Cerebrospinal fluid (CSF) contained within the brain ventricles contacts neuroepithelial progenitor cells during brain development. Dynamic properties of CSF movement may limit locally produced factors to specific regions of the developing brain. However, there is no study of in vivo CSF dynamics between ventricles in the embryonic brain. We address CSF movement using the zebrafish larva, during the major period of developmental neurogenesis.tnnt2a mutant fish (tnnt2a−/−) and chemical  treatment. Cilia motility was monitored at these stages using the Tg(βact:Arl13b–GFP) transgenic fish line.CSF movement was monitored at two stages of zebrafish development: early larva  and late larva  using photoactivatable Kaede protein to calculate average maximum CSF velocity between ventricles. Potential roles for heartbeat in early CSF movement were investigated using tnnt2a−/− fish and after BDM treatment. Brain cilia are immotile at the early larval stage.In wild-type early larva there is net CSF movement from the telencephalon to the combined diencephalic/mesencephalic superventricle. This movement directionality reverses at late larval stage. CSF moves directionally from diencephalic to rhombencephalic ventricles at both stages examined, with minimal movement from rhombencephalon to diencephalon. Directional movement is partially dependent on heartbeat, as indicated in assays of These data demonstrate directional movement of the embryonic CSF in the zebrafish model during the major period of developmental neurogenesis. A key conclusion is that CSF moves preferentially from the diencephalic into the rhombencephalic ventricle. In addition, the direction of CSF movement between telencephalic and diencephalic ventricles reverses between the early and late larval stages. CSF movement is partially dependent on heartbeat. At early larval stage, the absence of motile cilia indicates that cilia likely do not direct CSF movement. These data suggest that CSF components may be compartmentalized and could contribute to specialization of the early brain. In addition, CSF movement may also provide directional mechanical signaling.The online version of this article (doi:10.1186/s12987-016-0036-z) contains supplementary material, which is available to authorized users. Cerebrospinal fluid (CSF) is contained in the brain ventricles (chambers derived from the brain lumen) and contacts neuroepithelial progenitor cells during brain development and in adulthood. The CSF contains a unique composition of proteins (CSF proteome) –6, smallXenopus have investigated local intraventricular CSF dynamics in the developing brain  and late larva . Our study leads to four conclusions: (1) CSF moves preferentially anterior to posterior from the diencephalic (D) ) to rhombencephalic (R) ventricles. (2) Direction of CSF movement between the telencephalic (T) and diencephalic (D) ventricles reverses from early to late larval stages. (3) Directional CSF movement is partially dependent on heartbeat. (4) At early larval stages no motile cilia are present in the brain and therefore are not likely to direct the CSF movement observed. Together these data indicate that locally restricted CSF factors or physical signals associated with fluid movement may contribute to specialization of the early brain.max from D (D/M) to R ventricles. Reverse movement was present, but with about 25 % of the observed forward vmax. This raises two questions: (1) where does the excess volume of CSF entering the R ventricle go and (2) what mechanisms underlie directional CSF movement? First, with respect to CSF “destination”, the brain-CSF barrier is quite tight at early developmental stages  to late  larval stages. CSF movement is partially dependent on heartbeat. At early larval stages, the absence of motile cilia indicates that cilia likely do not direct CSF movement. These data suggest that CSF components may be compartmentalized and could contribute to specialization of the early brain and CSF movement may also provide directional mechanical cues.


Renal cell carcinoma (RCC) with rhabdoid features is a rare histology and exhibits clinically aggressive behavior. We report a case of a married couple in whom RCC with rhabdoid features concurrently occurred. The rarity of this event suggests that environmental factors may contribute to the etiology of RCC with rhabdoid features.A 76-year-old Japanese woman was diagnosed with a hypervascular mass in the right kidney and tumor thrombus extending into the right atrium by enhanced computed tomography (CT). She underwent radical nephrectomy and tumor thrombectomy following systemic therapy with the tyrosine kinase inhibitor sunitinib. The histological evaluation denoted clear cell RCC with rhabdoid features. The patient died of cancer 12 months postoperatively. A 76-year-old man, her husband, presented with gross hematuria 2 weeks after his wife had undergone surgery. He had a long history of asbestos exposure. An abdominal CT scan revealed a hypervascular mass in the right kidney and tumor thrombus extending into the inferior vena cava. He also underwent radical nephrectomy and tumor thrombectomy. The histological evaluation also showed clear cell RCC with rhabdoid features. Bone metastasis occurred 12 months postoperatively, but he died of an unrelated cause 18 months after surgery.Concurrent occurrence of RCC with rhabdoid features may not to be coincidental. Although further studies are warranted, asbestos exposure may contribute to the etiology of clear cell RCC with rhabdoid features. In large consecutive series of patients with malignant renal tumors, approximately 3–5% of RCCs showed rhabdoid features -4. GenerA 75-year-old womanwas referred to our hospital in May 2009 because enhanced computed tomography (CT) had confirmed the presence of a 70 mm mass on the upper pole of her right kidney and tumor thrombus extending into the right atrium Figure a. Based Postoperatively, the patient developed acute renal failure secondary to circulatory insufficiency, and she received hemodialysis for about a month. The pathological diagnosis of the tumor was clear cell carcinoma with rhabdoid features and sarcomatoid change  for publication of this Case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.


Cellular non-coding RNA (ncRNA) transcription and regulation has only recently been systematically investigated. Studies have demonstrated abundant transcription of a set of ncRNAs preferentially within tumors as opposed to normal tissue. In some cases these tumor-associated ncRNAs also associate with inflammatory cytokine production suggesting potential immunostimulatory qualities. Using a novel approach from statistical physics we quantify global transcriptome-wide motif usage for the first time in human and murine ncRNAs determining that most have motif usage consistent with the coding genome. However an outlier subset of tumor-associated ncRNAs typically of recent evolutionary origin has motif usage more associated with pathogen RNA. Here we show that a human repeat enhances immunostimulatory motifs CpG dinucleotides in AU-rich contexts which most of the human genome and human adapted viruses have evolved to avoid. We demonstrate that a key subset of these ncRNA function as immunostimulatory “self-agonists” and directly activate cells of the mononuclear phagocytic system to produce pro-inflammatory cytokines. These ncRNAs arise from endogenous repetitive elements that are normally silenced, yet are often very highly expressed in cancers. We conclude that the innate response in tumors partially originates from direct interaction of immunogenic ncRNAs expressed in cancer cells with innate pattern recognition receptors and thereby assign a new danger-associated function to a set of dark matter repetitive elements, potentially reconciling several observations concerning the role of ncRNA expression in cancers. We consider the possible roles they may play in the tumor microenvironment.


In patients with idiopathic intracranial hypertension (IIH) headache often persist as a disabling symptom even after intracranial pressure (ICP) has normalized. Yet very little is known about the mechanisms of chronification.To explore pain perception in patients with IIH in a controlled design at time of diagnosis and after 3 months of treatment.We explored pain perception in patients with newly diagnosed IIH by Quantitative Sensory Testing (QST) measuring cephalic and extra-cephalic supra-threshold pain ratings and pain thresholds for pressure and electrical stimulation. QST was performed at diagnosis and after one and three months. ICP was measured at baseline and at the 3-month follow-up. QST measurements from sex-matched controls were used for comparisons. Headache was assessed by monthly standardized interviews and headache diaries.At baseline IIH patients (n=28) showed no consistent abnormalities in pain sensitivity or thresholds . Although headache improved markedly and ICP normalized in 52%, there was no consistent change in pain sensitivity from baseline to follow-up . Patients with (54%) and without persistent chronic headache (46%) 3 months after diagnosis showed no different pain perception either at baseline or at the 3-month follow-up.Although headache persisted as a chronic symptom in half of the patients we found no evidence of increased central pain sensitivity suggesting that headache chronification in IIH is caused by mechanisms other than central sensitization.


The MacIntyre strain originated from the brain of a patient with lethal HSV encephalitis and has a unique limitation in its neuronal spread, moving solely in the retrograde direction.We used paired-end Illumina deep sequencing and  The MacIntyre strain originated from the brain of a patient with lethal HSV encephalitis  , 31. HSV34–KM222720.The HSV-1 MacIntyre strain genome sequence has been deposited at GenBank under the accession no.


