Early Assessment Window for Predicting Breast Cancer Neoadjuvant Therapy using Biomarkers, Ultrasound, and Diffuse Optical Tomography.
The purpose of the study was to assess the utility of tumor biomarkers, ultrasound (US) and US-guided diffuse optical tomography (DOT) in early prediction of breast cancer response to neoadjuvant therapy (NAT). This prospective HIPAA compliant study was approved by the institutional review board. Forty one patients were imaged with US and US-guided DOT prior to NAT, at completion of the first three treatment cycles, and prior to definitive surgery from February 2017 to January 2020. Miller-Payne grading was used to assess pathologic response. Receiver operating characteristic curves (ROCs) were derived from logistic regression using independent variables, including: tumor biomarkers, US maximum diameter, percentage reduction of the diameter (%US), pretreatment maximum total hemoglobin concentration (HbT) and percentage reduction in HbT (%HbT) at different treatment time points. Resulting ROCs were compared using area under the curve (AUC). Statistical significance was tested using two-sided two-sample student t-test with P < 0.05 considered statistically significant. Logistic regression was used for ROC analysis. Thirty-eight patients (mean age = 47, range 24-71 years) successfully completed the study, including 15 HER2 + of which 11 were ER + ; 12 ER + or PR + /HER2-, and 11 triple negative. The combination of HER2 and ER biomarkers, %HbT at the end of cycle 1 (EOC1) and %US (EOC1) provided the best early prediction, AUC = 0.941 (95% CI 0.869-1.0). Similarly an AUC of 0.910 (95% CI 0.810-1.0) with %US (EOC1) and %HbT (EOC1) can be achieved independent of HER2 and ER status. The most accurate prediction, AUC = 0.974 (95% CI 0.933-1.0), was achieved with %US at EOC1 and %HbT (EOC3) independent of biomarker status. The combined use of tumor HER2 and ER status, US, and US-guided DOT may provide accurate prediction of NAT response as early as the completion of the first treatment cycle. NCT02891681. https://clinicaltrials.gov/ct2/show/NCT02891681 , Registration time: September 7, 2016.


Se Isotopes as Groundwater Redox Indicators: Detecting Natural Attenuation of Se at an in Situ Recovery U Mine.
One of the major ecological concerns associated with the in situ recovery (ISR) of uranium (U) is the environmental release of soluble, toxic selenium (Se) oxyanions generated by mining. Post-mining natural attenuation by the residual reductants in the ore body and reduced down-gradient sediments should mitigate the risk of Se contamination in groundwater. In this work, we investigate the Se concentrations and Se isotope systematics of groundwater and of U ore bearing sediments from an ISR site at Rosita, TX, USA. Our results show that selenate (Se(VI)) is the dominant Se species in Rosita groundwater, and while several up-gradient wells have elevated Se(VI), the majority of the ore zone and down-gradient wells have little or no Se oxyanions. In addition, the δ82SeVI of Rosita groundwater is generally elevated relative to the U ore up to +6.14‰, with the most enriched values observed in the ore-zone wells. Increasing δ82Se with decreasing Se(VI) conforms to a Rayleigh type distillation model with an ε of -2.25‰ ± 0.61‰, suggesting natural Se(VI) reduction occurring along the hydraulic gradient at the Rosita ISR site. Furthermore, our results show that Se isotopes are excellent sensors for detecting and monitoring post-mining natural attenuation of Se oxyanions at ISR sites.


