Early intervention service intensity and young children's home participation.

BACKGROUND: Young children with developmental disabilities and delays spend significant amounts of time at home, show decreased participation in home-based activities, and receive home-based early intervention services to improve participation in activities. Yet, knowledge about the relationship between EI service use and children's home participation in activities remains poorly understood but needed for program improvement. The purpose of this study was to understand the relationships between EI service use and children's home participation. METHODS: In a cross-sectional design, data were gathered from caregivers (N = 139) who enrolled in a pilot trial of the Young Children's Participation in Environment Measure (YC-PEM) electronic patient-reported outcome (e-PRO), as implemented within 1 month of their child's next EI progress evaluation. A series of path analytic models were used to estimate EI service intensity as a predictor of parent-reported young children's home participation 1) frequency, 2) level of involvement, and 3) desired change, adjusting for family and child social and functional characteristics. Models included caregiver perceptions of home environmental support to test its indirect (i.e., mediation) effects on the relationship between EI service intensity and each of the three home participation dimensions. RESULTS: All three models fit the data well (comparative fit index = 1.00). EI service intensity was not a significant predictor of participation frequency. However, EI service intensity had a significant direct effect on a child's participation according to level of involvement and desired change, explaining between 13.3-33.5% of the variance in home participation. Caregiver perceptions of environmental support had a small yet significant indirect effect on the relationship between EI service intensity and level of involvement and desired change; these models explained between 18.5-38.1% of the variance in home participation. CONCLUSIONS: EI service intensity has important links with involvement in and desired change for home-based activities. Caregiver perceptions of environmental support appears to be a factor in the relationship between EI service intensity and home participation. Results warrant longitudinal replication with a control group, which would be possible with the implementation of the YC-PEM e-PRO in a routine EI clinical workflow. TRIAL RETROSPECTIVELY REGISTERED: NCT03904797 .

Pilot implementation of an electronic patient-reported outcome measure for planning and monitoring participation-focused care in early intervention.

BACKGROUND: Family-centered care is a valued approach to improving child and family outcomes in early intervention (EI), yet there is need to implement interventions that support information exchange for shared decision-making when planning and monitoring EI care. This study aims at estimating the feasibility, acceptability, and value of implementing the Young Children's Participation and Environment Measure (YC-PEM), a valid electronic patient-reported outcome (e-PRO) that is designed to support family engagement when planning care and monitoring outcomes of care. METHODS: Data were gathered from caregivers (N = 139) that were enrolled in a Phase 1 trial of the YC-PEM e-PRO as implemented within 1 month of their child's next EI evaluation of progress. YC-PEM e-PRO feasibility was estimated according to enrollment and completion rates, and mean completion time. Chi-square tests were used to examine parent perceptions of YC-PEM e-PRO acceptability by caregiver education and family income. Caregiver feedback via open-ended responses were content coded to inform intervention and protocol optimizations. YC-PEM e-PRO value was estimated via composite and item-level scores to capture the extent of participation difficulty in home and community activities, and common areas of need regarding caregivers desired change in their child's participation. RESULTS: Feasibility of implementing the YC-PEM e-PRO in routine EI care was mixed, as evidenced by low enrollment rates (21.0-29.2%), a high completion rate (85.3%), and limited missing data (80.6% of completed cases contained no missing data). More than half of the participants reported that the completion of the YC-PEM e-PRO was at least somewhat helpful, regardless of family income or caregiver education, providing support for its acceptability. As for its value, the YC-PEM e-PRO results were viewed by 64% of caregivers, whose desire for change most often pertained to the child's participation in non-discretionary activities at home and structured activities in the community. CONCLUSIONS: Results may support the implementation of YC-PEM e-PRO as a feasible, acceptable, and valued option for engaging families in planning the child's EI care. Results also inform select intervention and protocol optimizations prior to undertaking a multi-site pragmatic trial of its effectiveness on family engagement and shared decision-making within an EI clinical workflow. TRIAL REGISTRATION: Trial number: NCT03904797 . Trial registered at Clinicaltrials.gov . Registered 22 March 2019. Retrospectively registered.

