Mechanism of proton transfer in class A ß-lactamase catalysis and inhibition by avibactam.

Gram-negative bacteria expressing class A ß-lactamases pose a serious health threat due to their ability to inactivate all ß-lactam antibiotics. The acyl-enzyme intermediate is a central milestone in the hydrolysis reaction catalyzed by these enzymes. However, the protonation states of the catalytic residues in this complex have never been fully analyzed experimentally due to inherent difficulties. To help unravel the ambiguity surrounding class A ß-lactamase catalysis, we have used ultrahigh-resolution X-ray crystallography and the recently approved ß-lactamase inhibitor avibactam to trap the acyl-enzyme complex of class A ß-lactamase CTX-M-14 at varying pHs. A 0.83-Å-resolution CTX-M-14 complex structure at pH 7.9 revealed a neutral state for both Lys73 and Glu166. Furthermore, the avibactam hydroxylamine-O-sulfonate group conformation varied according to pH, and this conformational switch appeared to correspond to a change in the Lys73 protonation state at low pH. In conjunction with computational analyses, our structures suggest that Lys73 has a perturbed acid dissociation constant (pKa) compared with acyl-enzyme complexes with ß-lactams, hindering its function to deprotonate Glu166 and the initiation of the deacylation reaction. Further NMR analysis demonstrated Lys73 pKa to be ∼5.2 to 5.6. Together with previous ultrahigh-resolution crystal structures, these findings enable us to follow the proton transfer process of the entire acylation reaction and reveal the critical role of Lys73. They also shed light on the stability and reversibility of the avibactam carbamoyl acyl-enzyme complex, highlighting the effect of substrate functional groups in influencing the protonation states of catalytic residues and subsequently the progression of the reaction.

Design and Structure Determination of a Composite Zinc Finger Containing a Nonpeptide Foldamer Helical Domain.

A number of foldamer backbones have been described as useful mimics of protein secondary structure elements, enabling for example the design of synthetic oligomers with the ability to engage specific protein surfaces. Synthetic folded backbones can also be used to create artificial proteins in which a folded peptide segment (e.g., an α-helix, a loop) is replaced by its unnatural counterpart, with the expectation that the resulting molecule would maintain its ability to fold while manifesting new exploitable features. The similarities in screw sense, pitch, and polarity between peptide α-helices and oligourea 2.5-helices suggest that a tertiary structure could be retained when swapping the two backbones in a protein sequence. In the present work, we move a step toward the creation of such composite proteins by replacing the 10-residue long original α-helical segment in the Cys2His2 zinc finger 3 of transcription factor Egr1 (also known as Zif268) by an oligourea sequence bearing two appropriately spaced imidazole side chains for zinc coordination. We show by spectroscopic techniques and mass spectrometry analysis under native conditions that the ability of the peptide/oligourea hybrid to coordinate the zinc ion is not affected by the foldamer replacement. Moreover, detailed NMR analysis provides evidence that the engineered zinc finger motif adopts a folded structure in which the native ß-sheet arrangement of the peptide region and global arrangement of DNA-binding side chains are preserved. Titration in the presence of the Egr1 target DNA sequence supports binding to GC bases as reported for the wild-type zinc finger.

Effect of oral prophylactic instrumentation on the surface texture of all metal restorative materials.

INTRODUCTION: In the inaccessible areas on the crown the removal of calculus and stains by hand and ultrasonic instrumentation is the method for cleaning to preserve and increase the longevity of the restoration. However, when oral prophylaxis is performed on restorative crowns, it may produce some surface alterations and may favour plaque accumulation. STATEMENT OF PROBLEM: Many patients may have restored their teeth with artificial crowns and would come to the dental office for oral prophylaxis. If a routine oral prophylaxis is followed, its effect on the restorative materials and the plaque accumulation can be studied. MATERIALS AND METHODS: A total of 15 disc shaped wax patterns were invested and casted for cast titanium (Group A) and the remaining 15 disk shaped for nickel-chromium (Group B). The obtained castings were finished and polished. All the specimens were subjected to hand and ultrasonic scaling for 15 s. Profilometer and scanning electron microscopic was used to analyze and evaluate the surface roughness. Specimens of each group were embedded on the anterior lingual aspects of the removable lower retention plates. 5 volunteers were asked to wear it in the mouth for 24 h for 7 days. After 7 days, the specimens were stained with plaque disclosing solutions and the photomicrographs were taken by the optical stereomicroscope and the plaque accumulations were assessed in percentage. RESULTS: The difference in average surface roughness (µm) of the polished test specimens was maximum for ultrasonic scaling than hand scaling and maximum for Group A than Group B. Plaque accumulation in percentage on the treated specimens was found to be nonsignificant but, mean plaque accumulation was maximum on ultrasonic scaling surface than hand scaling and maximum for Group A than Group B. Surface roughness was found to be statistically significant after hand scaling (F = 9.377, P = 0.000) and ultrasonic scaling (F = 5.373, P = 0.0000) by Student t-test. CONCLUSION: The Surface roughness and plaque accumulation on the specimens were more for Group A than Group B and maximum produced by ultrasonic scaling than hand scaling.

