Rapid formation of sulfuric acid particles at near-atmospheric conditions.
We investigated the formation of new particles in a laboratory study, starting from H2SO4 produced in situ through the reaction of OH radicals with SO2. Newly formed particles were observed for H2SO4 concentrations above 7 x 10(6) per cubic centimeter. At 293 kelvin, a rough estimate yielded a nucleation rate of 0.3 to 0.4 particles per cubic centimeter per second for approximately 10(7) particles per cubic centimeter of H2SO4 (particle size >/= 3 nanometers). These findings are in agreement with observations from the atmosphere. The results demonstrate that under laboratory conditions similar to the atmosphere, particle formation occurs at atmospheric H2SO4 concentration levels.


Whole-body hyperthermia in the scope of von Ardenne's systemic cancer multistep therapy (sCMT) combined with chemotherapy in patients with metastatic colorectal cancer: a phase I/II study.
This phase I/II study evaluated the feasibility, toxicity and response rates of von Ardenne's systemic cancer multistep therapy (sCMT) when applied as an adjunct to cytostatic therapy in patients with metastatic colorectal cancer. sCMT consists of whole-body hyperthermia (WBH) at 41.8-42.1 degrees C, hyperglycaemia and hyperoxaemia. All patients who entered the trial first received three monthly courses of chemotherapy (folinic acid, 50 mg, days 1-5; 5-fluorouracil, 425 mg/m2, days 1-5; mitomycin 8 mg/m2, day 1), followed by response evaluation according World Health Organization (WHO) criteria. Responders (partial/complete remission) were assigned to three further courses of chemotherapy, whereas non-responders (stable/progressive disease) were allocated to additional sCMT on day 1 of every subsequent chemotherapy course. The WBH procedure was administered under general anaesthesia employing the Iratherm-2000 radiant heat device. Of 28 patients enrolled, 19 received more than three treatment courses. Eight of these 19 patients had responded to chemotherapy (PR) and thus obtained three further courses of chemotherapy alone. In 10 of 19 patients who had not responded (SD, PD), three additional courses of chemotherapy were combined with sCMT (with 25 sCMT applications). One patient who did not respond to initial treatment declined sCMT and was continued with chemotherapy alone. It was found that sCMT was feasible, but associated with a specific spectrum of grade III/IV toxicity (skin 20%, pain 16%, peripheral nerves 8% of treatment courses). The fact that three patients who did not respond to initial chemotherapy achieved a PR after additional sCMT suggests that sCMT may enhance the effect of chemotherapy in patients with colorectal cancer.


Relationships between fundamental movement skills and objectively measured physical activity in preschool children.
Gender differences in cross-sectional relationships between fundamental movement skill (FMS) subdomains (locomotor skills, object-control skills) and physical activity were examined in preschool children. Forty-six 3- to 5-year-olds (25 boys) had their FMS video assessed (Test of Gross Motor Development II) and their physical activity objectively monitored (Actigraph 7164 accelerometers). Among boys, object-control skills were associated with physical activity and explained 16.9% (p = .024) and 13.7% (p = .049) of the variance in percent of time in moderate-to-vigorous physical activity (MVPA) and total physical activity, respectively, after controlling for age, SES and z-BMI. Locomotor skills were inversely associated with physical activity among girls, and explained 19.2% (p = .023) of the variance in percent of time in MVPA after controlling for confounders. Gender and FMS subdomain may influence the relationship between FMS and physical activity in preschool children.


Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats.
We showed recently that mononuclear phagocyte system (MPS) cells provide a buffering mechanism for salt-sensitive hypertension by driving interstitial lymphangiogenesis, modulating interstitial Na(+) clearance, and increasing endothelial NO synthase protein expression in response to very high dietary salt via a tonicity-responsive enhancer binding protein/vascular endothelial growth factor C regulatory mechanism. We now tested whether isotonic saline and deoxycorticosterone acetate (DOCA)-salt treatment leads to a similar regulatory response in Sprague-Dawley rats. Male rats were fed a low-salt diet and received tap water (low-salt diet LSD), 1.0% saline (high-salt diet HSD), or DOCA+1.0% saline (DOCA-HSD). To test the regulatory role of interstitial MPS cells, we further depleted MPS cells with clodronate liposomes. HSD and DOCA-HSD led to Na(+) accumulation in the skin, MPS-driven tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated hyperplasia of interstitial lymph capillaries, and increased endothelial NO synthase protein expression in skin interstitium. Clodronate liposome MPS cell depletion blocked MPS infiltration in the skin interstitium, resulting in unchanged tonicity-responsive enhance binding protein/vascular endothelial growth factor C levels and absent hyperplasia of the lymph capillary network. Moreover, no increased skin endothelial NO synthase protein expression occurred in either clodronate liposome-treated HSD or DOCA-salt rats. Thus, absence of the MPS-cell regulatory response converted a salt-resistant blood-pressure state to a salt-sensitive state in HSD rats. Furthermore, salt-sensitive hypertension in DOCA-salt rats was aggravated. We conclude that MPS cells act as onsite controllers of interstitial volume and blood pressure homeostasis, providing a local regulatory salt-sensitive tonicity-responsive enhancer binding protein/vascular endothelial growth factor C-mediated mechanism in the skin to maintain normal blood pressure in states of interstitial Na(+) and Cl(-) accumulation. Failure of this physiological extrarenal regulatory mechanism leads to a salt-sensitive blood pressure response.


Protective effect of kombucha mushroom (KM) tea on phenol-induced cytotoxicity in albino mice.
The present study was carried out to evaluate the protective role of kombucha mushroom (KM) tea on cytotoxicity induced by phenol (PHE) in mice. We used weight gain and micronucleus (MN) frequency as indicators of cytotoxicity and supported these parameters with pathological findings. The animals were randomly divided into seven groups: (Group I) only tap water (Group II) 1000 microl kg(-1) b. wt KM-tea, (Group III) 35 mg kg(-1) body wt. PHE (Group IV) 35 mg kg(-1) body wt. PHE + 250 microl kg(-1) b. wt KM-tea (Group V) 35 mg kg(-1) b. wt PHE + 500 microl kg(-1) b. wt KM-tea (Group VI) 35 mg kg(-1) b. wt PHE + 750 microl kg(-1) b. wt KM-tea, (Group VII) 35 mg kg(-1) b. wt PHE + 1000 microl kg(-1) b. wt KM-tea, for 20 consecutive days by oral gavage. The results indicated that all KM-tea supplemented mice showed a lower MN frequency than erythrocytes in only PHE-treated group. There was an observable regression on account of lesions in tissues of mice supplemented with different doses of KM-tea in histopathological observations. In conclusion, the KM-tea supplementation decreases cytotoxicity induced by PHE and its protective role is dose-dependent.


Monolithically integrated selectable repetition-rate laser diode source of picosecond optical pulses.
We describe the characterization of a monolithically integrated photonic device for short pulse generation featuring a mode-locked laser diode, a Mach-Zehnder modulator (MZM), and a semiconductor optical amplifier (SOA). The integrated device is designed for fabrication by a generic foundry scheme with a view to ease of design, testing, and manufacture. Trains of 6.8 ps pulses are generated at repetition rates that are electronically switchable from 14 GHz to 109 MHz. The SOA boosts the peak power by 7.4 dB, and the pulses are compressible to 2.4 ps by dispersion compensation using single-mode telecommunications fiber.


Telomerase reverse transcriptase-dependent telomere equilibration mitigates tissue dysfunction in mTert heterozygotes.
Autosomal dominant mutations in telomere-associated factors elicit a disease known as dyskeratosis congenita (DKC), and patients suffer proliferative abnormalities associated with telomere erosion. Mice that are heterozygous for telomerase genes (Tert or Terc, hereafter referred to as mTert and mTerc) are useful models of telomerase haploinsufficiency, but do not strictly mimic DKC. In strains with long telomeres (>60 kbp), animals that are heterozygous for mTert undergo telomere erosion for nine generations and remain phenotypically normal. In an mTerc heterozygous strain with short telomeres (<15 kbp), early mortality arises after five to six generations, but dyskeratosis occurs only upon the further loss of mPot1b. We show that prolonged mTert heterozygosity (for greater than ten generations) did not elicit disease, even upon heterozygote interbreeding, and that telomeres reset to wild-type lengths. This lengthening did not occur in nullizygotes, and short telomeres inherited from mTert null parents were rescued only in heterozygous progeny. In the bone marrow, nullizygotes remained competent for radioprotection for three generations. Thus, gradual telomere erosion in the presence of telomerase may enable subsequent telomere extension, similar to that described in budding yeast. We speculate whether such adaptation occurs in normal human cells (or whether it could be induced in DKC-derived cells), and whether it might mitigate the impact of telomerase inhibition upon stem cells during cancer therapy.


Cerebellar inactivation impairs memory of learned prism gaze-reach calibrations.
Three monkeys performed a visually guided reach-touch task with and without laterally displacing prisms. The prisms offset the normally aligned gaze/reach and subsequent touch. Naive monkeys showed adaptation, such that on repeated prism trials the gaze-reach angle widened and touches hit nearer the target. On the first subsequent no-prism trial the monkeys exhibited an aftereffect, such that the widened gaze-reach angle persisted and touches missed the target in the direction opposite that of initial prism-induced error. After 20-30 days of training, monkeys showed long-term learning and storage of the prism gaze-reach calibration: they switched between prism and no-prism and touched the target on the first trials without adaptation or aftereffect. Injections of lidocaine into posterolateral cerebellar cortex or muscimol or lidocaine into dentate nucleus temporarily inactivated these structures. Immediately after injections into cortex or dentate, reaches were displaced in the direction of prism-displaced gaze, but no-prism reaches were relatively unimpaired. There was little or no adaptation on the day of injection. On days after injection, there was no adaptation and both prism and no-prism reaches were horizontally, and often vertically, displaced. A single permanent lesion (kainic acid) in the lateral dentate nucleus of one monkey immediately impaired only the learned prism gaze-reach calibration and in subsequent days disrupted both learning and performance. This effect persisted for the 18 days of observation, with little or no adaptation.


