Background. Cisplatin is a well known platinum-based chemotherapeutic agent used for the treatment of various malignant tumours. A frequent side effect of cisplatin therapy is ototoxicity. Unfortunately, currently there are no available treatments. Material and Methods. Experimental, clinical studies and reviews published between 2004 and 2014 in the English medical literature concerning ototoxicity were selected using Medline, PubMed, and Google Scholar databases. Inclusion criteria were cisplatin-induced ototoxicity and therapy aimed at preventing or curing this disorder. Molecular mechanisms and clinical, audiological, and histological markers of cisplatin-induced ototoxicity are described. Moreover, experimental and clinical strategies for prevention or treatment of hearing loss were also reviewed. Results and Discussion. Experimental studies demonstrate a wide range of otoprotective molecules and strategies efficient against cisplatin-induced hearing loss. However, only dexamethasone proved a slight otoprotective effect in a clinical study. Conclusion. Further research must be completed to bring future therapeutic options into clinical setting. Cisplatin (cis-diamminedichloroplatinum II) is a well-known chemotherapeutic alkylating agent very effective in the treatment of various malignant tumors, especially squamous cell cancers of the head and neck regions, in both the pediatric and adult age groups . Though A review of the literature from 2004 to 2014 was performed, using the Medline, PubMed, and Google Scholar databases. The search terms included cisplatin-induced hearing loss, protective therapy for inner ear diseases, intratympanic therapy, systemic therapy, and gene therapy. Only original experimental and clinical research papers were included. A total of 43 relevant papers were selected for the present review.Cisplatin inflicts injuries mainly to outer hair cells, progressing from the third to the first row and to some extent to inner hair cells of the organ of Corti in the basal turn of the cochlea followed by alterations in sensorial cells situated in the apex. Cisplatin also targets supporting cells, marginal cells of the stria vascularis, and the spiral ligament . The vesMolecular mechanisms of cisplatin-induced hearing loss involve the creation of reactive oxygen species and depletion of antioxidant glutathione and its regenerating enzymes as well as increased rate of lipid peroxidation, oxidative modifications of proteins, nucleic acids damage by caspase system activation , and S-nOxygen free radicals in the cochlea are produced principally in the wake of nicotinamide adenine dinucleotide phosphate oxidase 3 isoform (NOX3) activation. NOX3 is known to be upregulated by cisplatin. Cochlear tissues fight the oxidative stress by means of antioxidant defence systems including glutathione, glutathione reductase, superoxide dismutase, and catalase . CisplatThe extent of ototoxicity due to cisplatin administration can be assessed clinically through measurements of hearing loss by means of pretreatment and follow-up serial audiologic tests and experimentally through histological examinations . The forIn experimental animals, hearing loss after cisplatin treatment can be assessed by audiological study of the auditory brainstem responses where threshold measurement defines the lowest intensity of sound stimulus that evokes a clear, visually detectable, reproducible waveform .α) and other inflammatory cytokines  were also detected by immunostaining in the outer hair cells, stria vascularis, spiral ligament, and spiral ganglion neurons in cisplatin exposed cochleae [Histologic examinations of inner ear after cisplatin administration reveal destruction primarily of outer hair cells and to some extent inner hair cells and associated nerves, degeneration of the vestibular organs, stria vascularis edema, and detachment of the myelin sheath of the spiral ganglion cells . Light mcochleae .2 are used the hearing impairment may progress from high frequencies to involve the middle frequencies. Reducing the total amount of cisplatin by limitation of the total dose per cycle, dose intensity and the cumulative dose would diminish the antitumor effect which is not desirable. Various otoprotective compounds have been tested both in experimental animals and humans. If given systemically, they should be nontoxic, must attain efficient concentrations in the inner ear to protect labyrinthine tissues from cisplatin ototoxicity, and should not hamper the antitumor effect of cisplatin. Higher concentrations of otoprotective molecules can be achieved by intratympanic administration. This latter route provides direct access of the protective agents to inner ear structures while avoiding systemic side effects and interference with the antineoplastic activity of cisplatin [Cisplatin pharmacokinetics in the inner ear after intravenous injection is influenced by its strong binding to the plasma proteins rendering a large part of it nonactive and by the barrier systems in the cochlea, the blood-perilymph barrier, separating blood from perilymph, and the intrastrial fluid-blood barrier, separating blood from endolymph . The amoisplatin .Several otoprotective molecules and strategies against cisplatin-induced ototoxicity have been tested in experimental animals. Some, like diethyldithiocarbamate, exerted important side effects in humans . A summaHyperbaric oxygen therapy consists of intermittent inhalations of 100% oxygen at a pressure higher than 1 atm and is used as adjuvant therapy in pathological processes like soft tissue infections, radiation injury, gas gangrene, and decompressive disease. Its main effect is tissue hyperoxygenation through plasma dissolved oxygen and was successfully tested in guinea pigs as a protective agent against cisplatin ototoxicity. Efficacy of otoprotection by hyperbaric oxygen therapy after cisplatin administration was evaluated by otoacoustic emissions following hyperbaric treatment and by scanning electron microscopy examination. The study confirmed that cisplatin induces dose-dependent cochlear alterations consisting of cellular lesions and significant hair damage in outer hair cells. Analysis of anatomical changes in cochlear outer hair cells indicated signs of otoprotection against cisplatin in animals treated with hyperbaric oxygen therapy although in functional studies distortion product acoustic emission were absent reflecting a certain degree of hearing loss, most probably reversible and related to experimental artefacts. The study concluded that hyperbaric oxygen therapy has otoprotective effects against cisplatin-induced ototoxicity. However, further studies are necessary to test other effects of high pressure oxygen on the cochlea .Another study investigated the effect of epigallocatechin gallate (EGCG) on the transcription factor STAT1, an important mediator of cell death. STAT1 phosphorylation is involved in both hair cells and support cells transformation after experimental exposure of mouse utricule to cisplatin. EGCG proved its efficiency as an otoprotective agent against cisplatin ototoxicity due to its inhibition of STAT1. The hypothesis was further supported by the failure of EGCG to provide protection against cisplatin in STAT1-deficient mice .Former studies showed that lactate injected intratympanically in guinea pigs treated with ototoxic levels of cisplatin allowed near total preservation of otoacoustic emissions . Since lMost of the existing studies focus on exogenous administration of antioxidants. Pharmacological activation of intrinsic defence mechanisms against oxidative stress in the inner ear caused by cisplatin therapy also proved helpful as showed by an experimental animal study using systemic administration of thiamine pyrophosphate (TPP). Thiamine pyrophosphate functions as coenzyme for peroxisomes being a crucial factor for energy metabolism, antioxidation, and myelinisation of nerve cells. Its intraperitoneal injection increased the level of natural antioxidants like glutathione and antioxidant enzymes  and reduced the content of malonildialdehyde, an indicator of lipid peroxidation following increased levels of oxygen reactive species resulting from cisplatin toxicity. The histologic evaluation of cochleae harvested from TPP treated animals showed preservation of the morphology of the organ of Corti and outer hair cells and no destruction of spiral ganglion cells and stria vascularis following cisplatin therapy .The wide range of therapeutic molecules studied for their otoprotective effect against cisplatin-induced ototoxicity also includes sertraline, an antidepressant with neuroprotective effects in rats . The selAn experimental single dose model of cisplatin ototoxicity in guinea pigs showed the otoprotective effect of systemic histone deacetylase inhibitor sodium butyrate. Distortion product otoacoustic emissions testing were chosen to provide a sensitive assay of the functional state of outer hair cells after systemic cisplatin insult on the cochlea. The systemic administration of the otoprotective agent avoided the side effects of the more invasive tympanic local route of administration. Moreover, sodium butyrate did not interfere with the tumoricidal effect of cisplatin providing both protections from reactive oxygen species and a certain degree of antitumor activity according to former reports. Acetylation of different cell proteins, including histones, is responsible both for the protective effect against oxidative stress and for the cell division inhibition and subsequent anticancer activity. The experiment's weak point is that it only showed the effect of sodium butyrate in a single dose of cisplatin model whereas in clinical practice cisplatin is typically given repeatedly at a couple of weeks intervals for several months .β [The unique isoform of NADPH oxidase, NOX3, found in the cochlea and its involvement in the generation of reactive oxygen species was at the base of an animal study showing the efficacy of short interfering RNA in preventing cisplatin ototoxicity by reducing the expression of NOX3 in outer hair cells, spiral ganglion cells, and stria vascularis in the rat. Auditory brainstem responses were used to certify reduced threshold shifts in cisplatin treated animals who received transtympanic NOX3 siRNA. Since cisplatin administration has been previously associated with upregulation of NOX3 in the inner ear, Nox3 is thought to be a major source of free radicals in the cochlea following cisplatin exposure. The resulting free radicals initiate the inflammatory process in the cochlea by activating signal transducer and activator of transcription-1 (STAT1), followed by activation of p53 and increase in inflammatory mediators like TNF-alpha and interleukin-1β . A singlβ .Among various strategies that have been devised in experimental settings to prevent cisplatin ototoxicity, minocycline, a tetracycline derivative, proved its partial efficacy in vivo and in vitro. The anti-inflammatory and neuroprotective properties of minocycline have been previously reported. The biochemical mechanisms involve caspase-1 and caspase-3 inhibition, which decreases the amount of interleukin-1 and prevents apoptosis. The protective effect of minocycline has been tested both on cisplatin treated cell cultures and in experimental animals which underwent cisplatin intraperitoneal therapy after systemic administration of the otoprotective agent. Cell viability assays showed that minocycline had a protective effect against cisplatin toxic action. Yet, minocycline failed to protect cells at higher concentrations of cisplatin. Recordings of auditory brainstem responses and evaluation of the scanning electron microscopy sections of inner ears harvested from minocycline plus cisplatin treated animals indicated a partial preservation of the function and morphology of the outer hair cells as compared to those from animals treated with cisplatin alone .The effect of intraperitoneal administration of erdosteine on cisplatin-induced ototoxicity in a guinea pig model was also studied. Erdosteine is a thiol derivative with established antioxidant properties due to its active sulfhydryl groups following liver first-pass metabolism. Pre- and posttreatment auditory brainstem responses measurements were performed in living animals while outer hair cell counts were analyzed by scanning electron microscopy of the cochleae removed from euthanized animals. Although the study had limitations , the results outlined the systemic administration of erdosteine as a promising therapeutic strategy for cisplatin-induced ototoxicity .In a first murine model for cisplatin-induced ototoxicity, it was shown that intratympanic dexamethasone prevents hearing loss in a frequency related manner. Evoked brainstem responses audiometry indicated that 8 kHz and 16 kHz stimulus elicited responses in cisplatin plus dexamethasone treated mice while high frequency stimulus (32 kHz) perception was affected. Apparently, cisplatin had deleterious effects on outer and inner ear cells situated in the basal turn of the cochlea despite intratympanic administration of protective dexamethasone . FurtherThe intratympanic administration of dexamethasone avoids diminishing the tumoricidal activity of cisplatin. Downregulating apoptosis genes in tumour cells are responsible for this common side effect of systemic steroid therapy . An expeOtoprotection with dexamethasone against cisplatin-induced age-related hearing loss was investigated in a guinea pig model following observations that persons older than 65 years account for more than half of the newly diagnosed malignancies. Hearing loss due to the aging process shares the same cause  with hearing loss due to ototoxic chemotherapeutic agents. A single dose of cisplatin was administered intraperitoneally in old mice preceded and followed by dexamethasone injected intratympanically to counteract the cisplatin toxic effect on inner ear hair cells. Pre- and posttreatment auditory brainstem responses were recorded to evaluate hair cell function. The results of the study pointed out that no synergistic action between age related hearing loss and cisplatin-induced hearing loss exists since threshold shifts were smaller in older animals than those in young mice. Another finding of the study was that the protective effect of dexamethasone against cisplatin-induced ototoxicity was a function of stimulus frequency in old mice. Susceptibility to otoprotective effect of dexamethasone was higher in mid to basal cochlear regions (at and above 24 kHz) in old mice, whereas in young mice, dexamethasone bestowed more protection in apical regions of the cochlea (at 16 kHz and below). Age-related changes of the mechanism of distribution of dexamethasone in scala tympani perilymph after round window membrane application in guinea pigs seem to account for the frequency dependent otoprotective effect .Intratympanic dexamethasone failed to protect against cisplatin-induced ototoxicity in a multidose cisplatin ototoxicity mouse model. The study was prompted by typical clinical protocols of cancer treatments which require administration of multiple, smaller cisplatin doses, exerting their curative effect through cumulative dosing. Contrary to previous experimental studies, the mice received five doses of cisplatin throughout five days, mimicking the cumulative exposure seen in malignant tumours treatment. Intratympanic dexamethasone was administered on the same days as the intraperitoneal cisplatin. The results mirrored by auditory brainstem responses threshold measurements demonstrated continued change in hearing thresholds several weeks after cisplatin exposure and no protective effect of intratympanic dexamethasone against cisplatin ototoxicity .An experimental study focused on systemic administration of steroid for protection against cisplatin-induced ototoxicity showed no otoprotection following several days' prophylaxis with a high dose dexamethasone treatment. Only a slight decrease of TNF-alpha expression in the cochlea was demonstrated by immunohistochemical staining of anatomical samples harvested from systemic cisplatin plus dexamethasone treated animals. Dexamethasone also seemed to protect stria vascularis from morphological alterations, probably owing this effect to higher concentrations of steroid in the lateral cochlear wall following increased cochlear flow and a naturally highly vascularised stria vascularis. Still, a functional otoprotective effect of systemic dexamethasone against cisplatin-induced hearing loss was not observed .Among naturally occurring molecules, Rosmarinic acid, a water-soluble polyphenolic compound extracted from Dansam-Eum, was tested for its protective effect against cisplatin-induced ototoxicity in laboratory settings. The results of the study showed that Rosmarinic acid inhibited cisplatin-induced caspase-1 activation providing protection against stereocilia loss in the primary organ of Corti explants .Another natural remedy, the Maytenus ilicifolia aqueous extract, was evaluated for its possible otoprotection in guinea pigs. Despite the well-known South America plant's antioxidant effects , functional tests did not demonstrate any protective action on the cisplatin exposed cochleae. Yet, the extract improved the clinical status and weight of guinea pigs and diminished mortality after cisplatin exposure .Resveratrol, a polyphenol found in grape skin and seed, has antioxidant, neuroprotective, and dose dependent antiapoptotic properties . Recent Intratympanic dexamethasone was clinically tested for its otoprotective effect in patients suffering from neoplastic diseases for which the treatment protocol included cisplatin. Intratympanic dexamethasone has already been tested clinically for the treatment of idiopathic sudden sensorineural hearing loss and Meniere disease . IntratyTranstympanic L-N-acetylcysteine was also clinically tested in head and neck cancer patients undergoing cisplatin therapy. Thiol compounds are known to either directly bind cisplatin or act as free radical scavengers. Based on that, their intratympanic administration was suggested to avoid the decrease of oncologic effectiveness of cisplatin and to reduce the oxidative stress caused by it. Intratympanic L-N-acetylcysteine was well tolerated by patients receiving multiple doses of cisplatin as part of their oncologic treatment. The relation between dose and otoprotection was not taken into account. Higher concentrations may have yielded better otoprotection. The study protocol required the L-NAC injection to be approximately 1 hour before systemic administration of cisplatin, for the sake of better timing. The outcome of the pure tone audiometry testing at 1 and 2 months after the last cycle of cisplatin showed that L-N-acetylcysteine was overall not significantly otoprotective. Still, hearing loss was reduced in two patients out of eleven who completed the study. The study protocol had several challenges like the difficulty in maintaining high enough concentrations of aqueous solution of L-N-acetylcysteine in the middle ear due to the technique of administration. Another study flaw was the different initial hearing thresholds due to preexisting hearing loss .http://clinicaltrials.gov/ct2/results?term=cisplatin+ototoxicity/) are listed in Few clinical studies tested systemic otoprotective molecules for preventing cisplatin-induced hearing loss. Amifostine, a phosphorylated aminothiol designed to protect against radiation damage, was known to counteract the toxic effect of different anticancer treatments without interfering with the tumoricidal effect. Although significant protection of amifostine against haematological toxicity after high dose carboplatin therapy in a child with medulloblastoma was reported , a cliniThe well-isolated inner ear organ makes it prone to targeted genetic therapies. Viral or nonviral gene vectors can be delivered through a transtympanic route without the risk of dispersing them and reaching other tissues with subsequent undesirable genetic alteration. Long term effects after single administration, cellular selectivity, and replacement of genetically flawed nucleic acid sequences are the main benefits of gene therapy. Common viral vectors include herpes simplex virus, recombinant adenoassociated virus, recombinant adenovirus, and adenovirus, used to amplify the expression of targeted genes. Cells are infected with the vectors (transfection) which transfer genes whose expressed proteins influence important processes like growth, oxidative stress, and apoptosis. Chemical transfection can also be achieved with plasmid vectors. Short interfering RNA can be used to shut down target genes.Among inner ear target genes dealt with by the gene therapy studies are ATOH1 (Math1), CAT , SOD1 (Cu/Zn superoxide dismutase), SOD2 (Mn superoxide dismutase), BDNF (brain-derived neurotrophic factor), HGF (hepatocyte growth factor), GJB2 (gap junction protein), Bcl-xL (B-cell lymphoma-extra large), FGF2 (basic fibroblast growth factor). The gene therapy modifies the synthesis of a wide range of proteins including neurotrophic factors , apoptosis mediators , oxidases , an antioxidant response regulator (Nfe2l2), a cytoprotective enzyme (HO-1), copper transporters (Ctr1), a nonselective cation channel (Trpv1), and protein Otospiralin (Otos).Cisplatin-exposed tissues can benefit from genetically induced upregulation of neurotrophic factors, inhibition of apoptosis, and generation of endogenous antioxidant enzymes.Experimental animal studies and in vitro experiments show the efficacy of gene therapy for cisplatin-induced ototoxicity. Clinical applications require further studies regarding safety, immunogenicity, and consequences of genetic manipulation .Another strategy to avoid cisplatin-induced hearing loss would be the pretreatment genotyping to find out patients at risk for the ototoxic effect of cisplatin . GeneticForty-three publications were reviewed concerning prevention or treatment of cisplatin induced ototoxicity. Publications were devised in either experimental or clinical studies. Experimental studies sustained the efficiency of hyperbaric oxygen therapy, epigallocatechin therapy, and intratympanic lactate. The latter two therapies provide exogenous antioxidants while pharmacologic activation of endogenous antioxidants by means of intratympanic thiamine pyrophosphate was consistent with higher levels of natural antioxidants. Oral sertraline, besides its otoprotective effect against cisplatin induced ototoxicity, also has therapeutic value concerning the depression occurring frequently in oncologic patients. Sodium butirate proved its efficiency against cisplatin induced hearing loss in a monodose cisplatin model. Yet, in clinical practice the patient receives multiple doses of cisplatin. The production of endogenous radicals of oxygen species was reduced after intratympanic administration of short interfering RNA which reduces the expression of NOX3 in the cochlea. Minocycline appeared to be efficient only at low doses of cisplatin while systemic erdosteine showed promising results. Dexamethasone in experimental studies combined efficiency against cisplatin induced ototoxicity with preservation of the tumoricidal activity of cisplatin. When older mice were treated, the dexamethasone was more otoprotective at higher frequencies compared to experiments including younger subjects. Rosmarinic acid also proved to be otoprotective while the Maytenus ilicifolia aqueous extract was not. Resveratrol had contradictory effects, systemic low doses, and in vitro administration preventing ototoxicity, whereas high oral doses seem to enhance cisplatin ototoxicity. There also were experimental studies which showed inefficiency of intratympanic N-acetylcysteine and intratympanic and systemic dexamethasone. N-Acetylcysteine also had a damaging effect on middle and inner ear structures.Clinical studies proved a minor otoprotective effect of intratympanic dexamethasone and no effect of systemic amifostine and intratympanic L-N-acetylcysteine. New perspectives are brought about by genetic therapy using viral vectors and genotyping to anticipate interindividual variability in cisplatin ototoxicity.Hearing loss prevention and treatment during cisplatin therapy for cancer needs further research to find new strategies and optimize old ones. The intratympanic route of administration along with the gene therapy appears to be the most attractive objective for further experimental and clinical studies.


