Monitoring mastitis and maintaining biosecurity.
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Animal Husbandry↗
Biomedical subjects
J Davis
Publications and source records attributed to J Davis.
Hospital food. Today's special.
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Allied Health Personnel↗
Estrogen-derived steroidal metal complexes: agents for cellular delivery of metal centers to estrogen receptor-positive cells.
Targeted cellular delivery of drugs to specific tissues is an important goal in biomedical chemistry. Achieving this requires harnessing and applying molecular-level recognition events prevalent in (or specific to) the desired tissue type. Tissues rich in estrogen receptors (ERs), which include many types of breast cancer, accumulate molecules that have high binding affinities for these receptors. Therefore, molecules that (i) bind to the ER, (ii) have favorable cellular transport properties, and (iii) contain a second functionality (such as a center that may be used for diagnostic imaging or medical therapy) are exciting synthetic targets in the field of drug delivery. To this end, we have prepared a range of metallo-estrogens based on 17alpha-ethynylestradiol and examined their binding to the ER both as isolated receptor and in whole cell assays (ER positive MCF-7 cells). Estrogens functionalized with metal binding units are prepared by palladium-catalyzed cross-coupling reactions and a wide range of metal centers introduced readily. All the compounds prepared and tested exhibit effective binding to the estrogen receptor and are delivered across the cell membrane into MCF-7 cells. In the whole cell assays, despite their monocationic nature, the palladium and platinum complexes prepared exhibit similar (and even enhanced) receptor binding affinities compared to their corresponding neutral free ligands. It is unprecedented for a higher ER binding affinity to be observed for a cationic complex than for its metal-free ligand.
Biological Transport↗
Characterization of SH2D1A missense mutations identified in X-linked lymphoproliferative disease patients.
X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency characterized by extreme susceptibility to Epstein-Barr virus. The XLP disease gene product SH2D1A (SAP) interacts via its SH2 domain with a motif (TIYXXV) present in the cytoplasmic tail of the cell-surface receptors CD150/SLAM, CD84, CD229/Ly-9, and CD244/2B4. Characteristically, the SH2D1A three-pronged interaction with Tyr(281) of CD150 can occur in absence of phosphorylation. Here we analyze the effect of SH2D1A protein missense mutations identified in 10 XLP families. Two sets of mutants were found: (i) mutants with a marked decreased protein half-life (e.g. Y7C, S28R, Q99P, P101L, V102G, and X129R) and (ii) mutants with structural changes that differently affect the interaction with the four receptors. In the second group, mutations that disrupt the interaction between the SH2D1A hydrophobic cleft and Val +3 of its binding motif (e.g. T68I) and mutations that interfere with the SH2D1A phosphotyrosine-binding pocket (e.g. C42W) abrogated SH2D1A binding to all four receptors. Surprisingly, a mutation in SH2D1A able to interfere with Thr -2 of the CD150 binding motif (mutant T53I) severely impaired non-phosphotyrosine interactions while preserving unaffected the binding of SH2D1A to phosphorylated CD150. Mutant T53I, however, did not bind to CD229 and CD224, suggesting that SH2D1A controls several critical signaling pathways in T and natural killer cells. Because no correlation is present between identified types of mutations and XLP patient clinical presentation, additional unidentified genetic or environmental factors must play a strong role in XLP disease manifestations.
Amino Acid Sequence↗
Thoracolumbar spinal abnormalities in Stickler syndrome.
