A comprehensive space management model for facilitating programmatic research.
In FY04, the authors developed and implemented models to manage existing and incremental research space, and to facilitate programmatic research, at the University of Arizona College of Medicine. Benchmarks were set for recovery of total sponsored research dollars and for facilities and administrative (F&A) dollars/net square foot (nsf) of space, based on college-wide metrics. Benchmarks were applied to units (departments, centers), rather than to individual faculty. Performance relative to the benchmark was assessed using three-year moving averages, and applied to existing blocks of space. Space was recaptured or allocated, in all cases to programmatic themes, using uniform policies. F&A revenues were returned on the basis of performance relative to a benchmark. During the first two years after implementation of the model (FY05 and FY06), and for the 24 units occupying research space, median total sponsored research revenue/nsf increased from $393.96 to $474.46 (20.4%), and median F&A revenue/nsf increased from $57.42 to $91.86 (60.0%). These large increases in median values are driven primarily from redistribution and recapturing of space. Recruiting policies for unit heads were developed to facilitate joint hires among units. In combination, these policies created a comprehensive space management model for facilitating programmatic research. Although challenges remain in implementing the programmatic recruitment strategy, and selected modifications to the original policy were introduced later (e.g., research space for newly recruited junior faculty is now exempted from calculations for three years), overall, the models have created a climate of transparency that is now accepted and that allows efficient and equitable management of research space.


Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection.
Mycobacterium tuberculosis (MTB)-specific cytokine responses in the peripheral blood and at the site of infection may differ significantly within the same individual, but the under-lying T-cell subset changes are largely unknown. Here, we measured effector and memory T-cell markers on CD4⁺ T cells (CD45RO, cysteine chemokine receptor (CCR)7, and CD27) in peripheral blood and at the site of active tuberculosis (TB). Additionally, T cells were stimulated overnight with purified protein derivative (PPD) and early secretory antigenic target (ESAT)-6 to determine which T-cell subset produces MTB-specific interferon (IFN)-γ. A striking decrease in CCR7 and CD27 expression on T cells was noted at the site of active TB. Likewise, IFN-γ expressing, ESAT-6 specific CD4⁺CD45RO⁺CD27⁻ T cells were dramatically increased at the site of infection but were not detectable in peripheral blood. An antigen-specific expansion of differentiated T cells at the site of active TB infection was poorly reflected in peripheral blood. Insight in these changes in MTB-specific effector T cells in different compartments of the body could lead to new approaches for immune-based diagnosis and interventions.


Presence of active aliphatic amidases in Helicobacter species able to colonize the stomach.
Ammonia production is of great importance for the gastric pathogen Helicobacter pylori as a nitrogen source, as a compound protecting against gastric acidity, and as a cytotoxic molecule. In addition to urease, H. pylori possesses two aliphatic amidases responsible for ammonia production: AmiE, a classical amidase, and AmiF, a new type of formamidase. Both enzymes are part of a regulatory network consisting of nitrogen metabolism enzymes, including urease and arginase. We examined the role of the H. pylori amidases in vivo by testing the gastric colonization of mice with H. pylori SS1 strains carrying mutations in amiE and/or amiF and in coinfection experiments with wild-type and double mutant strains. A new cassette conferring resistance to gentamicin was used in addition to the kanamycin cassette to construct the double mutation in strain SS1. Our data indicate that the amidases are not essential for colonization of mice. The search for amiE and amiF genes in 53 H. pylori strains from different geographic origins indicated the presence of both genes in all these genomes. We tested for the presence of the amiE and amiF genes and for amidase and formamidase activities in eleven Helicobacter species. Among the gastric species, H. acinonychis possessed both amiE and amiF, H. felis carried only amiF, and H. mustelae was devoid of amidases. H. muridarum, which can colonize both mouse intestine and stomach, was the only enterohepatic species to contain amiE. Phylogenetic trees based upon the sequences of H. pylori amiE and amiF genes and their respective homologs from other organisms as well as the amidase gene distribution among Helicobacter species are strongly suggestive of amidase acquisition by horizontal gene transfer. Since amidases are found only in Helicobacter species able to colonize the stomach, their acquisition might be related to selective pressure in this particular gastric environment.


Children, adolescents, and advertising.
Advertising is a pervasive influence on children and adolescents. Young people view more than 40,000 ads per year on television alone and increasingly are being exposed to advertising on the Internet, in magazines, and in schools. This exposure may contribute significantly to childhood and adolescent obesity, poor nutrition, and cigarette and alcohol use. Media education has been shown to be effective in mitigating some of the negative effects of advertising on children and adolescents.


Osmoregulation and the control of phloem-sap composition in Ricinus communis L.
Phloem-sap composition was studied in plants of Ricinus communis L. grown on a waterculture medium. The sap possessed a relatively high K(+):Na(+) ratio and low levels of Ca(2+) and free H(+). Sucrose and K(+) (together with its associated anions) accounted for 75% of the phloem-sap solute potential (Ψs). In plants kept in continuous darkness, a decrease in phloem-sap sucrose levels over 24h was accompanied by an increase in K(+) levels. Measurements of phloem-sap Ψs and xylem water potential (Ψ) indicated that this resulted in a partial maintenance of phloem turgor pressure Ψp. In darkness there was also a marked decrease in the malate content of the leaf tissue, and it is possible that organic carbon from this source was mobilized for export in the phloem. The results support the concept of the phloem sap as a symplastic phase. We interpret the increase in K(+) levels in the phloem in darkness as an osmoregulatory response to conditions of restricted solute availability. This reponse can be explained on the basis of the sucrose-H(+) co-transport mechanism of phloem loading.


Potassium release from the rat submaxillary gland in vitro. I. Induction by catecholamines.
Slices of submaxillary gland were incubated in vitro in an enriched Krebs-Ringer-bicarbonate medium gassed with 95% O2-5% CO2 at 37 degrees C and the release of K+ into the medium was monitored after stimulation with alpha and beta adrenergic secretagogues under a variety of experimental conditions. K+ was released by the slice system after addition of norepinephrine, epinephrine or phenylephrine, but not after addition of isoproterenol. The extent of K+ release after norepinephrine depends on the dose of secretagogue and is higher when glucose, adenine and inosine, or all three substrates are absent from the medium. The effect of norepinephrine on K+ release is reversed by phentolamine but not by propranolol. Phentolamine also causes a 9.4-fold shift to the right in the dose-response curve to norepinephrine. Addition of ouabain to the incubation medium results in a higher extent of K+ release and prevents the reversal caused by phentolamine. The response to norepinephrine fails to occur when Ca++ is absent from the medium, either by chelation with ethylene glycol bis (beta-amino-ethyl ether)-N,N'-tetraacetic acid or by elimination from the Krebs-Ringer solution, and shows gradations depending on the Ca++ content of the medium. By itself, however, Ca++ does not induce K+ release from the slice system. The following conclusions are derived from these observations: 1) the release of K+ ions from the submaxillary gland is mediated by alpha adrenergic receptors; 2) the net amount of K+ released is the result of two opposing and almost simultaneous mechanisms, a passive extrusion and an active reuptake; 3) the active reuptake of K+ depends on the availability of energy and is mediated through the ouabain-sensitive Na+-K+ activated adenosine triphosphatase; 4) the reaction is critically dependent on the presence of Ca++ in the incubation medium and probably involves an influx of Ca++ upon stimulation with alpha adrenergic secretagogues.


Ocular auto-stimulation and its morbidity in stage 5 retinopathy of prematurity.
To evaluate the characteristics and morbidity due to ocular auto-stimulation (OAS) in stage 5 Retinopathy of Prematurity (ROP). Stage 5 ROP cases presenting to ROP clinic of a tertiary care centre from January 2017 to December 2017 were recruited. Eye-pressing was elicited on history from parents and categorized as infrequent (performed <50% of waking time) or frequent (≥50% of time). B-scan ultrasonography was performed for configuration of retinal detachment (open or closed funnel). Keratometry was performed in eyes undergoing vitrectomy under general anaesthesia using automated hand-held keratometer. The outcome measures were the presence and characteristics of OAS, enophthalmos, corneal opacity and keratometry values. Out of 93 eyes of 49 babies, 78.5% (n = 73) had OAS. Gestational age, birth weight, sex, retinal funnel configuration, and visual function did not significantly affect OAS. However, post-conceptional age was significantly greater in eyes with OAS (95% CI: 63.1 to 69.9 weeks) than those without OAS (95% CI: 52.4 to 63.4 weeks) (P = 0.018). OAS occurred frequently in 32.8% (n = 24/73) eyes, more commonly in eyes with light followability. Keratometry did not differ significantly with the presence of OAS (P = 0.88). Enophthalmos, corneal opacity, posterior synechiae were noted in 79.5% (58/73), 21.9% (16/73), and 28.8% (21/73) eyes with OAS, respectively. Enophthalmos occurred significantly in eyes with OAS (P = 0.001), while corneal opacity and posterior synechiae did not (P = 0.071 and 0.91, respectively). OAS and its resultant morbidity are common occurrences in stage 5 ROP. The post-conceptional age and residual visual function may govern the characteristics of OAS.


Validity of Measuring Metallic and Semiconducting Single-Walled Carbon Nanotube Fractions by Quantitative Raman Spectroscopy.
Although it is known that the Raman spectroscopic signature of single-walled carbon nanotubes (SWCNTs) is highly chirality dependent, using Raman spectroscopy with several laser excitations as a tool for quantifying fraction of either metallic or semiconducting nanotubes in a sample has become a widely used analytical method. In this work, using the electron diffraction technique as a basis, we have examined the validity of Raman spectroscopy for quantitative evaluation of metallic fractions (M%) in single-walled carbon nanotube samples. Our results show that quantitative Raman spectroscopic evaluations of M% by using several discrete laser lines, either by using integrated intensities of chirality-associated radial breathing modes (RBMs) or, as has been more commonly utilized in recent studies, by statistically counting the numbers of RBMs can be misrepresentative. Specifically, we have found that the occurrence numbers of certain types of RBMs in Raman spectral mapping depend critically on the diameter distribution, resonant coupling between transition energies and excitation laser energy, and the chirality-dependent Raman scattering cross sections rather than simply on the metallic and semiconducting SWCNT fractions. These dependencies are similar to those observed in the integrated intensities of RBMs. Our findings substantially advance the understanding of the proper use of Raman spectroscopy for carbon nanotube quantification, which is important for carbon nanotube characterization and crucial to guide research in SWCNT growth and their applications.