Solar UVB is carcinogenic. Nucleotide excision repair (NER) counteracts the carcinogenicity of UVB by excising potentially mutagenic UVB-induced DNA lesions. Despite this capacity for DNA repair, non-melanoma skin cancers and apparently normal sun-exposed skin contain huge numbers of mutations that are mostly attributable to unrepaired UVB-induced DNA lesions. UVA is about 20-times more abundant than UVB in incident sunlight. It does cause some DNA damage but this does not fully account for its biological impact. The effects of solar UVA are mediated by its interactions with cellular photosensitizers that generate reactive oxygen species (ROS) and induce oxidative stress. The proteome is a significant target for damage by UVA-induced ROS. In cultured human cells, UVA-induced oxidation of DNA repair proteins inhibits DNA repair. This article addresses the possible role of oxidative stress and protein oxidation in determining DNA repair efficiency – with particular reference to NER and skin cancer risk. It does not contain UVC. Germicidal UV is nevertheless a reasonable surrogate for some of the effects of sunlight on skin, including mutagenesis and carcinogenesis, because CPDs and 6:4 Py:Pys are also the predominant photoproducts of the shorter wavelengths of solar UVB. At longer wavelengths, the contribution of the canonical UV DNA photoproducts to cellular damage declines sharply. Biologically relevant UVA doses induce several orders of magnitude fewer CPDs (and effectively no 6:4 Py:Pys) 1.2CPDs and 6:4 Py:Pys are generated in oxygen-independent reactions whereas many of the biological effects of the longer UVA wavelengths are dependent on oxygen The canonical UV photoproducts appear not to be significant contributors to the biological effects of UVA. NER-defective XP cells that are extremely sensitive to UVC and UVB are not hypersensitive to UVA Taken together, the response of cells to UVA radiation and thorough analyses of UVA-damaged DNA suggest that damage to targets other than DNA is likely to be a significant contributor to the biological effects of UVA.1.3The oxygen dependence of the effects of UVA reflects the activation of endogenous photosensitizers to generate ROS. These cellular photosensitizers have not been fully characterized but candidates include porphyrins, flavins The thiopurine prodrug azathioprine  provides1O2) in a Type II photosensitized reaction. These ROS cause widespread DNA damage including oxidized bases The azathioprine metabolite 6-thioguanine (6-TG) replaces a small fraction of the patients’ DNA guanine PTCHTP53 genes The expectation that a contribution of azathioprine/UVA-induced DNA lesions to skin cancer development would be evident from novel signature mutations in transplant-related skin tumors was not fulfilled. The mutational spectra of the frequently mutated Clinical photosensitivity similar to that caused by azathioprine is a common side effect of drug treatment and is often associated with an increased skin cancer risk Riboflavin  is anothb]carbazole (FICZ) is a naturally-occurring UVA chromophore. FICZ  was described almost 50 years ago More recent experiments provide direct evidence that UVA can compromise DNA repair in human cells and that it does this by damaging DNA repair proteins. UVA combined with 6-TG The extensive protein damage induced by photosensitized UVA Importantly, these photosensitizers simply exacerbate the effects of UVA and at higher doses, UVA alone induces sufficient protein oxidation to inhibit DNA repair These findings emphasize the vulnerability of human DNA repair to inhibition by protein damage by ROS induced by UVA either alone or in combination with an exogenous photosensitizer.1.6If ROS induced by UVA cause protein damage that inhibits DNA repair, it is appropriate to ask whether NER is vulnerable to other interventions that induce oxidative stress. The excess ROS that define oxidative stress results from an imbalance between their formation and removal. This can be induced experimentally by compromising cellular antioxidant defences. Treatment with the glutamylcysteine synthetase inhibitor buthionine sulfoximine (BSO) depletes cells of the important antioxidant glutathione (GSH). The oxidative stress associated with GSH depletion results in an increased steady-state level of protein oxidation and BSO treatment enhances UVA-induced protein oxidation in human keratinocytes. The increased levels of protein oxidation are associated with an inhibition of NER and cells treated with UVA and BSO do not excise UVB-induced photoproducts 2O2 and causes oxidative DNA damage 2O2 itself is widely used to induce oxidative stress. Although rather unreactive, it is converted into the much more reactive hydroxyl radical (OH•) by the Fenton reaction. In addition to DNA damage, H2O2 also causes extensive protein oxidation and treatment of cultured human HaCaT keratinocytes with either H2O2 or high concentrations of ascorbate inhibits NER Pharmacologically active, high concentrations of ascorbate (vitamin C) sensitize cells to carboplatin, a cisplatin analog. At these high concentrations, ascorbate acts in a pro-oxidant fashion to induce oxidative stress. It generates HCells adapt to oxidative stress by diverting glucose metabolism from glycolysis to the pentose phosphate pathway (PPP). One outcome of this metabolic switch is a boost in the production of the NADPH that is required to maintain antioxidant defences by recycling oxidized GSH. By preserving reducing power, increased flux through the PPP protects against both DNA and protein oxidation. Silencing of glucose-6-phosphate dehydrogenase (G6PD), the first and rate-limiting step of the PPP, prevents this metabolic switch. G6PD silencing is associated with decreased NADPH levels, increased protein oxidation and inhibition of NER via the oxidative decarboxylation of isocitrate to α-ketoglutarate by isocitrate dehydrogenase (IDH). Heterozygous mutations in the IDH1 isoform are particularly common in gliomas, chondrosarcomas and some leukemias. Gain of function IDH1 mutations confer the ability to reduce α-ketoglutarate to α-hydroxyglutarate in a reaction that consumes NADPH The TCA cycle also supplies NADPH, in this case via increased protein oxidation.The therapeutic effectiveness of many anticancer agents is compromised by the removal of potentially lethal DNA lesions by NER and they are more effective against tumors in which NER is compromised. This is particularly evident with the platinum-based drugs and the spectacular success of cisplatin in treating testicular carcinomas is partly a reflection of their relatively low NER efficiency via its interaction with cellular photosensitizers, it seems pertinent to question the extent to which solar UVA affects the NER of UVB-induced DNA lesions in skin. How efficient is NER in sun-exposed skin? How good is the protection NER provides against mutation by solar UVB? DNA sequencing data from skin tumors suggests that the effectiveness of NER might be less than optimal.In summary, DNA repair proteins are susceptible to damage and inactivation by oxidation. Interventions that are known to induce oxidative stress damage DNA repair proteins and inhibit DNA repair. UVA inhibits NER 1.7A remarkable characteristic of tumors from sun-exposed skin is their high number of mutations. The mutational loads in BCCs and SCCs are more than an order of magnitude higher than those in tumors of other anatomical sites . Even mo2 UVC delivered to cultured cells. Despite this extensive UVB exposure, UVB phototherapy is not associated with a detectable cancer risk These huge mutational loads might simply reflect chronic sun exposure and the extremely powerful mutagenicity of UVB. In a different context, however, UVB is not a particularly potent carcinogen. UVB phototherapy is an effective treatment option for the management of chronic relapsing skin conditions such as psoriasis. It involves repeated  and escalating doses of narrowband UVB that produce levels of DNA damage roughly equivalent to those induced by two minimal erythema doses (MEDs) of solar radiation Skin cancer is common and available mutation data clearly implicate UVB photoproducts in its development. NER does protect against skin cancer and the extreme skin cancer susceptibility of NER-defective XP individuals testifies to the carcinogenicity of unrepaired UV-induced DNA damage. The topical application of liposomally-encapsulated DNA repair enzymes Most of us are and will remain unaffected by skin cancer. If oxidative protein damage by solar UVA does compromise NER and contribute to mutation and skin cancer risk, its effect is likely to be subtle and cumulative. In practical terms, the possibility that the long and short wavelengths of solar UV interact synergistically in cancer development dictates that truly effective skin cancer prevention requires protection against the whole solar spectrum with efficient screening of both UVA and UVB radiation.The authors declare no conflicts of interest.


Salmonella induces the up-regulation of connexin 43 (Cx43), a ubiquitous protein that forms GJs. This up-regulation allows the transfer of antigens between tumour cells and dendritic cells (DC) licensing them to induce an efficient anti-tumour response in a mouse model of melanoma .Most cancer cells down-regulate gap junctions (GJ) resulting in loss of communication with their surrounding microenvironment. We have previously shown that infection of mouse tumour cell lines with Herein, we tested the idea that through the formation of intercellular communication channels in tumour cells, human autologous dendritic cells could be loaded with tumour antigens, preprocessed by cancer cells, and could be used to generate a cancer vaccine.Salmonella Ty21a (Vivotif) to induce up-regulation of Cx43 and formation of GJ channels. HLA matched DCs were differentiated in vitro by peripheral blood purified monocytes from healthy donors. Expression of surface molecules, cytokine release and cell proliferation was determined by cytofluorimetry. Cytotoxicity was determined either by Delfia cell cytotoxicity assay (PerkinElmer) and by a cytofluorimetry based CD107 assay.Human melanoma cell lines were infected with a vaccine strain of Vivotif-infected tumor cells established GJs in human melanoma cell lines. We show that tumour derived antigens could transit from 'donor' melanoma cells' cytoplasm to DC's cytoplasm through GJs, generate a tumour-specific CTL response and reactivate tumour infiltrating lymphocyte (TIL) in vitro. The transfer of tumor antigens was GJ-dependent because it was abolished in the presence of a GJ-specific inhibitor. In vitro generated tumour-specific human CTLs lysed also non-donor melanoma cell lines indicating that DCs were loaded with tumour-associated antigens shared among melanoma cell lines.Moreover, in vitro generated CTLs were melanoma specific because they were unable to lyse HLA matched colorectal adenocarcinoma cell lines.We exploited an antimicrobial response present in tumour cells to activate cytotoxic CD8 T cells specific for tumour-peptides, through a new pathway of antigen loading of human dendritic cells via intercellular communication channels. This unique and novel approach can be applied across a wide range of tumour cell types and can be used clinically as therapeutic vaccine alone or in combination with gold standard treatments.


In new diagnoses of left ventricular (LV) systolic dysfunction it is important to exclude coronary artery disease (CAD) as the cause. Cardiac magnetic resonance imaging using late gadolinium enhancement (LGE CMR) highlights fibrosis from ischaemia or infarcts in a subendocardial distribution. Many consider that the absence of LGE indicates an absence of significant CAD. The evidence for this is debatable, with variable sensitivities depending upon the definition of CAD, the patient population, and the use of proximal coronary artery imaging (MRCA). We strived to ascertain the utility of LGE CMR to exclude prognostic CAD.2) on CMR or transthoracic echo were analysed. The presence and extent of subendocardial LGE was recorded with the 17 segment model. The degree of coronary stenosis at X-ray angiography was assessed visually and significant disease defined as stenosis of the LMS ≥50%, or proximal LAD ≥75%, or ≥70% in two main coronary vessels.We retrospectively reviewed a cohort of patients attending a district general hospital who underwent both X-ray angiography and LGE CMR since 2006. Records of those with European criteria for LV systolic dysfunction  with no false negative results.LGE CMR reliably excludes prognostic CAD in patients with LV systolic dysfunction.N/A.