Effects of public posting on driving speed in Icelandic traffic.
We replicated a study by Van Houten, Nau, and Marini (1980) that had revealed reductions in vehicle speeding following the posting of percentages of drivers not speeding on a sign at roadside. Our subjects were drivers entering a residential area where the speed limit changed from 90 km/hr (55.9 mph) to 60 km/hr (37.3 mph). A total of 4,409 vehicle speeds were taken from two observation sessions per day for 20 consecutive weekdays. The intervention consisted of a single posting condition, in which a hypothetical daily percentage of drivers not speeding was posted on a feedback sign, followed by a double posting condition, in which a sign posting a best result was erected beyond the feedback sign. Results revealed a significant speed reduction from an average of 69.0 km/hr (42.9 mph) during baseline to 63.4 km/hr (39.4 mph) during single posting. Average speed during double posting was 62.9 km/hr (39.1 mph). The percentage of drivers exceeding 70 km/hr (43.5 mph) dropped from 41.0 during baseline to 20.5 during single posting. The significant speed reductions add to the generality of findings of similar studies in Canada and Israel and offer possible explanations for the failure of feedback posting to reduce speed in the U.S.


Dynamics of magnetic lipoplexes studied by single particle tracking in living cells.
Magnetofection, gene delivery under the influence of a magnetic field, is a technique to increase transfection efficiency by enforcing gene vector contact with a target cell. Mechanisms of magnetic lipoplex internalization and intracellular details of magnetofection are still unknown. In this study, cellular dynamics of magnetic lipoplexes were examined in real time by means of highly sensitive dual-color fluorescence microscopy. Single particle tracking of magnetic lipoplexes provided trajectories representing the movement of the lipoplexes during internalization and subsequent intracellular processes. Magnetic lipoplexes show a three-phase behavior similar to polyplexes. During phase I lipoplexes are attached to the cell surface and show slow cooperative transport behavior. Phase II takes place inside the cell and was characterized by anomalous and confined diffusion. Phase III represented active transport along microtubules inside the cell. The majority of lipoplexes were internalized via endocytosis during phase I. On later time scales the formation of a perinuclear ring was observed. Persisting colocalization of fluid phase marker and lipoplexes after 24 h indicated slow endosomal release. In short, the internalization characteristics of magnetic lipoplexes are very similar to that of polyplexes. Furthermore our results suggest that the magnetic field induces an increased concentration of magnetic complexes on the cell surface resulting in higher transfection efficiency.


ASC-1, PAT2, and P2RX5 are cell surface markers for white, beige, and brown adipocytes.
White, beige, and brown adipocytes are developmentally and functionally distinct but often occur mixed together within individual depots. To target white, beige, and brown adipocytes for diagnostic or therapeutic purposes, a better understanding of the cell surface properties of these cell types is essential. Using a combination of in silico, in vitro, and in vivo methods, we have identified three new cell surface markers of adipose cell types. The amino acid transporter ASC-1 is a white adipocyte-specific cell surface protein, with little or no expression in brown adipocytes, whereas the amino acid transporter PAT2 and the purinergic receptor P2RX5 are cell surface markers expressed in classical brown and beige adipocytes in mice. These markers also selectively mark brown/beige and white adipocytes in human tissue. Thus, ASC-1, PAT2, and P2RX5 are membrane surface proteins that may serve as tools to identify and target white and brown/beige adipocytes for therapeutic purposes.


MYC, Metabolism, and Cancer.
The MYC oncogene encodes a transcription factor, MYC, whose broad effects make its precise oncogenic role enigmatically elusive. The evidence to date suggests that MYC triggers selective gene expression amplification to promote cell growth and proliferation. Through its targets, MYC coordinates nutrient acquisition to produce ATP and key cellular building blocks that increase cell mass and trigger DNA replication and cell division. In cancer, genetic and epigenetic derangements silence checkpoints and unleash MYC's cell growth- and proliferation-promoting metabolic activities. Unbridled growth in response to deregulated MYC expression creates dependence on MYC-driven metabolic pathways, such that reliance on specific metabolic enzymes provides novel targets for cancer therapy. MYC's expression and activity are tightly regulated in normal cells by multiple mechanisms, including a dependence upon growth factor stimulation and replete nutrient status. In cancer, genetic deregulation of MYC expression and loss of checkpoint components, such as TP53, permit MYC to drive malignant transformation. However, because of the reliance of MYC-driven cancers on specific metabolic pathways, synthetic lethal interactions between MYC overexpression and specific enzyme inhibitors provide novel cancer therapeutic opportunities.


Chaplain Documentation and the Electronic Medical Record: A Survey of ACPE Residency Programs.
This study explores the extent to which chaplaincy departments at ACPE-accredited residency programs make use of the electronic medical record (EMR) for documentation and training. Survey data solicited from 219 programs with a 45% response rate and interview findings from 11 centers demonstrate a high level of usage of the EMR as well as an expectation that CPE residents document each patient/family encounter. Centers provided considerable initial training, but less ongoing monitoring of chaplain documentation. Centers used multiple sources to develop documentation tools for the EMR. One center was verified as having created the spiritual assessment component of the documentation tool from a peer reviewed published model. Interviews found intermittent use of the student chart notes for educational purposes. One center verified a structured manner of monitoring chart notes as a performance improvement activity. Findings suggested potential for the development of a standard documentation tool for chaplain charting and training.


Randomized double blind trial of intraperitoneal instillation of bupivacaine and morphine for pain relief after laparoscopic gynecological surgeries.
Intraperitoneal injection of anesthetic has been proposed to minimize postoperative pain after laparoscopic surgery. So a randomized, placebo-controlled study was conducted to compare the effectiveness of intraperitoneal bupivacaine with or without morphine for postoperative analgesia after laparoscopic gynecological surgeries. A total of 90 ASA I and II female patients scheduled for laparoscopic gynecological procedures were enrolled in the randomized double blind prospective study. The drug was injected intraperitoneally before the removal of trocar at the end of surgery. In group BM (n=30): 0.25% bupivacaine 30 ml + 2 mg morphine, in group BO (n=30) 30 ml 0.25% bupivacaine and in group C (n=30) 30 ml of saline was injected intraperitoneally. Postoperative quality of analgesia was assessed by VAS (0-100), for 24 hours and when VAS >40, rescue analgesic was administered. Total dose of rescue analgesia and side effects were noted. INTRAPERITONEAL INSTILLATION OF BUPIVACAINE AND MORPHINE SIGNIFICANTLY REDUCES IMMEDIATE POSTOPERATIVE PAIN (VAS: 23.33±6.04 vs. 45.5±8.57). It also reduces pain at 4 hours after surgery in the BM group (VAS 24±12.13 vs. 41.17±7.27 in the BO group). The time of administration of first rescue analgesic was significantly higher in the BM group (6.15 hours) compared to the BO group (4.51 hours). The total dosage of rescue analgesic was more in the BO and C groups compared to the BM group. Addition of morphine to local anesthetic significantly prolonged the time to first rescue analgesic requirement and the total consumption of rescue analgesic in 24 hours without any significant increase in adverse events.


Consumption of vegetables and fruits and risk of subtypes of head-neck cancer in the Netherlands Cohort Study.
There is limited prospective data on the relationship between consumption of vegetables and fruits and the risk of head-neck cancer (HNC) subtypes [i.e., oral cavity cancer (OCC), oro-/hypopharyngeal cancer (OHPC) and laryngeal cancer (LC)]. Therefore, we investigated these associations within the Netherlands Cohort Study, in which 120,852 participants completed a 150-item food frequency questionnaire at baseline in 1986. After 20.3 years of follow-up, 415 cases of HNC (131 OCC, 88 OHPC, three oral cavity/pharynx unspecified or overlapping and 193 LC) and 3,898 subcohort members were available for case-cohort analysis using Cox proportional hazards models. Total vegetable and fruit consumption was inversely associated with risk of HNC overall [multivariable-adjusted rate ratios for highest vs. lowest quartile: 0.61, 95% confidence interval (CI) 0.44-0.85, p trend 0.002] and all HNC subtypes, with the strongest associations for OCC. Total vegetable intake and total fruit intake were also associated with a decreased risk of HNC overall and HNC subtypes. No significant interaction was found between vegetable and fruit intake and alcohol consumption or cigarette smoking. In conclusion, in this large-scale cohort study, consumption of vegetables and fruits was associated with a decreased risk of HNC overall and all subtypes. Consumption of vegetables and fruits (or of specific groups of them) may protect against HNC and its subtypes.


Temperature-dependent structure and dynamics of highly-branched poly(N-isopropylacrylamide) in aqueous solution.
Small-angle neutron scattering (SANS) and neutron spin-echo (NSE) have been used to investigate the temperature-dependent solution behaviour of highly-branched poly(N-isopropylacrylamide) (HB-PNIPAM). SANS experiments have shown that water is a good solvent for both HB-PNIPAM and a linear PNIPAM control at low temperatures where the small angle scattering is described by a single correlation length model. Increasing the temperature leads to a gradual collapse of HB-PNIPAM until above the lower critical solution temperature (LCST), at which point aggregation occurs, forming disperse spherical particles of up to 60 nm in diameter, independent of the degree of branching. However, SANS from linear PNIPAM above the LCST is described by a model that combines particulate structure and a contribution from solvated chains. NSE was used to study the internal and translational solution dynamics of HB-PNIPAM chains below the LCST. Internal HB-PNIPAM dynamics is described well by the Rouse model for non-entangled chains.


