neonatal herpes simplex virus infections in the acyclovir era.

OBJECTIVE: During the 2 decades in which effective antiviral therapies have been available for neonatal herpes simplex virus (HSV) disease, changes have been documented not only in the outcomes of infected infants, but also in the natural history of the disease itself. Numerous studies previously have reported that early institution of antiviral therapy is beneficial to the outcome of the disease. The objective of this study was to provide an update of neonatal HSV disease to identify means by which future improvements in the management of HSV-infected neonates can be made. DESIGN/METHODS: Neonates enrolled in 2 studies of parenteral acyclovir for the treatment of neonatal HSV disease provided the data source. The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group conducted the studies between 1981 and 1997. A total of 186 patients are summarized, all of whom were treated with acyclovir. Demographic and clinical characteristics of these patients are reported. RESULTS: Comparisons between patients treated in the periods between 1981-1988 and 1989-1997 according to extent of disease revealed that the mean time between the onset of disease symptoms and initiation of therapy has not changed significantly from the early 1980s to the late 1990s. Of all patients evaluated, 40% had fetal scalp monitors during the delivery process. A significant minority of patients did not have skin vesicles at the time of their presentation and did not develop them during the acute HSV disease (39% of patients with disseminated disease; 32% of patients with central nervous system [CNS] disease; and 17% of patients with skin, eye, and/or mouth disease). Among patients with CNS disease, mortality was associated with prematurity. Among patients with disseminated HSV disease treated with acyclovir at 30 mg/kg/d, mortality was associated with aspartate transaminase elevations of >/=10 times the upper limit of normal at the time of initiation of acyclovir therapy. Mortality was also associated with lethargy at initiation of antiviral therapy for patients with disseminated disease. Patients' morbidity status was associated with the extent of disease (skin, eye, and/or mouth disease vs CNS vs disseminated). For those patients with CNS disease, morbidity was also associated with seizures at initiation of antiviral therapy. CONCLUSION: Data presented in the current comparison of neonatal HSV disease over the 2 periods (1981-1988 vs 1989-1997) demonstrate that no progress has been made in decreasing the interval between onset of HSV symptoms and initiation of antiviral therapy. Additional strides in the improvement of disease outcome may occur only if the interval between onset of symptoms and initiation of therapy is shortened. The means by which this will be accomplished lie in increased consideration of neonatal HSV infections in acutely ill infants. Specific data and recommendations to facilitate this goal are contained within.

Acyclovir↗
PubMed2001

Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections.