The tumoricidal effect of radioembolization is predominantly due to radioactivity and not ischemia. This article will present a comprehensive review of the side effects that have been associated with radioembolization using 90Y microspheres. Some of the described side effects are associated with all transarterial procedures. Side effects specific to radioembolization will also be discussed in detail. Methods to decrease the incidence of these potential side effects will also be discussed.Limited therapeutic options are available for hepatic malignancies. Image guided targeted therapies have established their role in management of primary and secondary hepatic malignancies. Radioembolization with yttrium-90 ( Hepatocellular carcinoma (HCC) and intra-hepatic cholangiocarcinoma (ICC) are primary liver malignancies. HCC is much more common than ICC , 2. SurgMalignancies commonly metastasize to the liver . Hepatic90Y microspheres are used in treatment of hepatic malignancies. The details of 90Y are beyond the scope of this manuscript. Table 90Y microsphere devices.® are FDA-PMA  approved for metastatic colorectal cancer to the liver (® are FDA approved under HDE (humanitarian device exemption) for radiation treatment or as neo-adjuvant to surgery or transplantation in patients with HCC who can have appropriately placed hepatic arterial catheters Serum bilirubinb)Serum albuminc)PT/INRd)Encephalopathye)AscitesAppropriate laboratory tests including but not limited to liver function tests and corresponding tumor markers should be performed to ascertain baseline values. For patients with cirrhosis, it is essential to classify patients. The Child-Pugh classification is commonly employed by multiple disciplines and includes the following variables:a)Extent of diseaseb)Location of diseasec)Relative tumor hypervascularityd)Variant vascular anatomyA triphasic liver CT or MRI is usually performed to evaluate the following:Angiography prior to radioembolization is essential. This provides the interventional radiologist with knowledge of the hepatic arterial anatomy and aberrant vasculature . Figure An aortogram assesses aortic atherosclerosis and tortuosity. A superior mesenteric angiogram is essential to determine variant vessels to the liver. Delayed images can assess the patency of the portal vein. A celiac angiogram determines hepatic vasculature and variants. Segment 1 tumors require special attention given various potential contributing feeders . More seCoil embolization of communicating vessels that may lead to aberrant microsphere deposition can be performed if necessary. The aberrant deposition of microspheres in the gastrointestinal tract (GIT) or pancreas can have grave consequences –18. SomeExperience of the treating physicianPlanned location of radio-microsphere deliverySize of vesselPre-treatment prophylactic coil embolization is dependent on the following variables , 20:ExpCollateral hepaticoenteric flow can develop following coil embolization. This may increase aberrant microsphere deposition on following repeat treatments. Theoretically, if the interval between coil embolization and radioembolization is long, this phenomenon can also occur during the initial treatment. Further research on this issue is needed.Appropriate tumor targeting is now routinely confirmed by using C-arm CT. This method aids in accurately recognizing non-tumor/non-hepatic contrast delivery.Variant hepatic artery and parasitized hepatic artery can be coil embolized prior to radioembolization. This leads to intra-hepatic collateralization in preparation for radioembolization.A systematic review concluded that Angiotensin II could increase tumor to non-tumor blood flow by approximately up to threefold . HoweverA five patient analysis on the use of degradable starch microspheres as an embolizate to normal hepatic parenchyma during radioembolization was performed. Post-radioembolization SPECT/CT demonstrated sparing of normal parenchyma . This is99mTc-MAA scan is performed to assess the lung shunt fraction (LSF) and splanchnic shunting. Figure A 99mTc-MAA resulted in effective avoidance of free 99mTc-pertechnetate concentration and decreased incidence of equivocal findings in the gastroduodenal region  and 99mTc-sulfur colloid (SC) , dual tracer SPECT/CT may provide more accurate dose calculations as this method provides a more accurate dose to functional liver (DFL)  . Researcer (DFL) .® using the following formula:® package insert, the upper limit of injected activity to the lungs is 0.61 GBq  employed by the group showed no reportable events. In this analysis, planar scintigraphy was performed in 2 h following administration of Tc-99m MAA and LSF was determined. Final dosimetry calculations were performed while the patient was being transferred back from nuclear medicine to interventional radiology. This method decreased the costs and time between initial clinical assessment and radioembolization . It shouAt our institution, cross-sectional contrast enhanced imaging (triphasic CT or MRI) is obtained at 1 month following treatment and at 3 month intervals following the first post-treatment imaging. This protocol evaluates response, or lack thereof, to treatment.90Y to the duodenum identified on PET/CT performed after radioembolization  may aid in assessing response to therapy.The complications occurring after radioembolization  are discPlease note that it is important to standardize recording and reporting toxicities. Clinical and laboratory toxicities may be classified according to the standard criteria such as the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, whenever possible . Tables A post-radioembolization syndrome (PRS) includes fatigue, nausea/vomiting, abdominal pain/discomfort, and/or cachexia. PRS is less severe than that observed after embolic therapies. Hospitalization is rarely required –47. InciNausea and vomiting may occur following radioembolization. Based on this experience, antinauseants/antiemetics such as ondansetron are routinely administered prior to treatment. Antinauseants/antiemetics pro re nata (PRN) are usually sufficient to treat nausea/vomiting following treatment.Patients may experience right upper quadrant pain and/or generalized abdominal discomfort. Over the counter analgesics, PRN usually treat the discomfort/pain following radioembolization. Stronger analgesics such as opiates are rarely necessary.Pre-existing liver dysfunction is a significant confounding variable when assessing post-radioembolization liver toxicities in HCC patients . It is i®. The incidence of RILD after 90Y radioembolization ranges from 0 to 4% (Radiation-induced liver disease (RILD) is a potentially serious post-radioembolization complication . Given c 0 to 4% –32. RILDA recent article demonstrated repeated radioembolization to be a significant risk factor in development of radioembolization induced liver disease . Two of Prior exposure of the liver to external beam radiation therapy (EBRT) may lead to increased liver toxicity after radioembolization. This depends on fractional liver exposure and dose level. The authors concluded that radioembolization appears to be safe for the treatment of hepatic malignancies only in patients who have had limited hepatic exposure to prior EBRT .As biochemical aberrations may occur without clinical manifestations, follow-up liver function tests are routinely recommended 1 month after treatment. In rare cases of clinically manifest RILD, a biopsy of the normal parenchyma may help confirm the diagnosis. A case of post-radioembolization fulminant hepatic failure has been reported .®, liver function toxicity (grades 1 through 4) was seen in 58% of infusions. The median duration of LFT toxicities was 20–29 days. Grade 3 or greater toxicities occurred after 9% of infusions in their analysis. One patient died in 32 days of treatment with signs and symptoms compatible with radiation-induced liver disease . An analysis by Memon et al.  in patiePost-radioembolization biliary complications are potential side effects of radioembolization. The incidence of these complications is less than 10% . These m90Y radioembolization in the setting of tumor-related biliary obstruction has an acceptable safety profile Obstructive jaundice due to biliary stricturesb)Biliary necrosisRadiation pneumonitis is very rare (less than 1% if standard dosimetry models are used) , 36. Thi® and SIR-Sphere® radioembolization of liver cancer based on 99mTc-MAA SPECT/CT. According to Yu et al., this method provides a more accurate estimate of radiation risk to the lungs (Delivery to the lungs of greater than 30 Gray (Gy) in one treatment or a cumulative dose of greater than 50 Gy in multiple treatments is considered a relative contraindication. Planar scintigraphy is usually employed to calculate LSF. Yu et al. described a new method of calculating the mean lung dose for TheraSpherehe lungs . HoweverA restrictive ventilatory dysfunction following radioembolization has been reported . RadiatiSteroids may play a role in management. Other thoracic complications include atelectasis and/or pleural effusion.Diarrhea has been described following radioembolization. This is rarely significant enough to require hospitalization.Post-radioembolization GI complications occur secondary to hepaticoenteric arterial communications resulting in aberrant microsphere deposition . RecogniProphylactic coil embolization of the gastroduodenal and RGA may be considered. The left hepatic angiogram is performed to identify left gastric and inferior esophageal arteries. Delayed angiography of the left hepatic artery with opacification of the coronary vein confirms hepaticoenteric flow. The right hepatic angiogram is required to identify the supraduodenal and retroportal arteries .Prophylactic use of gastric acid suppressive agents (such as proton pump inhibitors) is recommended. If GI ulceration is clinically suspected, endoscopy is recommended to confirm the diagnosis , 61.p = 0.04), and proximal injection of the microspheres were also significant risk factors.A recent root cause analysis showed stasis during injection to be the strongest independent risk factor for development of gastroduodenal complications . Distal A potential complication of coil embolization of vessels, such as the GDA and RGA, is formation of collateral hepaticoenteric flow. This can result in increased enteric complications on repeat treatments.90Y Bremsstrahlung in the pancreas may be performed. Treatment is conservative.Acute pancreatitis is a potential but very rare complication of radioembolization . PatientPeriumbilical pain may occur due to aberrant microsphere deposition in the anterior abdominal wall via the falciform artery , 19, 20.Recognition of the falciform artery is essential. Prophylactic embolization of this vessel can be performed if needed to decrease the incidence of radiation dermatitis. Prophylactic topically applied ice prevents complications as it causes vasoconstriction which decreases cutaneous flow .Lymphopenia may be seen after glass microsphere radioembolization. Greater than 25% decrease in lymphocyte count after treatment is seen in the majority of patients , 64. HowA retrospective analysis demonstrated thrombocytopenia as a complication following radioembolization. Splenomegaly can be seen following radioembolization which was shown to be an independent risk factor for development of a low platelet count . No signa)Knowledge of prior anti-cancer therapyb)Stopping and resuming “blood thinners” appropriatelyc)Reviewing cross-sectional anatomy to determine vascular anatomy such as the furcation of the common femoral artery.The incidence of vascular injury may be prevented by the following:Newer anti-cancer drugs such as bevacizumab (Avastin) have been shown to make vasculature more friable and prone to injury, increasing the chances of dissection and vascular rupture. Abnormalities in vasculature and hepatic arterial flow in 12/16 (75%) patients who were on anti-cancer therapy has been reported. During angiography, a search for stenoses and abnormal flow should be undertaken . Murthy Dissection at the site of arteriotomy is rare but possible. A pre-closure common femoral angiogram assists in its diagnosis. However, this may not be routinely performed. The patient may present with a “cold” extremity and stenting/anti-platelet therapy may be required.Hematoma formation at the arteriotomy may be seen in radioembolization . StandarIf there is suspicion of pseudoaneurysm formation, ultrasound with Doppler may be needed. This is usually treated with ultrasound guided manual compression. Thrombin injection may be performed if necessary. Surgery is rarely necessary.It is important to know the patient’s baseline renal function prior to performing transarterial therapies such as radioembolization. Adequate hydration pre- and post-radioembolization and stringent use of iodinated contrast limit contrast induced nephrotoxicity.Anticipation of possible allergic reactions is essential. Most patients being considered for radioembolization have received prior iodinated contrast media for CT scans. An allergic reaction can range from a minor reaction such as a pruritic rash to an anaphylactoid reaction. If there is a history of prior minor allergic reactions (such as hives) to iodinated contrast, the patient may still received iodinated contrast after receiving an allergy preparation prior to planned transarterial procedure .Acute chills may occur during treatment, which usually respond to anti-histamines .99mTc-MAA scintigraphic imaging) is necessary to minimize side effects of radioembolization. The incidence of complications that may require intervention is low. Grade 3 or higher complications following radioembolization occur in less than 9% of patients. Aberrant microsphere deposition may lead to various complications such as radiation cholecystitis. Surgical therapy may be required in severe cases. As radioembolization is a transarterial procedure, knowledge of general complications associated with transarterial therapies is also important.Radioembolization is being employed for treatment of various hepatic malignancies. As with any other common therapy, knowledge of potential complications of this therapy is essential. Selecting appropriate patients using a multidisciplinary approach can improve outcomes and decrease complications. Meticulous pre-treatment planning (angiography and Riad Salem receives research support from Nordion. The other co-authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


