Structural and functional analysis of the human cone-rod homeobox transcription factor.

The cone-rod homeobox (CRX) protein is a critical K50 homeodomain transcription factor responsible for the differentiation and maintenance of photoreceptor neurons in the vertebrate retina. Mutant alleles in the human gene encoding CRX result in a variety of distinct blinding retinopathies, including retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis. Despite the success of using in vitro biochemistry, animal models, and genomics approaches to study this clinically relevant transcription factor over the past 25 years since its initial characterization, there are no high-resolution structures in the published literature for the CRX protein. In this study, we use bioinformatic approaches and small-angle X-ray scattering (SAXS) structural analysis to further understand the biochemical complexity of the human CRX homeodomain (CRX-HD). We find that the CRX-HD is a compact, globular monomer in solution that can specifically bind functional cis-regulatory elements encoded upstream of retina-specific genes. This study presents the first structural analysis of CRX, paving the way for a new approach to studying the biochemistry of this protein and its disease-causing mutant protein variants.

Solanumscalarium (Solanaceae), a newly-described dioecious bush tomato from Judbarra/Gregory National Park, Northern Territory, Australia.

A new species of functionally dioecious bush tomato of SolanumsubgenusLeptostemonum is described. Solanumscalarium Martine & T.M.Williams, sp. nov., is a member of the taxonomically challenging "Kimberley dioecious clade" in Australia and differs from other species in the group in its spreading decumbent habit and conspicuously prickly male floral rachis. The species is so far known from one site in Judbarra/Gregory National Park in the Northern Territory. Ex situ crosses and confirmation of inaperturate pollen grains produced in morphologically cosexual flowers indicate that these flowers are functionally female and the species is functionally dioecious. The scientific name reflects the ladder-like appearance of the inflorescence rachis armature of male individuals, the stone staircase that provides access to the type locality at the Escarpment Lookout Walk, and the importance of maintaining equitable and safe access to outdoor spaces. The common name Garrarnawun Bush Tomato is proposed in recognition of the lookout point at this site, a traditional meeting place of the Wardaman and Nungali-Ngaliwurru peoples whose lands overlap in this area.

Impact of pharmacist intervention on glucagon prescribing patterns in an outpatient internal medicine teaching clinic.

OBJECTIVES: To examine changes in the rate of glucagon prescribing within an internal medicine resident clinic following pharmacist-led interventions and to analyze glucagon prescribing patterns. SETTING: Urban, internal medicine residency teaching clinic. PRACTICE DESCRIPTION: Providers in the teaching clinic include internal medicine residents, supervised by faculty attending physicians. The pharmacy team consists of students, residents, and faculty pharmacists. PRACTICE INNOVATION: This uncontrolled quality improvement project consisted of a first analysis (September 2016 to August 2017) and a second analysis (September 2016 to January 2018) to determine the difference in rate of glucagon prescribing. Patients were at least 18 years old with a diagnosis of type 1 or type 2 diabetes mellitus (T1DM and T2DM) and managed with basal insulin plus at least one dose of bolus insulin or with premixed insulin. Pharmacist-led interventions included 2 distinct educational sessions about glucagon prescription for the residents and faculty members, and implementation of standardized written communication for recommendations. EVALUATION: Data collected were analyzed with rates and descriptive statistics. RESULTS: Of the patients with T1DM and T2DM who were included and deemed eligible for glucagon, 9 of 188 (4.79%) during first analysis versus 27 of 203 (13.30%) during second analysis were prescribed glucagon-an 8.51% increase. Hypoglycemia not leading to hospitalization (44.44%) was the primary trigger for glucagon prescribing, and the peak prescribing month was October 2017 (25.93%). CONCLUSION: Pharmacist-led intervention was associated with an increased rate of glucagon prescribing for patients with T1DM and T2DM within the resident teaching clinic. To improve further on the results, the research team plans to perform subsequent Plan, Do, Study, Act cycles to continuously improve the rate of prescriptions for at-risk patients. Overall, this project could encourage other pharmacy teams to evaluate strategies to increase glucagon prescribing and to evaluate clinical outcomes within outpatient primary care clinics.

Levamisole: A High Performance Cutting Agent.

Levamisole is an imidazothiazole chemical most frequently used as an antihelminthic agent in cattle. Over the last decade, levamisole has been increasingly encountered as an additive in both powder and crack cocaine. A white powder with a "fish scale" appearance, the chemical is physically similar to powder cocaine. In vivo, levamisole is metabolized to aminorex, a compound with amphetamine-like psychostimulatory properties and a long half-life; a priori, this property allows levamisole to potentiate and prolong the stimulatory effects of cocaine while bulking up the drug to increase profit for the dealer. As use of cocaine cut with levamisole becomes more prevalent, complications directly attributable to the chemical are increasingly being recognized.

A Sudden Infant Death Due to Congenital Diaphragmatic Hernia.

Congenital diaphragmatic hernia (CDH) is an uncommon condition in which the embryological elements of the diaphragm fail to fuse completely, leaving a defect in the barrier separating the thorax from the abdomen. Although most cases are symptomatic at birth and lead to prompt treatment, asymptomatic cases may go undetected, presenting later on as a result of sudden or exacerbated herniation of abdominal contents into the thoracic cavity. Presented here is the sudden death of a 6-week-old girl. At autopsy, the abdominal organs were found to be filling the left chest cavity, having herniated through a previously undetected posterior diaphragmatic hernia of Bochdalek. The literature on CDH is reviewed, including discussion of the embryological origin, clinical presentation, diagnosis, and treatment of the condition. Special emphasis is placed on the challenges posed by these late-presenting cases, particularly in their diagnosis and management, highlighting the importance of developing more direct methods of detection for these very reasons.

