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1.  Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence 
British Journal of Cancer  2011;105(6):796-806.
We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer.
We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo.
Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours.
Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.
PMCID: PMC3171020  PMID: 21847123
ErbB-2; trastuzumab; Notch-1; GSI; recurrence; resistance
2.  Recruitment and retention monitoring: facilitating the mission of the National Institute of Neurological Disorders and Stroke (NINDS) 
It is commonly accepted that inefficient recruitment and inadequate retention continue to threaten the completion of clinical trials intended to reduce the public health burden of neurological disease. This article will discuss the scientific, economic, and ethical implications of failure to recruit and retain adequate samples in clinical trials, including the consequences of failing to recruit adequately diverse samples. We will also discuss the more common challenges and barriers to efficient and effective recruitment and retention, and the impact these have on successful clinical trial planning. We will explain the newly established efforts within National Institute of Neurological Disorders and Stroke (NINDS) to monitor recruitment and retention with well-defined metrics and implementation of grant awards that include feasibility milestones for continued funding. Finally, we will describe our efforts to address some of the common challenges to recruitment and retention through assistance to investigators and coordinators with evidence-based support, tools, and resources for planning and strategizing recruitment and retention as well as a trans-NIH effort to improve awareness of clinical research in the general public.
PMCID: PMC3517027  PMID: 23230460
4.  Cost effectiveness of interferon α or peginterferon α with ribavirin for histologically mild chronic hepatitis C 
Gut  2006;55(9):1332-1338.
For patients with mild chronic hepatitis C the cost effectiveness of antiviral therapy is unknown.
To assess whether antiviral therapy (either interferon α or peginterferon α combined with ribavirin) is cost effective at a mild stage compared with waiting and only treating those cases who progress to moderate disease.
Cases with mild chronic hepatitis C.
A cost effectiveness model which estimates long term costs and outcomes for patients with mild chronic hepatitis C. The model uses effectiveness and cost data from the UK mild hepatitis C randomised controlled trial, combined with estimates of disease progression and cost from observational studies.
Antiviral treatment at a mild rather than a moderate stage improved outcomes measured by quality adjusted life years (QALYS) gained. The mean cost per QALY gained from antiviral treatment with interferon α‐2b and ribavirin, compared with no treatment at a mild stage, was £4535 ($7108) for patients with genotype non‐1 and £25 188 ($39 480) for patients with genotype 1. Providing peginterferon α‐2b and ribavirin at a mild rather than a moderate stage was also associated with a gain in QALYS; the costs per QALY gained were £7821 ($12 259) for patients with genotype non‐1 and £28 409 ($44 528) for patients with genotype 1.
For patients with chronic hepatitis C, it is generally more cost effective to provide antiviral treatment at a mild rather than a moderate disease stage. For older patients (aged 65 years or over) with genotype 1, antiviral treatment at a mild stage is not cost effective.
PMCID: PMC1860032  PMID: 15994216
cost effectiveness model; cost analysis; antiviral therapy
5.  Chlamydia trachomatis PCR positivity and inflammatory changes on cervical cytology 
Sexually Transmitted Infections  2005;81(4):360-361.
PMCID: PMC1745011  PMID: 16061550
6.  Regulation of vascular endothelial growth factor bioactivity in patients with acute lung injury 
Thorax  2005;60(2):153-158.
Methods: Forty one patients with ARDS, 12 at risk of developing ARDS, and 16 normal controls were studied. Bioactive VEGF, total VEGF, and sVEGFR-1 were measured by ELISA in plasma and bronchoalveolar lavage (BAL) fluid. Reverse transcriptase polymerase chain reaction for sVEGFR-1 was performed on BAL cells.
Results: sVEGFR-1 was detectable in the BAL fluid of 48% (20/41) of patients with early ARDS (1.4–54.8 ng/ml epithelial lining fluid (ELF)) compared with 8% (1/12) at risk patients (p = 0.017) and none of the normal controls (p = 0.002). By day 4 sVEGFR-1 was detectable in only 2/18 ARDS patients (p = 0.008). Patients with detectable sVEGFR-1 had lower ELF median (IQR) levels of bioactive VEGF than those without detectable sVEGFR-1 (1415.2 (474.9–3192) pg/ml v 4761 (1349–7596.6) pg/ml, median difference 3346 pg/ml (95% CI 305.1 to 14711.9), p = 0.016), but there was no difference in total VEGF levels. BAL cells expressed mRNA for sVEGFR-1 and produced sVEGFR-1 protein which increased following incubation with tumour necrosis factor α.
