A potential new brainstem reflex: The oculoglossal phenomenon.

BACKGROUND: A synchronized involuntary movement of the tongue to the same side as voluntary movements of the eyes, termed the oculoglossal phenomenon, has been observed. A description of the hypothesized pathway of this phenomenon could guide the development of a rapid clinical evaluation of the long segment of the brainstem and help facilitate further studies to establish a new reflex, if possible. The aim of this study is to describe and propose the simple concept of this pathway/phenomenon, the oculoglossal phenomenon. METHODS: This is an observational study. Of a newly observe brainstem phenomenon evaluated on a subject at the National Neuroscience Institute in king Fahad Medical City (KFMC), Riyadh, Saudi Arabia. After being observed incidentally in a single patient, 60 participants were tested between January and March 2020 to confirm the presence of the phenomenon. Each subject was instructed to protrude the tongue and then move their eyes horizontally to the side. If the tongue simultaneously and involuntarily moved to the same side as the eyes, the test was deemed confirmatory. A literature review was performed, and possible anatomical pathway was proposed. RESULTS: The oculoglossal reflex was present in most (50/60, 83.3%) of the subjects. Our proposed pathway begins at the frontal cortex, followed by a projection to the paramedian pontine reticular formation, then to the contralateral medial longitudinal fasciculus and bilaterally to the hypoglossal nuclei. CONCLUSION: An accurate description of this phenomenon could lead to additional studies and possibly establishing it as a legitimate reflex, thus conceivably adding a new tool in the neurological examination to evaluate the brainstem's integrity.

Aseptic Revision and Reoperation Risks After Meniscectomy at the Time of Anterior Cruciate Ligament Reconstruction.

BACKGROUND: An intact meniscus is considered a secondary stabilizer of the knee after anterior cruciate ligament reconstruction (ACLR). While loss of the meniscus can increase forces on the anterior cruciate ligament graft after reconstruction, it is unclear whether this increased loading affects the success of the graft after ACLR. PURPOSE: To identify the risk of subsequent knee surgery when meniscectomy, either partial or total, is performed at the time of index ACLR. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: We conducted a matched cohort study using data from the Kaiser Permanente Anterior Cruciate Ligament Reconstruction Registry. Patients were identified who had a primary ACLR performed between January 1, 2005 and December 31, 2016, with up to 12 years of follow-up. The study sample comprised patients with ACLR who had a lateral meniscectomy (n = 2581), medial meniscectomy (n = 1802), or lateral and medial meniscectomies (n = 666). For each meniscectomy subgroup, patients with ACLR alone were matched to patients with a meniscectomy on a number of patient and procedure characteristics. After the application of matching, Cox proportional hazards regression was used to evaluate the risk of aseptic revision, while competing risks regression was used to evaluate the risk of cause-specific ipsilateral reoperation between meniscectomy and ACLR alone. Analysis was performed for each meniscectomy subgroup. RESULTS: After the application of matching, we failed to observe a difference in aseptic revision risk for patients with ACLR and a meniscectomy-lateral (hazard ratio [HR], 0.80; 95% CI, 0.63-1.02), medial (HR, 0.95; 95% CI, 0.70-1.29), or both (HR, 1.25; 95% CI, 0.77-2.04)-as compared with ACLR alone. When compared with patients who had ACLR alone, patients with a lateral meniscectomy had a higher risk for subsequent lateral meniscectomy (HR, 1.89; 95% CI, 1.18-3.02; P = .008), and those with a medial meniscectomy had a lower risk for manipulation under anesthesia (HR, 0.13; 95% CI, 0.02-0.92; P = .041). CONCLUSION: No difference in aseptic revision risk was observed for patients undergoing primary ACLR between groups with and without meniscectomy at the time of index surgery. Partial lateral meniscectomy at the time of index ACLR did associate with a higher risk of subsequent lateral meniscectomy.

Association of RETN +299(G>A) polymorphism with type two diabetes mellitus.

