Malaysia Airlines flight 17 crashed on 17 July 2014 while flying over an area of armed conflict in eastern Ukraine. The first forensic trace evidence was collected after the human remains were transferred to a safe location in the Netherlands for identification and repatriation. Disaster victim identification processes were therefore undertaken in concert with the forensic investigation. Prior to these processes, X-ray and computed tomography scanners were used to reveal foreign objects in the human remains, and a large number of these fragments were recovered after the forensic triage. A distinct group of metal fragments was identified as being potential remnants of high-energy foreign objects. Forensic analysis revealed that they were explosively deformed unalloyed steel fragments, some of which had shapes consistent with pre-formed metal fragments found in a 9N314M warhead used in Buk SA-11 missiles. Furthermore, thin film deposits of cockpit glass and aluminium were identified on the most heavily deformed side of some of the explosively deformed metal fragments, suggesting they came from outside the airplane. These findings supported early suspicions that Malaysia Airlines flight 17 was struck by a Buk SA-11 missile.A multidisciplinary approach for combined identification and forensic investigation of human remains after a mass fatality incident.The combined use of complementary X-ray techniques for detection and provisional characterization of foreign objects in human remains.The use of sensitive and highly discriminative state of the art techniques for analysing foreign objects recovered from human remains. Hours after the crash, news reports showed images of wreckage containing multiple puncture holes and indentations.Malaysia Airlines flight 17 (MH17) was a scheduled passenger flight from Amsterdam to Kuala Lumpur. On 17 July 2014, MH17 crashed in an area of armed conflict in eastern Ukraine, killing all 283 passengers and 15 crew members. Contact with the Boeing 777-200ER aircraft was lost when it was approximately 50 km from the Ukraine–Russia border. This was Malaysia Airlines’ second aircraft loss in 2014 after the disappearance of Flight 370 on 8 March. Wreckage of the MH17 aircraft was spread across a 50 kmAccording to the International Civil Aviation Organization, the country in which an aviation incident occurs is responsible for the investigation into its cause, but that country may delegate the investigation to another state . In thisin situ. Materials and traces of relevance are then collected for further examination. In the case of MH17, two main problems existed. First, the crash site was in an area of armed conflict, making it unsafe for investigators to view the wreckage in situ. Second, the site was unguarded and therefore open to evidence tampering.To gather technical evidence from a crash site, investigators normally have the opportunity to visit the site and examine the debris In the days following the crash, it was unclear if and when the site would be accessible to forensic investigators. The first and at that time the only opportunity to look for evidence was during the identification of human remains. Therefore, the identification process was considered part of the criminal investigation. Prior to identification, the human remains were searched for traces that might be of forensic importance.The first coffins containing human remains were flown to the Netherlands on 23 July 2014. The identification of passengers and crew took place at the Korporaal van Oudheusden barracks in Hilversum and was coordinated by the National Forensic Investigation Team of the Netherlands. On 26 July, the first victim had been identified.By 5 December 2014, the Dutch-led disaster victim identification (DVI) team had identified 292 of the 298 passengers and crew. Later searches of the crash site led to the identification of four more passengers by April 2015. Sadly, the remains of two Dutch citizens on the flight have not been recovered.There were two main objectives for the teams working in Hilversum: (i) forensic investigation and (ii) victim identification. In the Korporaal van Oudheusden barracks in Hilversum, a forensic triage was used to sort remains for direct identification or identification after a forensic investigation. A forensic triage is a process for collecting, sorting and prioritising evidence of a crime when limited resources must be allocated. At the start of the triage, it was unclear what had caused MH17 to crash. Different scenarios were proposed, including: (i) an accident due to technical problems, (ii) an explosion inside the airplane caused by an improvised explosive device, (iii) an explosion outside the airplane caused by a missile and (iv) damage caused by 30 mm rounds or air-to-air missiles fired by a Sukhoi SU-25 jet.Identification of human remains began in Donetsk the day after the crash. The local pathologist took photographs, wrote descriptions, took bone samples from 12 bodies for DNA testing. Subsequently, the decision was made to continue the identification process in the Netherlands, and the human remains and DNA samples were transferred there . The idePrior to identification, selected human remains underwent a “forensic investigation” involving a search for traces of forensic relevance in a manner designed to avoid impacting the prioritised DVI. In addition, autopsies were carried out on a limited number of bodies. The forensic investigation and autopsies were carried out by staff of the Netherlands Forensic Institute (NFI).To facilitate the detection and recovery of foreign objects with minimal disruption to the DVI, an additional “forensic process” line equipped with computed tomography (CT) and X-ray scanners was introduced. After the coffins arrived in Hilversum, they were placed in cold storage containers. At the start of the process, the contents of each coffin were screened by military staff for chemical and biological hazards. Because of the formaldehyde treatment of remains in Ukraine, all staff wore gas masks. After the safety screening, post-mortem CT (PMCT) scans of the body bags from the coffins were made, following the process presented in During the triage, 227 coffins were processed, of which 156 were selected for direct identification and 71 underwent forensic examination . From apForeign objects in the human remains were detected using a medical CT scanner and a customs dual-energy X-ray scanner. An X-ray beam undergoes an attenuation that depends on the density and thickness of the object through which it passes. CT reconstructs three-dimensional (3 D) images from many two-dimensional images acquired by directing X-rays through an object at different angles. Industrial CT scanners rotate the object in the X-ray beam, whereas medical scanners rotate the X-ray tube around the body .PMCT has been used several times in recent DVI processes and become an integral part of autopsy practice . In a foBaggage and cargo X-ray scanners are used for scanning luggage and cargo for customs and security purposes. Similar to medical X-ray scanners, an X-ray beam undergoes attenuation dependent on the density and thickness of the object in the direction of the beam. Baggage and cargo scanners mechanically pass the object through the beam, and the transmitted X-rays are detected using a linear array, which builds up an image that can be seen by the operator.eff) of the material at each pixel location and is recognised as organic, inorganic or metallic. Most manufacturers use shades of orange to identify organic material (Zeff < 11) and shades of blue or purple to identify heavier elements (Zeff > 18) such as iron, steel, gold and silver. In the intermediate range (11 < Zeff < 18), shades of green identify materials such as glass, aluminium and some plastics, while materials that are impenetrable by X-rays appear black.In a dual-energy system, the detector is constructed in two layers to distinguish low- and high-energy X-rays . CompareDuring the triage, a self-made calibration standard was placed on top of the coffins and scanned simultaneously with the remains. The standard consisted of a Perspex strip embedded with 3-mm thick pieces of stone, aluminium alloys (two types), stainless steel, brass, copper, tungsten and lead. To reduce the number of objects detected, the standard settings of the scanner were adjusted so that aluminium, glass and bone fragments appeared orange and metals heavier than aluminium appeared green or blue. In Hilversum, a customs dual-energy system was operated at a tube voltage of 160 kVp.The CT scans identified foreign objects in a large number of the bodies of passengers and crew members. After X-ray scanning, 15 bodies underwent a full or limited autopsy and 56 underwent external and internal examinations to remove foreign objects. After identification, two further autopsies were performed at the NFI, one on the remains of a relief flight crew member and another on a cabin crew member.Upon removal of the foreign objects, a distinction was made between material found on the remains and that found within. Distinctions were also made between material found under and within the skin and between magnetic and non-magnetic materials. Objects with no obvious connection to the incident  were not removed for forensic purposes. Approximately 540 foreign objects with different origins were removed from approximately 33 human remains and sent to the NFI for further examination.Most foreign objects were detected in the remains of two flight crew members and a cabin crew member, all of whom were concluded to be in the cockpit at the time of the crash. In the remains of one flight crew member (flight crew member #1), about 200 foreign objects were detected. In the remains of the other flight crew member (flight crew member #2) and the cabin crew member, more than 100 foreign objects  were detected. During autopsy, approximately 220 foreign objects were removed from these three bodies for forensic examination. Based on the autopsies, it was concluded that the three crew members sustained multiple fatal injuries associated with the high-velocity impact of metal fragments.Relatively few foreign objects were detected in the remains of the other 295 passengers and crew. The passengers and other crew members suffered multiple fractures consistent with in-flight disintegration of the airplane and ground impact. The centre of the airplane was severely damaged and burnt. Consequently, most human remains from this section were fragmented and partly digested by fire. Fragmentation, fire and possibly decomposition and animal scavenging explain why few or no human remains were found for some of the passengers.When an explosive charge is detonated, the resulting shockwave causes fragmentation and very severe damage to all materials next to the seat of the explosion. Fragments are expelled at very high speeds by the hot and rapidly expanding gases resulting from the explosion. The main signatures of an explosion are sooting, heat scorching, melting, penetration, cratering (pitting) and the formation of heavily deformed fragments bearing characteristic morphological features .Fragments removed from the human remains were first screened for explosive residues using an ion-mobility spectrometer. They were then washed sequentially with methanol and ultrapure water to extract the organic and inorganic explosive residues, respectively. The results of the explosive residue analysis were not the subject of this study and are therefore not discussed further. After the explosive residue extraction, remnants of human tissue on the fragments were removed by washing in an aqueous enzyme solution. The cleaned fragments were then air-dried and photographed using a low-power microscope. Preliminary examination of the fragments involved measuring their weights and sizes, recording their magnetic properties and inspecting their surfaces for markings, paint and signatures of an explosion. Sooting was not a very discriminative signature because a large part of the airplane had been on fire.To reveal morphological features and elemental compositions, a selected number of foreign objects were investigated using light microscopy and either a Quanta 400 ESEM  or Quanta 3 D FEG 600 dual beam (FEI Company) scanning electron microscope (SEM). A dual beam SEM incorporates both a SEM and a focused ion beam (FIB) in a single system. The SEM accelerating voltage was 15–25 kV, depending on the particle characteristics and analytical goals. For chemical analysis, both SEMs were equipped with an energy-dispersive X-ray microanalysis system (EDS) comprising a silicon drift detector  and