OBJECTIVE: Cachexia is a nutrient deficient condition affecting millions of cancer patients. Cancers of the upper gastrointestinal tract, head and neck are often the most severely affected. Currently, there is no established therapy for cachexia, although several potential anti-cachectic agents are being explored. A meta-analysis was conducted to review the effect of eicosapentaenoic acid (EPA) enriched enteral nutrition on lean body mass (LBM) in esophageal, head and neck cancer patients at risk for progression of cachexia.

METHODS: An evidence based review was conducted beginning with a Pubmed database literature search using the terms ‘EPA esophageal cancer’, ‘Eicosapentaenoic acid esophageal cachexia’, ‘Eicosapentaenoic acid esophageal’, ‘Eicosapentaenoic acid cachexia head and neck cancer’, and ‘EPA cachexia head and neck cancer’ for human clinical trials. The results were reviewed for relevance and the data from original research was abstracted for amount of EPA enriched formula supplemented, EPA intake, method of intake, LBM measurements, study design, intervention duration, and population characteristics.

RESULTS: Three trials were identified that met the criteria and were reviewed.  EPA supplementation in enteral nutrition was provided at concentrations ranging between 1.6 g/day and 2.2 g/day for a time span ranging between 3 weeks and 14 weeks. Two randomized clinical trials showed maintenance of > 1.5 kg LBM relative to the control group while a single arm trial showed a gain of 3.2 kg LBM in patients. Differences in results could be attributed to variability in the degree of cachexia, the contents of each enteral nutrition formula, duration of supplementation, and cancer treatments that subjects in each trial were undergoing.

CONCLUSIONS: All three trials showed a trend in EPA enriched enteral nutrition improving the loss of LBM in esophageal, head and neck cancer patients at risk for cachexia progression. This type of formula should therefore be considered in treatment of these types of cancers and possibly, in the treatment of other seriously ill patients with cachexia.

Context and objective

Type 1 diabetes (T1D) is characterized by a β-cell deficit due to autoimmune inflammatory-mediated β-cell destruction. It has been proposed the deficit in β-cell mass in T1D may be in part due to β-cell degranulation to chromogranin-positive, hormone-negative (CPHN) cells.

Design, setting, and participants

We investigated the frequency and distribution of CPHN cells in the pancreas of 15 individuals with T1D, 17 autoantibody-positive nondiabetic individuals, and 17 nondiabetic controls.

Results

CPHN cells were present at a low frequency in the pancreas from nondiabetic and autoantibody-positive, brain-dead organ donors but are more frequently found in the pancreas from donors with T1D (islets: 1.11% ± 0.20% vs 0.26% ± 0.06 vs 0.27% ± 0.10% of islet endocrine cells, T1D vs autoantibody positive [AA+] vs nondiabetic [ND]; T1D vs AA+, and ND, P < .001). CPHN cells are most commonly found in the single cells and small clusters of endocrine cells rather than within established islets (clusters: 18.99% ± 2.09% vs 9.67% ± 1.49% vs 7.42% ± 1.26% of clustered endocrine cells, T1D vs AA+ vs ND; T1D vs AA+ and ND, P < .0001), mimicking the distribution present in neonatal pancreas.

Conclusions

From these observations, we conclude that CPHN cells are more frequent in T1D and, as in type 2 diabetes, are distributed in a pattern comparable with the neonatal pancreas, implying a possible attempted regeneration. In contrast to rodents, CPHN cells are insufficient to account for loss of β-cell mass in T1D.

