Primary Pancreatic Lymphoma in the Tail: A Rare Anatomic Presentation.

Non-Hodgkin's lymphoma is a common type of cancer, whose most common site of extranodal involvement is the gastrointestinal tract. However, primary presentation in the pancreas remains uncommon. Among cases with pancreatic involvement, the disease is often found in the head and rarely in the tail. Here, we present a case of a 56-year-old male patient with acute epigastric pain, early satiety, and abdominal distention. CT imaging showed a mass of the pancreatic tail with surrounding lymphadenopathy, concerning lymphoma. Endoscopic ultrasound-guided fine needle aspiration (EUS-guided FNA) diagnosed mature B-cell lymphoma, meeting novel diagnostic criteria for the rare diagnosis of primary pancreatic lymphoma (PPL).

Cross Talk between ARF1 and RhoA Coordinates the Formation of Cytoskeletal Scaffolds during Chlamydia Infection.

Chlamydia trachomatis is an obligate intracellular bacterium that has developed sophisticated mechanisms to survive inside its infectious compartment, the inclusion. Notably, Chlamydia weaves an extensive network of microtubules (MTs) and actin filaments to enable interactions with host organelles and enhance its stability. Despite the global health and economic burden caused by this sexually transmitted pathogen, little is known about how actin and MT scaffolds are integrated into an increasingly complex virulence system. Previously, we established that the chlamydial effector InaC interacts with ARF1 to stabilize MTs. We now demonstrate that InaC regulates RhoA to control actin scaffolds. InaC relies on cross talk between ARF1 and RhoA to coordinate MTs and actin, where the presence of RhoA downregulates stable MT scaffolds and ARF1 activation inhibits actin scaffolds. Understanding how Chlamydia hijacks complex networks will help elucidate how this clinically significant pathogen parasitizes its host and reveal novel cellular signaling pathways. IMPORTANCE Chlamydia trachomatis is a major cause of human disease worldwide. The ability of Chlamydia to establish infection and cause disease depends on the maintenance of its parasitic niche, called the inclusion. To accomplish this feat, Chlamydia reorganizes host actin and microtubules around the inclusion membrane. How Chlamydia orchestrates these complex processes, however, is largely unknown. Here, we discovered that the chlamydial effector InaC activates Ras homolog family member A (RhoA) to control the formation of actin scaffolds around the inclusion, an event that is critical for inclusion stability. Furthermore, InaC directs the kinetics of actin and posttranslationally modified microtubule scaffolds by mediating cross talk between the GTPases that control these cytoskeletal elements, RhoA and ADP-ribosylation factor 1 (ARF1). The precise timing of these events is essential for the maintenance of the inclusion. Overall, this study provides the first evidence of ARF1-RhoA-mediated cross talk by a bacterial pathogen to coopt the host cytoskeleton.

Poly(ADP)-Ribosylation Inhibition: A Promising Approach for Clear Cell Renal Cell Carcinoma Therapy.

Poly(ADP-ribose) polymerase 1 (PARP-1) and glycohydrolase (PARG) enzymes regulate chromatin structure, transcription activation, and DNA repair by modulating poly(ADP-ribose) (pADPr) level. Interest in PARP-1 inhibitors has soared recently with the recognition of their antitumor efficacy. We have shown that the development of clear cell renal cell carcinoma (ccRCC) is associated with extreme accumulation of pADPr caused by the enhanced expression of PARP-1 and decreased PARG levels. The most severe misregulation of pADPr turnover is found in ccRCC specimens from metastatic lesions. Both, classical NAD-like and non-NAD-like PARP-1 inhibitors reduced viability and clonogenic potential of ccRCC cell lines and suppressed growth of ccRCC xenograft tumors. However, classical NAD-like PARP-1 inhibitors affected viability of normal kidney epithelial cells at high concentrations, while novel non-NAD-like PARP-1 inhibitors exhibited activity against malignant cells only. We have also utilized different approaches to reduce the pADPr level in ccRCC cells by stably overexpressing PARG and demonstrated the prominent antitumor effect of this "back-to-normal" intervention. We also generated ccRCC cell lines with stable overexpression of PARG under doxycycline induction. This genetic approach demonstrated significantly affected malignancy of ccRCC cells. Transcriptome analysis linked observed phenotype with changes in gene expression levels for lipid metabolism, interferon signaling, and angiogenesis pathways along with the changes in expression of key cancer-related genes.