Genipin crosslinking decreases the mechanical wear and biochemical degradation of impacted cartilage in vitro.
High energy trauma to cartilage causes surface fissures and microstructural damage, but the degree to which this damage renders the tissue more susceptible to wear and contributes to the progression of post-traumatic osteoarthritis (PTOA) is unknown. Additionally, no treatments are currently available to strengthen cartilage after joint trauma and to protect the tissue from subsequent degradation and wear. The purposes of this study were to investigate the role of mechanical damage in the degradation and wear of cartilage, to evaluate the effects of impact and subsequent genipin crosslinking on the changes in the viscoelastic parameters of articular cartilage, and to test the hypothesis that genipin crosslinking is an effective treatment to enhance the resistance to biochemical degradation and mechanical wear. Results demonstrate that cartilage stiffness decreases after impact loading, likely due to the formation of fissures and microarchitectural damage, and is partially or fully restored by crosslinking. The wear resistance of impacted articular cartilage was diminished compared to undamaged cartilage, suggesting that mechanical damage that is directly induced by the impact may contribute to the progression of PTOA. However, the decrease in wear resistance was completely reversed by the crosslinking treatments. Additionally, the crosslinking treatments improved the resistance to collagenase digestion at the impact-damaged articular surface. These results highlight the potential therapeutic value of collagen crosslinking via genipin in the prevention of cartilage degeneration after traumatic injury. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:558-565, 2017.


Occurrence of green tobacco sickness and associated factors in farmers residing in Dom Feliciano Municipality, Rio Grande do Sul State, Southern Region of Brazil.
This study aimed to evaluate the occurrence of the green tobacco sickness (GTS) and its associated factors in tobacco familiar farmers residing in Dom Feliciano, Rio Grande do Sul State, Brazil. A cross-sectional study was conducted evaluating the sickness in 354 small tobacco farmers, between October 2011 and March 2012. The urinary concentration of cotinine, a biomarker of exposure to nicotine, was determined during the tobacco harvest period. Subjects presenting cotinine urinary levels ≥ 50ng/mL, that had contact with tobacco leaves up to 48 hours before the sample collection and reported at least one disease symptom were deemed as cases. A non-conditional logistic analysis was performed to evaluate the association between GTS and the population characteristics. A total of 122 (34.5%) cases were identified, with 39% of them being smokers and 61% being males. The median cotinine urinary concentrations were 75.6ng/mL (74.1ng/mg of creatinine) for non-cases and 755.8ng/mL (632.1ng/mg of creatinine) for the cases (p-value ≤ 0.01). The multivariate analysis showed a positive association between GTS and sunlight exposure time, exposure to pesticides, worse health status, and inverse association with wood cultivation. This study presented a high GTS prevalence and suggest that the use of urinary cotinine is a significant biomarker to determine GTS cases, influencing in the distribution by sex. Once the tobacco production involves health hazards, is important to implement measures to prevent the harm caused to tobacco farmers, as set in articles 17 and 18 of the World Health Organization Framework Convention on Tobacco Control.


Barriers to HIV testing among male clients of female sex workers in Indonesia.
Frequent engagement of men in sexual encounters with female sex workers (FSWs) without using condoms places them at a high risk for HIV infection. HIV testing has been noted to be among important strategies to prevent HIV transmission and acquisition. However, it is known that not all men willingly undertake an HIV test as a way to prevent HIV transmission and/or acquisition. This study aimed to identify barriers to accessing HIV testing services among men who are clients of FSWs (clients) in Belu and Malaka districts, Indonesia. A qualitative inquiry employing face to face open ended interviews was conducted from January to April 2017. The participants (n = 42) were clients of FSWs recruited using purposive and snowball sampling techniques. Data were analysed using a qualitative data analysis framework. Findings indicated three main barriers of accessing HIV testing services by clients. These included: (1) personal barriers (lack of knowledge of HIV/AIDS and HIV testing availability, and unwillingness to undergo HIV testing due to low self-perceived risk of HIV and fear of the test result); (2) health care service provision barriers (lack of trust in health professionals and limited availability of medication including antiretroviral (ARV)); and (3) social barriers (stigma and discrimination, and the lack of social supports). These findings indicated multilevelled barriers to accessing HIV testing services among participants, who are known to be among key population groups in HIV care. Actions to improve HIV/AIDS-related health services accessibility are required. The dissemination of the knowledge and information on HIV/AIDS and improved available of HIV/AIDS-related services are necessary actions to improve the personal levelled barriers. System wide barriers will need improved practices and health policies to provide patients friendly and accessible services. The societal levelled barriers will need a more broad societal approach including raising awareness in the community and enhanced discussions about HIV/AIDS issues in order to normalise HIV in the society.