The real benefit of alternative cannulation technique for repair of acute type A aortic dissection remains controversial.We evaluated our results of ascending aortic cannulation compared with femoral cannulation in acute type A aortic dissection.From January 2000 to December 2014, 121 patients were operated on for acute type A aortic dissection. Cannulation was accomplished in 79 patients through the ascending aorta and 42 patients through the femoral artery.Patient characteristics such as preoperative complications and shock status were almost similar between the groups. Although intraoperative parameters such as total cardiopulmonary bypass time, hypothermic circulatory arrest time, minimum bladder temperature and percentage of total arch replacement were also similar between the groups, ascending aortic cannulation significantly reduced arterial pressure on cardiopulmonary bypass circuit , core-cooling time  and operation time . There were no significant differences in postoperative 30-day mortality and in-hospital mortality between the groups. However, incidence of temporary neurological dysfunction  and respiratory failure  as postoperative complications were significantly lower in the aortic cannulation group, although the incidence of stroke and renal failure did disclose any differences between the groups. Moreover, ascending aortic cannulation significantly reduced the hospital stay .The ascending aortic cannulation for repair of acute type A aortic dissection can be advantageous to rapid cooling after the establishment of cardiopulmonary bypass. It might offer benefit on the incidence of postoperative complications and the length of hospitalization in patients with of acute type A aortic dissection.


