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Biomedical subjects

J C Clark

Publications and source records attributed to J C Clark.

At least 37 records · Page 2Linked to original sources

Differences in forensic pathology practice between Scotland and England.

Scotland and England are part of the United Kingdom but have separate legal systems. These legal differences have a substantial effect on forensic pathology practice, and are probably best appreciated by those pathologists who have worked on both sides of the border. This paper seeks to highlight the differences in forensic pathology practice between Scotland and England, discussing the investigation of death in both countries. It concludes that a knowledge of the Scottish procurator fiscal system of death investigation may be beneficial to those contemplating changes to the coroner system. All three authors have practised forensic pathology in Scotland and England or Wales.

Autopsy↗

Rescue of SP-B knockout mice with a truncated SP-B proprotein. Function of the C-terminal propeptide.

The function of the 102-amino acid C-terminal propeptide of surfactant protein B (SP-B) was analyzed by characterizing the phenotype associated with loss of expression of this peptide domain in transgenic mice. A construct encoding the signal peptide, N-terminal propeptide, and mature peptide of human SP-B (hSP-BDeltac) was cloned under the control of the 3.7-kilobase human SP-C promoter and injected into fertilized eggs of the FVB/N mouse strain. Founder mice expressing the hSP-BDeltac transgene were bred with heterozygous SP-B knockout mice (SP-B +/-). Offspring containing the transgene and one allele of mouse SP-B were identified and subsequently crossed to generate a transgenic line that expressed SP-BDeltac in a null background (SP-B(-/-)/hSP-BDeltac(+/+)). Expression of hSP-BDeltac in SP-B(-/-) mice was restricted to type II cells and resulted in a 2-fold increase in mature SP-B relative to wild type littermates. These mice survived without any evidence of respiratory problems and had normal lung function, normal alveolar surfactant phospholipid pool sizes, and typical tubular myelin indicating that the 102-residue C-terminal propeptide of SP-B is not required for normal structure and function of extracellular surfactant. However, proteolytic processing of the SP-C proprotein was perturbed resulting in the accumulation of a processing intermediate, Mr = 11,000, similar to the phenotype detected in SP-B(-/-) mice; furthermore, lamellar bodies in type II cells of SP-B(-/-)/hSP-BDeltac(+/+) mice were much larger than in the wild type animal and saturated phosphatidylcholine content in lung tissue was significantly increased although the incorporation of choline into saturated phosphatidylcholine was normal. Collectively, these results demonstrate a role for the C-terminal propeptide of SP-B in SP-C proprotein processing and the maintenance of lamellar body size. The C-terminal propeptide may be an important determinant of intracellular surfactant pool size.

Animals↗

Production of [11C]CH3I by single pass reaction of [11C]CH4 with I2.

We report a single pass gas phase route to [11C]CH3I based on production of I from I2 at elevated temperature. I abstracts H from CH4 to yield CH3, which reacts with I2 to form CH3I. A fiber optic spectrometer was used to measure the I2 vapor concentration. [11C]CH3I yield increased with I2 concentration until excessive amounts of condensed I2 began to trap the 11C. The yield of [11C]CH3I was > 50% from [11C]CH4I; its specific activity was 12,000 Ci/mmole. The synthesis takes only 4 min after 11CH4 production and can be repeated without system cleanup.

Carbon Radioisotopes↗

Pulmonary dysfunction in neonatal SP-B-deficient mice.