Hepatitis C Testing Among Perinatally Exposed Infants.
Hepatitis C virus (HCV) prevalence doubled among pregnant women from 2009 to 2014, reaching 3.4 per 1000 births nationwide. Infants exposed to HCV may acquire HCV by vertical transmission. National guidelines recommend that infants exposed to HCV be tested; however, it is unclear if these recommendations are being followed. Our objectives were to determine if infants exposed to HCV were tested and to determine hospital- and patient-level factors associated with differences in testing. In this retrospective cohort study of infants exposed to HCV who were enrolled in the Tennessee Medicaid program, we used vital statistics-linked administrative data for infants born between January 1, 2005, and December 31, 2014. Infants were followed until 2 years old. Multilevel logistic regression was used to assess the association of HCV testing and hospital- and patient-level characteristics. Only 23% of 4072 infants exposed to HCV were tested. Infants whose mothers were white versus African American (96.6% vs 3.1%; P <.001), used tobacco (78% vs 70%; P <.001), and had HIV (1.3% vs 0.4%; P = .002) were more likely to be tested. Infants exposed to HCV who had a higher median of well-child visits (7 vs 6; P <.001) were more likely to be tested. After accounting for maternal and infant characteristics and health care use patterns, African American infants were less likely to undergo general testing (adjusted odds ratio 0.32; 95% confidence interval, 0.13-0.78). Testing occurred in <1 in 4 infants exposed to HCV and less frequently among African American infants. Public health systems need to be bolstered to ensure that infants exposed to HCV are tested for seroconversion.


Impact of regular collaboration between infectious diseases and critical care practitioners on antimicrobial utilization and patient outcome.
Antimicrobial stewardship programs have been shown to help reduce the use of unnecessary antimicrobial agents in the hospital setting. To date, there has been very little data focusing on high-use areas, such as the medical ICU. A prospective intervention was done to assess guideline compliance, antimicrobial expenditure, and healthcare cost when an infectious disease fellow interacts regularly with the medical ICU team. A 3-month retrospective chart review was followed by a 3-month prospective intervention the following year. Two hundred forty-six total charts were reviewed to assess generally accepted guideline compliance, demographics, and microbiologic results. Twenty-four-bed medical ICU at an 861-bed tertiary care, university teaching hospital in North Carolina. Patients receiving antibiotics in the medical ICU. During the intervention period, the infectious disease fellow reviewed the charts, including physician notes and microbiology data, and discussed antimicrobial use with the medical ICU team. Antimicrobial use, treatment duration, Acute Physiology and Chronic Health Evaluation II scores, length of stay, mechanical ventilation days, and mortality rates were compared during the two periods. No baseline statistically significant differences in the two groups were noted (i.e., age, gender, race, or Acute Physiology and Chronic Healthcare Evaluation II scores). Indications for antibiotics included healthcare-associated (53%) and community-acquired pneumonias (17%). Significant reductions were seen in extended-spectrum penicillins (p=0.0080), carbapenems (p=0.0013), vancomycin (p=0.0040), and metronidazole (p=0.0004) following the intervention. Antimicrobial modification led to an increase in narrow-spectrum penicillins (p=0.0322). The intervention group had a significantly lower rate of treatments that did not correspond to guidelines (p<0.0001). There was a reduction in mechanical ventilation days (p=0.0053), length of stay (p=0.0188), and hospital mortality (p=0.0367). The annual calculated healthcare savings was $89,944 in early antibiotic cessation alone. Active communication with an infectious disease practitioner can significantly reduce medical ICU antibiotic overuse by earlier modification or cessation of antibiotics without increasing mortality. This in turn can reduce healthcare costs, foster prodigious education, and strengthen relations between the subspecialties.


The Extended Role of Health Facility Cleaners in Maternity Care in Kenya.
A growing body of evidence indicates that nonclinical health care facility staff provide support beyond their traditional roles, particularly in low- and middle-income countries. It is important to examine the role of health facility cleaners in Kenya-from their perspective-to better understand their actual and perceived responsibilities in maternity care. In-depth, face-to-face interviews using a semistructured guide were conducted with 14 cleaners working at three public health facilities in Nairobi and Kiambu Counties, Kenya, in August and September 2016. Results were coded and categorized using a thematic content analysis approach. Cleaners reported performing a range of services beyond typical maintenance responsibilities, including providing emotional, informational and instrumental support to maternity patients. They described feeling disrespected when patients were untidy or experienced bleeding; however, such examples revealed cleaners' need to better understand labor and childbirth processes. Cleaners also indicated a desire for training on interpersonal skills to improve their interactions with patients. Cleaners' direct involvement in maternity patients' care is an alarming symptom of overburdened health facilities, insufficient staffing and inadequate training. This key yet overlooked cadre of health care staff deserves appropriate support and further research to understand and alleviate health system shortcomings, and to improve the quality of maternity health care provision.


Service screening with mammography of women aged 50-69 years in Sweden: effects on mortality from breast cancer.
To estimate the effect of the population based service screening programme in Sweden on mortality from breast cancer among women aged 50-69. SETTING; In 1986, population based service screening with mammography started in Sweden, and by 1997 screening had been introduced in all counties. Half of the counties invite women from 40 years of age whereas women 50 and older are invited in the other counties. The upper age limit was either 69 or 74. Women in the age group 50-69 years are thus invited to screening in all counties. The counties which started with mammographic screening in 1986-87 constituted the study group and were compared with the counties which started in 1993 or later. In 1987 the mean number of women aged 50-69 was 161,986 and 98,608 in the study and control groups, respectively. Refined excess mortality (smoothed with the Lowess method) from breast cancer and refined cause specific mortality from breast cancer were used as effect measures. To adjust for geographical differences in mortality from breast cancer a reference period was used. Allowance was made for two potential biases: (a) inclusion bias implying the inclusion of cases diagnosed before invitation to screening in the first screening round, and (b) lead time bias. After a mean follow up time of 10.6 years since the start of screening and a mean individual follow up time of 8.4 years, a non-significant reduction in refined excess mortality for breast cancer was estimated as relative risk (RR) 0.84 (95% confidence interval (95% CI) 0.67 to 1.05). After adjustment for inclusion and lead time biases the RR was 0.80 (20% reduction). Only 27% of the deaths from breast cancer in the total mortality for women aged 50-79 at death consisted of women aged 50-69 at diagnosis who were diagnosed after the start of screening. This figure has important implications for judgement of the impact of screening on age specific national breast cancer mortalities. A non-significant reduction in mortality from breast cancer was found in counties performing service screening with mammography in Sweden. Adjustment for possible biases changed the result towards a larger effect of screening. The results do not contradict the effects found in the Swedish randomised mammography trials.


Retinal light damage: structural and functional effects of the antioxidant glutathione peroxidase-1.
The role of the antioxidant enzyme glutathione peroxidase-1 (GPx1) in protecting the retina against photo-oxidative damage was investigated in GPx1-deficient and wild-type mice. Albino GPx1-deficient and age-matched wild-type mice were examined. Baseline electroretinograms (ERGs) were recorded. Thereafter, mice were exposed to intense light for 12 hours. After a 24-hour recovery in darkness, post-light-insult ERGs were recorded and compared with baseline. Structural effects of light insult were evaluated by retinal histology. Antioxidant expression was investigated by quantitative reverse transcription-PCR (qRT-PCR). Light insult significantly affected ERG responses, with reduced a- and b-wave amplitudes. Structurally, photoreceptor layers were predominantly affected. As expected, GPx1 expression was negligible in GPx1-deficient mice but was upregulated in wild-type mice in response to light insult. Similarly, hemeoxygenase-1 and thioredoxin-1 expression increased significantly in wild-type retinas after light exposure. Catalase, GPx isoforms (GPx2 to -4), peroxiredoxin-6, glutaredoxin-1, and thioredoxin-2 expression was unaffected by GPx1 deficiency and light insult, whereas significant increases in glutaredoxin-2 occurred in non-light-exposed (baseline) GPx1-deficient retinas. Compared with baseline wild-type retinas, lipid peroxidation (TBARS assay), an indicator of oxidative stress, was elevated in baseline GPx1-deficient retinas. Unexpectedly, the light insult induced diminution of retinal function, in terms of ERG amplitude, and structural damage was significantly greater in wild-type than in with GPx1-deficient retinas. The data showing increased oxidative damage in baseline GPx-deficient retina give rise to the hypothesis that increased oxidative stress provides a "preconditioning" environment in which protective mechanisms paradoxically render GPx1-deficient retinas less vulnerable to light-induced oxidative damage. This study identified glutaredoxin-2 as a potential candidate.


Alternans and the influence of ionic channel modifications: Cardiac three-dimensional simulations and one-dimensional numerical bifurcation analysis.
Cardiac propagation is investigated by simulations using a realistic three-dimensional (3D) geometry including muscle fiber orientation of the ventricles of a rabbit heart and the modified Beeler-Reuter ionic model. Electrical excitation is introduced by a periodic pacing of the lower septum. Depending on the pacing frequency, qualitatively different dynamics are observed, namely, normal heart beat, T-wave alternans, and 2:1 conduction block at small, intermediate, and large pacing frequencies, respectively. In a second step, we performed a numerical stability and bifurcation analysis of a pulse propagating in a one-dimensional (1D) ring of cardiac tissue. The precise onset of the alternans instability is obtained from computer-assisted linear stability analysis of the pulse and computation of the associated spectrum. The critical frequency at the onset of alternans and the profiles of the membrane potential agree well with the ones obtained in the 3D simulations. Next, we computed changes in the wave profiles and in the onset of alternans for the Beeler-Reuter model with modifications of the sodium, calcium, and potassium channels, respectively. For this purpose, we employ the method of numerical bifurcation and stability analysis. While blocking of calcium channels has a stabilizing effect, blocked sodium or potassium channels lead to the occurrence of alternans at lower pacing frequencies. The findings regarding channel blocking are verified within three-dimensional simulations. Altogether, we have found T-wave alternans and conduction block in 3D simulations of a realistic rabbit heart geometry. The onset of alternans has been analyzed by numerical bifurcation and stability analysis of 1D wave trains. By comparing the results of the two approaches, we find that alternans is not strongly influenced by ingredients such as 3D geometry and propagation anisotropy, but depends mostly on the frequency of pacing (frequency of subsequent action potentials). In addition, we have introduced numerical bifurcation and stability analysis as a tool into heart modeling and demonstrated its efficiency in scanning a large set of parameters in the case of models with reduced conductivity. Bifurcation analysis also provides an accurate test for analytical theories of alternans as is demonstrated for the case of the restitution hypothesis.


