EGR4 is critical for cell-fate determination and phenotypic maintenance of geniculate ganglion neurons underlying sweet and umami taste.

The sense of taste starts with activation of receptor cells in taste buds by chemical stimuli which then communicate this signal via innervating oral sensory neurons to the CNS. The cell bodies of oral sensory neurons reside in the geniculate ganglion (GG) and nodose/petrosal/jugular ganglion. The geniculate ganglion contains two main neuronal populations: BRN3A+ somatosensory neurons that innervate the pinna and PHOX2B+ sensory neurons that innervate the oral cavity. While much is known about the different taste bud cell subtypes, considerably less is known about the molecular identities of PHOX2B+ sensory subpopulations. In the GG, as many as 12 different subpopulations have been predicted from electrophysiological studies, while transcriptional identities exist for only 3 to 6. Importantly, the cell fate pathways that diversify PHOX2B+ oral sensory neurons into these subpopulations are unknown. The transcription factor EGR4 was identified as being highly expressed in GG neurons. EGR4 deletion causes GG oral sensory neurons to lose their expression of PHOX2B and other oral sensory genes and up-regulate BRN3A. This is followed by a loss of chemosensory innervation of taste buds, a loss of type II taste cells responsive to bitter, sweet, and umami stimuli, and a concomitant increase in type I glial-like taste bud cells. These deficits culminate in a loss of nerve responses to sweet and umami taste qualities. Taken together, we identify a critical role of EGR4 in cell fate specification and maintenance of subpopulations of GG neurons, which in turn maintain the appropriate sweet and umami taste receptor cells.

Reactions of Tri-tert-Butylphosphatetrahedrane as a Spring-Loaded Phosphinidene Synthon Featuring Nickel-Catalyzed Transfer to Unactivated Alkenes.

Cage-opening reactions of the highly strained tri-tert-butylphosphatetrahedrane (1), shown here to function as a synthon of (tri-tert-butylcyclopropenyl)phosphinidene, are described. Treatment of 1 with a base-stabilized silylene led to the corresponding phosphasilene, which was isolated in 72% yield as a red crystalline solid. Phosphinidene transfer was also observed when 1 (2 equiv) was combined with the Wittig reagent Ph3PCH2 to form a diphosphirane (50% isolated yield). The reaction is proposed to proceed through a generated phosphaalkene intermediate, which was characterized by NMR spectroscopy. In addition, we report on nickel-catalyzed phosphinidene transfer to styrene, ethylene, neohexene, and 1,3-cyclohexadiene; the corresponding phosphiranes were isolated in 51-64% yield. Computational studies suggest the intermediacy of a nickel phosphinidene species. Treatment of the ethylene-derived phosphirane product with triflic acid delivered elimination of [tBu3C3]OTf and formation of a P-H bond, illustrating the ability of the tri-tert-butyl cyclopropenyl group to serve as a protecting group that is removable following phosphinidene transfer.

Staudinger Reactivity and Click Chemistry of Anthracene (A)-Based Azidophosphine N3PA.

11-Azido-9,10-dihydro-9,10-phosphanoanthracene (N3PA) has been demonstrated recently as a transfer reagent for molecular phosphorus mononitride (PN) because it easily dissociates at room temperature into dinitrogen (N2), PN, and anthracene (A). Here we report further reactivity studies of the N3PA molecule including strain-promoted 1,3-dipolar cycloaddition with cyclooctyne and Staudinger-type reactivity. Calculations at the DLPNO-CCSD(T)/cc-pVTZ//PBE0-D3(BJ)/cc-pVTZ level of theory indicate that the click reaction is faster than the dissociation of N3PA. The Staudinger-type reactivity enabled transfer of the NPA fragment to a base-stabilized silylene. The previously reported intermediate of vanadium trisanilide with an NPA ligand could be isolated in 61% yield and structurally characterized in a single-crystal X-ray diffraction experiment. In line with the previously reported phosphinidene reactivity of the transient vanadium phosphorus mononitride complex, thermolysis or irradiation of the complex leads to A elimination and formation of the corresponding vanadium PN dimer or trimer, respectively.

