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1.  Data of continuous harvest of stem cells via partial detachment from thermoresponsive nanobrush surfaces 
Data in Brief  2016;6:603-608.
This data article contains two figures and one table supporting the research article entitled: “Continuous harvest of stem cells via partial detachment from thermoresponsive nanobrush surface” [1]. The table shows coating conditions of three copolymers, poly(styrene-co-acrylic acid) grafted with oligovitronectin, poly(styrene-co-N-isopropylacrylamide) and poly(styrene-co-polyethylene glycol methacrylate) to prepare thermoresponsive surface. XPS spectra show the nitrogen peak of the polystyrene surface coated with poly(styrene-co-acrylic acid) grafted with oligovitronectin. The surface coating density analyzed from sorption of poly(styrene-co-acrylic acid) grafted with oligovitronectin by UV–vis spectroscopy is also presented.
doi:10.1016/j.dib.2015.12.056
PMCID: PMC4731461  PMID: 26909373
2.  Long-term xeno-free culture of human pluripotent stem cells on hydrogels with optimal elasticity 
Scientific Reports  2015;5:18136.
The tentative clinical application of human pluripotent stem cells (hPSCs), such as human embryonic stem cells and human induced pluripotent stem cells, is restricted by the possibility of xenogenic contamination resulting from the use of mouse embryonic fibroblasts (MEFs) as a feeder layer. Therefore, we investigated hPSC cultures on biomaterials with different elasticities that were grafted with different nanosegments. We prepared dishes coated with polyvinylalcohol-co-itaconic acid hydrogels grafted with an oligopeptide derived from vitronectin (KGGPQVTRGDVFTMP) with elasticities ranging from 10.3 to 30.4 kPa storage moduli by controlling the crosslinking time. The hPSCs cultured on the stiffest substrates (30.4 kPa) tended to differentiate after five days of culture, whereas the hPSCs cultured on the optimal elastic substrates (25 kPa) maintained their pluripotency for over 20 passages under xeno-free conditions. These results indicate that cell culture matrices with optimal elasticity can maintain the pluripotency of hPSCs in culture.
doi:10.1038/srep18136
PMCID: PMC4677349  PMID: 26656754
4.  Isolation and Characterisation of Degradation Impurities in the Cefazolin Sodium Drug Substance 
Scientia Pharmaceutica  2013;81(4):933-950.
Two unknown impurities were detected in the cefazolin sodium bulk drug substance using gradient reversed-phase high-performance liquid chromategraphy (HPLC). These impurities were isolated by preparative HPLC and characterized by using spectroscopic techniques like LC-MS, LC-MS/MS, 1D, 2D NMR, and FT-IR. Based on the spectral data, the impurities have been characterized as N-(2,2-dihydroxyethyl)-2-(1H-tetrazol-1-yl)acetamide (Impurity-I) and 2-{carboxy[(1H-tetrazol-1-ylacetyl)amino]methyl}-5-methylidene-5,6-dihydro-2H-1,3-thiazine-4-carboxylic acid (Impurity-II). The structures of these impurities were also established unambiguously by co-injection into HPLC to confirm the retention time. To the best of our knowledge, these two impurities were not reported elsewhere.
doi:10.3797/scipharm.1304-14
PMCID: PMC3867249  PMID: 24482765
Cefazolin sodium; Degradation Impurities; LC-MS/MS; NMR; β-Lactam
5.  Identification and Characterization of Process-Related Impurities of Trans-Resveratrol 
Scientia Pharmaceutica  2013;81(3):683-695.