AZTEC or INCA software (Oxford Instruments). SEM-EDS analyses were typically performed in the low vacuum (10–20 Pa) mode of the SEM. The focused ion beam FIB of the Quanta 3DFEG 600 microscope was used to sputter material from the surface and make cross-sectional cuts in the surface of some fragments. The electrons induced by the ion beam were used to create an image of the cross sectional cuts.The elemental composition of some foreign objects was analysed in greater detail using laser ablation inductively coupled plasma mass spectrometry (LA-ICPMS). This is an highly discriminative analytical technique by which very small quantities of material are ablated and brought into a gas stream as an aerosol. In an argon plasma the aerosol particles are evaporated, atomised and ionised. Subsequently, the ions are identified and quantified with a mass spectrometer.Anti-aircraft weaponry and improvised explosive devices packed with bolts or nails spread shrapnel and heavy objects towards their target. Therefore, the forensic investigation focused on heavier materials such as steel, tungsten and lead.A CT topogram and X-ray image from flight crew member #1 are shown in Some of the foreign objects recovered from the remains of flight crew member #1 are shown in One of the fragments secured from flight crew member #1 had a distinctive bowtie or butterfly shape . This frIn early August 2014, a FIB was used to expose surface layers of some deformed steel fragments. A representative cross-section of one of the fragments recovered from the remains of flight crew member #2 is shown is Further examination of the bowtie-shaped fragment showed it was heavily deformed on one side. Deposits of glass and aluminium were mainly found in a re-solidified state on the deformed side of the fragments, indicating that the fragments impacted the airplane at a very high velocity. The consequential frictional heat melted the glass and aluminium and a thin, solidified layer of these materials was deposited on the heavily deformed side of the fragments. Although their velocity was reduced after impacting the airplane, these fragments continued on their trajectory and impacted the crew members, wherein they were found.In December 2014, the first pieces of wreckage arrived in the Netherlands. During the examination of the wreckage, more steel fragments were recovered. LA-ICPMS was used to compare the chemical composition of selected steel fragments recovered from the wreckage with that of fragments recovered from the human remains. Principal component analysis of these data showed that the fragments clustered into groups with similar chemical composition. Notably, the bowtie fragment recovered from the remains of flight crew member #1  appeared2. The gross chemical composition of the fragments recovered from the flight crew and cockpit could not be differentiated from that of the pre-formed fragments from the dismantled warheads.The bowtie-shaped metallic fragment recovered from the body of flight crew member #1  was charAnother important fragment was recovered from the remains of one of the two relief flight crew members, although its importance was not recognised until late 2014. The stainless steel fragment depicted in Nothing of forensic interest was found among the remains from passengers and other crew members. Most of the foreign objects were identified as personal belongings , objects originating from the airplane , or objects from the ground . Many of the recovered objects consisted of aluminium-like fragments. During the forensic triage hundreds of foreign objects were recovered from the human remains. Among these fragments, about thirty were found that provided vital clues to the cause of the downing of Malaysian Airline flight 17 in Ukraine on 17 July 2014.With the help of the results from the triage, within a few weeks early suspicions that MH17 was downed by a BUK-missile were supported. The airplane was hit on the front side by high energy steel fragments with shapes that were consistent with shapes of fragments from a 9N314M warhead, typically used in Buk SA-11 Missiles. The thin deposits of cockpit glass and aluminium on the recovered steel fragments indicate that the fragments were coming from outside the airplane. If the fragments were coming from an improvised explosive device within the airplane, the deposits of cockpit glass on fragments recovered from human remains would be inexplicable. The other postulated scenarios were also not supported. In particular, no materials characteristic of 30 mm anti-aircraft rounds or air-to-air missiles were found, indicating MH17 was not shot down by a Sukhoi SU-25 jet.Finally, the DSB and the JIT concluded that flight MH17 was struck by a Buk SA-11 surface-to-air missile launched from pro-Russian separatist-controlled territory in Ukraine. According to the JIT, the Buk missile used originated from the 53rd Anti-Aircraft Missile Brigade of the Russian Federation and had been transported from Russia on the day of the crash, fired from a field in a rebel-controlled area, and the launcher returned to Russia after it was used to shoot down MH17 .Erwin Vermeij participated in the triage and examination, evaluated the results and drafted the manuscript. Peter Zoon participated in the triage and examination, evaluated the results and reviewed the manuscript. Reza Gerretsen participated in the triage and reviewed the manuscript. Vincent Otieno-Alego participated in the examination and edited the manuscript. All authors contributed to the final text and approved it.


Examination of the temporal changes of vegetation indices and LST showed that the values of all indices decreased while the LST increased. The negative correlation between NDVI value and LST indicates that the vegetation in our study was subject to drought-induced shocks. This study reveals the current situation of the vegetation health in the north-western region of Bangladesh in relation to the drought conditions. The findings of this study have practical implications for the policymakers in implementing necessary measures for agriculture, forests, water development, and economic zone planning.Drought is a widespread hazard that can tremendously affect the biodiversity, habitat of wild species, and ecosystem functioning and stability, especially in the dry region. Due to its geographic location, the north-western region of Bangladesh has a comparatively arid climate which is very much susceptible to drought occurrence and is marked as a red zone. Despite the growing evidence of the impact of drought on food security and ecosystem functioning, little effort has been paid to mitigate the drought in this region. The present study aimed to assess the drought condition of the north-western region of Bangladesh using earth observation techniques. For this purpose, Landsat data from 1990 to 2020 was used to determine various vegetation indices such as Normalized Difference Vegetation Index (NDVI), Water Index (NDWI), Moisture Index (NDMI) and Soil Adjusted Vegetation Index (SAVI), along with Land Surface Temperature (LST). Results show that the depletion of forests (2832 km  •Drought conditions in north-western region of Bangladesh were examined for 30 years.•Depletion of forests and waterbodies resulted from the expansion of settlement.•Vegetation greenness was negatively correlated with land surface temperature.•Decreasing rate of vegetation indices value was higher in 2010–2020 than in 1990–2005. Globa6 tons .Dr. Mohammed Abdus Salam was supported by https://earthexplorer.usgs.gov/Data associated with this study has been deposited at The authors declare no competing interests.The article contains one supplementary material.


In recent years, the impact of various chronic eye diseases on quality of life has become increasingly apparent. Therefore, it is particularly important to control the progress of chronic diseases at an early stage. Many studies have used neuroimaging methods to explore the effects of chronic eye diseases on the brain, and to identify changes in brain function that may act as markers for early diagnosis and treatment. This article reviews the clinical application of different techniques of functional magnetic resonance imaging in chronic eye diseases. As a resting-state functional magnetic resonance imaging (MRI) analysis tool, the amplitude of low-frequency fluctuation (ALFF) has high accuracy and repeatability and does not require definition of regions of interest (ROI) in advance. By calculating the root mean square of the blood oxygen level dependent (BOLD) signal power spectrum at low frequencies 0.01HZ−0.08HZ), the neuronal activity in different brain regions is expressed and is an indicator of spontaneous neuronal activity HZ−0.08HZ. ChangesVoxel-wise degree centrality (DC) is another commonly used technique in resting state functional MRI technology. It assesses functional connectivity within the brain by measuring the topological structure of brain functional connectors at voxel level, and provides the correlation between different nodes and the importance of each node in the network structure . The degRegional homogeneity (ReHo) is a widely used analytical method in resting state MRI, and plays an important role in exploring changes in local synchronization of voxels in brain regions . The anaFunctional connectivity (FC) is a seed-based or ROI-based functional connection, in which areas functionally related to activities in the seed area may be found . In seedVoxel-based morphometry (VBM) is an MRI whole-brain analysis technique for measuring density and volume changes of gray and white matter at the voxel level, and is used to enhance understanding of the anatomical structure of the brain . In contVoxel-mirrored homotopic connectivity (VMHC) is a new resting-state FC analysis method to measure the functional connection between hemispheres . This meThe fractional amplitude of low-frequency fluctuation (fALFF) provides a measure of inherent spontaneous brain activity . MeasureIn summary, each magnetic resonance imaging technique has its own characteristics. To summarize the above, both ALFF and fALFF show regional differences in the brain, with high accuracy and repeatability, and do not need to pre-define regions of interest (ROI) , while fIn recent years, MRI has been increasingly widely used to explore disease-related changes in brain activity and functional connections. It provides a useful imaging index for understanding the mechanism and monitoring the progress of pathological changes in disease. Its role as a disease marker has been confirmed in many studies. Most chronic eye diseases are characterized by occult and chronic progression, which easily leads to missed diagnosis and misdiagnosis. Using MRI, changes in spontaneous brain activity which occur with eye diseases may be detected at an early stage and monitored, and then accurately locate the brain region where lesions occur, and combine clinical symptoms based on the consistent physiological functions of different brain regions to improve the accuracy of diagnosis, aiding both early diagnosis and treatment of chronic eye diseases. However, the application of magnetic resonance imaging as a marker in chronic eye diseases has some limitations, since physiological and hardware-related factors may affect the experimental results. In addition, due to overlapping functions of different brain regions, it may not be possible to accurately locate the affected areas of the diseased brain. Despite these limitations, MRI technology has great potential and scope to provide indicators of onset and progression of chronic eye diseases. With the continuous progress of technology, MRI technology will usher in a broader range of applications, increasing the scope for exploration of chronic eye diseases.C-YY was responsible for the writing of the manuscript. RH was responsible for data analysis and the later submission. S-QL was responsible for collecting and screening the data. YS was responsible for the revision of the paper. All authors contributed to the article and approved the submitted version.The Central Government Guides Local Science and Technology Development Foundation (20211ZDG02003); Key Research Foundation of Jiangxi Province (No: 20181BBG70004); Excellent Talents Development Project of Jiangxi Province (20192BCBL23020); Natural Science Foundation of Jiangxi Province (20181BAB205034); Grassroots Health Appropriate Technology Spark Promotion Plan Project of Jiangxi Province (No: 20188003); Health Development Planning Commission Science Foundation of Jiangxi Province (No: 20201032); Health Development Planning Commission Science TCM Foundation of Jiangxi Province (No: 2018A060).