Physicochemical and functional characterization of MYL-1501D, a proposed biosimilar to insulin glargine.

Insulin glargine is a long-acting analogue of human insulin that has been used to manage hyperglycemia in patients with diabetes mellitus (DM) for nearly 20 years. Insulin glargine has a relatively constant concentration-time profile that mimics basal levels of insulin and allows for once-daily administration. MYL-1501D is a biosimilar insulin glargine designed to offer greater access of insulin glargine to patients, with comparable efficacy and safety to the marketed reference product. We conducted a comprehensive panel of studies based on a formal analysis of critical quality attributes to characterize the structural and functional properties of MYL-1501D and reference insulin glargine products available in the United States and European Union. MYL-1501D was comprehensively shown to have high similarity to the reference products in terms of protein structure, metabolic activity (both in vitro cell-based assays and in vivo rabbit bioassays), and in vitro cell-based assays for mitogenic activity. The structural analyses demonstrated that the primary protein sequence was identical, and secondary and tertiary structures are similar between the proposed biosimilar and the reference products. Insulin receptor binding affinity and phosphorylation studies also established analytical similarity. MYL-1501D demonstrated high similarity in different metabolic assays of glucose uptake, adipogenesis activity, and inhibition of stimulated lipolysis. Rabbit bioassay studies showed MYL-1501D and EU-approved insulin glargine are highly similar to US-licensed insulin glargine. These product quality studies show high similarity between MYL-1501D and licensed or approved insulin glargine products and suggest the potential of MYL-1501D as an alternative cost-effective treatment option for patients and clinicians.

Comparison of cannabidiol to citalopram in targeting fear memory in female mice.

BACKGROUND: Cannabidiol (CBD) and selective serotonin reuptake inhibitors (SSRIs) are currently used to treat post-traumatic stress disorder (PTSD). However, these drugs are commonly studied after dosing just prior to extinction training, and there are gaps in our understanding of how they affect fear memory formation, their comparative effects on various types of memory, and of sexual dimorphisms in effects. Also, more studies involving female subjects are needed to balance the gender-inequality in the literature. Therefore, the purpose of this study was to directly compare the effects of CBD to citalopram in affecting the formation of auditory cued, contextual, and generalized fear memory, and to evaluate how extinction of these different memories was altered by pre-acquisition treatment in female mice. We also evaluated the impact of the estrous cycle on each of these. METHODS: Auditory-cued trace fear conditioning was conducted shortly after dosing female C57BL/6 mice, with either CBD or citalopram (10 mg/kg each), by pairing auditory tones with mild foot shocks. Auditory-cued, contextual, and generalized fear memory was assessed by measuring freezing responses, with an automated fear conditioning system, 24 h after conditioning. Each memory type was then evaluated every 24 h, over a 4-day period in total, to create an extinction profile. Freezing outcomes were statistically compared by ANOVA with Tukey HSD post hoc analysis, N = 12 mice per experimental group. Evaluation of sexual dimorphism was by comparison to historical data from male mice. RESULTS: Auditory cue-associated fear memory was not affected with CBD or citalopram; however, contextual memory was reduced with CBD by 11%, p < 0.05, but not citalopram, and generalized fear memory was reduced with CBD and citalopram, 20% and 22%, respectively, p < 0.05. Extinction learning was enhanced with CBD and citalopram, but, there was considerable memory-type variability between drug effects, with freezing levels reduced at the end of training by 9 to 17% for CBD, and 10 to 12% with citalopram. The estrous cycle did not affect any outcomes. CONCLUSIONS: Both drugs are potent modifiers of fear memory formation; however, there is considerable divergence in their targeting of different memory types which, overall, could support the use of CBD as an alternative to SSRIs for treating PTSD in females, but not males. A limitation of the study was that it compared data from experiments done at different times to evaluate sexual dimorphism. Overall, this suggests that more research is necessary to guide any therapeutic approach involving CBD.

Contrasting Roles of Cannabidiol as an Insecticide and Rescuing Agent for Ethanol-induced Death in the Tobacco Hornworm Manduca sexta.

