Accuracy of Femoral Tunnel Placement between Anteromedial and Anterolateral Visualisation Portals in Anterior Cruciate Ligament Reconstruction - Outcomes of a CT based Cross-Sectional Study.

Introduction: Anatomical femoral tunnel placement is critical for anterior cruciate ligament reconstruction (ACLR). Tunnel placement may vary with different surgical techniques. The aim of this study was to compare the accuracy of femoral tunnel placement between the Anteromedial (AM) and Anterolateral (AL) visualisation portals on post-operative CT scans among a cohort of ACLR patients. Materials and methods: This cross-sectional study was conducted from January 2018 to March 2020 after obtaining ethics clearance. Patients who went for arthroscopic ACLR in our institute were divided into an AM (group 1) and an AL (group 2) based on the visualisation portal for creating the femoral tunnel and a 3D CT scan was done. The femoral tunnel position was calculated in deep to shallow and high to low direction using the Bernard Hertel grid. Femoral tunnel angle was measured in the 2D coronal image. Statistical analysis was done with the data collected. Results: Fifty patients with an average age of 26.36 (18-55) years ±7.216 SD were enrolled in the study. In this study, the AM technique was significantly more accurate (p<0.01) than the AL technique in terms of femoral tunnel angle. Furthermore, the deep to the shallow position was significantly (p= 0.018) closer to normative values, as determined by the chi-square test. The chances of error in tunnel angle in femoral condyle are 2.6 times greater in the AL technique (minimal clinical difference). Conclusion: To conclude, in ACLR the anteromedial visualisation portal can facilitate accurate femoral tunnel placement compared to the anterolateral visualisation portal.

Prediction of plan adaptation in head and neck cancer proton therapy using clinical, radiographic, and dosimetric features.

PURPOSE: Because proton head and neck (HN) treatments are sensitive to anatomical changes, plan adaptation (re-plan) during the treatment course is needed for a significant portion of patients. We aim to predict re-plan at plan review stage for HN proton therapy with a neural network (NN) model trained with patients' dosimetric and clinical features. The model can serve as a valuable tool for planners to assess the probability of needing to revise the current plan. METHODS AND MATERIALS: Mean beam dose heterogeneity index (BHI), defined as the ratio of the maximum beam dose to the prescription dose, plan robustness features (clinical target volume (CTV), V100 changes, and V100 > 95% passing rates in 21 robust evaluation scenarios), as well as clinical features (e.g., age, tumor site, and surgery/chemotherapy status) were gathered from 171 patients treated at our proton center in 2020, with a median age of 64 and stages from I-IVc across 13 HN sites. Statistical analyses of dosimetric parameters and clinical features were conducted between re-plan and no-replan groups. A NN was trained and tested using these features. Receiver operating characteristic (ROC) analysis was conducted to evaluate the performance of the prediction model. A sensitivity analysis was done to determine feature importance. RESULTS: Mean BHI in the re-plan group was significantly higher than the no-replan group (p < .01). Tumor site (p < .01), chemotherapy status (p < .01), and surgery status (p < .01) were significantly correlated to re-plan. The model had sensitivities/specificities of 75.0%/77.4%, respectively, and an area under the ROC curve of .855. CONCLUSION: There are several dosimetric and clinical features that correlate to re-plans, and NNs trained with these features can be used to predict HN re-plans, which can be used to reduce re-plan rate by improving plan quality.

Effect of a multicomponent intervention on achievement and improvements in quality-of-care indices among people with Type 2 diabetes in South Asia: the CARRS trial.

