Enteric glia regulate Paneth cell secretion and intestinal microbial ecology.

Glial cells of the enteric nervous system (ENS) interact closely with the intestinal epithelium and secrete signals that influence epithelial cell proliferation and barrier formation in vitro. Whether these interactions are important in vivo, however, is unclear because previous studies reached conflicting conclusions [1]. To better define the roles of enteric glia in steady state regulation of the intestinal epithelium, we characterized the glia in closest proximity to epithelial cells and found that the majority express PLP1 in both mice and humans. To test their functions using an unbiased approach, we genetically depleted PLP1+ cells in mice and transcriptionally profiled the small and large intestines. Surprisingly, glial loss had minimal effects on transcriptional programs and the few identified changes varied along the gastrointestinal tract. In the ileum, where enteric glia had been considered most essential for epithelial integrity, glial depletion did not drastically alter epithelial gene expression but caused a modest enrichment in signatures of Paneth cells, a secretory cell type important for innate immunity. In the absence of PLP1+ glia, Paneth cell number was intact, but a subset appeared abnormal with irregular and heterogenous cytoplasmic granules, suggesting a secretory deficit. Consistent with this possibility, ileal explants from glial-depleted mice secreted less functional lysozyme than controls with corresponding effects on fecal microbial composition. Collectively, these data suggest that enteric glia do not exert broad effects on the intestinal epithelium but have an essential role in regulating Paneth cell function and gut microbial ecology.

Pyloric Gastric Adenoma: Endoscopic Detection, Removal, and Echoendosonographic Characterization.

Pyloric gland adenomas (PGAs) are rare neoplasms found not only in the gastrointestinal tract but also in other extragastrointestinal organs. They have potential for malignant conversion, and early detection and removal is imperative to prevent invasive disease. PGAs prove difficult in management and surveillance given their rarity. However, increasing familiarity with histological appearance and use of advanced tools such as echoendosonography can bring greater understanding of their clinical history. We describe a unique case of a PGA detected within a hiatal hernia sac characterized with echoendosonography and highlight the need to develop surveillance protocols for these types of lesions.

Gastrointestinal Kaposi Sarcoma: A Rare Case of an Isolated Rectal Lesion in an Immunocompetent HIV-Negative Patient.

Kaposi sarcoma (KS) is a pathological endothelial growth associated with human herpes virus-8 which primarily affects the skin. In HIV-negative men who have sex with men, the clinical presentation of KS resembles the classic form limited to cutaneous or multifocal disease. In this report, we present a unique case of a healthy 61-year-old man who has sex with men with an isolated gastrointestinal KS who does not meet criteria for any of the typical KS clinical variants. Proper follow-up and regular HIV screenings are needed to evaluate the potential progression course of the disease in these patients.

Lewy body disease as a potential negative outcome modifier of glioblastoma treatment: a case report.

BACKGROUND: Elderly patients with glioblastoma are particularly susceptible to the adverse effects of ionizing radiation to the brain. This population also has an increasing prevalence of dementia in the successive seventh, eighth and nineth decade of life, and dementia with Lewy bodies is characterized by pathologic α-synucleins, proteins that take part in neuronal DNA damage repair. CASE PRESENTATION: We report a 77-year-old man, with a history of coronary artery disease and mild cognitive impairment, who experienced subacute behavioral changes over 3 months with wording-finding difficulty, memory loss, confusion, perseveration, and irritable mood. Neuroimaging studies disclosed a 2.5 × 2.4 × 2.7 cm cystic enhancing mass with central necrosis in the left temporal lobe of the brain. Gross total resection of the tumor revealed IDH-1 wild-type glioblastoma. After treatment with radiation and temozolomide chemotherapy, his cognitive status deteriorated rapidly, and he died from unexpected sudden death 2 months after radiation. Autopsy of his brain revealed (i) tumor cells with atypical nuclei and small lymphocytes, (ii) neuronal cytoplasmic inclusions and Lewy bodies that were positive for α-synuclein in the midbrain, pons, amygdala, putamen and globus pallidus, and (iii) no amyloid plaques and only rare neurofibrillary tangles near the hippocampi. CONCLUSIONS: This patient most likely had pre-clinical limbic subtype of dementia with Lewy bodies prior to his diagnosis of glioblastoma. The radiation and temozolomide that was used to treat his tumor may have accelerated neuronal damage due to induction of DNA breakage when his brain was already compromised by pathologic α-synucleins. α-Synucleinopathy could be a negative outcome modifier in glioblastoma patients.

