Another PMA-related fatality in Adelaide.
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Adult↗
Biomedical subjects
R A James
Publications and source records attributed to R A James.
Medicolegal complications of pseudologia fantastica.
A 46-year-old woman allegedly on a witness protection scheme who died under unusual circumstances with a factitious history of two previous homicide attempts and multiple medical problems including paraplegia and lung carcinoma is presented to demonstrate difficulties that may arise in the medicolegal investigation of such cases. A diagnosis of pseudologia fantastica was made once no corroboration of the presenting history or medical illnesses could be made. Death was due to haemorrhage from a self-inflicted incised wound to the arm.
Journal Article↗
The future of somatostatin analogue therapy.
Since its discovery almost 30 years ago, the mode of action and therapeutic applications of somatostatin have been defined. In particular the cloning and characterization of somatostatin receptor subtypes has facilitated the development of high affinity analogues. In the context of pituitary disease, long-acting somatostatin analogues (octreotide, lanreotide) have been used to treat a variety of pituitary tumours but are most efficacious for the treatment of GH and TSH-secreting adenomas. In patients with acromegaly, depot preparations of these analogues are administered intramuscularly every 10-28 days and provide consistent suppression of GH levels to < 5 mU/l in approximately 50-65% of all cases. Even more specific somatostatin receptor analogues are under development. Finally, radiolabelled somatostatin analogue scintigraphy and, in larger doses, therapy, are now established tools in the evaluation and treatment of neuroendocrine tumours.
Acromegaly↗
Murder-suicides involving children: a 29-year study.
Review was undertaken from February 1969 to January 1998 at the State forensic science center (Forensic Science) in Adelaide, South Australia, of all cases of murder-suicide involving children <16 years of age. A total of 13 separate cases were identified involving 30 victims, all of whom were related to the perpetrators. There were 7 male and 6 female perpetrators (age range, 23-41 years; average, 31 years) consisting of 6 mothers, 6 father/husbands, and 1 uncle/son-in-law. The 30 victims consisted of 11 daughters, 11 sons, 1 niece, 1 mother-in-law, and 6 wives of the assailants. The 23 children were aged from 10 months to 15 years (average, 6.0 years). The 6 mothers murdered 9 children and no spouses, with 3 child survivors. The 6 fathers murdered 13 children and 6 wives, with 1 child survivor. This study has demonstrated a higher percentage of female perpetrators than other studies of murder-suicide. The methods of homicide and suicide used were generally less violent among the female perpetrators compared with male perpetrators. Fathers killed not only their children but also their wives, whereas mothers murdered only their children. These results suggest differences between murder-suicides that involve children and adult-only cases, and between cases in which the mother rather than the father is the perpetrator.
Adolescent↗
Putrefactive pleural effusions as an alternative sample for drug quantification.
In the investigation of drug-related deaths it is occasionally necessary to examine putrefied bodies. In such cases the availability of conventional body fluids for toxicologic analysis is usually limited, whereas blood-stained pleural effusion is often present in adequate quantity in the pleural cavity. Fifty-five cases involving numerous drugs are presented in which pleural effusion drug concentrations are compared with corresponding blood or liver concentrations. More than 90% of comparisons produced coincident interpretations of the role that drugs played in the deaths. In most instances pleural effusion analysis was shown to be a valid alternative to the analysis of blood or other conventional fluids or tissues in cases exhibiting advanced putrefaction.
Autopsy↗
Cloning of the mouse somatostatin receptor subtype 5 gene: promoter structure and function.
Somatostatin is a peptide hormone whose actions are mediated by five somatostatin receptor subtypes (sstl-5). In the pituitary, somatostatin inhibits TSH release from thyrotropes and GH release from somatotropes. We have shown that sst5 transcripts and protein are induced by thyroid hormone in TtT-97 thyrotropic tumors. To map sequences responsible for promoter activity in pituitary cells, we cloned the mouse sst5 coding region of 362 amino acids and 12 kb of upstream DNA. Initial transfection studies in TtT-97 or GH3 cells mapped high levels of basal promoter activity to a 5.6-kb fragment upstream of the translational start, whereas shorter genomic fragments had low activity. To identify the transcriptional start site we used 5' RACE with TtT-97 poly A+ RNA and a sst5 antisense coding region primer. Sequence comparison between the complementary DNA and the gene revealed that the mouse sst5 gene contains 3 exons and 2 introns. The entire coding region was contained in exon 3. Two differently sized RACE products demonstrated alternate exon splicing of two untranslated exons in TtT-97 cells. A promoter fragment from -290/+48 linked to a luciferase reporter demonstrated 600- and 900-fold higher activity over a promoterless control in GH3 mammosomatotropes and TtT-97 thyrotropes, respectively, whereas a larger fragment extending to -6400 exhibited no additional promoter activity. Cloning of the sst5 gene will facilitate the mapping of basal and regulated responses at the transcriptional level.
