Effect of hepatic dysfunction on oral cyclosporin pharmacokinetics in marrow transplant patients

The effect of hepatic dysfunction, defined as abnormal serum bilirubin level, on oral cyclosporin (CSP) pharmacokinetics was examined in 28 marrow transplant patients who received CSP for prophylaxis of graft-v- host disease. Serum CSP concentrations were measured by radioimmunoassay. Forty-one concentration-time courses were studied, divided among patients with no (less than 1.2 mg/dL), mild (1.2 to 2.0 mg/dL), and moderate (2.0 to 5.0 mg/dL) hepatic dysfunction. CSP elimination, as determined by elimination rate constant and clearance, was delayed in patients with moderate hepatic dysfunction compared to those with no hepatic dysfunction (P less than .05). The volume of distribution, lag time for absorption, maximum serum concentration, and time at which the maximum concentration was achieved was not affected by hepatic function. These data indicate that patients with moderate hepatic dysfunction have delayed CSP or CSP metabolite elimination and may be at higher risk for developing CSP-related toxicity.     

Prevalence of depressive symptoms and its associated factors in older adults: a cross-sectional study in Kathmandu,Nepal

Objective: Globally, depression is one of the most prevalent and burdensome conditions in older adults. However, there are few population-based studies of depression in older adults in developing countries. In this paper, we examine the prevalence of depressive symptoms and explore possible contributory risk factors in older adults living in Nepal.

Methods: A cross-sectional study was conducted in two semi-urban communities in Kathmandu, Nepal. Depression was assessed using the 15-item Geriatric Depression Scale in 303 participants, aged 60 years and over. Multivariate logistic regression was then used to assess associations between potential risk factors and depression.

Results: More than half of the participants (n = 175, 60.6%) had significant depressive symptomatology, with 27.7% having scores suggesting mild depression. Illiteracy (aOR = 2.01, 95% CI: 1.08–3.75), physical immobility (aOR = 5.62, 95% CI: 1.76–17.99), the presence of physical health problems (aOR = 1.97, 95% CI: 1.03–3.77), not having any time spent with family members (aOR = 3.55, 95% CI: 1.29–9.76) and not being considered in family decision-making (aOR = 4.02, 95% CI: 2.01–8.04) were significantly associated with depression in older adults.

Conclusion: The prevalence of depression was significant in older adults. There are clear associations of depression with demographic, social support and physical well-being factors in this population. Strategies that increase awareness in the community along with the health and social care interventions are needed to address the likely drivers of depression in older adults.     

Interaction of high molecular weight kininogen, factor XII, and fibrinogen in plasma at interfaces

Using ellipsometry, anodized tantalum interference color, and Coomassie blue staining in conjunction with immunologic identification of proteins adsorbed at interfaces, we have previously found that fibrinogen is the main constituent deposited by plasma onto many man- made surfaces. However, the fibrinogen deposited from normal plasma onto glass and similar wettable materials is rapidly modified during contact activation until it can no longer be identified antigenically. In earlier publications, we have called this modification of the fibrinogen layer "conversion," to indicate a process of unknown nature. Conversion of adsorbed fibrinogen by the plasma was not accompanied by marked change in film thickness, so that we presumed that this fibrinogen was not covered but replaced by other protein. Conversion is now showen to be markedly delayed in plasma lacking high molecular weight kininogen, slightly delayed in plasma lacking factor XII, and normal in plasma that lack factor XI or prekallikrein. We conclude that intact plasma will quickly replace the fibrinogen it has deposited on glass-like surfaces by high molecular weight kininogen and, to a smaller extent, by factor XII. Platelets adhere preferentially to fibrinogen-coated surfaces; human platelets adhere to hydrophobic nonactivating surfaces, since on these, adsorbed firbinogen is not exchanged by the plasma. The adsorbed fibrinogen will be replaced on glass-like surfaces during surface activation of clotting, and platelets failing to find fibrinogen will not adhere.     