Pulmonary function was assessed in newborn wild-type and homozygous and heterozygous surfactant protein B (SP-B)-deficient mice after birth. SP-B +/+ and SP-B+/- mice became well oxygenated and survived postnatally. Although lung compliance was decreased slightly in the SP-B+/- mice, lung volumes and compliances were decreased markedly in homozygous SP-B-/- mice. They died rapidly after birth, failing to inflate their lungs or oxygenate. SP-B proprotein was absent in the SP-B-/- mice and was reduced in the SP-B+/- mice, as assessed by Western analysis. Surfactant protein A, surfactant proprotein C, surfactant protein D, and surfactant phospholipid content in lungs from SP-B+/- and SP-B-/- mice were not altered. Lung saturated phosphatidylcholine and precursor incorporation into saturated phosphatidylcholine were not influenced by SP-B genotype. Intratracheal administration of perfluorocarbon resulted in lung expansion, oxygenation, and prolonged survival of SP-B-/- mice and in reduced lung compliance in SP-B+/+ and SP-B+/- mice. Lack of SP-B caused respiratory failure at birth, and decreased SP-B protein was associated with reduced lung compliance. These findings demonstrate the critical role of SP-B in perinatal adaptation to air breathing.

Animals↗

Decreased lung compliance and air trapping in heterozygous SP-B-deficient mice.

Genetic ablation of the murine SP-B gene in transgenic mice caused lethal perinatal respiratory distress in homozygous offspring, whereas heterozygous SP-B (+/-) mice survived postnatally. In adult SP-B(+/-) mice, surfactant protein B mRNA and the alveolar lavage SP-B protein were reduced by 50% compared with wild-type littermates, consistent with the inactivation of a single SP-B allele. Expression of SP-A, SP-C, and SP-D proteins was not affected in SP-B(+/-) mice. Heterozygous SP-B(+/-) mice reached maturity in numbers expected by Mendelian inheritance of a recessive gene. Lung morphology and both intracellular and extracellular phospholipid pool size and composition were unaltered in the SP-B(+/-) mice. Despite normal survival, pulmonary function studies demonstrated a consistent decrease in lung compliance in SP-B(+/-) mice. Abnormalities of inflation/deflation curves demonstrated airway collapse at low deflation pressures. Residual volumes were increased in the SP-B(+/-) mice. In summary, SP-B mRNA and SP-B protein were reduced by 50% in SP-B(+/-) mice, resulting in abnormalities of lung compliance and air trapping, suggesting a potential susceptibility to pulmonary dysfunction associated with SP-B deficiency.

Animals↗

Caring in full circle: the legacy of Edith Honeycutt.

Edith Folsom Honeycutt, now retired, is the only staff nurse in the United States to be honored by a funded chair at a major university. In 1990, a chair of oncology nursing was established in her name at Emory University by the Metropolitan Atlanta Community Foundation. A life history method was used to examine the professional life of Edith Honeycutt through interviews and with a focus group of nurses who had worked with her. Three themes emerged: teaching by showing; expecting excellent practice; and investing in each other. A synthesized overall theme of "caring in full circle" was identified as the core descriptor. The findings of this study demonstrate how clinical education and expertise are shared and learned among staff nurses. Findings also suggest how nursing knowledge can be, and is, developed at the bedside. The connection between Emory University and Edith Honeycutt demonstrates an enduring link between a university setting and a practice arena.

Georgia↗

The development of in vivo tracer methods to obtain new information about human disease: a study of the hallucinating brain.

An outline is provided of the development of methodological strategies to address the question of focal cerebral activation during hallucinations in schizophrenic patients. In so doing, the innovation and diligence required to tailor in vivo tracer procedures to specific clinical research issues are highlighted. Attention is drawn to the complexity of methodological advances and the way in which they are based upon close scientific and technical collaboration between clinical scientists, and non-clinical scientists and research support staff.

Hallucinations↗

Improved detection of varicella zoster infection with a spin amplification shell vial technique and blind passage.

