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Biomedical subjects

Paul Young

Publications and source records attributed to Paul Young.

18 recordsLinked to original sources
PubMed2006

Agglomerate strength and dispersion of salmeterol xinafoate from powder mixtures for inhalation.

PURPOSE: The study investigated the role of agglomeration and the effect of fine lactose size on the dispersion of salmeterol xinafoate (SX) from SX-lactose mixtures for inhalation. METHODS: Particle size distributions were characterised by Malvern Mastersizer S, Aerosizer and Spraytec, and imaging conducted by scanning electron microscopy (SEM). Inter-particulate adhesion was quantified by atomic force microscopy. Deposition of SX was measured using a twin stage impinger. SX was analysed using validated high-performance liquid chromatography method (r(2)=1.0, CV=0.4-1.0%). RESULTS: Addition of fine lactose with a volume median diameter (VMD) of 7.9 microm to a SX-lactose carrier and carrier-free mixture resulted in significantly better dispersion (16.8% for 20% added fine lactose) than fractions with VMD of 3.0, 17.7 and 33.3 microm (less than 9.1% for 20% fine lactose). Using the carrier-free mixtures, particle sizing of the aerosol cloud using the Spraytec, coupled with the application of the Aerosizer using differing dispersion energies and SEMs of the samples, indicated that an open packed, agglomerate structure improved SX dispersion. The highest extent of SX dispersion occurred when SX and fine lactose were detached from the surface, usually in the form of loose agglomerates. CONCLUSIONS: The outcomes of this research demonstrated how agglomerate structure influenced dispersion and the key role of fine lactose particle size in SX dispersion from mixtures for inhalation.

Administration, Inhalation↗
PubMed2006

[Cutaneous infection due to Mycobacterium chelonae in a hemodialysed patient].

We report a case of a hemodialysed patient who developed a cutaneous Mycobacterium chelonae infection. This infection was only localised on the left upper limb, downstream from the arteriovenous fistula. M. chelonae is an unusual human pathogen, which is present in soil, dust, and stagnant water. Various factors, especially immunosuppression can favour this sort of infection in humans. Because of the ubiquity of the mycobacterium, the source of the inoculation sometimes remains unknown. However, a great number of cases are related to nosocomial infections. The preferential localizations are cutaneous, ocular, and pulmonary. Some cases of cutaneous infections due to M. chelonae, or caused by other atypical mycobacterium, are described in renal transplantation, peritoneal dialysis and hemodialysis. In the case we describe here, the source of contamination was not identified. The outcome was favourable with clarithromycin. This treatment is still continued because of a reappearance of the lesions when treatment was discontinued.

Anti-Bacterial Agents↗
PubMed2005

Surface energy and interparticle forces correlations in model pMDI formulations.

PURPOSE: To compare experimental measurements of particle cohesion and adhesion forces in a model propellant with theoretical measurements of the interfacial free energy of particulate interactions; with the aim of characterizing suspension stability of pressurized metered dose inhalers (pMDIs). METHODS: Interparticulate forces of salbutamol sulfate, budesonide, and formoterol fumarate dihydrate were investigated by in situ atomic force microscopy (AFM) in a model propellant 2H,3H perfluoropentane. The surface thermodynamic properties were determined by contact angle (CA) and inverse gas chromatography (IGC). Experimental data were compared with theoretical work of adhesion/cohesion using a surface component approach (SCA), taking into account both dispersive and polar contributions of the surface free energy. RESULTS: Results indicated that the measured forces of interaction between particles in model propellant could not be accounted for by theoretical treatment of the dispersive surface free energies via CA and IGC. A correlation between theoretical work of adhesion/cohesion and AFM measurements was observed upon the introduction of the polar interfacial interactions within the SCA model. CONCLUSIONS: It is suggested that the polar contributions of the surface free energy measurements of particles may play a crucial role in particle interaction within propellant-based systems. Together with the application of a SCA model, this approach may be capable of predicting suspension stability of pMDI formulations.

Albuterol↗
PubMed2005

Purification, crystallization and preliminary X-ray analysis of Enterococcus faecium aminoglycoside-2''-phosphotransferase-Ib [APH(2'')-Ib].