Synaptic Mechanisms of Memory Consolidation during Sleep Slow Oscillations.
Sleep is critical for regulation of synaptic efficacy, memories, and learning. However, the underlying mechanisms of how sleep rhythms contribute to consolidating memories acquired during wakefulness remain unclear. Here we studied the role of slow oscillations, 0.2-1 Hz rhythmic transitions between Up and Down states during stage 3/4 sleep, on dynamics of synaptic connectivity in the thalamocortical network model implementing spike-timing-dependent synaptic plasticity. We found that the spatiotemporal pattern of Up-state propagation determines the changes of synaptic strengths between neurons. Furthermore, an external input, mimicking hippocampal ripples, delivered to the cortical network results in input-specific changes of synaptic weights, which persisted after stimulation was removed. These synaptic changes promoted replay of specific firing sequences of the cortical neurons. Our study proposes a neuronal mechanism on how an interaction between hippocampal input, such as mediated by sharp wave-ripple events, cortical slow oscillations, and synaptic plasticity, may lead to consolidation of memories through preferential replay of cortical cell spike sequences during slow-wave sleep. Sleep is critical for memory and learning. Replay during sleep of temporally ordered spike sequences related to a recent experience was proposed to be a neuronal substrate of memory consolidation. However, specific mechanisms of replay or how spike sequence replay leads to synaptic changes that underlie memory consolidation are still poorly understood. Here we used a detailed computational model of the thalamocortical system to report that interaction between slow cortical oscillations and synaptic plasticity during deep sleep can underlie mapping hippocampal memory traces to persistent cortical representation. This study provided, for the first time, a mechanistic explanation of how slow-wave sleep may promote consolidation of recent memory events.


Replacement of the human topoisomerase linker domain with the plasmodial counterpart renders the enzyme camptothecin resistant.
A human/plasmodial hybrid enzyme, generated by swapping the human topoisomerase IB linker domain with the corresponding domain of the Plasmodium falciparum enzyme, has been produced and characterized. The hybrid enzyme displays a relaxation activity comparable to the human enzyme, but it is characterized by a much faster religation rate. The hybrid enzyme is also camptothecin resistant. A 3D structure of the hybrid enzyme has been built and its structural-dynamical properties have been analyzed by molecular dynamics simulation. The analysis indicates that the swapped plasmodial linker samples a conformational space much larger than the corresponding domain in the human enzyme. The large linker conformational variability is then linked to important functional properties such as an increased religation rate and a low drug reactivity, demonstrating that the linker domain has a crucial role in the modulation of the topoisomerase IB activity.


Permanent dissipative structures in water: the matrix of life? Experimental evidences and their quantum origin.
This paper presents a short review of the evidence - both experimental and theoretical - of the formation of dissipative structures in liquid water induced by three kinds of physical perturbations having a low energy content: extremely diluted solution (EDS), iteratively filtered water (IFW), and iteratively nafionated water (INW). Particular attention is devoted to the very recent discovery that such structures are tremendously persistent even in the solid phase: large ponderal quantities of supramolecular aggregates of water (with each nucleus hundreds of nanometers in size) have been observed - at ambient pressure and temperature - using easily-reproducible experimental methods. The nature of these dissipative structures is analyzed and explained in terms of the thermodynamics of far-from-equilibrium systems and irreversible processes, showing their spontaneous quantum origin. Are these kinds of structures the matrix itself of life?.


A rare congenital anomaly of the pancreas: a cadaveric case report.
The pancreas is formed by ventral and dorsal pancreatic buds which arise from the endodermal lining of the gut. When the duodenum rotates to the right, the ventral pancreatic bud migrates dorsally and finally come and lie below the dorsal pancreatic bud. The developmental errors in the rotation of these components lead to annular pancreas. We report a rare type of the incomplete annular pancreas around the contents of right free margin of lesser omentum. There was an extra pancreatic mass situated horizontally immediately above the superior border of the pancreas, situated behind the lesser omentum. The right end of this mass extended into the epiploic foramen and incompletely encircled the portal vein, bile duct and hepatic artery proper from behind. The left end of the extra pancreatic mass was extended towards the lesser curvature of the stomach. Further, this mass completely surrounded the origin of three branches of the celiac trunk. Its right end was found to be continuous with the head of the pancreas, close to the pylorus. Histology of the extra pancreatic mass revealed the presence of normal pancreatic tissue. preoperative diagnosis of this rare anomaly is of clinical importance during surgeries involving the contents of right free margin of lesser omentum and epiploic foramen.


AR Signaling in Breast Cancer.
Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.


Comparison of inflammatory markers and angiographic outcomes after implantation of sirolimus and paclitaxel-eluting stents.
We compared the degree of systemic inflammation and its relation to the angiographic outcomes after drug-eluting stent (DES) implantations. We implanted a single DES in 79 stable angina patients (50 men; 60.4 (9.5) years of age; sirolimus-eluting stent (SES), n = 38; paclitaxel-eluting stent (PES), n = 41). The high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) levels were determined before and at 24 hours, 72 hours, and 4 weeks after the percutaneous coronary intervention (PCI). An angiography and intravascular ultrasound (IVUS) were performed. The hs-CRP and IL-6 levels at baseline did not differ between the two groups. The hs-CRP increased significantly from baseline at 24 hours and 72 hours after the PCI in both groups and there was a significant increase in the IL-6 level at 24 hours after the PCI in both groups. However, there was no significant difference between the two groups in any of the hs-CRP or IL-6 measurements. At follow-up, the late lumen loss was significantly higher in the PES group than in the SES group (0.57 (0.56) mm vs 0.28 (0.58) mm, respectively, p = 0.020). The neointimal hyperplasia (NIH) volume in the PES group was significantly higher than that in the SES group (23.1 (22.7) vs 3.8 (7.1) mm(3), respectively, p = 0.000). The percentage luminal volume reduction was higher in the PES group than in the SES group (18.9 vs 3.9%, p = 0.002). The absolute values or change in the inflammatory markers did not correlate with the NIH or stent volume reduction. Our study showed that the benefits obtained from the SES, which reduce neointimal proliferation, are not probably mediated by the attenuation of the systemic inflammatory markers hs-CRP or IL-6.


The role of antigen presenting cells in the induction of HIV-1 latency in resting CD4(+) T-cells.
Combination antiretroviral therapy (cART) is able to control HIV-1 viral replication, however long-lived latent infection in resting memory CD4(+) T-cells persist. The mechanisms for establishment and maintenance of latent infection in resting memory CD4(+) T-cells remain unclear. Previously we have shown that HIV-1 infection of resting CD4(+) T-cells co-cultured with CD11c(+) myeloid dendritic cells (mDC) produced a population of non-proliferating T-cells with latent infection. Here we asked whether different antigen presenting cells (APC), including subpopulations of DC and monocytes, were able to induce post-integration latent infection in resting CD4(+) T-cells, and examined potential cell interactions that may be involved using RNA-seq. mDC (CD1c(+)), SLAN(+) DC and CD14(+) monocytes were most efficient in stimulating proliferation of CD4(+) T-cells during syngeneic culture and in generating post-integration latent infection in non-proliferating CD4(+) T-cells following HIV-1 infection of APC-T cell co-cultures. In comparison, plasmacytoid DC (pDC) and B-cells did not induce latent infection in APC-T-cell co-cultures. We compared the RNA expression profiles of APC subpopulations that could and could not induce latency in non-proliferating CD4(+) T-cells. Gene expression analysis, comparing the CD1c(+) mDC, SLAN(+) DC and CD14(+) monocyte subpopulations to pDC identified 53 upregulated genes that encode proteins expressed on the plasma membrane that could signal to CD4(+) T-cells via cell-cell interactions (32 genes), immune checkpoints (IC) (5 genes), T-cell activation (9 genes), regulation of apoptosis (5 genes), antigen presentation (1 gene) and through unknown ligands (1 gene). APC subpopulations from the myeloid lineage, specifically mDC subpopulations and CD14(+) monocytes, were able to efficiently induce post-integration HIV-1 latency in non-proliferating CD4(+) T-cells in vitro. Inhibition of key pathways involved in mDC-T-cell interactions and HIV-1 latency may provide novel targets to eliminate HIV-1 latency.


Assessment of a nanoparticle bridge platform for molecular electronics measurements.
A combination of electron beam lithography, photolithography and focused ion beam milling was used to create a nanogap platform, which was bridged by gold nanoparticles in order to make electrical measurements and assess the platform under ambient conditions. Non-functionalized electrodes were tested to determine the intrinsic response of the platform and it was found that creating devices in ambient conditions requires careful cleaning and awareness of the contributions contaminants may make to measurements. The platform was then used to make measurements on octanethiol (OT) and biphenyldithiol (BPDT) molecules by functionalizing the nanoelectrodes with the molecules prior to bridging the nanogap with nanoparticles. Measurements on OT show that it is possible to make measurements on relatively small numbers of molecules, but that a large variation in response can be expected when one of the metal-molecule junctions is physisorbed, which was partially explained by attachment of OT molecules to different sites on the surface of the Au electrode using a density functional theory calculation. On the other hand, when dealing with BPDT, high yields for device creation are very difficult to achieve under ambient conditions. Significant hysteresis in the I-V curves of BPDT was also observed, which was attributed primarily to voltage induced changes at the interface between the molecule and the metal.


The T alpha 2 nuclear protein binding site from the human T cell receptor alpha enhancer functions as both a T cell-specific transcriptional activator and repressor.
T cell-specific expression of the human T cell receptor alpha (TCR-alpha) gene is regulated by the interaction of variable region promoter elements with a transcriptional enhancer that is located 4.5 kb 3' of the TCR-alpha constant region (C alpha) gene segment. The minimal TCR-alpha enhancer is composed of two nuclear protein binding sites, T alpha 1 and T alpha 2, that are both required for the T cell-specific activity of the enhancer. The T alpha 1 binding site contains a consensus cAMP response element (CRE), and binds a set of ubiquitous nuclear proteins. The T alpha 2 binding site does not contain known transcriptional enhancer motifs. However, it binds at least two nuclear protein complexes, one of which is T cell specific. We now report that although the T alpha 2 nuclear protein binding site displays transcriptional activator activity in the context of the TCR-alpha enhancer, this site alone can function as a potent, T cell-specific transcriptional repressor when positioned either upstream, or downstream of several heterologous promoter and enhancer elements. These results demonstrate that a single nuclear protein binding site can function as a T cell-specific transcriptional activator or repressor element, depending upon the context in which it is located.