BACKGROUND: Among the methods available for the diagnosis of varicella zoster virus (VZV) infections, only tissue culture yields an isolate available for antiviral susceptibility testing or pathogenesis studies. However, conventional tube tissue culture (TC) has a low sensitivity. OBJECTIVE: To increase the recovery rate of VZV in tissue culture. STUDY DESIGN: Clinical specimens submitted for VZV isolation were processed by TC and rapid shell vial (SV) techniques followed by a blind passage (BP). For SV, two incubation times and two mAbs, directed against viral-early or immediate-early antigens, were compared. RESULTS: Isolation of VZV using the SV stained at 72 h postinoculation was more sensitive (88-96%) than TC (50-67%), or the SV technique at 48 h (66-70%). It was also more rapid than TC (9.6 days). The comparison of mAbs yielded similar results in SV. Blind passage of SV at 7 days postinoculation further increased detection. CONCLUSIONS: SV combined with BP is the method of choice for VZV isolation.

Journal Article↗

Pathology of deaths associated with "ecstasy" and "eve" misuse.

AIMS: To study the postmortem pathology associated with ring substituted amphetamine (amphetamine derivatives) misuse. METHODS: The postmortem findings in deaths associated with the ring substituted amphetamines 3,4-methylenedioxymethyl-amphetamine (MDMA, ecstasy) and 3,4-methylenedioxyethylamphetamine (MDEA, eve) were studied in seven young white men aged between 20 and 25 years. RESULTS: Striking changes were identified in the liver, which varied from foci of individual cell necrosis to centrilobular necrosis. In one case there was massive hepatic necrosis. Changes consistent with catecholamine induced myocardial damage were seen in five cases. In the brain perivascular haemorrhagic and hypoxic changes were identified in four cases. Overall, the changes in four cases were the same as those reported in heart stroke, although only two cases had a documented history of hyperthermia. Of these four cases, all had changes in their liver, three had changes in their brains, and three in their heart. Of the other three cases, one man died of fulminant liver failure, one of water intoxication and one probably from a cardiac arrhythmia associated with myocardial fibrosis. CONCLUSIONS: These data suggest that there is more than one mechanism of damage in ring substituted amphetamine misuse, injury being caused by hyperthermia in some cases, but with ring substituted amphetamines also possibly having a toxic effect on the liver and other organs in the absence of hyperthermia.

3,4-Methylenedioxyamphetamine↗

Hepatitis virus infection and liver disease in injecting drug users who died suddenly.

AIM: To determine the extent of liver damage resulting from infection with hepatitis B, C and D viruses (HBV, HCV and HDV) in intravenous drug users (IDUs). METHODS: Liver sections taken at necropsy performed to investigate the cause of sudden death in 48 IDUs were scored for necroinflammatory activity and fibrosis. Evidence of infection was by detection of viral antibodies in serum, hepatitis B surface antigen (HBsAg) and HCV RNA by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Evidence of HCV infection was present in 43 (90%) of 48 serum samples. Six (12%) HBsAg positive serum samples had markers indicative of chronic HBsAg carriage, including three with antibody directed against HDV. Evidence of past HBV infection was found in 27 (69%) of 39 HBsAg negative serum samples. HIV was detected in one (2%) of 48 samples. In five (10%) of 48 samples there was no evidence of current or past infection with HCV, HBV or HIV. All 43 liver sections from HCV positive IDUs scored > or = 1 for necroinflammatory activity, whereas three IDUs without HCV scored 0. Scores for stage of fibrosis were > or = 1 in 15 (35%) of 43 and zero of five IDUs, respectively. Fibrosis scores of > or = 3 were seen only in three IDUs positive for HBV, HDV and HCV. CONCLUSION: Inflammatory activity in the liver is present in a high proportion of IDUs in Glasgow and is strongly associated with HCV infection. Severe chronic liver damage was limited to HBsAg carriers superinfected with HDV and HCV.

Adolescent↗

Targeted disruption of the surfactant protein B gene disrupts surfactant homeostasis, causing respiratory failure in newborn mice.