Classifying infants and toddlers with developmental vulnerability: who is most likely to receive early intervention?

BACKGROUND: Infants and toddlers with developmental difficulties represent a heterogeneous group who often receives early intervention (EI). Notable population heterogeneity exists and complicates unmet need and effectiveness research. However, a mix of relatively homogeneous clinically policy relevant 'subgroups' may create the apparent heterogeneity. To date, methodological challenges have impeded identifying these potential groups and their policy-relevance. METHODS: From the 2005-2006 National Survey of Children with Special Health Care Needs, we derived a sample (n = 965) of infants and toddlers with parent-reported developmental difficulties. We used latent class analysis (LCA) to identify subgroups of developmental vulnerability based upon functional, social and biological characteristics that would make children eligible for EI. Mixture modelling estimated the likelihood of each subgroup receiving parent-reported EI, controlling for race/ethnicity, child's age, and state of residence. RESULTS: LCA identified four distinct subgroups of developmental vulnerability: developmental disability (Group 1), mild developmental delay (Group 2), socially at risk with behaviour problems (Group 3), and socially at risk with functional vision difficulties (Group 4). Black, non-Hispanic children are significantly more likely than their white counterparts to be in Group 3 (ß = 1.52, P = 0.001) or group 4 (ß = 1.83, P < 0.001). Compared with children with a mild developmental delay (Group 2), children in group 1 (ß = -0.61, P < 0.001), group 3 (ß = -0.47, P = 0.001) and group 4 (ß = -0.38, P = 0.009) are significantly less likely to receive EI. CONCLUSIONS: Racial and ethnic differences exist with regard to membership in developmental vulnerability subgroups. Observed inconsistencies in access to EI suggest the need for improved surveillance, referral and outreach.

Maternal depression and perceived social support as predictors of cognitive function trajectories during the first 3 years of life for preterm infants in Wisconsin.

BACKGROUND: Among families of infants born preterm, the association between post-natal depression and children's cognitive function is not well understood, but thought to be compromised. The purpose of this study is to investigate maternal depressive symptoms and perceived social support as predictors of children's cognitive function trajectories. METHODS: This is a longitudinal study of a sample of infants born preterm (less than 37 weeks) in Wisconsin. This study includes 130 infants who were hospitalized in one of three Wisconsin neonatal intensive care units in 2002-2005 and followed until 36 months of age. Maternal depressive symptoms were measured using the Center for Epidemiologic Studies Depression Scale. Social support was measured using the Maternal Support Scale. Children's cognitive function was measured using the Bayley Scales of Infant Development, 2nd Edition, and the Stanford-Binet Intelligence Scale, 5th Edition. RESULTS: Children's cognitive function trajectories declined initially and then increased. Being female (coefficient = 5.14, SE = 1.89) and non-poor (coefficient = 11.26, SE = 5.78), and having a mother who has a graduate degree (coefficient = 7.67, SE = 3.37) was associated with higher levels of cognition initially. Being white was associated with a more optimal cognitive trajectory. Although depression did not predict children's cognitive trajectories, the presence of clinically elevated depressive symptoms at 9 months post term was associated with lower cognitive functioning at 16 months when mothers reported low social support. CONCLUSION: Post-natal depressive symptoms appear to have a meaningful, dynamic influence on the cognitive outcomes of children born preterm, above and beyond family socio-demographic risk when the presence and timing of perceived social support are considered. Interventions to ameliorate developmental risk associated with preterm birth should include repeated assessments of maternal social support and post-natal depression and be targeted towards socially disadvantaged families.

Cytochrome p450 2C enzymes contribute to peritransplant ischemic injury and cardiac allograft vasculopathy.

