bluuebunny/crossref_metadata_2025 huggingface dataset:
Ionized Intracellular Calcium Concentration Predicts Excitotoxic Neuronal Death: Observations with Low-Affinity Fluorescent Calcium Indicators
Authors: Hyrc Krzysztof , Handran Shawn D. , Rothman Steven M. , Goldberg Mark P.
Published: April 2018

Cytosolic calcium ([Ca2+]i) is an important mediator of neuronal signal transduction, participating in diverse biochemical reactions that elicit changes in synaptic efficacy, metabolic rate, and gene transcription. Excessive [Ca2+]ialso has been implicated as a cause of acute neuronal injury, although measurement of [Ca2+]iin living neurons by fluorescent calcium indicators has not consistently demonstrated a correlation between [Ca2+]iand the likelihood of neuronal death after a variety of potentially lethal insults. Using fluorescence videomicroscopy and microinjected calcium indicators, we measured [Ca2+]iin cultured cortical neurons during intense activation with either NMDA (300 μm) or AMPA (450 μm). At these concentrations NMDA killed >80% of the cultured neurons by the next day, whereas neuronal death from AMPA was <20%. Using the conventional calcium indicator, fura-2/AM, we estimated [Ca2+]ielevations to be ∼300–400 nmduring exposure to either glutamate agonist. In contrast, indicators with lower affinity for calcium, benzothiazole coumarin (BTC), and fura-2/dextran reported [Ca2+]ilevels >5 μmduring lethal NMDA exposure, but [Ca2+]ilevels were <1.5 μmduring nonlethal activation of AMPA receptors or voltage-gated calcium channels. Fura-2 reported [Ca2+]iresponses during brief exposure to glutamate, NMDA, AMPA, kainate, and elevated extracellular K+between 0.5 and 1 μm. With the use of BTC, only NMDA and glutamate exposures resulted in micromolar [Ca2+]ilevels. Neurotoxic glutamate receptor activation is associated with sustained, micromolar [Ca2+]ielevation. The widely used calcium indicator fura-2 selectively underestimates [Ca2+]i, depending on the route of entry, even at levels that appear to be within its range of detection.
Serotonergic Inhibition of the T-Type and High Voltage-Activated Ca2+Currents in the Primary Sensory Neurons ofXenopusLarvae
Authors: Sun Qian-Quan , Dale Nicholas
Published: April 2018

The primary sensory Rohon–Beard (R–B) neurons ofXenopuslarvae are highly analogous to the C fibers of the mammalian pain pathway. We explored the actions of 5-HT by studying the modulation of Ca2+currents. In ∼80% of the acutely isolated R–B neurons, 5-HT inhibited the high voltage-activated (HVA) currents by 16% (n= 29) and the T-type currents by 24% (n= 41). The modulation of the T-type and the HVA currents was mimicked by selective 5-HT1Aand 5-HT1Dagonists: 8-OH-DPAT and L-694,247. The effects of the agonists were blocked by their respective 5-HT1Aor 5-HT1Dantagonists:p-MPPI and GR127935, suggesting that both 5-HT1Aand 5-HT1Dreceptors were involved. Approximately 70% of the actions of 5-HT on HVA currents was occluded by ω-conotoxin-GVIA (N-type channel blocker), whereas the rest of the modulation (∼30%) was occluded by <100 nmω-agatoxin-TK (P/Q-type channel blocker). This suggests that 5-HT acts on N- and P/Q-type Ca2+channels. Neither the modulation of the T-type nor that of the HVA currents was accompanied by changes in their voltage-dependent kinetics. Cell-attached patch-clamp recordings suggest that the modulation of the T-type channel occurs through a membrane-delimited second messenger. We have studied the functional consequences of the modulation of T-type Ca2+channels and have found that these channels play a role in spike initiation in R–B neurons. Modulation of T-type channels by 5-HT therefore could modulate the sensitivity of this sensory pathway by increasing the thresholds of R–B neurons. This is a new and potentially important locus for modulation of sensory pathways in vertebrates.
NAC-1, a Rat Brain mRNA, Is Increased in the Nucleus Accumbens Three Weeks after Chronic Cocaine Self-Administration
Authors: Cha Xian-Yuan , Pierce R. Christopher , Kalivas Peter W. , Mackler Scott A.
Published: April 2018

Chronic cocaine use leads to biochemical and behavioral changes that can persist for weeks to months after drug administration is discontinued. Alterations in gene expression in the mammalian CNS may contribute to these long-term neural consequences of cocaine abuse. A combinedin situtranscription–PCR amplification strategy was used to isolate a novel mRNA, NAC-1, from the nucleus accumbens of rats 3 weeks after discontinuing 3 weeks of intravenous cocaine self-administration. In rats that self-administered cocaine, levels of NAC-1 were increased ∼50% in the nucleus accumbens but not in the dorsal striatum or hippocampus, when compared with levels from yoked-saline controls.In situhybridization analysis demonstrated increased numbers of NAC-1-expressing cells in the nucleus accumbens of rats who had self-administered cocaine. NAC-1 mRNA exists as one form, ∼4400 nucleotides (nt) in size, and also is present at much lower amounts in non-neural tissues. A full-length cDNA clone was isolated from a whole brain library. The predicted polypeptide sequence contains a POZ domain in the first 120 amino acids; the same POZ domain sequence mediates protein–protein interactions among some transcriptional regulators. NAC-1 mRNA levels were also increased in the nucleus accumbens 1 week after 6 d of noncontingent cocaine treatments. Regulation of NAC-1 mRNA in the nucleus accumbens demonstrates a long-term effect of cocaine use on cellular function that may be relevant in behavioral sensitization or cocaine self-administration.
Dissection of Functional Domains of the Voltage-Dependent Ca2+Channel α2δ Subunit
Authors: Felix Ricardo , Gurnett Christina A. , De Waard Michel , Campbell Kevin P.
Published: April 2018

