Demographic and pregnancy-related predictors of postnatal contraception uptake: A cross-sectional study.

OBJECTIVE: To examine the uptake of postnatal contraception (PNC) and experiences of PNC care across a geographical region of England. DESIGN: Cross-sectional online survey. SETTING: The North East and North Cumbria Integrated Care System (ICS). POPULATION: Women who had completed a pregnancy in the previous 3 years. METHODS: The uptake of PNC by accessed method(s) and the availability of preferred method(s) is described, and adjusted odds ratios are reported for group differences in uptake by characteristics of interest. MAIN OUTCOME MEASURES: Uptake of medically prescribed/administered contraception and uptake of long-acting reversible contraception (LARC) during the postnatal period, and access to preferred PNC methods. RESULTS: Although almost half of respondents (47.1%; n = 1178) reinitiated some form of sexual activity during the postnatal period, only 38.7% (n = 969) of respondents accessed a medically prescribed/administered contraceptive method postnatally, and only 15.5% (n = 389) of respondents accessed a LARC. It is a matter of concern that 18.8% (n = 451) of respondents indicated that they were unable to access their preferred PNC. In multivariate analysis, younger age, lower household income, higher multiparity, operative delivery, unplanned pregnancy and not breastfeeding were significant predictors of higher PNC uptake. CONCLUSIONS: The uptake of PNC in this cohort was low, with almost a fifth of women unable to access their preferred method. However, there was some evidence that women belonging to groups perceived to be at risk of rapid repeat pregnancy were more likely to access reliable PNC methods.

Mapping Information Needs over the Diagnosis, Treatment, and Survivorship Trajectory for Esophago-gastric Cancer Patients and Their Main Supporters: a Retrospective Survey.

This study reports preliminary data about the information needs of esophago-gastric cancer survivors and their supporters across diagnosis and treatment by identifying time-specific needs and whether the information provided aligned with the needs at each time point. Survivors (n = 26) and supporters (n = 15) were recruited from a public teaching hospital in South Australia. Both groups provided recall data describing personal information domain challenges at 6 clinically significant time points ranging from diagnosis to > 2 years post diagnosis. Responses were analyzed using descriptive statistics for non-normally distributed data. Needs relating to communication, tests, disease, and the physical effects information domains were consistently high across time and in groups. Supporters' overall needs were greater than those of survivors, particularly at times of high need. At times of low need, both groups reported information overload. Our results confirm that survivors and supporters require information throughout the cancer trajectory, up to 2 years after diagnosis, and supporters' needs are likely to be even greater. Results highlight the importance of timely and relevant information provision and provide a basis for the development of resources to empower survivors and supporters to identify and articulate their personal information needs. Patient navigators may provide an avenue to facilitate this approach.

Cocaine-induced plasticity in the nucleus accumbens is cell specific and develops without prolonged withdrawal.

Cocaine induces plasticity at glutamatergic synapses in the nucleus accumbens (NAc). Withdrawal was suggested to play an important role in the development of this plasticity by studies showing that some changes only appear several weeks after the final cocaine exposure. In this study, the requirement for prolonged withdrawal was evaluated by comparing the changes in glutamatergic transmission induced by two different noncontingent cocaine treatments: a short treatment followed by prolonged withdrawal, and a longer treatment without prolonged withdrawal. Recordings were performed from mouse medium spiny neurons (MSNs) in the NAc at the same time after the first cocaine injection under both treatments. A similar increase in the frequency of glutamate-mediated miniature EPSCs was observed in D(1)-expressing MSNs after both cocaine treatments, demonstrating that prolonged withdrawal was not required. Furthermore, larger AMPA receptor-to-NMDA receptor ratios, higher spine density, and enlarged spine heads were observed in the absence of withdrawal after a long cocaine treatment. These synaptic adaptations expressed in D(1)-containing MSNs of the NAc core were not further enhanced by protracted withdrawal. In conclusion, a few repeated cocaine injections are enough to trigger adaptations at glutamatergic synapses in D(1)-expressing MSNs, which, although they take time to develop, do not require prolonged cocaine withdrawal.

Dopamine D2 receptor overexpression alters behavior and physiology in Drd2-EGFP mice.

