Genome-wide analyses reveal a role for peptide hormones in planarian germline development.

Bioactive peptides (i.e., neuropeptides or peptide hormones) represent the largest class of cell-cell signaling molecules in metazoans and are potent regulators of neural and physiological function. In vertebrates, peptide hormones play an integral role in endocrine signaling between the brain and the gonads that controls reproductive development, yet few of these molecules have been shown to influence reproductive development in invertebrates. Here, we define a role for peptide hormones in controlling reproductive physiology of the model flatworm, the planarian Schmidtea mediterranea. Based on our observation that defective neuropeptide processing results in defects in reproductive system development, we employed peptidomic and functional genomic approaches to characterize the planarian peptide hormone complement, identifying 51 prohormone genes and validating 142 peptides biochemically. Comprehensive in situ hybridization analyses of prohormone gene expression revealed the unanticipated complexity of the flatworm nervous system and identified a prohormone specifically expressed in the nervous system of sexually reproducing planarians. We show that this member of the neuropeptide Y superfamily is required for the maintenance of mature reproductive organs and differentiated germ cells in the testes. Additionally, comparative analyses of our biochemically validated prohormones with the genomes of the parasitic flatworms Schistosoma mansoni and Schistosoma japonicum identified new schistosome prohormones and validated half of all predicted peptide-encoding genes in these parasites. These studies describe the peptide hormone complement of a flatworm on a genome-wide scale and reveal a previously uncharacterized role for peptide hormones in flatworm reproduction. Furthermore, they suggest new opportunities for using planarians as free-living models for understanding the reproductive biology of flatworm parasites.

The role of human milk nutrients in preventing necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an intestinal disease that primarily impacts preterm infants. The pathophysiology of NEC involves a complex interplay of factors that result in a deleterious immune response, injury to the intestinal mucosa, and in its most severe form, irreversible intestinal necrosis. Treatments for NEC remain limited, but one of the most effective preventative strategies for NEC is the provision of breast milk feeds. In this review, we discuss mechanisms by which bioactive nutrients in breast milk impact neonatal intestinal physiology and the development of NEC. We also review experimental models of NEC that have been used to study the role of breast milk components in disease pathophysiology. These models are necessary to accelerate mechanistic research and improve outcomes for neonates with NEC.

Identification of serum biomarkers for necrotizing enterocolitis using aptamer-based proteomics.

Introduction: Necrotizing enterocolitis (NEC) is a potentially fatal intestinal disease primarily affecting preterm infants. Early diagnosis of neonates with NEC is crucial to improving outcomes; however, traditional diagnostic tools remain inadequate. Biomarkers represent an opportunity to improve the speed and accuracy of diagnosis, but they are not routinely used in clinical practice. Methods: In this study, we utilized an aptamer-based proteomic discovery assay to identify new serum biomarkers of NEC. We compared levels of serum proteins in neonates with and without NEC and identified ten differentially expressed serum proteins between these groups. Results: We detected two proteins, C-C motif chemokine ligand 16 (CCL16) and immunoglobulin heavy constant alpha 1 and 2 heterodimer (IGHA1 IGHA2), that were significantly increased during NEC and eight that were significantly decreased. Generation of receiver operating characteristic (ROC) curves revealed that alpha-fetoprotein (AUC = 0.926), glucagon (AUC = 0.860), and IGHA1 IGHA2 (AUC = 0.826) were the proteins that best differentiated patients with and without NEC. Discussion: These findings indicate that further investigation into these serum proteins as a biomarker for NEC is warranted. In the future, laboratory tests incorporating these differentially expressed proteins may improve the ability of clinicians to diagnose infants with NEC rapidly and accurately.

Heterogeneity among Clinical Intestinal Escherichia coli Isolates upon Acquired Streptomycin Resistance.