Amino Acid Sequence↗
Octreotide and ectopic Cushing's syndrome--a commentary.
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ACTH Syndrome, Ectopic↗
Cerebral venous sinus thrombosis: a late sequel of invasive fibrous thyroiditis.
Riedel's invasive fibrous thyroiditis (IFT) is a rare disease of unknown etiology characterized by a dense fibrosis involving the thyroid gland and its surrounding tissues. Clinically, patients present with a stony hard goiter frequently associated with compressive symptoms. Involvement of the surrounding neck structures by IFT can lead to various clinical sequelae. We report the case of a 55-year-old woman with known IFT who developed thrombosis in the right internal jugular vein that progressed to the right sigmoid, transverse, and superior sagittal sinuses. IFT could have predisposed to cerebral venous sinus thrombosis by causing venous stasis, vascular damage and possibly a hypercoagulable state. To our knowledge, this is the first report of cerebral venous sinus thrombosis that developed as a complication of IFT.
Cerebral Veins↗
Sudden death due to intravenous infusion of hair conditioner.
A case of sudden death in a 14-year-old girl due to self administration of hair conditioner through an intravenous infusion pump is described. This report demonstrates difficulties that may occur in determining the manner of death in such cases and outlines a specific danger that may occur when adolescents have unsupervised access to intravenous infusion equipment.
Adolescent↗
Hyperpyrexia associated with fatal paramethoxyamphetamine (PMA) abuse.
Investigation of a suspicious death became confused when apparently contradictory findings arose on examination of the body. Subsequent identification of amphetamine abuse including PMA resolved these issues. The reported case highlights some atypical features which may cause difficulty in this small but increasing group of deaths. Three rapid deaths attributed to PMA have been identified in Adelaide in the 12 months before June 1996.
Adult↗
Chloroform-induced olfactory mucosal degeneration and osseous ethmoid hyperplasia are not associated with olfactory deficits in Fischer 344 rats.
Adult female F-344 rats were trained (avoidance rate > 70%) over four days with a coupled tone- (n = 10 rats/dose) or 2 ppm acetaldehyde-cued (n = 6 rats/dose) foot shock paradigm. Rats were gavaged with chloroform dissolved in corn oil for 5 days/week for 3 week at 0 or 400 (tone-cued) or 0, 34, 100, or 400 (odor-cued) mg/kg body weight/day. Tone-cued response was reevaluated 6, 16, and 38 days after the first chloroform dose (day 1). Olfaction was assessed on days 6-7, 20-21, and 41-42 using 2 or 0.0002 ppm acetaldehyde. Nasal histopathology (n = 4-5 rats/dose) was assessed on days 6, 20, and 42. Significantly decreased body weights were observed following a single 100 or 400 mg/kg chloroform dose. Body weights in the 400 mg/kg/day chloroform group remained depressed for 17 days. Histopathology revealed degenerative changes in olfactory mucosa and underlying ethmoid turbinate bones that were essentially identical in nature and severity, including dose-response and progression, to those reported previously for chloroform gavage (Larson et al., Food Chem. Toxicol., 1995;33:443 456). At all dose level and sacrifice timepoints, however, regions of morphologically normal olfactory mucosa were present, especially in dorsal medial and ventral lateral regions of the nose. Neither odor- nor tone-cued avoidance behaviors were affected, indicating that even fairly severe and extensive chloroform-induced olfactory mucosal degeneration is not associated with a detectable olfactory deficit in rats.
Animals↗
Pit-1 and GATA-2 interact and functionally cooperate to activate the thyrotropin beta-subunit promoter.
The molecular determinants governing cell-specific expression of the thyrotropin (TSH) beta-subunit gene in pituitary thyrotropes are not well understood. The P1 region of the mouse TSHbeta promoter (-133 to -88) region interacts with Pit-1 and an additional 50-kDa factor at an adjacent site that resembles a consensus GATA binding site. Northern and Western blot assays demonstrated the presence of GATA-2 transcripts and protein in TtT-97 thyrotropic tumors. In electrophoretic mobility shift assays, a comigrating complex was observed with both TtT-97 nuclear extracts and GATA-2 expressed in COS cells. The complex demonstrated binding specificity to the P1 region DNA probe and could be disrupted by a GATA-2 antibody. When both Pit-1 and GATA-2 were combined, a slower migrating complex, indicative of a ternary protein-DNA interaction was observed. Cotransfection of both Pit-1 and GATA-2 into CV-1 cells synergistically stimulated mouse TSHbeta promoter activity 8.5-fold, while each factor alone had a minimal effect. Mutations that abrogated this functional stimulatory effect mapped to the P1 region. Finally, we show that GATA-2 directly interacts with Pit-1 in solution. In summary, these data demonstrate functional synergy and physical interaction between homeobox and zinc finger factors and provide insights into the transcriptional mechanisms of thyrotrope-specific gene expression.
