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Biomedical subjects

David Graham

Publications and source records attributed to David Graham.

At least 19 recordsLinked to original sources
PubMed2007

Risk factors for statin-associated rhabdomyolysis.

PURPOSE: To identify and characterize risk factors for rhabdomyolysis in patients prescribed statin monotherapy or statin plus fibrate therapy. METHODS: A nested case-control study was conducted within a cohort of 252,460 new users of lipid-lowering medications across 11 geographically dispersed U.S. health plans. Twenty-one cases of rhabdomyolysis confirmed by medical record review were compared to 200 individually matched controls without rhabdomyolysis. A conditional logistic regression model was applied to evaluate the effects of age, gender, comorbidities, concurrent medication use, dosage, and duration of statin use on the development of rhabdomyolysis. RESULTS: Statin users 65 years of age and older have four times the risk of hospitalization for rhabdomyolysis than those under age 65 (odds ratio (OR) = 4.36, 95% confidence interval (CI): 1.5,14.1). We also observed a joint effect of high statin dosage and renal disease (p = 0.022). When these two variables were added to the model with age, we obtained an OR of 5.73 for dosage (95%CI: 0.63, 52.6) and 6.26 for renal disease (95%CI: 0.46, 63.38). Although not statistically significant, we did observe a greater than twofold increase in risk for rhabdomyolysis among females (OR = 2.53, 95%CI: 0.91, 7.32). CONCLUSIONS: Findings of this study indicate that older age is a risk factor for rhabdomyolysis among statin users. Although the evidence is not as strong, high statin dosage, renal disease, and female gender may be additional risk factors. Patients at higher risk of developing rhabdomyolysis should be closely monitored for signs and symptoms of the disease.

Adult↗
PubMed2006

SSR180711, a novel selective alpha7 nicotinic receptor partial agonist: (1) binding and functional profile.

In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective alpha7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human alpha7 n-AChRs (K(i) of 22+/-4 and 14+/-1 nM, respectively). Ex vivo (3)[H]alpha-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID(50)=8 mg/kg p.o.). In functional studies performed with human alpha7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC(50)=4.4 and 0.9 microM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small alpha-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic alpha7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 muM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the alpha7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse alpha7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.

Animals↗
PubMed2006

Results of a Phase I trial of concurrent chemotherapy and escalating doses of radiation for unresectable non-small-cell lung cancer.

PURPOSE: This trial was performed to determine the maximum tolerated dose (MTD) of radiation that can be administered with carboplatin and paclitaxel. METHODS AND MATERIALS: This trial included 15 patients with unresectable non-small-cell lung cancer. Paclitaxel (50 mg/m2) and carboplatin (area under the curve=2) were given weekly during radiation therapy (RT). The RT included 2 Gy daily to an initial dose of 70 Gy, and the dose was increased in 4 Gy increments until determining the MTD. The MTD was defined as the highest safely tolerated dose where at most 1 patient of 6 experienced dose-limiting toxicity (DLT) with the next higher dose having at least 2 of 6 patients experiencing DLT. Three-dimensional treatment planning techniques were used without prophylactic nodal RT. RESULTS: Two patients were not evaluable because they did not receive therapy according to the protocol. No DLTs occurred in the 3 patients who received 70 Gy, 1 DLT occurred in the 6 patients who received 74 Gy, and 2 DLTs occurred in the 4 patients who received 78 Gy. The DLTs included Grade 3 pneumonitis (n=2) and Grade 4 pneumonitis (n=1). There have been 3 deaths during follow-up ranging from 14 to 38 months (median, 28 months). CONCLUSIONS: The MTD of the RT was 74 Gy with weekly carboplatin and paclitaxel. The Phase II portion of this trial is currently under way. The goal is to improve local control and survival with higher doses of RT delivered with this combined modality approach.

Aged↗
PubMed2006

Can sutures get wet? Prospective randomised controlled trial of wound management in general practice.

OBJECTIVE: To compare standard management of keeping wounds dry and covered with allowing wounds to be uncovered and wet in the first 48 hours after minor skin excision. DESIGN: Prospective, randomised controlled, multicentre trial testing for equivalence of infection rates. SETTING: Primary care in regional centre, Queensland, Australia. PARTICIPANTS: 857 patients randomised to either keep their wound dry and covered (n = 442) or remove the dressing and wet the wound (n = 415). RESULTS: The incidence of infection in the intervention group (8.4%) was not inferior to the incidence in the control group (8.9%) (P < 0.05). The one sided 95% confidence interval for the difference of infection rates was infinity to 0.028. CONCLUSION: These results indicate that wounds can be uncovered and allowed to get wet in the first 48 hours after minor skin excision without increasing the incidence of infection.