Intracranial Metastasis of Extracranial Chondrosarcoma: Systematic Review With Illustrative Case.

BACKGROUND: Cerebral chondrosarcoma metastases are rare and aggressive neoplasms. The rarity of presentation has precluded rigorous analysis of diagnosis, risk factors, treatment, and survival. We analyzed every reported case through exhaustive literature review. We further present the first case with Maffucci syndrome. METHODS: Three databases, PubMed, Embase, and Google Scholar, and crossed references were queried for cerebral chondrosarcoma metastases. Extracted variables included demographics, risk factors, tumor characteristics, interventions, and outcomes. Univariate and multivariate analyses were performed. RESULTS: Fifty-six patients were included from 1,489 literature results. The average age at brain metastasis was 46.6±17.6 years and occurred at a median of 24±2.8 months from primary diagnosis. Primary tumor histology (dedifferentiated 5.0±1.5 months, mesenchymal 24±3.0 months, conventional 41±7.4 months, p<0.05) and grade (low grade 54±16.7 months vs. high-grade 10±6.4 months, p<0.001) correlated with time interval until brain metastasis. A multiple enchondromatosis syndrome occurred in 13.2% of cases. At time of brain metastases diagnosis, extracranial metastases were identified in 76.2% of cases. Median survival after the development of brain metastasis was 2.0±0.78 months with a 1-year survival of 10.0%. On regression analysis, surgery reduced brain metastasis mortality risk and radiation trended towards reduced mortality risk (surgery: hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.064-0.763, p=0.017; radiation: HR 0.31, 95% CI 0.091-1.072, p=0.064). CONCLUSION: We present a systematic review of cerebral chondrosarcoma metastases. Primary tumor histology and grade correlate with time until cerebral metastasis. Following cerebral metastasis, these tumors have poor prognosis and modestly benefit from surgery.

Fatal Post COVID mRNA-Vaccine Associated Cerebral Ischemia.

Background: Venous thromboses have been linked to several COVID-19 vaccines, but there is limited information on the Moderna vaccine's effect on the risk of arterial thrombosis. Here we describe a case of post-Moderna COVID-19 vaccination arterial infarct with vaccine-associated diffuse cortical edema that was complicated by refractory intracranial hypertension. Case Summary: 24 hrs after receiving her first dose of the Moderna COVID-19 vaccine, a 30-year-old female developed severe headache. Three weeks later she was admitted with subacute headache and confusion. Imaging initially showed scattered cortical thrombosis with an elevated opening pressure on lumbar puncture. An external ventricular drain was placed, but she continued to have elevated intracranial pressure. Ultimately, she required a hemicraniectomy, but intractable cerebral edema resulted in her death. Pathology was consistent with thrombosis and associated inflammatory response. Conclusion: Though correlational, her medical team surmised that the mRNA vaccine may have contributed to this presentation. The side effects of COVID-19 infection and vaccination are still incompletely understood. Though complications are rare, clinicians should be aware of presentations like this one.

Cerebral Metastases in Appendiceal Cancer: Comprehensive Review and Report of Rare Medullary Carcinoma Histology.

