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Biomedical subjects

A Donnelly

Publications and source records attributed to A Donnelly.

At least 19 recordsLinked to original sources
PubMed2001

Phage display mutagenesis of the chimeric dual cytokine receptor agonist myelopoietin.

Myelopoietins comprise a class of chimeric cytokine receptor agonists consisting of an hIL-3 (human interleukin-3) receptor agonist and an hG-CSF (human granulocyte colony-stimulating factor) receptor agonist linked head-to-tail at their respective carboxy and amino termini. The combination of an early acting cytokine (hIL-3) with a late acting one (hG-CSF) allows efficient hematopoeitic reconstruction following myeloablative insult, and drives differentiation of non-myelocytic lineages (ie thrombocytic lineages) that are inaccessible using hG-CSF alone, in both preclinical models and clinical settings. A myelopoietin species was displayed and mutagenized on filamentous bacteriophage: both component agonists of myelopoietin were presented in biologically functional conformations as each recognized its corresponding receptor. Five amino acid positions in a short region of the hG-CSF receptor agonist module of myelopoietin that had been identified as important for proliferative activity were mutagenized. Display was used because it allows very 'deep' mutagenesis at selected residues: >10(5) substitution variants were affinity-screened using the hG-CSF receptor and 130 new, active variants of myelopoietin were identified and characterized. None of the selected variants were significantly more active than the parental myelopoietin species in a hG-CSF-dependent cell proliferation assay, though many were as active. Many of these relatively high-activity variants contained parental amino acids at several positions, suggesting the parental sequence may already be optimal at these positions for the assays used, and potentially accounting for the failure to identify enhanced bioactivity variants. Analysis of substitutions of high-activity variants complements and extends previous alanine scanning, and other genetic and biochemical data for hG-CSF variants.

Cytokines↗
PubMed2001

Improving the health of Oklahomans: status and goals of adult immunization.

This article will discuss the prevalence and impact of the infectious diseases affecting adult Oklahomans for which vaccines are available. Evidence for vaccine utilization and the present status and future aspirations for population-wide immunization rates in Oklahoma will also be reviewed. The information and data herein are taken mainly from recommendations established by the US Preventive Services Task Force (USPSTF); the Centers for Disease Control (CDC) publication Epidemiology and Prevention of Vaccine-Preventable Disease; the findings of the Advisory Committee on Immunization Practices (ACIP) as published in the CDC's Morbidity and Mortality Weekly Report; the Oklahoma State Department of Health (OSDH) State of the State's Health Report; and the Behavioral Risk Factor Surveillance System (BRFSS), a telephone survey conducted by the CDC.

Adult↗
PubMed2000

Commercial hospital discharge packs for breastfeeding women.

BACKGROUND: Exclusive breastfeeding until around six months of age, followed by the introduction of solids with continued breastfeeding, is considered to be the optimal nutritional start for newborn infants. OBJECTIVES: To determine whether the exclusivity and duration of breastfeeding is affected by giving mothers commercial discharge packs in hospital which contain artificial formula or promotional material for artificial formula. These packs are those which are commonly given to mothers on leaving hospital after giving birth (thus discharge packs). SEARCH STRATEGY: Comprehensive electronic search of the register of clinical trials maintained and updated by the Cochrane Pregnancy and Childbirth Group and CINAHL and MEDLINE. SELECTION CRITERIA: All randomised controlled trials with or without blinding to examine the effects of commercial discharge packs on breastfeeding. PARTICIPANTS: Consenting postpartum women who initiate breastfeeding while in hospital or immediately upon discharge. INTERVENTIONS: Commercial discharge packs which contain free samples of infant formula or promotional material versus non commercial discharge packs (specifically those from which free samples of infant formula have been removed or have been replaced with e.g. breast pads) or no pack. MAIN OUTCOME MEASURES: The proportion of women breastfeeding at six weeks and 3 months (13 weeks) postpartum. Other outcomes: Rates of breastfeeding at other fixed time points between 0 and 6 months postpartum. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and checked by a second reviewer. MAIN RESULTS: Nine randomised controlled trials involving a total of 3730 women were analysed. The studies only included women from North America. The meta-analysis showed that when comparing commercial discharge packs with any of the controls (no intervention, non-commercial pack and combinations of these), exclusive breastfeeding was reduced at all time points in the presence of commercial hospital discharge packs. There was no evidence to support the conjecture that use of hospital discharge packs causes the early termination of non-exclusive breastfeeding. Where the introduction of solid food was measured, giving a commercial pack (with or without formula) reduced the time before solid food was introduced. REVIEWER'S CONCLUSIONS: The giving of commercial hospital discharge packs (with or without formula) appears to reduce the number of women exclusively breastfeeding at all times but has no significant effect upon the earlier termination of non-exclusive breastfeeding.