Serum sex hormone levels are related to breast cancer risk in postmenopausal women.
We conducted a nested case-control study to prospectively evaluate the relationship of serum estrogens and androgens to risk of breast cancer in postmenopausal women. From 1977 to 1987, 3375 postmenopausal women free of cancer and not taking replacement estrogens donated blood to the Breast Cancer Serum Bank in Columbia, Missouri. Of these, 72 were subsequently diagnosed with breast cancer. For each case, two controls matched on age and date and time of day of blood collection were selected using incidence density matching. The median age of subjects at blood collection was 62 years; the time from blood collection to diagnosis ranged from less than 1 to 9.5 years with a median of 2.9 years. Risk of breast cancer was positively and significantly associated with serum levels of estrogens and androgens. Compared to women in the lowest quartile, those in the highest quartile for non-sex hormone-binding globulin (non-SHBG) bound (bioavailable) estradiol had a relative risk of 5.2 (95% confidence interval [CI] = 1.5-18.5) and those in the highest quartile for testosterone had a relative risk of 6.2 (95% CI = 2.0-19.0). Our results lend considerable support to the hypothesis that serum concentrations of estrogens and androgens are related to the subsequent diagnosis of breast cancer in postmenopausal women.


Digital microfluidics using a differentially polarized interface (DPI) to enhance translational force.
Direct current (DC)-digital microfluidics (DMF) enables the manipulation of droplets to revolutionize medical diagnostics, environmental assays, and fundamental biology. However, DC-DMF requires high voltages to generate droplet motion, which often breaks dielectric layers at the micro/nano scale, causing electrolysis. To minimize these issues, oil-fillers are commonly used to decrease the voltage requirement by reducing the surface tension of the droplet to the surrounding fluid. However, these oil-fillers increase DC-DMF complexity and decrease versatility. In this study, by adapting a differentially polarized interface (DPI) to generate an effective electromechanical force, the voltage required to manipulate a droplet was reduced from 600 V to 85 V without an oil-filler or special dielectric materials. By analyzing the temporal profiles of the contact angles during droplet motion under this DPI condition, this study, for the first time, distinguished the contributions of electrowetting and electromechanical forces to the translational movement of droplets. Dominant contribution of electrowetting is observed at the initial stage of the droplet translation with 52.8% reduction in the advancing contact angle and 20% reduction in the receding contact angle. However, after saturation in the temporal change of the contact angle, the effect of electrowetting contribution gradually decreases and electromechanical forces predominate. DPI-based digital microfluidics reduces the overall cost and complexity of stand-alone DC-DMF platforms, enabling filler-less and low-voltage applications for manipulating a wide range of liquid samples.


Microfluidics and catalyst particles.
In this review article, we discuss the latest advances and future perspectives of microfluidics for micro/nanoscale catalyst particle synthesis and analysis. In the first section, we present an overview of the different methods to synthesize catalysts making use of microfluidics and in the second section, we critically review catalyst particle characterization using microfluidics. The strengths and challenges of these approaches are highlighted with various showcases selected from the recent literature. In the third section, we give our opinion on the future perspectives of the combination of catalytic nanostructures and microfluidics. We anticipate that in the synthesis and analysis of individual catalyst particles, generation of higher throughput and better understanding of transport inside individual porous catalyst particles are some of the most important benefits of microfluidics for catalyst research.


Simultaneous resection for colorectal cancer with synchronous liver metastases is a safe procedure: Outcomes at a single center in Turkey.
The optimal surgical strategy for treating colorectal cancer with synchronous liver metastases is subject to debate. The current study sought to evaluate the outcomes of simultaneous colorectal cancer and liver metastases resection in a single center. Prospectively collected data on all patients with synchronous colorectal liver metastases who underwent simultaneous resection with curative intent were analyzed retrospectively. Patient outcomes were compared depending on the primary tumor location and type of liver resection (major or minor). Between January 2005 and August 2016, 108 patients underwent simultaneous resection of primary colorectal cancer and liver metastases. The tumor was localized to the right side of the colon in 24 patients (22%), to the left side in 40 (37%), and to the rectum in 44 (41%). Perioperative mortality occurred in 3 patients (3%). Postoperative complications were noted in 32 patients (30%), and most of these complications (75%) were grade 1 to 3 according to the Clavien-Dindo classification. Neither perioperative mortality nor the rate of postoperative complications after simultaneous resection differed among patients with cancer of the right side of the colon, those with cancer of the left side of the colon, and those with rectal cancer (4%, 2.5%, and 2%, respectively, p = 0.89) and (17%, 33%, and 34%, respectively; p = 0.29)]. The 5-year overall survival of the entire sample was 54% and the 3-year overall survival was 67 %. In conclusion, simultaneous resection for primary colorectal cancer and liver metastases is a safe procedure and can be performed without excess morbidity in carefully selected patients regardless of the location of the primary tumor and type of hepatectomy.


Mobile human network management and recommendation by probabilistic social mining.
Recently, inferring or sharing of mobile contexts has been actively investigated as cell phones have become more than a communication device. However, most of them focused on utilizing the contexts on social network services, while the means in mining or managing the human network itself were barely considered. In this paper, the SmartPhonebook, which mines users' social connections to manage their relationships by reasoning social and personal contexts, is presented. It works like an artificial assistant which recommends the candidate callees whom the users probably would like to contact in a certain situation. Moreover, it visualizes their social contexts like closeness and relationship with others in order to let the users know their social situations. The proposed method infers the social contexts based on the contact patterns, while it extracts the personal contexts such as the users' emotional states and behaviors from the mobile logs. Here, Bayesian networks are exploited to handle the uncertainties in the mobile environment. The proposed system has been implemented with the MS Windows Mobile 2003 SE Platform on Samsung SPH-M4650 smartphone and has been tested on real-world data. The experimental results showed that the system provides an efficient and informative way for mobile social networking.


Isolation of novel multipotent neural crest-derived stem cells from adult human inferior turbinate.
Adult human neural crest-derived stem cells (NCSCs) are of extraordinary high plasticity and promising candidates for the use in regenerative medicine. Here we describe for the first time a novel neural crest-derived stem cell population within the respiratory epithelium of human adult inferior turbinate. In contrast to superior and middle turbinates, high amounts of source material could be isolated from human inferior turbinates. Using minimally-invasive surgery methods isolation is efficient even in older patients. Within their endogenous niche, inferior turbinate stem cells (ITSCs) expressed high levels of nestin, p75(NTR), and S100. Immunoelectron microscopy using anti-p75 antibodies displayed that ITSCs are of glial origin and closely related to nonmyelinating Schwann cells. Cultivated ITSCs were positive for nestin and S100 and the neural crest markers Slug and SOX10. Whole genome microarray analysis showed pronounced differences to human ES cells in respect to pluripotency markers OCT4, SOX2, LIN28, and NANOG, whereas expression of WDR5, KLF4, and c-MYC was nearly similar. ITSCs were able to differentiate into cells with neuro-ectodermal and mesodermal phenotype. Additionally ITSCs are able to survive and perform neural crest typical chain migration in vivo when transplanted into chicken embryos. However ITSCs do not form teratomas in severe combined immunodeficient mice. Finally, we developed a separation strategy based on magnetic cell sorting of p75(NTR) positive ITSCs that formed larger neurospheres and proliferated faster than p75(NTR) negative ITSCs. Taken together our study describes a novel, readily accessible source of multipotent human NCSCs for potential cell-replacement therapy.


Expert and lay perspectives on burden, risk, tolerability, and acceptability of clinical interventions for genetic disorders.
The Clinical Genome Resource (ClinGen) Actionability Working Group (AWG) developed a semiquantitative scoring metric to rate clinical actionability of genetic disorders and associated genes in four domains: (1) severity of the outcome, (2) likelihood of the outcome, (3) effectiveness of the intervention to prevent/minimize the outcome, and (4) nature of the intervention with respect to burden, risk, tolerability, and acceptability to the patient. This study aimed to assess whether nature of the intervention scores assigned by AWG experts reflected lay perceptions of intervention burden, risk, tolerability, and acceptability given the subjectivity of this domain. In July 2017, a general population sample of 1344 adults completed the study. Each participant was asked to read 1 of 24 plain language medical intervention synopses and answer questions related to its burden, risk, tolerability, and acceptability. We conducted three multilevel mixed model analyses predicting the perceived burden, perceived risk, and perceived overall nature of the intervention. As AWG nature of the intervention scores increased, lay perceptions of intervention burden and risk decreased, and perceptions of tolerability and acceptability increased. The findings show alignment between the ClinGen actionability scoring metric and lay perceptions of the nature of the intervention.


Dataset and figures on time-series analysis of child restraint policy impact in Chile.
The main objective of this data article is to present the data set which depicts the impact of child restraint legislation in Chile and its regions. The population of the study consisted of all car crashes records provided by the national police from 2002 to 2014, which included children aged 0-3. Auto Regressive Integrated Moving Average ARIMA and Poisson model were used to present the association between the dependent and independent variables of interest. When the data are analyzed, it will help to determine the degree of relationship and the strength of significance between child restraint legislation policies enacted in 2005 and 2007, and child occupant fatalities and injuries. The data are related to "Impact of child restraint policies on child occupant fatalities and injuries in Chile and its regions: An interrupted time-series study" (Nazif-Munoz et al., 2018).