Bacteria artificial chromosome (BAC) transgenic mice expressing the reporter protein enhanced green fluorescent protein (EGFP) under the control of the D1 and D2 dopamine receptor promoters (Drd1-EGFP and Drd2-EGFP) have been widely used to study striatal function and have contributed to our understanding of the physiological and pathological functions of the basal ganglia. These tools were produced and promptly made available to address questions in a cell-specific manner that has transformed the way we frame hypotheses in neuroscience. However, these mice have not been fully characterized until now. We found that Drd2-EGFP mice display an ∼40% increase in membrane expression of the dopamine D2 receptor (D2R) and a twofold increase in D2R mRNA levels in the striatum when compared with wild-type and Drd1-EGFP mice. D2R overexpression was accompanied by behavioral hypersensitivity to D2R-like agonists, as well as enhanced electrophysiological responses to D2R activation in midbrain dopaminergic neurons. Dopamine (DA) transients evoked by stimulation in the nucleus accumbens showed slower clearance in Drd2-EGFP mice, and cocaine actions on DA clearance were impaired in these mice. Thus, it was not surprising to find that Drd2-EGFP mice were hyperactive when exposed to a novel environment and locomotion was suppressed by acute cocaine administration. All together, this study demonstrates that Drd2-EGFP mice overexpress D2R and have altered dopaminergic signaling that fundamentally differentiates them from wild-type and Drd1-EGFP mice.

Effects of Anthocyanin-rich Berries on the Risk of Metabolic Syndrome: A Systematic Review and Meta-analysis.

OBJECTIVE: Metabolic syndrome (MetS) can lead to fatal complications, including cardiovascular disease. Emerging evidence suggests has emerged that increased fruit and vegetable intake and decreased intake of saturated fats, simple sugars, and processed foods can improve cardiovascular health. Anthocyanins (color pigments) have anti-inflammatory and antioxidant capacities but are of low bioavailability. In this systematic review and metaanalysis, we investigate the possible beneficial effects of the intake of berries high in anthocyanins on MetS risk factors. We also investigate the influences of high-density lipoprotein (HDL), lowdensity lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC). METHODS: We identified 2,274 articles from PUBMED and EMBASE following a search input designed to include studies of interest of these, 21 met inclusion criteria. RESULTS: The studies showed an overall reduction in low-density lipoprotein (p=0.04). Increases in HDL were found with cranberry and freeze-dried berry intake during a 4-6-week intervention. No statistically significant findings were detected for fasting glucose, Hb1Ac, insulin levels, blood pressure, oxidized LDL (OX-LDL), BMI, and overall HDL. CONCLUSIONS: We conclude from this systematic review and meta-analysis that increased berry intake improves MetS key risk factors and reduces the risk of cardiovascular disease. Pronounced effects were apparent for concentrated berry products, such as freeze-dried strawberries.

High altitude is associated with pTau deposition, neuroinflammation, and myelin loss.

Mammals are able to adapt to high altitude (HA) if appropriate acclimation occurs. However, specific occupations (professional climbers, pilots, astronauts and other) can be exposed to HA without acclimation and be at a higher risk of brain consequences. In particular, US Air Force U2-pilots have been shown to develop white matter hyperintensities (WMH) on MRI. Whether WMH are due to hypoxia or hypobaria effects is not understood. We compared swine brains exposed to 5000 feet (1524 m) above sea level (SL) with 21% fraction inspired O2 (FiO2) (Control group [C]; n = 5) vs. 30,000 feet (9144 m) above SL with 100% FiO2 group (hypobaric group [HYPOBAR]; n = 6). We performed neuropathologic assessments, molecular analyses, immunohistochemistry (IHC), Western Blotting (WB), and stereology analyses to detect differences between HYPOBAR vs. Controls. Increased neuronal insoluble hyperphosphorylated-Tau (pTau) accumulation was observed across different brain regions, at histological level, in the HYPOBAR vs. Controls. Stereology-based cell counting demonstrated a significant difference (p < 0.01) in pTau positive neurons between HYPOBAR and C in the Hippocampus. Higher levels of soluble pTau in the Hippocampus of HYPOBAR vs. Controls were also detected by WB analyses. Additionally, WB demonstrated an increase of IBA-1 in the Cerebellum and a decrease of myelin basic protein (MBP) in the Hippocampus and Cerebellum of HYPOBAR vs. Controls. These findings illustrate, for the first time, changes occurring in large mammalian brains after exposure to nonhypoxic-hypobaria and open new pathophysiological views on the interaction among hypobaria, pTau accumulation, neuroinflammation, and myelination in large mammals exposed to HA.

