Pharmacokinetics of human leptin in mice and rhesus monkeys.

ObjectiveThe pharmacokinetic characteristics of human leptin were examined in rhesus monkeys and in C57BL/6J mice fed a normal chow or a high-fat diet.DesignFor the monkey study, in nine rhesus monkeys (body weight 12.4 +/- 2.4 kg; mean +/- s.d.), recombinant met-human leptin was injected intravenously or subcutaneously (1 mg/kg). For the mouse study, after 6 months of feeding C57BL/6J mice a high-fat diet (body weight 32.9 +/- 3.6 g; n = 8) or a control diet (24.5 +/- 1.2 g; n = 6), recombinant met-human leptin was administered intraperitoneally (10 microg/g). Blood samples were collected for leptin measurement at specific time points after leptin administration.MeasurementsPlasma leptin concentrations were determined by radioimmunoassay and pharmacokinetic analysis was performed.ResultsDisposition of human leptin in rhesus monkeys was biphasic following intravenous administration, with a terminal phase half-life of 96.4 +/- 16.5 min and clearance of 1.8 +/- 0.2 ml/min/kg. Subcutaneously administered leptin was absorbed slowly, perhaps by a zero-order process as leptin levels appeared to plateau and remained elevated throughout the 8 h sampling period. In C57BL/6J mice, the absorption and elimination of human leptin were both first-order following intraperitoneal administration. Pharmacokinetic parameters did not differ between normal-weight mice fed a chow diet and obese mice fed a high-fat diet. The elimination half-life was 47.0 +/- 26.4 min in mice fed a high-fat diet and 49.5 +/- 12.0 min in mice fed a control diet.ConclusionThe kinetics of leptin in rhesus monkeys were biphasic and clearance was similar to values previously reported in humans. The estimated half-life was 96.4 min in rhesus monkeys and 49.5 min in normal weight mice. The was no difference in leptin kinetics between high-fat fed and control mice, suggesting that the increased baseline leptin levels in the obese mice are due to increased leptin production and secretion

Entrepreneurial capital, social values and Islamic traditions: exploring the growth of women-owned enterprises in Pakistan

Main ArticleThis study seeks to explore the variables contributing to the growth of women-owned enterprises in the Islamic Republic of Pakistan. Based on a previously established multivariate model, it uses two econometric approaches: first classifying variables into predetermined blocks; and second, using the general to specific approach. Statistical analyses and in-depth interviews confirm that women entrepreneurs’ personal resources and social capital have a significant role in their business growth. Further, it reveals that the moral support of immediate family, independent mobility and being allowed to meet with men play a decisive role in the sales and employment growth of women-owned enterprises in an Islamic country such as Pakistan

The inevitable youthfulness of known high-redshift radio galaxies

Radio galaxies can be seen out to very high redshifts, where in principle they can serve as probes of the early evolution of the Universe. Here we show that for any model of radio-galaxy evolution in which the luminosity decreases with time after an initial rapid increase (that is, essentially all reasonable models), all observable high-redshift radio-galaxies must be seen when the lobes are less than 10^7 years old. This means that high-redshift radio galaxies can be used as a high-time-resolution probe of evolution in the early Universe. Moreover, this result helps to explain many observed trends of radio-galaxy properties with redshift [(i) the `alignment effect' of optical emission along radio-jet axes, (ii) the increased distortion in radio structure, (iii) the decrease in physical sizes, (iv) the increase in radio depolarisation, and (v) the increase in dust emission] without needing to invoke explanations based on cosmology or strong evolution of the surrounding intergalactic medium with cosmic time, thereby avoiding conflict with current theories of structure formation.Comment: To appear in Nature. 4 pages, 2 colour figures available on request. Also available at http://www-astro.physics.ox.ac.uk/~km

CXCR2 deficient mice display macrophage-dependent exaggerated acute inflammatory responses

CXCR2 is an essential regulator of neutrophil recruitment to inflamed and damaged sites and plays prominent roles in inflammatory pathologies and cancer. It has therefore been highlighted as an important therapeutic target. However the success of the therapeutic targeting of CXCR2 is threatened by our relative lack of knowledge of its precise in vivo mode of action. Here we demonstrate that CXCR2-deficient mice display a counterintuitive transient exaggerated inflammatory response to cutaneous and peritoneal inflammatory stimuli. In both situations, this is associated with reduced expression of cytokines associated with the resolution of the inflammatory response and an increase in macrophage accumulation at inflamed sites. Analysis using neutrophil depletion strategies indicates that this is a consequence of impaired recruitment of a non-neutrophilic CXCR2 positive leukocyte population. We suggest that these cells may be myeloid derived suppressor cells. Our data therefore reveal novel and previously unanticipated roles for CXCR2 in the orchestration of the inflammatory response

Selective serotonin reuptake inhibitors in the treatment of generalized anxiety disorder

Selective serotonin reuptake inhibitors have proven efficacy in the treatment of panic disorder, obsessive–compulsive disorder, post-traumatic stress disorder and social anxiety disorder. Accumulating data shows that selective serotonin reuptake inhibitor treatment can also be efficacious in patients with generalized anxiety disorder. This review summarizes the findings of randomized controlled trials of selective serotonin reuptake inhibitor treatment for generalized anxiety disorder, examines the strengths and weaknesses of other therapeutic approaches and considers potential new treatments for patients with this chronic and disabling anxiety disorder

