Tamm-Horsfall Protein Regulates Mononuclear Phagocytes in the Kidney.

Tamm-Horsfall protein (THP), also known as uromodulin, is a kidney-specific protein produced by cells of the thick ascending limb of the loop of Henle. Although predominantly secreted apically into the urine, where it becomes highly polymerized, THP is also released basolaterally, toward the interstitium and circulation, to inhibit tubular inflammatory signaling. Whether, through this latter route, THP can also regulate the function of renal interstitial mononuclear phagocytes (MPCs) remains unclear, however. Here, we show that THP is primarily in a monomeric form in human serum. Compared with wild-type mice, THP-/- mice had markedly fewer MPCs in the kidney. A nonpolymerizing, truncated form of THP stimulated the proliferation of human macrophage cells in culture and partially restored the number of kidney MPCs when administered to THP-/- mice. Furthermore, resident renal MPCs had impaired phagocytic activity in the absence of THP. After ischemia-reperfusion injury, THP-/- mice, compared with wild-type mice, exhibited aggravated injury and an impaired transition of renal macrophages toward an M2 healing phenotype. However, treatment of THP-/- mice with truncated THP after ischemia-reperfusion injury mitigated the worsening of AKI. Taken together, our data suggest that interstitial THP positively regulates mononuclear phagocyte number, plasticity, and phagocytic activity. In addition to the effect of THP on the epithelium and granulopoiesis, this new immunomodulatory role could explain the protection conferred by THP during AKI.

Refractory and super-refractory status epilepticus in children and adolescents: A population-based study.

PURPOSE: Refractory (RSE) and super-refractory status epilepticus (SRSE) are serious medical emergencies whose long-term outcomes depend on the timeliness of their management. Population-based clinical and epidemiological data on these conditions are sparse. We aimed to provide a detailed description of the epidemiology and clinical course of RSE and SRSE in children and adolescents and identify potential prognostic biomarkers. METHODS: In this retrospective population-based study, patients aged one month to 18 years who fulfilled the RSE/SRSE diagnostic criteria and were admitted to the intensive care unit of Haukeland University Hospital from 2012 to 2021 were considered eligible. Detailed clinical and laboratory findings along with information on management and outcomes were systematically analyzed. RESULTS: Forty-three patients with 52 episodes of RSE/SRSE were identified. The incidence rate was 3.13 per 100,000 per year. The median time from SE onset to the administration of the first rescue drug was 13 min, and from the first rescue drug to second- and third-line treatments, 83 and 66 min, respectively. All patients were alive at discharge. CONCLUSION: Delays in treatment were observed in various stages of the clinical course of RSE/SRSE. Improvement measures targeting the prompt administration of recuse mediation and subsequent treatment escalation are needed.

Assisting decision-making on age of neutering for German Short/Wirehaired Pointer, Mastiff, Newfoundland, Rhodesian Ridgeback, Siberian Husky: associated joint disorders, cancers, and urinary incontinence.

Spaying female and castrating male dogs, hereinafter referred to as neutering, is a US convention for the first year in the dog's life. Research on 35 breeds of dogs revealed that early neutering increases risks of joint disorders, such as hip dysplasia (HD), elbow dysplasia (ED), or cranial cruciate ligament (CCL) tear, or cancers, such as lymphosarcoma (LSA), mast cell tumor (MCT), hemangiosarcoma (has), or osteosarcoma (OSA), for some breeds. Joint disorder risks are heightened for some larger breeds and for mixed-breed dogs weighing more than 20 kg. Some breeds had elevated risks for cancers. Several other research teams have reported health complications associated with neutering. The study goal includes using the same methodology for data collection and analyses as in the study on 35 breeds for five additional dog breeds weighing at least 20 kg. The breeds were: German Short/Wirehaired Pointer, Mastiff, Newfoundland, Rhodesian Ridgeback, and Siberian Husky. Major differences among breeds appeared in vulnerability to joint disorders and cancers with early neutering: male and female Pointer breeds had elevated joint disorders and increased cancers; male Mastiff breeds had increased CCL and LSA and females had non-significant elevated CCL risks; female Newfoundland breeds had heightened risks for joint disorders and males had non-significant elevated risks; female Ridgeback breeds had heightened MCT with very early neutering; and Siberian Huskies showed no significant effects on joint disorders or cancers, but female breeds showed a non-significant but elevated CCL. Updated guidelines cover 40 dog breeds. These results further emphasize the importance of personalized decisions regarding the neutering of dogs, considering the dog's breed, sex, and context.

