Coupled social and ecological change drove the historical extinction of the California grizzly bear (Ursus arctos californicus).

Large carnivores (order Carnivora) are among the world's most threatened mammals due to a confluence of ecological and social forces that have unfolded over centuries. Combining specimens from natural history collections with documents from archival records, we reconstructed the factors surrounding the extinction of the California grizzly bear (Ursus arctos californicus), a once-abundant brown bear subspecies last seen in 1924. Historical documents portrayed California grizzlies as massive hypercarnivores that endangered public safety. Yet, morphological measurements on skulls and teeth generate smaller body size estimates in alignment with extant North American grizzly populations (approx. 200 kg). Stable isotope analysis (δ13C, δ15N) of pelts and bones (n = 57) revealed that grizzlies derived less than 10% of their nutrition from terrestrial animal sources and were therefore largely herbivorous for millennia prior to the first European arrival in this region in 1542. Later colonial land uses, beginning in 1769 with the Mission era, led grizzlies to moderately increase animal protein consumption (up to 26% of diet), but grizzlies still consumed far less livestock than otherwise claimed by contemporary accounts. We show how human activities can provoke short-term behavioural shifts, such as heightened levels of carnivory, that in turn can lead to exaggerated predation narratives and incentivize persecution, triggering rapid loss of an otherwise widespread and ecologically flexible animal.

Gastroesophageal junction adenocarcinoma 1-year after sleeve gastrectomy.

Gastroesophageal malignancy after sleeve gastrectomy is rare. A 70-year-old male with a BMI of 46 underwent laparoscopic sleeve gastrectomy with normal endoscopy. By 10 months postop, the patient had reduced BMI to 30.5. Eleven months postop, he presented with emesis and endoscopy showed severe stenosis at the gastroesophageal junction with EUS showing a circumferential mass. Patient had adenocarcinoma of the distal esophagus HER 3+ and MMR proficient, clinical T2N1. He underwent esophageal stent placement followed by FOLFOX switched to carboplatin-Taxol with radiation therapy complicated by a localized perforation requiring antibiotics. After PET scan of esophageal mass indicated response, he underwent an open distal esophagectomy, total gastrectomy with Roux-en-Y esophagojejunostomy, and placement of feeding tube. Pathology revealed poorly differentiated invasive adenocarcinoma with negative margins. In the USA, this represents only the second adenocarcinoma following a sleeve gastrectomy and the first in a non-immune compromised patient.

Analogies for a No-Analog World: Tackling Uncertainties in Reintroduction Planning.

Species reintroductions involve considerable uncertainty, especially in highly altered landscapes. Historical, geographic, and taxonomic analogies can help reduce this uncertainty by enabling conservationists to better assess habitat suitability in proposed reintroduction sites. We illustrate this approach using the example of the California grizzly, an iconic species proposed for reintroduction.

Bilateral variations of brachial plexus involving the median nerve and lateral cord: An anatomical case study with clinical implications.

During the routine dissection of upper limbs of a Caucasian male cadaver, variations were observed in the brachial plexus. In the right extremity, the lateral cord was piercing the coracobrachialis muscle. The musculocutaneous nerve and lateral root of the median nerve were observed to be branching inferior to the lower attachment of coracobrachialis muscle. The left extremity exhibited the passage of the median nerve through the flat tendon of the coracobrachialis muscle near its distal insertion into the medial surface of the body of humerus. A variation in the course and branching of the nerve might lead to variant or dual innervation of a muscle and, if inappropriately compressed, could result in a distal neuropathy. Identification of these variants of brachial plexus plays an especially important role in both clinical diagnosis and surgical practice.

Single- and multiple-dose pharmacokinetics of darunavir plus ritonavir and etravirine in semen and rectal tissue of HIV-negative men.