All but one of the linear models incorporating height-structured metrics showed significantly higher adjusted-r2 values than their counterparts without additional metrics. The interior forest guild richness showed a consistent low association with height-structured metrics. Our results suggest that height heterogeneity, beyond canopy height alone, supplements habitat characterization and richness models of forest bird species. The metrics and models derived in this study demonstrate practical examples of utilizing three-dimensional vegetation data for improved characterization of spatial patterns in species richness.Avian diversity is under increasing pressures. It is thus critical to understand the ecological variables that contribute to large scale spatial distribution of avian species diversity. Traditionally, studies have relied primarily on two-dimensional habitat structure to model broad scale species richness. Vegetation vertical structure is increasingly used at local scales. However, the spatial arrangement of vegetation height has never been taken into consideration. Our goal was to examine the efficacies of three-dimensional forest structure, particularly the spatial heterogeneity of vegetation height in improving avian richness models across forested ecoregions in the U.S. We developed novel habitat metrics to characterize the spatial arrangement of vegetation height using the National Biomass and Carbon Dataset for the year 2000 (NBCD). The height-structured metrics were compared with other habitat metrics for statistical association with richness of three forest breeding bird guilds across Breeding Bird Survey (BBS) routes: a broadly grouped woodland guild, and two forest breeding guilds with preferences for forest edge and for interior forest. Parametric and non-parametric models were built to examine the improvement of predictability. Height-structured metrics had the strongest associations with species richness, yielding improved predictive ability for the woodland guild richness models (r Avian diversity has been under increasing pressure from anthropogenic disturbances such as habitat loss and fragmentation Traditionally large scale habitat heterogeneity has been quantified mostly as topographical variability Until recently, there have been relatively few studies utilizing three-dimensional habitat information due to difficulties of acquiring measurements of vertical vegetation structure beyond the plot scale over extended geographical areas Related advances have been made in the development of statistical fusion models that provide a means to effectively combine remotely sensed data from radar, lidar, optical remote sensing systems and forest inventory data, yielding wall-to-wall high resolution vegetation structure maps at the continental scale The overall goal of our study is to examine the potential of three-dimensional habitat structure in improving avian richness models at broad geographical scales. In doing so we hope to expand our understanding of the relationship between habitat structure and the spatial distribution of avian species richness, and to lay the foundation for constructing habitat metrics that better utilize increasingly available three-dimensional habitat data. Specifically we address the following questions:How do the height-structured metrics compare with traditional habitat metrics in their ability to associate and predict forest bird richness in the forested ecoregion of the U.S.? Does incorporating the height-structured metrics improve the explanatory ability of avian richness models that use traditional habitat metrics?How do the predictive abilities of richness models vary among forest bird guilds with contrasting preferences to habitat edges?First, we introduce the conceptual similarities and differences between traditional habitat metrics and two types of height-structured metrics. Next, we describe the data and the methods we used to create the habitat metrics in this study. We then use correlation analysis and multivariate regression models to examine the relationships between different combinations of metrics and the species richness of three forest breeding bird guilds. Lastly, we examine the models’ explanatory abilities and the importance of individual metrics in predicting the richness of the three guilds.Traditional habitat metrics are based primarily on two-dimensional habitat structure, such as land cover types, patch size and shape statistics. Developing such metrics generally depends on two steps: a) classifying scene space into binary habitat and non-habitat land cover types; b) delineating habitat patches based on the rule of contiguity  [38]. ThSome studies have applied three-dimensional habitat information in habitat quality and species diversity models To account for more height heterogeneity, we created two groups of height-structured habitat metrics, the first of which integrates vegetation height information into the habitat patch framework while the second one characterizes canopy height distribution directly using second-order texture algorithms.At the canopy level, vertical differences in vegetation create boundaries that segment contiguous habitats into smaller patches, each with similar height values . We firsBesides utilizing habitat patch and edge metrics to capture vegetation height heterogeneity, the second approach we introduce here involves calculation of the second-order (co-occurrence) texture statistics The study area includes 21 predominately forested ecological regions (provinces) Adjustments were made to take into account the detection probability bias The National Biomass and Carbon Database of the year 2000 (NBCD) 2 areas to characterize the surrounding habitat around BBS locations We adapted a method to use 19 km  radius buffers placed on the centroid of each BBS route, encompassing ∼1100 kmAll the metrics created are listed in We first explored the statistical correlation between richness of the three avian guilds and the habitat metrics to evaluate the association between individual habitat metrics and the richness of different guilds. The woodland species richness models were based on data of all 21 forested ecoregions, and the interior forest and forest edge guild models were limited to data of the 10 forested ecoregions from Eastern U.S. as noted earlier .We selected 2 metrics from each of metric set (C) and (D) that on average had the best association with the richness of the three guilds as the best performing height-structured metrics (BPHMs). These four BPHMs were later combined with the traditional habitat metrics in multivariable models for comparisons of improvement. We limited our choice to only the four best metrics to avoid subsequent overfitting of our multivariate models while still maintaining enough representativeness.We next constructed 6 multivariate linear models to explain each guild’s richness. The first 4 models were created using the complete list of metrics from set (A), (B), (C), and (D) respectively. They served to compare the explanatory abilities of models that characterize habitat condition with very different approaches. The two other models combined metric set (A) and (B) individually with the 4 BPHMs. We created the combined models to examine the impacts of adding spatial arrangement of height in richness models characterizing habitat in traditional ways.2 values and AIC values to assess models’ explanatory ability and goodness of fit, as well as the variability of these measures. The bootstrap resampling was repeated 3000 times for each model. To examine the significance level of model improvements the 95% confidence interval of adjusted-r2 values and AIC values were obtained with the bias-corrected and accelerated (BCA) bootstrap algorithm We used a bootstrapping technique to provide the mean value and confidence intervals for the richness models’ adjusted-rLastly we explored the effect of combining the 26 metrics from all four metric sets using a non-parametric Random Forest (RF) model. The RF model The predictor metrics that correlate best with bird species richness varied among guilds. For woodland species richness, (D) the second order texture metrics generally had the greatest predicative ability, followed by (B) the traditional patch-based metrics, and (C) the height-structured patch metrics. For forest edge bird richness, the metrics with the strongest correlation were (C) the height-structured patch-based metrics followed by (D) the second order texture metrics and (A) the summary height statistics . InterioThe direction of the correlation between metrics and the bird richness was generally consistent across three guild types except for metrics with weak correlation . Among tAfter incorporating vegetation height heterogeneity in patch-based metrics, the metrics characterizing patch number and area  showed a decreased correlation with the woodland guild richness. Conversely, the strength of the correlation between edge metrics  and the woodland guild richness increased. For the forest edge species both the patch and edge related metrics showed a prominent increase of correlation after incorporating vegetation height heterogeneity. The direction of the correlation for some patch-based metrics also changed. The NP metric showed an exceptionally large change for the woodland guild richness: from −0.45 to 0.25 after incorporating vertical patches .2 = 0.11), but the forest edge guild richness was predicted moderately well (r2 = 0.47) and the predictive model was strong for the woodland guild (r2 = 0.63)  from the four metric sets were the ones with greatest ability to predict species richness for each guild . Among t = 0.63) . The mos = 0.63) .For the RF models, our results consistently showed that adding height-structured metrics improved the model predictive ability. Specifically, the explained variance of the all-inclusive RF models for woodland and forest edge guild were up to 0.27 and 0.21 higher respectively than the RF models with only traditional habitat metrics. In addition for these two guilds, when the RF models were combined with the four BPHMs, the improvement for explained variance were up to 0.21 (woodland guild) and 0.13 (forest edge guild). The interior forest guild however showed only minor improvements when combined with any height-structured metrics. In general for woodland and forest edge guild, RF models’ predictabilities were higher than the comparable linear models by a prominent margin. .The linear models had a lower explanatory ability than their RF counterparts. For a specific combination of habitat metrics, the linear models explained the most amount of variation in the woodland guild richness and the least in the interior forest guild richness. The one exception was the model using summary statistics of height (set A), which showed the highest predictability for forest edge guild richness, followed by woodland guild richness, and then the interior forest guild richness . In ever2 values in the woodland and forest edge models Click here for additional data file.Table S2Species list and guild classification.(XLSX)Click here for additional data file.Table S3Metric descriptions.(DOCX)Click here for additional data file.Table S4Metrics correlation with species richness.(XLSX)Click here for additional data file.Table S5Model performances for different multivariable models.(DOCX)Click here for additional data file.Supporting Information S1Contrast matrix for weighted-edge metrics.(PDF)Click here for additional data file.


