Genetic architecture and evolution of color variation in American black bears.

Color variation is a frequent evolutionary substrate for camouflage in small mammals, but the underlying genetics and evolutionary forces that drive color variation in natural populations of large mammals are mostly unexplained. The American black bear, Ursus americanus (U. americanus), exhibits a range of colors including the cinnamon morph, which has a similar color to the brown bear, U. arctos, and is found at high frequency in the American southwest. Reflectance and chemical melanin measurements showed little distinction between U. arctos and cinnamon U. americanus individuals. We used a genome-wide association for hair color as a quantitative trait in 151 U. americanus individuals and identified a single major locus (p < 10-13). Additional genomic and functional studies identified a missense alteration (R153C) in Tyrosinase-related protein 1 (TYRP1) that likely affects binding of the zinc cofactor, impairs protein localization, and results in decreased pigment production. Population genetic analyses and demographic modeling indicated that the R153C variant arose 9.36 kya in a southwestern population where it likely provided a selective advantage, spreading both northwards and eastwards by gene flow. A different TYRP1 allele, R114C, contributes to the characteristic brown color of U. arctos but is not fixed across the range.

Clinical Experience With Pharmacological Venous Thromboembolism Prophylaxis in the Underweight and Critically Ill.

BACKGROUND: The optimal regimen for pharmacological prophylaxis of venous thromboembolism (VTE) in underweight, critically ill patients is unknown. OBJECTIVE: To describe prescribing patterns for VTE prophylaxis in underweight (≤50 kg or body mass index ≤18.5 kg/m(2)), critically ill patients and identify the prevalence of VTE and bleeding. METHODS: This was a retrospective cohort study that included patients who received standard- or reduced-dose VTE prophylaxis for ≥48 hours. RESULTS: A total of 295 individuals were included in the study. The majority of underweight patients in this study (79.7%) received unfractionated heparin, 5000 units 3 times daily. No statistically significant difference in the prevalence of clinically relevant VTEs between the reduced- and standard-dose groups was observed (4.4% vs 5.6%, P = 1.00), but a higher proportion of bleeding events was identified within the standard-dose group (6.7% vs 11.2%, P = 0.4). CONCLUSIONS: Empirical dose reductions of VTE prophylaxis are infrequently used in underweight, critically ill patients. Further studies need to be conducted that assess the safety and efficacy of reduced-dose VTE prophylactic regimens in this population to determine if acceptable efficacy can be achieved, with lower risks of bleeding.

Levodopa Withdrawal Presenting as Fever in a Critically Ill Patient Receiving Concomitant Enteral Nutrition.

Nutritional protein may decrease levodopa absorption and has resulted in withdrawal and neuroleptic malignant-like syndromes in critically ill patients. A 72-year-old male was admitted with shortness of breath. His medical history included Parkinson's disease for over 30 years for which he took carbidopa/levodopa 5 times daily. The patient's home medications were continued. On day 2, he was intubated and transferred to the intensive care unit (ICU). He was extubated the next day and reintubated on day 4. Enteral nutrition was initiated at 85 mL/h overnight. The patient's carbidopa/levodopa was administered to limit coadministration with nutrition. Throughout his ICU stay, the patient did not demonstrate changes in mental status. Despite resolution of his pneumonia, he developed fever after administration of one dose overlapping with nutrition, with defervescence throughout the rest of the day. On hospital day 10, that dose was empirically increased. After this dosing change, the patient failed to develop fever during the rest of his hospital stay. On day 16, the patient was discharged to a long-term care facility without any other complications. Our case highlights the interaction between levodopa and enteral nutrition and the potential of fever as the sole sign of withdrawal.

Multiple estimates of effective population size for monitoring a long-lived vertebrate: an application to Yellowstone grizzly bears.