Long-term results of segmental prosthesis fixation by extracortical bone-bridging and ingrowth.
The technique of extracortical bone-bridging and ingrowth fixation with a porous coating over the shoulder region of the implant and augmentation by autogenous bone-grafting was introduced to improve the longevity of implant fixation. The potential advantages of this technique are that new-bone formation across the bone-prosthesis junction may share stress and may prevent osteolysis by sealing off this critical region against the infiltration of wear particles. The objectives of this study were to examine the prevalence of stem-loosening with use of the extracortical bone-bridging and ingrowth technique, the amount of bone formation over the porous-coated region of this prosthesis, and the characteristics of bone formation over the porous-coated region and adjacent bone. Forty-three patients who had prosthetic reconstruction with the extracortical bone-bridging and ingrowth technique from 1976 to 1990 were included in this retrospective study. The mean length of follow-up was 9.7 years (range, two to twenty-one years). All but one patient were managed with autogenous bone graft; five, with allograft and autograft; and one, with allograft only. Extracortical bone formation was measured over a 2-cm length of the porous-coated region of the prosthesis in four zones (the medial and lateral aspects on anteroposterior radiographs and the anterior and posterior aspects on lateral radiographs) and was reported as the percentage of the total length (8 cm) covered by extracortical bone with a thickness of >1 mm. The Spearman rank coefficient was used to assess the correlation between pairs of continuous variables. The final average percentage of the porous-coated region that was covered by extracortical bone formation was 76% +/- 34% for all patients and anatomical sites of reconstruction. Use of bone cement was associated with less bone formation (p = 0.04), and this value remained lower at the final measurement (p = 0.06). One stem had aseptic loosening, but no sign of osteolysis was found. The radiographic appearance of the bone formation had stabilized at two years of follow-up. All patients with allograft augmentation had greater bone formation. The amount of extracortical bone formation did not differ in relation to the type of porous coating, anatomical sites, pathological disorder, sex or age of the patient, or length of reconstruction. As shown by the low prevalence of stem-loosening (two of fifty-six stems or one of forty-three patients), the use of the extracortical bone-bridging and ingrowth fixation technique is associated with improved stem fixation in segmental bone-replacement prostheses applied for limb salvage. In the demanding biomechanical environment and with the risk of stress and particle-related bone resorption, the extracortical bone-bridging and ingrowth fixation is an attractive method to provide long-lasting implant fixation.


Differential Effect on Bone Lesions of Targeting Integrins: Randomized Phase II Trial of Abituzumab in Patients with Metastatic Castration-Resistant Prostate Cancer.
Integrins play a critical role in the progression of prostate cancer and its bone metastases. We investigated the use of the pan-αv integrin inhibitor abituzumab in chemotherapy-naïve patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. PERSEUS (NCT01360840) was a randomized, double-blind phase II study. Men with pathologically confirmed prostate cancer and radiologic progression of bone lesions in the 28 days prior to randomization were assigned to receive abituzumab 750 mg or 1,500 mg or placebo (1:1:1) every 3 weeks in combination with luteinizing hormone-releasing hormone agonist/antagonist therapy. The primary endpoint was progression-free survival (PFS). The intent-to-treat population comprised 180 patients, 60 in each arm. The primary endpoint of PFS was not significantly different with abituzumab-based therapy compared with placebo [abituzumab 750 mg, 3.4 months, HR = 0.89; 95% confidence interval (CI), 0.57-1.39; abituzumab 1,500 mg, 4.3 months, HR = 0.81; 95% CI, 0.52-1.26; placebo, 3.3 months], but the cumulative incidence of bone lesion progression was lower with abituzumab than with placebo for up to 24 months (cumulative incidence 23.6% vs. 41.1% at 6 months, 26.1% vs. 45.4% at 12 months). Two partial tumor responses were observed (1 abituzumab 1,500 mg and 1 placebo). Approximately 85% to 90% of patients experienced at least one treatment-emergent adverse event (TEAE) in the different arms, but the incidences of serious TEAEs and TEAEs with fatal outcome were similar in the three arms. Although PFS was not significantly extended, abituzumab appears to have specific activity in prostate cancer-associated bone lesions that warrants further investigation. Clin Cancer Res; 22(13); 3192-200. ©2016 AACR.


Pain, Headache, and Other Non-motor Symptoms in Myasthenia Gravis.
Myasthenia gravis (MG) is traditionally conceptualized as a disease with purely motor manifestations. This paper reviews the supporting evidence and pathophysiology of non-motor symptoms in MG, including pain, headache, special sense and autonomic dysfunction, sleep disturbance, and cognitive and psychosocial issues. Work in this area has been limited. Recent studies have identified bodily pain and headache as common complaints in patients with MG. A growing literature also suggests that there may be an association of MG and sleep disturbance (both obstructive sleep apnea and sleep cycle dysfunction). Few studies suggest some measurable abnormalities of olfaction, gustation, audition, and autonomic function. The cognitive and psychosocial aspects of MG represent an emerging area of clinical and research interest, but large-scale data is sparse in the USA. The pathophysiology of MG is complex, and our understanding of the immunologic basis of this disease is expanding. The classic view of MG as a purely motor disorder may be incomplete. Recent work highlights non-motor symptoms that may impact patient management and quality of life.


Effect of a Primary Care Management Intervention on Mental Health-Related Quality of Life Among Survivors of Sepsis: A Randomized Clinical Trial.
Survivors of sepsis face long-term sequelae that diminish health-related quality of life and result in increased care needs in the primary care setting, such as medication, physiotherapy, or mental health care. To examine if a primary care-based intervention improves mental health-related quality of life. Randomized clinical trial conducted between February 2011 and December 2014, enrolling 291 patients 18 years or older who survived sepsis (including septic shock), recruited from 9 intensive care units (ICUs) across Germany. Participants were randomized to usual care (n = 143) or to a 12-month intervention (n = 148). Usual care was provided by their primary care physician (PCP) and included periodic contacts, referrals to specialists, and prescription of medication, other treatment, or both. The intervention additionally included PCP and patient training, case management provided by trained nurses, and clinical decision support for PCPs by consulting physicians. The primary outcome was change in mental health-related quality of life between ICU discharge and 6 months after ICU discharge using the Mental Component Summary (MCS) of the 36-Item Short-Form Health Survey (SF-36 [range, 0-100; higher ratings indicate lower impairment; minimal clinically important difference, 5 score points]). The mean age of the 291 patients was 61.6 years (SD, 14.4); 66.2% (n = 192) were men, and 84.4% (n = 244) required mechanical ventilation during their ICU stay (median duration of ventilation, 12 days [range, 0-134]). At 6 and 12 months after ICU discharge, 75.3% (n = 219 [112 intervention, 107 control]) and 69.4% (n = 202 [107 intervention, 95 control]), respectively, completed follow-up. Overall mortality was 13.7% at 6 months (40 deaths [21 intervention, 19 control]) and 18.2% at 12 months (53 deaths [27 intervention, 26 control]). Among patients in the intervention group, 104 (70.3%) received the intervention at high levels of integrity. There was no significant difference in change of mean MCS scores (intervention group mean at baseline, 49.1; at 6 months, 52.9; change, 3.79 score points [95% CI, 1.05 to 6.54] vs control group mean at baseline, 49.3; at 6 months, 51.0; change, 1.64 score points [95% CI, -1.22 to 4.51]; mean treatment effect, 2.15 [95% CI, -1.79 to 6.09]; P = .28). Among survivors of sepsis and septic shock, the use of a primary care-focused team-based intervention, compared with usual care, did not improve mental health-related quality of life 6 months after ICU discharge. Further research is needed to determine if modified approaches to primary care management may be more effective. isrctn.org Identifier: ISRCTN61744782.


Taxonomic variation in the supraorbital region of catarrhine primates.
This study aimed to test the taxonomic utility of the catarrhine supraorbital region using 3D geometric morphometrics, with the aim of establishing its potential use in elucidating the position of more debated hominin groups. 230 3D coordinates were used to record the supraorbital morphology of two datasets: one containing 460 non-hominin catarrhine primates from species and subspecies of Gorilla, Pan, Papio, and Macaca; and the other containing 55 Pleistocene hominins from Homo, Australopithecus, and Paranthropus. Principal component analyses in tangent, form, and allometry-free shape space were used to assess differentiation of taxa, with biological distinctiveness of taxa being established using step-wise discriminant analysis with subsampling. Results indicated that the recorded supraorbital morphology could be used to separate non-hominin catarrhine primate genera, species, and subspecies, although accuracy was found to decrease with decreasing Linnaean rank. In addition, analyses in tangent space were found to produce the highest accuracy when classifying primates of known taxonomy. Biological distinctiveness of the middle and later Homo species was comparable to or higher than that of the non-hominin primates, and relatively lower for the earlier groups of Homo. This study indicates that the supraorbital region preserves taxonomic information that can be used to delineate between closely related groups, both within hominins and wider catarrhine primates. Therefore, this region may be used to provide insight when assessing the taxonomic affiliation of disputed hominin specimens.


Changes in agonist neural drive, hypertrophy and pre-training strength all contribute to the individual strength gains after resistance training.
Whilst neural and morphological adaptations following resistance training (RT) have been investigated extensively at a group level, relatively little is known about the contribution of specific physiological mechanisms, or pre-training strength, to the individual changes in strength following training. This study investigated the contribution of multiple underpinning neural [agonist EMG (QEMGMVT), antagonist EMG (HEMGANTAG)] and morphological variables [total quadriceps volume (QUADSVOL), and muscle fascicle pennation angle (QUADSθ p)], as well as pre-training strength, to the individual changes in strength after 12 weeks of knee extensor RT. Twenty-eight healthy young men completed 12 weeks of isometric knee extensor RT (3/week). Isometric maximum voluntary torque (MVT) was assessed pre- and post-RT, as were simultaneous neural drive to the agonist (QEMGMVT) and antagonist (HEMGANTAG). In addition QUADSVOL was determined with MRI and QUADSθ p with B-mode ultrasound. Percentage changes (∆) in MVT were correlated to ∆QEMGMVT (r = 0.576, P = 0.001), ∆QUADSVOL (r = 0.461, P = 0.014), and pre-training MVT (r = -0.429, P = 0.023), but not ∆HEMGANTAG (r = 0.298, P = 0.123) or ∆QUADSθ p (r = -0.207, P = 0.291). Multiple regression analysis revealed 59.9% of the total variance in ∆MVT after RT to be explained by ∆QEMGMVT (30.6%), ∆QUADSVOL (18.7%), and pre-training MVT (10.6%). Changes in agonist neural drive, quadriceps muscle volume and pre-training strength combined to explain the majority of the variance in strength changes after knee extensor RT (~60%) and adaptations in agonist neural drive were the most important single predictor during this short-term intervention.