This article deals with the identification and characterization of process-related impurities of trans-resveratrol (3,5,4′-trihydroxystilbene), which exhibits several health benefits, including cancer prevention. During the synthesis of the bulk drug resveratrol, three new impurities were observed. The impurities were detected using the high-performance liquid chromatographic (HPLC) method, whose area percentages ranged from 0.05 to 0.3%. A systematic study was carried out to characterize them. These impurities were isolated by preparative HPLC and characterized by spectral data, subjected to co-injection in HPLC, and were found to be matching with the impurities present in the sample. LC-MS was performed to identify the mass of these impurities. Based on their spectral data (IR, NMR, and Mass), these impurities were characterized as 2-benzyl-5-[(E)-2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol [Impurity-B], 3-(benzyloxy)-5-[(E)-2-(4-hydroxyphenyl)ethenyl]phenol [Impurity-C], 5-{(E)-2-[4-(benzyloxy)phenyl]ethenyl}benzene-1,3-diol [Impurity-D). These compounds are not reported earlier as process-related impurities.
doi:10.3797/scipharm.1301-17
PMCID: PMC3791933  PMID: 24106667
Resveratrol; Impurities; Structure characterization; HPLC; Structural elucidation; NMR; LC-MS
6.  Antimicrobial Activity and Phytochemical Constituents of Leaf Extracts of Cassia auriculata 
Plants produce a wide variety of phytochemical constituents, which are secondary metabolites and are used either directly or indirectly in the pharmaceutical industry. ‘For centuries, man has effectively used various components of plants or their extracts for the treatment of many diseases, including bacterial infections. In the present study methanol, chloroform and aqueous extracts of Cassia auriculata leaf were subjected for antimicrobial activity by well-diffusion method against six bacterial strains namely Bacillus cereus, Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Proteus mirabilis. The results revealed that the methanol and chloroform extracts exhibited strong inhibitory activity against all the tested organisms (zone of inhibition of 12-20 mm), except Pseudomonas aeruginosa (zone of inhibition 10 mm or nil). The aqueous extracts showed moderate activity by ‘Zone of inhibition ≤12 or nil). The extracts were screened for their phytochemical constituents by standard protocols’ and were shown to contain carbohydrates, proteins, alkaloids, flavonoids, steroids, saponins and tannins. The antibacterial activity of these extracts is possibly linked to the presence of flavonoids, steroid, saponins and/or tannins. Further studies are needed to determine the precise active principles from Cassia auriculata.
doi:10.4103/0250-474X.113546
PMCID: PMC3719143  PMID: 23901174
Antibacterial activity; Cassia auriculata; phytochemical constituents
7.  A High Affinity Red Fluorescence and Colorimetric Probe for Amyloid β Aggregates 
Scientific Reports  2016;6:23668.
A major challenge in the Alzheimer’s disease (AD) is its timely diagnosis. Amyloid β (Aβ) aggregates have been proposed as the most viable biomarker for the diagnosis of AD. Here, we demonstrate hemicyanine-based benzothiazole-coumarin (TC) as a potential probe for the detection of highly toxic Aβ42 aggregates through switch-on, enhanced (~30 fold) red fluorescence (Emax = 654 nm) and characteristic colorimetric (light red to purple) optical outputs. Interestingly, TC exhibits selectivity towards Aβ42 fibrils compared to other abnormal protein aggregates. TC probe show nanomolar binding affinity (Ka = 1.72 × 107 M−1) towards Aβ42 aggregates and also displace ThT bound to Aβ42 fibrils due to its high binding affinity. The Aβ42 fibril-specific red-shift in the absorption spectra of TC responsible for the observed colorimetric optical output has been attributed to micro-environment change around the probe from hydrophilic-like to hydrophobic-like nature. The binding site, binding energy and changes in optical properties observed for TC upon interaction with Aβ42 fibrils have been further validated by molecular docking and time dependent density functional theory studies.
doi:10.1038/srep23668
PMCID: PMC4817056  PMID: 27032526
8.  pH Induced Conformational Transitions in the Transforming Growth Factor β-Induced Protein (TGFβIp) Associated Corneal Dystrophy Mutants 
Scientific Reports  2016;6:23836.
