Paradoxical Neurobehavioral Rescue by Memories of Early-Life Abuse: The Safety Signal Value of Odors Learned during Abusive Attachment

Caregiver-associated cues, including those learned in abusive attachment, provide a sense of safety and security to the child. Here, we explore how cues associated with abusive attachment, such as maternal odor, can modify the enduring neurobehavioral effects of early-life abuse. Two early-life abuse models were used: a naturalistic paradigm, where rat pups were reared by an abusive mother; and a more controlled paradigm, where pups underwent peppermint odor-shock conditioning that produces an artificial maternal odor through engagement of the attachment circuit. Animals were tested for maternal odor preference in infancy, forced swim test (FST), social behavior, and sexual motivation in adulthood—in the presence or absence of maternal odors (natural or peppermint). Amygdala odor-evoked local field potentials (LFPs) via wireless electrodes were also examined in response to the maternal odors in adulthood. Both early-life abuse models induced preference for the maternal odors in infancy. In adulthood, these early-life abuse models produced FST deficits and decreased social behavior, but did not change sexual motivation. Presentation of the maternal odors rescued FST and social behavior deficits induced by early-life abuse and enhanced sexual motivation in all animals. In addition, amygdala LFPs from both abuse animal models showed unique activation within the gamma frequency (70–90 Hz) bands in response to the specific maternal odor present during early-life abuse. These results suggest that attachment-related cues learned during infancy have a profound ability to rescue neurobehavioral dysregulation caused by early-life abuse. Paradoxically, abuse-associated cues seem to acquire powerful and enduring antidepressive properties and alter amygdala modulation.     

Academic detailing to improve antihypertensive prescribing patterns

Several studies indicate that treatment of hypertension in the United States does not follow recommendations from expert bodies. We thus implemented a program using academic detailers to increase practitioner compliance with antihypertensive treatment guidelines. Five Veterans Affairs medical facilities including academic medical centers and community based outpatient clinics were chosen for the intervention. Pharmacists were trained as academic detailers, and the intervention included lectures, educational materials, provider profiling, and meetings with 25 to 50 providers each. After intervention, the proportion of hypertensives receiving calcium antagonists decreased from 43% to 38% (P <.001), whereas the proportion receiving a beta blocker or thiazide diuretic increased from 58% to 64% (P <.001). For hypertensive subjects with diabetes mellitus or congestive heart failure, the proportion receiving an angiotensin converting enzyme inhibitor or angiotensin receptor blocker increased from 72% to 76% for the former and from 74% to 78% for the latter (P <.001 for both). Among hypertensive subjects with coronary artery disease an increase in beta blocker use was noted after intervention (P <.001 for change from baseline). Prescribing patterns after academic detailing more closely followed national recommendations.     

The BiZiFED project: Biofortified zinc flour to eliminate deficiency in Pakistan

Zinc deficiency is a global public health problem, affecting ~17% of the world's population, with the greatest burden in low‐ and middle‐income countries. An increasing body of evidence suggests that biofortification may be a cost‐effective and sustainable approach to reducing zinc and other micronutrient deficiencies. Biofortification enhances the nutritional quality of food crops through conventional plant breeding techniques and agronomic practices. This paper presents ongoing research on biofortification in Pakistan, where over 40% of women are zinc deficient. The Biofortified Zinc Flour to Eliminate Deficiency (BiZiFED) project aims to investigate the impact of biofortification as a strategy to alleviate zinc deficiency in Pakistan. The project is supported by the Biotechnology and Biological Sciences Research Council (BBSRC) Global Challenges Research Fund from May 2017 to April 2019. This paper outlines the four objectives and work packages within the BiZiFED project: (1) a double‐blind, randomised controlled trial to examine the effect of consuming flour made from a high zinc variety of biofortified wheat (Zincol‐2016/NR‐421) on dietary zinc intake and status; (2) a cost‐effectiveness study to assess the health and economic impact of agronomic biofortification of wheat; (3) a mixed methods study to explore the cultural acceptability and sustainability of biofortification in Pakistan; (4) capacity building and development of long‐term research partnerships in Pakistan. The findings will contribute to the evidence base for the potential impact of biofortification to alleviate zinc deficiency among the poorest communities.     