Adult↗
PubMed2006

Impaired fibrinolysis and traumatic brain injury in mice.

Traumatic brain injury (TBI) has been associated with intravascular coagulation, which may be a result of thromboplastin released following brain injury. Clots thus formed are lysed by plasmin, which is activated by tissue-type and urokinase-type plasminogen activators (uPA). To evaluate the association between traumatic intravascular coagulation and post-traumatic outcome, uPA knockout (uPA-/-) transgenic mice (n=12) or wild-type littermates (WT; n=12) were anesthetized and subjected to controlled cortical impact (CCI) brain injury. A second group of uPA-/- (n=12) and WT mice (n=12) were subjected to sham injury. Motor function was assessed over 2 weeks using the composite neuroscore test and cognition (learning) was assessed with the Morris Water Maze (MWM) at 2 weeks post-injury, whereupon the animals were sacrificed for cortical lesion volume analysis. Motor function was significantly worse in the brain-injured uPA-/- mice when compared to brain-injured WT mice at 48 h (p<0.05) and one week post-injury (p<0.05). These differences resolved by 2 weeks post-injury. There was no significant difference in post-injury cognitive function between uPA-/- mice and WT mice. However, at 2 weeks post-injury, the brain-injured uPA-/- had a significantly larger volume of cortical tissue loss than their WT counterparts (p<0.05). These results demonstrate that the absence of uPA in mice aggravates acute motor deficit and exacerbates cortical tissue loss following CCI brain injury, and suggests a neuroprotective role of the fibrinolytic process following TBI.

Animals↗
PubMed2005

Proinflammatory effects of bacterial recombinant human C-reactive protein are caused by contamination with bacterial products, not by C-reactive protein itself.

Intravenous administration to human volunteers of a commercial preparation of recombinant human C-reactive protein (CRP) produced in Escherichia coli was recently reported in this journal to induce an acute phase response of serum amyloid A protein (SAA) and of CRP itself, and to activate the coagulation system. The authors concluded that CRP is probably a mediator of atherothrombotic disease. Here we confirm that this recombinant CRP preparation was proinflammatory both for mouse macrophages in vitro and for mice in vivo, but show that pure natural human CRP had no such activity. Furthermore mice transgenic for human CRP, and expressing it throughout their lives, maintained normal concentrations of their most sensitive endogenous acute phase reactants, SAA and serum amyloid P component (SAP). The patterns of in vitro cytokine induction and of in vivo acute phase stimulation by the recombinant CRP preparation were consistent with contamination by bacterial products, and there was 46.6 EU of apparent endotoxin activity per mg of CRP in the bacterial product, compared with 0.9 EU per mg of our isolated natural human CRP preparation. The absence of any proinflammatory activity in natural CRP for macrophages or healthy mice strongly suggests that the in vivo effects of the recombinant preparation observed in humans were attributable to proinflammatory bacterial products and not human CRP.

Acute-Phase Reaction↗
PubMed2005

PHARMAC and Ventolin in New Zealand.

Recently, PHARMAC undertook an unfortunate experiment on asthma sufferers when it fundamentally changed its funding support for reliever medications. Ventolin metered dose inhaler (MDI), the backbone of asthma relief for over 30 years, was dropped in favour of Salamol, a post-patent salbutamol in a device which, within the first few weeks of use, has been found to be ineffective by many patients, and thus potentially dangerous. PHARMAC has agreed to reconsider its decision, but how was this decision reached in the first place?

Adult↗
PubMed2005

Impact of mailed warning to prescribers on the co-prescription of tramadol and antidepressants.

PURPOSE: An evaluation was made of the effectiveness in changing prescribing behavior of 'Dear Health Professional (DHP)' letters mailed by the manufacturer to physicians and other health professionals advising them of safety information on co-prescribing of tramadol and antidepressants. METHODS: A retrospective cohort analysis of prescription claims of all plan members from 12 UnitedHealth Group-affiliated health plans who received a first prescription for tramadol between 1 April 1995 and 31 December 1996. The prevalence of co-prescribing of antidepressants and tramadol relative to the date of the 'DHP' communication was determined. RESULTS: 9218 plan members received an initial prescription for tramadol within the observation period. Prior to the date of the 'DHP' communication 1061/4774 (22.2%) members received a prescription for an antidepressant within 30 days of their first prescription for tramadol. Following the date of the communication 844/4444 (19.0%) of members received an antidepressant within 30 days of their first prescription for tramadol. An overall decreasing linear trend in antidepressant co-prescribing was evident over the observation period, but there was no statistically significant acceleration in the decrease following this communication. CONCLUSIONS: The mailed 'DHP' advisory letter did not affect the rate of co-prescribing of tramadol with antidepressants.

Adult↗
PubMed2005

Vibrio parahaemolyticus disruption of epithelial cell tight junctions occurs independently of toxin production.

