murine-mesenteric-lymphadenectomy-for-selective-disruption-lymphatic

Murine Mesenteric Lymphadenectomy for Selective Disruption of Lymphatic Communication with Region-Specific Gut

Immunosurveillance versus antigen-tolerance is a fine balance within the gut microenvironment, during which the critical role of circulating T cell ...

Yale University School of Medicine

Fatty acid oxidation (FAO) disorders are frequently reported as the cause of sudden and unexpected death, but their postmortem recognition remains difficult. We have devised a biochemical protocol in which informative findings in liver tissue are microvesicular steatosis, elevated concentrations of C8-C16 fatty acids, glucose depletion, and low carnitine concentration.

Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life.

Potassium leak conductances were recently revealed to exist as independent molecular entities. Here, the genomic structure, cardiac localization, and biophysical properties of a murine example are considered. Kcnk3 subunits have two pore-forming P domains and unique functional attributes. At steady state, Kcnk3 channels behave like open, potassium-selective, transmembrane holes that are inhibited by physiological levels of proton. With voltage steps, Kcnk3 channels open and close in two phases, one appears to be immediate and one is time-dependent (tau = approximately 5 ms). Both proton block and gating are potassium-sensitive; this produces an anomalous increase in outward flux as external potassium levels rise because of decreased proton block. Single Kcnk3 channels open across the physiological voltage range; hence they are "leak" conductances; however, they open only briefly and rarely even after exposure to agents that activate other potassium channels.

Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3.

The homotetrameric structure of the ryanodine-sensitive intracellular calcium (Ca2+) release channel (ryanodine receptor (RyR)) suggests that the four RyR subunits either combine to form a single pore or that each RyR subunit is an independently conducting pathway. Previously we showed that methanethiosulfonate ethylammonium (MTSEA+) covalently modifies the RyR to reduce current amplitudes in a time-dependent and stepwise manner. To ascertain the number of functionally conducting pores in the RyR, two approaches were combined: modification of the receptor by MTSEA+ and the use of different sized current carriers. Previous reports (Tinker, A., and Williams, A. J. (1993) J. Gen. Physiol. 102, 1107-1129) have shown that the organic cations methylamine, dimethylamine, ethylamine, and trimethylamine are permeant through the RyR but with reduced current amplitude depending upon the diameter of the respective amine. Experiments using the thiol reagent MTSEA+ to modify the channel protein showed that the current amplitudes decrease in steps leading to complete block of the channel when cesium (Cs+) is the current carrier. MTSEA+ modification decreased the number of channel substates as the diameter of the current carrier increased. Comparison of the degree of inhibition of MTSEA+-modified currents allows for differentiation between the two models for channel architecture. These results demonstrate that the conduction pathway for the RyR is comprised of a single central pore.

Methanethiosulfonate ethylammonium block of amine currents through the ryanodine receptor reveals single pore architecture.

Impairments in attention, working memory, and executive function are common among substance users and may adversely affect SUD treatment outcomes. The ability of cognitive remediation (CR) interventions to improve these deficits is hindered in part because levels of engagement in CR training may be inadequate to achieve benefit. This pilot study aimed to increase CR engagement and improve outcome by implementing contingency management (CM) procedures that reinforce performance improvements on CR tasks. Participants were forty individuals (50% male; 65% African American) in an outpatient substance use treatment facility with mild cognitive impairment who had ≥30-days of abstinence from alcohol and drugs. They were randomized to standard (CR-S; n=21) or CM-enhanced (CR-CM; n=19) cognitive remediation training. CR consisted of 1-hour sessions, three times per week for four weeks (12 sessions). A neuropsychological assessment battery was administered prior to and after the four-week intervention. Both groups had high rates of CR session attendance (mean CR-S=11.7, CR-CM=10.9 sessions). Performance on 8 of the 9 CR tasks significantly improved over time for both conditions, with the CR-CM condition demonstrating greater improvement on a CR Sequenced Recall task [F(1,37)=5.81, p<.05]. Significant improvement was also evident on 4 of 9 neuropsychological assessment measures, with the CR-CM condition showing differential improvement on the Trail Making Test - Part B [F (1,37)=5.34, p<.05]. These findings support the feasibility of using CM procedures to enhance substance users' engagement with CR training and suggest the potential value of more research in this area.

Performance-Based Contingency Management in Cognitive Remediation Training: A Pilot Study.