Appendiceal cancer is an extremely rare malignancy, and its metastatic spread to the brain is even more unusual. We describe a 47-year-old female who presented with a rare cerebral appendiceal carcinoma metastasis, a case that is further remarkable for representing the first histologic diagnosis of primary medullary carcinoma in the appendix. Based on a comprehensive review of the English literature using PubMed, Embase, and Google Scholar, only six other cases of cerebral appendiceal metastases have been described.

Enteric glia in homeostasis and disease: From fundamental biology to human pathology.

Glia, the non-neuronal cells of the nervous system, were long considered secondary cells only necessary for supporting the functions of their more important neuronal neighbors. Work by many groups over the past two decades has completely overturned this notion, revealing the myriad and vital functions of glia in nervous system development, plasticity, and health. The largest population of glia outside the brain is in the enteric nervous system, a division of the autonomic nervous system that constitutes a key node of the gut-brain axis. Here, we review the latest in the understanding of these enteric glia in mammals with a focus on their putative roles in human health and disease.

Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis.

Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.

Change in Prevalence of Family History During Long-term Follow-up of Patients With Pediatric-onset Inflammatory Bowel Disease.

OBJECTIVES: The aim of the study was to prospectively study changes in prevalence of positive family history (FH+) in pediatric-onset inflammatory bowel disease (IBD) in contrast to previously published cross-sectional data. METHODS: An observational cohort study was performed using a prospective pediatric-onset IBD database including 485 patients with disease duration ≥10 years as of December 2016. Proband characteristics and FH+ were obtained at diagnosis and subsequently from the database, medical records, and follow-up telephone interviews in 2006 and 2016. RESULTS: Updated 2016 information was obtained from 322 (66%) patients and included in analysis with median follow-up of 18 years (interquartile range 14, 26). Prevalence of FH+ increased from 13.7% at diagnosis to 26.6% at 20 years for first-degree relatives and from 38.5% to 52.2% for all relatives. At 20-year follow-up, an additional 10.0% of probands had a sibling, 6.1% had a parent, 1.9% had a grandparent, and 4.5% had a cousin diagnosed with IBD. FH+ at diagnosis was associated with greater risk for additional FH+ at 20 years (43% vs 22%, P < 0.001). Non-Jewish Caucasians had significantly lower risk of a FH+ compared to Jewish Caucasians (P = 0.002), but similar risk to African Americans (P = 0.55). FH+ at diagnosis was not associated with disease type (P = 0.33) or age at diagnosis (P = 0.24). CONCLUSIONS: This prospective study documents changes in family history of IBD in pediatric-onset IBD patients over time. Prevalence of FH+ increased for first-degree and all relatives at 20 years by 12.9% and 13.7%, respectively. FH+ at diagnosis was associated with a 2-fold greater likelihood of subsequent FH+ at 20 years.

Peptidomic analyses of mouse astrocytic cell lines and rat primary cultured astrocytes.

Astrocytes play an active role in the modulation of synaptic transmission by releasing cell-cell signaling molecules in response to various stimuli that evoke a Ca2+ increase. We expand on recent studies of astrocyte intracellular and secreted proteins by examining the astrocyte peptidome in mouse astrocytic cell lines and rat primary cultured astrocytes, as well as those peptides secreted from mouse astrocytic cell lines in response to Ca2+-dependent stimulations. We identified 57 peptides derived from 24 proteins with LC-MS/MS and CE-MS/MS in the astrocytes. Among the secreted peptides, four peptides derived from elongation factor 1, macrophage migration inhibitory factor, peroxiredoxin-5, and galectin-1 were putatively identified by mass-matching to peptides confirmed to be found in astrocytes. Other peptides in the secretion study were mass-matched to those found in prior peptidomics analyses on mouse brain tissue. Complex peptide profiles were observed after stimulation, suggesting that astrocytes are actively involved in peptide secretion. Twenty-six peptides were observed in multiple stimulation experiments but not in controls and thus appear to be released in a Ca2+-dependent manner. These results can be used in future investigations to better understand stimulus-dependent mechanisms of astrocyte peptide secretion.