Conclusion: This study shows for the first time the presence of sVEGFR-1 in the BAL fluid of patients with ARDS. This may explain the presence of reduced bioactive VEGF in patients early in the course of ARDS.
PMCID: PMC1747283  PMID: 15681505
7.  Fatigue is not a necessary stimulus for strength gains during resistance training 
Background: High resistance training enhances muscular strength, and recent work has suggested an important role for metabolite accumulation in this process.
Objective: To investigate the role of fatigue and metabolite accumulation in strength gains by comparing highly fatiguing and non-fatiguing isotonic training protocols.
Methods: Twenty three healthy adults (18–29 years of age; eight women) were assigned to either a high fatigue protocol (HF: four sets of 10 repetitions with 30 seconds rest between sets) to maximise metabolic stress or a low fatigue protocol (LF: 40 repetitions with 30 seconds between each repetition) to minimise changes. Subjects lifted on average 73% of their 1 repetition maximum through the full range of knee extension with both legs, three times a week. Quadriceps isometric strength of each leg was measured at a knee joint angle of 1.57 rad (90°), and a Cybex 340 isokinetic dynamometer was used to measure the angle-torque and torque-velocity relations of the non-dominant leg.
Results: At the mid-point of the training, the HF group had 50% greater gains in isometric strength, although this was not significant (4.5 weeks: HF, 13.3 (4.4)%; LF, 8.9 (3.6)%). This rate of increase was not sustained by the HF group, and after nine weeks of training all the strength measurements showed similar improvements for both groups (isometric strength: HF, 18.2 (3.9)%; LF, 14.5 (4.0)%). The strength gains were limited to the longer muscle lengths despite training over the full range of movement.
Conclusions: Fatigue and metabolite accumulation do not appear to be critical stimuli for strength gain, and resistance training can be effective without the severe discomfort and acute physical effort associated with fatiguing contractions.
PMCID: PMC1724546  PMID: 12351337
8.  The Effects of Carbamazepine and Lorazepam on Single versus Multiple Previous Alcohol Withdrawals in an Outpatient Randomized Trial 
Benzodiazepines are the mainstay of treatment for mild-to-moderate alcohol withdrawal in outpatient settings, but they can interact with alcohol, cause motor incoordination, or be abused. This study compared the therapeutic responses of the benzodiazepine lorazepam and the anticonvulsant carbamazepine for the outpatient treatment of acute alcohol withdrawal in terms of patients' previous detoxification histories, and compared the effects of these 2 medications on drinking behaviors in the immediate postdetoxification period.
This was a randomized double-blind trial comparing patient responses to carbamazepine and lorazepam across 2 levels of detoxification histories (0–1 or ≥2 previous medicated detoxifications).
A university medical center substance abuse clinic in Charleston, SC.
One hundred thirty-six patients in moderate alcohol withdrawal were randomized. Major exclusions were significant hepatic or hematologic abnormalities and use of medications that could alter withdrawal symptoms.
Patients received 600–800 mg of carbamazepine or 6–8 mg of lorazepam in divided doses on day 1 tapering to 200 mg of carbamazepine or 2 mg of lorazepam.
The Clinical Institute Withdrawal Assessment for Alcohol-Revised was used to assess alcohol withdrawal symptoms on days 1 through 5 and postmedication at days 7 and 12. Daily drinking was measured by patient report using a daily drinking log and a breath alcohol level with each visit. Side effects were recorded daily.
Carbamazepine and lorazepam were equally effective at decreasing the symptoms of alcohol withdrawal. In the post-treatment period, 89 patients drank on at least 1 day; on average, carbamazepine patients drank less than 1 drink per drinking day and lorazepam patients drank almost 3 drinks per drinking day (P = .003). Among those with multiple past detoxifications, the carbamazepine group drank less than 1 drink per day on average and the lorazepam group drank about 5 drinks per day on average (P = .033). Lorazepam-treated patients had a significant rebound of alcohol withdrawal symptoms post-treatment (P = .007) and the risk of having a first drink was 3 times greater (P = .04) than for carbamazepine-treated patients. Twenty percent of lorazepam-treated patients had dizziness, motor incoordination, or ataxia and did not recognize their impairment. Twenty percent of carbamazepine-treated patients reported pruritus but no rash.
