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1.  Incorporating Target Shedding Into a Minimal PBPK–TMDD Model for Monoclonal Antibodies 
Shedding of a pharmacological target from cells, giving rise to a soluble target that can also bind therapeutic proteins, is a common phenomenon. In this study, a minimal physiologically based pharmacokinetic model was used to simulate the pharmacokinetics of trastuzumab and the simultaneous binding of the compound to soluble (in blood and tissue interstitial space) and membrane-bound (in the tissue interstitial space) forms of human epidermal growth factor receptor 2 (HER2). The parameter values describing binding of trastuzumab to HER2 were largely derived from in vitro data, and the effects of varying HER2 levels, the affinity difference between membrane-bound HER2 and shed antigen, and slow binding kinetics were investigated. The model simulates a sharp decrease in trough drug concentrations at concentrations of soluble target between 500 and 1,000 ng/ml in plasma. This corresponds with the clinical concentration range of soluble target wherein changes in half-life of trastuzumab have been observed.
doi:10.1038/psp.2013.73
PMCID: PMC3910015  PMID: 24477089
2.  Clinical investigation of an outbreak of alveolitis and asthma in a car engine manufacturing plant 
Thorax  2007;62(11):981-990.
Background
Exposure to metal working fluid (MWF) has been associated with outbreaks of extrinsic allergic alveolitis (EAA) in the USA, with bacterial contamination of MWF being a possible cause, but is uncommon in the UK. Twelve workers developed EAA in a car engine manufacturing plant in the UK, presenting clinically between December 2003 and May 2004. This paper reports the subsequent epidemiological investigation of the whole workforce. The study had three aims: (1) to measure the extent of the outbreak by identifying other workers who may have developed EAA or other work‐related respiratory diseases; (2) to provide case detection so that those affected could be treated; and (3) to provide epidemiological data to identify the cause of the outbreak.
Methods
The outbreak was investigated in a three‐phase cross‐sectional survey of the workforce. In phase I a respiratory screening questionnaire was completed by 808/836 workers (96.7%) in May 2004. In phase II 481 employees with at least one respiratory symptom on screening and 50 asymptomatic controls were invited for investigation at the factory in June 2004. This included a questionnaire, spirometry and clinical opinion. 454/481 (94.4%) responded and 48/50 (96%) controls. Workers were identified who needed further investigation and serial measurements of peak expiratory flow (PEF). In phase III 162 employees were seen at the Birmingham Occupational Lung Disease clinic. 198 employees returned PEF records, including 141 of the 162 who attended for clinical investigation. Case definitions for diagnoses were agreed.
Results
87 workers (10.4% of the workforce) met case definitions for occupational lung disease, comprising EAA (n = 19), occupational asthma (n = 74) and humidifier fever (n = 7). 12 workers had more than one diagnosis. The peak onset of work‐related breathlessness was Spring 2003. The proportion of workers affected was higher for those using MWF from a large sump (27.3%) than for those working all over the manufacturing area (7.9%) (OR = 4.39, p<0.001). Two workers had positive specific provocation tests to the used but not the unused MWF solution.
Conclusions
Extensive investigation of the outbreak of EAA detected a large number of affected workers, not only with EAA but also occupational asthma. This is the largest reported outbreak in Europe. Mist from used MWF is the likely cause. In workplaces using MWF there is a need to carry out risk assessments, to monitor and maintain fluid quality, to control mist and to carry out respiratory health surveillance.
doi:10.1136/thx.2006.072199
PMCID: PMC2117138  PMID: 17504818
3.  Prevalence of and associated risk factors for shedding Cryptosporidium parvum oocysts and Giardia cysts within feral pig populations in California. 
Applied and Environmental Microbiology  1997;63(10):3946-3949.
Populations of feral pigs (Sus scrofa) may serve as an environmental reservoir of Cryptosporidium parvum oocysts and Giardia sp. cysts for source water. We conducted a cross-sectional study to determine the prevalence of and associated demographic and environmental risk factors for the shedding of C. parvum oocysts and Giardia sp. cysts. Feral pigs were either live-trapped or dispatched from 10 populations located along the coastal mountains of western California, and fecal samples were obtained for immunofluorescence detection of C. parvum oocysts and Giardia sp. cysts. We found that 12 (5.4%) and 17 (7.6%) of 221 feral pigs were shedding C. parvum oocysts and Giardia sp. cysts, respectively. The pig's sex and body condition and the presence of cattle were not associated with the probability of the shedding of C. parvum oocysts. However, younger pigs (< or = 8 months) and pigs from high-density populations (> 2.0 feral pigs/km2) were significantly more likely to shed oocysts compared to older pigs (> 8 months) and pigs from low-density populations (< or = 1.9 feral pigs/km2). In contrast, none of these demographic and environmental variables were associated with the probability of the shedding of Giardia sp. cysts among feral pigs. These results suggest that given the propensity for feral pigs to focus their activity in riparian areas, feral pigs may serve as a source of protozoal contamination for surface water.
