The extent to which muscle synergies represent the neural control of human behavior remains unknown. Here, we tested whether certain sets of muscle synergies that are fundamentally necessary across behaviors exist. We measured the electromyographic activities of 26 muscles, including bilateral trunk and lower limb muscles, during 24 locomotion, dynamic and static stability tasks, and we extracted the muscle synergies using non-negative matrix factorization. Our results show that 13 muscle synergies that may have unique functional roles accounted for almost all 24 tasks by combinations of single and/or merging of synergies. Therefore, our results may support the notion of the low dimensionality in motor outputs, in which the central nervous system flexibly recruits fundamental muscle synergies to execute diverse human behaviors. Further studies are required to validate the neural representation of the fundamental components of muscle synergies. To execute human movements, the central nervous system (CNS) must control many degrees of freedom from thousands of motor units within hundreds of skeletal muscles . SeveralIt has been proposed that muscle synergies are shared across various motor tasks ,10,15. SWhile the low dimensionality and robustness of muscle synergy models account for the advantages of redundant control of movement, the flexibility of combining muscle synergies to adapt to various mechanical demands is also considered necessary to achieve efficient movement execution ,22,23. AThe aim of the present study was to test the hypothesis that different subsets of muscle synergies are used in a variety of movement and postural tasks. To test this hypothesis, we first extracted muscle synergies from an EMG recording dataset made from 24 motor tasks based on the assumption that these muscle synergies represent the basic units for explaining 24 motor tasks that share common neuromechanical requirements such as supporting the body and maintaining balance statically, dynamically, and during locomotion ,26. We tTen healthy volunteers  participated in the study. Each participant provided written informed consent for participation in the study. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee of the University of Tokyo.We focused on fundamental movement and postural tasks that serve as the building blocks for efficient and effective execution of a variety of daily-living activities and high-skilled performances, such as sports ,27,28. SEMG activity was recorded from the following 26 muscles distributed across the trunk and lower limbs : tibialis anterior (TA), gastrocnemius medialis (MG), vastus medialis (VM), rectus femoris (RF), biceps femoris , gluteus maximus (GM), gluteus medius (Gmed), rectus abdominis (RA), oblique externus (OE), erector spinae at L2 (ESL2), erector spinae at Th9 (EST9), erector spinae at Th1 (EST1), and latissimus dorsi (LD). EMG activity was recorded using a wireless EMG system . The EMG signals were bandpass filtered (20–450 Hz), amplified (with a 300-gain preamplifier), and sampled at 1000 Hz. Three-dimensional ground reaction force (GRF) data were recorded at 1000 Hz from the force plates under each belt of the treadmill. GRF data were used to define each trial/stride data point in the walking and running tasks . We also used an electrical trigger to define each trial of the other tasks as the period between the start and end of the movement. The starting point was initiated with the verbal cue ‘go’ with the electrical trigger manually pressed once by the examiner. After participants completed the tasks and returned to a resting posture for about 1 s, the end of the movement was indicated by a 1-second verbal cue ‘end’ with the electrical trigger pressed twice.The low-pass cut-off frequency influences the smoothing of EMG patterns and thus impacts the number of extracted modules . To adeqWe created the following two types of EMG matrices for each subject to examine the repertoire of fundamental muscle synergies that could explain all datasets and how these synergies are combined in each task. Similar to previous studies ,22,32, wIn our analysis, we first identified the muscle synergies of each task for each subject using a factorization algorithm of single-task EMG matrices, and then synergies of all tasks were extracted from all-task EMG matrices using the same algorithm. We then proceeded to characterize representative muscle synergies of individual tasks and all tasks across all participants using a hierarchical clustering algorithm. Lastly, we analyzed the similarity between synergy cluster centroids of each individual task and single or merged synergies of the all-task matrix to investigate how muscle synergies utilized by all tasks contribute to the execution of each individual movement.M  is a linear combination of the following muscle weighting components: W  and C . e is the residual error matrix. Each EMG vector in the matrix corresponding to each muscle activity was normalized to the maximum amplitude across all tasks so that all muscle scales ranged from 0 to 1. Prior to extracting muscle synergies, each muscle vector in the data matrix was standardized to have unit variance, thus ensuring that the activity in all muscles was equally weighted. However, after each synergy extraction, the unit variance scaling was removed from the data so that each muscle variable ranged from 0 to 1 for data inspection and interpretation [n from 1 to 26 from each dataset. The variance accounted for (VAF) by the reconstructed EMG (M) was calculated at each iteration to extract the optimal number of muscle synergies. VAF was defined as a 100 × square of the uncentered Pearson’s correlation coefficient [n as the number fulfilling the following two criteria: First, n was selected as the smallest number of modules that accounted for >90% of the VAF [n was the smallest number to which adding another module did not increase VAF by >5% [To explore muscle synergies, nonnegative matrix factorization (NMF) was used for each subject from the single-task EMG matrices and the all-task EMG matrix. NMF has previously been described as a linear decomposition technique ,34 accorretation . To detefficient ,37. To pfficient . We defi the VAF . Second,F by >5% .We identified the representative synergy vectors across participants using hierarchical clustering analysis  of muscle synergies for each task and all tasks ,39. The To explore whether the muscle synergy defined by the all-task matrix contributes to executing each task of movements and postures, the similarity between muscle synergies of single-task and all-task matrices was quantified by using the SP between these centroids of the synergy clusters . For every comparison, each of the synergy cluster centroids of all-task was matched to a synergy cluster centroid of each task by maximizing the total scalar product values. Synergy clusters that could not be matched with SP ≥ 0.75, were classified as unmatched .kW is the kth muscle synergy vector from each individual task, iW is the ith muscle synergy vector derived from an all-task matrix, bN is the number of synergies that contribute to the merging, and iD is a non-negative coefficient that scales the ith synergy in the merging. iD was obtained from a non-negative least-squares fit, implemented using MATLAB (function lsqnonneg). kW and iW were normalized as unit vectors. Following criteria from previous studies [bN ≥ 2, iD ≥ 0.2 for all i, and the SP between kW was ≥0.75.We also expected that all-task muscle synergies can be merged to execute each single task of movement and posture . Thus, t studies ,41, the To assess whether the synergies from each task can be explained as merging of synergies from all tasks, we first identified the synergy cluster centroids of single-task and synergies of the all-task (described above) and reconstructed each synergy cluster centroid of each individual task by merging every possible combination of the synergy cluster centroids of all tasks.All of the muscle activity was accounted for by 10.6 ± 1.58 muscle synergies of all-task EMG matrices, and the mean VAF was 0.91 ± 0.001 in ten participants. Visual inspection revealed that muscle synergies W1 to W5 were largely composed of the right-side muscles, while muscle synergies W6 to W10 were mainly composed of the left-side muscles. Thus, we categorized W1 to W5 as muscle synergies with right-side dominant patterns and W6 to W10 as muscle synergies with left-side dominant patterns. The following pairs showed high similarity when the muscles in W6 to W10 were reordered so that muscles on the left side of W6 to W10 corresponded to the same muscles on the right side of W1 to W5: W1 and W6 (SP = 0.93), W2 and W7 (SP = 0.97), W3 and W8 (SP = 0.97), W4 and W9 (SP = 0.85), W5, and W10 (SP = 0.93). Others, such as W11, W12, and W13, were categorized as bilateral patterns.For each task, two to four synergy clusters were identified using cluster analysis. Variability in the number of muscle synergies and VAF in subjects, and the degree of similarity within each synergy cluster of each task are presented in Of note, all synergies of each task except the one for the left single-leg stance could be explained by either single or linear combination of multiple synergies from the all-task EMG matrices (SP > 0.75). The details of the contributions of muscle synergies of all tasks to each task execution are presented in The relationships between muscle synergies from the all-task EMG matrices and those from the other single-task EMG matrices are shown in Several studies have investigated shared or merged muscle synergies across different tasks, such as walking and running ,42, walkWe applied cluster analysis to the muscle synergies from the all-task EMG matrix across participants and identified 13 synergy clusters. As shown in If we assume that the muscle synergy extracted from the whole-task EMG matrices in our data may have a unique set of networks in which each synergy provides functionally necessary compositions in muscle activities, then one can expect that any combinations of these synergies may provide stable and predictable motor outputs in a diverse range of human behaviors . The strC in Equation (1) [task in ) located at different levels from the driving layers in the motor hierarchy to execute highly variable tasks  ,47. BaseOur hypothesis is possibly equivalent to a generalized two-level CPG model for the control of locomotor muscle activity . The modC presents synchronous recruitments of the fundamental muscle synergies that have distinct functional roles in organizing muscle synergies for the 24 locomotion and stability tasks, it is possible that the CNS may also coordinate other simple or complex human behaviors using certain combinations of these synergies. Thus, muscle synergies during human behaviors found in previous extensive research may reflect layered structures composed of the fundamental muscle synergies extracted from our study. The advantage of these hypothetical mechanisms is that it prevents the sum of all muscle synergies from exceeding the number of relevant muscles utilized during diverse human behaviors, supporting the premise of compendium in coordinative patterns to execute several movements under different biomechanical conditions [Since we propose that upstream driver nditions . Furthernditions .The results of this study may have several clinical implications. First, several studies have investigated muscle synergies in individuals with different characteristics, such as musculoskeletal and neurological disorders ,51,52 asOur study had several limitations. First, it has been reported that the number of recording muscles may affect the amount and structure of muscle synergies . AlthougIn this paper, we extracted a repertoire of fundamental muscle synergies from the EMGs applying a factorization algorithm during a variety of human behaviors that involve trunk and lower limb movements in healthy individuals. We found that the 13 fundamental muscle synergies in either the independent or merging state can account for almost all 24 behaviors, including locomotion and stability tasks. Our findings may support the notion that the CNS may flexibly recruit the fundamental muscle synergies to meet the various mechanical demands in a diverse range of human behaviors.


The transient receptor potential channels (TRPs) have been related to several different physiologies that range from a role in sensory physiology (including thermo- and osmosensation) to a role in some pathologies like cancer. The great diversity of functions performed by these channels is represented by nine sub-families that constitute the TRP channel superfamily. From the mid-2000s, several reports have shown the potential role of the TRP channels in cancers of multiple origin. The pancreatic cancer is one of the deadliest cancers worldwide. Its prevalence is predicted to rise further. Disappointingly, the treatments currently used are ineffective. There is an urgency to find new ways to counter this disease and one of the answers may lie in the ion channels belonging to the superfamily of TRP channels. In this review, we analyse the existing knowledge on the role of TRP channels in the development and progression of pancreatic ductal adenocarcinoma (PDAC). The functions of these channels in other cancers are also considered. This might be of interest for an extrapolation to the pancreatic cancer in an attempt to identify potential therapeutic interventions. The cha2+ in a pathway which sees SIRT6 modulating intracellular ADPr levels [TRPM2 mutations have been associated with the survival time in patients with PDAC. Higher mRNA values of the channel correlate with lower survival times of the patients . The in r levels .The study of this channel in pancreatic cancer started in zebrafish with a report stating that TRPM7 is functionally required for pancreatic epithelial proliferation . In 2012The first TRPM channel being reported in pancreatic cancer was TRPM8. In 2010, much like TRPM7 and TRPM2, TRPM8 was reported to be overexpressed in pancreatic cancer cell lines (PANC-1 and BxPC-3) when compared to pancreatic ductal epithelia . FurtherIn addition, TRPM8 expression could have a positive correlation with cancer development and metastasis formation. In BxPC-3 and MIAPaCa-2 cell lines, TRPM8 is crucial for the invasive ability of the cancer cells . FurtherTRPM8 targeting can also be used to enhance the effects of gemcitabine, a common drug used in chemotherapy, in vitro . Combini2+-selective TRP channels. TRPV2 has an important role in the pancreatic endocrine system, more specifically in the process of insulin secretion [The Vanilloid subfamily of TRP got its name in 1997 because one of its members, TRPV1, was shown to be activated by the vanilloid compound capsaicin . This suecretion . Althougecretion ,71,72. Fecretion . The preecretion ,73.In 2006 studies connected the role of TRPV1 channels to pancreatic cancer. Hartel et al. demonstrated the overexpression of the TRPV1 in patients with both PDAC and chronic pancreatitis. This overexpression was higher in PDAC than in the chronic pancreatitis. Moreover, there was a positive correlation between pain levels and expression of TRPV1 in PDAC patients . More reKras and Trp53 genes, which allows the study of PDAC in immunocompetent animals, while experiencing several features observed in human PDAC. TRPV1 might be controlling Zeb1 in pancreatic cancer as it has been shown in hepatocellular carcinoma. The knockout of TRPV1 channels in mice leads to an upregulation of Zeb1 and subsequent promotion of