Because of the specific anatomical and physiological properties of the human intestine, a specific oxygen gradient builds up within this organ that influences the intestinal microbiota. The intestinal microbiome has been intensively studied in recent years, and certain respiratory substrates used by gut inhabiting microbes have been shown to play a crucial role in human health. Unfortunately, a systematic analysis has not been previously performed to determine the respiratory capabilities of human gut microbes (HGM). Here, we analyzed the distribution of aerobic and anaerobic respiratory reductases in 254 HGM genomes. In addition to the annotation of known enzymes, we also predicted a novel microaerobic reductase and novel thiosulfate reductase. Based on this comprehensive assessment of respiratory reductases in the HGM, we proposed a number of exchange pathways among different bacteria involved in the reduction of various nitrogen oxides. The results significantly expanded our knowledge of HGM metabolism and interactions in bacterial communities. The features of the human gut create two steep oxygen gradients Espey, . A lengtThe combination of intestinal oxygen gradients and various products of food digestion produce a large variety of ecological niches for gut-inhabiting microorganisms. The radial oxygen gradient has been shown to strictly correlate with the spatial distribution of bacterial species in the human gut .Investigations of the human microbiome are also hindered by the abundance of studies that have been based on the analysis of metagenomic data. Metagenome analysis is a powerful technology for determining the composition of the human gut microbiome in healthy and diseased states  and GenomeExplorer program package  was additionally used to search for all of the proteins from one family. Multiple protein alignments were performed using the ClustalX v 2.0 tool  , and all of the protein sequences for the annotated genes in FASTA format are represented in file Sequences S2 in the Supplementary Materials.All of the annotated genes are represented as a subsystem in PubSEED  had a finished status and were definitely complete  are membrane electron-transfer proteins. The gene FAEPRAA2165_01779 (referred to as cyfA) is an extracellular oxygen- and thiol-binding protein, whereas FAEPRAA2165_02924 (referred to as cyfF) is an extracellular flavin-binding protein  another flavin-binding component is used in the Cyf system in these organisms or (2) the extracellular reduction of oxygen is independent of flavins in these organisms. Because F. prausnitzii A2-165 flavin-dependent respiration has only been previously observed under microaerobic conditions . These enzymatic components of reductases bind and reduce electron acceptors and determine the specificity of the entire reductase . An analysis of the phylogenetic tree for this family Figure  to prediE. coli protein YdeP, which does not have a sufficiently clear function  genes; however, the gene for the catalytic subunit nosZ was not found in this genome, although the detected putative operon also contained the gene for the cytochrome c-552/4-like protein. Because c-type cytochromes are often involved in anaerobic respiration  encodes a novel thiosulfate reductase, and the genes of this operon were renamed tsrABCDEFGHIJ.In addition to the expansion of reductase specificities to homologous proteins, we also predicted one thiosulfate reductase that has no known homologs with the same specificity. In the genome of Helicobacter bilis ATCC 43879 contain microaerophilic reductases. Consequently, all of the analyzed aerobic organisms are most likely capable of living in different parts of the intestine under both oxygen-rich and oxygen-limited conditions. Another 92 finished and probably complete genomes were defined as microaerophilic, which indicated that they included microaerobic but not aerobic reductases. Remarkably, 27 of these microorganisms should be strong microaerobes because they include microaerobic reductases and are absent anaerobic reductases. The residual 87 finished and probably complete genomes were defined as anaerobic because of the absence of either microaerobic or aerobic reductases. For incomplete genomes, we confidently identified 4 genomes as aerophilic because of the presence of genes for aerobic reductases. Microaerobic reductases were detected in 19 incomplete genomes; therefore, these genomes were classified as at least microaerophilic because we cannot to be sure about the absence of aerobic reductases in these organisms. No reductases were found in 27 incomplete genomes; therefore, these organisms were classified as most likely anaerobic . Both of these genomes were predicted to be probably complete, but no aerobic or microaerobic reductases were found; nonetheless, this species was shown to be aerotolerant  P. acidilactici contains an unknown aerobic/microaerobic reductase with no homologs among the known aerobic/microaerobic reductases.Another type of inconsistency between our results and the data from the literature was observed for six genomes assigned as facultative anaerobes or microaerophiles. Among this group, we assigned four genomes as most likely anaerobic. These genomes were predicted to be incomplete, and most of the genes for aerobic and/or microaerobic reductases will be found eventually in genome regions that are not currently available. The remaining two genomes belong to the species Thus, among 254 reference genomes, only 29 genomes (11%) are aerophilic, 111 (44%) are microaerophilic, and 115 (45%) are anaerobic. The details of the annotated respiratory reductases are captured as a subsystem “Respiration HGM” in the PubSEED database . These organisms are characterized by large copy numbers of reductases of the same type. Consequently, we identified 12 non-identical copies of Dms reductase in G. pamelaeae. Large numbers of reductases (between 10 and 20) were found in genomes of Enterobacteriaceae, Desulfovibrionaceae, and Ralstonia sp. 5_7_47FAA. In 151 genomes, one to seven reductases were found, and in 79 genomes, no reductases were detected. Two alternative explanations for this lack of respiratory reductases are possible: (1) these organisms contain only unknown reductases, which are not similar to any known reductases, or (2) these organisms exclusively use fermentation for energy production.The largest number of respiratory reductases was found in Various nitrogen oxides are often used as electron acceptors under anaerobic conditions Figure ; therefoRalstonia sp. 5_7_47FAA. Only nitrate (not nitrite) reductases were detected in 11 genomes. For example, in eight genomes of Lactobacillus spp., we found cytoplasmic nitrate reductase NarGHI and nitrite-nitrite antiporter NarK, which is required to nitrate/nitrite exchange between cytoplasm and periplasm. However, 29 genomes from the order Bacteroidales only included genes for periplasmic respiratory nitrite reductase Nrf. The Actinomyces odontolyticus genome also only contains genes for a partial denitrifying pathway, and this bacterium most likely can only reduce nitrate to nitric oxide. The most intriguing combination of reducing reactions was found in Lactobacillus fermentum IFO 3956 and Veillonella spp. These genomes have enzymes for the reduction of nitrate to nitrite and reduction of nitric oxide to nitrous oxide; however, they lack the enzymes for the intermediate stage in which nitrite is reduced to nitric oxide. Overall, 44 of the finished and probably complete genomes that were analyzed have partial pathways for the reduction of nitrogen oxides. All of these organisms can live under microaerobic conditions (see above) and are capable of inhabiting the same zone of the human intestine; therefore, no apparent barrier to metabolite exchange occurs between them. Thus, we propose that organisms with partial pathways could exchange nitrite and nitric oxide  for the iron-sulfur cluster protein, but membrane components were not found. Moreover, although identified TorA proteins . Surprisingly, no inconsistencies were observed when the predictions were compared with the IMG data derived from pathway assertion. Only certain cases of inconsistent results can be explained by the incompleteness of the analyzed genomes, and such inconsistencies will most likely be eliminated after the complete version of the genomes becomes available. Other inconsistencies, such as a lack of aerobic enzymes in the probably complete or finished genomes for organisms identified as aerobes, can be explained by the occurrence of unknown aerobic reductases. One such reductase was predicted in the Lactobacillus spp. analyzed in this research, only 16 shared genes for the microaerobic reductase Cyd (Table cyd genes are clearly distinguishable, the absence of exclusive microaerobic reductase and changes in oxygen tolerance cannot be explained as artifacts of analysis. In the analysis and prediction of features as complex as lifestyle or ecological niche, the maximal number of different methods must be used, and a maximal level of criticism and attentiveness is demanded.The bulk of inconsistencies included the following: a certain microorganism was considered to be an anaerobe according to the data derived from databases or the literature; however, the genomic analysis revealed the presence of genes for aerobic reductases. To prevent such inconsistency, a change of habit is required. First, dividing microbes into only two groups, aerobes and anaerobes, is too crude and usually based on fragmentary data. In most of the analyzed data from the literature (references are shown in Table This study was focused on the analysis of a limited number of respiratory reductases in only 254 reference genomes. Such limitations are not an obstacle for determining a broader picture of respiratory capacities in human gut microbiomes, but they may require inferring certain details. For example, the patterns of respiratory reductases described above can be sufficiently changed after the addition of novel genomes to the reference set. Such possible skewing of results because of these limitations denotes two directions for further analysis. The first direction includes an addition of novel genomes of human gut microbes to the analysis and a re-analysis of draft genomes after their finished versions are complete. The second direction is an analysis of additional respiratory reductases. In this research, we concentrated on the analysis of known reductases and one novel microaerobic reductase, and anaerobic thiosulfate reductase Tsr was predicted occasionally and serendipitously. To improve our understanding of respiration in human gut microbes, systematic predictions of novel respiratory reductases should be performed. In this research, this type of analysis was performed for only one type of respiratory proteins, the catalytic molybdopterin-binding subunits of anaerobic reductases. The analysis of other families of respiratory proteins, such as reductase membrane components or heme and iron-sulfur cluster proteins, may be helpful for the prediction of novel respiratory reductases. The specificities of these novel reductases can be further predicted by various comparative genomics and genome-context based methods or identified by experimental analysis. In addition, the analysis of a family of related proteins can provide additional data for further investigations in evolutionary genomics.The last direction recommended by the present work is to include data on respiration in the genomics-based metabolic models for individual microorganisms and the microbial community of the human intestine. However, before this inclusion, the complete respiratory chains should be reconstructed for a maximal number of genomes. Therefore, in the immediate future, this research will be extended to ATP synthases, respiratory dehydrogenases and their electron donors, and the genes for quinone biosynthesis. The final reconstruction of respiratory chains and their inclusion in metabolic models will further improve our knowledge and understanding of the metabolism of human gut bacteria as well as their interactions with each other and the human organism. We would also be extremely grateful if these predictions or others became a subject of experimental verification.Dmitry A. Ravcheev and Ines Thiele conceived and designed the research project and wrote the manuscript. Dmitry A. Ravcheev performed genomic analysis of the respiratory systems. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