Introducing N-Heterocyclic Iminophosphoranes (NHIPs): Synthesis by [3 + 2] Cycloaddition of Azophosphines with Alkynes and Reactivity Studies.

Azophosphines (Ar-N═N-PR2) were prepared from N-aryl-N'-(trimethylsilyl)diazenes (Ar-N═N-SiMe3) and R2PCl by Me3SiCl elimination or oxidation of phosphinohydrazines (Ar-NH-NH-PR2) by 2,5-dialkyl-1,4-benzoquinones. Azophosphines underwent 1,3-dipolar cycloaddition with cyclooctyne and dimethylacetylene dicarboxylate to give N-heterocyclic iminophosphoranes (NHIPs), which are structurally similar to cyclic (alkyl)(amino)carbenes. The cycloaddition reaction is compatible with various phosphorus atom substituents including phenyl (NHIP-1,4,6), isopropyl (NHIP-2), cyclohexyl (NHIP-3), and dimethylamino (NHIP-5) groups. The pKBH+ values of the NHIPs in acetonitrile range from 13.13 to 23.14. On the basis of the Huynh electronic parameter, NHIP-1 and NHIP-2 have σ-donor strengths comparable with that of 1,8-diazabicyclo[5.4.0]undec-7-ene. NHIP-1 underwent facile 1,2-addition with pentafluoropyridine to form a rare fluorophosphorane. The treatment of NHIP-1 with triphenylsilane resulted in P-N bond cleavage, accompanied by the reduction of phosphorus(V) to phosphorus(III). A homoleptic, cationic CuI-NHIP-1 complex was also prepared. The potential utility of π-donating NHIPs was demonstrated by the stabilization of a reactive iminoborane (Cl-B≡N-SiMe3). The facile scalable synthesis, tunability of steric demands, and basicity of NHIPs suggest that this new heterocycle class may find a wide range of applications in synthetic chemistry.

Proximal tibial dimensions in a formalin-fixed neonatal cadaver sample: an intraosseous infusion approach.

PURPOSE: Methods to administer intramedullary medication and fluid infusion in both adults and children date to the early twentieth century. Studies have shown that intraosseous access in the proximal tibia is ideal for resuscitation efforts as fewer critical structures are at risk, and neither is the blood flow to the lower limbs compromised. Insertion of a needle in children younger than 5 years does have the risk to damage to the epiphyseal growth plate. Therefore, the aim of this study was to determine the ideal intraosseous insertion site distal to the epiphyseal growth plate in neonates. METHODS: The samples consisted of both the left and right sides of 15 formalin-fixed neonatal cadavers. The dimensions were measured on the superior surfaces of each section, anteromedial border, cortical thickness, and medullary space. RESULTS: The most desirable location to gain vascular access is at 10 mm inferior to the tibial tuberosity. CONCLUSION: The smallest cortical thickness (1.32 mm), the largest medullary space (4.50 mm), and the largest anteromedial surface (7.72 mm) were observed at 10 mm inferior to the tibial tuberosity. It is imperative that health care professionals are familiar with the osteological sites that could be safely used for an intraosseous infusion procedure.

Frustrated Lewis Pair Stabilized Phosphoryl Nitride (NPO), a Monophosphorus Analogue of Nitrous Oxide (N2O).