Therapeutic use of ganciclovir for invasive cytomegalovirus infection in cadaveric renal allograft recipients.
Between November 1987 and September 1989, 419 cadaveric renal transplants were performed at our university. Of the patients 36 (8.6%) had invasive cytomegalovirus infection documented by gastric or duodenal mucosal biopsy in 23 (64%), bronchoalveolar lavage in 12 (33%), allograft biopsy or nephrectomy specimen in 5 (14%) and/or liver biopsy in 1 (3%). Cytomegalovirus severity was defined as mild in 27 patients, moderate in 6 and severe in 3. Ganciclovir [9-(1,3-dihydroxy-2-propoxymethyl)-guanine] was begun once the diagnosis was confirmed by histology or culture at a median of 56 days from transplantation (range 28 to 133 days). Duration of ganciclovir therapy was a minimum of 7 days or until fever was absent for 5 consecutive days (mean 12.2 +/- 3.5 days, range 4 to 21). Ganciclovir was well tolerated and side effects were limited to de novo neutropenia (7 patients), thrombocytopenia (2) and rash (1). Initial clinical improvement was observed in all patients. Two patients had recurrent cytomegalovirus infections that responded to a second course of ganciclovir. The 1-year actuarial patient survival was 100%. At a mean followup of 12.7 +/- 6.2 months 19 patients retained allograft function with a mean serum creatinine of 2.5 mg./dl. (range 1.2 to 4.6). Ganciclovir appears to be a safe and effective drug for the treatment of tissue invasive cytomegalovirus infection in cadaver renal transplant recipients. Prompt institution of this drug at diagnosis of invasive cytomegalovirus may lower the mortality rate formerly associated with this disease.


Impulsive choice and altruistic punishment are correlated and increase in tandem with serotonin depletion.
Human cooperation may partly depend on the presence of individuals willing to incur personal costs to punish noncooperators. The psychological factors that motivate such 'altruistic punishment' are not fully understood; some have argued that altruistic punishment is a deliberate act of norm enforcement that requires self-control, while others claim that it is an impulsive act driven primarily by emotion. In the current study, we addressed this question by examining the relationship between impulsive choice and altruistic punishment in the ultimatum game. As the neurotransmitter serotonin has been implicated in both impulsive choice and altruistic punishment, we investigated the effects of manipulating serotonin on both measures. Across individuals, impulsive choice and altruistic punishment were correlated and increased following serotonin depletion. These findings imply that altruistic punishment reflects the absence rather than the presence of self control, and suggest that impulsive choice and altruistic punishment share common neural mechanisms.


Germination properties of a spore coat-defective mutant of Bacillus subtilis.
The presence of the gerE36 mutation in strains of Bacillus subtilis 168 resulted in poor germination of their spores in a range of germinants, as measured by the fall in absorbance of spore suspensions. Although resistant to heat and organic solvents, spores were sensitive to lysozyme; electron microscopy revealed that their coat structure was incomplete. These spores responded to germinants by losing heat resistance and changing from phase bright to phase gray. The release of dipicolinic acid and the fall in absorbance of spore suspensions reached only 75 and 50% of wild-type levels, respectively, but followed the same time course as the loss of heat resistance. Although the germination response was incomplete, the concentration of L-alanine required to elicit it was the same for the mutant as for the wild type. The properties of mutant spores suggest that an intact spore coat is not required for the initial interaction between germinant and spore, but that the coat layers may contain molecules important in later stages of germination. In transduction with phage SPP1, the gerE36 mutation mapped between citF and ilvB and was 90% cotransduced with citF2. The gerE mutation identifies the location of a gene important for the progress of late stages of spore formation.


Relationship of dietary iodide and drinking water disinfectants to thyroid function in experimental animals.
The importance of dietary iodide on the reported hypothyroid effect of drinking water disinfectants on thyroid function was investigated. Previous studies have also showed differences in the relative sensitivity of pigeons and rabbits to chlorinated water. Pigeons and rabbits were exposed for 3 months to diets containing high (950 ppb) or low (300 ppb) levels of iodide and to drinking water containing two levels of chlorine. Results showed that the high-iodide diet prevented the hypothyroid effect observed in pigeons given the low-iodide diet and chlorinated drinking water. Similar trends were observed in rabbits exposed to the same treatment; however, significant hypothyroid effects were not observed in this animal model. The factor associated with the observed effect of dietary iodide on the chlorine-induced change in thyroid function is unknown, as is the relative sensitivity of rabbits and pigeons to the effect of chlorine. Several factors may explain the importance of dietary iodide and the relative sensitivity of these species. For example, the iodine formed by the known reaction of chlorine with iodide could result in a decrease in the plasma level of iodide because of the relative absorption rates of iodide and iodine in the intestinal tract, and the various types and concentrations of chloroorganics (metabolites) formed in the diet following the exposure of various dietary constituents to chlorine could affect the thyroid function. The former factor was investigated in the present studies. Results do not confirm a consistent, significant reduction in the plasma level of iodide in rabbits and pigeons exposed to chlorinated water and the low-iodide diet. The latter factor is being investigated.


The Health Economics of the spinal cord injury or disease among veterans of war: A systematic review.
Information on health-care utilization and the economic burden of disease are essential to understanding service demands, service accessibility, and practice patterns. This information may also be used to enhance the quality of care through altered resource allocation. Thus, a systematic review of literature on the economic impact of caring for SCI/D veterans would be of great value. To systematically review and critically appraise the literature on the economics of the management of veterans with SCI/D. Medline, EMBASE and PsycINFO databases were searched for articles on economic impact of management of SCI/D veterans, published from 1946 to September/2016. The STROBE statement was used to determine publication quality. The search identified 1,573 publications of which 13 articles fulfilled the inclusion/exclusion criteria with 12 articles focused on costs of management of SCI/D veterans; and, one cost-effectiveness analysis. Overall, the health care costs for the management of SCI/D veterans are substantial ($30,770 to $62,563 in 2016 USD per year) and, generally, greater than the costs of caring for patients with other chronic diseases. The most significant determinants of the higher total health-care costs are cervical level injury, complete injury, time period (i.e. first year post-injury and end-of-life year), and presence of pressure ulcers. There is growing evidence for the economic burden of SCI/D and its determinants among veterans, whereas there is a paucity of comparative studies on interventions including cost-effectiveness analyses. Further investigations are needed to fulfill significant knowledge gaps on the economics of caring for veterans with SCI/D.


Follow-up assessment of standing mobility device users.
The use of standing devices by spinal cord-injured subjects was investigated through a national survey of a sample of individuals who returned their manufacturer's warranty card to two companies. We obtained a 32% response rate (99/310). The majority of respondents were male (87%) with a median age between 41 and 50 years. Seventy-seven percent were paraplegic and 21% were quadriplegic. Forty percent had between 1 and 5 years experience with their device, and 84% of those responding were currently using their standing device. Forty-one percent used their standing device one to six times a week; two-thirds stood between 30 minutes and 1 hour for each use. Less than 10% of subjects experienced any side effects, such as nausea or headaches, from standing. Twenty-one percent of subjects reported being able to empty their bladder more completely. There was also a favorable response by some individuals on the effects of the standing devices on bowel regularity, reduction of urinary tract infections, leg spasticity, and number of bed sores. Finally, 79% of subjects highly recommended use of standing devices to other people with spinal cord injury. The positive responses of individuals using standing devices is a strong recommendation for the assistive technology community to make these devices more available to individuals with spinal cord injury.


Hck tyrosine kinase activity modulates tumor necrosis factor production by murine macrophages.
The hematopoietic cell kinase (hck) is a member of the src family of tyrosine kinases, and is primarily expressed in myeloid cells. Hck expression increases with terminal differentiation in both monocyte/macrophages and granulocytes and is further augmented during macrophage activation. Recent evidence has implicated src-related tyrosine kinases in critical signaling pathways in other hematopoietic lineages. Herein we demonstrate that manipulation of the level of hck expression in the murine macrophage cell line BAC1.2F5 alters the responsiveness of these cells to activation by bacterial lipopolysaccharide (LPS) but does not affect survival or proliferation. Overexpression of an activated mutant of hck in BAC1.2F5 cells augments tumor necrosis factor (TNF) production in response to LPS, whereas inhibition of endogenous hck expression, by antisense oligonucleotides, interferes with LPS-mediated TNF synthesis. Together, these observations suggest that hck is an important component of the signal transduction pathways in activated macrophages.


The relationship between healthcare services and the political economy with reference to the Jamaican experience.
The availability of and equitable access to, health services have challenged healthcare providers with a greater degree of urgency since the end of World War II. Prior to that time, concepts such as equity and social justice were just that, concepts but no real attempts were ever made to operationalize them. Goods and services were still produced and distributed based on market forces, that is, one's ability and willingness to pay for something. Health in that context was a service, some say a commodity, to be bought and sold, hence its availability was not necessarily commensurate with its accessibility.


Species, Risk Factors, and Antimicrobial Susceptibility Profiles of Bacterial Isolates from HIV-Infected Patients Suspected to Have Pneumonia in Mekelle Zone, Tigray, Northern Ethiopia.
Pneumonia is a condition, where bacterial infections are implicated as the most common causes of morbidity and mortality in humans. The actual burden of HIV-infected patients with pneumonia is not well documented in Mekelle region of Ethiopia. This study estimated the prevalence of bacterial pneumonia in HIV patients, antimicrobial susceptibility patterns of pathogens implicated in pneumonia, and associated risk factors in Mekelle zone, Tigray, Northern Ethiopia, during August-December 2016. Sputum specimens were collected from 252 HIV seropositive individuals with suspected pneumonia. Data on sociodemographics and risk factors were also collected using a structured questionnaire. Blood, Chocolate, and Mac Conkey agar plates (Oxoid, Hampshire, UK) were used to grow the isolates. The isolated colonies were identified based on Gram stain, colony morphology, pigmentation, hemolysis, and biochemical tests. The antimicrobial susceptibility test was performed using the modified Kirby-Bauer disc diffusion method. The analysis was performed using SPSS version 22 and p-value < 0.05 with corresponding 95% confidence interval (CI) was considered statistically significant. Out of the 252 samples, 110 (43.7%) were positive for various bacterial species. The predominant bacterial species were Klebsiella pneumoniae (n=26, 23.6 %) followed by Streptococcus pneumoniae (n=17, 15.5 %), Escherichia coli (n=16, 14.5%), Klebsiella spp. (n=15, 13.6%), Staphylococcus aureus (n=9, 8.2%), Enterobacter spp. (n=7, 6.3%), Pseudomonas aeruginosa (4, n=3.6%), Proteus spp. (n=4, 3.6%), Citrobacter freundii (n=7, 6.3%), Streptococcus pyogenes (3, 2.7%), and Haemophilus influenzae (n=2, 1.8%). Young age (18-29), recent CD4+ count less than 350 cells/mL, alcohol consumption, and HIV WHO stage II showed significant association with the occurrence of bacterial pneumonia. Resistance to penicillin, co-trimoxazole, and tetracycline was observed in 81.8%, 39.8%, and 24.5% of the isolates, respectively. The problem of pneumonia among HIV patients was significant in the study area. The high prevalence of drug-resistant bacteria isolated from the patient's samples possesses a health risk in immunocompromised HIV patients. There is a need to strengthen and expand culture and susceptibility procedures for the administration of appropriate therapy to improve patients management and care which may aid in decreasing the mortality.


