Cross-cultural comparison of the neural correlates of true and false memory retrieval.

Prior work has shown Americans have higher levels of memory specificity than East Asians. Neuroimaging studies have not investigated mechanisms that account for cultural differences at retrieval. In this study, we use fMRI to assess whether mnemonic discrimination, distinguishing novel from previously encountered stimuli, accounts for cultural differences in memory. Fifty-five American and 55 Taiwanese young adults completed an object recognition paradigm testing discrimination of old targets, similar lures and novel foils. Mnemonic discrimination was tested by comparing discrimination of similar lures from studied targets, and results showed the relationship between activity in left fusiform gyrus and behavioural discrimination between target and lure objects differed across cultural groups. Parametric modulation analyses of activity during lure correct rejections also indicated that groups differed in left superior parietal cortex response to variations in lure similarity. Additional analyses of old vs. new activity indicated that Americans and Taiwanese differ in the neural activity supporting general object recognition in the hippocampus, left inferior frontal gyrus and middle frontal gyrus. Results are juxtaposed against comparisons of the regions activated in common across the two cultures. Overall, Americans and Taiwanese differ in the extent to which they recruit visual processing and attention modulating brain regions.

Association of robotic approach with patient-reported outcomes after pancreatectomy: a prospective cohort study.

BACKGROUND: Robotic-assisted pancreatectomy continues to proliferate despite limited evidence supporting its benefits from the patient's perspective. We compared patient-reported outcomes (PROs) between patients undergoing robotic and open pancreatectomies. METHODS: PROs, measured with the FACT-Hep, FACT-G, and HCS, were assessed in the immediate postoperative (i.e., preoperative to discharge) and recovery (i.e., discharge to three months postoperative) periods. Linear mixed models estimated the association of operative approach on PROs. Minimally important differences (MIDs) were also considered. RESULTS: Among 139 patients, 105 (75.5%) underwent robotic pancreatectomies. Compared to those who underwent open operations, those who underwent robotic operations experienced worse FACT-Hep scores that were both statistically and clinically significant (mean difference [MD] 8.6 points, 95% CI 1.0-16.3). Declines in FACT-G (MD 4.3, 95% CI -1.0 to 9.6) and HCS (MD 4.3, 95% CI 0.8-7.9) scores appeared to contribute equally in both operative approaches to the decline in total FACT-Hep score. Patients who underwent robotic versus open operations both statistically and clinically significantly improved due to improvements in HCS (MD 6.1, 95% CI 2.3-9.9) but not in FACT-G (MD 1.2, 95% CI - 5.1-7.4). CONCLUSION: The robotic approach to pancreas surgery might offer, from the patient's perspective, greater improvement in symptoms over the open approach by three months postoperatively.

Effect of fenfluramine on convulsive seizures in CDKL5 deficiency disorder.

CDKL5 deficiency disorder (CDD) is an X-linked pharmacoresistant neurogenetic disorder characterized by global developmental delays and uncontrolled seizures. Fenfluramine (FFA), an antiseizure medication (ASM) indicated for treating convulsive seizures in Dravet syndrome, was assessed in six patients (five female; 83%) with CDD whose seizures had failed 5-12 ASMs or therapies. Median age at enrollment was 6.5 years (range: 2-26 years). Mean FFA treatment duration was 5.3 months (range: 2-9 months) at 0.4 mg/kg/day (n = 2) or 0.7 mg/kg/day (n = 4; maximum: 26 mg/day). One patient had valproate added for myoclonic seizures. The ASM regimens of all other patients were stable. Among five patients with tonic-clonic seizures, FFA treatment resulted in a median 90% reduction in frequency (range: 86%-100%). Tonic seizure frequency was reduced by 50%-60% in two patients with this seizure type. One patient experienced fewer myoclonic seizures; one patient first developed myoclonic seizures on FFA, which were controlled with valproate. Adverse events were reported in two patients. The patient with added valproate experienced lethargy; one patient had decreased appetite and flatus. No patient developed valvular heart disease or pulmonary arterial hypertension. Our preliminary results suggest that FFA may be a promising ASM for CDD. Randomized clinical trials are warranted.

Mycotic Abdominal Aortic Aneurysm Caused by Streptococcus equi.