Surfactant protein B (SP-B) is an 8.7-kDa, hydrophobic protein that enhances the spreading and stability of surfactant phospholipids in the alveolus. To further assess the role of SP-B in lung function, the SP-B gene was disrupted by homologous recombination in murine mouse embryonic stem cells. Mice with a single mutated SP-B allele (+/-) were unaffected, whereas homozygous SP-B -/- offspring died of respiratory failure immediately after birth. Lungs of SP-B -/- mice developed normally but remained atelectatic in spite of postnatal respiratory efforts. SP-B protein and mRNA were undetectable and tubular myelin figures were lacking in SP-B -/- mice. Type II cells of SP-B -/- mice contained no fully formed lamellar bodies. While the abundance of SP-A and SP-C mRNAs was not altered, an aberrant form of pro-SP-C, 8.5 kDa, was detected, and fully processed SP-C peptide was markedly decreased in lung homogenates of SP-B -/- mice. Ablation of the SP-B gene disrupts the routing, storage, and function of surfactant phospholipids and proteins, causing respiratory failure at birth.

Animals↗

Gene structure and expression of human thyroid transcription factor-1 in respiratory epithelial cells.

The human gene encoding thyroid transcription factor-1 (TTF-1), a homeodomain-containing nuclear transcription protein of the Nkx2 gene family, was isolated and characterized. Human TTF-1 was encoded by a single gene locus spanning approximately 3.3 kilobases and consisted of two exons and a single intron. The TTF-1 cDNA and polypeptide of 371 amino acids have been highly conserved, sharing 98% identity with the rat TTF-1 polypeptide. Human TTF-1 mRNA and polypeptide were selectively expressed in human and mouse pulmonary adenocarcinoma cell lines. In addition to its presence in thyroid gland epithelium, the human TTF-1 protein was detected by immunohistochemistry in human fetal lung as early as 11 weeks of gestation, being localized in the nuclei of epithelial cells of the developing airways. After birth, TTF-1 was selectively expressed in Type II epithelial cells in the alveoli and in subsets of bronchiolar epithelial cells in the conducting regions of the lung. The 5'-flanking region of the human TTF-1 gene directed transcription of luciferase cDNA in a lung epithelial cell-selective manner. The conservation and distribution of TTF-1 in the human respiratory tract support its role in the regulation of lung development and surfactant homeostasis.

Adult↗

Deaths from methadone use.

All deaths from methadone poisoning occurring between 1991 and 1994 in Sheffield, UK, were studied. There were 18 deaths: 17 adults (14 men, 3 women), age range of 17-45 years (mean 29), and a 3-year-old female child. Blood methadone concentrations ranged from 200 microg/l to 1863 microg/l (mean 560 microg/l). Multiple drug use was common. Ten people had been prescribed methadone, whilst eight had obtained their methadone illegally. Only 3 people were long-term methadone users. The others were probably first time users or recently new to methadone programmes. Two, including the child, were apparently forced to drink methadone. Methadone is a potent drug with serious side-effects. Naïve users are particularly at risk of death. Toxic effects may be delayed, allowing large amounts to be ingested, giving both user and medical practitioner a false sense of security. Caution should be exercised when prescribing to new patients in methadone programmes. Controlled administration of methadone may prevent overdosage and ingestion by those to whom it is not prescribed.

Journal Article↗

Fibrogenic potentials of coal slags used as abrasive blasting substitutes.

This study was designed to examine the fibrogenic potentials of four coal slags that are being used as substitutes for silica sand in abrasive blasting. Six groups of 100 male Sprague-Dawley rats, including four coal slag groups, a vehicle control, and a positive control for fibrosis (Minusil quartz), were used. Each dust treatment group was given a single 40-mg dose of test agent via intratracheal instillation. Interim sacrifices of 15 animals per group were performed at 2 d, 3 mo, and 6 mo posttreatment, with the terminal sacrifice conducted at 12 mo. Hematoxylin and eosin stained histologic sections were prepared from designated formalin-fixed tissues collected at each necropsy and examined microscopically. Pulmonary silicon analyses were performed for each group at the 2-d and 12-mo sacrifices. Pulmonary function analyses were conducted for each group at the 3-, 6-, and 12-mo sacrifices. Lung hydroxyproline analyses were conducted for 15 animals in each group at the terminal sacrifice. The pulmonary fibrogenic potentials of the four coal slag groups were compared histologically with the Minusil and vehicle controls. A mild to moderate interstitial fibrosis, which was progressive with time, was noted in each of the coal slag groups. However, the coal slag-induced lung fibrosis was much less than that produced by Minusil. Differences in fibrosis among the individual coal slags were relatively minor and certainly not as striking as those between the slags and Minusil. Other data derived from this study, such as lung hydroxyproline content, pulmonary particulate burdens, pulmonary function, and animal body weights, provided further evidence of a reduced toxicity for the coal slags compared to Minusil.