The global prevalence of type-two diabetes mellitus (T2DM) makes it a disease of public health concern. T2DM is strongly linked with insulin resistance caused by increased levels of visceral fat. Visceral fat secretes several adipocytokines that regulate body metabolism. Resistin is one of these adipocytokines which is encoded by the RETN gene. Herein, we tested the association of the RETN +299(G>A) and -420(C>G) single nucleotide polymorphisms (SNPs) with T2DM. T2DM patients (n=282) and healthy subjects (n=125) were included in the study. Subjects with metabolic syndromes other than diabetes were excluded. Genotyping of subjects was performed using PCR-RFLP. The +299(G>A) SNP was associated with T2DM (P=0.038). The AA genotype was higher in T2DM (17%) compared to controls (8%) with an odd ratio of 2.16 and 95% CI of 1.34 to 4.56. With respect to -420(C>G) SNP, no significant association was found with the risk of T2DM (P=0.128). The haplotype analysis of the examined SNPs indicated that the CA haplotype of the -420 and +299 SNPs in RETN was associated with T2DM risk (P=0.004; odd ration 4.0, 95% CI: 1.56-10.0). In conclusion, the present findings suggest a role of the RETN locus in modulating the risk of T2DM.

Prognostic significance of hemoglobin level and autoimmune hemolytic anemia in SARS-CoV-2 infection.

Higher levels of D-dimer, LDH, and ferritin, all have been associated with the poor prognosis of COVID-19. In a disease where there are acute inflammation and compromised oxygenation, we investigated the impact of initial hemoglobin (Hgb) levels at Emergency Department (ED) triage on the severity and the clinical course of COVID-19. We conducted a cross-sectional study on 601 COVID-19 patients in a COVID-19 national referral center between 13 and 27 June 2020. All adult patients presented at our hospital that required admission or hotel isolation were included in this study. Patients admitted to the intensive care unit (ICU) had a lower initial Hgb than those admitted outside the ICU (12.84 g/dL vs. 13.31 g/dL, p = 0.026) and over the course of admission; the prevalence of anemia (Hgb < 12.5 g/dL) was 65% in patients admitted to ICU, whereas it was only 43% in non-ICU patients (odds ratio of 2.464, 95% CI 1.71-3.52). Anemic ICU patients had a higher mortality compared with non-anemic ICU patients (hazard ratio = 1.88, log-rank p = 0.0104). A direct agglutination test (DAT) for all anemic patients showed that 14.7% of ICU patients and 9% of non-ICU patients had autoimmune hemolytic anemia (AIHA). AIHA patients had significantly longer length of hospital stay compared with anemic patients without AIHA (17.1 days vs. 14.08 days, p = 0.034). Lower Hgb level at hospital presentation could be a potential surrogate for COVID-19 severity.

Results of laser enhancement for residual myopia after primary laser in situ keratomileusis.

PURPOSE: The purpose of the study is to evaluate and analyze the results and outcomes after laser enhancement for residual myopia after primary laser in situ keratomileusis (LASIK). MATERIALS AND METHODS: This retrospective interventional consecutive case series clinical study was performed on 112 consecutive eyes (82 patients) that had undergone primary LASIK before the enhancement procedure. The study was done in the Refractive Surgery Unit in Yemen Magrabi Hospital between 2006 and 2014. The retreatment was for residual myopia with or without astigmatism. Either the original flap was lifted or surface ablation was performed. Parameters evaluated were uncorrected visual acuity (UCVA) and best spectacle-corrected visual acuity (VA), spherical equivalent (SE) refraction, corneal topography, and pachymetry. Complications after laser enhancement were also evaluated. RESULTS: Mean age of the study group was 26.72 ± 6.89 years (range from 18 to 44 years). Males accounted for 37/82 (45.1%) and females for 45/82 (54.9%). The right eye was treated in 67/112 (59.8%) and the left eye in 45/112 (40.2%). Before primary LASIK, the mean SE (MSE) was -5.78 ± 1.89 D. Before enhancement, the MSE was -1.32 ± 0.61 D (range -3.25 D to -0.50 D), and none of the eyes had an UCVA of 20/40 or better. Twelve months after retreatment, the percentage of eyes having UCVA of 20/40 or better increased to 67.9% (76 of 112). There were no vision-threatening complications seen. CONCLUSION: Retreatment or enhancement after LASIK surgery by lifting the original flap or surface ablation is a safe and effective method for the treatment of regressed or undercorrected myopia. The risk of postoperative complications is very minimal.

Comparison of awareness of diabetes mellitus type II with treatment's outcome in term of direct cost in a hospital in Saudi Arabia.