Improving the chemical shift dispersion of multidimensional NMR spectra of intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) have recently attracted the attention of the scientific community challenging the well accepted structure-function paradigm. In the characterization of the dynamic features of proteins nuclear magnetic resonance spectroscopy (NMR) is a strategic tool of investigation. However the peculiar properties of IDPs, with the lack of a unique 3D structure and their high flexibility, have a strong impact on NMR observables (low chemical shift dispersion, efficient solvent exchange broadening) and thus on the quality of NMR spectra. Key aspects to be considered in the design of new NMR experiments optimized for the study of IDPs are discussed. A new experiment, based on direct detection of (13)C(α), is proposed.

Prosthetic rehabilitation of a hemisected maxillary molar: a rare entity.

Gingival recession beyond grade III and grade IV level involving furcation defects can lead to tooth loss if not intervened at appropriate time. The treatment options include scaling and root planing, Furcation-plasty, Tunnel preparation, Root separation and resection. The chief complaint of the patient was pain in the upper left first molar because of grade III furcation involvement. Since it was a four rooted molar, the treatment of choice was hemisection of the tooth and extraction of the distal half following endodontic treatment. As the second molar was mesially tilted the prosthodontic rehabilitation was done with a hybrid prosthesis involving a full coverage conventional porcelain fused to metal retainer on the hemisected molar and a resin bonded partial coverage retainer on the tilted second molar. The resultant prosthesis is termed as "Hybrid prosthesis".

Discovery of KRB-456, a KRAS G12D Switch-I/II Allosteric Pocket Binder That Inhibits the Growth of Pancreatic Cancer Patient-derived Tumors.

Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery of a small molecule, KRB-456, that binds KRAS G12D and inhibits the growth of pancreatic cancer patient-derived tumors. Protein nuclear magnetic resonance studies revealed that KRB-456 binds the GDP-bound and GCP-bound conformation of KRAS G12D by forming interactions with a dynamic allosteric binding pocket within the switch-I/II region. Isothermal titration calorimetry demonstrated that KRB-456 binds potently to KRAS G12D with 1.5-, 2-, and 6-fold higher affinity than to KRAS G12V, KRAS wild-type, and KRAS G12C, respectively. KRB-456 potently inhibits the binding of KRAS G12D to the RAS-binding domain (RBD) of RAF1 as demonstrated by GST-RBD pulldown and AlphaScreen assays. Treatment of KRAS G12D-harboring human pancreatic cancer cells with KRB-456 suppresses the cellular levels of KRAS bound to GTP and inhibits the binding of KRAS to RAF1. Importantly, KRB-456 inhibits P-MEK, P-AKT, and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from patients with pancreatic cancer whose tumors harbor KRAS G12D and KRAS G12V and who relapsed after chemotherapy and radiotherapy. These results warrant further development of KRB-456 for pancreatic cancer. SIGNIFICANCE: There are no clinically approved drugs directly abrogating mutant KRAS G12D. Here, we discovered a small molecule, KRB-456, that binds a dynamic allosteric binding pocket within the switch-I/II region of KRAS G12D. KRB-456 inhibits P-MEK, P-AKT, and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from patients with pancreatic cancer. This discovery warrants further advanced preclinical and clinical studies in pancreatic cancer.

Exclusively heteronuclear (13) C-detected amino-acid-selective NMR experiments for the study of intrinsically disordered proteins (IDPs).