STUDY DESIGN: Retrospective review of clinical and radiographic records of patients with Stickler syndrome. OBJECTIVES: To describe thoracolumbar spinal abnormalities and their correlation with age and back pain among patients with Stickler syndrome. SUMMARY OF BACKGROUND DATA: Stickler syndrome (hereditary arthro-ophthalmopathy) is an autosomal dominant connective tissue disorder characterized by skeletal, ocular, oral-facial, cardiac, and auditory manifestations. Prevalence is approximately 1 in 10,000 (similar to that of Marfan syndrome). No one has investigated spinal abnormalities in a large series of patients. METHODS: A single-center evaluation of 53 patients from 24 families with Stickler syndrome (age range, 1-70 years) in a multidisciplinary genetics clinic. Thoracolumbar radiographs were analyzed for spinal abnormalities and correlation with age and back pain. RESULTS: Thirty-four percent of patients had scoliosis, 74% endplate abnormalities, 64% Schmorl's nodes, 43% platyspondylia, and 43% Scheuermann-like kyphosis. Sixty-seven percent of patients and 85% of adults reported chronic back pain. Endplate abnormalities and Schmorl's nodes were associated with adult age; endplate abnormalities, Schmorl's nodes, and adult age were associated with back pain. Only one adult patient was free of spinal abnormalities. CONCLUSIONS: Spinal abnormalities are nearly uniformly observed in Stickler syndrome, progress with age, and are associated with back pain. Although common, scoliosis is generally self-limited (only one patient needed surgical treatment). Correct diagnosis of this syndrome facilitates early identification and management of other potentially severe systemic manifestations and genetic counseling for affected families. Moreover, recognition of Stickler syndrome allows accurate prognosis for skeletal abnormalities and anticipation of potential surgical complications.
Adolescent↗
Sib understanding of genetics and attitudes toward carrier testing for X-linked severe combined immunodeficiency.
X-linked severe combined immunodeficiency (XSCID) is the most common genetic form of SCID, a rare disease with profoundly impaired immunity. SCID was previously fatal but now can be treated by bone marrow transplantation. Mapping of XSCID in 1985 and identification of the disease gene, IL2RG, in 1993 made possible patient and carrier diagnosis. We assessed understanding of the genetics of XSCID in adult sibs recruited from families in which a proband had enrolled in our protocols and had attended an XSCID family workshop. Thirty-seven female and three male sibs completed a questionnaire and semistructured interview. Overall knowledge of genetics of XSCID was excellent. An overwhelming majority of participants (93%) believed that daughters should be tested for XSCID carrier status; 89% would prefer to have their own daughter tested prior to age 18 years (M = 9, median = 12), and 34% would test at birth. Moreover, 89% felt they would disclose carrier results to their daughter before adulthood (M = 12 years, median = 12); 51% would tell prior to adolescence. XSCID sibs were optimistic about medical science and assertive in their search for the latest information. Genetic information should be made available to families over time and should include discussion of reproductive risks for sons surviving with XSCID and daughters as they grow up. We recommend that genetic counseling for XSCID include children in age-appropriate discussions and that counselors help parents weigh benefits of early testing and disclosure versus the potential harm of loss of child autonomy.
Adult↗
Auditory dysfunction in Stickler syndrome.
OBJECTIVES: To characterize the natural history and possible mechanisms of hearing loss in Stickler syndrome (OMIM 108300; or hereditary progressive arthro-ophthalmopathy) and to determine if the auditory phenotype is a useful discriminating feature for the differential diagnosis of this group of disorders. DESIGN: Multifamily study. SETTING: Outpatient audiology and otolaryngology clinics at the Warren Grant Magnuson Clinical Center of the National Institutes of Health, Rockville, Md. SUBJECTS: Forty-six affected individuals from 29 different families segregating Stickler syndrome. INTERVENTIONS: Clinical audiologic and otolaryngological examinations were performed on all individuals, including pure-tone audiometry, speech audiometry, and middle ear immittance testing. Otoacoustic emissions, auditory brainstem response, infrared video electronystagmography, and temporal bone computed tomography were performed on a subset of participants. RESULTS: The hearing loss was most often sensorineural in adults, and approximately 28 (60%) of the 46 adult patients had 2 or more thresholds greater than the corresponding 95th percentile values for an age-matched, otologically normal population. The hearing loss most often affected high frequencies (4000-8000 Hz) and was generally no more progressive than that due to age-related hearing loss. Type A(D) tympanograms (classification using the Jerger model), indicating hypermobile middle ear systems, were observed in 21 (46%) of the 46 affected individuals. Computed tomography of the temporal bones revealed no inner ear malformations in 19 affected individuals. CONCLUSIONS: The hypermobile middle ear systems observed in ears with normal-appearing tympanic membranes represent a novel finding for Stickler syndrome and are likely to be a useful diagnostic feature for this disorder. The overall sensorineural hearing loss in type I Stickler syndrome is typically mild and not significantly progressive. It is less severe than that reported for types II and III Stickler syndrome linked to COL11A2 (OMIM 120290) and COL11A1 (OMIM 120280) mutations, respectively, or the closely related Marshall syndrome. This difference will be a useful discriminatory feature in the differential diagnosis of this group of disorders.