Cannabis sativa, also known as marijuana or hemp, produces a non-psychoactive compound cannabidiol (CBD). To investigate the defensive role of CBD, a feeding preference assay was performed with tobacco hornworm Manduca sexta. The larvae clearly show feeding preference towards the Cannabis tissue containing low CBD over high CBD. While the larva avoided the high CBD diet, we investigated detrimental effects of CBD in the insects' diet. Contrasted to the performance on low CBD-infused artificial diet (AD), larvae reared on the high CBD diet suffer significantly reduced growth and increased mortality. Through testing different carriers, we found that the increase of EtOH in the diet is negatively correlated with insect development and behaviors. Notably, CBD treatment significantly improved ethanol-intoxicated larval survival rate by 40% and also improved diet searching activity, resulting in increased diet consumption. Electrophysiology results revealed that the CBD-treated ganglia had delayed but much larger response with electric stimuli in comparison to the larvae reared on AD only and EtOH-added diet. Our results show CBDs' defensive role against pest insects, which suggests its possible use as an insecticide. We also provide evidence that CBD alleviates alcohol-induced stress; consequently, improving the performance and viability of M. sexta larvae.

Reducing mortality in near-hanging patients with a novel early management protocol.

BACKGROUND: Hanging is one of the most common causes of suicide world-wide, more prevalent in developing countries. There are no established protocols for early management of near-hanging patients who present to the emergency department (ED). The use of early intubation, strict blood pressure control and targeted temperature management has shown promise in small studies. OBJECTIVE: To detect changes in mortality and neurological deficits in near-hanging patients before and after implementation of a novel early management protocol in a tertiary care hospital in India. METHODS: Prospective cohort study conducted at a tertiary-care hospital in Tamil Nadu, India from August 2014-July 2016. For first year of study (pre-implementation), near-hanging patients were treated without a structured protocol. For second year of study (post-implementation), near-hanging patients were treated per a protocol including early intubation, strict blood pressure control and targeted temperature management. Primary outcomes included: (1) in-hospital mortality and (2) hospital discharge without neurological deficit. RESULTS: 65 patients were included (27 in the pre-implementation phase and 38 in the post-implementation phase.) At presentation, there was no difference between the two groups in mean heart rate, mean arterial pressure, mean oxygen saturation, Glasgow coma score, or mean respiratory rate. Protocol implementation decreased mortality (10/27 (37%) versus 2/38 (5%), P < 0.05) and increased the number of patients discharged without neurological deficit (10/27 (37%) versus 35/38 (92%), P < 0.05). CONCLUSIONS: This novel early management protocol reduced mortality and increased the number discharged without neurological deficit in near-hanging patients in a single tertiary care center in India.

Core decompression and arthroplasty outcomes for atraumatic osteonecrosis of the humeral head.

BACKGROUND: Humeral head osteonecrosis treatment varies depending on the stage and symptoms. Successful outcomes for humeral head core decompression for stage I/II disease in chronic steroid-induced (CSI) osteonecrosis have been reported, but fewer data exist for sickle cell disease (SCD) etiology. Resurfacing and hemiarthroplasty or total shoulder arthroplasty (TSA) are common for advanced collapse, with mixed results. METHODS: We evaluate radiographic and functional outcomes after procedures for humeral head atraumatic avascular necrosis (HAAVN), decompression efficacy in CSI and SCD populations, and report outcomes of advanced disease requiring arthroplasty. Twenty-five shoulders were treated surgically for HAAVN. Post-traumatic AVN patients were excluded. Stage I/II disease received core decompression and ultrasound bone stimulation. Stage III received surface replacement or hemiarthroplasty, and arthroplasty was performed for stage IV/V. Radiographs and clinical scores were recorded preoperatively and postoperatively. RESULTS: Included were 25 HAAVN shoulders (13 SCD and 12 CSI). Eleven shoulders (stage I/II disease) underwent core decompression. Seven of 8 shoulders (88%) progressed to stage III/IV after decompression. All SCD patients progressed to collapse. The procedure in 19 shoulders was surface replacement, hemiarthroplasty, or TSA. Constant, American Shoulder and Elbow Surgeons, Simple Shoulder Test-12, and University of California Los Angeles Shoulder scores were significantly higher at 1- and 2-year follow-up with arthroplasty; 13 of 16 arthroplasty patients (81%) had satisfactory to excellent results. One surface replacement was revised to reverse TSA. CONCLUSIONS: Results suggest core decompression for AVN in SCD patients does not alter osteonecrosis progression and humeral head collapse. Resurfacing and hemiarthroplasty are viable treatment options for stage III, whereas shoulder replacement for stage IV/V disease appears to offer better functional results.

