Modulation of secreted beta-amyloid precursor protein and amyloid beta-peptide in brain by cholesterol

The effects of dietary cholesterol on brain amyloid precursor protein (APP) processing were examined using an APP gene-targeted mouse, genetically humanized in the amyloid beta-peptide (Abeta) domain and expressing the Swedish familial Alzheimer's disease mutations. These mice express endogenous levels of APP holoprotein and abundant human Abeta. Increased dietary cholesterol led to significant reductions in brain levels of secreted APP derivatives, including sAPPalpha, sAPPbeta, Abeta1-40, and Abeta1-42, while having little to no effect on cell-associated species, including full-length APP and the COOH-terminal APP processing derivatives. The changes in levels of sAPP and Abeta in brain all were negatively correlated with serum cholesterol levels and levels of serum and brain apoE. These results demonstrate that secreted APP processing derivatives and Abeta can be modulated in the brain of an animal by diet and provide evidence that cholesterol plays a role in the modulation of APP processing in vivo. APP gene-targeted mice lacking apoE, also have high serum cholesterol levels but do not show alterations in APP processing, suggesting that effects of cholesterol on APP processing require the presence of apoE.     

AI in medical education--another grand challenge for medical informatics

The potential benefits of artificial intelligence in medicine (AIM) were never realized as anticipated. This paper addresses ways in which such potential can be achieved. Recent discussions of this topic have proposed a stronger integration between AIM applications and health information systems, and emphasize computer guidelines to support the new health care paradigms of evidence-based medicine and cost-effectiveness. These proposals, however, promote the initial definition of AIM applications as being AI systems that can perform or aid in diagnoses. We challenge this traditional philosophy of AIM and propose a new approach aiming at empowering health care workers to become independent self-sufficient problem solvers and decision makers. Our philosophy is based on findings from a review of empirical research that examines the relationship between the health care personnel's level of knowledge and skills, their job satisfaction, and the quality of the health care they provide. This review supports addressing the quality of health care by empowering health care workers to reach their full potential. As an aid in this empowerment process we argue for reviving a long forgotten AIM research area, namely, AI based applications for medical education and training. There is a growing body of research in artificial intelligence in education that demonstrates that the use of artificial intelligence can enhance learning in numerous domains. By examining the strengths of these educational applications and the results from previous AIM research we derive a framework for empowering medical personnel and consequently raising the quality of health care through the use of advanced AI based technology.     

Adenovirus-mediated gene transfer of cGMP-dependent protein kinase increases the sensitivity of cultured vascular smooth muscle cells to the antiproliferative and pro-apoptotic effects of nitric oxide/cGMP

Studies in vitro have underestimated the importance of cGMP-dependent protein kinase (PKG) in the modulation of vascular smooth muscle cell (SMC) proliferation and apoptosis in vivo. This is attributable, in part, to a rapid decline in PKG levels as vascular SMC are passaged in culture. We used a recombinant adenovirus encoding PKG (Ad.PKG) to augment kinase activity in cultured rat pulmonary artery SMC (RPaSMC). Incubation of Ad. PKG-infected RPaSMC (multiplicity of infection = 200) with 8-Br-cGMP decreased serum-stimulated DNA synthesis by 85% and cell proliferation at day 5 by 74%. The effect of 8-Br-cGMP on DNA synthesis in Ad.PKG-infected RPaSMC was blocked by KT5823 (PKG inhibitor), but not by KT5720 (cAMP-dependent protein kinase inhibitor). A nitric oxide (NO) donor compound, S-nitrosoglutathione, at concentrations as low as 100 nM, inhibited DNA synthesis in Ad. PKG-infected RPaSMC, but not in uninfected cells or in cells infected with a control adenovirus. In addition, 8-Br-cGMP and S-nitrosoglutathione induced apoptosis in serum-deprived RPaSMC infected with Ad.PKG, but not in uninfected cells or in cells infected with a control adenovirus. These results demonstrate that modulation of PKG levels in vascular SMC can alter the sensitivity of these cells to NO and cGMP. Moreover, these observations suggest an important role for PKG in the regulation of vascular SMC proliferation and apoptosis by NO and cGMP.     

Effect of GF120918, a potent P-glycoprotein inhibitor, on morphine pharmacokinetics and pharmacodynamics in the rat

PURPOSE: Studies have shown that 11% to 18% of patients with an abdominal aortic aneurysm (AAA) have a first-degree relative with an AAA. A familial pattern among patients with peripheral arterial aneurysms and arteriomegaly has not been reported. The objective of this study was to examine familial patterns among patients with peripheral arterial aneurysm and arteriomegaly and compare them with patterns among patients with AAA. METHODS: Pedigrees were constructed for first-degree relatives of patients who received the diagnosis of peripheral arterial aneurysm, arteriomegaly, or AAA from 1988 through 1996. The presence of aneurysms and risk factors was confirmed for patients and relatives by means of telephone interviews and review of hospital and physician records. RESULTS: Seven hundred three first-degree relatives older than 50 years were contacted for 140 probands with peripheral arterial aneurysm, AAA, or arteriomegaly. There were differences in risk factors for hernia and diabetes mellitus among the probands with peripheral arterial aneurysm, AAA, or arteriomegaly but none for relatives. Patients with peripheral arterial aneurysm (n = 40) had a 10% (4/40) familial incidence rate of an aneurysm, patients with AAA (n = 86) had a 22% (19/86) familial incidence rate, and patients with arteriomegaly (n = 14) had a 36% (5/14) familial incidence rate. AAA (24/28, or 86%) was the aneurysm diagnosed most commonly among first-degree relatives. Most aneurysms (85%) occurred among men. CONCLUSION: There appears to be a gradation of familial patterns from peripheral arterial aneurysm to AAA to arteriomegaly among patients with degenerative aneurysmal disease, and there appears to be a predominance among men. Relatives of patients with any of the 3 lesions-peripheral arterial aneurysm, AAA, arteriomegaly--most frequently have AAA. Relatives of patients with AAA, peripheral arterial aneurysm, or arteriomegaly may be screened by means of a physical examination for peripheral aneurysmal disease. Screening by means of ultrasound examination of the aorta should be limited to first-degree relatives of patients with aortic aneurysms or arteriomegaly.     