The acquisition of coping skills has long been considered one of the putative mechanisms of cognitive behavioral therapy (CBT) for substance use disorders, yet consistent statistical support is lacking. This study sought to replicate and extend prior findings regarding the quality of coping skills as a mediator of abstinence outcomes from a computerized CBT program for substance users. Participants were methadone-maintained, cocaine dependent individuals enrolled in a clinical trial evaluating the efficacy of computer-based training for CBT ('CBT4CBT') as an add-on to treatment as usual (TAU+CBT4CBT) compared to TAU only. A subsample (N=71) completed a role play assessment to measure coping skills, the Drug Risk Response Test (DRRT), which was administered before, during (week 4), and after the 8-week treatment period. Participants' verbal responses to various high-risk situations for cocaine use were recorded and independent evaluators rated the quality of the coping responses. Results of repeated measures analyses revealed a main effect of time for the quality of overall responses [F(1, 141.26)=4.29, p<0.01], indicating improvement in the quality of coping skills across groups, yet no differential effect of treatment. Despite the significant association between coping responses and abstinence outcomes, analyses did not support the quality of coping skills as a mediator of treatment effects. However, among the high-risk situations wherein individuals provided lower quality responses at baseline, those assigned to TAU+CBT4CBT showed greater improvement compared to those assigned to TAU only [F(1, 697.65)=6.47, p=0.01].

Effect of computerized cognitive behavioral therapy on acquisition of coping skills among cocaine-dependent individuals enrolled in methadone maintenance.

We identified a child with KLF1-E325K congenital dyserythropoietic anemia type IV who experienced a severe clinical course, fetal anemia, hydrops fetalis, and postnatal transfusion dependence only partially responsive to splenectomy. The child also had complete sex reversal, the cause which remains undetermined. To gain insights into our patient's severe hematologic phenotype, detailed analyses were performed. Erythrocytes from the patient and parents demonstrated functional abnormalities of the erythrocyte membrane, attributed to variants in the α-spectrin gene. Hypomorphic alleles in SEC23B and YARS2 were also identified. We hypothesize that coinheritance of variants in relevant erythrocyte genes contribute to the clinical course in our patient and other E325K-linked congenital dyserythropoietic anemia IV patients with severe clinical phenotypes.

KLF1 E325K-associated Congenital Dyserythropoietic Anemia Type IV: Insights Into the Variable Clinical Severity.

Previous trials have demonstrated the efficacy and durability of computer-based cognitive-behavioral therapy (CBT4CBT) as an add-on to standard outpatient care in a range of treatment-seeking populations. In this study, the authors evaluated the efficacy and safety of CBT4CBT as a virtual stand-alone treatment, delivered with minimal clinical monitoring, and clinician-delivered cognitive-behavioral therapy (CBT) compared with treatment as usual in a heterogeneous sample of treatment-seeking outpatients with substance use disorders.

Randomized Clinical Trial of Computerized and Clinician-Delivered CBT in Comparison With Standard Outpatient Treatment for Substance Use Disorders: Primary Within-Treatment and Follow-Up Outcomes.

To differentiate electrograms representing sites of active atrial fibrillation (AF) drivers from passive ones.

Recurrence quantification analysis of complex-fractionated electrograms differentiates active and passive sites during atrial fibrillation.

Testicular salvage rates for torsion are time-dependent. Door to detorsion time has been identified as an independent testicular survival factor. We describe an initiative to reduce door to incision (DTI) time for pediatric testicular torsion.

Article	Year
Retrospective biochemical screening of fatty acid oxidation disorders in postmortem livers of 418 cases of sudden death in the first year of life. The Journal of pediatrics\| PubMed ID: 9627580	1998
Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3. The Journal of biological chemistry\| PubMed ID: 10748056	2000
Methanethiosulfonate ethylammonium block of amine currents through the ryanodine receptor reveals single pore architecture. The Journal of biological chemistry\| PubMed ID: 12963712	2003
Performance-Based Contingency Management in Cognitive Remediation Training: A Pilot Study. Journal of substance abuse treatment\| PubMed ID: 27590364	2017
Effect of computerized cognitive behavioral therapy on acquisition of coping skills among cocaine-dependent individuals enrolled in methadone maintenance. Journal of substance abuse treatment\| PubMed ID: 29021121	2017
KLF1 E325K-associated Congenital Dyserythropoietic Anemia Type IV: Insights Into the Variable Clinical Severity. Journal of pediatric hematology/oncology\| PubMed ID: 29300242	2018
Randomized Clinical Trial of Computerized and Clinician-Delivered CBT in Comparison With Standard Outpatient Treatment for Substance Use Disorders: Primary Within-Treatment and Follow-Up Out... The American journal of psychiatry\| PubMed ID: 29792052	2018
Recurrence quantification analysis of complex-fractionated electrograms differentiates active and passive sites during atrial fibrillation. Journal of cardiovascular electrophysiology\| PubMed ID: 31507008	2019
Implementation of a health system intervention to reduce time from presentation to surgical intervention for pediatric testicular torsion. Journal of pediatric urology\| PubMed ID: 38030428	2024

J. Buck

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