Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-ß plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3ß, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.

Psychedelics for alzheimer's disease-related dementia: Unveiling therapeutic possibilities and pathways.

Psychedelics have traditionally been used for spiritual and recreational purposes, but recent developments in psychotherapy have highlighted their potential as therapeutic agents. These compounds, which act as potent 5-hydroxytryptamine (5HT) agonists, have been recognized for their ability to enhance neural plasticity through the activation of the serotoninergic and glutamatergic systems. However, the implications of these findings for the treatment of neurodegenerative disorders, particularly dementia, have not been fully explored. In recent years, studies have revealed the modulatory and beneficial effects of psychedelics in the context of dementia, specifically Alzheimer's disease (AD)-related dementia, which lacks a definitive cure. Psychedelics such as N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and Psilocybin have shown potential in mitigating the effects of this debilitating disease. These compounds not only target neurotransmitter imbalances but also act at the molecular level to modulate signalling pathways in AD, including the brain-derived neurotrophic factor signalling pathway and the subsequent activation of mammalian target of rapamycin and other autophagy regulators. Therefore, the controlled and dose-dependent administration of psychedelics represents a novel therapeutic intervention worth exploring and considering for the development of drugs for the treatment of AD-related dementia. In this article, we critically examined the literature that sheds light on the therapeutic possibilities and pathways of psychedelics for AD-related dementia. While this emerging field of research holds great promise, further studies are necessary to elucidate the long-term safety, efficacy, and optimal treatment protocols. Ultimately, the integration of psychedelics into the current treatment paradigm may provide a transformative approach for addressing the unmet needs of individuals living with AD-related dementia and their caregivers.

Unconventional Breathing Currents Far beyond the Quantum Tunneling Distances in Large-Gapped Nanoplasmonic Systems.

Localized surface plasmon resonance (LSPR) in plasmonic nanoparticles propels the field of plasmo-electronics, holding promise for transformative optoelectronic devices through efficient light-to-current conversion. Plasmonic excitations strongly influence the charge distribution within nanoparticles, giving rise to electromagnetic fields that can significantly impact the macroscopic charge flows within the nanoparticle housing material. In this study, we present evidence of ultralow, unconventional breathing currents resulting from dynamic irradiance interactions between widely separated nanoparticles, extending far beyond conventional electron (quantum) tunneling distances. We develop an electric analogue model and derive an empirical expression to elucidate the generation of these unconventional breathing currents in cascaded nanoplasmonic systems under irradiance modulation. This technique and theoretical model have significant potential for applications requiring a deeper understanding of current dynamics, particularly on large nanostructured surfaces relevant to photocatalysis, energy harvesting, sensing, imaging, and the development of future photonic devices.

Integration of biochar with nitrogen in acidic soil: A strategy to sequester carbon and improve the yield of stevia via altering soil properties and nutrient recycling.

The health of agroecosystems is subsiding unremittingly, and the over-use of chemical fertilizers is one of the key reasons. It is hypothesized that integrating biochar, a carbon (C)-rich product, would be an effective approach to reducing the uses of synthetic fertilizers and securing crop productivity through improving soil properties and nutrient cycling. The bamboo biochar at different quantities (4-12 Mg ha-1) and combinations with chemical fertilizers were tested in stevia (Stevia rebaudiana) farming in silty clay acidic soil. The integration of biochar at 8 Mg ha-1 with 100% nitrogen (N), phosphorus (P), and potassium (K) produced statistically (p ≤ 0.05) higher leaf area index, dry leaf yield, and steviol glycosides yield by about 18.0-33.0, 25.8-44.9, and 20.5-59.4%, respectively, compared with the 100% NPK via improving soil physicochemical properties. Soil bulk density was reduced by 5-8% with biochar at ≥ 8 Mg ha-1, indicating the soil porosity was increased by altering the soil macrostructure. The soil pH was significantly (p ≤ 0.05) augmented with the addition of biochar alone or in the combination of N because of the alkaline nature of the used biochar (pH = 9.65). Furthermore, integrating biochar at 8 Mg ha-1 with 100% NPK increased 22.7% soil organic C compared with the sole 100% NPK. The priming effect of applied N activates soil microorganisms to mineralize the stable C. Our results satisfy the hypothesis that adding bamboo biochar would be a novel strategy for sustaining productivity by altering soil physicochemical properties.