Maintaining DNA integrity is essential for cell survival and proper functioning. Therefore, many cancer therapies, including radiotherapy and several chemotherapeutic drugs, induce damage to the DNA leading to genomic instability . There aWe have used NMR based targeted profiling  to compaWe observed several similarities in the metabolic responses caused by different DDRs and also identified specific metabolite markers on treatment with these DNA damaging agents. PARP inhibition restored most of the metabolic changes observed in MMS-treated cells suggesting that the metabolic response observed after MMS treatment may be predominantly due to PARP activation.In this study, we identified several similarities and differences in metabolic responses induced by different types of DDRs, which suggests the redirection of metabolic fluxes in a DNA damage-dependent manner. We also observed that recruitment of PARP during the DNA repair process can lead to widespread metabolic changes by observing the effect of PARP inhibition in MMS-treated cells. These results have identified novel metabolic responses in cancer cells following DNA damage and on inhibiting activity of proteins involved in DNA repair processes.


Helicobacter pylori infection remains one of the most challenging infectious diseases causing high mortality and morbidity. The prevalence of infection varies greatly between industrial and developing countries as well as between different geographic areas.Helicobacter pylori (H. Pylori) infection remains one of the most challenging infectious diseases causing high mortality and morbidity. The prevalence of infection varies greatly between industrial and developing countries as well as between different geographic areas  and indirect (non-invasive). Direct methods involve biopsies of ulcer margins by endoscopy and microscopic examination, endoscopy with phenols staining, rapid urease test, and histological specimen culture and polymerase chain reaction. Indirect methods include antibody serology test, stool antigen test, urea breath test, examining of teeth plaque, urine and gastric juice examination  have been completely observed by the author.None declared.


Naegleria fowleriBalamuthia mandrillarisAcanthamoeba species.Infections caused by free-living amebae (FLA) are severe and life-threatening. These infections include primary amebic meningoencephalitis (PAM) caused by B. mandrillaris and Acanthamoeba species infections treated with a miltefosine-containing regimen is small, it appears that a miltefosine-containing treatment regimen does offer a survival advantage for patients with these often fatal infections  protocol in effect with the Food and Drug Administration to make miltefosine available directly from CDC for treatment of FLA in the United States. The expanded access IND use of miltefosine for treatment of FLA is partly supported by 26 case reports of FLA infection in which miltefosine was part of the treatment regimen . Miltefosine generally is well-tolerated, with gastrointestinal symptoms the most commonly reported adverse effects. Clinicians who suspect they have a patient with FLA infection who could benefit from treatment with miltefosine should contact CDC to consult with an FLA expert. For diagnostic assistance, specimen collection guidance, specimen shipping instructions, and treatment recommendations, clinicians should contact the CDC Emergency Operations Center at 770-488-7100.


We report a unique first case of benign heterotopic pancreas arising within the proximal hepatic bile duct, containing a focus of intraductal papillary mucinous neoplasm (IPMN). The condition was diagnosed on pathological explant after left hepatic lobectomy with total extrahepatic bile duct excision. The condition of heterotopic pancreas is a relatively common finding, where small foci of pancreatic rest tissue arise in intra-abdominal sites other than the pancreas. First described in 1727, aberrant pancreatic tissue is defined as ectopic location of pancreatic tissue without vascular, neural, or anatomic connections to the anatomically normal pancreas . The majAn obese otherwise healthy 47-year-old female (body mass index 36) presented with intermittent nausea and right upper quadrant discomfort after intentional weight loss of 27 kg. The serum lipase was found to be mildly elevated at 132 units. Abdominal ultrasound demonstrated focal dilatation of the intrahepatic left hepatic ducts, and a subsequent contrast-enhanced magnetic resonance cholangiopancreatogram (MRCP) and endoscopic retrograde cholangiopancreatogram (ERCP) demonstrated an occlusive filling defect within the proximal main biliary tree . An intrThe imaging findings were concerning proximal hepatic duct cholangiocarcinoma (Klatskin tumor), although the CA19-9 was not elevated. The patient then underwent surgical exploration where a palpable filling defect was identified within the proximal hepatic duct. Intraoperative ultrasound demonstrated no additional lesions. For oncological clearance, a left hepatectomy with caudate lobectomy was completed, which required a triple right-sided bile duct Roux-en-Y reconstruction (two posterior and one anterior right bile ducts) over temporary externalized 5 French stents. No blood products were required, and no inflow occlusion was used. She had a smooth and relatively uncomplicated recovery other than a superficial wound infection.Surgical pathology demonstrated histological features consistent with heterotopic pancreatic tissue with IPMN contained within the proximal biliary tree .Sections showed superficial atypia with areas suggestive of papillary formation. There was also prominent bland duct proliferation with lobular architecture and microscopic foci of pancreatic acini surrounding the bile duct. The histological diagnosis was consistent with heterotopic pancreatic tissue. The superficial atypia with papillae suggests a low grade IPMN of the bile duct.At follow-up at 2 months, the patient had recovered fully, and the biliary stents were removed uneventfully.Continued advancement in cross-sectional and other imaging modalities facilitates early diagnosis and more precise treatment for hepatobiliary malignancies. We describe an extremely rare condition of IPMN arising within heterotopic pancreatic tissue obstructing the proximal hepatic duct. We believe this to be the first report of this condition arising within and obstructing the biliary tree. Interestingly SpyGlass cholangiography was able to demonstrate the lesion but was not able to precisely define the pathology. Furthermore, obstruction of the proximal biliary tree necessitated definitive resectional treatment. Had we been confident preoperatively of the benign nature of the filling defect, a less aggressive localized bile duct resection with hepatic parenchymal preservation could potentially have been entertained. However, the presence of IPMN change with potential for malignant transformation would still have provided concern. Preoperative diagnosis of heterotopic pancreas may be challenging and typically this is an incidental finding.Heterotopic pancreas is most commonly found in the proximal jejunal wall of the gastrointestinal tract. Pathological changes that occur within the native pancreas may also occur rarely within the heterotopic gland, including pancreatitis, abscess, and occasionally malignant transformation . IPMNs aIn conclusion, although the condition of heterotopic pancreas is usually asymptomatic and is often discovered incidentally, IPMN with potential for malignant transformation may rarely occur remotely within the biliary tree.