Duration of Ureteral Stenting Following Ureteroscopic Perforation in a Porcine Model.

Objectives: Ureteroscopic ureteral perforations have been reported in up to 6% of cases, with recent studies suggesting a decline to less than 2%. Ureteroscopic perforations are managed with prolonged ureteral stenting of up to 6 weeks based on historical data. We sought to evaluate the time of urothelial healing and duration of ureteral stenting following a ureteroscopic perforation in a porcine model. Materials and Methods: Part A: Ureteral perforation using a semirigid ureteroscope was performed in 37 ureters. The ureters were stented using 4.7F × 22 cm stents for 3, 7, 10, or 14 days, and retrograde pyelograms performed after stent removal. Injured ureteral segments were collected for histologic evaluation. Part B: 8 ureters had endoscopic perforation and stenting for 7 days and then survived for 4 weeks for evaluation of urinary extravasation or hydronephrosis and histologic evaluation. Results: Part A: At 3 days of ureteral stenting, there was urinary extravasation on retrograde pyelograms and gross defect in all ureters; average creatinine increased (1.55-1.75 mg/dL). Starting at 7 days, no evidence of gross urothelial defects or extravasation, and average creatinine was stable. Histologic evaluation revealed urothelial healing by 7 days with ongoing tissue healing. Granulation tissue predominated in early phase of healing. Part B: With only 7 days of ureteral stenting, no extravasation or hydronephrosis developed a month after stent removal. Conclusions: Following ureteroscopic ureteral perforation in a porcine model, the urothelium is functionally intact with 7 days of stenting. These results are sustained without complications for at least 4 weeks after stent removal. While further studies are warranted, these results challenge the current practice of maintaining ureteral stenting for several weeks following ureteral perforation during ureteroscopy.

Organic vs. Inorganic Tracheobronchial Airway Foreign Body Aspiration: Does Type/Duration Matter?

OBJECTIVE: We sought to determine the time course of clinical and histologic differences between aspirated inorganic and organic foreign bodies. STUDY DESIGN: In-vivo. METHODS: Twenty Sinclair miniature swine (Sus scrofa domesticus) were divided into two groups-inorganic or organic foreign bodies. Either an organic (peanut) or an inorganic (Lego) foreign body was placed within a bronchus and left for 3, 5, 7, 14 or 21 days. The airway was reassessed at the predetermined endpoint at which time endoscopic, gross, and histopathological findings were documented. Specimens were scored with a pathologic scoring system to assess injury severity from the foreign body. RESULTS: Foreign bodies were successfully placed in all 20 swine. Two animals required early euthanasia due to respiratory compromise. The foreign body was identified grossly in eight (40%) animals. An additional three (15%) had microscopic evidence suggestive of a previous foreign body of an undetermined duration. There was no difference in injury severity between organic and inorganic foreign bodies. The 3-day group had injuries limited to the bronchial lining, whereas the longer duration groups had bronchial and adjacent lung parenchymal involvement. There was no difference in injury severity between days 5 and 21. CONCLUSIONS: Airway foreign bodies initially cause bronchial damage. After 5 days, the foreign body causes lung parenchymal changes. There was no difference in airway lesion severity between organic and inorganic foreign bodies. LEVEL OF EVIDENCE: N/A Laryngoscope, 131:490-495, 2021.

Laryngeal Thermal Injury Model.

A lack of reliable laryngeal thermal injury models precludes laryngeal burn wound healing studies and investigation of novel therapeutics. We hypothesize that a swine laryngeal burn model can allow for laryngeal burn evaluation over time. Twelve Yorkshire crossbreed swine underwent tracheostomy and endoscopically directed laryngeal burns using heated air (150-160°C). Swine larynges were evaluated and sectioned/stained at 12 hours, 1, 3, 7, 14, and 21 days. A board-certified veterinary pathologist assessed anatomic regions (left and right: epiglottis, true/false vocal folds, and subglottis) using a nine criteria histological injury scoring scale. Six swine were euthanized at scheduled endpoints, three prematurely (airway concerns), and three succumbed to airway complications after 16 to 36 hours. Endoscopic and gross examination from scheduled endpoints revealed massive supraglottic edema and tissue damage, particularly around the arytenoids, extending transglottically. Swine from premature endpoints had comparatively increased edema throughout. Microscopic evaluation documented an inverse relationship between injury severity score and time from injury. Inflammation severity decreased over time, nearly resolving by 14 days. Neutrophils predominated early with histiocytes appearing at 3 days. Granulation tissue appeared at 3 days, and early epiglottic and/or subglottic fibrosis appeared by 7 days and matured by 14 days. Edema, abundant initially, decreased by day 3 and resolved by day 7. This approach is the first to provide longitudinal analysis of laryngeal thermal injuries, reflecting some of the first temporal wound healing characteristic data in laryngeal thermal injuries and providing a platform for future therapeutic studies.