Hydrological performance of rain gardens having Calendula officinalis plant with varied planting mixtures.

The rain gardens (RGs) have been one of the best management practices in cities to reduce the impact of urban flooding. However, very little is known about various design parameters of RGs, viz., the type of plantation, planting mixtures, and RG dimensions. This study pertains to examining the influence of planting mixtures on the variations of percolation rates of the RG with Calendula officinalis plant and without plants. Six types of planting mixtures in different experimental RGs have been tried. It has been observed that the percolation rate increases with a higher percentage of compost in the planting mixture for RGs with and without plants. The percolation rate is highest for the planting mixture having 25% compost. The runoff rate reduces with a higher percentage of compost in the planting mixture for RGs with C. officinalis and bare surfaces. No runoff is produced in RGs with plant having a compost of more than 20% in the planting mixture. The outcome of the study will be useful in deciding the composition of the planting mixture which will keep the RG plant healthy and at the same time improve the hydrological performance leading to lowering urban flooding magnitude.

Municipal Wastewater Treatment uses Vertical Flow Followed by Horizontal Flow in a Two-Stage Hybrid-Constructed Wetland Planted with Calibanus hookeri and Canna indica (Cannaceae).

The utilization of hybrid-constructed wetland systems has recently expanded due to more rigorous municipal wastewater discharge and also complex wastewaters treated in hybrid-constructed wetlands (HCWs). A lab-scale two-stage experimental setup of vertical flow followed by horizontal flow hybrid-constructed wetland (VFHCW-HFHCW) configuration was built. First-stage vertical flow hybrid-constructed wetland reactor with the surface area was 1963.49 cm2 and second-stage horizontal flow hybrid-constructed wetland reactor with the surface area was 2025 cm2. The HCW unit was planted with two type plants: Calibanus hookeri and Canna indica (Cannaceae). Influent Municipal wastewater flow rate 112.32 l/day, hydraulic loading rate (HLR) 0.55 m/day, and hydraulic retention time of 1 day. The efficiency was evaluated in municipal wastewater quality improvement and physico-chemical analysis in our laboratory. The removal rate after the second-stage horizontal flow of BOD3 at 27 °C, COD, TSS, TP, NH3-N, and NO3-N reached 92.75%, 89.90%, 85.45%, 88.83%, 99.09%, and 96.05%, respectively. The results shown after both stage hybrid-constructed wetland VFHCW-HFHCW, treated effluent of Municipal wastewater produced high-quality effluent which may be reused in gardening, agriculture, and flushing in toilet purpose according to Bureau of Indian Standards (BIS) code for practices. However, in the future, hybrid-constructed wetlands could be standards design criteria developing and enhancing the performance standards and economic meets both to make more popular technology of the hybrid-constructed wetland (HCW). Supplementary Information: The online version contains supplementary material available at 10.1007/s11270-022-05984-0.

A Review of Publicly Available Automatic Brain Segmentation Methodologies, Machine Learning Models, Recent Advancements, and Their Comparison.