In vitro studies elucidating the correlation between coating additive and DCB performance are however rare but considered important for the understanding of DCB requirements and the improvement of established DCB. In this regard, we examined three different DCB-systems, which were developed in former studies based on the ionic liquid cetylpyridinium salicylate, the body-own hydrogel hyaluronic acid and the pharmaceutically well-established hydrogel polyvinylpyrrolidone, considering coating morphology, coating thickness, drug-loss, drug-transfer to the vessel wall, residual drug-concentration on the balloon surface and entire drug-load during simulated use in an in vitro vessel model. Moreover, we investigated particle release of the different DCB during simulated use and determined the influence of the three coatings on the mechanical behavior of the balloon catheter. We could show that coating characteristics can be indeed correlated with the performance of DCB. For instance, paclitaxel incorporation in the matrix can reduce the drug wash-off and benefit a high drug transfer. Additionally, a thin coating with a smooth surface and high but delayed solubility can reduce drug wash-off and decrease particle burden. As a result, we suggest that it is very important to characterize DCB in terms of mentioned properties in vitro in addition to their clinical efficacy in order to better understand their function and provide more data for the clinicians to improve the tool of DCB in coronary angioplasty.Drug-coated balloons (DCB), which have emerged as a therapeutic alternative to drug-eluting stents in percutaneous cardiovascular intervention, are well described with regard to clinical efficacy and safety within a number of clinical studies.  In recent years, drug-coated balloons (DCB) providing a short-term transfer of the antiproliferative drug paclitaxel (PTX) to the arterial wall have emerged as an upcoming therapeutic alternative to drug-eluting stents (DES) in the field of vascular intervention . In factet al.  . How. Howin v studies  14], ar, arin viin vitro vessel model.The HA/PTX DCB evidence lower drug transfer rates what does not directly correlate with former published data in  where weAs further performance parameter of DCB, we measured the generation of particles ≥10 μm and ≥25 μm during transit of the balloon and upon balloon dilatation in the stenotic model. While the estimated mechanism of drug delivery from DCB indeed involves delivery of drug particles to the inner lumen of coronary arteries, release of drug particles or coating fragments in the coronary arteries might be associated with complications such as occlusions of small vessels or capillaries, possibly leading to micro embolization . For theInterestingly, the particle burden of Cetpyrsal/PTX DCB is even lower in comparison to commercially available DCB with an urea-based coating , tested under same experimental conditions, and corresponding in vivo studies concerning efficacy and safety of the same commercial DCB are favorable , PTX parIn addition to the drug delivery performance, we considered the influence of the different drug-loaded matrices on the mechanical behavior of the balloon catheter as an important factor. If the balloon catheter is only hardly deliverable through the vascular system, mechanical stress and friction would increase which could lead to a severe injury of the vessel lumen. Moreover, the balloon coating might be harmed resulting in increased drug wash-off rates which on the other hand would decrease the drug transfer and furthermore the efficacy of the DCB.During the transit of the tortuous path, we observed a mentionable difference in trackability of the different DCB or in comparison to an uncoated balloon catheter of the same type. The force-distance curves of the trackability measurements reflect the geometry of the tortuous test path. The increasing forces at 80 mm, 115 mm and 140 mm travel distance represent the passage of the balloon at the respective curves of the vessel model .in vivo experiments. Obviously, the PVP/PTX DCB had minor problems entering the stenotic model although we used a conventional guide wire resulting in force peaks between 10 mm and 20 mm.In comparison, differences between the different DCB and the uncoated reference balloon catheter when passaging the stenotic model during the performed crossability test could be determined. We assume that because the coating thickness of the hydrogel-coated DCB, thus the outer diameter of the balloon, is more than doubled, the difference in distal reaction force while passing the lesion is up to 0.04 N higher for the hydrogel-coated DCB . In addiTo summarize we conclude that the studied coating matrices had only a minor influence on the mechanical behavior of the balloon catheter because the coated area respectively the coated balloon is very small in contrast to the balloon shaft and the catheter. As a result we could not detect decreased frictional properties of the hydrogel-coated balloons, as one might have imagined, as the influence of the coated balloon on the catheter is negligible.in vitro vessel model according to ASTM standards. Additionally, we examined the influence of the coatings on the mechanic behavior of the balloon catheter. In particular, we have shown that different additives lead to DCB with different coating morphologies and thicknesses, drug wash-off rates, drug transfer rates and particle burden. As a result, we worked out the following requirements for good DCB performance, being low drug-wash and high drug transfer during dilatation combined with low particle burden: (i) good PTX incorporation within the coating, (ii) thin coating with a smooth surface and (iii) good but delayed water solubility of the coating additive. This kind of solubility is important for the transfer of the drug into the stenosis, on the one hand the coating should not dissolve during tracking or before dilatation but on the other hand a water insoluble coating could generate particles due to friction within the vasculature. Among tested matrices, the IL Cetpyrsal combines all these requirements and thus achieved efficient drug transfer at low particle burden. For sure, further applicability of all presented coating designs concerning sterilizability and storage stability but most notably the in vivo safety and efficacy of the developed DCB however affords further research.Within this study, we evaluated three new coating matrices developed in former studies concerning their coating morphology and coating thickness and investigated their performance during a simulated angioplasty in an To summarize, it is very important to characterize DCB in terms of mentioned properties in addition to their clinical efficacy clarifying the differences between a well and insufficient performing DCB system, e.g. higher drug loss during transit of the balloon than during dilatation. We hereby suggest a series of methods to evaluate either established DCB as well as new developed ones concerning an efficient use, to work out differences between especially the matrices and to provide more data for the clinicians to improve the tool of DCB in coronary angioplasty.S1 TableCoating Thickness of PVP-Coated PEBAX-Tubes without PTX incorporation, the indicated thickness ± SD has been averaged over 8 positions along the PEBAX tube fitted to a stainless steel pin with ten measurement points each.(PDF)Click here for additional data file.


The recurrent Heubner’s artery is the distal part of the medial striate artery. Occlusion of the recurrent artery of Heubner, classically contralateral hemiparesis with fasciobrachiocrural predominance, is attributed to the occlusion of the recurrent artery of Heubner and is widely known as a stroke syndrome in adults. However, isolated occlusion of the deep perforating arteries following mild head trauma also occurs extremely rarely in childhood.Here we report the case of an 11-year-old boy with pure motor stroke. The brain MRI showed an acute ischemia in the recurrent artery of Heubner supply area following mild head trauma. His fasciobrachial hemiparesis and dysarthria were thought to be secondary to the stretching of deep perforating arteries leading to occlusion of the recurrent artery of Heubner.Post-traumatic pure motor ischemic stroke can be secondary to stretching of the deep perforating arteries especially in childhood. The recurrent artery of Heubner (RAH), the junction of the anterior cerebral artery and ACoA or distal A1 segment coursing backward along the A1 segment, arises as a single vessel from the portion near to the anterior communicating artery (ACoA) . ClassicHere we report the case of an 11-year-old boy with a pure motor stroke secondary to an acute ischemic infarction at the RAH supply area immediately following mild head trauma.An 11-year-old boy was brought to the emergency room (ER) because of difficulty in speech and weakness on his right arm, which appeared soon after he hit his head upon falling from his bicycle. He was not unconscious but 20 minutes after falling difficulty in speech and right arm paresis was seen. In his initial neurological examination GCS was 14 and his pupils were reactive to light and isochoric. He had dysarthria and right fasciobrachial hemiparesis with muscle strength of 4/5. The brain CT revealed neither skull fracture nor hemorrhagia of the intra-/extra-axial structures. A brain MRI after 24 hours showed a hyperintense lesion at the left putamen and globus pallidus interna and externa on T2 weighted images , and difDuring the hospitalization period he did not develop any further neurological deficits or convulsive episodes. A physical rehabilitation program was applied and he was discharged ten days later. The latest neurological examination after discharge was performed six months later and he had full muscle strength on the right side. Apart from the possibility of a mild cognitive dysfunction, his school performance was acceptable.Moderate to severe head injuries in children can lead to skull fractures, shearing injury or infarct/oedema , 6. The The deep perforators of the carotid system refers to the anterior choroidal artery and posterior communicating artery, the lateral lenticulostriate arteries that originate from the middle cerebral artery and the medial lenticulostriate arteries and the RAH that originates from the anterior cerebral artery , 11, 12.According to a recent report history, mild head trauma is one of the most frequent risk factors for ischemic stroke of basal ganglia in children . SeveralAlthough the affected area is relatively small, this can cause contralateral hemiparesis with fasciobrachiocrural predominance. Together with this, dysarthria, epilepsy, athetosis, and cognitive and behavioural disturbances are reported . SometimWe concluded that post-traumatic pure motor ischemic stroke can be secondary to stretching of the deep perforating arteries during hemispheric movement at a perpendicular angle, leading to occlusion of RAH.


