Indo-Pacific Walker circulation drove Pleistocene African aridification.

Today, the eastern African hydroclimate is tightly linked to fluctuations in the zonal atmospheric Walker circulation1,2. A growing body of evidence indicates that this circulation shaped hydroclimatic conditions in the Indian Ocean region also on much longer, glacial-interglacial timescales3-5, following the development of Pacific Walker circulation around 2.2-2.0 million years ago (Ma)6,7. However, continuous long-term records to determine the timing and mechanisms of Pacific-influenced climate transitions in the Indian Ocean have been unavailable. Here we present a seven-million-year-long record of wind-driven circulation of the tropical Indian Ocean, as recorded in Mozambique Channel Throughflow (MCT) flow-speed variations. We show that the MCT flow speed was relatively weak and steady until 2.1 ± 0.1 Ma, when it began to increase, coincident with the intensification of the Pacific Walker circulation6,7. Strong increases during glacial periods, which reached maxima after the Mid-Pleistocene Transition (0.9-0.64 Ma; ref. 8), were punctuated by weak flow speeds during interglacial periods. We provide a mechanism explaining that increasing MCT flow speeds reflect synchronous development of the Indo-Pacific Walker cells that promote aridification in Africa. Our results suggest that after about 2.1 Ma, the increasing aridification is punctuated by pronounced humid interglacial periods. This record will facilitate testing of hypotheses of climate-environmental drivers for hominin evolution and dispersal.

Phase I study of axitinib combined with paclitaxel, docetaxel or capecitabine in patients with advanced solid tumours.

BACKGROUND: Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, enhanced the efficacy of chemotherapy in human xenograft tumour models. This phase I study investigated the safety, tolerability, pharmacokinetics and antitumour activity of axitinib combined with chemotherapy. METHODS: A total of 42 patients with advanced solid tumours received a continuous axitinib starting dose of 5 mg twice daily (b.i.d.) plus paclitaxel (90 mg m(-2) weekly), docetaxel (100 mg m(-2) every 3 weeks) or capecitabine (1000 or 1250 mg m(-2) b.i.d., days 1-14). RESULTS: Common treatment-related adverse events across all cohorts were nausea (45.2%), hypertension (45.2%), fatigue (42.9%), diarrhoea (38.1%), decreased appetite (33.3%) and hand-foot syndrome (31.0%). There was one complete response, nine partial responses and seven patients with stable disease. Ten patients (23.8%) remained on therapy for >8 months. Paclitaxel and capecitabine pharmacokinetics were similar in the absence or presence of axitinib, but docetaxel exposure was increased in the presence of axitinib. Axitinib pharmacokinetics were similar in the absence or presence of co-administered agents. CONCLUSIONS: Axitinib combined with paclitaxel or capecitabine was well tolerated; no additive increase in toxicities was observed. Antitumour activity was observed for each treatment regimen and across multiple tumour types.

An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer.

BACKGROUND: Sunitinib has shown single-agent activity in patients with previously treated metastatic breast cancer (MBC). We investigated the safety of the combination of sunitinib and paclitaxel in an exploratory study of patients with locally advanced or MBC. METHODS: Patients received oral sunitinib 25 mg/day (with escalation to 37.5 mg/day as tolerated) on a continuous daily dosing schedule and paclitaxel 90 mg/m(2) on days 1, 8, and 15 of each 28-day cycle. Study endpoints included safety (primary endpoint), pharmacokinetics, and antitumor activity. RESULTS: Twenty-two patients were enrolled. The most frequent adverse events (AEs) were fatigue/asthenia (77%), dysgeusia (68%), and diarrhea (64%). Grade 3 AEs included neutropenia (43%), fatigue/asthenia (27%), neuropathy (18%), and diarrhea (14%). No drug-drug interaction was observed on the basis of pharmacokinetic analysis. Of 18 patients with measurable disease at baseline, 7 (38.9%) achieved objective responses (including 2 complete and 5 partial responses). Clinical responses were observed in three of nine patients with triple-negative receptor status (estrogen receptor negative, progesterone receptor negative, and human epidermal growth factor receptor-2 negative). CONCLUSIONS: These data indicate that sunitinib and paclitaxel in combination are well tolerated in patients with locally advanced or MBC. No drug-drug interaction was detected and there was preliminary evidence of antitumor activity.

Task-relevant late positive component of the auditory event-related potential in monkeys resembles P300 in humans.