The association of hypnotics with incident cardiovascular disease and mortality in older women with sleep disturbances.

BACKGROUND/OBJECTIVE: Insomnia is common in older women and is associated with higher cardiovascular disease (CVD) risk. Nonbenzodiazepine GABA agonists (Z-drugs) are the most commonly prescribed sleep aids. The study objective was to determine whether the use of Z-drugs is associated with the risk of developing CVD and mortality in older women with sleep disturbances. PATIENTS/METHODS: The study cohort included post-menopausal women who, at baseline, scored ≥9 with the Women's Health Initiative Insomnia Rating Scale (N = 40,728). Members of the cohort were categorized as users of Z-drugs, users of other prescription hypnotics, or non-users. Outcomes were composite CVD (congestive heart failure, stroke, and fatal/non-fatal myocardial infarction) and mortality. Hazard ratios were estimated from Cox proportional hazards regression models adjusted for demographics, medical history, and sleep measures. To address potential confounding by indication, we also adjusted for propensity to be prescribed hypnotics. RESULTS: The mean age of our cohort was 63.57 years (SD = 7.23) and mean follow-up time after the initial follow-up visit was 14.0 years (SD = 6.3). Z-drug use was significantly associated with an increased risk of composite CVD (HR = 1.35, 95%CI: 1.02-1.79) and all-cause mortality (HR = 1.38, 95%CI: 1.13-1.69). When groups were divided by heavy and casual use, only heavy users (≥3 times per week) had an increased risk of mortality. CONCLUSIONS: Z-drugs use was associated with an increased risk for death and CVD in post-menopausal women being treated for sleep disturbances. Additional research is needed to evaluate both frequency and duration of Z-drug use.

Transcutaneous Electrical Nerve Stimulation as a Treatment for Neuropathic Cough: A Tolerability and Feasibility Study.

Transcutaneous electrical nerve stimulation (TENS) is a form of electroanalgesia used for neuropathic pain disorders. Refractory chronic cough, or "neuropathic cough," may be physiologically similar to other neuropathic pain conditions. This study explored the tolerability and feasibility of using TENS as a treatment for neuropathic cough. Laryngeal TENS was administered to five subjects with neuropathic cough. One electrode was placed over the lateral thyrohyoid membrane, and a second over the cricothyroid space. A frequency of 120 Hz was applied for 30 min. Participants rated symptoms pre-, during, and post-TENS treatment using a Likert scale. Laryngeal TENS was well tolerated by all subjects. Adverse effects included brief neck discomfort when increasing TENS intensity and an event of mild post-treatment hoarseness. The self-reported scores trended toward a reduction in symptom severity during and after treatment. Controlled trials using this method would elucidate the use of TENS for treatment of patients suffering from chronic cough.

Examining Referral Patterns between Otolaryngology and Gastroenterology: A Window into Potential Inter-Specialty Knowledge Gaps.

OBJECTIVE: The objective of this study was to examine referral patterns between otolaryngology and gastroenterology in order to delineate areas of clinical overlap, as well as to identify areas that might benefit from improved inter-specialty communication and collaboration. METHODS: Montefiore's Clinical Looking Glass tool was used to define parameters for electronic medical record data extraction from 2015 to 2018. Two cohorts were generated, one representing referrals placed by gastroenterology to otolaryngology and a second representing referrals placed by otolaryngology to gastroenterology. The ICD-10 codes in both cohorts were reviewed and 13 distinct "reason for referral" categories were defined. The rates of referral for each category were then calculated for each of the referral cohorts. RESULTS: Otolaryngology referred to gastroenterology at a greater rate than gastroenterology referred to otolaryngology, despite seeing fewer total patients than gastroenterology. For referrals from gastroenterology to otolaryngology, the three most frequent referral reasons were oral cavity/oropharyngeal pathology (28.3%), dysphagia (28.3%), and gastroesophageal reflux disease/laryngopharyngeal reflux disease (GERD/LPRD) (11.3%). For referrals from otolaryngology to gastroenterology, the three most frequent referral reasons were GERD/LPRD (61.7%), dysphagia (18.6%), and esophageal pathology (5.3%). CONCLUSIONS: GERD/LPRD was more frequently referred out by otolaryngology than it was by gastroenterology, suggesting the need for further characterization of the discrepancy in management of a disease commonly treated by both specialties. The discrepant rates of referral for dysphagia also suggest a need to better understand what factors contribute to the differences in management of another clinical condition commonly assessed by both specialties. LEVEL OF EVIDENCE: 4.