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Idiopathic pulmonary fibrosis (IPF) is characterized by uncontrolled progressive lung fibrosis with a median survival of 3 to 5 years. Although currently available pharmacotherapy cannot cure the disease, antifibrotics including pirfenidone and nintedanib were shown to slow disease progression and improve survival in IPF. Nevertheless, there is a knowledge gap on the safety of antifibrotics in patients after liver transplantation receiving concomitant immunosuppressive therapy. This case report of a 68-year-old male patient with IPF illustrates how a complex medical history has led to diagnostic and therapeutic challenges considerably affecting clinical decisions and impacting the patient's journey. The increasing severity of lung function impairment due to the progressive natural history of IPF ultimately led to severe respiratory failure. Double lung transplantation (LTx) was performed as the only therapeutic option in end-stage disease with the potential to improve quality of life and survival. To the best of our knowledge, this is the first case report describing the feasibility and safety of antifibrotic therapy with pirfenidone for IPF in a 68-year-old patient with a history of liver transplantation receiving concomitant immunosuppressive therapy with tacrolimus who underwent successful double lung transplantation when alternative medical interventions had been exhausted. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease of unknown etiology characterized by the radiographic and histopathologic pattern of usual interstitial pneumonia (UIP). It is known to have outcomes worse than many cancers, with a median survival of 3–5 years after diagnosis, although the disease course varies significantly in individuals . RepetitThis is a case report on a 68-year-old man who underwent double lung transplantation in February 2020 due to advanced respiratory failure in the course of IPF. The patient's medical history relevant to lung fibrotic disease dates to 2013 when during the diagnostic evaluation before the planned liver transplantation, lung fibrosis was detected for the first time on chest CT while the patient was still asymptomatic. Previous exposures relevant for this case included a 15 pack-year history of smoking and a distant three-year period of parrot breeding. His past medical history included type 2 diabetes, gastroesophageal hernia, paroxysmal atrial fibrillation, and several endoscopic sclerosing interventions for esophageal varices. In 2014, the patient underwent a liver transplantation procedure for advanced toxic hepatocirrhosis. After the successful liver transplant, the patient was maintained on immunosuppressive therapy with tacrolimus. In 2017, the patient started to complain of major effort dyspnea and cough. Physical examination at that time revealed bilateral crackles at the base of the lungs on auscultation and finger clubbing. The HRCT showed extensive bilateral interstitial fibrosis with peripheral basilar predominant reticular opacities accompanied by peripheral traction bronchiectasis and subpleural honeycombing. The findings were compatible with the criteria of a definite UIP pattern. It is of note that the patient did not have any family history of lung fibrosis. Detailed differential diagnosis towards autoimmune diseases and hypersensitivity pneumonitis (HP) was conducted showing negative serological results. At this point of time, the exclusion of known causes of interstitial lung fibrosis with concurrent clinical and radiological context prompted the suspicion of IPF. Nevertheless, IPF was not confirmed until 2019, when a multidisciplinary team at one of the Polish reference centers for interstitial lung diseases (ILD) ultimately made a confident diagnosis of IPF. Despite the available antifibrotic therapy in Poland reimbursed by the National Health Fund, the treatment was not initiated due to the lack of data on the safety of antifibrotic drugs in patients who had undergone liver transplantation and were receiving concomitant treatment with tacrolimus; as such patients were not participating in the pivotal clinical trials of the two antifibrotics. It is of note that both drugs, pirfenidone and nintedanib, may have potential hepatotoxic adverse effects, and data on possible interactions with tacrolimus are also lacking.CO) was 38% pred. Resting oxygen saturation (SpO2) was 97%, but he desaturated to SpO2 76% in the six-minute walk test (6MWT) after 390 meters covered with 3 points on the Borg dyspnea scale at the end of the test. Taking into consideration the function of the transplanted liver and concomitant therapy with tacrolimus, the initial low dose of 267 mg pirfenidone 3 times daily was initiated under weekly monitoring of the serum liver parameters and of tacrolimus whole blood levels. For safety reasons, the decision for a longer than recommended drug titration period was made. With no relevant deterioration of liver function parameters and good drug tolerance, the dose was escalated to 534 mg 3 times daily after 4 weeks. The full recommended dose of 801 mg of pirfenidone given 3 times daily was reached after 8 weeks, without any safety signals or drug intolerance symptoms. Exertional desaturations below 90% were treated with a portable source of supplemental oxygen.The next step in the prolonged patient journey was the second opinion at one of the European university centers for ILD in March 2019. Conclusions from the second opinion consultation confirmed the correctness of the patient's IPF diagnosis and lack of data on the safety of antifibrotic treatment in patients after liver transplantation and receiving concomitant immunosuppressive therapy with tacrolimus. The contact with both antifibrotic drug manufacturers confirmed a knowledge gap in this clinical situation. Nevertheless, given the poor prognosis in IPF and the lack of alternative treatment options, a trial of antifibrotic therapy with a more vigilant approach was proposed. Following the second opinion consultation, the patient contacted another Polish university reference center for ILD, where after careful case evaluation, he was enrolled in the antifibrotic treatment program with pirfenidone in May 2019. At this point, his forced vital capacity (FVC) was 76% of the predicted value (% pred.) and the single-breath transfer factor of the lung for carbon monoxide  during the test. Echocardiography indicated the probability of pulmonary hypertension , which was confirmed in a consecutive right heart catheterization procedure by the mean pulmonary artery pressure of 29 mmHg. Ultimately, the patient was considered preliminarily qualified for double lung transplantation and complementation of further procedure-related investigations was recommended.Despite the initiated antifibrotic therapy, the patient's general condition was slowly deteriorating. By the lack of other therapeutic options, a decision of the patient's preliminary qualification for lung transplantation was made. The patient was referred to the lung transplantation center in June 2019 for specialist consultation. Upon assessment at the lung transplantation center, pulmonary function tests revealed restrictive lung disorder with the following results: FVC of 72% pred., total lung capacity (TLC) of 68% pred., residual volume (RV) of 56% pred., RV/TLC ratio of 81%, and TL,2 of 55%. The patient's serious condition demanded endotracheal intubation and mechanical ventilation. Chest radiography revealed bilateral, irregular interstitial opacifications. Based on the clinical suspicion of community-acquired pneumonia (CAP), empirical antibiotic therapy with ceftriaxone was implemented together with methylprednisolone intravenously. Over five consecutive days, the patient's condition improved, and he was discharged home with respiratory failure at rest demanding long-term home oxygen therapy. Two months after the acute episode of respiratory hospitalization with significant deterioration of lung function, the patient was admitted to the transplantation unit of the Silesian Center for Heart Diseases due to the availability of a compatible lung donor. Uncomplicated sequential double lung transplantation (LTx) was performed on February 14, 2020, followed by immunosuppressive maintenance therapy including tacrolimus, mycophenolate mofetil, and prednisone. Additionally, prophylaxis of cytomegalovirus and fungal infections with valganciclovir and voriconazole was introduced. Six weeks after the surgery, the patient was successfully discharged from the hospital in a good general condition. The patient's pulmonary function had significantly improved, as shown in the spirometry four months after LTx with the forced expiratory volume in 1 second (FEV1) of 97% pred. and FVC of 84% pred. During the 6MWT, the patient covered the distance of 265 m with 1 point on the Borg scale and without desaturation throughout the test. Currently, 2 years after LTx, the patient remains in good general condition without any posttransplant medical complications.After six months since the initiation of pirfenidone therapy, the patient decided on his own to discontinue the medication due to a progressive decrease of appetite, noted from the third month of treatment, and loss of weight. Four weeks later, he was admitted to the local hospital due to acute respiratory deterioration with increased dyspnea, tachypnea, productive cough, and resting SpOOur case report illustrates real-life diagnostic and management challenges and confirms considerable diagnostic and treatment delays in IPF , 19. TheAlthough IPF is a rare disease, physicians should consider IPF as a potential cause of unexplained exertional dyspnea and/or cough in elderly patients and refer them to a pulmonologist for further evaluation. Establishing an accurate diagnosis of IPF requires specialist expertise in ILD diagnosis , 13. In Our case was even more challenging due to the history of liver transplantation and concomitant immunosuppressive therapy with tacrolimus. Despite confirmation of the IPF diagnosis at the reference ILD center, the decision regarding the initiation of antifibrotic therapy was postponed due to concerns of safety in such a clinical case scenario, since there were no data available on the safety of either pirfenidone or nintedanib in patients with IPF after liver transplantation and concomitant therapy with tacrolimus. This situation resulted in an additional delay in accessing treatment with the disease-modifying drug in our patient. A subsequent second opinion of our complex case at a European ILD center confirmed the accuracy of IPF diagnosis and the gap in the safety data of antifibrotic therapy in patients after liver transplantation and concomitant immunosuppression. Nevertheless, given the poor prognosis and the lack of alternative options, a pragmatic approach of a trial of antifibrotic therapy was proposed. Our case report confirms the feasibility and safety of pirfenidone therapy in such a case scenario. For safety reasons, the drug titration period was extended from 2 weeks to 8 weeks. Good drug tolerance and no safety signals were observed during that time. Despite the initial good tolerance of pirfenidone therapy, the patient decided to discontinue drug intake after 6 months because of the progressive decrease of appetite and loss of weight; both are known pirfenidone-related adverse events. In the recent aforementioned real-world data (RWD) study on the Polish experience of pirfenidone therapy in IPF, decreased appetite and weight loss were reported by around one-third of treated patients and the gastrointestinal ADR category was the most frequent reason for pirfenidone discontinuation . MoreoveFinally, the disease progression and respiratory deterioration prompted LTx. At this point when medical options have been exhausted, the only treatment left with the potential to improve quality of life and survival is LTx . The pooThe present case report illustrates how a complex medical history led to diagnostic and therapeutic challenges which considerably affected clinical decisions and impacted the IPF patient's journey. Moreover, our patient's history underscores the importance of MDD in establishing early and accurate diagnosis of IPF and access to appropriate IPF management without delay. Finally, to the best of our knowledge, this is the first case report describing the feasibility and safety of antifibrotic therapy with pirfenidone for IPF in a patient with a history of liver transplantation and concomitant immunosuppressive therapy with tacrolimus who underwent successful LTx.