A long-latency (300-millisecond), vertex-positive component of the event-related potential recorded from monkeys was present only when the eliciting stimulus was relevant to the task. The amplitude of this component varied inversely with stimulus probability and was dissociable from motor responses.

Endogenous late positive component of the evoked potential in cats corresponding to P300 in humans.

A long-latency component of the averaged evoked potential recorded from cats was present only when the evoking stimulus was relevant to the task. The amplitude of this component varied inversely with stimulus probability and was independent of stimulus modality.

Acute effects of alcohol on auditory brainstem potentials in humans.

Auditory brainstem potentials were recorded from human subjects before and after an intoxicating dose of alcohol. Following alcohol ingestion there were significant, progressive increases in the latencies of brainstem potential peaks III through VII. No changes in peak amplitudes were found. The results indicate that alcohol has a depressive effect on neural transmission within the primary auditory brainstem pathway.

Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling.

Several distinct mutations within the kinase domain of the epidermal growth factor receptor (EGFR) are associated with non-small cell lung cancer, but mechanisms underlying their oncogenic potential are incompletely understood. Although normally ligand-induced kinase activation targets EGFR to Cbl-mediated receptor ubiquitinylation and subsequent degradation in lysosomes, we report that certain EGFR mutants escape this regulation. Defective endocytosis characterizes a deletion mutant of EGFR, as well as a point mutant (L858R-EGFR), whose association with c-Cbl and ubiquitinylation are impaired. Our data raise the possibility that refractoriness of L858R-EGFR to downregulation is due to enhanced heterodimerization with the oncogene product HER2, which leads to persistent stimulation.

Bone marrow edema: pathophysiology, differential diagnosis, and imaging.

Bone marrow edema (BME) has been a topic of increasing interest in the literature in recent years. BME is associated with numerous pathologies and is becoming recognized not only as a considerable pain generator, but also as an entity which is, in some cases, significantly linked to the worsening of patient prognosis. To date, no thorough imaging review of BME has been published. An electronic literature search was conducted through PubMed with a time parameter of January 1975 through December 2007. The primary search parameter was "bone marrow edema." Over 800 papers were listed as written in English and involving humans. Other refining parameters included "AND syndrome," "AND transient," "AND arthritis," "AND infection," "AND tumor," "AND neoplasm," "AND iatrogenic," "AND radiation therapy," and "AND inflammation." More current articles were favored over dated articles on the same topic. A total of 106 journal articles were collected concerning BME and multiple pathologic processes. The data contained therein was compiled and organized into a comprehensive format. BME can be caused by, and found concurrent with, a broad spectrum of pathologies which exhibit a variety of imaging findings. BME is also associated with the deterioration of certain pathologies. This presentation is a comprehensive discussion of different pathological conditions inducing or associated with BME. Differential diagnosis through appropriate imaging is vital to case management and could contribute to the prevention or decreased progression of certain pathologies. Continued investigation into the imaging of BME and its associated diseases, as well as the effect of BME on prognosis, is warranted.

Nuclear and cytoplasmic expression of ErbB-4 in prostate cancer.

PURPOSE: To evaluate cytoplasmic and nuclear ErbB-4 expression in prostate cancer specimens and its association with outcome. BASIC PROCEDURES: Specimens of 50 prostate cancer patients were investigated for ErbB-4 overexpression using Immunohistochemistry staining. Cytoplasmic and nuclear staining was graded as 0-3 according to its intensity. The prognostic parameters were tumor stage, PSA level, Gleason score, probability of positive lymph nodes (Partin's tables and Roach equation), and 5-year disease free survival (Kattan nomogram). MAIN FINDINGS: Overexpression of ErbB-4 (> or = 1) was detected in 30 (60%) patients and overexpression using cytoplasmic and nuclear staining was > or = 2 in 19 (38%) and 17 (34%) patients, respectively. In only one third of the specimens was there any similarity between the 2 types of staining. Advanced tumor stage, high pretreatment PSA levels and high Gleason scores were evenly distributed among the patients with low (< or = 1) and intermediate/high (> or = 2) ErbB-4 expression. The probability of lymph node involvement and 5-year disease free survival were similar in both types of staining. PRINCIPAL CONCLUSIONS: ErbB-4 was overexpressed (cytoplasmic and nuclear staining) in approximately one third of prostate cancer patients. The rate of similarity between the 2 staining types was only 33%: overexpression was evenly distributed among intermediate/high and low risk prostate cancer patients with both staining methods.