BACKGROUND: Antiretroviral therapy has become a central component of combination in HIV prevention efforts. Defining the individual exposure of commercially available antiretroviral therapy in genital secretions and vulnerable mucosal tissues is paramount to designing future prevention interventions. METHODS: A pharmacokinetic (PK) study was performed in 12 HIV-negative men receiving 600 mg of darunavir, 100 mg of ritonavir, and 200 mg of etravirine orally, twice daily for 8 days. Seven blood plasma (BP) samples were collected over 12 hours on day 1 (PK1) and days 7 and 8 (PK2). One rectal tissue (RT) sample from each subject was collected during PK1 and PK2. During PK1, 2 seminal plasma (SP) samples were collected from each subject. During PK2, 6 SP samples were collected from each subject over 2 days. RESULTS: Antiretrovirals were detected in SP and RT within 1 hour after a single dose. Over PK1 and PK2, SP exposures were lower than BP by 80%-92% (DRV), 89-95% (RTV), and 83-88% (ETR). However, protein binding in SP (14% for darunavir, 70% for ritonavir, and 97% for etravirine) was lower than in BP. Rectal tissue exposures were higher than BP by 39- to 155-fold for darunavir, 12- to 61-fold for ritonavir, and 20- to 40-fold for etravirine. CONCLUSIONS: Lower SP protein binding resulted in higher pharmacologically active darunavir and etravirine concentrations compared with BP. High RT concentrations may also be favorable for suppressing viral replication in the gastrointestinal mucosa. The high protein-unbound exposures in SP and total exposures in RT support further investigations of darunavir plus ritonavir and etravirine in secondary prevention.

Exploration of CYP450 and drug transporter genotypes and correlations with nevirapine exposure in Malawians.

AIM: Genetic polymorphisms have the potential to influence drug metabolism and vary among ethnic groups. This study evaluated the correlation of genetic polymorphisms with nevirapine pharmacokinetics exposure in Malawians. MATERIALS & METHODS: CYP450 2B6, 2D6, 3A4 and 3A5, ABCB1 and constitutive androstane receptor and pregnane X receptor, were analyzed for polymorphisms in 26 subjects. RESULTS: Allele frequencies (variant) were: CYP2B6 514G>T (0.31) CYP2D6*4 (0.02); CYP2D6*17 (0.35); CYP3A4*1B (0.77); CYP3A5*3 (0.25); ABCB1 2677G>T (0.0), ABCB1 3435C>T (0.21), NR1I3 13711152T>C (0.02), NR1I2 44477T>C (0.10), NR1I2 63396C>T (0.33), NR1I2 6-bp indel (del: 0.17). CYP2B6 516G>T (non-wild-type/wild-type) correlated with nevirapine pharmacokinetic parameters; geometric mean ratios (95% CI): 1.75 (1.27-2.40) for area under the concentration time curve (AUC)(0-12 h), 1.58 (1.03-2.42) for C(0), and 0.53 (0.31-0.91) for clearance. In a multivariable model, nevirapine AUC increased by 1.5% per year of age (p < 0.0001), CYP2B6 516 T allele increased AUC by 92% (p < 0.0001), and CYP3A5*3 decreased AUC by 31% (p = 0.0027). CONCLUSION: Allele frequencies were similar to other sub-Saharan African populations. The T allele for CYP2B6 516 was significantly associated with nevirapine exposure.

Single and multiple dose pharmacokinetics of maraviroc in saliva, semen, and rectal tissue of healthy HIV-negative men.

BACKGROUND: Antiretroviral pharmacology in seminal plasma (SP) and rectal tissue (RT) may provide insight into antiretroviral resistance and the prevention of sexual transmission of human immunodeficiency virus (HIV). Saliva may be of utility for noninvasively measuring adherence. METHODS: A pharmacokinetic study was performed in 12 HIV-negative men receiving maraviroc 300 mg twice daily for 8 days. Seven time-matched pairs of blood plasma (BP) and saliva samples were collected over 12 h on day 1 (PK1) and days 7 and 8 (PK2). One RT sample from each subject was collected during PK1 and PK2. Two SP samples were collected from each subject during PK1, and 6 SP samples were collected from each subject during PK2. RESULTS: SP AUCs were ∼50% lower than BP. However, protein binding in SP ranged from 4% to 25%, resulting in protein-free concentrations >2-fold higher than BP. RT AUCs were 7.5- to 26-fold higher than BP. Maraviroc saliva AUCs were ∼70% lower than BP, but saliva concentrations correlated with BP (r(2) = 0.58). CONCLUSIONS: More pharmacologically available maraviroc was found in SP than BP. High RT concentrations are promising for preventing rectal HIV acquisition. Saliva correlation with BP suggests that this may be useful for monitoring adherence. CLINICAL TRIALS REGISTRATION: NCT00775294.