The internal thoracic artery (ITA) is a descendant branch of the subclavian artery. The former is located bilaterally in both internal sides of the thorax near the sternum and is accompanied by two internal thoracic veins (ITV). From a practical point of view, the ITA (and the ITV) identification is important because these vessels can be injured when pericardiocentesis with the parasternal approach is used. Other advantage of the ITA recognition is to check the patency of the ITA grafts in coronary artery revascularizated patients with new onset chest pain. The purpose of this article is to introduce a simple ultrasonographic technique for recognition of the aforementioned vessels and to highlight the utility of this finding in clinical practice.With linear probe and along paraesternal line, the internal thoracic vessels are recognized on grayscale imaging as an anechoic tubular structure immediately anterior to pleural line. Color Doppler identifies a pulsatile (ITA) and a non-pulsatile (ITV) flow. Spectral Doppler normally shows a high resistance velocity profile in non-grafted ITA and a phasic flow in ITV. A biphasic low resistance velocity profile is normally expected in the grafted and permeable ITA.The ITA (non-grafted) and ITV are recognized routinely along the parasternal line. The operators should identify these vessels when the parasternal approach pericardiocentesis is required and should also consider obtaining spectral Doppler images to check permeability of grafted ITA in coronary artery bypass graft patients with chest pain. The internal thoracic artery  is a prescalenic collateral descendant branch of the subclavian artery. Its origin is medial with respect to the phrenic nerve (PN), and it is posterior regarding the venous brachiocephalic trunk (VBT). The ITA descends and reaches the lower edge of the VBT, where the PN is anteromedially located, and then the ITA is directed forward in search of the medial border of the first rib, where it is folded in an oblique inward journey to reach the vicinity of the lateral edge of the sternum, where it becomes downward again. In most cases, at the level of the sixth rib cartilage, it is divided into its two terminal branches: the superior epigastric and musculophrenic arteries Figure  1]. The. The1]. The importance of the ITA  is largely recognized because it is often used for coronary artery bypass grafting (CABG) to bypass the left anterior descending or the circumflex artery .Another aspect of the ITA (and the ITV) is the possibility of needlestick injury when pericardiocentesis is practiced with the parasternal approach. This one can be especially necessary in anterior located pericardial effusions , when thAlthough the occurrence of these complications have not been studied comparatively with the blind technique versus the ultrasound-guided procedure, in the large study of Tsang et al. , the ITAIn a study of 60 embalmed specimens of anterior thoracic walls obtained from adult Indian cadavers of both sexes, it was observed that the ITA (both the right and left) near their terminal end approaches closer towards the lateral sternal border and suggests precautions while performing emergency pericardiocentesis, preferably using real-time ultrasound guidance .Finally, the ITA identification in post-CABG patients with new onset chest pain adds the possibility to check the permeability of the graft and assess coronary flow reserve ,3],12],[12]3],3],.Previous publications described how to locate the ITA with phased array ultrasound transducers, especially when this vessel is used in CABG, usually bypassing the anterior descending artery ,3],12],[12]3],3],. ActuallIn two publications ,10], th, th10], Technically, with linear probe 5 to 10 MHz) and in longitudinal view, following the pleural line (PL) from anterolateral to near the sternum  if they are properly recognized with ultrasound. Another potentiality of ultrasound identification of the ITA is to, non-invasively, assess the permeability of the ITA after CABG in addition to the evaluation of coronary flow reserve.ITA: internal thoracic arteryPN: phrenic nerveVBT: venous brachiocephalic trunkITV: internal thoracic veinsCABG: coronary artery bypass graftingPL: pleural linePW: pulsed wave spectral DopplerThe authors declare that they have no competing interests.PB observed the cases and collected the videos and conceived and wrote the manuscript. GV contributed to the writing the manuscript. Both authors read and approved the final manuscript.Technique for localization of the internal thoracic vessels.Click here for fileIdentification of the internal thoracic vessels superficial to the pleural line.Click here for fileColor Doppler identification of the ITA.Click here for fileColor Doppler identification of the ITV.Click here for file


Over the years, different operational definitions have been elaborated to identify frail older persons, but none of them has received unanimous consensus. This, in turn, has hampered the clinical implementation of frailty as well as the design of targeted interventions. To overcome the current limitations in the field, a novel operationalization of physical frailty (PF) is proposed which grounds its roots in the recognition of sarcopenia as its central biological substrate. This conceptualization is based on the fact that the clinical picture of PF overlaps substantially with that of sarcopenia. The two conditions may therefore be merged into a new clinical entity, the PF & sarcopenia (PF&S) syndrome, in which muscle loss represents both the biological substrate for the development of PF and a major pathway whereby the negative health outcomes of PF occur. All of the components defining the PF&S syndrome are measurable in an objective manner, which will facilitate its incorporation into standard practice. The recognition of a precise biological substratum for PF&S  also opens new venues for the development of preventive and therapeutic interventions. I.Healthcare systems are increasingly faced with a growing population of older adults characterized by the co-existence of multiple, chronic disabling conditions . The gapIn this scenario, the geriatric syndromes of frailty and sarcopenia have gained special interest due to their association with a number of potentially preventable adverse health outcomes. These syndromes may therefore well serve as paradigmatic conditions around which healthcare systems can be re-shaped and optimized to address the specific medical needs of older persons ,5.impasse might be overcome through the development and validation of a conceptual framework specifically elaborated to facilitate the translation of frailty and sarcopenia in clinical practice. To this aim, the pathophysiological and clinical foundations of the two conditions should be precisely defined, in order to assist in the design and implementation of ad hoc preventive and therapeutic interventions. Such an ambitious task represents a major objective of the «Sarcopenia and Physical fRailty IN older people: multi-componenT Treatment strategies» (SPRINTT) study, a research project recently funded by the Innovative Medicine Initiatives (IMI) [Despite the efforts of many researchers, frailty and sarcopenia are still “orphan” of firmly established operational definitions and evaluation methodologies, and this has so far impeded their translation into every-day clinical practice . The ultes (IMI) .II.In the literature, different criteria have been proposed to identify frail older persons, which mainly refer to two conceptual models: the cumulative deficit approach, proposed by Rockwood et al. , and theAlthough the pathways leading to the development of frailty and its progression towards disability are complex, and encompass a variety of mechanisms besides those centered on muscle structure and function, the frailty phenotype shows substantial overlaps with the clinical picture of sarcopenia . Indeed,Notably, all of the components describing the PF&S model are measurable and quantifiable. The implementation of such a paradigm would therefore allow the accurate operationalization of PF&S, a clear identification of the affected population, and the rapid translation of research findings to the clinical arena. Such a conceptualization would also make PF&S comparable to other chronic degenerative conditions of old age  because mirroring the paradigm of a biological substratum for a specific set of symptoms/signs determining a measurable decreased function . The PF&III.As previously elaborated, the proposed conceptualization of PF&S involves a set of objectively measurable domains that encompass the full spectrum of the condition, from biological substrate to clinical framing . The musAt the clinical level, the manifestations of PF&S  can be measured in an objective manner using specific tools, such as the Short Physical Performance Battery (SPPB) –18. ThisIV.The ongoing demographic transition is accompanied by substantial changes in medical needs and nosographic scenarios, which imposes the development of counteractions against highly prevalent disabling conditions. The traditional paradigm of a “standalone-disease medicine” has clearly become outdated in a clinical world dominated by older persons suffering from multiple chronic conditions and mutually interacting syndromes . On the


Hepatocellular adenoma is a rare benign tumor that was increasingly diagnosed in the 1980s and 1990s. This increase has been attributed to the widespread use of oral hormonal contraceptives and the broader availability and advances of radiological tests. We report two cases of patients with large hepatic adenomas who were subjected to minimally invasive treatment using arterial embolization. One case underwent elective embolization due to the presence of multiple adenomas and recent bleeding in one of the nodules. The second case was a victim of blunt abdominal trauma with rupture of a hepatic adenoma and clinical signs of hemodynamic shock secondary to intra-abdominal hemorrhage, which required urgent treatment. The development of minimally invasive locoregional treatments, such as arterial embolization, introduced novel approaches for the treatment of individuals with hepatic adenoma. The mortality rate of emergency resection of ruptured hepatic adenomas varies from 5 to 10%, but this rate decreases to 1% when resection is elective. Arterial embolization of hepatic adenomas in the presence of bleeding is a subject of debate. This observation suggests a role for transarterial embolization in the treatment of ruptured and non-ruptured adenomas, which might reduce the indication for surgery in selected cases and decrease morbidity and mortality. Magnetic resonance imaging showed a reduction of the embolized lesions and significant avascular component 30 days after treatment in the two cases in this report. No novel lesions were observed, and a reduction in the embolized lesions was demonstrated upon radiological assessment at a 12-month follow-up examination. The incidence of hepatocellular carcinoma is 1 to 3/100,000 inhabitants/year in the general population according to current estimates.Hepatocellular adenoma is a rare benign solid liver tumor of epithelial origin that primarily affects women of reproductive age. The prevalence of this adenoma increased remarkably in the 1980s and 1990s, which was attributed to the widespread use of oral hormonal contraceptivesWe report two patients with large hepatic adenomas who were subjected to minimally invasive treatment using selective arterial embolization of the lesions. Elective embolization was indicated in one case due to the presence of multiple adenomas and a recent history of bleeding in one of the nodules. The other case was a victim of blunt abdominal trauma associated with the rupture of a previously unknown hepatic adenoma.The first case was a 30-year-old female with a history of obesity and oral hormonal contraception use. She complained of sudden abdominal pain in the right hypochondrium without signs of peritoneal irritation in January 2011.Laboratory testing showed a reduced hemoglobin level and negative hepatitis B and C serology. Magnetic resonance imaging of the abdomen showed multiple solid, nodular, hypervascular lesions primarily in the right liver lobe, and a dense, heterogeneous, 10.1 × 6.2cm structure in the caudate lobe, providing interface between the right and left liver lobes, compressing the inferior vena cava, dislocating the middle and right hepatic veins and the portal branches of the right lobe. The features of this lesion were compatible with intraparenchymal hematoma related to a bleeding hepatic adenoma.The patient remained asymptomatic during the outpatient follow-up period, but magnetic resonance imaging three months later revealed multiple hypervascular nodules scattered across both liver lobes, suggestive of new adenomas. Digital angiography of the liver confirmed the presence of multiple hypervascular lesions in the right liver lobes. Selective arterial embolization of the largest lesions in the right liver lobe was performed with 300- to 500-micron calibrated microspheres due to the high risk of bleeding and rupture .Magnetic resonance imaging 30 days after embolization showed reduced embolized lesions and a significant avascular component. No new liver lesions were found on radiological images 12 months later, and the embolized lesions were smaller .Case two was a 23-year-old female using oral hormonal contraception who suffered blunt abdominal trauma after falling two meters and hitting the right hypochondrium against a table. She complained of severe abdominal pain and exhibited signs of peritoneal irritation, skin and mucous membrane pallor, and hemodynamic shock.Laboratory testing showed a reduced hemoglobin level. Initial care in the emergency department, including fluid resuscitation and analgesia, controlled the hemodynamic shock. Computed tomography of the abdomen revealed the presence of multiple solid, hypervascular, nodular lesions, and liquefied hypoattenuating lesions mostly in segments VI and VII. The remainder of the approximately 10 lesions were primarily located in the liver right lobe, and the largest lesion was in segment II/III. The test also identified a large amount of free fluid beside the inferior liver margin and right paracolic gutter that extended to the pelvis. The lower margin of the liver lesions was slightly irregular, which suggested active bleeding into the peritoneum.The patient was transferred to the interventional radiology unit, and digital angiography of the liver was performed to confirm the presence of multiple hypervascular liver lesions. Selective arterial embolization of the largest lesions in the right lobe was performed with 300- to 500-micron calibrated microspheres . The hemThe present article reports two cases of hepatic adenomas that were treated using arterial embolization under two different clinical conditions. Arterial embolization in the first case was an elective treatment following an episode of self-limited, spontaneous hemorrhage. The second case was an emergency treatment due to the hemodynamic instability of a patient with bleeding adenoma following abdominal trauma. The therapy was successful in both cases. Bleeding did not relapse during the 12 month follow-up period, and the size of the treated lesions was substantially reduced.. However, individuals in whom hepatic adenomas negatively impact their quality of life or who exhibit signs of malignant conversion on imaging tests should be indicated for tumor resection.The development of minimally invasive locoregional treatments for the liver, such as arterial embolization and radiofrequency ablation, introduced new approaches for the management of individuals with non-ruptured hepatic adenomas,7. The indication for arterial embolization of hepatic adenomas in the presence of active bleeding is the subject of recent debate in the literature. The reduced mortality rate suggests a role for the transarterial embolization of tumors in the management of ruptured and non-ruptured hepatic adenomas. Follow-up examinations after embolization support the usefulness of this conservative treatment, which might reduce the indication for surgery in selected cases and decrease the morbidity and mortality. The exceptional nature of the treatment of the bleeding hepatic tumor elicited by blunt abdominal trauma further supports the usefulness of arterial embolization under different clinical conditions.The mortality rates for the emergency resection of ruptured hepatic adenomas vary from 5 to 10%, but these rates are reduced to approximately 1% when resection is elective,9. Contrast imaging studies, such as tomography and magnetic resonance imaging, are crucial components of the patients' follow-up examinations.Patients with hepatic adenomas should discontinue oral contraception because these tumors regress after these agents are interruptedIn conclusion, transarterial embolization is an acceptable treatment for hepatic adenomas independent of the presence or absence of bleeding. The use of this therapy facilitates hemodynamic control in cases with bleeding and reduces tumor size. These findings should be confirmed in prospective multicenter studies.