Promoting breast-feeding in a deprived area: the influence of a peer support initiative.
The present article describes a qualitative study designed to evaluate the effectiveness of a peer-support intervention to promote breast-feeding in a deprived area. The aims of the study were to: explore stakeholders' experiences of the intervention; explore the development of a 'culture' of breast-feeding; and consider the potential of the initiative for building community capacity. The methods used in the research were in-depth interviews, diaries and direct observation. The findings describe the social and cultural barriers to breast-feeding experienced by women, and the ways in which professional and lay participants in the peer-support project attempt to reduce them. The advantages of partnership working between health professionals and lay volunteers are then explored. These include: sharing the workload; providing an informal tier of support to mothers; and importantly, offering support and advice stemming from personal experience. For lay supporters, the benefits of taking part in the project range from personal satisfaction at being recognised as skilled, to gains in confidence which potentially open up further educational and training opportunities. In conclusion, it is suggested that the 'success' of such interventions is unlikely to be captured solely by monitoring breast-feeding rates, but needs to take into account the wider context of community development.


Differential effects of early hippocampal pathology on episodic and semantic memory.
Global anterograde amnesia is described in three patients with brain injuries that occurred in one case at birth, in another by age 4, and in the third at age 9. Magnetic resonance techniques revealed bilateral hippocampal pathology in all three cases. Remarkably, despite their pronounced amnesia for the episodes of everyday life, all three patients attended mainstream schools and attained levels of speech and language competence, literacy, and factual knowledge that are within the low average to average range. The findings provide support for the view that the episodic and semantic components of cognitive memory are partly dissociable, with only the episodic component being fully dependent on the hippocampus.


Genetic determinants of mate recognition in Brachionus manjavacas (Rotifera).
Mate choice is of central importance to most animals, influencing population structure, speciation, and ultimately the survival of a species. Mating behavior of male brachionid rotifers is triggered by the product of a chemosensory gene, a glycoprotein on the body surface of females called the mate recognition pheromone. The mate recognition pheromone has been biochemically characterized, but little was known about the gene(s). We describe the isolation and characterization of the mate recognition pheromone gene through protein purification, N-terminal amino acid sequence determination, identification of the mate recognition pheromone gene from a cDNA library, sequencing, and RNAi knockdown to confirm the functional role of the mate recognition pheromone gene in rotifer mating. A 29 kD protein capable of eliciting rotifer male circling was isolated by high-performance liquid chromatography. Two transcript types containing the N-terminal sequence were identified in a cDNA library; further characterization by screening a genomic library and by polymerase chain reaction revealed two genes belonging to each type. Each gene begins with a signal peptide region followed by nearly perfect repeats of an 87 to 92 codon motif with no codons between repeats and the final motif prematurely terminated by the stop codon. The two Type A genes contain four and seven repeats and the two Type B genes contain three and five repeats, respectively. Only the Type B gene with three repeats encodes a peptide with a molecular weight of 29 kD. Each repeat of the Type B gene products contains three asparagines as potential sites for N-glycosylation; there are no asparagines in the Type A genes. RNAi with Type A double-stranded RNA did not result in less circling than in the phosphate-buffered saline control, but transfection with Type B double-stranded RNA significantly reduced male circling by 17%. The very low divergence between repeat units, even at synonymous positions, suggests that the repeats are kept nearly identical through a process of concerted evolution. Information-rich molecules like surface glycoproteins are well adapted for chemical communication and aquatic animals may have evolved signaling systems based on these compounds, whereas insects use cuticular hydrocarbons. Owing to its critical role in mating, the mate recognition pheromone gene will be a useful molecular marker for exploring the mechanisms and rates of selection and the evolution of reproductive isolation and speciation using rotifers as a model system. The phylogenetic variation in the mate recognition pheromone gene can now be studied in conjunction with the large amount of ecological and population genetic data being gathered for the Brachionus plicatilis species complex to understand better the evolutionary drivers of cryptic speciation.


A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood.
Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF-15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ∼5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC-1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 × 10-35), was significantly associated with blood MIC-1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the"COPI-mediated anterograde transport" gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels.


Specialist palliative and end-of-life care for patients with cancer and SARS-CoV-2 infection: a European perspective.
Specialist palliative care team (SPCT) involvement has been shown to improve symptom control and end-of-life care for patients with cancer, but little is known as to how these have been impacted by the COVID-19 pandemic. Here, we report SPCT involvement during the first wave of the pandemic and compare outcomes for patients with cancer who received and did not receive SPCT input from multiple European cancer centres. From the OnCovid repository (N = 1318), we analysed cancer patients aged ⩾18 diagnosed with COVID-19 between 26 February and 22 June 2020 who had complete specialist palliative care team data (SPCT+ referred; SPCT- not referred). Of 555 eligible patients, 317 were male (57.1%), with a median age of 70 years (IQR 20). At COVID-19 diagnosis, 44.7% were on anti-cancer therapy and 53.3% had ⩾1 co-morbidity. Two hundred and six patients received SPCT input for symptom control (80.1%), psychological support (54.4%) and/or advance care planning (51%). SPCT+ patients had more 'Do not attempt cardio-pulmonary resuscitation' orders completed prior to (12.6% versus 3.7%) and during admission (50% versus 22.1%, p < 0.001), with more SPCT+ patients deemed suitable for treatment escalation (50% versus 22.1%, p < 0.001). SPCT involvement was associated with higher discharge rates from hospital for end-of-life care (9.7% versus 0%, p < 0.001). End-of-life anticipatory prescribing was higher in SPCT+ patients, with opioids (96.3% versus 47.1%) and benzodiazepines (82.9% versus 41.2%) being used frequently for symptom control. SPCT referral facilitated symptom control, emergency care and discharge planning, as well as high rates of referral for psychological support than previously reported. Our study highlighted the critical need of SPCTs for patients with cancer during the pandemic and should inform service planning for this population.


A longitudinal study on Anopheles mosquito larval abundance in distinct geographical and environmental settings in western Kenya.
As the ecology of mosquito larvae can be complex there is need to develop a rational framework for undertaking larval ecological studies. Local environmental characteristics, such as altitude, climate and land use, can significantly impact on phenology and population dynamics of mosquito larvae, and indirectly affect the dynamics of mosquito-borne diseases. The aim of this study was to assess the feasibility of implementing an integrated approach to larval source management under the distinct ecological settings. The study was conducted in two highland villages and one village, at a lower altitude, in the Lake Victoria basin, where malaria is endemic and transmitted by the same Anopheles mosquito species. In each village the stability of mosquito larval habitats was classified as either temporary or permanent. The productivity of these habitat types was quantified by carrying out weekly larval sampling using a standard dipping method for a period of two years. During sampling the physical characteristic of the larval habitat, including the vegetation cover were noted. Ambient temperature, rainfall and relative humidity were recorded on a 21 × Micro-datalogger in each study site. Anopheles gambiae sensu lato larvae were found in all study sites. Anopheles arabiensis was more abundant (93%) in Nyalenda (Lake Victoria basin) and Fort Ternan (highland area; 71%). In Lunyerere (highland area), An. gambiae sensu stricto comprised 93% of the total An. gambiae s.l. larvae. Larvae of An. gambiae s.l. mosquitoes were present in both temporary and permanent habitats with monthly variations dependent on rainfall intensity and location. Anopheles larvae were more likely to be found in man-made as opposed to natural habitats. Grassy habitats were preferred and were, therefore, more productive of Anopheles larvae compared to other habitat types. Weekly rainfall intensity led to an increase or decrease in mosquito larval abundance depending on the location. The majority of mosquito breeding habitats were man made in all sites. Both temporary and permanent habitats were suitable for An. gambiae breeding. In Fort Ternan temporary sites were favoured for mosquito breeding above permanent sites. Significant differences in larval abundance were found depending on weekly rainfall intensity. Larval source management programmes should target permanent and temporary habitats equally and work closely with land and home owners as a majority of the breeding habitats are man made.


Chronic hyperosmotic stress converts GABAergic inhibition into excitation in vasopressin and oxytocin neurons in the rat.
In mammals, the increased secretion of arginine-vasopressin (AVP) (antidiuretic hormone) and oxytocin (natriuretic hormone) is a key physiological response to hyperosmotic stress. In this study, we examined whether chronic hyperosmotic stress weakens GABA(A) receptor-mediated synaptic inhibition in rat hypothalamic magnocellular neurosecretory cells (MNCs) secreting these hormones. Gramicidin-perforated recordings of MNCs in acute hypothalamic slices prepared from control rats and ones subjected to the chronic hyperosmotic stress revealed that this challenge not only attenuated the GABAergic inhibition but actually converted it into excitation. The hyperosmotic stress caused a profound depolarizing shift in the reversal potential of GABAergic response (E(GABA)) in MNCs. This E(GABA) shift was associated with increased expression of Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) in MNCs and was blocked by the NKCC inhibitor bumetanide as well as by decreasing NKCC activity through a reduction of extracellular sodium. Blocking central oxytocin receptors during the hyperosmotic stress prevented the switch to GABAergic excitation. Finally, intravenous injection of the GABA(A) receptor antagonist bicuculline lowered the plasma levels of AVP and oxytocin in rats under the chronic hyperosmotic stress. We conclude that the GABAergic responses of MNCs switch between inhibition and excitation in response to physiological needs through the regulation of transmembrane Cl(-) gradients.