Escherichia coli isolates from inflammatory bowel disease (IBD) patients are often multidrug resistant, including to streptomycin. Streptomycin resistance (StrR) mutations can alter bacterial behavior, which may influence intestinal disease. We generated a spontaneous StrR strain of the intestinal adherent-invasive E. coli (AIEC) strain NC101. Whole-genome sequencing revealed a single missense mutation in rpsL that commonly confers StrR, rpsL-K43N. StrR NC101 exhibited a striking loss of aggregation and significantly increased motility, behaviors that can impact host-microbe interactions. Behavioral changes were associated with reduced transcription of csgA, encoding the biofilm component curli, and increased transcription of fliC, encoding flagellin. Scanning electron microscopy (SEM) detailed morphologic changes consistent with the observed alterations in multicellular behavior. Because intestinal E. coli isolates exhibit remarkable strain-specific differences, we generated spontaneous StrR mutants of 10 clinical E. coli phylotype B2 strains from patients with IBD, colorectal cancer, and urinary tract infection. Out of these 10 StrR clinical strains, two had altered colony morphology on Congo red agar (suggesting changes in extracellular products), and three had significant changes in motility. These changes were not associated with a particular rpsL mutation nor with the presence of virulence genes encoding the inflammation-associated E. coli metabolites yersiniabactin or colibactin. We conclude that common mutations in rpsL, which confer StrR, can differentially alter disease-associated phenotypes across intestinal E. coli strains. These findings highlight the heterogeneity among seemingly similar intestinal E. coli strains and reveal the need to carefully study the strain-specific effects of antibiotic resistance mutations, particularly when using these mutations during strain selection studies. IMPORTANCE We demonstrate that StrR, commonly acquired through a single point mutation in rpsL (a gene encoding part of the 30S bacterial ribosome), strikingly alters the morphology and behavior of a key intestinal AIEC strain, NC101. These changes include remarkably diminished aggregation and significantly increased motility, traits that are linked to AIEC-defining features and disease development. Phenotypic changes were heterogeneous among other StrR clinical E. coli strains, underscoring the need to evaluate the strain-specific effects of commonly acquired antibiotic resistance mutations. This is important, as the results of studies using mutant StrR Enterobacteriaceae strains (e.g., for cloning or in vivo selection) may be confounded beyond our demonstrated effects. Long term, these findings can help researchers better distinguish the contribution of specific E. coli traits to functional changes in the microbiota. Evaluating these strain-level differences could provide insight into the diversity of IBD symptoms and lead to improved therapies for microbiota-driven intestinal disorders.

Necrotizing enterocolitis: Bench to bedside approaches and advancing our understanding of disease pathogenesis.

Necrotizing enterocolitis (NEC) is a devastating, multifactorial disease mainly affecting the intestine of premature infants. Recent discoveries have significantly enhanced our understanding of risk factors, as well as, cellular and genetic mechanisms of this complex disease. Despite these advancements, no essential, single risk factor, nor the mechanism by which each risk factor affects NEC has been elucidated. Nonetheless, recent research indicates that maternal factors, antibiotic exposure, feeding, hypoxia, and altered gut microbiota pose a threat to the underdeveloped immunity of preterm infants. Here we review predisposing factors, status of unwarranted immune responses, and microbial pathogenesis in NEC based on currently available scientific evidence. We additionally discuss novel techniques and models used to study NEC and how this research translates from the bench to the bedside into potential treatment strategies.

Hepatitis C continuum of care and utilization of healthcare and harm reduction services among persons who inject drugs in Seattle.

BACKGROUND: To describe the "continuum of care" for hepatitis C virus (HCV) and related health service utilization among persons who inject drugs (PWID) in the Seattle metropolitan area. METHODS: The study analyzed data from the 2015 National HIV Behavioral Surveillance system focused on PWID, which included local questions on HCV treatment and testing. We calculated respondent driven sampling (RDS)-adjusted percentages of participants who had completed each step of the care continuum and compared healthcare harm reduction services among participants who were HCV + vs. HCV- using bivariate analyses. RESULTS: 513 PWID were screened for HCV antibodies (Ab). Of those, 59.7% were HCV Ab+. Among those HCV Ab+, 86.4% had been tested for HCV at least once; 69.9% reported a previous diagnosis. Of those diagnosed, 55.9% had received a confirmatory test, 17.2% had ever received any medications for HCV, and 7.2% had completed treatment. The majority of HCV Ab + participants had seen a health care provider in the past 12 months (85.6%). CONCLUSIONS: There is a large gap between HCV screening and treatment among Seattle area PWID.