Carbon-13 direct-detection NMR methods have proved to be very useful for the characterization of intrinsically disordered proteins (IDPs). Here we present a suite of experiments in which amino-acid-selective editing blocks are encoded in CACON- and CANCO-type sequences to give (13) C-detected spectra containing correlations arising from a particular type or group of amino acid(s). These two general types of experiments provide the complementary intra- and inter-residue correlations necessary for sequence-specific assignment of backbone resonance frequencies. We demonstrate the capabilities of these experiments on two IDPs: fully reduced Cox17 and WIP(C) . The proposed approach constitutes an independent strategy to simplify crowded spectra as well as to perform sequence-specific assignment, thereby demonstrating its potential to study IDPs.

Common variants of SLAMF1 and ITLN1 on 1q21 are associated with type 2 diabetes in Indian population.

Though multiple studies link chromosomal regions 1q21-q23 and 20q13 with type 2 diabetes, fine mapping of these regions is yet to confirm gene(s) explaining the linkages. These candidate regions remain unexplored in Indians, which is a high-risk population for type 2 diabetes. Hypothesizing regulatory regions to have a more important role in complex disorders, we examined association of 207 common variants in proximal promoter and untranslated regions of genes on 1q21-23 and 20q13 with type 2 diabetes in 2115 North Indians. Further, top signals were replicated in an independent group of 2085 North Indians. Variants-rs11265455-SLAMF1 (odds ratios (OR)=1.32, P=1.1 × 10(-3)), rs1062827-F11R (OR=1.36, P=1.7 × 10(-3)) and rs12565932-F11R (OR=1.35, P=1.8 × 10(-3)) were top signals for association with type 2 diabetes whereas rs1333062-ITLN1 (OR=1.28, P=3.4 × 10(-3)) showed strongest association in body mass index-stratified analysis. Replication of these four variants confirmed associations of rs11265455-SLAMF1 (OR=1.27, P=9.1 × 10(-3)) and rs1333062-ITLN1 (OR=1.25, P=1.1 × 10(-3)) with type 2 diabetes. Meta-analysis further corroborated the association of rs11265455-SLAMF1 (OR random effect=1.29, P random effect=3.9 × 10(-5)) and rs1333062-ITLN1 (OR random effect=1.19, P random effect=1.8 × 10(-4)). In conclusion, the study demonstrates that variants of SLAMF1 and ITLN1, both implicated in inflammation, are associated with type 2 diabetes in Indians.

Analysis of 32 common susceptibility genetic variants and their combined effect in predicting risk of Type 2 diabetes and related traits in Indians.

AIMS: Recent genome-wide association studies have identified several Type 2 diabetes-related loci. We investigated the effect of susceptibility genetic variants, individually, together and in combination with conventional risk factors, on Type 2 diabetes and diabetes-related traits in Indians. METHODS: We genotyped 33 variants in 1808 Indian patients and 1549 control subjects and performed association analyses with Type 2 diabetes and related traits using an additive model for individual variant and for genetic risk score based on 32 polymorphisms. The discriminatory value of genetic risk over conventional risk factors was analysed using receiver-operating characteristics curve analysis. RESULTS: The allelic odds ratio ranged from 1.01 (95% CI 0.85-1.19) to 1.66 (95% CI 1.32-2.01) for single-variant analyses. Although, only 16 variants had significant odds ratios, the direction of association for others was similar to earlier reports. The odds ratio for Type 2 diabetes at each genetic risk score point was 1.11 (95% CI 1.09-1.14; P = 5.6 × 10(-17)) and individuals with extremes of genetic risk score (≥ 29.0 and ≤ 17.0) had a 7.5-fold difference in risk of Type 2 diabetes. The discrimination rate between control subjects and patients improved marginally on addition of genetic risk score to conventional risk factors (area under curve = 0.959 and 0.963, respectively; P = 0.001). Of all the quantitative traits analysed, MC4R variants showed strong association with BMI (P = 4.1 × 10(-4)), fat mass per cent (P = 2.4 × 10(-4)) and other obesity-related traits, including waist circumference and hip circumference (P = 2.0 × 10(-3) for both), as well as insulin resistance (P =0.02). CONCLUSIONS: We replicated the association of well-established common variants with Type 2 diabetes in Indians and observed a similar association as reported in Western populations. Combined analysis of 32 variants aids identification of subgroups at increased risk of Type 2 diabetes, but adds only a minor advantage over conventional risk factors.