Effect of active site-modified thrombin on the hydrolysis of platelet- associated glycoprotein V by native thrombin

To determine the relationship between equilibrium binding of thrombin to sites on the platelet surface and the cleavage of membrane glycoprotein V (GPV) by thrombin, we examined the effect of active site- modified thrombin (1-chloro-3-tosylamido-7-amino-L-2-heptanone thrombin toslysCH2-thrombin) on the binding of native thrombin to platelets and on the hydrolysis of GPV by native thrombin. ToslysCH2-thrombin inhibited binding of native thrombin to high affinity sites on the platelet surface. In contrast, hydrolysis of GPV by native thrombin, even at threshold thrombin concentrations, was not inhibited by pretreatment with toslysCH2-thrombin at concentrations up to 210 nmol/L. ToslysCH2-thrombin also had no appreciable effect on platelet aggregation or release of 14C-serotonin induced by native thrombin. Because toslysCH2-thrombin does not inhibit platelet release, aggregation, or GPV hydrolysis by native thrombin but does inhibit high affinity surface binding by native thrombin, these results indicate that thrombin binding and hydrolysis of GPV are separate and unrelated events.     

Bone marrow imaging: magnetic resonance studies related to age and sex

Measurements of T1 and T2 relaxation values and spin density of the lumbar vertebral bone marrow were performed in 212 patients, and the results were correlated with the patients' age and sex. T1 and T2 relaxation times for bone marrow in the lumbar vertebral bodies showed a progressive decrease with age for both sexes (except for the T2 relaxation values in female patients). The replacement of hematopoietic marrow by fatty marrow could explain the decrease in T1 and T2. The T1 and T2 values were in the same range for the first two age groups (age 1-10 years and age 21-40 years) and became slightly greater for the older female patients (age 51 years and older) than for the older males. This could be due to the loss of bone and mineral content, which is more rapid and significant for women. These normal T1 and T2 values may provide a baseline for future evaluation of diseases involving the lumbar spine.     

Regulation of protein kinase C and role in cancer biology

Protein kinase C (PKC) is a family of closely related lipid-dependent and diacyglycerol-activated isoenzymes known to play an important role in the signal transduction pathways involved in hormone release, mitogenesis and tumor promotion. Reversible activation of PKC by the second messengers diacylglycerol and calcium is an established model for the short term regulation of PKC in the immediate events of signal transduction. PKC can also be modulated long term by changes in the levels of activators or inhibitors for a prolonged period or by changes in the levels of functional PKC isoenzymes in the cell during development or in response to hormones and/or differentiation factors. Indeed, studies have indicated that the sustained activation or inhibition of PKC activityin vivo may play a critical role in regulation of long term cellular events such as proliferation, differentiation and tumorigenesis. In addition, these regulatory events are important in colon cancer, where a decrease in PKC activators and activity suggests PKC acts as an anti-oncogene, in breast cancer, where an increase in PKC activity suggests an oncogenic role for PKC, and in multidrug resistance (MDR) and metastasis where an increase in PKC activity correlates with increased resistance and metastatic potential. These studies highlight the importance and significance of regulation of PKC activityin vivo.     

Arthrogryposis multiplex congenita. Search for prenatal factors in 66 sporadic cases

In a family and epidemiological survey of 66 cases of arthrogryposis multiplex congenita all cases were found to be sporadic and no family association with clubfoot, congenital dislocation of the hip, or hereditary neuromuscular disease was found. The mothers were significantly older than average. Oligohydramnios was noted in only one-third of cases but many other complications of pregnancy, including probable attempts at abortion, had occurred. It is likely that most cases of arthrogryposis are nongenetic and result from a defective intrauterine environment, whether hormonal, vascular, mechanical, or possibly infective.     

Efficacy of "high-intensity" blue-light and "standard" daylight phototherapy for non-haemolytic hyperbilirubinaemia

We report our clinical experience with phototherapy in 3802 infants; 3629 were exposed to "standard" daylight phototherapy and 173 to "high-intensity" blue-light phototherapy. High-intensity blue-light phototherapy was twice as effective as standard daylight phototherapy in decreasing bilirubin concentrations. No failures occurred with high-intensity phototherapy compared with an overall failure rate of 1.84/1000 with daylight lamps; these cases were transferred to high-intensity phototherapy with prompt response. Rebound after cessation of phototherapy was greater in those exposed to high-intensity blue light with a significantly greater number requiring a second exposure. However, the incidence was still low. No third exposure was required in any infant. Nursing of infants under high-intensity blue light was more difficult and inconvenient as was clinical monitoring. The light also caused more stress on the nursing and medical personnel. However, the infants tolerated both types of phototherapy equally well. High-intensity blue-light phototherapy would seem to be the treatment of choice for infants with rapidly increasing or very high bilirubin levels, as well as in those not responding adequately to daylight phototherapy.