Hyperammonemic encephalopathy may occur when urease-positive bacteria in the urinary tract produce ammonium which directly enters systemic circulation. Predisposing conditions such as a neurogenic bladder can increase both urinary tract infection and urine stagnation.We describe the case of a 66 years old woman with a neurogenic bladder who twice developed hyperammonemic encephalopathy following urinary tract infection. During the second episode Escherichia coli and Enterococcus faecalis have been isolated in the urine. The neurologic examination showed psychomotor slowing, weak photomotor reflex, nystagmus in the lateral gaze and asterixis. The EEG showed triphasic waves which disappeared along with clinical recovery.Escherichia coli and Enterococcus faecalis are commonly considered urease-negative bacteria. Although frequently involved in urinary tract infections, their role in causing hyperammonemic encephalopathy have not been previously reported. Moreover, despite only one case with a neurogenic bladder have been described so far, our is the first patient with reoccurring hyperammonemic encephalopathy secondary to urinary tract infections. The occurrence of hyperammonemic encephalopathy is frequently related to liver disease and portal hypertension, where hepatic detoxification process is impaired. In patients with urinary divertion, vesico-colonic fistula or congenital anomalies affecting urinary tract function, ammonium may bypass portal circulation draining directly into the hypogastric veins and inferior vena cava. During urinary tract infections (UTI), urea splitting organisms may determine ammonium production primarily within the urinary system. There are rare conditions when the urine remains into a dilated bladder long enough to allow ammonium reach systemic circulation: this can be due to large diverticula , a neuroWe report the case of a patient with a neurogenic bladder who presented two episodes of hyperammonemic encephalopathy three years apart as a result of UTI. During the last episode, urine culture revealed Escherichia coli and Enterococcus faecalis which are considered urease-negative bacteria.A 66-years-old female, with a history of urinary retention and recurrent UTI, became progressively somnolent during one week, complaining at the same time dysuria and bladder pain, for which she had been assuming trimethoprim-sulfamethoxazole. She was conducted to our department after the execution of a brain CT  and the detection of hyperammonemia (89 μmol/L) in the emergency room. The neurologic examination showed psychomotor slowing, weak photomotor reflex, nystagmus in the lateral gaze and asterixis. Her past medical history highlighted that, three years before, she had experienced a similar event . She underwent laboratory blood and urine tests, which showed increased pH (8.0) and a urinary tract infection caused by Escherichia coli and Enterococcus faecalis along with mild increase of serum creatinine, but without impairment of hepatic function; EEG showed alterations consistent with toxic metabolic encephalopathy Figure . UnderlyHyperammonemic encephalopathy occurs when hyperammonemia causes glutamine-mediated effects on the brain, such as astrocytic swelling, cerebral edema, and raised intracranial pressure . An incrOur patient has been suffering from urinary retention for many years because of an idiopathic neurogenic bladder. Urinary retention not only predisposed her to the infection, but also increased the absorption of ammonia from the leftover urine through the bladder walls .Although hyperammonemic encephalopathy determines a similar clinical and EEG picture independently of the cause (UTI or hepatic failure), the urinary origin is likely to result in a faster (days or weeks) onset of the symptoms, compared with the chronic and peculiar clinical picture of patients with hepatic dysfunction.To our knowledge this is the first described case where urinary retention was associated with urinary tract infection and recurring hyperammonemic encephalopathy. Moreover no previous cases have been reported where urinary tract infection by Escherichia coli and Enterococcus faecalis caused hyperammonemia.The present case focuses on urinary tract infection related to neurogenic bladder as a potential cause of hyperammonemia, which nevertheless can lead to metabolic encephalopathy. It is important to underline that bacteria usually considered urease-negative may be related to ammonium production within the urinary tract.Written informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.UTI: Urinary tract infection; CT: Computed tomography; EEG: Electroencephalogram.The authors declare that they have no competing interests.All the authors have read and approved the manuscript. In addition all authors have contributed in the composition, write-up, and review of the manuscript.


However, recent experiments in which sensory-evoked local dendritic spikes were observed in vivo have provided valuable constraints on possible spatiotemporal patterns of synaptic input [Theoretical modelling and experiments e neuron ,2. Whileic input -5. For eic input . Here, win vivo [in vivo experiments [First, we adapted a detailed active compartmental model of a neocortical layer 2/3 pyramidal neuron [in vivo , such asin vivo occur preferentially when excitatory synaptic inputs are interspersed with inhibitory synaptic inputs. Furthermore, local spikes preceding backpropagating action potentials lead to the highest instantaneous dendritic spike frequencies. The highest sustained frequencies are generated by local spikes initiated sequentially in several neighbouring dendritic branches. Notably, only some of the high frequency dendritic events are effective in evoking action potential output, while others remain local. We use cluster analysis to establish the local and global conditions under which specific spatiotemporal patterns of synaptic input can influence neuronal output.Next we analyzed which spatiotemporal synaptic input patterns precede the generation of local dendritic events. We find that local spikes are preferentially triggered by excitatory synapses which are spatially and temporally clustered in the local dendritic branch and neighbouring branches. While there is great variability in the spatial distribution of synapses triggering local dendritic spikes, temporal patterns of excitatory synaptic input are stereotyped and tend to be sparse. High-frequency dendritic spikes similar to those observed In summary, we have derived spatial and temporal rules for synaptic input and identify input patterns that locally exploit the non-linear integration capacities of dendrites. Which computations can be implemented by spiking dendrites receiving such synaptic input patterns? These constraints on synaptic input patterns, together with the realistic intrinsic properties displayed by the model, put us in a position to investigate the role of dendritic excitability in shaping the input-output relation of the neuron.


RAS proteins are key signalling hubs that are oncogenically mutated in 30% of all cancer cases. Three genes encode almost identical isoforms that are ubiquitously expressed, but are not functionally redundant. The network responses associated with each isoform and individual oncogenic mutations remain to be fully characterized. In the present article, we review recent data defining the differences between the RAS isoforms and their most commonly mutated codons and discuss the underlying mechanisms. RAS proteins are membrane-bound small GTPases that act as molecular switches downstream of cell-surface receptors. Upon GTP binding, RAS changes conformation, revealing an effector-binding site that can interact with proteins harbouring a RAS-binding domain . RelocalIn the human genome, three genes encode HRAS, KRAS and NRAS. Alternative splicing of HRAS and KRAS generates protein variants with altered C-termini . The N-tDespite their similarity, RAS proteins are not functionally redundant. Furthermore, the oncogenic mutations that make RAS constitutively active may not all be equivalent in their functional consequences. We discuss the evidence for this together with the potential mechanisms underlying these phenomena.RAS proteins cycle between the inactive GDP-bound and the active GTP-bound conformations . This cyThe reason for the bias in RAS mutations associated with individual cancers is unclear, although several models have been proposed. One simple possibility is that isoform-specificity could mean that a more oncogenic network response is generated when KRAS is rendered constitutively active by mutation compared with the other RAS isoforms. This is supported by mouse models harbouring G12D mutated KRAS that exhibited widespread colonic hyperplasia and neoplasia. In contrast, NRAS G12D stimulated cell survival pathways . FurtherKRAS revealed a strong bias for rare codon usage resulting in significantly reduced protein translation compared with a codon-optimized KRAS sequence [RAS is known to induce senescence rather than proliferation [KRAS leads to low endogenous protein levels, meaning that oncogenically activated KRAS would not be expressed highly enough to induce the senescent phenotype. Absolute quantification of RAS isoform protein abundance in normal tissues has not been performed to date; however, comparative analysis of RAS isoform protein levels in a panel of cancer cell lines revealed that KRAS is typically the most abundant isoform  of RAS isoforms change their orientation with respect to the membrane . The extKRAS knockout resulted in embryonic lethality [HRAS into the endogenous KRAS locus, resulting in normal embryonic development, but induced dilated cardiomyopathy during adulthood [Finally, relative expression differences of the isoforms will influence competition for regulator and effector binding and therefore signalling network responses. An example of this can be seen in studies of mouse development. Whereas ethality , a subsedulthood . This suRAS alleles, panels of cancer cell lines and mouse models.This illustrates the importance of studying isoform-specific function in an endogenous context, since a subset of isoform-specific differences may result from the disparity in their expression. Future work is likely to rely less on ectopic overexpression and more on isogenic cells harbouring endogenous wild-type and mutant RAS proteins exhibit a spectrum of isoform-, codon-, point-mutation- and context-specific network responses. These remain poorly understood, which precludes simple prediction of the likely consequences of any given mutation. Wherever possible, it is important to study RAS function in an endogenous context to avoid the perturbing influence of overexpression on the signalling networks. With the recent emergence of new cellular tools, xenopatient and genetically engineered mouse models and more sophisticated systems biology approaches to studying RAS function, there are likely to be significant improvements in our understanding of RAS biology in the near future.


Familial Mediterranean fever (FMF) is an autosomal recessive auto-inflammatory disease, presenting with recurrent episodes of fever and polyserositis. Diagnosis of FMF is may be challenging especially in pediatric population. Mitochondrial fatty acid oxidation disorders and porphyrias can present with periodic abdominal and muscle pain. Incidence of both FMF and inherited metabolic disorders (IMD) are increased in Turkish patients partially due to high consanguinity rates.The aim of the present study is determine the inherited metabolic disorders in differential diagnosis of Turkish pediatric FMF patients.174 patients who were diagnosed as FMF enrolled the study. In all patients, a fasting dry spot blood sample was taken for acyl-carnitine analyses by tandem mass spectrometry. Fresh, light-protected spot urine test was performed for porphobilinogen screening. Second-tier test with urine organic acid analysis and urine porphyrin metabolites were performed if pathologic findings were detected in acyl-carnitine profile or in porphobilinogen screening, for confirmation. An age matched healthy 50 children served as control group.Of the 174 patients diagnosed with FMF, none of our patients was diagnosed with porphyria; two patients with fatty acid oxidation defect, one with multiple acyl-CoA dehydrogenase deficiency and one with possible medium-chain acyl-CoA dehydrogenase deficiency were detected during the study.Our data revealed that screening for porphobilinogen for pediatric FMF patients is unnecessary, but an investigation of tandem mass based acyl-carnitine analyses can be helpful for the differential or additional diagnosis of FMF in developing countries that does not have nationwide expanded newborn screening programme.