Effects of ciprofloxacin and ofloxacin on adult human cartilage in vitro.
Chondrocyte toxicity and necrosis were seen with electron microscopy after incubation of human adult cartilage biopsy specimens in ciprofloxacin or ofloxacin. In vitro exposure of chondrocytes to fluoroquinolones did not affect apoptosis as determined by flow cytometry. While the immediate clinical significance of this finding remains unclear, the possibility of long-term cartilage damage after fluoroquinolone treatment cannot be excluded.


Fatal Complication of Mouthguard Used to Treat Awake Bruxism in Patient With Frontotemporal Dementia.
Awake bruxism is an understudied manifestation of frontotemporal dementia, yet awake bruxism can have fatal consequences in the aging population. This report presents a patient suffering from awake bruxism associated with frontotemporal dementia being treated with a mouthguard, which ultimately becomes lodged in her posterior oropharynx leading to asphyxiation. The case highlights the need for investigation into the occurrence and treatment of awake bruxism among patients with dementia, and the unique risk-benefit analysis that must be performed to develop proper treatment plans for patients with dementia.


Uniportal VATS Lobectomy and Decortication: Not an Everyday Occurrence.
Management of trapped lung with an underlying lung lesion and hydropneumothorax remains controversial. Furthermore, Aspergillus empyema and aspergilloma are rare pathologies for which uniportal video-assisted thoracoscopic (VATS) surgical management remains controversial. We present a young patient referred to our service after recent hospitalization for pneumonia. The patient was found to have a chronic effusion with a right lower lobe cystic parenchymal lesion and was taken to the operating room. The patient underwent right uniportal VATS surgery with evacuation of empyema, total pulmonary decortication, and right lower lobectomy. His postoperative course was unremarkable, and he was discharged home. Postoperative workup demonstrated lymphocyte variant hypereosinophilia. He continues to follow with thoracic surgery at the time of this report and remains asymptomatic. We conclude that uniportal VATS is a most minimally invasive, safe, and efficient approach for management of complex intrathoracic pathology including total pulmonary decortication and lobectomy.


Growth and Survival Variation among Scots Pine (Pinus sylvestris L.) Provenances.
Tree height, basal diameter, and survival were examined in thirteen-year-old provenance test established by 30 seed sources of Scots pine (Pinus sylvestris L.) at two exotic sites of the species in Southern part of Turkey. Variations within provenance and among provenances and relations among the traits were estimated to compare Scots pine provenance and two other native species. Averages of tree height and basal diameter were 350 cm and 52.7 mm in Aydogmus site and 385 cm and 51.2 mm in Kemer site, respectively. There were large differences within and among provenances for the characters. Sites were similar (p > 0.05) for the characters, while there were significant differences (p ≤ 0.05) among provenances within site according to results of variance analysis (ANOVA). Scots pine provenances were higher and had more thickness than that of black pine (Pinus nigra Arnold) and Taurus cedar (Cedrus libani A. Rich.) which were natural species of the region. There were positive and significant (p < 0.05) correlations between height and basal diameter in the species. Average survivals were 56% and 35% of the provenances in the sites. They were 71% and 11% in black pine and 53% in Taurus cedar for the sites respectively.


Mechanisms of homologous and heterologous desensitization of PTH/PTHrP receptor signaling in LLC-PK1 cells.
Parathyroid hormone (PTH) activates multiple intracellular effectors, including adenylyl cyclase (AC) and phospholipase C (PLC), via a single receptor [PTH/parathyroid hormone-related protein receptor (PTHR)] expressed in bone and kidney. Homologous desensitization of PTHR signaling occurs, but the relative importance of reduced receptor expression vs. impaired receptor-effector coupling in this process remains unclear. It also is not known if AC and PLC responses to PTH are desensitized independently or interdependently. In LLC-PK1 cells that expressed transfected wild-type PTHRs, PTH caused dose- and time-dependent desensitization of both the AC and PLC-responses to PTH without altering PTHR expression. Desensitization of AC was blocked in mutant cells resistant to adenosine 3',5'-cyclic monophosphate but not when cells expressed mutant PTHRs with defective PLC coupling. Desensitization of PLC was unaffected by PKA blockade, partially mimicked by phorbol ester, and not reproduced by agents that selectively activated AC. The finding that homologous PTHR desensitization in LLC-PK1 cells is signal specific suggests that prior exposure of other cells to PTH also may induce discordant regulation of subsequent PTHR signaling, altering the character as well as the intensity of the hormonal response.