Increasing Trends in the Use of Hospital Observation Services for Older Medicare Advantage and Privately Insured Patients.

Policy and financial pressures have driven up use of observation stays for patients in traditional Medicare and the Veterans' Affairs Healthcare System. Using claims data (2004-2014) from OptumLabs™ Data Warehouse, we examined whether people in private Medicare Advantage (MA) and commercial plans experienced similar changes. We found that use of observation increased rapidly for patients in MA plans-even though MA plans were not subject to the same pressures as government-run programs. In contrast, use of observation remained constant for people in commercial plans-except for enrollees 65 and older, for whom it increased somewhat. Privately insured patients returning to the hospital after an inpatient stay were increasingly likely to be placed under observation. Our results suggest that observation is rapidly replacing inpatient admissions and readmissions for many older patients in MA and commercial plans, while younger patients continue to be admitted as inpatients at relatively constant rates.

Observation Status or Inpatient Admission: Impact of Patient Disposition on Outcomes and Utilization Among Emergency Department Patients With Chest Pain.

OBJECTIVES: to compare healthcare utilization including coronary angiography, percutaneous coronary intervention (PCI), rehospitalization, and rate of subsequent acute myocardial infarction (AMI) within 30 days, among patients presenting to the emergency department (ED) with chest pain admitted as short-term inpatient (≤2 days) versus observation (in-ED observation units combined with in-hospital observation). METHODS: We identified adults diagnosed with acute chest pain in the ED from 2010 to 2014 using administrative claims from privately insured and Medicare Advantage. Patients having AMI during the index visit were excluded. One-to-one propensity-score matching and logistic regression were used. Odds ratios (ORs) with 95% confidence intervals (CIs) were reported. RESULTS: A total of 774,017 chest pain visits were included. After matching, healthcare utilization was lower among observation versus short inpatient, with 10.9% versus 24.4% (OR = 0.38, 95% CI = 0.36 to 0.39) undergoing cardiac catheterization and 1.8% versus 7.6% (OR = 0.23, 95% CI = 0.21 to 0.24) having PCI. The incidence of subsequent AMI within the following 30 days was similar in patients admitted as observation versus short inpatient (0.23% vs. 0.21%; OR = 1.09, 95% CI = 0.84 to 1.42). CONCLUSIONS: There were higher rates of cardiac catheterization and PCI among those admitted as a short inpatient compared to observation, while the incidence of subsequent AMI within 30 days was similar.

Knowledge of blood loss at delivery among postpartum patients.

BACKGROUND: Postpartum hemorrhage (PPH) is a leading cause of obstetric morbidity. There is limited understanding of patients' knowledge about blood loss at delivery, PPH, and PPH-related morbidities, including transfusion and anemia. METHODS: We surveyed 100 healthy postpartum patients who underwent vaginal or cesarean delivery about blood loss, and whether they received information about transfusion and peripartum hemoglobin (Hb) testing. Responses were compared between women undergoing vaginal delivery vs. cesarean delivery; P < 0.05 considered as statistically significant. RESULTS: In our cohort, 49 women underwent vaginal delivery and 51 women underwent cesarean delivery. Only 29 (29%) of women provided blood loss estimates for their delivery. Women who underwent cesarean delivery were more likely to receive clear information about transfusion therapy than those undergoing vaginal delivery (43.1% vs. 20.4% respectively; P = 0.04). Women who underwent vaginal delivery were more likely to receive results of postpartum Hb tests compared to those undergoing cesarean delivery (49% vs. 29.4%; P = 0.02). CONCLUSION: Our findings suggest that women are poorly informed about the magnitude of blood loss at delivery. Hematologic information given to patients varies according to mode of delivery. Further research is needed to better understand the clinical implications of patients' knowledge gaps about PPH, transfusion and postpartum anemia.