Microglia are macrophage-like resident immune cells that contribute to the maintenance of homeostasis in the central nervous system (CNS). Abnormal activation of microglia can cause damage in the CNS, and accumulation of activated microglia is a characteristic pathological observation in neurologic conditions such as trauma, stroke, inflammation, epilepsy, and neurodegenerative diseases. Activated microglia secrete high levels of glutamate, which damages CNS cells and has been implicated as a major cause of neurodegeneration in these conditions. Glutamate-receptor blockers and microglia inhibitors  have been examined as therapeutic candidates for several neurodegenerative diseases; however, these compounds exerted little therapeutic benefit because they either perturbed physiological glutamate signals or suppressed the actions of protective microglia. The ideal therapeutic approach would hamper the deleterious roles of activated microglia without diminishing their protective effects. We recently found that abnormally activated microglia secrete glutamate via gap-junction hemichannels on the cell surface. Moreover, administration of gap-junction inhibitors significantly suppressed excessive microglial glutamate release and improved disease symptoms in animal models of neurologic conditions such as stroke, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer's disease. Recent evidence also suggests that neuronal and glial communication via gap junctions amplifies neuroinflammation and neurodegeneration. Elucidation of the precise pathologic roles of gap junctions and hemichannels may lead to a novel therapeutic strategies that can slow and halt the progression of neurodegenerative diseases. Microglia are macrophage-like immune cells that reside in the central nervous system (CNS), where they play multiple roles: presenting antigen to initiate immunological reactions, directing attack against non-self antigens, debris clearance, support of neuronal circuit development . CaMK activates neuronal nitric oxide synthase (nNOS) and increases the intracellular concentration of nitric oxide (NO). NO in turn inhibits mitochondrial respiratory chain complex IV, resulting in a rapid reduction in intracellular ATP levels. Ultimately, the loss of intracellular energy pools suppresses dendritic and axonal transport, leading to bead-like accumulation of cytoskeletal and motor proteins along neurites and the formation of neuritic beading. Thus, a low-energy state results in neuronal dysfunction. Persistence of this neuronal dysfunction eventually causes neuronal death [i.e., excitotoxic neuronal death or non-cell-autonomous neuronal death , metabolites , and nucleotides  between adjacent cells . These toxic molecules are propagated from injured cells to healthier cells through gap junctions. Ischemic conditions also induce uncoupled hemichannels to open, leading to paracrine transfer of toxic molecules  and an animal model of this disease, experimental autoimmune encephalomyelitis (EAE). In particular, downregulation of oligodendrocytic Cx32 and Cx47 and astrocytic Cx43 have been observed in the active lesions of MS patients and EAE mice , Cx43 (43gap 27), or Panx1 (10panx1) non-specifically block both connexins and pannexins  (Block et al., 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.


Multivariate analyses identified significant spatial and temporal variation in benthic fluxes, demonstrating key differences between the Northeast Pacific and Salish Sea. Moreover, Northeast Pacific slope fluxes were generally lower than shelf fluxes. Spatial and temporal variation in benthic fluxes in the Salish Sea were driven primarily by differences in temperature and quality of organic matter on the seafloor following phytoplankton blooms. These results demonstrate the utility of multivariate approaches in differentiating among potential drivers of seafloor ecosystem functioning, and indicate that current and future predictive models of organic matter remineralization and ecosystem functioning of soft-muddy shelf and slope seafloor habitats should consider bottom water temperature variation. Bottom temperature has important implications for estimates of seasonal and spatial benthic flux variation, benthic–pelagic coupling, and impacts of predicted ocean warming at high latitudes.The upwelling of deep waters from the oxygen minimum zone in the Northeast Pacific from the continental slope to the shelf and into the Salish Sea during spring and summer offers a unique opportunity to study ecosystem functioning in the form of benthic fluxes along natural gradients. Using the ROV ROPOS we collected sediment cores from 10 sites in May and July 2011, and September 2013 to perform shipboard incubations and flux measurements. Specifically, we measured benthic fluxes of oxygen and nutrients to evaluate potential environmental drivers of benthic flux variation and ecosystem functioning along natural gradients of temperature and bottom water dissolved oxygen concentrations. The range of temperature and dissolved oxygen encountered across our study sites allowed us to apply a suite of multivariate analyses rarely used in flux studies to identify bottom water temperature as the primary environmental driver of benthic flux variation and organic matter remineralization. Redundancy analysis revealed that bottom water characteristics (temperature and dissolved oxygen), quality of organic matter (chl  Marine carbon, nitrogen, and phosphate cycles are linked through their fixation by phytoplankton in surface waters and their remineralization in the water column and on the seafloor . The decOn the continental shelf, close benthic–pelagic coupling typically occurs over time scales of days. The benthic community generally responds rapidly to increased particulate organic carbon (POC) flux to the seafloor, resulting in measurable increases in benthic respiration . This rein situ studies that utilize natural variation such as those that occur along environmental gradients could potentially highlight the main environmental drivers of benthic fluxes, organic matter remineralization and ecosystem functioning in natural systems 76], OPD Bio-irrigation may also have influenced oxygen uptake; Archer and Devol  found thGiven that the marine nitrogen cycle arguably represents the most complex of all biogeochemical cycles in the ocean , a compla:phaeo and C:N), bottom water DO, and sediment MGS as the best predictors of silicate benthic efflux variation. Because we did not measure bio-irrigation, we cannot directly link silicate effluxes with this variable. However, increased oxygen penetration with bottom water oxygen concentration suggests higher bio-irrigation at the shallower and more oxygenated shelf sites than in deeper and oxygen-depleted slope sites on the NE Pacific. Lower oxygen concentration can also change macrobenthic community structure to one that primarily inhabits and reworks the surface of the seafloor and poorly bio-irrigates sediment at depth [Our study shows generally higher silicate effluxes from shallower shelf sites than deeper slope sites, with some seasonal variation. Silicate variation often reflects small-scale differences in sediment properties, bioturbation, and irrigation . Hammondat depth . Much hiat depth . Moreoveat depth  suggesteat depth . We ther-2 d-1 in BC300) to release (697.0 μmol m-2 d-1 in SoGC-05). Although Nixon et al. [a:phaeo, porosity, MGS and prokaryote abundance can explain 88% of the variation in phosphate flux. Our study apparently encompassed most of the key drivers for phosphate flux, allowing us to predict benthic phosphate flux at these locations. These results are supported by a recent study that modelled benthic phosphate fluxes using three of the variables that we identified  along with mineral bound inorganic phosphorous [Many factors influence seafloor phosphate fluxes , which vn et al.  reportedn et al.  reportedsphorous .a:phaeo and C:N ratios, 11.8 and 7.9% respectively) and sediment characteristics . In their Beaufort Sea study, Link et al. [a and phaeopigments, and bottom water dissolved oxygen as key environmental drivers of multivariate benthic flux variation. However, in contrast to our study, where temperatures varied by >5.5°C across sampling locations and dates, temperatures recorded at the time of sampling varied by <2°C and therefore contributed little to benthic flux variation, just as Rowe and Phoel [Multivariate dbRDA allowed us to examine all benthic fluxes simultaneously within the same analysis. Environmental drivers related to bottom water characteristics, quality of organic matter, and sediment characteristics, explained 51.5% of the variability in overall oxygen and nutrient fluxes. Bottom water characteristics explained most of the variability , followed by quality of organic matter  in the same analysis to determine the best combination of environmental drivers for all benthic fluxes, hence of seafloor organic matter remineralization. On the other hand, the multiple linear regression approach analysed each benthic flux separately  to determine the best combination of environmental drivers for each specific benthic flux. Given some commonalities in benthic fluxes but different degrees of influence by some environmental drivers on each benthic flux , the linear regression method identifies the environmental drivers of each benthic flux whereas the dbRDA method identifies the common environmental drivers that influence all benthic fluxes and examines seafloor organic matter remineralization as a whole.The dbRDA and multiple linear regression approaches identified some differences in environmental drivers of benthic fluxes. On the one hand, the dbRDA approach combines all benthic fluxes  on flux rates of oxygen, nitrate, phosphate, silicate and, for the most part, ammonium, where flux rates changed only after oxygen decreased by 50–80% from ambient values , 74. Thia:phaeo and C:N ratios) following significant deposition of particulate organic matter to the seafloor and, to a lesser extent, sediment characteristics (MGS and porosity). Although multiple biological and environmental factors influence different seafloor flux rates (O2 and nutrients), our study used a suite of multivariate approaches in tandem to demonstrate that a subset  of the large number of environmental variables measured  could explain benthic flux variation. We also found that simultaneous and single flux analyses in tandem provided a more comprehensive understanding of the interplay between OM remineralization and flux of O2 and individual nutrients.Our study indicates strong variation in spatial and temporal flux, driven primarily by differences in bottom water characteristics (bottom water DO and temperature), quality of organic matter  at our study sites allowed us to identify bottom water temperature as the key driver of benthic flux variation. These results indicate that current and future predictive models of organic matter remineralization and ecosystem functioning of shelf and slope soft-muddy seafloor habitats should consider bottom water temperature variation. Temperature could have important implications for estimates of seasonal and spatial benthic flux variation, benthic-pelagic coupling, and potential impacts of predicted ocean warming, particularly at high latitudes.S1 Appendix(DOCX)Click here for additional data file.


