Homolanthionine excretion in homocystinuria.

Patients with homocystinuria excrete in their urine small amounts of an amino acid indistinguishable from authentic L-homolanthionine. This compound could be formed from homocysteine and homoserine by a condensation analogous to that normally leading to cystathionine. The only other known occurrence of homolanthionine in nature is in a methionine-requiring mutant strain of Escherichia coli.

Homocystinuria: excretion of a new sulfur-containing amino Acid in urine.

An unusual homocysteine-containing compound, 5-amino-4-imidazolecarboxamide-5'-S-homocysteinylriboside, was isolated from the urine of a child with homocystinuria and detected in the urines of six homocystinurics. Its metabolic origin is not clear, and the data suggest the existence in man of now unknown alternate pathways for the metabolism of methionine and of purines.

Estimation of the costs of acute gastrointestinal illness in British Columbia, Canada.

The costs associated with gastrointestinal infection (GI) in the province of British Columbia, Canada, were estimated using data from a population-based survey in three health service delivery areas, namely Vancouver, East Kootenay and Northern Interior. The number of cases of disease, consequent expenditure of resources and associated economic costs were modeled as probability distributions in a stochastic model. Using 2004 prices, the estimated mean annual cost per capita of gastrointestinal infection was CAN$128.61 (207.96 euros), with a mean annual cost per case of CAN$1,342.57 (2,170.99 euros). The mean estimate of the overall economic burden to British Columbia was CAN$514.2 million (831.5 million euros) (95% CFI CAN$161.0 million to CAN$5.8 billion; 260.3 million euros to 9.38 billion euros). The major element of this cost was the loss of productivity associated with time away from paid employment by both the sick and their caregivers. Sensitivity analysis suggested that the uncertainty associated with the base model assumptions did not significantly affect the estimates. The results are comparable to those obtained in an earlier study using a similar analytical framework and data from the city of Hamilton, Ontario, Canada.

Cryptococcus gattii infections on Vancouver Island, British Columbia, Canada: emergence of a tropical fungus in a temperate environment.

BACKGROUND: Cryptococcus gattii causes disease among immunocompetent individuals in the tropics and subtropics. We document the appearance of C. gattii infections on Vancouver Island (VI), a temperate region, and discuss reasons for this emergence. METHODS: Data on Cryptococcus hospitalizations for the calendar years 1995 through 2004 were reviewed. Viable historic isolates stored at the provincial public health laboratory between 1987 and 2000 were serotyped. Human cases were mapped by place of residence. RESULTS: Cryptococcosis among HIV negative individuals diagnosed on VI increased sharply after 1999. C. gattii was not detected in stored isolates prior to 1999. C. gattii cases lived in a specific biogeoclimatic zone on VI. Higher rates of illness were associated with exposure to the central region of VI. CONCLUSIONS: The emergence of C. gattii in a temperate region is unprecedented. Clinicians should consider C. gattii in the differential diagnosis of individuals who travelled to certain areas in British Columbia.

Receptor signalling: to sevenless, a daughter.

Genetic studies with Drosophila identified what appeared to be a linear signalling cassette connecting extracellular signals to nuclear responses. But the discovery of a substrate for the Sevenless receptor indicates that the concept of a single, linear pathway may be an oversimplification.

A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction.