Vibrio parahaemolyticus is a leading cause of seafood-borne gastroenteritis worldwide. Virulence is commonly associated with the production of two toxins, thermostable direct hemolysin (TDH) and TDH-related hemolysin (TRH). Although the majority of clinical isolates produce TDH and/or TRH, clinical samples lacking toxin genes have been identified. In the present study, we investigated the effects of V. parahaemolyticus on transepithelial resistance (TER) and paracellular permeability in Caco-2 cultured epithelial cells. We found that V. parahaemolyticus profoundly disrupts epithelial barrier function in Caco-2 cells and that this disruption occurs independently of toxin production. Clinical isolates with different toxin genotypes all led to a significant decrease in TER, which was accompanied by an increased flux of fluorescent dextran across the Caco-2 monolayer, and profound disruption of actin and the tight junction-associated proteins zonula occludin protein 1 and occludin. Purified TDH, even at concentrations eightfold higher than those produced by the bacteria, had no effect on either TER or paracellular permeability. We used lactate dehydrogenase release as a measure of cytotoxicity and found that this parameter did not correlate with the ability to disrupt tight junctions. As the effect on barrier function occurs independently of toxin production, we used PCR to determine the toxin genotypes of V. parahaemolyticus isolates obtained from both clinical and environmental sources, and we found that 5.6% of the clinical isolates were toxin negative. These data strongly indicate that the effect on tight junctions is not due to TDH and suggest that there are other virulence factors.

Animals↗
PubMed2004

Neuropathological examination in forensic context.

Different diseases of and trauma to the central nervous system (CNS), as well as their consequences are common causes of death and therefore it is important to examine the CNS appropriately in forensic autopsy, bearing in mind that the site of the disease is often as crucial as its nature. The CNS is a complex organ and its examination requires special methods and knowledge and often consultation with a neuropathologist. The prerequisite for the proper examination is correct handling and processing of the CNS. Because of its soft consistency fixation of the CNS in toto before detailed macroscopic analysis is recommended but guidance for an expedited limited examination is also given. The key features to which attention should be paid during the removal and later macroscopic examination of the CNS are described. Processing CNS for microscopy also requires special techniques and in addition to the routine stains both special histological and selected immunohistochemical stainings are often needed to reach the correct diagnosis.

Antibodies↗
PubMed2004

In vitro papillomavirus capsid assembly analyzed by light scattering.

Pentamers of the L1 major capsid protein of human papillomavirus (HPV type 11) were purified after expression in E. coli and analyzed for the kinetics of in vitro capsid self-assembly using multi-angle light scattering (MALS). Pentamers self-assembled into capsid-like structures at a rate that was a function of protein concentration. The kinetics of capsid formation were sigmoidal with a concentration-dependent lag phase, followed by a rapid increase in polymerization. Nucleation size and the rate order of subsequent subunit addition were calculated from the concentration dependence of the extent of capsid formation and the rate of the fast phase, respectively. Assembly was second order with a nucleation size of two pentamers. Thus, we suggest that dimers of pentamers are the nucleus for L1 assembly into capsid-like structures, with rapid sequential addition of single pentamers to the growing shell. Although studied in vitro without accessory factors that may be present in vivo, these data are in contrast with the "five-around-one" assembly nucleus previously proposed for polyomaviruses.

Capsid↗
PubMed2004

Anti-HHV-8/KSHV antibodies in infected individuals inhibit infection in vitro.

OBJECTIVE: To detect human herpesvirus (HHV)-8/Kaposi's sarcoma-associated herpesvirus (KSHV) neutralizing antibodies (nAb). DESIGN: Antibodies capable of inhibiting HHV-8 infection were measured by infecting transformed dermal microvascular endothelial cells (tDMVEC) with HHV-8 that had been pre-incubated with serum from HHV-8-seropositive or -seronegative subjects. The level of infection was quantified 48 h later. METHODS: HHV-8 was prepared from JSC-1 primary effusion lymphoma cells; the titre of enveloped virions was determined by electron microscopy. Virus was incubated with serum samples for 60 min before inoculating tDMVEC. The level of infection was quantified by indirect immunofluorescence assay, staining for HHV-8 latency-associated nuclear antigen (LANA)-1. Inhibition of infection was determined by comparing the level of infection obtained with HHV-8-seropositive subject serum with the level obtained by incubation with seronegative serum. RESULTS: Up to 61% of cells were infected with HHV-8 in the absence of human serum; this level was not affected by pre-incubating the virus with HHV-8-seronegative serum. At dilutions of 1:10 and 1:50, HHV-8-seropositive sera significantly inhibited infection compared to seronegative controls (P = 0.036 for both serum dilutions, Mann-Whitney). The endpoint of inhibition was 1:100, when the serum of one of five subjects inhibited virus infection. At 1:500 dilution, there was no difference in the level of infection after virus incubation with seropositive or seronegative sera (P = 0.578). Depletion of antibody from serum with protein A reversed the inhibitory effect, confirming it was antibody-mediated. CONCLUSIONS: This study is the first to identify HHV-8 antibodies in infected subjects that reduce in vitro infectivity of the virus.