Patients With MEN1 Are at an Increased Risk for Venous Thromboembolism.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder predisposing the development of multiple functional and nonfunctional neuroendocrine tumors (NETs). Only uncommon MEN1-associated functional NETs such as glucagonomas (<1%) and adenocorticotropic hormone-producing tumors (<5%) are known to be associated with hypercoagulability. It is unknown if patients with MEN1 generally have an increased risk of venous thromboembolism (VTE). METHODS: We queried a prospective natural history study of germline mutation-positive MEN1 patients (n = 286) between 1991 and 2019 for all lifetime events of VTE. The search terms were: DVT, thromb, embol, PE, pulmonary embolism, clot, hematology consult, anticoagulant, coumadin, lovenox, xarelto, warfarin, aspirin, rivaroxaban, and apixaban. Incidence rates were calculated, accounting for age and sex. Comparisons were made to published incidence rates in healthy populations, different types of cancer, and Cushing's syndrome. RESULTS: Thirty-six subjects (median age 45 years, range 16-75) experienced a VTE event, yielding a prevalence rate of 12.9%. The age-sex adjusted incidence rate of VTE is 9.11 per 1000 patient-years, with a sex-adjusted lifetime incidence rate of 2.81 per 1000 patient-years. MEN1-associated lifetime incidence rates are ~2-fold higher than the estimated annual incidence rate in the general population and are comparable to the known risk in the setting of various types of cancer. Approximately 80% of patients who had a VTE were diagnosed with pancreatic NETs, of which 24% were insulinomas. Fourteen patients (42%) experienced perioperative VTE events. CONCLUSIONS: MEN1 patients have an increased risk of VTE. Further mechanistic investigation and validation from other MEN1 cohorts are needed to confirm the increased prevalence of VTE in MEN1.

The comfort in touch: Immediate and lasting effects of handholding on emotional pain.

Consoling touch is a powerful form of social support that has been repeatedly demonstrated to reduce the experience of physical pain. However, it remains unknown whether touch reduces emotional pain in the same way that it reduces physical pain. The present research sought to understand how handholding with a romantic partner shapes experiences of emotional pain and comfort during emotional recollection, as well as how it shapes lasting emotional pain associated with emotional experiences. Participants recalled emotionally painful memories or neutral memories with their partners, while holding their partner's hand or holding a squeeze-ball. They additionally completed a follow-up survey to report how much emotional pain they associated with the emotional experiences after recalling them in the lab with their partners. Although consoling touch did not reduce emotional pain during the task, consoling touch increased feelings of comfort. Moreover, participants later recalled emotional memories that were paired with touch as being less emotionally painful than those that were not paired with touch. These findings suggest that touch does not decrease the immediate experience of emotional pain and may instead support adaptive processing of emotional experiences over time.

c-MET inhibition: novel treatment for sporadic and MEN1-associated GEP NETs.

Gastroenteropancreatic neuroendocrine tumors (GEP NETs) comprise a heterogenous and diverse group of neoplasms arising from a common neuroendocrine cell origin. The majority of these tumors occur sporadically while ~20% manifest within the context of hereditary syndromes. Germline MEN1 mutations cause a syndrome with an increased susceptibility to multifocal primary GEP NETs. In addition, somatic MEN1 mutations also occur in these sporadic lesions. MEN1 alterations are the most frequent somatic mutation found in pancreatic neuroendocrine tumors. In this review, we explore the implication of the loss of the MEN1-encoded protein menin as a key pathogenic driver in subsets of GEP NETs with downstream consequences including upregulation of the oncogenic receptor c-MET (hepatocyte growth factor receptor). Furthermore, the review will summarize the data related to the clinical presentation, therapeutic standards, and outcomes of these tumors in both sporadic and germline MEN1 mutation-associated contexts. Finally, we present the data on c-MET expression in GEP NETs, clinical trials using c-MET inhibitors and provide an overview of the molecular mechanisms by which c-MET inhibition in these lesions represents a potential precision-medicine targeted approach.

