An internally controlled peripheral biomarker for Alzheimer's disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin

Cognitive impairment has recently been found to correlate with changes in peripheral inflammatory signals such as TNF-alpha and IL-1beta. PKC isozymes regulate levels of TNF-alpha and IL-6 and the release of other cytokines and also show deficits in Alzheimer's disease (AD) brains and skin fibroblasts. Here, we investigate MAPK Erk1 and Erk2 phosphorylation in response to the inflammatory agonist bradykinin, which activates PKC pathways. An internally controlled comparison of Erk1 and Erk2 produced an AD index that accurately distinguished fibroblasts of AD from those of normal controls and of non-AD dementias. This accuracy was demonstrated for Coriell Cell Repository (Coriell Institute of Medical Research, Camden, NJ) samples, as well as for samples analyzed on gels with autopsy diagnostic confirmation. AD Erk1 and Erk2 index values were inversely correlated with disease duration, suggesting maximal efficacy for early diagnosis. Finally, the results also demonstrate that, when the AD index agreed with the clinical diagnosis on the presence of AD, there was a high probability of accuracy based on autopsy validation. Thus, this peripheral molecular biomarker, based on differential Erk1 and Erk2 phosphorylation, could have important clinical utility for providing increased certainty in the positive diagnosis of AD, particularly in the early phase of disease progression.     

Modulating role of estradiol on arginase II expression in hyperlipidemic rabbits as an atheroprotective mechanism

We evaluated the effects of a 0.5% cholesterol-enriched diet (HCD) on nitric-oxide synthase (NOS) and arginase expression and the modulating role of 17beta-estradiol (E(2)) on this phenomenon. Thirty oopherectomized rabbits were divided into three groups and treated for 15 weeks. Group I received normal chow; group II, HCD; and group III, HCD plus E(2) pellets. Animals in group II showed an increase in plasma lipids, and they demonstrated atheromatous lesions as well as expression of arginase I and II accompanied by a significant number of BrdU-positive cells in endothelial cells and intimal muscle cells, suggestive of an increase in cellular proliferation. There was significant expression of inducible NOS and increased staining of nitrotyrosine-positive areas. These were not observed in group I animals. In both groups, E(2) levels were low. In group III animals, E(2) supplementation led to a decrease in atheromatous lesions and BrdU-positive cells and reduced expression of both inducible NOS and arginase I and II accompanied by a decrease in nitrotyrosine staining. E(2) levels were increased. Our results suggest that E(2) was responsible for these effects, despite the animals being hyperlipidemic, similar to those in group II. Because arginase is responsible for cell proliferation by converting l-arginine to polyamines, our results indicate that expression of arginase may play an important role in cellular proliferation in atherosclerosis, and inhibition of arginase expression by E(2) may be another potential mechanism in attenuating atherogenesis.     

Development of New Localized Drug Delivery System Based on Ceftriaxone-Sulbactam Composite Drug Impregnated Porous Hydroxyapatite: A Systematic Approach for <Emphasis Type="Italic">In Vitro</Emphasis> and <Emphasis Type="Italic">In Vivo</Emphasis> Animal Trial

Purpose  

Present investigation deals with an extensive approach incorporating in vitro and in vivo experimentation to treat chronic osteomyelitis, using hydroxyapatite porous scaffolds.     

Twenty-eight days repeated oral dose toxicity study of gemifloxacin in Wistar albino rats

The purpose of this study was to investigate the potential toxicity of gemifloxacin by 28-day repeated oral dose in Wistar albino rats. The test article, was administered daily by gavage to male and female rats at dose levels of 0, 50, 100, 200 mg/kg/day. At the end of treatment period, 12 rats/sex/group was sacrificed, while six extra rats/sex in the vehicle control and highest dose groups sacrificed after 14 days recovery period. During the treatment and recovery periods, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, phototoxicity, hematology, serum biochemistry, synovial fluid biochemistry, electrocardiogram (ECG), gross findings, organ weights, microscopic examination of synovial fluid, and histopathology were examined. Hematological and serum biochemical investigations revealed a dose-dependent increase in the total white blood cell (WBC), total bilirubin (T-BIL), glucose (GLU), alanine aminotransferase (ALT) and significant decreases in total protein (TP) were observed in both sexes at the same dose, at the end of treatment period, but the levels returned toward normal during the recovery period. Histopathology of talar joint showed that erosion of the articular surface of that joint in both sexes at the end of treatment period at the dose level of 200 mg/kg/day. Degenerative changes in tendinocytes were observed in Achilles tendon of both sexes at the high dose level at the end of treatment period. In histopathological study shows partial effacement of liver architecture and focal ulceration in gastric mucosa at the high dose level at the end of treatment period. Based on these results, it was concluded that 28 days repeated oral dose of gemifloxacin caused increases in the liver weight, WBC count, T-BIL, glucose level, ALT, decreasing the TP, cause chronic hepatitis and acute gastritis, erosion of the articular surface of joint and histopathologic changes in Achilles tendon in rats at the dose level of 200 mg/kg/day.     

Comparative evaluation of aqueous and plasma concentration of topical moxifloxacin alone and with flurbiprofen in patients of cataract surgery

Objectives:

To determine the aqueous and plasma concentrations of moxifloxacin administered topically alone and with flurbiprofen in patients undergoing cataract surgery.

Materials and Methods:

A total of 50 subjects scheduled for routine cataract surgery were randomly allocated to two groups (n = 25 each). Group-1 patients were treated with topical moxifloxacin alone: One drop 6 times/day for 3 days before surgery and one drop 4 times on the day of surgery: Group-2 patients were treated with topical moxifloxacin as in Group-1 and with topical flurbiprofen: One drop 4 times/day for 3 days before and on the day of surgery. The interval between two drugs was 30 min for last 3 days and 15 min on the day of surgery. Last dose was administered 1 h before aqueous humor and blood sampling for both the groups. The antibiotic concentration in aqueous humor and plasma were determined by using high performance liquid chromatography.