[Coping with breast cancer: a case study on families of mastectomized women].
This study sought to analyze strategies for coping with the disease and the implications of breast cancer for the affected families. Semi-structured interviews and observations were conducted in households with 5 families of women diagnosed with breast cancer in various stages of development and care, which were treated in a hospital specialized in Oncology. 21 people had been interviewed: 5 patients and 16 familiar members. The categories investigated were: Search for information, direct action, inhibition of action, intrapsychic efforts, back up to the other. Findings show a disparity between strategies adopted by patients and family members. The process of coping with cancer emphasized the dialectical relationship between patients and relatives, the active and constant participation by members of the families of origin, relations and friends, the characteristics of the institution where women with breast cancer were treated and the implications of this type of cancer.


Hippocampal neurons in the monkey with activity related to the place in which a stimulus is shown.
In order to analyze the functions of the hippocampus in the primate, and to advance the understanding of amnesia, the activity of 994 single hippocampal neurons in the monkey was analyzed during the performance of a task known to be affected by hippocampal damage in which both an object, and its position in space, must be remembered. The serial multiple object-place memory task required a memory for the position on a video monitor in which a given object had appeared previously. It was found that 9.3% of neurons recorded in the hippocampus and hippocampal gyrus had spatial fields in this and related tasks, in that they responded whenever there was a stimulus in some but not in other positions on the screen. We found that 2.4% of the neurons responded to a combination of spatial information and information about the object seen, in that they responded more the first time a particular object was seen in any position. Six of these neurons were found that showed this combination even more clearly, in that, for example, they responded only to some positions and only if it was the first time that a particular stimulus had appeared there. It is concluded that there are neurons in the primate hippocampus which (1) respond to position in space and (2) in some cases combine information about stimuli and their position in space, responding to a stimulus only the first time it is seen in a position in space, for example. Thus, not only is spatial information processed by the primate hippocampus, but it can be combined with information about which stimuli have been seen before. The ability of the hippocampus to form such conjunctions may be an important property for its role in memory.


Examine all available evidence before making decisions on sunscreen ingredient bans.
Coral bleaching is a worldwide problem and more needs to be done to determine causes and potential solutions. A myopic focus on sunscreen ingredients as the proximate cause of coral bleaching provides consumers a false belief that enacted bans of these ingredients will erase decades of coral reef decline. Instead, these bans will likely only lead to decreased sunscreen use and exposure to potentially harmful UV radiation. A closer examination of all available evidence on the causes of coral reef bleaching needs to be undertaken, including a more thorough appraisal of studies conducted under artificial conditions using higher concentrations of sunscreen ingredients.


Structural Insights for the Optimization of Dihydropyrimidin-2(1H)-one Based mPGES-1 Inhibitors.
The recently crystallized structure of microsomal prostaglandin E2 synthase 1 (mPGES-1) in complex with the inhibitor LVJ (PDB code: 4BPM) offered new structural information for the optimization of the previously identified lead compound 1 (IC50 = 4.16 ± 0.47 μM), which contains the privileged dihydropyrimidin-2-one chemical core. Systematic optimization of 1, through accurate structure-based design, provided compound 4 with a 10-fold improved mPGES-1 inhibitory activity (IC50 = 0.41 ± 0.02 μM). Here we highlight the optimal scaffold decoration pattern of 4 and propose a three-dimensional model for the interaction with this complex trimeric membrane protein. The reported computational insights, together with the accessible one-pot synthetic procedure, stimulate for the generation of further potent dihydropyrimidine-based mPGES-1 inhibitors.


Chemical composition and antioxidant activity of Strobilanthes crispus leaf extract.
This study investigated the components present in and the total antioxidant activity of leaves of Strobilanthes crispus (L.) Bremek or Saricocalyx crispus (L.) Bremek (Acanthacea). Proximate analyses and total antioxidant activity using ferric thiocyanate and thiobarbituric acid methods were employed. Minerals content was determined using the atomic absorption spectrophotometer, whereas the water-soluble vitamins were determined by means of the UV-VIS spectrophotometer (vitamin C) and fluorimeter (vitamins B(1) and B(2)). Catechin, tannin, caffeine, and alkaloid contents were also studied. All data were compared to the previously reported results of Yerbamate, green tea, black tea, and Indian tea. The dried leaves contained a high amount of total ash (21.6%) as a result of a high amount of minerals including potassium (51%), calcium (24%), sodium (13%), iron (1%), and phosphorus (1%). High content of water-soluble vitamins (C, B(1), and B(2)) contributed to the high antioxidant activity of the leaves. The leaves also contained a moderate amount of other proximate composition as well as other compounds such as catechins, alkaloids, caffeine, and tannin, contributing further to the total antioxidant activity. Catechins of Strobilanthes crispus leaves showed highest antioxidant activity when compared to Yerbamate and vitamin E. Consumption of the leafy extract daily (5 g/day) as an herbal tea could contribute to the additional nutrients and antioxidants needed in the body to enhance the defense system, especially toward the incidence of degenerative diseases.


Cardiac and vascular structural changes in normotensive subjects with parental hypertension.
To evaluate whether a predisposition to hypertension is associated with early cardiac and vascular alterations. Twenty-five normotensive subjects with both parents hypertensive (group 1) and 28 age- and sex-matched control subjects with both parents normotensive (group 2). In the two groups the measurements included: clinic blood pressure; left ventricular end-diastolic diameter, septal wall thickness and posterior wall thickness (by echocardiography); minimal forearm and calf vascular resistances (i.e. resistance assessed immediately after prolonged ischaemia, which depends on arteriolar wall thickness); and baseline and postischaemic radial artery compliance-pressure curves over the systolodiastolic pressure range (by echotracking device and finger blood pressure). Group 1 had a slightly higher clinic blood pressure, and septal and posterior wall thickness, than group 2. Minimal forearm vascular resistance was clearly greater in group 1 than in group 2, whereas minimal calf vascular resistance was not significantly different in the two groups. Radial artery compliance was also similar in the two groups. Parental predisposition to hypertension is accompanied by cardiac and arteriolar structural changes qualitatively similar to those found in hypertensive patients, although arteriolar structural changes do not involve all vascular beds. Arterial compliance is not altered in this condition. Vascular changes may be determined by mechanisms other than blood pressure elevation.


Immunosenescence-Related Transcriptomic and Immunologic Changes in Older Individuals Following Influenza Vaccination.
The goal of annual influenza vaccination is to reduce mortality and morbidity associated with this disease through the generation of protective immune responses. The objective of the current study was to examine markers of immunosenescence and identify immunosenescence-related differences in gene expression, gene regulation, cytokine secretion, and immunologic changes in an older study population receiving seasonal influenza A/H1N1 vaccination. Surprisingly, prior studies in this cohort revealed weak correlations between immunosenescence markers and humoral immune response to vaccination. In this report, we further examined the relationship of each immunosenescence marker (age, T cell receptor excision circle frequency, telomerase expression, percentage of CD28- CD4+ T cells, percentage of CD28- CD8+ T cells, and the CD4/CD8 T cell ratio) with additional markers of immune response (serum cytokine and chemokine expression) and measures of gene expression and/or regulation. Many of the immunosenescence markers indeed correlated with distinct sets of individual DNA methylation sites, miRNA expression levels, mRNA expression levels, serum cytokines, and leukocyte subsets. However, when the individual immunosenescence markers were grouped by pathways or functional terms, several shared biological functions were identified: antigen processing and presentation pathways, MAPK, mTOR, TCR, BCR, and calcium signaling pathways, as well as key cellular metabolic, proliferation and survival activities. Furthermore, the percent of CD4+ and/or CD8+ T cells lacking CD28 expression also correlated with miRNAs regulating clusters of genes known to be involved in viral infection. Integrated (DNA methylation, mRNA, miRNA, and protein levels) network biology analysis of immunosenescence-related pathways and genesets identified both known pathways (e.g., chemokine signaling, CTL, and NK cell activity), as well as a gene expression module not previously annotated with a known function. These results may improve our ability to predict immune responses to influenza and aid in new vaccine development, and highlight the need for additional studies to better define and characterize immunosenescence.


Animation of fiber fuse damage, demonstrating periodic void formation.
A series of optical micrographs showing the front region of fiber fuse damage were obtained to reveal the periodic void formation process. They were collected from a number of samples and were sorted in order of increasing distance between the top of the first large void and the top of the first regular void. The micrographs clearly show that the first large void sheds its tail, which shrinks to form a regular void. This mechanism leads to the formation of bullet-shaped regular voids as the result of the balance between the internal pressure of the optical discharge and the increasing viscosity of the surrounding glass that occurs during pinching off.


ABCD2 alters peroxisome proliferator-activated receptor α signaling in vitro, but does not impair responses to fenofibrate therapy in a mouse model of diet-induced obesity.
Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) α ligand that has been widely used as a lipid-lowering agent in the treatment of hypertriglyceridemia. ABCD2 (D2) is a peroxisomal long-chain acyl-CoA transporter that is highly induced by fenofibrate in the livers of mice. To determine whether D2 is a modifier of fibrate responses, wild-type and D2-deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARα signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that knockdown of D2 modified genomic responses to fibrate treatment. We next evaluated the impact of D2 on effects of fibrates in a mouse model of diet-induced obesity. Fenofibrate treatment opposed the development of obesity, hypertriglyceridemia, and insulin resistance. However, these effects were unaffected by D2 genotype. We concluded that D2 can modulate genomic responses to fibrates, but that these effects are not sufficiently robust to alter the effects of fibrates on diet-induced obesity phenotypes.