Adolescent↗
Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophy.
Human disuse muscle atrophy frequently accompanies orthopedic injury, arthritis, or bed rest, and recovery is often incomplete despite current rehabilitation programs. We have studied the vastus lateralis muscle in 12 patients with chronic disuse atrophy associated with chronic osteoarthritis of the hip both preoperatively and after total hip arthroplasty. Semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated an increase in the level of expression of myostatin, insulin-like growth factor-1 (IGF-1) and leukemia inhibitory factor (LIF) mRNAs compared to healthy control muscle. In all patients there was a significant correlation preoperatively between increasing myostatin mRNA expression and reduction in type 2A and 2B fiber area. In the 8 female patients there was a significant correlation between increased myostatin mRNA expression and the atrophy factor calculated for 2A and 2B fiber types preoperatively. We hypothesize that a complex interaction occurs between muscle growth regulating factors in the genesis of muscle wasting. Our results indicate that myostatin is a muscle-wasting factor contributing to type 2B and 2A atrophy. Other muscle growth factors, such as IGF-1 and LIF, may be upregulated in a counterregulatory fashion or may be involved in the fiber type switching seen in disuse muscle wasting.
Adult↗
Dendritic spine hypoplasticity and downregulation of reelin and GABAergic tone in schizophrenia vulnerability.
In this review, we will first present a brief overview of the current understanding of: (a) the biology of reelin; (b) the putative reelin signaling pathways via integrin receptor stimulation; (c) the cytosolic adapter protein DAB1, which appears to be operative in the transduction of reelin's pleiotropic actions in embryonic, adolescent, and adult brain; (d) the regulation of GABAergic function, including some aspects of GABAergic system development; and (e) dendritic spine function and its role in the regulation of synaptic plasticity. We argue that a downregulation of reelin expression occurring in prefrontal cortex and in every brain structure of schizophrenia patients so far studied may be associated with a decrease in dendritic spine expression that in turn may provide an important reduction of cortical function as documented by the downregulation of glutamic acid decarboxylase67 (GAD67) expression, which might be secondary to a reduction of GABAergic axon terminals. This hypothesis is supported by a genetic mouse model of reelin haploinsufficiency that replicates the above-described dendritic and presynaptic GABAergic defects documented in schizophrenia brains.
Adolescent↗
Coxsackie virus infection of the placenta associated with neurodevelopmental delays in the newborn.
OBJECTIVE: To determine if viral infection of the placenta was associated with long-term neurodevelopmental delays in the newborn. METHODS: Placental tissue from seven newborn infants with severe respiratory failure and subsequent neurodevelopmental abnormalities as well as ten normal controls and five cases of known placental infection (cytomegalovirus, herpes simplex virus, and parvovirus) were tested by in situ hybridization or reverse transcriptase in situ polymerase chain reaction (PCR) for adenovirus, coxsackie virus, cytomegalovirus, Epstein Barr virus, herpes simplex virus, influenza A virus, picornavirus, polyoma virus, parvovirus, respiratory syncytial virus, rotavirus, and varicella zoster virus. RESULTS: Coxsackie virus RNA was detected in six of the seven cases, and in none of the ten normal controls or five cases with known viral infection. Viral RNA localized primarily to the Hofbauer cells and trophoblasts of the terminal villi. Immunohistochemical analysis for the coxsackie virus antigen VP1 yielded equivalent results. CONCLUSIONS: In utero coxsackie virus of the placenta is associated with the development of severe respiratory failure and central nervous system sequelae in the newborn. This underscores the importance of detailed pathologic and viral examination of the placenta in cases of systemic illness in the newborn.