Human dental pulp inflammation can progress to periapical lesion formation and conventional root canal treatment (RCT) has been the traditional method for disease management. This observational study presents two cases of vital pulp therapy in mature molars diagnosed with irreversible pulpitis and associated with apical periodontitis. In these two clinical cases, the involved teeth had deep carious lesions with a history of spontaneous/lingering pain and radiographic examinations revealed the presence of apical radiolucencies. A conservative miniature pulpotomy (MP) using calcium-enriched mixture (CEM) was performed and the teeth were permanently restored with amalgam. Clinical evaluations indicated resolution of pain 24 hours after treatment; the teeth showed normal vitality, remained asymptomatic and maintained normal function after recall examinations. Furthermore, the 18-month radiographic evaluation showed healing of the apical lesions. Vital pulp therapy using the MP technique with CEM appeared successful in avoiding RCT intervention. These two reports of case outcome suggest that simple MP using a CEM bioregenerative technique may provide a favorable outcome for permanent teeth diagnosed with irreversible pulpitis and associated with apical periodontitis.  Irreversible pulpitis is an inflammatory condition of the dental pulp characterized by long lasting or lingering pain after removal of a specific stimulus. If this inflammatory process progresses, immune responses in the periapical region, can advance and eventually lead to the development of apical periodontitis. It has been demonstrated that periradicular lesions may be detected before the actual necrosis of dental pulp . Scientipy (RCT) . Vital pulp therapy (VPT) is a simple, biologic, regenerative, conservative and economic method that shows a favorable success rate; treatment includes direct/indirect pulp capping and miniature/partial/complete pulpotomy using various pulp capping agents , 8. MiniMineral trioxide aggregate (MTA), which has the ability to induce hard tissue formation, is universally used in VPT  but it hThis clinical report describes successful MP treatment of two mandibular molars diagnosed with irreversible pulpitis and associated with periapical involvement using CEM cement. Case 1A 38-year-old female presented to our clinic with the chief complaint of spontaneous and severe lingering pain provoked by chewing and exposure to cold fluids. The patient’s medical history was noncontributory and clinically, the left mandibular second molar exhibited a deep carious lesion. The involved tooth responded with prolonged exaggerated pain (>10 seconds) to a cold test and demonstrated sensitivity to percussion. Radiographic examination revealed a deep carious lesion and complete root-end apical closure, widening of periodontal ligament and presence of a periapical lesion . AccordiA mouth rinse with 0.2% chlorhexidine gluconate was first initiated and the patient then received inferior alveolar nerve block anesthesia with 2% lidocaine and 1:80000 adrenalin . The tooth was isolated with a dental dam and then caries were completely excavated under magnification. The exposed surface of the dental pulp was lightly brushed with a sterile round diamond bur  using a high-speed handpiece and copious water irrigation; the removal of the pulp did not exceed 1 mm. Hemostasis was achieved by irrigation with sterile saline solution and gentle application of moistened sterile cotton pellets for three min. CEM cement powder and liquid  were mixed according to the manufacturer’s instructions. A small bulk of the cement was gently condensed into the pulpal cavity using dry sterile cotton pellets. After 5 min [Case 2A healthy 40-year-old man was referred to our clinic with a chief complaint of spontaneous and temperature related pain including pain on chewing in the left mandible. Clinically, the mandibular left first molar exhibited an advanced distal carious lesion  and was The patient was recalled after one week and the tooth was clinically asymptomatic. The tooth showed normal vitality to cold testing, with no evidence of clinical or radiographic pathology at the 18-month recall. An important radiographic finding was formation of a hard tissue bridge beneath CEM cement and complete resolution of the apical lesions .As our knowledge in pulpal biology and endodontic biomaterials advances, the initial management of vital teeth with associated apical lesions employing simple VPT procedures may now be considered a potential treatment strategy. VPT is a valuable treatment, particularly for teeth with open apices and vital pulps which are mechanically or cariously exposed -15. UsuaIn this report, two cases with irreversible pulpitis and symptomatic apical periodontitis were treated by MP using CEM bioceramic. Follow-up examinations demonstrated favorable outcomes that maintained pulpal vitality and promoted periapical healing using CEM as a VPT bioceramic. The biological response to VPT is highly influenced by the healing potential of the inflamed pulp as well as the biocompatibility and sealing ability of pulp capping agent . The sucMP is a conservative VPT strategy, which results in removal of injured odontoblast cells, operative debris, potentially infected tissue and exposes deeper layers of the pulp to the proximity of the capping agent where mesenchymal or dental pulp stem cells are present. The advantages of MP include better irrigation and cleaning of the surgical pulp wound from contaminated dentinal chips and accessibility to areas with less pulpal inflammation where hemostasis can be more easily attained. The procedure also creates adequate space for the suitable pulp capping agent or biomaterial, thus producing a superior three dimensional antibacterial seal . Current research data indicates that the hard tissue barriers generated under CEM cement are thicker than those produced by MTA and that the layer of odontoblast-like cells formed underneath the capping material appears to be more consistent in CEM specimens . It has The mechanism by which CEM encourages pulp healing still remains unclear. However, this feature may be attributed to several properties including sealing ability, antimicrobial effect, low cytotoxicity, similarity to dentine, hydroxyapatite formation and the ability to induce hard barrier formation , 27-30. Miniature pulpotomy provides an easy, conservative, and biologically-based treatment that maintains pulpal vitality and shows the ability to resolve emerging apical pathosis under certain conditions. Although more clinical trials with larger sample sizes and longer-term follow-ups may be required, using CEM cement or other bioceramic materials for MP may be considered an alternative option to conventional RCT in symptomatic vital permanent teeth diagnosed with irreversible pulpitis.