YB-1 bridges neural stem cells and brain tumor-initiating cells via its roles in differentiation and cell growth.
The Y-box binding protein 1 (YB-1) is upregulated in many human malignancies including glioblastoma (GBM). It is also essential for normal brain development, suggesting that YB-1 is part of a neural stem cell (NSC) network. Here, we show that YB-1 was highly expressed in the subventricular zone (SVZ) of mouse fetal brain tissues but not in terminally differentiated primary astrocytes. Conversely, YB-1 knockout mice had reduced Sox-2, nestin, and musashi-1 expression in the SVZ. Although primary murine neurospheres were rich in YB-1, its expression was lost during glial differentiation. Glial tumors often express NSC markers and tend to loose the cellular control that governs differentiation; therefore, we addressed whether YB-1 served a similar role in cancer cells. YB-1, Sox-2, musashi-1, Bmi-1, and nestin are coordinately expressed in SF188 cells and 9/9 GBM patient-derived primary brain tumor-initiating cells (BTIC). Silencing YB-1 with siRNA attenuated the expression of these NSC markers, reduced neurosphere growth, and triggered differentiation via coordinate loss of GSK3-β. Furthermore, differentiation of BTIC with 1% serum or bone morphogenetic protein-4 suppressed YB-1 protein expression. Likewise, YB-1 expression was lost during differentiation of normal human NSCs. Consistent with these observations, YB-1 expression increased with tumor grade (n = 49 cases). YB-1 was also coexpressed with Bmi-1 (Spearmans 0.80, P > 0.001) and Sox-2 (Spearmans 0.66, P > 0.001) based on the analysis of 282 cases of high-grade gliomas. These proteins were highly expressed in 10/15 (67%) of GBM patients that subsequently relapsed. In conclusion, YB-1 correlatively expresses with NSC markers where it functions to promote cell growth and inhibit differentiation.


A millennium-long reconstruction of damaging hydrological events across Italy.
Damaging hydrological events are extreme phenomena with potentially severe impacts on human societies. Here, we present the hitherto longest reconstruction of damaging hydrological events for Italy, and for the whole Mediterranean region, revealing 674 such events over the period 800-2017. For any given year, we established a severity index based on information in historical documentary records, facilitating the transformation of the data into a continuous time-series. Episodes of hydrological extremes disrupted ecosystems during the more severe events by changing landforms. The frequency and severity of damaging hydrological events across Italy were likely influenced by the mode of the Atlantic Multidecadal Variability (AMV), with relatively few events during the warm Medieval Climate Anomaly dominated by a positive phase of the AMV. More frequent and heavier storms prevailed during the cold Little Ice Age, dominated by a more negative phase of the AMV. Since the mid-19th century, a decreasing occurrence of exceptional hydrological events is evident, especially during the most recent decades, but this decrease is not yet unprecedented in the context of the past twelve centuries.


Preconditioning of mesenchymal stromal cells with low-intensity ultrasound: influence on chondrogenesis and directed SOX9 signaling pathways.
Continuous low-intensity ultrasound (cLIUS) facilitates the chondrogenic differentiation of human mesenchymal stromal cells (MSCs) in the absence of exogenously added transforming growth factor-beta (TGFβ) by upregulating the expression of transcription factor SOX9, a master regulator of chondrogenesis. The present study evaluated the molecular events associated with the signaling pathways impacting SOX9 gene and protein expression under cLIUS. Human bone marrow-derived MSCs were exposed to cLIUS stimulation at 14 kPa (5 MHz, 2.5 Vpp) for 5 min. The gene and protein expression of SOX9 was evaluated. The specificity of SOX9 upregulation under cLIUS was determined by treating the MSCs with small molecule inhibitors of select signaling molecules, followed by cLIUS treatment. Signaling events regulating SOX9 expression under cLIUS were analyzed by gene expression, immunofluorescence staining, and western blotting. cLIUS upregulated the gene expression of SOX9 and enhanced the nuclear localization of SOX9 protein when compared to non-cLIUS-stimulated control. cLIUS was noted to enhance the phosphorylation of the signaling molecule ERK1/2. Inhibition of MEK/ERK1/2 by PD98059 resulted in the effective abrogation of cLIUS-induced SOX9 expression, indicating that cLIUS-induced SOX9 upregulation was dependent on the phosphorylation of ERK1/2. Inhibition of integrin and TRPV4, the upstream cell-surface effectors of ERK1/2, did not inhibit the phosphorylation of ERK1/2 and therefore did not abrogate cLIUS-induced SOX9 expression, thereby suggesting the involvement of other mechanoreceptors. Consequently, the effect of cLIUS on the actin cytoskeleton, a mechanosensitive receptor regulating SOX9, was evaluated. Diffused and disrupted actin fibers observed in MSCs under cLIUS closely resembled actin disruption by treatment with cytoskeletal drug Y27632, which is known to increase the gene expression of SOX9. The upregulation of SOX9 under cLIUS was, therefore, related to cLIUS-induced actin reorganization. SOX9 upregulation induced by actin reorganization was also found to be dependent on the phosphorylation of ERK1/2. Collectively, preconditioning of MSCs by cLIUS resulted in the nuclear localization of SOX9, phosphorylation of ERK1/2 and disruption of actin filaments, and the expression of SOX9 was dependent on the phosphorylation of ERK1/2 under cLIUS.


Common membrane trafficking defects of disease-associated dynamin 2 mutations.
Dynamin (Dyn) is a multidomain and multifunctional GTPase best known for its essential role in clathrin-mediated endocytosis (CME). Dyn2 mutations have been linked to two human diseases, centronuclear myopathy (CNM) and Charcot-Marie-Tooth (CMT) disease. Paradoxically, although Dyn2 is ubiquitously expressed and essential for embryonic development, the disease-associated Dyn2 mutants are autosomal dominant, but result in slowly progressing and tissue-specific diseases. Thus, although the cellular defects that cause disease remain unclear, they are expected to be mild. To gain new insight into potential pathogenic mechanisms, we utilized mouse Dyn2 conditional knockout cells combined with retroviral-mediated reconstitution to mimic both heterozygous and homozygous states and characterized cellular phenotypes using quantitative assays for several membrane trafficking events. Surprisingly, none of the four mutants studied exhibited a defect in CME, but all were impaired in their ability to support p75/neurotrophin receptor export from the Golgi, the raft-dependent endocytosis of cholera toxin and the clathrin-independent endocytosis of epidermal growth factor receptor (EGFR). While it will be important to study these mutants in disease-relevant muscle and neuronal cells, given the importance of neurotrophic factors and lipid rafts in muscle physiology, we speculate that these common cellular defects might contribute to the tissue-specific diseases caused by a ubiquitously expressed protein.


Rate of thrombosis in children and adolescents hospitalized with COVID-19 or MIS-C.
Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with thrombotic complications in adults, but the incidence of COVID-19-related thrombosis in children and adolescents is unclear. Most children with acute COVID-19 have mild disease, but coagulopathy has been associated with multisystem inflammatory syndrome in children (MIS-C), a postinfectious complication. We conducted a multicenter retrospective cohort study to determine the incidence of thrombosis in children hospitalized with COVID-19 or MIS-C and evaluate associated risk factors. We classified patients into 1 of 3 groups for analysis: COVID-19, MIS-C, or asymptomatic SARS-CoV-2. Among a total of 853 admissions (COVID-19, n = 426; MIS-C, n = 138; and asymptomatic SARS-CoV-2, n = 289) in 814 patients, there were 20 patients with thrombotic events (TEs; including 1 stroke). Patients with MIS-C had the highest incidence (9 [6.5%] of 138) vs COVID-19 (9 [2.1%] of 426) or asymptomatic SARS-CoV-2 (2 [0.7%] of 289). In patients with COVID-19 or MIS-C, a majority of TEs (89%) occurred in patients age ≥12 years. Patients age ≥12 years with MIS-C had the highest rate of thrombosis at 19% (9 of 48). Notably, 71% of TEs that were not present on admission occurred despite thromboprophylaxis. Multivariable analysis identified the following as significantly associated with thrombosis: age ≥12 years, cancer, presence of a central venous catheter, and MIS-C. In patients with COVID-19 or MIS-C, hospital mortality was 2.3% (13 of 564), but it was 28% (5 of 18) in patients with TEs. Our findings may help inform pediatric thromboprophylaxis strategies.


Residual tactile sensitivity with self-directed stimulation in hemianaesthesia.
A case of hemianaesthesia caused by right hemisphere stroke was found to have good sensitivity and cutaneous localisation when she touched her impaired hand with her good contralateral hand or with a probe held by that hand. The capacity did not depend solely upon movement or positioning of her right arm, and she could also discriminate whether her own left fingers, as opposed to someone else's inter-digitated fingers, were being touched, but only when she did the touching. Thus, the threshold of the impaired hand appeared to be markedly affected by active involvement of the contralateral limb in delivering the stimulus.


Which activities threaten independent living of elderly when becoming problematic: inspiration for meaningful service robot functionality.
In light of the increasing elderly population and the growing demand for home care, the potential of robot support is given increasing attention. In this paper, an inventory of activities was made that threaten independent living of elderly when becoming problematic. Results will guide the further development of an existing service robot, the Care-O-bot®. A systematic literature search of PubMed was performed, focused on the risk factors for institutionalization. Additionally, focus group sessions were conducted in the Netherlands, United Kingdom and France. In these focus group sessions, problematic activities threatening the independence of elderly people were discussed. Three separate target groups were included in the focus group sessions: (1) elderly persons (n = 41), (2) formal caregivers (n = 40) and (3) informal caregivers (n = 32). Activities within the International Classification of Functioning domains mobility, self-care, and interpersonal interaction and relationships were found to be the most problematic. A distinct set of daily activities was identified that may threaten independent living, but no single activity could be selected as the main activity causing a loss of independence as it is often a combination of problematic activities that is person-specific. Supporting the problematic activities need not involve a robotic solution.


Photophysics and ex vivo biodistribution of β-cyclodextrin-meso-tetra(m-hydroxyphenyl)porphyrin conjugate for biomedical applications.
Low aqueous solubility of porphyrin-based photosensitizers hampers their clinical use in photodynamic therapy because of complex delivery. In this study, we explore meso-tetra(m-hydroxyphenyl)-21,23H-porphyrin (mTHPP), a potent photosensitizer, covalently attached to β-cyclodextrin (CD-mTHPP) with a focus on topical delivery and cellular uptake. The photophysical properties of CD-mTHPP were examined using steady-state fluorescence and lifetime measurements verifying increased aqueous solubility. Confocal and fluorescence lifetime imaging microscopy on human squamous carcinoma cells (A431) evidenced a cytoplasmic uptake of CD-mTHPP in predominantly monomeric form. CD-mTHPP was also delivered to human skin ex vivo and the skin penetration was assessed using two-photon fluorescence microscopy. The results indicated that CD-mTHPP exhibits improved skin distribution compared to mTHPP alone using aqueous vehicles. Thus the CD-mTHPP conjugate demonstrates improved biodistribution ex vivo compared to mTHPP and is a promising multimodal system for photodynamic therapy.