Truvada is licenced for HIV-1 prevention in the USA and is available in the private sector. Tenofovir performed as well as Truvada in the PARTNERS PrEP study and is used as HIV pre-exposure prophylaxis (PreP) in some settings. The clinical efficacy of Tenofovir for PrEP outside a clinical trial is unknown. Antiretroviral therapy (ART) at acute HIV-1 infection (AHI) limits the size of the reservoir, optimizing the chance of maintaining viral control off therapy. As such ART at acute HIV infection is proposed to offer a functional cure in a minority of subjects. We present two cases where Tenofovir PrEP failed to prevent HIV acquisition and failed to limit viral reservoir.Two individuals receiving tenofovir monotherapy for Hepatitis B monoinfection were diagnosed with AHI as defined by a negative HIV antibody test within three months of a positive HIV test following unsafe sex with casual male partners. In-depth histories were taken. Viral genotypes and Tenofovir drug levels were measured from samples taken as close to HIV seroconversion as possible and subsequent samples were analyzed for proviral Total HIV-1 DNA by qPCR.Patient A had received tenofovir for the preceding six years and always maintained an undetectable Hepatitis B viral load with no concerns about adherence. Two weeks preceding the positive HIV antibody test, he experienced mild symptoms  of HIV seroconversion. HIV status was confirmed by a repeat fourth generation HIV antibody test and by Western Blot and an HIV viral load was undetectable. Tenofovir trough level at HIV diagnosis was within normal limits. The regimen was intensified to Eviplera and a total HIV-1 DNA was 1381 copies/million CD4 T cells. Patient B received four regimens for hepatitis B treatment before starting tenofovir monotherapy in 2011 and subsequently maintained an undetectable hepatitis B viral load. After three years of tenofovir monotherapy he developed a severe symptomatic seroconversion illness and tested HIV antibody positive. The baseline HIV viral load was 103,306 copies/mL. The regimen was intensified and total HIV-1 DNA was 2746 copies/million CD4 T cells.Further investigation into the efficacy of tenofovir for PrEP outside a clinical trial is required. ART at AHI does not always lead to a low viral reservoir. To explore the possibility of replication incompetent virus, viral outgrowth assays are underway.


Drug desensitization is the induction of temporary clinical unresponsiveness to drug antigens to which patients have presented severe hypersensitivity reactions (HSR). Rapid desensitization in patients suffering immediate hypersensitivity reactions with chemotherapeutic agents and monoclonal antibodies have been widely described and have shown to be successful. Non-immediate hypersensitivity reactions with other drugs have usually required desensitization with several days' protocols to achieve total doses.Forty three desensitization procedures were performed in 6 patients with a 12-13 step, 6-hour protocol. All patients had developed a delayed maculopapular rash with the use of chemotherapeutic and/or biological agents. Four patients were pretreated with corticosteroids, paracetamol and antihistamines before each desensitization procedure.All the 43 desensitizations undertaken were successfully completed . We observed HSR during 11 (25%) of desensitizations, including 5 inmediate exantema, 3 delayed local macular exantema and 3 delayed maculopapular lesions. Four patients were treated with corticosteroids and anti-histamines after the desensitization protocol to avoid more delayed HSR.Rapid desensitization protocols are safe and effective in getting over delayed HSR to chemotherapeutic and monoclonal antibodies and allow patients with severe diseases to continue their treatment.


In the editorial "Prophylactic Left Internal Mammary Artery Graft In Mildly-StenosedCoronary Lesions. Still An Open Discussion", adjust the name of author AndréSchmidit to André Schmidt.In the original article "New Exercise-Dipyridamole Combined Test for NuclearCardiology in Insufficient Effort: Appropriate Diagnostic Sensitivity KeepingExercise Prognosis", consider Vidal I as the correct form for the name of the authorInés Vidal Cortinas.Consider correct and use to citation the author's name Wojciech Wanha to the article"First- Versus Second-Generation Drug-Eluting Stents in Acute Coronary Syndromes(Katowice-Zabrze Registry)".


Immunity exhibits extraordinarily high levels of variation. Evolution of the immune system in response to host-pathogen interactions in particular ecological contexts appears to be frequently associated with diversifying selection increasing the genetic variability. Many studies have documented that immunologically relevant polymorphism observed today may be tens of millions years old and may predate the emergence of present species. This pattern can be explained by the concept of trans-species polymorphism (TSP) predicting the maintenance and sharing of favourable functionally important alleles of immune-related genes between species due to ongoing balancing selection. Despite the generality of this concept explaining the long-lasting adaptive variation inherited from ancestors, current research in TSP has vastly focused only on major histocompatibility complex (MHC). In this review we summarise the evidence available on TSP in human and animal immune genes to reveal that TSP is not a MHC-specific evolutionary pattern. Further research should clearly pay more attention to the investigation of TSP in innate immune genes and especially pattern recognition receptors which are promising candidates for this type of evolution. More effort should also be made to distinguish TSP from convergent evolution and adaptive introgression. Identification of balanced TSP variants may represent an accurate approach in evolutionary medicine to recognise disease-resistance alleles. Immune function is highly heritable –4, goverTrans-species polymorphism (TSP) refers to the occurrence of identical or similar alleles in related species, excluding instances where the similarity arose by convergence or introgression , 20. By http://dx.doi.org/10.1155/2015/838035). Surprisingly, our knowledge on TSP in other immune gene classes is only limited. Is TSP unique to MHC or does it represent a general evolutionary pattern masked by little endeavour paid to its investigation outside the MHC family? In the present review we compile present evidence on TSP in human and animal immune genes and outline main directions for further evolutionary immunogenetic research.The TSP concept was proposed three decades ago by Klein  who suppLong-lasting TSP in immune genes is dependent on balancing selection. This type of selection maintains genetic variation in populations for extensive periods of time based on three possible mechanisms: (1) heterozygote advantage , 30, (2)MHC groups several extremely polymorphic and dynamically evolving members of the immunoglobulin superfamily playing a crucial role in the adaptive immune defence against pathogens in jawed vertebrates , 37. MHCα-chain composed of α1, α2, α3 domains and β2-microglobulin . Articles dealing with TSP in blood group systems and serological allomorphs were not included into this survey.