Coexpression of the cloned voltage-dependent Ca2+channel α2δ subunit with the pore-forming α1subunit results in a significant increase in macroscopic current amplitude. To gain insight into the mechanism underlying this interaction, we have examined the regulatory effect of either the α2δ complex or the δ subunit on the Ca2+channel α1subunit. Transient transfection of tsA201 cells with the cardiac L-type α1Csubunit alone resulted in the expression of inward voltage-activated currents as well as measurable [3H]-PN200-110 binding to membranes from transfected cells. Coexpression of the α2δ subunit significantly increased the macroscopic current amplitude, altered the voltage dependence and the kinetics of the current, and enhanced [3H]-PN200-110 binding. Except for the increase in amplitude, coexpression of the δ subunit reproduced entirely the effects of the full-length α2δ subunit on the biophysical properties of the α1Ccurrents. However, no effect on specific [3H]-PN200-110 binding was observed on δ subunit coexpression. Likewise, profound effects on current kinetics of the neuronal α1Asubunit were observed on coexpression of the α2δ complex inXenopusoocytes. Furthermore, by using a chimeric strategy, we localized the region involved in this regulation to the transmembrane domain of the δ subunit. These data strongly suggest that the molecular determinants involved in α2δ regulation are conserved across L-type and non-L type Ca2+channels. Taken together, our results indicate that the region of the α2δ subunit involved in the modulation of the gating properties of the high voltage-activated calcium channels is localized in the δ domain of the protein. In contrast, the level of membrane expression of functional channels relies on the presence of the α2domain of the α2δ complex.
The Dopamine Transporter: Comparative Ultrastructure of Dopaminergic Axons in Limbic and Motor Compartments of the Nucleus Accumbens
Authors: Nirenberg Melissa J. , Chan June , Pohorille Alicia , Vaughan Roxanne A. , Uhl George R. , Kuhar Michael J. , Pickel Virginia M.
Published: April 2018

The dopamine transporter (DAT) regulates extracellular dopamine concentrations, transports neurotoxins, and acts as a substrate for cocaine reinforcement. These functions are known to differ in the limbic-associated shell and motor-associated core compartments of the nucleus accumbens (NAc). Previous studies have shown differential expression of DAT in the NAc shell and core but were limited in resolution to the regional level. Thus, it is not known whether there are differences in the amount, subcellular localization, or plasmalemmal targeting of DAT within individual dopaminergic axons in the two regions. We used high-resolution electron microscopic immunocytochemistry to investigate these possibilities. We show that in both the shell and core, DAT immunogold labeling is present in tyrosine hydroxylase-immunoreactive varicose axons that form symmetric synapses. Within these labeled axons, most DAT gold particles are located on extrasynaptic plasma membranes, but some are associated with intracellular membranes. Dopaminergic axons in the shell contain lower mean densities of both total DAT gold particles (per square micron) and plasmalemmal DAT gold particles (per micron) than those in the core. Within labeled axons in the NAc shell and core, however, there are no detectable differences in the subcellullar distribution of DAT or the percentage of total DAT gold particles that are located on plasma membranes. These studies are the first to examine and compare the subcellular localization of DAT in the NAc shell and core. As a result, they identify intrinsic, cell-specific differences in the expression of DAT within dopaminergic axons in these functionally distinct striatal compartments.
Selective Expression of Insulin-Like Growth Factor II in the Songbird Brain
Authors: Holzenberger Martin , Jarvis Erich D. , Chong Christopher , Grossman Matthew , Nottebohm Fernando , Scharff Constance
Published: April 2018

Neuronal replacement occurs in the forebrain of juvenile and adult songbirds. To address the molecular processes that govern this replacement, we cloned the zebra finch insulin-like growth factor II (IGF-II) cDNA, a factor known to regulate neuronal development and survival in other systems, and examined its expression pattern byin situhybridization and immunocytochemistry in juvenile and adult songbird brains. The highest levels of IGF-II mRNA expression occurred in three nuclei of the song system: in the high vocal center (HVC), in the medial magnocellular nucleus of the neostriatum (mMAN), which projects to HVC, and to a lesser extent in the robust nucleus of the archistriatum (RA), which receives projections from HVC. IGF-II mRNA expression was developmentally regulated in zebra finches. In canary HVC, monthly changes in IGF-II mRNA expression covaried with previously reported monthly differences in neuron incorporation. Combining retrograde tracers within situhybridization and immunocytochemistry, we determined that the HVC neurons that project to area X synthesize the IGF-II mRNA, whereas the adjacent RA-projecting neurons accumulate the IGF-II peptide. Our findings raise the possibility that within HVC IGF-II acts as a paracrine signal between nonreplaceable area X-projecting neurons and replaceable RA-projecting neurons, a mode of action that is compatible with the involvement of IGF-II with the replacement of neurons. Additional roles for IGF-II expression in songbird brain are likely, because expression also occurs in some brain areas outside the song system, among them the cerebellar Purkinje cells in which neurogenesis is not known to occur.
Transgenic Mice Expressing the Intracellular Domain of the p75 Neurotrophin Receptor Undergo Neuronal Apoptosis
Authors: Majdan Marta , Lachance Christian , Gloster Andrew , Aloyz Raquel , Zeindler Christine , Bamji Shernaz , Bhakar Asha , Belliveau Daniel , Fawcett James , Miller Freda D. , Barker Philip A.
Published: April 2018