Carbamazepine and lorazepam were both effective in decreasing the symptoms of alcohol withdrawal in relatively healthy, middle-aged outpatients. Carbamazepine, however, was superior to lorazepam in preventing rebound withdrawal symptoms and reducing post-treatment drinking, especially for those with a history of multiple treated withdrawals.
PMCID: PMC1495040  PMID: 12047731
alcohol; withdrawal; detox; carbamazepine; lorazepam; relapse; randomized trial
9.  Effect of exposure to diesel exhaust particles on the susceptibility of the lung to infection. 
Environmental Health Perspectives  2001;109(Suppl 4):609-612.
There are at least three mechanisms by which alveolar macrophages play a critical role in protecting the lung from bacterial or viral infections: production of inflammatory cytokines that recruit and activate lung phagocytes, production of antimicrobial reactive oxidant species, and production of interferon (an antiviral agent). In this article we summarize data concerning the effect of exposure to diesel exhaust particles on these alveolar macrophage functions and the role of adsorbed organic chemicals compared to the carbonaceous core in the toxicity of diesel particles. In vitro exposure of rat alveolar macrophages to diesel exhaust particles decreased the ability of lipopolysaccharide (LPS), a bacterial product] to stimulate the production of inflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha). Methanol extract exhibited this potential but methanol-washed diesel particles did not. Exposure of rats to diesel exhaust particles by intratracheal instillation also decreased LPS-induced TNF-alpha and IL-1 production from alveolar macrophages. In contrast, carbon black did not exhibit this inhibitory effect. Exposure of rats to diesel exhaust particles by inhalation decreased the ability of alveolar macrophages to produce antimicrobial reactive oxidant species in response to zymosan (a fungal component). In contrast, exposure to coal dust increased zymosan-stimulated oxidant production. In vivo exposure to diesel exhaust particles but not to carbon black decreased the ability of the lungs to clear bacteria. Inhalation exposure of mice to diesel exhaust particles but not to coal dust depressed the ability of the lung to produce the antiviral agent interferon and increased viral multiplication in the lung. These results support the hypothesis that exposure to diesel exhaust particles increases the susceptibility of the lung to infection by depressing the antimicrobial potential of alveolar macrophages. This inhibitory effect appears to be due to adsorbed organic chemicals rather than the carbonaceous core of the diesel particles.
PMCID: PMC1240590  PMID: 11544172
10.  Analysis and treatment of finger sucking. 
We analyzed and treated the finger sucking of 2 developmentally typical children aged 7 and 10 years. The functional analysis revealed that the finger sucking of both children was exhibited primarily during alone conditions, suggesting that the behavior was maintained by automatic reinforcement. An extended analysis provided support for this hypothesis and demonstrated that attenuation of stimulation produced by the finger sucking resulted in behavior reductions for both children. Treatment consisted of having each child wear a glove on the relevant hand during periods when he or she was alone. Use of the glove produced zero levels of finger sucking for 1 participant, whereas only moderate reductions were obtained for the other. Subsequently, an awareness enhancement device was used that produced an immediate reduction in finger sucking.
PMCID: PMC1284221  PMID: 10738951
11.  Chronic pain--what a pain. 
Western Journal of Medicine  1999;171(1):64.
PMCID: PMC1305749  PMID: 10483354
12.  Surviving social assistance: 12-month prevalence of depression in sole-support parents receiving social assistance 
BACKGROUND: Although it is generally recognized that poverty and depression can coexist among single parents receiving social assistance, there is insufficient research on this topic. The goals of this study therefore were to investigate the prevalence, correlates and health care expenditures associated with depression among sole-support parents receiving social assistance. METHODS: Sole-support parents who had applied for social assistance in 2 regions of southwestern Ontario were included in the study. Depression was diagnosed with the 1994 University of Michigan Composite International Diagnostic Interview short forms. RESULTS: The 12-month prevalence rate of depressive disorder among the parents interviewed was 45.4% (345/760). A total of 247 (32.5%) had major depressive disorder alone, 19 (2.5%) had dysthymia, and 79 (10.4%) had both major depressive disorder and dysthymia ("double depression"). Those with major depressive disorder, particularly double depression, had significantly higher rates of coexisting psychiatric disorder than those without depressive disorders. Parents with depression reported higher rates of developmental delay and behaviour problems in their children than parents without depression. Expenditures for health care services were higher for parents with depression and for their children than for parents without depressive disorder and their children. INTERPRETATION: Single parents receiving social assistance have high rates of depression. Such parents with depression also have higher rates of other psychiatric disorders and higher expenditures for health care services, and their children have higher rates of developmental delay and behaviour problems.
