Border Cave and the beginning of the Later Stone Age in South Africa

The transition from the Middle Stone Age (MSA) to the Later Stone Age (LSA) in South Africa was not associated with the appearance of anatomically modern humans and the extinction of Neandertals, as in the Middle to Upper Paleolithic transition in Western Europe. It has therefore attracted less attention, yet it provides insights into patterns of technological evolution not associated with a new hominin. Data from Border Cave (KwaZulu-Natal) show a strong pattern of technological change at approximately 44-42 ka cal BP, marked by adoption of techniques and materials that were present but scarcely used in the previous MSA, and some novelties. The agent of change was neither a revolution nor the advent of a new species of human. Although most evident in personal ornaments and symbolic markings, the change from one way of living to another was not restricted to aesthetics. Our analysis shows that: (i) at Border Cave two assemblages, dated to 45-49 and >49 ka, show a gradual abandonment of the technology and tool types of the post-Howiesons Poort period and can be considered transitional industries; (ii) the 44-42 ka cal BP assemblages are based on an expedient technology dominated by bipolar knapping, with microliths hafted with pitch from Podocarpus bark, worked suid tusks, ostrich eggshell beads, bone arrowheads, engraved bones, bored stones, and digging sticks; (iii) these assemblages mark the beginning of the LSA in South Africa; (iv) the LSA emerged by internal evolution; and (v) the process of change began sometime after 56 ka.     

Zaleplon and zolpidem objectively alleviate sleep disturbances in mountaineers at a 3,613 meter altitude

STUDY OBJECTIVES: To assess the effects of zolpidem and zaleplon on nocturnal sleep and breathing patterns at altitude, as well as on daytime attention, fatigue, and sleepiness. DESIGN: Double-blind, randomized, placebo-controlled, cross-over trial. SETTING: 3 day and night alpine expedition at 3,613 m altitude. PARTICIPANTS: 12 healthy male trekkers. PROCEDURE: One week spent at 1,000 m altitude (baseline control), followed by 3 periods of 3 consecutive treatment nights (N1-3) at altitude, to test 10 mg zolpidem, 10 mg zaleplon, and placebo given at 21:45. MEASURES: Sleep from EEG, actigraphy and sleep logs; overnight arterial saturation in oxygen (SpO2) from infrared oximetry; daytime attention, fatigue and sleepiness from a Digit Symbol Substitution Test, questionnaires, and sleep logs; acute mountain sickness (AMS) from the Lake Louise questionnaire. RESULTS: Compared to baseline control, sleep at altitude was significantly impaired in placebo subjects as shown by an increase in the amount of Wakefulness After Sleep Onset (WASO) from 17 +/- 8 to 36 +/- 13 min (P<0.05) and in arousals from 5 +/- 3 to 20 +/- 8 (P<0.01). Slow wave sleep (SWS) and stage 4 respectively decreased from 26.7% +/- 5.8% to 20.6% +/- 5.8% of total sleep time (TST) and from 18.2% +/- 5.2% to 12.4% +/- 3.1% TST (P<0.05 and P<0.001, respectively). Subjects also complained from a feeling of poor sleep quality combined with numerous 02 desaturation episodes. Subjective fatigue and AMS score were increased. Compared to placebo control, WASO decreased by approximately 6 min (P<0.05) and the sleep efficiency index increased by 2% (P<0.01) under zaleplon and zolpidem, while SWS and stage 4 respectively increased to 22.5% +/- 5.4% TST (P<0.05) and to 15.0% +/- 3.4% TST (P<0.0001) with zolpidem only; both drugs further improved sleep quality. No adverse effect on nighttime SpO2, daytime attention level, alertness, or mood was observed under either hypnotic. AMS was also found to be reduced under both medications. CONCLUSIONS: Both zolpidem and zaleplon have positive effects on sleep at altitude without adversely affecting respiration, attention, alertness, or mood. Hence, they may be safely used by climbers.     

Transforming a hospital nursing research fellowship into an evidence-based practice fellowship

An established hospital-based nursing research fellowship program was transformed into an evidence-based practice fellowship despite its previous high satisfaction ratings from nursing leaders and nurse fellow participants. The faculty for the fellowship program determined that the long-term outcomes of the research program were insufficient in light of the hospital resources committed to the fellowship program. An evidence-based practice approach was then created in anticipation that greater short-term and more sustained longer-term benefits for the hospital would be realized. The transformation of the fellowship and the short-term outcomes are described.     

Trajectories of health‐related quality of life among renal transplant patients associated with graft failure and symptom distress: Analysis of the BENEFIT and BENEFIT‐EXT trials

Understanding the correlation between transplant symptoms, health‐related quality of life (HRQoL), and graft outcomes is needed to support patient‐focused drug development and posttransplant management. A post‐hoc analysis of patient‐reported outcomes from the Phase III belatacept trials was conducted in order to investigate the interrelationship between trajectories of HRQoL, symptom experience, and allograft outcomes. HRQoL and symptom experience were evaluated using Short‐Form 36 Survey (SF‐36) and Modified Transplant Symptom Occurrence and Distress Scale (MTSOSD‐59R), respectively. HRQoL was captured in 831 eligible renal transplant patients at baseline, 12, 24, and 36 months posttransplant. Following transplantation, patients reported improvements in all SF‐36 subscales compared to baseline. Latent class analysis revealed four trajectories in perceived general health, which were associated with graft failure after adjustment. Compared to patients with good perceived health, patients with fair and poor perceived health had 4.7 (95% confidence interval [CI] 1.5‐14.8, P < .01) and 19.8 (95% CI 5.9‐66.0, P < .01) times the risk of graft failure, respectively. Using multinomial logistic regression, different sets of symptoms were associated with perceived general health at baseline and 12 months posttransplant. The study supports monitoring HRQoL and symptom experience to capture each patient's health perspective, improve drug development, and optimize posttransplant management.     