BACKGROUND: Mammalian phosphoinositide 3-kinases (PI 3-kinases) are involved in receptor-mediated signal transduction and have been implicated in processes such as transformation and mitogenesis through their role in elevating cellular phosphatidylinositol (3,4,5)-trisphosphate. Additionally, a PI 3-kinase activity which generates phosphatidylinositol 3-phosphate has been shown to be required for protein trafficking in yeast. RESULTS: We have identified a family of three distinct PI 3-kinases in Drosophila, using an approach based on the polymerase chain reaction to amplify a region corresponding to the conserved catalytic domain of PI 3-kinases. One of these family members, PI3K_92D, is closely related to the prototypical PI 3-kinase, p110 alpha; PI3K_59F is homologous to Vps34p, whereas the third, PI3K_68D, is a novel PI 3-kinase which is widely expressed throughout the Drosophila life cycle. The PI3K_68D cDNA encodes a protein of 210 kDa, which lacks sequences implicated in linking p110 PI 3-kinases to p85 adaptor proteins, but contains an amino-terminal proline-rich sequence, which could bind to SH3 domains, and a carboxy-terminal C2 domain. Biochemical analyses demonstrate that PI3K_68D has a novel substrate specificity in vitro, restricted to phosphatidylinositol and phosphatidylinositol 4-phosphate, and is unable to phosphorylate phosphatidylinositol (4,5)-bisphosphate, the implied in vivo substrate for p110. CONCLUSIONS: A family of PI 3-kinases in Drosophila, including a novel class represented by PI3K_68D, is described. PI3K_68D has the potential to bind to signalling molecules containing SH3 domains, lacks p85-adaptor-binding sequences, has a Ca(2+)-independent phospholipid-binding domain and displays a restricted in vitro substrate specificity, so it could define a novel signal transduction pathway.

Drinking water consumption patterns in British Columbia: an investigation of associations with demographic factors and acute gastrointestinal illness.

A cross-sectional telephone survey was performed in the province of British Columbia, Canada, to investigate drinking water consumption patterns and their associations with various demographic characteristics and acute gastrointestinal illness (AGI). Water consumption included plain water and water used in the preparation of cold beverages. The median amount of water consumed daily was four-250 mL servings (1.0 L), although responses were highly variable (0 to 9.0 L). Alternative water use was common: bottled water was the primary source of drinking water (i.e. >or=75% of the total daily water intake) for 23% of respondents and 47% of households used in-home water treatment methods. Approximately 10% of respondents reported an episode of AGI (vomiting or diarrhea) in the previous 4-week period. Such illness was associated with age (continuous variable in years, OR=-0.98), sex (male vs. female, OR=0.8) and the amount of water consumed (continuous variable in 250-mL servings, OR=1.06); however, a causal relationship with water consumption cannot be established based on this study alone. Overall, the associations of drinking water patterns with age, sex, education, and household income serve as important reminders to researchers and public health professionals of the non-uniform nature of drinking water consumption, and indicate potential differences in exposure to waterborne hazards in this population.

UK practice in the prevention of central venous catheter-associated thrombosis in adults on home parenteral nutrition.

BACKGROUND: Maintaining central access is imperative for the delivery of home parenteral nutrition (HPN) in those with intestinal failure. Methods to reduce central venous catheter infection are well recognised; however, the prevention of line thrombosis is less well studied. METHODS: This paper reviews the current evidence and reports a survey of current practice within the UK. Using an electronic survey, respondents were asked to detail their use of anticoagulation in different patient groups and the type of anticoagulation used. RESULTS: 41 replies were received from 31 centres. Only one responder used low-dose warfarin routinely; 80% however anticoagulated those with a previous line thrombosis and 65% anticoagulated those that had any deep vein thrombosis or pulmonary embolus. The most commonly used anticoagulant was dose-adjusted warfarin aiming for an international normalised ratio of 2-3. CONCLUSIONS: The evidence from the current literature in both HPN and the wider field is that there is no clear evidence that anticoagulation is either beneficial or harmful in the prevention of line thrombosis. This survey suggested that practice is varied across the UK likely reflecting the lack of evidence within the current literature.

Partial structure and hormonal regulation of rabbit liver inhibitor-1; distribution of inhibitor-1 and inhibitor-2 in rabbit and rat tissues.