Peritransplant ischemia and reperfusion (I/R) injury contributes to posttransplant vascular dysfunction and cardiac allograft vasculopathy (CAV). We have previously shown that cytochrome p450 (CYP) 2C inhibition significantly reduces I/R-induced myocardial infarction and postischemic vascular dysfunction. In the latter study, pretreatment with sulfaphenazole (SP), a specific inhibitor of CYP 2C, restored postischemic NO-mediated, endothelium-dependent vasodilation and reduced vascular superoxide production. Given the association between I/R injury, early vascular dysfunction and CAV, we hypothesized that CYP 2C may also contribute to the onset of CAV. Lewis-to-Fisher rat heterotopic heart transplants were performed. Donors and recipients were treated with 5 mg/kg SP or vehicle control 1 h prior to surgery. SP did not affect posttransplant morbidity, mortality or weight gain. Coronary blood vessels from rats treated with SP exhibited significantly reduced luminal narrowing and demonstrated a corresponding decrease in smooth muscle cell (SMC) proliferation compared to controls. SP did not reduce diffuse, focal, epicardial, endocardial or perivascular immune infiltration nor did it significantly alter TUNEL positivity in myocardial, endothelial or SMC populations. In conclusion, CYP 2C contributes to SMC proliferation CAV without affecting general immune infiltration.

Profound inhibition of myogenic tone in rat cardiac allografts is due to eNOS- and iNOS-based nitric oxide and an intrinsic defect in vascular smooth muscle contraction.

BACKGROUND: The physiological consequences of inducible NO synthase (iNOS) expression were studied in allograft coronary arteries by pressure myography. METHODS AND RESULTS: Septal coronary arteries (diameter, 200.6+/-3.3 microm) were harvested from allograft and isograft hearts, and their myogenic properties were measured before and after iNOS and nonselective NOS inhibition with aminoguanidine (AG, 100 micromol/L) and N(G)-nitro-L-arginine methyl ester (L-NAME) (200 micromol/L). Fura 2 fluorescence microscopy was used to measure [Ca(2+)](i) in isolated endothelial cells. Monoclonal anti-iNOS immunostains demonstrated iNOS protein in day 2, 7, 14, and 28 allograft vessels, but only in day 2 isograft vessels. Myogenic tone was profoundly inhibited in allograft vessels from day 4 onward. In day 4 allograft vessels, these differences were abolished by L-NAME but not AG, suggesting greater basal release of eNOS-based NO from allograft endothelium. Fluorescence measurements confirmed elevation of [Ca(2+)](i) in day 4 allograft endothelium, providing a mechanism for enhanced eNOS activity. For days 7 to 28, AG potentiated myogenic tone in allograft but not isograft vessels, indicating that vasoactive iNOS-based NO was present. In mature vessels, constriction via agonist- and depolarization-mediated mechanisms showed parallel inhibition, suggesting an intrinsic defect in vascular smooth muscle cell contraction. CONCLUSIONS: Our data indicate that the profound inhibition of myogenic tone in allograft arteries involves direct vasodilation by eNOS- and iNOS-based NO, as well as an intrinsic defect in vascular smooth muscle contraction. The hemodynamic profile resulting from these changes in allograft resistance vessel function would favor movement of extracellular fluid from the intravascular space into the myocardial interstitium, resulting in edema, increased ventricular stiffness, and poor ventricular performance.

New method for detection of heart allograft rejection: validation of sensitivity and reliability in a rat heterotopic allograft model.