Lead extraction is becoming increasingly common as indications for pacing and ICD insertion expand. Periop management varies between extraction centers, and no clinical guidelines have addressed the need for perioperative anticoagulation. We report a case of massive thrombosis which occurred shortly after laser lead extraction and is undoubtedly related to the trauma of the extraction and ensuing hypercoagulabiilty. Routine post-operative anticoagulation has been advocated as a means to prevent access vein (subclavian) stenosis, but many centres do not employ a routine post-extraction anticoagulation strategy. Pulmonary embolism following lead extraction is a known complication of this procedure and late mortality following lead extraction is a significant and underappreciated problem. We propose that further research attention should be directed at addressing the issue of routine post-extraction anticoagulation. A 60 year-old man was referred to our center for lead extraction after developing a pocket infection following a routine generator change. His original dual-chamber device was implanted in 2002 for symptomatic bradycardia and standard right atrial appendage and right ventricular apical lead positions were confirmed on preoperative chest x-ray. A transesophageal echocardiogram was done to rule out any vegetations or thrombus on the leads and blood cultures drawn before the extraction were negative. The patient was not pacemaker dependent and underwent removal of his pulse generator prior to arriving to our center; swabs from the pocket done at this time showed methicillin-sensitive Staphylococcus aureus. Laser lead extraction was acutely successful and no immediate complications were noted. Post-operative anticoagulation was not administered. A routine transthoracic echocardiogram performed 30 hours following the procedure demonstrated extensive thrombosis extending from the right atrium all the way to the right ventricular outflow . AnticoaLead extraction has become increasingly important as more patients receive cardiac implantable electronic devices (CIEDs). Perioperative management protocols vary widely between centers, including concerning postoperative anticoagulation. The risk of postoperative subclavian vein occlusion, which occurs in at least 8% of cases , has bee


Fractional flow reserve (FFR) has been recognized as an effective tool to determine functional significance in intermediate coronary lesions and FFR-guided percutaneous coronary intervention (PCI) improves clinical outcomes. However, hemodynamic interaction between serial stenoses within one coronary artery complicates the assessment of functional severity of each individual lesion. We present a case in which FFR measurement by intracoronary bolus injection of adenosine helps to make appropriate revascularization decision in serial stenoses when the procedures are performed systemically and properly.  Fractional flow reserve (FFR) has been recognized as an effective tool to determine functional significance in intermediate coronary lesions. FFR is defined as the ratio between mean distal coronary pressure and mean aortic pressure at maximal hyperemia. A 0.014-inch wire with pressure sensor tip is introduced and advanced across the target lesions. The FFR value is measured after continuous intravenous infusion or intracoronary bolus injection of adenosine to induce maximal coronary artery vasodilatation. Several landmark outcome trials showed that FFR-guided PCI significantly reduced major adverse cardiac events including death and urgent revascularization in patients with stable coronary artery disease . Functioμg of intracoronary adenosine and FFR became 0.92 after 96 μg of intracoronary adenosine when the pressure sensor was pulled back and positioned between the two lesions . Echocardiography showed left ventricular hypertrophy and normal systolic function with ejection fraction of 67%. Myocardial perfusion scan revealed a large area of myocardial ischemia at the lateral and inferior segments of left ventricle . Invasiv lesions . Percutadenosine . PCI usidenosine . The patThis case demonstrates that measurement of FFR in an intermediate lesion is critical in guiding PCI but can be easily misinterpreted in the presence of a serial lesion in the same artery.Pd − [(Pm/Pa)∗Pw])/((Pa − Pm)+(Pd − Pw)) [Pa), pressure between the two stenoses (Pm), distal pressure (Pd), and coronary occlusion wedge pressure (Pw) during maximum hyperemia. The higher coronary wedge pressure created by a more severe distal lesion results in an even more pronounced underestimation for the proximal lesion as our case evidently displayed. Nonetheless, FFR remains a helpful tool to improve PCI outcomes and reduce unnecessary intervention in these complex lesions. Kim et al. studied a total of 131 patients with multiple intermediate stenoses and 182 out of the 298 lesions were deferred according to FFR measurements. There were no events related to the deferred lesion at follow-up [When serial or multiple stenoses are present in the same coronary artery, hemodynamic interaction between stenoses complicates the assessment of functional severity of individual lesions. FFR value of each stenosis is usually underestimated and this influence is more pronounced for the proximal lesion than for the distal one. Individual FFR of each stenosis can be predicted by the following equation: FFR predicted = ( − Pw)) . The equollow-up .μg/kg/min [Most of the FFR studies were performed with a continuous intravenous administration of adenosine at a rate 140 g/kg/min . Previouμg in the RCA and 200 μg in the LCA induced maximum hyperemia while being associated with minimal side effects [Despite the recommended use of intravenous route of adenosine administration, intracoronary adenosine is still frequently used in clinical practice and published data . Intraco effects .A recent development in functional measurement of coronary stenosis using a hyperemia-free, pressure-derived hemodynamic index can potentially mitigate problems associated with hyperemic FFR in serial lesions. Instant wave-free ratio (iFR) is a resting index calculated as the ratio of distal coronary pressure to proximal aortic pressure over a specific wave-free period in diastole. During this cardiac cycle, resistance is naturally constant and minimized without administration of vasodilator drugs. This resting index measured at basal state can eliminate the flow interaction between stenoses under hyperemia. An iFR-pullback method can create a physiological map in complex serial stenoses and diffuse vessels and predict an expected iFR value for the treatment of selected stenosis , 13. MorThis case highlighted the importance of FFR in evaluating intermediate lesion and how it could be easily misinterpreted if operators are not familiar with this diagnostic tool. It also demonstrated that FFR measurement using intracoronary adenosine in serial lesions is a feasible and timesaving approach if correct and necessary procedures are performed systemically.


Aminoglycosides are commonly used in tuberculosis treatment and are drugs of choice especially for MDR patients. They inhibit protein synthesis in susceptible bacteria by interacting with steps of translation. Several explanations have been put forward to explain the mechanism of aminoglycosides resistance but still our knowledge is fragmentary. Many culture filtrate proteins of pathogen represent potential targets for drugs, diagnostic probes and vaccine components; analysis of mycobacterial culture filtrate proteome in relation to aminoglycoside drug resistance is urgently required.M. tuberculosis sensitive and resistant clinical isolates were cultured in Sauton’s medium. After four weeks, cells were removed by centrifugation; supernatant was filtered by 0.45 & 0.22µ filters and precipitated using SDS –TCA precipitation method. Culture filtrate proteins were resolved by two dimensional gel electrophoresis and differentially expressed proteins (more than two fold) were selected for identification by matrix assisted LASER desorption/ionization time of flight mass spectrometry (MALDI TOF/MS) and characterization by bioinformatic tools (drug-protein docking).On comparing the protein profile of isolates, twelve proteins were found differentially expressed which were identified by MALDI TOF/MS. These proteins were not only involved in various metabolic pathways (site for drug targets) but also involved in survival of mycobacteria (various heat shock proteins).These results might help in new drug development through provision of new drug targets and in further revision of therapeutics & vaccines against aminoglycoside drug resistant tuberculosis.


Endovascular therapy for iliac artery chronic total occlusions is nowadays associated with low rates of procedure-related complications and improved clinical outcomes, and it is predominantly used as first-line therapy prior to aortobifemoral bypass grafting. Herein, we describe the case of a patient presenting with an ischemic left foot digit ulcer and suffering complex aortoiliac lesions, who received common iliac arteries kissing stents, illustrating at final antegrade and retrograde angiograms the early recognition of a blood flow obstructing valve-like calcified intimal flap protruding through the stent struts, which was obstructing antegrade but not retrograde unilateral iliac arterial axis blood flow. The problem was resolved by reconstructing the aortic bifurcation at a more proximal level. Completion angiogram verified normal patency of aorta and iliac vessels. Additionally, a severe left femoral bifurcation stenosis was also corrected by endarterectomy-arterioplasty with a bovine patch. Postintervention ankle brachial pressure indices were significantly improved. At the 6-month and 2-year follow-up, normal peripheral pulses were still reported without intermittent claudication suggesting the durability of the procedure. Through stent-protruding calcified intimal flap, is a very rare, but existing source of antegrade blood flow obstruction after common iliac arteries kissing stents. Aortobifemoral bypass is still considered the gold standard treatment for chronic total occlusions (CTOs) of iliac arteries that belong to Transatlantic Intersociety Consensus (TASC II) guidelines C/D lesions . This prOccasionally, procedure-related complications may occur in both single- or kissing stent technique, necessitating various troubleshooting techniques or bailout procedures . We desc2). A clinical examination demonstrated an absent ipsilateral and a weak contralateral femoral pulse. His ankle brachial indexes were 0.32 and 0.64, respectively. Digital subtraction angiography revealed CTO of the left iliac axis and common femoral artery, and severe (~80%) right CIA stenosis  was placed percutaneously through the right femoral artery and advanced into the aorta. A similar, but through open femoral cut-down, guide wire was placed within the occluded left iliac axis, supported by a 5 × 6 cm Optimed  percutaneous transluminal angioplasty dilatation catheter. This eventually crossed the lesion intraluminally, and was then advanced into the aorta. Balloon angioplasty was performed initially to predilate iliac arteries lesions before self-expandable stents (SEs) were implanted. Subsequently, primary CIA stenting was performed using standard techniques with a 10 × 40 mm Complete SEs  on the right and a 10 × 100 mm E-Luminexx SEs  on the left side, raising the aortic blood flow divider by 2-3 mm. After stent deployment, concomitant postdilatation was performed using the kissing balloon technique. At a later stage, the left-sided SEs were extended up to the distal end of external iliac artery with a new E-Luminexx SEs (7 × 60 mm), to fully cover the occluded lesion and completely recanalize the left iliac artery axis.Considering his severe comorbidities, the patient was scheduled for an endovascular approach. A Arrow catheter  placed into the aorta, 1-2 cm above the kissing stents   inside the SEs (telescope technique), thus trapping the calcified intimal plaque. New angiograms (antegrade and retrograde) obtained after concomitant expansion of the stents verified normal aortoiliac blood flow  using new kissing balloon expandable stents  can be challenging. Treatment of iliac CTOs may initially be limited primarily by an inability to cross the occlusion and later by the failure of balloon angioplasty . HoweverCurrently, there is no consensus whether the kissing stents technique offers an advantage over the single-stent stenting strategy , 4. FurtTASC II C/D lesions are generally regarded as challenging targets to treat due to their high plaque burden and their anatomical proximity of the aorta and both CIAs. Occlusion of a contralateral CIA due to unfavorable plaque shift has a low incidence using the single-stent technique . HoweverIt has been shown also that patients in whom the proximal end of the kissing stents overlapped more than half of their angiographic width within the aorta had significantly lower primary and assisted primary patency rates at 2 years, compared to those in whom the proximal ends of the stents overlapped half of their width or less . In our The potential shortfall of retrograde completion angiography and the contrasting benefit of antegrade angiography in depicting neointimal flaps were shown recently in aortobifemoral grafts . As in oNovel minimally invasive techniques such as the single-stent procedure eventually result in the tacking of intimal calcified flaps or calcified plaques that protrude through prior stents and allow for normal antegrade blood flow without hemodynamic compromise. However, ostia CIA flaps require kissing stents to compress them between the stent and the arterial wall, simultaneously protecting the contralateral side. Similar stent-in-stent techniques have been used to treat plaque prolapse in stents placed in the coronary circulation . AlthougThrough bare metal stent-protruding heavily calcified intimal flap overcoming the radial force of the stent is a very rare but existing source of antegrade blood flow obstruction after CIA's kissing stents for aortoiliac occlusive disease. Interventionalists should remember this procedural complication and all effective ways to treat it endovascularly when treating complex aortic bifurcation lesions. As such, no clinical consequences for the patient will arise making the procedure extremely safe.