AIMS: To evaluate whether and what combinations of diabetes quality metrics were achieved in a multicentre trial in South Asia evaluating a multicomponent quality improvement intervention that included non-physician care coordinators to promote adherence and clinical decision-support software to enhance physician practices, in comparision with usual care. METHODS: Using data from the Centre for Cardiometabolic Risk Reduction in South Asia (CARRS) trial, we evaluated the proportions of trial participants achieving specific and combinations of five diabetes care targets (HbA1c <53 mmol/mol [7%], blood pressure <130/80 mmHg, LDL cholesterol <2.6 mmol/L, non-smoking status, and aspirin use). Additionally, we examined the proportions of participants achieving the following risk factor improvements from baseline: ≥11-mmol/mol (1%) reduction in HbA1c , ≥10-mmHg reduction in systolic blood pressure, and/or ≥0.26-mmol/l reduction in LDL cholesterol. RESULTS: Baseline characteristics were similar in the intervention and usual care arms. Overall, 12.3%, 29.4%, 36.5%, 19.5% and 2.2% of participants in the intervention group and 16.2%, 38.3%, 31.6%, 11.3% and 0.8% of participants in the usual care group achieved any one, two, three, four or five targets, respectively. We noted sizeable improvements in HbA1c , blood pressure and cholesterol, and found that participants in the intervention group were twice as likely to achieve improvements in all three indices at 12 months that were sustained over 28 months of the study [relative risk 2.1 (95% CI 1.5,2.8) and 1.8 (95% CI 1.5,2.3), respectively]. CONCLUSIONS: The intervention was associated with significantly higher achievement of and greater improvements in composite diabetes quality care goals. However, among these higher-risk participants, very small proportions achieved the complete group of targets, which suggests that achievement of multiple quality-of-care goals is challenging and that other methods may be needed in closing care gaps.

System Xc- Antiporter Inhibitors: Azo-Linked Amino-Naphthyl-Sulfonate Analogues of Sulfasalazine.

The cystine/glutamate antiporter system Xc- (SXc-) mediates the exchange of intracellular L-glutamate (L-Glu) with extracellular L-cystine (L-Cys2). Both the import of L-Cys2 and the export of L-Glu take on added significance in CNS cells, especially astrocytes. When the relative activity of SXc- overwhelms the regulatory capacity of the EAATs, the efflux of L-Glu through the antiporter can be significant enough to trigger excitotoxic pathology, as is thought to occur in glioblastoma. This has prompted considerable interest in the pharmacological specificity of SXc- and the development of inhibitors. The present study explores a series of analogues that are structurally related to sulfasalazine, a widely employed inhibitor of SXc-. We identify a number of novel aryl-substituted amino-naphthylsulfonate analogues that inhibit SXc- more potently than sulfasalazine. Interestingly, the inhibitors switch from a competitive to noncompetitive mechanism with increased length and lipophilic substitutions, a structure-activity relationship that was previously observed with aryl-substituted isoxazole. These results suggest that the two classes of inhibitors may interact with some of the same domains on the antiporter protein and that the substrate and inhibitor binding sites may be in close proximity to one another. Molecular modeling is used to explore this possibility.

Blastoschizomyces capitatus pulmonary infections in immunocompetent patients: case report, case series and literature review.

Blastoschizomyces capitatus is an uncommon opportunistic yeast associated with infections in neutropaenic patients secondary to haematological malignancies, with a special predilection for the lungs. Globalisation and population migration impact on the epidemiology of infection with this organism but its effect on the immunocompetent population has rarely been described. We present here a case report, an overview of 11 other cases published between 2000 and 2016, and a comprehensive literature review of Blastoschizomyces pneumonia in the non-immunocompromised. The median age at diagnosis was 68 years (range 40-86 years) and more than half the cases reported a positive history of either current or past tobacco smoking. Six cases had either clinical or radiological evidence of chronic obstructive pulmonary disease and three had a history of prior treated tuberculosis. Fluconazole and itraconazole, alone or in combination, was the most utilised treatment. We conclude that unlike most other invasive yeast species, B. capitatus poses an infectious risk for immunocompetent patients, usually of middle to older age with risk factors for distorted lung architecture. Further research is warranted into the pathophysiology of Blastoschizomyces infections in the immunocompetent, including standardised treatment options.

The impact of comorbidity and PSA doubling time on the risk of death in men experiencing PSA failure following radiation therapy with or with androgen deprivation therapy for unfavorable-risk prostate cancer.