The significant location of the Southern Caspian corridor between high mountains of Alborz and the Caspian Sea, provided a special biogeographical zone and a refugium. This exceptional physio-geographic condition brings forward the Southern Caspian corridor as a potential place of admixture of different hominin species including Neanderthals and homo sapiens.The study of the cultural materials associated with the Neanderthal physical remains from the sites in the Caucasus, Central Asia and Siberian Altai and adjacent areas documents two distinct techno-complexes of Micoquian and Mousterian. These findings potentially outline two dispersal routes for the Neanderthals out of Europe. Using data on topography and Palaeoclimate, we generated computer-based least-cost-path modelling for the Neanderthal dispersal routes from Caucasus towards the east. In this regard, two dispersal routes have been identified: A northern route from Greater Caucasus associated with Micoquian techno-complex towards Siberian Altai and a southern route from Lesser Caucasus associated with Mousterian towards Siberian Altai via the Southern Caspian Corridor. Based on archaeological, bio- and physio-geographical data, our model hypothesises that during climatic deterioration phases (e.g. MIS 4) the connection between Greater and Lesser Caucasus was limited. This issue perhaps resulted in the separate development and spread of two cultural groups of Micoquian and Mousterian with an input from two different population sources of Neanderthal influxes: eastern and southern Europe refugia for these two northern and southern dispersal routes respectively. Of these two, we focus on the southern dispersal route, for it comprises a ‘ This progress—including the identification of a “potheses . Recent potheses –4 and capotheses . In theipotheses –9.Recent studies observed genetic variability among the Neanderthal groups and could potentially show high range of migration between them . MitochoIn the Greater Caucasus, at Mezmaiskaya Cave, Middle Palaeolithic (MP) industry is known by foliate and Micoquian artefacts –16. ThisMoving to the lower latitudes (ca. N 35–30°) , in the At about 35 ka, a small and isolated group of Neanderthals appeared in Teshik-Tash Cave, in Uzbekistan; Central Asia. It is believed that this group of migrants was possibly assimilated, and their arrival did not result in long-lasting changes in the material culture of the local, possibly, Denisovan population . The cavThe current data proved the presence of Neanderthals in the whole Caucasus area located at the gateway of Europe and in Central Asia and Siberian Altai, as the eastern-most yet-known territory of this species . HoweverThe Caucasus area has a rather complicated picture in this time. Climatic deterioration phases of Late Pleistocene perhaps limited the Neanderthals’ contact between Greater and Lesser Caucasus. Palaeolithic cultural varieties recognised in this area divided the Caucasus into at least two biogeographical and cultural groups of northern (Micoquian) and southern Caucasus (Mousterian) which fits with the geographical division of the mountains into Greater and Lesser Caucasus. The high species diversity of fauna and endemism in the Caucasus demonstrates it as a biodiversity hot spot  connectiIn this regard, we present a robust biogeographical model using Least-Cost-Path (LCP) analysis to characterize Neanderthal population dispersals with distinct material cultures from Caucasus (Greater and Lesser) towards east (Siberian Altai). Our focus is the time frame of MIS 4 (71–57 ka), the period that has contained extreme cold and dry climatic condition .LCP analysis is the most commonly used method to reconstruct dispersal corridors of ancient hominins . In thishigh contrast topography’ applied already for the MP sites of the Zagros [In our LPC model, we assume the Caspian Sea, as the world’s largest closed sea located between Caucasus and Central Asia, was a natural barrier. Accordingly, every dispersal route towards east must be passed either from the vast plains located in the Russian Plain in the north or the narrow land of SCC in the south. Caspian Sea level experienced high fluctuations during different periods. The present water level is at– 27 m asl. While transgressions occurred during interglacial (Khazarian highstand at -10 m asl during MIS 5) and some pleniglacial periods , during the first cold stage of the Last Glacial (Atelian lowstand during MIS 4) the water level was even lower than present, possibly as low as -140 m asl . In addie Zagros . The MP e Zagros .terrain function in the raster package [terrain function calculates slope as a function of elevation [LCP was performed using QGIS 3.16 . Since s package . The terlevation . The elelevation .Areas which experienced little climatic fluctuations acted as refugia for different taxa including mammal species . Thus, wWe also mapped precipitation and temperature of MIS 4 for the study area in QGIS 3.16  using paelevational gradient range, diverse topography and strong environmental heterogeneity offered a flora and faunal diversity. In its eastern-most part, Alborz Mountains join the Kopet-Dagh-Khorassan Mountains, while from north-west and west it connects to the Lesser Caucasus and Zagros respectively. Biogeographical studies show that the Alborz Mountains is the host of numerous local endemics acting as a strong east-west biogeographical link [The SCC area is bounded by the northern slopes of the highly rugged and east-west oriented Alborz Mountain ranges that separate the inner lowland deserts of the Iranian Plateau in the south from the Caspian Sea in the north. Despite being narrow, this area includes diverse geographical elements; from sand dunes close to the Sea shore in the north to the high Alborz Mountains in the south. A wide cal link .refugium of Hyrcania’ [The SCC is partly covered by the Caspian Hyrcanian forest. This forest covers around 55,000 square kilometres. Its western extension reaches to the Lesser Caucasus. Dating back to between 25 to 50 ma, Caspian Hyrcanian mixed forest has been refugium for numerous fauna and flora species persisting during glacial intervals. The Caspian Hyrcanian forest is ecologically important because it contains many already extinct or endangered species elsewhere as well as the highest local endemic flora diversity in the Iranian Plateau , 70. Thiyrcania’ , 73.The heterogeneous environment  provides diverse niche space hypothesising SCC as a reservoir for detecting hominins genetic variation, biodiversity, biogeographical development and evolution. Based on patterns observed from the other parts of the Iranian Plateau (mainly Zagros), we observed that in the altitude above ca. 1800 meters, the hominin settlements decreased . TherefoPalaeolithic settlements in SCC were influenced by different elements including climatic conditions and sea level fluctuations.Our main data on the paleoclimate of the Iranian Plateau during MIS 5 comes from speleothem growth and δ18O records of Qale Kord  and Pir Generally, MIS 4 is associated with cold and probably dry climatic conditions in the high altitudes of the Caucasus and in many places of the Iranian Plateau including the Alborz highlands. Palynological data from Caucasus shows that during the stadials, continental cold and arid climatic conditions, caused by the influence of glaciers, covered a huge area . As a rePalaeoclimatic records from Lake Urmia in Iran documents a cold and arid phase during MIS 4 , 80. MISThe present-day climate of the SCC is influenced by the Alborz Mountains in the south, the Caspian Sea in the north, the Caucasus Mountains in the west and deserts and steppe landforms in the east and northeast . Mean anThe Caspian Sea is one of the barriers on the dispersal routes between west and east . The shoCaspian Sea level changes depended on the hydro-climatological processes caused by water evaporation and precipitation during different glacial and interglacial cycles , 82 Fig. During During MIS 4 the Caspian Sea level was at the minimum level. This stage, which is locally named Atelian lasted to around 48 ka , 83, 86.After the Atelian regression, the Caspian Sea high stand of the Early Khvalynian transgression occurred . It was Based on the transgression and regression pattern of the Caspian Sea, we suggest dispersal routes and timings of the Neanderthals’ dispersals via SCC and during MIS 4 (Atelian regression).MP sites with Neanderthal physical remains are scarce in the study region. This is due to the small scale of excavations. However, few sites at the extremities of the study region yielded physical remains associated with material culture including Mezmaiskaya and Azokh caves in Greater and Lesser Caucasus respectively, Teshik-Tash in Central Asia, Denisova, Okladnikov and Chagyrskaya caves in the Siberian Altai. In western Iranian Plateau in the Zagros Mountains, Shanidar Cave and Bawa Yawan Rockshelter and in central western Iran Qale Kord Cave yielded Neanderthal remains associated with the MP Mousterian techno-complex .In addition, we plotted the sites with MP material culture confirming hominin occupation during MIS 5–3. In the lack of absolute dating, a rough chronology has been applied for the sites. Our goal, however, was not to create a specific ‘date’ for the sites, but instead to place them within a glacial or interglacial cycles of Late Pleistocene.For conducting route determination for two possible dispersal routes from Caucasus towards Siberian Altai, we chose two starting points in the Caucasus which yielded Neanderthal fossil remains associated with MP lithic artefacts . MezmaisThe northern dispersal route has its start point on Mezmaiskaya Cave on Greater Caucasus and the end point on the Chagyrskaya Cave in Siberian Altai, since the two sites share similar cultural materials of Micoquian. The northern dispersal route assumed to be