OBJECTIVE: The objective of this investigation was to establish the safety of high-dose (HD) acyclovir for the treatment of neonatal herpes simplex virus (HSV) disease. In addition, an estimate of therapeutic efficacy was sought, both with respect to mortality and to morbidity. Virologic efficacy of HD acyclovir was also assessed. PARTICIPANTS: Infants who were </=28 days old and whose disease was considered to be caused by HSV were enrolled in this study. Patients with central nervous system (CNS; N = 28) or disseminated (N = 41) HSV infection were offered participation in the trial. A small number of patients with HSV disease limited to the skin, eyes, or mouth (SEM; N = 10) or whose disease was clinically consistent with HSV but who did not have virologic confirmation of infection (N = 9) also were enrolled on a compassionate basis. Only patients with virologically confirmed HSV disease were included in efficacy analyses. All enrolled patients were included in safety analyses. METHODS: The study was an open-label evaluation of intravenous acyclovir at dosages higher than the 30 mg/kg/d standard dosage approved by the US Food and Drug Administration. The first 16 patients enrolled received intermediate-dose (ID) acyclovir (45 mg/kg/d), and the next 72 patients received HD acyclovir (60 mg/kg/d). Acyclovir was administered in 3 divided daily doses for 21 days. Neonates were assessed prospectively throughout treatment and at scheduled follow-up visits for the first 4 years of life. Data were compared with those of a previous National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group trial in which patients received standard-dose (SD) acyclovir for 10 days and in which identical methods (with the exception of acyclovir dosage and duration of therapy) were used. RESULTS: Six (21%) of 29 HD acyclovir recipients whose HSV disease remained localized to the SEM or CNS experienced neutropenia. One of the 6 had an absolute neutrophil count <500/mm(3), and 5 patients had an absolute neutrophil count (ANC) between 500/mm(3) and 1000/mm(3). In all 6 cases, the ANC recovered during continuation of acyclovir at the same dosage or after completion of acyclovir therapy, and there were no apparent adverse sequelae of the transient neutropenia. No other drug-related adverse events were reported among ID or HD recipients, and no other laboratory aberrations could be correlated specifically with antiviral therapy. The survival rate for the patients with disseminated HSV disease treated with HD acyclovir was significantly higher than for those in the previous study treated with SD acyclovir, with an odds ratio (OR) of 3.3 (95% confidence interval [CI]: 1.4-7.9). For patients with CNS disease, however, survival rates were similar for the HD and SD groups. To assess the effect of HD acyclovir on survival for the entire population with neonatal HSV disease, the Cox proportional hazards regression analysis was performed with stratification for disease category (CNS versus disseminated). In performing this analysis, differences in mortality for each disease category were weighted to allow statistical comparison of the treatment dosage groups (HD, ID, and SD). This analysis indicated that the survival rate for patients treated with HD acyclovir was statistically significantly higher than for patients treated with SD acyclovir (OR: 3.3; 95% CI: 1.5-7.3). Recipients of HD acyclovir had a borderline significant decrease in morbidity compared with SD recipients, after stratification for the extent of disease (SEM vs CNS vs disseminated) and controlling for the potential confounding factors of HSV type (HSV-1 vs. HSV-2), prematurity, and disease severity (seizures). Patients treated with HD acyclovir were 6.6 times (adjusted OR; 95% CI: 0.8-113.6) as likely to be developmentally normal at 12 months of age as patients treated with SD therapy. CONCLUSION: These data support the use of a 21-day course of HD (60 mg/kg/d) intravenous acyclovir to treat neonatal CNS and disseminated HSV disease. Throughout the course of HD acyclovir therapy, serial ANC determination should be made at least twice weekly. Decreasing the acyclovir dosage or administering granulocyte colony-stimulating factor should be considered if the ANC remains below 500/mm(3) for a prolonged period.

Acyclovir↗
PubMed2000

Statistical models for predicting response to interferon-alpha and spontaneous seroconversion in children with chronic hepatitis B.

To develop prognostic models for identifying children with hepatitis B who are likely to respond to interferon-alpha (IFN-alpha) or to spontaneously seroconvert, we evaluated results of a multinational controlled trial comprising 70 children with chronic hepatitis B who received IFN-alpha and 74 children who did not receive therapy. Prognostic models were developed using SMILES (similarity of least squares), which is a data analysis network that incorporates multidimensional relationships in the clinical data of complex diseases. Commonly collected clinical data included age, gender, serum aminotransferase (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and hepatitis B virus (HBV) DNA levels, and IFN-alpha dose. Additional data included pretreatment directional information (e.g. increases or decreases in serum aminotransferase and HBV DNA levels), liver biopsy results, race and transmission mode. Using data available prior to initiation of treatment, the SMILES models achieved prospective predictions of 89% for responders, 96% for non-responders, 100% for seroconverters and 93% for non-seroconverters. Although not predictive by themselves, the variables that had the greatest impact on predictions for IFN-alpha response were HBV DNA pretreatment direction, baseline HBV DNA, IFN-alpha dose and gender. The variables that had the greatest impact on predictions for spontaneous seroconversion were ALT pretreatment direction, baseline HBV DNA level, age and AST pretreatment direction. Therefore, these models may be useful in determining, in children with hepatitis B, the likelihood of response to IFN-alpha and spontaneous seroconversion.

Adolescent↗
PubMed2000

Use of a repetitive DNA probe to type clinical and environmental isolates of Aspergillus flavus from a cluster of cutaneous infections in a neonatal intensive care unit.