Breast Feeding↗
PubMed2000

Prokaryotic diversity in Zostera noltii-colonized marine sediments.

The diversity of microorganisms present in a sediment colonized by the phanerogam Zostera noltii has been analyzed. Microbial DNA was extracted and used for constructing two 16S rDNA clone libraries for Bacteria and Archaea. Bacterial diversity was very high in these samples, since 57 different sequences were found among the 60 clones analyzed. Eight major lineages of the Domain Bacteria were represented in the library. The most frequently retrieved bacterial group (36% of the clones) was delta-Proteobacteria related to sulfate-reducing bacteria. The second most abundant group (27%) was gamma-Proteobacteria, including five clones closely related to S-oxidizing endosymbionts. The archaeal clone library included members of Crenarchaeota and Euryarchaeota, with nine different sequences among the 15 analyzed clones, indicating less diversity when compared to the Bacteria organisms. None of these sequences was closely related to cultured Archaea organisms.

Archaea↗
PubMed1999

Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation.

The X-chromosome breakpoint in a female patient with a balanced translocation t(X;12)(q24;q15), bipolar affective disorder and mental retardation was mapped within the glutamate receptor 3 (GRIA3) gene by fluorescence in situ hybridization. The GRIA3 cDNA of 5894 bp was cloned, and the gene structure and pattern of expression were determined. The most abundant GRIA3 transcript is composed of 17 exons. An additional 5 exons (2a, 2b, 5a, 5b, and 5c) from the 5' end of the GRIA3 open reading frame were identified by EST analysis (ESTs AI379066 and AA947914). Two new polymorphic microsatellite repeats, (TC)(n=12-26) and (AC)(n=15-19), were identified within GRIA3 5' and 3'UTRs. No mutations were detected in families segregating disorders mapping across GRIA3, one with X-linked bipolar affective disorder (BP) and one with a nonspecific X-linked mental retardation (MRX27). To assess the possibility of the involvement of the GRIA3 gene in familial cases of complex BP, a large set of 373 individuals from 40 pedigrees segregating BP were genotyped using closely linked (DXS1001) and intragenic (DXS1212 and GRIA3 3' UTR (AC)(n))) GRIA3 STR markers. No evidence of linkage was found by parametric Lod score analysis (the highest Lod score was 0. 3 at DXS1212, using the dominant transmission model) or by affected sib-pair analysis.

Adult↗
PubMed1999

Fibroblast growth factor homologous factor 2 (FHF2): gene structure, expression and mapping to the Börjeson-Forssman-Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a BFLS-like patient.

Börjeson-Forssman-Lehmann syndrome (BFLS) is a syndromal X-linked mental retardation, which maps by linkage to the q26 region of the human X chromosome. We have identified a male patient with BFLS-like features and a duplication, 46,Y,dup(X)(q26q28), inherited from his phenotypically normal mother. Fluorescence in situ hybridisation using yeast artificial chromosome clones from Xq26 localised the duplication breakpoint to an approximately 400-kb interval in the Xq26.3 region between DXS155 and DXS294/DXS730. Database searches and analysis of available genomic DNA sequence from the region revealed the presence of the fibroblast growth factor homologous factor gene, FHF2, within the duplication breakpoint interval. The gene structure of FHF2 was determined and two new exons were identified, including a new 5' end exon, 1B. FHF2 is a large gene extending over approximately 200 kb in Xq26.3 and is composed of at least seven exons. It shows tissue-specific alternative splicing and alternative transcription starts. Northern blot hybridisation showed highest expression in brain and skeletal muscle. The FHF2 gene localisation and tissue-specific expression pattern suggest it to be a candidate gene for familial cases of the BFLS syndrome and other syndromal and non-specific forms of X-linked mental retardation mapping to the region.

