Bentham Science Publishers

Plasma low-density lipoprotein cholesterol (LDL-C) is one of the biomarkers of cardiovascular disease (CVD) risk. LDL is cleared from the circulation preferentially through the LDL receptor (LDLR) pathway. Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes the degradation of the LDLR. PCSK9 inhibition is attractive as a new strategy for lowering LDL-C levels, especially in combination with lipid lowering drugs such as statins. We review data from the available studies which focus on PCSK9 as a potential target in the treatment of hyperlipidemia. Further studies are still necessary to investigate the potential underlying mechanisms involved.

COPD Assessment Test (CAT) is an 8-items questionnaire for assessment of health status in patients with chronic obstructive pulmonary disease (COPD). To evaluate the course of CAT scores during bacterial exacerbations of COPD treated in outpatient setting. We performed an observational, prospective study including 81 outpatients (57 males and 24 females, aged 43 to 74 years) with bacterial exacerbation of COPD. All participants completed CAT at initial visit (i.e. at the time of diagnosis of exacerbation and beginning of its treatment), 10 and 30 days after initial visit. Mean scores of each item, as well as the overall mean score, at these time points were compared. The mean scores for each CAT question at initial visit varied from 2.6 to 3.5, whereas the mean scores for each CAT question 10 days after initial visit varied from 1.7 to 2.6. We registered significant reduction of the mean overall CAT score 10 days after initial visit as compared to its value at initial visit of 6.9 ±...

After more than 30 years of continuous research as well as unselfish efforts, tremendous and exciting developments have been achieved towards the evolution of HIV treatments both in the directions of antiretroviral therapy and effective vaccine for HIV positive patients. Recent research shows that triple-drug antiretroviral therapy can 'functionally cure' [1, 2] the HIV positive patients, which is a milestone in the therapeutic treatments of AIDS. Despite the significant progress on the evolution of AIDS/HIV treatments, it is still a curse for the humanity and until today the world's most serious epidemic as well as leading infectious killer disease. However, Millennium Development Goals (MDGs) Getting to Zero shows a hope to build up a new world without AIDS. In this paper we investigate and focus on those issues of the overall present scenarios of AIDS treatment for the preventive strategies of HIV infections. A mathematical model is analyzed with numerical simulations showing its importance in diseases control and preventions. Optimal control theory is applied to compare the results in the presence of state constraints.

Asthma treatment guidelines advocate the use of long-acting β 2 -agonists (LABA) in addition to inhaled corticosteroids (ICS) in patients whose asthma is uncontrolled by ICS alone, thereby addressing two processes fundamental to asthma: bronchoconstriction and inflammation. Superior control -including a reduction in severe exacerbations -of asthma and COPD by ICS/LABA combination therapy has been demonstrated. Results from clinical studies suggest additive and potentially synergistic effects when the two agents are used in combination. No new safety-related issues have been identified with ICS/LABA compared with the monocomponents.

The heterogeneous nature of rheumatoid arthritis (RA) complicates early recognition and treatment. In recent years, a growing body of evidence has demonstrated that intervention during the window of opportunity can improve the response to treatment and slowor even stop-irreversible structural changes. Advances in therapy, such as biologic agents, and changing approaches to the disease, such as the treat to target and tight control strategies, have led to better outcomes resulting from personalized treatment to patients with different prognostic markers. The various biomarkers identified either facilitate early diagnosis or make it possible to adjust management to disease activity or poor outcomes. However, no single biomarker can bridge the gap between disease onset and prescription of the first DMARD, and traditional biomarkers do not identify all patients requiring early aggressive treatment. Furthermore, the outcomes of early arthritis cohorts are largely biased by the treatment prescribed to patients; therefore, new challenges arise in the search for prognostic biomarkers. Herein, we discuss the value of traditional and new biomarkers and suggest the need for intensive treatment as a new surrogate marker of poor prognosis that can guide therapeutic decisions in the early stages of RA.