Analysis of Variance↗

Synthesis and structure-activity relationships in a series of antiinflammatory corticosteroid analogues, halomethyl androstane-17 beta-carbothioates and -17 beta-carboselenoates.

The preparation and topical antiinflammatory potencies of a series of halomethyl 17 alpha-(acyloxy)- 11 beta-hydroxy-3-oxoandrosta-1,4-diene-17 beta-carbothioates, carrying combinations of 6 alpha-fluoro, 9 alpha-fluoro, 16-methyl, and 16-methylene substituents, are described. Key synthetic stages were the preparation of carbothioic acids and their reaction with dihalomethanes. The carbothioic acids were formed from 17 beta-carboxylic acids by initial reaction with dimethylthiocarbamoyl chloride followed by aminolysis of the resulting rearranged mixed anhydride with diethylamine, or by carboxyl activation with 1,1'-carbonyldiimidazole (CDI) or 2-fluoro-N-methylpyridinium tosylate (FMPT) and reaction with hydrogen sulfide, the choice of reagent being governed by the 17 alpha-substituent. Carboxyl activation with FMPT and reaction with sodium hydrogen selenide led to the halomethyl 16-methyleneandrostane-17 beta-carboselenoate analogues. Anti-inflammatory potencies were measured in humans using the vasoconstriction assay and in rats and mice by a modification the Tonelli croton oil ear assay. Best activities were shown by fluoromethyl and chloromethyl carbothioates with a 17 alpha-propionyloxy group. S-Fluoromethyl 6 alpha, 9 alpha-difluoro-11 beta-hydroxy-16 alpha-methyl-3-oxo-17 alpha- (propionyloxy)androsta-1,4-diene-17 beta-carbothioate (fluticasone propionate, FP) was selected for clinical study as it showed high topical antiinflammatory activity but caused little hypothalamic-pituitary-adrenal suppression after topical or oral administration to rodents.

Adrenal Cortex Hormones↗

Dosimetry of intravenously administered oxygen-15 labelled water in man: a model based on experimental human data from 21 subjects.

Models based on uniform distribution of tracer in total body water underestimate the absorbed dose from H2(15)O because of the short half-life (2.04 min) of 15O, which leads to non-uniform distribution of absorbed dose and also complicates the direct measurement of organ retention curves. However, organ absorbed doses can be predicted by the present kinetic model based on the convolution technique. The measured time course of arterial H2(15)O concentration following intravenous administration represents the input function to organs. The impulse response of a given organ is its transit time function determined by blood flow and the partition of water between tissue and blood. Values of these two parameters were taken from the literature. Integrals of the arterial input function and organ transit time functions were used to derive integrals of organ retention functions (organ residence times). The latter were used with absorbed dose calculation software (MIRDOSE-2) to obtain estimates for 24 organs. From the mean values of organ absorbed doses, the effective dose equivalent (EDE) and effective dose (ED) were calculated. From measurements on 21 subjects, the average value for both EDE and ED was calculated to be 1.2 microSv.MBq-1 compared with a value of about 0.5 microSv.MBq-1 predicted by uniform water distribution models. Based on the human data, a method of approximating H2(15)O absorbed dose values from body surface area is described.

Adult↗