BACKGROUND: The noninvasive study of the structure and functions of the brain using neuroimaging techniques is increasingly being used for its clinical and research perspective. The morphological and volumetric changes in several regions and structures of brains are associated with the prognosis of neurological disorders such as Alzheimer's disease, epilepsy, schizophrenia, etc. and the early identification of such changes can have huge clinical significance. The accurate segmentation of three-dimensional brain magnetic resonance images into tissue types (i.e., grey matter, white matter, cerebrospinal fluid) and brain structures, thus, has huge importance as they can act as early biomarkers. The manual segmentation though considered the "gold standard" is time-consuming, subjective, and not suitable for bigger neuroimaging studies. Several automatic segmentation tools and algorithms have been developed over the years; the machine learning models particularly those using deep convolutional neural network (CNN) architecture are increasingly being applied to improve the accuracy of automatic methods. PURPOSE: The purpose of the study is to understand the current and emerging state of automatic segmentation tools, their comparison, machine learning models, their reliability, and shortcomings with an intent to focus on the development of improved methods and algorithms. METHODS: The study focuses on the review of publicly available neuroimaging tools, their comparison, and emerging machine learning models particularly those based on CNN architecture developed and published during the last five years. CONCLUSION: Several software tools developed by various research groups and made publicly available for automatic segmentation of the brain show variability in their results in several comparison studies and have not attained the level of reliability required for clinical studies. The machine learning models particularly three dimensional fully convolutional network models can provide a robust and efficient alternative with relation to publicly available tools but perform poorly on unseen datasets. The challenges related to training, computation cost, reproducibility, and validation across distinct scanning modalities for machine learning models need to be addressed.

A high-frequency single nucleotide polymorphism in the MtrB sensor kinase in clinical strains of Mycobacterium tuberculosis alters its biochemical and physiological properties.

The DNA polymorphisms found in clinical strains of Mycobacterium tuberculosis drive altered physiology, virulence, and pathogenesis in them. Although the lineages of these clinical strains can be traced back to common ancestor/s, there exists a plethora of difference between them, compared to those that have evolved in the laboratory. We identify a mutation present in ~80% of clinical strains, which maps in the HATPase domain of the sensor kinase MtrB and alters kinase and phosphatase activities, and affects its physiological role. The changes conferred by the mutation were probed by in-vitro biochemical assays which revealed changes in signaling properties of the sensor kinase. These changes also affect bacterial cell division rates, size and membrane properties. The study highlights the impact of DNA polymorphisms on the pathophysiology of clinical strains and provides insights into underlying mechanisms that drive signal transduction in pathogenic bacteria.

Reconstruction of sedimentation rates based on the chronological framework of Lake Pykara, Tamil Nadu, India.

This work presents a piece of initial information about the estimation of the sedimentation rate for Lake Pykara. In this investigation, a chronological sequence of sediment core was set up dependent on 137Cs and 210Pbex analysis to study sediment accumulation rates in Lake Pykara. Caesium-137 (Cs) is an artificial radionuclide and is regularly utilized in building up the chronology of lake sediments in the Anthropocene period. The unsupported 210Pb profile shows a non-exponential decline of 210Pb activity with sediment depth. Sedimentation rates dependent on global atmospheric nuclear weapon maximum fallout of 137Cs (1963) bolster the utilization of the consistent rate of 210Pb supply (CRS) model in core sediments. The geochronology studies of the core were performed using the 137Cs method, to evaluate the model of time changes in the sediment. The 137Cs radioactivity was resolved directly by gamma spectrometry and fluctuated from 13.11 ± 1.3 Bq kg-1 for top layers to 1.21 ± 0.1 Bq kg-1 for the bottom of the core. Two trademark peaks of 137Cs radioactivity identified with the global fallouts after atomic weapons testing and the Chernobyl mishap were observed and used to affirm the 210Pb dating method. Radioactivity of 210Pbex ranged from 8.00 ± 1.0 to 1.40 ± 0.1 Bq kg-1. The mean sedimentation rate evaluated from both models was 0.71 ± 0.06 cm year-1, while the estimated age of Lake Pykara was 514.08 years (137Cs) and 521.43 years (210Pbex), respectively.

Machine Learning-Assisted Array-Based Detection of Proteins in Serum Using Functionalized MoS2 Nanosheets and Green Fluorescent Protein Conjugates.