Effective population size (N(e)) is a key parameter for monitoring the genetic health of threatened populations because it reflects a population's evolutionary potential and risk of extinction due to genetic stochasticity. However, its application to wildlife monitoring has been limited because it is difficult to measure in natural populations. The isolated and well-studied population of grizzly bears (Ursus arctos) in the Greater Yellowstone Ecosystem provides a rare opportunity to examine the usefulness of different N(e) estimators for monitoring. We genotyped 729 Yellowstone grizzly bears using 20 microsatellites and applied three single-sample estimators to examine contemporary trends in generation interval (GI), effective number of breeders (N(b)) and N(e) during 1982-2007. We also used multisample methods to estimate variance (N(eV)) and inbreeding N(e) (N(eI)). Single-sample estimates revealed positive trajectories, with over a fourfold increase in N(e) (≈100 to 450) and near doubling of the GI (≈8 to 14) from the 1980s to 2000s. N(eV) (240-319) and N(eI) (256) were comparable with the harmonic mean single-sample N(e) (213) over the time period. Reanalysing historical data, we found N(eV) increased from ≈80 in the 1910s-1960s to ≈280 in the contemporary population. The estimated ratio of effective to total census size (N(e) /N(c)) was stable and high (0.42-0.66) compared to previous brown bear studies. These results support independent demographic evidence for Yellowstone grizzly bear population growth since the 1980s. They further demonstrate how genetic monitoring of N(e) can complement demographic-based monitoring of N(c) and vital rates, providing a valuable tool for wildlife managers.

Nalbuphine-induced psychosis treated with naloxone.

PURPOSE: A case of nalbuphine-induced psychosis, which resolved after the administration of naloxone, is described. SUMMARY: A 25-year-old African-American woman with a history of systemic lupus erythematosus was admitted to the hospital for management of cholecystitis. A laparoscopic cholecystectomy was performed, and the patient received multiple doses of i.v. hydromorphone for postoperative pain management. Four days later, shortly after receiving a dose of i.v. nalbuphine for opioid-induced pruritus, she experienced an acute psychotic event, with symptoms including intense headache, akathisia, altered mental status, and formication (a hallucinatory sensation of insects crawling on the skin). The neuropsychiatric symptoms abated within 5 minutes of two consecutively administered doses of i.v. naloxone. During this event, which lasted 25-30 minutes, there was no evidence of metabolic abnormalities and were no signs of infection. The patient did not have a history of mental illness or substance abuse. The patient did not receive further doses of nalbuphine and did not experience similar events during her hospital stay; she was discharged home 10 days later without further complications. According to the algorithm of Naranjo et al., the case was assigned a score of 6, indicating a probable adverse reaction to nalbuphine. CONCLUSION: A patient developed an acute psychotic reaction that was probably secondary to administration of i.v. nalbuphine for opioid-induced pruritus. Evidence supporting this diagnosis included correlation between the timing of administration of nalbuphine and symptom onset and the marked improvement in mentation following the administration of naloxone.

Methylprednisolone sodium succinate-associated macroglossia in a critically ill patient.

Allergic hypersensitivity reactions are a rare adverse effect of corticosteroids. Previous reports have identified patients who developed symptoms of urticaria, dyspnea, hypotension, bronchospasm, and angioedema occurring within minutes to an hour after corticosteroid administration. A 35-year-old woman is described who developed an atypical reaction of isolated macroglossia after receiving intravenous methylprednisolone sodium succinate for myasthenic crisis. Macroglossia was identified on day 2 of therapy and worsened through day 5. On day 5, she was transitioned to prednisone 50 mg daily administered by feeding tube. Tongue swelling improved by day 7 and on day 10, the patient was extubated. The patient required reintubation due to stridor, but received a tracheostomy and was weaned off mechanical ventilation by day 15. The reaction was not confirmed with skin-prick tests, intradermal tests, or a drug rechallenge; however, she had previously received and tolerated all other drugs administered during this time. Due to the timing of administration and onset of symptoms, we feel this adverse drug reaction was likely due to administration of methylprednisolone. Applying the Naranjo adverse drug reaction probability scale to this case, a score of six was obtained, indicating a probable association between the administration of methylprednisolone and the development of macroglossia. As intravenous corticosteroids are often used in the treatment of allergic reactions, they may be overlooked as a cause of macroglossia and other allergic reactions; therefore, practitioners need to be aware of the possibility of this adverse effect secondary to corticosteroid administration. In the event of methylprednisolone sodium succinate-induced macroglossia, alternative nonesterified corticosteroids, such as dexamethasone or prednisone, should be considered if continuation of therapy is required.