Deficits in neuroplasticity are hypothesized to underlie the pathophysiology of major depressive disorder (MDD): the effectiveness of antidepressants is thought to be related to the normalization of disrupted synaptic transmission and neurogenesis. The cyclic adenosine monophosphate (cAMP) signaling cascade has received considerable attention for its role in neuroplasticity and MDD. However components of a closely related pathway, the cyclic guanosine monophosphate (cGMP) have been studied with much lower intensity, even though this signaling transduction cascade is also expressed in the brain and the activity of this pathway has been implicated in learning and memory processes. Cyclic GMP acts as a second messenger; it amplifies signals received at postsynaptic receptors and activates downstream effector molecules resulting in gene expression changes and neuronal responses. Phosphodiesterase (PDE) enzymes degrade cGMP into 5'GMP and therefore they are involved in the regulation of intracellular levels of cGMP. Here we review a growing body of evidence suggesting that the cGMP signaling cascade warrants further investigation for its involvement in MDD and antidepressant action. . The cGMP signaling pathway. Presynaptic (top) and postsynaptic (bottom) elements of the cGMP signaling cascade are represented. AMPAR = 2-amino-3-(5-methyl-3-oxo-1,2-oxal-4-yl)propanoic acid receptor; CaMK = calcium-calmodium-dependent kinase; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; CNG = cyclic nucleotide gated channels; NO = nitric oxide; nNO = neuronal NO; PDE = phosphodiesterase; PI3K/AKT/Gsk3 = phosphoinositide 3-kinase/protein kinase B (aka AKT)/glycogen synthase kinase 3; PKGI = cGMP dependent protein kinase I; PKGII = cGMP dependent protein kinase II; sGC = soluble guanylate cyclase; VASP = vasodilator-stimulated phosphoprotein. CNG NMDAR CNG NMDAR AMPAR AMPAR AMPAR AMPAR CREB Genetic Changes Nucleus Transcription apparatus PKG cGMP PKGI PKGII VASP VASP PI3K/Akt/Gsk3 Neurogensis AMPA receptor insertion Synaptic protein accumulation sGC NO O2 Ca2+ nNOs L-Arginine L-Citrulline CaMK NO Glutamate sGC cGMP PKGI PDE cAMP cGMP Signaling, Phosphodiesterases and Major Depression Disorder

Biphalin (Tyr-D-Ala-Gly-Phe-NH-NH-Phe-Gly-D-Ala-Tyr) is an opioid octapeptide with a dimeric structure based on two identical pharmacophore portions, derived from enkephalins, joined "tail to tail" by a hydrazide bridge. This particular structure enhances the antinociceptive activity of the native enkephalins with an unknown mechanism, probably based on a cooperative binding and improved enzymatic stability. Biphalin has excellent binding affinity for and receptors and it is a highly potent analgesic, as potent as or more than ethorphine. A definitive explanation of the extraordinary in vivo potency shown by this compound, which has pronounced efficacy in pain modulation, is still not available; it has been suggested, however, that the high agonist activity may be related to its binding mode at both and opioid receptors. Biphalin has significantly higher potency than other analgesics with novel biological profiles; in particular, most recent data show that biphalin is unlikely to produce dependency in chronic use. In the past 20 years, there have been many attempts to modify its structure to obtain products unaffected by the action of enkephalinases, to enhance its antinociceptive activity and to modify the BBB penetration. In addition, structure-activity relationship studies (SAR) were performed in order to understand the elements responsible for biphalin's high activity. The aim of the studies reported in this review was to clarify: i) the role of the hydrazide bridge, ii) the role of residues in position 4, 4' and 3, 3', iii) the consequences of molecular simplifications (truncation, delection), iv) the consequences of cyclization through a disulfide bridge, v) conjugation with PEG and fluorescet residues, and vi) radiolabeling on Tyr 1 . activity of enkephalin analogs, the enhanced activity was not observed for other D-amino acid residues ; iii) C-terminal methionine or leucine residues can be replaced by a large number of substituents, not only by L-or D-amino acids, without decreasing the compound's activity .