H ferritin knockout mice: a model of hyperferritinemia in the absence of iron overload

Ferritin, the iron-storing molecule, is made by the assembly of various proportions of 2 different H and L subunits into a 24-mer protein shell. These heteropolymers have distinct physicochemical properties, owing to the ferroxidase activity of the H subunit, which is necessary for iron uptake by the ferritin molecule, and the ability of the L subunit to facilitate iron core formation inside the protein shell. It has previously been shown that H ferritin is indispensable for normal development, since inactivation of the H ferritin gene by homologous recombination in mice is lethal at an early stage during embryonic development. Here the phenotypic analysis of the mice heterozygous for the H ferritin gene (Fth(+/-) mice) is reported, and differences in gene regulation between the 2 subunits are shown. The heterozygous Fth(+/-) mice were healthy and fertile and did not present any apparent abnormalities. Although they had iron-overloaded spleens at the adult stage, this is identical to what is observed in normal Fth(+/+) mice. However, these heterozygous mice had slightly elevated tissue L ferritin content and 7- to 10-fold more L ferritin in the serum than normal mice, but their serum iron remained unchanged. H ferritin synthesis from the remaining allele was not up-regulated. This probably results from subtle changes in the intracellular labile iron pool, which would stimulate L ferritin but not H ferritin synthesis. These results raise the possibility that reduced H ferritin expression might be responsible for unexplained human cases of hyperferritinemia in the absence of iron overload where the hereditary hyperferritinemia-cataract syndrome has been excluded. (Blood. 2001;98:525-532)     

Psychometric properties of a brief,clinically relevant measure of pain in patients with hepatocellular carcinoma

Purpose

Due to diagnosis at advanced stages, comorbidities, and the impact of treatment, patients with hepatocellular carcinoma (HCC) may experience pain. The purpose of this study was to evaluate the psychometric properties of a brief, clinically relevant measure of pain in HCC.

Methods

We conducted a secondary data analysis from four longitudinal studies of patients with HCC (total n = 304). All patients completed the FACT-Hepatobiliary (FACT-Hep) questionnaire, and 49 patients completed the Brief Pain Inventory (BPI) Interference scale. We conducted confirmatory factor analysis (CFA), Rasch modeling, and correlational analysis to assess the psychometrics of the three items on the FACT-Hep that assess HCC-relevant pain scale.

Results

Patients had an average age of 63.5 (±12.2) and were mostly male (76 %). The mean three-item pain subscale score was 8.5 ± 3.0. Seventy-four (24.3 %) patients reported no pain (score = 12). Results of a one-factor CFA supported unidimensionality of the items, and all items fit the Rasch model. An item-person map demonstrated that the three items covered all patients with non-extreme scores. Pain scores were significantly associated with baseline general health-related quality of life (FACT-General, r = 0.60, p < 0.001) and pain interference (BPI, r = ?0.63, p < 0.001).

Conclusions

The three FACT-Hep pain items are unidimensional, cover the range of pain experienced by most patients with HCC, and demonstrate convergent validity. This pain subscale is, if future research demonstrates its sensitivity to change, potentially useful for HCC clinical trials.     

Preclinical pharmacology of pramlintide in the rat: Comparisons with human and rat amylin

The pancreatic β-cell hormone, amylin, is absent or reduced in individuals with type I diabetes mellitus and in many insulin-treated patients with type II diabetes. Amylin replacement therapy may be beneficial in these individuals, but the pharmaceutically inconvenient physicochemical properties of native human amylin led to the development instead of the amylin agonist, [Pro^25,28,29]human amylin, or pramlintide (formerly designated AC137). Here we compare for rat amylin, human amylin and pramlintide, receptor binding and biological actions in rats in vivo and in rat soleus muscle. In the rat, the spectrum of actions and pharmacokinetic and pharmacodynamic properties of pramlintide are either very similar to, or indistinguishable from, those of rat or human amylin. © 1996 Wiley-Liss, Inc.     

Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects

RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.Subject terms: Acute lymphocytic leukaemia, Acute myeloid leukaemia, Drug development, Targeted therapies     

Effects of estrogen deficiency and low bone mineral density on healthy knee cartilage in rabbits

The purpose of this study was to compare the effects of estrogen deficiency and bone mass loss on normal knee cartilage in mature rabbits. Bilateral ovariectomy (OVX) was performed in 13 rabbits, 6 of which also received systemic glucocorticoid for 4 weeks. Seven additional healthy rabbits were used as controls. Bone mineral density (BMD) was measured by dual X‐ray absorptiometry in lumbar spine, knee, and subchondral bone of the knee at baseline and 22 weeks after OVX. After sacrifice, the knees were dissected, macroscopy was assessed, and histological cartilage abnormalities were evaluated according to the Mankin score. Correlations of Mankin with BMD at different regions were also performed. When compared to baseline, differences in BMD were only found in spine and knee of the animals receiving glucocorticoids. All the animals subjected to OVX had a significantly higher Mankin score than controls. Mankin was upper in OVX animals receiving glucocorticoids, but differences were not significant. The Mankin score was inversely related with BMD in lumbar spine (r = ?0.67; p < 0.01). Although low bone mineral density contributes to the minor osteoarthritic alterations observed in our model, estrogen deficiency itself seems to act directly to induce the main pathogenic effects in healthy cartilage of the rabbit. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:812–818, 2010