Inhibitor-1 purified from rabbit liver could not be distinguished from the skeletal muscle protein by chromatographic, electrophoretic and immunological criteria. Amino acid sequences comprising 68% of rabbit liver inhibitor-1 were identical to the skeletal muscle protein indicating that they are products of a single gene. Total inhibitor-1 activity in heat-treated rabbit liver extracts was similar to that in skeletal muscle extracts, and the phosphorylation state of inhibitor-1 increased from 14% to 42% in rabbit liver in vivo after an intravenous injection of glucagon. Monospecific antibodies to rabbit skeletal muscle inhibitor-1 recognised a single major protein of identical electrophoretic mobility (26 kDa) in each rabbit tissue examined (skeletal muscle, liver, brain, heart, kidney, uterus and adipose). The antibodies also recognised a single major (30 kDa) protein in the same rat tissues, except liver. The results show that while there are interspecies differences in apparent molecular mass, inhibitor-1 is likely to be the same gene product in each mammalian tissue. Inhibitor-1 was not detected in rat liver, either by activity measurements or immunoblotting, irrespective of the age, sex or strain of the animals. Immunoblotting also failed to detect inhibitor-1 in mouse liver, although it was present in guinea pig, porcine and sheep liver. The absence of inhibitor-1 in rat liver indicates that phosphorylation of this protein cannot underlie the increased phosphorylation of hydroxymethylglutaryl-CoA reductase observed after stimulation by glucagon. Monospecific antibodies to rabbit skeletal muscle inhibitor-2 recognised a 31 kDa protein in each rabbit tissue, and a 33 kDa protein in all rat tissues including liver. The results suggest that inhibitor-2 is the same gene product in each mammalian tissue.

Geographical distribution of acute lymphoblastic leukaemia subtypes: second report of the collaborative group study.

Childhood acute lymphoblastic leukemia (ALL) T and B precursor subtypes have been identified by standardised immunophenotyping in different geographic and ethnic settings. Comparison of the relative frequencies and estimated incidence rates of the major subtypes indicates very similar values, with the striking exception of black childhood populations in Africa in which there appears to be a significant and selective deficit in the incidence of the common (B-cell precursor) subset of ALL. There is suggestive evidence for a similar bias in ALL subtypes in South Africans of mixed ethnic origin and in Mapuche Indians from Chile. Several interpretations of these data are possible but the one favoured attributes these differences primarily to socio-economic factors and patterns of infection in infancy.

Mechanisms of anemia in protein-energy malnutrition in Johannesburg.

Studies of red cell metabolism, erythropoeitin concentration, iron and folate status were made in 48 children with protein-energy malnutrition in Johannesburg (altitude 1800 m). Biochemical evidence of iron deficiency was presented in 26% cases on admission and developed in 90% during recovery. Biochemical evidence of folate deficiency was present in 14% of cases on admission and resolved on dietary therapy alone. Serum erythropoeitin was increased on admission and remained elevated during recovery. There was no relationship between serum erythropoeitin and Hb concentrations. Key enzymes in the red cell glycolytic and hexose monophosphate pathways and red cell membrane showed increased activity. Red cell adenosine triphosphate concentration was increased and unstable. Red cell potassium was decreased and, in the fatal cases, red cell sodium was increased. The possible significance and practical implications of these findings are discussed.

Fanconi anemia: another disease of unusually high prevalence in the Afrikaans population of South Africa.

We have investigated the prevalence of homozygous and heterozygous Fanconi anemia (FA) in the Afrikaans community of the southern Transvaal Province. The minimum birth incidence of FA in white, Afrikaans-speaking South Africans was estimated to be 1 in 22,000, with the calculated heterozygote prevalence being approximately 1 in 77. Alternatively, based on a point prevalence of 1 in 26,000, the carrier rate may be estimated as 1 in 83. It is postulated that this unusually high frequency of the gene for FA is attributable to founder effect.

Fanconi anemia in black African children.