The sun is the primary energy source of our planet and potentially can supply all societies with more than just their basic energy needs. Demand of electric energy can be satisfied with photovoltaics, however the global demand for fuels is even higher. The direct way to produce the solar fuel hydrogen is by water splitting in photoelectrochemical (PEC) cells, an artificial mimic of photosynthesis. There is currently strong resurging interest for solar fuels produced by PEC cells, but some fundamental technological problems need to be solved to make PEC water splitting an economic, competitive alternative. One of the problems is to provide a low cost, high performing water oxidizing and oxygen evolving photoanode in an environmentally benign setting. Hematite, -Fe 2 O 3 , satisfies many requirements for a good PEC photoanode, but its efficiency is insufficient in its pristine form. A promising strategy for enhancing photocurrent density takes advantage of photosynthetic proteins. In this paper we give an overview of how electrode surfaces in general and hematite photoanodes in particular can be functionalized with light harvesting proteins. Specifically, we demonstrate how low-cost biomaterials such as cyanobacterial phycocyanin and enzymatically produced melanin increase the overall performance of virtually no-cost metal oxide photoanodes in a PEC system. The implementation of biomaterials changes the overall nature of the photoanode assembly in a way that aggressive alkaline electrolytes such as concentrated KOH are not required anymore. Rather, a more environmentally benign and pH neutral electrolyte can be used.

Ostra białaczka szpikowa stanowi najczęstsze wskazanie do allogenicznego przeszczepienia krwiotwórczych komórek macierzystych (allo-HSCT) u dorosłych. Metaanaliza prospektywnych badań klinicznych z randomizacją genetyczną opartą na dostępności zgodnego w zakresie ludzkich antygenów leukocytarnych dawcy rodzinnego wskazuje, że procedura allo-HSCT powinna być rozważana w pierwszej całkowitej remisji u chorych z grup pośredniego i wysokiego ryzyka nawrotu, definiowanej na podstawie kariotypu. Szczegółowe wskazania, w tym obejmujące przeszczepienie od dawców niespokrewnionych, różnią się w poszczególnych europejskich grupach badawczych. Preferowanym źródłem komórek macierzystych jest szpik kostny. Przeszczepienia z użyciem komórek krwiotwórczych uzyskanych z krwi obwodowej wiążą się z większym ryzykiem przewlekłej choroby przeszczep przeciw gospodarzowi i należy je rozważać głównie w zaawansowanych stadiach choroby oraz w przypadku wysokiego ryzyka śmiertelnych powikłań, wynikających z długiego okresu cytopenii. Przygotowanie mieloablacyjne, oparte na napromienianiu całego ciała (TBI), wydaje się wiązać z lepszymi wynikami odległymi w porównaniu z doustnie stosowanym busulfanem. Protokoły oparte na chemioterapii podawanej dożylnie wymagają porównania z TBI w formie prospektywnych badań. Allogeniczne przeszczepienie krwiotwórczych komórek macierzystych z przygotowaniem niemieloablacyjnym jest opcją dla chorych w starszych grupach wiekowych oraz z obecnością chorób współistniejących obciążających rokowanie. Słowa kluczowe: allogeniczne przeszczepienie krwiotwórczych komórek macierzystych, ostra białaczka szpikowa, wskazania

Non-steroidal anti-inflammatory drugs (NSAIDs), commonly used for the treatment of chronic inflammatory diseases suffer from several undesired side effects, the most important being gastrointestinal (GI) irritation and ulceration. The prodrug designing is one of the several strategies used to overcome this drawback. The rationale behind the prodrug concept is to achieve temporary blockade of the free carboxylic group present in the NSAIDs till their systemic absorption. In this paper, a review on the concept of prodrugs designing of NSAIDs to improve their efficacy and reduce the toxicity is being presented.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have unacceptable morbidity and mortality due to their gastrointestinal toxicity. Attempts so far to improve the safety profile of NSAIDs have met with limited clinical acceptance. Nitric oxide (NO) functions as an endogenous mediator of gastric mucosal health and defense. Recent medicinal chemistry approaches attempt to exploit the tissue-protective function of NO against NSAID-induced gastric injury. Both nitroxybutyl-ester and nitrosothiol NSAID derivatives have been synthesized. Profiling of these NO-donating NSAIDs in both the laboratory and the clinic suggests that they might offer a unique solution to the problem of NSAID-induced gastropathy without sacrificing the well-accepted pharmacological activity of these agents in the management of pain and inflammation.