used in the time period of 70 to 55 ka . GeneralThe MP Micoquian settlements are known in the Central Trans-Ural Mountains between the starting and ending points along the northern dispersal route . The rouGenetic and archaeological data , 12, hypDespite of the presence of Micoquian at Mezmaiskaya, this cultural group is totally absent in the Lesser Caucasus. We hypothesise that the severe climatic condition during stadial period (MIS 4) has limited contact between the settlements in Greater and Lesser Caucasus. The Lesser Caucasus has generally lower altitude and a more arid climate than the Greater Caucasus. This issue limited proceeding ice sheets to 700 m asl during glacial periods . It has cultural boundary” [biogeographical and social barrier” for the Late Pleistocene populations [Homo sapiens could better spread across Caucasus during the interstadial stages and climatic amelioration [It has been proposed that the reason behind the difference between MP techno-complexes on northern and southern sides of the Caucasus, namely Eastern Micoquian with foliates of the north and the Mousterian with different kinds of scrapers from the south, is the impassable mountains which acted as a “oundary” . This booundary” . The disulations . Homo saioration .en route to the Central Asia [McBurney in his mission to Iran in 1960s, proposed that any hominin movement from west might be expected to pass SCC ral Asia . The Uppral Asia . This reral Asia .rapid dispersal route” [Here, we evaluate the “l route”  by generhigh contrast topography” model employing the environmental and geographic conditions, once suggested for the early UP sites in the Southern Zagros Mountains of Iran [For evaluating the rapid dispersal route towards east, a number of values have been considered to find the best route including climate, topography and actual and potential shelter sites along the suggested route. In addition to simulation using these variables, we examine the “ of Iran . This moThe glaciation intervals of MIS 4 led to global decreases in sea-levels and increasing aridity caused the desert condition in some regions . During In general, the SCC with ca. 800 km length has a central role in the southern dispersal route. Geologically, the SCC is an area of tectonic subsidence, whereas Alborz Mountains experienced tectonic uplift , 112. ThWhere the northern Caspian Sea was highly affected by the sea level fluctuations, the southern coast remained relatively less affected by regression and transgression of the sea during glacial and interglacial cycles . This naNorthern and Southern Caspian routes presented in the dispersal model of the Neanderthals towards east here, are hypothetical and formed based on archaeological and physiological data in hand. Regarding Neanderthals’ dispersals, this model generates several hypotheses for future scope of research in a relatively unknown areas of Iran and the Central Asia. From two routes suggested by LCP modelling, the southern route shows that the narrow area of SCC, provides the closest and fastest and more optimised route connecting Caucasus to Central Asia and eventually the Siberian Altai.Preliminary archaeological data indicates that this area probably acted as dual role of biogeographical corridor of expansion and habitat and witnessed a series of human evolutionary events that occurred during Late Pleistocene .The biogeographical studies in SCC document this area as a biodiversity hot spot for flora and faunal endemism. Despite its limited size, this area fosters a high number of local endemics as well as acting as biogeographical connections between west towards east .During glacial periods Siberia could not serve as refugium, therefore, the areas further south including the Levant and Zagros have been suggested as potential refugia . Due to Recent survey in SCC especially in the eastern part of it, led to the discovery of several Palaeolithic sites, including shelter and open-air sites . Fig 10 southern Refugia; [Our dispersal model shows two separated LCPs confirmed by two cultural material groups of Micoquian and Mousterian on Greater and Lesser Caucasus respectively. The absolute lack of Micoquian at Lesser Caucasus points to the lack of communication between two parts of the Greater and Lesser Caucasus during MIS 4. The bearers of Micoquian techno-complex in Eastern Europe took a long journey over 4000 km to the complex of sites in Siberian Altai (e.g. Chagyrskaya and Okladnikov)  penetratRefugia; ). The rehomo sapiens and Denisovans, or ghost lineage) are crucial to encrypt the puzzling picture of hominin settlements in this odd refugium. Conducting intensive archaeological research in this unknown region of south-western Asia is important for our understanding of Neanderthals’ dispersals and admixture with homo sapiens and other hominin species. For now, we can hypothesise that interbreeding between the immigrant Neanderthals and the indigenous hominin of SCC was highly possible. SCC was the home range overlapped for Neanderthals from west, homo sapiens newcomers from inner parts of the Iranian Plateau via north-south corridors connecting southern and northern slopes and foothills of the Alborz Mountains and other hominins (i.e. Denisovans) from east. However, our knowledge on the inhabitants of the SCC during Pleistocene comes only from the cultural materials (i.e. lithics). Given the assumption of Late Pleistocene population expansion into east through SCC, this area might have been highly populated at the warm and moist stages of MIS 5 [The archaeologically distinct Neanderthals of Lesser Caucasus could be routed into the southern European refugium, who through Anatolia reached the Iranian Plateau and penetrated northwards until the Lesser Caucasus. They might be the population who took the back-and-forth movements to the southern latitude, admix with the populations there and generated the new facies of Mousterian namely Zagros- and Levantine Mousterian. In the lack of any fossil and genetic studies, this hypothesis stays unresolved and awaits more evidence. The location of SCC between Caucasus and Central Asia, gives rise to the hypothesis of SCC as one of the hot spots for tracking hominin admixture and introgression, as it was the case for some faunal species , 69. Howof MIS 5  and lateof MIS 5 , 38, 115of MIS 5 . The genof MIS 5 . Recent of MIS 5 , 118.homo sapiens and colonisation of new ecological niches. The geographical expansion range of human populations largely depends on the spatial distribution of suitable habitats and corridors connecting these habitats. Regarding Neanderthals’ distribution from Europe eastwards, the immediate areas are the piedmonts of the Caucasus and Alborz mountains. However, the role of these corridors for early expansion processes is closely related to the complex pattern of favourable climatic circumstances. Despite highly fluctuated sea level, the SCC remained one of the most important areas for MP population dynamics. During MIS 4 the Caspian Sea level was at the minimum level, large plains have been exposed and provided a large dispersal corridor in the SCC. Moreover, in contrast to the inner basins of the Iranian Plateau, the SCC provided a rich source of freshwater from numerous permanent rivers and terrestrial and marine food resources throughout the year. Together with numerous caves and rockshelters located higher than the boundary of sea level fluctuations, this area was a suitable reservoir and refugium during climatic deterioration. This natural circumstance becomes highly important in terms of the possible interaction between different hominin species arriving from west and east ending up in the meeting point of SCC.Recent research on western Eurasia has increased our knowledge on the migration and dispersal routes of the Neanderthals, their admixture with other hominin types namely Denisovans and In this regard, our computer-based model identified two major possible routes for the Neanderthals from the gate of Europe in Caucasus to the east. As the map of presence and dispersals of the Neanderthals towards east is at the beginning to be completed, these suggested routes are bounded by major questions and building the future research.The suggested routes are not only limited for MIS 4, but also conceivable and practical for periods before and after it (i.e. MIS 5–3). We argue that these routes could be repeatedly used by Neanderthals and other hominin species during different phases. In glacial periods these routes lost the connection with each other which resulted into the development of distinct cultural and genetic groups.We mainly focused on the southern dispersal routes via SCC and hypothesise that during glacial periods, this area due to its exceptional physiogeographic condition could be used as both biogeographical corridor of expansion and settlement. Where other parts of the Iranian Plateau were influenced by cold and dry climatic conditions during MIS 4, SCC benefited from a special condition which made it a remarkable refugium. SCC opens windows of potential contact, Neanderthal demographic influx from western Iranian Plateau and Caucasus into SCC and possible competition with other hominins there. Survey in the SCC as well as the excavation at promising sites, together with detailed climatic reconstruction are needed to confirm that this area has been highly populated at the warm and moist stages of MIS 5 and later as refugium during glacial periods.The location of Azokh and Teshik-Tash caves at both extremities of the SCC together with the newly discovered sites in this corridor indicate that still promising places in Asia remained largely unexplored, and previously identified sites and materials are in need of renewing studies. Our model shows the complex nature of MP population dynamics in this part of Eurasia than simply characterizing this area was occupied during MP period.