18F-FDOPA PET/CT accurately identifies MEN1-associated pheochromocytoma.

SUMMARY: Pheochromocytoma (PHEO) in multiple endocrine neoplasia type 1 (MEN1) is extremely rare. The incidence is reported as less than 2%. We report a case of a 76-year-old male with familial MEN1 who was found to have unilateral PHEO. Although the patient was normotensive and asymptomatic, routine screening imaging with CT demonstrated bilateral adrenal masses. The left adrenal mass grew from 2.5 to 3.9 cm over 4 years with attenuation values of 9 Hounsfield units (HU) pre-contrast and 15 HU post-contrast washout. Laboratory evaluation demonstrated an adrenergic biochemical phenotype. Both 18F-fluorodeoxyglucose (18F-FDG) PET/CT and 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy demonstrated bilateral adrenal uptake. In contrast, 18F-fluorodihydroxyphenylalanine (18F-FDOPA) PET/CT demonstrated unilateral left adrenal uptake (28.7 standardized uptake value (SUV)) and physiologic right adrenal uptake. The patient underwent an uneventful left adrenalectomy with pathology consistent for PHEO. Post-operatively, he had biochemical normalization. A review of the literature suggests that adrenal tumors >2 cm may be at higher risk for pheochromocytoma in patients with MEN1. Despite a lack of symptoms related to catecholamine excess, enlarging adrenal nodules should be biochemically screened for PHEO. 18F-FDOPA PET/CT may be beneficial for localization in these patients. LEARNING POINTS: 18F-FDOPA PET/CT is a beneficial imaging modality for identifying pheochromocytoma in MEN1 patients. Adrenal adenomas should undergo routine biochemical workup for PHEO in MEN1 and can have serious peri-operative complications if not recognized, given that MEN1 patients undergo frequent surgical interventions. MEN1 is implicated in the tumorigenesis of PHEO in this patient.

First Report of Alphapartitiviruses Infecting Alfalfa (Medicago sativa L.) in the United States.

Evidence is presented demonstrating that alfalfa cultivars in the United States could be widely infected with cryptic virus of the genus Alphapartitivirus. The nucleotide sequences of several U.S. isolates were obtained. The biological significance or negative effects of the virus on alfalfa are unknown and require further investigation.

Resistant and susceptible responses in alfalfa (Medicago sativa) to bacterial stem blight caused by Pseudomonas syringae pv. syringae.

Bacterial stem blight caused by Pseudomonas syringae pv. syringae is a common disease of alfalfa (Medicago sativa L). Little is known about host-pathogen interactions and host defense mechanisms. Here, individual resistant and susceptible plants were selected from cultivars Maverick and ZG9830 and used for transcript profiling at 24 and 72 hours after inoculation (hai) with the isolate PssALF3. Bioinformatic analysis revealed a number of differentially expressed genes (DEGs) in resistant and susceptible genotypes. Although resistant plants from each cultivar produced a hypersensitive response, transcriptome analyses indicated that they respond differently at the molecular level. The number of DEGs was higher in resistant plants of ZG9830 at 24 hai than in Maverick, suggesting that ZG9830 plants had a more rapid effector triggered immune response. Unique up-regulated genes in resistant ZG9830 plants included genes encoding putative nematode resistance HSPRO2-like proteins, orthologs for the rice Xa21 and soybean Rpg1-b resistance genes, and TIR-containing R genes lacking both NBS and LRR domains. The suite of R genes up-regulated in resistant Maverick plants had an over-representation of R genes in the CC-NBS-LRR family including two genes for atypical CCR domains and a putative ortholog of the Arabidopsis RPM1 gene. Resistance in both cultivars appears to be mediated primarily by WRKY family transcription factors and expression of genes involved in protein phosphorylation, regulation of transcription, defense response including synthesis of isoflavonoids, and oxidation-reduction processes. These results will further the identification of mechanisms involved in resistance to facilitate selection of parent populations and development of commercial varieties.