PMCID: PMC1229183  PMID: 9559013
13.  Open randomized study of cefepime versus piperacillin-gentamicin for treatment of febrile neutropenic cancer patients. 
An open-label randomized trial comparing the efficacy and safety of cefepime versus piperacillin plus gentamicin (P+G) given intravenously for the treatment of febrile episodes in neutropenic patients with underlying malignancy was conducted at two oncology centers. Over a 30-month period 111 patients were enrolled and 99 patients were found to be suitable for evaluation. At the 72-h time of evaluation, cefepime monotherapy and P+G combination therapy produced comparable clinical response rates (78% for both). P+G and cefepime produced comparable response rates in microbiologically documented (78 versus 71%), clinically documented (100 versus 100%), and possible (75 versus 79%) infections. The P+G and cefepime treatments achieved comparable microbiological eradication of gram-negative (100 versus 71%) (P = 0.09) and gram-positive (44 versus 70%) (P = 0.37) organisms. There were no statistically significant differences in the rates of superinfection between the groups; however, more superinfections of fungal origin were noted in the P+G group. Cefepime was demonstrated to be an effective and safe treatment for febrile episodes in neutropenic patients with malignancies, and its lack of nephrotoxicity compared to P+G was noteworthy. Cefepime appears to be a candidate for monotherapy in febrile neutropenic cancer patients.
PMCID: PMC163989  PMID: 9257745
14.  Epidemiology of group C rotavirus infection in Western New York women of childbearing age. 
Journal of Clinical Microbiology  1997;35(2):486-488.
Umbilical cord serum samples (380), an average of 10 per month for 3 years (1990 to 1992), were tested by indirect immunofluorescence assay for group C rotavirus immunoglobulin G. Thirty percent were positive, suggesting that approximately one-third of women of childbearing age in western New York have experienced group C rotavirus infection.
PMCID: PMC229607  PMID: 9003623
16.  Lipopeliosis: fat induced sinusoidal dilatation in transplanted liver mimicking peliosis hepatis. 
Journal of Clinical Pathology  1992;45(12):1109-1110.
A distinct peliosis-like lesion arose in the liver allograft of a 51 year old man. This lesion was caused by necrotic, fat-laden hepatocytes that released fat globules into the sinusoids. These then became strikingly distended with cysts, thus mimicking peliosis hepatitis. It is suggested that this lesion be called lipopeliosis.
PMCID: PMC495007  PMID: 1479038
17.  Constitutive and UV-mediated activation of RecA protein: combined effects of recA441 and recF143 mutations and of addition of nucleosides and adenine. 
Journal of Bacteriology  1991;173(18):5869-5875.
The recF143 mutant of Escherichia coli is deficient in certain functions that also require the RecA protein: cell survival after DNA damage, some pathways of genetic recombination, and induction of SOS genes and temperate bacteriophage through cleavage of the LexA and phage repressors. To characterize the role of RecF in SOS induction and RecA activation, we determined the effects of the recF143 mutation on the rate of RecA-promoted cleavage of LexA, the repressor of the SOS genes. We show that RecA activation following UV irradiation is delayed by recF143 and that RecF is specifically involved in the SOS induction pathway that requires DNA replication. At 32 degrees C, the recA441 mutation partially suppresses the defect of recF mutants in inducing the SOS system in response to UV irradiation (A. Thomas and R. G. Lloyd, J. Gen. Microbiol. 129:681-686, 1983; M. R. Volkert, L. J. Margossian, and A. J. Clark, J. Bacteriol. 160:702-705, 1984); we find that this suppression occurs at the earliest detectable phase of LexA cleavage and does not require protein synthesis. Our results support the idea that following UV irradiation, RecF enhances the activation of RecA into a form that promotes LexA cleavage (A. Thomas and R. G. Lloyd, J. Gen. Microbiol. 129:681-686, 1983; M. V. V. S. Madiraju, A. Templin, and A. J. Clark, Proc. Natl. Acad. Sci. USA 85:6592-6596, 1988). In contrast to the constitutive activation phenotype of the recA441 mutant, the recA441-mediated suppression of recF is not affected by adenine and nucleosides. We also find that wild-type RecA protein is somewhat activated by adenine in the absence of DNA damage.