Leaf removal is a canopy management practice widely applied in viticulture to enhance the phenol composition and concentration of grapes, which then results in improved wine quality. Many studies were carried out on red berried varieties, but information on white ones is scanty. The aim of the study was to assess the effect of basal leaf defoliation in post fruit set on the phenol composition, ascorbate level and antioxidant activity of Trebbiano grapes. Electron paramagnetic resonance was also employed to monitor the decay kinetics of 1,1-diphenyl-2-picrylhydrazyl which allowed the identification of antioxidants with different action rates. The results show that defoliation caused an increase in the phenolic acid (hydroxycinnamic and hydroxybenzoic acids) and flavonol concentrations of berries without changes in the composition. Both ascorbate and antioxidant activity were also enhanced in the berries from defoliated vines. Besides increasing the number of fast-rate antioxidants, leaf removal resulted in the formation of intermediate-rate ones. In the Trebbiano variety, leaf removal in the post fruit set may represent an effective strategy to enhance the phenolic composition and the antioxidant defense system of berries. Bars shown in Figures represent the standard error of the means of three independent experiments (n = 3) each analyzed twice.Data were analyzed using the Costat 6.4 program . The effects of leaf removal were evaluated by one-way ANOVA and significant differences between means were assessed by the least significant difference test at 95% confidence level (


Over the last 25 years, the human endocannabinoid system (ECS) has come into the limelight as an imperative neuro-modulatory system. It is mainly comprised of endogenous cannabinoid (endocannabinoid), cannabinoid receptors and the associated enzymes accountable for its synthesis and deterioration. The ECS plays a proven role in the management of several neurological, cardiovascular, immunological, and other relevant chronic conditions. Endocannabinoid or endogenous cannabinoid are endogenous lipid molecules which connect with cannabinoid receptors and impose a fashionable impact on the behavior and physiological processes of the individual. Arachidonoyl ethanolamide or Anandamide and 2-arachidonoyl glycerol or 2-AG were the endocannabinoid molecules that were first characterized and discovered. The presence of lipid membranes in the precursor molecules is the characteristic feature of endocannabinoids. The endocannabinoids are released upon rapid enzymatic reactions into the extracellular space via activation through G-protein coupled receptors, which is contradictory to other neurotransmitter that are synthesized beforehand, and stock up into the synaptic vesicles. The current review highlights the functioning, synthesis, and degradation of endocannabinoid, and explains its functioning in biological systems. Cannabinoids have, for the last 40 years, been considered to be molecules or substances which are responsible for the psychoactive properties of marijuana and other associated derivatives of cannabis sativa. Its other medicinal properties are also under exploration. The endogenous cannabinoid system is an omnipresent lipid signaling pathway which performs and controls numerous physiological roles within the body and appeared early in its evolution. Cannabis-like molecules or principal endocannabinoid compounds are small functional molecules which have been isolated from arachidonic acid, a membrane layer, and have been named anandamide (arachidonoylethanolamide) and 2-arachidonoylgylcerol . These mIn 1988, Vincenzo Di Marzo, a globally renowned cannabinoid scientist, established the role of endocannabinoid in human physiology and certain bodily functions including mood alteration, sleep, memory, perception to pain and also in maintaining balance in the body. The endocannabinoid system is named after its source of discovery, the Cannabis plant, and is a prominent physiological system that is indulged in establishing and maintaining human health. The system comprises of lipid based retrograde neurotransmitters called endocannabinoid which conjugate with the cannabinoid CB1 and CB2 receptors and induce physiological and molecular responses in the body. The cannabinoid receptors are present throughout the body, including in brain, immune cells, connective tissue organs, and different glands and tissues of the body . The endThe endocannabinoids were discovered to be the products of arachidonic acid, a molecule similar to other associated transmitters of lipid like leukotrienes, prostaglandins, and eicosanoids. The endocannabinoids are mainly arachidonic acid derivatives and are conjugated with ethanolamine or glycerol and are present in plasma, the brain, and peripheral tissues . AccumulThe endocannabinoid molecules are endogenously also synthesized from omega-3 and omega-6 polyunsaturated fatty acids (PUFA). They are the products of fats obtained from the diet, and any changes in the dietary intake can modulate their levels in the body, which results in the displacement of arachidonic acid from the membranes of cells by eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) based endocannabinoids, thereby reducing the levels of 2-AG and anandamide . The resAnandamide has been known to be a potent endocannabinoid molecule for a long time, and belongs to a category of naturally occurring molecules. N-palmitoylethanolamine (PEA) is one of its members, and has been reported in humans for more than 50 years. The physiological roles of PEA are being explored through extensive research. PEA and other related naturally occurring molecules share degradative mechanisms with endocannabinoid molecules and target the cannabinoid receptors competitively by inhibiting their hydrolysis or by modulating the binding site of receptor allosterically, and are also known as endocannabinoid-like molecules. Another agent with noted activity of suppression of appetite namely N-oleolylethanolamine (OEA) has also been listed as an endocannabinoid-like molecule. The biological activity of OEA engages the activation of PPAR α and transient receptor potential vanilloid type 1 (TRPV1), which is one of the renowned non-CB receptor targets for endocannabinoids and is also activated by both anandamide and 2-AG. OEA presents the highest affinity towards PPAR α in comparison to all endocannabinoid like compounds. Other endocannabinoid like compounds, namely 2-oleoylglycerol (2-OG), PEA and OEA, have a tendency to activate GPR119, which is a GPCR expressed predominantly in pancreas of rats and humans indicating the action of OEA on dietary intake and presented hypophagic effects in mice. PEA and OEA molecules have also been found to engage additional receptors such as GPR55 at high concentrations. Another naturally occurring endocannabinoid like molecule, namely N-stearoylethanolamine (SAE), has been also found to be a controller of cell growth with additional anti-inflammatory and immunomodulatory activities. SEA in combination with PEA plays an anti-nociceptive role in humans and also presents anorexia effects. The concentrations of PEA, SEA, OEA and 2-OG endogenously can be affected by the intake of different diet regimes and can impact differently the brain tissues compared to peripheral tissues. They are being extensively explored through advanced research to elucidate their actual physiological relevance in the human body. PEA is currently marketed for management of pelvic and neuropathic pain due to its lack of adverse effects centrally at CB1 receptors . Less inThe signaling of endocannabinoids is mainly ceased by a two-step process which includes its transportation into cells which is further hydrolyzed by specific enzymatic systems. Most of the steps are crucial and ensure a tightened monitoring of endocannabinoid concentrations in tissues, and promptly eliminate the substances that initiate signaling. The uptake of endocannabinoids is mediated by a transporter which is extensively dispensed throughout the brain ,22. The The cannabinoid receptors are mainly of two types, and belong to the super family of GPCR. The primary receptor, CB1, is majorly found in the peripheral and central neuronal cells terminus, glial cells, reproductive system (mainly testes), micro circulation, and other major glands of human body . The canThe central nervous system has plentiful supply of CB1 receptors, particularly in the region of the cortex, basal ganglia, cerebellum and hippocampus. These receptors are particularly present on the axonal terminals and on the pre-terminal segments of the axon and spare the active zone on the neuron cell. The CB1 receptors in the hippocampus and cortex are rich in cholecsytokinin (CCK)-positive inter-neurons and are also extensively articulated at lower levels in the glutamatergic neurons. In addition, the medium spiny neurons of the ventral and dorsal striatum region contain an abundant number of CB1 receptors . The expAccumulation of genetic and animal model experimentation data suggested a significant role of CB2 receptors in schizophrenia; however, the presence of CB2 receptors whether in neuronal, microglia or neuro-developmental neurons, is still under evaluation .Research efforts have intensified in the past two decades, especially since the discovery of the cannabinoid CB1 receptor and anandamide, leading to the identification of several drugs which directly interact with the chief elements of the endogenous cannabinoid system . SeveralThe role of CB1 receptors was suggested in regulating the contractility in the gastrointestinal tract more than a decade before they were discovered. The motility of the gastrointestinal tract in mice was inhibited by the oral consumption of the primary psychoactive cannabis molecule, namely Δ-tetrahydrocannabinol (THC), thereby adjusting its principal protective role in the human gastrointestinal system. The CB1 receptors are located in the vagal sensory terminals and neurons of the enteric nervous system of the human gastrointestinal tract, while CB2 receptors were found in immune cells . CB1 recThe CB1 receptors are inhibited by the endogenous and synthetic cannabinoids in a dependent fashion and electrically evoke contractions in the small intestine isolated from guinea pigs, thereby modifying the intestinal motility upon their exposure. Anandamide was also found to inhibit the release of acetylcholine through generation of electrical signals via stimulation of CB1 receptors and simultaneously acts on the TRPV1 receptors. The functional activity of anandamide in modulating the motility of the intestine is being explored by investigating its physiological and pathophysiological states. The inhibitors of FAAH enzyme have demonstrated reduced motility of intestines which can be overcome by administering antagonists of CB1 receptors. The hypomotility of the intestine, which is a typical characteristic of paralytic ileus, is also thought to occur due to enhanced levels and expression of anandamide and CB1 receptors, which demonstrates that the acetic acid induced ileus can be elevated by SR1415716A, a CB1 receptor antagonist and can be worsened by inhibiting the cellular uptake of anandamide by VDM11 ,50.The rate of gastric emptying and motility of the small intestines in humans and rodents was slowed upon administration of Δ9-THC intravenously. The cannabinol and Δ9-THC were also noted to reduce the motility of intestines in mice, but, relatively, were not particularly effective in emptying the gastric contents. Upon administration of CB1 agonists, namely CP55,940 and WIN55,212-2, and blocking the activity of SR141716A, a selective antagonist of CB1 receptor the above results were confirmed. The contraction of pyloric muscles and intragastric pressure was also found to be decreased upon intravenous administration of Δ9-THC. The ganglionic blockers, vagotomy and antagonists of CB1 receptors like SR141716 significantly modulated the changes in the motor functioning of the gastrointestinal tract. Apart from CB1 receptors, the role of CB2 receptors has also been established in controlling the mortality of the gastrointestinal tract and gastric emptying ,51. The The role of endocannabinoids has been established in regulating the secretion of acid from gastric mucosa through several studies. Bioassay studies performed on the stomach isolated from rats showed that high doses of Δ9-THC successfully counteracted the secretion of gastric acid in response to histamine activation. The gastric secretions in rats mainly induced by pentagastrin were successfully blocked upon administration of WIN55,212-2 and HU-210 through peripheral mechanisms. These effects were mainly inhibited by the antagonists of CB1 receptor, which demonstrated the anti-gastric acid secretary effects of cannabinoids by preventing the activation of CB1 receptors which are mainly located on the cholinergic pathways of preganglionic and postganglionic sites. Excessive gastric acid production causes conditions like peptic ulcers and gastritis in