Invention of polymerase chain reaction (PCR) technology by Kary Mullis in 1984 gave birth to real-time PCR. Real-time PCR-detection and expression analysis of gene(s) in real-time-has revolutionized the 21 st century biological science due to its tremendous application in quantitative genotyping, genetic variation of inter and intra organisms, early diagnosis of disease, forensic, to name a few. We comprehensively review various aspects of real-time PCR, including technological refinement and application in all scientific fields ranging from medical to environmental issues, and to plant.

Galectins control cell behavior by acting on different signaling pathways. Most of the biological activities ascribed to these molecules rely upon recognition of extracellular glycoconjugates and establishment of multivalente interactions, which trigger adaptive biological responses. However, galectins are also detected within the cell in different compartments, where their regulatory functions still remain poorly understood. A deeper understanding of the entire galectin signalosome and its impact in cell behavior is therefore essential in order to delineate new strategies to specifically manipulate both galectin expression and function. This review summarizes our current knowledge of the signaling pathways activated by galectins, their glycan dependence and the cellular compartment where they become activated and are biologically relevant.

Since thousands of years natural products have played a very important role in health care and in prevention of disease. To evaluate the anti-microbial & antidiabetic activities of leaf extracts (chloroform and methanol) of ixora chinensis. A complete literature survey of ixora chinensis revealed that most of the activities reported on leaves and flowers were anti-oxidants, anticancer, anti-microbial activities. For preliminary phytochemical screening of the extracts, we performed tests for alkaloids, carbohydrates, flavanoids, tannins, glycosides, saponins, proteins and steroids. From this study, we can conclusively state that methanol, chloroform leaf extracts of Ixora chinensis has anti-hyperglycemic activity, anti-microbial activity. These results support the use of the plant in folk medicine to manage microbial infections, diabetics and other related diseases.

In the post-genome era, high throughput gene expression profiling has been successfully used to develop genomic biomarker panels (GBP) that can be integrated into clinical decision making. The development of GBPs in the context of personalized medicine is a scientifically challenging and resource-intense process. It needs to be accomplished in a systematic phased approach to address biological variation related to a clinical phenotype (e.g. disease etiology, gender, etc.) and minimize technical variation (noise). Here we present the methodological aspects of GBP development based on the experience of the Cardiac Allograft Rejection Gene Expression Observation (CARGO) study, a study that lead to the development of a molecular classifier for rejection screening in heart transplant patients.

Invention of polymerase chain reaction (PCR) technology by Kary Mullis in 1984 gave birth to real-time PCR. Real-time PCR-detection and expression analysis of gene(s) in real-time-has revolutionized the 21 st century biological science due to its tremendous application in quantitative genotyping, genetic variation of inter and intra organisms, early diagnosis of disease, forensic, to name a few. We comprehensively review various aspects of real-time PCR, including technological refinement and application in all scientific fields ranging from medical to environmental issues, and to plant.

Background:The tibial pilon fractures represent a complex therapeutic problem for the orthopedic surgeon, given the frequent complications and outcomes disabling. The recent medical literature indicates that the best strategy to reduce amount of complications in tibial pilon fractures is two-stages procedure. We describe our experience in the primary stabilization of these fractures.Methods:We treated 36 cases with temporary external fixation in a simple configuration, called "tripolar": this is an essential structure (only three screws and three rods), that is possible to perform even without the availability of X-rays and with simple anesthesia or sedation.Results:We found a sufficient mechanical stability for the nursing post-operative, in absence of intraoperative and postoperative problems. The time between trauma and temporary stabilization ranged between 3 and 144 hours; surgical average time was 8.4 minutes. Definitive treatment was carried out with a delay of a mi...