BACKGROUND: Saudi Arabia is among the top 10 countries with the highest prevalence of diabetes. Cost of prevention and the indirect cost must be calculated to increase the awareness of society and to emphasize disease prevention and limit further complications. AIM: To understand the importance of awareness and the impact on the expenditure of diabetes mellitus and treatments outcomes. METHODS: A prospective descriptive and comparative survey was carried out among patients with diabetes mellitus in Saudi Arabia. RESULTS: One hundred and one participants were included in the study of which 40% were female and one third were above the age of 50. The mean of the first HbA1c reading was 6.95, and the median was 7. The mean of the second reading of HbA1c was 7.26, and the median was 7. The mean body mass index was 32.1, and the median was 30.9. The average yearly cost of the medication was 995.14 SR. Comparing participants who think that a healthy low-sugar diet can affect blood sugar with those who do not, showed a statistically significant difference when cost was considered (P value = 0.03). Also, when comparing the group of participants who know when to take their oral hyperglycemic medicine and their yearly direct cost and those who do not know when to take it, by using independent sample T test, showed significant statistical difference (P value = 0.046). CONCLUSION: It is essential for the governments to invest in ways to prevent and help in the early detection of such an expensive disease by performing national screening and education programs. Many pharmaco-economic studies can be done to help the decision-maker in our hospitals think about strategies to help the patient to be physically fit by offering gymnasium or places to walk or contract.

Oral Health Practices Among Pakistani Physicians.

Introduction In most healthcare models, the first interaction of a patient is with a general physician. The inspection of the oral cavity is a mandatory component of the general physical examination performed by a physician. This helps detect any oral pathology and make suitable referrals. Therefore, adequate oral health awareness is essential for physicians. Our study aimed at evaluating the oral health practices among physicians working in a private teaching setup in Islamabad, Pakistan. Methods A cross-sectional study involving 144 physicians teaching undergraduate medical students at Shifa College of Medicine and its affiliated hospital, Shifa International Hospital, was conducted. Participants were interviewed through a self-designed questionnaire. Later, each participant demonstrated their teeth brushing technique on a standard model of the oral cavity, which was assessed against a checklist conforming to the modified bass technique. A video clip showing the aforementioned brushing technique was shown at the end of the interview. The collected data was analyzed on IBM's statistical package for the social sciences (SPSS) version 21.  Results Toothpaste was the top choice (97.2%) of teeth cleaning tool with 69% participants brushing their teeth two times a day and 56.9% using toothbrushes with bristles of medium texture. The use of mouthwash (32.6%) and dental floss (11.1%) was considerably low. Dental caries and teeth discoloration were seen in 46.5% and 43.8% physicians, respectively. An alarmingly low number of physicians (31.9%) claimed to have read guidelines regarding oral health. This translated into most participants (78.5%) visiting a dentist only when needed. Only 4.9% participants performed all components of the modified bass technique to clean teeth on the oral cavity model, with up to 22.9% unable to perform a single step accurately.  Conclusion The oral health knowledge and practices of physicians were found to be suboptimal and necessitate the integration of oral health awareness in the medical curriculum. A multiprofessional approach with physicians in crucial roles is required to address the burden of dental diseases globally.

Oral Hygiene Practices and Teeth Cleaning Techniques Among Medical Students.

Objectives Oral health is essential for general health and quality of life. It is a state of being free from mouth and facial pain, oral and throat cancer, oral infections and sores, periodontal disease, tooth decay, tooth loss, and other diseases and disorders that limit an individual's capacity to bite, chew, smile, and speak; it affects psychosocial well-being too. The objective of our study was to assess teeth cleaning techniques and oral hygiene practices among medical students. Methods The data of the study were collected in two stages. The first stage involved the administration of a self-constructed questionnaire among medical students. In the second step, the students were asked to demonstrate their teeth cleaning techniques on a model. A standard teeth cleaning checklist was used to evaluate the students. The students were then given the checklist and a video on teeth cleaning techniques was shown to them. The data obtained was analyzed on IBM's statistical package for the social sciences (SPSS) version 21.  Results Out of a total of 444 students, 256 (57.7 percent) were males while 188 (42.3 percent) were females. About 254 (57.2 percent) participants were preclinical medical students while 190 (42.8 percent) were clinical year medical students. A majority of medical students used medium consistency toothbrushes (177; 39.9 percent) and soft consistency toothbrushes (137; 30.9 percent). Most medical students (248; 55.9 percent) brushed two times a day while 163 (36.7 percent) brushed only one time. About 212 (47.7 percent) of the medical students used mouthwash along with a toothbrush while only 36 (8.1 percent) used floss along with a toothbrush. About 157 participants (35.4 percent) changed their toothbrush once in two months while 132 (26.7 percent) changed their toothbrush once in three months. The mean duration that participants brushed their teeth was 134.99 ± 69.01 seconds. Conclusion Medical students were found to have a faulty teeth cleaning technique. There is a dire need to spread awareness about correct teeth cleaning techniques because poor oral hygiene can have a detrimental effect on the overall health and quality of life of an individual.