Regulation of Monocarboxylic Acid Transporter 1 Trafficking by the Canonical Wnt/ß-Catenin Pathway in Rat Brain Endothelial Cells Requires Cross-talk with Notch Signaling.

The transport of monocarboxylate fuels such as lactate, pyruvate, and ketone bodies across brain endothelial cells is mediated by monocarboxylic acid transporter 1 (MCT1). Although the canonical Wnt/ß-catenin pathway is required for rodent blood-brain barrier development and for the expression of associated nutrient transporters, the role of this pathway in the regulation of brain endothelial MCT1 is unknown. Here we report expression of nine members of the frizzled receptor family by the RBE4 rat brain endothelial cell line. Furthermore, activation of the canonical Wnt/ß-catenin pathway in RBE4 cells via nuclear ß-catenin signaling with LiCl does not alter brain endothelialMct1mRNA but increases the amount of MCT1 transporter protein. Plasma membrane biotinylation studies and confocal microscopic examination of mCherry-tagged MCT1 indicate that increased transporter results from reduced MCT1 trafficking from the plasma membrane via the endosomal/lysosomal pathway and is facilitated by decreased MCT1 ubiquitination following LiCl treatment. Inhibition of the Notch pathway by the γ-secretase inhibitorN-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butyl ester negated the up-regulation of MCT1 by LiCl, demonstrating a cross-talk between the canonical Wnt/ß-catenin and Notch pathways. Our results are important because they show, for the first time, the regulation of MCT1 in cerebrovascular endothelial cells by the multifunctional canonical Wnt/ß-catenin and Notch signaling pathways.

Regulation of monocarboxylic acid transporter-1 by cAMP dependent vesicular trafficking in brain microvascular endothelial cells.

In this study, a detailed characterization of Monocarboxylic Acid Transporter-1 (Mct1) in cytoplasmic vesicles of cultured rat brain microvascular endothelial cells shows them to be a diverse population of endosomes intrinsic to the regulation of the transporter by a brief 25 to 30 minute exposure to the membrane permeant cAMP analog, 8Br-cAMP. The vesicles are heterogeneous in size, mobility, internal pH, and co-localize with discreet markers of particular types of endosomes including early endosomes, clathrin coated vesicles, caveolar vesicles, trans-golgi, and lysosomes. The vesicular localization of Mct1 was not dependent on its N or C termini, however, the size and pH of Mct1 vesicles was increased by deletion of either terminus demonstrating a role for the termini in vesicular trafficking of Mct1. Using a novel BCECF-AM based assay developed in this study, 8Br-cAMP was shown to decrease the pH of Mct1 vesicles after 25 minutes. This result and method were confirmed in experiments with a ratiometric pH-sensitive EGFP-mCherry dual tagged Mct1 construct. Overall, the results indicate that cAMP signaling reduces the functionality of Mct1 in cerebrovascular endothelial cells by facilitating its entry into a highly dynamic vesicular trafficking pathway that appears to lead to the transporter's trafficking to autophagosomes and lysosomes.

Cumulative total effective whole-body radiation dose in critically ill patients.