Variability in drug metabolizing enzyme activity in HIV-infected patients.

AIMS: To evaluate variability in cytochrome P450 (CYP) 1A2, CYP2D6, CYP3A, N-acetyltransferase 2 (NAT2), and xanthine oxidase (XO) activity in HIV-infected patients and compare this with data from uninfected, healthy volunteers. METHODS: Ten HIV-infected men and seven women on medication affecting CYP enzyme activity were phenotyped four times over 2 months using caffeine, dextromethorphan, and midazolam. Urinary caffeine and dextromethorphan metabolite ratios were used to phenotype CYP1A2, NAT2, XO, and CYP2D6 activity and midazolam plasma clearance was used to phenotype CYP3A activity. Plasma and urine samples were analyzed by validated LC/UV or LC/MS methods for midazolam, caffeine, and dextromethorphan. Noncompartmental pharmacokinetics and nonparametric statistical analyses were performed, and the data compared with those of healthy volunteer historic controls. RESULTS: Compared with age and sex-matched healthy volunteers, HIV-infected subjects had 18% lower hepatic CYP3A4 activity, 90% lower CYP2D6 activity, 53% lower NAT2 activity, and 22% higher XO activity. No significant difference was found in CYP1A2 activity. Additionally, 25% genotype-phenotype discordance in CYP2D6 activity was noted in HIV-infected subjects. Intraindividual variability in enzyme activity increased by 42-62% in HIV-infected patients for CYP1A2, NAT2, and XO, and decreased by 33% for CYP2D6. Interindividual variability in enzyme activity increased by 27-63% in HIV-infected subjects for CYP2D6, CYP1A2, and XO, and decreased by 38% for NAT2. Higher plasma TNFalpha concentrations correlated with lower CYP2D6 and CYP3A4 activity. CONCLUSIONS: Infection with HIV or stage of HIV infection may alter Phase I and II drug metabolizing enzyme activity. HIV infection was related to an increase in variability of these drug-metabolizing enzymes. Altered metabolism may be a consequence of immune activation and cytokine exposure.

Drug interactions with new and investigational antiretrovirals.

More than 20 individual and fixed-dose combinations of antiretrovirals are approved for the treatment of human immunodeficiency virus (HIV) infection. However, owing to the ongoing limitations of drug resistance and adverse effects, new treatment options are still required. A number of promising new agents in existing or new drug classes are in development or have recently been approved by the US FDA. Since these agents will be used in combination with other new and existing antiretrovirals, understanding the potential for drug interactions between these compounds is critical to their appropriate use. This article summarizes the drug interaction potential of new and investigational protease inhibitors (darunavir), non-nucleoside reverse transcriptase inhibitors (etravirine and rilpivirine), chemokine receptor antagonists (maraviroc, vicriviroc and INCB 9471), integrase inhibitors (raltegravir and elvitegravir) and maturation inhibitors (bevirimat).

A simple and sensitive bioanalytical assay for simultaneous determination of omeprazole and its three major metabolites in human blood plasma using RP-HPLC after a simple liquid-liquid extraction procedure.

A simple, sensitive and specific reverse-phase high-performance liquid chromatography (HPLC) assay for the simultaneous quantitative determination of omeprazole and its three metabolites in human plasma was developed and validated. This method provides excellent chromatographic resolution and peak shape for the four components and the internal standard within a 17 min run time. The simple extraction method results in a clean base line and relatively high extraction efficiency. The method was validated over the range of 2-2000 ng/mL, with 2.0 ng/mL as the lower limit of quantification. Within- and between-day accuracies for five different concentrations ranged from 95 to 102%, and 95 to 114%, respectively. Within- and between-day precision ranged from 1.1 to 6.3% and 0.5 to 6.2%, respectively. Simplicity and high throughput make this method suitable for clinical pharmacokinetic studies.