Human leukocyte antigen (HLA) Class I and Class II antigens can be genetically extremely diverse, play a central role in immunity and are of primary importance in several branches of medicine. By presenting fragments of pathogens or altered ‘self’ proteins, HLA molecules activate T lymphocytes and are essential in adaptive immune responses against infection or cancer. Clinically, certain HLA types are associated with severity, treatment outcomes or risk of particular infections  . HLA areWith > 7000 alleles HLA is the most polymorphic region of the human genome . The comde novo each time they transmit. This hinders the adaptation of pathogens to the population of hosts as a whole and also favours in hosts many, rare HLA alleles [Each HLA type ‘sees’ a unique set of pathogen targets (epitopes). Individuals carrying different alleles at a given HLA locus (heterozygotes) produce both molecules thereby increasing the number of potentially targeted epitopes and so, on average enjoy broadened immunity and likely stronger protection . Such ad alleles . HLA div alleles . Such beStudies of HIV and Hepatitis C virus suggest that rapidly evolving RNA viruses are able to escape HLA-dependent defences in human populations . HLA is


This study was performed to establish the frequency of pre-hospital airway compromise in trauma patients attended by a UK physician-led pre-hospital service and the role of advanced airway interventions in the treatment of the compromise.Over a one year period (April 2012-March 2013) all pre-hospital trauma patients attended by the doctor-paramedic LAA team who were identified as having airway compromise or an indication for any airway intervention on scene were included in a prospective observational study. The doctor paramedic team recorded any airway compromise on arrival and prior interventions carried out by ambulance service personnel.472 patients met the inclusion criteria. Ambulance service personnel attended before the enhanced care team in 469/472 (99.4%) of cases. 200 patients had no evidence of compromise of which 134 (67%) had received airway interventions by the ambulance service. 269 (57%) had airway compromise at the point of arrival of the enhanced care team. Of the 269 with airway compromise, 174 had complete or partial airway obstruction and 145 had gross contamination with blood or vomit. Ninety-eight patients received paramedic advanced airway management interventions (intubation without drugs or supraglottic airway insertion). 48/50 (92%) supraglottic airway insertions and 29/45 (64%) intubations were successful. All patients had successful pre-hospital intubation by the enhanced care team before transport to hospital.The reported results suggest a requirement for on-scene advanced airway management in a relatively small number of severely injured trauma patients. Standard ambulance service interventions do not appear to adequately treat airway compromise in a small proportion of trauma patients. Intubation without drugs had a high failure rate. These results suggest that the airway management problems reported in the NCEPOD report: Trauma who cares? in 2007 still exist.


A 9-year-old girl with grade 4-5 right vesico-ureteric reflux (VUR) into a solitary collecting system was initially treated with endoscopic Deflux injection. Micturition cystourethrogram (MCUG) performed after 6 months showed a grade 1-2 reflux. After 3 years, MCUG was repeated due to recurrent urinary tract infection (UTI) showed severe VUR. DMSA renal scan showed a non-functioning right kidney. The patient underwent a right nephrectomy by retroperitoneoscopic approach. A small distal ureteral stump (DUS) was left. One year after surgery, another MCUG was performed due to recurrent UTI showed an active VUR in the ureteral stump . The 5-cm long DUS  was surgically removed. The child is asymptomatic at follow-up of 5 years.The management of a poorly functioning kidney associated with primary VUR is nephrectomy with total or proximal ureterectomy. The retroperitoneal laparoscopic approach is particularly beneficial owing to a small residual distal ureteral stump (DUS) shorter than that achievable via a single flank incision. However, it does not allow the stump dissection down to the bladder base.[1] The transperitoneal laparoscopic approach is preferable for total removal of the ureter.[2]Reflux in DUS is a rare complication due to partial excision of ureter. Recurrent UTI after nephrectomy is a useful signal to suspect the presence of reflux in DUS which act as a reservoir resulting in stasis and infections.[4] A long stump could be a risk factor in the pathogenesis of ureteric stump syndrome. A long refluxing stump inevitably acts as a diverticulum from which the urine cannot be effectively drained thus leading to outbreaks of UTI.[3] In our case a short ureteral stump became symptomatic due to reflux into it. We recommend transperitoneal laparoscopic approach for the management of a poorly functioning kidney which allows nephrectomy and complete ureterectomy up till the bladder base thus avoids reflux into the DUS.Source of Support: NilConflict of Interest: None declared


We read with interest the study by Zhou and colleagues because it represents an important effort towards advancing the knowledge in current sedation strategies . HoweverRecent randomized trials demonstrate that sedation strategies with similar short-term mortality rates and ICU length of stay may still be associated with different short-term and long-term cognitive outcomes ,3. LimitMultiple studies demonstrate that ICU delirium is a prevalent syndrome that can be detected with simple validated diagnostic tools ,5. ICU-a


Persistent left superior vena cava (PLSVC) is a rare congenital anomaly of the superior venous system that may be discovered at the time of cardiac implantable electronic device (CIED) implantation.We present a subject who needed cardiac resynchronization therapy (CRT)-CIED implantation and was discovered to have PLSVC with absent innominate vein during the implant procedure. We were able to successfully implant a CRT-CIED using a right-sided approach via the right superior vena cava (SVC). We present a description of our implant technique and a brief review of the different aspects of CIED implantation in subjects with variants of PLSVC.Superior venous anomalies such as PLSVC can make CIED implantation technically challenging. However, with increasing operator experience, cardiac imaging and appropriate tools successful CIED implantation is possible in almost all cases. Persistent left superior vena cava (PLSVC) is a congenital venous developmental abnormality of the sinus venosus with an incidence of 0.47% in patients undergoing cardiac implantable electronic devices. The two variants include a double superior vena cava  or a single left sided SVC (without a right SVC) . ImplantA 59-years old gentleman with non-ischemic dilated cardiomyopathy, severe LV systolic dysfunction (left ventricular ejection fraction = 25%), LBBB (QRS width 180 ms), NYHA class III symptoms  and morbid obesity (body weight 160 kg) was referred to our service for CRT-CIED insertion. The procedure was performed under general anesthesia and full therapeutic anticoagulation as the subject had a history of paroxysmal atrial fibrillation with CHADS2 score of 3. A left superior venogram performed to guide left subclavian venous access revealed the presence of a PLSVC draining into the proximal segment of the coronary sinus (CS). The combined PLSVC and CS confluence drained into the right atrium. The venogram also revealed the absence of an innominate vein connecting the PLSVC to the right SVC. A venogram performed from the right side demonstrated the presence of a right SVC draining into the right atrium .The left subclavian vein was accessed using the Seldinger technique and a CS sub-selector catheter (Medtronic Attain Select soft-tipped guide catheterTM ) was introduced over a guide wire to cannulate the coronary sinus, distal to its confluence with the PLSVC. The selective coronary sinus venogram demonstrated a suitable lateral tributary for coronary sinus pacing lead insertion . HoweverWe were able to successfully implant a CRT-CIED system using a right-sided approach. A straight coronary sinus cannulation catheter (Medtronic 7F catheterTM) was introduced over a deflectable decapolar electrophysiological diagnostic catheter into the CS, distal to its confluence with the PLSVC. A venogram demonstrated the presence of a lateral CS tributary of adequate caliber for CS pacing lead placement. An endocardial bipolar pace-sense CS lead (Medtronic 6F 4194 leadTM) was introduced over a 0.014" coronary guide wire  into this tributary  and 4. TOur case highlights a rare congenital venous anomaly that could potentially make CIED implantation technically challenging. The important factors increasing the complexity of lead placement from the left side include the tendency for the RV lead to be deflected away from the tricuspid annulus, torrential CS blood flow, acute angulation at the point where the PLSVC joins the CS and other anomalies making lead placement extremely difficult -5. In ouThe presence of PLSVC can be inferred from the presence of dilated CS on echocardiography. If the presence of PLSVC is suspected prior to CIED insertion cardiac imaging CT/MRI/3-D echo) can be used to understand superior venous anatomy. This will assist the operator in selecting the most appropriate approach and the necessary tools  for CIED implantation, possibly increasing the chance of success. In view of the very low incidence of PLSVC, in subjects without congenital heart disease, routine cardiac imaging to detect superior venous anomalies in patients may not be indicated. Given the higher incidence 10-15%) superior venous anomalies in subjects with congenital heart disease a case can be made for cardiac imaging prior to CIED insertion, especially in subjects needing CRT 0-15% sup. Torrent-D echo cThe variant of PLSVC without a right SVC or innominate vein connecting the PLSVC to the right atrium makes LV pacing lead insertion via the CS very difficult. In such subjects experienced operators have used a variety of special stylets, catheters and pacing leads to successfully implant CRT-CIED using an endovascular left-sided approach -4. OtherThe variant of PLSVC with right-sided SVC, with or without an innominate vein connecting the right and left SVC, makes it more likely that a CRT-CIED can be inserted exclusively using an endovascular approach. In this situation operators have used right or left sided approaches to insert all three pacing leads . Other operators have used a hybrid approach inserting the RA and RV pacing leads from the right side and the CS pacing lead from the left side using the PLSVC. The CS pacing lead was then tunneled through the subcutaneous plane to the right side . Very raSuperior venous anomalies such as PLSVC can make CIED implantation technically challenging. However, with increasing operator experience, cardiac imaging and appropriate tools successful CIED implantation is possible in almost all cases.