Fundamentals of cone beam computed tomography for a prosthodontist

Cone beam computed tomography (CBCT, also referred to as C-arm computed tomography [CT], cone beam volume CT, or flat panel CT) is a medical imaging technique of X-ray CT where the X-rays are divergent, forming a cone.[1] CBCT systems have been designed for imaging hard tissues of the maxillofacial region. CBCT is capable of providing sub-millimeter resolution in images of high diagnostic quality, with short scanning times (10–70 s) and radiation dosages reportedly up to 15–100 times lower than those of conventional CT scans. Increasing availability of this technology provides the dental clinician with an imaging modality capable of providing a three-dimensional representation of the maxillofacial skeleton with minimal distortion. The aim of this article is to sensitize the Prosthodontist to CBCT technology, provide an overview of currently available maxillofacial CBCT systems and review the specific application of various CBCT display modes to clinical Prosthodontic practice. A MEDLINE search for relevant articles in this specific area of interest was conducted. The selected articles were critically reviewed and the data acquired were systematically compiled.Key Words: Artefact reduction, cone beam computed tomography, dose reduction, fundamentals, imaging accuracy, prosthodontics     

Evaluation of noncytotoxic DNMT1-depleting therapy in patients with myelodysplastic syndromes

BACKGROUND. Mutational inactivation in cancer of key apoptotic pathway components, such as TP53/p53, undermines cytotoxic therapies that aim to increase apoptosis. Accordingly, TP53 mutations are reproducibly associated with poor treatment outcomes. Moreover, cytotoxic treatments destroy normal stem cells with intact p53 systems, a problem especially for myeloid neoplasms, as these cells reverse the low blood counts that cause morbidity and death. Preclinical studies suggest that noncytotoxic concentrations of the DNA methyltransferase 1 (DNMT1) inhibitor decitabine produce p53-independent cell-cycle exits by reversing aberrant epigenetic repression of proliferation-terminating (MYC-antagonizing) differentiation genes in cancer cells.METHODS. In this clinical trial, patients with myelodysplastic syndrome (n = 25) received reduced decitabine dosages (0.1–0.2 mg/kg/day compared with the FDA-approved 20–45 mg/m²/day dosage, a 75%–90% reduction) to avoid cytotoxicity. These well-tolerated doses were frequently administered 1–3 days per week, instead of pulse cycled for 3 to 5 days over a 4- to 6-week period, to increase the probability that cancer S-phase entries would coincide with drug exposure, which is required for S-phase–dependent DNMT1 depletion.RESULTS. The median subject age was 73 years (range, 46–85 years), 9 subjects had relapsed disease or were refractory to 5-azacytidine and/or lenalidomide, and 3 had received intensive chemoradiation to treat other cancers. Adverse events were related to neutropenia present at baseline: neutropenic fever (13 of 25 subjects) and septic death (1 of 25 subjects). Blood count improvements meeting the International Working Group criteria for response occurred in 11 of 25 (44%) subjects and were highly durable. Treatment-induced freedom from transfusion lasted a median of 1,025 days (range, 186–1,152 days; 3 ongoing), and 20% of subjects were treated for more than 3 years. Mutations and/or deletions of key apoptosis genes were frequent (present in 55% of responders and in 36% of nonresponders). Noncytotoxic DNMT1 depletion was confirmed by serial BM γ-H2AX (DNA repair/damage marker) and DNMT1 analyses. MYC master oncoprotein levels were markedly decreased.CONCLUSION. Decitabine regimens can be redesigned to minimize cytotoxicity and increase exposure time for DNMT1 depletion, to safely and effectively circumvent mutational apoptotic defects.TRIAL REGISTRATION. Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01165996","term_id":"NCT01165996"}}NCT01165996.FUNDING. NIH (R01CA138858, {"type":"entrez-nucleotide","attrs":{"text":"CA043703","term_id":"24344623","term_text":"CA043703"}}CA043703); Department of Defense (PR081404); Clinical and Translational Science Award (CTSA) (UL1RR024989); and the Leukemia and Lymphoma Society (Translational Research Program).     

Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow

Production of the cells that ultimately populate the thymus to generate α/β T cells has been controversial, and their molecular drivers remain undefined. Here, we report that specific deletion of bone-producing osteocalcin (Ocn)-expressing cells in vivo markedly reduces T-competent progenitors and thymus-homing receptor expression among bone marrow hematopoietic cells. Decreased intrathymic T cell precursors and decreased generation of mature T cells occurred despite normal thymic function. The Notch ligand DLL4 is abundantly expressed on bone marrow Ocn⁺ cells, and selective depletion of DLL4 from these cells recapitulated the thymopoietic abnormality. These data indicate that specific mesenchymal cells in bone marrow provide key molecular drivers enforcing thymus-seeding progenitor generation and thereby directly link skeletal biology to the production of T cell–based adaptive immunity.Bone mesenchymal cells are central participants in hematopoiesis, providing niches regulating stem and progenitor cells. Lymphopoiesis depends on tissues outside the bone marrow for terminal maturation, but antigen-independent specification of lymphoid lineages is hypothesized to occur in bone marrow. B cell generation has been definitively shown to involve osteolineage cells, whereas T cell generation remains controversial (Visnjic et al., 2004; Zhu et al., 2007; Wu et al., 2008). Deletion of CXCL12 in early osteolineage cells decreased B cell progenitors, whereas deletion of osteocytes produced dramatic metabolic changes, primary damage to thymus, and decreased B and T cell generation through an undefined molecular mechanism (Ding and Morrison, 2013; Greenbaum et al., 2013; Sato et al., 2013). Co-culture of hematopoietic progenitors with bone marrow stroma cells overexpressing Notch ligands enabled T cell lineage generation in vitro (Holmes and Zúñiga-Pflücker, 2009), but whether this recapitulates in vivo events in the bone marrow microenvironment is unclear (Uhmann et al., 2011).The details of the prethymic process are of increasing interest given that early thymic progenitors may serve as a limiting substrate in immune reconstitution after transplant (Zlotoff et al., 2011). It has been shown that providing ex vivo generated human pro–T cells improved T cell reconstitution, thymic architecture, and immunological competence in immunodeficient mice (Zakrzewski et al., 2006; Awong et al., 2013). Therefore, understanding and modulating the production of bone marrow–derived cells that can populate the thymus may have practical consequences in medicine.     