the duodenum region of intestine and stomach. The vagal efferent pathways comprising of CB1 receptors are prominently involved in reducing the production of gastric acid in the stomach and prevent such gastrointestinal disorders . Upon acThe endocannabinoid system has also been found through various studies to modulate the intake of food through activity of cannabinoid receptors located in the brain and in peripheral tissues. The CB1 receptors, upon selectively interacting with the capsaicin sensitive sensory terminals, can modulate the intake of food and thereby present an unexpected role of endocannabinoids in control and monitoring of diet, and can regulate feeding ,56. The Endocannabinoids possess anti-nauseous and antiemetic effects which were established upon clinical investigation in cancer patients who were subjected to chemo and radiation therapies, and also in patients who received human immune virus (HIV) treatment. Both central and peripheral sites of the patients were involved for activity of endocannabinoid receptors ,60. The The cannabinoid receptors have been found to be widely distributed throughout the cardiovascular system. The CB1 receptors are present in the coronary artery, endothelial cells, myocardial cells, and smooth muscle cells besides the sympathetic nerve terminals present on presynaptic site which intervene with the cardiovascular system . The preA significant action of endocannabinoids has been established on the blood pressure and rate of heart beats of animals selected in several cardiovascular studies, and the responses noted were dependent on the condition of the animal, whether they were conscious or anesthetized, which may be due to alteration in the sympathetic activity of basal levels due to anesthesia as the endocannabinoid also respond by modulating the autonomic nervous system and act through vagal and sympathetic activity . AnandamA hypotensive effect has been found to be prolonged upon administration of anandamide in anesthetized rats compared to rats in normotensive conditions. The agonists of CB1 receptors and FAAH enzyme inhibitors normalize the blood pressure and decrease myocardial contractions in anesthetized hypertensive animals . HoweverShock is a condition which is mainly characterized by diminished cardiac output, which further reduces the blood pressure of an individual and affects tissue perfusion. The decrease in blood pressure due to hemorrhagic shock can be prevented by administering antagonists of CB1 as per a study performed by Wagner and colleagues in 1997. The researchers stated that synthesis of anandamide and 2-AG by platelets and monocytes was the responsible cause for activation of CB1 receptors in condition of shock. Later, many studies were performed to evaluate the role of CB1 receptors in conditions of cardiogenic and endotoxic shock post episodes of myocardial infarction . Upon ceUpon activation, the CB2 receptors ominously reduce the prevalence of ventricular arrythmia during occlusion of coronary arteries. The arrhythmias induced by epinephrine is also condensed by the independent stimulation of cannabinoid receptors in response to anandamide release. Recently, both anandamide and 2-AG were shown to be ineffective towards ventricular fibrillation and ischemia, although an antagonist of CB1 receptors did present positive impact despite subsequent ischemic stages. The samples isolated from rabbits showed subsided duration of action potential amplitude upon stimulation of CB1 receptors by anandamide . Upon inThe endocannabinoids also play a significant role in controlling the functioning of the immune system and help to maintain immune homeostasis. The immune cells express both the types of endocannabinoid receptors CB1 and CB2, and lead to further secretion and transportation of these molecules and regulate the breakdown mechanisms. The receptors of endocannabinoid are highly expressed in immune B cells, followed by monocytes, natural killer cells, neutrophils polymorphonucleated, CD4 and CD8 lymphocytes. The CB1 receptors facilitate neurobehavioral effects due to their dense expression in the central nervous system . The CB2The major role of our immune system is to protect the host from foreign antigens and pathogens. The reactive role of endocannabinoids against infectious pathogens and antigens has been established for over 40 years. The combination of lipopolysaccharides with THC has been found to be extremely toxic in mice, and administration of THC showed lethal activity to heat and kill bacteria. In addition, resistance to several other pathogens including listeria and herpes simplex virus was also demonstrated ,83,84. TThe analgesic and anti-emetic effects of endocannabinoids have led to their administration in cancer patients as palliative medicine. The anti-tumor property of several endocannabinoids has also been suggested; since most of the studies were done as in vitro or in immune competent animal models, the data from humans is still hearsay ,87,88. TSeveral preclinical studies performed in patients with autoimmune diseases established the clinical application of cannabinoid substances in immune-mediated disorders. The cannabinoids were evaluated to successfully generate a balance between the regulatory T-cells and inflammatory Th17, indicating the presence of a regulatory phenotype. The clinical action of endocannabinoids was studied by administering these molecules in various autoimmune and inflammatory disorders. Rheumatoid arthritis is the dominant autoimmune disease and present as a major cause of disability globally, leading to increased inflammation in synovial joints followed by pain and destruction of joint cartilage. The endocannabinoid treatment was found to be successful in selectively blocking the arthritic progression in a collagen-induced arthritis animal model. The conditions of synovitis and joint destruction were also found to be attenuated in collagen-induced arthritic mice upon activation and stimulation of CB2 receptors. The elevation of endocannabinoids upon administration of FAAH inhibitors was also found to be helpful in alleviating symptoms in murine arthritic models. The endocannabinoids anandamide and 2-AG besides an increased levels of FAAH were detected in the synovial fluid of a patient suffering with osteoarthritis and rheumatoid arthritis, indicating their application in management of the diseases . PatientThe role of cannabinoid molecules has been determined explicitly in several neurodegenerative disorders. These molecules act by modulating the acute processes involved in functioning of the brain by enhancing neurogenesis, and hence impose a potent beneficial role in management of neurological disorders. The endocannabinoid system has been studied to decrease the instances of neuroinflammation and prevent the detrimental effects that led to new row degradation by supporting pathways that encourage natural repair and protection of neurons. The endocannabinoids present neuroprotective action by encouraging neurogenesis and preventing neuroinflammation and neurotoxicity ,93.The cannabinoid molecules have shown promising activity in regulating the pathways associated with neurogenesis. The progenitor cells in the hippocampal region in adults, and the embryonic cells, produce endocannabinoids, which are mainly expressed upon stimulation of CB1 receptors and suppression of FAAH enzyme . ProlifeThe cannabinoids possess neuroprotective roles via their extensive linking to the inflammatory and excitatory nonreceptor-mediated pathways. They have shown proven protection against conditions of acute hypoxia, oxidative stress, traumatic insults, and excitotoxicity. The levels of endocannabinoid 2-AG were dramatically elevated in mice with a closed head injury. Further administration of 2-AG exogenously diminished edema in the brain, decreased the infarct volume, prevented death of hippocampal neuronal cells, and facilitated a better clinical recovery . The losParkinson’s disease is a late onset chronic progressive neurodegenerative disease characterized by symptoms of involuntary motor tremors, rigidity in muscles, unstable posture, abnormal gait, and akinesia. The disease is typically idiopathic and is also genetically associated. The substantia nigra parts compacta region of the brain is mainly affected in this disease, with over 70 to 80% of occurrence of neuropathological atrophy leading to extensive loss of dopaminergic neurons even before the diagnosis and onset of clinical symptoms of the disease . The dopAnxiety affects over more than 40 million people alone in United States and is an important condition for research as anti-anxiety drugs are among the topmost prescription drugs sold in the market. Cannabis has been extensively used since millennial times as a medicinal agent and is believed to help the consumer and produce soothing effects. However, direct data from experimental studies on exploration of endocannabinoids in patients with anxiety is still limited. The several physiological actions of endocannabinoids and their major role in release of neurotransmitters apparently suggests their effect in management of anxiety, which is an outburst of stressful conditions in humans. An anxiolytic effect of FAAH Enzyme inhibitors, namely URB532 and URB597, has been detected in rats undergoing an elevated zero maze test due to elevation of anandamide levels in the brain in lieu of blocking the activity of CB1 receptors. This led to the confirmation of anxiolytic activity of anandamide . The eviSeveral studies performed to date have established the presence of depressive symptoms under lower concentrations of endocannabinoids, and anti-depressant effects upon higher levels of endocannabinoids, supporting the evident role of endocannabinoids in management of depression. The hypothesis supporting this activity is the considerable neurogenic effects produced by endocannabinoids since the process of neurogenesis is downregulated in depressive patients ,109,110.Research into cannabis was initially initiated with a limited aim of understanding the action of this illicit drug. After thorough research on the chemistry of the plant and its logical and psychological activities, the compound THC was isolated. This research began most intently in 1960s and early 1970s. By the mid-1980s, two major specific receptors and their associated ligands linked with the endocannabinoid system were identified, and their biological processes showed a wide spectrum of clinical implications. The discovery of the endocrine system has opened wide areas of research in life sciences, particularly in the area of the central nervous system. The main action initiated upon activation of the cannabinoid receptors chiefly CB1 receptors leads to inhibition of neurotransmitter release. In lieu of this activity, the endocannabinoids are believed to reduce excitation of presynaptic neurons and are responsible for the major renowned marijuana effects, including anxiety and cognition impairment. Immunosuppression is also a major consequence of activation of cannabinoid CB2 receptors, which helps to reduce inflammation and prevents associated injury in tissues. The enhancement of expression of CB2 receptors has been targeted to cure numerous diseases, and has generated a protective effect in a wide array of physiological systems. The current review summarizes the physiological roles attained by endocannabinoids and their relevance in treatment and management of several chronic diseases.


We endeavoured to ascertain if using a specific tool rating insight adds benefit over and above the insight ratings on violence risk assessment or recovery based tools currently in use and to see if they may be helpful in guiding clinical decision making.A cross sectional study of 104 forensic in-patients was completed. All current inpatients were rated for self-rated and clinician-rated insight using the VAGUS tool, a validated and reliable measure of insight into psychotic symptoms. All participants completed the self-rated scale independent of the clinician to avoid bias. Patients were also rated with the HCR-20, the Dundrum-3 and Dundrum-4, and the PANSS measures. Patients’ scores on the VAGUS tool and the other tools were compared to ascertain if any correlations could be identified.Higher scores on the VAGUS tool were associated with a greater degree of insight into psychotic symptoms. Clinician and self-ratings of insight on the VAGUS tool were different from but complimentary to the ratings for insight on the HCR-20 , the DUNDRUM-3  and DUNDRUM-4 . An inverse relationship between the VAGUS scores and the scores on the PANSS measures  was found, correlating lower levels of insight with a higher degree of positive and negative psychotic symptoms. There was also a correlation between greater insight and progress through the care pathway to lower secure wards.Using a specific tool to rate insight adds benefit over and above the insight ratings on other tools currently in use and may be helpful in guiding clinical decision making in the forensic setting.