hepatocarcinogenesis [Another important program in PDAC progression is epithelial-to-mesenchymal transition (EMT). One of the EMT activators is Zeb1. Krebs et al. demonstrated that the depletion of Zeb1 leads to reduced invasion, distant metastasis and colonization capabilities in KPC mice . These mogenesis . So far,Chronic pancreatitis is a major risk factor for the development of PDAC and other pancreatic cancers. The risk of PDAC in a chronic pancreatitis patient is elevated 16-fold . Chronic2+ mobilization in PSCs which is TRPV4-dependent. Furthermore, this process is enhanced by TNF-α. TRPV4 might be an important player in the development of PDAC from pancreatitis as it modulates Ca2+ mobilization in stellate cells and is up-regulated in pancreatic cancer tissues [2+ overload which leads to mitochondrial depolarization and trypsinogen activation in pancreatic acinar cells [2+ elevation. In a mouse model of pancreatitis due to pressure (by pancreatic duct obstruction), TRPV4-KO mice are significantly more protected [A correlation between high fat/alcohol and TRPV4 was found in pancreatic stellate cells from Lewis rats . The hig tissues . More re tissues . The conar cells . TRPV4 irotected . This rerotected ,86.TRPV6 is one of the newest TRP channels studied in the context of PDAC. However, it has several connections to the pancreas. This channel has been described to regulate proliferation of INS-1E cells, which are a model of pancreatic β-cells, and BON-1 cells, which are a model of endocrine tumor cells ,88. FurtThe TRPML subfamily is represented in mammals by TRPML1, 2 and 3 . Mutations on TRPML1 or TRPML3 can lead to several disorders such as Mucolipidosis type IV (TPLM1) or deafness and pigmentation defects (TPLM3). On the other hand, no disease phenotype has been associated with TRPML2 . FurtherTRPML1 is the founding member of the mucolipins subfamily of TRP. In pancreatic cancer this channel might predict poor survival of the patients with PDAC. In a study with 80 PDAC patients, high levels of TRPML1 are associated with a short overall survival and relapse-free survival compared to the patients with lower levels of the channel. Furthermore, downregulating the expression of TRPLM1 in BxPC-3 and PANC-1 pancreatic cancer cell lines leads to lower proliferation levels. When transfecting PANC-1 cells into the mice, the tumors have significantly less volume when the TRPML1 channel was silenced .TRPML3 belongs to a set of nine genes whose signature was identified in an in-silico analysis to predict overall survival of PDAC patients . Based oThis subfamily consists in seven members (TRPC1-7), all expressed in humans, except for TRPC2, which is a pseudogene. Although these channels contribute to the progression of several different cancers, their function in pancreatic cancer cells has not yet been studied in greater detail. However, a role of this subfamily has been described for pancreatic stellate cells.2+ by TGF-β. Furthermore, they confirmed that TGF-β can induce PTEN suppression and increase cell motility PKC-α dependently [2+ influx after pressure incubation. These differences were not noticed under control conditions [The role of TRPC1 in migration of PDAC cell lines (BxPC-3) was investigated ,103. Firendently . The onlendently ,104. Usinditions .2+ sensitive K+ channel of intermediate conductance, KCa3.1. Moreover, the suggested hypothesis is that the KCa3.1 takes advantage of Ca2+ entering the cells through TRPC3 channels to activate calpain and promote deadhesion of the stellate cells [Not much is known about the role of TRPC3 in PDAC, but a recent study in RLT-PSC (pancreatic stellate cell line) opened the discussion on this channel. TRPC3 plays a role in the migration of stellate cells. It does so through an interplay with the Cate cells .2+ influx and cytokine secretion in a TRPC6-dependent manner in pancreatic stellate cells. These TRPC6-dependent processes can lead to a continuous autocrine activation of pancreatic stellate cells and PDAC progression [As observed with TRPC1 and TRPC3, TRPC6 also modulates pancreatic stellate cell behaviour . In primgression .TRPC6 channels are also crucial for CXCR2-mediated responses of neutrophils. This has a great importance due to the role of neutrophils in the development of PDAC . NeutropThe current treatment of PDAC varies depending on the phase the cancer is diagnosed. Surgery is the still the only way to cure PDAC, but that it is a choice for patients diagnosed with resectable tumors only. Such an early diagnosis only occurs in ~20% of the cases ,108. ThiNonetheless, to this day, no pharmacological agents targeting TRP channels have succeed in becoming a normalized treatment. A phase I clinical trial has been undertaken for an antagonist for TRPV6 in solid tumors. As mentioned above, this trial demonstrated that the use of SOR-C13 leads to reduced tumor size and CA19-9 marking. This treatment was made on patients with advanced tumors. One of the biggest obstacles to the development of TRP-related therapies might be to find specific inhibitors for each TRP channel. Not all TRP channels possess a specific antagonist like TRPM3  or TRPV4For palliative care, a targeted therapy against TRPV1 might be of interest. As stated before, the intensity of pain reported by PDAC patients is correlated with the expression of TRPV1 . Using aDespite of multiple efforts to understand and treat PDAC, the overall survival of the patients has not been vastly improved. Nonetheless, a lot of data has been surging in the past years. Taking advantage of that, in the last decade, the TRP channels have been appearing in a diversity of scientific works concerning their expression in the tumor tissue and the possible effects that they exert on the development and progression of PDAC. Almost every TRP subfamily present in humans seems to play a role in this disease. These ion channels might be a crucial tool, not only in the diagnosis of PDAC, but also as a therapeutic target that can be combined with traditional treatments. Numerous possibilities might arise from further studies on the TRP family, as there are still many unanswered questions. How can we translate this knowledge from bench to bed-side? There is a gap in our understanding of redundancy among these channels. Several studies demonstrated that the knockdown of a TRP channel leads to the upregulation of other TRP channels in order to balance it ,114,115.The critical need for better diagnosis tools and new therapeutics might have a solution in this big family of ion channels that can affect both pancreatic cancer cells and pancreatic stellate cells and have roles in cell proliferation, migration, invasion, and death, as summarized in