BACKGROUND: The optimal management of men with PSA failure following initial prostate cancer (PC) therapy stratified by comorbidity is unknown. We investigated the impact that PSA doubling time (DT) and comorbidity had on the risk of all-cause mortality (ACM), prostate cancer-specific mortality (PCSM) and other-cause mortality (OCM) following PSA failure. METHODS: Between 1995 and 2001, 206 men with unfavorable-risk PC were randomized to receive radiation therapy alone or in combination with 6 months of androgen deprivation therapy (ADT); 108 men experienced PSA failure and formed the study cohort. Cox and Fine-Gray regression analysis was used to determine whether PSA DT was associated with the risk of ACM and PCSM/OCM, respectively, stratified by comorbidity status using a validated metric. RESULTS: After a median follow-up of 13.71 years following PSA failure, 81 of the 108 men (75%) died. Longer PSA DT was associated with a decreased risk of PCSM in men with no/minimal (adjusted hazard ratio (AHR) 0.33, 95% confidence interval (CI) 0.17-0.65, P=0.001) and moderate/severe comorbidity (AHR 0.014, 95% CI 0.002-0.129, P=0.0002). However, because of the different contributions of the risk of OCM to risk of ACM within comorbidity subgroups, increasing PSA DT was only associated with a decreased risk of ACM in men with no/minimal (AHR 0.69, 95% CI 0.50-0.96, P=0.03) but not moderate/severe comorbidity (AHR 0.95, 95% CI 0.51-1.78, P=0.87). CONCLUSIONS: Both the extent of comorbidity and the PSA DT should be taken into consideration when deciding on appropriate management and/or clinical trial eligibility at the time of PSA failure.

Interleukin-6 mediated upregulation of CYP1B1 and CYP2E1 in colorectal cancer involves DNA methylation, miR27b and STAT3.

BACKGROUND: The pro-inflammatory cytokine interleukin-6 (IL6) promotes colorectal cancer (CRC) development. It is also known to regulate cytochrome P450 (CYP450) enzymes, which are involved in CRC tumour initiation and promotion via activation of chemical carcinogens. Here, IL6 regulation of CYP450 expression was investigated in CRC. METHODS: The effect of IL6 on CYP 1A1, 1B1 and 2E1 expression was determined in vitro using CRC cell lines HCT116 and SW480, and CYP450 expression was determined by immunohistochemistry in CRC tissues previously shown to have increased levels of IL6. RESULTS: In mechanistic studies, IL6 treatment significantly induced CYP1B1 and CYP2E1, but not CYP1A1, gene expression in HCT116 and SW480 cells. CYP2E1 expression regulation occurred via a transcriptional mechanism involving STAT3. For CYP1B1 regulation, IL6 downregulated the CYP1B1-targeting microRNA miR27b through a mechanism involving DNA methylation. In clinical samples, the expression of CYP1B1 and CYP2E1, but not CYP1A1, was significantly increased in malignant tissue overexpressing IL6 compared with matched adjacent normal tissue. CONCLUSIONS: Colonic inflammation with the presence of IL6 associated with neoplastic tissue can alter metabolic competency of epithelial cells by manipulating CYP2E1 and CYP1B1 expression through transcriptional and epigenetic mechanisms. This can lead to increased activation of dietary carcinogens and DNA damage, thus promoting colorectal carcinogenesis.

In vitro evaluation of Midwest Caries ID: a novel light-emitting diode for caries detection.

INTRODUCTION: Traditional detection techniques have limits in diagnosing occlusal caries. Thus, more accurate methods are needed. This study evaluates the ability of the Midwest Caries ID (Midwest) to detect caries. METHODS: Two hundred sixty-four extracted, nonrestored premolars and molars were cleaned and stored in 0.2% sodium azide. Teeth were divided into three groups of 88. One examination site on each occlusal surface was chosen. Each site was inspected by a calibrated examiner via visual, Midwest, and histologic exams. First, a visual exam was performed following the International Caries Detection and Assessment guidelines. Next, the same site was inspected using the Midwest device. Finally, the tooth was sectioned mesiodistally through the site. The half with greater caries progression was visualized under a stereomicroscope (64×). Histologic appearance was scored based on the Downer system. Data were analyzed using Kendall tau-b, partial correlation coefficients, and the receiver operating characteristics curve. RESULTS: Overall, the Midwest scoring assessment correlated with histologic assessments (tau = 0.32; p<0.0001), but the visual exam had a stronger correlation (tau = 0.53; p<0.0001) with the histologic exam. The sensitivity and specificity of the Midwest was also reported at 0.56 and 0.84, compared with 0.92 and 0.43, respectively, for the visual exam. CONCLUSIONS: Midwest Caries ID is a novel caries detection device that has limitations and should not be used as the sole means to detect occlusal caries.

Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system Xc(-) cystine/glutamate exchanger.

The system xc(-) antiporter is a plasma membrane transporter that mediates the exchange of extracellular l-cystine with intracellular l-glutamate. This exchange is significant within the context of the CNS because the import of l-cystine is required for the synthesis of the antioxidant glutathione, while the efflux of l-glutamate has the potential to contribute to either excitatory signaling or excitotoxic pathology. Changes in the activity of the transport system have been linked to the underlying pathological mechanisms of a variety of CNS disorders, one of the most prominent of which is its highly enriched expression in glial brain tumors. In an effort to produce more potent system xc(-) blockers, we have been using amino-3-carboxy-5-methylisoxazole propionic acid (ACPA) as a scaffold for inhibitor development. We previously demonstrated that the addition of lipophilic aryl groups to either the #4 or #5 position on the isoxazole ring markedly increased the inhibitory activity at system xc(-). In the present work a novel series of analogues has been prepared in which aryl groups have been introduced at both the #4 and #5 positions. In contrast to the competitive action of the mono-substituted analogues, kinetic analyses indicate that the di-substituted isoxazoles block system xc(-)-mediated uptake of (3)H-l-glutamate into SNB-19 cells by a noncompetitive mechanism. These new analogues appear to be the first noncompetitive inhibitors identified for this transport system, as well as being among the most potent blockers identified to date. These diaryl-isoxazoles should be of value in assessing the physiological roles and molecular pharmacology of system xc(-).

Neuromedin B stimulates the hypothalamic-pituitary-gonadal axis in male rats.

Neuromedin B (NMB) is a highly conserved bombesin-related peptide found in mammals. NMB mRNA is detected in the central nervous system (CNS) and is highly expressed in the rat hypothalamus, in particular the medial preoptic area and the arcuate nucleus. The mammalian bombesin family of receptors consists of three closely related G protein coupled receptors, BB1, BB2 and BB3. The BB1 receptor subtype has the highest affinity for NMB. NMB has well documented roles in the regulation of the thyroid axis and the stress axis in rats. However, there is little available data regarding the role of NMB in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis. It is known that the NMB receptor is expressed in immortalised gonadotrophin releasing hormone (GnRH) releasing GT1-7 cells and murine forebrain GnRH neurons, and that anterior pituitary NMB-immunoreactivity is altered by changes in the sex steroid environment. The objective of these studies was thus to further investigate the effects of NMB on the HPG axis. Intracerebroventricular (ICV) administration of NMB (10 nmol) to adult male rats significantly increased plasma luteinising hormone (LH) levels 30 min after injection (plasma LH ng/ml; saline 0.69±0.07, 10 nmol NMB 1.33±0.17, P<0.01). In vitro, NMB stimulated GnRH release from hypothalamic explants from male rats and from hypothalamic GT1-7 cells. NMB had no significant effect on LH release from anterior pituitary explants from male rats, or from pituitary LßT2 cells in vitro. These results suggest a previously unreported role for NMB in the stimulation of the HPG axis via hypothalamic GnRH. Further work is now required to determine the receptor mediating the effects of NMB on the reproductive axis and the physiological role of NMB in reproduction.

Overexpression of the adiponectin receptor AdipoR1 in rat skeletal muscle amplifies local insulin sensitivity.