The value of an anticipated rewarding event is a crucial component of the decision to engage in its pursuit. But little is known of the networks responsible for encoding and retrieving this value. By using biosensors and pharmacological manipulations, we found that basolateral amygdala (BLA) glutamatergic activity tracks and mediates encoding and retrieval of the state-dependent incentive value of a palatable food reward. Projection-specific, bidirectional chemogenetic and optogenetic manipulations revealed that the orbitofrontal cortex (OFC) supports the BLA in these processes. Critically, the function of ventrolateral and medial OFC→BLA projections is doubly dissociable. Whereas lateral OFC→BLA projections are necessary and sufficient for encoding of the positive value of a reward, medial OFC→BLA projections are necessary and sufficient for retrieving this value from memory. These data reveal a new circuit for adaptive reward valuation and pursuit and provide insight into the dysfunction in these processes that characterizes myriad psychiatric diseases.

Objective

To describe the phenotype of a patient with classical features of X-linked L1 syndrome associated with novel brain malformations.

Methods

Diagnostic analysis included physical and dysmorphology examinations, MRI of the brain, and exome sequencing of the family trio.

Results

We report a 2.5-year-old boy with developmental delay, dysmorphic facies, and adducted thumbs. MRI of the brain showed a truncated corpus callosum and periventricular heterotopias associated with polymicrogyria (PMG). Variant segregation analysis with exome sequencing discovered a novel maternally derived hemizygous variant in exon 14 of the L1CAM gene (c.1759 G>C; p.G587R).

Conclusions

This novel L1CAM mutation was located in the protein's sixth immunoglobin domain and involved glycine-587, a key residue in the structure of L1CAM because of its interactions with lysine-606, which indicates that any mutation at this site would likely affect the secondary structure and function of the protein. The replacement of the small nonpolar glycine residue with a large basic arginine would have an even more dramatic result. The presentation of periventricular nodular heterotopias with overlying PMG is very uncommon, and its association with L1CAM may provide insight into other similar cases. Furthermore, this presentation indicates the important role that L1CAM plays in neuronal migration and brain development and extends the phenotype associated with L1CAM-associated disorders.

BACKGROUND: Environmental reward-predictive stimuli provide a major source of motivation for adaptive reward pursuit behavior. This cue-motivated behavior is known to be mediated by the nucleus accumbens (NAc) core. The cholinergic interneurons in the NAc are tonically active and densely arborized and thus well suited to modulate NAc function. However, their causal contribution to adaptive behavior remains unknown. Here we investigated the function of NAc cholinergic interneurons in cue-motivated behavior. METHODS: We used chemogenetics, optogenetics, pharmacology, and a translationally analogous Pavlovian-to-instrumental transfer behavioral task designed to assess the motivating influence of a reward-predictive cue over reward-seeking actions in male and female rats. RESULTS: The data show that NAc cholinergic interneuron activity critically opposes the motivating influence of appetitive cues. Chemogenetic inhibition of NAc cholinergic interneurons augmented cue-motivated behavior. Optical stimulation of acetylcholine release from NAc cholinergic interneurons prevented cues from invigorating reward-seeking behavior, an effect that was mediated by activation of β2-containing nicotinic acetylcholine receptors. CONCLUSIONS: NAc cholinergic interneurons provide a critical regulatory influence over adaptive cue-motivated behavior and therefore are a potential therapeutic target for the maladaptive cue-motivated behavior that marks many psychiatric conditions, including addiction and depression.

Background

Environmental reward-predictive stimuli provide a major source of motivation for adaptive reward pursuit behavior. This cue-motivated behavior is known to be mediated by the nucleus accumbens (NAc) core. The cholinergic interneurons in the NAc are tonically active and densely arborized and thus well suited to modulate NAc function. However, their causal contribution to adaptive behavior remains unknown. Here we investigated the function of NAc cholinergic interneurons in cue-motivated behavior.

Methods

We used chemogenetics, optogenetics, pharmacology, and a translationally analogous Pavlovian-to-instrumental transfer behavioral task designed to assess the motivating influence of a reward-predictive cue over reward-seeking actions in male and female rats.

Results

The data show that NAc cholinergic interneuron activity critically opposes the motivating influence of appetitive cues. Chemogenetic inhibition of NAc cholinergic interneurons augmented cue-motivated behavior. Optical stimulation of acetylcholine release from NAc cholinergic interneurons prevented cues from invigorating reward-seeking behavior, an effect that was mediated by activation of β₂-containing nicotinic acetylcholine receptors.