Fanconi anemia (FA) has rarely been reported in black children either in the United States or Africa. This report describes 25 black African children with FA seen in Johannesburg over an 11-year period. The prevalence of homozygotes was estimated to be 1:476,000. Clinical manifestations, mean age at diagnosis, and hematologic and chromosome abnormalities were similar to those described in other ethnic groups. Response to androgens was poor and most patients required regular transfusions. Seventeen (68%) of the children died during the 11-year observation period. Leukemia was the terminal event in 2 patients. The mean age at death was 9.8 years and the mean time between diagnosis and death 2.3 years. The poor response to androgens, high mortality, and early mean age at death would favor consideration of early bone marrow transplantation in these children.

Comparative study of Fanconi anemia in children of different ethnic origin in South Africa.

A comparative study of clinical, hematologic, and cytogenetic findings was made in 40 black and 35 white children with Fanconi anemia. The black children were Bantu-speaking Negroid stock of diverse tribal origin. The white children were predominantly Afrikaans stock of Dutch/German/French Huguenot origin. All of the patients had IFAR scores of 2 to 4+ and over 80% in each group had increased spontaneous and/or mutagen-induced chromosomal breakage (CB-positive). There were no significant clinical differences between black and white patients or between CB-pos and CB-neg patients, with the exception of white children in whom significantly more CB-pos patients had thumb and radial anomalies than the CB-neg patients. The age-at-onset of hematologic manifestations was the same for all groups, but more black than white CB-pos patients were severely anemic at the time of diagnosis. Response to androgen and steroid therapy occurred in only 33% of black children compared with 86-90% of white children; 81% of black patients died during the 18 year study period compared with 30% of white children, but the age at death was similar. More sophisticated studies are required to determine whether these differences are genetically determined or related to cultural, educational, and socio-economic differences between the two ethnic groups.

Hormone replacement therapy awareness in a biracial cohort of women aged 50-54 years.

OBJECTIVES: Previous studies of hormone replacement therapy (HRT) among women have focused on factors associated with the use of such therapy. Most of the studies involved populations of white women. Consequently, little is known about HRT awareness among the general population of women, and particularly among black women. The present study focused on factors associated with HRT awareness among a cohort of black and white women aged 50-54 years. DESIGN: Of more than 2,700 women, aged 50-54 years, who were members of a health maintenance organization, 700 were randomly selected and mailed a questionnaire addressing their awareness of HRT, as well as their menopausal status, medical history, and sources of information on HRT. RESULTS: Of the 700 women, 479 (68.4%) responded to the questionnaire. After exclusions, 421 (88%) were analyzed. On adjusted analysis, the factors most strongly associated with HRT awareness were a higher educational level, the perception of going or having gone through menopause, the presence of menopausal symptoms, and having undergone a bilateral oophorectomy. Black race (independent of educational level) was associated with a lower likelihood of HRT awareness. The most common source of information on HRT for women in this cohort was the physician, followed by the media. CONCLUSIONS: HRT awareness among women is strongly influenced by race, educational level, and the perception of going or having gone through menopause. Public health efforts to encourage wider use of HRT among older women should focus on increasing HRT awareness among black women and women with a lower educational level.

Dirofilaria repens manifesting as a breast nodule. Diagnostic problems and epidemiologic considerations.

Human dirofilarial infections characteristically manifest as pulmonary 'coin' lesions or as subcutaneous nodules. Reported is a case of subcutaneous Dirofilaria infection that first manifested as a painful breast nodule, necessitating excisional biopsy and frozen section interpretation to rule out incipient carcinoma. Histologic examination revealed a viable, adult female Dirofilaria repens, a nematode commonly found in dogs and cats throughout parts of Europe, Africa, and Asia. The patient, a Greek national, had been traveling in Greece and Italy within the previous 8 months. Dirofilariasis is seen infrequently in the United States, and when present is usually caused by the endemic species D. immitis or D. tenuis. Several other species also may infect humans but are rarely seen or may be misidentified as one of the more common species. Identification of dirofilariae from tissue sections is difficult, but knowledge of the parasite's geographic distribution and the patient's travel history are particularly helpful.

Chromosome patterns in 26 South African children with acute nonlymphocytic leukemia (ANLL).