Alternative Splicing↗
PubMed1999

Indirect evidence of human skeletal muscle damage and collagen breakdown after eccentric muscle actions.

Indirect markers of muscle damage and collagen breakdown were recorded for up to 9 days after a bout of concentric, followed by a bout of eccentric, muscle actions. Nine untrained participants performed two bouts of 50 maximum effort repetitions on an isokinetic dynamometer (angular velocity 1.05 rad x s(-1), range of motion 1.75 rad). An initial concentric bout of muscle actions was followed by an eccentric bout 21 days later, using the same knee extensors. Concentric actions induced no changes in maximum voluntary isometric contraction force (MVC), nor induced any changes in the serum enzyme activities of creatine kinase, a lactate dehydrogenase isoenzyme (LDH-1), or alkaline phosphatase. Similarly, concentric actions induced no change in markers of collagen breakdown, namely plasma hydroxyproline and serum type 1 collagen concentration. In contrast, eccentric actions induced a 23.5+/-19.0% (mean+/-s) decrease in MVC immediately post-exercise (P < 0.05), and increased the serum enzyme activities of creatine kinase and LDH-1 to 486+/-792 and 90+/-11 IU.l(-1) respectively on day 3 post-exercise, and to 189+/-159 and 96+/-13 IU x l(-1) respectively on day 7 post-exercise (all P< 0.05). Eccentric actions induced no significant changes in plasma hydroxyproline, but increased collagen concentration on days 1 and 9 post-exercise (48.6% and 44.3% increases above pre-exercise on days 1 and 9 respectively; both P < 0.05). We conclude that eccentric but not concentric actions may result in temporary muscle damage, and that collagen breakdown may also be affected by eccentric actions. With caution, indices of collagen breakdown may be used to identify exercise-induced damage to connective tissue.

Adult↗
PubMed1999

Skin signs of systemic disease.

BACKGROUND: Dermatological problems are a common presentation in general practice and skin disorders may be a manifestation of underlying systemic disease. OBJECTIVE: To describe cutaneous manifestations of some commonly occurring systemic diseases. DISCUSSION: This article alerts the general practitioner to those skin conditions that may warrant further assessment for underlying disease and those that may complicate known disorders such as diabetes.

Diabetes Complications↗
PubMed1999

Changes in indices of antioxidant status, lipid peroxidation and inflammation in human skeletal muscle after eccentric muscle actions.

This study investigated the effects of chronic muscle inflammation on indices of antioxidant status and muscle injury after eccentric exercise. Eight subjects each performed 70 maximal voluntary eccentric muscle actions on an isokinetic dynamometer, using the knee extensors of a single leg. Venous blood samples were collected into serum and EDTA tubes 5 and 3 days before exercise, immediately before exercise, and then again on days 3, 4, 5, 6, 7, 10 and 12 after the bout. Needle biopsies were taken from the vastus lateralis of six subjects, a week before exercise (baseline), and again on days 4 and 7 post-exercise. The concentrations of malondialdehyde in plasma and muscle were used as markers of lipid peroxidation. Creatine kinase activity, beta-glucuronidase activity and total antioxidant capacity were determined in serum. In muscle, aqueous and bound total antioxidant capacity, the aqueous sulphydryl concentration, and beta-glucuronidase and glucose-6-phosphate dehydrogenase activity were determined. No changes were detected in serum total antioxidant capacity, serum creatine kinase and beta-glucuronidase after the baseline biopsy. After exercise serum creatine kinase and beta-glucuronidase were elevated although other serum measures were unchanged. In muscle, aqueous and bound total antioxidant capacity, sulphydryls, glucose-6-phosphate dehydrogenase and beta-glucuronidase were all elevated. Despite evidence of inflammation in this study, muscle antioxidant status was not compromised, and malondialdehyde was unaltered in muscle and plasma. Therefore, this study provides no evidence that chronic muscle inflammation compromises antioxidant status or increases lipid peroxidation.

Adult↗
PubMed1998

A novel mutation in exon b (R259C) of the MTM1 gene is associated with a mild myotubular myopathy. Mutation in brief no. 125. Online.