We have asked whether p75NTRmay play a role in neuronal apoptosis by producing transgenic mice that express the p75NTRintracellular domain within peripheral and central neurons. These animals showed profound reductions in numbers of sympathetic and peripheral sensory neurons as well as cell loss in the neocortex, where there is normally little or no p75NTRexpression. Developmental loss of facial motor neurons was not observed, but induced expression of the p75NTRintracellular domain within adult animals led to increased motor neuron death after axotomy. Biochemical analyses suggest that these effects were not attributable to a p75NTR-dependent reduction in trk activation but instead indicate that the p75NTRintracellular domain may act as a constitutive activator of signaling cascades that regulate apoptosis in both peripheral and central neurons.
Recalling Routes around London: Activation of the Right Hippocampus in Taxi Drivers
Authors: Maguire Eleanor A. , Frackowiak Richard S. J. , Frith Christopher D.
Published: April 2018

Functional imaging to date has examined the neural basis of knowledge of spatial layouts of large-scale environments typically in the context of episodic memory with specific spatiotemporal references. Much human behavior, however, takes place in very familiar environments in which knowledge of spatial layouts has entered the domain of general facts often referred to as semantic memory. In this study, positron emission tomography (PET) was used to examine the neural substrates of topographical memory retrieval in licensed London taxi drivers of many years experience while they recalled complex routes around the city. Compared with baseline and other nontopographical memory tasks, this resulted in activation of a network of brain regions, including the right hippocampus. Recall of famous landmarks for which subjects had no knowledge of their location within a spatial framework activated similar regions, except for the right hippocampus. This suggests that the hippocampus is involved in the processing of spatial layouts established over long time courses. The involvement of similar brain areas in routes and landmarks memory indicates that the topographical memory system may be primed to respond to any relevant topographical stimulation; however, the right hippocampus is recruited specifically for navigation in large-scale spatial environments. In contrast, nontopographical semantic memory retrieval involved the left inferior frontal gyrus, with no change in activity in medial temporal regions.
Sequence-Based Analysis of Lipid-Related Metabolites in a Multiethnic Study
Authors: Feofanova Elena V , Yu Bing , Metcalf Ginger A , Liu Xiaoming , Muzny Donna , Below Jennifer E , Wagenknecht Lynne E , Gibbs Richard A , Morrison Alanna C , Boerwinkle Eric
Published: April 2018

Small molecule lipid-related metabolites are important components of fatty acid and steroid metabolism—two important contributors to human health. This study investigated the extent to which rare and common genetic variants spanning the human genome influence the lipid-related metabolome. Sequence data from 1552 European-Americans (EA) and 1872 African-Americans (AA) were analyzed to examine the impact of common and rare variants on the levels of 102 circulating lipid-related metabolites measured by a combination of chromatography and mass spectroscopy. We conducted single variant tests [minor allele frequency (MAF) > 5%, statistical significance P-value ≤ 2.45 × 10−10] and tests aggregating rare variants (MAF ≤ 5%) across multiple genomic motifs, such as coding regions and regulatory domains, and sliding windows. Multiethnic meta-analyses detected 53 lipid-related metabolites-locus pairs, which were inspected for evidence of consistent signal between the two ethnic groups. Thirty-eight lipid-related metabolite-genomic region associations were consistent across ethnicities, among which seven were novel. The regions contain genes that are related to metabolite transport (SLC10A1) and metabolism (SCD, FDX1, UGT2B15, and FADS2). Six of the seven novel findings lie in expression quantitative trait loci affecting the expression levels of 14 surrounding genes in multiple tissues. Imputed expression levels of 10 of the affected genes were associated with four corresponding lipid-related traits in at least one tissue. Our findings offer valuable insight into circulating lipid-related metabolite regulation in a multiethnic population.
Genetic Control of Genomic Alterations Induced in Yeast by Interstitial Telomeric Sequences
Authors: Moore Anthony , Dominska Margaret , Greenwell Patricia , Aksenova Anna Y , Mirkin Sergei , Petes Thomas
Published: April 2018

In many organisms, telomeric sequences can be located internally on the chromosome in addition to their usual positions at the ends of the chromosome. In humans, such interstitial telomeric sequences (ITSs) are nonrandomly associated with translocation breakpoints in tumor cells and with chromosome fragile sites (regions of the chromosome that break in response to perturbed DNA replication). We previously showed that ITSs in yeast generated several different types of instability, including terminal inversions (recombination between the ITS and the “true” chromosome telomere) and point mutations in DNA sequences adjacent to the ITS. In the current study, we examine the genetic control of these events. We show that the terminal inversions occur by the single-strand annealing pathway of DNA repair following the formation of a double-stranded DNA break within the ITS. The point mutations induced by the ITS require the error-prone DNA polymerase ζ. Unlike the terminal inversions, these events are not initiated by a double-stranded DNA break, but likely result from the error-prone repair of a single-stranded DNA gap or recruitment of DNA polymerase ζ in the absence of DNA damage.
Increasing PCP and Hospital Medicine Physician Verbal Communication During Hospital Admissions
Authors: Zackoff Matthew W. , Graham Camille , Warrick Denise , Pulda Kathleen , Gosdin Craig , Simpson Blair , Marischen Jessica , Bunch Paul , Vossmeyer Michael , Mussman Grant M.
Published: April 2018

OBJECTIVES:

During hospital admission, communication between primary care physicians (PCPs) and hospital medicine (HM) physicians provides an opportunity for collaboration. Two-way communication facilitates collaboration by allowing the receiver to ask and respond to questions. At our institution, most HM-to-PCP communication occurred by telephone call after discharge. Our specific aim was to increase the percentage of patients for whom a telephone conversation occurred between HM and PCPs during hospital admission from 40% to >80%.

METHODS:

An improvement team that included PCPs and HM physicians redesigned the process for communication with PCPs to emphasize collaboration during hospitalization. Interventions were used to target key drivers of information transparency, PCP and HM provider buy-in, the value of early call initiation, process standardization, accommodating provider availability, and preoccupation with failure. We used improvement-science methods and run charts to measure our progress and attain our goal.