Molecular Link between Leaf Coloration and Gene Expression of Flavonoid and Carotenoid Biosynthesis in Camellia sinensis Cultivar 'Huangjinya'.

'Huangjinya' is an excellent albino tea germplasm cultivated in China because of its bright color and high amino acid content. It is light sensitive, with yellow leaves under intense light while green leaves under weak light. As well, the flavonoid and carotenoid levels increased after moderate shading treatment. However, the mechanism underlying this interesting phenomenon remains unclear. In this study, the transcriptome of 'Huangjinya' plants exposed to sunlight and shade were analyzed by high-throughput sequencing followed by de novo assembly. Shading 'Huangjinya' made its leaf color turn green. De novo assembly showed that the transcriptome of 'Huangjinya' leaves comprises of 127,253 unigenes, with an average length of 914 nt. Among the 81,128 functionally annotated unigenes, 207 differentially expressed genes were identified, including 110 up-regulated and 97 down-regulated genes under moderate shading compared to full light. Gene ontology (GO) indicated that the differentially expressed genes are mainly involved in protein and ion binding and oxidoreductase activity. Antioxidation-related pathways, including flavonoid and carotenoid biosynthesis, were highly enriched in these functions. Shading inhibited the expression of flavonoid biosynthesis-associated genes and induced carotenoid biosynthesis-related genes. This would suggest that decreased flavonoid biosynthetic gene expression coincides with increased flavonoids (e.g., catechin) content upon moderate shading, while carotenoid levels and biosynthetic gene expression are positively correlated in 'Huangjinya.' In conclusion, the leaf color changes in 'Huangjinya' are largely determined by the combined effects of flavonoid and carotenoid biosynthesis.

Coral recovery in the central Maldives archipelago since the last major mass-bleaching, in 1998.

Increasing frequency and severity of disturbances is causing global degradation of coral reef ecosystems. This study examined temporal changes in live coral cover and coral composition in the central Maldives from 1997 to 2016, encompassing two bleaching events, a tsunami, and an outbreak of Acanthaster planci. We also examined the contemporary size structure for five dominant coral taxa (tabular Acropora, Acropora muricata, Acropora humilis, Pocillopora spp, and massive Porites). Total coral cover increased throughout the study period, with marked increases following the 1998 mass-bleaching. The relative abundance of key genera has changed through time, where Acropora and Pocillopora (which are highly susceptible to bleaching) were under-represented following 1998 mass-bleaching but increased until outbreaks of A. planci in 2015. The contemporary size-structure for all coral taxa was dominated by larger colonies with peaked distributions suggesting that recent disturbances had a disproportionate impact on smaller colonies, or that recruitment is currently limited. This may suggest that coral resilience has been compromised by recent disturbances, and further bleaching (expected in 2016) could lead to highly protracted recovery times. We showed that Maldivian reefs recovered following the 1998 mass-bleaching event, but it took up to a decade, and ongoing disturbances may be eroding reef resilience.

Transcriptomic Analysis Reveals the Molecular Mechanisms of Drought-Stress-Induced Decreases in Camellia sinensis Leaf Quality.

