Although COVID-19 is most well known for causing substantial respiratory pathology, it can also result in several extrapulmonary manifestations. These conditions include thrombotic complications, myocardial dysfunction and arrhythmia, acute coronary syndromes, acute kidney injury, gastrointestinal symptoms, hepatocellular injury, hyperglycemia and ketosis, neurologic illnesses, ocular symptoms, and dermatologic complications. Given that ACE2, the entry receptor for the causative coronavirus SARS-CoV-2, is expressed in multiple extrapulmonary tissues, direct viral tissue damage is a plausible mechanism of injury. In addition, endothelial damage and thromboinflammation, dysregulation of immune responses, and maladaptation of ACE2-related pathways might all contribute to these extrapulmonary manifestations of COVID-19. Here we review the extrapulmonary organ-specific pathophysiology, presentations and management considerations for patients with COVID-19 to aid clinicians and scientists in recognizing and monitoring the spectrum of manifestations, and in developing research priorities and therapeutic strategies for all organ systems involved.

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Extrapulmonary manifestations of COVID-19.

Prostate cancer afflicts one man in nine over the age of 65 and represents the most frequently diagnosed cancer in American men (Coffey 1993). Early detection through serum testing for prostate specific antigen (PSA) and improved procedures for surgical intervention and radiation therapy have significantly reduced the number of fatalities; however, there is still no effective cure for men with advanced disease. Therefore, much research has been dedicated to identifying prognostic markers that distinguish indolent versus aggressive forms of prostate cancer. In contrast, significantly less research has been devoted to understanding the molecular mechanisms that underlie normal prostate growth and development or cancer initiation and progression. In this review, we address recent progress toward the central objectives of understanding parameters of normal versus abnormal prostatic development and of elucidating a molecular pathway for prostate cancer progression. We focus on key regulatory molecules that have been implicated by analysis of patterns of allelic loss in human prostate cancers and/or by reverse genetic approaches in the mouse.

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Molecular genetics of prostate cancer

Improved understanding and management of COVID-19, a potentially life-threatening disease, could greatly reduce the threat posed by its etiologic agent, SARS-CoV-2. Toward this end, we have identified a core peripheral blood immune signature across 63 hospital-treated patients with COVID-19 who were otherwise highly heterogeneous. The signature includes discrete changes in B and myelomonocytic cell composition, profoundly altered T cell phenotypes, selective cytokine/chemokine upregulation and SARS-CoV-2-specific antibodies. Some signature traits identify links with other settings of immunoprotection and immunopathology; others, including basophil and plasmacytoid dendritic cell depletion, correlate strongly with disease severity; while a third set of traits, including a triad of IP-10, interleukin-10 and interleukin-6, anticipate subsequent clinical progression. Hence, contingent upon independent validation in other COVID-19 cohorts, individual traits within this signature may collectively and individually guide treatment options; offer insights into COVID-19 pathogenesis; and aid early, risk-based patient stratification that is particularly beneficial in phasic diseases such as COVID-19.

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A dynamic COVID-19 immune signature includes associations with poor prognosis.

Developmental biology of the pancreas: a comprehensive review.

A novel coronavirus-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-emerged in humans in Wuhan, China, in December 2019 and has since disseminated globally1,2. As of April 16, 2020, the confirmed case count of coronavirus disease 2019 (COVID-19) had surpassed 2 million. Based on full-genome sequence analysis, SARS-CoV-2 shows high homology to SARS-related coronaviruses identified in horseshoe bats1,2. Here we show the establishment and characterization of expandable intestinal organoids derived from horseshoe bats of the Rhinolophus sinicus species that can recapitulate bat intestinal epithelium. These bat enteroids are fully susceptible to SARS-CoV-2 infection and sustain robust viral replication. Development of gastrointestinal symptoms in some patients with COVID-19 and detection of viral RNA in fecal specimens suggest that SARS-CoV-2 might cause enteric, in addition to respiratory, infection3,4. Here we demonstrate active replication of SARS-CoV-2 in human intestinal organoids and isolation of infectious virus from the stool specimen of a patient with diarrheal COVID-19. Collectively, we established the first expandable organoid culture system of bat intestinal epithelium and present evidence that SARS-CoV-2 can infect bat intestinal cells. The robust SARS-CoV-2 replication in human intestinal organoids suggests that the human intestinal tract might be a transmission route of SARS-CoV-2.

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Infection of bat and human intestinal organoids by SARS-CoV-2.