Animals↗
Genetic diversity in black howler monkeys (Alouatta pigra) from Belize.
To assess the level of genetic variation in a threatened black howler monkey (Alouatta pigra) population, we examined 36 allozyme loci and restriction fragment profiles of mitochondrial DNA (mtDNA). Mean heterozygosity at allozyme loci was only 0.021 and 5.6 percent of the loci were polymorphic. Analyses of mtDNA also revealed low genetic diversity compared with other primates. F-statistics revealed no significant genetic heterogeneity among troops within the Bermudian Landing preserve, but did indicate a deficiency of heterozygotes at one of the two loci. We explore several explanations for this result, which is unexpected in a socially structured primate. Low genetic diversity in this population may reflect its history of demographic bottlenecks.
Alleles↗
Genotoxicity and cytotoxicity in male B6C3F1 mice following exposure to mixtures of 1,3-butadiene and styrene.
1,3-Butadiene and styrene are oxidized, in part, by cytochrome P450 2E1 and have been shown to metabolically interact in rodents exposed by inhalation to mixtures of both compounds. Because the reactive metabolites of butadiene and styrene are thought to be responsible for the toxicity of each compound, metabolic interactions may alter the response in animals exposed to mixtures of butadiene and styrene compared with the response in animals exposed to butadiene alone or styrene alone. The purpose of this study was to quantitate alterations in genotoxicity and cytotoxicity in male B6C3F1 mice exposed to mixtures of butadiene and styrene. Male B6C3F1 mice were exposed to 6.25, 62.5, 200, or 625 ppm butadiene alone, 50 ppm styrene alone, or mixtures of 6.25, 62.5, 200, or 625 ppm butadiene and 50 ppm styrene. Genotoxicity was assessed by quantitating the frequency of micronucleated polychromatic erythrocytes in bone marrow. Cytotoxicity was assessed by counting total spleen and thymus cells and by quantitating the frequency of polychromatic erythrocytes in the peripheral blood. Butadiene and mixtures of butadiene and styrene were genotoxic in mice, as shown by a significant increase in the frequency of micronucleated polychromatic erythrocytes. The increased frequency following exposure to mixtures of butadiene and styrene was not significantly different compared with the frequency following exposure to butadiene alone. Styrene and mixtures of butadiene and styrene were cytotoxic in mice, as shown by significantly decreased number of spleen cells. Exposure to mixtures of butadiene and styrene with butadiene concentrations of 62.5 or 625 ppm significantly reduced the number of thymus cells. Exposure to 200 ppm or 625 ppm butadiene alone, or to mixtures of 200 ppm or 625 ppm butadiene and 50 ppm styrene, significantly reduced the frequency of polychromatic erythrocytes in the peripheral blood. The results of the study demonstrate that exposure to mixture of butadiene and styrene does not reduce the respective genotoxicity of butadiene or cytotoxicity of styrene.
Animals↗
Determination of postmortem interval by sampling vitreous humour.
Estimation of postmortem interval (PMI) by analyses of vitreous humor has certain advantages over analyses of blood and cerebrospinal fluid (CSF). Certain substances, including potassium and hypoxanthine (Hx), have been shown to exhibit postmortem increase in concentration in vitreous humor in a linear fashion. In the present study, potassium and Hx concentrations were measured in 100 subjects with known PMIs. Three previously published equations were used to estimate the PMI using these measurements, and the accuracy of the equations was assessed. Simple linear regression analyses were performed on the data collected, and new equations for estimation of PMI were constructed. Estimates made using these equations were of comparable or better accuracy than those made using the published equations. It was observed that using both potassium and Hx measurements to estimate the PMI were associated with increased accuracy in all circumstances.
Adolescent↗
Thyroid hormone-induced expression of specific somatostatin receptor subtypes correlates with involution of the TtT-97 murine thyrotrope tumor.
