Definitions of major bleeding for predicting mortality in critically ill adult patients who survived 24 hours while supported with peripheral veno-arterial extracorporeal membrane oxygenation for cardiogenic shock: a comparative historical cohort study.

PURPOSE: The severity of bleeding events is heterogeneously defined during peripheral veno-arterial extracorporeal membrane oxygenation (pVA-ECMO). We studied three bleeding definitions in pVA-ECMO: the Extracorporeal Life Support Organization (ELSO)-serious bleeding, the Bleeding Academic Research Consortium (BARC), and the universal definition of postoperative bleeding (UPDB) classifications. METHODS: We included consecutive adult patients supported by pVA-ECMO for refractory cardiogenic shock admitted to Lille academic hospitals between January 2013 and December 2019. We assessed the association of bleeding definitions with the primary endpoint of 28-day all-cause mortality with the use of multivariate models accounting for time-dependent and competing variables. We compared models' performances using the Harrell's C-Index and the Akaike information criteria. RESULTS: Twenty-eight-day mortality occurred in 128/308 (42%) 308 patients. The ELSO-serious bleeding (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.09 to 2.56) and BARC ≥ type 2 (HR, 1.55; 95% CI, 1.01 to 2.37) were associated with 28-day mortality (Harrell's C-index, 0.69; 95% CI, 0.63 to 0.74 for both). Predictors of ELSO-serious bleeding were postcardiotomy, body mass index, baseline platelets count, fibrinogen, and hemoglobin levels. CONCLUSION: Extracorporeal Life Support Organization-serious bleeding and BARC ≥ type 2 are relevant definitions of major bleeding regarding their association with mortality in critically ill patients who survived the first 24 hr while supported with pVA-ECMO for cardiogenic shock. STUDY REGISTRATION: CERAR (IRB 00010254-2022-050, Paris, France); first submitted on 18 April 2022.

RéSUMé: OBJECTIF: La gravité des événements hémorragiques est définie de manière hétérogène pendant une oxygénation par membrane extracorporelle veino-artérielle périphérique (ECMO-VA périphérique). Nous avons étudié trois définitions du saignement sous ECMO-VA périphérique : les classifications des saignements graves selon l'Extracorporeal Life Support Organization (ELSO), celles du Bleeding Academic Research Consortium (BARC) et la définition universelle du saignement postopératoire (UPDB). MéTHODE: Nous avons inclus des patient·es adultes pris·es en charge de manière consécutive par ECMO-VA périphérique à la suite d'un choc cardiogénique réfractaire et admis·es dans les centres hospitaliers universitaires de Lille entre janvier 2013 et décembre 2019. Nous avons évalué l'association des définitions du saignement avec le critère d'évaluation principal de mortalité toutes causes confondues à 28 jours à l'aide de modèles multivariés tenant compte des variables dépendantes du temps et concurrentes. Nous avons comparé les performances des modèles à l'aide de l'indice C de Harrell et du critère d'information d'Akaike. RéSULTATS: La mortalité à 28 jours est survenue chez 128/308 (42 %) patient·es. Le saignement grave selon l'ELSO (rapport de risque [RR], 1,67; intervalle de confiance [IC] à 95 %, 1,09 à 2,56) et une classification BARC ≥ type 2 (RR, 1,55; IC 95 %, 1,01 à 2,37) étaient associés à une mortalité à 28 jours (indice C de Harrell, 0,69; IC 95 %, 0,63 à 0,74 pour les deux). Les prédicteurs d'hémorragie grave selon l'ELSO étaient la postcardiotomie, l'indice de masse corporelle, la numération plaquettaire initiale, le taux de fibrinogène et les taux d'hémoglobine. CONCLUSION: Les définitions du saignement grave de l'Extracorporeal Life Support Organization et une classification BARC ≥ type 2 sont des définitions pertinentes des saignements majeurs en ce qui touche à leur association avec la mortalité chez les personnes gravement malades qui ont survécu aux premières 24 heures alors qu'elles étaient prises en charge par ECMO-VA périphérique à la suite d'un choc cardiogénique. ENREGISTREMENT DE L'éTUDE: CERAR (IRB 00010254-2022-050, Paris, France); soumis pour la première fois le 18 avril 2022.

Revisiting fertility regulation and family ties in Tunisia.