Inhibition of UDP‐glucosylceramide synthase in mice prevents Gaucher disease‐associated B‐cell malignancy

Clonal B‐cell proliferation is a frequent manifestation of Gaucher disease – a sphingolipidosis associated with a high risk of multiple myeloma and non‐Hodgkin lymphoma. Gaucher disease is caused by genetic deficiency of acid β‐glucosidase, the natural substrates of which (β‐d ‐glucosylceramide and β‐d ‐glucosylsphingosine) accumulate, principally in macrophages. Mice with inducible deficiency of β‐glucosidase [Gba(tm1Karl/tm1Karl)Tg(MX1‐cre)1Cgn/0] serve as an authentic model of human Gaucher disease; we have recently reported clonal B‐cell proliferation accompanied by monoclonal serum paraproteins and cognate tumours in these animals. To explore the relationship between B‐cell malignancy and the biochemical defect, we treated Gaucher mice with eliglustat tartrate (GENZ 112638), a potent and selective inhibitor of the first committed step in glycosphingolipid biosynthesis. Twenty‐two Gaucher mice received 300 mg/kg of GENZ 112638 daily for 3–10 months from 6 weeks of age. Plasma concentrations of β‐d ‐glucosylceramide and the unacylated glycosphingolipid, β‐d ‐glucosylsphingosine, declined. After administration of GENZ 112638 to Gaucher mice for 3–10 months, serum paraproteins were not detected and there was a striking reduction in the malignant lymphoproliferation: neither lymphomas nor plasmacytomas were found in animals that had received the investigational agent. In contrast, 14 out of 60 Gaucher mice without GENZ 112638 treatment developed these tumours; monoclonal paraproteins were detected in plasma from 18 of the 44 age‐matched mice with Gaucher disease that had not received GENZ 112638. Long‐term inhibition of glycosphingolipid biosynthesis suppresses the development of spontaneous B‐cell lymphoma and myeloma in Gaucher mice. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Performance of an Early Infant Diagnostic Test,AmpliSens DNA-HIV-FRT,Using Dried Blood Spots Collected from Children Born to Human Immunodeficiency Virus-Infected Mothers in Ukraine

An accurate accessible test for early infant diagnosis (EID) is crucial for identifying HIV-infected infants and linking them to treatment. To improve EID services in Ukraine, dried blood spot (DBS) samples obtained from 237 HIV-exposed children (≤18 months of age) in six regions in Ukraine in 2012 to 2013 were tested with the AmpliSens DNA-HIV-FRT assay, the Roche COBAS AmpliPrep/COBAS TaqMan (CAP/CTM) HIV-1 Qual test, and the Abbott RealTime HIV-1 Qualitative assay. In comparison with the paired whole-blood results generated from AmpliSens testing at the oblast HIV reference laboratories in Ukraine, the sensitivity was 0.99 (95% confidence interval [CI], 0.95 to 1.00) for the AmpliSens and Roche CAP/CTM Qual assays and 0.96 (95% CI, 0.90 to 0.98) for the Abbott Qualitative assay. The specificity was 1.00 (95% CI, 0.97 to 1.00) for the AmpliSens and Abbott Qualitative assays and 0.99 (95% CI, 0.96 to 1.00) for the Roche CAP/CTM Qual assay. McNemar analysis indicated that the proportions of positive results for the tests were not significantly different (P > 0.05). Cohen''s kappa (0.97 to 0.99) indicated almost perfect agreement among the three tests. These results indicated that the AmpliSens DBS and whole-blood tests performed equally well and were comparable to the two commercially available EID tests. More importantly, the performance characteristics of the AmpliSens DBS test meets the World Health Organization EID test requirements; implementing AmpliSens DBS testing might improve EID services in resource-limited settings.