Phosphoryl nitride (NPO) is a highly reactive intermediate, and its chemistry has only been explored under matrix isolation conditions so far. Here we report the synthesis of an anthracene (A) and phosphoryl azide based molecule (N3P(O)A) that acts as a molecular synthon of NPO. Experimentally, N3P(O)A dissociates thermally with a first-order kinetic half-life that is associated with an activation enthalpy of ΔH⧧ = 27.5 ± 0.3 kcal mol-1 and an activation entropy of ΔS⧧ = 10.6 ± 0.3 cal mol-1 K-1 that are in good agreement with calculated DLPNO-CCSD(T)/cc-pVTZ//PBE0-D3(BJ)/cc-pVTZ energies. In solution N3P(O)A undergoes Staudinger reactivity with tricyclohexylphosphine (PCy3) and subsequent complexation with tris(pentafluorophenyl)borane (B(C6F5)3, BCF) to form Cy3P-NP(A)O-B(C6F5)3. Anthracene is cleaved off photochemically to form the frustrated Lewis pair (FLP) stabilized NPO complex Cy3P⊕-N═P-O-B⊖(C6F5)3. An intrinsic bond orbital (IBO) analysis suggests that the adduct is zwitterionic, with a positive and negative charge localized on the complexing Cy3P and BCF, respectively.

Alleviating Strain in Organic Molecules by Incorporation of Phosphorus: Synthesis of Triphosphatetrahedrane.

Phosphatetrahedranes (tBuCP)2 and (tBuC)3P were recently reported and represent the first tetrahedranes containing a mixed carbon/phosphorus core. Herein, we report that tetrahydrofuran (THF) solutions of the parent triphosphatetrahedrane HCP3 may be generated in 31% yield (NMR internal standard yield) by combining [Na(THF)3][P3Nb(ODipp)3] (Dipp = 2,6-diisopropylphenyl), INb(ODipp)3(THF), and bromodichloromethane in thawing THF. While HCP3 was found to be stable in dilute THF solutions for extended periods of time, the concentration of the solution at -40 °C led to the formation of a black precipitate, which has been tentatively assigned as a polymerized form of HCP3. HCP3 reacts readily with (dppe)Fe(Cp*)Cl (dppe = 1,2-bis(diphenylphosphino)ethane, Cp*= η5-C5Me5) in the presence of Na[BPh4] to form a purple cationic iron complex of triphosphatetrahedrane (50% yield), which was structurally characterized in a single-crystal X-ray diffraction experiment. Additionally, we present a series of homodesmotic equations analyzed via quantum chemical calculations that suggest triphosphatetrahedrane is the least strained of the mixed C/P phosphatetrahedranes.

Dimerization and Cycloaddition Reactions of Transient Tri-tert-butylphosphacyclobutadiene Generated by Lewis Acid Induced Isomerization of Tri-tert-butylphosphatetrahedrane.

Tri-tert-butylphosphatetrahedrane (1) is shown here to act as a synthon of isomeric tri-tert-butylphosphacyclobutadiene in the presence of a Lewis acid or transition-metal complex. When it is combined with a substoichiometric amount of triphenylborane, compound 1 forms a ladderane-type dimer of tri-tert-butylphosphacyclobutadiene in 72% isolated yield. Trapping of a generated intermediate was achieved by repeating the experiment in the presence of excess styrene (20 equiv) or ethylene (1 atm), and the corresponding [4 + 2] cycloadducts of tri-tert-butylphosphacyclobutadiene were isolated in 88% and 74% yields, respectively. The platinum complex (Ph3P)2Pt(C2H4) also reacts with 1 to form an orange η2 complex of tri-tert-butylphosphacyclobutadiene in 80% isolated yield. Additionally, we report a novel method for generating a phosphinidenoid species via fluoride-induced trimethylsilyl fluoride elimination, leading to an improved preparative procedure for 1 (182 mg, 33% isolated yield).

An Azophosphine Synthetic Equivalent of Mesitylphosphaazide and Its 1,3-Dipolar Cycloaddition Reactions.