RESULTS:

The median weekly percentage of patients with a phone call completed during hospitalization increased from 40% to 85% at the satellite campus and 40% to 80% at the main campus. In addition to the standardized use of a telephone operator system to route calls and follow-up on unplaced calls, critical interventions included feedback on PCP call preferences to providers and the provider script for calls.

CONCLUSIONS:

PCPs and HM physicians applied quality-improvement methodology to ensure reliable HM-PCP communication during hospital admission. Interventions to facilitate communication between providers and learners (who may otherwise have limited interaction), such as the scripting of phone calls and feedback from PCPs to HM physicians, were important for success.
Medical Emergency Team Event Characteristics from an Australian Pediatric Hospital: A Single-Center, Retrospective Study
Authors: Martinez F. Eduardo , Kelty Erin , Barr Samantha , McLeod Monique , Smalley Nathan
Published: April 2018

OBJECTIVES:

To describe the characteristics of medical emergency team (MET) events at an Australian pediatric, tertiary-care center in a way that would allow for comparison with other MET systems.

METHODS:

A retrospective, single-center, observational study. Consecutive MET events that occurred between January 2013 and July 2014 at Princess Margaret Hospital for Children in Perth, Western Australia, were included.

RESULTS:

There were 46 445 hospital admissions during the study period and 197 MET events in children. This gives a rate of 4.2 MET events per 1000 admissions. Out of 197 pediatric MET events analyzed, there were 2 deaths (1.0%) that occurred during the MET events. All 197 patients were actively treated, with none receiving “do not attempt resuscitation” orders. Of pediatric MET events, 24% (48 of 197) were admitted to the PICU, and 75% (149 of 197) stayed in the ward where the call was made.

CONCLUSIONS:

In this tertiary-care, pediatric hospital in Australia, the MET event rate and the rate of admission to the PICU because of MET events are lower than those reported for US pediatric hospitals. Despite these differences, Australian data suggest that outcomes are similar to US pediatric hospitals.
Recalcitrant Atopic Keratoconjunctivitis in Children: A Case Report and Literature Review
Authors: Li Jing , Luo Xiaohui , Ke Hongmin , Liang Lingyi
Published: April 2018

Atopic keratoconjunctivitis (AKC) is the most severe type of allergic conjunctivitis and may eventually lead to blindness. Although AKC is reported to be more prevalent in adults, we report a child with AKC whose clinical characteristics were not inconsistent with those typically seen in adult patients with AKC, and who was refractory to traditional topical anti-inflammatory and immunosuppressant therapies. An 11-year-old boy presented with a 3-month history of ocular redness and itching and decreased vision for a week in both eyes. Slit-lamp examination revealed typical signs of vernal keratoconjunctivitis, including cobblestone papillae in both upper conjunctiva, superficial punctate keratopathy on the right cornea, and a sterile shield-shaped ulcer on the left cornea. Physical examination revealed eczematous lid changes and a generalized body rash, particularly on the face, neck, and flexor surfaces of the limbs. He was diagnosed to have AKC in both eyes and atopic dermatitis. The patient did not respond well to conventional topical antihistamine, mast cell stabilizers, corticosteroids, or tacrolimus, even in combination with amniotic membrane transplant. After using systemic immunosuppressants, the symptoms were relieved; the inflammation on the skin and ocular surface subsided, the cobblestone papillae disappeared, and the corneal ulcer healed gradually within 8 weeks. This case reveals that pediatric AKC should be differentiated from vernal keratoconjunctivitis because both disorders include upper cobblestone papillae, but the former is accompanied by atopic dermatitis. Pediatric AKC requires appropriate and aggressive treatment to prevent sight-threatening corneal complications. Systemic immunosuppressant should be considered when traditional topical anti-inflammatory therapies have failed.
Some Limitations for Early Diagnosis of Congenital Chagas Infection by PCR
Authors: Volta Bibiana Julieta , Perrone Alina Elizabet , Rivero Rocío , Scollo Karenina , Bustos Patricia Laura , Bua Jacqueline
Published: April 2018

Trypanosoma cruzi, the causing agent of Chagas disease, can be transmitted to the offspring of infected pregnant women, thus being an epidemiologically important way of parasite transmission in humans. In addition, the migration of infected women from endemic areas to nonendemic countries may export this parasite infection. The diagnosis of congenital Chagas disease relies on the detection of the parasite because maternal antibodies are passively transferred to infants during pregnancy. The diagnosis of congenital infection can also be confirmed by detection of infant-specific anti–T cruzi antibodies at 10 months after delivery. Because early detection of T cruzi infection in newborns allows an efficient trypanocidal treatment and cure, more sensitive molecular techniques such as DNA amplification are being used for a prompt parasitological diagnosis of children born to seropositive mothers. In this report, we describe a diagnosis case of a child congenitally infected with T cruzi who tested negative for parasite detection both by microscopic observation and DNA amplification at 20 days and 6 months after delivery. However, at 7 months of age, a hemoculture was made from the infant’s blood, and the infective parasite was finally isolated and classified as T cruzi discrete typing unit I. In a retrospective study, real-time polymerase chain reaction also allowed detecting the parasite but failed to detect any parasite load in earlier control samples. This case report stresses that even when molecular techniques are negative, a long-term follow-up is necessary for the diagnosis of infants congenitally infected with T cruzi.
The Medical Home and Health Care Transition for Youth With Autism
Authors: Rast Jessica E. , Shattuck Paul T. , Roux Anne M. , Anderson Kristy A. , Kuo Alice
Published: April 2018

BACKGROUND:

Our objective in this study was to describe the association between the receipt of health care transition services (HCTS) and having a medical home in youth with autism spectrum disorder (ASD). Youth with ASD receive HCTS less often than other youth with special health care needs but are in particular need of continuous, comprehensive health care.