Physician Decision Making and Clinical Outcomes With Laboratory Polysomnography or Limited-Channel Sleep Studies for Obstructive Sleep Apnea: A Randomized Trial.
The clinical utility of limited-channel sleep studies (which are increasingly conducted at home) versus laboratory polysomnography (PSG) for diagnosing obstructive sleep apnea (OSA) is unclear. To compare patient outcomes after PSG versus limited-channel studies. Multicenter, randomized, noninferiority study. (Australian New Zealand Clinical Trials Registry: ACTRN12611000926932). 7 academic sleep centers. Patients (n = 406) aged 25 to 80 years with suspected OSA. Sleep study information disclosed to sleep physicians comprised level 1 (L1) PSG data (n = 135); level 3 (L3), which included airflow, thoracoabdominal bands, body position, electrocardiography, and oxygen saturation (n = 136); or level 4 (L4), which included oxygen saturation and heart rate (n = 135). The primary outcome was change in Functional Outcomes of Sleep Questionnaire (FOSQ) score at 4 months. Secondary outcomes included the Epworth Sleepiness Scale (ESS), the Sleep Apnea Symptoms Questionnaire (SASQ), continuous positive airway pressure (CPAP) compliance, and physician decision making. Change in FOSQ score was not inferior for L3 (mean difference [MD], 0.01 [95% CI, -0.47 to 0.49; P = 0.96]) or L4 (MD, -0.46 [CI, -0.94 to 0.02; P = 0.058]) versus L1 (noninferiority margin [NIM], -1.0). Compared with L1, change in ESS score was not inferior for L3 (MD, 0.08 [CI, -0.98 to 1.13; P = 0.89]) but was inconclusive for L4 (MD, 1.30 [CI, 0.26 to 2.35; P = 0.015]) (NIM, 2.0). For L4 versus L1, there was less improvement in SASQ score (-17.8 vs. -24.7; P = 0.018), less CPAP use (4.5 vs. 5.3 hours per night; P = 0.04), and lower physician diagnostic confidence (P = 0.003). Limited-channel studies were simulated by extracting laboratory PSG data and were not done in the home. The results support manually scored L3 testing in routine practice. Poorer outcomes with L4 testing may relate, in part, to reduced physician confidence. National Health and Medical Research Council and Repat Foundation.


Progestins increase insulin receptor content and insulin stimulation of growth in human breast carcinoma cells.
The effects of progesterone on the growth of breast carcinoma cells are undefined. In the present study we investigated the effect of progestins on insulin receptor gene expression and insulin action in human breast cancer cells. Treatment of T47D cells with the synthetic progestin R5020 induced a time- and dose-dependent increase in insulin receptor content as measured by both ligand-binding studies and radioimmunoassay. Binding was half-maximally stimulated at 300 pM R5020 and maximal levels were reached after 4 days of treatment. Progesterone was 10-fold less potent than R5020. Cortisol had no effect on insulin receptor levels, while 17 beta-estradiol and dihydrotestosterone had minimal effects. Progestin treatment both increased insulin receptor mRNA levels and altered the relative distribution of the multiple insulin receptor mRNA transcripts. In order to study the functional significance of the increased insulin receptor levels, we incubated T47D cells with progesterone and then treated them with insulin. Insulin alone had a small effect on cell growth; however, the effect of insulin was markedly potentiated by progesterone treatment. These studies in breast cancer cells demonstrate, therefore, that insulin receptor gene expression is under the regulation of progestins and raise the possibility that progestin-insulin interactions may regulate breast cancer cell growth in vivo.