Most stromal corneal dystrophies are associated with aggregation and deposition of the mutated transforming growth factor-β induced protein (TGFβIp). The 4th_FAS1 domain of TGFβIp harbors ~80% of the mutations that forms amyloidogenic and non-amyloidogenic aggregates. To understand the mechanism of aggregation and the differences between the amyloidogenic and non-amyloidogenic phenotypes, we expressed the 4th_FAS1 domains of TGFβIp carrying the mutations R555W (non-amyloidogenic) and H572R (amyloidogenic) along with the wild-type (WT). R555W was more susceptible to acidic pH compared to H572R and displayed varying chemical stabilities with decreasing pH. Thermal denaturation studies at acidic pH showed that while WT did not undergo any conformational transition, the mutants exhibited a clear pH-dependent irreversible conversion from αβ conformation to β-sheet oligomers. The β-oligomers of both mutants were stable at physiological temperature and pH. Electron microscopy and dynamic light scattering studies showed that β-oligomers of H572R were larger compared to R555W. The β-oligomers of both mutants were cytotoxic to primary human corneal stromal fibroblast (pHCSF) cells. The β-oligomers of both mutants exhibit variations in their morphologies, sizes, thermal and chemical stabilities, aggregation patterns and cytotoxicities.
doi:10.1038/srep23836
PMCID: PMC4814907  PMID: 27030015
9.  Activation of microglial P2Y12 receptor is required for outward potassium currents in response to neuronal injury 
Neuroscience  2016;318:22-33.
Microglia, the resident immune cells in the central nervous system, constantly survey the surrounding neural parenchyma and promptly respond to brain injury. Activation of purinergic receptors such as P2Y12 receptors (P2Y12R) in microglia has been implicated in chemotaxis towards ATP that is released by injured neurons and astrocytes. Activation of microglial P2Y12R elicits outward potassium current that is associated with microglial chemotaxis in response to injury. This study aimed at investigating the identity of the potassium channel implicated in microglial P2Y12R-mediated chemotaxis following neuronal injury and understanding the purinergic signaling pathway coupled to the channel. Using a combination of two-photon imaging, electrophysiology and genetic tools, we found the ATP-induced outward current to be largely dependent on P2Y12R activation and mediated by G-proteins. Similarly, P2Y12R-coupled outward current was also evoked in response to laser-induced single neuron injury. This current was abolished in microglia obtained from mice lacking P2Y12R. Dissecting the properties of the P2Y12R-mediated current using a pharmacological approach revealed that both the ATP and neuronal injury-induced outward current in microglia was sensitive to quinine (1 mM) and bupivacaine (400 μM), but not TEA (10 mM) and 4-AP (5 mM). These results suggest that the quinine/bupivacaine-sensitive potassium channels are the functional effectors of the P2Y12R–mediated signaling in microglia activation following neuronal injury.
Graphic Abstract
Schematic representation showing that the ATP, ADP and UDP released following neuronal injury directly /indirectly acts on microglial P2Y12 receptor, a G-protein coupled receptor linked to a potassium channel, eliciting an outward potassium current. Inhibitors of G-proteins blocked the P2Y12 receptor mediated outward potassium current. Moreover, this outward current was found to be sensitive to certain potassium channel blockers such as quinine and bupivacaine, while being insensitive to TEA and 4-AP. arrow-headed lines and bar-headed lines to indicate activation and inhibition, respectively. Dotted lines represent hypothetical associations.
doi:10.1016/j.neuroscience.2016.01.008
PMCID: PMC4753827  PMID: 26791526
Microglia; P2Y12 receptor; ATP; K+ channels
10.  Protocolized fluid therapy in brain-dead donors: The multi-center randomized MOnIToR trial 
Intensive care medicine  2015;41(3):418-426.
BACKGROUND
Critical shortages of organs for transplantation jeopardize many lives. Observational data suggest that better fluid management for deceased organ donors could increase organ recovery. We conducted the first large multi-center randomized trial in brain-dead donors to determine whether protocolized fluid therapy increases organs transplanted.
METHODS
We randomly assigned donors to either protocolized or usual care in eight organ procurement organizations. A “protocol-guided fluid therapy” algorithm targeting cardiac index, mean arterial pressure and pulse pressure variation was used. Our primary outcome was the number of organs transplanted per donor and our primary analysis was intention-to-treat. Secondary analyses included: 1) modified intention-to-treat where only subjects able to receive the intervention were included, and 2) twelve-month survival in transplant recipients. The study was stopped early.