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Magnaporthe oryzae attack and drought stress enabled us to obtain insights about cross-talk among hormone biosynthesis pathways at the transcriptional level. We identified some master transcription regulators that co-ordinate different hormone biosynthesis pathways under stress. We found that Abscisic acid and Brassinosteroid regulate Cytokinin conjugation; conversely Brassinosteroid biosynthesis is affected by both Abscisic acid and Cytokinin. Jasmonic acid and Ethylene biosynthesis may be modulated by Abscisic acid through DREB transcription factors. Jasmonic acid or Salicylic acid biosynthesis pathways are co-regulated but they are unlikely to influence each others production directly. Thus, multiple hormones may modulate hormone biosynthesis pathways through a complex regulatory network, where biosynthesis of one hormone is affected by several other contributing hormones.Crosstalk among different hormone signaling pathways play an important role in modulating plant response to both biotic and abiotic stress. Hormone activity is controlled by its bio-availability, which is again influenced by its biosynthesis. Thus, independent hormone biosynthesis pathways must be regulated and co-ordinated to mount an integrated response. One of the possibilities is to use cis-regulatory elements to orchestrate expression of hormone biosynthesis genes. Analysis of CREs, associated with differentially expressed hormone biosynthesis related genes in rice leaf under  Plants being sessile creatures are forced to adapt to various adverse conditions to successfully complete their life-cycles. A repertoire of complex signaling systems was acquired by plants to respond to physiological and environmental cues. Phytohormones are one of the key mediators that afford plants the ability to rapidly respond to external cues by adjusting their metabolism. Previous research efforts have revealed importance of individual hormones in plant development and stress response  and jasmonic acid (JA) promote resistance against pathogens Figure . EthylenMagnaporthe oryzae attack  and drought stress. Results of this work allowed us to map the CRE-mediated regulation of differentially up-regulated rice hormone biosynthesis (HB) genes under blast and drought conditions. Through analysis of CREs associated with differentially expressed HB genes we were able to develop insights about effect of different hormones and stress conditions on regulation of all HB pathways. We were also able to identify key transcription factors for CRE elements that integrate and modulate these pathways.Regulation of hormone biosynthetic pathways at both transcriptional and post transcriptional level has been well documented  of rice loci is collected from Rice Genome Annotation Project, version 6.1  database   from each experiment (4 dpi of GSE7256 and panicle stage leaf of GSE26280) were considered for further analysis.Gene expression data were collected from Gene Expression Omnibus (GEO) . A series of filtering steps  separately. The locus-locus co-enriched CRE network was developed using the up-regulated HB genes and the over-represented CREs at their promoters. Each node of the network was specified by individual locus and two loci were interconnected if they have at least one common over-represented CRE.k) is interpreted as a complete (fully connected) subgraph having k number of nodes. In CRE co-occurrence network, a clique represents a combination of co-occurring CREs having statistically significant co-occurrence relationship with every other CREs of the same clique. CFinder , genes associated with Gibberellin biosynthesis were absent. Similarly Salicylic acid biosynthesis associated genes were absent from drought dataset (GSE26280) Table . This inOs07g05940.1 was associated with highest number of CREs, sixteen in number. This locus was common to both blast and drought datasets. Lowest number of CREs was associated with JA biosynthesis locus Os06g11210.1, it had a single CRE element  were over-represented in individual promoters. Promoter of ABA biosynthesis locus nt Table .The co-occurrence tendency for all possible CRE pairs present in the promoters of differentially up-regulated HB genes for each condition (37 for blast and 26 for drought) were calculated and significantly co-occurring pairs based on the filtering steps , whereas, number of common interacting edges were relatively small in number (24) Figure . This inThe locus-locus co-enriched CRE network was developed using the up-regulated HB genes having over-represented CREs at their promoters. Each node of the network represents individual locus and two loci are interconnected if they have at least one common over-represented CREs. Thus, the interacting edges represent the regulatory similarities among the promoters (loci) where the edge weight shows the number of common over-represented CREs among them. Interestingly we found that loci of same HB pathways as well as of different HB pathways share abundant edges. This indicates that different HB pathways may have common regulators Figures .k = 3–8) analysis was performed on CRE co-occurrence network for each condition. In case of blast and drought 76 and 29 cliques were observed, respectively. Twenty one cliques in case of blast and a single clique in case of drought were found to encompass all the HB pathways. Whereas 55 cliques in blast and 28 cliques in drought were found to be present only in loci of particular HB pathways. It was interesting to note that in case of Blast we did not find any clique which are exclusive to a single HB pathway; in case of drought we found two  exclusive to cytokinin biosynthesis genes. Under blast infection 7 cliques were associated with all 37 up-regulated HB loci, whereas under drought condition a single clique was associated with 25 (out of 26) up-regulated HB loci and another was associated with 22 up-regulated HB loci. These 9 cliques were composed of 10 CREs of which 6 were common to both blast and drought loci  followed by CK (93.7%), JA (85.5%) and SA (75.0%) Figure . In caseMagnaporthe oryzae infection and drought stress, demonstrates that some genes are differentially up-regulated under both conditions whereas some are exclusively up-regulated in either condition. These findings indicated that differential regulation of hormone biosynthesis may contribute to stress response. Analysis of CREs in promoters of these up-regulated HB genes allowed us to extract insights about regulation of HB pathways and CREs (and/or transcription factors) that may integrate and modulate hormone biosynthesis.Expression analysis of HB pathway associated genes under Role of cytokinins in regulating plant growth and development by promoting cell division and stimulating sink strength is well established. Recently evidence has accumulated demonstrating importance of CK in environmental stress response as well. Endogenous CK levels were reported to alter stress tolerance of plants and conversely stress conditions were found to change CK content in plants , a key gene of ABA biosynthesis  and 8 (out of 16) CK HB loci in drought and blast infected leaves were also associated with various ABA response CREs respectively Table . As all ET and JA interactions and their response play important role in abiotic and biotic stress management  functions are considered important under osmotic stress  and ZPF252 (Os12g39400.1) expression is known to be induced by salt and drought stress  and Os08g17500.1 (cinnamoyl-CoA reductase), CK  response elements were present. These loci are associated with initial steps of BR biosynthesis. Os08g17500.1 and another loci with similar annotation Os02g08420.1 were also associated with ABA responsive element DRE2COREZMRAB17. Therefore, our results indicate that in case of blast CK and ABA both may interact directly with BR HB loci likewise BR may also interact directly with CK HB loci  and CK  response elements. As BR-response elements are not present in PLACE database we scanned all the CK and BR HB up-regulated loci promoters for the presence of BR response element (CGTG[T/C]G) . These common CRE were associated with 72.4 % of cliques (combination of CREs) for blast infection. These observations indicate that JA and SA HB loci may be co-regulated under fungal attack. Previous research has shown that interactions between SA and JA are complex and condition specific . Os04g43800.1 is a phenylalanine ammonia-lyase which is also associated with secondary metabolite phenylpropanoid derivative synthesis. Analysis of CRE in up-regulated JA and SA HB genes under both drought and blast revealed no CRE (except one JA responsive CRE in SA loci) that can be tied to SA or JA response directly, so it is highly unlikely that these hormones directly affect each-other's biosynthesis.JA HB genes LOX and four OPR were found to be up-regulated but none of them had any SA-responsive CRE in their promoters. Similarly out of three only one SA HB gene Our investigations into CRE-mediated regulation of differentially up-regulated hormone biosynthesis associated loci under blast infection and drought stress revealed that hormone biosynthesis pathways are subjected to hormone cross-talk. Plant response to blast and drought is associated with transcriptional modulation of biosynthesis genes of several hormones and these hormones modulate bio-availability of each other through a complex regulatory network. Abscisic acid and Brassinosteroid regulates Cytokinin by modulating its conjugation. Conversely Brassinosteroid biosynthesis is effected by both Abscisic acid and Cytokinin. Through our analysis we found that DREB transcription factors may be important in modulation of both Jasmonic acid and Ethylene biosynthesis. Moreover we found that though DREB response are known to be ABA independent but at least DREB2A response may be regulated by ABA signaling through C2H2 zinc finger protein transcription factors. Interestingly we found no indication of direct interaction of Jasmonic acid or Salicylic acid with each other's biosynthesis pathways. Thus, multiple hormones may modulate several hormone biosynthesis pathways through a complex regulatory networks, where biosynthesis of one hormone is effected by several other contributing hormones.AD, RG, and SK conceived the idea and designed the study. AD and RG collected the data. AD developed and executed computational pipelines and took part in result analysis. RG performed literature survey and result analysis. AD and RG wrote the manuscript. SK edited the manuscript and supervised the study. AD and RG contributed equally to this study. All authors read and approved the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.