Abnormal concentrations of a specific protein or the presence of some biomarker proteins may indicate life-threatening diseases. Pattern-based detection of specific analytes using affinity-regulated receptors is one of the potential alternatives to specific antigen-antibody-based detection. In this report, we have schemed a sensor array by using various functionalized two-dimensional (2D)-MoS2 nanosheets and green fluorescent protein (GFP) as the receptor and the signal transducer, respectively. Two-dimensional MoS2 has been used as a promising candidate for recognition of the bioanalytes because of its high surface-to-volume ratio compared to those of other nanomaterials. Easy surface tunability of this material provides additional advantages to analyze the target of interest. The optimized 2D-MoS2-GFP conjugates are able to discriminate 15 different proteins at 50 nM concentration with a detection limit of 1 nM. Moreover, proteins in the binary mixture and in the presence of serum were discriminated successfully. Ten different proteins in serum media at relevant concentrations were classified successfully with 100% jackknifed classification accuracy, which proves the potentiality of the above system. We have also implemented and discussed the implication of using different machine learning models on the pattern recognition problem associated with array-based sensing.

Acetylation of Response Regulator Protein MtrA in M. tuberculosis Regulates Its Repressor Activity.

MtrA is an essential response regulator (RR) protein in M. tuberculosis, and its activity is modulated after phosphorylation from its sensor kinase MtrB. Interestingly, many regulatory effects of MtrA have been reported to be independent of its phosphorylation, thereby suggesting alternate mechanisms of regulation of the MtrAB two-component system in M. tuberculosis. Here, we show that RR MtrA undergoes non-enzymatic acetylation through acetyl phosphate, modulating its activities independent of its phosphorylation status. Acetylated MtrA shows increased phosphorylation and enhanced interaction with SK MtrB assessed by phosphotransfer assays and FRET analysis. We also observed that acetylated MtrA loses its DNA-binding ability on gene targets that are otherwise enhanced by phosphorylation. More interestingly, acetylation is the dominant post-translational modification, overriding the effect of phosphorylation. Evaluation of the impact of MtrA and its lysine mutant overexpression on the growth of H37Ra bacteria under different conditions along with the infection studies on alveolar epithelial cells further strengthens the importance of acetylated MtrA protein in regulating the growth of M. tuberculosis. Overall, we show that both acetylation and phosphorylation regulate the activities of RR MtrA on different target genomic regions. We propose here that, although phosphorylation-dependent binding of MtrA drives its repressor activity on oriC and rpf, acetylation of MtrA turns this off and facilitates division in mycobacteria. Our findings, thus, reveal a more complex regulatory role of RR proteins in which multiple post-translational modifications regulate the activities at the levels of interaction with SK and the target gene expression.

Evolution of Antibodies to Epitopes of PE_PGRS51 in the Spectrum of Active Pulmonary Tuberculosis.

BACKGROUND: Intrafamily homology has impeded correlation of expression of individual PE_PGRS proteins with stage of tuberculosis (TB). We investigated the in vivo expression of PE_PGRS51, which has 3 unique regions. METHODS: Sera from patients across the spectrum of TB were used to screen peptide arrays spanning PE_PGRS51. RESULTS: Antibodies against a subset of conserved "core epitopes" within PE/PGRS domains are elicited during early TB. The epitope repertoire expands to adjacent regions with disease progression. Antiunique region antibodies appear only during cavitary TB. CONCLUSIONS: Elicitation of antiunique region antibodies can serve as markers for in vivo expression of PE_PGRS proteins.

Protocol development for discovery of angiogenesis inhibitors via automated methods using zebrafish.

Their optical clarity as larvae and embryos, small size, and high fecundity make zebrafish ideal for whole animal high throughput screening. A high-throughput drug discovery platform (HTP) has been built to perform fully automated screens of compound libraries with zebrafish embryos. A Tg(kdrl:EGFP) line, marking endothelial cell cytoplasm, was used in this work to help develop protocols and functional algorithms for the system, with the intent of screening for angiogenesis inhibitors. Indirubin 3' Monoxime (I3M), a known angiogenesis inhibitor, was used at various concentrations to validate the protocols. Consistent with previous studies, a dose dependant inhibitory effect of I3M on angiogenesis was confirmed. The methods and protocols developed here could significantly increase the throughput of drug screens, while limiting human errors. These methods are expected to facilitate the discovery of novel anti-angiogenesis compounds and can be adapted for many other applications in which samples have a good fluorescent signal.

Role of laparoscopic cholecystectomy in the management of chronic right upper quadrant pain due to biliary dyskinesia: a systematic review and meta-analysis.