OTOF mutations revealed by genetic analysis of hearing loss families including a potential temperature sensitive auditory neuropathy allele.

INTRODUCTION: The majority of hearing loss in children can be accounted for by genetic causes. Non-syndromic hearing loss accounts for 80% of genetic hearing loss in children, with mutations in DFNB1/GJB2 being by far the most common cause. Among the second tier genetic causes of hearing loss in children are mutations in the DFNB9/OTOF gene. METHODS: In total, 65 recessive non-syndromic hearing loss families were screened by genotyping for association with the DFNB9/OTOF gene. Families with genotypes consistent with linkage or uninformative for linkage to this gene region were further screened for mutations in the 48 known coding exons of otoferlin. RESULTS: Eight OTOF pathological variants were discovered in six families. Of these, Q829X was found in two families. We also noted 23 other coding variant, believed to have no pathology. A previously published missense allele I515T was found in the heterozygous state in an individual who was observed to be temperature sensitive for the auditory neuropathy phenotype. CONCLUSIONS: Mutations in OTOF cause both profound hearing loss and a type of hearing loss where otoacoustic emissions are spared called auditory neuropathy.

The Starr-Edwards valve.

This report reviews the results obtained with the current models of the Silastic ball valve, classifying the experience with the mitral and aortic models into the periods (formula: see text) before and after 1973. Valve failure is defined according to the Stanford method and includes any valve-related death or complication necessitating valve removal (there have been no mechanical failures). Comparison of the valve model used today with the same model used in the late 1960s shows that the results have improved dramatically, especially with regard to thromboembolism. The results obtained with valves implanted after 1973 compare favorably with those of other contemporary valves introduced in the early 1970s.

Survival 15 to 20 years after coronary bypass surgery for angina.

OBJECTIVES: The aim of this study was to determine the 15- to 20-year outcome of coronary bypass surgery in patients with angina. BACKGROUND: Coronary bypass surgery has been performed for > 20 years; we need to know the expected outcome of a very long-term follow-up. METHODS: Using actuarial techniques, we determined the outcome of coronary bypass surgery performed for chronic stable and unstable angina in 7,529 patients from 1969 to 1988. RESULTS: The 5-, 10-, 15- and 20-year survival rates (mean +/- SE) were 88 +/- 1, 73 +/- 1, 53 +/- 1 and 38 +/- 3%, respectively, for the whole group. Compared with patients operated on in 1974 to 1988 (n = 7,026), patients operated on in 1969 to 1973 (n = 503) were younger and had less coronary artery disease but had a higher operative mortality rate and a shorter long-term survival time; 15- and 20-year survival of the 1969 to 1973 cohort was 47 +/- 2% and 33 +/- 3%, respectively. The 1974 to 1988 cohort of patients had a 2.1% operative mortality rate and a 10- and 15-year survival probability of 74 +/- 1% and 55 +/- 2%, respectively. For 2,128 patients with "normal" left ventricular function, the 10- and 15-year survival probability was 82 +/- 1% and 64 +/- 3%, respectively, and for 2,413 patients with "abnormal" left ventricular function, it was 66 +/- 1% and 47 +/- 3%, respectively (p < 0.0001); for men it was 74 +/- 1% and 56 +/- 2%, respectively, and for women, 70 +/- 2% and 52 +/- 5%, respectively, p < 0.05. The actuarial percentages of reoperation and myocardial infarction at 15 years were 33 +/- 2% and 26 +/- 2%, respectively; these values did not differ significantly between men and women. There was a significant (p < 0.001) difference between men and women in angina status; 81% of the men versus 74% of the women had no angina or mild angina at the most recent follow-up study. CONCLUSIONS: Coronary bypass surgery is an effective form of therapy for angina (for 15 to 20 years) in both men and women.

Thrombosis of mechanical cardiac valves: a qualitative comparison of the silastic ball valve and the tilting disc valve.

A review of 817 mitral and aortic Silastic ball valve implantations with a follow-up of 3,554 total patient-years yielded only seven cases of valve thrombosis. Time-related risk was 0.4% per patient-year in the mitral position and 0.1% per patient-year in the aortic position. Four of five mitral and one of two aortic ball valve thromboses were successfully managed by valve rereplacement . At least five of the seven patients presented with a prodrome (lasting at least 3 months) of symptoms of progressive heart failure and, occasionally, embolic episodes due to gradually increasing prosthetic stenosis by thrombus. This lengthy time course is in contrast to the more frequent rapid catastrophic thrombosis that occurs with the Björk-Shiley tilting disc valve. Recognition of the prodrome of Silastic ball valve thrombosis provides an opportunity for life-saving surgical intervention.