Adolescent↗
The nonpharmacologic treatment of generalized anxiety disorder.
This article describes the latest nonpharmacologic therapies for generalized anxiety disorder. In addition, a review of available nonpharmacologic treatment outcome studies and studies that compare the efficacy of pharmacologic and nonpharmacologic treatment is presented. The authors conclude that, of the nonpharmacologic therapies available, cognitive-behavioral therapy may be the preferred first-line treatment. Results of comparison studies have suggested that medication acts more quickly than does therapy in reducing symptoms, whereas therapy has more long-lasting effects. The authors recommend that further research be conducted in identifying the essential components of treatment and the most efficacious treatment combinations.
Anxiety Disorders↗
Bioanalytical utility of sonovoltammetry.
Dopamine dissolved within egg homogenate was used as a model system to study the effects of electrode contamination and its subsequent reactivation through ultrasonically mediated in situ cleaning effects. The merits in conducting electroanalytical investigations under the influence of the ultrasonic field were also appraised. Maintaining the ultrasound field during oxidative measurements was found to yield hydrodynamic profiles that were linear over the concentration range 2-20 microM dopamine. The resulting sonolinear sweep voltammograms were compared with conventional rotating disk measurements, with the former found to provide significantly increased limiting currents that were attenuable through the manipulation of the field intensity. The problem of retaining selectivity in the presence of high concentrations of ascorbate was also assessed with the addition of cupric ion prior to commencing the measurements found to efficiently negate an otherwise substantive interference.
Dopamine↗
Biochemical responses in cultured cells following exposure to (89)SrCl(2): potential relevance to the mechanism of action in pain palliation.
(89)SrCl(2) is currently used as a systemic radioactive palliative treatment for painful osseous metastases associated with an osteoblastic reaction in bone. However, the biological mechanism by which (89)SrCl(2) mediates pain palliation remains unclear. In this study, attempts were made to elucidate the mechanisms by which (89)SrCl(2) might influence pain at these sites. Both the direct radiotoxic effects of (89)SrCl(2) on cell viability and its influence on cellular biosynthetic activity were investigated. The direct radiotoxic effects of (89)SrCl(2) and X-rays were compared using the prostate carcinoma cell line, PC-3. Comparable effects upon PC-3 cell viability were seen in response to exposure to an equivalent dose given by (89)SrCl(2) and X-rays (2 Gy). Experiments to investigate the indirect action of (89)SrCl(2) exposure employed the MC3T3-E1 cell line and focused on their production of Prostaglandin E(2) (PGE(2)) and interleukin-6 (IL-6). Exposure of the MC3T3-E1 cell line to (89)SrCl(2) resulted in an increased production of PGE(2) in a concentration-dependent manner. No increased PGE(2) production was seen by the MC3T3-E1 cells in response to X-ray exposure either in the presence or absence of SrCl(2). IL-6 was produced by the MC3T3-E1 cells in response to (89)SrCl(2) exposure via a PGE(2)-mediated pathway. This study demonstrates the release of potent biochemical modifiers of bone turnover in response to the systemically applied radiotherapeutic (89)SrCl(2). This strongly suggests the mechanism of pain palliation by (89)SrCl(2) is likely to result from a complex interaction of direct and indirect radiation-induced effects.
Bone Neoplasms↗
In vivo-in vitro correlation (IVIVC) modeling incorporating a convolution step.
The purpose of in vivo-in vitro correlation (IVIVC) modeling is described. These models are usually fitted to deconvoluted data rather than the raw plasma drug concentration/time data. Such a two-stage analysis is undesirable because the deconvolution step is unstable and because the fitted model predicts the fraction of a dosage unit dissolved/absorbed in vivo which generally is not the primary focus of our attention. Interest usually centers on the plasma drug concentration or some function of it (e.g., AUC, Cmax). Incorporation of a convolution step into the model overcomes these difficulties. Odds, hazards, and reversed hazards models which include a convolution step are described. The identity model (which states that average in vivo and in vitro dissolution/time curves are coincident or directly superimposable) is a special case of these models. The odds model and the identity model were fitted to data sets for two different products using nonlinear mixed effects model fitting software. Results show that the odds model describes both data sets reasonably well and is a significantly better fit than the identity model in each case.