Jaw bone lesions are common pathologic conditions. The role of ultrasonography in evaluation of the extra-osseous lesions is confirmed, however, this imaging modality is not the diagnostic routine for the intra-osseous jaw lesions. The purpose of this study was to evaluate the efficiency of ultrasonography in diagnosis of intra-osseous jaw lesions concerning their size and content and also to study its correlation with the histopathological findings. For this study, 15 patients with intra-osseous jaw lesions in the maxilla and mandible were selected from those referred to the Department of Oral Surgery. Panoramic imaging, computed tomography (CT) or cone beam computed tomography (CBCT) and ultrasonography (USG) were performed for all the lesions. The size of the lesions was measured by USG and then compared with CT or CBCT. Moreover, the correlation amongst the echographic patterns and histopathologic results was evaluated. In 12 cases, size values were in complete agreement with CT or CBCT. The size of 3 lesions could not be measured by the radiologist due to the thickness of buccal cortical plate. Findings of this study suggested that USG might be feasible in estimating the size of intra-osseous jaw lesions with little underestimation. This study also confirmed that ultrasound imaging was a very useful imaging technique which could provide significant diagnostic information regarding the content of jaw bone lesions where the buccal bone thickness was thin enough. Imaging techniques play a crucial role in detecting, diagnosis, treatment and follow-up assessments of intra-osseous maxillofacial lesions. Because of the wide variation of jaw bone lesions, the diagnosis is often complex.-2Following the advancements in technology, various imaging modalities have been introduced to professional use in this field; however, panoramic radiography is still the gold standard for the first-step two-dimensional assessment of jaw lesions among other conventional techniques. Despite Cone beam computed tomography (CBCT) is a more recent alternative to panoramic radiography with the benefit of lower radiation exposure.Meanwhileet al.[et al. in 2002, 2003[et al. in 2006[et al. in 2009,[The number of studies investigating the role of ultrasound in evaluation of bony lesions is limited. In 1996, Lauria . in 2006 assessed in 2009, suggesteThe purpose of our study was to evaluate the intra-osseous jaw bone lesions by means of conventional radiography, CT or CBCT scans, and USG regarding the size and content of these lesions and to compare the correlation between the ultrasonographic findings and histopathologic results. Out of the patients referring to maxillofacial surgeons in Shiraz, 15 cases with intraosseous jaw lesions in the maxilla or mandible were enrolled in this study. After receiving approval from the Ethics Committee, all the patients consented to participate in the study and were informed about the techniques used and any potential risks or benefits. An expert dental radiologist and an expert radiologist-each with a minimum of 15 years of clinical experience- were recruited as observers and to take measurements from the images obtained. After the clinical examination and taking panoramic radiographs  that confirmed the presence of lesion in maxilla or mandible, CBCT  with field of view of 5×4 cm, CBCT Newtom VGi  with minimum and maximum field of view of 6×6 up to 15×15, or spiral CT scan  was taken. The radiographs were viewed and evaluated on a viewing box under normal operating illumination. Panoramic images with low quality conditions were excluded from the project.On order to detect lesions and to evaluate their size and content, ultrasound examination was performed for all patients by means of Medison ultrasound unit  with a 5-13 MHz linear-array probe of 40mm or convex-array probe of 80mm (for lesions>5cm). The ultrasound probe was positioned outside the mouth on the skin overlying the intra-osseous lesion while USG evaluation was performed real-time, measuring the specific slice in which the lesion appeared with its largest dimensions. The USG survey was performed in a room with flexible light on a high-resolution 19-inch monitor of Medison unit. The radiologist was blinded to the previous radiographs. All the patients underwent a biopsy followed by surgical treatment and the specimens were submitted for histopathologic evaluation where a definitive diagnosis was made.  Size of all lesions was initially analyzed by using CT or CBCT. Measurements in CBCT scans were made using accurate inherent software by a maxillofacial radiologist with a precision of 0.1mm.The size of the lesions in CT scans was measured by the scale supported for all slices. Any measurement was applied on the specific slice in which the lesion appeared with its largest dimensions. An expert radiologist also measured the lesion size in the specific USG slice in which the lesion manifested its greatest dimension. The aforementioned data was then compared with CT or CBCT as gold standards. Intraclass correlation coefficient (ICC) between both modalities (US and CT) was then evaluated to assess their agreement regarding size evaluation.To facilitate the comparison with histopathologic results, USG findings were classified into the following 5 groups; anechoic: characteristic of cystic lesions because of liquid content; hypoechoic: characteristic of cystic lesions with dense liquid content  and odontogenic tumors with semisolid content; hyperechoic: characteristic of solid tumors with solid content; mixed echogenic: characteristic of solid odontogenic lesions consisting both cystic and solid components, irregular hyperechoic pattern inside anechoic area, and a unique sonographic appearance of lesions consisting air inside.According to these echographic patterns, jaw lesions in this study were categorized into three groups: cystic (liquid content) manifesting anechoic pattern with posterior enhancement, semisolid (dense liquid content) showing mixed echoic pattern or hypoechoic pattern, and solid illustrating hyperechoic pattern without any posterior enhancement. Echographic pattern of all the lesions was then compared with histopathologic results. In this study, 15 intraosseous jaw lesions were assessed in 15 patients. Ten lesions were located in the mandible and 5 in the maxilla. The size measurement data of all lesions analyzed by CBCT/CT is displayed in As stated in et al.[et al.[As stated previously, only a limited number of studies have investigated the role of ultrasound in diagnosis of jaw bone lesions, particularly in evaluation of the size of these lesions. Our findings regarding the content of lesions were comparable with Lauria et al. and Sumel.[et al. who concTo the best of our knowledge, this study is the first one that has simultaneously evaluated the size and content of the jaw lesions by means of USG and compared it with gold standards (CT or CBCT) and histopathological results. The size of lesions was more regarded in this study.Since CT and CBCT are the gold standards in lesion size assessment, the measIn 3 other cases in which the size of lesions was larger than 5 cm, convex probe was used to cover a larger field of view that could measure the whole lesion. In these cases the results were very close to CT or CBCT results.In three cases, because of thickness of buccal cortical plate, the radiologist could not measure the lesions accurately. The loss of continuity of buccal cortex, not the content of these lesions, was more important in assessment of the size of lesions in USG. All measurements were underestimated using USG compared with CT or CBCT. Based on our findings, this might be due to the projection of acoustic shadow of the bony edges on the lateral walls. Therefore, placement of the electronic calipers for exact measurements is difficult. As mentioned previously, ICC between the two modalities (US and CT) was 0.99, confirming their complete agreement.Echographic pattern in all these lesions were evaluated with USG. Five out of 15 lesions showed anechoic pattern  with respect to their cystic content. These odontogenic cysts included radicular, residual, and dentigerous cysts .A hypoechoic area is an area on the image with fewer reflected echoes, darker than the surrounding tissues which can be an indication of a semi-solid content.-11 ThreeA hyperechoic area has higher echo intensity (demonstrates more reflected echoes) than the surrounding tissues, and it almost always indicates solid content. Three lesions which revealed a hyperechoic pattern were ameloblastoma, mural ameloblastoma, and Pindborg tumor . These tumors had a solid content which was consistent with their histopathologic results .USG pattern of three lesions including two central giant cell granulomas and one odontogenic myxoma was hyperechoic-hypoechoic (mixed echogenic), indicating solid and mixed content of these lesions, 12Figu.Based on our findings, the irregular hyperechoic pattern in anechoic area detected in the case of simple bone cyst was highly suggestive of air similar to the echographic appearance of the air in other parts of the body such as lungs., 13-14 BIn all the aforementioned cases, there was complete agreement between the USG and histopathologic results regarding content assessment.Ultrasound does not eliminate the necessity of using invasive procedures namely aspiration, incisional and excisional biopsies to obtain final diagnosis for intraosseous lesions. However, based on our findings this safe modality is highly recommended whenever possible  prior to any invasive diagnostic procedure for evaluation of intraosseous jaw lesions in size and content. USG is not routinely used to evaluate the size or content of the intraosseous jaw lesions in the literature, therefore, the number of cases in this study seems to be reasonable. Future studies with bigger sample size would help disclosing more feasible aspects of USG in assessment of jaw osseous lesions. Findings of this study suggest that USG might be feasible in estimating the size of intraosseous jaw lesions with an ignorable underestimation. This study confirms that ultrasound imaging is a very useful imaging technique which can give significant diagnostic information regarding the content of jaw bone lesions where the buccal bone thickness is thin enough. Further studies in this field seem inevitable to clarify ultrasound findings.