Assembly mechanism of early Hsp90-Cdc37-kinase complexes.

Molecular chaperones have an essential role for the maintenance of a balanced protein homeostasis. Here, we investigate how protein kinases are recruited and loaded to the Hsp90-Cdc37 complex, the first step during Hsp90-mediated chaperoning that leads to enhanced client kinase stability and activation. We show that conformational dynamics of all partners is a critical feature of the underlying loading mechanism. The kinome co-chaperone Cdc37 exists primarily in a dynamic extended conformation but samples a low-populated, well-defined compact structure. Exchange between these two states is maintained in an assembled Hsp90-Cdc37 complex and is necessary for substrate loading. Breathing motions at the N-lobe of a free kinase domain partially expose the kinase segment trapped in the Hsp90 dimer downstream in the cycle. Thus, client dynamics poise for chaperone dependence. Hsp90 is not directly involved during loading, and Cdc37 is assigned the task of sensing clients by stabilizing the preexisting partially unfolded client state.

Autonomous Tool for Monitoring Multi-Morbidity Health Conditions in UAE and India.

Multi-morbidity is the presence of two or more long-term health conditions, including defined physical or mental health conditions, such as diabetes or schizophrenia. One of the regular and critical health cases is an elderly person with a multi-morbid health condition and special complications who lives alone. These patients are typically not familiar with advanced Information and Communications Technology (ICT), but they are comfortable using smart devices such as wearable watches and mobile phones. The use of ICT improves medical quality, promotes patient security and data security, lowers operational and administrative costs, and gives the people in charge to make informed decisions. Additionally, the use of ICT in healthcare practices greatly reduces human errors, enhances clinical outcomes, ramps up care coordination, boosts practice efficiencies, and helps in collecting data over time. The proposed research concept provides a natural technique to implement preventive health care innovative solutions since several health sensors are embedded in devices that autonomously monitor the patients' health conditions in real-time. This enhances the elder's limited ability to predict and respond to critical health situations. Autonomous monitoring can alert doctors and patients themselves of unexpected health conditions. Real-time monitoring, modeling, and predicting health conditions can trigger swift responses by doctors and health officials in case of emergencies. This study will use data science to stimulate discoveries and breakthroughs in the United Arab Emirates (UAE) and India, which will then be reproduced in other world areas to create major gains in health for people, communities, and populations.

ICT Enabled Disease Diagnosis, Treatment and Management-A Holistic Cost-Effective Approach Through Data Management and Analysis in UAE and India.

This concept paper addresses specific challenges identified in the UN 2030 Agenda Sustainable Development Goals (SDG) as well as the National Health Policy of India (NHP-India) and the Ministry of Health Policy of UAE (MHP-UAE). This policy calls for a digital health technology ecosystem. SDG Goal 1 and its related objectives are conceptualized which serves as the foundation for Virtual Consultations, Tele-pharmacy, Virtual Storage, and Virtual Community (VCom). SDG Goals 2 and 3 are conceptualized as Data Management & Analytical (DMA) Architecture. Individual researchers and health care professionals in India and the UAE can use DMA to uncover and harness PHC and POC data into practical insights. In addition, the DMA would provide a set of core tools for cross-network initiatives, allowing researchers and other users to compare their data with DMA data. In rural, urban, and remote populations of the UAE and India, the concept augments the PHC system with ICT-based interventions. The ICT-based interventions may improve patient health outcomes. The open and flexible design allows users to access various digital materials. Extendable data/metadata format, scalable architecture for petabyte-scale federated discovery. The modular DMA is designed using existing technology and resources. Public health functions include population health assessment, policy development, and monitoring policy implementation. PHC and POC periodically conduct syndromic surveillance to identify population risk patterns. In addition, the PHC and POC deploy medical and non-medical preventive measures to prevent disease outbreaks. To assess the impact of social and economic factors on health, epidemiologists must first understand diseases. Improved health due to compliance with holistic disease treatment plans and access to scientific health information.

High-resolution characterization of intrinsic disorder in proteins: expanding the suite of (13)C-detected NMR spectroscopy experiments to determine key observables.