PMCID: PMC168707  PMID: 9327560
4.  Enzootic pneumonia: comparison of cough and lung lesions as predictors of weight gain in swine. 
A prospective cohort study was undertaken in a commercial swine herd to determine the relationship between weight gain and the occurrence of enzootic pneumonia (EP). Estimates of the association between EP and weight gain were obtained from multiple linear regression models, using coughing episodes or slaughter checks as indicators of EP status. Models were estimated for pigs in 2 different age groups: roasters (n = 1084, sold at 32 to 50 kg) and market hogs (n = 1162, sold at 100 to 110 kg). The relationship between presence of lung lesions at slaughter and previous coughing episodes was also investigated. Throughout the study period, clinical evaluations were performed weekly, and coughing episodes recorded for each pig. Lungs were inspected at slaughter, and scores were expressed as the percentage of the lung with gross pneumonic lesions. Coughing and lung scores were significantly correlated, after adjusting for other covariates (R = 0.32 and 0.59, respectively, for market hogs and roasters). However, the agreement beyond chance between coughing history and lung lesions at slaughter was poor among both roasters and market hogs (kappa = 0.17 and 0.07, respectively). Although very specific, weekly assessment of coughing was not a sensitive indicator of lung lesions at slaughter. In multiple regression, lung score was a highly significant predictor of lower final weight in pigs of both age groups (P < 0.001 in the selected regression models).(ABSTRACT TRUNCATED AT 250 WORDS)
PMCID: PMC1263766  PMID: 8521353
5.  Effect of birthweight, total protein, serum IgG and packed cell volume on risk of neonatal diarrhea in calves on two California dairies. 
The objective of the study was to determine if there was a relationship between hematological, immunological and physiological variables of newborn calves and risk of diarrhea during the neonatal period. Four hundred and seventeen heifer calves from two dairies (A and B) in the San Joaquin Valley of California were enrolled at birth and scored daily, to 28 days of age, for evidence and severity of diarrhea (0 to 3). Calves were weighted at birth and blood sampled at two to five days of age to determine packed cell volume (PCV), total protein (TP) and IgG serum concentration. The Cox proportional hazards model was used to determine if age at onset of the first diarrhea episode and length of the first episode were associated with the hypothesized variables (PCV, TP, IgG and birthweight). The IgG concentration was not associated with the age at onset of diarrhea (p = 0.6052, Dairy A; p = 0.4393, Dairy B) but a high IgG concentration was associated with a decreased length of episode (p = 0.0325, Dairy A; p = 0.0912, Dairy B), particularly for calves born in the winter on dairy A (p = 0.0211). For calves born in the winter, those with either a high or a low birthweight had diarrhea at a younger age (p = 0.0102, Dairy A; p = 0.0020, Dairy B). Associations were also found for PCV and TP with both the age at onset and length of the first episode of diarrhea. Results suggest that parameters measurable at, or shortly after birth may have important prognostic value in evaluating risk of calf diarrhea.
PMCID: PMC1263635  PMID: 8269362
6.  Optic nerve avulsion due to forced rotation of the globe by a snooker cue. 
We report a case of partial avulsion of the optic nerve caused by sudden rotation of the globe due to a snooker cue injury. Minimal direct ocular trauma occurred. This case supports the belief that sudden rotation of the globe is the major mechanism of optic nerve avulsion. We include the first results of ultrasound examination that demonstrate optic nerve injury in such a case and believe that, in conjunction with fluorescein angiography and computerised tomography, it is important in the full evaluation of such cases.
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PMCID: PMC1042185  PMID: 2390529
7.  Isolation of a human T-lymphotropic virus type I strain from Australian aboriginals. 
Journal of Virology  1993;67(2):843-851.