The allogeneic bone marrow transplantation is a therapeutic weapon for treating severe and drug-resistant autoimmune diseases determining the resolution and improvement in the quality of life. On the other hand autoimmune disorders can develop after a hematopoietic stem cell transplantation (HSCT).AF came to our attention when she was 14 years old for swelling and pain  in the proximal interphalangeal (IFP) joint of the II and III finger of the right hand, painful IFP of the III finger of the left hand accompanied by morning stiffness which lasted for 2 hours and swelling with functional impairment of hands, wrists and knees.Blood count showed increased inflammatory indexes, antinuclear antibody (ANA) positivity (1:640 in Hep2 cells) and rheumatoid factor negative. The RM of the hands showed endoarticular fluid in both carpal bones and in the radioulnar joint with signs of synovitis; synovitis alone was also present in metacapophalangeal joint of the II, III and IV finger of the left hand and II and III on the right, IFP of III finger left and II and III right, carpometacarpal joint of the I finger bilaterally. This clinical findings were characteristic of Juvenile Idiopathic Arthritis polyarticular rheumatoid factor negative subtype according to the ILAR classification.The past medical history of our young girl was particularly important. When she was 18 month old, she was diagnosed of acute lymphoblastic leukemia and started chemotherapy according to AEIOP LAL 9502 protocol. One month after the re-induction phase she presented a disease relapse in the bone marrow so she started a chemotherapy cycle of second degree and the research for an unrelated donor because no familiar HLA-matched donor was present. When she was 3 years old, she underwent hematopoietic stem cells transplantation of peripheral-derived source. Ten months later, during the tapering of immunosuppressive therapy, she presented skin lesions resembling chronic GVHD so she started again immunosuppressive therapy with tacrolimus and mycophenolate mofetil. Later she developed restrictive respiratory syndrome, ovarian insufficiency in replacement therapy and a thyroiditis ultrasonography aspect without hormonal alterations.This important personal history challenged us in the choice of therapy. She started with NSAID (Naproxen) with only partial relief. For the severe polyarticular involvement, after the discussion with the hematologists, we decided to introduce a steroid agent. The girl had a good response but, during steroid tapering, pain and functional impairment of legs and arms reappeared with morning stiffness and swelling of hands. For this reason we finally decided to start Methotrexate.We don't know exactly if juvenile idiopathic arthritis in our patient is a de novo autoimmune disease induced by the transfer of a heterologous immunological system or a rare presentation of graft-versus-host-disease, however MTX therapy was effective and improved the symptomatology with a complete remission after 2 months.None declared.


Cases of ossification and increased bone mineral density (BMD) at sites of bone metastasis following zoledronic acid (ZA) treatment have not been reported. The current study presents the case of a 65-year-old patient with lung adenocarcinoma and bone metastases in the lumbar vertebrae and femurs. Ossification and an increase in BMD at the metastatic sites was achieved following treatment with ZA and irradiation of the bone metastatic sites. The patient was able to maintain a normal lifestyle for over two years, despite the bone metastases. Therefore, as treatment with ZA was demonstrated to improve patient quality of life, physicians should consider this treatment strategy, particularly for the treatment of metastasis in weight-bearing bones. Lumbar vertebrae and femur bone metastases are associated with an increased risk of fracture and a decreased quality of life for the affected individual ,2. Zoled99mTc in the vertebrae , femurs and ribs  after presenting with lumbago and pain around the hip joints for five months. At admission, chest radiography and computed tomography (CT) scans revealed a 3.5×2.5 cm mass in the lower right lobe of the lungs, with multiple intrapulmonary metastases . Bone scand ribs . In addiOssification of the metastatic site in the left femoral neck was observed using plain radiography three months following the initiation of ZA treatment . The BMDZA is a third-generation nitrogen-containing parenteral bisphosphonate prescribed for the treatment of bone metastases caused by solid tumors . In patiet al reported a patient with large cell lung cancer who received ZA treatment and subsequently exhibited marked regression of the thoracic vertebrae following irradiation applied to the metastatic site (et al also presented two cases of patients with NSCLC who were successfully treated with irradiation applied to the metastatic sites, systemic chemotherapy and ZA (There have been a few reported cases of ossification at the metastatic site following administration of ZA . Kawai etic site . Ikeda ey and ZA . Ossificy and ZA . The BMDy and ZA , pediatry and ZA  and chily and ZA . HoweverIn conclusion, the results of the present study indicated that ZA enhanced ossification in the metastatic sites. In addition, an increase in the BMD occurred as a result of the formation of the metastatic bone lesions by irradiation, systemic chemotherapy and ZA. As the patient was able to maintain a normal lifestyle following treatment, the new bone appeared to have similar mechanical properties to that of normal non-metastatic bone. However, whether the increase in BMD with ossification in metastatic sites depends only on the efficacy of ZA remains inconclusive. Nonetheless, therapies that include ZA have been shown to improve the quality of life of patients; thus, should be considered for the treatment of bone metastasis, whilst considering potential side effects, such as BRONJ.


Context. The possibility of cephalic venous hypertension with the resultant facial edema and elevated cerebrospinal fluid pressure continues to challenge head and neck surgeons who perform bilateral radical neck dissections during simultaneous or staged procedures. Case Report. The staged procedure in patients who require bilateral neck dissections allows collateral venous drainage to develop, mainly through the internal and external vertebral plexuses, thereby minimizing the risks of deleterious consequences. Nevertheless, this procedure has disadvantages, such as a delay in definitive therapy, the need for a second hospitalization and anesthesia, and the risk of cutting lymphatic vessels and spreading viable cancer cells. In this paper, we discuss the rationale and feasibility of preserving the external jugular vein. Considering the limited number of similar reports in the literature, two cases in which this procedure was accomplished are described. The relevant anatomy and technique are reviewed and the patients' outcomes are discussed. Conclusion. Preservation of the EJV during bilateral neck dissections is technically feasible, fast, and safe, with clinically and radiologically demonstrated patency. Since 1906, when Crile first described the radical neck dissection [By 1950, with the availability of modern anesthetic techniques and routine tracheotomy, the staged procedure was accepted as feasible and relatively safe. Staged surgery allows the development of the internal and external vertebral venous plexuses and collaterals . Other alternative routes include the deep cervical and the pharyngeal plexuses.Comerota et al.  proposedThe preservation of the external jugular vein (EJV) was first proposed by Leclerc and Roy in 1932  and lateThe EJV is formed by the union of the retromandibular and posterior auricular veins, with the former vessel deriving from the confluence of the internal maxillary vein (directly from the pterygoid plexus that drains the cavernous sinus) and the superficial temporal vein. The EJV courses down and crosses the externocleidomastoid muscle obliquely, just under the platysma muscle on the superficial layer of the deep cervical fascia, before penetrating the fascia and entering the subclavian vein (in 70% of cases) or the IJV (in 30% of cases) .The EJV is easily identified during physical examination, especially in thin patients. The depth of the skin incision over the vein during dissection of the neck requires special attention in order to preserve the vessel. Once identified under the platysma, the vessel can be spared by elevating the skin flaps along the plane of the vein. The EJV is approached during the superior flap elevation in the vicinity of the parotid gland and then preserving it after the dissection and ligature of all its collateral veins down to its junction with the ipsilateral subclavian vein.A 54-year-old male patient presented with a 5 cm wide lesion in the anterior floor of the mouth (FOM) that had persisted for seven months. Physical examination revealed invasion of the ventral portion of the tongue and alveolar ridge and a 3 cm node in the right submandibular triangle; the node was staged as T4aN1M0 squamous cell carcinoma (SCC). The patient underwent a right radical neck dissection, a left selective neck dissection , marginal mandibulectomy, tumor resection, a pectoralis major myocutaneous flap, and tracheotomy.The pathologist's report indicated a grade II SCC, a microscopic positive surgical margin, no metastasis in 97 nodes examined, and one node with paracoccidioidomycosis. Postoperative radiotherapy was delayed because of local complications (mandible exposure and fistula). A needle biopsy done in the third month of follow-up revealed a 1 cm level I metastasis on the left side of the neck. The patient underwent a left radical neck dissection, with preservation of the EJV . This tiThe patient received full postoperative radiotherapy at the primary tumor site and in the neck and did not receive chemotherapy because he developed kidney failure, and with such condition that kind of treatment was prohibitive. In the postoperative period, he developed mild facial edema but no symptoms of increased CNS venous pressure. An imaging scan with Doppler ultra-sound (duplex) in the early postoperative period and at 18 months of follow-up showed a patent EJV and the development of collateral veins . He lostA 43-year-old male patient presented with a tracheotomy tube inserted in Japan because of severe airway obstruction. Investigation revealed an extensive transglottic SCC, with invasion of the base of the tongue, left pyriform sinus, thyroid/cricoid cartilages, and strap muscles, as well as bilateral, clinically positive neck node metastasis (staged as T4aN2cM0). The patient underwent a total laryngectomy, partial pharyngectomy, left radical neck dissection (preserving the left EJV), and a right modified neck dissection  .The pathology report showed a grade III transglottic SCC, three positive nodes out of 33 in the right neck, and five positive nodes out of 12 in the left neck, all with extracapsular invasion. Although the patient developed a pharyngocutaneous fistula, he did not experience any facial edema or changes in his mental status in the postoperative period. An early postoperative duplex scan showed a patent left EJV and a distal flux in the right IJV stump, below the level of the thyrolinguofacial trunk. Three months after surgery, the patient developed bone pain, and a bone scan revealed metastasis in the ribs and right proximal femur. The patient eventually developed retroperitoneal disease with bilateral pleural effusions and died five months after the initial treatment.The first radical neck dissection was done by Crile  and, in Moore and Frazell reported complications in 60% of their cases , with thThe effects of a surgical intervention such as that described here are difficult to predict in a given patient. Although there are several ways of measuring intracranial pressure , many meP < 0.05) with concerning decrease of symptoms such as headache and dizziness due to preservation of the external jugular vein, as well as the reduction of the risk of intracranial hypertension due to preservation of the external jugular vein [A review of the literature in the last 65 years revealed that few reports have dealt with IVJ reconstruction , 7 and elar vein . In the Preservation of the EJV during bilateral neck dissections is technically feasible, fast, and safe, with clinically and radiologically demonstrated patency. Since this procedure has a favorable postoperative outcome, preservation of the EJV is valid for patients submitted to simultaneous or staged bilateral neck dissections for metastatic disease. This procedure merits further investigation to determine whether there is a substantial reduction in the postoperative frequency of facial edema and high CNS pressure.