Pathology is common in subsequent visits after admission for non-specific abdominal pain.

INTRODUCTION: Although not supported by evidence, there may be a risk of overlooking pathological findings at patients' return visit after emergency admission for non-specific abdominal pain (NSAP). The primary aim of this study was to evaluate the risk of missed acute pathology in patients primarily discharged with NSAP and re-admitted within three months. METHODS: This was a retrospective review of hospital records within a three-month period (1 September-30 November, 2014) in a university hospital with unrestricted referral of abdominal emergency patients. Patients fulfilling the criteria for NSAP were included in the study. RESULTS: Among the 1,474 patients admitted with acute abdominal pain, 390 (26%) were discharged with NSAP; 16% of the patients who were discharged with NSAP were re-admitted for abdominal pain. At their return visit, 39% received a verified specific diagnosis, corresponding to 6% of all patients with the NSAP diagnosis. A total of 40% of the early re-admissions of patients with NSAP were related to the biliary tract (cholelithiatis, cholangitis and cholecystitis). Co-morbidity, nausea, vomiting and increased white blood cell count at the primary admission were significantly associated with a risk of missing a specific diagnosis (p < 0.05). CONCLUSIONS: This study found that only 6% of the patients who were admitted for acute abdominal pain and were discharged with no diagnosis had a somatic condition. However, risk of pathological findings at the return visit was relatively high among patients discharged with NSAP. FUNDING: none. TRIAL REGISTRATION: not relevant.

Cercopithecine Herpesvirus 9 (Simian Varicella Virus) Infection after Total-Body Irradiation in a Rhesus Macaque (Macaca mulatta).

This case report describes a rhesus macaque (Macaca mulatta; male; age, 5 y; weight, 6.7 kg) with anorexia, dehydration, lethargy, ataxia, and generalized skin rashes that occurred 30 d after total-body irradiation at 6.5 Gy ((60)Co γ-rays). Physical examination revealed pale mucus membranes, a capillary refill time of 4 s, heart rate of 180 bpm. and respirations at 50 breaths per minute. Diffuse multifocal maculopapulovesicular rashes were present on the body, including mucocutaneous junctions. The CBC analysis revealed a Hct of 48%, RBC count of 6.2 × 10(6)/µL, platelet count of 44 × 10(3)/µL, and WBC count of 25 × 10(3)/µL of WBC. The macaque was euthanized in light of a grave prognosis. Gross examination revealed white foci on the liver, multifocal generalized petechiation on serosal and mucosal surfaces of the gastrointestinal tract, hemorrhagic lymph nodes, and hemorrhagic fluid in the thoracic cavity. Microscopic examination revealed cutaneous vesicular lesions with intranuclear eosinophilic viral inclusions within the epithelial cells, consistent with herpesvirus. Immunohistochemistry was positive for herpesvirus. The serum sample was negative for antibodies against Macacine herpesvirus 1 and Cercopithecine herpesvirus 9 (simian varicella virus, SVV). Samples submitted for PCR-based identification of the etiologic agent confirmed the presence of SVV DNA. PCR analysis, immunohistochemistry, and histology confirmed that lesions were attributed to an active SVV infection in this macaque. This case illustrates the importance of screening for SVV in rhesus macaques, especially those used in studies that involve immunosuppressive procedures.

Non-human Primate Total-body Irradiation Model with Limited and Full Medical Supportive Care Including Filgrastim for Biodosimetry and Injury Assessment.