Dibenzo-7-phosphanorbornadiene-substituted diazene MesN2PA (1, where Mes = mesityl, A = anthracene, or C14H10), a synthetic equivalent of mesitylphosphaazide (MesN2P) and anthracene, was synthesized by treatment of [Ph3BPA][Na(OEt2)2] with [MesN2]OTf (OTf = CF3SO3-) in thawing tetrahydrofuran (14% isolated yield). Treatment of 1 with unsaturated molecules cyclooctyne, [Na(dioxane)2.5][OCP] (phosphaethynolate), and Ad-C≡P (Ad = adamantyl) results in the corresponding [3 + 2] phosphaazide-(phospha)alkyne cycloadducts, with concomitant loss of anthracene in 65%, 49%, and 38% isolated yield, respectively. Structural data for the phosphaethynolate cycloadduct ([3][Na(12-crown-4)2]) were obtained in a single-crystal X-ray diffraction study. A diazatriphosphole was generated by combining 1 with P2A2, a thermally activated anthracene-based molecular precursor to diphosphorus (P2). Thermolysis (33-65 °C) of 1 in benzene-d6 leads to anthracene extrusion. This process has a unimolecular kinetic profile and proceeds with activation parameters of ΔH⧧ = 21.6 ± 0.3 kcal/mol and ΔS⧧= -4.9 ± 0.8 cal/(mol K).

Taste activity in the parabrachial region in adult rats following neonatal chorda tympani transection.

The chorda tympani is a gustatory nerve that fails to regenerate if sectioned in rats 10 days of age or younger. This early denervation causes an abnormally high preference for NH4Cl in adult rats, but the impact of neonatal chorda tympani transection on the development of the gustatory hindbrain is unclear. Here, we tested the effect of neonatal chorda tympani transection (CTX) on gustatory responses in the parabrachial nucleus (PbN). We recorded in vivo extracellular spikes in single PbN units of urethane-anesthetized adult rats following CTX at P5 (chronic CTX group) or immediately prior to recording (acute CTX group). Thus, all sampled PbN neurons received indirect input from taste nerves other than the CT. Compared to acute CTX rats, chronic CTX animals had significantly higher responses to stimulation with 0.1 and 0.5 M NH4Cl, 0.1 and 0.5 M NaCl, and 0.01 M citric acid. Activity to 0.5 M sucrose and 0.01 M quinine stimulation was not significantly different between groups. Neurons from chronic CTX animals also had larger interstimulus correlations and significantly higher entropy, suggesting that neurons in this group were more likely to be activated by stimulation with multiple tastants. Although neural responses were higher in the PbN of chronic CTX rats compared to acute-sectioned controls, taste-evoked activity was much lower than observed in previous reports, suggesting permanent deficits in taste signaling. These findings demonstrate that the developing gustatory hindbrain exhibits high functional plasticity following early nerve injury.NEW & NOTEWORTHY Early and chronic loss of taste input from the chorda tympani is associated with abnormal taste behaviors. We found that compared to when the chorda tympani is sectioned acutely, chronic nerve loss leads to amplification of spared inputs in the gustatory pons, with higher response to salty and sour stimuli. Findings point to plasticity that may compensate for sensory loss, but permanent deficits in taste signaling also occur following early denervation.

Incidence and Risk Factors for Diaphragmatic Herniation Following Esophagectomy for Cancer.