BACKGROUND: The objective of this study was to evaluate the surgical outcomes and feasibility of performing laparoscopic cholecystectomy (LC) in patients with longstanding right upper quadrant pain secondary to biliary dyskinesia. METHODS: A systematic review of the literature including published randomized, controlled trials, non-randomized trials and comparative trials of any type, reporting outcomes of LC in the management of chronic right upper quadrant pain in patients with biliary dyskinesia, using the principles of meta-analysis on RevMan 5.3 statistical software, was undertaken. RESULTS: Thirteen studies including 740 patients evaluating the symptomatic improvement following LC in patients with biliary dyskinesia presenting as chronic right upper quadrant pain were included. There were 542 patients in LC group and 198 patients in Non-LC group. Successful complete resolution of symptoms was more likely to be achieved in LC group [risk ratio (RR), 0.21; 95% confidence interval (CI), 0.09-0.50, P=0.00001]. In addition, the risk of failure to resolve symptoms (risk ratio, 0.15; 95% CI, 0.05-0.39, P=0.00001) was lower in LC group. CONCLUSIONS: LC may be considered as an acceptable surgical intervention in patients with biliary dyskinesia presenting with chronic right upper quadrant pain. Currently there is insufficient evidence to recommend the routine use of LC in every patient with biliary dyskinesia. Paucity of high power randomised, controlled trials is the major reason for this lack of evidence which should be addressed soon and until then current study may be used to provide the basis for offering LC in selected group of patients.

Acetylation of Response Regulator Proteins, TcrX and MtrA in M. tuberculosis Tunes their Phosphotransfer Ability and Modulates Two-Component Signaling Crosstalk.

Two-component signal transduction (TCS) cascades involve stimulus-dependent activation and phosphorylation of a sensor kinase (SK), which then transfers the phosphoryl moiety to the response regulator (RR) protein. The fidelity of this phosphotransfer reaction from the SK to the RR provides specificity to TCS signaling. In the present study, we show that for TcrX, a transcriptionally autoregulated RR of Mycobacterium tuberculosis, acetylation enhances its net phosphorylation from cognate SK TcrY and lowers it from a non-cognate SK MtrB. Similar acetylation mediated increase in phosphorylation was also observed for another RR MtrA from cognate SK MtrB. Thus, we establish a novel TCS signaling design wherein acetylation of RRs results in enhanced cognate phosphorylation and suppresses non-cognate phosphorylation. Using wild-type or acetylation-deficient TcrX proteins in M. tuberculosis H37Ra, we demonstrate that non-acetylated TcrX acts as a "phosphate sink" for MtrB and suppressing signal propagation from MtrB to MtrA in vivo, linking metabolism to TCS signaling. Overall, we report that acetylation of RRs shields TCSs from crosstalk, modulates the phosphatase activities and alters the DNA-binding activities of RRs, all of which are non-intuitive behavior of TCS systems.

Self-Strangulation Turning into Partial Hanging for a Suicide Victim.

Hanging is the most common asphyxial method of suicide, whereas suicide by strangulation is unusual. Here, we are reporting a particular methodology of the asphyxial method of suicide in which a case of self-strangulation culminated into partial hanging. A 30-year-old male wrapped one end of the cable wire around his neck. He then passed the other end over a curtain rod and tied that end around the right hand. He pulled the hand down, using the curtain rod as a fulcrum, to tighten the noose around the neck in an attempt to strangulate himself. However, he lost consciousness during the process and the body slipped down, pulling the right hand up which got stuck at the curtain rod. This led the body hanged in the kneeling position. This bizarre scenario raised suspicion of homicide but the crime scene, autopsy and victim characteristics were in favor of suicide.

ATM-ROS-iNOS axis regulates nitric oxide mediated cellular senescence.