Chronic inflammatory lung diseases are characterized by uncontrolled immune response in the airways as their main pathophysiological manifestation. The lack of specific diagnostic and therapeutic biomarkers for many pulmonary diseases represents a major challenge for pulmonologists. The majority of the currently approved therapeutic approaches are focused on achieving disease remission, although there is no guarantee of complete recovery. It is known that angiotensin-converting enzyme 2 (ACE2), an important counter-regulatory component of the renin–angiotensin–aldosterone system (RAAS), is expressed in the airways. It has been shown that ACE2 plays a role in systemic regulation of the cardiovascular and renal systems, lungs and liver by acting on blood pressure, electrolyte balance control mechanisms and inflammation. Its protective role in the lungs has also been presented, but the exact pathophysiological mechanism of action is still elusive. The aim of this study is to review and discuss recent findings about ACE2, including its potential role in the pathophysiology of chronic inflammatory lung diseases:, i.e., chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. Additionally, in the light of the coronavirus 2019 disease (COVID-19), we will discuss the role of ACE2 in the pathophysiology of this disease, mainly represented by different grades of pulmonary problems. We believe that these insights will open up new perspectives for the future use of ACE2 as a potential biomarker for early diagnosis and monitoring of chronic inflammatory lung diseases.  ACE2 gene is located on the X chromosome (cytogenetic location: Xp22.2) and consists of 18 exons that encode for protein of 805 amino acids. ACE2 is a type 1 integral membrane glycoprotein with two domains, the amino-terminal catalytic domain and carboxy-terminal transmembrane domain. The active domain of ACE2 is exposed to the extracellular surface, facilitating the metabolism of circulating peptides . ,10. 5,10RAAS could be activated/regulated in two opposite pathways, depending on physiological conditions. The classical pathway, formed by ACE/Ang II/AT1R, is associated with vasoconstriction, cell proliferation, organ hypertrophy, sodium retention and aldosterone release . By the As has already been mentioned, the RAAS functions through the ACE/AngII/AT1 and ACE2/AngI (1-7)/MasR axes with opposite effects ,20. Due Inflammation is the natural defense mechanism associated with many acute and chronic inflammatory diseases, including pulmonary diseases. It is a biological response of the immune system that can be triggered by a variety of factors. These factors include toxic compounds, pathogens and damaged cells. In the background of inflammation pathophysiology is the recruitment of the immune cells into the affected tissue aiming to remove the “danger signals”, such as pathogenic microorganism, irritants or dead cell debris. Most agents associated with chronic inflammation cause insidious but progressive and often extensive tissue necrosis accompanied by ongoing repair and fibrosis. The amount of fibrosis in the tissues is a function of the duration of chronic inflammation . ChronicIt is also pointed out that the decrease in the catalytic function of ACE2 disrupts the RAAS in lungs, resulting in increased inflammation and vascular permeability mediated by ACE/AngII/AT1 axis . On the Promoting the ACE2/Ang1-7/MasR signaling by rhACE2 or the Ang 1-7 receptor agonist could also be a promising therapeutic approach in lung disease from diverse etiologies . For exaChronic obstructive pulmonary disease (COPD) is a systemic disease characterized by lung tissue destruction and progressive airflow limitation that is not fully reversible . COPD afThe combination of corticosteroids and bronchodilators is a recommended treatment protocol for severe COPD and standard of care in treating the COPD exacerbations. Some of the latest studies have shown that inhaled corticosteroids used in stabilizing a chronic obstructive disease in patients hospitalized for COVID-19 infection decreased the expression of ACE2 receptors . HoweverAsthma is a heterogeneous disease of the respiratory tract, characterized by a chronic inflammation of the airways. It is estimated that more than 339 million people worldwide have asthma . Asthma Pulmonary hypertension (PH) is a chronic progressive disease defined by the mean pulmonary arterial pressure (mPAP) > 20 mmHg, measured during right heart catheterization . The keyThe COVID-19 pandemic has restored the interest in ACE2 because it serves as a receptor for SARS-CoV-2 virus entry into the cell . In the The incidence and prevalence rates of chronic inflammatory lung diseases are increasing despite all the available medications and therapies. Given the fact that the majority of the described models of ACE2 receptor involvement in chronic inflammatory lung diseases came from animal models of acute inflammatory lung diseases, it is necessary to conduct more studies on humans, aiming to gain better insight into the pathogenesis of the disease. Our research group is largely focused on the genetic diversity of different genes involved in the innate immune response in patients with COPD and lung cancer, and functional studies of disease-associated variants. We would be very interested to see how specific genetic variants of ACE2, in these groups of patients, affect protein function and regulation of the RAAS, and whether these changes are potentially responsible for the pathological condition. It is also worth mentioning that ACE2 was analyzed as a potential biomarker for SARS-CoV-2 infection risk in lung cancer patients. It seems that upregulated expression of ACE2 in lung tumors might increase the susceptibility to COVID-19 infection . On the


Limited information is available on the long-term follow-up and seizure recurrence in dogs with reactive seizures due to suspected exogenous toxicity. The purpose of this study was to report the long-term follow-up of 13 dogs referred to a single referral hospital, diagnosed with reactive seizures and treated with a standardized levetiracetam protocol. All dogs received a loading levetiracetam dose of 60 mg/kg/IV once, followed by a maintenance dose of 20 mg/kg every 8 h as part of an open-label clinical study. Levetiracetam was withdrawn after a 6-months seizure-free period by reducing levetiracetam to 20 mg/kg every 12 h for a 4-week seizure-free period, followed by levetiracetam 20 mg/kg every 24 h for a 4-week seizure-free period, before levetiracetam treatment was stopped. No adverse effects of the treatment were reported. No dogs experienced any seizures after discharge or after levetiracetam withdrawal. Median follow-up time from time of discharge was of 78 months (=6 years 6 months). The result of this study supports the use of levetiracetam for treatment of reactive seizures due to exogenous substance intoxication. Moreover, our results do not support the need for long-term antiepileptic treatment in cases of reactive seizures due to exogenous intoxication. Reactive seizures (RS) have been defined as seizures “occurring as a natural response from the normal brain to a transient disturbance in function (metabolic or toxic in nature) which is reversible when the cause or disturbance is rectified” . ReporteThis was a prospective open-label clinical study including 13 dogs referred to a single referral hospital  with seizures due to highly suspected exogenous intoxication between January 2009 and December 2015. The study was conducted as a prospective, observational cohort study, approved by the clinical research and ethical committees of the Animal Health Trust . Inclusion criteria were: evidence/high suspicion of exogenous toxin ingestion resulting in RS based on anamnestic information given by the owners who witnessed/suspected ingestion of foreign material with or without consecutive presence of gastroinstinal signs , a neurological examination performed by a board-certified neurologist and treatment with LEV (emergency treatment followed by maintenance treatment). Levetiracetam treatment was standardized as follow: at admission all dogs received a LEV loading dose of 60 mg/kg/IV once. The treatment was continued with LEV 20 mg/kg every 8 h orally (PO) or IV until the patient was able to receive medications PO. Levetiracetam treatment was continued in all dogs at a dosage of 20 mg/kg every 8 h (or the nearest dosage based on available formulation and body weight) for a 6-month seizure free period. Levetiracetam was withdrawn by reducing LEV to 20 mg/kg every 12 h PO for a 4-week seizure free period, followed by LEV 20 mg/kg every 24 h PO for a 4-week seizure free period, after which LEV treatment was interrupted. All owners were contacted, as last follow-up, in December 2019. Dogs with a previous history of seizures due to any etiologies prior to the known or suspected intoxication, were excluded