Results:

The mean concentration of moxifloxacin in aqueous humor was 1.71 ± 0.82 mg/ml in Group-1 and 2.39 ± 1.34 mg/ml in Group-2. Concentrations of moxifloxacin in aqueous humor were significantly higher in Group-2 than that of Group-1.

Conclusion:

Flurbiprofen may increase the concentration of moxifloxacin in aqueous humor.KEY WORDS: Aqueous humor, cataract surgery, flurbiprofen, moxifloxacin     

Microemulsion based intranasal delivery system for treatment of insomnia

The aim of this investigation was to prepare and characterize microemulsions/mucoadhesive microemulsions of Diazepam (D), Lorazepam (L) and Alprazolam (A), evaluate their pharmacodynamic performances by performing comparative sleep induction studies in male albino rats to assess their role in effective management of insomnia patients. Microemulsions of Diazepam (DME), Lorazepam (LME) and Alprazolam (AME) were prepared by titration method and characterized for drug content, globule size distribution and zeta potential, nasal toxicity and sleep induction. DME, LME and AME were transparent and stable with mean globule size and zeta potential in the range of 95.6?nm to 141.7?nm and -2.205?to -0.111?mV respectively. The prepared microemulsions exhibited reversible nasal toxicity. Onset of sleep and duration of sleep were observed in the following order: Lorazepam > Alprazolam>Diazepam. Faster onset of sleep following intranasal administration of microemulsions (<20?min) compared to oral administration (29-33?min) and control group (>45?min) for all three drugs suggested selective nose-to-brain transport of drug(s). Intranasal administration of microemulsion based formulations resulted in even faster onset of sleep (<12?min) with intranasal mucoadhesive microemulsion(s) resulting in fastest onset of sleep (<9?min). Duration of sleep was longest with the intranasal mucoadhesive microemulsions. These results are suggestive of larger extent of distribution of drug(s) to brain after intranasal administration of mucoadhesive microemulsion(s). These results are further corroborated with by loss or rightening reflex and startle reflex at earlier time points (within 10?min and 15?min respectively) with mucoadhesive microemulsions. Thus, the results of this investigation indicated rapid and larger extent of drug transport to the rat brain resulting in rapid induction of sleep followed by prolonged duration of sleep in rats following intranasal administration of mucoadhesive microemulsion(s). However, the role of microemulsion based formulations developed in this investigation in clinical practice can only be established after animal studies in two different animal models followed by extensive clinical trials.     

Implication of receptor for advanced glycation end product (RAGE) in pulmonary health and pathophysiology

Receptor for advanced glycation end products (RAGE) is a membrane bound receptor and member of the immunoglobulin super family and is normally present in a highly abundant basal level expression in lung. This high expression of RAGE in lung alveolar epithelial type I (ATI) cells is presumably involved in the proliferation and differentiation of pulmonary epithelial cells. However, typically higher than basal level expression of RAGE may indicate the existence of severe pathophysiological condition in lung, e.g. acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). During pulmonary tissue injury an endogenous secretory isoform of RAGE called EsRAGE is noticed at high levels in broncho-alveolar lavage (BAL) and plasma. Recently, a soluble form of RAGE (sRAGE) produced by recombinant gene technology was shown to exhibit a therapeutic potential in experimental animal models. Detailed study of RAGE in the pulmonary tissues will facilitate the understanding of the importance of RAGE signaling in the pulmonary health and pathophysiology.     

Kinematics of a selectively constrained radiolucent anterior lumbar disc: Comparisons to hybrid and circumferential fusion

Background

Despite encouraging clinical outcomes of one-level total disc replacements reported in literature, there is no compelling evidence regarding the stability following two-level disc replacement and hybrid constructs. The current study is aimed at evaluating the multidirectional kinematics of a two-level disc arthroplasty and hybrid construct with disc replacement adjacent to rigid circumferential fusion, compared to two-level fusion using a novel selectively constrained radiolucent anterior lumbar disc.

Methods

Nine osteoligamentous lumbosacral spines (L1–S1) were tested in the following sequence: 1) Intact; 2) One-level disc replacement; 3) Hybrid; 4) Two-level disc replacement; and 5) Two-level fusion. Range of motion (at both implanted and adjacent level), and center of rotation in sagittal plane were recorded and calculated.

Findings

At the level of implantation, motion was restored when one-level disc replacement was used but tended to decrease with two-level disc arthroplasty. The findings also revealed that both one-level and two-level disc replacement and hybrid constructs did not significantly change adjacent level kinematics compared to the intact condition, whereas the two-level fusion construct demonstrated a significant increase in flexibility at the adjacent level. The location of center of rotation in the sagittal plane at L4–L5 for the one-level disc replacement construct was similar to that of the intact condition.

Interpretation

The one-level disc arthroplasty tended to mimic a motion profile similar to the intact spine. However, the two-level disc replacement construct tended to reduce motion and clinical stability of a two-level disc arthroplasty requires additional investigation. Hybrid constructs may be used as a surgical alternative for treating two-level lumbar degenerative disc disease.     

Chemokines and chemokine receptors in susceptibility to HIV-1 infection and progression to AIDS

A multitude of host genetic factors plays a crucial role in susceptibility to HIV-1 infection and progression to AIDS, which is highly variable among individuals and populations. This review focuses on the chemokine-receptor and chemokine genes, which were extensively studied because of their role as HIV co-receptor or co-receptor competitor and influences the susceptibility to HIV-1 infection and progression to AIDS in HIV-1 infected individuals.