BACKGROUND: We revisit fertility regulation in Tunisia by examining the role of the extended family. As marriage is the exclusive acknowledged childbearing context, we examine fertility analysis in Tunisia through the sequence: woman's marriage age, post-marriage delay in the first use of contraception, and past and current contraceptive use. We trace the family socio-economic influences that operate through these decisions. METHODS: Using data from the 2001 PAP-FAM Tunisian survey, we estimate the duration and probability models of these birth control decisions. RESULTS: In Tunisia, family ties and socio-cultural environment appear to hamper fertility regulation that operates through the above decisions. This is notably the case for couples whose marriages are arranged by the extended family or who benefit from financial support from both parental families. CONCLUSION: This calls for family planning policies that address more the extended families.

Discovery of Small-Molecule Inhibitors of the PTK7/ß-Catenin Interaction Targeting the Wnt Signaling Pathway in Colorectal Cancer.

Colorectal cancer (CRC), the second cause of death due to cancer worldwide, is a major public health issue. The discovery of new therapeutic targets is thus essential. Pseudokinase PTK7 intervenes in the regulation of the Wnt/ß-catenin pathway signaling, in part, through a kinase domain-dependent interaction with the ß-catenin protein. PTK7 is overexpressed in CRC, an event associated with metastatic development and reduced survival of nonmetastatic patients. In addition, numerous alterations have been identified in CRC inducing constitutive activation of the Wnt/ß-catenin pathway signaling through ß-catenin accumulation. Thus, targeting the PTK7/ß-catenin interaction could be of interest for future drug development. We have developed a NanoBRET screening assay recapitulating the interaction between PTK7 and ß-catenin to identify compounds able to disrupt this protein-protein interaction. A high-throughput screening allowed us to identify small-molecule inhibitors targeting the Wnt pathway signaling and inducing antiproliferative and antitumor effects in vitro in CRC cells harboring ß-catenin or adenomatous polyposis coli (APC) mutations. Thus, inhibition of the PTK7/ß-catenin interaction could represent a new therapeutic strategy to inhibit cell growth dependent on the Wnt signaling pathway. Moreover, despite a lack of enzymatic activity of its tyrosine kinase domain, targeting the PTK7 kinase domain-dependent functions appears to be of interest for further therapeutic development.

Post-acute delivery of α5-GABAA antagonist, S 44819, improves functional recovery in juvenile rats following stroke.

Hypo-excitability was reported in the peri-infarct tissue following stroke, an effect counteracted by a blockage of α5-GABAA receptors in adult rodents. Our present study aims to evaluate the effect of a selective α5-GABAA receptor antagonist, S 44819, in stroke in juvenile animals. We have set up and characterized an original model of transient ischemic stroke in 28 day-old Sprague-Dawley rats (45-min occlusion of the middle cerebral artery by intraluminal suture). In this model, S 44819 (1, 3 and 10 mg/kg, b.i.d) was orally administered from day 3 to day 16 after stroke onset. Sensorimotor recovery was assessed on day 1, day 9 and day 16 after stroke onset. Results show that rats treated with S 44819 at the doses of 3 and 10 mg/kg displayed a significant improvement of the neurological deficits (neuroscore) on day 9 and day 16, when compared with animals treated with vehicle. Grip-test data analysis reveals that rats treated with S 44819 at the dose of 3 mg/kg displayed a better recovery on day 9 and day 16. These results are in agreement with those previously observed in adult rats, demonstrating that targeting α5-GABAA receptors improves neurological recovery after stroke in juvenile rats.

Artificial Intelligence, Machine Learning, and Deep Learning in Real-Life Drug Design Cases.

The discovery and development of drugs is a long and expensive process with a high attrition rate. Computational drug discovery contributes to ligand discovery and optimization, by using models that describe the properties of ligands and their interactions with biological targets. In recent years, artificial intelligence (AI) has made remarkable modeling progress, driven by new algorithms and by the increase in computing power and storage capacities, which allow the processing of large amounts of data in a short time. This review provides the current state of the art of AI methods applied to drug discovery, with a focus on structure- and ligand-based virtual screening, library design and high-throughput analysis, drug repurposing and drug sensitivity, de novo design, chemical reactions and synthetic accessibility, ADMET, and quantum mechanics.

Mid-Term Survival and Risk Factors Associated With Myocardial Injury After Fenestrated and/or Branched Endovascular Aortic Aneurysm Repair.