The tea plant [Camellia sinensis (L.) O. Kuntze] is an important commercial crop rich in bioactive ingredients, especially catechins, caffeine, theanine and other free amino acids, which the quality of tea leaves depends on. Drought is the most important environmental stress affecting the yield and quality of this plant. In this study, the effects of drought stress on the phenotype, physiological characteristics and major bioactive ingredients accumulation of C. sinensis leaves were examined, and the results indicated that drought stress resulted in dehydration and wilt of the leaves, and significant decrease in the total polyphenols and free amino acids and increase in the total flavonoids. In addition, HPLC analysis showed that the catechins, caffeine, theanine and some free amino acids in C. sinensis leaves were significantly reduced in response to drought stress, implying that drought stress severely decreased the quality of C. sinensis leaves. Furthermore, differentially expressed genes (DEGs) related to amino acid metabolism and secondary metabolism were identified and quantified in C. sinensis leaves under drought stress using high-throughput Illumina RNA-Seq technology, especially the key regulatory genes of the catechins, caffeine, and theanine biosynthesis pathways. The expression levels of key regulatory genes were consistent with the results from the HPLC analysis, which indicate a potential molecular mechanism for the above results. Taken together, these data provide further insights into the mechanisms underlying the change in the quality of C. sinensis leaves under environmental stress, which involve changes in the accumulation of major bioactive ingredients, especially catechins, caffeine, theanine and other free amino acids.

Efficacy of leaves (drumstick, mint and curry leaves) powder as natural preservatives in restructured chicken block.

The use of natural preservatives to increase the shelf-life of meat products is promising as they possess antioxidant and antimicrobial properties. Earlier, a highly acceptable restructured chicken slice without the addition of extra fat was developed in the same laboratory which was acceptable up to 10th day of storage under refrigeration and spoilage was mainly due to oxidation. Hence, the present study was planned to determine the efficacy of certain plant leaves' (drumstick, mint and curry leaves) powder at 1 % level as natural preservatives to enhance the shelf life of restructured chicken slices under refrigerated storage. The quality attributes of the products containing different natural preservativs were compared with the control and reference products. The control product contained no preservative and the reference product contained BHT (200 ppm) only. Incorporation of the leaf powders at 1 % level did not show any significant differences for both cooking yield (99.5-99.6 %) and proximate composition (moisture 72.2-72.3 %, protein 19.2-19.4 %, fat 4.2-4.3 % and total ash 2.3-2.4 %) of the restructured chicken slices compared to both control and reference products during storage. All products containing leaf powders showed significantly (P < 0.01) lower microbial counts (2.9-3.7 log10 CFU/g) compared to both control and BHT added products. Yeast and mould were not detected in any of the products throughout the storage period. Sensory evaluation scores showed that the restructured chicken slices incorporated with the leaf powders were as acceptable as the reference product and rated good to very good for appearance, flavor, juiciness and overall acceptability. Restructured chicken slices with the leaf powders could be safely stored without much loss in quality up to 20 days under refrigeration.

AMPK: a cellular metabolic and redox sensor. A minireview.

AMPK is a serine/threonine kinase that is found in all eukaryotes and is ubiquitously expressed in all organ systems. Once activated, AMPK stimulates hepatic fatty acid oxidation and ketogenesis, inhibits cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibits adipocyte lipolysis and lipogenesis, stimulates skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulates insulin secretion by the pancreas. Thus its importance in many critical cellular processes is well established. For cells it is critical that energy supply and demand are closely matched. AMPK is recognized as a critical integrator of this balance. It is known to be allosterically activated by an increased AMP:ATP ratio. Activation of the kinase switches on catabolic pathways while switching off anabolic ones. It also acts as a redox sensor in endothelial cells where oxidative stress can disturb NO signaling. Abnormal NO signaling leads to disturbed vasodilatory responses. By inhibiting the formation of reactive oxygen species in the endothelium, AMPK can optimize the redox balance in the vasculature. Here, we review the role of AMPK in the cell.

Vascular inflammation is a missing link for diabetes-enhanced atherosclerotic cardiovascular diseases.