Biomechanical Evaluation of a Mandibular Spanning Plate Technique Compared to Standard Plating Techniques to Treat Mandibular Symphyseal Fractures.

Purpose. The purpose of this study is to compare the biomechanical behavior of the spanning reconstruction plate compared to standard plating techniques for mandibular symphyseal fractures. Materials and Methods. Twenty-five human mandible replicas were used. Five unaltered synthetic mandibles were used as controls. Four experimental groups of different reconstruction techniques with five in each group were tested. Each synthetic mandible was subjected to a splaying force applied to the mandibular angle by a mechanical testing unit until the construct failed. Peak load and stiffness were recorded. The peak load and stiffness were analyzed using ANOVA and the Tukey test at a confidence level of 95% (P < 0.05). Results. The two parallel plates' group showed statistically significant lower values for peak load and stiffness compared to all other groups. No statistically significant difference was found for peak load and stiffness between the control (C) group, lag screw (LS) group, and the spanning plate (SP1) group. Conclusions. The spanning reconstruction plate technique for fixation of mandibular symphyseal fractures showed similar mechanical behavior to the lag screw technique when subjected to splaying forces between the mandibular gonial angles and may be considered as an alternative technique when increased reconstructive strength is needed.

No effect of prenatal alcohol exposure on activity in three inbred strains of mice.

AIMS: Prenatal exposure to alcohol can have adverse effects on the developing fetus. Two of the hallmarks of children exposed to alcohol prenatally are attention deficits and hyperactivity. While hyperactivity has been observed in rats following prenatal ethanol exposure, few studies have examined these effects in mice. The present study investigated the effects of prenatal ethanol exposure on activity in mice from three inbred strains: C57BL/6 (B6), Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS). METHODS: On Days 7 through 18 of gestation, mice were intragastrically intubated twice daily with either 3.0 g/kg ethanol (E) or an isocaloric amount of maltose-dextrin (MD); non-intubated control (NIC) litters were also generated. Offspring activity was monitored at 30, 60, 90 and 150 days of age. RESULTS: While results showed no effects of prenatal ethanol exposure on any measures of activity, we did observe differences in baseline activity among the strains. ISS mice were more active than B6 and ILS for all activity measures except stereotypy; B6 mice had higher measures of stereotypy than ILS and ISS. Younger mice were more active than older mice. The only sex effects were on measures of stereotypy, where males had higher scores. CONCLUSIONS: Mice are an excellent organism to study genetic influences on many phenotypes. However, our study and others have shown few effects of prenatal ethanol exposure on behavior in mice. It appears as if the prenatal period in mice, corresponding to organogenesis, is not a sensitive period for producing behavioral deficits following ethanol exposure. It is likely that the first 2 weeks postnatally, corresponding to the brain growth spurt, are more sensitive for producing behavioral effects.

Relationship between platelet imidazoline receptor-binding peptides and candidate imidazoline-1 receptor, IRAS.

A candidate human imidazoline-1 receptor, designated imidazoline receptor antisera-selected (IRAS) protein, was cloned based on immunoreactivity with antiserum against a purified imidazoline receptor binding peptide (IRBP antiserum). Human IRAS is 167 kD in size, different from 33- to 85-kD IRBP bands previously linked to the human platelet I(1) receptor. To explore the possible relationship between IRAS and these smaller proteins, seven different epitope-specific antisera against IRAS were raised in rabbits for comparison with IRBP antiserum. Focus was on antiserum(227-241), corresponding to amino acids No. 227 to 241 in IRAS, because this antiserum was found uniquely able to immunoprecipitate non-denatured 85-kD and 170-kD forms of IRAS from a human megakaryoblastoma cell line (MEG01), a model of platelet-producing cells. Human platelets lacked the 170-kD form of IRAS, but 33-kD and 85-kD bands were detectable and seemed to be possible fragments of full-length IRAS. The intensity of the 85-kD band detected by antiserum(227-241) was significantly correlated (r = 0.62, P = 0.04) with the intensity of the 33-kD band across 11 human platelet samples. A positive correlation between the intensities of the 33-kD and 85-kD bands is consistent with both being fragments of IRAS.

Ecstasy (MDMA) deaths in New York City: a case series and review of the literature.

MDMA ("ecstasy") has gained renewed popularity as a drug of abuse. To access the epidemiology and causes of death of MDMA-positive fatalities, all deaths investigated by the OCME that tested positive for MDMA (22 deaths) between January 1997 and June 2000 were reviewed. There were three deaths in each 1997 and 1998, eleven in 1999, and five in the first part of 2000. Of these 22 deaths, 13 were due to acute drug intoxications, 7 due to mechanical injury (blunt trauma, gunshot wounds), and 2 due to a combination of natural disease and acute drug intoxication. Evidence of recent opiate and/or cocaine use was found in 7 of the acute intoxication deaths and in none of the traumatic or combination natural/intoxication deaths. The race of all decedents was White between the ages of 17-41 years, and 18 of 22 were men.