OBJECTIVE: Myocardial injury after non-cardiac surgery (MINS) is an independent predictor of post-operative mortality in non-cardiac surgery patients and may increase health costs. Few data are available for MINS in vascular surgery patients, in general, and those undergoing fenestrated/branched endovascular aortic repairs (F/BEVAR), in particular. The incidence of MINS after F/BEVAR, the associated risk factors, and prognosis have not been determined. The aim of the present study was to help fill these knowledge gaps. METHODS: A single centre, retrospective study was carried out at a high volume F/BEVAR centre in a university hospital. Adult patients who underwent F/BEVAR between October 2010 and December 2018 were included. A high sensitivity troponin T (HsTnT) assay was performed daily in the first few post-operative days. MINS was defined as a HsTnT level ≥ 14 ng/L (MINS14) or ≥ 20 ng/L (MINS20). After assessment of the incidence of MINS, survival up to two years was estimated in a Kaplan-Meier analysis and the groups were compared according to MINS status. A secondary aim was to identify predictors of MINS. RESULTS: Of the 387 included patients, 240 (62.0%) had MINS14 and 166 (42.9%) had MINS20. In multivariable Cox models, both conditions were significantly associated with poor two year survival (MINS14: adjusted hazard ratio [aHR] 2.15, 95% confidence interval [CI] 1.10 - 4.19; MINS20: aHR 2.43, 95% CI 1.36 - 4.34). In a multivariable logistic regression, age, revised cardiac risk index, duration of surgery, pre-operative estimated glomerular filtration rate (eGFR), and haemoglobin level were independent predictors of MINS. CONCLUSION: After F/BEVAR surgery, the incidence of MINS was particularly high, regardless of the definition considered (MINS14 or MINS20). MINS was significantly associated with poor two year survival. The modifiable predictors identified were duration of surgery, eGFR, and haemoglobin level.

Fr-PPIChem: An Academic Compound Library Dedicated to Protein-Protein Interactions.

Protein-protein interactions (PPIs) mediate nearly every cellular process and represent attractive targets for modulating disease states but are challenging to target with small molecules. Despite this, several PPI inhibitors (iPPIs) have entered clinical trials, and a growing number of PPIs have become validated drug targets. However, high-throughput screening efforts still endure low hit rates mainly because of the use of unsuitable screening libraries. Here, we describe the collective effort of a French consortium to build, select, and store in plates a unique chemical library dedicated to the inhibition of PPIs. Using two independent predictive models and two updated databases of experimentally confirmed PPI inhibitors developed by members of the consortium, we built models based on different training sets, molecular descriptors, and machine learning methods. Independent statistical models were used to select putative PPI inhibitors from large commercial compound collections showing great complementarity. Medicinal chemistry filters were applied to remove undesirable structures from this set (such as PAINS, frequent hitters, and toxic compounds) and to improve drug likeness. The remaining compounds were subjected to a clustering procedure to reduce the final size of the library while maintaining its chemical diversity. In practice, the library showed a 46-fold activity rate enhancement when compared to a non-iPPI-enriched diversity library in high-throughput screening against the CD47-SIRPα PPI. The Fr-PPIChem library is plated in 384-well plates and will be distributed on demand to the scientific community as a powerful tool for discovering new chemical probes and early hits for the development of potential therapeutic drugs.

Chemistry-driven Hit-to-lead Optimization Guided by Structure-based Approaches.

For several decades, hit identification for drug discovery has been facilitated by developments in both fragment-based and high-throughput screening technologies. However, a major bottleneck in drug discovery projects continues to be the optimization of primary hits from screening campaigns in order to derive lead compounds. Computational chemistry or molecular modeling can play an important role during this hit-to-lead (H2L) stage by both suggesting putative optimizations and decreasing the number of compounds to be experimentally synthesized and evaluated. However, it is also crucial to consider the feasibility of organically synthesizing these virtually designed compounds. Furthermore, the generated molecules should have reasonable physicochemical properties and be medicinally relevant. This review focuses on chemistry-driven and structure-based computational methods that can be used to tackle the difficult problem of H2L optimization, with emphasis being placed on the strategy developed in our laboratory.

Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach.

Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient integrated strategy for H2L optimization as well as a partially automated design of potent chemical probes consisting of a focused-chemical-library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation. The virtual library is generated by combining an activated fragment, corresponding to the substructure binding to the target, with a collection of functionalized building blocks using in silico encoded chemical reactions carefully chosen from a list of one-step organic transformations relevant in medicinal chemistry. The proof of concept was demonstrated using the optimization of bromodomain inhibitors as a test case, leading to the validation of several compounds with improved affinity by several orders of magnitude.

Prediction of drug induced liver injury using molecular and biological descriptors.