RESULTS
We enrolled 556 donors; 279 protocolized care, 277 usual care. Groups had similar characteristics at baseline. The study protocol could be implemented in 76% of subjects randomized to the intervention. There was no significant difference in mean number of organs transplanted per donor: 3.39 organs per donor, (95%CI: 3.14-3.63) with protocolized care, compared to usual care 3.29 (95%CI: 3.04-3.54) (mean difference, 0.1, 95%CI: -0.25 to 0.45; p=0.56). In modified intention-to-treat analysis the mean number of organs increased (3.52 organs per donor, 95%CI: 3.23-3.8) but was not statistically significant (mean difference, 0.23, 95%CI: -0.15-0.61; p=0.23). Among the 1430 recipients of organs from study subjects, with data available, 56 deaths (7.8%) occurred in the protocolized care arm and 56 (7.9%) in the usual care arm in the first year (Hazard Ratio: 0.97, p=0.86).
CONCLUSIONS
In brain-dead organ donors, protocol-guided fluid therapy compared to usual care may not increase the number of organs transplanted per donor.
doi:10.1007/s00134-014-3621-0
PMCID: PMC4351113  PMID: 25583616
Organ donation; clinical trial; transplantation; functional hemodynamic monitoring; fluid management; brain death
11.  A Retrospective Study of the Pattern of Sexually Transmitted Infections in Males: Viral Infections in Emerging Trend 
Introduction
Sexually transmitted infections (STIs) continue to be a major public health problem with significant burden on the society even after so many health care programmes being organized by the governmental and non-governmental organizations and awareness created among general public about STIs. Male patients are common visitors to STI clinic than females who are generally traced as a contact in our society.
Aim
The aim of this study was to give an overview of the pattern of STIs among males at a tertiary care teaching hospital over a period of 5 years.
Materials and Methods
A retrospective chart review of the data collected from the clinical records of all male patients, who had attended the STI clinic of Chengalpattu Medical College Hospital, Chengalpattu, Tamil Nadu, for various complaints during the 5 year period from 2010 to 2014 was carried out. All male patients with confirmed STIs were included in the study and those patients without any evidence of STIs either clinically or serologically were excluded from the study.
Results
Out of the 4454 male cases who had attended the STI clinic, 175 (3.93%) patients had STIs. Genital wart accounted for the maximum number among the STIs with 61 cases (34.86%), followed by genital herpes 56 (32%), urethral discharge 19(10.86%), non-herpetic genital ulcerative diseases 17(9.71%) and serological test for syphilis (RPR) was reactive in 22 (12.57%) patients. HIV was positive in 68 (1.53%) among the total 4454 male patients attended the clinic.
Conclusion
Viral STIs occur significantly more than the bacterial STIs because of its incurable and recurrent nature. Health programmes should be still more focused on creating awareness about the minor STIs and to remove the stigma so that the patients attend the proper health care facilities in the early stage itself for treatment thereby, complications and further transmission of the STIs can be avoided.
doi:10.7860/JCDR/2016/16142.7138
PMCID: PMC4740688  PMID: 26894160
Genital wart; Genital herpes; Syndromic management; Stigma
13.  Beta-endorphin Cell Therapy for Cancer Prevention 
Beta-endorphin (BEP) producing neuron in the hypothalamus plays a key role in brining the stress axis to a state of homeostasis and maintaining body immune defense system. Long-term delivery of BEP to obtain beneficial effect on chemoprevention is challenging, since the peptide rapidly develop tolerance. Using rats as animal model, we show here that transplantation of beta-endorphin neurons into the hypothalamus suppressed carcinogens- and hormone-induced cancers in various tissues and prevented growth and metastasis of established tumors via activation of innate immune functions. Additionally, we show that intracerebroventricular administration of nanosphere-attached dibutyryl cyclic adenosine monophosphate (dbcAMP) increased the number of BEP neurons in the hypothalamus, reduced the stress response, enhanced the innate immune function and prevented tumor cell growth, progression and metastasis. Beta-endorphin neuronal supplementation did not produce any deleterious effects on general health but was beneficial in suppressing age-induced alterations in physical activity, metabolic and immune functions. We conclude that the neuroimmune system has significant control over cancer growth and progression and that activation of the neuroimmune system via beta-endorphin neuronal supplementation/induction may have therapeutic value for cancer prevention and improvement of general health.
doi:10.1158/1940-6207.CAPR-14-0254
PMCID: PMC4289651  PMID: 25403848
14.  A novel H395R mutation in MKKS/BBS6 causes retinitis pigmentosa and polydactyly without other findings of Bardet-Biedl or McKusick-Kaufman syndrome 
Molecular Vision  2016;22:73-81.