Possible case of nafcillin-induced acute interstitial nephritis.

PURPOSE: To report a case of acute interstitial nephritis (AIN) secondary to nafcillin. SUMMARY: A 55-year-old Hispanic man (height, 63 in.; weight, 61.2 kg) with a history of deep vein thrombosis in the right lower extremity, hypertension, hyperlipidemia, and hepatitis C infection was admitted to the hospital with right-sided chest pain that radiated down his right arm and leg. The patient was diagnosed with methicillin-sensitive Staphylococcus aureus endocarditis. A renal ultrasound was performed on hospital day 9 after the patient developed acute renal failure and showed diffusely increasing echogenicity of the renal parenchymal bilaterally with an interpolar cyst in the left kidney. A urine analysis, serum chemistry panels, and complete blood counts were consistent with AIN. The patient received a total of seven days of nafcillin, and cefazolin was initiated. A renal ultrasound and renal biopsy were performed, which confirmed the diagnosis of AIN. The patient received short-term hemodialysis, after which his renal function slowly returned to baseline. He then underwent an aortic valve replacement and tricuspid valve repair. His antibiotics were changed to rifampin and vancomycin after methicillin-resistant S. aureus was found in an aortic valve culture on hospital day 26. Cefazolin was discontinued 3 days after rifampin and vancomycin were added. The patient received 18 more days of antibiotics and was discharged on the last day of therapy (hospital day 45). CONCLUSION: A 55-year-old, critically ill man developed a possible case of nafcillin-induced AIN after receiving a 7-day course of treatment with the drug.

Fidaxomicin for the treatment of Clostridium difficile infections.

OBJECTIVE: To evaluate the pharmacology, microbiology, safety, and efficacy of fidaxomicin for treatment of Clostridium difficile infections (CDI). DATA SOURCES: Literature was identified through Ovid MEDLINE (1948-December 2011) and International Pharmaceutical Abstracts (1970-December 2011) using the search terms fidaxomicin, OPT-80, PAR-101, OP-118, difimicin, tiacumicin, lipiarmycin, Clostridium difficile, Clostridium difficile infection, Clostridium difficile-associated diarrhea, and cost. Drug monographs were retrieved from manufacturers' Web pages, and the Red Book component of Micromedex was used for cost information. STUDY SELECTION AND DATA EXTRACTION: All pertinent Phase 1, 2, and 3 studies published in English were included. DATA SYNTHESIS: Fidaxomicin is a macrocyclic compound bactericidal against C. difficile and inhibits toxin and spore production. It has poor oral absorption with high fecal concentrations. Available Phase 2 and 3 data with fidaxomicin 200 mg orally every 12 hours demonstrate similar effectiveness in treating CDI compared to oral vancomycin. Fidaxomicin was shown to have less frequency of recurrent infections. Adverse effects are uncommon and occur at similar rates as with oral vancomycin. The most frequently reported adverse effects are gastrointestinal, hematologic, and electrolyte disorders. Available data are lacking in several areas, including the efficacy and safety of fidaxomicin compared to established regimens for mild-to-moderate, life-threatening, and recurrent CDIs. The cost of a 10-day course of fidaxomicin is significantly more than that of metronidazole and vancomycin for treatment of mild-to-moderate CDI. CONCLUSIONS: Fidaxomicin appears to be an effective and safe alternative to oral vancomycin for treatment of mild-to-moderate and severe CDI. Data on its use compared to guideline-recommended therapies for mild-to-moderate and life-threatening CDI are needed. Further data assessing the cost-effectiveness of fidaxomicin are needed. Currently, it cannot be recommended over vancomycin for treatment of CDI. However, it may be considered for treatment of recurrent infections.

Computer-based simulation training to improve learning outcomes in mannequin-based simulation exercises.