CheriABI: Enforcing Valid Pointer Provenance and Minimizing Pointer Privilege in the POSIX C Run-time Environment

The CHERI architecture allows pointers to be implemented as capabilities (rather than integer virtual addresses) in a manner that is compatible with, and strengthens, the semantics of the C language. In addition to the spatial protections offered by conventional fat pointers, CHERI capabilities offer strong integrity, enforced provenance validity, and access monotonicity. The stronger guarantees of these architectural capabilities must be reconciled with the real-world behavior of operating systems, run-time environments, and applications. When the process model, user-kernel interactions, dynamic linking, and memory management are all considered, we observe that simple derivation of architectural capabilities is insufficient to describe appropriate access to memory. We bridge this conceptual gap with a notional \emph{abstract capability} that describes the accesses that should be allowed at a given point in execution, whether in the kernel or userspace. To investigate this notion at scale, we describe the first adaptation of a full C-language operating system (FreeBSD) with an enterprise database (PostgreSQL) for complete spatial and referential memory safety. We show that awareness of abstract capabilities, coupled with CHERI architectural capabilities, can provide more complete protection, strong compatibility, and acceptable performance overhead compared with the pre-CHERI baseline and software-only approaches. Our observations also have potentially significant implications for other mitigation techniques.This work was supported by the Defense Advanced Research Projects Agency (DARPA) and the Air Force Research Laboratory (AFRL), under contracts FA8750-10-C-0237 (``CTSRD'') and HR0011-18-C-0016 (``ECATS''). The views, opinions, and/or findings contained in this report are those of the authors and should not be interpreted as representing the official views or policies of the Department of Defense or the U.S. Government. We also acknowledge the EPSRC REMS Programme Grant (EP/K008528/1), the ERC ELVER Advanced Grant (789108), Arm Limited, HP Enterprise, and Google, Inc. Approved for Public Release, Distribution Unlimited

Facial expressions depicting compassionate and critical emotions: the development and validation of a new emotional face stimulus set

Attachment with altruistic others requires the ability to appropriately process affiliative and kind facial cues. Yet there is no stimulus set available to investigate such processes. Here, we developed a stimulus set depicting compassionate and critical facial expressions, and validated its effectiveness using well-established visual-probe methodology. In Study 1, 62 participants rated photographs of actors displaying compassionate/kind and critical faces on strength of emotion type. This produced a new stimulus set based on N = 31 actors, whose facial expressions were reliably distinguished as compassionate, critical and neutral. In Study 2, 70 participants completed a visual-probe task measuring attentional orientation to critical and compassionate/kind faces. This revealed that participants lower in self-criticism demonstrated enhanced attention to compassionate/kind faces whereas those higher in self-criticism showed no bias. To sum, the new stimulus set produced interpretable findings using visual-probe methodology and is the first to include higher order, complex positive affect displays

Is Incarceration a Contributor to Health Disparities? Access to Care of Formerly Incarcerated Adults

Despite the disproportionate prevalence of incarceration in communities of color, few studies have examined its contribution to health disparities. We examined whether a lifetime history of incarceration is associated with recent access to medical and dental care. We performed a secondary data analysis of the 2007 Los Angeles County Health Survey, a population-based random-digit-dialing telephone survey of county households. Any history of incarceration in a prison/jail/detention center as an adult was assessed for a random subsample. Bivariate and multivariate logistic regression analyses examined whether incarceration history was associated with access to care, controlling for other characteristics. Ten percent of our study population reported a history of incarceration. While persons with an incarceration history were similar to their peers with regard to health and insurance status, their access to medical and dental care was worse. Incarceration history was independently associated with disparities in access to care. Interventions to improve the health of communities affected by high rates of incarceration could include efforts that enable access to care for formerly incarcerated adults

The predictive role of serum and bronchoalveolar lavage cytokines and adhesion molecules for acute respiratory distress syndrome development and outcome

BACKGROUND: The predictive role of many cytokines and adhesion molecules has not been studied systematically in acute respiratory distress syndrome (ARDS). METHODS: We measured prospectively tumour necrosis factor alpha (TNF-α), interleukin (IL)-1, soluble vascular adhesion molecule-1 (VCAM-1) and soluble intercellular adhesion molecule-1 (ICAM-1) in serum and bronchoalveolar lavage fluid (BALF) within 2 hours following admission, in 65 patients. The patients were divided into: those fulfilling the criteria for ARDS (n = 23, group A), those who were pre-ARDS and who developed ARDS within 24 hours (n = 14, group B), and those on pre-ARDS but who never developed ARDS (n = 28, group C). RESULTS: All the measured molecules were only found at higher levels in the serum of patients that died either with or without ARDS (P < 0.05 – P < 0.0001). Patients at risk exhibited a good negative predictive value (NPV) of the measured molecules for ARDS development both in their serum (89 to 95%) and BALF (86 to 92%) levels. In contrast to BALF, serum levels of IL-1 and adhesion molecules exhibited a good NPV (68 to 96%), sensitivity (60 to 88%) and survival specificity (74 to 96%) in all groups. All molecules in serum and BALF IL-1 were correlated with the APACHE II (P < 0.05 – P < 0.0001). Serum and BALF IL-1 as well as BALF TNF-α were negatively correlated to PaO(2)/FiO(2) (all P < 0.05). CONCLUSIONS: The studied molecules have good NPV for ARDS development both in serum and BALF. Serum rather than BALF levels seem to be related to outcome