Purpose
To identify the causative mutation in two siblings from a consanguineous family in India with retinitis pigmentosa (RP) and polydactyly without other findings of Bardet-Biedl syndrome (BBS). We also performed functional characterization of the mutant protein to explore its role in this limited form of BBS.
Methods
The siblings underwent a thorough ophthalmological examination, including retinal optical coherence tomography (OCT) imaging, and an extensive physical examination with abdominal ultrasonography to characterize the disease phenotype. Next-generation sequencing (NGS) using a panel targeting retinal degeneration genes was performed on genomic DNA samples from the siblings and parents. Upon identification of the causative mutation, functional characterization was accomplished by performing protein–protein interaction studies in human embryonic kidney (HEK-293T) and human adult retinal pigmented epithelium (ARPE-19) cells.
Results
The two siblings showed signs of RP and polydactyly. The patients did not have truncal obesity, renal anomalies, hydrometrocolpos, congenital heart disease, or overt cognitive defects. NGS identified a homozygous c.1184A>G mutation in the MKKS/BBS6 gene in both patients resulting in a p.H395R substitution in the MKKS/BBS6 protein. This mutant protein decreased the interaction of MKKS/BBS6 with BBS12 but did so to a different extent in the HEK-293T versus ARPE-19 cells. Nonetheless, the effect of the H395R variant on disrupting interactions with BBS12 was not as profound as other reported MKKS/BBS6 mutations associated with syndromic RP.
Conclusions
We identified a novel H395R substitution in MKKS/BBS6 that results in a unique phenotype of only RP and polydactyly. Our observations reaffirm the notion that mutations in MKKS/BBS6 cause phenotypic heterogeneity and do not always result in classic MKKS or BBS findings.
PMCID: PMC4734152  PMID: 26900326
16.  Facilitating Mitochondrial Calcium Uptake Improves Activation-Induced Cerebral Blood Flow and Behavior after mTBI 
Mild to moderate traumatic brain injury (mTBI) leads to secondary neuronal loss via excitotoxic mechanisms, including mitochondrial Ca2+ overload. However, in the surviving cellular population, mitochondrial Ca2+ influx, and oxidative metabolism are diminished leading to suboptimal neuronal circuit activity and poor prognosis. Hence we tested the impact of boosting neuronal electrical activity and oxidative metabolism by facilitating mitochondrial Ca2+ uptake in a rat model of mTBI. In developing rats (P25-P26) sustaining an mTBI, we demonstrate post-traumatic changes in cerebral blood flow (CBF) in the sensorimotor cortex in response to whisker stimulation compared to sham using functional Laser Doppler Imaging (fLDI) at adulthood (P67-P73). Compared to sham, whisker stimulation-evoked positive CBF responses decreased while negative CBF responses increased in the mTBI animals. The spatiotemporal CBF changes representing underlying neuronal activity suggested profound changes to neurovascular activity after mTBI. Behavioral assessment of the same cohort of animals prior to fLDI showed that mTBI resulted in persistent contralateral sensorimotor behavioral deficit along with ipsilateral neuronal loss compared to sham. Treating mTBI rats with Kaempferol, a dietary flavonol compound that enhanced mitochondrial Ca2+ uptake, eliminated the inter-hemispheric asymmetry in the whisker stimulation-induced positive CBF responses and the ipsilateral negative CBF responses otherwise observed in the untreated and vehicle-treated mTBI animals in adulthood. Kaempferol also improved somatosensory behavioral measures compared to untreated and vehicle treated mTBI animals without augmenting post-injury neuronal loss. The results indicate that reduced mitochondrial Ca2+ uptake in the surviving populations affect post-traumatic neural activation leading to persistent behavioral deficits. Improvement in sensorimotor behavior and spatiotemporal neurovascular activity following kaempferol treatment suggests that facilitation of mitochondrial Ca2+ uptake in the early window after injury may sustain optimal neural activity and metabolism and contribute to improved function of the surviving cellular populations after mTBI.