Methodology of studies evaluating death certificate accuracy were flawed.

BACKGROUND AND OBJECTIVE: Statistics on causes of death are important for epidemiologic research. Studies that evaluate the source data often give conflicting results, which raise questions about comparability and validity of methods. METHODS: For 44 recent evaluation studies we examined the methods employed and assessed the reproducibility. RESULTS: Thirty studies stated who reviewed the source data. Six studies reported reliability tests. Twelve studies included all causes of death, but none specified criteria for identifying the underlying cause when several, etiologically independent conditions were present. We assessed these as not reproducible. Of 32 studies that focussed on a specific condition, 21 provided diagnostic criteria such that the verification of the focal diagnosis is reproducible. Of 16 that discussed the difference between dying "with" and "from" a condition, eight described how competing causes had been handled. For these eight, the selection of a principal cause is reproducible, but in three the selection strategy conflicts with the international instructions issued by the World Health Organization. CONCLUSION: Methods and criteria are often insufficiently described. When described, they sometimes disagree with the international standard. Explicit descriptions of methods and criteria would contribute to methodologic improvement and would allow readers to assess the generalizability of the conclusions.

An assessment of pregnancy-related mortality in the United States.

Deaths from pregnancy complications remain an important public health concern. Nationally, two systems collect information on the number of deaths and characteristics of the women who died from complications of pregnancy. The Centers for Disease Control and Prevention's (CDC) National Center for Health Statistics (NCHS) reports maternal mortality through the National Vital Statistics System (NVSS); CDC National Center for Chronic Disease Prevention and Health Promotion's Pregnancy Mortality Surveillance System (PMSS) conducts epidemiological surveillance of pregnancy-related deaths. The numbers of deaths reported by these two systems have differed over the past two decades; our objective was to determine the magnitude and nature of these differences. For 1995-97, we compared maternal deaths in the NVSS with pregnancy-related deaths in PMSS for the 50 States, Washington DC and New York City. Pregnancy-related deaths whose underlying cause was assigned to ICD-9 codes 630-676 by NVSS were classified as maternal deaths; those coded outside 630-676 were not. There were 1387 pregnancy-related deaths in PMSS and 898 maternal deaths in the NVSS; 54% of these deaths were reported in both systems, 40% in PMSS only, and 6% in NVSS only. Pregnancy-related deaths due to haemorrhage, embolism, and hypertensive complications of pregnancy were proportionately more often identified by NVSS as maternal deaths than those from cardiovascular complications, medical conditions or infection. From the 1471 unduplicated deaths classified as maternal or pregnancy-related from either reporting system, we estimated a combined pregnancy-related mortality ratio of 12.6/100,000 live births for 1995-97, compared with 11.9 for PMSS only and 7.5 for NVSS only. The identification and classification of these events is dependent on the provision of complete and accurate cause-of-death information on death certificates. Changes in the guidelines for coding maternal deaths under ICD-10 may change the relationship in the number of deaths resulting from pregnancy reported by these two systems.

Estimating deaths attributable to obesity in the United States.

Estimates of deaths attributable to obesity in the United States rely on estimates from epidemiological cohorts of the relative risk of mortality associated with obesity. However, these relative risk estimates are not necessarily appropriate for the total US population, in part because of exclusions to control for baseline health status and exclusion or underrepresentation of older adults. Most deaths occur among older adults; estimates of deaths attributable to obesity can vary widely depending on the assumptions about the relative risks of mortality associated with obesity among the elderly. Thus, it may be difficult to estimate deaths attributable to obesity with adequate accuracy and precision. We urge efforts to improve the data and methods for estimating this statistic.

Disease classification: measuring the effect of the Tenth Revision of the International Classification of Diseases on cause-of-death data in the United States.