Adult↗
PubMed2004

Comparison of aspects of preregistration house officer training from traditional and new medical curricula.

As medical graduates from the new (problem-based learning) curriculum at University of Liverpool undertook their first post in the postgraduate clinical setting, this study investigated whether their views of preregistration training in the Mersey Deanery differed from the last cohort of preregistration house officers who had graduated from the traditional lecture-based medical curriculum at University of Liverpool.

Curriculum↗
PubMed2004

Reliability and validity of a manual dexterity test to predict preclinical grades.

The University of California, San Francisco School of Dentistry wanted to determine if a predental school manual dexterity test predicts: 1) subsequent grades in preclinical restorative courses, and 2) faculty perceptions of satisfactory performance in these skills that would indicate the student is ready to advance to the clinic. The study population was comprised of all 244 applicants admitted to UCSF School of Dentistry's D.D.S. program from Classes of 2000 to 2002 and who matriculated into the program. The manual dexterity test (MDT) consisted of a two-hour block-carving test. Three preclinical faculty, three clinical faculty, and two basic science faculty graded the blocks. Even after instruction and calibration, faculty varied greatly in their grading (intra-rater reliability kappa statistics ranging from 0.34 to 1.00). Two of three preclinical raters gave No Passes for the MDT in 9.8 percent of the incoming, first-year dental students. Of these twenty-three students, only four (17 percent) were in the lower 10 percent of their classes according to their five preclinical restorative laboratory courses after two years, and four (33 percent) were among the twelve students the three preclinical laboratory directors identified as laboratory cautions. The MDT did not significantly (p=0.342) predict students in the bottom 10 percent after five restorative preclinical laboratory courses, above and beyond current admissions criteria. Among current admissions criteria, PAT score was the only item at least moderately correlated with preclinical average percentile class rank (Spearman correlation = 0.34). In conclusion, the MDT did not appear to add information to the current admissions criteria.

Aptitude Tests↗
PubMed2003

The treatment of multiple myeloma with docetaxel (an ECOG study).

BACKGROUND: Docetaxel has activity against multiple malignancies. In a previous ECOG study of untreated patients with multiple myeloma, paclitaxel was found to have mild activity, but had excessive toxicity. Docetaxel was evaluated in patients with relapsing or refractory multiple myeloma. METHOD: Well-documented patients with relapsing or refractory multiple myeloma, who had received no more than two prior combination chemotherapy regimens, were treated with docetaxel 75 mgm(-2) intravenously over 1h every 3 weeks. Patients were evaluated after two and four cycles of treatment. Standard ECOG criteria were used to evaluate for response and toxicity. RESULTS: The study accrued 31 patients with 28 eligible for response and 30 for toxicity analysis. No objective responses (partial or complete) were found. One patient died due to pneumonia. The majority of patients (80%) developed grade 3-4 granulocytopenia and 23% experienced grade 3-4 thrombocytopenia. The median number of cycles was three. The median survival was 9.9 months. CONCLUSION: Docetaxel was inactive in patients with relapsing or refractory multiple myeloma. In addition, at 75 mgm(-2) every 3 weeks, there was extensive hematological toxicity. It is unlikely that a change in dose or a different schedule would significantly improve response, limit toxicity, and improve survival in patients with multiple myeloma.

Adult↗
PubMed2003

Unsuspected meningoencephalitis in a case of assault by blunt force trauma.

Reported is a case of an assault causing extensive blunt force injuries in which the clinical, radiologic, and postmortem findings were all consistent with death resulting from brain damage arising from the assault. The assailant was charged with murder. Subsequent full neuropathologic (including histologic) examination revealed the unsuspected finding of a widespread meningoencephalitis but no evidence of significant traumatic brain damage. The contributions of the infective process and of the trauma to death were felt to be unclear and a guilty plea to attempted murder was accepted. This case highlights the importance of a full neuropathologic examination, including histology, in cases of trauma to the head, even when the cause of death may initially appear obvious.

Adult↗
PubMed2003

Factors influencing teaching and learning in the preregistration year.

Preregistration training is a transitional period in the career of new medical graduates as they complete their final year of basic medical education in practice settings. This study gathered the views of both preregistration house officers and their educational supervisors on preregistration training in the Mersey Deanery between August 2000 and August 2001.

Attitude of Health Personnel↗