BACKGROUND: Patients with inflammatory heart muscle diseases would benefit from a safe, convenient, rapidly performed diagnostic technique with real-time results not involving tissue removal. We have performed a detailed evaluation of detection of heart allograft rejection by autofluorescence in a heterotopic abdominal rat heart allograft model ex vivo. METHODS AND RESULTS: Recipient rats with allograft (Lewis to Fisher 344; n=71) and isograft (Lewis to Lewis; n=33) hearts, treated with cyclosporine or untreated, were killed at days 2, 4, 7, 14, 21, 28, and 56 after transplant. Nontransplant controls with (n=24) or without (n=24) immunosuppressive therapy were also studied. When the rats were killed, autofluorescence spectra were acquired under blue-light excitation from midtransverse ventricular sections of native and transplanted hearts. Corresponding sections were then evaluated pathologically by a modified International Society for Heart and Lung Transplantation (ISHLT) grading schema. The spectral differences between rejecting and nonrejecting hearts were quantified by linear discriminant functions, producing scores that decreased progressively with increasing severity of tissue rejection. Mean+/-SD discriminant function scores were 2.9+/-1.6, 1.8+/-2.2, -0.1+/-2.8, -1.2+/-2.3, and -2.3+/-3.0 for isografts and allograft ISHLT grades 0, I, II, and III, respectively (Spearman rank-order correlation -0.6; P<0.001, test for trend). Cyclosporine had no detectable effect on the spectra. CONCLUSIONS: The correlation between changes in autofluorescence spectra and ISHLT rejection grade strongly supports the possibility of catheter-based, fluorescence-guided surveillance of rejection.

Interaction of viral proteins with host cell death machinery.

In recent years, intense research has been directed towards understanding molecular mechanisms involved in viral pathogenesis. It is now known that many viruses manipulate host defense mechanisms to prevent apoptosis in order to maximize viral replication. Towards the end of their replication cycle, certain viruses direct the synthesis of proteins that induce apoptosis or cell lysis thereby facilitating viral release from the cell. The present review summarizes the current understanding of interactions between viral proteins and the host cell death machinery.

Insensitivity of right ventricular endomyocardial biopsy in the diagnosis of myocarditis.

The clinical suspicion of myocarditis relies strongly on endomyocardial biopsy for confirmation, yet the sensitivity of the procedure in this setting has not been clearly defined. Biopsy sensitivity was determined in 14 hearts with histologically proved myocarditis studied ex vivo, including 12 autopsy hearts and 2 native hearts explanted at cardiac transplantation. With use of the Stanford and Cordis bioptomes, endoymocardial biopsy was performed near the apex on the right side of the ventricular septum (four to five samples/bioptome per patient) and repeated in the nonapical portion of the septum from the moderator band to the subpulmonary infundibulum (additional three to five samples/bioptome per patient). In a casewise assessment, 43% to 57% of the endomyocardial samples were diagnostic for myocarditis, as calculated separately for each bioptome in each region of sampling (apical/nonapical). Both apical and nonapical sensitivity improved to 64% when the findings of the two bioptomes were combined (eight to nine samples/patient in each region). By collectively analyzing all available samples for each patient, 11 (79%) of 14 cases could be diagnosed, but this required a mean of 17.2 samples/patient, a number clinically unrealistic. The exclusion of four cases of fungal myocarditis from analysis did not significantly alter the results. In transmural ventricular sections, none of four patients with sudden death had inflammatory disease confined to the conduction system. In conclusion, despite six to eight negative biopsy samples/patient with suspected myocarditis, repeat biopsy may still be warranted.

Postnatal atresia of extraparenchymal pulmonary veins, fulminant necrotizing pulmonary arteritis and elevated circulating immune complexes.

An infant with operatively corrected total anomalous pulmonary venous connection developed postnatal atresia of the extraparenchymal left pulmonary veins with secondary arteritis of the ipsilateral intraparenchymal pulmonary arteries. Atresia of the right or left main pulmonary veins or of the common pulmonary vein is a rare occurrence and it is believed that association of such with necrotizing pulmonary arteritis has never been reported. This case illustrates the potential consequences of severe pulmonary venous obstruction in the absence of a left to right shunt.

Fatal vasculitis (periarteritis nodosa) of the coronary arteries: angiographic ambiguities and absence of aneurysms at autopsy.

A 30 year old man died during coronary artery bypass grafting for presumed premature atherosclerotic coronary disease. Autopsy revealed vasculitis with characteristics of periarteritis nodosa of the coronary arteries with severe luminal narrowing, but without aneurysms. This is the first report of a patient with these findings studied angiographically and at autopsy.

Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans.