In this paper we report quantitative structure-activity models linking in vivo Drug-Induced Liver Injury (DILI) of organic molecules with some parameters both measured experimentally in vitro and calculated theoretically from the molecular structure. At the first step, a small database containing information of DILI in humans was created and annotated by experimentally observed information concerning hepatotoxic effects. Thus, for each compound a binary annotation "yes/no" was applied to DILI and seven endpoints causing different liver pathologies in humans: Cholestasis (CH), Oxidative Stress (OS), Mitochondrial injury (MT), Cirrhosis and Steatosis (CS), Hepatitis (HS), Hepatocellular (HC), and Reactive Metabolite (RM). Different machine-learning methods were used to build classification models linking DILI with molecular structure: Support Vector Machines, Artificial Neural Networks and Random Forests. Three types of models were developed: (i) involving molecular descriptors calculated directly from chemical structure, (ii) involving selected endpoints as "biological" descriptors, and (iii) involving both types of descriptors. It has been found that the models based solely on molecular descriptors have much weaker prediction performance than those involving in vivo measured endpoints. Taking into account difficulties in obtaining of in vivo data, at the validation stage we used instead five endpoints (CH, CS, HC, MT and OS) measured in vitro in human hepatocyte cultures. The models involving either some of experimental in vitro endpoints or their combination with theoretically calculated ones correctly predict DILI for 9 out of 10 reference compounds of the external test set. This opens an interesting perspective to use for DILI predictions a combination of theoretically calculated parameters and measured in vitro biological data.

Pancreatic surgery in the very old: face to face with a challenge of the near future.

BACKGROUND: The proportion of octogenarians requiring surgery for pancreatic disease is rapidly growing. This trend will be continued during the next decades, posing a challenge to surgeons and the health care system worldwide. This study aimed to analyze the results of pancreatic surgery in octogenarians in terms of safety and survival based on a cohort of patients at a European high-volume center. METHODS: During a 7-year period, 1,705 operations were performed, 76 in patients ≥ 80 years of age. Data on the octogenarians were retrospectively reviewed and compared to those of the whole collective and to contemporary data from the literature. Primary endpoints were mortality, morbidity, and survival. RESULTS: Overall, 80 % had a malignant disease, and resections were performed in 50 % of all cases. Mortality was 11.8 % and morbidity 72.4 %. There were significantly more medical than surgical complications: 56.6 versus 34.2 %. Pancreatic fistula occurred in 5.3 %, postoperative bleeding in 3.9 %, and delayed gastric emptying in 19.7 %. The median hospital stay was 15 days and the intensive care unit stay 2 days. Mean survival was 28.2 months and in patients with cancer 22.6 months. The 1-, 3-, and 5-year survival rates were 61.4, 31.3, and 18.8 %, respectively. CONCLUSIONS: Despite high mortality and morbidity rates, surgery remains the only chance for cure in most octogenarians with pancreatic disease. Careful patient selection is the key to success and improved long-term survival in this group, which will represent a substantial fraction of the population in the near future.

Equivalent income and fair evaluation of health care.

We argue that the economic evaluation of health care (cost-benefit analysis) should respect individual preferences and should incorporate distributional considerations. Relying on individual preferences does not imply subjective welfarism. We propose a particular non-welfarist approach, based on the concept of equivalent income, and show how it helps to define distributional weights. We illustrate the feasibility of our approach with empirical results from a pilot survey.

Models for identification of erroneous atom-to-atom mapping of reactions performed by automated algorithms.

Machine learning (SVM and JRip rule learner) methods have been used in conjunction with the Condensed Graph of Reaction (CGR) approach to identify errors in the atom-to-atom mapping of chemical reactions produced by an automated mapping tool by ChemAxon. The modeling has been performed on the three first enzymatic classes of metabolic reactions from the KEGG database. Each reaction has been converted into a CGR representing a pseudomolecule with conventional (single, double, aromatic, etc.) bonds and dynamic bonds characterizing chemical transformations. The ChemAxon tool was used to automatically detect the matching atom pairs in reagents and products. These automated mappings were analyzed by the human expert and classified as "correct" or "wrong". ISIDA fragment descriptors generated for CGRs for both correct and wrong mappings were used as attributes in machine learning. The learned models have been validated in n-fold cross-validation on the training set followed by a challenge to detect correct and wrong mappings within an external test set of reactions, never used for learning. Results show that both SVM and JRip models detect most of the wrongly mapped reactions. We believe that this approach could be used to identify erroneous atom-to-atom mapping performed by any automated algorithm.