Adiponectin is an adipokine whose plasma levels are inversely related to degrees of insulin resistance (IR) or obesity. It enhances glucose disposal and mitochondrial substrate oxidation in skeletal muscle and its actions are mediated through binding to receptors, especially adiponectin receptor 1 (AdipoR1). However, the in vivo significance of adiponectin sensitivity and the molecular mechanisms of muscle insulin sensitization by adiponectin have not been fully established. We used in vivo electrotransfer to overexpress AdipoR1 in single muscles of rats, some of which were fed for 6 wk with chow or high-fat diet (HFD) and then subjected to hyperinsulinemic-euglycemic clamp. After 1 wk, the effects on glucose disposal, signaling, and sphingolipid metabolism were investigated in test vs. contralateral control muscles. AdipoR1 overexpression (OE) increased glucose uptake and glycogen accumulation in the basal and insulin-treated rat muscle and also in the HFD-fed rats, locally ameliorating muscle IR. These effects were associated with increased phosphorylation of insulin receptor substrate-1, Akt, and glycogen synthase kinase-3ß. AdipoR1 OE also caused increased phosphorylation of p70S6 kinase, AMP-activated protein kinase, and acetyl-coA carboxylase as well as increased protein levels of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif-1 and adiponectin, peroxisome proliferator activated receptor-γ coactivator-1α, and uncoupling protein-3, indicative of increased mitochondrial biogenesis. Although neither HFD feeding nor AdipoR1 OE caused generalized changes in sphingolipids, AdipoR1 OE did reduce levels of sphingosine 1-phosphate, ceramide 18:1, ceramide 20:2, and dihydroceramide 20:0, plus mRNA levels of the ceramide synthetic enzymes serine palmitoyl transferase and sphingolipid Δ-4 desaturase, changes that are associated with increased insulin sensitivity. These data demonstrate that enhancement of local adiponectin sensitivity is sufficient to improve skeletal muscle IR.

Functional signaling biases in G protein-coupled receptors: Game Theory and receptor dynamics.

Pharmacotherapeutic targeting of G protein-coupled receptors (GPCRs) is perhaps the most important field of drug design, as agents designed to control these receptors constitute more than half of the pharmacopeia. Initially GPCRs were considered to be unitary entities, possessing all of their potential functionality in their characteristic heptahelical core. Early models of the functional activity of GPCRs considered them to possess just a simple 'on' or 'off' status. Recent research however has allowed us to realize that GPCR functionality is dependent upon many other proteins outside of the heptahelical core, on the site of GPCR expression in a tissue or a microdomain in a cell, and, most importantly, on the formation of differential 'active' states preferentially coupled to specific signal transduction structures. The recognition of such signaling diversity has facilitated the ability to appreciate and identify ligands for GPCRs that demonstrate a bias towards one signaling form of a receptor to another. However while potentially increasing our ability for selective signal targeting, our approach to understanding the physiological ramifications of systemic signaling manipulation is underdeveloped. This explosion in the complexity of GPCR signaling is now becoming familiar territory to receptor biologists, yet the application of this knowledge to drug design is relatively limited. This review will attempt to outline potential pitfalls and unseen benefits of using signaling bias in therapeutic design as well as highlighting new applications such as Game Theory for uncovering new therapeutic applications for biased agonists.

Effect of silver diamine fluoride on microtensile bond strength to dentin.

The aim of this in vitro study was to investigate the effect of the cariostatic and preventive agent silver diamine fluoride (SDF) on the microtensile bond strength of resin composite to dentin. Forty-two caries-free, extracted molars were flattened occlusally and apically using a diamond saw, and the exposed occlusal dentin was polished with a series of silicon carbide papers, all under water irrigation. The teeth were then randomly divided into six groups of seven teeth each that were treated as follows: 1) Peak SE self-etch bonding agent; 2) 12% SDF + Peak SE; 3) 38% SDF + Peak SE; 4) Peak LC etch-and-rinse bonding agent; 5) 12% SDF + Peak LC; and 6) 38% SDF + Peak LC. Four-millimeter buildups of Amelogen Plus were incrementally placed on all teeth; after a 24-hour storage period in distilled water, the specimens were sectioned perpendicular to the adhesive interface to produce beams of cross-sectional surface area measuring approximately 1 mm(2). The beams were placed on a microtensile testing machine, which utilized a single-speed pump motor and force gauge at 20 kgf × 0.01 second to record maximum tensile force before failure occurred. Two-way analysis of variance and post hoc Tukey tests were performed to compare the effects of the SDF on microtensile bond strength, with statistical significance set at α = 0.05. None of the experimental groups treated with different concentrations of SDF showed a significant difference in bond strength compared to the control groups, and there was no significant difference in bond strength between self-etch and etch-and-rinse groups. However, the effect of SDF on self-etch bonded teeth compared to etch-and-rinse bonded teeth was statistically significant (p=0.0363), specifically at the 12% concentration. SDF does not adversely affect the bond strength of resin composite to noncarious dentin.