PMCID: PMC208321  PMID: 1715863
18.  Junior doctors' years: training, not education. 
BMJ : British Medical Journal  1991;302(6770):225-228.
PMCID: PMC1669052  PMID: 1998767
19.  A medical malaise in hospital. 
BMJ : British Medical Journal  1991;302(6769):163-166.
PMCID: PMC1668840  PMID: 1995138
20.  The NHS observed. Navigating the seas of change. 
BMJ : British Medical Journal  1991;302(6767):34-37.
PMCID: PMC1668769  PMID: 1991186
22.  High street eye tests. 
BMJ : British Medical Journal  1990;300(6731):1076.
PMCID: PMC1662766  PMID: 2344527
23.  Simian virus 40 origin auxiliary sequences weakly facilitate T-antigen binding but strongly facilitate DNA unwinding. 
Molecular and Cellular Biology  1990;10(4):1719-1728.
The complete simian virus 40 (SV40) origin of DNA replication (ori) consists of a required core sequence flanked by two auxiliary sequences that together increase the rate of DNA replication in monkey cells about 25-fold. Using an extract of SV40-infected monkey cells that reproduced the effects of ori-auxiliary sequences on DNA replication, we examined the ability of ori-auxiliary sequences to facilitate binding of replication factors and to promote DNA unwinding. Although the replicationally active form of T antigen in these extracts had a strong affinity for ori-core, it had only a weak but specific affinity for ori-auxiliary sequences. Deletion of ori-auxiliary sequences reduced the affinity of ori-core for active T antigen by only 1.6-fold, consistent with the fact that saturating concentrations of T antigen in the cell extract did not reduce the stimulatory role of ori-auxiliary sequences in replication. In contrast, deletion of ori-auxiliary sequences reduced the efficiency of ori-specific, T-antigen-dependent DNA unwinding in cell extracts at least 15-fold. With only purified T antigen in the presence of topoisomerase I to unwind purified DNA, ori-auxiliary sequences strongly facilitated T-antigen-dependent DNA conformational changes consistent with melting the first 50 base pairs. Under these conditions, ori-auxiliary sequences had little effect on the binding of T antigen to DNA. Therefore, a primary role of ori-auxiliary sequences in DNA replication is to facilitate T-antigen-dependent DNA unwinding after the T-antigen preinitiation complex is bound to ori-core.
PMCID: PMC362278  PMID: 2157141
24.  Severe delayed-onset hypersensitivity reactions to amoxicillin in children. 
Amoxicillin, a semisynthetic aminopenicillin, has achieved widespread use in recent years for the treatment of respiratory tract and otic infections. Serious reactions have been relatively infrequent. From July 1986 to June 1987, 11 children aged 6 months to 10 years presented with delayed-onset hypersensitivity reactions. In 10 the symptoms were consistent with a serum-sickness-like illness, including urticaria, angioedema, arthritis and arthralgia. Radioallergosorbent testing for IgE antibodies to penicillin yielded negative results, and lymphocyte transformation testing gave a positive result in only one patient. Because of the negative immunologic test results and the occurrence of reactions only in children, who had received an amoxicillin solution, the reactions may have been caused by the excipient.
PMCID: PMC1268893  PMID: 2467730
25.  Measurement of total circulating blood volume following subarachnoid haemorrhage: methodological aspects. 
The total circulating blood volume (TCBV) and total body/venous haematocrit ratio (Htb/Hv) was determined by simultaneous measurement of the red cell volume (RCV) and the plasma volume (PV) in 10 subarachnoid haemorrhage (SAH) patients, 10 supine bedresting control patients and 20 ambulant out-patients. The mean Htb/Hv of the SAH patients, 0.866, was found to be significantly lower than that of the supine controls, 0.908, and the ambulant patients, 0.909, (p less than 0.01). Using the ratio 0.866 the total circulating blood volume of the SAH patients was calculated from either their RCV or their PV and compared with their measured TCBV. Expressed as a percentage of measured TCBV the mean errors of these single volume determinations were 2.84% and 1.76% respectively. The significance of these changes in the Htb/Hv ratio of SAH patients is discussed in relation to the circulatory disturbances they suffer.
PMCID: PMC1032343  PMID: 3668563

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