DARPP-32: regulator of the efficacy of dopaminergic neurotransmission

Dopaminergic neurons exert a major modulatory effect on the forebrain. Dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein (32 kilodaltons) (DARPP-32), which is enriched in all neurons that receive a dopaminergic input, is converted in response to dopamine into a potent protein phosphatase inhibitor. Mice generated to contain a targeted disruption of the DARPP-32 gene showed profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication. The results show that DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission.     

Decreased growth of Streptococcus uberis in milk from mammary glands of cows challenged with the same mastitis pathogen

Milk samples from mammary glands challenged with Streptococcus uberis and from unchallenged mammary glands were selected for analyses of bacterial growth, antibody response, and lactoperoxidase activity. All challenged mammary glands became infected with isolation of S. uberis and elevated somatic cell counts in milk during the first week after challenge. In vitro growth of the homologous challenge strain and a heterologous strain of S. uberis was significantly lower in milk from challenged mammary glands than in milk from control mammary glands at 3, 5, and 7 days after challenge. Removal of casein significantly reduced bacterial growth. In general, antibodies specific to S. uberis started to increase at day 3 post-challenge and were higher in milk from challenged mammary glands than in milk from control mammary glands. There was also a marked increase in total IgG in milk from challenged mammary glands. Growth of S. uberis increased following heat treatment at 56 degrees C of pooled milk or whey samples from challenged mammary glands. Growth of S. uberis correlated negatively with the specific antibody response to the bacteria (P < 0.001). Lactoperoxidase activity varied among cows and among different samples over time and did not appear to contribute to decreased growth of S. uberis. These results suggest that decreased growth of S. uberis in milk from challenged mammary glands in comparison to milk from control mammary glands could result from the interaction of antibodies with complement components.     

Conjunctival impression cytology for vitamin A deficiency in the presence of infectious trachoma

BACKGROUND/AIMS: Increased morbidity and mortality from a number of infectious diseases have been associated with vitamin A deficiency. Trachoma and vitamin A deficiency are both important causes of blindness in Nepal. The purpose of this study was to determine the association between the diagnosis of vitamin A deficiency by conjunctival impression cytology and the diagnosis of infectious trachoma by the polymerase chain reaction (PCR) in the Lumbini zone of Nepal. METHODS: 70 children under the age of 11 in a rural village in the Lumbini zone were examined for clinical evidence of active trachoma. The conjunctiva of each child was tested for ocular Chlamydia trachomatis infection using PCR, and for loss of goblet cells (a sign of subclinical vitamin A deficiency) using conjunctival impression cytology. RESULTS: The presence of infectious trachoma was associated with the loss of goblet cells on conjunctival impression cytology (p = 0.02). This relation was present and significant even when adjusted for age (p = 0.05) and degree of inflammation (p = 0.02). In fact, even subclinical infection with chlamydia was associated with an abnormal conjunctival impression cytology (p = 0.02). CONCLUSIONS: Children with infectious trachoma are significantly more likely to have an abnormal conjunctival impression cytology, even if the infection is subclinical. Thus, the diagnosis of vitamin A deficiency from conjunctival impression cytology alone should be made with some caution in areas with endemic trachoma. Further studies will be needed to determine the cause of this association.     

Role of extracellular [Ca2+] in fatigue of isolated mammalian skeletal muscle

The possible role of altered extracellular Ca2+ concentration ([Ca2+]o) in skeletal muscle fatigue was tested on isolated slow-twitch soleus and fast-twitch extensor digitorum longus muscles of the mouse. The following findings were made. 1) A change from the control solution (1.3 mM [Ca2+]o) to 10 mM [Ca2+]o, or to nominally Ca2+-free solutions, had little effect on tetanic force in nonfatigued muscle. 2) Almost complete restoration of tetanic force was induced by 10 mM [Ca2+]o in severely K+-depressed muscle (extracellular K+ concentration of 10-12 mM). This effect was attributed to a 5-mV reversal of the K+-induced depolarization and subsequent restoration of ability to generate action potentials (inferred by using the twitch force-stimulation strength relationship). 3) Tetanic force depressed by lowered extracellular Na+ concentration (40 mM) was further reduced with 10 mM [Ca2+]o. 4) Tetanic force loss at elevated extracellular K+ concentration (8 mM) and lowered extracellular Na+ concentration (100 mM) was partially reversed with 10 mM [Ca2+]o or markedly exacerbated with low [Ca2+]o. 5) Fatigue induced by using repeated tetani in soleus was attenuated at 10 mM [Ca2+]o (due to increased resting and evoked forces) and exacerbated at low [Ca2+]o. These combined results suggest, first, that raised [Ca2+]o protects against fatigue rather than inducing it and, second, that a considerable depletion of [Ca2+]o in the transverse tubules may contribute to fatigue.