Microbial diversity and community structure in Fynbos soil.
The Fynbos biome in South Africa is renowned for its high plant diversity and the conservation of this area is particularly important for the region. This is especially true in the case of endangered vegetation types on the lowlands such as Sand Fynbos, of which only small fragments remain. The question is thus whether the diversity of the above-ground flora is mirrored in the below-ground microbial communities. In order to determine the relationship of the above- and below-ground communities, the soil community composition of both fungal and bacterial groups in Sand Fynbos was characterized over space and time. A molecular approach was used based on the isolation of total soil genomic DNA and automated ribosomal intergenic spacer analysis of bacterial and fungal communities. Soil from four different sites was compared to resolve the microbial diversity of eubacterial and fungal groups on a local (alpha diversity) scale as well as a landscape scale (beta diversity). The community structures from different sites were compared and found to exhibit strong spatial patterns which remained stable over time. The plant community data were compared with the fungal and the bacterial communities. We concluded that the microbial communities in the Sand Fynbos are highly diverse and closely linked to the above-ground floral communities.


James Lind Alliance research priorities: what role do carbohydrates, fats and proteins have in the management of Type 2 diabetes, and are there risks and benefits associated with particular approaches?
To assess the role played by carbohydrates, fat and proteins in the management of Type 2 diabetes. Diabetes research tends to reflect the interests of academics or the pharmaceutical industry, rather than those of people living with Type 2 diabetes. The James Lind Alliance and Diabetes UK addressed this issue by defining the research priorities of people living with Type 2 diabetes. Three of the top 10 research priority questions focused on lifestyle. A narrative review was undertaken with a structured search strategy using three databases. Search terms included the three macronutrients and Type 2 diabetes. No restrictions were placed on macronutrient quantity or length of study follow-up. Outcomes included changes in HbA1c , body weight, insulin sensitivity and cardiovascular risk. There is no strong evidence that there is an optimal ratio of macronutrients for improving glycaemic control or reducing cardiovascular risk. Challenges included defining the independent effect of macronutrient manipulation and identifying the effects of macronutrients, independent of foods and dietary patterns. Extreme intakes of macronutrients may be associated with health risks. It is challenging to formulate food-based guidelines from studies based on macronutrient manipulation. Structured education should be offered to support individuals in discovering their optimal, individual dietary approach. Recommendations for dietary guidelines should be expressed in terms of foods and not macronutrients.


Connectivity Among Populations of the Top Shell Gibbula divaricata in the Adriatic Sea.
Genetic connectivity studies are essential to understand species diversity and genetic structure and to assess the role of potential factors affecting connectivity, thus enabling sound management and conservation strategies. Here, we analyzed the patterns of genetic variability in the marine snail Gibbula divaricata from five coastal locations in the central-south Adriatic Sea (central Mediterranean) and one in the adjacent northern Ionian Sea, using 21 described polymorphic microsatellite loci. Observed and expected heterozygosity varied from 0.582 to 0.635 and 0.684 to 0.780, respectively. AMOVA analyses showed that 97% of genetic variation was observed within populations. Nevertheless, significant, although small, genetic differentiation was found among nearly all of the pairwise F ST comparisons. Over a general pattern of panmixia, three groups of populations were identified: eastern Adriatic populations, western Adriatic populations, and a third group represented by the single northern Ionian Sea population. Nonetheless, migration and gene flow were significant between these groups. Gibbula divaricata is thought to have a limited dispersal capacity related to its lecithotrophic trochophore larval stage. Our results indicated high levels of self-recruitment and gene flow that is mainly driven through coastline dispersion, with populations separated by the lack of suitable habitats or deep waters. This stepping-stone mode of dispersion together with the high levels of self-recruitment could lead to higher levels of population structuring and differentiation along the Adriatic Sea. Large effective population sizes and episodic events of long-distance dispersal might be responsible for the weak differentiation observed in the analyzed populations. In summary, the circulation system operating in this region creates natural barriers for dispersion that, together with life-history traits and habitat requirements, certainly affect connectivity in G. divaricata. However, this scenario of potential differentiation seems to be overridden by sporadic events of long-distance dispersal across barriers and large effective population sizes.


Disruption of the alox5ap gene ameliorates focal ischemic stroke: possible consequence of impaired leukotriene biosynthesis.
Leukotrienes are potent inflammatory mediators, which in a number of studies have been found to be associated with ischemic stroke pathology: gene variants affecting leukotriene synthesis, including the FLAP (ALOX5AP) gene, have in human studies shown correlation to stroke incidence, and animal studies have demonstrated protective properties of various leukotriene-disrupting drugs. However, no study has hitherto described a significant effect of a genetic manipulation of the leukotriene system on ischemic stroke. Therefore, we decided to compare the damage from focal cerebral ischemia between wild type and FLAP knockout mice. Damage was evaluated by infarct staining and a functional test after middle cerebral artery occlusion in 20 wild type and 20 knockout male mice. Mortality-adjusted median infarct size was 18.4 (3.2-76.7) mm3 in the knockout group, compared to 72.0 (16.7-174.0) mm3 in the wild type group (p < 0.0005). There was also a tendency of improved functional score in the knockout group (p = 0.068). Analysis of bone marrow cells confirmed that knockout animals had lost their ability to form leukotrienes. Since the local inflammatory reaction after ischemic stroke is known to contribute to the brain tissue damage, the group difference seen in the current study could be a consequence of a milder inflammatory reaction in the knockout group. Our results add evidence to the notion that leukotrienes are important in ischemic stroke, and that blocked leukotriene production ameliorates cerebral damage.


Treatment and Outcomes of Primary Urethra Cancer.
Urethral cancer is a rare malignancy, representing <1% of all malignancies. Optimal management, due to its rarity, presents as a treatment dilemma for physicians. There is a lack of consensus regarding treatment as large randomized trials cannot be performed; thus, optimal management decisions rely on study of retrospective cases. This is a review of our institutional experience with urethral cancer treated with various treatment modalities. A retrospective chart review was performed on 31 patients treated for primary cancer of the urethra from 1958 to 2008. The patients were stratified by sex, histologic type, stage, date of diagnosis, type of treatment, and last follow-up. Early stage cases were designated as Tis-T2N0M0 and advanced cases were designated as T3-4, N+ or M+. Analysis was performed based on clinical stage, treatment modalities and outcomes. Fourteen early stage cases and 17 advanced stage cases of urethral cancer were analyzed. The majority of early stage cases occurred in men (M:F=8:6) and the majority of advanced stage cases occurred in women (M:F=5:12). The most common histology was squamous cell carcinoma for both early and advanced stage cases. Surgery was the preferred modality of treatment for early stage cases (surgery used in 13 cases vs. chemo/radiotherapy used in 1 case) while for advanced cases, radiation ±chemotherapy was commonly used. Overall survival for this series was 45% at mean follow-up of 7 years. Eight of the 14 cases of early stage cancer remained disease free at last follow-up. Comparatively, only 5 of 17 with advanced cancers had no apparent disease at last follow-up. All but one of those patients were treated with combined modality therapy. Patients with early stage urethral cancers do well with single modality therapy, whereas patients who present with advanced cancers may benefit from combined modality therapy. More extensive study is required to recommend a particular treatment protocol. However, in this rare malignancy, institutional experiences provide the best evidence currently due to the lack of multi-institutional trials.


Making UFOs make sense: Ufology, science, and the history of their mutual mistrust.
Reports of unidentified flying objects and alien encounters have sparked amateur research (ufology), government investigations, and popular interest in the subject. Historically, however, scientists have generally greeted the topic with skepticism, most often dismissing ufology as pseudoscience and believers in unidentified flying objects and aliens as irrational or abnormal. Believers, in turn, have expressed doubts about the accuracy of academic science. This study examines the historical sources of the mutual mistrust between ufologists and scientists. It demonstrates that any science doubt surrounding unidentified flying objects and aliens was not primarily due to the ignorance of ufologists about science, but rather a product of the respective research practices of and relations between ufology, the sciences, and government investigative bodies.


Sonic hedgehog-induced neural precursor proliferation after adult rodent spinal cord injury.
The glycoprotein molecule sonic hedgehog (Shh) has been shown to play a critical role in neuraxial development. To assess its role in the repair of demyelination following spinal cord injury (SCI), escalating doses of Shh were injected into demyelinated lesions in adult rat spinal cords. Twenty-seven adult rats underwent thoracic laminectomy and chemical demyelination of the spinal cord dorsal columns without neurological deficit A subset of 20 rats was treated after 3 days by direct injection of Shh at two different doses. Rats were killed at 7 or 21 days after SCI, and tissue samples underwent immediate fixation or were placed into cell culture. Diffuse cellular proliferative responses throughout the gray and white matter were observed in up to 70% of Shh-treated rats. Proliferation around the central canal, believed to be derived from the ventricular ependyma consistent with neuronal stem cell induction, was demonstrated in up to 60% of the treated rats. No significant proliferation in these areas was detected in control rats. Dorsal areas of nestin-positive cells were also observed in 70% of rats treated with high doses of Shh, and these observations were reproduced in cell culture as well as in cultures of dorsal spinal cord explants. Cell counts revealed significant increases in the percentage of oligodendrocyte precursors and neurons in treated compared with control rats. Exogenous Shh administration promotes nestin-positive cell proliferation after SCI in adult rodents. These cells are believed to be derived from neural precursor cells. The populations of oligodendrocyte precursors and neurons were likewise increased in Shh-treated rats, suggesting that these cells may be derived from neural stem cells.