Dolichospermum circinale and Aphanizomenon flos-aquae) but by taxa, which were present only in low biomass in the samples (Microcystis cf. aeruginosa and Planktothrix rubescens). The phytoplankton successions during the study period revealed an increase of cyanobacterial populations. The findings contribute to the changes that have been investigated in Lake Stechlin since the mid-1990s. The possible reasons behind these developments may be climate change, special weather conditions and an increased nutrient pool.Massive developments of potentially toxic cyanobacteria in Lake Stechlin, an oligo-mesotrophic lake in the Baltic Lake District of Germany raised concerns about toxic contamination of these important ecosystems. Field samples in the phase of mass developments of cyanobacteria were used for genetic and toxicological analyses. Microcystins and microcystin genes were detected in field samples of the lake for the first time. However, the toxins were not produced by the dominant taxa ( The Baltic Lake District in northeastern Germany hosts a multitude of lakes formed during the last glacial period  MCYST-RR variant was detected from this isolated strain. We also screened isolated strains of Dolichospermum circinale (two strains), Aphanizomenon flos-aquae (one strain), Microcystis cf. aeruginosa (two strains) but did not detect any gene responsible for cyanotoxin production . Nevertheless, the presence of Microcystis, with the potential to produce microcystin in Lake Stechlin, could be shown here for the first time by obtaining a sequence of the mcyE fragment from a field sample. Analytical results of field samples also evidenced the presence of microcystins in Lake Stechlin.The occurrence of a microcystin producing genotype of Stechlin . In thisP. agardhii was present in Lake Stechlin along with the dominating Dolichospermum circinale. We could get only sequences of the mcyE gene related to Microcystis from screened clones of the studied field sample. Toxicity is not species-specific in cyanobacteria, and toxin production varies greatly among the different strains of the same species + peak. After the determination of mass values, post-source decay (PSD) measurements were performed directly from the same sample on the template, and microcystins and other peptides were identified by the PSD fragment structure analysis [Lyophilised waterbloom-samples were screened for microcystins by MALDI-TOF MS. For the analyses, five mg of the lyophilised sample was mixed with 200 μL of 50% aqueous methanol, sonicated for five min, and allowed to stand for one h. The samples were examined in the positive-ion mode using a Bruker Biﬂex MALDI-TOF mass spectrometer equipped with delayed-ion extraction. A 337-nm nitrogen laser was used for desorption/ionisation of the sample molecules. Spectra from multiple (at least 100) laser shots were summarised using a 19-kV accelerating and 20-kV reﬂectron voltage. External calibration was applied using the [M−Naanalysis .Aphanizomenon and Dolichospermum taxa. The toxicological analysis revealed different MCYST variants in the field samples. The molecular biological analysis of the mcyE gene fragments did show that Microcystis aeruginosa and Planktothrix rubescens, both minor members of the community, were the microcystin producers in Lake Stechlin. The present study clearly showed that, while focusing on the main players (bloom forming) in lake ecosystems, it is essential to study other cyanobacterial taxa present in the minority. Those should be taken into consideration during the monitoring of toxic cyanobacterial blooms . This is the first report of the mcyE gene fragment of microcystin genes amplified from field samples, and of the simultaneous detection of toxins in the oligo–mesotrophic Lake Stechlin. All lakes of this type were endangered by mass developments of cyanobacteria with potential toxin production due to global or local changes. The findings of this study contribute to the understanding of toxin presence in nutrient-poor lakes.In the oligo- to mesotrophic Lake Stechlin, cyanobacteria mass developments in 2011 and 2012 were dominated by the


Elevated dynamic plantar foot pressures significantly increase the risk of foot ulceration in diabetes mellitus. The aim was to determine which factors predict plantar pressures in a population of diabetic patients who are at high-risk of foot ulceration.Patients with diabetes, peripheral neuropathy and a history of ulceration were eligible for inclusion in this cross sectional study. Demographic data, foot structure and function, and disease-related factors were recorded and used as potential predictor variables in the analyses. Barefoot peak pressures during walking were calculated for the heel, midfoot, forefoot, lesser toes, and hallux regions. Potential predictors were investigated using multivariate linear regression analyses. 167 participants with mean age of 63 years contributed 329 feet to the analyses.The regression models were able to predict between 6% (heel) and 41% (midfoot) of the variation in peak plantar pressures. The largest contributing factor in the heel model was glycosylated haemoglobin concentration, in the midfoot Charcot deformity, in the forefoot prominent metatarsal heads, in the lesser toes hammer toe deformity and in the hallux previous ulceration. Variables with local effects (e.g. foot deformity) were stronger predictors of plantar pressure than global features .The presence of local deformity was the largest contributing factor to barefoot dynamic plantar pressure in high-risk diabetic patients and should therefore be adequately managed to reduce plantar pressure and ulcer risk. However, a significant amount of variance is unexplained by the models, which advocates the quantitative measurement of plantar pressures in the clinical risk assessment of the patient. In patients with diabetes mellitus, foot ulceration as a complication of the disease is associated with significant burden and increased mortality . ElevateA number of studies have investigated the relationship between clinical and structural variables and either in-shoe or barefoot plantar pressure in diverse diabetes populations demonstrating contrasting results –19. ImpoOff-loading plantar pressures is a key target in healing and preventing ulceration in diabetes . After hPatients with diabetes mellitus, peripheral neuropathy, and a recent history of plantar foot ulceration were eligible for inclusion. The study is a cross sectional study and a sub analysis of data collected in the DIAbetic Foot Orthopedic Shoe (DIAFOS) trial . ExclusiEthical approval was obtained from the medical ethics committee of the Academic Medical Centre, University of Amsterdam and all participants provided written informed consent prior to study entry.Demographic information was recorded at study entry including: age, gender, duration of diabetes, glycosylated haemoglobin levels and body mass. Foot deformity was recorded as present or absent with regard to the following: Charcot midfoot deformity, pes planus, pes cavus, hammer toes, claw toes, hallux abducto valgus and amputation . The scoring of deformity was undertaken during physical examination by one of three trained investigators and confirmed by two teams of two trained observers who scored standardised images of the feet and reached consensus on outcome. The presence of midfoot deformity based on Charcot neuro-osteoarthropathy was additionally verified from the medical records of affected patients. Hallux abducto valgus was defined as lateral deviation of the hallux relative to the first metatarsal, hammer toes as hyperflexion at the proximal interphalangeal joints with corresponding apical ground contact and claw toes as hyperextension at the metatarso-phalangeal (MTP) joints with hyperflexion at the interphalangeal joints of the lesser toes. Pes cavus was defined as a high medial-longitudinal arch and pes planus as a lowered medial-longitudinal arch; both were assessed weight-bearing. Presence of abundant callus at study entry and prior ulceration specific to each region were recorded dichotomously.Prominent metatarsal heads, defined as palpable bony prominences, were diagnosed based on physical assessment by one of the three trained investigators. Ankle joint range of motion (ROM) was recorded via goniometry in the supine position. The range of dorsiflexion of the hallux was recorded relative to the first metatarsal shaft; bisection lines were drawn medially along the shaft of the first metatarsal and the proximal phalanx of the hallux and measured with a goniometer in the supine position . Weight-2 and was sampled at 70Hz. Pressures were analysed using Novel multimask software (version 13.3.65) in five distinct regions of the foot based on functional regions and areas susceptible to local deformity: the heel, midfoot, forefoot , lesser toes and hallux. The mean peak pressure from the four trials in each of the regions was used in the analysis as the outcome variable.Barefoot plantar pressures during normal walking were recorded using an EMED-X  pressure platform using the two-step method  from fouOnly variables with a realistic potential contribution to the outcome variable based on indications from the scientific literature were included. Therefore, for example, forefoot deformities were not considered relevant to the heel model . PotentiStatistical analyses were performed using SPSS 20.0 . Demographic and group characteristics were summarised with the mean , median (interquartile range) or number of cases. Differences in peak plantar pressures between presence and absence of dichotomous predictor variables  were assessed for each foot region using Mann-Whitney U tests. Relationships were explored between peak plantar pressures in each region and continuous predictor variables  using Spearman’s correlation. Data were pooled for left and right limbs to increase statistical power and avoid missing relevant feet. The majority of independent predictors entered into the model are at the foot rather than the person level, therefore the anticipated interdependency between limbs is low.Pressure variables with skewed data were log transformed. Univariate regression analyses were used to explore the relationship of each potential predictor variable with peak plantar pressure in each of the five regions of the foot. Significant factors with a value of P<0.20 were included in the multivariable linear regression model with backward selection and considered significant with P<0.05. All results were checked with regard to assumptions of multivariate regression analysis including multicollinearity, normality, homoscedascity and independence of residuals.171 patients  were recruited from 10 Dutch hospitals between January 2008 and October 2010. Four participants were unable to perform barefoot pressure measurement and five participants had below knee or foot amputation affecting one limb and were unable to provide barefoot plantar pressures on one side. Therefore, a total of four participants and an additional five feet were excluded resulting in 167 participants  contributing 329 feet to the barefoot pressure analysis. The included participants had a mean (SD) age of 63 (10) years with mean (SD) duration of diabetes of 17 (13) years. A variety of foot deformities were present with hammer toes being the most prevalent deformity. Twenty-two feet had Charcot midfoot deformity and amputations ranged from partial digital