The genetic basis of the relatively mild myopathic symptoms exhibited in a male was investigated. Mutation screening of a candidate gene, MTM1, represented a chance of establishing the molecular defect and the mode of inheritance. SSCA detected variation of the exon b PCR products from the proband and his mother, compared to that observed upon analysis of the PCR products from other members of the family and 159 unrelated X chromosomes. Sequencing revealed a C775 to T transition, in the proband and his mother, but not in his unaffected brother. To confirm the presence of a base change in this region, a Cfol site was introduced into the PCR product of the wildtype allele by using the forward primer 5'-AGAAAATAAGACGGTCATTGcG-3' (mismatch base in small font) with the exon b reverse primer as used by Laporte et al (1996). Analysis of DNA from other members of the family using this method revealed that this is a new mutation in the proband's mother. This mutation would result in a Arg259->Cys substitution.

Alleles↗
PubMed1998

Carbamazepine-10,11-epoxide in therapeutic drug monitoring.

Carbamazepine (CBZ) is widely used in the treatment of epilepsy, frequently in combination with other anticonvulsants. Its metabolite, carbamazepine-10,11-epoxide, is pharmacologically active and is increased with concurrent use of valproate and other anticonvulsants. This pharmacokinetic interaction may be particularly important because CBZ, its epoxide, phenytoin, and lamotrigine all act on fast voltage-dependent sodium channels. Over a 2-month period, routine serum requests for CBZ (n=47) (excluding known cases of overdose) were also analyzed for CBZ epoxide, phenytoin, and lamotrigine using a simultaneous high performance liquid chromatographic (HPLC) method. Valproate was measured using fluorescence polarization immunoassay (FPIA). With concurrent phenytoin and lamotrigine administration, there was a relative increase in CBZ epoxide and a significant decrease in the ratio of CBZ to epoxide (from more than 5 to 3). If valproate was also present, the concentration of parent and metabolite increased significantly, causing potential toxicity. Two patients in this latter group had significant clinical toxicity, with parent CBZ concentrations in the reference range; a third patient suffered from poor control of seizures. This study illustrates the importance of awareness of the contribution of active metabolites in therapeutic drug monitoring and raises questions about the role of the routine monitoring of such metabolites.

Adult↗
PubMed1998

Absorption enhancers as tools to determine the route of nasal absorption of peptides.

The nasal absorption of a series of peptides was studied in order to examine the relationship between extent of absorption and lipophilicity and absorption enhancers were used to probe the mechanism of peptide absorption. An in situ rat nasal perfusion technique was employed to assess the nasal absorption of a series of peptides, D-FGGGGG (D-FG5), D-FD-FGGGG (D-F2G4) and D-FD-FD-FGGG (D-F3G3), [D-ala2, D-leu5]enkephalin (YD-AGFD-L) and thyrotrophin releasing hormone (TRH). The enhancers sodium tauro-24,25 dihydrofusidate (STDHF), ethylene diamine tetraacetic acid (EDTA and dimethyl-beta-cyclodextrin (DMbetaCD) were utilized to improve and elucidate the mechanisms of peptide absorption. There was no significant relationship between extent of peptide absorption and lipophilicity as determined by C log P values. STDHF was a potent absorption enhancer but demonstrated overt toxicity. Conversely, EDTA did not demonstrate extensive toxicity but was found to be a poor absorption enhancer. DMbetaCD displayed some toxicity and was also found to inhibit the absorption of D-FG5,D-F2G4 and D-F3G3. This reduction is likely to be a result of the peptide/DMbetaCD complex formation. The peptides studied appear to be predominantly absorbed by a passive paracellular mechanism.

Absorption↗
PubMed1996

Speed of onset of action of Tilarin.