doi:10.3389/fnsys.2016.00019
PMCID: PMC4782040  PMID: 27013987
TBI; mitochondria; CBF; dietary; calcium uniporter; kaempferol; whisker barrel; oxidative metabolism
17.  The role of natriuretic peptides in volume assessment and mortality prediction in Haemodialysis patients 
BMC Nephrology  2015;16:218.
Background
Maintaining optimal fluid balance is essential in haemodialysis (HD) patients but clinical evaluation remains problematic. Other technologies such as bioimpedance are emerging as valuable adjuncts. This study was undertaken to explore the potential utility of the natriuretic peptides – atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) in the assessment of fluid status and cardiovascular risk in this setting.
Methods
This was a cross-sectional study carried out in an unselected cohort of 170 prevalent HD patients. Volume status was assessed by clinical parameters – the presence or absence of peripheral oedema, raised jugular venous pressure and basal lung crepitations; by extracellular fluid volume (ECFV) status determined by whole body bioimpedance; and by serum levels of BNP and ANP (pre- and post –dialysis). The relationships of ANP and BNP levels to clinical and bioimpedance parameters of volume status was determined. Patients were followed up for 5 years to assess the relationship of natriuretic peptide levels to mortality.
Results
Bioimpedance estimates of ECFV expansion (>105 % of ideal ECFV) was present in 52 % of patients pre-dialysis. A significant proportion (21 %) of pre-dialysis patients had a depleted ECFV (<95 % of ideal ECFV) pre-dialysis. The situation was reversed post-dialysis. A raised JVP >3 cm was the most reliable clinical sign of ECFV expansion inferred from bioimpedance measurements and natriuretic peptide levels. The vast majority of patients with this sign also had lung crepitations or peripheral oedema or both. BNP was a stronger predictor of ECFV expansion than either pre- or post-dialysis ANP. BNP was also a stronger predictor of five-year survival.
Conclusion
Serum levels of BNP have a strong relationship to both volume status and survival in HD patients. We found no clear role for measurement of ANP, though changes in blood levels may be a sensitive indicator of acute changes in volume status. Whether monitoring levels of these peptides has a role in the management of volume status and cardiovascular risk requires further study.
doi:10.1186/s12882-015-0212-4
PMCID: PMC4696232  PMID: 26714753
18.  Angiotensin 1-7 Protects against Angiotensin II-Induced Endoplasmic Reticulum Stress and Endothelial Dysfunction via Mas Receptor 
PLoS ONE  2015;10(12):e0145413.
Angiotensin 1–7 (Ang 1–7) counter-regulates the cardiovascular actions of angiotensin II (Ang II). The present study investigated the protective effect of Ang 1–7 against Ang II-induced endoplasmic reticulum (ER) stress and endothelial dysfunction. Ex vivo treatment with Ang II (0.5 μM, 24 hours) impaired endothelium-dependent relaxation in mouse aortas; this harmful effect of Ang II was reversed by co-treatment with ER stress inhibitors, l4-phenylbutyric acid (PBA) and tauroursodeoxycholic acid (TUDCA) as well as Ang 1–7. The Mas receptor antagonist, A779, antagonized the effect of Ang 1–7. The elevated mRNA expression of CHOP, Grp78 and ATF4 or protein expression of p-eIF2α and ATF6 (ER stress markers) in Ang II-treated human umbilical vein endothelial cells (HUVECs) and mouse aortas were blunted by co-treatment with Ang 1–7 and the latter effect was reversed by A779. Furthermore, Ang II-induced reduction in both eNOS phosphorylation and NO production was inhibited by Ang 1–7. In addition, Ang 1–7 decreased the levels of ER stress markers and augmented NO production in HUVECs treated with ER stress inducer, tunicamycin. The present study provides new evidence for functional antagonism between the two arms of the renin-angiotensin system in endothelial cells by demonstrating that Ang 1–7 ameliorates Ang II-stimulated ER stress to raise NO bioavailability, and subsequently preserves endothelial function.