Late results of combined mitral valve replacement and coronary bypass surgery.

The incremental risk of coronary bypass surgery was analyzed in 718 patients undergoing mitral valve replacement between 1971 and 1983. Ninety-eight patients (14%) had significant coronary artery disease requiring coronary bypass surgery. In 70 of these patients, the origin of the mitral valve disease was nonischemic, whereas 28 patients had ischemic mitral regurgitation unsuitable for conservative valve surgery. There were six operative deaths (9%) and four perioperative myocardial infarctions (6%) after mitral valve replacement and coronary bypass surgery for nonischemic mitral valve disease. Operative mortality was related to low output cardiac failure before operation or perioperative myocardial infarction. Actuarial curves predict survival (+/- standard error) of 55 +/- 7% at 5 years and 43 +/- 8% at 10 years. Preoperative functional class was the only significant predictor of long-term survival in this group (p less than 0.05). The actuarial survival of the 620 patients without coronary artery disease who underwent mitral valve replacement alone was 63 +/- 3% at 10 years. This was significantly better than that of the 70 patients who underwent mitral valve replacement and coronary bypass surgery for nonischemic mitral valve disease (p less than 0.001). Conversely, 5 year survival of the 28 patients with ischemic mitral regurgitation was 43 +/- 10%. This confirms the negative detrimental effect of an ischemic origin of mitral valve disease on survival after mitral valve replacement and coronary bypass surgery (p less than 0.0001).

Auditory brain-stem, middle- and long-latency evoked potentials in mild cognitive impairment.

OBJECTIVE: Mild cognitive impairment (MCI) is a selective episodic memory deficit in the elderly with a high risk of Alzheimer's disease. The amplitudes of a long-latency auditory evoked potential (P50) are larger in MCI compared to age-matched controls. We tested whether increased P50 amplitudes in MCI were accompanied by changes of middle-latency potentials occurring around 50 ms and/or auditory brain-stem potentials. METHODS: Auditory evoked potentials were recorded from age-matched controls (n = 16) and MCI (n = 17) in a passive listening paradigm at two stimulus presentation rates (2/s, 1/1.5 s). A subset of subjects also received stimuli at a rate of 1/3 s. RESULTS: Relative to controls, MCI subjects had larger long-latency P50 amplitudes at all stimulus rates. Significant group differences in N100 amplitude were dependent on stimulus rate. Amplitudes of the middle-latency components (Pa, Nb, P1 peaking at approximately 30, 40, and 50 ms, respectively) did not differ between groups, but a slow wave between 30 and 49 ms on which the middle-latency components arose was significantly increased in MCI. ABR Wave V latency and amplitude did not differ significantly between groups. CONCLUSIONS: The increase of long-latency P50 amplitudes in MCI reflects changes of a middle-latency slow wave, but not of transient middle-latency components. There was no evidence of group difference at the brain-stem level. SIGNIFICANCE: Increased slow wave occurring as early as 50 ms may reflect neurophysiological consequences of neuropathology in MCI.

Curcumin synergistically potentiates the growth inhibitory and pro-apoptotic effects of celecoxib in pancreatic adenocarcinoma cells.

BACKGROUND AND AIM: Adenocarcinoma of the Pancreas is a leading cause of cancer-related mortality, accounting for an estimated 30,000 deaths per year in the United States. Multiple studies have indicated that specific cyclooxygenase-2 (COX-2) inhibitors may serve in the prevention and treatment of a variety of malignancies including pancreatic adenocarcinoma. Recent studies had shown that the long-term use of high concentration of COX-2 inhibitors is not toxic free and may be limited due to serious gastrointestinal and cardiovascular side effects. The chemopreventive efficacy of the phytochemical, curcumin has been demonstrated in several in vitro and animal models. In this study we investigated whether curcumin potentiates the growth inhibition effect of a COX-2 inhibitor (celecoxib, Pfizer, NY, USA) in human pancreatic cancer cells. METHODS: P-34 (expressing high levels of COX-2), and MIAPaCa (expressing low levels of COX-2) and Panc-1 (no expression of COX-2) evaluated cell lines were exposed to different concentrations of celecoxib (0-40 microM), curcumin (0-20 microM) and their combination. Cell viability was by XTT assay. Apoptosis was assessed by flow cytometry and COX-2 expression was measured by Western blotting analysis. RESULTS: In P-34 cells, curcumin synergistically potentiated the inhibitory effect of celecoxib on cell growth. The growth inhibition was associated with inhibition of proliferation and induction of apoptosis. Western blot analysis showed that COX-2 expression was down-regulated by the combination therapy. CONCLUSION: Curcumin synergistically augments the growth inhibition inserted by celecoxib in pancreatic cancer cells expressing COX-2. The synergistic effect was mediated through inhibition of COX-2. This may enable the use of celecoxib at lower and safer concentrations and may pave the way for a more effective treatment in this devastating disease.