Two studies have been carried out specifically to examine the speed of onset of action of intranasal nedocromil sodium 1% (Tilarin) for the relief of symptoms due to ragweed allergic rhinitis. One, a multicentre placebo-controlled comparative study using a QID regimen, 1 spray per nostril, was designed to assess the speed of onset of action of nedocromil sodium during the first week of treatment in patients with rhinitis symptoms, and to evaluate the efficacy and safety of nedocromil sodium during 6 weeks of treatment (1). A 1-week baseline, the start of which was timed to coincide with the start of the ragweed season, was followed by 6 weeks double-blind trial treatment; only patients (n = 166) who were symptomatic at the end of baseline were included in the double-blind phase. Non-parametric analyses of all variables including a summary score (stuffy nose, runny nose, itchy nose and sneezing) showed that the onset of action of nedocromil sodium occurred on the first day of treatment. Further, patients using nedocromil sodium had less symptoms during the 10 days of peak pollen, at which time physician assessment showed reduced mucosal oedema and nasal discharge, and both patient and clinician opinions favoured nedocromil sodium. No significant adverse events were reported during this 6-week study. In the second study (2), 104 patients were randomly allocated to receive either nedocromil sodium or placebo, QID. They then spent 10 hours per day for 2 consecutive days in Iowa City Park during the peak of the ragweed season. Only patients showing significant symptoms of seasonal allergic rhinitis (SAR) during 3 hourly baseline assessments were included. Over the 2-day period, symptom scores for stuffy nose, runny nose, itchy nose and sneezing, and global symptom summary scores, were recorded at 19 hourly time points. At home in the evening, patients recorded symptom scores for the post-exposure period. In comparison with placebo, nedocromil sodium significantly improved rhinitis symptoms within 2 hours, and this reduction in SAR symptoms was maintained throughout the 2-day exposure period. Post exposure symptom summary scores were also significantly lower in patients treated with nedocromil sodium than in those patients treated with placebo. Overall, very few adverse events were reported, none of them serious. In conclusion, nedocromil sodium 1% nasal spray acts rapidly, within 2 hours on the first day of treatment, to reduce ongoing symptoms of SAR. Relief of rhinitis symptoms is maintained throughout the peak pollen period with nedocromil sodium QID, which appears to be a safe and well tolerated treatment for ragweed SAR.

Adolescent↗
PubMed1996

[Announcing the trisomy 21 diagnosis and care of the infant in the maternity ward: counseling offered to the parents].

Which solutions to child care are proposed to parents just after the diagnosis of Down's syndrome? The situation of Down's syndrome babies born in 1980-89 and abandoned at birth in Paris was studied. Semi-structured interviews were conducted with medical and social staffs of 13 maternity hospitals where 60% of these DS babies were abandoned. In 10 years, 102 DS babies were given up to the Child Welfare Agency and to private adoption agencies. They represent 10% of all abandoned children at birth and 22% of DS live births in Paris. Relations between abandonment, type of maternity hospital and social class of parents are analysed. Several factors influence the parents' decision in planning for the child: handicap, advice and way of presenting alternatives: in 1/3 of the cases, adoption was proposed directly. In the great majority, the child abandonment was decided in a situation of emergency and profound emotional stress, and outside of the legal procedure. Health care workers should listen to parents more so they can be better informed about their child's prognosis and all care alternatives before making their decision.

Adoption↗
PubMed1995

Cytologic diagnosis of cat scratch disease (CSD) by fine-needle aspiration.

Cat scratch disease (CSD) is usually a benign, self-limited lymphadenitis, characterized by suppurative granulomas. It can, however, produce a wide spectrum of clinical symptoms and cytologic changes and be the source of diagnostic dilemmas. Identification of pleomorphic bacilli (PB) with silver impregnation stains aids in the diagnosis, but this has not been well documented in cytologic preparations or in cases without the classic morphologic changes. We reviewed 13 aspirations from eight patients (aged 13-36 yr) occurring over a 15 mo time period, all clinically or cytologically suspicious for CSD. Sites included: axilla (6), parotid (3), epitrochlear (1), neck (1), submental (1), and intraclavicular (1) nodes. Neoplasia was initially suspected clinically in 38% of the cases. All but two patients had cat exposure on subsequent interview. The cytologic differential included bacterial abscess and lymphoproliferative disorders in 31%. Neither granulomas nor suppurative inflammation were seen in all cases. Changes included: granulomas (77%), PMNs (62%), dispersed epithelioid histiocytes (46%), and suppurative granulomas (38%). A modified silver stain (Modified Steiner, Sigma Diagnostics, St. Louis, MO) was performed on all specimens. Silver positive organisms were seen in 69% of cases and were not limited to those preparations with suppurative granulomas. Fine-needle aspiration biopsy (FNAB) is an effective method for diagnosing CSD despite its heterogeneous appearance; and, when combined with clinical information and silver staining, may obviate the need for excision.

Adolescent↗