Environmental Influences on HIV Medication Adherence: The Role of Neighborhood Disorder.
We hypothesized that highly disordered neighborhoods would expose residents to environmental pressures, leading to reduced antiretroviral (ARV) medication adherence. Using targeted sampling, we enrolled 503 socioeconomically disadvantaged HIV-positive substance users in urban South Florida between 2010 and 2012. Participants completed a 1-time standardized interview that took approximately 1 hour. We tested a multiple mediation model to examine the direct and indirect effects of neighborhood disorder on diversion-related nonadherence to ARVs; risky social networks and housing instability were examined as mediators of the disordered neighborhood environment. The total indirect effect in the model was statistically significant (P = .001), and the proportion of the total effect mediated was 53%. The model indicated substantial influence of neighborhood disorder on nonadherence to ARVs, operating through recent homelessness and diverter network size. Long-term improvements in diversion-related ARV adherence will require initiatives to reduce demand for illicit ARV medications, as well as measures to reduce patient vulnerability to diversion, including increased resources for accessible housing, intensive treatment, and support services.


Directional second-harmonic generation controlled by sub-wavelength facets of an organic mesowire.
Directional harmonic generation is an important property characterizing the ability of nonlinear optical antennas to diffuse the signal in a well-defined region of space. Herein, we show how sub-wavelength facets of an organic molecular mesowire crystal can be utilized to systematically vary the directionality of second-harmonic generation (SHG) in the forward-scattering geometry. We demonstrate this capability on crystalline diamonoanthraquinone (DAAQ) mesowires with sub-wavelength facets. We observed that the radial angles of the SHG emission can be tuned over a range of 130 deg. This angular variation arises due to spatially distributed nonlinear dipoles in the focal volume of the excitation as well as the geometrical cross section and facet orientation of the mesowire. Numerical simulations of the near-field excitation profile corroborate the role of the mesowire geometry in localizing the electric field. In addition to directional SHG from the mesowire, we experimentally observe optical waveguiding of the nonlinear two-photon excited fluorescence (TPEF). Interestingly, we observed that for a given pump excitation, the TPEF signal is isotropic and delocalized, whereas the SHG emission is directional and localized at the location of excitation. All the observed effects have direct implications not only in active nonlinear optical antennas but also in nonlinear signal processing.


Incidence, persistence, and progression of tinnitus symptoms in older adults: the Blue Mountains Hearing Study.
Temporal population-based data on tinnitus are lacking. We used a representative older population-based cohort to establish 5-yr incidence, persistence, and progression of tinnitus symptoms. Two thousand six participants of the Blue Mountains Hearing Study (1997-1999) had complete tinnitus data, and of these, 1214 participants were followed up at 5-yr examinations in 2002-2004. Presence of prolonged tinnitus was assessed by a positive response to a single question administered by an audiologist. Incident tinnitus was defined in participants who were free of tinnitus symptoms at the baseline study in 1997-1999 but who reported tinnitus symptoms at the 5-yr follow-up in 2002-2004. Progression of tinnitus was defined as the increase in annoyance of tinnitus symptoms from baseline to the 5-yr follow-up study. Persistence of tinnitus symptoms was defined as the presence of tinnitus symptoms at both the baseline and follow-up examinations. Hearing impairment was measured as the pure-tone average (PTA) of audiometric hearing thresholds at 500, 1000, 2000, and 4000 Hz (PTA0.5-4 kHz), defining bilateral hearing loss as PTA0.5-4 kHz >25 dB HL. Five-year incidence of tinnitus was 18.0%. A significant age trend was observed for the 5-yr incidence (p = 0.005), with incident tinnitus decreasing with age. Hearing loss increased the risk of developing incident tinnitus, age-sex adjusted odds ratio 2.13 (95% confidence interval, 1.40 to 3.24). Most (55.5%) incident tinnitus cases reported symptoms that were only mildly annoying. Tinnitus at baseline persisted in 81.6% of participants. Of those reporting mildly annoying tinnitus at baseline, 39.6% progressed to moderately annoying and 5.9% to severely annoying tinnitus. At the follow-up, a higher frequency of participants with persistent tinnitus (old cases) reported their symptoms as very/extremely annoying compared with the new (incident) cases of tinnitus (p = 0.01). A high proportion (85.2%) of subjects receiving tinnitus treatment (mainly medications and hearing aid) at baseline still reported tinnitus at 5-yr examinations. Incident tinnitus was frequent, with nearly one in five older adults suffering from this condition after 5 yrs. Tinnitus symptoms persisted in more than three-quarters of the cohort, during the 5 yrs. Longitudinal data are an important contribution to the research evidence base to support timely intervention and effective management of this frequent symptom.