Apolipoprotein E (apo E) deficiency (or its abnormalities in humans) is associated with a series of pathological conditions including dyslipidemia, atherosclerosis, Alzheimer's disease, and shorter life span. The purpose of this study was to characterize these conditions in apo E-deficient C57BL/6J mice and relate them to human disorders. Deletion of apo E gene in mice is associated with changes in lipoprotein metabolism [plasma total cholesterol (TC) (>+400%), HDL cholesterol (-80%), HDL/TC, and HDL/LDL ratios (-93% and -96%, respectively), esterification rate in apo B-depleted plasma (+100%), plasma triglyceride (+200%), hepatic HMG-CoA reductase activity (-50%), hepatic cholesterol content (+30%)], decreased plasma homocyst(e)ine and glucose levels, and severe atherosclerosis and cutaneous xanthomatosis. Hepatic and lipoprotein lipase activities, hepatic LDL receptor function, and organ antioxidant capacity remain unchanged. Several histological/immunohistological stainings failed to detect potential markers for neurodegenerative disease in the brain of 37-wk-old male apo E-KO mice. Apo E-KO mice may have normal growth and development, but advanced atherosclerosis and xanthomatosis may indirectly reduce their life span. Apo E plays a crucial role in regulation of lipid metabolism and atherogenesis without affecting lipase activities, endogenous antioxidant capacity, or appearance of neurodegenerative markers in 37-wk-old male mice.

Homocyst(e)ine and coronary artery disease. Clinical evidence and genetic and metabolic background.

Many studies have demonstrated a strong association between elevated plasma total homocyst(e)ine levels and vascular diseases. Consequently, hyperhomocyst(e)inemia is now generally accepted as an independent risk factor for coronary artery disease. We critically reviewed the results of 35 human studies in which the levels of plasma total homocysteine were measured in patients with atherosclerotic diseases (n = 4338) and in controls (n = 22,593). Total homocysteine levels were consistently higher in patients than in controls. The average of this increment among 23 case-control studies was 26%. New insights into the biochemical pathways of total homocysteine metabolism, the factors that influence total homocysteine levels, genetic contributions to hyperhomocyst(e)inemia, the pathogenesis of homocyst(e)ine-induced vascular damage, and current recommendations for treatment of hyperhomocyst(e)inemia were also reviewed. Various lines of evidence now link hyperhomocyst(e)inemia with vascular diseases. Although there are no data from double-blind, placebo-controlled clinical trials of treatment for hyperhomocyst(e)inemia, the strong epidemiologic and experimental evidence argues for treatment of hyperhomocyst(e)inemia; in fact, its treatment with low doses of vitamins is thought to be safe and is inexpensive.

Bcl-2 increases emptying of endoplasmic reticulum Ca2+ stores during photodynamic therapy-induced apoptosis.

Photodynamic therapy (PDT) is clinically approved for the treatment of several types of cancer as well as age-related macular degeneration, the leading cause of blindness in the elderly. PDT using the photosensitizer verteporfin has been previously shown to induce rapid apoptosis via a mitochondrial-caspase activation pathway. The impact of PDT on other cellular organelles such as the endoplasmic reticulum (ER) is undefined. The effect of PDT on intracellular Ca2+ ([Ca2+]i) in control and Bcl-2-overexpressing HeLa cells was assessed. A greater [Ca2+]i transient was observed for Bcl-2 overexpressing cells in response to PDT. The PDT-induced Ca2+ release was due to the emptying of Ca2+ from ER and possibly mitochondrial stores and was not due to an influx of Ca2+ from the medium. For Bcl-2-transfected cells, the release of Ca2+ was incomplete as determined by a further [Ca2+]i transient produced by the addition of the Ca2+ ionophore ionomycin after PDT. Furthermore, extrusion of Ca2+ was not hindered while ER-mediated sequestration of Ca2+ was impaired after PDT. Impairment of ER-mediated sequestration of Ca2+ may be due to the immediate caspase-independent depletion of sarco/endoplasmic reticulum Ca2+ ATPase-2 (SERCA2) that occurred in response to PDT in birth HeLa/Neo and Bcl-2 overexpressed HeLa cells. In summary, PDT induced the rapid degradation of SERCA2 and release of ER and mitochondrial Ca2+ stores. Although overexpression of Bcl-2 did not protect against SERCA2 degradation, it may influence the release of Ca2+ from ER and mitochondrial stores in PDT-treated cells.