Evaluation of the impact of HIV serostatus, tobacco smoking and CD4 counts on epidermoid anal cancer survival.

Tobacco smoking and HIV infection increase the risk of epidermoid anal cancer (EAC). No published studies have examined smoking and EAC outcomes, and the literature is discrepant regarding outcomes of HIV-positive patients with EAC. The goal of this study was to examine smoking history, HIV status and outcomes in EAC patients. We conducted a retrospective analysis of adults with invasive EAC treated in the University of Washington hospital system from 1 January 1994 to 31 December 2008. Sixty-three patients were included. Forty-seven patients (75%) had primary chemoradiation, of whom 42 (89%) completed therapy. Two patients (3%) received radiotherapy alone. Fourteen patients (22%) underwent primary surgery, of whom 11 (79%) underwent tumour excision and three (21%) abdominoperineal resection (APR). We analysed smoking history, HIV status and CD4 count (≥ 200 cells/µL/<200 cells/µL for HIV-positive patients) versus outcomes. Forty-five patients (71%) were in remission, and 44 (70%) were alive at last follow-up. Overall survival was significantly better for never-smokers than for ever-smokers. There were no differences in outcomes according to HIV status or CD4 counts. Patients with anal cancer who smoke have worse overall survival than non-smoking patients. HIV infection does not appear to affect anal cancer outcomes.

The adaptor protein APPL1 increases glycogen accumulation in rat skeletal muscle through activation of the PI3-kinase signalling pathway.

APPL1 is an adaptor protein that binds to both AKT and adiponectin receptors and is hypothesised to mediate the effects of adiponectin in activating downstream effectors such as AMP-activated protein kinase (AMPK). We aimed to establish whether APPL1 plays a physiological role in mediating glycogen accumulation and insulin sensitivity in muscle and the signalling pathways involved. In vivo electrotransfer of cDNA- and shRNA-expressing constructs was used to over-express or silence APPL1 for 1 week in single tibialis cranialis muscles of rats. Resulting changes in glucose and lipid metabolism and signalling pathway activation were investigated under basal conditions and in high-fat diet (HFD)- or chow-fed rats under hyperinsulinaemic-euglycaemic clamp conditions. APPL1 over-expression (OE) caused an increase in glycogen storage and insulin-stimulated glycogen synthesis in muscle, accompanied by a modest increase in glucose uptake. Glycogen synthesis during the clamp was reduced by HFD but normalised by APPL1 OE. These effects are likely explained by APPL1 OE-induced increase in basal and insulin-stimulated phosphorylation of IRS1, AKT, GSK3ß and TBC1D4. On the contrary, APPL1 OE, such as HFD, reduced AMPK and acetyl-CoA carboxylase phosphorylation and PPARγ coactivator-1α and uncoupling protein 3 expression. Furthermore, APPL1 silencing caused complementary changes in glycogen storage and phosphorylation of AMPK and PI3-kinase pathway intermediates. Thus, APPL1 may provide a means for crosstalk between adiponectin and insulin signalling pathways, mediating the insulin-sensitising effects of adiponectin on muscle glucose disposal. These effects do not appear to require AMPK. Activation of signalling mediated via APPL1 may be beneficial in overcoming muscle insulin resistance.

RP-HPLC Method for the Estimation of Dutasteride in Tablet Dosage Form.

A simple, sensitive and precise RP-HPLC method was developed for the determination of dutasteride in tablet dosage form. The RP-HPLC separation was achieved on phenomenex C(18) column (250 mm, id 4.6 mm, 5 mum) using mobile phase methanol:water (90:10 v/v) at a flow rate of 1 ml/min at an ambient temperature. Quantification was achieved with photodiode array detection at 235 nm over the concentration range 1-12 mug/ml. The method was validated statistically and was applied successfully for the determination of dutasteride in tablets.

Personalizing Stem Cell Research and Therapy: The Arduous Road Ahead or Missed Opportunity?