Diabetes is associated with major life-threatening complications such as a markedly increased risk of cardiovascular disease, even in the presence of rigid glycemic control. Indeed, nearly 75% of diabetic patients eventually die of cardiovascular disease or cardiovascular complications. A striking feature of the diabetic cardiovascular phenotype is the appearance of accelerated atherosclerosis, which resembles atherosclerosis that may be encountered in the non-diabetic individual, except that it is more extensive, aggressive, and occurs at an earlier age. Atherosclerosis (or atherosclerotic vascular disease; ASVD), is a pathological syndrome affecting arterial vessels characterized by narrowing of the vascular lumen secondary to intravascular buildup of fatty material such as cholesterol, aggregated cellular debris, and inflammatory change in the vascular endothelium. Seemingly distinct, these two well-defined disorders are nevertheless, intimately and intricately linked. In fact, these two pathologies appear to be linked by common signaling pathways and shared regulatory systems that appear to go awry in an as yet poorly understood manner. In recent years, a body of evidence has been growing that suggests that inflammation peculiar to the vascular system, occurs in the diabetic patient. This review aims to present the empirical underpinning of the hypothesis that inflammatory change in the vasculature might be the integrated mechanism that connects a diabetic phenotype with its attendant vascular complications.

2-Deoxy-D-glucose treatment of endothelial cells induces autophagy by reactive oxygen species-mediated activation of the AMP-activated protein kinase.

Autophagy is a cellular self-digestion process activated in response to stresses such as energy deprivation and oxidative stress. However, the mechanisms by which energy deprivation and oxidative stress trigger autophagy remain undefined. Here, we report that activation of AMP-activated protein kinase (AMPK) by mitochondria-derived reactive oxygen species (ROS) is required for autophagy in cultured endothelial cells. AMPK activity, ROS levels, and the markers of autophagy were monitored in confluent bovine aortic endothelial cells (BAEC) treated with the glycolysis blocker 2-deoxy-D-glucose (2-DG). Treatment of BAEC with 2-DG (5 mM) for 24 hours or with low concentrations of H(2)O(2) (100 µM) induced autophagy, including increased conversion of microtubule-associated protein light chain 3 (LC3)-I to LC3-II, accumulation of GFP-tagged LC3 positive intracellular vacuoles, and increased fusion of autophagosomes with lysosomes. 2-DG-treatment also induced AMPK phosphorylation, which was blocked by either co-administration of two potent anti-oxidants (Tempol and N-Acetyl-L-cysteine) or overexpression of superoxide dismutase 1 or catalase in BAEC. Further, 2-DG-induced autophagy in BAEC was blocked by overexpressing catalase or siRNA-mediated knockdown of AMPK. Finally, pretreatment of BAEC with 2-DG increased endothelial cell viability after exposure to hypoxic stress. Thus, AMPK is required for ROS-triggered autophagy in endothelial cells, which increases endothelial cell survival in response to cell stress.

Arterial stiffness: a brief review.

Physical stiffening of the large arteries is the central paradigm of vascular aging. Indeed, stiffening in the larger central arterial system, such as the aortic tree, significantly contributes to cardiovascular diseases in older individuals and is positively associated with systolic hypertension, coronary artery disease, stroke, heart failure and atrial fibrillation, which are the leading causes of mortality in the developed countries and also in the developing world as estimated in 2010 by World Health Organizations. Thus, better, less invasive and more accurate measures of arterial stiffness have been developed, which prove useful as diagnostic indices, pathophysiological markers and predictive indicators of disease. This article presents a review of the structural determinants of vascular stiffening, its pathophysiologic determinants and its implications for vascular research and medicine. A critical discussion of new techniques for assessing vascular stiffness is also presented.

AMPK in cardiovascular health and disease.

AbstractAdenosine Monophosphate-activated Protein Kinase (AMPK), a serine/threonine kinase and a member of the Snf1/AMPK protein kinase family, consists of three protein subunits that together make a functional enzyme. AMPK, which is expressed in a number of tissues, including the liver, brain, and skeletal muscle, is allosterically activated by a rise in the AMP: ATP ratio (ie in a low ATP or energy depleted state). The net effect of AMPK activation is to halt energy consuming (anabolic) pathways but to promote energy conserving (catabolic) cellular pathways. AMPK has therefore often been dubbed the "metabolic master switch". AMPK also plays a critical physiological role in the cardiovascular system. Increasing evidence suggest that AMPK might also function as a sensor by responding to oxidative stress. Mostly importantly, AMPK modulates endogenous antioxidant gene expression and/or suppress the production of oxidants. AMPK promotes cardiovascular homeostasis by ensuring an optimum redox balance on the heart and vascular tissues. Dysfunctional AMPK is thought to underlie several cardiovascular pathologies. Here we review this kinase from its structure and discovery to current knowledge of its adaptive and maladaptive role in the cardiovascular system.