Cross-Over Studies↗
Stem cell transplantation for chronic myeloid leukaemia: the role of infused marrow cell dose.
INTRODUCTION: Allogeneic stem cell transplantation is a potentially curative option for patients with CML. The optimal donor is an HLA-identical sibling but transplants using unrelated volunteers can also be successful. The factors influencing survival after allogeneic SCT for CML are reasonably well defined. Recently however, the Seattle group have emphasised the influence of a high marrow cell dose on outcome following volunteer unrelated donor SCT for high risk acute leukaemia. MATERIALS AND METHODS: We have sought to define factors impacting on transplant related mortality (TRM) in a population of CML patients after allografting with matched sibling or alternative stem cell donors at a single centre over a 20-year period, with emphasis on infused marrow cell dose. Factors entered into a multivariate analysis were: recipient age, recipient CMV serostatus, disease phase, donor sex, cell dose and frequency of CTLP reactivity. RESULTS: In multivariate analysis four factors had an adverse effect on TRM when using a VUD: low marrow cell dose (<3.65 x 10(8) TNC/kg, relative risk 2.05, CI 1.08-3.90, P = 0.029), late disease phase (relative risk 1.68, CI 1.03-2.74, P = 0.038), patient CMV seropositivity (relative risk 1.98, CI 1.25-3.13, P = 0.004) and high frequency of CTLP (relative risk 1.93, CI 1.18-3.13, P = 0.008). For HLA-identical sibling donor transplants the only factor that adversely impacted on TRM was late disease phase (P = 0.0004 in univariate analysis). CONCLUSION: High infused cell dose is a new modifiable factor associated with reduced TRM following allogeneic SCT using an unrelated donor for the treatment of CML. The data support the recommendation that bone marrow harvest teams should aim to collect the highest possible number of nucleated cells for recipients of unrelated donor transplants.
Adult↗
Electroanalytical exploitation of quinone-thiol interactions: application to the selective determination of cysteine.
Square wave voltammetry was applied to the detection of cysteine through the use of an indirect assay that exploits the reaction of the thiol with a quinone indicator. Voltammetric discrimination between unreacted quinone and the corresponding quinone-cysteine adduct is possible with clear resolution of the latter peak providing a linear response from 5 to 47 microM. The selectivity of the approach was assessed with no interference from cystine, lysine, paracetamol or 4-aminophenol. The response recorded in the presence of a massive excess of ascorbic acid was also investigated and the integrity of the approach confirmed. The effects of other sulfhydryl thiols, homocysteine and glutathione, were also assessed and found to present no appreciable change in the voltammetric profile. The practical utility of the approach was investigated through examining the response to cysteine in urine.
Benzoquinones↗
Voltammetric investigation of hair dye constituents: application to the quantification of p-phenylenediamine.
The application of electrochemical techniques to the determination of common hair dye constituents was investigated. Cyclic voltammetry was used to probe the electrode response to p-phenylenediamine (PPD), 4-chlororesorcinol and m-aminophenol with square wave voltammetry used to effect quantitative measurements. The nature of the electrode response was characterised and issues of surface fouling resulting from the deposition of electrogenerated reaction products were addressed. A procedure designed to allow the facile determination of PPD in hair care products is presented.
Carbon↗
Improving access for rural Australians to treatment for anxiety and depression: The University of Melbourne Depression and Anxiety Research and Treatment Group-Bendigo Health Care Group initiative.
Rural Australians have limited access to care for mental health problems. We describe a collaboration between the University of Melbourne Departments of Psychology and Psychiatry and a rural Area Mental Health Service to provide a specialist anxiety and depression treatment service in rural Victoria. The clinical service and the education and training approach are described.
Academic Medical Centers↗