OBJECTIVE: To evaluate the incidence and risk factors of diaphragmatic herniation following esophagectomy for cancer (DHEC), and assess the results of surgical repair. SUMMARY BACKGROUND DATA: The current incidence of DHEC is discussed with conflicting data regarding its treatment and natural course. METHODS: Monocentric retrospective cohort study (2009-2018). From 902 patients, 719 patients with a complete follow-up of CT scans after transthoracic esophagectomy for cancer were reexamined to identify the occurrence of a DHEC. The incidence of DHEC was estimated using Kalbfleisch and Prentice method and risk factors of DHEC were studied using the Fine and Gray competitive risk regression model by treating death as a competing event. Survival was analyzed. RESULTS: Five-year DHEC incidence was 10.3% [95% CI, 7.8%-13.2%] (n = 59), asymptomatic in 54.2% of cases. In the multivariable analysis, the risk factors for DHEC were: presence of hiatal hernia on preoperative CT scan (HR = 1.72 [1.01-2.94], P = 0.046), previous hiatus surgery (HR = 3.68 [1.61-8.45], P = 0.002), gastroesophageal junction tumor location (HR = 3.51 [1.91-6.45], P < 0.001), neoadjuvant chemoradiotherapy (HR = 4.27 [1.70-10.76], P < 0.001), and minimally invasive abdominal phase (HR = 2.98 [1.60-5.55], P < 0.001). A cure for DHEC was achieved in 55.9%. The postoperative mortality rate was nil, the overall morbidity rate was 12.1%, and the DHEC recurrence rate was 30.3%. Occurrence of DHEC was significantly associated with a lower hazard rate of death in a time-varying Cox's regression analysis (HR = 0.43[0.23-0.81], P = 0.010). CONCLUSIONS: The 5-year incidence of DHEC is 10.3% and is associated with a favorable prognosis. Surgical repair of symptomatic or progressive DHEC is associated with an acceptable morbidity. However, the optimal surgical repair technique remains to be determined in view of the large number of recurrences.

31P NMR Chemical Shift Tensors: Windows into Ruthenium Phosphinidene Complex Electronic Structures.

A series of octamethylcalix[4]pyrrole/ruthenium phosphinidene complexes (Na2[1=PR]) can be accessed by phosphinidene transfer from the corresponding RPA (A = C14H10, anthracene) compounds (R = tBu, iPr, OEt, NH2, NMe2, NEt2, NiPr2, NA, dimethylpiperidino). Isolation of the tert-butyl and dimethylamino derivatives allowed comparative studies of their 31P nuclear shielding tensors by magic-angle-spinning solid-state nuclear magnetic resonance spectroscopy. Density functional theory and natural chemical shielding analyses reveal the relationship between the 31P chemical shift tensor and the local ruthenium/phosphorus electronic structure. The general trend observed in the 31P isotropic chemical shifts for the ruthenium phosphinidene complexes was controlled by the degree of deshielding in the δ11 principal tensor component, which can be linked to the σRuP/πRuP* energy gap. A "δ22-δ33 crossover" effect for R = tBu was also observed, which was caused by different degrees of deshielding associated with polarizations of the σPR and σPR* natural bond orbitals.

Understanding the Nature and Properties of Hydrogen-Hydrogen Bonds: The Stability of a Bulky Phosphatetrahedrane as a Case Study.

Recently, the first mixed C/P phosphatetrahedranes (tBuC)3P and (tBuCP)2 were reported. Unlike (tBuCP)2, (tBuC)3P exhibits remarkable thermal stability, which can be partially attributed to a network of nine hydrogen-hydrogen bonds (HHBs) localized between the tert-butyl substituents. The stabilizing contribution arising from this network of HHBs was obtained from local energy decomposition (LED) analysis calculated at the domain-based local pair natural orbital CCSD(T) (DLPNO-CCSD(T)) level of theory. These calculations suggest that each HHB contributes approximately -0.7 kcal/mol of stabilization; however, the net stabilization energy likely lies between -0.25 and -0.5 kcal/mol because of steric repulsion. Spatial analysis of the London dispersion energy via a dispersion interaction density (DID) plot reveals that the DID surface is localized at key C-H groups involved in HHBs, consistent with London dispersion interactions predominantly arising from HHBs. In addition, we present a computed mechanism that supports a phosphinidenoid species as a key reaction intermediate in the synthesis of (tBuC)3P.

Vitamin D Signaling in Gastro-Rheumatology: From Immuno-Modulation to Potential Clinical Applications.