Aim2 deficiency stimulates the expression of IFN-inducible Ifi202, a lupus susceptibility murine gene within the Nba2 autoimmune susceptibility locus.
Murine Aim2 and p202 proteins (encoded by the Aim2 and Ifi202 genes) are members of the IFN-inducible p200 protein family. Both proteins can sense dsDNA in the cytoplasm. However, upon sensing dsDNA, only the Aim2 protein through its pyrin domain can form an inflammasome to activate caspase-1 and induce cell death. Given that the p202 protein has been predicted to inhibit the activation of caspase-1 by the Aim2 protein and that increased levels of the p202 protein in female mice of certain strains are associated with lupus susceptibility, we compared the expression of Aim2 and Ifi202 genes between Aim2-deficient and age-matched wild-type mice. We found that the Aim2 deficiency in immune cells stimulated the expression of Ifi202 gene. The increased levels of the p202 protein in cells were associated with increases in the expression of IFN-β, STAT1, and IFN-inducible genes. Moreover, after knockdown of Aim2 expression in the murine macrophage cell line J774.A1, IFN-β treatment of cells robustly increased STAT1 protein levels (compared with those of control cells), increased the activating phosphorylation of STAT1 on Tyr-701, and stimulated the activity of an IFN-responsive reporter. Notably, the expression of Aim2 in non-lupus-prone (C57BL/6 and B6.Nba2-C) and lupus-prone (B6.Nba2-ABC) splenic cells and in a murine macrophage cell line that overexpressed p202 protein was found to be inversely correlated with Ifi202. Collectively, our observations demonstrate an inverse correlation between Aim2 and p202 expressions. We predict that defects in Aim2 expression within immune cells contribute to increased susceptibility to lupus.


The situation of former adolescent self-injurers as young adults: a follow-up study.
Nonsuicidal self-injury (NSSI) in adolescence has been described as comorbid condition in affective or anxiety disorders, as well as borderline personality disorder (BPD) and is a risk factor for later suicide attempts. Prevalence rates of NSSI decline steeply from adolescence to young adulthood. Yet, to the best of our knowledge, the longitudinal development of adolescent psychiatric patients with NSSI into their young adulthood has not been investigated. The aim of this study was to assess current NSSI and psychological impairment of young adults, who had been in treatment for NSSI in their adolescence. Former patients of the departments of child and adolescent psychiatry and psychotherapy in Ulm and Ravensburg, Germany (N = 52), who presented with NSSI in their adolescence, were recruited (average age: 21.5 years (SD = 2.6)). Data was assessed using questionnaires and structured clinical interviews. Two groups of participants with prevailing NSSI and ceased NSSI were compared concerning their current psychological impairment, history of NSSI, suicide attempts, and BPD diagnosis. Around half of all participants had engaged in NSSI within the last year, and around half met diagnostic criteria for BPD. Although there was no significant association between current NSSI and BPD, an earlier age of onset of NSSI and a longer duration of NSSI during adolescence was significantly predictive of adult BPD. Two thirds of participants still met criteria of an axis 1 psychiatric disorder. Suicide attempts were reported by 53.8 % of all participants. Participants with current NSSI were more likely to meet criteria for a current axis 1 disorder, had engaged in NSSI more often in their lifetime, and reported more suicide attempts. Reduction of NSSI from adolescence to young adulthood was lower than described in previous community samples. This may be due to the initial high psychiatric impairment of this sample in adolescence. Early onset of NSSI seemed to be a risk factor for a longer duration of NSSI during adolescence but not for NSSI prevailing into adulthood. However, it was a risk factor for adult BPD. Furthermore, the occurrence of suicidal thoughts and behaviors and prevailing NSSI was highly associated.


Extensive review of popular functional foods and nutraceuticals against obesity and its related complications with a special focus on randomized clinical trials.
Obesity is a multifactorial chronic disease or syndrome mainly caused by an imbalance in energy expenditure and intake. Obesity and its associated complications make it the fifth leading cause of global mortality. The benefits of the current anti-obesity treatment regimen have been marked by high cost and numerous adverse effects. Therefore, many researchers focus on plant-derived/natural products or altered dietary patterns for the management of obesity and its related complications (co-morbidities). Several epidemiological studies have confirmed that the consumption of functional foods/nutraceuticals could considerably lower the risk of various chronic diseases, like obesity, diabetic mellitus, and cancer, but the underpinning mechanism is still unclear. This comprehensive review briefs on the prevalence of obesity, the complications related to obesity, the current treatment regimen and the importance of functional foods and nutraceuticals (molecular mechanism) for the management of body weight and alleviation of its co-morbid conditions. This is the first comprehensive review revealing the in-depth anti-obesity mechanisms of various popular functional foods and nutraceuticals with a special reference to randomized clinical trials (RCTs). Overall, this contribution highlights the importance and beneficial role of functional foods/nutraceuticals on weight management (anti-obesity) and their contributions to the current treatment status, especially related to clinical trials, which could help in the development of novel functional foods/nutraceuticals for combatting obesity and its co-morbidities.


Cataract Preventive Role of Isolated Phytoconstituents: Findings from a Decade of Research.
Cataract is an eye disease with clouding of the eye lens leading to disrupted vision, which often develops slowly and causes blurriness of the eyesight. Although the restoration of the vision in people with cataract is conducted through surgery, the costs and risks remain an issue. Botanical drugs have been evaluated for their potential efficacies in reducing cataract formation decades ago and major active phytoconstituents were isolated from the plant extracts. The aim of this review is to find effective phytoconstituents in cataract treatments in vitro, ex vivo, and in vivo. A literature search was synthesized from the databases of Pubmed, Science Direct, Google Scholar, Web of Science, and Scopus using different combinations of keywords. Selection of all manuscripts were based on inclusion and exclusion criteria together with analysis of publication year, plant species, isolated phytoconstituents, and evaluated cataract activities. Scientists have focused their attention not only for anti-cataract activity in vitro, but also in ex vivo and in vivo from the review of active phytoconstituents in medicinal plants. In our present review, we identified 58 active phytoconstituents with strong anti-cataract effects at in vitro and ex vivo with lack of in vivo studies. Considering the benefits of anti-cataract activities require critical evaluation, more in vivo and clinical trials need to be conducted to increase our understanding on the possible mechanisms of action and the therapeutic effects.


Can occult cystobiliary fistulas in hepatic hydatid disease be predicted before surgery?
Biliary fistulas because of the cystobiliary communication is the most frequent and undesirable postoperative complication of hepatic hydatid surgery. We aimed to identify the predicting factors of the occult cystobiliary communication in this study. The patients who underwent surgical treatment for hepatic hydatid disease between 2003 and 2008 were reviewed retrospectively. The patients who had jaundice history, preoperative high total bilirubin and direct bilirubin levels, dilated bile duct in preoperative radiologic imagings were not included the study. Patients were divided into two groups: group A; without postoperative biliary fistula, group B; with biliary fistula. The two groups were compared according to preoperative descriptive findings, cystic specialties, and laboratory findings. There were 53 patients and 15 patients in groupA and groupB, respectively. The 20 (37.7%) of 53 patients were male in group A and the 10 (66.7%) patients were male in group B (p<0.05). The age, number of cysts, Garbi scores of cysts, the rate of recurrent cysts, the level of preoperative bilirubin, alkalene phosphatase, and transaminases were similar in both groups (p>0.05). GGT was significantly different between two groups (p<0.05). The cystotomy + drainage, cystotomy + omentopexy, and intracystic biliary suture rates were similar in both groups. Postoperative non biliary complications were determined in 4 (7.5%) patients in group A and 7 patients (46.7%) in group B (p<0.05). Hospital stay was longer in group B significantly (p<0.05). In conclusion, GGT as a laboratory [corrected] test for predicting occult CBC preoperatively have been shown to be useful in the clinical practice. However, larger prospective studies are needed on this subject. Occult cysto-biliary fistulas can only be exposed during surgery when suspected by a surgeon. If occult CBC is found, the opening in the biliary system should be sutured with absorbable material, with or without cystic duct drainage. If no biliary opening is found, cystic duct drainage may be performed if preoperative factors predict the presence of CBC. As the development of external biliary fistulas increases the morbidity and the hospitalization period, novel surgical methods to prevent the development of bile fistulas are required in such patients.


Performance of Sokolow-Lyon index in detection of echocardiographically diagnosed left ventricular hypertrophy in a normal Eastern German population - results of the CARLA study.
Arterial hypertension is a common disease with high prevalence in the general population. Left ventricular hypertrophy (LVH) is an independent risk factor in arterial hypertension. Electrocardiographic indices like the Sokolow-Lyon index (SLI) are recommended as diagnostic screening methods for LVH. We assessed the diagnostic performance of the SLI in a cohort of a large general population. We used electrocardiographic and echocardiographic data from the prospective, population-based cohort study CARdio-vascular Disease, Living and Ageing in Halle (CARLA). Linear and logistic regression models were used to assess the association of SLI with LVH. To assess the impact of the body-mass-index (BMI), we performed interaction analyses. AUC of SLI to predict LVH was 55.3 %, sensitivity of the SLI was 5 %, specificity 97 %. We found a significant association of SLI after covariate-adjustment with echocardiographically detected LVH (increase of left-ventricular mass index, LVMI 7.0 g/m(2) per 1 mV increase of SLI, p < 0.0001). However, this association was mainly caused by an association of SLI with the left-ventricular internal diameter (LVIDd, increase of 0.06 cm/m(2) per 1 mV increase of SLI, p < 0.0001). In obese (BMI > 30 kg/m(2)) we found the strongest association with an increase of 9.2 g/m(2) per 1 mV. Although statistically significant, relations of SLI and echocardiographic parameters of LVH were weak and mainly driven by the increase in LVIDd, implicating a more eccentric type of LVH in the collective. The relations were strongest when obese subjects were taken into account. Our data do not favour the SLI as a diagnostic screening test to identify patients at risk for LVH, especially in non-obese subjects without eccentric LVH.