Effects of FTY720 and rapamycin on inflammation in taurocholate-induced acute pancreatitis in the rat.

OBJECTIVES: This study aimed at T-cell inhibition by immunosuppressants to reduce cell damage and improve the course of severe acute pancreatitis (SAP). METHODS: A taurocholate-induced SAP was used and 5 groups were compared: (1) rapamycin + FTY720, (2) rapamycin, (3) FTY720, (4) cortisol, and (5) control: sodium chloride. Drugs were applied intravenously at SAP induction; 6 hours later, rats were killed. Interleukin (IL)-1, IL-6, IL-10, tumor necrosis factor α, platelet-activating factor, amylase, and lipase were measured in serum and myeloperoxidase tissue activity in pancreas, kidney, lung, liver, and spleen. Edema, inflammation, and necrosis were histologically determined in pancreas. CD4/CD8 immunohistochemistry was performed. RESULTS: Inflammation was ameliorated in all 4 treated groups. Necrosis development was suppressed by FTY720, FTY720 + rapamycin, and cortisol. IL-6 and IL-10 were significantly lower in these groups. Amylase was higher in all treatment groups compared to the controls except for the cortisol group. Tumor necrosis factor α, lipase, and myeloperoxidase activity were not affected by therapy. CD4+/CD8+ cells were significantly less in FTY720-treated pancreata. CONCLUSION: Rapamycin and FTY720 ameliorated the severity of SAP, which may be due to early suppression of helper T cells. FTY720 reduced the development of pancreatic necrosis. The combination of both immunosuppressants did not show advantage to treatment with FTY720 alone.

Context-dependent modulation of hippocampal and cortical recruitment during remote spatial memory retrieval.

According to systems consolidation, as hippocampal-dependent memories mature over time, they become additionally (or exclusively) dependent on extra-hippocampal structures. We assessed the recruitment of hippocampal and cortical structures on remote memory retrieval in a performance-degradation resistant (PDR; no performance degradation with time) versus performance-degradation prone (PDP; performance degraded with time) context. Using a water-maze task in two contexts with a hidden platform and three control conditions (home cage, visible platform with or without access to distal cues), we compared neuronal activation (c-Fos imaging) patterns in the dorsal hippocampus and the medial prefrontal cortex (mPFC) after the retrieval of recent (5 days) versus remote (25 days) spatial memory. In the PDR context, the hippocampus exhibited greater c-Fos protein expression on remote than recent memory retrieval, be it in the visible or hidden platform group. In the PDP context, hippocampal activation increased at the remote time point and only in the hidden platform group. In the anterior cingulate cortex, c-Fos expression was greater for remote than for recent memory retrieval and only in the PDR context. The necessity of the mPFC for remote memory retrieval in the PDR context was confirmed using region-specific lidocaine inactivation, which had no impact on recent memory. Conversely, inactivation of the dorsal hippocampus impaired both recent and remote memory in the PDR context, and only recent memory in the PDP context, in which remote memory performance was degraded. While confirming that neuronal circuits supporting spatial memory consolidation are reorganized in a time-dependent manner, our findings further indicate that mPFC and hippocampus recruitment (i) depends on the content and perhaps the strength of the memory and (ii) may be influenced by the environmental conditions (e.g., cue saliency, complexity) in which memories are initially formed and subsequently recalled.

Protective role of endogenous melatonin in the early course of human acute pancreatitis.

Melatonin plays a protective role in experimental acute pancreatitis (AP) because of its antioxidative, antiinflammatory, and immunomodulatory effects. This study presents the first data on the dynamic changes of endogenous melatonin in the early phase of human AP. Morning (08:00 hr) serum melatonin concentrations were measured by ELISA in 75 patients with AP for the first 5 days after the onset of pain. According to the Atlanta classification, 26 patients suffered a mild AP (MAP). The other 49 developed a severe AP (SAP). Median melatonin concentrations of healthy volunteers were used as a control. Median melatonin level in healthy controls was 18.5 pg/mL. Levels of melatonin were significantly higher in the first 24 hr after onset of disease in patients with MAP compared to those with SAP, 51.2 versus 8.7 pg/mL (P = 0.01). Melatonin values were the same in MAP and SAP during the remainder of the study period. Melatonin concentrations during the first 24 hr after the onset of pain in younger patients (<35 yrs old) were significantly higher than levels in older patients (>35 yrs): 73 versus 8.7 pg/mL (P = 0.01). No correlation existed between melatonin levels and the following parameters: gender, etiology (biliary versus alcohol induced), and histological findings (edematous versus necrotizing versus infected necrosis). High endogenous melatonin serum levels in the first 24 hr after the onset of AP played a protective role and favoured a mild course of the disease in humans, especially in young patients.