doi:10.1371/journal.pone.0145413
PMCID: PMC4692500  PMID: 26709511
19.  Group planarian sudden mortality: Is the threshold around global geomagnetic activity ≥K6? 
Sudden deaths in groups of animals have been observed by field and laboratory biologists. We have measured mortalities in large group-housed planarian during the infrequent periods of very intense geomagnetic activity. In 13 separate episodes over the last 5 y we have observed the sudden death in our laboratory of hundreds of planarian if their density was about 1 worm per cc and the global geomagnetic activity was K≥6 the day before or the day of the observation of the mortality. Such mortality never occurred in other conditions or days. Both estimates of the "magnetic moment" of a planarian in magnetic fields above this threshold of sustained magnetic flux density as well as the magnetic energy within the planarian volume predict values that could affect phenomenon associated with the total numbers of pH-dependent charges within each worm. These conditions could affect the Levin-Burr bioelectrical signals and networks that affect patterning information and sustainability in whole living systems. The establishment of a central reservoir for the report of these transient events might allow Life Scientists to more fully appreciate the impact of these pervasive global stimuli upon dense groups of animals.
doi:10.1080/19420889.2015.1095413
PMCID: PMC4802799  PMID: 27066174
biophysical mechanisms; bioelectric fields; geomagnetic activity; sudden planarian death
22.  Metastatic squamous cell carcinoma urinary bladder coexisting with tuberculosis in pelvic lymph nodes 
BMJ Case Reports  2013;2013:bcr2013202173.
Squamous cell carcinoma (SCC) of the urinary bladder is usually associated with Schistosoma haematobium and chronic bladder irritation. We report a case of coexistent metastatic SCC and tuberculosis in obturator lymph nodes in radical cystoprostatectomy and pelvic lymphadenectomy specimens. Though tubercular iliac lymphadenitis and metastatic transitional carcinoma following intravesical BCG has been reported, the concurrent presence of non-transitional cell cancer and primary lymph nodal tuberculosis in regional lymph nodes is rare. This case is reported to highlight the paucity of management guidelines available presently in the treatment of such patients who require systemic chemotherapy and antitubercular therapy.
doi:10.1136/bcr-2013-202173
PMCID: PMC3863055  PMID: 24296773
23.  PROTECTIVE EFFECTS OF HYPOTHALAMIC BETA-ENDORPHIN NEURONS AGAINST ALCOHOL-INDUCED LIVER INJURIES AND LIVER CANCERS IN RAT ANIMAL MODELS 
Background
Recently, retrograde tracing has provided evidence for an influence of hypothalamic β-endorphin (BEP) neurons on the liver, but functions of these neurons are not known. We evaluated the effect of BEP neuronal activation on alcohol-induced liver injury and hepatocellular cancer.
Methods
Male rats received either BEP neuron transplants or control transplants in the hypothalamus and randomly assigned to feeding alcohol-containing liquid diet or control liquid diet for 8 weeks or to treatment of a carcinogen diethylnitrosamine (DEN). Liver tissues of these animals were analyzed histochemically and biochemically for tissue injuries or cancer.
Results
Alcohol-feeding increased liver weight and induced several histopathological changes such as prominent microvesicular steatosis and hepatic fibrosis. Alcohol feeding also increased protein levels of triglyceride, hepatic stellate cell activation factors and catecholamines in the liver and endotoxin levels in the plasma. However, these effects of alcohol on the liver were reduced in animals with BEP neuron transplants. BEP neuron transplants also suppressed carcinogen-induced liver histopathologies such as extensive fibrosis, large focus of inflammatory infiltration, hepatocelluar carcinoma, collagen deposition, numbers of preneoplastic foci, levels of hepatic stellate cell activation factors and catecholamines, as well as inflammatory milieu and the levels of NK cell cytotoxic factors in the liver.