BACKGROUND: Uncertainty exists about a safe dose limit to minimize radiation-induced cancer. Maximum occupational exposure is 20 mSv/y averaged over 5 years with no more than 50 mSv in any single year. Radiation exposure to the general population is less, but the average dose in the United States has doubled in the past 30 years, largely from medical radiation exposure. We hypothesized that patients in a mixed-use surgical ICU (SICU) approach or exceed this limit and that trauma patients were more likely to exceed 50 mSv because of frequent diagnostic imaging. METHODS: Patients admitted into 15 predesignated SICU beds in a level I trauma center during a 30-day consecutive period were prospectively observed. Effective dose was determined using Huda's method for all radiography, CT imaging, and fluoroscopic examinations. Univariate and multivariable linear regressions were used to analyze the relationships between observed values and outcomes. RESULTS: Five of 74 patients (6.8%) exceeded exposures of 50 mSv. Univariate analysis showed trauma designation, length of stay, number of CT scans, fluoroscopy minutes, and number of general radiographs were all associated with increased doses, leading to exceeding occupational exposure limits. In a multivariable analysis, only the number of CT scans and fluoroscopy minutes remained significantly associated with increased whole-body radiation dose. CONCLUSIONS: Radiation levels frequently exceeded occupational exposure standards. CT imaging contributed the most exposure. Health-care providers must practice efficient stewardship of radiologic imaging in all critically ill and injured patients. Diagnostic benefit must always be weighed against the risk of cumulative radiation dose.

Regulation of Mct1 by cAMP-dependent internalization in rat brain endothelial cells.

In the cerebrovascular endothelium, monocarboxylic acid transporter 1 (Mct1) controls blood-brain transport of short chain monocarboxylic and keto acids, including pyruvate and lactate, to support brain energy metabolism. Mct1 function is acutely decreased in rat brain cerebrovascular endothelial cells by ß-adrenergic signaling through cyclic adenosine monophosphate (cAMP); however, the mechanism for this acute reduction in transport capacity is unknown. In this report, we demonstrate that cAMP induces the dephosphorylation and internalization of Mct1 from the plasma membrane into caveolae and early endosomes in the RBE4 rat brain cerebrovascular endothelial cell line. Additionally, we provide evidence that Mct1 constitutively cycles through clathrin vesicles and recycling endosomes in a pathway that is not dependent upon cAMP signaling in these cells. Our results are important because they show for the first time the regulated and unregulated vesicular trafficking of Mct1 in cerebrovascular endothelial cells; processes which have significance for better understanding normal brain energy metabolism, and the etiology and potential therapeutic approaches to treating brain diseases, such as stroke, in which lactic acidosis is a key component.

Interventions to improve patient-centered care during times of emergency department crowding.

Patient-centered care is defined by the Institute of Medicine (IOM) as care that is responsive to individual patient needs and values and that guides treatment decisions. This article is the result of a breakout session of the 2011 Academic Emergency Medicine consensus conference "Interventions to Assure Quality in the Crowded Emergency Department" and focuses on three broad domains of patient-centered care: patient satisfaction, patient involvement, and care related to patient needs.The working group provided background information and an overview of interventions that have been conducted in the domains of patient satisfaction, patient involvement (patients' preferences and values in decision-making), and patient needs (e.g., comfort, information, education). Participants in the breakout session discussed interventions reported in the medical literature as well as initiated at their institutions, discussed the effect of crowding on patient-centered care, and prioritized, in a two-step voting process, five areas of focus for establishing a research agenda for studying patient-centered care during times of crowding. The research priorities for enhancing patient-centered care in all three domains during periods of crowding are discussed. These include assessing the effect of other quality domains on patient satisfaction and determining the effects of changes in ED operations on patient satisfaction; enhancing patient involvement by determining the effect of digital records and health information technology (HIT); rapid assessment areas with focused patient-provider communication; and meeting patients' needs through flexible staffing, use of HIT to enhance patient communication, discharge instructions, and postdischarge telephone calls.

Copper Inhibits NMDA Receptor-Independent LTP and Modulates the Paired-Pulse Ratio after LTP in Mouse Hippocampal Slices.