Hydration stability of intracorneal hydrogel implants.
A hydrogel intracorneal lens for refractive keratoplasty must have predictable and stable optics when implanted in the corneal stroma. A series of experiments was performed to evaluate the hydrogel hydration stability when in the corneal stromal environment. Hydrogel ICLs of 54%, 63%, 66% and 71% water content showed no loss of hydration (by weight) after one week in the rabbit corneal stroma. In vitro experiments with hydrogel discs of 56%, 65%, 69.5% and 75% water content were subjected to swelling pressures ranging from 55 to 150 mmHg in a suction chamber. Only the hydrogel of 75% water content showed a significant loss of hydration at the physiologic swelling pressure of 55 mmHg. This study shows that hydrogel materials with up to 69.5% water content can be expected to be dimensionally stable when used in keratorefractive surgery.


Complex pharmacology of novel allosteric free fatty acid 3 receptor ligands.
Analysis of the roles of the short chain fatty acid receptor, free fatty acid 3 receptor (FFA3), has been severely limited by the low potency of its endogenous ligands, the crossover of function of these on the closely related free fatty acid 2 receptor, and a dearth of FFA3-selective synthetic ligands. From a series of hexahydroquinolone-3-carboxamides, we demonstrate that 4-(furan-2-yl)-2-methyl-5-oxo-N-(o-tolyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxamide is a selective and moderately potent positive allosteric modular (PAM)-agonist of the FFA3 receptor. Modest chemical variations within this series resulted in compounds completely lacking activity, acting as FFA3 PAMs, or appearing to act as FFA3-negative allosteric modulators. However, the pharmacology of this series was further complicated in that certain analogs displaying overall antagonism of FFA3 function actually appeared to generate their effects via a combined positive allosteric binding cooperativity and negative allosteric effect on orthosteric ligand maximal signaling response. These studies show that various PAM-agonist and allosteric modulators of FFA3 can be identified and characterized. However, within the current chemical series, considerable care must be taken to define the pharmacological characteristics of specific compounds before useful predictions of their activity and their use in defining specific roles of FFA3 in either in vitro and in vivo settings can be made.


Exogenous neuropeptide Y promotes in vivo hippocampal neurogenesis.
Adult neurogenesis mainly occurs in two brain regions, the subventricular zone and the dentate gyrus (DG) of the hippocampus. Neuropeptide Y (NPY) is widely expressed throughout the brain and is known to enhance in vitro hippocampal cell proliferation. Mice lacking either NPY or the Y1 receptor display lower levels of cell proliferation, thereby suggesting a role for NPY in basal in vivo neurogenesis. Here, we investigated whether exogenous NPY stimulates DG progenitors proliferation in vivo. We show that intracerebroventricular administration of NPY increases DG cell proliferation and promotes neuronal differentiation in C57BL/6 adult mice. In these mice, the proliferative effect of NPY is mediated by the Y1 and not the Y2 receptor, as a Y1 ([Leu(31) ,Pro(34) ]), but not a Y2 (NPY(3-36) ), receptor agonist enhanced proliferation. In addition, no NPY-induced DG cellular proliferation is observed following NPY injection when coadministered with a Y1 antagonist or in the Y1 receptor knockout mouse. These results are in line with data obtained in Y1(-/-) mice, demonstrating that NPY regulates in vivo hippocampal neurogenesis. © 2010 Wiley-Liss, Inc.