Regulation of intracellular calcium in cortical neurons transgenic for human Abeta40 and Abeta42 following nutritive challenge.

The pathogenesis of Alzheimer's Disease (AD) is not fully understood. Amyloid plaques could be causally linked to neuronal loss in AD. Two proteolytic products of the Amyloid Precursor Protein (APP), Amyloid beta40 (Abeta40) and Amyloid beta42 (Abeta42), are considered to be critical in the neurodegeneration seen in AD. However, in transgenic mice that overexpress human Abeta40 or Abeta42, it was shown that Abeta42 was much more amyloidogenic than Abeta40. In contrast to this observation, we have found that cultured cortical neurons from mice transgenic for human Abeta40 and for Abeta42 are both and statistically equally vulnerable to nutritive challenge induced by trophic factor withdrawal (TFW). Aberrant regulation of InsP(3)R (Inositol triphosphate receptor)-mediated calcium release has been implicated in neuronal cell death. It is however not clear whether this pathway plays a critical role in cortical neurons transgenic for different species of human Abeta. We now report that Abeta40 and Abeta42 equally exacerbated intracellular calcium response to TFW in cortical neurons following TFW. When bradykinin (BK), a potent stimulant of InsP(3)R-mediated calcium release from ER, was applied to these cells, wild-type (WT) neurons exhibited a steep rise in [Ca(2+)](i) but this was not observed in either Abeta transgenic type. Similarly, when 1 muM Xestopongin C (XeC), a specific blocker of InsP(3)R, was applied to these neurons, WT cells showed a significant attenuation of increase in [Ca(2+)](i) following TFW, while elevation in [Ca(2+)](i) induced by TFW remained largely unchanged in Abeta40 and Abeta42 cells. Finally, when we treated these cells with a Ca(2+) chelator (BAPTA; 10 muM), all three cell types had a marked attenuation of [Ca(2+)](i). These findings indicate that the exacerbated calcium dysregulation following TFW in Abeta transgenic neurons are likely to be mediated by calcium channels other than ER InsP3R receptors. Overall, our results also suggest that a highly amyloidogenic Abeta species, such as Abeta42, might not necessarily be significantly more neurotoxic than a less or non-amyloidogenic Abeta species, such as Abeta40.

Cortical neurons transgenic for human Abeta40 or Abeta42 have similar vulnerability to apoptosis despite their different amyloidogenic properties.

Alzheimer's disease (AD) is a leading cause of chronic dementia in the United States. Its incidence is increasing with an attendant increase in associated health care costs. Amyloid beta peptide (Abeta; a 39-42 amino acid molecule) is the major component of senile plaques, the hallmark lesion of AD. The toxic mechanism of Abeta peptides has not been well characterized. Specifically, the impact of Abeta1-40 (Abeta40) and its slightly longer counterpart fragment, Abeta1-42 (Abeta42), is not clearly understood. It has been suggested that, while Abeta40 might play a more physiologically relevant role, Abeta42 is likely the key amyloidogenic fragment leading to amyloid deposition in the form of plaques in AD, a pivotal process in Alzheimer's pathology. This notion was further supported by a recent study employing transgenic mouse models that expressed either Abeta40 or Abeta42 in the absence of human amyloid beta protein precursor (APP) overexpression. It was found that mice expressing Abeta42, but not Abeta40, developed compact amyloid plaques, congophilic amyloid angiopathy, and diffuse Abeta deposits. Since neuronal loss is one of the hallmark features in AD pathology, we hypothesize that cortical neurons from these two strains of transgenic mice for Abeta might show different vulnerability to cell death induced by classical inducers of apoptosis, such as trophic factor withdrawal (TFW). Contrary to our expectations, we found that, while overexpression of either Abeta40 or 42 significantly increased the vulnerability of primary cortical neurons to WFT-induced cell death, there was no significant difference between the two transgenic lines. Mitochondrial dysfunction, levels of oxidative stress, caspase activation and nuclear fragmentation are increased to about the same extent by both Abeta species in transgenic neurons. We conclude that Abeta40 or Abeta42 induce similar levels of neurotoxicity following TFW in these transgenic mice despite the difference in their amyloidogenic properties.