from the study. Cluster seizures was defined as two or more seizures in 24 h with complete recovery of consciousness between seizures. Status epilepticus was defined as a single seizure lasting longer than 5 min, or two or more seizures without complete recovery of consciousness in between  to induce emesis. Hematology and serum biochemistry results did not reveal any abnormalities that would result in seizure activity in any of the 13 dogs. In all but 2 dogs  a bile acid stimulation test and ammonia serum level were performed, and results revealed no significant abnormalities. Urinalysis revealed no significant abnormalities in the 5 dogs in which it was performed . Magnetic resonance imaging of the brain and cerebrospinal fluid analysis were performed in all dogs and no abnormalities were detected. Based on the medical history, clinical presentation, clinical course, diagnostic investigation results and follow-up, all dogs were diagnosed with RS triggered by highly suspected ingestion of an unknown toxic substance.Thirteen dogs met the inclusion criteria. The signalment of the 13 dogs is described in Details of ASD treatment in each dog are presented in No dogs experienced any seizures after discharge, nor after LEV withdrawal. Median follow-up time from time of discharge was of 78 months . Nine of the 13 dogs were alive at the time of last follow-up. Dog 4 was euthanised 77 months after discharge, due to recurrence of paraplegia secondary to intervertebral disc herniation. Dog 5 was euthanised after 48 months from discharge because of haemoabdomen due to a ruptured splenic neoplasia and suspected secondary lung metastasis. Dog 7 was euthanised after 84 months from discharge after diagnosis of immune-mediated anemia and dog 9 was euthanised after 49 months from discharge due to gastric torsion.Relatively little data is available on the efficacy of LEV monotherapy for the treatment of seizures or epilepsy in dogs, and to the best of the authors' knowledge there is no published data on LEV monotherapy for the treatment of RS due to suspected exogenous toxicity in dogs , 8. The The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The animal study was reviewed and approved by Animal Health Trust Ethical Committee. Written informed consent was obtained from the owners for the participation of their animals in this study.FS and LD have drafted, written, and corrected the paper together. All authors contributed to the article and approved the submitted version.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.


The objective of this study is to report the clinical characteristics and treatment of patients with progressive cerebellar ataxia associated with anti-GAD antibodies. We performed a retrospective review of all patients with anti-GAD ataxia managed at the Sheffield Ataxia Centre over the last 25 years. We identified 50 patients  with anti-GAD ataxia. The prevalence was 2.5% amongst 2000 patients with progressive ataxia of various causes. Mean age at onset was 55 and mean duration 8 years. Gaze-evoked nystagmus was present in 26%, cerebellar dysarthria in 26%, limb ataxia in 44% and gait ataxia in 100%. Nine patients (18%) had severe, 12 (24%) moderate and 29 (58%) mild ataxia. Ninety percent of patients had a history of additional autoimmune diseases. Family history of autoimmune diseases was seen in 52%. Baseline MR spectroscopy of the vermis was abnormal at presentation in 72%. Thirty-five patients (70%) had serological evidence of gluten sensitivity. All 35 went on gluten-free diet (GFD). Eighteen (51%) improved, 13 (37%) stabilised, 3 have started the GFD too recently to draw conclusions and one deteriorated. Mycophenolate was used in 16 patients, 7 (44%) improved, 2 stabilised, 6 have started the medication too recently to draw conclusions and one did not tolerate the drug. There is considerable overlap between anti-GAD ataxia and gluten ataxia. For those patients with both, strict GFD alone can be an effective treatment. Patients with anti-GAD ataxia and no gluten sensitivity respond well to immunosuppression. Glutamic acid decarboxylase (GAD) is the rate-limiting enzyme in the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). GAD is found in both the central and peripheral nervous systems (including the enteric nervous system) as well as in pancreatic beta cells . AntibodThe first neurological disease to be linked with GAD65 antibodies was stiff-person syndrome (SPS) –11.The first case series of patients with so-called anti-GAD ataxia was published in 2001 . It has We have previously demonstrated significant overlap between anti-GAD-associated neurological diseases and gluten sensitivity . Here, wThis report is based on a retrospective observational case series of patients regularly attending the Sheffield Ataxia Centre. The South Yorkshire Research Ethics Committee has confirmed that no ethical approval is indicated given that all investigations/interventions were clinically indicated and did not form part of a research study.We performed a retrospective review of all patients with progressive ataxia and high serological titres of GAD antibodies . Estimation of anti-GAD was made using a commercial assay (RSR Limited) according to the manufacturers’ instructions. Briefly, the wells are coated with GAD 65, and the samples are added and incubated. GAD65-biotin is added to the wells and incubated. Streptavidin-peroxidase is added to the wells. TMB substrate is added and incubated, and the plate is read at 405 nm . Plate also includes calibrators 2000, 250, 120, 35, 18 and 5 U/mL and positive and negative control samples. The wells are washed in between each stage.All patients have been seen, and most are still under active follow-up at the Sheffield Ataxia Centre, Sheffield, UK. All of these patients have been extensively investigated for other causes of ataxia including extensive genetic testing using next-generation sequencing . The revWe identified 50 patients with anti-GAD ataxia . Sixty-two percent were female. The prevalence of anti-GAD ataxia amongst 2000 patients with progressive ataxia of various causes attending the Sheffield Ataxia Centre was 2.5%. Mean age at onset of the ataxia was 55 years range 13–88) and mean duration 8 years (range 1–24). Gaze-evoked nystagmus was seen in 26%, cerebellar dysarthria in 26%, limb ataxia in 44% and gait ataxia in 100%. Using an established simple rating scale for severity of ataxia, 9 patients (18%) had severe ataxia (wheelchair bound), 12 (24%) moderate  and the remainder 29 (58%) mild  . Twenty-3–88 and Baseline MRI and MRS was available in 47/50 patients. Cerebellar vermian atrophy was present in 47% and cerebellar hemispheric atrophy in 36%. The atrophy of the vermis was graded as 1 (mild) in 15 of the patients, and the hemispheric atrophy was graded as 1 also in 15 patients. This meant that only 7 patients had either moderate or severe vermian atrophy with only 2 having moderate atrophy of the hemisphere. Progression of any atrophy over time was only observed in 2 patients.The mean value of NAA/Cr ratio was reduced across the cohort at 0.892 . Thirty-four out of 47 (72%) patients had abnormal MRS of the vermis at the time of initiation of treatment, in keeping with what is often seen in immune-mediated ataxias .Neurophysiological assessments were done according to clinical indications. Twelve patients (24%) had clinical evidence of myoclonus which on EEG/EMG polygraphy recordings and quantitative analysis with jerk-locked averaging revealed a cortical generator of the myoclonus in three (2 had gluten sensitivity and one had IgA deficiency). The recording methodology and quantitative data analysis for the electrophysiological assessment of myoclonus is described in detail in previous publications . SomatosThe 35 patients with serological evidence