Aspergillus flavus is second to A. fumigatus as a cause of invasive aspergillosis, but no standard method exists for molecular typing of strains from human sources. A repetitive DNA sequence cloned from A. flavus and subcloned into a pUC19 vector, pAF28, was used to type 18 isolates from diverse clinical, environmental, and geographic sources. The restriction fragment length polymorphisms generated with EcoRI- or PstI-digested genomic DNA and probed with digoxigenin-labeled pAF28 revealed complete concordance between patterns. Eighteen distinct fingerprints were observed. The probe was used to investigate two cases of cutaneous A. flavus infection in low-birth-weight infants in a neonatal intensive care unit (NICU). Both infants were transported by the same ambulance and crew to the NICU on the same day. A. flavus strains of the same genotype were isolated from both infants, from a roll of tape used to fasten their umbilical catheters, from a canvas bag used to store the tape in the ambulance, and from the tape tray in the ambulance isolette. These cases highlight the need to consider exposures in critically ill neonates that might occur during their transport to the NICU and for stringent infection control practices. The hybridization profiles of strains from a second cluster of invasive A. flavus infections in two pediatric hematology-oncology patients revealed a genotype common to strains from a definite case patient and a health care worker. A probable case patient was infected with a strain with a genotype different from that of the strain from the definite case patient but highly related to that of an environmental isolate. The high degree of discrimination and reproducibility obtained with the pAF28 probe underscores its utility for typing clinical and environmental isolates of A. flavus.

Ambulances↗
PubMed1999

Role of intracellular calcium in Pasteurella haemolytica leukotoxin-induced bovine neutrophil leukotriene B4 production and plasma membrane damage.

Isolated neutrophils were used to study the intracellular calcium ([Ca2+]i) dependency of Pasteurella haemolytica leukotoxin-induced production of leukotriene B4 and plasma membrane damage. Exposure of neutrophils to leukotoxin caused a rapid and concentration-dependent increase in [Ca2+]i, followed by simultaneous plasma membrane damage and production of leukotriene B4. Removal of extracellular Ca2+, replacement of Ca2+ with other divalent cations, or exposure to high concentration of verapamil, an inhibitor of voltage-dependent calcium channels, inhibited leukotoxin-induced increases in [Ca2+]i, leukotriene B4 production, and membrane damage, thus indicating that influx of extracellular Ca2+ is necessary to produce these leukotoxin-induced neutrophil responses.

Animals↗
PubMed1998

Differential behaviour of two cyanobacterium species to UV radiation. Artificial UV radiation induces phycoerythrin synthesis.

Altitude is an important factor contributing to the local UV-B climate. In the European Alps solar UV-B increases approximately 21% 1000 m-1. A Nostoc muscorum (UTEX 389) originating from Scotland and a Nostoc sp. isolated from a highland lake (Yanaqocha) located 3980 m above sea level (Cusco, Perú) have been used in a study where the tolerance to UV radiation (UVR) stress of both species was determined. Following irradiation doses of 15 kJ UV (UV-A plus UV-B, equivalent to approximately 6 h exposure to unfiltered solar light at noon for a standard midlatitude region with normal ozone concentration), the viability of Nostoc sp. is 30% compared to 3% for Nostoc muscorum. UV-B induces the reduction of the number of phycobilisomes per cell, phycobilisome disassembly and/or degradation as well as phycobilisome uncoupling. Following UV exposure, phycoerythrin (PE) fluorescence emission increases dramatically in both species, indicating accumulation of PE in the phycobilisome rods. The detected increase in PE due to UVR is confirmed using a monoclonal antibody anti-PE.

Cyanobacteria↗
PubMed1998

Interferon alfa therapy for chronic hepatitis B in children: a multinational randomized controlled trial.

BACKGROUND & AIMS: Treatment of chronic hepatitis B with interferon alfa is not approved in children. The aim of this study was to evaluate the safety and efficacy of interferon alfa (IFN-alpha) in children with chronic hepatitis B and increased transaminase levels. METHODS: Children were given either IFN-alpha2b (6 megaunits/m2 thrice weekly for 24 weeks) or no treatment. Clearance of markers of viral replication was evaluated 24 weeks after therapy and after 48 weeks of observation in controls. RESULTS: Of 149 children enrolled, 144 were evaluable (70 treated and 74 controls). Serum hepatitis B e antigen and viral DNA became negative in 26% of treated children and 11% of controls (P < 0.05). Serum aminotransferase levels normalized and liver histology improved among responders. Hepatitis B surface antigen became undetectable in 10% of treated patients and 1% of controls. Female gender and interferon treatment were the only significant predictors of response. Ethnic origin, baseline aminotransferase level, initial DNA levels, and histology did not correlate with response. Most adverse reactions were mild or moderate, and dose was reduced in 24% of children. CONCLUSIONS: In children with chronic hepatitis B, INF-alpha promotes loss of viral replication markers and surface antigen and improves aminotransferases and histology.