Copper misregulation has been implicated in the pathological processes underlying deterioration of learning and memory in Alzheimer's disease and other neurodegenerative disorders. Supporting this, inhibition of long-term potentiation (LTP) by copper (II) has been well established, but the exact mechanism is poorly characterized. It is thought that an interaction between copper and postsynaptic NMDA receptors is a major part of the mechanism; however, in this study, we found that copper (II) inhibited NMDA receptor-independent LTP in the CA3 region of hippocampal slices. In addition, in the CA3 and CA1 regions, copper modulated the paired-pulse ratio (PPR) in an LTP-dependent manner. Combined, this suggests the involvement of a presynaptic mechanism in the modulation of synaptic plasticity by copper. Inhibition of the copper-dependent changes in the PPR with cyclothiazide suggested that this may involve an interaction with the presynaptic AMPA receptors that regulate neurotransmitter release.

Control of MCT1 function in cerebrovascular endothelial cells by intracellular pH.

Monocarboxylic Acid Transporter 1 (MCT1) is expressed on the plasma membrane of cerebrovascular endothelial cells where it is the only known facilitator of lactic acid transport across the blood brain barrier. During stroke, brain injury, and certain other brain pathologies, anaerobic glycolysis produces severe lactic acidosis of brain tissue leading to brain cell damage. Therefore, a better understanding of factors that control MCT1 function may be the key to better understanding the origins and treatment of pathological lactic acidosis. In this study, we characterized the effects of intracellular pH in controlling MCT1 function and showed that microtubule disruption targeted this mechanism in rat cerebrovascular endothelial cells. Acidic intracellular pH values were shown to strongly inhibit lactic acid transport into the cytoplasmic space, while alkalinization of the cytoplasm significantly enhanced this transport function. These results support a better understanding of how cerebrovascular endothelial MCT1 may contribute to the development of lactic acidosis in brain pathologies, and suggest targeting it as a novel therapy.

Learning clinical versus leadership competencies in the emergency department: strategies, challenges, and supports of emergency medicine residents.

BACKGROUND: Emergency medicine residents are expected to master 6 competencies that include clinical and leadership skills. To date, studies have focused primarily on teaching strategies, for example, what attending physicians should do to help residents learn. Residents' own contributions to the learning process remain largely unexplored. The purpose of this study was to explore what emergency medicine residents believe helps them learn the skills required for practice in the emergency department. METHODS: This qualitative study used semistructured interviews with emergency medicine residents at a major academic medical center. Twelve residents participated, and 11 additional residents formed a validation group. We used phenomenologic techniques to guide the data analysis and techniques such as triangulation and member checks to ensure the validity of the findings. RESULTS: We found major differences in the strategies residents used to learn clinical versus leadership skills. Clinical skill learning was approached with rigor and involved a large number of other physicians, while leadership skill learning was unplanned and largely relied on nursing personnel. In addition, with each type of skills, different aspects of the residents' personalities, motivation, and past nonclinical experiences supported or challenged their learning process. CONCLUSION: The approaches to learning leadership skills are not well developed among emergency medicine residents and result in a narrow perspective on leadership. This may be because of the lack of formal leadership training in medical school and residency, or it may reflect assumptions regarding how leadership skills develop. Substantial opportunity exists for enhancing emergency medicine residents' learning of leadership skills as well as the teaching of these skills by the attending physicians and nurses who facilitate their learning.

Stereospecific interactions are necessary for Alzheimer disease amyloid-ß toxicity.

Previous studies suggest membrane binding is a key determinant of amyloid ß (Aß) neurotoxicity. However, it is unclear whether this interaction is receptor driven. To address this issue, a D-handed enantiomer of Aß42 (D-Aß42) was synthesized and its biophysical and neurotoxic properties were compared to the wild-type Aß42 (L-Aß42). The results showed D- and L-Aß42 are chemically equivalent with respect to copper binding, generation of reactive oxygen species and aggregation profiles. Cell binding studies show both peptides bound to cultured cortical neurons. However, only L-Aß42 was neurotoxic and inhibited long term potentiation indicating L-Aß42 requires a stereospecific target to mediate toxicity. We identified the lipid phosphatidylserine, as a potential target. Annexin V, which has very high affinity for externalized phosphatidylserine, significantly inhibited L-Aß42 but not D-Aß42 binding to the cultured cortical neurons and significantly rescued L-Aß42 neurotoxicity. This suggests that Aß mediated toxicity in Alzheimer disease is dependent upon Aß binding to phosphatidylserine on neuronal cells.