Bacterial resistance to the aminoglycoside antibiotics is primarily the result of deactivation of the drugs. Three families of enzymes are responsible for this activity, with one such family being the aminoglycoside phosphotransferases (APHs). The gene encoding one of these enzymes, APH(2'')-Ib, has been cloned and the protein (comprising 299 amino-acid residues) expressed in Escherichia coli, purified and crystallized in the presence of 16%(w/v) PEG 3350 and gentamicin. The crystals belong to the monoclinic space group P2(1), with approximate unit-cell parameters a = 79.7, b = 58.8, c = 81.4 A, beta = 98.4 degrees, and preliminary X-ray diffraction analysis is consistent with the presence of two molecules in the asymmetric unit. Synchrotron diffraction data to approximately 2.65 A resolution were collected from a native APH(2'')-Ib crystal at beamline BL9-2 at SSRL (Stanford, CA, USA). Selenium-substituted crystals have also been produced and structure determination is proceeding.

Bacterial Proteins↗
PubMed2005

Invasive filamentous fungal infections in allogeneic hematopoietic stem cell transplant recipients after recovery from neutropenia: clinical, radiologic, and pathologic characteristics.

Invasive filamentous fungal infection (IFFI) is an important cause of mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. We reviewed 22 consecutive cases of IFFI in allogeneic HSCT recipients at Roswell Park Cancer Institute. IFFI was diagnosed after neutrophil recovery in 21 patients (95%). All had received corticosteroids within 1 month prior to IFFI diagnosis. Fourteen (64%) presented with dyspnea, and only 7 (32%) were febrile. Aspergillus species were isolated in 18 (82%) cases. Thirty day mortality after IFFI diagnosis was associated with a higher mean daily dose of corticosteroids (P=0.02) and receiving OKT3 (P=0.01) within 1 month prior to IFFI diagnosis and serum creatinine>2 mg/dl at the time of diagnosis (P=0.004). Histopathologic material from biopsy or autopsy was available in 15 patients (68%). In 8 (53%), the predominant lung histopathology was an acellular coagulative necrosis and hyphal angioinvasion was observed in some of these cases. These findings have generally been observed in neutropenic patients but not in non-neutropenic HSCT recipients. The predominance of coagulative necrosis in our series may reflect the high doses of corticosteroids used to treat graft-versus-host disease (GVHD), which may have disabled leukocyte trafficking and hyphal killing.

Adrenal Cortex Hormones↗
PubMed2005

LNX1 is a perisynaptic Schwann cell specific E3 ubiquitin ligase that interacts with ErbB2.

Non-myelinating perisynaptic Schwann cells wrap motor axon terminals and are required for both functional and structural integrity of the neuromuscular junction. Several lines of evidence indicate that fine-tuning of neuregulin-1/ErbB signaling is critical for maintaining perisynaptic Schwann cells at synapses and that this control may be achieved by the developmental downregulation of the ErbB2 receptor. Here, we identify a direct interaction between ErbB2 and LNX1, an E3 ubiquitin ligase that can target interacting proteins for degradation through ubiquitination. Immunostaining shows that LNX1 is specifically localized in perisynaptic Schwann cells but not in Schwann cells along the motor axon. Developmentally, levels of LNX1 protein are inversely correlated with the responsiveness of perisynaptic Schwann cells to neuregulin-1. Furthermore, the LNX1 staining disappears upon denervation, whereas ErbB2 reappears in Schwann cells after denervation. Taken together, these data suggest that LNX1 may play a role in regulating neuregulin-1/ErbB signaling in perisynaptic Schwann cells.

Animals↗
PubMed2005

Real-time reverse transcriptase PCR for the endogenous koala retrovirus reveals an association between plasma viral load and neoplastic disease in koalas.