The euphoria of stem cell therapy has diminished, allowing scientists, clinicians and the general public to seriously re-examine how and what types of stem cells would effectively repair damaged tissue, prevent further tissue damage and/or replace lost cells. Importantly, there is a growing recognition that there are substantial person-to-person differences in the outcome of stem cell therapy. Even though the small molecule pharmaceuticals have long remained a primary focus of the personalized medicine research, individualized or targeted use of stem cells to suit a particular individual could help forecast potential failures of the therapy or identify, early on, the individuals who might benefit from stem cell interventions. This would however demand collaboration among several specialties such as pharmacology, immunology, genomics and transplantation medicine. Such transdisciplinary work could also inform how best to achieve efficient and predictable stem cell migration to sites of tissue damage, thereby facilitating tissue repair. This paper discusses the possibility of polarizing immune responses to rationalize and individualize therapy with stem cell interventions, since generalized "one-size-fits-all" therapy is difficult to achieve in the face of the diverse complexities posed by stem cell biology. We also present the challenges to stem cell delivery in the context of the host related factors. Although we focus on the mesenchymal stem cells in this paper, the overarching rationale can be extrapolated to other types of stem cells as well. Hence, the broader purpose of this paper is to initiate a dialogue within the personalized medicine community by expanding the scope of inquiry in the field from pharmaceuticals to stem cells and related cell-based health interventions.

Neurogenesis: role for microRNAs and mesenchymal stem cells in pathological states.

Implantation of adult human mesenchymal stem cells (MSCs) to treat neural disorders shows promise. Depending on their microenvironment, MSCs could potentially be used for the repair and/or replacement of neurons in traumatic brain injury or the treatment of Parkinson's disease. This cross-disciplinary review incorporates aspects of neuroscience, stem cell biology, cancer biology and immunology to discuss interactions between inflammatory mediators and MSCs. We first discuss the role of microRNAs (miRNAs) in neurological development. Secondly, we discuss the ability of MSCs to transdifferentiate into functional neurons, which are regulated by miRNAs, and the implications of these cells for the therapy of neuropathological states. The administration of effective and safe MSC therapy must acknowledge immune mediators that may predispose the early differentiating MSCs to oncogenic insults. Thus, we discuss a key gene, RE-1 silencing transcription factor (REST), based on its dual role in neurogenesis and cancer development. Immune mediators could be central to MSC responses within a region of tissue injury and are also discussed in detail. Exploring the predisposition of MSCs to oncogenesis is critical for translational science since the implementation of safeguarding measures prior to therapy can lead to the successful delivery of stem cells to patients. The method by which MSCs could be applied for future therapies might require trans-disciplinary approaches for personalized treatments.

Simultaneous spectrophotometric estimation of imipramine hydrochloride and chlordiazepoxide in tablets.

A binary mixture of imipramine HCl and chlordiazepoxide was determined by three different spectrophotometric methods. The first method involved determination of imipramine HCl and chlordiazepoxide using the simultaneous equations and the second method involved absorbance ratio method. Imipramine has absorbance maxima at 251 nm, chlordiazepoxide has absorbance maxima at 264.5 nm and isoabsorptive point is at 220 nm in methanol. Linearity was obtained in the concentration ranges of 1-25 and 1-10 mug/ml for Imipramine HCL and Chlordiazepoxide, respectively. The third method involved determination of these two drugs using the first-derivative spectrophotometric technique at 219 and 231.5 nm over the concentration ranges of 1-20 and 2-24 mug/ml with mean accuracies 99.46+/-0.78 and 101.43+/-1.20%, respectively. These methods were successively applied to pharmaceutical formulations because no interferences from the tablet excipients were found. The suitability of these methods for the quantitative determination of the compounds was proved by validation.

Biology of hypoxia-inducible factor-2alpha in development and disease.

The transcriptional response to hypoxia is primarily mediated by two hypoxia-inducible factors--HIF-1alpha and HIF-2alpha. While these proteins are highly homologous, increasing evidence suggests they have unique transcriptional targets and differential impact on tumor growth. Furthermore, non-transcriptional effects of the HIF-alpha subunits, including effects on the Notch and c-Myc pathways, contribute to their distinct functions. HIF-2alpha transcriptional targets include genes involved in erythropoiesis, angiogenesis, metastasis, and proliferation. Therefore, HIF-2alpha contributes significantly to both normal physiology as well as tumorigenesis. Here, we summarize the function of HIF-2alpha during development as well as its contribution to pathologic conditions, such as tumors and vascular disease.