A novel head-neck cooling device for concussion injury in contact sports.

Emerging research on the long-term impact of concussions on athletes has allowed public recognition of the potentially devastating effects of these and other mild head injuries. Mild traumatic brain injury (mTBI) is a multifaceted disease for which management remains a clinical challenge. Recent pre-clinical and clinical data strongly suggest a destructive synergism between brain temperature elevation and mTBI; conversely, brain hypothermia, with its broader, pleiotropic effects, represents the most potent neuro-protectant in laboratory studies to date. Although well-established in selected clinical conditions, a systemic approach to accomplish regional hypothermia has failed to yield an effective treatment strategy in traumatic brain injury (TBI). Furthermore, although systemic hypothermia remains a potentially valid treatment strategy for moderate to severe TBIs, it is neither practical nor safe for mTBIs. Therefore, selective head-neck cooling may represent an ideal strategy to provide therapeutic benefits to the brain. Optimizing brain temperature management using a National Aeronautics and Space Administration (NASA) spacesuit spinoff head-neck cooling technology before and/or after mTBI in contact sports may represent a sensible, practical, and effective method to potentially enhance recover and minimize post-injury deficits. In this paper, we discuss and summarize the anatomical, physiological, preclinical, and clinical data concerning NASA spinoff head-neck cooling technology as a potential treatment for mTBIs, particularly in the context of contact sports.

Neurenteric cyst of the area postrema.

Neurenteric cysts are CNS lesions most frequently occurring in the spinal cord. Intracranial neurenteric cysts are rarer, typically presenting with headache, mass effect, or location-specific symptoms. The area postrema is known as the emetic center of the brain; lesions can cause nausea and vomiting. Our case, featuring a neurenteric cyst of the area postrema, illustrates the importance of considering a neurological etiology for nonspecific symptoms that otherwise elude explanation. Our patient presented with acute decompensated hydrocephalus upon exploratory abdominal laparoscopy for unresolving abdominal pain. The patient had an eight-month history of unexplained intermittent nausea, vomiting, and abdominal pain. These bouts increased in frequency during the weeks before acute presentation, prompting exploratory abdominal laparoscopy. The acute decompensation was managed by ventriculostomy, and cranial MRI revealed a cystic mass by the floor of the fourth ventricle. After the patient stabilized and returned to neurological baseline, suboccipital craniectomy and resection were performed. The mass was histologically identified as a neurenteric cyst. The patient was free from neurological complaints at one-year follow-up, indicating that the successful resection of the area postrema-associated neurenteric cyst resolved her previous symptoms. Thus, some intracranial lesions can masquerade as nonspecific symptoms, presenting a challenge to accurate diagnosis.

Brain temperature and its fundamental properties: a review for clinical neuroscientists.

Brain temperature, as an independent therapeutic target variable, has received increasingly intense clinical attention. To date, brain hypothermia represents the most potent neuroprotectant in laboratory studies. Although the impact of brain temperature is prevalent in a number of common human diseases including: head trauma, stroke, multiple sclerosis, epilepsy, mood disorders, headaches, and neurodegenerative disorders, it is evident and well recognized that the therapeutic application of induced hypothermia is limited to a few highly selected clinical conditions such as cardiac arrest and hypoxic ischemic neonatal encephalopathy. Efforts to understand the fundamental aspects of brain temperature regulation are therefore critical for the development of safe, effective, and pragmatic clinical treatments for patients with brain injuries. Although centrally-mediated mechanisms to maintain a stable body temperature are relatively well established, very little is clinically known about brain temperature's spatial and temporal distribution, its physiological and pathological fluctuations, and the mechanism underlying brain thermal homeostasis. The human brain, a metabolically "expensive" organ with intense heat production, is sensitive to fluctuations in temperature with regards to its functional activity and energy efficiency. In this review, we discuss several critical aspects concerning the fundamental properties of brain temperature from a clinical perspective.