Alzheimer’s (AD) and Parkinson’s Diseases (PD) are common neurodegenerative disorders growing in incidence and prevalence and for which there are no disease-modifying treatments. While there are considerable complexities in the presentations of these diseases, the histological pictures of these pathologies, as well as several rare genetic predispositions for each, point to the involvement of maladaptive protein processing and inflammation. Importantly, the common presentations of AD and PD are connected to aging and to dysmetabolism, including common co-diagnosis of metabolic syndrome or diabetes. Examination of anti-diabetic therapies in preclinical models and in some observational clinical studies have suggested effectiveness of the first generation insulin sensitizer pioglitazone in both AD and PD. Recently, the mitochondrial pyruvate carrier (MPC) was shown to be a previously unrecognized target of pioglitazone. New insulin sensitizers are in development that can be dosed to full engagement of this previously unappreciated mitochondrial target. Here we review molecular mechanisms that connect modification of pyruvate metabolism with known liabilities of AD and PD. The mechanisms involve modification of autophagy, inflammation, and cell differentiation in various cell types including neurons, glia, macrophages, and endothelium. These observations have implications for the understanding of the general pathology of neurodegeneration and suggest general therapeutic approaches to disease modification. Drug discovery efforts generally focus on narrowly defined syndromes in search of precision solutions. However, effective therapeutics for neurodegenerative diseases remain a significantly unmet medical need likely because of the broad and complex presentations and the limited heritability of these progressive diseases. Alzheimer’s disease (AD) is the most common cause of age-related dementia and manifests in a variety of presentations and symptoms . Work inUnfortunately, while advances in understanding the genetics of some rare subsets of AD and PD have identified rational therapeutic targets and some animal models have been created, effective disease modifying agents in clinical trials have not been forthcoming. Efforts are complicated by the fact that individual mutations in the spectrum of AD and PD, even when they reflect a component of the pathological phenotype, describe at best a very small percentage of people with these diseases. Disease modifying therapeutics have remained elusive and these neurodegenerative diseases remain a significant affliction of aging and a major unmet need in global health care.Herein, we discuss an alternate approach to treating neurodegenerative diseases by correcting the upstream metabolic drivers that are in common across neurodegenerative diseases. We summarize data generated from the growing descriptions of the pathophysiology of AD and PD and the emerging understanding of the molecular action of compounds known as insulin sensitizers. The confluence of these data suggests an approach to slowing disease progression by reprogramming metabolism. Metabolism impacts myriad cellular and molecular processes that modulate known pathophysiological mechanisms including autophagy, inflammation, and cell differentiation in multiple cell types. Thus, a metabolic approach would not only impact multiple molecular pathways in parallel but would also have the potential to positively impact both AD and PD.th leading cause of death in the US for people over the age of 65. Critically, AD has an oversized impact on public health because of the level of care required as the disease progresses because patients may require intensive and round the clock care for many years. While there are clear differences in a clinical diagnosis of the various forms of AD that differ from aging per se, age has a significant impact on disease progression regardless of the specifics of clinical diagnosis (Alzheimer’s disease (AD) is a common disease associated with aging that involves progressive loss of neurons and deposition of plaques composed of the Aβ protein. The prevalence of AD is continuing to increase, and it is currently the 5iagnosis . The phyiagnosis . Rare muiagnosis . As a coiagnosis . While tPD is neurodegenerative disease with characteristic motor dysfunction. However, the clinical presentation often includes many non-motor defects ranging from constipation to neuropsychiatric issues . The phyA summary of common factors that influence disease progression in both AD and PD is presented in Although the details of molecular mechanisms remain the subject of much debate and investigation, metabolic dysfunction or dysmetabolism is likely both a cause and consequence of insulin resistance and type 2 diabetes mellitus . As disAbnormalities in brain insulin sensitivity are an early sign of AD. Indeed, many have described AD as “Type III diabetes”  due to mThe association between type 2 diabetes and PD has also recently been reviewed . ObservaMitochondrial function is a key common feature of metabolism that connects AD, PD, and aspects of the metabolic syndrome including diabetes . MutatioMitochondrial dysfunction initiates intracellular signaling cascades that can impair many processes known to be important in the progression of the disease including autophagy, inflammation, and cellular responses to growth factors. Obviously, mitochondrial dysfunction has implications for many cell types in all tissues . It is iA review of the clinical studies of anti-diabetic drugs on the incidence of dementia in people with diabetes demonstrated a unique efficacy of pioglitazone . Of partIn the 1990s, three drugs that improved insulin sensitivity  were approved for the treatment of type 2 diabetes. These drugs all share a common chemical structure; a thiazolidinedione (TZD) ring. As we have previously reviewed, thiazolidinediones were selected and developed in the mid 1980s based on their insulin sensitizing effects before there was a molecular hypothesis of their mechanism of action . Years aPertinent to this discussion, there have been numerous preclinical studies with TZDs showing multiple beneficial effects in models of neurodegeneration. In alignment with the earlier discussion on the importance of mitochondria in these pathologies, many of these studies have suggested that the actions of these agents on the mitochondria might be a key factor in the pharmacology (reviewed in 34). A more recent intriguing observational clinical study conducted in Germany demonstrated a 47% reduction in the incidence of dementia in people with diabetes who had been treated long-term with pioglitazone. In fact, for subjects treated more than 2 years, their risk of developing dementia was even lower than subjects who had not developed diabetes . An exce125I-labeled photoaffinity crosslinker and unbiased proteomics revealed that the mitochondrial target of the TZDs was the mitochondrial pyruvate carrier (MPC)  . Studieser (MPC) . The effer (MPC) . Thus, nTwo inner mitochondrial membrane proteins, MPC1 and MPC2, constitute the MPC, which is the obligate entry point of pyruvate into the mitochondrion . Since tIt is likely that MPC inhibition modulates the activity of various energy-sensing signaling cascades such as AMP-activated protein kinase (AMPK), NAD + -sensing deacetylases, or the mechanistic target of rapamycin (mTOR) kinase. Since these signaling pathways are known to regulate insulin sensitivity, inflammation, and autophagy, which are cellular processes known to be involved in the response to neurodegenerative stimuli, inhibition of the MPC may mediate beneficial effects by modulating the activity of these energy-sensing signaling cascades.Alternatively, or in addition, other work has demonstrated a beneficial effect of MPC inhibition on neuronal death in response to excitatory amino acids. Divakaruni and colleagues showed that MPC inhibitors protected neurons at least in part by stimulating the metabolism of glutamate and other amino acids as an adaptive response to diminished flux through the MPC . Since eOur understanding of the specific role of that the MPC plays in regulating metabolism in various cell types is now growing based on a variety of cell type-specific knockouts . The abiagainst the direct activation of PPARγ  was prevented in the MSDC-0160-treated patients (N = 16). These results are supportive of a neuroprotective effect. There were also several other brain regions, typical of amyloid deposits, that demonstrated a treatment-induced decrease in the 18F-2-FDG PET uptake. This would be expected of an anti-inflammatory action, which the authors suggest should be directly evaluated in future clinical trials. The study was not powered to detect changes in cognition, however ADAS-Cog measurements tended to worsen in the placebo group while there was no change in the MSDC-0160-treated group (MSDC-0160 has been studied in a Phase 2 dose-ranging study in subjects with diabetes where it demonstrated the same anti-diabetic activities as pioglitazone without evidence of dose-tolerability issues . A 3-moned group .+/−) genetic mouse model of PD that demonstrates a progressive loss of the differentiated status of dopamine neurons. Progression of neurodegeneration in all of these cellular and mouse models of PD was accompanied by both an increase in mTOR activation and increased inflammation. In each case, the beneficial effects of MSDC-0160 treatment coincided with a reduction in mTOR activity and a decrease in inflammation toward the levels that occurred in the control models. MSDC-0160 treatment also prevented dopamine neuron loss in both an MPP+ and α-synuclein–based Caenorhabditis elegans model. Selective knockdown of either the C. elegans orthologs of MPC1 or mTOR prevented the protective effects in these worms. MSDC-0160 treatment was not effective in rodent models of alpha-synuclein overexpression that did not exhibit underlying inflammation or defective autophagy (There has been more detailed study of the mechanistic action of MSDC-0160 in pre-clinical models of PD. utophagy .In further support of the importance of pyruvate metabolism in affecting PD pathology, The collection of data summarized here point to the importance of metabolism in the progression of both AD and PD. While the milieu including glycemic state is likely important , we havein vitro (Outcomes of disease progression and mitigation involve effects on multiple cell types and also might involve intercellular communication between various cell types of the brain. This has important implications for a range of processes from maintenance of synaptic connections to regulation of cerebral blood flow and involves cell types not routinely considered in drug development programs aimed at specific neurodegenerative diseases . Ongoingin vitro .In conclusion, there are multiple molecular mechanisms associated with metabolism that impact the progression of AD and PD. This is likely true of age-related neurodegenerative issues in general, some of which may fall outside narrow clinical definitions. The identification of the MPC as a target of the insulin sensitizer TZDs provides a logical explanation for the pleotropic effects of these compounds. The elucidation of these common pathways that mediate disease progression may facilitate new approaches to disease-modifying treatments for AD and PD.