Cellular senescence is an outcome of the accumulation of DNA damage which induces the growth arrest in cells. Physiologically, it is presumed to be mediated by accumulation of reactive oxygen species (ROS). Here, we show that another free radical, nitric oxide (NO) produced during inflammation or present as an environmental pollutant can also induce cellular senescence. In primary cells and various immortalized cell lines, exposure to chronic NO, through external addition or internally generated by iNOS expression, leads to the activation of DNA damage response and causes cellular senescence. The phenotype generated by NO includes robust growth arrest, increase in the levels of the DNA damage foci, ROS, SAß-gal staining, and inflammatory cytokines like IL-6 and IL-8, all hallmarks of cellular senescence similar to replicative senescence. Mechanistically, inhibitor and knockdown analysis revealed that NO mediates senescence through ATM kinase activation and the viability of cells is dependent on both ROS and ATM kinase involving the ATM-ROS-iNOS axis. Overall, we demonstrate that nitric oxide mediates cellular senescence through a novel free radical dependent genotoxic stress pathway.

Novel regulatory role of neuropilin-1 in endothelial-to-mesenchymal transition and fibrosis in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an intense fibrotic reaction termed tumor desmoplasia, which is in part responsible for its aggressiveness. Endothelial cells have been shown to display cellular plasticity in the form of endothelial-to-mesenchymal transition (EndMT) that serves as an important source of fibroblasts in pathological disorders, including cancer. Angiogenic co-receptor, neuropilin-1 (NRP- 1) actively binds TGFß1, the primary mediator of EndMT and is involved in oncogenic processes like epithelial-to-mesenchymal transition (EMT). NRP-1 and TGFß1 signaling have been shown to be aberrantly up-regulated in PDAC. We report herein a positive correlation between NRP-1 levels, EndMT and fibrosis in human PDAC xenografts. Loss of NRP-1 in HUVECs limited TGFß1-induced EndMT as demonstrated by gain of endothelial and loss of mesenchymal markers, while maintaining endothelial cell architecture. Knockdown of NRP-1 down-regulated TGFß canonical signaling (pSMAD2) and associated pro-fibrotic genes. Overexpression of NRP-1 exacerbated TGFß1-induced EndMT and up-regulated TGFß signaling and expression of pro-fibrotic genes. In vivo, loss of NRP-1 attenuated tumor perfusion and size, accompanied by reduction in EndMT and fibrosis. This study defines a previously unrecognized role of NRP-1 in regulating TGFß1-induced EndMT and fibrosis, and advocates NRP-1 as a therapeutic target to reduce tumor fibrosis and PDAC progression.

Laparoscopic management of a cystic artery pseudoaneurysm in a patient with calculus cholecystitis.

INTRODUCTION: Pseudoaneurysm of the cystic artery is very rare. In the majority of cases it has been reported as a post-operative complication of laparoscopic cholecystectomy, however it has also been associated with the presence of acute cholecystitis or pancreatitis. When these pseudoaneurysms rupture they can lead to intraperitoneal bleeding, haemobilia and upper gastrointestinal haemorrhage. Radiological as well as open surgical approaches have been described for control of this rare pathology. PRESENTATION OF CASE: We report the laparoscopic surgical management of an incidental, unruptured cystic artery pseudoaneurysm in a patient presenting with acute cholecystitis. DISCUSSION: Cystic artery pseudoaneurysm is a rare entity and as such there is no consensus on the clinical management of this condition. A variety of treatment strategies have been reported in the literature including radiological selective embolisation and coiling, open cholecystectomy with ligation of the aneurysm, or a two-step approach involving radiological management of the pseudoaneurysm followed by an elective cholecystectomy. CONCLUSION: In this report we have demonstrated that laparoscopic management of a cystic artery pseudoaneurysm with simultaneous laparoscopic cholecystectomy is feasible and safe. This avoids multiple invasive procedures and decreases morbidity associated with open surgery.

Laparoscopic management of Bouveret syndrome.

Bouveret syndrome is a proximal form of gallstone ileus where a large gallstone lodges in the pylorus or proximal duodenum, having passed through a bilioenteric fistula that has formed secondary to previous cholecystitis. We describe the laparoscopic extraction of a giant 'Bouveret' gallstone from the duodenum of an elderly man with morbid obesity.