Koala retrovirus (KoRV) is a newly described endogenous retrovirus and is unusual in that inserts comprise a full-length replication competent genome. As koalas are known to suffer from an extremely high incidence of leukaemia/lymphoma, the association between this retrovirus and disease in koalas was examined. Using quantitative real-time reverse transcriptase PCR it was demonstrated that KoRV RNA levels in plasma are significantly increased in animals suffering from leukaemia or lymphoma when compared with healthy animals. Increased levels of KoRV were also seen for animals with clinical chlamydiosis. A significant positive association between viral RNA levels and age was also demonstrated. Real-time PCR demonstrated as much as 5 log variation in KoRV proviral DNA levels in genomic DNA extracted from whole blood from different animals. Taken together these data indicate that KoRV is an active endogenous retrovirus and suggests that it may be causally linked to neoplastic disease in koalas.

Animals↗
PubMed2004

The surface roughness of lactose particles can be modulated by wet-smoothing using a high-shear mixer.

The surface morphology of a-lactose monohydrate particles was modified by a new wet-smoothing process performed in a high-shear mixer using solvents. Successive steps of wetting and drying of lactose powders during rolling in the mixer's cylindrical bowl were performed. Smoothed particles were tested for size distribution, flow, and packing. The wet-smoothing process flattened the surface and rounded the edges of lactose particles. In comparison with original lactose, an improvement of powder packing and flow properties was evidenced. When the process was performed in the presence of a ternary agent such as magnesium stearate, the smoothing was improved. The evolution of rugosity during the smoothing process was assessed through a fractal descriptor of SEM picture. Atomic force microscopy and surface area measurements quantified the surface rugosity. A very significant reduction of the rugosity, more remarkable in the presence of magnesium stearate, was measured. This new process of powder wet-smoothing allows the preparation of lactose particles with different degrees of smoothed surface for the control of flow and packing properties and particle-particle interactions.

Lactose↗
PubMed2004

Labeling neurons in vivo for morphological and functional studies.

Increasingly sophisticated strategies for labeling cells in vivo are providing unprecedented opportunities to study neurons in living animals. Transgenic expression of genetically encoded reporters enables us to monitor changes in neuronal activity in response to sensory stimuli, and the labeling of single neurons with fluorescent proteins allows the dynamics of neuronal connectivity to be observed in transgenic animals over periods ranging from minutes to months. Advances in transient labeling techniques such as viral infection and electroporation provide a rapid means by which to analyze neuronal gene function in vivo. These new approaches to labeling, manipulating and imaging neurons in intact organisms are transforming the way in which the nervous system is studied.

Animals↗
PubMed2004

Osteoarticular complications of erysipelas.

BACKGROUND: Rare osteoarticular complications occurring after erysipelas have been reported. We describe 9 patients in whom various osteoarticular complications developed during erysipelas. OBJECTIVE: We sought to analyze osteoarticular complications during erysipelas, paying special attention to clinical, bacteriologic, and radiologic data. METHODS: Data were retrospectively recorded from the files of patients seen in 3 dermatologic centers between 1998 and 2000. They included laboratory tests, bacteriologic cultures, radiologic investigations, and treatment modalities and outcome of both erysipelas and osteoarticular complications. RESULTS: We observed 9 patients (7 men and 2 women; mean age 49.6 years) who first presented with typical erysipelas of the lower limb and then osteoarticular complications developed during the course of their disease, always localized to a joint contiguous to the erysipelas plaque. These complications included: relatively benign complications, ie, bursitis (n = 5) or algodystrophy (n = 1), occurring after erysipelas with favorable course; and more severe complications, ie, osteitis (n = 1), arthritis (n = 1), and septic tendinitis (n = 1), occurring after erysipelas characterized by local cutaneous complications (abscess, necrosis). CONCLUSIONS: Osteoarticular complications of erysipelas can be divided into the 2 groups of nonseptic complications (mainly bursitis), which are characterized by a favorable outcome, and septic complications (osteitis, arthritis, tendinitis), which require specific, often prolonged treatment and, sometimes, operation. Their diagnosis is on the basis of clinical and radiologic findings rather than joint aspirations, which are usually not possible through infected skin tissue.

Adult↗
PubMed2003

Fetal brain activity in response to a visual stimulus.