In the last decades, the comprehension of the pathophysiology of bone metabolism and its interconnections with multiple homeostatic processes has been consistently expanded. The branch of osteoimmunology specifically investigating the link between bone and immune system has been developed. Among molecular mediators potentially relevant in this field, vitamin D has been recently pointed out, and abnormalities of the vitamin D axis have been described in both in vitro and in vivo models of inflammatory bowel diseases (IBD) and arthritis. Furthermore, vitamin D deficiency has been reported in patients affected by IBD and chronic inflammatory arthritis, thus suggesting the intriguing possibility of impacting the disease activity by the administration vitamin D supplements. In the present review, the complex interwoven link between vitamin D signaling, gut barrier integrity, microbiota composition, and the immune system was examined. Potential clinical application exploiting vitamin D pathway in the context of IBD and arthritis is presented and critically discussed. A more detailed comprehension of the vitamin D effects and interactions at molecular level would allow one to achieve a novel therapeutic approach in gastro-rheumatologic inflammatory diseases through the design of specific trials and the optimization of treatment protocols.

3,5-Diphenyl-2-phosphafuran: Synthesis, Structure, and Thermally Reversible [4 + 2] Cycloaddition Chemistry.

Treatment of trans-chalcone with dibenzo-7-phosphanorbornadiene EtOPA (A = C14H10, anthracene), a source of ethoxyphosphinidene, followed by formal elimination of ethanol yields 3,5-diphenyl-2-phosphafuran (DPF) in 43% yield. We show that the phosphadiene moiety of DPF is a potent diene in the Diels-Alder reaction and reacts with dienophiles dimethyl acetylenedicarboxylate (DPF·DMAD, 68%), norbornene (DPF·norbornene, 73%), and ethylene (DPF·C2H4, 80%) under ambient conditions. Mild heating of DPF·C2H4 results in the corresponding retro-Diels-Alder reaction, establishing DPF as a molecule that is able to reversibly bind ethylene.

Bitter taste receptors are expressed in human epithelial ovarian and prostate cancers cells and noscapine stimulation impacts cell survival.

Bitter taste receptors (Tas2Rs) are a subfamily of G-protein coupled receptors expressed not only in the oral cavity but also in several extra-oral tissues and disease states. Several natural bitter compounds from plants, such as bitter melon extract and noscapine, have displayed anti-cancer effects against various cancer types. In this study, we examined the prevalence of Tas2R subtype expression in several epithelial ovarian or prostate cancer cell lines, and the functionality of Tas2R14 was determined. qPCR analysis of five TAS2Rs demonstrated that mRNA expression often varies greatly in cancer cells in comparison to normal tissue. Using receptor-specific siRNAs, we also demonstrated that noscapine stimulation of ovarian cancer cells increased apoptosis in ovarian cancer cells in a receptor-dependent, but ROS-independent manner. This study furthers our understanding of the function of Tas2Rs in ovarian cancer by demonstrating that their activation has an impact on cell survival.

Anti-Markovnikov Hydroarylation of Unactivated Olefins via Pyridyl Radical Intermediates.

The intermolecular alkylation of pyridine units with simple alkenes has been achieved via a photoredox radical mechanism. This process occurs with complete regiocontrol, where single-electron reduction of halogenated pyridines regiospecifically yields the corresponding radicals in a programmed fashion, and radical addition to alkene substrates occurs with exclusive anti-Markovnikov selectivity. This system is mild, tolerant of many functional groups, and effective for the preparation of a wide range of complex alkylpyridines.

Contributory role of sex differences in the variations of gustatory function.