Social influences on microglial reactivity and neuronal damage after cardiac arrest/cardiopulmonary resuscitation.

Social isolation presents a risk factor and worsens outcome to cerebrovascular diseases; however, the underlying mechanisms remain underspecified. This study examines the effect of social environment on microglial reactivity after global cerebral ischemia, to test the hypothesis that social isolation leads to greater microglial responses. Adult female and male mice were pair-housed or socially isolated for one week prior to cardiac arrest/cardiopulmonary resuscitation (CA/CPR) or the sham procedure, and following either 2 or 24 h of reperfusion, microglia samples were enriched and analyzed for gene expression. At the 2-hour time point, microglia from both females and males exhibited ischemia-induced inflammation, characterized by the gene expression increase of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1ß) and interleukin 6 (IL-6), regardless of the housing conditions. However, at 24 h post-ischemia, social housing attenuated microglial pro-inflammatory gene expression in a sex-specific manner. At this time point, the ischemia-induced increased expression of IL-1ß and IL-6 was attenuated by social interaction in microglia from male mice, while among female mice social attenuation of the inflammatory response was observed in the microglial expression of cell surface protein major histocompatibility complex II (MHC II). A second study examined behavioral and physiological measures 96 h after ischemic injury. At this time point, female and male mice displayed increased locomotion and exploratory behavior following CA/CPR relative to controls. Regardless of sex, ischemia also elicited neuroinflammation and neurodegeneration, both of which were modulated by the social environment. Hippocampal nitric oxide (iNOS), cortical TNF-α, and counts of Fluoro-Jade C positive stained cells in the CA1 region of the hippocampus, were increased in the isolated CA/CPR group relative to sham controls and the pair-housed CA/CPR groups. Together, these data indicate that female and male mice exhibit similar outcome measures and social modulation at 96 h post-ischemic injury, nonetheless, that social environment influences microglial reactivity to global cerebral ischemia in a sex-specific manner.

Social interaction modulates the neuroinflammatory response to global cerebral ischemia in male mice.

Social isolation is a risk factor for cardiovascular and cerebrovascular diseases, although the underlying mechanisms remain underspecified. Considering the potential of microglia to become sensitized by stressors and their role in neuroinflammation, we hypothesized that social isolation primes microglia, resulting in an exaggerated neuroimmune response to experimental cerebral ischemia. First, major histocompatibility complex II (MHC II) gene expression, an indicator of microglial priming, was compared between mice that were socially isolated or pair-housed. MHC II increased in the hippocampus and cortex of socially isolated mice, which is suggestive of isolation-induced microglial priming. In experiment 2, isolated and pair-housed mice underwent ∼8min of global cerebral ischemia. Hippocampal mRNA expression of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) was significantly increased among both isolated and pair-housed ischemia groups relative to sham controls. Hippocampal expression of interleukin 1 beta (IL-1ß) and cortical TNF-α, IL-1ß and IL-6, were significantly increased 24-h post ischemia in isolated mice, but not pair-housed mice, relative to controls. Ischemia-induced increases in microglial cell body area and percent area fraction of ionized calcium binding adaptor molecule 1 (Iba-1) positive staining were also observed in isolated, but not pair-housed mice, relative to controls. For experiment 3, brain sections from socially isolated and pair-housed mice underwent 15min of oxygen glucose deprivation (OGD), an ex vivo model of cerebral ischemia. IL-6 gene expression was significantly elevated following OGD only in hippocampi from mice that had been socially isolated, indicating that isolation prior to ischemia is sufficient to modulate the neuroinflammatory response. Together, these data suggest microglial priming as a possible mechanism underlying the detrimental effects of social isolation on cerebral ischemia outcome.