Phenotypic correction of feline lipoprotein lipase deficiency by adenoviral gene transfer.

Previous studies have revealed that adenovirus-mediated ectopic liver expression of human LPL (huLPL) can efficiently mediate plasma triacylglycerol (TG) catabolism in mice despite its native expression in adipose and muscle tissue. We aimed to explore the feasibility of liver-directed gene transfer and enzyme replacement for human LPL deficiency in a larger, naturally occurring feline animal model of complete LPL deficiency that is remarkably similar in phenotype to the human disorder. A cohort of LPL-deficient (LPL -/-) cats was given an intravenous injection of 8 x 10(9) PFU/kg of a CMV promoter/enhancer-driven, E1/E3-deleted adenoviral (Ad) vector containing a 1.36-kb huLPL cDNA (Ad-LPL) or reporter alkaline phosphatase gene (Ad-AP). After Ad-LPL administration, active, heparin-releasable huLPL was readily detected along with a 10-fold reduction in plasma TGs, disappearance of plasma TG-rich lipoproteins up to day 14, and enhanced clearance of an excess intravenous fat load on day 9. However, antibody against the huLPL protein was detected on day 14 in cats receiving Ad-LPL and adenovirus-specific neutralizing antibody was present 7 days after gene transfer in both cat cohorts. Tissue-specific expression of the huLPL transgene relative to controls was confirmed by RT-PCR. While huLPL expression was evident in the liver, other tissues including spleen and lung expressed huLPL message, in direct correlation with histological evidence of increased Oil red O (ORO)-positive neutral lipid influx. In contrast, intravenous LPL enzyme replacement therapy (ERT) led to rapid disappearance of 9000 mU/kg of active bovine LPL enzyme from the circulation, with t1/2 occurring at <10 min in two LPL-/- cats. Heparin injection 1 hr later released <10% of the original bovine LPL, further indicating its rapid systemic clearance, inactivation, or degradation as well as its ineffectiveness as a viable therapeutic alternative for complete LPL deficiency. Although LPL gene transfer and expression via this first-generation Ad vector was limited by the immune response against both the human LPL protein and adenovirus our results clearly provide a key advance supporting further development of LPL gene therapy as a viable therapeutic option for clinical LPL deficiency.

Rapid cytochrome c release, activation of caspases 3, 6, 7 and 8 followed by Bap31 cleavage in HeLa cells treated with photodynamic therapy.

Photodynamic therapy (PDT) is a clinical approach that utilizes light-activated drugs for the treatment of a variety of pathologic conditions. The initiating events of PDT-induced apoptosis are poorly defined. It has been shown for other proapoptotic stimuli that the integral endoplasmic reticulum protein Bap31 is cleaved by caspases 1 and 8, but not by caspase-3. Further, a 20 kDa Bap31 cleavage fragment is generated which can induce apoptosis. In the current report, we sought to determine whether Bap31 cleavage and generation of p20 is an early event in PDT-induced apoptosis. The mitochondrial release of cytochrome c, involvement of caspases 1, 2, 3, 4, 6, 7, 8, and 10 and the status of several known caspase substrates, including Bap31, were evaluated in PDT-treated HeLa cells. Cytochrome c appeared in the cytosol immediately following light activation of the photosensitizer benzoporphyrin derivative monoacid ring A. Activation of caspases 3, 6, 7, and 8 was evident within 1-2 h post PDT. Processing of caspases 1, 2, 4, and 10 was not observed. Cleavage of Bap31 was observed at 2-3 h post PDT. The caspase-3 inhibitor DEVD-fmk blocked caspase-8 and Bap31 cleavage suggesting that caspase-8 and Bap31 processing occur downstream of caspase-3 activation in PDT-induced apoptosis. These results demonstrate that release of mitochondrial cytochrome c into the cytoplasm is a primary event following PDT, preceding caspase activation and cleavage of Bap31. To our knowledge, this is the first example of a chemotherapeutic agent inducing caspase-8 activation and demonstrates that caspase-8 activation can occur after cytochrome c release.