Streptococcus equi is a bacterium common in equine species and an uncommon pathogen in humans. Reported human infections can be severe and include meningitis, septic arthritis, and endocarditis. We report the case of a 64-year-old male who S. equi with several months of constitutional symptoms, back pain, and abdominal pain. Imaging demonstrated a large abdominal aortic aneurysm with a contained retroperitoneal rupture, with cultures from the aneurysm and blood cultures both positive for S. equi. The patient was successfully treated with open repair and placement of a Dacron graft and intravenous antibiotics and will remain on lifelong antibiotic prophylaxis.

Using the Jigsaw Teaching Method to Enhance Internal Medicine Residents' Knowledge and Attitudes in Managing Geriatric Women's Health.

Introduction: Although studies surveying internal medicine (IM) residency program directors identify geriatric women's health as an essential curriculum topic, there are limited published women's health curricula for IM residents. Our IM residency program performed a needs assessment, which revealed that the majority of residents were unsatisfied with our current curricula and most were not confident managing geriatric women's health. We developed and assessed a structured curriculum to improve IM residents' knowledge and confidence in addressing geriatric women's health. Methods: This 2-hour interactive workshop used the jigsaw teaching method (a cooperative learning strategy where peers deliver specific content in teams) to teach 84 categorical IM residents of all PGY levels about the diagnosis and management of menopause, osteoporosis, urinary incontinence, and abnormal uterine bleeding. Participants completed a pretest and immediate posttest to assess knowledge and confidence about the targeted topics. We compared baseline and postworkshop responses using chi-square and Wilcoxon signed rank tests. Results: Seventy-four (88%) IM residents completed the pretest, and 62 (74%) completed the posttest. Mean knowledge scores improved from 51% to 69% (p < .0001). Residents who reported feeling somewhat confident or confident in addressing women's health topics increased from 14% to 44% (p < .0001). The majority were satisfied or very satisfied with the workshop (94%) and requested additional women's health education (92%). Discussion: Our results suggest that workshops using the jigsaw teaching method can effectively increase IM resident knowledge and confidence in managing geriatric women's health.

The loss of NMDAR-dependent LTD following cannabinoid self-administration is restored by positive allosteric modulation of CB1 receptors.

Glutamatergic plasticity in the nucleus accumbens core (NAcore) is a key neuronal process in appetitive learning and contributes to pathologies such as drug addiction. Understanding how this plasticity factors into cannabis addiction and relapse has been hampered by the lack of a rodent model of cannabis self-administration. We used intravenous self-administration of two constituents of cannabis, Δ9 -tetrahydrocannabinol (THC) and cannabidiol (CBD) to examine how contingent cannabis use and cue-induced cannabinoid-seeking alters glutamatergic neurotransmission and synaptic plasticity in NAcore. NMDA receptor (NMDAR)-dependent long-term depression (LTD) in the NAcore was lost after cannabinoid, but not sucrose self-administration. Surprisingly, when rats underwent cue-induced cannabinoid seeking, LTD was restored. Loss of LTD was accompanied by desensitization of cannabinoid receptor 1 (CB1R). CB1R are positioned to regulate synaptic plasticity by being expressed on glutamatergic terminals and negatively regulating presynaptic excitability and glutamate release. Supporting this possibility, LTD was restored by promoting CB1R signaling with the CB1 positive allosteric modulator GAT211. These data implicate NAcore CB1R as critical regulators of metaplasticity induced by cannabis self-administration and the cues predicting cannabis availability.

Chronic treatment with N-acetylcysteine decreases extinction responding and reduces cue-induced nicotine-seeking.

N-acetylcysteine (NAC), a promising glutamatergic therapeutic agent, has shown some clinical efficacy in reducing nicotine use in humans and has been shown to reverse drug-induced changes in glutamatergic neurophysiology. In rats, nicotine-seeking behavior is associated with alterations in glutamatergic plasticity within the nucleus accumbens core (NAcore). Specifically, cue-induced nicotine-seeking is associated with rapid, transient synaptic plasticity (t-SP) in glutamatergic synapses on NAcore medium spiny neurons. The goal of the present study was to determine if NAC reduces nicotine-seeking behavior and reverses reinstatement-associated NAcore glutamatergic alterations. Rats were extinguished from nicotine self-administration, followed by subchronic NAC administration (0 or 100 mg/kg/d) for 4 days prior to cue-induced reinstatement. NAcore synaptic potentiation was measured via dendritic spine morphology and mRNA and protein of relevant glutamatergic genes were quantified. Nicotine-seeking behavior was not reduced by subchronic NAC treatment. Also, NAcore transcript and protein expression of multiple glutamatergic genes, as well as spine morphological measures, were unaffected by subchronic NAC. Finally, chronic NAC treatment (15 days total) during extinction and prior to reinstatement significantly decreased extinction responding and reduced reinstatement of nicotine-seeking compared to vehicle. Together, these results suggest that chronic NAC treatment is necessary for its therapeutic efficacy as a treatment strategy for nicotine addiction and relapse.