The correlation between elevated cardiac troponin I and pulmonary artery obstruction index in ED patients with pulmonary embolism.

OBJECTIVES: The aim of this study is to investigate the correlation between cardiac troponin I (cTnI) values and the pulmonary artery obstruction index assessed with spiral computed tomography (CT) scan in emergency department (ED) patients with pulmonary embolism (PE). METHODS: This is a retrospective cohort study of all 179 ED patients diagnosed with PE between December 2004 and January 2007. Study population consisted of 104 (58.1%) of 179 patients with PE in whom both cTnI was measured and a contemporaneously performed CT scan was available for review. In these patients, the levels of cTnI measured in the ED were correlated with the degree of pulmonary vascular obstruction determined by applying the modified Computed Tomography Obstruction Index to the spiral CT scan performed in the ED. RESULTS: Troponin values were elevated in 20 (19.2%) of 104 patients (95% confidence interval [CI], 11.6-26.8) with a mean cTnI concentration of 0.38 +/- 0.44 microg/L. Elevated cTnI value had a significant correlation with main pulmonary arteries involvement using the modified Computed Tomography Obstruction Index score (P = .0001). Elevated ED cTnI value had 53.8% (95% CI, 37.6-66) sensitivity and 92.3% (95% CI, 87-96.4) specificity, 70% (95% CI, 49-86) PPV, and 85.7% (95% CI, 80.7-90) NPV for predicting main pulmonary artery obstruction on CT. Increased cTnI values were highly correlated to intensive care unit admission of patients with PE (RR, 12.83; 95% CI, 3.87-42.4). CONCLUSIONS: Measuring cTnI value might be considered in ED patients who are suspected of having PE. Elevated cTnI should raise the clinician's concern for the possibility of central pulmonary vascular obstruction.

Stimulus pattern dependence of the Alzheimer's disease amyloid-beta 42 peptide's inhibition of long term potentiation in mouse hippocampal slices.

Increasing evidence has pointed to inhibition of Long Term Potentiation (LTP) by soluble A beta 42 oligomers as central in the etiology of the learning and memory deficits that are hallmarks of Alzheimer Disease. These effects are thought to occur by an interaction between A beta 42 and certain cellular effectors that induce LTP, however, the precise identity of the A beta 42-interactive signaling molecules is unknown. Identification of such effectors is made more difficult because LTP induced by different stimulation protocols can be expressed through heterogeneous signaling pathways. The aim of this study was to compare differences in the A beta 42-dependent levels of inhibition of LTPs that were induced using high frequency stimulation (HFS), versus theta burst stimulation (TBS). Our results show that untreated control brain slices tetanized with either HFS or TBS gave similar levels of LTP and post tetanic stimulation (PTP), suggesting that the response induced by either protocol was comparable. However, A beta 42 peptide significantly blocked LTP and PTP induced by HFS, but not when TBS was used. NMDA receptor antagonists, D-AP5 and ifenprodil, both blocked LTPs that were induced by HFS or TBS. We propose that unknown signaling effectors, other than the NMDA receptor, which are differentially involved in the induction of LTP by TBS, as compared to HFS, may be responsible for this resistance of TBS-induced LTP to A beta 42 dependent inhibition.

Rapid restoration of cognition in Alzheimer's transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta.