Adolescent↗
PubMed1996

Confidentiality in group psychotherapy: empirical findings and the law.

Empirical research suggests that group therapists generally discuss with prospective clients the importance of maintaining confidentiality, but are unlikely to inform them of the significant potential for violations of confidentiality. Therapists believe information about the risk of unauthorized disclosures will reduce the number of patients willing to enter group therapy and will inhibit the therapeutic dialogue. Therapists' failure to provide information sufficient to obtain informed consent, however, produces serious ethical problems and potential legal problems as well. The law of informed consent varies in different jurisdictions such that identical factual scenarios could produce different legal outcomes depending on the jurisdiction in which the case occurs. In spite of the proliferation of group interventions, empirical studies of confidentiality in group therapy have lagged behind similar research in individual psychotherapy.

Confidentiality↗
PubMed1996

Absence of continuous epitopes in the house dust mite major allergens Der p I from Dermatophagoides pteronyssinus and Der f I from Dermatophagoides farinae.

BACKGROUND: The house dust mite has been shown to be an important source of domestic allergens associated with immediate hypersensitivities. The Group I mite allergens Der p I from Dermatophagoides pteronyssinus and Der f I from D. farinae display extensive amino acid sequence homology and have similarities with cysteine protease enzymes. OBJECTIVE: The availability of the complete amino acid sequences for these allergens allowed us to search for the allergic determinants within these molecules. The aim of the present investigation was to identify any continuous IgE-binding epitopes within these amino acid sequences. We also sought to test the validity of previously reported Der p I peptide epitope sequences. METHODS: In order to identify any continuous IgE epitopes, the amino acid sequences of Der p I and Der f I were synthesized as decapeptides overlapping in sequence and coupled to plastic pins. The specific IgE-binding capacity of these peptides was assayed using an enzyme-linked biotin-streptavidin procedure and sera from patients known to be sensitive to these allergens. Previously reported Der p I peptide epitopes were synthesized as free peptides and tested for their ability to inhibit specific IgE binding to allergen extract discs. RESULTS: None of the pin-coupled Der p I or Der f I peptides was found by the continuous epitope mapping procedure to bind significantly to specific IgE in the sera of hypersensitive patients. The previously reported Der p I peptide epitopes did not inhibit specific IgE binding to mite extract discs. CONCLUSION: The specific IgE binding epitopes of the house dust mite allergens Der p I and Der f I are discontinuous in nature.

Allergens↗
PubMed1996

Population pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group.

The population pharmacokinetics of ganciclovir was investigated in a group of 27 newborns with symptomatic congenital cytomegalovirus infection by nonlinear mixed-effects modeling analysis. Individual characteristics including approximated creatinine clearance from serum (ASCC) and body weight (WGE) were identified to significantly influence total clearance from plasma (CL) and the apparent total volume of distribution (V) of ganciclovir, respectively. The regression equations used to model these relationships were expressed as CL (in liters per hour) = 0.262 + (0.00271 x ASCC) and V (in liters) = 0.627 + (0.437 x WGE). By using this model, typical values of the pharmacokinetic parameter CL and V were 0.428 +/- 0.079 liters/h and 1.773 +/- 0.320 liters, respectively. Upon validation with a larger number of newborns, this model should allow for the definition of possible relationships between the pharmacokinetic disposition of ganciclovir and pharmacodynamic events in neonates.

Antiviral Agents↗
PubMed1996

Laparoscopically assisted vaginal hysterectomy (LAVH)--an alternative to total abdominal hysterectomy.