Overexpression of Bcl-X(L) prevents caspase-3-mediated activation of DNA fragmentation factor (DFF) produced by treatment with the photochemotherapeutic agent BPD-MA.

Photodynamic therapy (PDT) is a clinically effective cancer treatment. For human promyelocytic leukemia HL-60 cells, cleavage of pro-caspase-3 (CPP32/Yama/apopain) into its proteolytically active subunits rapidly follows the photodynamic treatment of these cells with cytotoxic levels of the photosensitizer benzoporphyrin derivative monoacid ring A and visible light. Cleavage of a recently identified cytosolic 45 kDa protein, DNA fragmentation factor (DFF), is required for endonuclease activation leading to DNA fragmentation. In the present study, DFF was rapidly processed following PDT. Overexpression of the anti-apoptotic Bcl-X(L) gene in HL-60 cells prevented PDT-induced caspase activation, DFF cleavage and DNA fragmentation. These results demonstrate for the first time an example of chemotherapeutic drug-induced activation of DFF and its regulation by Bcl-X(L).

Lipid phenotypes, apolipoprotein genotypes and cardiovascular risk in nonagenarians.

Despite great interest in the role of lipids in overall and disease-free survival, virtually no information is available on the lipids, lipoproteins and apolipoproteins of persons over 90 years of age. Furthermore, the genetic underpinnings of atherosclerosis and the particular genetic factors responsible for protection against coronary artery disease remain speculative. In Bloomfield, Nebraska, we studied 41 nonagenarians (10 males, 31 females), with a mean age of 92.7 years, in whom lipids, lipoproteins, apolipoproteins and restriction fragment length polymorphisms (RFLPs) of genes for apolipoprotein B (apo B), aop AI and apo CIII were assessed. Nearly complete historical, physical and laboratory data were obtained on 39 subjects. The mean diastolic and systolic blood pressures for this group were nonhypertensive, body mass indices (weight/height2) had a mean of 23.9 and triceps skinfold thickness measurements an overall mean of 14.8 mm. The mean total serum cholesterol was 5.42 mmol/l. HDL-cholesterol levels in females persisted to be higher when compared to males (P less than 0.013). The allele frequencies for apo AI (MspI and PstI), apo CIII (Sst) and apo B (XbaI) gene RFLPs were typical for larger population studies. In these preliminary studies, we did not identify a distinctive phenotype, genotype, or phenotype-genotype relationship. Diversity of cardiovascular risk was the hallmark of these nonagenarians.

Fatal water intoxication, schizophrenia, and diuretic therapy for systemic hypertension.

Clinical and morphologic findings are described in a 37-year-old hypertensive man with chronic schizophrenia who had two well-documented episodes of water intoxication. The use of diuretics for control of systemic hypertension in the setting of chronic schizophrenia appears ill-advised.

Giant cell arteritis of the legs. Clinical isolation of severe disease with gangrene and amputations.

Giant cell arteritis rarely presents as clinically advanced extra-ocular ischemia or gangrene. Clinically isolated leg involvement with amputation is even more unusual. A 69-year-old woman is described who had giant cell arteritis necessitating bilateral leg amputations. No other clinical sequelae have ensued during a four-year follow-up period. Temporal artery biopsy subsequent to the amputations revealed no arteritis. Disparities between the usual patterns of clinical and anatomic involvement in giant cell arteritis underlie the potential diagnostic difficulties in this disease. Although typically diagnostic, temporal artery biopsy does not always bridge the clinical and anatomic disparities.