METHODS:

We used the National Survey of Children with Special Health Care Needs to describe the receipt of HCTS in youth with ASD and its association with presence of a medical home. Descriptive statistics are presented, and logistic regression is used to assess the association between medical home and HCTS.

RESULTS:

Twenty-one percent of youth with ASD met the criteria for receiving HCTS. Youth with ASD and a medical home were almost 3 times as likely to receive HCTS as youth without a medical home, and youth who received family-centered care and have adequate care coordination within the medical home were more than twice as likely to receive HCTS as those who did not.

CONCLUSIONS:

Youth with ASD are not receiving HCTS at the same rate as their peers. Increasing provider awareness of autism, the components of a medical home, and of the importance of HCTS could greatly help increase the percentage of youth who receive effective HCTS.
A National Research Agenda for the Transition of Youth With Autism
Authors: Shattuck Paul T. , Lau Lynette , Anderson Kristy A. , Kuo Alice A.
Published: April 2018

In this article, we outline a national research agenda to improve the transition to adulthood among youth with autism. We synthesized the results from 5 interconnected sets of activities: (1) a scoping review of published autism research and research priority statements, (2) a series of key informant interviews with stakeholders, (3) a 2-day National Research Agenda meeting, (4) a modified Delphi survey of stakeholders, and (5) 2 formal reviews of published literature on autism and transition. We identified 2 overarching priorities to advance research about autism and transition: (1) increased focus on community- and systems-level factors that influence outcomes with population-level approaches to measuring outcomes and (2) greater involvement of people with autism in establishing research priorities, designing research studies, and producing study findings and recommendations. We discuss how the life course framework can guide future inquiry that addresses gaps in extant research.
Blue Diaper Syndrome and PCSK1 Mutations
Authors: Distelmaier Felix , Herebian Diran , Atasever Claudia , Beck-Woedl Stefanie , Mayatepek Ertan , Strom Tim M. , Haack Tobias B.
Published: April 2018

Blue diaper syndrome (BDS) (Online Mendelian Inheritance in Man number 211000) is an extremely rare disorder that was first described in 1964. The characteristic finding is a bluish discoloration of urine spots in the diapers of affected infants. Additional clinical features of the first described patients included diarrhea, inadequate weight gain, hypercalcemia, and nephrocalcinosis. An intestinal defect of tryptophan absorption was postulated as the underlying pathology. However, functional evidence for this theory is lacking. No genetic cause has been identified so far. Here, we report on a boy who presented with neonatal-onset diarrhea, metabolic acidosis, transient hepatopathy, recurrent hypoglycemia, and blue-stained urine spots in his diapers. An ultra-performance liquid chromatography–electrospray ionization–tandem mass spectrometry analysis of urine samples at different time points demonstrated the constant presence of indigo derivatives, thereby confirming the diagnosis of BDS. Of note, the visibility of indigo derivatives in the urine was highly dependent on the urine’s pH. To identify the underlying genetic cause of the disease, whole-exome sequencing was performed, leading to the identification of a homozygous frameshift mutation in proprotein convertase subtilisin/kexin type 1 (PCSK1; NM_000439.4: c.679del, p.[Val227Leufs*12]). PCSK1 encodes prohormone convertase 1/3, and mutations within this gene have been reported as a rare cause of early-onset malabsorptive diarrhea and multiple endocrine dysfunction. In our report, we suggest that BDS can be caused by PCSK1 mutations.
Pneumocystis Jirovecii Pneumonia During Sirolimus Therapy for Kaposiform Hemangioendothelioma
Authors: Russell Thomas B. , Rinker Emily K. , Dillingham Claire S. , Givner Laurence B. , McLean Thomas W.
Published: April 2018

Sirolimus is an effective therapy for children with kaposiform hemangioendothelioma with or without the Kasabach-Merritt phenomenon. We report the case of a child with kaposiform hemangioendothelioma and the Kasabach-Merritt phenomenon who developed Pneumocystis carinii pneumonia (PCP) while on sirolimus and a prednisolone taper, after lack of adequate response to prednisolone, propranolol, and vincristine. He had a prompt positive clinical and laboratory response to sirolimus, but 4 weeks after starting it, at the age of 4 months, he developed PCP. This led to respiratory failure, which required extracorporeal membrane oxygenation. Sirolimus was temporarily discontinued, and he was successfully treated for PCP with sulfamethoxazole-trimethoprim and methylprednisolone. He was restarted on sirolimus 3 weeks after discharge and given sulfamethoxazole-trimethoprim prophylaxis. At the age of 22 months, while still on sirolimus, the lesion continued to improve with test results revealing stable hemoglobin and platelet counts. PCP is a rare but life-threatening side effect of sirolimus therapy, especially in the setting of concurrent steroid treatment. Pneumocystis prophylaxis should be considered for patients receiving sirolimus.
A Novel Presentation of Littoral Cell Angioma and Lymphatic Malformations in a Neonate
Authors: Gakenheimer-Smith Lindsey , Mohlman Jeffrey , VandenHeuvel Kate , Jackson William Daniel , Thomsen William , Stevenson Adam , Cipriano Frank
Published: April 2018