OBJECTIVE: To assess the feasibility of performing laparoscopically assisted vaginal hysterectomy (LAVH) on women referred for total abdominal hysterectomy (TAH). DESIGN: Prospective intervention study on women referred for TAH from a gynaecological outpatient clinic. SETTING: Groote Schuur Hospital, Cape Town. This institution accepts patient referrals from community hospitals and family physicians for hospitalised care. PATIENTS: Forty-one consecutive women referred for TAH were suitable for LAVH. Women able to undergo conventional vaginal hysterectomy, women with uterine fibroids exceeding 14 weeks in size and subjects with malignant disease were excluded. The most common indication for hysterectomy was persistent abnormal bleeding. INTERVENTION: Of the 41 women assessed pre-operatively as suitable for LAVH, the procedure was successfully performed in 40 by means of a bipolar desiccation and scissors transection technique with re-usable equipment. MAIN OUTCOME MEASURES: Assessment of intra-operative and postoperative morbidity, surgical complications, operating time, length of hospitalisation and assessment at postoperative visit 6 weeks after surgery. RESULTS: Only 1 woman was unable to undergo successful LAVH because she had pelvic adhesions and densely adherent loops of bowel; a TAH was performed. No operative complication occurred. One woman had postoperative vaginal bleeding controlled with a vaginal pack, and a diagnosis of von Willebrand's disease was subsequently established. No patient had febrile morbidity and when reviewed at clinic 6 weeks later all women were well. CONCLUSIONS: LAVH is possible in many women in whom hysterectomy is indicated but conventional vaginal hysterectomy is not feasible. In this study LAVH was found to be a safe procedure with minimal complications.

Adolescent↗
PubMed1995

Fossil fuel biodegradation: laboratory studies.

Biodegradation of the polycyclic aromatic hydrocarbons of creosote by undefined bacterial cultures was shown to be accompanied by the accumulation of neutral and acidic oxidation products. Formation of a number of identified neutral products is accounted for by demonstration of anomalous actions of an arene dioxygenase on the benzylic methylene and methylene carbons of napthenoaromatic hydrocarbons. Both neutral and acidic water-soluble fractions are also formed when various mixed bacterial cultures degrade weathered crude oil. While constituents of these fractions are not yet identified, the neutral materials have been shown to be toxic to developing embryos of invertebrates. These observations are discussed in relation to chemical and toxicological assessments of biodegradation of the complex chemical mixtures of fossil fuels.

Biodegradation, Environmental↗
PubMed1995

Multiple granulocyte transfusions facilitating successful unrelated bone marrow transplantation in a patient with very severe aplastic anemia complicated by suspected fungal infection.

The successful use of granulocyte transfusions in a patient undergoing volunteer unrelated donor BMT for very severe aplastic anemia complicated by presumed fungal infection is described. Granulocytes were obtained by leukapheresis of normal volunteer donors stimulated by granulocyte colony-stimulating factor. The yields of granulocytes obtained by this method were sufficient to produce sustained neutrophil increments in the recipient throughout the transplant course. In vitro studies indicated that granulocytes were functionally normal, a finding which was supported clinically by the rapid resolution of infection, even in the setting of immunosuppression post-transplantation. This demonstrated the potential value of granulocyte transfusions in high-risk BMT.

Adult↗
PubMed1992

Charting infant distress: an aid to defining colic.

The value of a 24-hour distress diary, previously validated against a voice-activated audiotape record, was investigated in 30 infants with colic and 30 control infants. The infants with colic had significantly more distress behavior (300.0 minutes vs 102.5 minutes; p < 0.001), although overlap of duration of distress was noted. On the basis of a clinical definition of colic--total distress lasting 180 minutes in a 24-hour period--the diary had a sensitivity of 77% and a specificity of 87%. The sensitivity of the chart was confirmed in a separate study of another 90 infants with colic.

Child Behavior↗
PubMed1987

Response to injury in children with closed femur fractures.

Fifty children admitted with closed femur fracture as a single major injury were monitored for change in vital signs and hematocrit. Hypotension was not observed. No child required blood replacement. Only 33% of the children had a measurable change in hematocrit, averaging a four-point drop. There was a marked febrile response to injury in 80% of the children which lasted an average of 4 days. Children admitted with femur fractures who develop hypotension or rapid drop in hematocrit should be promptly evaluated for another source of blood loss.

Adolescent↗