As a disease-modifying approach for Alzheimer's disease (AD), clioquinol (CQ) targets beta-amyloid (Abeta) reactions with synaptic Zn and Cu yet promotes metal uptake. Here we characterize the second-generation 8-hydroxy quinoline analog PBT2, which also targets metal-induced aggregation of Abeta, but is more effective as a Zn/Cu ionophore and has greater blood-brain barrier permeability. Given orally to two types of amyloid-bearing transgenic mouse models of AD, PBT2 outperformed CQ by markedly decreasing soluble interstitial brain Abeta within hours and improving cognitive performance to exceed that of normal littermate controls within days. Nontransgenic mice were unaffected by PBT2. The current data demonstrate that ionophore activity, inhibition of in vitro metal-mediated Abeta reactions, and blood-brain barrier permeability are indices that predict a potential disease-modifying drug for AD. The speed of recovery of the animals underscores the acutely reversible nature of the cognitive deficits associated with transgenic models of AD.

Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease.

Amelyoid-beta peptide (Abeta) is a major causative agent responsible for Alzheimer's disease (AD). Abeta contains a high affinity metal binding site that modulates peptide aggregation and toxicity. Therefore, identifying molecules targeting this site represents a valid therapeutic strategy. To test this hypothesis, a range of L-PtCl(2) (L = 1,10-phenanthroline derivatives) complexes were examined and shown to bind to Abeta, inhibit neurotoxicity and rescue Abeta-induced synaptotoxicity in mouse hippocampal slices. Coordination of the complexes to Abeta altered the chemical properties of the peptide inhibiting amyloid formation and the generation of reactive oxygen species. In comparison, the classic anticancer drug cisplatin did not affect any of the biochemical and cellular effects of Abeta. This implies that the planar aromatic 1,10-phenanthroline ligands L confer some specificity for Abeta onto the platinum complexes. The potent effect of the L-PtCl(2) complexes identifies this class of compounds as therapeutic agents for AD.

The search for common ground: developing emergency medicine in Iran.

Academic ties between Iran and the United States were extensive before the 1979 revolution in Iran. After 20 years of negligible academic exchanges, there has been a growing trend of professional contacts between the two countries over the past few years. The genuine warmth of friendship and commitment to excellence in emergency medicine (EM) among Iranians has transcended the political barriers to allow international contribution of EM development in the country. Since 1999, there has been a successful academic collaboration between Iranian and U.S. universities to help develop EM in Iran. Today, remarkable progresses have been achieved through recognition of EM as a distinct profession, developing EM residency programs, improving emergency medical services, establishing qualified emergency departments, training faculty and staff, starting physician exchange programs, and building mutual contributions with professionals throughout the world. A supportive policy environment and a high-quality health care system have had incredible impacts on EM development in the country.

Modulation of monocarboxylic acid transporter-1 kinetic function by the cAMP signaling pathway in rat brain endothelial cells.

MCT1 (monocarboxylic acid transporter 1) facilitates bidirectional monocarboxylic acid transport across membranes. MCT1 function and regulation have not been characterized previously in cerebral endothelial cells but may be important during normal cerebral energy metabolism and during brain diseases such as stroke. Here, by using the cytoplasmic pH indicator 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-acetoxymethyl ester, the initial rates of monocarboxylate-dependent cytoplasmic acidification were measured as an indication of MCT1 kinetic function in vitro using the rat brain endothelial cell (RBE4) model of blood-brain transport. The initial rate of L-lactate-dependent acidification was significantly inhibited by 5-10-min incubations with agonists of intracellular cAMP-dependent cell signaling pathways as follows: dibutyryl cAMP, forskolin, and isoproterenol. Isoproterenol reduced V(max) but did not affect K(m) values. The effects of forskolin were completely reversed by the protein kinase A inhibitor H89, whereas H89 alone increased transport rates. Cytoplasmic cAMP levels, measured by radioimmunoassay, were increased by forskolin or isoproterenol, and the effect of isoproterenol was inhibited by propranolol. MCT1-independent intracellular pH control mechanisms did not contribute to the forskolin or H89 effects on MCT1 kinetic function as determined with amiloride, monocarboxylate-independent acid loading, or the transport inhibitor alpha-cyano-4-hydroxycinnamate. The data demonstrate the direct modulation of MCT1 kinetic function in cerebral endothelial cells by agents known to affect the beta-adrenergic receptor/adenylyl cyclase/cAMP/protein kinase A intracellular signaling pathway.