An assessment of multiple biomarkers from radiation casualties undergoing limited- or full-supportive care including treatment with filgrastim is critical to develop rapid and effective diagnostic triage strategies. The efficacy of filgrastim with full-supportive care was compared with results with limited-supportive care by analyzing survival, necropsy, histopathology and serial blood samples for hematological, serum chemistry and protein profiles in a non-human primate (Macaca mulatta, male and female) model during 60-d post-monitoring period following sham- and total-body irradiation with 6.5 Gy 60Co gamma-rays at 0.6 Gy min-1 Filgrastim (10 µg kg-1) was administered beginning on Day 1 post-exposure and continued daily until neutrophil counts were ≥2,000 µL-1 for two consecutive days. Filgrastim and full-supportive care significantly decreased the pancytopenia duration and resulted in improved animal survival and recovery compared to animals with a limited-supportive care. These findings also identified and validated a multiparametric biomarker panel to support radiation diagnostic device development.

Strain variation in the adaptation of C57Bl6 and BALBc mice to chronic hypobaric hypoxia.

The interplay of environmental and genetic factors may lead to a spectrum of physiological and behavioral outcomes. How environmental stress factors interact with the diverse mouse genomes is still poorly understood and elucidating the underlying interactions requires specific stress models that can target integrated physiological systems. Here, we employ behavioral tests and whole-body plethysmography to examine the effects of 12 weeks of simulated high altitude (HA) exposure on two inbred mouse strains, BALBc and C57Bl6. We find that HA induced- weight loss recovers at significantly different rates in these two strains. Even at 12 weeks, however, both strains fail to reach body weight levels of controls. Performance on two motor tasks, rotarod and treadmill, improve with HA exposure but more prominently in BALBc mice. Whole-body plethysmography outcomes indicate that compensation to chronic HA includes increased respiratory frequencies and tidal volumes in both strains. However, the effects on tidal volume are significantly greater in BALBc mice and showed a biphasic course. Whole- body metabolic rates are also increased in both strains with prolonged HA exposure, but were more pronounced in BALBc mice suggestive of less successful adaptation in this strain. These adaptations occur in the absence of gross pathological changes in all major organs. Together these results indicate that chronic HA exposure results in environmental stressors that impact the specific physiological responses of BALBc more than C57Bl6 mice. Thus, these strains provide a promising platform for investigating how genetic backgrounds can differentially reinforce the effects of long-lasting environmental stressors and their potential to interact with psychological stressors.

Hemorrhage Exacerbates Radiation Effects on Survival, Leukocytopenia, Thrombopenia, Erythropenia, Bone Marrow Cell Depletion and Hematopoiesis, and Inflammation-Associated microRNAs Expression in Kidney.

Exposure to high-dose radiation results in detrimental effects on survival. The effects of combined trauma, such as radiation in combination with hemorrhage, the typical injury of victims exposed to a radiation blast, on survival and hematopoietic effects have yet to be understood. The purpose of this study was to evaluate the effects of radiation injury (RI) combined with hemorrhage (i.e., combined injury, CI) on survival and hematopoietic effects, and to investigate whether hemorrhage (Hemo) enhanced RI-induced mortality and hematopoietic syndrome. Male CD2F1 mice (10 weeks old) were given one single exposure of γ- radiation (60Co) at various doses (0.6 Gy/min). Within 2 hr after RI, animals under anesthesia were bled 0% (Sham) or 20% (Hemo) of total blood volume via the submandibular vein. In these mice, Hemo reduced the LD50/30 for 30-day survival from 9.1 Gy (RI) to 8.75 Gy (CI) with a DMF of 1.046. RI resulted in leukocytopenia, thrombopenia, erythropenia, and bone marrow cell depletion, but decreased the caspase-3 activation response. RI increased IL-1ß, IL-6, IL-17A, and TNF-α concentrations in serum, bone marrow, ileum, spleen, and kidney. Some of these adverse alterations were magnified by CI. Erythropoietin production was increased in kidney and blood more after CI than RI. Furthermore, CI altered the global miRNAs expression in kidney and the ingenuity pathway analysis showed that miRNAs viz., let-7e, miR-30e and miR-29b that were associated with hematopoiesis and inflammation. This study provides preliminary evidence that non-lethal Hemo exacerbates RI-induced mortality and cell losses associated with high-dose γ-radiation. We identified some of the initial changes occurring due to CI which may have facilitated in worsening the injury and hampering the recovery of animals ultimately resulting in higher mortality.

Laparoscopic colpotomy using monopolar electrocautery: does power really matter?