Order in disorder: The characterization of intrinsically disordered proteins by NMR spectroscopy is a necessity on the one hand and a continuous challenge on the other. We propose two experiments that provide diagnostic parameters to monitor the degree of unfolding of a polypeptide. The test was performed on the yeast Cox17 protein, known to gain its function through maturation from an intrinsically disordered state (see figure).

N-H...F hydrogen bonds in fluorinated benzanilides: NMR and DFT study.

Using (19)F and (1)H-NMR (with (14)N decoupling) spectroscopic techniques together with density functional theoretical (DFT) calculations, we have investigated weak molecular interactions in isomeric fluorinated benzanilides. Simultaneous presence of through space nuclear spin-spin couplings ((1h)J(N-HF)) of diverse strengths and feeble structural fluctuations are detected as a function of site specific substitution of fluorine atoms within the basic identical molecular framework. The transfer of hydrogen bonding interaction energies through space is established by perturbing their strengths and monitoring the effect on NMR parameters. Multiple quantum (MQ) excitation, up to the highest possible MQ orders of coupled protons, is utilized as a tool for accurate (1)H assignments. Results of NMR studies and DFT calculations are compared with the relevant structural parameters taken from single crystal X-ray diffraction studies.

R659X mutation in the MLH1 gene in hereditary non-polyposis colorectal cancer(HNPCC) in an Indian extended family.

BACKGROUND & OBJECTIVE: Hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome), is a genetically heterogeneous disorder that is believed to account for 2-10 per cent of all the colorectal cancer cases. The disease follows autosomal dominant inheritance pattern with high penetrance (85%) and younger age of onset when compared to patients with sporadic tumours. HNPCC is associated with germ-line mutations in the DNA mismatch repair (MMR) genes namely MLH1, MSH2, MSH6, and PMS2. The present study was aimed at analyzing mismatch repair gene(s) in an extended Indian family satisfying the Amsterdam criteria, and extending the analysis to general population to estimate frequency of the mutations/polymorphisms observed. METHODS: A total 12 members of the HNPCC family were studied for genetic investigation. Ethnically matched 250 normal individuals were also included as controls to study the observed mutations/polymorphisms at population level. RESULTS: The analysis resulted in identification of a 1975C>T mutation in exon 17, resulting in substitution of arginine residue with stop codon at codon 659. 655A>G substitution was also observed, resulting in replacement of isoleucine with valine at codon 219. Similar analysis on 250 ethnically matched control subjects revealed complete absence of R659X mutation, while I219V variant was found in 9.8 per cent of the controls. INTERPRETATION & CONCLUSION: R659X mutation correlates with disease phenotype, and 655A>G locus is highly polymorphic. Our study suggested that R659X substitution was prime cause for the disease phenotype in this family. I219V substitution is a polymorphism having no association with the disease onset or segregation. The family members harbouring this mutation were advised to be under regular medical surveillance.

G6036A substitution in mitochondrial COX I gene compromises cytochrome c oxidase activity in thiamine responsive Leigh syndrome patients.

Cytochrome c oxidase (COX) deficiency is known to be associated with Leigh syndrome (LS), however there are limited studies on genetic screening of mitochondrial (mt) DNA encoding COX genes as well as the functional validation of identified variants. In our previous studies, we cared for total 165 LS patients and analyzed the nucleotide variations across entire mt genome. We observed a high level of genetic heterogeneity in these patients. We identified various reported and novel variation across entire genome including COX genes. In our present study we have further studied and functionally validated the selected novel nucleotide variant of COX I and COX II gene using different in-silico tools and trans mitochondrial cybrid based assays. As a result of our study, G6036A (G45S) variant of COX I gene, reduced the COX activity in both spectrophotometric as well as In-gel BN-PAGE assays. FACS analysis also revealed this variant to affect the mitochondrial membrane potential in the respective cybrids. Interestingly most of our in-silico studies indicated that this variant might affect the secondary structure and confirmation of COX I protein. Thus we report the first missense mutation in the COX I gene of LS patients and justify its pathogenic role in these patients by different assays. Variant A7746G (N54K) in COX II gene was also predicted to affect the secondary structure as well as stability of COX II protein. Though, the effect of this variant was not significant, however it will be interesting to investigate its significance by other assays in future.

Role of aneurysm projection in "A2" fork orientation for determining the side of surgical approach.

