Clinical findings and recommendations made during home visits by a palliative care specialist physician.

Little has been reported regarding the nature of home visits by palliative care specialist physicians to assist in the management of complex cases. We determined the characteristics, actionable clinical findings and recommendations made during consecutive home visits conducted by a specialist physician for patients registered with a community palliative care service. Patient demographic information and clinical records were reviewed. Ninety-one patients received a total of 104 home and residential facility visits. Median patient age was 59 (Q1-Q3, 43-72). Ten children (under the age of 14) received a total of 15 visits. Seventy-three patients (80%) had a cancer diagnosis. Median visit duration was 60 min (Q1-Q3, 45-60). The major actionable clinical findings were pain (120), gastrointestinal (115), neuropsychiatric (58), mouth and skin (33) and respiratory (29). One-third of recommendations involved changes in analgesia regimen (opioids 67, adjuvants 44). The specialist physician home visit resulted in multiple patient care recommendations. This information may help palliative care programmes improve their care for patients and families in the community.

Relationships between non-occupational cadmium exposure and expression of nine cytochrome P450 forms in human liver and kidney cortex samples.

This study was undertaken to assess associations between age, gender, cigarette smoke and non-workplace cadmium exposure, and liver pathology and inter-individual variation in cytochrome P450 (CYP) expression in human tissues. Autopsy specimens of twenty-eight Queensland residents whose ages ranged from 3 to 89 years were analyzed for the presence of nine CYP protein isoforms by immunoblotting. All subjects were Caucasians and their liver cadmium contents ranged from 0.11 to 3.95 microg/g wet weight, while their kidney cadmium contents were in the range of 2 to 63 microg/g wet weight. CYP1A2, CYP2A6, CYP2D6, CYP3A4, and CYP3A5 were detected in liver but not in kidney, and CYP1A1 and CYP1B1 were not found in liver or kidney. Lowered liver CYP2C8/19 protein contents were found to be associated with liver pathology. Importantly, we show elevated levels of CYP2C9 protein to be associated with cadmium accumulation in liver. No mechanism that explains this association is apparent, but there are two possibilities that require further study. One is that variation in CYP2C9 protein levels may be, in part, attributed to an individual's non-workplace exposure to cadmium, or an individual's CYP2C9 genotype may be a risk factor for cadmium accumulation. A positive correlation was found between liver CYP3A4 protein and subject age. Levels of liver CYP1A2 protein, but not other CYP forms, were increased in people more exposed to cigarette smoke, but there was no association between CYP1A2 protein and cadmium. CYP2A6 protein was found in all liver samples and CYP2A6 gene typing indicated the absence of CYP2A6 null allele (CYP2A6(D)) in this sample group, confirming very low prevalence of homozygous CYP2A6(D) in Caucasians. CYP2A6 gene types W/W, W/C, and C/C were not associated with variations in liver microsomal CYP2A6 protein. CYP2D6 protein was absent in all twenty-five kidney samples tested but was detectable in liver samples of all but two subjects, indicating the prevalence of the CYP2D6 null allele (CYP2D6(D)) in this sample group to be about 7%, typical of Caucasian populations.

Changes in zinc and copper homeostasis in human livers and kidneys associated with exposure to environmental cadmium.

This study was undertaken to assess changes in zinc and copper homeostasis in human tissues that could be attributed to human exposure to environmental cadmium, using samples of lung, liver and kidney cortex of 61 Queensland residents, aged 2 to 89 years, who had died of accidental causes. None of the subjects were exposed to cadmium in the workplace. Levels of zinc in liver and kidney cortex samples showed inverse associations with donor age whereas zinc in lung only showed inverse association with gender. Lung zinc levels in females were 14% lower than in males. Zinc in liver and kidney cortex samples were found to exist in at least two pools; one was associated with cadmium that bound to metallothionein (MT) and the other was associated with non-MT bound copper. In liver, the amounts of zinc in the MT pool were smaller compared to those in non-MT pool given that only 7% of zinc variations were explained by cadmium whereas 22% of the liver zinc variations were accounted for by non-MT bound copper. In sharp contrast, larger amounts of zinc in kidney cortex samples were in the MT pool, compared to those in the non-MT pool given that cadmium was found to explain 69% of total zinc variation whereas copper explained only 17% of kidney zinc variations. The levels of copper in liver were found to be increased by 45-50% in subjects with high cadmium exposure level, compared to subjects of similar ages with medium exposure level. The levels of zinc and copper in kidney cortex samples in the subjects with high cadmium exposure were both found to be significantly elevated compared to those found in the medium-exposure group whereas copper contents were about 19-23% greater than in medium- as well as low-exposure groups. Taken together these results indicate increased sequestration of zinc and copper in liver and kidney cortex samples. The increases in metal sequestrations were observed in liver samples having cadmium contents of greater than 1 microg/g wet weight and in kidney cortex having cadmium contents of greater than 26 microg/g wet weight. Zinc and copper contents in lung of this sample group, however, were not associated with cadmium due probably to lower exposure levels compared to those of liver and kidney.