OBJECTIVE: The purpose of this study was to assess the extent and rate of vaginal tissue injury associated with the utilization of various monopolar electrosurgical power settings when laparoscopically transecting vaginal tissue. METHODS: This is an Institutional Animal Care and Use Committee-approved prospective, paired, single-blinded study. Externalized porcine vagina was transected using monopolar energy at 30, 50, and 80 W in the cut mode with laparoscopic Endo Shears. The slides were prepared and stained with both hematoxylin-eosin and Masson trichrome and were examined by board-certified veterinary pathologists blinded to the study. RESULTS: There were 18 swine; each animal was tested on all 3 power settings (n = 54). Tissue injury was measured to a mean (SD) of 767 (519) µm at 30 W, 690 (600) µm at 50 W, and 556 (470) µm at 80 W. When comparing the monopolar settings, the results were as follows: 30 versus 50 W (P = 0.33), 30 versus 80 W (P = 0.067), and 50 versus 80 W (P = 0.17). The mean (SD) time for complete transection was measured at each power setting (n = 18), with 35.8 (5.4) seconds for 30 W, 13.5 (5.5) seconds for 50 W, and 8.4 (5.1) seconds for 80 W (P < 0.001). There was a statistically significant difference in the mean (SD) rates of injury, with 20.8 (8.8) µm/s at 30 W, 39.8 (11.8) µm/s at 50 W, and 50.1 (19.2) µm/s at 80 W (P = 0.01). CONCLUSIONS: Using various power settings of monopolar energy may not make a significant difference in swine vaginal tissue damage at the time of colpotomy. However, there was a significant difference in the times and rates at which tissue was transected when using higher powers. We recommend using the 50- or 80-W setting, as this will likely decrease surgical times without altering vaginal tissue damage.

Accelerated hematopoietic syndrome after radiation doses bridging hematopoietic (H-ARS) and gastrointestinal (GI-ARS) acute radiation syndrome: early hematological changes and systemic inflammatory response syndrome in minipig.

PURPOSE: To characterize acute radiation syndrome (ARS) sequelae at doses intermediate between the bone marrow (H-ARS) and full gastrointestinal (GI-ARS) syndrome. METHODS: Male minipigs, approximately 5 months old, 9-12 kg in weight, were irradiated with Cobalt-60 (total body, bilateral gamma irradiation, 0.6 Gy/min). Endpoints were 10-day survival, gastrointestinal histology, plasma citrulline, bacterial translocation, vomiting, diarrhea, vital signs, systemic inflammatory response syndrome (SIRS), febrile neutropenia (FN). RESULTS: We exposed animals to doses (2.2-5.0 Gy) above those causing H-ARS (1.6-2.0 Gy), and evaluated development of ARS. Compared to what was observed during H-ARS (historical data: Moroni et al. 2011a , 2011c ), doses above 2 Gy produced signs of increasingly severe pulmonary damage, faster deterioration of clinical conditions, and faster increases in levels of C-reactive protein (CRP). In the range of 4.6-5.0 Gy, animals died by day 9-10; signs of the classic GI syndrome, as measured by diarrhea, vomiting and bacterial translocation, did not occur. At doses above 2 Gy we observed transient reduction in circulating citrulline levels, and animals exhibited earlier depletion of blood elements and faster onset of SIRS and FN. CONCLUSIONS: An accelerated hematopoietic subsyndrome (AH-ARS) is observed at radiation doses between those producing H-ARS and GI-ARS. It is characterized by early onset of SIRS and FN, and greater lung damage, compared to H-ARS.

Gastrointestinal acute radiation syndrome in Göttingen minipigs (Sus scrofa domestica).

In the absence of supportive care, exposing Göttingen minipigs to γ-radiation doses of less than 2 Gy achieves lethality due to hematopoietic acute radiation syndrome. Doses of 2 to 5 Gy are associated with an accelerated hematopoietic syndrome, characterized by villus blunting and fusion, the beginning of sepsis, and a mild transient reduction in plasma citrulline concentration. We exposed male Göttingen minipigs (age, 5 mo; weight, 9 to 11 kg) to γ-radiation doses of 5 to 12 Gy (total body; (60)Co, 0.6 Gy/min) to test whether these animals exhibit classic gastrointestinal acute radiation syndrome (GI-ARS). After exposure, the minipigs were monitored for 10 d by using clinical signs, CBC counts, and parameters associated with the development of the gastrointestinal syndrome. Göttingen minipigs exposed to γ radiation of 5 to 12 Gy demonstrate a dose-dependent occurrence of all parameters classically associated with acute GI-ARS. These results suggest that Göttingen minipigs may be a suitable model for studying GI-ARS after total body irradiation, but the use of supportive care to extend survival beyond 10 d is recommended. This study is the first step toward determining the feasibility of using Göttingen minipigs in testing the efficacy of candidate drugs for the treatment of GI-ARS after total body irradiation.