This case report describes a novel presentation of littoral cell angioma (LCA) and lymphatic malformations involving the omentum and mesentery. To our knowledge, these 2 entities have not been reported in the same patient. A 1-month term infant male presented with chylous ascites. During his workup, imaging detected splenic nodules. Biopsies revealed that the nodules were LCA and the chylous ascites was secondary to microscopic mesenteric and omental lymphatic malformations. Evaluation for a secondary malignancy, an underlying immunologic defect, and genetic causes were unrevealing. The presence of LCA and lymphatic malformations in the same patient suggests a genetic link between these 2 rare vascular disorders and may help elucidate the etiopathogenesis of these 2 poorly understood anomalies.
El fenómeno de la percepción en Aristóteles y Merleau-Ponty
Authors: Honorato Diego
Published: April 2018

Se realiza un estudio comparativo del problema de la percepción en Aristóteles y Maurice Merleau-Ponty, considerando el marco antropológico en el que se inscriben sus propuestas. Se establecen sus posibles puntos de contacto y sus diferencias más importantes. Se presta especial atención al vínculo entre el acto senso-perceptual yel movimiento, así como al problema de la conciencia perceptual y a la cuestión de la actualidad común entre el sentiente y el sensible.
Opiniones sobre el debate entre William Duica y Ángela Uribe
Authors: Díaz Jorge Aurelio
Published: April 2018

He leído el artículo de William Duica titulado “Redescribirnos: una alternativa pragmatista a la imposibilidad del perdón”, así como la crítica de Ángela Uribe; lectura que me ha movido a “meter baza” en el asunto.
ANALISIS MULTILAYER VARIABILITAS UPWELLING DI PERAIRAN SELATAN JAWA
Authors: Sukresno Bambang , Jatisworo Denarika , Kusuma Denny Wijaya
Published: April 2018

Variabilitas upwelling di perairan selatan Jawa telah diidentifikasi. Analisis multilayer dilakukan dengan menggunakan data ARGO Float. Variabilitas suhu permukaan laut (SPL) dan klorofil-a (klor-a) dianalisis dengan menggunakan data satelit MODIS Aqua. Pengaruh El Nino Southern Oscillation (ENSO) terhadap upwelling dilakukan dengan menggunakan indeks Oceanic Nino Index (ONI), sedangkan pengaruh Indian Ocean Dipole (IOD) direpresentasikan dengan menggunakan indeks Dipole Mode Index (DMI). Dari hasil penelitian diketahui bahwa ENSO mempengaruhi intensitas upwelling. Pada periode el nino intensitas upwelling mengalami peningkatan yang diikuti oleh penurunan SPL dan naiknya konsentrasi klor-a, sebaliknya pada periode la nina terjadi penurunan intensitas upwelling yang diikuti naiknya SPL dan turunnya konsentrasi klor-a. Peningkatan intensitas upwelling juga terdeteksi pada saat terjadi periode IOD positif, sedangkan penurunan intensitas upwelling terjadi pada periode IOD negatif.
KARAKTERISTIK SEBARAN SEDIMEN PANTAI UTARA JAWA STUDI KASUS: KECAMATAN BREBES JAWA TENGAH
Authors: GEMILANG WISNU ARYA , RAHMAWAN GUNTUR ADHI , DHIAUDDIN RUZANA , WISHA ULUNG JANTAMA
Published: April 2018

Dinamika kawasan pesisir mencakup proses erosi dan sedimentasi merupakan hal penting untuk mengetahui kondisi pantai. Pesisir Kecamatan Brebes merupakan salah satu kawasan di Pantai Utara Pulau Jawa yang memiliki dinimika perubahan pesisir sangat kuat. Studi sebaran jenis sedimen yang dilakukan secara terpadu di perairan Kecamatan Brebes ditunjukkan untuk memberikan gambaran proses transportasi dan pengendapan sedimen berdasarkan distribusi ukuran butir sedimen. Penelitian dilakukan dengan pengambilan sampel sedimen dasar perairan secara acak dan tersebar di sepanjang pesisir dengan metode grab sampler, kemudian dilakukan analisis lebih lanjut dengan metode granulometri. Hasil penelitian menunjukkan bahwa secara umum, pola sebaran sedimen permukaan dasar laut Kec.Brebes didominasi oleh sedimen berukuran lempung-pasir. Jenis sedimen berdasarkan ukuran butirnya yaitu pasir, pasir lanauan, lanau pasiran dan lanau. Kondisi hidro-oseanografi yang fluktuatif memberikan nilai sortasi buruk hingga sedang, dominasi ukuran halus tersebar pada bagian Timur, sedangkan fraksi kasar tersebar dibagian Barat dekat dengan laut lepas.  Kondisi tersebut menjadikan salah satu faktor tererosinya bagian pesisir Kecamatan Brebes dengan dinamika hidro-oseanografi yang berubah-ubah.
PEMODELAN HIDRODINAMIKA DAN TRANSPOR SEDIMEN DI SEKITAR TANJUNG PONTANG, KABUPATEN SERANG – BANTEN
Authors: Prihantono Joko , Fajrianto Irfan Arif , Kurniadi Yessi Nirwana
Published: April 2018

Tanjung Pontang yang terletak di Provinsi Banten mengalami abrasi pantai dan kekeruhan yang cukup serius. Penelitian abrasi pantai ini telah dibuktikan oleh peneliti lain berdasarkan analisis perubahan garis pantai menggunakan citra satelit dengan tahun yang berbeda, namun penelitian dengan menggunakan pemodelan transpor sedimen belum pernah dilakukan di daerah tersebut. Pemodelan numerik hidrodinamika dan transpor sedimen menggunakan perangkat lunak MIKE 21 telah berhasil dilakukan pada penelitian ini untuk membuktikan proses abrasi dan kekeruhan di sekitar Tanjung Pontang. Hasil pemodelan hidrodinamika dengan parameter angin menunjukkan adanya arus sejajar garis pantai pada saat musim barat dan musim timur. Pada saat musim barat arus sejajar pantai di Tanjung Pontang dominan bergerak ke arah timur, sedangkan pada saat musim timur sebagian arus sejajar pantai di Tanjung Pontang bergerak ke arah timur, dan sebagian bergerak ke selatan menuju Teluk Banten. Selain itu analisis perubahan bed level menunjukkan adanya penurunan bed level yang mengindikasikan abrasi di sekitar Tanjung Pontang dan adanya sedimentasi di Sungai Ciujung Baru. Kekeruhan terjadi di sekitar Tanjung Pontang dan Teluk Banten disebabkan oleh karena adanya tingginya sedimen tersuspensi di Sungai Ciujung Lama dan terbawa oleh arus sejajar garis pantai di sekitar Tanjung Pontang.
ANALISIS RESIKO USAHA PABRIK PAKAN IKAN MANDIRI
Authors: Wardono Budi , Rahadian Rikrik , Tajerin Tajerin
Published: April 2018