Anatomical and echocardiographic correlates of normal cardiac morphology in the late first trimester fetus.
To describe the normal cardiac morphology as seen by transvaginal ultrasound imaging in the first trimester fetus and to compare it with the morphology of the heart as seen by microdissection at the same gestational age. In 53 mothers undergoing early sonography, the fetal heart was examined and the images recorded. The gestational age range was 5-12 weeks of gestation, which represents 21 to 70 days after conception. Images were analysed frame by frame and compared with the anatomy of embryos and fetuses at the same gestational ages. After the 9th week of gestation, four cardiac chambers, the aortic origin, and the pulmonary artery could be identified on cross sectional echocardiography in conjunction with colour flow Doppler. At 9 weeks, the apex pointed anteriorly and the right ventricle and pulmonary artery lay to the right of the midline. By the 11th week of gestation, the apex pointed to the left and the pulmonary artery lay to the left of the midline as in the older fetus. Between 9 and 12 weeks' gestation the aorta was larger than the pulmonary artery. These findings were confirmed in the microdissected hearts. The current quality of ultrasound images obtained using transvaginal transducers in the first trimester fetus allows the study of fetal cardiac anatomy. Some of the later developmental changes can be demonstrated. As technology improves further the details of earlier cardiac morphogenesis may also become visible.


"CLICKable" azide-functionalized phosphonates for the surface-modification of molecular and solid-state metal oxides.
The covalent functionalization of metal oxide surfaces with organic ligands gives unique organic-inorganic hybrids. Here we report a bifunctional organic tether combining a phosphonate for metal oxide anchoring with an organic azide for attachment of organic groups. Stable binding of the tether to molecular and solid-state metal oxides is demonstrated and the subsequent "CLICKability" of the TiO2-anchored tether is shown. The phosphonate-azide reported could in future allow the general linkage of functional organic groups to metal oxides.


Non-Invasive Radiofrequency Field Treatment to Produce Hepatic Hyperthermia: Efficacy and Safety in Swine.
The Kanzius non-invasive radio-frequency hyperthermia system (KNiRFH) has been investigated as a treatment option for hepatic hyperthermia cancer therapy. The treatment involves exposing the patient to an external high-power RF (13.56 MHz) electric field, whereby the propagating waves penetrate deep into the tumor causing targeted heating based on differential tissue dielectric properties. However, a comprehensive examination of the Kanzius system alongside any associated toxicities and its ability to induce hepatic hyperthermia in larger animal models, such as swine, are the subjects of the work herein. Ten Yucatan female mini-swine were treated with the KNiRFH system. Two of the pigs were treated a total of 17 times over a five-week period to evaluate short- and long-term KNiRFH-associated toxicities. The remaining eight pigs were subjected to single exposure sessions to evaluate heating efficacy in liver tissue. Our goal was to achieve a liver target temperature of 43°C and to evaluate toxicities and burns post-treatment. Potential toxicities were evaluated by contrast-enhanced MRI of the upper abdomen and blood work, including complete metabolic panel, complete blood count, and liver enzymes. The permittivities of subcutaneous fat and liver were also measured, which were used to calculate tissue specific absorption rates (SAR). Our results indicate negligible KNiRFH-associated toxicities; however, due to fat overheating, liver tissue temperature did not exceed 38.5°C. This experimental limitation was corroborated by tissue permittivity and SAR calculations of subcutaneous fat and liver. Significant steps must be taken to either reduce subcutaneous fat heating or increase localized heating, potentially through the use of KNiRFH-active nanomaterials, such as gold nanoparticles or single-walled carbon nanotubes, which have previously shown promising results in murine cancer models.


Structural and geometrical constraints on the outer dynein arm in situ.
This study considers the relationship between two structural forms of the 22S dynein arm of Tetrahymena thermophila: the bouquet and the compact arm. The compact arm differs from the bouquet and from other proposed forms (e.g., the "toadstool") in that the globular domains are situated transversely across the interdoublet gap with one globular subunit, the head, proximal to the adjacent doublet microtubule. The other models place all three globular domains proximal to the neighboring doublet microtubule. When sliding of an isolated axoneme is induced, at least 57% of total attached arms on exposed doublets are in the compact form within dimensions of 24 x 24 x 12 nm, and only about 2% of the arms are bouquets. Toadstools are incompatible with the images seen. Bouquets are not found in regions of the doublet protected by a neighboring doublet. When axonemes with exposed doublets are treated with 0.5 M KCl for 30 min, the compact arms and the dynein heavy (H)-chains disappear, while isolated bouquets and dynein H-chains appear in the medium, suggesting that the compact arms give rise to the bouquets as they are solubilized. The bouquet is the predominant form of isolated 22S dynein molecules, which are found in two apparently enantiomorphic forms, within dimensions 45 x 39 x 13 nm; bouquets attached to doublets have dimensions similar to those of isolated bouquets. Computer modeling indicates that in an intact standard-diameter axoneme, these dimensions are incompatible with the interdoublet volume available for an arm; the bouquet therefore represents an unfolded compact arm. A plausible sequence of changes can be modeled to illustrate the conversion of an attached compact arm to an attached and then free bouquet. The toadstool is probably an artifact that arises after unfolding. Consistent with the conformational difference, H-chains of attached compact arms differ from those of isolated bouquets in their susceptibility to limited proteolysis. These results suggest that the compact arm, rather than the unfolded bouquet or the toadstool, is the functional form of the outer arm in the intact axoneme.


Unilateral retrobulbar hematoma following maxillary nerve block in a dog.
To describe the clinical findings and management of a case of retrobulbar hematoma formation secondary to performance of a maxillary nerve block in a dog. An 11-year-old dog was presented for a routine dental procedure including dental extraction to be performed under general anesthesia. After premedication with intramuscular methadone, anesthesia was induced with intravenous alfaxalone until depth of anesthesia was sufficient to allow orotracheal intubation. Anesthesia was maintained with isoflurane delivered in 100% oxygen. A bilateral maxillary nerve block was performed. During administration of the left nerve block, blood was aspirated. Twenty minutes after placement of the left maxillary nerve block, exophthalmos, periorbital swelling, extensive scleral hemorrhage, and ecchymosis with a 2 × 2 cm region of moderate swelling on the palatal mucosa around the injection site were noted. These lesions were the result of retrobulbar hematoma formation following vessel puncture. Treatment included immediate creation of a drainage tract and administration of anti-inflammatories (carprofen 2 mg/kg PO q 12 h for 7 days), broad spectrum antimicrobial therapy (cefovicin 8 mg/kg SC once), and eye drops (viscotears, 2 drops OS q 12 h for 7 days). The periorbital swelling was significantly reduced within 1 hour of drainage and had almost completely resolved 1 week later. This clinical report details the development and successful management of a unilateral retrobulbar hemorrhage following maxillary nerve block. Management of this condition requires prompt recognition and treatment to prevent permanent damage to the eye. The cornerstone of treatment is drainage, which rapidly decreases the increased intraorbital and intraocular pressure. To our knowledge, this is the first documentation of this complication in the English language literature.


The caulobacter Tol-Pal complex is essential for outer membrane integrity and the positioning of a polar localization factor.
Cell division in Caulobacter crescentus involves constriction and fission of the inner membrane (IM) followed about 20 min later by fission of the outer membrane (OM) and daughter cell separation. In contrast to Escherichia coli, the Caulobacter Tol-Pal complex is essential. Cryo-electron microscopy images of the Caulobacter cell envelope exhibited outer membrane disruption, and cells failed to complete cell division in TolA, TolB, or Pal mutant strains. In wild-type cells, components of the Tol-Pal complex localize to the division plane in early predivisional cells and remain predominantly at the new pole of swarmer and stalked progeny upon completion of division. The Tol-Pal complex is required to maintain the position of the transmembrane TipN polar marker, and indirectly the PleC histidine kinase, at the cell pole, but it is not required for the polar maintenance of other transmembrane and membrane-associated polar proteins tested. Coimmunoprecipitation experiments show that both TolA and Pal interact directly or indirectly with TipN. We propose that disruption of the trans-envelope Tol-Pal complex releases TipN from its subcellular position. The Caulobacter Tol-Pal complex is thus a key component of cell envelope structure and function, mediating OM constriction at the final step of cell division as well as the positioning of a protein localization factor.


Automated test of behavioral flexibility in mice using a behavioral sequencing task in IntelliCage.
There has been a long-standing need to develop efficient and standardized behavioral test methods for evaluating higher-order brain functions in mice. Here, we developed and validated a behavioral flexibility test in mice using IntelliCage, a fully automated behavioral analysis system for mice in a group-housed environment. We first developed a "behavioral sequencing task" in the IntelliCage that enables us to assess the learning ability of place discrimination and behavioral sequence for reward acquisition. In the serial reversal learning using the task, the discriminated spatial patterns of the rewarded and never-rewarded places were serially reversed, and thus, mice were accordingly expected to realign the previously acquired behavioral sequence. In general, the tested mice showed rapid acquisition of the behavioral sequencing task and behavioral flexibility in the subsequent serial reversal stages both in intra- and inter-session analyses. It was found that essentially the same results were obtained among three different laboratories, which confirm the high stability of the present test protocol in different strains of mice (C57BL/6, DBA/2, and ICR). In particular, the most trained cohort of C57BL/6 mice achieved a markedly rapid adaptation to the reversal task in the final phase of the long-term serial reversal test, which possibly indicated that the mice adapted to the "reversal rule" itself. In conclusion, the newly developed behavioral test was shown to be a valid assay of behavioral flexibility in mice, and is expected to be utilized in tests of mouse models of cognitive deficits.


A Semi-supervised Multi-scale Arbitrary Dilated Convolution Neural Network for Pediatric Sleep Staging.
Sleep staging is essential for assessing sleep quality and diagnosing sleep disorders. However, sleep staging is a labor-intensive process, making it arduous to obtain large quantities of high-quality labeled data for automatic sleep staging. Meanwhile, most of the research on automatic sleep staging pays little attention to pediatric sleep staging. To address these challenges, we propose a semi-supervised multi-scale arbitrary dilated convolution neural network (SMADNet) for pediatric sleep staging using the scalogram with a high height-to-width ratio generated by the continuous wavelet transform (CWT) as input. To extract more extended time dimensional feature representations and adapt to scalograms with a high height-to-width ratio in SMADNet, we introduce a multi-scale arbitrary dilation convolution block (MADBlock) based on our proposed arbitrary dilated convolution (ADConv). Finally, we also utilize semi-supervised learning as the training scheme for our network in order to alleviate the reliance on labeled data. Our proposed model has achieved performance comparable to state-of-the-art supervised learning methods with 30% labels. Our model is tested on a private pediatric dataset and achieved 79% accuracy, 72% kappa, and 75% MF1. Therefore, our model demonstrates a powerful feature extraction capability and has achieved performance comparable to state-of-the-art supervised learning methods with a small number of labels.