Previous studies have demonstrated the use of functional magnetic resonance imaging (fMRI) to assess fetal brain activity. To extend these studies, a fetal fMRI experiment using a visual stimulus has been performed at 0.5 T. This used a block fMRI paradigm with a bright, constant-intensity light source being shone at the maternal abdomen for 8 sec followed by 16 sec of darkness. This was repeated typically 40 times on nine subjects all of whom were greater than 36 weeks gestational age. Of these, one could not be analysed due to motion, three did not show significant activation, and five showed significant activation (P < 0.0085). In all cases, activation was localised within the frontal cortex. Exact localisation was difficult but this may correspond to the frontal eye fields and dorsolateral prefontal cortex. In no cases was significant activation present within the occipital region as would have been expected and was observed in 2/8 adult subjects. Hum. Brain Mapping 20:239-245, 2003.

Brain↗
PubMed2003

Association between child sexual abuse and sexual revictimization in adulthood among women sex partners of injection drug users.

Community-recruited women (n = 1490) were interviewed about their early and adult sexual victimization histories to determine whether there was an association between child sexual abuse and adult revictimization by sex partners and strangers/nonsex partners. Adolescent sexual abuse, lifetime sex-trading, drug treatment, and mental health treatment were examined as mediating variables. One-fourth of the women had been revictimized (i.e., experienced child sexual abuse and at least one instance of adult sexual victimization). Child sexual abuse was associated with both rape and other sexual victimization by a sex partner in adulthood, as well as adult rape by a stranger/nonsex partner. Drug and mental health treatments reduced abused women's chances of being raped by a sex partner; drug treatment also decreased the likelihood of other sexual victimization by a sex partner. Sex-trading increased abused women's likelihood of rape by a stranger or nonsex partner. Intervention--including drug treatment--can help women with child sexual abuse histories overcome some of the abuse-related sequelae that make them vulnerable to adult revictimization.

Adolescent↗
PubMed2003

Dengue vaccines: preparing to roll back dengue.

Dengue is an emerging viral pathogen of growing global importance, infecting up to 100 million people annually. Although there have been many efforts over the last six decades to produce a vaccine to combat this infection, few have been able to meet the challenges posed by the unusual interplay between this virus and its human host. However, recent progress in molecular-based vaccine strategies, as well as a renewed commitment by the World Health Organisation to co-ordinate global efforts on vaccine development, finally provides hope that control of this serious disease may be at hand.

Animals↗
PubMed2002

The spectrin repeat: a structural platform for cytoskeletal protein assemblies.

Spectrin repeats are three-helix bundle structures which occur in a large number of diverse proteins, either as single copies or in tandem arrangements of multiple repeats. They can serve structural purposes, by coordination of cytoskeletal interactions with high spatial precision, as well as a 'switchboard' for interactions with multiple proteins with a more regulatory role. We describe the structure of the alpha-actinin spectrin repeats as a prototypical example, their assembly in a defined antiparallel dimer, and the interactions of spectrin repeats with multiple other proteins. The alpha-actinin rod domain shares several features common to other spectrin repeats. (1) The rod domain forms a rigid connection between two actin-binding domains positioned at the two ends of the alpha-actinin dimer. The exact distance and rigidity are important, for example, for organizing the muscle Z-line and maintaining its architecture during muscle contraction. (2) The spectrin repeats of alpha-actinin have evolved to make tight antiparallel homodimer contacts. (3) The spectrin repeats are important interaction sites for multiple structural and signalling proteins. The interactions of spectrin repeats are, however, diverse and defy any simple classification of their preferred interaction sites, which is possible for other domains (e.g. src-homology domains 3 or 2). Nevertheless, the binding properties of the repeats perform important roles in the biology of the proteins where they are found, and lead to the assembly of complex, multiprotein structures involved both in cytoskeletal architecture as well as in forming large signal transduction complexes.

Actinin↗
PubMed2002

A comparison of oral and topical corticosteroids in patients with bullous pemphigoid.