Gradient index metamaterials.

Metamaterials--artificially structured materials with tailored electromagnetic response--can be designed to have properties difficult or impossible to achieve with traditional materials fabrication methods. Here we present a structured metamaterial, based on conducting split ring resonators (SRRs), which has an effective index of refraction with a constant spatial gradient. We experimentally confirm the gradient by measuring the deflection of a microwave beam by a planar slab of the composite metamaterial over a range of microwave frequencies. The gradient index metamaterial may prove an advantageous alternative approach to the development of gradient index lenses and similar optics, especially at higher frequencies. In particular, the gradient index metamaterial we propose may be suited for terahertz applications, where the magnetic resonant response of SRRs has recently been demonstrated.

The use of a virtual three-dimensional model to evaluate the intraosseous space available for percutaneous screw fixation of acetabular fractures.

We created virtual three-dimensional reconstruction models from computed tomography scans obtained from patients with acetabular fractures. Virtual cylindrical implants were placed intraosseously in the anterior column, the posterior column and across the dome of the acetabulum. The maximum diameter which was entirely contained within the bone was determined for each position of the screw. In the same model, the cross-sectional diameters of the columns were measured and compared to the maximum diameter of the corresponding virtual implant. We found that the mean maximum diameter of virtual implant accommodated by the anterior columns was 6.4 mm and that the smallest diameter of the columns was larger than the maximum diameter of the equivalent virtual implant. This study suggests that the size of the screw used for percutaneous fixation of acetabular fractures should not be based solely on the measurement of cross-sectional diameter and that virtual three-dimensional reconstructions might be useful in pre-operative planning.

Validating the GTP-cyclohydrolase 1-feedback regulatory complex as a therapeutic target using biophysical and in vivo approaches.

BACKGROUND AND PURPOSE: 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4 ) is an essential cofactor for nitric oxide biosynthesis. Substantial clinical evidence indicates that intravenous BH4 restores vascular function in patients. Unfortunately, oral BH4 has limited efficacy. Therefore, orally bioavailable pharmacological activators of endogenous BH4 biosynthesis hold significant therapeutic potential. GTP-cyclohydrolase 1 (GCH1), the rate limiting enzyme in BH4 synthesis, forms a protein complex with GCH1 feedback regulatory protein (GFRP). This complex is subject to allosteric feed-forward activation by L-phenylalanine (L-phe). We investigated the effects of L-phe on the biophysical interactions of GCH1 and GFRP and its potential to alter BH4 levels in vivo. EXPERIMENTAL APPROACH: Detailed characterization of GCH1-GFRP protein-protein interactions were performed using surface plasmon resonance (SPR) with or without L-phe. Effects on systemic and vascular BH4 biosynthesis in vivo were investigated following L-phe treatment (100 mg·kg(-1) , p.o.). KEY RESULTS: GCH1 and GFRP proteins interacted in the absence of known ligands or substrate but the presence of L-phe doubled maximal binding and enhanced binding affinity eightfold. Furthermore, the complex displayed very slow association and dissociation rates. In vivo, L-phe challenge induced a sustained elevation of aortic BH4 , an effect absent in GCH1(fl/fl)-Tie2Cre mice. CONCLUSIONS AND IMPLICATIONS: Biophysical data indicate that GCH1 and GFRP are constitutively bound. In vivo, data demonstrated that L-phe elevated vascular BH4 in an endothelial GCH1 dependent manner. Pharmacological agents which mimic the allosteric effects of L-phe on the GCH1-GFRP complex have the potential to elevate endothelial BH4 biosynthesis for numerous cardiovascular disorders.