Applicability domains for classification problems: Benchmarking of distance to models for Ames mutagenicity set.

The estimation of accuracy and applicability of QSAR and QSPR models for biological and physicochemical properties represents a critical problem. The developed parameter of "distance to model" (DM) is defined as a metric of similarity between the training and test set compounds that have been subjected to QSAR/QSPR modeling. In our previous work, we demonstrated the utility and optimal performance of DM metrics that have been based on the standard deviation within an ensemble of QSAR models. The current study applies such analysis to 30 QSAR models for the Ames mutagenicity data set that were previously reported within the 2009 QSAR challenge. We demonstrate that the DMs based on an ensemble (consensus) model provide systematically better performance than other DMs. The presented approach identifies 30-60% of compounds having an accuracy of prediction similar to the interlaboratory accuracy of the Ames test, which is estimated to be 90%. Thus, the in silico predictions can be used to halve the cost of experimental measurements by providing a similar prediction accuracy. The developed model has been made publicly available at http://ochem.eu/models/1 .

Assessment of pancreatic hardness-surgeon versus durometer.

BACKGROUND: This study reports the first results of durometrically measured hardness of human pancreas and investigates its correlation to palpatory determined hardness, grade of pancreatic fibrosis, and preoperatively determined radiodensity. METHODS: Fifty-two patients with pancreatic resections were prospectively recruited. Hardness of samples from pancreatic cancer, chronic pancreatitis, and normal pancreas was measured using a durometer on a 0-100 Shore units (SU) scale. Three pancreatic surgeons palpated the pancreas and reported their assessment of hardness on a subjective 0-100 "Bochum units" (BU) scale. Radiodensity and fibrosis of pancreatic tissue were used for comparison. RESULTS: Pancreatic hardness differed significantly in normal pancreas, chronic pancreatitis, and pancreatic cancer; 30 SU, 51 SU, and 65.8 SU, respectively. Palpatory hardness of normal pancreas was 20 BU and of pancreatitis 60 BU. It correlated well to durometric readings: r(2)=0.56, P<0.00001. Fibrosis grade and radiodensity correlated neither to durometry nor to palpation. Pancreatic leak developed 4/20 (20%) patients with normal pancreas vs. 1/32 (3.1%) with chronic pancreatitis in the resection margin, P<0.05. CONCLUSIONS: Palpatory assessment of pancreatic hardness performed by experienced surgeons correlated well to durometric measurements and remains the method of choice for intraoperative decision making. Durometry was more precise and should be considered in studies on pancreatic texture and for teaching purposes. Hardness and fibrosis grade appeared to be independent characteristics of pancreatic texture.

Functional assessment of pancreatic beta-cell area in humans.

OBJECTIVE: beta-Cell mass declines progressively during the course of diabetes, and various antidiabetic treatment regimens have been suggested to modulate beta-cell mass. However, imaging methods allowing the monitoring of changes in beta-cell mass in vivo have not yet become available. We address whether pancreatic beta-cell area can be assessed by functional test of insulin secretion in humans. RESEARCH DESIGN AND METHODS: A total of 33 patients with chronic pancreatitis (n = 17), benign pancreatic adenomas (n = 13), and tumors of the ampulla of Vater (n = 3) at various stages of glucose tolerance were examined with an oral glucose load before undergoing pancreatic surgery. Indexes of insulin secretion were calculated and compared with the fractional beta-cell area of the pancreas. RESULTS: beta-Cell area was related to fasting glucose concentrations in an inverse linear fashion (r = -0.53, P = 0.0014) and to 120-min postchallenge glycemia in an inverse exponential fashion (r = -0.89). beta-Cell area was best predicted by a C-peptide-to-glucose ratio determined 15 min after the glucose drink (r = 0.72, P < 0.0001). However, a fasting C-peptide-to-glucose ratio already yielded a reasonably close correlation (r = 0.63, P < 0.0001). Homeostasis model assessment (HOMA) beta-cell function was unrelated to beta-cell area. CONCLUSIONS: Glucose control is closely related to pancreatic beta-cell area in humans. A C-peptide-to-glucose ratio after oral glucose ingestion appears to better predict beta-cell area than fasting measures, such as the HOMA index.