Evidence for a synergistic interaction between cadmium and endotoxin toxicity and for nitric oxide and cadmium displacement of metals in the kidney.

This study was undertaken to examine changes in Zn and Cu homeostasis in the liver and kidney of rats caused by cadmium (Cd) or lipopolysaccharide (LPS) administration. Twenty-five male, 7- to 8-week-old Wistar rats were divided into five groups: saline only treatment, saline treatment and food deprivation, exposure to a single dose of Cd, exposure to LPS alone, and exposure to Cd + LPS. Changes in plasma nitrate concentrations and hepatic and renal Zn and Cu contents were measured together with urinary excretion rates for the metals and nitrate on 3 consecutive days: 24 h before treatment and 24 and 48 h after treatments. Cd exposure alone for 48 h caused a nearly 2-fold increase in plasma nitrate levels with no changes in urinary nitrate excretion whereas LPS treatment caused plasma nitrate levels to increase by 10-fold and urinary nitrate excretion to increase by 4-fold. Administration of LPS 24 h after Cd exposure caused a 10-fold increase in plasma nitrate concentrations and a 100-fold increase in urinary nitrate excretion compared to the rates prior to LPS administration. These results indicate a synergistic interaction between Cd and LPS toxicity. Cd exposure also caused a marked increase in hepatic Zn levels, but LPS did not cause any changes in hepatic Zn or Cu content. In sharp contrast, both Zn and Cu contents were decreased in the kidneys by 16 and 36% in animals exposed to Cd or LPS. A correlation analysis of measured variables reveals that renal Cu contents were inversely associated with plasma nitrate concentrations while urinary Cu excretion on day 3 showed a strong positive correlation with both urinary nitrate and Cd excretions on the same day. A linear regression analysis shows 20% of the variation in urinary Cu excretion was associated with urinary Cd excretion on the same day. It is concluded that reductions in renal Cu contents caused by Cd or LPS administration may be a result of Cd and NO displacement of Cu previously bound to metallothionein.

Pyrrolizidine alkaloids in human diet.

Pyrrolizidine alkaloids are the leading plant toxins associated with disease in humans and animals. Upon ingestion, metabolic activation in liver converts the parent compounds into highly reactive electrophiles capable of reacting with cellular macromolecules forming adducts which may initiate acute or chronic toxicity. The pyrrolizidine alkaloids present a serious health risk to human populations that may be exposed to them through contamination of foodstuffs or when plants containing them are consumed as medicinal herbs. Some pyrrolizidine alkaloids (PA) adducts are persistent in animal tissue and the metabolites may be re-released and cause damage long after the initial period of ingestion. PAs are also known to act as teratogens and abortifacients. Chronic ingestion of plants containing PAs has also led to cancer in experimental animals and metabolites of several PAs have been shown to be mutagenic in the Salmonella typhimurium/mammalian microsome system. However, no clinical association has yet been found between human cancer and exposure to PAs. Based on the extensive reports on the outcome of human exposure available in the literature, we conclude that while humans face the risk of veno-occlusive disease and childhood cirrhosis PAs are not carcinogenic to humans.

Expression of cytochrome P450 3A7 in Escherichia coli: effects of 5' modification and catalytic characterization of recombinant enzyme expressed in bicistronic format with NADPH-cytochrome P450 reductase.

Cytochrome P450 3A7 is the major P450 form present in fetal liver tissue and may be responsible for the detoxification of many drugs that reach the fetal circulation. We report the development of bacterial expression systems for P450 3A7. Maximal yields (up to 50 nmol P450/liter culture) were obtained with a construct in which the 5'-terminus of the 3A7 cDNA was modified to include the MALLLAVFL N-terminal sequence of recombinant bovine P450 17A (H. J. Barnes, M. P. Arlotto, and M. R. Waterman, Proc. Natl. Acad. Sci. USA 88, 5597-5601, 1991) and to incorporate several downstream amino acid substitutions derived from the P450 3A5 sequence. This sequence also appeared optimal for expression of P450 3A4 and 3A5. Recombinant P450 3A7 was partially purified using ion-exchange and hydroxylapatite chromatography and reconstituted with NADPH-cytochrome P450 reductase, cytochrome b5, and lipids. Activity comparable to that of P450 3A4 was demonstrated toward a number of procarcinogens. An alternative approach was used to further characterize recombinant 3A7 due to low yields of recombinant protein in the expression and poor recovery in the purification. P450 3A7 was subcloned into a bicistronic vector containing human NADPH-cytochrome P450 reductase and expressed in bacteria. Recombinant P450 3A7 coexpressed in bacterial membranes with NADPH-cytochrome P450 reductase showed similar levels of activity toward erythromycin (N-demethylation) and ethylmorphine (N-demethylation) to P450 3A4 and 3A5 expressed in the same system, whereas 3A7 was less active toward midazolam (1'- and 4-hydroxylation) and nifedipine (oxidation).

