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The all-trans-retinoic acid (atRA) hydroxylase Cyp26a1 is essential for embryonic development and may play a key role in regulating atRA clearance also in adults. We hypothesized that loss of Cyp26a1 activity via inducible knockout in juvenile or adult mice would result in decreased atRA clearance and increased tissue atRA concentrations and atRA-related adverse effects. To test these hypotheses, Cyp26a1 was knocked out in juvenile and adult male and female Cyp26a1 floxed mice using standard Cre–Lox technology and tamoxifen injections. Biochemical and histological methods were used to study the effects of global Cyp26a1 knockout. The Cyp26a1 knockout did not result in consistent histopathological changes in any major organs. Cyp26a1(−/−) mice gained weight normally and exhibited no adverse phenotypes for up to 1 year after loss of Cyp26a1 expression. Similarly, atRA concentrations were not increased in the liver, testes, spleen, or serum of these mice, and the Cyp26a1 knockout did not cause compensatory induction of lecithin:retinol acetyltransferase (Lrat) or retinol dehydrogenase 11 (Rdh11) mRNA or a decrease in aldehyde dehydrogenase 1a1 (Aldh1a1) mRNA in the liver compared with tamoxifen-treated controls. However, the Cyp26a1(−/−) mice showed increased bone marrow cellularity and decreased frequency of erythroid progenitor cells in the bone marrow consistent with a retinoid-induced myeloid skewing of hematopoiesis. In addition, the Cyp26a1 knockout decreased clearance of exogenous atRA by 70% and increased atRA half-life 6-fold. These findings demonstrate that despite lacking a major impact on endogenous atRA signaling, Cyp26a1 critically contributes as a barrier for exogenous atRA exposure.

Subsets of non-acute promyelocytic leukemia (APL) acute myelogenous leukemia (AML) exhibit aberrant retinoid signaling and demonstrate sensitivity to retinoids in vitro. We present the results of a phase 1 dose-escalation study that evaluated the safety, pharmacodynamics, and efficacy of IRX195183, a novel retinoic acid receptor α agonist, in patients with relapsed or refractory myelodysplastic syndrome (MDS) or AML. In this single center, single arm study, eleven patients with relapsed or refractory MDS/AML were enrolled and treated. Oral IRX195183 was administered at two dose levels: 50 mg daily or 75 mg daily for a total of two 28-day cycles. Patients with stable disease or better were allowed to continue on the drug for four additional 28-day cycles. Common adverse events included hypertriglyceridemia, fatigue, dyspnea, and edema. Three patients at the first dose level developed asymptomatic Grade 3 hypertriglyceridemia. The maximally tolerated dose was not reached. Four of the eleven patients had (36%) stable disease or better. One had a morphological complete remission with incomplete hematologic recovery while on the study drug. Two patients had evidence of in vivo leukemic blast maturation, as reflected by increased CD38 expression. In a pharmacodynamics study, plasma samples from four patients treated at the lowest dose level demonstrated the capacity to differentiate leukemic cells from the NB4 cell line in vitro. These results suggest that IRX195183 is safe, achieves biologically meaningful plasma concentrations and may be efficacious in a subset of patients with MDS/AML. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02749708.

All-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule in all chordates. Global knockouts of the atRA clearing enzymes Cyp26a1 or Cyp26b1 are embryonic lethal. In adult rodents, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, postnatal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA clearing Cyp in postnatal mammals. This hypothesis was tested by generating tamoxifen-inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis, and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T lymphocytes into the skin and hyperkeratosis/hyperplasia of the nonglandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also had a reduced lifespan, failed to gain weight, and showed fat atrophy. There were significant changes in vitamin A homeostasis. Postnatal knockout of Cyp26b1 resulted in increased atRA concentrations in the skin while the postnatal knockout of both Cyp26a1 and Cyp26b1 resulted in increased atRA concentrations in the liver, serum, skin, spleen, and intestines. This study demonstrates the paramount role of Cyp26b1 in regulating retinoid homeostasis in postnatal life.

Despite the decreased incidence of human immunodeficiency virus (HIV)-associated nephropathy due to the widespread use of combined active antiretroviral therapy, it remains one of the leading causes of end-stage renal disease (ESRD) in HIV-1 seropositive patients. Patients usually present with low CD4 count, high viral load and heavy proteinuria, with the pathologic findings of collapsing focal segmental glomerulosclerosis. Increased susceptibility exists in individuals with African descent, largely due to polymorphism in APOL1 gene. Other clinical risk factors include high viral load and low CD4 count. Advanced kidney disease and nephrotic range proteinuria have been associated with progression to ESRD. Improvement in kidney function has been observed after initiation of combined active antiretroviral therapy. Other treatment options, when clinically indicated, are inhibition of the renin-angiotensin system and corticosteroids. Further routine management approaches for patients with chronic kidney disease should be implemented. In patients with progression to ESRD, kidney transplant should be pursued, provided that viral load control is adequate. Screening for the presence of kidney disease upon detection of HIV-1 seropositivity in high-risk populations is recommended.

