PTHrP and insulin levels following oral glucose and calcium administration

BACKGROUND: Parathyroid hormone-related peptide (PTHrP), identified as a tumor product, is responsible for humoral malignant hypercalcemia. Unlike PTH, PTHrP is found in almost every body tissue including pancreatic alpha, beta, delta, and pp cells, where it is processed into multiple secretory forms, co-packaged with insulin, and secreted in a regulated fashion in response to insulin secretagogues. Ionized calcium is a stimulator for the release of several peptide hormones. METHODS: In the present study, we examined the effect of an oral calcium (1 g elemental calcium) and glucose (75 g) load on insulin and PTHrP release in 16 healthy volunteers and of an oral calcium load in 16 non-insulin-dependent diabetes mellitus (NIDDM) patients. Serum calcium, glucose, insulin, and PTHrP levels were determined at 0, 5, 10, 15, 30, and 60 min. RESULTS: Our results indicate that, at each time point, type 2 diabetic patients exhibited greater basal values of PTHrP than controls (200.3+/-110.5 pg/ml vs. 82.0+/-22.3 pg/ml, respectively, p<0.0001). The PTHrP level was consistently higher in response to the glucose load than the calcium load at each time point observed (p<0.0001). NIDDM patients exhibited greater basal serum PTHrP levels than the control group. CONCLUSION: PTHrP was proven for the first time to be released from beta cells in parallel to insulin and in response to glucose stimulation.     

Tyrosine kinase inhibitors suppress the growth of non-hodgkin B lymphomas

Non-Hodgkin lymphomas usually become resistant to chemotherapy and relapse due to the their intense antiapoptotic robustness. Furthermore, the slow growth of these malignancies limits the effectiveness of drugs aimed mainly at the proliferative pathways. Because protein tyrosine kinases (PTKs) play a key role in both proliferative and antiapoptotic pathways we screened our library of PTK inhibitors for agents that induce growth arrest and apoptosis in non-Hodgkin B cell lymphoma cell lines. Herein, we describe the identification of a family of PTK inhibitors whose most potent member is AGL 2592. This agent induces growth arrest and massive apoptosis in a number of non-Hodgkin lymphoma cell lines. We also show that the lymphoma cell lines are much more sensitive to this class of agents compared with other malignant carcinoma cells. AGL 2592 induces a dose-dependent and time-dependent inhibition of tyrosine phosphorylation of numerous proteins, including Stat3, and an increase of Bcl-2 phosphorylation, both biochemical hallmarks of growth inhibition and apoptosis.     

Cognitive,interpersonal, and behavioral predictors of patients' and spouses' depression

BACKGROUND: This study examined the relationship between five theory-based variables and the severity of depression. The variables were self-concept, self and spouse ascribed hostility, spouses' level of depression, and involvement in home activities. METHODS: Based on DSM-IV criteria and Beck Depression Inventory (BDI) scores, 75 wife-depressed couples and 59 husband-depressed couples were included in the study. In addition to the BDI, both spouses completed questionnaires relating to self-concept, self- and spouse ascribed hostility, and involvement in home activities. RESULTS: Multiple regression analyses for male and female patients and spouses revealed that in the four groups self-concept was significantly related to the severity of depression. Irrespective of clinical status, involvement in home activities was significantly associated with the severity of depression of women. The relationship between spouse ascribed hostility and the level of depression of both spouses in husband-depressed couples approached significance so did the relationship between patient's and spouse's level of depression in wife-depressed couples. In husband-depressed couples the association between spouses' level of depression reached significance. CONCLUSIONS: The shared and gender-related predictors of severity of depression support an integrative theoretical approach to depression and offer practical implications.     

Activity-dependent neuroprotective protein: a novel gene essential for brain formation

We have recently cloned the novel homeobox-containing activity-dependent neuroprotective protein (ADNP). In the current study, mouse ADNP was shown to be expressed at the time of neural tube closure, detected at E7.5 and increased on E9.5. Expression was augmented in the brain (E12.5), sustained throughout embryogenesis and regulated by VIP. To assess the function of ADNP, knockout mice were established. Detailed analysis revealed cranial neural tube closure failure and death on E8.5-9.0 of the ADNP-knockout embryos. The expression of Oct4, a gene associated with germ-line maintenance was markedly augmented in the knockout embryos. In contrast, the expression of Pax6, a gene crucial for cerebral cortex formation, was abolished in the brain primordial tissue of the knockout embryos. Thus, Pax6 and Oct4 constitute a part of the mechanism of action of ADNP on brain formation, inhibiting germ-line division while activating morphogenesis. In conclusion, ADNP is identified here as a new key gene essential for organogenesis in the developing embryo and may be implicated as a clinical target associated with proper neurodevelopment.     

Low serum LDL cholesterol levels and the risk of fever, sepsis, and malignancy

Lipid lowering therapy of serum LDL cholesterol (LDL) has proved beneficial in reducing cardiovascular morbidity and mortality. Lately the recommended target LDL level in very high risk patients was reduced to <70 mg/dl, raising the question of what the price of such a low level will be. To elucidate this concern, we investigated the associations of low serum LDL cholesterol levels (< or = 70 mg/dl) and the incidences of fever, sepsis, and malignancy. Retrospective analysis of 203 patients' charts was carried out. Patients were divided into 2 groups: Group 1 (n = 79) had serum LDL levels < or = 70 mg/dl, while Group 2 (n = 124) had levels >70 mg/dl. The first group demonstrated increased odds of hematological cancer by more than 15-fold (OR 15.7, 95% CI 1.78-138.4, p = 0.01). Each 1 mg/dl increase in LDL was associated with a relative reduction of 2.4% in the odds of hematological cancer (OR 0.976, 95% CI 0.956-0.997, p = 0.026). Low LDL levels also increased the odds of fever and sepsis between the groups (OR 5.3, 95% CI 1.8-15.7, p = 0.02). In summary, low serum LDL cholesterol level was associated with increased risks of hematological cancer, fever, and sepsis.     

Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model

Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate essential genes. Because complete ADNP deficiency is embryonic lethal, the outcome of partial ADNP deficiency was examined. ADNP(+/-) mice exhibited cognitive deficits, significant increases in phosphorylated tau, tangle-like structures, and neurodegeneration compared with ADNP(+/+) mice. Increased tau hyperphosphorylation is known to cause memory impairments in neurodegenerative diseases associated with tauopathies, including the most prevalent Alzheimer's disease. The current results suggest that ADNP is an essential protein for brain function and plays a role in normal cognitive performance. ADNP-deficient mice offer an ideal paradigm for evaluation of cognitive enhancers. NAP (NAPVSIPQ) is a peptide derived from ADNP that interacts with microtubules and provides potent neuroprotection. NAP treatment partially ameliorated cognitive deficits and reduced tau hyperphosphorylation in the ADNP(+/-) mice. NAP is currently in phase II clinical trials assessing effects on mild cognitive impairment.