The Gottingen minipig is a model of the hematopoietic acute radiation syndrome: G-colony stimulating factor stimulates hematopoiesis and enhances survival from lethal total-body γ-irradiation.

PURPOSE: We are characterizing the Gottingen minipig as an additional large animal model for advanced drug testing for the acute radiation syndrome (ARS) to enhance the discovery and development of novel radiation countermeasures. Among the advantages provided by this model, the similarities to human hematologic parameters and dynamics of cell loss/recovery after irradiation provide a convenient means to compare the efficacy of drugs known to affect bone marrow cellularity and hematopoiesis. METHODS AND MATERIALS: Male Gottingen minipigs, 4 to 5 months old and weighing 9 to 11 kg, were used for this study. We tested the standard off-label treatment for ARS, rhG-CSF (Neupogen, 10 µg/kg/day for 17 days), at the estimated LD70/30 total-body γ-irradiation (TBI) radiation dose for the hematopoietic syndrome, starting 24 hours after irradiation. RESULTS: The results indicated that granulocyte colony stimulating factor (G-CSF) enhanced survival, stimulated recovery from neutropenia, and induced mobilization of hematopoietic progenitor cells. In addition, the administration of G-CSF resulted in maturation of monocytes/macrophages. CONCLUSIONS: These results support continuing efforts toward validation of the minipig as a large animal model for advanced testing of radiation countermeasures and characterization of the pathophysiology of ARS, and they suggest that the efficacy of G-CSF in improving survival after total body irradiation may involve mechanisms other than increasing the numbers of circulating granulocytes.

Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use.

A hallmark of addiction is the loss of control over drug intake, which is seen in only a fraction of those exposed to stimulant drugs such as cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use remain unknown. We found that individual variability in the development of highly motivated and perseverative behavior toward cocaine is associated with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens (NAc) of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was associated with resilience toward compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals.

Oral anticoagulation and antiplatelets in atrial fibrillation patients after myocardial infarction and coronary intervention.

OBJECTIVES: The purpose of this study was to investigate the risk of thrombosis and bleeding according to multiple antithrombotic treatment regimens in atrial fibrillation (AF) patients after myocardial infarction (MI) or percutaneous coronary intervention (PCI). BACKGROUND: The optimal antithrombotic treatment strategy is unresolved in patients with multiple indications. METHODS: A total of 12,165 AF patients hospitalized with MI and/or undergoing PCI between 2001 and 2009 were identified by nationwide registries (60.7% male; mean age 75.6 years). Risk of MI/coronary death, ischemic stroke, and bleeding according to antithrombotic treatment regimen was estimated by Cox regression models. RESULTS: Within 1 year, MI or coronary death, ischemic stroke, and bleeding events occurred in 2,255 patients (18.5%), 680 (5.6%), and 769 (6.3%), respectively. Relative to triple therapy (oral anticoagulation [OAC] plus aspirin plus clopidogrel), no increased risk of recurrent coronary events was seen for OAC plus clopidogrel (hazard ratio [HR]: 0.69, 95% confidence interval [CI]: 0.48 to 1.00), OAC plus aspirin (HR: 0.96, 95% CI: 0.77 to 1.19), or aspirin plus clopidogrel (HR: 1.17, 95% CI: 0.96 to 1.42), but aspirin plus clopidogrel was associated with a higher risk of ischemic stroke (HR: 1.50, 95% CI: 1.03 to 2.20). Also, OAC plus aspirin and aspirin plus clopidogrel were associated with a significant increased risk of all-cause death (HR: 1.52, 95% CI: 1.17 to 1.99 and HR: 1.60, 95% CI: 1.25 to 2.05, respectively). When compared to triple therapy, bleeding risk was nonsignificantly lower for OAC plus clopidogrel (HR: 0.78, 95% CI: 0.55 to 1.12) and significantly lower for OAC plus aspirin and aspirin plus clopidogrel. CONCLUSIONS: In real-life AF patients with indication for multiple antithrombotic drugs after MI/PCI, OAC and clopidogrel was equal or better on both benefit and safety outcomes compared to triple therapy.