Conclusion
These findings are the first evidence for a role of hypothalamic BEP neurons in influencing liver functions. Additionally, the data identify that BEP neuron transplantation prevents hepatocellular injury and hepatocellular carcinoma formation possibly via influencing the immune function.
doi:10.1111/acer.12580
PMCID: PMC4293083  PMID: 25581653
Neuroimmune system; hepatocellular carcinoma; alcoholic liver disease; stress hormones; natural killer cells
24.  Plasma inflammatory and apoptosis markers are associated with dialysis dependence and death among critically ill patients receiving renal replacement therapy 
Nephrology Dialysis Transplantation  2014;29(10):1854-1864.
…in critically ill patients receiving RRT, elevated concentrations of inflammatory and apoptosis biomarkers are stigmata of death for both kidneys and patients…
Background
Survivors of critical illness complicated by acute kidney injury requiring renal replacement therapy (RRT) are at an increased risk of dialysis dependence and death but the mechanisms are unknown.
Methods
In a multicenter, prospective, cohort study of 817 critically ill patients receiving RRT, we examined association between Day 1 plasma inflammatory [interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-18; macrophage migration inhibitory factor (MIF) and tumor necrosis factor]; apoptosis [tumor necrosis factor receptor (TNFR)-I and TNFR-II and death receptor (DR)-5]; and growth factor (granulocyte macrophage colony stimulating factor) biomarkers and renal recovery and mortality at Day 60. Renal recovery was defined as alive and RRT independent.
Results
Of 817 participants, 36.5% were RRT independent and 50.8% died. After adjusting for differences in demographics, comorbid conditions; premorbid creatinine; nephrotoxins; sepsis; oliguria; mechanical ventilation; RRT dosing; and severity of illness, increased concentrations of plasma IL-8 and IL-18 and TNFR-I were independently associated with slower renal recovery [adjusted hazard ratio (AHR) range for all markers, 0.70–0.87]. Higher concentrations of IL-6, IL-8, IL-10 and IL-18; MIF; TNFR-I and DR-5 were associated with mortality (AHR range, 1.16–1.47). In an analysis of multiple markers simultaneously, increased IL-8 [AHR, 0.80, 95% confidence interval (95% CI) 0.70–0.91, P < 0.001] and TNFR-I (AHR, 0.63, 95% CI 0.50–0.79, P < 0.001) were associated with slower recovery, and increased IL-8 (AHR, 1.26, 95% CI 1.14–1.39, P < 0.001); MIF (AHR, 1.18, 95% CI 1.08–1.28, P < 0.001) and TNFR-I (AHR, 1.26, 95% CI 1.02–1.56, P < 0.03) were associated with mortality.
Conclusions
Elevated plasma concentrations of inflammatory and apoptosis biomarkers are associated with RRT dependence and death. Our data suggest that future interventions should investigate broad-spectrum immune-modulation to improve outcomes.
doi:10.1093/ndt/gfu051
PMCID: PMC4173817  PMID: 24619058
acute kidney injury; biomarkers; mortality; renal recovery; renal replacement therapy
25.  Skeletal Muscle Tissue Engineering: Methods to Form Skeletal Myotubes and Their Applications 
Skeletal muscle tissue engineering (SMTE) aims to repair or regenerate defective skeletal muscle tissue lost by traumatic injury, tumor ablation, or muscular disease. However, two decades after the introduction of SMTE, the engineering of functional skeletal muscle in the laboratory still remains a great challenge, and numerous techniques for growing functional muscle tissues are constantly being developed. This article reviews the recent findings regarding the methodology and various technical aspects of SMTE, including cell alignment and differentiation. We describe the structure and organization of muscle and discuss the methods for myoblast alignment cultured in vitro. To better understand muscle formation and to enhance the engineering of skeletal muscle, we also address the molecular basics of myogenesis and discuss different methods to induce myoblast differentiation into myotubes. We then provide an overview of different coculture systems involving skeletal muscle cells, and highlight major applications of engineered skeletal muscle tissues. Finally, potential challenges and future research directions for SMTE are outlined.
doi:10.1089/ten.teb.2013.0534
PMCID: PMC4193686  PMID: 24320971

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