Cerebral Flow Autoregulation (CFA) is the dynamic process by which cerebral blood flow is maintained within physiologically acceptable bounds during fluctuations of cerebral perfusion pressure. The distinction is made with "static" flow autoregulation under steady-state conditions of perfusion pressure, described by the celebrated "autoregulatory curve" with a homeostatic plateau. This paper studies the dynamic CFA during changes in perfusion pressure, which attains critical clinical importance in patients with stroke, traumatic brain injury and neurodegenerative disease with a cerebrovascular component. Mathematical and computational models have been used to advance our quantitative understanding of dynamic CFA and to elucidate the underlying physiological mechanisms by analyzing the relation between beat-to-beat data of mean arterial blood pressure (viewed as input) and mean cerebral blood flow velocity(viewed as output) of a putative CFA system. Although previ...

Autophagy is an intracellular bulk degradation process for elimination of damaged macromolecules and organelles. In the past decades, the scientific community has gained increasingly detailed understanding of the role of autophagy in myocardial homeostasis, although still many controversies remain. In the ischemic myocardium, autophagy appears to be beneficial for survival, whereas upon reperfusion the process may induce cell death. However, the overall effect of autophagy seems to depend on the duration and intensity of stress, as along with the extent of autophagy within myocardial tissue. Reperfusion of an ischemic heart maybe harmful, but it is an essential process for myocardial survival. One of the major adverse consequences of reperfusion is the occurrence of ventricular fibrillation (VF). In the present study, we investigated the possible connection between autophagy and VF. Isolated mouse hearts were subjected to ischemia/reperfusion (I/R) and divided into two groups based on the development of VF at the beginning of reperfusion. Western blot analysis was conducted for autophagy-associated proteins LC3B, ATG-5, ATG-7, ATG-12, Bcl-2 and Beclin-1 proteins. Significantly higher level of Beclin-1 and LC3B-II/LC3B-I ratio (both definitive autophagy biomarkers) was observed in the fibrillated myocardium, versus tissue from the nonfibrillated hearts. Interestingly, although Bcl-2 is a major regulator of Beclin-1, level of this protein was not significantly altered in tissue from fibrillated, versus non-fibrillated hearts. Moreover, Atg7 expression showed a trend, albeit nonsignificant, towards elevation in fibrillated versus non-fibrillated hearts. Results of the present investigation demonstrate a possible link between VF and autophagy. Studies by authors of this report to evaluate potential etiologic relationships between the two processes are ongoing.

Target discovery using the molecular approach, as opposed to the more traditional systems approach requires the study of the cellular or biological process underlying a condition or disease. The approaches that are employed by the “bench” scientist may be genetic, genomic or proteomic and each has its rightful place in the drug-target discovery process. Affinity-based proteomic techniques currently used in drug-discovery draw upon several disciplines, synthetic chemistry, cell-biology, biochemistry and mass spectrometry. An important component of such techniques is the probe that is specifically designed to pick out a protein or set of proteins from amongst the varied thousands in a cell lysate. A second component, that is just as important, is liquid-chromatography tandem massspectrometry (LC-MS/MS). LC-MS/MS and the supporting theoretical framework has come of age and is the tool of choice for protein identification and quantification. These proteomic tools are critical to maintai...

Plasma low-density lipoprotein cholesterol (LDL-C) is one of the biomarkers of cardiovascular disease (CVD) risk. LDL is cleared from the circulation preferentially through the LDL receptor (LDLR) pathway. Proprotein convertase subtilisin/kexin 9 (PCSK9) promotes the degradation of the LDLR. PCSK9 inhibition is attractive as a new strategy for lowering LDL-C levels, especially in combination with lipid lowering drugs such as statins. We review data from the available studies which focus on PCSK9 as a potential target in the treatment of hyperlipidemia. Further studies are still necessary to investigate the potential underlying mechanisms involved.