to transmetatarsal. Prior ulceration occurred across all foot regions; only one case occurred in the heel, therefore this variable was not included in the regression analyses for the heel region. Results for demographic and disease related predictor variables are summarised in Barefoot peak pressures recorded were highest in the forefoot region, median (IQR) 830kPa , and lowest in the midfoot region, 141kPa  for the entire cohort. Plantar pressure data were not normally distributed in three of the five regions  and were log transformed prior to regression analyses. A descriptive summary of all outcome variables is presented for the entire cohort and also grouped by categorical predictor variable for each region of the foot in In the univariate analyses, all factors, with the exception of vibration perception threshold, were associated (P <0.20) with peak plantar pressure in at least one of the five studied regions of the foot and were therefore entered into at least one of the multivariate models. In the multivariate regression analyses for each region the following factors were significantly independently associated with peak plantar pressure (P<0.05): glycosylated haemoglobin and pes planus in the heel; Charcot midfoot deformity, body mass, ankle joint ROM, previous ulceration and pes planus in the midfoot; prominent metatarsal heads, claw toes, abundant callus, amputation, ankle joint ROM, previous ulceration and age in the forefoot; hammer toes, non-weight bearing hallux dorsiflexion ROM, and previous ulceration in the lesser toes; prominent metatarsal heads, pes cavus, pes planus, weight bearing hallux dorsiflexion ROM, abundant callus and previous ulceration in the hallux region. The multivariate models were capable of explaining between 6% and 41% of the variance in barefoot plantar pressure. The univariate and multivariate regression results are summarised in The aims of this study were to determine which factors could predict barefoot plantar pressures in a high-risk population with diabetic neuropathy and a history of ulceration and to establish recommendations for foot screening and management in this high-risk group. The predictor variables were capable of explaining between 6% and 41% of the variance in peak pressures in the multivariate regression analyses in the five different foot regions. In the midfoot region the most variation in plantar pressures (41%) was explained of all foot regions, with the most significant contribution from the presence of Charcot midfoot deformity. Furthermore, Charcot deformity showed the highest predictor value (Beta coefficient 0.504) of any factor in any of the foot regions studied. In the forefoot region, 31% of variation in pressure was explained with the largest contribution from the presence of prominent metatarsal heads, followed by claw toes. These factors were expected and confirm findings from previous studies with regard to the role of foot deformity in plantar pressure in diabetic patients ,15,18,19Few global factors were significantly associated with pressure in the multivariate models: age in the forefoot model, body mass in the midfoot model and HbA1c in the heel model. Age related changes to stiffness of the plantar soft tissues  and reduAnkle joint ROM emerged as a significant predictor variable in three of the five models . Limited joint mobility in diabetes, also known as diabetic cheiroarthopathy, is associated with collagen glycosylation resulting in proliferation of peri-articular tissue . ReducedHallux dorsiflexion ROM was a significant predictor in the hallux and lesser toe models. This confirms previous observations of an association between either static or dynamic hallux ROM and plantar pressure ,16,33. SWith regard to the lesser-toe pressures, the largest single contribution came from hammer toe deformity which is in agreement with previous research . InteresThe models were capable of explaining only between 6% and 41% of variance in barefoot plantar pressures in the studied cohort. Adding factors that were not recorded in this study on clinical correlates may improve predictive value. Data on dynamic gait, such as kinematics and kinetics, is one such factor . AnotherThis study was subject to limitations: first, the study was part of a larger trial and pragmatically it was not possible to collect all potential variables that may be of interest in explaining foot pressure. The main interest was to investigate whether prediction of barefoot pressures was possible from standard clinical measures. Secondly, the presence of multiple deformities in the same foot was not controlled for and may have been a potential limitation of the study in contributing to a lower explained variance in the models. Finally, the study focused on a high-risk population, which by virtue of the inclusion criteria may have resulted in masking the importance of certain variables. For example, VPT was not a strong predictor in any of the models, likely because participants who entered the study were all neuropathic. However, the inclusion of only a high-risk sample population was also a key strength of this study due to the morbidity associated with foot ulceration and the high ulcer recurrence rates in this group. Therefore, any new insights add to our current understanding of this high-risk population. Furthermore, this sample of high-risk patients was recruited from ten academic or large community-based Dutch hospitals and therefore the results are generalizable to the high-risk diabetic population.In conclusion, this study has demonstrated poor to moderate prediction of barefoot plantar pressures in diabetic patients who are at highest risk of developing plantar foot ulcers, those with neuropathy and a history of plantar ulceration. Local factors (such as deformity) were better predictors than global features (such as age or body mass) and deformity should therefore be adequately managed to reduce plantar pressure and ulcer risk. While it is acknowledged that no clear data yet indicate that the screening for barefoot plantar pressures can help to reduce the incidence of foot ulceration, the study results suggest that measurement of plantar pressure as a ‘surrogate’ of foot injury should be an integral part of foot screening as no single factor in this study has emerged as an adequate proxy measure.


Mathematical models and computer simulations are useful experimental tools for building and testing theories, assessing quantitative conjectures, answering specific questions, determining sensitivities to changes in parameter values, and estimating key parameters from data. Understanding the transmission characteristics of infectious diseases in communities, regions, and countries can lead to better approaches to decreasing the transmission of these diseases.The present special issue aims at providing a platform for the discussion of major research challenges and recent achievements regarding the computational aspect of theoretical models describing human diseases associated with infectious pathogens. Appropriate mathematical models with new insights, relevant analysis, and validation with the help of numerical simulations are discussed.Y. E. García et al. in Mexico in “A Bayesian Outbreak Detection Method for Influenza-Like Illness” considered a theoretical eruption detection method for influenza-like illness from surveillance data. It is well known that epidemic outbreak detection is an important problem in public health. The development of reliable methods for outbreak detection remains an active research area. During the early phase of the outbreak, surveillance data changes from autoregressive dynamics to a regime of exponential growth. Bayesian model selection and Bayesian regression are used to identify the breakpoint. In particular no free parameters need to be tuned and historical information regarding the spread of the disease is incorporated into the model. Furthermore synthetic, seasonal, and pandemic outbreak data are analysed in order to show and discuss the performance of the method.F. Nyabadza et al. in South Africa and USA in “The Implications of HIV Treatment on the HIV-Malaria Coinfection Dynamics: A Modeling Perspective” investigated the scenario of hosts harbouring multiple pathogens at the same time in disease epidemiology. Multiple pathogens have the potential for interaction resulting in negative impacts on host fitness or alterations in pathogen transmission dynamics. They developed a mathematical model describing the dynamics of HIV-malaria coinfection. Additionally, they examined the role treatment  plays in altering populations' evolution. The model consists of 13 interlinked equations describing multiple aspects of HIV-malaria transmission and treatment. Qualitative analysis of the model including positivity and boundedness of solutions was performed. Furthermore, reproduction numbers corresponding to submodels were evaluated and the long-term behaviour of the submodels was investigated.Z. Shi et al. in USA in “Mathematical Model of Innate and Adaptive Immunity of Sepsis: A Modeling and Simulation Study of Infectious Disease” examined a mathematical model of a systemic inflammatory response to infection known as sepsis. Both innate and adaptive immunities are included, and simulated results have shown that adaptive immunity has significant impacts on the outcomes of sepsis progression. Further investigation has found that the intervention timing, intensity of anti-inflammatory cytokines, and initial pathogen load are highly predictive of outcomes of a sepsis episode. Sensitivity and stability analyses were carried out using bifurcation analysis to explore system stability with various initial and boundary conditions. The stability analysis suggested that the system could diverge at an unstable equilibrium; after perturbations the maximum release rate of tumour necrosis factor by neutrophil falls below a certain level. This finding conforms to clinical findings and the existing literature regarding the lack of efficacy of anti-TNF antibody therapy.+T Cells” and “Modelling the Aggregation Process of Cellular Slime Mold by the Chemical Attraction,” the authors made use of homotopy decomposition method (HDM) to find approximate solutions of nonlinear differential systems. Numerical solutions are given and some properties show evidence of biologically practical reliance on parameter values. The reliability of HDM and the reduction in computations give HDM a wider applicability.Other papers in this special issue cover applications of fractional differential equations arising in the modelling of human diseases associated with pathogens. In the papers “On the Mathematical Analysis of Ebola Hemorrhagic Fever: Deathly Infection Disease in West African Countries” and “Model of Break-Bone Fever via Beta-Derivatives,” A. Atangana et al. made use of a new derivative called beta-derivatives. They used novel fractional analytic methods to show the existence and uniqueness of the associated evolution equations. Stability of the steady states was investigated using Lyapunov methods. In particular, iteration methods were considered in order to approximate the solution and project its long-term behaviour. In the papers “Computational Analysis of the Model Describing HIV Infection of CD4The editorial board trust that the set of papers accepted in this special issue will provide a benchmark for future theoretical analysis in this fast evolving research area.