Aspek keberlanjutan merupakan permasalahan utama dalam upaya pengembangan pabrik pakan ikan mandiri. Masih diperlukan berbagai upaya agar Program Gerakan Pakan Ikan Mandiri (GERPARI) mampu menjadi solusi kebutuhan pakan ikan. Analisis risiko merupakan salah satu upaya untuk mengetahui sejauh mana usaha pakan ikan mandiri dapat berkelanjutan. Tujuan penelitian untuk mengetahui tingkat risiko tentang keberlanjutan usaha dengan pendekatan NPV at risk. Penelitian dilakukan pada bulan Mei-Desember 2016, di pabrik pakan ikan di Kabupaten Sleman dan Gunungkidul, Propinsi Daerah Istimewa Yogyakarta. Data yang digunakan adalah data primer dan data sekunder. Data primer meliputi data usaha yaitu penyediaan bahan baku dan bahan lainnya, biaya produksi, pendapatan, sistem distribusi dan pemasaran pakan. Analisis yang digunakan adalah analisis risiko usaha dengan pendekatan NPV risk. Hasil analisis menunjukkan pada kondisi eksisting ternyata usaha pabrik pakan mandiri belum menguntungkan. Berdasarkan simulasi usaha pabrik pakan mandiri mampu memberikan keuntungan dengan syarat kontinuitas produksi dan bahan baku terpenuhi. Strategi yang dilakukan agar usaha memberikan margin positif dan NPV lebih besar dari 0, ialah menaikkan tingkat produksi dari 35% menjadi 50% dari kapasitas terpasang dan strategi kedua dengan menaikkan harga jual sebesar Rp. 500 menjadi Rp. 8.000/kg yang masih jauh dibawah harga pasaran Title: Risk Analysis of The Business Self-Sufficient Fish Feed PlantThe sustainability aspect is a major problem in the development of community-based selfsufficient fish feed plant. Various efforts are still necessary to make the self-sufficient fish feed movement program (Gerakan Pakan Ikan Mandiri/GERPARI) into a solution for the needs of fish feed. Risk analysis is one of the effort on measuring the sustainability of self-sufficient fish feed business. This research purpose was to identify the level of risk on business sustainability using the NPV at risk approach. The research was conducted in May-December 2016 at fish feed factory in Sleman and Gunungkidul regencies of Yogyakarta province. Primary and secondary data were used in this study. Primary data were in terms of raw and other materials supply, production costs, income, distribution system and marketing. Risk analysis with NPV risk approach was used in this study. Results of the study showed that fish feed business has not been profitable. Based on the simulation, self sufficient fish feed business is profitable provided that continuity of raw materials and days of production are fulfilled. Therefore, there are 2 strategies to provide positive margin and NPV greater than 0, first, increasing production rate from 35% to 50% of installed capacity, and second, increasing the selling price by Rp. 500 to Rp. 8,000/kgs which is still far below the market price.
Editorial: The development of health professional educators
Authors: Rogers Gary D.
Published: April 2018

This article was migrated. The article was marked as recommended. No abstract.
Medical Students’ Recognition and Response to Clinical Deterioration in Simulated Patient Scenarios
Authors: Alsaba Nemat , Brazil Victoria
Published: April 2018

This article was migrated. The article was not marked as recommended. IntroductionThe recognition and initial response of clinical teams to patients who suffer a deterioration in their condition is an essential capability of healthcare institutions. Simulation can provide some of this training, but creating appropriate 'cues' for recognising unwell patients can be challenging. We aimed to investigate how medical students recognise whether a patient is 'sick', and what they do in response to that recognition, using scenarios of clinically deteriorating simulated patients.MethodsSenior medical students at Bond University participating in simulation scenarios were invited to participate in this study. Scenarios were delivered with simulated patients (SPs). During the post simulation debrief and in subsequent interviews, students were asked questions related to their recognition of, and response to, sick 'patients' in their scenarios. Debriefing sessions involving the students were audio recorded and transcribed. Thematic analysis of responses was conducted.ResultsResults suggest that verbal and non-verbal cues from SPs were the most significant influence on student's recognition of clinical deterioration. Responses to that recognition were varied, but calling for help was perceived by the students to be an effective response.ConclusionEffective simulation training for medical students to recognise and respond to clinical deterioration requires scenarios that offer strong cues in patient appearance, speech and behaviour, and suggests that human simulated patients are effective educators for this purpose.
Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids
Authors: Vilches Clara , Boiadjieva-Knöpfel Emilia , Bodoy Susanna , Camargo Simone , López de Heredia Miguel , Prat Esther , Ormazabal Aida , Artuch Rafael , Zorzano Antonio , Verrey François , Nunes Virginia , Palacín Manuel
Published: April 2018

Background Reabsorption of amino acids (AAs) across the renal proximal tubule is crucial for intracellular and whole organism AA homeostasis. Although the luminal transport step is well understood, with several diseases caused by dysregulation of this process, the basolateral transport step is not understood. In humans, only cationic aminoaciduria due to malfunction of the basolateral transporter y+LAT1/CD98hc (SLC7A7/SLC3A2), which mediates the export of cationic AAs, has been described. Thus, the physiologic roles of basolateral transporters of neutral AAs, such as the antiporter LAT2/CD98hc (SLC7A8/SLC3A2), a heterodimer that exports most neutral AAs, and the uniporter TAT1 (SLC16A10), which exports only aromatic AAs, remain unclear. Functional cooperation between TAT1 and LAT2/CD98hc has been suggested by in vitro studies but has not been evaluated in vivo.