PURPOSE: To determine factors that help decide the side of approach for anterior communicating artery (AComA) aneurysms, based on a prospective study. METHODS: Between January 2004 and January 2006, 93 cases with AComA aneurysms were treated through pterional approach. They were classified as Type I, II (IIa, IIb), III and IV, based on the various projections and size of aneurysm. The principle for the choice of operative side was designed based on the type of aneurysm and the A2 fork orientation (the interrelations between the plane of bilateral A2, AComA, and mid-saggital plane). RESULTS: There were 55 aneurysms of Type I, 10 of Type IIa, 14 of Type IIb, 12 of Type III, and 2 of Type IV. In Types I and IIa, the side posteriorly placed to A2 was chosen for the approach. In Type IIb, the side of the dominant A1 was selected. In Type III, the side anteriorly placed to A2 was chosen. Type IV aneurysms were difficult to handle even if approached from the dominant A1. There were 11 cases treated from the side of non-dominant A1. The overall outcome in the treatment of AComA aneurysms were considered excellent in 90.8% of cases according to the Glasgow Outcome Scale, with complete occlusion of aneurysms and complete patency of parent or perforating arteries. CONCLUSIONS: Applying three-dimensional computed tomography and magnetic resonance angiography, we classified AComA aneurysms as four types and undertook surgical clipping from the chosen side of approach, according to the type of aneurysm and the A2 fork orientation. The selective side of approach on the basis of individual decision-making has led to favourable outcomes.

Genetic heterogeneity of mitochondrial genome in thiamine deficient Leigh syndrome patients.

In our previously published study, we cared for 165 thiamine deficient Leigh syndrome (LS) patients who presented in acute life threatening conditions with severe neurological abnormalities. However the molecular basis for this atypical phenotype was not explored. This study is an effort to undermine the possible molecular defects in mitochondria of those patients and put-forth an explanation towards this clinical presentation. Protein coding genes of mitochondrial (mt) DNA were sequenced in total 165 LS patients and 94 age matched controls. To understand their pathogenic significance, nucleotide variations were also studied using various in-silico tools. Histochemical and electron microscopic analysis was also done in tissue samples obtained from 23 patients. We observed a very high level of genetic heterogeneity across the mt DNA of all these patients. In the concordance of published literature we also observed a large number of variations in ND5 gene (hot spot for LS). We also observed a total 13 nucleotide variations across COX genes, which is otherwise not common in LS. As per in-silico analysis, many of these variations were suggested to be pathogenic. Histochemical and electron microscopic studies also suggested the defects in the mitochondria of these patients. As these patients were thiamine deficient, hence we propose that genetic defects and thiamine deficiency may together severely affect the ATP levelof these patients, leading to acute and life threatening clinical presentation. Present study has opened up many avenues for further research towards understanding the genetic basis and possible role of thiamine deficiency in LS patients.

High prevalence of infantile encephalitic beriberi with overlapping features of Leigh's disease.

Infantile encephalitic beriberi (IEBB) is a rare form of thiamine deficiency and is poorly described. A proportion of Leigh's disease (LD) patients have similar clinical picture and response to thiamine as beriberi, leading to confusion in diagnosis and management. Data on IEBB and LD is scarce and status of thiamine deficiency in India is controversial. We report several infants with life-threatening respiratory and central nervous system symptoms that overlap between IEBB and LD. Majority had low erythrocyte transketolase levels and responded dramatically to thiamine supplementation suggesting a diagnosis of IEBB. However, presence of characteristic lesions on brain imaging and residual damage in several patients on follow-up does not rule out LD completely. Our study highlights the importance of thiamine deficiency in India, especially in the breast-feds and its overlapping features with LD. Awareness of this common mode of presentation may save patients' lives by early diagnosis and timely thiamine supplementation.

Fast eating syndrome: a case report.

Choking while consuming food is a cause of death that has long been known and studied. Such deaths were popularly known as 'café coronary deaths', which denoted a fatal occlusion of the upper airway by food substances. The event commonly occurs while also consuming large quantities of ethyl alcohol or drugs, or in a psychiatric patient. Here, we present a case of an individual who choked to death while on duty and the main reason for choking was his eating habit which deviated from the known common causes of choking. We also discuss some causes of choking in elderly individuals.