According to a survey from the HIV Cost and Services Utilization Study (HCSUS), approximately 53% of HIV-infected patients reported drinking alcohol and 8% were classified as heavy drinkers. The role of alcohol as a risk factor for HIV infection has been widely studied and recent research has found a significant association between heavy alcohol consumption and lower levels of CD4 T cells among HIV-infected alcoholics. Although there is evidence on the role of alcohol as a risk factor for HIV transmission and disease progression, there is a need for population studies to determine the genetic mechanisms that affect alcohol's role in HIV disease progression. One of the mechanisms of interest is the dopaminergic system. To date, the effects of dopamine on HIV neuroimmune pathogenesis are not well understood; however, dopaminergic neural degeneration due to HIV is known to occur by viral invasion into the brain via immune cells, and modulation of dopamine in the CNS may be a common mechanism by which different types of substances of abuse impact HIV disease progression. Although previous studies have shown an association of D(2) dopamine receptor (DRD2) polymorphisms with severity of alcohol dependence, the expression of this allele risk on HIV patients with alcohol dependence has not been systematically explored. In the current study, DRD2 Taq1A and C957T SNP genotyping analyses were performed in 165 HIV-infected alcohol abusers and the results were examined with immune status and CD4 counts.

Biphalin (Tyr-D-Ala-Gly-Phe-NH-NH-Phe-Gly-D-Ala-Tyr) is an opioid octapeptide with a dimeric structure based on two identical pharmacophore portions, derived from enkephalins, joined "tail to tail" by a hydrazide bridge. This particular structure enhances the antinociceptive activity of the native enkephalins with an unknown mechanism, probably based on a cooperative binding and improved enzymatic stability. Biphalin has excellent binding affinity for and receptors and it is a highly potent analgesic, as potent as or more than ethorphine. A definitive explanation of the extraordinary in vivo potency shown by this compound, which has pronounced efficacy in pain modulation, is still not available; it has been suggested, however, that the high agonist activity may be related to its binding mode at both and opioid receptors. Biphalin has significantly higher potency than other analgesics with novel biological profiles; in particular, most recent data show that biphalin is unlikely to produce dependency in chronic use. In the past 20 years, there have been many attempts to modify its structure to obtain products unaffected by the action of enkephalinases, to enhance its antinociceptive activity and to modify the BBB penetration. In addition, structure-activity relationship studies (SAR) were performed in order to understand the elements responsible for biphalin's high activity. The aim of the studies reported in this review was to clarify: i) the role of the hydrazide bridge, ii) the role of residues in position 4, 4' and 3, 3', iii) the consequences of molecular simplifications (truncation, delection), iv) the consequences of cyclization through a disulfide bridge, v) conjugation with PEG and fluorescet residues, and vi) radiolabeling on Tyr 1 . activity of enkephalin analogs, the enhanced activity was not observed for other D-amino acid residues ; iii) C-terminal methionine or leucine residues can be replaced by a large number of substituents, not only by L-or D-amino acids, without decreasing the compound's activity .

A large amount of structural information on AChE and AChE-inhibitor complexes is currently available. Based on that, molecular modeling studies can be intensively used to gain insight into the mechanism of action of the enzyme and the molecular determinants that modulate the potency of inhibitors. In turn, this knowledge can be exploited to design new compounds leading to more effective cholinergic strategies. This manuscript reviews recent developments in the design of reversible acetylcholinesterase inhibitors.

A number of study have suggested a relationship between Helicobacter pylori infection and oxidative stress in the gastric epithelium. The oxidant-induced changes in zinc, iron, and vitamin C increase susceptibility to oxidative injury. Understanding of pathophysiologic mechanisms may provide new therapeutic strategies in treatment of oxidative injury of mucosa .