The purpose of this paper is to describe the statistical impact of the Tenth Revision of the International Classification of Diseases (ICD-10) on cause-of-death data for the United States. ICD-10 was implemented in the U.S. effective with deaths occurring in 1999. The paper is based on cause-of-death information from a large sample of 1996 death certificates filed in the 50 States and the District of Columbia. Cause-of-death information in the sample includes underlying cause of death classified by both ICD-9 and ICD-10. Preliminary comparability ratios by cause of death presented in this paper indicate the extent of discontinuities in cause-of-death trends from 1998 to 1999 resulting from implementing ICD-10. For some leading causes (for example, septicaemia, influenza and pneumonia, Alzheimer's disease, and nephritis, nephrotic syndrome and nephrosis) the discontinuity in trend is substantial. Results of this study, although preliminary, are essential to analysing trends in mortality statistics between ICD-9 and ICD-10. In particular, the results provide a means for interpreting changes between 1998, which is the last year in which ICD-9 was used, and 1999, the year in which ICD-10 was implemented for mortality in the United States. Published in 2003 by John Wiley & Sons, Ltd.

Increase in deaths caused by HIV infection due to changes in rules for selecting underlying cause of death.

With implementation of the (ICD-10), for U.S. vital statistics in 1999, the criteria for selecting HIV infection as the underlying cause of death were expanded. To estimate the effect of ICD-10 rules on the number of deaths attributed to HIV infection, we applied a simplified version of ICD-10 rules to data on causes of death from all U.S. death certificates for 1998 (previously classified by rules of the 9th revision of ICD [ICD-9]) and calculated the resulting increase in deaths for which HIV infection was selected as the underlying cause. Of the 17,186 deaths in 1998 with any mention of HIV infection on the death certificate, ICD-10 rules selected HIV infection as the underlying cause for 15,145, which was 1,719 (13%) more than the 13,426 for which it had been selected by ICD-9 rules. The proportional increase differed by demographic group, being less among non-Hispanic blacks (9%) and Hispanics (13%) than among non-Hispanic whites (18%). Thus, comparison of deaths attributed to HIV infection in 1999 or later with those in 1998 or earlier should take into account the changes in ICD rules for selecting the underlying cause of death.

Annual report to the nation on the status of cancer, 1973-1999, featuring implications of age and aging on U.S. cancer burden.

BACKGROUND: The American Cancer Society, the National Cancer Institute, the North American Association of Central Cancer Registries (NAACCR), the National Institute on Aging (NIA), and the Centers for Disease Control and Prevention, including the National Center for Health Statistics (NCHS) and the National Center for Chronic Disease Prevention and Health Promotion, collaborated to provide an annual update on cancer occurrence and trends in the United States. This year's report contained a special feature focusing on implications of age and aging on the U.S. cancer burden. METHODS: For 1995 through 1999, age-specific rates and age-adjusted rates were calculated for the major cancers using incidence data from the Surveillance, Epidemiology, and End Results Program, the National Program of Cancer Registries, and the NAACCR, and mortality data from NCHS. Joinpoint analysis, a model of joined line segments, was used to examine 1973-1999 trends in incidence and death rates by age for the four most common cancers. Deaths were classified using the eighth, ninth, and tenth revisions of the International Classification of Diseases. Age-adjusted incidence and death rates were standardized to the year 2000 population, which places more emphasis on older persons, in whom cancer rates are higher. RESULTS: Across all ages, overall cancer death rates decreased in men and women from 1993 through 1999, while cancer incidence rates stabilized from 1995 through 1999. Age-specific trends varied by site, sex, and race. For example, breast cancer incidence rates increased in women aged 50-64 years, whereas breast cancer death rates decreased in each age group. However, a major determinant of the future cancer burden is the demographic phenomenon of the aging and increasing size of the U.S. population. The total number of cancer cases can be expected to double by 2050 if current incidence rates remain stable. CONCLUSIONS: Despite the continuing decrease in cancer death rates and stabilization of cancer incidence rates, the overall growth and aging of the U.S. population can be expected to increase the burden of cancer in our nation.