of gluten sensitivity (with and without coeliac disease) received detailed dietetic advice on strict adherence to a gluten-free diet (GFD). This was along the same lines as advice given for the treatment of gluten ataxia (GA) . In 18 oMycophenolate was used in 16 patients , 7 (44%) of which improved, 2 stabilised, 6 only recently started the medication and one did not tolerate mycophenolate. Only those patients with gluten sensitivity who stabilised but did not improve and the one who worsened despite GFD went on to be treated with mycophenolate.At the time of starting treatment, the mean NAA/Cr ratio was 0.883 . Follow-up MRS after treatment was available in 20 patients to date with mean follow-up interval of 2.75 years (median 2 years and IQR 2.5 years). In keeping with clinical improvement, the follow-up MRS improved after treatment in 16 , worsened in 3 and was unchanged in 1. The mean NAA/Cr ratio after treatment for the 16 patients that improved increased to 0.954  which was now within the normal range. Clinical improvement was observed in all 16 patients with increased NAA/Cr ratio on MRS. This was in keeping with what we have already published, that is, significant positive correlation between MRS and clinical improvement as assessed by the scale for assessment and rating of ataxia (SARA) .Three patients (not gluten sensitive) received intravenous immunoglobulins but with no evidence of sustained improvement. One patient received rituximab after no response to intravenous immunoglobulins, partial response to mycophenolate and cyclophosphamide . Another patient also received cyclophosphamide with good response. Only 9 of the 50 patients did not have any therapeutic intervention. This was either due to patient choice (6) or due to no clinical and MR spectroscopy evidence of disease progression (3).Overall treatment with GFD and/or immunosuppression was associated with clinical improvement or stabilisation in 84% of those patients treated.A 50-year-old lady presented initially to audiovestibular medicine with a history of dizziness and vertigo in 1996. Investigations at the time did not identify any inner ear pathology; hence, she was referred to neurology for further evaluation. There was a past history of hypothyroidism and no family history of any neurological illness. She complained primarily of gait instability but was able to walk without walking aids and had no falls. Clinical examination showed some difficulties in tandem walking in keeping with gait ataxia but no other neurological dysfunction. Investigations at the time (including genetic testing) and MRI were normal. CSF examination showed normal protein, no cells and was negative for oligoclonal bands. She was monitored on a 6 monthly basis with little evidence of any progression. In 2002 at the age of 56 she developed IDDM and started insulin injections. In 2003 she was tested for the first time for anti-GAD antibodies and was positive with titres > 2000 U/ml. Despite the absence of any serological evidence of gluten sensitivity, she tried GFD for a year without any evidence of clinical improvement. Close monitoring with clinical evaluation of her ataxia showed that her balance was getting worse  as a result of which in 2006 she had 2 courses of intravenous immunoglobulins without any evidence of improvement. In 2009 she was found to have low vitamin B12 (positive intrinsic factor) and started on B12 injections. After a period of stability, she again started deteriorating during 2011 when in addition to the progression of gait ataxia she complained of vertigo. Examination showed no evidence of vestibular pathology to account for the vertigo. In 2011 she underwent MR spectroscopy assessment of the cerebellum for the first time. In 2013 she started treatment with mycophenolate resulting in clinical stabilisation with MR spectroscopy evidence of improvement in NAA/Cr ratio of the vermis  and a family history of autoimmune diseases in first-degree relatives in 52%. This suggests that anti-GAD antibodies are a marker of multiple autoimmunity of which the cerebellar ataxia may be one of many autoimmune manifestations.The association between anti-GAD antibodies, multiple autoimmunity and gluten sensitivity merits close consideration. Italian researchers have noted that the prevalence of additional autoimmune diseases in children with coeliac disease (CD) is significantly lower than in those patients with CD diagnosed in adulthood . They coOur results also highlight the preferential involvement of the cerebellar vermis, something that is commonly seen in immune-mediated ataxias . The sevThe pathological role of anti-GAD antibodies in the genesis of this immune ataxia is unclear. Since GAD65 is intracellularly located and is associated with a range of neurological conditions  as well as IDDM, some have argued that anti-GAD65 antibodies have no pathogenic role to play. On the other hand, recent physiological studies in vitro and in vivo have demonstrated that binding of GAD65 by anti-GAD65 antibodies induces loss of GAD65 functions relating to GABA release, with an epitope dependence, leading to the development of cerebellar ataxia . Given tAlthough detailed neurophysiological assessments have not been done in all patients, there was electrophysiological evidence of cortical myoclonus in only three, two of which had serological evidence of gluten sensitivity and one had IgA deficiency . Gluten sensitivity is a well-recognised cause of cerebellar ataxia with cortical myoclonus and in this instance could have been a synergistic factor leading to the development of cortical myoclonus . We haveThe presence of high titre of anti-GAD antibodies should not always preclude the investigation for other causes of ataxia. We have encountered 3 patients (not included in these series) with progressive ataxia, positive anti-GAD antibodies (> 2000 U/ml) but with alternative aetiology for their ataxia. The clinical suspicion of an alternative aetiology was as follows: One patient progressed rapidly and developed autonomic dysfunction fulfilling the criteria for probable MSA-C, a second patient in his 20s had severe global cerebellar atrophy  which lead to genetic testing confirming a pathogenic mutation for ANO10 and a third patient had mild spastic paraparesis and waddling gait which lead to a genetic diagnosis of SPG7.Whilst it is extremely rare to find such high levels of anti-GAD in genetic ataxias  in clinical scenarios where an alternative diagnosis is suspected examination of the CSF may prove helpful in demonstrating the intrathecal production of GAD antibodies thus further supporting the diagnosis of anti-GAD ataxia . Indeed Finally, we did not include in these series patients with SPS. In our experience, patients with SPS almost always have a degree of cerebellar ataxia, but their primary presentation is distinct and characterised by axial rigidity and spasms. SPS is also rare and in our experience less common than anti-GAD ataxia. Over the same period of time (25 years), we have encountered 18 patients with classic SPS (another area of our interest) as compared to 50 patients with anti-GAD ataxia. However, there may well be some ascertainment bias given that the patients with ataxia were seen at the Sheffield Ataxia Centre, one of only 2 National Ataxia Centres in the UK.To conclude, we present here clinical data of a large series of patients with anti-GAD ataxia and highlight a significant overlap between anti-GAD and GA. This has significant therapeutic implications. We share our experience of treating these patients with GFD and/or immunosuppression and propose that early treatment intervention is more likely to be associated with better outcomes and limit permanent disability even if the initial presentation suggests a mild slowly progressive disease.