Remarkable variability between males and females occurs for an array of taste-guided behaviors in both rodents and humans. Sex differences have been noted for taste preference, detection thresholds, and reactivity to taste stimuli. Manipulating sex hormones during early postnatal development or altering the amount of circulating estrogen in adulthood can dramatically alter the pattern of these behaviors. Receptors for sex hormones appear to be prominent in several nuclei associated with central gustatory pathways, indicating that steroid hormones may modulate central taste processing. Electrophysiological recordings from the rat brainstem suggest that taste-elicited activity to sweet stimuli is organized by hormones during early development, and activity during bitter stimulation is altered by circulating ovarian hormones. Sex differences in gustatory function appear to emerge at the level of the taste bud. Among ovariectomized rats, estradiol treatment decreases activity in the chorda tympani nerve during NaCl stimulation. Although there is no evidence that chorda tympani responses to NaCl differ between intact male and female rats, glossopharyngeal nerve responses are lower in intact females for both NaCl and sodium acetate. Responses in the glossopharyngeal nerve to citric acid stimulation are also higher in female rats relative to males. These findings suggest that, in addition to differential central modulation of taste input based on sex, taste information from the periphery varies between males and females. Although the extent of sex differences in taste processing and the underlying causal mechanisms require further clarification, it is clear that studying one sex alone provides an incomplete picture of gustatory function. © 2016 Wiley Periodicals, Inc.

Long-term alterations in peripheral taste responses to NaCl in adult rats following neonatal chorda tympani transection.

The peripheral taste system of the adult rodent is highly resilient against damage, with morphological, behavioral, and functional recovery evident after regeneration of a transected nerve. If chorda tympani transection (CTX) occurs at early postnatal ages however, the nerve fails to regenerate and effects on tongue morphology and behavior are more severe and longer-lasting compared to adult denervation. To examine whether neonatal CTX induces functional changes in intact nerves, whole-nerve electrophysiology was performed on the glossopharyngeal (GL) and chorda tympani (CT) nerves of adult rats that received CTX at P10. Attenuation of NaCl-elicited GL responses were observed in CTX rats 2 months after surgery, with bilateral denervation causing the largest decreases in responses. When assessed 1 year after neonatal CTX, amiloride-sensitive responses to NaCl in the contralateral CT increased while amiloride-insensitive responses decreased. Responses to other tastants were consistent with control animals. This is the first evidence of long-term functional changes to the peripheral taste system after injury in rats fed a normal diet. This study further characterizes the developing peripheral taste system as highly susceptible to change following neural injury.

Can cardiac resynchronization therapy improve cognitive function? A systematic review.

INTRODUCTION: Cognitive impairment (CI) comprises a measurable deficit of different cognitive domains (memory, attention, problem solving, and motor speed), and has a high prevalence among congestive heart failure (CHF) patients. Only a few pilot studies have investigated the effects of cardiac resynchronization therapy (CRT) on cognitive performance. The purpose of this systematic review is to outline and evaluate results of published studies that assess the impact of CRT on neuropsychological function in CHF. METHODS: Electronic databases were searched for articles containing the following terms: CRT, cognition, cognitive, and neurocognitive. A data extraction was performed according to our objective from each study. Effect sizes were computed using Hedges' g. The within-group formula was used for cohort studies with a pre-post design, while the between-group formula was used for studies that compared independent groups. Multiple outcomes were combined in domain-specific synthetic scores as well as in a global score for each study, and a fixed-effect model was used to estimate the summary effects. RESULTS: Only three studies met criteria for inclusion in the analysis. The results of these studies were discordant and methodological limitations were identified. The meta-analysis of cognitive outcomes showed a nonsignificant overall effect (Hedges' g = 0.131, 95% confidence interval: -0.16 to 0.422), while the summary effects on executive functioning and attention reached statistical significance (Hedges' g = 0.374, 95% confidence interval: 0.085-0.662 and Hedges' g = 0.343, 95% confidence interval: 0.051-0.635, respectively). CONCLUSION: CI and related negative consequences have been largely documented in patients with heart failure but very few studies have assessed the plausible benefits of CRT on patients' cognitive function. Despite the statistical significance of the domain-specific pooled effects, their validity and clinical relevance is lacking due to methodological limitations.