Activation of ERK and NF-κB during HARE-Mediated Heparin Uptake Require Only One of the Four Endocytic Motifs.
Fifteen different ligands, including heparin (Hep), are cleared from lymph and blood by the Hyaluronan (HA) Receptor for Endocytosis (HARE; derived from Stabilin-2 by proteolysis), which contains four endocytic motifs (M1-M4). Endocytosis of HARE•Hep complexes is targeted to coated pits by M1, M2, and M3 (Pandey et al, Int. J. Cell Biol. 2015, article ID 524707), which activates ERK1/2 and NF-κB (Pandey et al J. Biol. Chem. 288, 14068-79, 2013). Here, we used a NF-κB promoter-driven luciferase gene assay and cell lines expressing different HARE cytoplasmic domain mutants to identify motifs needed for Hep-mediated signaling. Deletion of M1, M2 or M4 singly had no effect on Hep-mediated ERK1/2 activation, whereas signaling (but not uptake) was eliminated in HARE(ΔM3) cells lacking NPLY2519. ERK1/2 signaling in cells expressing WT HARE(Y2519A) or HARE(Y2519A) lacking M1, M2 and M4 (containing M3-only) was decreased by 75% or eliminated, respectively. Deletion of M3 (but not M1, M2 or M4) also inhibited the formation of HARE•Hep•ERK1/2 complexes by 67%. NF-κB activation by HARE-mediated uptake of Hep, HA, dermatan sulfate or acetylated LDL was unaffected in single-motif deletion mutants lacking M1, M2 or M4. In contrast, cells expressing HARE(ΔM3) showed loss of HARE-mediated NF-κB activation during uptake of each of these four ligands. NF-κB activation by the four signaling ligands was also eliminated in HARE(Y2519A) or HARE(M3-only;Y2519A) cells. We conclude that the HARE NPLY2519 motif is necessary for both ERK1/2 and NF-κB signaling and that Tyr2519 is critical for these functions.


Frequency-place map for electrical stimulation in cochlear implants: Change over time.
The relationship between the place of electrical stimulation from a cochlear implant and the corresponding perceived pitch remains uncertain. Previous studies have estimated what the pitch corresponding to a particular location should be. However, perceptual verification is difficult because a subject needs both a cochlear implant and sufficient residual hearing to reliably compare electric and acoustic pitches. Additional complications can arise from the possibility that the pitch corresponding to an electrode may change as the auditory system adapts to a sound processor. In the following experiment, five subjects with normal or near-to-normal hearing in one ear and a cochlear implant with a long electrode array in the other ear were studied. Pitch matches were made between single electrode pulse trains and acoustic tones before activation of the speech processor to gain an estimate of the pitch provided by electrical stimulation at a given insertion angle without the influence of exposure to a sound processor. The pitch matches were repeated after 1, 3, 6, and 12 months of experience with the sound processor to evaluate the effect of adaptation over time. Pre-activation pitch matches were lower than would be estimated by a spiral ganglion pitch map. Deviations were largest for stimulation below 240° degrees and smallest above 480°. With experience, pitch matches shifted towards the frequency-to-electrode allocation. However, no statistically significant pitch shifts were observed over time. The likely explanation for the lack of pitch change is that the frequency-to-electrode allocations for the long electrode arrays were already similar to the pre-activation pitch matches. Minimal place pitch shifts over time suggest a minimal amount of perceptual remapping needed for the integration of electric and acoustic stimuli, which may contribute to shorter times to asymptotic performance.


Lag effects in the impacts of mass coral bleaching on coral reef fish, fisheries, and ecosystems.
Recent episodes of coral bleaching have led to wide-scale loss of reef corals and raised concerns over the effectiveness of existing conservation and management efforts. The 1998 bleaching event was most severe in the western Indian Ocean, where coral declined by up to 90% in some locations. Using fisheries-independent data, we assessed the long-term impacts of this event on fishery target species in the Seychelles, the overall size structure of the fish assemblage, and the effectiveness of two marine protected areas (MPAs) in protecting fish communities. The biomass of fished species above the size retained in fish traps changed little between 1994 and 2005, indicating no current effect on fishery yields. Biomass remained higher in MPAs, indicating they were effective in protecting fish stocks. Nevertheless, the size structure of the fish communities, as described with size-spectra analysis, changed in both fished areas and MPAs, with a decline in smaller fish (<30 cm) and an increase in larger fish (>45 cm). We believe this represents a time-lag response to a reduction in reef structural complexity brought about because fishes are being lost through natural mortality and fishing, and are not being replaced by juveniles. This effect is expected to be greater in terms of fisheries productivity and, because congruent patterns are observed for herbivores, suggests that MPAs do not offer coral reefs long-term resilience to bleaching events. Corallivores and planktivores declined strikingly in abundance, particularly in MPAs, and this decline was associated with a similar pattern of decline in their preferred corals. We suggest that climate-mediated disturbances, such as coral bleaching, be at the fore of conservation planning for coral reefs.


Multiplanar osteotomy with limited wide margins: a tissue preserving surgical technique for high-grade bone sarcomas.
Limb-salvage surgery has been used during the last several decades to treat patients with high-grade bone sarcomas. In the short- and intermediate-term these surgeries have been associated with relatively good function and low revision rates. However, long-term studies show a high rate of soft tissue, implant, and bone-related complications. Multiplanar osteotomy with limited wide margins uses angled bone cuts to resect bone tumors with the goal of complete tumor removal while sparing host tissue although its impact on local recurrence is not known. We determined whether multiplanar osteotomy was associated with local recurrences, reconstruction failures, and allograft nonunions. We retrospectively reviewed the charts of six patients. Four patients had an osteosarcoma, one had a Ewing's sarcoma, and one had a chondrosarcoma. Patient and treatment factors such as age, diagnosis, percent of tumor necrosis (if applicable), margin status, and time to allograft union were recorded. In all patients, reconstruction was performed with an intercalary allograft cut to fit the residual defect. The minimum followup was 25 months (average, 39 months; range, 24-66 months). No patient experienced a local recurrence or metastasis, and all patients were alive and disease-free at the most recent followup. All allografts healed during the study period. With careful patient selection, the multiplanar osteotomy resection technique may be considered an option for treating patients with high-grade bone sarcomas, and, when compared with traditional surgical techniques, may lead to improved healing and function of the involved extremity. Level IV, therapeutic study. See the guidelines online for a complete description of levels of evidence.


Impacts of mobile tablet computing on provider productivity, communications, and the process of care.
Health information technology investments continue to increase while the value derived from their implementation and use is mixed. Mobile device adoption into practice is a recent trend that has increased dramatically and formal studies are needed to investigate consequent benefits and challenges. The objective of this study is to evaluate practitioner perceptions of improvements in productivity, provider-patient communications, care provision, technology usability and other outcomes following the adoption and use of a tablet computer connected to electronic health information resources. A pilot program was initiated in June 2013 to evaluate the effect of mobile tablet computers at one health provider organization in the southeast United States. Providers were asked to volunteer for the evaluation and were each given a mobile tablet computer. A total of 42 inpatient and outpatient providers were interviewed in 2015 using a survey style questionnaire that utilized yes/no, Likert-style, and open ended questions. Each had previously used an electronic health record (EHR) system a minimum of one year outside of residency, and were regular users of personal mobile devices. Each used a mobile tablet computer in the context of their practice connected to the health system EHR. The survey results indicate that more than half of providers perceive the use of the tablet device as having a positive effect on patient communications, patient education, patient's perception of the provider, time spent interacting with patients, provider productivity, process of care, satisfaction with EHR when used together with the device, and care provision. Providers also reported feeling comfortable using the device (82.9%), would recommend the device to colleagues (69.2%), did not experience increased information security and privacy concerns (95%), and noted significant reductions in EHR login times (64.1%). Less than 25% of participants reported negative impacts on any of these areas as well as on time spent on order submission, note completion time, overall workload, patient satisfaction with care experience and patient outcomes. Gender, number of years in practice, practice type (general practitioner vs. specialist), and service type (inpatient/outpatient) were found to have a significant effect on perceptions of patient satisfaction, care process, and provider productivity. Providers found positive gains from utilizing mobile devices in overall productivity, improved communications with their patients, the process of care, and technology efficiencies when used in combination with EHR and other health information resources. Demographic and health care work environment play a role in how mobile technologies are integrated into practice by providers.


Topovectorial mechanisms control the juxtamembrane proteolytic processing of Nrf1 to remove its N-terminal polypeptides during maturation of the CNC-bZIP factor.
The topobiological behaviour of Nrf1 dictates its post-translational modification and its ability to transactivate target genes. Here, we have elucidated that topovectorial mechanisms control the juxtamembrane processing of Nrf1 on the cyto/nucleoplasmic side of endoplasmic reticulum (ER), whereupon it is cleaved and degraded to remove various lengths of its N-terminal domain (NTD, also refolded into a UBL module) and acidic domain-1 (AD1) to yield multiple isoforms. Notably, an N-terminal ~12.5-kDa polypeptide of Nrf1 arises from selective cleavage at an NHB2-adjoining region within NTD, whilst other longer UBL-containing isoforms may arise from proteolytic processing of the protein within AD1 around PEST1 and Neh2L degrons. The susceptibility of Nrf1 to proteolysis is determined by dynamic repositioning of potential UBL-adjacent degrons and cleavage sites from the ER lumen through p97-driven retrotranslocation and -independent pathways into the cyto/nucleoplasm. These repositioned degrons and cleavage sites within NTD and AD1 of Nrf1 are coming into their bona fide functionality, thereby enabling it to be selectively processed by cytosolic DDI-1/2 proteases and also partiality degraded via 26S proteasomes. The resultant proteolytic processing of Nrf1 gives rise to a mature ~85-kDa CNC-bZIP transcription factor, which regulates transcriptional expression of cognate target genes. Furthermore, putative ubiquitination of Nrf1 is not a prerequisite necessary for involvement of p97 in the client processing. Overall, the regulated juxtamembrane proteolysis (RJP) of Nrf1, though occurring in close proximity to the ER, is distinctive from the mechanism that regulates the intramembrane proteolytic (RIP) processing of ATF6 and SREBP1.