The embryonic origin of endocrine cells of the gastrointestinal tract.

The distribution of gastrin-, cholecystokinin-, glucagon-, secretin-, vasoactive intestinal polypeptide-, substance P-, bombesin-, neurotensin-, motilin-, somatostatin- and avian pancreatic polypeptide-like cells, demonstrated by indirect immunocytochemistry, was studied in samples from the following regions: proventriculus, gizzard, pylorus, duodenum, upper and lower ileum, caeca and rectum. The pylorus is particularly rich in gastrin-, neurotensin- and somatostatin-like cells. No cells immunoreactive for gastric inhibitory polypeptide or insulin were detected. In a number of instances the same cells were found to stain with antisera raised to different gut peptides. This happened with antisera detecting gastrin- and neurotensin-like cells, with antisera to avian pancreatic polypeptide and glucagon and with antisera to secretin, vasoactive intestinal polypeptide, glucagon and substance P. The possibility that antigenic determinants to more than one peptide are contained in certain endocrine-like cells is considered.

An immunocytochemical survey of endocrine cells in the gastrointestinal tract of chicks at hatching.

Gut and pancreatic amine precursor uptake and decarboxylation cells are not neural crest derivatives.

Araldite sections of formalin-fixed pancreas from chicks at hatching were treated by an indirect immuno-enzyme technique to reveal cells containing APP, somatostatin, glucagon and insulin. APP cells were found scattered in the exocrine parenchyma. A few were associated with insulin-containing B islets and occasional cells occurred in and around glucagon-containing A islets. Somatostatin-immunoreactive cells were distributed peripherally in A and B islets and were dispersed in the exocrine tissue. APP cells were roughly as numerous in the exocrine parenchyma as somatostatin-immunoreactive cells. Since certain published observations point to the possible occurrence of APP and somatostatin in the same cells, consecutive sections were stained for these hormones. In no case did the two peptides occur in the same cell. Sections subjected to double-staining confirmed this result. Therefore it is likely that the described differences between APP and somatostatin-immunoreactive cells are valid.

An immunocytochemical study of the distribution of pancreatic endocrine cells in chicks, with special reference to the relationship between pancreatic polypeptide and somatostatin-immunoreactive cells.

To determine whether mesenchyme plays a part in the differentiation of gut endocrine cells, proventricular endoderm from 4- to 5-day chick or quail embryos was associated with mesenchyme from the dorsal pancreatic bud of chick embryos of the same age. The combinations were grown on the chorioallantoic membranes of host chick embryos until they reached a total incubation age of 21 days. Proventricular or pancreatic endoderm of the appropriate age and species reassociated with its own mesenchyme provided the controls. Morphogenesis in the experimental grafts corresponded closely to that in proventricular controls, i.e. the pancreatic mesenchyme supported the development of proventricular glands from proventricular endoderm. Insulin, glucagon and somatostatin cells and cells with pancreatic polypeptide-like immunoreactivity differentiated in the pancreatic controls. The latter three endocrine cell types, together with neurotensin and bombesin/gastrin-releasing polypeptide (GRP) cells, developed in proventricular controls and experimental grafts. The proportions of the major types common to proventriculus and pancreas (somatostatin and glucagon cells) were in general similar when experimental grafts were compared with proventricular controls but different when experimental and pancreatic control grafts were compared. Hence pancreatic mesenchyme did not materially affect the proportions of these three cell types in experimental grafts, induced no specific pancreatic (insulin) cell type and allowed the differentiation of the characteristic proventricular endocrine cell types, neurotensin and bombesin/GRP cells. However, an important finding was a significant reduction in the proportion of bombesin/GRP cells, attributable in part to a decrease in their number and in part to an increase in the numbers of endocrine cells of the other types. This indicates that mesenchyme may well play a part in determining the regional specificity of populations of gut endocrine cells.

B. B. Rawdon

Papers

The embryonic origin of endocrine cells of the gastrointestinal tract.

An immunocytochemical survey of endocrine cells in the gastrointestinal tract of chicks at hatching.

Gut and pancreatic amine precursor uptake and decarboxylation cells are not neural crest derivatives.

An immunocytochemical study of the distribution of pancreatic endocrine cells in chicks, with special reference to the relationship between pancreatic polypeptide and somatostatin-immunoreactive cells.

The effect of pancreatic mesenchyme on the differentiation of endocrine cells from gastric endoderm.