This is a case report of an HIV positive patient who was successfully treated with trimethoprim-sulfamethoxazole (TMP-SMX) for pulmonary nocardiosis in the setting of acute renal failure. TMP-SMX has been considered a mainstay of nocardiosis treatment for many years, although its use has traditionally been limited in the context of renal impairment. Alternative regimens have been shown to be effective in many cases of nocardiosis, although in our patient who developed acute kidney failure requiring dialysis his clinical status did not improve with other therapies. TMP-SMX ultimately was shown to be the most effective treatment and despite its risk of renal toxicity, the patient recovered renal function. This case also highlights the importance of early and aggressive treatment of nocardiosis to prevent invasive disease in immunocompromised individuals.

A plethora of socioenvironmental issues, and growing concerns over the effects of climate change, are forcing cities to rethink conventional urban water management practices. However, change towards more sustainable practices has been remarkably slow. This paper examines two cases of greening projects aimed at urban rehabilitation in Stockholm and Barcelona, which have turned into examples of innovative approaches to urban rain management. Both cities share high densities and flooding problems in certain neighborhoods. Specifically, the paper attempts to answer three questions: 1) what were the driving forces and key factors that facilitated the breakthrough of urban rainwater-harvesting (URH) schemes based on the two cases?; 2) who were the actors involved and what were their roles in moving towards URH schemes?; and 3) how can URH schemes become part of multifunctional, sustainable urban systems? To answer these questions, the paper uses concepts of adaptive context and capacity, and of actor agency, drawn from the transitions literature, and opportunistic and guided flexibility planning drawn from the planning literature. Empirical material for both case studies was obtained from policy documents and semi-structured interviews with key actors. The main results show first political support for flexibility in public planning, the adaptive context and the capacity of the actors, especially in taking advantage of windows of opportunity for the materialisation of new ideas. Second, the design and implementation of these systems widened the number and scope of actors in urban water management, incorporating new professionals such as architects and involving more city agencies and organizations. Third, small scale URH systems contributed not only to control urban drainage but performed other functions such as the much-needed greening of dense areas in both cities.

Introduction: The epidemiology of Clostridium difficile infection (CDI) has changed in the last two decades. There is a lack of information regarding incidence and severity of CDI, especially in the developing world. Methods: This was a retrospective and observational study from four hospitals of three Mexican cities. Patients were diagnosed with CDI when presented with loose stools and had at least one of the following tests positive: toxins assay, real-time PCR, or an endoscopic image compatible with pseudomembranous colitis. CDI was classified according to international guidelines. Demographic and clinical data as well as information regarding total hospital admissions, total length-of-hospital stay, and other variables related to hospitalization were gathered from the epidemiology and administration departments of each hospital. Results: A total of 2050 hospital beds were analyzed with 288,171 patients hospitalized accumulating 1,576,446 days of hospitalization during the study period. The average rate of CDI per 1000 hospital-days was lower than the rates reported in the US and Europe, although in 2015 CDI rates were almost persistently above the mean rate for the study period. More than half of PCR positive patients were ribotype 027. Conclusion: Hospital rates of CDI are increasing in Mexican hospitals with a predominance of infections caused by ribotype 027. Keywords: Clostridium difficile, Hospital acquired infections, Hospital diarrhea, Infection rates

Hematopoietic stem cells (HSCs) reside in a complex microenvironment that enforces the balance between self-renewal and differentiation. The exact physiologic mechanisms by which the niche controls HSC fate remain elusive. Retinoic acid (RA) is a powerful morphogen that controls stem cell behavior across a variety of systems. In bone marrow (BM), mesenchymal stroma cells (MSCs) express cytochrome P450 (CYP)26 enzymes and can inactivate endogenous and pharmacological retinoids (Ghiaur G et al PNAS 2013, Su M et al. PlosOne 2015, Alonso S et al. 2016). Stromal CYP26 activity is required to maintain human HSCs ex vivo (Ghiaur G et al PNAS 2013). Here we set to study the role of CYP26 in HSC homeostasis in vivo. For this, we induced CYP26 knockout via injection of Tamoxifen in ROSA26CreERT CYP26A1loxP/loxPCYP26B1loxP/loxPmice (CYP26KO) and ROSA26CreERT wildtype mice (CTR). After 5 daily tamoxifen injections, the knockout was confirmed at DNA and RNA level in multiple tissues of CYP26KO mice. Within 4 weeks, CYP26KO mice showed profound leukocytosis (5.97 ±0.37 vs. 21.12 ±3.81 k/mm3, n=4, p Figure. Figure. Disclosures No relevant conflicts of interest to declare.