Fractures around the hip in the geriatric population not only lead to functional but also psychological impairment. Psychiatric disturbances can be associated with poor participation in rehabilitation, increased risk of falling again, and higher rates of mortality. The present study was undertaken to assess the association between the psychological status and functional outcome of surgically managed elderly Indian patients who had sustained fractures around the hip.The present study was a hospital based prospective, single centre study. One hundred and two geriatric patients who had sustained hip fracture and had been managed surgically, having no cognitive dysfunction, living independently, having unhindered walking capability before the fracture, were included in the study. They were called for follow-up at 3rd, 6th, and 12th month after the hip surgery. Psychological assessment was done by the Hospital Anxiety and Depression Scale (HADS) and functional outcome by using the Harris hip score (HHS).Our study did not show association between psychological status and functional outcome except in one sub-group. Significant correlation was observed between the psychological status and functional outcome in most of the patients in the extra-capsular group. We have identified improvement in the depression, anxiety and functional scores during the follow-up.We conclude that psychiatric disturbances in a geriatric patient after undergoing a surgery for hip fracture may lead to poor recovery. We recommend that all such geriatric patients should undergo a psychological assessment and proper therapy should be instituted to achieve good functional recovery. The major factors attributed to the occurrence of these fractures are old age, osteoporosis and frequent falls. These are due to problems in coordination, arthritis, impaired activity of daily living, visual impairment, malnutrition, disability prior to fractures and neuropsychiatric disturbances5.Geriatric population is not only prone to fractures but also to their adverse outcomes6. The risk of sustaining a fracture around the hip in a person's lifetime is high, and it ranges from 40% to 50% among females and 13% to 22% among the males6. In contrast to other general hospital populations, the elderly hip fracture population has high reported rates of psychiatric illness, which is a cause of adverse outcomes. The commonest psychiatric disturbances to be reported in the elderly with fracture around the hip are depression, anxiety and cognitive impairment like delirium and dementia8. Depression is considered as one of the conditions possibly associated to osteoporotic fractures and studies have reported its association to low bone mineral density9.Fractures around the hip have been recognised as the common fractures in the elderly and are associated with significant morbidity, mortality and disability10. Depression and anxiety can be associated with poor participation in rehabilitation11 and increased risk of falling again7. It may also affect the recovery of independent walking, lead to higher rates of mortality and increased susceptibility to infectious disease12. The prevalence of depression in the elderly following a hip fracture has been reported as varying between 9% and 47%7. Despite all the developments in current surgical practices, anaesthesia techniques, post-operative care and rehabilitation, studies revealed that women sustaining a hip fracture had a 5-fold increase and men almost an 8-fold increase in relative likelihood of death within the first three months13. In other words, a poor psychological status is associated with adverse outcomes in geriatric patients who undergo surgery for fractures around the hip. Though there are many studies which have established this association, most of these have been reported in the Western literature.These psychiatric disorders lead to partial recovery in the psychosocial and physical factors and are found to be more prevalent in patients who sustain fracture around the hip when compared to patients who undergo a surgery which is non-orthopaedicThe main aim of the present study was to (1) find out the association between psychological status  and functional outcome, (2) find out the correlation between psychological status  and functional outcome and (3) identify the changes in the psychological status  and functional outcome in surgically managed fractures around the hip in Indian geriatric patients.The present study was a hospital based prospective, single centre study conducted between January 2017 and September 2019. One hundred and two geriatric patients who had sustained a fracture around the hip joint and had been managed surgically, of age >60 years, having no cognitive dysfunction , were living independently, having unhindered walking capability before the fracture, were included in the study. Patients having multiple fractures, any pathological fracture other than fragility fracture, those who were visually handicapped or had cognitive dysfunction were excluded from the study.An informed written consent was taken from all the patients willing to participate in the study on an Informed consent form (ICF) as per the guidelines of Institutional Ethical Committee (IEC). The protocol, case report form and informed consent were approved by the Institutional Ethical Committee.Sample Size: Sample size based on estimation of Mean,Where the following applies:σ= Standard deviationd= Precision= Confidence level alpha (α) =1.96σ= 9.3d=2n=83 Total obtained sample size was 92.All the patients included in the study were divided into two groups, Group A and Group B. Patients of Group A were cases of intracapsular fractures and patients of Group B included cases of extracapsular fractures. Group A was further subdivided into two sub-groups, A1 and A2. All cases of fresh un-displaced fracture neck of femur fell into group A1 and all cases of old (>3 weeks) / displaced fracture neck of femur fell into group A2. Similarly, patients of the stable intertrochanteric fracture fell into group B1 and cases of the unstable intertrochanteric fracture fell into group B2. The patients in group A1 were treated using osteosynthesis techniques like three Cannulated Cancellous screw / Dynamic Hip Screw (DHS) and patients in group A2 were managed by performing Hemi-arthroplasty with Austin Moore Prosthesis (AMP) / Bipolar prosthesis. Patients in B1 group were treated using Dynamic hip screw / Proximal femoral nail (PFN) and patients in group B2 were treated using PFN / PFNA.14 and the psychological outcome was assessed using the HADS15 score at 3rd, 6th, and 12th month after the surgery. The HHS is an outcome scoring system dependent on the clinicians. The questionnaire has 10 questions and score ranges from 0-100 with higher values exhibiting good functions and better results. A score between 90-100 is graded excellent, 80-89 is a good score, 70-79 is fair score and a score less than 70 is a poor score. The hospital anxiety and depression scale (HADS)15 assess the anxiety and depression on a scale of 0-21 score separately. A score between 0-7 is considered normal, 8-10 is borderline abnormal and 11-21 is abnormal.Quadriceps exercises and calf pumps were initiated as early as the patient was weaned off from the effects of anesthesia. Full range of motion exercises for knee and ankle was started from day one. In sub-group A1, B1 and B2 toe Touchdown weight bearing was started from day three by