p53, proliferating cell nuclear antigen, and Ki-67 expression in extrauterine leiomyosarcomas.

Extrauterine leiomyosarcomas, because of their relative rarity, are poorly understood in regards to their malignant potential and biologic markers. Many human tumors are characterized by overexpression of p53, a tumor suppressor protein, and by expression of nuclear proteins associated with proliferation, such as proliferating cell nuclear antigen (PCNA) and Ki-67. We examined expression of these markers in 44 extrauterine leiomyosarcomas from 10 men and 25 women who ranged in age from 25 to 82 years (mean, 56 yr). Clinical follow-up was obtained in 34 (97%) of 35 patients, p53 expression was studied with two monoclonal antibodies (1801, D07) by use of an antigen retrieval method. p53 overexpression was present in 19 (43%) of 44 cases, whereas Ki-67 and PCNA staining were seen in 29 (66%) and 36 (82%) of 44 cases, respectively. There was no correlation between overall survival or recurrence and p53 or PCNA and Ki-67 expression. We conclude that p53, Ki-67, and PCNA are expressed in a large number of extrauterine leiomyosarcomas. In this study, the expression of these markers did not predict biologic behavior.

Value of ancillary studies in fine needle aspiration cytology of the lung.

The importance of ancillary studies in surgical pathology of the lung is well documented. Less well established is the utility of these methods in fine needle aspiration (FNA) cytology of the lung. We reviewed our experience over a two-year period (1990-1991) with the use of ancillary studies in addition to routine light microscopy in FNA of the lung. Three hundred forty-five percutaneous aspirations were performed under radiologic guidance during this period. A diagnosis of malignancy was made in 233 (68%) cases. Thirty-two aspirates provided specific benign inflammatory or infectious diagnoses of mass lesions. Approximately one-half the cases required no additional studies (181/345, 52%). Immunocytochemistry was performed in 50 cases (14.5%), electron microscopy (EM) in 28 cases (8%), microbiologic staining in 42 cases (12%), mucin staining in 72 cases (21%) and cell blocks in 77 cases (22%). Immunocytochemistry and EM were generally used to classify poorly differentiated neoplasms, confirm the diagnosis of bronchioloalveolar cell carcinoma, determine neuroendocrine differentiation and establish primary sites for suspected metastatic malignancies. Immunocytochemistry provided significant additional information in 20 (40%) of the cases in which it was attempted and confirmed the light microscopic impression in an additional 18 cases (36%). Similarly, EM provided significant additional information in 10 cases (67%) and confirmed the light microscopic impression in an additional 4 cases (27%). Microbiologic staining was performed when an infectious etiology was suspected clinically or an inflammatory (especially granulomatous) background was present in the smears. In 11 cases (27%) the staining was positive for organisms. Mucin staining was performed in an attempt to better classify poorly differentiated non-small cell malignancies and was contributory in 68% of the cases. In conclusion, ancillary studies are helpful in confirming the cytologic impression and making a more specific diagnosis in FNA of the lung.

Multicentric Castleman's disease in a child with prominent thymic involvement: a case report and brief review of the literature.

A fatal case of multicentric Castleman's disease (giant lymph node hyperplasia) with prominent thymic involvement in a 12-yr-old girl is presented. Multicentric Castleman's disease is a poorly understood lymphoproliferative disorder generally occurring in elderly individuals. To our knowledge, this is the first case in the English literature of multicentric Castleman's disease in a child. Thymic involvement has not been described previously in the multicentric variant or in a child. Besides the characteristic findings of Castleman's disease (CD), such as hyaline-vascular follicles and a prominent plasmacytic infiltrate, the thymus was also marked by prominent epithelial hyperplasia in the medulla. The clinical and pathologic findings are presented with a review of the literature, particularly thymic involvement in CD and CD in the pediatric population.