A Model of Δ9-Tetrahydrocannabinol Self-administration and Reinstatement That Alters Synaptic Plasticity in Nucleus Accumbens.

BACKGROUND: Cannabis is the most widely used illicit drug, but knowledge of the neurological consequences of cannabis use is deficient. Two primary components of cannabis are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). We established a THC+CBD model of self-administration and reinstated drug seeking to determine if, similar to other addictive drugs, cannabis produces enduring synaptic changes in nucleus accumbens core (NAcore) thought to contribute vulnerability to drug reinstatement. METHODS: Sprague Dawley rats were trained to self-administer THC+CBD (n = 165) or were used as vehicle self-administering control animals (n = 24). Reinstatement was initiated by context, cues, drug priming, and stress (yohimbine injection). Enduring neuroadaptations produced by THC+CBD self-administration were assayed using four measures: dendritic spine morphology, long-term depression, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratios, and behavioral pharmacology. RESULTS: We described a novel rodent model of cannabis relapse involving intravenous THC+CBD self-administration and drug seeking induced by conditioned context, cues, and stress. Cued reinstatement of THC+CBD seeking depended on a sequence of events implicated in relapse to other addictive drugs, as reinstatement was prevented by daily treatment with N-acetylcysteine or acute intra-NAcore pretreatment with a neuronal nitric oxide synthase or matrix metalloprotease-9 inhibitor, all of which normalize impaired glutamate homeostasis. The capacity to induce N-methyl-D-aspartate long-term depression in NAcore medium spiny neurons was abolished and dendritic spine density was reduced, but alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid/N-methyl-D-aspartate ratio was unaltered in THC+CBD-trained animals, akin to opioids, but not to psychostimulants. CONCLUSIONS: We report enduring consequences of THC+CBD use on critical relapse circuitry and synaptic physiology in NAcore following rat self-administration and provide the first report of cue- and stress-induced reinstatement with this model.

A Rare Presentation of Cryptococcal Meningoencephalitis in an Immunocompetent Individual.

Cryptococcal meningoencephalitis is a leading of morbidity and mortality in immunocompromised individuals worldwide. However, there are few documented cases in immunocompetent patients. We present a rare case of disseminated Cryptococcus with progression to meningoencephalitis in an immunocompetent patient, with a possible atypical presentation. Magnetic resonance imaging of the brain and electroencephalogram to rule out brain metastasis were negative. Lumbar puncture resulted positive for Cryptococcus neoformans antigen at titers of 1:2048 and a detailed history later revealed occupational exposure to bird dander by cleaning floors and cages. Diagnosis is challenging, with delays often resulting in increased morbidity and mortality. Cerebrospinal fluid and serum Cryptococcus antigen play a key role in both diagnosis and determining treatment efficacy. Furthermore, current treatment guidelines are used for immunocompromised individuals. Due to the significant side effects of these medications, further research is needed to determine the optimal treatment duration for immunocompetent patients to minimize the need for unnecessary therapy.

Addiction-like Synaptic Impairments in Diet-Induced Obesity.

BACKGROUND: There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core considered hallmarks of addiction. METHODS: Sprague Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO-prone and DIO-resistant subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed ratio 1, 3, and 5 and progressive ratio schedules. Subsequently, nucleus accumbens brain slices were prepared, and we tested for changes in the ratio between α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate currents and the ability to exhibit long-term depression. RESULTS: We found that propensity to develop DIO is linked to deficits in the ability to induce long-term depression in the nucleus accumbens, as well as increased potentiation at these synapses as measured by AMPA/N-methyl-D-aspartate currents. Consistent with these impairments, we observed addictive-like behavior in DIO-prone rats, including 1) heightened motivation for palatable food; 2) excessive intake; and 3) increased food seeking when food was unavailable. CONCLUSIONS: Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction.

Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections.

It is widely accepted that D1 dopamine receptor-expressing striatal neurons convey their information directly to the output nuclei of the basal ganglia, whereas D2-expressing neurons do so indirectly via pallidal neurons. Combining optogenetics and electrophysiology, we found that this architecture does not apply to mouse nucleus accumbens projections to the ventral pallidum. Thus, current thinking attributing D1 and D2 selectivity to accumbens projections akin to dorsal striatal pathways needs to be reconsidered.

Mediators of cognitive-behavioral therapy for insomnia: a review of randomized controlled trials and secondary analysis studies.

The examination of treatment mechanisms in randomized controlled trials (RCTs) has considerable implications for research and clinical practice. Insomnia is a highly prevalent and distressing disorder, associated with many adverse outcomes. Although extensive work has focused on the cognitive-behavioral treatment of insomnia (CBT-I), few studies have directly examined the mechanisms of this intervention. CBT-I is a short-term, multi-component treatment that has demonstrated strong efficacy in treating insomnia. The purpose of the present study is: (a) to investigate if CBT-I works in accordance with its proposed mechanisms, and (b) to evaluate how the field is progressing in its understanding of these processes. This study comprehensively reviewed CBT-I RCTs for their inclusion of mediator variables. Secondary analysis studies were also surveyed for relevant mediator variables. Results demonstrated that 21 RCTs (39% of the total RCTs) and 11 secondary analysis studies examined at least one of the proposed mediators. Results of this review highlight that, although CBT-I appears to be targeting the hypothesized sleep processes, more research is needed to better understand whether CBT-I works in accordance with its theorized mechanisms. Inclusion of mediational analyses in future RCTs and secondary analysis studies would allow for further refinement of CBT-I and improved treatment outcomes.

Diacylglycerol enrichment of endoplasmic reticulum or lipid droplets recruits perilipin 3/TIP47 during lipid storage and mobilization.

Fatty acid-induced triacylglycerol synthesis produces triacylglycerol droplets with a protein coat that includes perilipin 3/TIP47 and perilipin 4/S3-12. This study addresses the following two questions. Where do lipid droplets emerge, and how are their coat proteins recruited? We show that perilipin 3- and perilipin 4-coated lipid droplets emerge along the endoplasmic reticulum (ER). Blocking membrane trafficking with AlF(4)(-) during fatty acid-induced triacylglycerol synthesis drove perilipin 3 to the tubular ER. Forskolin, which like AlF(4)(-) activates adenylate cyclase, did not redistribute perilipin 3, but when added together with AlF(4)(-) perilipin 3 was recruited to lipid droplets rather than the ER. Thus inhibiting trafficking with AlF(4)(-) redistributed perilipin 3 differently under conditions of triacylglycerol synthesis (fatty acid addition) versus hydrolysis (forskolin) suggesting a shared acylglycerol-mediated mechanism. We tested whether diacylglycerol (DG), the immediate precursor of triacylglycerol and its first hydrolytic product, affects the distribution of perilipin 3. Stabilizing DG with the DG lipase inhibitor RHC80267 enhanced the perilipin 3 recruited to lipid droplets and raised DG levels in this fraction. Treating cells with a membrane-permeable DG recruited perilipin 3 to the ER. Stabilizing DG, by blocking its hydrolysis with RHC80267 or its acylation with triacsin C, enhanced recruitment of perilipin 3 to the ER. Expressing the ER enzyme DGAT1, which removes DG by converting it to triacylglycerol, attenuated perilipin 3 DG-induced ER recruitment. Membrane-permeable DG also drove perilipin 4 and 5 onto the ER. Together the data suggest that these lipid droplet proteins are recruited to DG-enriched membranes thereby linking lipid coat proteins to the metabolic state of the cell.

A simple and rapid method to assay triacylglycerol in cells and tissues.

We have developed a reliable, rapid, and economical assay for the quantification of triacylglycerol (TG) in cells and animal tissues. In a few hours, this assay quantifies microgram amounts of TG from tens or even hundreds of samples. The protocol includes an organic extraction to partition TG away from proteins and other hydrophilic molecules found in cells and tissues that may interfere with the colorimetric enzyme-linked TG detection method. In addition, this assay is economical, as no expensive reagents, supplies, or equipment are needed. Another benefit of this assay is that it does not require environmentally unfriendly halogenated solvents.