RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3.

Receptor-interacting protein kinase (RIPK)-1 is involved in RIPK3-dependent and -independent signaling pathways leading to cell death and/or inflammation. Genetic ablation of ripk1 causes postnatal lethality, which was not prevented by deletion of ripk3, caspase-8, or fadd. However, animals that lack RIPK1, RIPK3, and either caspase-8 or FADD survived weaning and matured normally. RIPK1 functions in vitro to limit caspase-8-dependent, TNFR-induced apoptosis, and animals lacking RIPK1, RIPK3, and TNFR1 survive to adulthood. The role of RIPK3 in promoting lethality in ripk1(-/-) mice suggests that RIPK3 activation is inhibited by RIPK1 postbirth. Whereas TNFR-induced RIPK3-dependent necroptosis requires RIPK1, cells lacking RIPK1 were sensitized to necroptosis triggered by poly I:C or interferons. Disruption of TLR (TRIF) or type I interferon (IFNAR) signaling delayed lethality in ripk1(-/-)tnfr1(-/-) mice. These results clarify the complex roles for RIPK1 in postnatal life and provide insights into the regulation of FADD-caspase-8 and RIPK3-MLKL signaling by RIPK1.

Apoptosis-Inducing-Factor-Dependent Mitochondrial Function Is Required for T Cell but Not B Cell Function.

The role of apoptosis inducing factor (AIF) in promoting cell death versus survival remains controversial. We report that the loss of AIF in fibroblasts led to mitochondrial electron transport chain defects and loss of proliferation that could be restored by ectopic expression of the yeast NADH dehydrogenase Ndi1. Aif-deficiency in T cells led to decreased peripheral T cell numbers and defective homeostatic proliferation, but thymic T cell development was unaffected. In contrast, Aif-deficient B cells developed and functioned normally. The difference in the dependency of T cells versus B cells on AIF for function and survival correlated with their metabolic requirements. Ectopic Ndi1 expression rescued homeostatic proliferation of Aif-deficient T cells. Despite its reported roles in cell death, fibroblasts, thymocytes and B cells lacking AIF underwent normal death. These studies suggest that the primary role of AIF relates to complex I function, with differential effects on T and B cells.

Implementation of caregiver depression screening in an urban, community-based asthma clinic: a quality improvement project.

OBJECTIVE: Caregiver depressive symptoms are prevalent among children with asthma and associated with greater asthma morbidity. Identifying caregivers with depression and connecting them to appropriate treatment may reduce child asthma morbidity. The goal of this project was to implement a workflow for caregiver depression screening and treatment referral in an urban, community-based, asthma clinic serving under-resourced children. METHODS: The Model for Improvement with weekly Plan-Do-Study-Act cycles was utilized. A two-item depression screening tool (Patient Health Questionnaire-2; PHQ-2) and an acceptability question using a 5-point Likert scale were added to an existing social needs screening checklist administered to all caregivers during the child's clinic visit. Caregivers with a positive PHQ-2 score (≥3) received the PHQ-9. Positive screens on the PHQ-9 (≥5) received information and referrals by level of risk. PHQ-9 positive caregivers received a follow-up phone call two weeks post-visit to assess connection to support, improvement in depressive symptoms, and satisfaction with resources provided. RESULTS: The PHQ-2 was completed by 84.4% of caregivers (233/276). Caregivers had a mean age of 33.8 years (SD = 8.3; Range: 18-68) and were predominately female (86.4%), Black (80.4%), and non-Hispanic (78.4%). The majority (72.3%) found the screening acceptable (agree/strongly agree). Nearly one in six caregivers (37/233, 15.9%) reported depressive symptoms (PHQ-2 ≥ 3); 11.6% (27/233) had clinically significant symptoms (PHQ-9 score ≥ 10); and 2.1% (5/233) reported suicidal thoughts. Of those with depressive symptoms, 70.3% (26/37) participated in the follow-up phone call. While 50% (13/26) reported the resources given in clinic were "extremely helpful," no caregivers contacted or used them. CONCLUSIONS: Caregiver depression screening was successfully integrated into a pediatric asthma clinic serving under-resourced children. While caregivers found screening to be acceptable, it did not facilitate short-term connection to treatment among those with depressive symptoms.

A Common Infection in a Highly Atypical Patient: Hematochezia From a Cytomegalovirus Colonic Ulcer in a Young and Healthy Immunocompetent Patient.

Gastrointestinal (GI) cytomegalovirus (CMV) infections are far more common in immunocompromised as opposed to immunocompetent patients. Immunocompetent patients who develop GI tract CMV infections are typically older with medical comorbidities. As such, descriptions of GI CMV infections in younger immunocompetent patients are lacking. Here, we present a case of a GI CMV infection in a young and healthy immunocompetent patient. A 41-year-old male with hyperlipidemia and hypothyroidism presented with painless, intermittent hematochezia. He denied changes in bowel habits or appetite, abdominal pain, fevers, chills, fatigue, or weight loss. His history was pertinent for insertive and receptive intercourse with one male partner. Medications were emtricitabine/tenofovir for pre-exposure prophylaxis, levothyroxine, and atorvastatin. A colonoscopy revealed a cecal ulcer surrounded by nodular-appearing mucosa that felt firm and friable when biopsied. The remaining colon and terminal ileum were normal. There was no diverticulosis or hemorrhoids. Pathology was positive for CMV. A subsequent serological evaluation revealed a normal complete blood count and comprehensive metabolic panel. Tests for human immunodeficiency virus, syphilis, viral hepatitis, chlamydia, and gonorrhea were negative. He was treated with valganciclovir 900 mg twice daily for 21 days. A subsequent test for CMV deoxyribonucleic acid polymerase chain was negative. Hematochezia resolved. A repeat colonoscopy revealed normal mucosa in the cecum. GI CMV infections in immunocompetent patients are rare and typically occur in older patients with medical comorbidities. Further, such case reports are needed to inform clinicians about risk factors and the presentation of GI CMV infections in young healthy immunocompetent patients.

Complementary and Alternative Medicine Use in First-time and Recurrent Kidney Stone Formers.

OBJECTIVE: To describe the patterns of complementary and alternative medicine (CAM) among patients with kidney stones and analyze the alkali content of commonly used CAM therapies. METHODS: We prospectively conducted structured interviews with patients who presented to a specialty stone clinic for the management of kidney stones. Open-ended questions were used to elicit information regarding CAM knowledge, formulation/dosing, and patterns of use. Several common CAM therapies were then analyzed for their alkali, organic anion, and sugar content. RESULTS: Of 103 subjects, 82 (80%) patients reported knowledge of CAM and 52 (50%) reported using CAM. Patients with recurrent kidney stones were more likely to report using CAM than patients with first-time episodes (56% vs 26%, P = 0.04). Some respondents reported their condition decreased in severity or frequency since starting CAM therapy (17%) and improvements in pain (12%). Total alkali content per serving of the tested supplements was 0 mEq (Stonebreaker), 1.5 mEq (Ocean Spray Cranberry Juice Cocktail), 4.7 mEq (Lakewood Pure Cranberry Juice), 0.6 mEq (Braggs Apple Cider Vinegar), 11.9 mEq (LithoBalance), 9.5 mEq (Simply Grapefruit Juice), 19.8 mEq (KSP-Key Lime), and 20.2 mEq (KSP-Very Berry). CONCLUSION: Patients with kidney stones may use CAM to alleviate symptoms or prevent recurrence. Commercially available CAM therapies may contain comparable alkali content to commonly prescribed citrate therapy. These data suggest that providers should be prepared to discuss the role of CAM with their patients.