Methods To study the functional relationship of TAT1 and LAT2/CD98hc in vivo, we generated a double-knockout mouse model lacking TAT1 and LAT2, the catalytic subunit of LAT2/CD98hc (dKO LAT2-TAT1 mice).

Results Compared with mice lacking only TAT1 or LAT2, dKO LAT2-TAT1 mice lost larger amounts of aromatic and other neutral AAs in their urine due to a tubular reabsorption defect. Notably, dKO mice also displayed decreased tubular reabsorption of cationic AAs and increased expression of y+LAT1/CD98hc.

Conclusions The LAT2/CD98hc and TAT1 transporters functionally cooperate in vivo, and y+LAT1/CD98hc may compensate for the loss of LAT2/CD98hc and TAT1, functioning as a neutral AA exporter at the expense of some urinary loss of cationic AAs. Cooperative and compensatory mechanisms of AA transporters may explain the lack of basolateral neutral aminoacidurias in humans.
Circuitos económicos solidarios turísticos un desafío de sostenibilidad
Authors: Contreras Díaz Jackeline , Mancheno Ponce Diego , Cifuentes Vega Sebastian
Published: April 2018

A pesar de que el turismo se ha identificado como una de las actividades con mayores ventajas para conseguir el desarrollo regional. Una de las limitaciones para su consolidación ha sido la sostenibilidad. El artículo resalta la importancia de considerar a la sostenibilidad socio económica de la actividad a través de la construcción de circuitos económicos solidarios turísticos bajo los principios de la economía popular y solidaria.  Este desafío plantea la necesidad de realizar una evaluación in situ  de cómo los actores han construido en sus imaginarios la posibilidad y ventaja de trabajar en redes articuladas  a través de los circuitos económicos solidarios; y, si la institucionalidad estatal nacional y local creada ha favorecido o facilitado este propósito. En base a la observación- participativa y una serie de encuestas y entrevistas a los actores-socios de dichas organizaciones se consultó sobre los elementos favorables y limitantes para la constitución de estos circuitos económicos solidarios en el sector turístico. Entre los principales resultados, se identificó que el tejido social y las relaciones entre los actores son elementos centrales para generar mayor sostenibilidad socioeconómica de la actividad turística. Finalmente se pudo concluir que la generación de conocimiento endógeno en los circuitos económicos turísticos requiere de la intervención y promoción de las autoridades públicas; y son vitales para la consolidación y desarrollo de estos circuitos.
La creatividad en el sector turístico americano y europeo: Caso Croacia
Authors: Núñez Barriopedro Estela , Ruíz López Josué , Ravina-Ripoll Rafael
Published: April 2018

El turismo cinematográfico se ha estudiado durante décadas como un fenómeno que puede resultar beneficioso para un destino turístico cuando es elegido como locación para el rodaje de una producción audiovisual. El principal objetivo de esta investigación es demostrar que, gracias a que en la ciudad de Dubrovnik (Croacia) se han filmado escenas de la serie «Juegos de Tronos», han aumentado significativamente tanto en la ciudad como en el país las visitas de turistas internacionales, además de conocer los factores de satisfacción turística. En el presente estudio se han utilizado dos tipos de fuentes, por un lado, datos secundarios proporcionados por el Instituto Croata para el Turismo y el Patronato de Turismo de Dubrovnik en forma de cifras globales de llegadas de turistas y pernoctaciones en toda Croacia y Dubrovnik específicamente, para el período comprendido entre 2007 y 2016, previo y post el lanzamiento de «Juego de Tronos» en 2011. Por otro lado, se han analizado datos primarios mediante encuesta implementado por el Patronato de Turismo de Dubrovnik en el verano de 2015 a 264 turistas esta ciudad. Finalmente, como factores de atracción del enclave croata, destacan la naturaleza, ser territorio de interés cultural, y destino de sol y playa. Asimismo, se diferencian dos dimensiones de satisfacción, una orientada al «enriquecimiento cultural y la autorrealización» y otra en la «vida material y terrenal».
Evaluación de la sostenibilidad económica del turismo de cruceros. Una aproximación metodológica en el Litoral Mediterráneo español
Authors: Peláez Verdet Antonio , Loscertales Sánchez Pilar
Published: April 2018

El turismo de cruceros es un poderoso dinamizador del turismo en los destinos en los que opera, y ha sido largamente estudiado desde el punto de vista del comportamiento del consumidor. También las dimensiones de la sostenibilidad medioambiental y social de este tipo de turismo han sido analizadas con detenimiento por la literatura. No obstante, y a pesar de un creciente número de investigaciones relacionadas con su impacto económico, no se ha llegado aún a una conclusión robusta sobre el efecto económico neto que tiene sobre los destinos. En este trabajo se estudia el impacto económico del turismo de cruceros en cuatro destinos del mediterráneo español con características distintas, usando datos de EGATUR y datos financieros de las empresas turísticas localizadas en los distintos destinos. Tras la aplicación de técnicas multivariantes se establecen los umbrales en los que el turismo de cruceros tiene un efecto más beneficioso para la rentabilidad de las empresas turísticas que directamente se benefician del tráfico crucerista en destino.