The pedunculopontine tegmental nucleus (PPTN) has been thought to be involved in the control of behavioral state. Projections to the entire thalamus and reciprocal connections with the basal ganglia nuclei suggest a potential role for the PPTN in the control of various rhythmic behaviors, including waking/sleeping and locomotion. Recently, rhythmic activity in the local field potentials was recorded from the PPTN of patients with Parkinson's disease who were treated with levodopa, suggesting that rhythmic firing is a feature of the functioning PPTN and might change with the behaving conditions even within waking. However, it remains unclear whether and how single PPTN neurons exhibit rhythmic firing patterns during various behaving conditions, including executing conditioned eye movement behaviors, seeking reward, or during resting. We previously recorded from PPTN neurons in healthy monkeys during visually guided saccade tasks and reported task-related changes in firing rate, and in this paper, we reanalyzed these data and focused on their firing patterns. A population of PPTN neurons demonstrated a regular firing pattern in that the coefficient of variation of interspike intervals was lower than what would be expected of theoretical random and irregular spike trains. Furthermore, a group of PPTN neurons exhibited a clear periodic single spike firing that changed with the context of the behavioral task. Many of these neurons exhibited a periodic firing pattern during highly active conditions, either the fixation condition during the saccade task or the free-viewing condition during the intertrial interval. We speculate that these task context-related changes in rhythmic firing of PPTN neurons might regulate the monkey's attentional and vigilance state to perform the task. The rhythmic firing of neurons in the reticular activating system is thought to be essential for the neural encoding process . One of Another line of evidence for the rhythmic activity is emerging from recording the population activity of the PPTN in Parkinson’s patients. Treatment with levodopa in patients with Parkinson's disease led to the appearance of alpha band activity (~10 Hz) in the local field potential recorded from the PPTN , 14. FurWe previously recorded single unit activity of PPTN neurons with high temporal fidelity in healthy monkeys during reward conditioned visually guided saccade tasks, and reported task execution- and reward prediction-related tonic increases or decreases in firing rate of PPTN neurons , 17. OneHere we investigated firing dynamics of single PPTN neurons by reanalyzing data to focus on the regularity of firing during different behavioral conditions such as an active fixation condition during the saccade task (FX-condition) where monkeys predicted given reward size  by the shape of the fixation target (FT), and a free viewing condition without any task demand during the intertrial interval (ITI) periods (FV-condition). The tendency of PPTN neurons to fire regularly and rhythmically was assessed using the coefficient of variation (CV) of interspike intervals (ISI) and spectral analysis, respectively.Macaca fuscata; monkey 1, male; monkey 2, female) while they executed a reward-conditioned, visually guided saccade task [Guidelines for the Care and Use of Laboratory Animals. This study was approved by the Committee for Animal Experiments and Ethics at the Osaka University (Permit Number: FBS-13-006). Animals were obtained from Primate Reseach Institute of Kyoto University. Each monkey was kept in individual primate cage at the animal facility in Osaka University, with environmental enrichment (toys) under 12 hour light/dark cycle. They had visual, auditory and olfactory contact with other monkeys. Food and water were available ad libitium at the home cage after each training and recording session. Additionaly, the monkeys were fed a variety of vegetables, fruits, and grains everyday. To assess the monkeys' health, their weight was routinely monitored and expert veterinarian assistance was available on site.We reanalyzed previously recorded PPTN neuronal activity data obtained from 2 Japanese macaque monkeys . Eye position was sampled at spatial resolution of 0.05° and time resolution of 1 ms using search coil method. The visual stimuli were presented on the screen of a 21-inch cathode ray tube monitor at 28 cm from the monkeys.The monkeys performed a reward-conditioned visually guided saccade task to increase the range of the monkey’s arousal and motivational level to perform the task as described in detail previously . BrieflyWe used tungsten microelectrodes  for recording the activity of single neurons. Single unit activities were isolated by the shape of action potentials using a template matching algorithm  and the timing of each spike that matched a spike waveform template were recorded.The recording chamber was aimed at the PPTN of the monkeys based on MRI  under general anesthesia with ketamine hydrochloride (10 mg/kg) and pentobarbital  . The eleTo comfirm the locations of the recorded neurons, the monkey 2 was deeply anesthetized with pentobarbital  at the conclusion of the recording experiments, and the brains were perfused with 10% formaldehyde. We reconstructed the recording sites for both monkeys from the readings of the micromanipulators and those of the guide grids of the recording chamber referenced to a single marker site  and MRI Our database consisted of 466 neurons in monkey 1 , and 171 neurons in monkey 2 . Only neurons for which there were data from over 40 trials and over 150 spikes were included, which slightly biased our sample toward neurons with high average firing rates. We analyzed the firing pattern of PPTN neurons during 2 different behaving conditions, such as active fixation condition during the saccade task  and free viewing condition during ITI . We calculated the firing rate and CV as the reciprocal of mean and the coefficient of variation during 5 successive ISI window, respectively.The mean firing rate and CV were calculated by moving the ISI window in 1 ISI step throughout the analyzing epoch across all trials. A high CV was indicative of a random and irregular firing pattern, and a low CV of a rhythmic and regular firing pattern , 22.To quantify the regularity of firing, we performed simulations of Poisson-like random spike trains with a refractory period of 5 ms for a range of mean firing rates between 5 and 100 spikes/s to determine the theoretical relationship between firing rate and CV. We used the results of this simulation as a theoretical borderline (mean—2 SD) to distinguish irregular and regular firing patterns.The modulation index of the mean firing rate and the CV were calculated for each neuron as:A positive value of the modulation index for firing rate and CV indicated an increase in firing rate and CV, respectively, during the FX-condition compared to the FV-condition.The periodicity and frequency characteristics of PPTN neurons were also quantified using Fourier analyses. The power spectra of the spike trains were calculated using the Fourier transform of the spike trains separately for the FX- and FV-conditions. A neuron was considered to fire periodically if a significant peak was found in the power spectrum between 4 and 150 Hz. For every peak we calculated the threshold from the mean and 4 SD of the power spectrum (200–500 Hz).p < 0.05, Wilcoxon rank-sum test) [We also analyzed the relationship between the changes in firing regularity and changes in firing rate that we previously reported , 17. We um test) .We also investigated the relationship between spike durations and the rhythmic firing of neurons, because previous studies reported that the neurotransmitter released by PPTN neurons might be related to their spike durations , 24. SpiPrevious studies suggested that firing dynamics might play an important role in neuronal computation , 26. We We then analyzed the firing regularity of PPTN neurons by calculating the CV of the spike trains . A high To further investigate the firing regularity of PPTN neurons, we then analyzed the relationship between the firing rate and the CV Fig  and 2B. Then we analyzed how the relationship between the changes in firing rate and firing regularity of individual neurons for the behavioral task changed from the FV- to FX-conditions. Then we analyzed and compared changes in firing dynamics under different conditions that predicted large or small reward during the FX-condition. We previously reported that a group of PPTN neurons showed significant changes in firing rate correlated with the predicted size of given reward and motivation to perform the task , 17. TheThe rhythmic firing of neurons is thought to be essential for the neural encoding process . TherefoSome neurons exhibited a periodic firing pattern either during the FX-condition (N = 72) or the FV-condition (N = 24), while the others fired periodically throughout the entire behavioral conditions (N = 46). Then we summarized the relationship between the periodic firing patterns and task-related changes in firing rate between the FX- and FV-conditions . GeneralAs shown in the analyses of recordings from the example neuron in p >0.05). On the other hand, within the periodic firing neurons, the frequencies of periodic firing were inversely correlated with the duration of spikes, during both the FX- and FV-conditions , but others exhibited high frequency firing up to 100 Hz . These nWe previously reported that many PPTN neurons showed a tonic increase or decrease in firing rate related to task execution and reward prediction , 17. HerClassically, the ascending reticular activating system including the PPTN is thought to play a role in controlling the sleep/wake state –9. ActuaThese context-dependent changes in firing rates and firing patterns of PPTN neurons suggest that external inputs play a role in triggering and maintaining the rhythmic firing of PPTN neurons. For the excitatory inputs, the primate PPTN receives direct cortical inputs from multiple motor-related areas of the frontal lobe . FurtherOn the other hand, for the inhibitory inputs to the PPTN, there are massive GABAergic inhibitory projections from the basal ganglia output nuclei, including the globus pallidus and substantia nigra pars reticulata , 38. TheFor non-rhythmically firing PPTN neurons, there were also changes in firing regularity with changing firing rate. The changes in firing regularity reflect the changes in firing rate between the FX- and FV-conditions, such that when the firing rate becomes higher the CV becomes lower . This reThe PPTN is a heterogeneous nucleus and contains cholinergic, glutamatergic, and GABAergic neurons , 3. We fIn previous studies, the neurotransmitter of recorded PPTN neurons might be related to their spike durations , 24; thoWe found that periodic firing neurons were distributed slightly caudal part of the PPTN  and exhiThe PPTN is critically related to Parkinson’s disease. Previous studies reported the loss of PPTN cholinergic neurons in Parkinson's disease, and experimental lesions of the PPTN of normal monkeys produced contralateral hemi-parkinsonism . Thus, tThe PPTN has recently been introduced as a new therapeutic target for deep brain stimulation in Parkinson's patients , and effThe single spike rhythmic firing of PPTN neurons, here we reported, should be a basis of the rhythmic population activity. One possible explanation is that the phases of each periodic single unit firing were aligned and might produce oscillatory population response. Although, in our single unit recording study, we have no data about synchronized activity; some previous findings support the oscillatory firing of PPTN neurons, such as the presence of electrically coupled pairs of neurons in the PPTN , and the