Measures of small-area deprivation may be valuable in geographically targeting limited resources to prevent, diagnose, and effectively manage chronic conditions in vulnerable populations. We developed a census-based small-area socioeconomic deprivation index specifically to predict chronic disease burden among publically insured Medicaid recipients in South Carolina, a relatively poor state in the southern United States. We compared the predictive ability of the new index with that of four other small-area deprivation indicators.To derive the ZIP Code Tabulation Area-Level Palmetto Small-Area Deprivation Index , we evaluated ten census variables across five socioeconomic deprivation domains, identifying the combination of census indicators most highly correlated with a set of five chronic disease conditions among South Carolina Medicaid enrollees. In separate validation studies, we used both logistic and spatial regression methods to assess the ability of Palmetto SADI to predict chronic disease burden among state Medicaid recipients relative to four alternative small-area socioeconomic deprivation measures: the Townsend index of material deprivation; a single-variable poverty indicator; and two small-area designations of health care resource deprivation, Primary Care Health Professional Shortage Area and Medically Underserved Area/Medically Underserved Population.Palmetto SADI was the best predictor of chronic disease burden (presence of at least one condition and presence of two or more conditions) among state Medicaid recipients compared to all alternative deprivation measures tested.A low-cost, regionally optimized socioeconomic deprivation index, Palmetto SADI can be used to identify areas in South Carolina at high risk for chronic disease burden among Medicaid recipients and other low-income Medicaid-eligible populations for targeted prevention, screening, diagnosis, disease self-management, and care coordination activities. In the United States persons with chronic conditions are overrepresented in Medicaid , a publiIncreasingly, small-area measures of social and material deprivation  are usedAlthough the Townsend deprivation index, single-variable poverty index, and health care resource deprivation designations are used widely in health planning and evaluation, these measures may not be optimally suited for purposes of community health need assessment in all geographic regions or across diverse population groups. Indeed, a marked trend exists in the development of region/population-specific small-area deprivation indexes for health research. Since 2000, for example, deprivation measures have been constructed and applied in health studies in Quebec, Canada ; Verona,To our knowledge, no socioeconomic deprivation measure has been developed specifically for assessment of a Medicaid population in the United States. To facilitate health policy and programming, we developed a census-based small-area socioeconomic deprivation index optimized to predict chronic disease burden among Medicaid recipients in South Carolina, a largely impoverished Southern state where more than one in five residents are enrolled in the Medicaid system . Based oThe US Census Bureau provides detailed population and housing data at multiple geographic levels. US census and survey data products are updated regularly and are available online at no cost, making them especially valuable to state and local health planners with limited financial resources. We sought to create a census-based index of socioeconomic deprivation to predict chronic disease burden among South Carolina Medicaid enrollees at the ZIP Code Tabulation Area (ZCTA) level. Census-defined ZCTAs are comprised of whole census blocks and spatially approximate USPS five-digit ZIP Code mail delivery areas . These sBased on a literature review, we evaluated a range of Census 2000 population and housing indicators  for inclWe evaluated chronic disease burden among South Carolina Medicaid recipients across five adverse chronic health conditions: cardiovascular disease (CVD); diabetes; end-stage renal disease (ESRD); hypertension; and obesity. These diagnostic categories are among the most common and costliest chronic conditions affecting South Carolina Medicaid enrollees. Chronic disease status for the state’s approximately 1 million Medicaid recipients was determined using primary and secondary diagnosis codes contained in South Carolina Medicaid administrative data sets from fiscal year 2010 (July 2009 to June 2010) . ZCTA-leXi) using Fisher’s Z-transformation to create a set of Z-score variables (Zi) defined for ni observations j = 1,…,ni based on the associated original variableith predictor. This transformation ensures that each of the Z-score variables is standardized to have mean 0 and variance 1. We then calculated the mean correlation of each transformed variable across the set of five chronic condition prevalence rates. The single predictor with the highest mean correlation was the first component Condi)N = 392).In developing the new socioeconomic deprivation index, we sought to minimize the total number of census-based predictor variables while maximizing correlation with ZCTA-level Medicaid chronic disease rates. We scaled each predictor . Two chronic disease burden indicators—one reflecting the presence of at least one chronic condition and the other representing the presence of two or more conditions—were created for a random sample of 5,000 Medicaid recipients geocoded at the ZCTA level using recipient residential address data. Utilizing this sample, we performed logistic regression analyses to evaluate the ability of Palmetto SADI and four alternative measures of small-area deprivation to predict chronic disease burden among Medicaid enrollees based on their ZCTA of residence.AUCOo isAUCi is the area under the curve of the model estimated from the ith bootstrap sample.In these analyses Palmetto SADI, Townsend, and poverty were evaluated as continuous measures; PC-HPSA and MUA/MUP were modeled as binomial variables. We evaluated the performance of all models using the area under the Receiver Operating Characteristic curve (AUC). This statistic summarizes a model’s discrimination, i.e., ability to correctly classify individuals’ chronic disease status. AUC values close to 1 show near perfect discrimination. The model fit was evaluated using the corrected Akaike information criterion measure (AIC). This is a measure of the model’s deviance or difference from a saturated (perfectly predicting) model. Lower values of AIC indicate a preferable model. Bootstrapping was used to estimate standard errors of the AUC and AIC values which allowed assessment of significant differences across models; by this approach, we generated 199 random samples (with replacement) from the original data and re-estimated each of the five models. Approximate standard errors were given by the standard deviation of results from the bootstrap samples. For example, the standard error of the observed area under the curve N = 1,024,034). We further derived two ZCTA-level chronic disease burden counts (presence of at least one chronic condition and presence of two or more conditions). We calculated odds ratios to assess associations between high socioeconomic deprivation as measured by Palmetto SADI, the Townsend index, and the poverty measure (top versus bottom quartile of each continuous deprivation measure distribution) and each of the seven chronic condition indicators . Similarly, we calculated odds ratios to evaluate associations between two binomial measures of health care provider resource deprivation  and each of the seven chronic condition measures.Next, we derived ZCTA-level total Medicaid population and chronic disease counts for each of the five chronic conditions represented in logistic regression analyses, based on georeferenced data for the entire Medicaid population (N = 372). The operationalization of small-area deprivation measures for this set of ZCTAs is summarized in Table We performed Ordinary Least Squares (OLS) and spatial regression analyses to further evaluate small-area deprivation measure associations with chronic disease burden at the ZCTA level, again based on georeferenced data for the entire Medicaid population. Chronic disease prevalence rates were calculated for five conditions . Two chronic disease burden prevalence rates (presence of at least one chronic condition and presence of two or more conditions) also were calculated. As in previous logistic regression analyses, Palmetto SADI and four alternative measures of small-area deprivation were modeled. Preliminary OLS regression analyses with spatial diagnostics (Moran’s I) indicated statistically significant spatial autocorrelation in all models tested. Spatial regression models  were employed to account for the spatial autocorrelation of modeled variables. Spatial regression results are reported. AIC and Schwarz Bayesian information criterion (BIC) values from spatial regressions were used to evaluate goodness of fit for each small-area deprivation model, with lower values indicating preferable models. To ensure greater prevalence rate stability and protect recipient confidentiality in mapped results, all ZCTA-level index validation analyses were restricted to ZCTAs with at least 30 Medicaid enrollees N = 37. The opeP < 0.001) and a significantly lower AIC (P < 0.001) compared to all four alternative models  were highest when Palmetto SADI was used to identify high socioeconomic deprivation Table .Table 4ZConsistent with logistic regression results, spatial regression analyses identified Palmetto SADI as the best small-area deprivation predictor of chronic disease burden  among all Medicaid recipients at the ZCTA level. Compared to the four alternative deprivation models tested, the Palmetto SADI model yielded lower AIC and BIC values, thus indicating the preferability of the derived index Table . SeparatFigure We found significantly higher levels of chronic disease in high- versus low-deprivation ZCTAs, regardless of the deprivation measure used, a result that is consistent with a growing international body of literature indicating higher rates of wide-ranging adverse health outcomes in resource-poor communities , 30, 52.Although small-area deprivation measures have proven useful in geospatial assessments of population health and health inequality, such measures are subject to criticism, particularly in terms of variable selection and index construction . We baseBeyond the recognition of conceptual and methodological challenges associated with the construction of any socioeconomic deprivation measure, several limitations specific to the development, validation, and application of Palmetto SADI should be identified. First, chronic disease status was determined using diagnostic codes in Medicaid administrative data sets. Administrative data are widely used in health studies and the validity of such data sets has been established . More acAs indicated by specific policy or programming requirements, the methodology described might be used to construct census-based socioeconomic deprivation measures for both smaller  and larger  areas. “Tailored” deprivation indexes  also migThe development of Palmetto SADI is consistent with calls for better measures of social and health deprivation that permit the identification and reduction of health disparities across time and space  and thatDecision making to prevent and more effectively manage chronic disease in vulnerable populations requires consideration of factors other than small-area socioeconomic deprivation. Palmetto SADI may be most valuable as a policy and program planning tool when combined with other small-area assessment strategies measuring such factors as healthy food availability , health As a predictor of chronic disease burden among South Carolina Medicaid recipients, Palmetto SADI outperformed all alternative small-area deprivation measures tested. Palmetto SADI can be used to identify areas in South Carolina at high risk for chronic disease burden among Medicaid recipients and other low-income Medicaid-eligible populations for targeted prevention, disease management, and care coordination activities.


In field conditions, plants are often simultaneously exposed to multiple biotic and abiotic stresses resulting in substantial yield loss. Plants have evolved various physiological and molecular adaptations to protect themselves under stress combinations. Emerging evidences suggest that plant responses to a combination of stresses are unique from individual stress responses. In addition, plants exhibit shared responses which are common to individual stresses and stress combination. In this review, we provide an update on the current understanding of both unique and shared responses. Specific focus of this review is on heat–drought stress as a major abiotic stress combination and, drought–pathogen and heat–pathogen as examples of abiotic–biotic stress combinations. We also comprehend the current understanding of molecular mechanisms of cross talk in relation to shared and unique molecular responses for plant survival under stress combinations. Thus, the knowledge of shared responses of plants from individual stress studies and stress combinations can be utilized to develop varieties with broad spectrum stress tolerance. Arabidopsis thaliana plants accumulate sucrose instead of proline  more severely than the individual stresses  increased indicating the synthesis of proline from glutamate. However, under combined stress, a decrease in the activity of P5CS and increase in the activity of ornithine aminotransferase (OAT) was observed suggesting that under the combined stress, proline synthesis occurred from ornithine through ornithine aminotransferase (OAT). The occurrence of proline synthesis through OAT has been observed in plants under some conditions . Cappelli is characterized by higher WUE and lower stomatal conductance compared to Ofanto. The combined stress led to a higher leaf temperature in Cappelli as compared to Ofanto  plants heat stress response was found to be the most dominating (Supplementary Table T. aestivum plants by cDNA amplified fragment length polymorphism (cDNA-AFLP). The study revealed that 380 genes were modulated in all the three stress conditions. Out of 242 up-regulated genes, 44, 15, and 90 genes were specifically induced by heat, drought and combined stress, respectively. While 18 genes were commonly up-regulated in heat and drought stress, 51 and 24 up-regulated genes were common among individual heat, drought and the combined heat and drought stress, respectively. Therefore, in case of T. aestivum, the response under combined stress constituted more of unique than shared response. Similarly, transcriptomic analysis of individual and combined stressed Sorghum bicolor plants  genes, dehydrin, photosynthesis related genes, and genes encoding enzymes involved in pentose pathway and anthocyanin biosynthesis , ROS detoxification enzymes, and enzymes involved in photosynthesis and glycolysis  and thioredoxin peroxidase (TPX). Drought stress led to the induction of catalase (CAT) and glutathione peroxidase (GPX). However, under combined stress, genes encoding alternative oxidase (AOX), GPX, glutathione reductase (GR), copper–zinc superoxide dismutase (CuZnSOD), and glutathione S transferase (GST) were found to be specifically induced.Although combined and individual stress response of plants constituted a number of commonly regulated genes, differences were observed in their expression levels in individual and combined stress conditions i.e., the expression was tailored to combined stress condition. For example, when compared to individual drought and heat stressed plants, combined stressed plants exhibited higher induction of HSP coding genes  protein] was found to be up-regulated exclusively under heat stress. Sb01g021320 (homologous to LEA D34 protein) and Sb05g017950  were found to be up-regulated exclusively under drought and combined stress , small GTP-binding proteins, MYB transcription factors, transporters, aquaporin membrane intrinsic protein  radiation, and nutrient stress dramatically alters the response of plants to biotic stresses. Similarly, interaction of plants with pathogens affects their responses to abiotic stresses. The outcomes of these interactions can either provide resistance or susceptibility toward any of the two stresses depending on the plant species, pathogen and stress intensity.L. esculentum, drought stress reduced infection of necrotrophic fungus Botrytis cinerea  by 50% and suppressed the biotrophic fungus Oidium neolycopersici  infection with concomitant two-fold increase in ABA compared to well-watered infected plants  resulted in increased plant tolerance to drought stress due to de novo xylem formation resulting in enhanced water flow  in a concentration dependent manner , increasing leaf senescence and resulting in premature defoliation , exhibit severe cell death, whereas in the drought acclimated plants the extent of cell death was much reduced  causes pathogen-induced drought in Vitis vinifera by reducing water potential —and resistance (R)—gene mediated defense responses to P. syringae pathovars  and viral elicitors were compromised at high temperatures, allowing increased growth of these pathogens  and Tomato spotted wilt virus . TMV is able to overcome the N-gene mediated resistance at temperatures above 28°C in N. tabacum  and combined drought and TuMV indicated the presence of both shared and unique molecular response in combined stressed plants  which is responsible for synthesis of osmoprotectants galactinol and raffinose. The response characteristically seen under combined stresses in V. vinifera plants consisted of early induction of ABA biosynthesis gene, 9-cis epoxycarotenoid dioxygenase (NCED), and calceneurin B like interacting protein kinase (CIPK). Overall, drought stress and bacterial infection in this case led to activation of ABA mediated drought response that led to enhanced development of disease  infection were more susceptible to viral infection. The authors observed that combination of heat and viral infection led to enhanced transcript accumulation of P3 gene, which is a marker for viral replication  infection, eight also responded to abiotic stresses substantiating them as an important point of cross talk , Capsicum annum WRKY40 (CaWRKY40), MAPK like Gossypium hirsutum MPK16 (GhMPK16), and OsNAC6 have been successfully used to impart biotic and abiotic stress resistance to plants (Supplementary Table A number of transcription factors belonging to myeloblastosis (MYB) transcription factors family e.g., OsMYB4, ethylene responsive factors (ERF) like GmERF and botrytis-susceptible1 (BOS1) are important regulators of different hormone signaling pathways and have a role in imparting biotic and abiotic stress resistance to plants , glutathione-S-transferase F12 (GSTF12), mitogen activated protein kinase 9 (AtMAPKK9), MAPKK16 are common to drought and combined virus and drought stress response of A. thaliana plants subjected to combined drought and TuMV infection (Prasch and Sonnewald, The transcriptome analysis of The stress response mechanism of plants against the abiotic and biotic stress combinations is governed by interaction between responses evoked by individual stresses at both physiological and molecular level. As already stated, the interaction is governed by factors like severity of stresses, age of plant, and whether the plant is tolerant or susceptible to any one of the individual stress. Even plants belonging to same genus may show different molecular response to a stress combination (Aprile et al., The increasing demand for food, deteriorating environmental conditions as well as emergence of newly evolved pathogens have necessitated the development of crops which are better equipped to deal with biotic and abiotic stresses and produce better yields. The fact that occurrence of combination of stresses instead of individual stress are important challenges for crop production demands thorough and intensive studies to understand plants response to stress combinations. A couple of studies in this direction throwing light on shared and unique responses of plants under combined stresses have already been published. It is now required to extend these studies to major crop plants. For proper understanding of plants responses to combined stress which occur under field conditions, the experiments should be carefully designed so that they nearly mimic the field conditions. It is also pertinent to identify the stages vulnerable to the combined stresses by studying the stage specific effect of combined stresses on the transcriptome of different plants. The transcriptomic analysis of plants under combined stresses can generate useful and substantial information regarding common and unique genes modulated under combined stresses. The advances in NGS and high throughput sequence analysis platforms for precise detection and accurate quantification of even small changes in the transcriptome as well as the recently developed genetic engineering tools can be useful in exploring the molecular responses of plants under combined stresses.The reviewer Yasuhiro Ishiga declares that, despite having previously collaborated with the authors Muthappa Senthil-Kumar and Venkategowda Ramegowda, the review process was conducted objectively. The reviewer Ramu S. Vemanna also declares that, despite having previously collaborated with the author Muthappa Senthil-Kumar, the review process was conducted objectively. 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.