Of 46 black leukemic children 52% had acute nonlymphocytic leukemia (ANLL), whereas only 11% of 62 white leukemic children had the disease. An abnormal karyotype was found in 73% of the 26 children with ANLL, and the majority of abnormal karyotypes were pseudodiploid. "Balanced" translocations were noted in 10 children, of whom four had t(8;21) associated with M2 ANLL, two had t(15;17) and M3 ANLL, two had a t(9;22), one child with M5 ANLL had t(10p;11q), and an infant with congenital M5 ANLL had t(8;16). Monosomy #7 was detected in two preleukemic children who subsequently developed M4 ANLL. Hyperdiploidy was present in only three cases. These patterns were compared with those of other published series, confirming the increased frequency of chromosome abnormalities in children with ANLL. The differing ratio of ANLL:ALL, some of the distinctive clinical features, and the high frequency of detectable chromosome abnormalities in black children may be reflections of a particular oncogenic agent(s) within their environmental background that could be responsible for the initiation of the leukemic process.

A unique 8;16 translocation in two infants with poorly differentiated monoblastic leukemia.

Acute monoblastic leukemia is nonrandomly associated with abnormalities involving 11q. Two infants, one a neonate and the other 19 months of age, had the same hitherto undescribed karyotypic abnormality, t(8;16)(p11;p13), associated with acute nonlymphocytic leukemia M5a. The older child had an additional translocation, t(10;11)(q11;p15), but the chromosome arms affected were the opposite to those described in acute nonlymphocytic leukemia M5a of childhood. Therefore, it is postulated that genes involved in monocytic differentiation may be situated on 8p11 or 16p13, as well as on 11q.

Karyotype analysis in acute nonlymphocytic leukemia (ANLL): comparison with ethnic group, age, morphology, and survival.

The karyotype, leukemia cell morphology (FAB classification), ethnic group, age, sex, and survival were compared in 60 patients with acute nonlymphocytic leukemia (ANLL), to determine their diagnostic and prognostic significance. An ethnic age difference was observed; a significantly greater number of black patients were children. The majority of children were males. A higher frequency of chromosome abnormalities was detected in children, yet they survived longer than adults. A specific, significant association between a (8; 21) karyotype and M2-ANLL was confirmed; four of ten patients with M2-ANLL showed this translocation. The more mature morphology of M2-ANLL was associated with a longer survival irrespective of karyotype, ethnic group, and age. The specificity of t(15; 17) in M3-ANLL and nonrandom monosomy 7 in preleukemic children was confirmed. Patients, particularly adults, with normal karyotypes tended to survive longer than those with abnormal karyotypes. The patient's age and the differentiative capacity of the leukemic cell appear to be as important as the karyotype in determining survival. The nonrandom association of certain chromosome aberrations in ANLL appears to be worldwide.

Immunolocalisation of protein phosphatase inhibitor-1 in the cerebral cortex of the rat, cat and ferret.

The distribution of inhibitor-1 was analysed in the neocortex of cat, ferret and rat by immunocytochemistry (at the light and electron microscope levels) and by immunoblotting using an affinity purified antibody which recognises both the phosphorylated and dephosphorylated forms of the protein. In each mammalian cortex immunocytochemical techniques identified inhibitor-1 predominantly in infragranular pyramidal neurons and, at a lower concentration, in supragranular pyramidal neurons of cortical layers II-III, and V-VI. Within the cortical layers, neuronal cell bodies and apical dendrites were stained strongly but no immunoreactivity was associated with dendritic spines. Regional differences in intensity of staining were revealed when appropriate antibody concentrations were used; the concentration of inhibitor-1 appeared to follow a gradient with the highest levels in layer VI and the lowest in layer I. The results were confirmed by immunoblotting of microdissected cortical regions which identified the inhibitor-1 protein unambiguously. The distribution of inhibitor-1 is different from that reported by other investigators.