OBJECTIVE: To assess the impact of computer-based simulation on the achievement of student learning outcomes during mannequin-based simulation. DESIGN: Participants were randomly assigned to rapid response teams of 5-6 students and then teams were randomly assigned to either a group that completed either computer-based or mannequin-based simulation cases first. In both simulations, students used their critical thinking skills and selected interventions independent of facilitator input. ASSESSMENT: A predetermined rubric was used to record and assess students' performance in the mannequin-based simulations. Feedback and student performance scores were generated by the software in the computer-based simulations. More of the teams in the group that completed the computer-based simulation before completing the mannequin-based simulation achieved the primary outcome for the exercise, which was survival of the simulated patient (41.2% vs. 5.6%). The majority of students (>90%) recommended the continuation of simulation exercises in the course. Students in both groups felt the computer-based simulation should be completed prior to the mannequin-based simulation. CONCLUSION: The use of computer-based simulation prior to mannequin-based simulation improved the achievement of learning goals and outcomes. In addition to improving participants' skills, completing the computer-based simulation first may improve participants' confidence during the more real-life setting achieved in the mannequin-based simulation.

Cephalosporin-induced leukopenia following rechallenge with cefoxitin.

OBJECTIVE: To describe a case of cefazolin-induced leukopenia in a critically ill patient who developed this adverse reaction upon rechallenge with cefoxitin. CASE SUMMARY: A 22-year-old male was admitted after a motor vehicle crash. beta-Lactam therapy was initiated with vancomycin, cefepime, and metronidazole and, upon identification of methicillin-sensitive Staphylococcus aureus bacteremia 4 days later, therapy was narrowed to cefazolin 1 g every 12 hours. The dose was adjusted to 1 g every 12 hours during continuous venovenous hemodialysis. Imipenem was given for 2 days, resulting in a total of 18 days of beta-lactam treatment, at which time he developed significant leukopenia (white blood cell [WBC] count 0.9 x 10(3)/microL). Antimicrobial treatment was changed to tigecycline and continued for suspected pleural space infection. The patient's WBC count recovered within 4 days after the change in therapy. He was taken to surgery 8 days after cefazolin was discontinued and received perioperative prophylaxis with cefoxitin (total dose 3 g). Subsequently, the patient again became severely leukopenic (WBC count 2.4 x 10(3)/microL). Within a week after surgery, the patient developed septic shock secondary to multidrug-resistant Escherichia coli bacteremia and died. DISCUSSION: beta-Lactam-induced leukopenia is a rare but well-described adverse drug reaction. It is a cumulative dose-dependent phenomenon reported to occur most often after 2 weeks of therapy. The mechanism of leukopenia is thought to be secondary to either an immune-mediated response or direct bone marrow toxicity. Rechallenge with a different beta-lactam antibiotic has not been shown to consistently cause recurrent leukopenia. The case described here suggests an immune-related mechanism for the development of leukopenia. Use of the Naranjo probability scale determined the association between cephalosporin use and leukopenia to be probable. CONCLUSIONS: Cefazolin was a probable cause of this patient's leukopenia. It is important for clinicians to recognize beta-lactam-induced leukopenia and maybe recommend use of a drug from a different antibiotic class if continued treatment is indicated.

Efficacy of aminophylline for treatment of recurrent symptomatic bradycardia after spinal cord injury.

Cardiac dysrhythmias and cardiac arrest can occur after acute spinal cord injury (SCI). Disrupted sympathetic innervation after SCI results in unopposed parasympathetic activity leading to baseline bradycardia. Hence, vagal stimulation can result in episodes of exaggerated symptomatic bradycardia. Data supporting pharmacologic intervention for treatment of symptomatic bradycardia after SCI are limited. We describe a patient who sustained a high cervical SCI and subsequently developed episodic symptomatic bradycardia. The addition of aminophylline to the patient's therapeutic regimen was associated with resolution of the bradycardia. Throughout her treatment course, the patient's serum theophylline concentrations were 1.9-3.4 mg/L. These levels were consistent with those identified in other case reports describing treatment with methylxanthines to prevent episodic bradycardia after SCI. Our understanding of drug pharmacokinetics and pharmacodynamics in patients with acute SCI is limited and provides an ideal opportunity for further study in this area.