A human T-lymphotropic virus type I (HTLV-I) strain was isolated in a CD4+ T-lymphocyte culture established from a healthy seropositive Australian Aboriginal. This isolate, identified as HTLV-IMSHR-1, was detected by immunofluorescence with monoclonal antibodies, by the presence of gag-encoded protein p24 in the culture supernatant, and by cocultivation leading to infection and transformation of lymphocytes from an HTLV-I-negative donor. By using the polymerase chain reaction technique, the env gene and segments of the pol and pX regions of the proviral genome of HTLV-I(MSHR-1) were amplified and sequenced. Comparison with the envelope sequences of prototype strains revealed up to 7% divergence at the nucleotide level and 3.1 to 4.3% divergence in the predicted amino acid sequence. Phylogenetic analysis showed that the Australian and Melanesian isolates are related. Differential reactivity with monoclonal antibodies suggests that gag protein p19 of HTLV-I(MSHR-1) is also divergent. The potential for antigenic divergence between the prototype HTLV-I isolates and the Austro-Melanesian variants requires further investigation, because it would have implications for serodiagnosis and vaccine development.
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PMCID: PMC237438  PMID: 8093491
8.  Environmental source of mycobacteriosis in a California swine herd. 
Between July 1985 and April 1986, mycobacterial lymphadenitis was recorded in six of 2407 slaughter pigs from a commercial swine herd in which the majority of pigs were raised in confinement. Records showed that all six affected pigs had access to dirt-floored pens at least 81 days prior to slaughter. The mycobacteriosis lesion rate for pigs exposed to dirt pens was 9.4% while in nonexposed pigs the lesion rate was zero. The risk associated with movement of pigs from concrete floored pens to dirt pens was evaluated by a field trial. In the field trial, two litters (5 of 15 pigs) exposed to dirt pens at 12-24 days of age but none of nine nonexposed litters (39 pigs) developed lesions. Mycobacterium avium-complex bacteria were recovered from both exposed litters (9 of 15 pigs) but from none of nine nonexposed litters. Serovars of M. avium-complex isolated from trial pigs included 1, 4, 8, 9, the dual serovar 4/8, and an untypable serovar. Incense-cedar bark (Calocedrus decurrens) used as a flooring material in the pens was demonstrated to be a potential source of M. avium-complex serovar 9. The dual serovar 4/8 and an untypable M. avium-complex were isolated from the dirt-floored pens. No evidence of cross-transmission of M. avium-complex infection was detected. The sporadic pattern of mycobacteriosis observed in the herd probably resulted from infrequent exposure to a common environmental source.
PMCID: PMC1255509  PMID: 2914225
9.  Macrophage function in Mycobacterium lepraemurium infection: morphological and functional changes of peritoneal and splenic macrophages in vitro. 
Infection and Immunity  1983;39(1):353-361.
Morphological and functional changes in peritoneal macrophages (PM) and splenic macrophages (SM) from mice infected with Mycobacterium lepraemurium were investigated. A decrease in the number but an increase in the size of PM were observed during the infection. PM were vacuolated, and a small proportion of them were observed in cell division. They demonstrated greater ability to adhere and spread in vitro, enhanced phagocytosis of immunoglobulin G (IgG) and IgM erythrocytes, and greater phagocytosis and killing of Candida sp., when compared with normal resident PM. In contrast, parasitized SM demonstrated significantly reduced phagocytic ability, whereas heavily parasitized SM neither spread nor phagocytosed Candida sp. The random migration and chemotactic responsiveness of PM from infected animals were also enhanced. These results indicated the persistent activation of PM but the suppression of some activities of SM during M. lepraemurium infection.
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PMCID: PMC347946  PMID: 6337101
10.  Age-related decline in the resistance of mice to infection with intracellular pathogens. 
Infection and Immunity  1977;16(2):593-598.
Resistance to infection with Toxoplasma gondii and Listeria monocytogenes in BALB/c female mice decreased with increasing age. The decrease was apparent as early as 9 months of age and was more marked as the animals aged further. This age-related decline in resistance was not restricted to BALB/c female mice, as male and female mice of the C57BL/6 strain exhibited similar responses. With both pathogens, aged mice showed a more marked susceptibility to the strain of lesser virulence. Transfer of normal serum from old mice to young or old mice before infection with T. gondii resulted in an increased susceptibility to this organism, suggesting the presence of inhibitory factors or the absence of potentiating factors that are present in the serum of young mice.
PMCID: PMC420997  PMID: 405325

Results 1-10 (10)