BACKGROUND: Bullous pemphigoid is the most common autoimmune blistering skin disease of the elderly. Because elderly people have low tolerance for standard regimens of oral corticosteroids, we studied whether highly potent topical corticosteroids could decrease mortality while controlling disease. METHODS: A total of 341 patients with bullous pemphigoid were enrolled in a randomized, multicenter trial and stratified according to the severity of their disease (moderate or extensive). Patients were randomly assigned to receive either topical clobetasol propionate cream (40 g per day) or oral prednisone (0.5 mg per kilogram of body weight per day for those with moderate disease and 1 mg per kilogram per day for those with extensive disease). The primary end point was overall survival. RESULTS: Among the 188 patients with extensive bullous pemphigoid, topical corticosteroids were superior to oral prednisone (P=0.02). The one-year survival rate was 76 percent in the topical-corticosteroid group and 58 percent in the oral-prednisone group. Disease was controlled at three weeks in 92 of the 93 patients in the topical-corticosteroid group (99 percent) and 86 of the 95 patients in the oral-prednisone group (91 percent, P=0.02). Severe complications occurred in 27 of the 93 patients in the topical-corticosteroid group (29 percent) and in 51 of the 95 patients in the oral-prednisone group (54 percent, P=0.006). Among the 153 patients with moderate bullous pemphigoid, there were no significant differences between the topical-corticosteroid group and the oral-prednisone group in terms of overall survival, the rate of control at three weeks, or the incidence of severe complications. CONCLUSIONS: Topical corticosteroid therapy is effective for both moderate and severe bullous pemphigoid and is superior to oral corticosteroid therapy for extensive disease.

Administration, Oral↗
PubMed2002

Gab3, a new DOS/Gab family member, facilitates macrophage differentiation.

Using the FDC-P1 cell line expressing the exogenous macrophage colony-stimulating factor (M-CSF) receptor, Fms, we have analyzed the role of a new mammalian DOS/Gab-related signaling protein, called Gab3, in macrophage cell development of the mouse. Gab3 contains an amino-terminal pleckstrin homology domain, multiple potential sites for tyrosine phosphorylation and SH2 domain binding, and two major polyproline motifs potentially interacting with SH3 domains. Among the growing family of Gab proteins, Gab3 exhibits a unique and overlapping pattern of expression in tissues of the mouse compared with Gab1 and Gab2. Gab3 is more restricted to the hematopoietic tissues such as spleen and thymus but is detectable at progressively lower levels within heart, kidney, uterus, and brain. Like Gab2, Gab3 is tyrosine phosphorylated after M-CSF receptor stimulation and associates transiently with the SH2 domain-containing proteins p85 and SHP2. Overexpression of exogenous Gab3 in FD-Fms cells dramatically accelerates macrophage differentiation upon M-CSF stimulation. Unlike Gab2, which shows a constant mRNA expression level after M-CSF stimulation, Gab3 expression is initially absent or low in abundance in FD cells expressing the wild-type Fms, but Gab3 mRNA levels are increased upon M-CSF stimulation. Moreover, M-CSF stimulation of FD-FmsY807F cells (which grow but do not differentiate) fails to increase Gab3 expression. These results suggest that Gab3 is important for macrophage differentiation and that differentiation requires the early phosphorylation of Gab2 followed by induction and subsequent phosphorylation of Gab3.

Adaptor Proteins, Signal Transducing↗
PubMed2002

Value of interphase FISH for the diagnosis of t(11:14)(q13;q32) on skin lesions of mantle cell lymphoma.

The diagnosis of skin lesions of mantle cell lymphoma (MCL) may be difficult at the onset of the disease. We observed 2 patients with papules of the trunk and 1 with diffuse infiltration of the trunk and the face and 2 subcutaneous nodules. Skin samples showed diffuse infiltration of the dermis (n = 1) or perivascular infiltration (n = 2). The infiltrate corresponded to centrocytic cells (n = 2) or pleomorphic blastoid cells (n = 1) with a B-cell phenotype: CD3-, CD5+ (2/3), CD20+, CD23-, and CD43+. In only 1 case was cyclin D1 immunoreactivity detected, and the t(11;l4)(q13;q32) breakpoint was amplified from both lymph node and skin DNA. Competitive reverse transcriptase-polymerase chain reaction was not contributive for skin specimens. In all 3 cases, interphase fluorescence in situ hybridization (FISH) demonstrated t(11;14) fusion signals either on paraffin sections or on fresh frozen touch preparations of skin biopsies. The recognition of skin lesions of MCL from other B-cell infiltrates can be established by interphase FISH.

Aged↗