Conclusions

NAc cholinergic interneurons provide a critical regulatory influence over adaptive cue-motivated behavior and therefore are a potential therapeutic target for the maladaptive cue-motivated behavior that marks many psychiatric conditions, including addiction and depression.

N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1 mutations (c.1858 G>A and c.1858 G>C; both p.G620R). Both individuals presented at birth with developmental delay and hypotonia associated with behavioral abnormalities and stereotypical movements. Recombinant NMDARs containing the mutant GluN1-G620R together with either GluN2A or GluN2B were evaluated for changes in their trafficking to the plasma membrane and their electrophysiological properties. GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ~2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg²⁺ block, and a significant reduction of current responses to a maximal effective concentration of agonists. GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface associated with similarly altered electrophysiology. These results indicate these individuals may have suffered neurodevelopmental deficits as a result of the decreased presence of GluN1-G620R/GluN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of GluN1-G620R-containing NMDARs after birth. These cases emphasize the importance of comprehensive functional characterization of de novo mutations and illustrates how a combination of several distinct features of NMDAR expression, trafficking and function can be present and influence phenotype.

Abstract: Introduction: Though urinary incontinence (UI) after prostate treatment often contributes to emotional distress and significantly impacts quality of life, many patients do not discuss this condition with their physicians. We analyzed the patient perspective by examining online support group posts to gain insight into specific challenges associated with different UI management methods. Methods: We examined discussion board threads from multiple patient‐focused forums on experiences of UI due to prostate treatment (threads from January 2016 to January 2022). Principles of grounded theory in thematic analysis were used to analyze the threads. Results: Three hundred and eighteen posts from 84 unique users were analyzed. Among users, 47 (56%) reported UI following radical prostatectomy (RP), 5 (6%) secondary to radiation therapy (RT), 12 (14%) after a combination of RP and RT, and 20 (24%) were ambiguous. UI management methods included pads/diapers/liners, condom catheters/external clamps, Kegels/pelvic floor physiotherapy, and surgical treatment (artificial urinary sphincter or sling placement). We identified challenges common to all management methods: “requires trial and error,” “physical discomfort,” and “difficult to be in public.” Factors influencing management choices included the ability to “feel normal” and the development of a management routine. Conclusion: The current study identifies opportunities for improved expectation‐setting and education regarding post‐procedural UI and its management. These findings can serve as a guide for providers to counsel patients on the advantages and disadvantages of UI management devices.

Purpose

We evaluate the efficacy and safety profiles of currently available conservative management options for penile and urethral lichen sclerosus.

Materials and methods

A systematic review of existing literature on lichen sclerosus was conducted utilizing the PubMed, Embase, and Web of Science databases. References were assessed for relevance to nonsurgical management of male genital lichen sclerosus by title and abstract by 3 independent reviewers, then reviewed in full and in duplicate by 5 independent reviewers.

Results

Seventeen studies describing conservative management of histologically confirmed penile and urethral lichen sclerosus in male patients were included in the final review. We present available evidence supporting the use of 4 major treatment modalities represented in the existing literature: topical corticosteroids, tacrolimus, platelet-rich plasma, and CO₂ laser. We also briefly discuss the limited studies on the use of oral acitretin and polydeoxyribonucleotide injections. Outcomes assessed include symptoms, clinical appearance, quality of life, sexual satisfaction, adverse effects, and long-term efficacy of treatment.

Conclusions

Topical corticosteroids remain the mainstay of conservative management of penile and urethral lichen sclerosus, with current literature supporting the use of other therapies such as tacrolimus and platelet-rich plasma as alternatives or adjuvant treatments when escalation of treatment is necessary. Future research should further explore the efficacy and safety of newer therapies through additional controlled clinical trials in the targeted population.