Former stepparents' contact with their stepchildren after midlife.

OBJECTIVES: Based on the life course perspective and gender differences in stepparental roles, this study examines frequency of social contact between mid- to late-life stepparents and their stepchildren after stepparents' marriage to their stepchildren's biological parent has been dissolved through widowhood or divorce. METHOD: Using 5 waves of panel data on stepparent-stepchild pairs from the Health and Retirement Study (N = 12,947 stepchild observations on 4,063 stepchildren belonging to 1,663 stepparents) spanning 10 years (1998-2008), I estimate ordered logit multilevel models predicting former stepparent-stepchild contact frequency. RESULTS: Results indicate that former stepparents have notably less frequent contact with their stepchildren than current stepparents, particularly following divorce. Widowed stepparents' contact with their stepchildren diminishes gradually following union disruption, whereas divorced stepparents' contact frequency drops abruptly. Former stepfathers have less contact with their stepchildren than former stepmothers. Finally, I uncover evidence of the moderating role of (step)parents' marriage length and stepparents' number of biological children on widowed stepparent-stepchild contact frequency. DISCUSSION: Older stepparents' social contact with their stepchildren is largely conditional on stepparents' enduring marital bond to their stepchildren's biological parent. This study contributes to a growing literature portraying relatively weak ties between older adults and their stepchildren.

An insulin-like peptide regulates size and adult stem cells in planarians.

Animal growth depends on nutritional intake during development. In many animals, nutritional status is uncoupled from moderation of adult stature after adult size is achieved. However, some long-lived animals continue to regulate adult size and fertility in a nutrition-dependent manner. For example, the regenerating flatworm Schmidtea mediterranea becomes smaller, or degrows, during periods of starvation. These animals provide an opportunity to readily observe adult stem cell population dynamics in response to nutritional cues. We explored the role of insulin signaling in S. mediterranea. We disrupted insulin signaling via RNA interference and showed that animals, despite eating, degrew similarly to starved animals. Utilizing in situ hybridization and immunofluorescence, we assessed cellular changes in proliferative populations including the planarian adult stem cell population (neoblasts) and the germline. Both impaired insulin signaling and nutritional deprivation correlated with decreased neoblast proliferation. Additionally, insulin signaling played a role in supporting spermatogenesis that was distinct from the effects of starvation. In sum, we have demonstrated that insulin signaling is responsible for regulation of adult animal size and tissue homeostasis in an organism with plastic adult size. Importantly, insulin signaling continued to affect stem cell and germline populations in a mature organism. Furthermore, we have shown that adult organisms can differentially regulate specific cell populations as a result of environmental challenges.

Partner caregiving in older cohabiting couples.

OBJECTIVES: Despite the rapidly increasing prevalence of cohabitation among older adults, the caregiving literature has exclusively focused on formally married individuals. Extending prior work on intra-couple care, this study contrasts frail cohabitors' patterns of care receipt from a partner to that of frail spouses. METHODS: Using nationally representative panel data from the Health and Retirement Study (2000, 2002, 2004, and 2006), we estimate random effects cross-sectional times series models predicting frail cohabitors' likelihood of receiving partner care compared with their married counterparts'. Conditional on the receipt of intra-couple care, we also examine differences in marital and nonmarital partners' caregiving hours and caregiving involvement relative to other helpers. RESULTS: Net of sociodemographic, disability, and comorbidity factors, we find that cohabitors are less likely to receive partner care than married individuals. However, caregiving nonmarital partners provide as many hours of care as spouses while providing a substantially larger share of disabled respondents' care than marital partners. DISCUSSION: Cohabitation and marriage have distinct implications for older adults' patterns of partner care receipt. This study adds weight to a growing body of research emphasizing the importance of accounting for older adults' nontraditional union forms and of examining the ramifications of cohabitation for older adults' well-being.