using a walking frame and continued up to six weeks, followed by full weight bearing depending on the fracture union. In subgroup A2 patient’s full weight bearing was initiated at the 3rd post-operation day depending on the pain tolerance of the patient. The functional outcome was assessed using the Harris hip scoreSPSS 20.0 Version was used for statistical analysis. One-way ANOVA was computed to find the significant association between psychological status  and functional outcome. Pearson’s correlation co-efficient was used to find the correlation between psychological status  and functional outcome among participants in different groups. Repeated measures of ANOVA were computed to observe changes, in the score of psychological status  and the functional outcome.A total of 102 patients were included in the study after they had fulfilled the inclusion criteria. Patients who were either lost to follow-up or in whom complications like non-union was observed and required secondary operative procedure were not included in the final analysis. The final data analysis was performed on 92 patients only. The mean age of participants was 74.59±10.11 years. Out of the 92 patients, 56 were males and 36 were females. Demographic characteristics and distribution of the Patients in different sub-groups are shown in One-way ANOVA was computed to find the significant association between psychological status  and functional outcome. It revealed that there was no statistically significant association observed between psychological status  and functional outcome among participants in different sub-groups at p>0.05, except the B2 sub-group for depression and their functional outcome at p=0.01 .The correlation between psychological status  and functional outcome among participants in different sub-groups  was compThere was a weak negative correlationship between depression scores and Harris Hip scores in B1 sub-group, ‘r’ value is -0.18 and it was not statistically significant (p=0.52) and there was a strong positive correlationship between anxiety scores and Harris Hip scores in B1 sub-group, ‘r’ value is 0.81 and it was statistically significant (p=0.001). There was a moderate positive correlationship between depression scores and Harris Hip scores in B2 sub-group, ‘r’ value is 0.43 and it was statistically significant (p=0.04) and there was a moderate positive correlationship between anxiety scores and Harris Hip scores in B2 sub-group, ‘r’ value was 0.53 and it was statistically significant (p=0.01).The data presented in the The data presented in Neuropsychiatric complications have always been a great concern in elderly patients after hip fracture surgeries. These conditions are not only related to their poor functional recovery but also to the increased mortality. Our study on surgically managed fractures around the hip in Indian geriatric patients has not shown significant association between psychological status and functional outcome, except the B2 sub-group of patients with unstable intertrochanteric fracture, where significant correlation was observed between the psychological status and functional outcome in most of the patients in the extra-capsular group. Our study has identified an improvement in the depression, anxiety and functional scores during the follow-up period except in A1 sub-group of patients with fresh undisplaced fracture neck of femur, which have shown an increasing trend in depression scores. We have observed significant improvement in the psychological and functional scores of the patients with fresh displaced fracture neck of femur (sub-group A2) as compared to the patients with fresh non-displaced fracture neck of femur (sub-group A1) during follow-up. The improvement was not significant in terms of psychological scores, but functional scores were observed to be significant in patients with the unstable intertrochanteric fracture (subgroup B2) as compared to patients with the stable intertrochanteric fracture (sub-group B1) during follow-up.et al (2017)16 conducted a study with 50 patients after primary unilateral THA and observed a significant relationship of the changes in anxiety and depression scores with hip functionality. The scale used was the general depression scale known as ADS-L; in the pre-operative period the score was 16.8±8.8 which decreased to 11.9±6.2, five weeks after the operation and the state anxiety was 44.1±12.3 at the start and thereafter, decreased to 35.1±10.2. The Harris Hip score was increased from 49.6±19.8 to 73.3±8.8. They emphasise the important role of psychological factors on the outcome16 17 on forty patients who were managed surgically for the hip fracture were divided into two sub-groups, one received counselling and the control without counselling. Short Form-36-item Health Survey Questionnaire, State–Trait Anxiety Inventory and Hamilton Rating Scale for Depression scores were recorded and the patients undergoing counselling showed decreasing HAMS-D scores and STAI-Y1 scores after 30 days when compared to the baseline evaluation. They remained stable in the non-counselling group, but physical functioning improved in all patients. The scores in non-counseling group correlate with our study. They also stated that, it is an obsolete and wrong conception that treatment ends with the surgical procedure and physical rehabilitation, because a patient’s psychological status plays a critical role in regaining good performance levels17  investigated the role of injury-related beliefs and hopelessness on depression and anxiety in 103 hip fracture patients at two time points and observed that approximately one month following injury, 16% and 25% of the sample had moderate or higher levels of depressive and anxiety symptoms, respectively. There appeared to be an improvement in anxiety symptoms and depression remained considerably stable relative to the first assessment. The results were comparable to our study. They had supported a possibility for psychological intervention on the basis, of their findings8 (Another study by Gambatesa levels17 . Bruggemindings8 .With the increase in the elderly population, health status of the elderly gained lots of importance and there is evidence of a rise in morbidity, mortality and loss of functional status which are related to psychological conditions in elderly patients. We recommend that, every geriatric patient of fracture around the hip should undergo a regular neuropsychiatric assessment targeted to their mental health needs. The limitation of the present study is that it was a single centre study and sample size was small, due to which generalisation of the study population may not be possible.Studies have proved the existence of depression and anxiety in the post-operative period, and it is more evident to geriatric patients. In our study on surgically managed fractures around the hip in Indian geriatric patients a significant correlation was observed for depression and anxiety with the functional outcome in many of the patients; it was also observed that patient's depression and anxiety scores improve with the functional outcome. Thus, we conclude that these psychiatric disturbances in a geriatric patient after undergoing a surgery for the hip fracture may lead to a poor recovery. We recommend that all such geriatric patients should undergo a psychological assessment to recognise their special needs and proper therapy should be instituted in order, to achieve a good functional recovery.