A major obstacle to anticipating the cross-species transmission of zoonotic diseases and developing novel strategies for their control is the scarcity of data informing how these pathogens circulate within natural reservoir populations. Vampire bats are the primary reservoir of rabies in Latin America, where the disease remains among the most important viral zoonoses affecting humans and livestock. Unpredictable spatiotemporal dynamics of rabies within bat populations have precluded anticipation of outbreaks and undermined widespread bat culling programs. By analysing 1146 vampire bat-transmitted rabies (VBR) outbreaks in livestock across 12 years in Peru, we demonstrate that viral expansions into historically uninfected zones have doubled the recent burden of VBR. Viral expansions are geographically widespread, but severely constrained by high elevation peaks in the Andes mountains. Within Andean valleys, invasions form wavefronts that are advancing towards large, unvaccinated livestock populations that are heavily bitten by bats, which together will fuel high transmission and mortality. Using spatial models, we forecast the pathways of ongoing VBR epizootics across heterogeneous landscapes. These results directly inform vaccination strategies to mitigate impending viral emergence, reveal VBR as an emerging rather than an enzootic disease and create opportunities to test novel interventions to manage viruses in bat reservoirs. A centrDesmodus rotundus) are the most important source of human and animal rabies, a lethal encephalitis transmitted by the bites of infected animals )Travelling waves have been identified in several other wildlife zoonoses (e.g. Ebola virus , rabies This study demonstrates the power of animal health surveillance systems to generate high-resolution insights into the spatiotemporal dynamics of zoonotic viruses that would probably be impossible to detect relying on studies within a wildlife reservoir alone. The travelling waves that we detected in Peru directly inform management of viral spillover from bats by providing recommendations for where and when livestock should be vaccinated and educational campaigns should be carried out, while creating a unique opportunity to trail experimental interventions in bat populations to block spatially replicated advancing epizootics.


It should be highlighted that ‘cancer’ is a namegenerically given to a widely heterogeneous group of diseases; in comparison to solidtumors, hematological neoplasms show a number peculiar features. Among the most relevant,it should be emphasized the urgency of starting anti-cancer therapy, as often required inhigh-grade hematological neoplasms as acute leukemia and aggressive lymphomas. Specificresearch on this subgroup is warranted, considering the potential prognostic impact of theunderlying neoplasm behavior and center-specific features .Advances in treatment of cancer patients and improved understanding of pathophysiologicalmechanisms behind malignant diseases contribute to increased survival and, consequently,increasing needs of intensive care support for this population. Currently,refusing ICU admissions based only on the type of hematological cancer is no longerjustifiable. Therefore, the intensive care specialty faces new challenges represented byseverely ill patients with malignant underlying diseases requiring, in addition totraditional intensive care, progressively more specific knowledge on oncology.In the past two decades, intensive care units (ICU) increasingly played a relevant role,both treating infective intercurrences and severe complications related to the canceritself and its therapy; and preventive admissions of high-risk patients undergoingchemotherapy. A suitable example of such cooperation is giving urgent intravenouschemotherapy to hematological patients during their ICU stay. This cooperation has beenshown feasible, adding a positive impact on selected patients’ prognosis, including forthose with highly severe diseases.,5These new and progressive challenges require the intensivist to be capable of offering boththe best clinical care and appropriate advice for patient and family members regardingprognosis, therapeutic options and preferences. Therefore, some behavioral changes arerequired, particularly regarding improved cooperation between intensivists andoncologists/hematologists. In addition to influencing the clinical practice and decisionmaking on anti-cancer therapy, this interaction may contribute to appropriately selectpatients who may better benefit from intensive care.,7Now, the challenge is to evaluate if these findings translate into bedside benefits indifferent scenarios. So far, most ofthe studies assessing this population outcomes in Brazilian ICUs have included solidtumors, rendering difficult interpreting the results.Some independent aspects associated to poor prognosis in severely ill hematological cancerpatients have been identified, such as the need of invasive respiratory support, more organdysfunctions, poor performance status and neoplasm organ infiltrations. Although conducted inone single center, this study adds relevant information on the scenario of hematologicalpatients in Brazilian ICUs. The authors observed a high prevalence of cancer, 81.6% of thishematological patients’ sample. This translated into one out every six ICU admissions inthis timeframe. The reported ICU and hospital mortality rates were 47.8% and 73.2%,respectively. Multiple factors may have contributed to such high rates. Among them, thedisease severity upon ICU admission, assessed by SAPS 3 score, was shown to be anindependent mortality predictor. These findings highlight the results of recent studiesstressing the relevance of early intensive care in severely ill patients. Expertrecommendations for widening criteria for admitting hematological cancer patients to theICU and full intensive care within the first days should be aligned with identifying earlystage of critical diseases. Ideally, before organ dysfunctions are installed. Thus, a possible intervention target isapparent, particularly in Brazil, where the access to intensive care is jeopardized bysystem ineffectiveness and/or shortness of intensive care beds. Recently a European study including hematological cancerpatients in 17 ICUs located in France and Belgium identified that ICU admission within thefirst 24 hours after hospital admission is associated to better survival rates incomparison to the a priori anticipated. The reported hospital mortalitywas 39%, and both cancer disease control and health-related quality of life followingdischarge were considered satisfactory, suggesting that appropriate cost-benefit ratio wasachieved.In this issue of RBTI, Barreto et al. report on the two-year assessment of 157hematological disease adult patients admitted to a general ICU in a Brazilian universityhospital. regards the encouraging hospital survivalrates found in patients undergoing noninvasive mechanic ventilation (NIMV). These rateswere similar to those found in patients requiring no respiratory support at all. Yet inpatients failing to NIMV, the mortality rate was high, even above the rate observed inpatients whose first respiratory support option was invasive mechanic ventilation. Theseresults confirm previous results,14 supporting both decisions for electinginvasive respiratory support in selected patients and the importance of earlyidentification of NIMV failure associated features. In the study by Barreto et al. thesubgroup failing to NIMV had more severe respiratory dysfunction and increased use ofhemodynamic support within the first 24 hours following ICU admission; this agrees with theliterature. According to thecurrent knowledge, upon identification of these features, invasive respiratory supportwould be the preferable starting strategy.Respiratory failure is known to be the main cause leading hematological patients tointensive care admission; another relevant contribution by Barreto et al. reportson relevant information about features of hematological diseases in severely ill patients.However, additional research is warranted to better understand the profile of thispopulation of patients, increasingly admitted to Brazilian ICUs. New data on long-termmortality, health-related quality of life following ICU discharge and characterization ofpossibly outcome-related ICU issues are necessary for better assessing the care provided tothese patients.The study by Barreto et al.