Following the protracted hypothyroid state, treatment with thyroid hormone will induce a decline in TSH and reduce thyrotrope hyperplasia. Somatostatin is a hypothalamic peptide that has been implicated in the negative regulation of TSH secretion in the thyrotrope. Moreover, analogs of native somatostatin have potent TSH-reducing and growth-retarding effects on human thyrotropinomas. The TtT-97 tumor is an in vivo murine thyrotropic model that has retained its physiological response to thyroid hormone. This study investigates the regulation of somatostatin receptor subtypes in this tumor. TtT-97 tumors, actively growing in hypothyroid mice, did not express any significant somatostatin receptor messenger RNA (mRNA) or protein. T4 administration resulted in a reduction in TSH beta mRNA expression and a marked degree of tumor involution. Analysis of residual tumors from thyroid hormone-treated mice showed the specific up-regulation of SSTR1 and SSTR5 mRNA subtypes and the appearance of abundant, high affinity SSTR receptor-binding sites within the tumor. Thus, the TtT-97 tumor provides a thyrotrope-specific model in which to study the regulation of somatostatin receptor subtypes by thyroid hormone and correlate this expression with both antisecretory and antiproliferative effects.
Animals↗
Progesterone regulated expression of flavin-containing monooxygenase 5 by the B-isoform of progesterone receptors: implications for tamoxifen carcinogenicity.
Progesterone is a key developmental, proliferative, and differentiative hormone in the breast and endometrium, and it can accelerate carcinogenesis in the mammary gland epithelium. In the breast and uterus, progesterone acts through two coexpressed isoforms of progesterone receptors, the B- and A-receptors. To study the function of each isoform in isolation, we previously constructed two breast cancer cell lines that stably and independently express either B-receptors (YB cells) or A-receptors (YA cells). In the present study, YA or YB cells were left untreated, or were treated with the synthetic progestin R5020, and the messages present in each cell line under the two conditions were analyzed by differential display. Two message species are described that are regulated only by B-receptors. One of these is regulated in a ligand-independent manner. A third set of messages, encoding flavin-containing monooxygenase 5 (FMO5), was induced by R5020 only in YB cells. A-receptors appear to be inhibitory. FMOs are involved in the metabolic activation of drugs and xenobiotic compounds, including the antiestrogen tamoxifen, to carcinogenic intermediates. It is possible, therefore, that by upregulating the levels of FMO5, progesterone enhances the carcinogenicity of tamoxifen in target tissues that overexpress progesterone B-receptors.
Breast Neoplasms↗
Experimental peri-implant tissue breakdown around hydroxyapatite-coated implants.
This study monitored experimental peri-implant tissue breakdown around hydroxyapatite (HA)-coated titanium dental implants. Thirty-two HA-coated cylindrical implants, in groups of two, were bilaterally inserted in the posterior maxilla and mandible in 4 Macaca mulatta monkeys. Two months after healing-abutment connection, a 2-month plaque control program was initiated. Clinical and radiographic recordings and peri-implant submucosal microbial samples were then obtained (baseline). Cotton ligatures were next placed around the healing-abutments and plaque control measures were abandoned. Clinical and radiographic recordings were repeated at 5 and 10 months post-baseline. Microbial samples were repeated at 10 months post-baseline, and ligatures were removed. Clinical, radiographic, and microbial examinations were again repeated at 11 months post-baseline. Mean modified plaque index (mPI; P < 0.01), gingival index (G]; P < 0.01), and bleeding on probing (BOP; P < 0.05) scores increased over the plaque accumulation period. The mPI, and GI scores decreased after ligature removal (P < 0.001). Mean probing depth (PD) and clinical attachment level (AL) increased between baseline and the 5- and 10-month examinations (delta PD 3.0 mm; delta AL 2.7 mm; P < 0.05). PD values were reduced following ligature removal (P < 0.05). AL values and BP scores remained unchanged. A significant negative correlation was found between induced defect depth and width of keratinized mucosa at baseline (P = 0.03). At baseline, the submucosal microbiota was dominated by coccoid cells. Following ligature placement, the microbiota included a large proportion of Gram-negative anaerobic rods, predominantly Porphyromonas gingivalis, Bacteroides forsythus, and Fusobacterium species as well as beta-hemolytic streptococci. Ligature removal had a limited effect on the composition of the submucosal microbiota. This non-human primate study indicates that ligature-enhanced plaque accumulation is a precursor of progressive peri-implant tissue breakdown around HA-coated implants. The associated microbiota resembles that of peri-implantitis and destructive periodontal disease in humans. This preclinical model may be useful to study modalities aimed at arresting peri-implant tissue breakdown and at regeneration of bone in peri-implantitis defects.
Alveolar Bone Loss↗