Myosuppressin influences fecundity in the Colorado potato beetle, Leptinotarsa decemlineata.
Insect neuropeptides regulate various physiological processes, such as reproduction, feeding, growth and development, and have been considered as viable targets in the development of alternative strategies for pest control. Amongst these neuropeptides is myosuppressin (MS), a very conserved neuropeptide that has been reported to regulate cardiac and skeletal muscle contractility, feeding and pupal diapause in insects. In this study, we investigated the involvement of MS in fecundity in a notorious defoliator of potato and other solanaceous plants, the Colorado potato beetle (CPB), Leptinotarsa decemlineata. We identified an MS-precursor-encoding transcript in the L. decemlineata transcriptomic database and then evaluated its transcript levels in various CPB tissues. MS transcript levels were found to be highest in the central nervous system, gut and muscle of CPB males and females. To investigate the role of MS in fecundity, MS was silenced in adult CPBs through RNA interference (RNAi). This resulted in a significant reduction in oviposition (over 80%) and oocyte size (69%) in the treated beetles compared to the controls. Also, the reduction in oviposition in treated females was confirmed to be dependent on MS knockdown and independent of male fertilization. Furthermore, MS-knockdown in females resulted in decreased levels of ecdysteroid hormone titers and the transcript levels of its receptor. Interestingly, the injection of 20-hydroxyecdysone into females following MS knockdown could rescue ovary development. Altogether, this study highlights the important role played by MS in regulating fecundity in CPB.


Analogous responses in the nucleus accumbens and cingulate cortex to pain onset (aversion) and offset (relief) in rats and humans.
In humans, functional magnetic resonance imaging (fMRI) activity in the anterior cingulate cortex (ACC) and the nucleus accumbens (NAc) appears to reflect affective and motivational aspects of pain. The responses of this reward-aversion circuit to relief of pain, however, have not been investigated in detail. Moreover, it is not clear whether brain processing of the affective qualities of pain in animals parallels the mechanisms observed in humans. In the present study, we analyzed fMRI blood oxygen level-dependent (BOLD) activity separately in response to an onset (aversion) and offset (reward) of a noxious heat stimulus to a dorsal part of a limb in both humans and rats. We show that pain onset results in negative activity change in the NAc and pain offset produces positive activity change in the ACC and NAc. These changes were analogous in humans and rats, suggesting that translational studies of brain circuits modulated by pain are plausible and may offer an opportunity for mechanistic investigation of pain and pain relief.


Oncology drugs in the crosshairs of pharmaceutical crime.
Oncology drugs clearly have become a target for pharmaceutical crime. In 2016, falsified oncology drugs ranked fifth in the most commonly falsified drug category among the reports received by the Pharmaceutical Security Institute. Although the prevalence of illicit oncology drugs in the legal supply chains appears to be small, these drugs are difficult to detect, particularly in clinical practice. Forthcoming countermeasures to detect illicit drugs in high-income countries include compulsory antitampering devices and product verification technology for a risk-based selection of medicines. Health-care professionals must implement these new procedures into their workflow and remain vigilant about those medicines that are not selected. Although countermeasures should firmly tighten supply chain security, there are concerns about how quickly pharmaceutical crime will adapt to these protections. Because patients and health-care professionals have shown a lenient attitude towards purchasing medicines from unreliable sources, measures against the highly accessible illegal medicine supply chain remain necessary. To improve detectability in clinical practice, reporting of ineffectiveness and unusual drug effects as adverse events or adverse drug reactions is essential.


Impaired grasping in a patient with optic ataxia: primary visuomotor deficit or secondary consequence of misreaching?
Optic ataxia is defined as a spatial impairment of visually guided reaching, but it is typically accompanied by other visuomotor difficulties, notably a failure to scale the handgrip appropriately while reaching to grasp an object. This impaired grasping might reflect a primary visuomotor deficit, or it might be a secondary effect arising from the spatial uncertainty associated with poor reaching. To distinguish between these possibilities, we used a new paradigm to tease apart the proximal and distal components of prehension movements. In the "far" condition objects were placed 30 cm from the hand so that subjects had to make a reaching movement to grasp them, whereas in the "close" condition objects were placed adjacent to the hand, thereby removing the need for a reaching movement. Stimulus eccentricity was held constant. We tested a patient with optic ataxia (M.H.), whose misreaching affects only his right hand within the right visual hemifield. M.H. showed a clear impairment in grip scaling, but only when using his right hand to grasp objects in the right visual hemifield. Critically, this grip-scaling impairment was absent in M.H. in the "close" condition. These data suggest that M.H.'s grip scaling is impaired as a secondary consequence of making inaccurate reaching movements, and not because of any intrinsic visuomotor impairment of grasping. We suggest that primary misgrasping is not a core symptom of the optic ataxia syndrome, and that patients will show a primary deficit only when their lesion extends anteriorly within the intraparietal sulcus to include area aIPS.


Characteristic findings on imaging of cervical spondylolisthesis: Analysis of computed tomography and X-ray photography in 101 spondylolisthesis patients.
The characteristics of cervical spondylolisthesis are not currently fully understood, because of the shortage of reports covering the large population of patients with cervical spondylolisthesis. The purpose of this study was to elucidate the characteristics of cervical spondylolisthesis by examining a relatively large number of cases. We analyzed 101 cases with more than 2 mm of vertebral listhesis as determined from X-ray or computed tomography (CT) images among 731 patients who underwent surgery at a single institute. We considered the C2-7 angle, range of motion, and C2-7 sagittal vertical axis on lateral X-ray images. From sagittal CT images, classifications into five grades based on the slipped disc and adjacent caudal levels were made. We examined the orientation of facet joints at the slipped level using axial CT images. Spondylolisthesis was recognized in 101 cases at 124 levels. Anterior and posterior spondylolisthesis were detected in 68 and 40 cases, respectively. Anterior spondylolisthesis developed predominantly at C3 or C4, usually at the level adjacent to the narrowed disc, or at C7, adjacent to the stiffened thoracic spine. The disc height was relatively preserved at the anterior slipped level. Posterior spondylolisthesis developed predominantly at the level of the significantly narrowed disc associated with advanced intervertebral osteoarthritis. At the segment with listhesis in the lower cervical spine, the direction of the facet joint in the axial plane tended to be posteromedial. Cervical degenerative spondylolisthesis was classified into two types. The first and more common listhesis occurred adjacent to stiffened levels, and anterior slippage was common in this type. The second and less common listhesis occurred within progressively degenerated segments, and posterior slippage was prominent. We have uniquely described the morphological changes in orientation of the cervical facet joints at the slipped level in the transverse plane.


Anthropomorphic measurements that include central fat distribution are more closely related with key risk factors than BMI in CKD stage 3.
Body Mass Index (BMI) as a marker of obesity is an established risk factor for chronic kidney disease (CKD) and cardiovascular disease (CVD). However, BMI can overestimate obesity. Anthropomorphic measurements that include central fat deposition are emerging as a more important risk factor. We studied BMI, waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR) and conicity index (CI) in a cohort of patients with CKD stage 3 and compared the associations with other known risk factors for CKD progression and CVD. 1740 patients with CKD stage 3 were recruited from primary care for the Renal Risk in Derby study. Each participant underwent clinical assessment, including anthropomorphic measurements and pulse wave velocity (PWV), as well as urine and serum biochemistry tests. The mean age of the cohort was 72.9±9 years with 60% females. The mean eGFR was 52.5±10.4 ml/min/1.73 m(2) and 16.9% of the cohort had diabetes. With the cohort divided into normal and increased risk of morbidity and mortality using each anthropomorphic measurement, those measurements that included increased central fat distribution were significantly associated with more risk factors for CKD progression and CVD than increased BMI. Univariable analysis demonstrated central fat distribution was correlated with more risk factors than BMI. Subgroup analyses using recognised BMI cut-offs to define obesity and quartiles of WHR and CI demonstrated that increasing central fat distribution was significantly associated with more CKD and CVD risk factors than increasing BMI. Anthropomorphic measurements that include a measure of central fat deposition are related to more key risk factors in CKD stage 3 patients than BMI. Central fat deposition may be of greater importance as a risk factor in CKD than BMI and reliance on BMI alone may therefore underestimate the associated risk.


A multicenter, randomized, double-blind, placebo-controlled trial of oral type I collagen treatment in patients with diffuse cutaneous systemic sclerosis: I. oral type I collagen does not improve skin in all patients, but may improve skin in late-phase disease.
To investigate the safety and efficacy of oral bovine type I collagen (CI) treatment in patients who have had diffuse cutaneous systemic sclerosis (dcSSc; scleroderma) for <or=10 years. One hundred sixty-eight patients with dcSSc were enrolled in a double-blind, placebo-controlled trial of oral CI (500 microg/day) or placebo administered over 12 months, with a followup visit at month 15. The primary outcome was the modified Rodnan skin thickness score (MRSS). Other clinical and immune system parameters were also assessed. Intent-to-treat and modified intent-to-treat analyses showed that for the total population of patients with dcSSc, there were no significant differences in the mean change in MRSS or other key clinical parameters between the CI and placebo treatment groups at 12 months or at 15 months. However, in a subanalysis of the available data at month 15, the CI-treated group of patients with late-phase dcSSc experienced a significant reduction in the MRSS compared with that in the placebo-treated patients with late-phase dcSSc (change in MRSS at month 15 -7.9 versus -2.9; P = 0.0063). Although the results from this trial did not meet the primary outcome goals, the findings from exploratory analyses indicated that CI treatment may benefit patients with late-phase dcSSc. This new treatment strategy and preliminary clinical observations in patients with dcSSc need to be corroborated.