New International Classification of Functioning, Disability and Health.
The WHO International Classification of Functioning, Disability and Health (ICF) provides a coherent view of health from a biological, individual and social perspective. This view may be defined both as multi- and interdisciplinary management of one's functioning and health. This new classification is currently being assessed in multiple centres in 32 countries, on 12 health conditions. The Institute of Hygiene and Medical Ecology, School of Medicine, University of Belgrade, is one of them, serving as the centre where the classification is being tested in obese population. The objective of this paper is to provide information needed for further development and practical application of this classification in various health conditions. The new language of ICF is an exciting landmark event for preventive medicine and rehabilitation. It may lead to a stronger position of rehabilitation within the medical community, change multiprofessional communication and improve communication between patients and health professionals.


Moral Suasion and the Private Provision of Public Goods: Evidence from the COVID-19 Pandemic.
We study how moral suasion that appeals to two major ethical theories, Consequentialism and Deontology, affects individual intentions to contribute to a public good. We use the COVID-19 pandemic as an exemplary case where there is a large gap between private and social costs and where moral suasion has been widely used as a policy instrument. Based on a survey experiment with a representative sample of around 3500 Germans at the beginning of the pandemic, we study how moral appeals affect contributions with low and high opportunity costs, hand washing and social distancing, to reduce the infection externality as well as the support for governmental regulation. We find that Deontological moral suasion, appealing to individual moral duty, is effective in increasing planned social distancing and hand-washing, while a Consequentialist appeal only increases planned hand-washing. Both appeals increase support for governmental regulation. Exploring heterogeneous treatment effects reveals that younger respondents are more susceptible to Deontological appeals. Our results highlight the potential of moral appeals to induce intended private contributions to a public good or the reduction of externalities, which can help to overcome collective action problems for a range of environmental issues.


Recent advances in drug discovery of phototherapeutic non-porphyrinic anticancer agents.
In the search of novel strategies for the treatment of cancer, photodynamic therapy (PDT) has emerged as an effective, safe for repeated use, and non-invasive method. This technique involves the use of two major non-toxic components, a photosensitizer (PS) and a visible or near-infrared (NIR) light source, combined to induce cellular damage in an oxygen-dependent or -independent manner. Macrocyclic compounds, involving porphyrin and their derivatives, represent the major class of PS agents used in PDT. However, due to the drawbacks associated with these PS, like photosensitivity, dark toxicity, and low wavelength absorbance, new classes of PS appear to be needed. This review summarizes over the recent advances in drug discovery of non-porphyrinic PS suitable as anticancer therapeutics in PDT. The different compounds are grouped by chemical classes and discussed in terms of phototoxicity, together with the critical aspects of design and structure-activity relationship.


Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma.
Acquired resistance to targeted drugs is emerging as an obstacle to successful cancer treatment. Recently, a BCL2-selective BH3 mimetic termed ABT-199 showed promising therapeutic results in BCL2-dependent tumors. Based on its high affinity for BCL2, we studied potential mechanisms conferring resistance upon ABT-199 therapy, aiming to anticipate its occurrence in the clinic. Two models of resistant lymphomas were established by continuous ABT-199 exposure. In resistant Bcl2-expressing mouse lymphoma cells, 2 missense mutations within the Bcl2 BH3 domain were identified. Both F101C and F101L mutations impeded ABT-199 binding to the BH3 domain, therefore suppressing mitochondrial apoptosis. In resistant human lymphoma cells, a missense mutation in the C-terminal transmembrane domain of proapoptotic BAX (G179E) was found, which abrogated BAX anchoring to mitochondria and blocked ABT-199-induced apoptosis both in vitro and in vivo. Importantly, G179E BAX mutation also induced partial cross-resistance to other antineoplastic drugs. Our study reveals the acquisition of mutations in BCL2 family proteins as a novel mechanism of apoptosis resistance in cancer. These results anticipate the potential development of such mutations in patients treated with ABT-199, providing a basis to preventing their occurrence and to designing drugs able to circumvent the acquired resistance.


Effects of Pilates and Elastic Taping on Balance and Postural Control in Early Stage Parkinson's Disease Patients: A Pilot Randomised Controlled Trial.
The purpose of this study is to investigate the effects of Pilates training and elastic taping on balance and postural control in patients with early stage Parkinson's Disease (PD). Patients were randomly divided into Pilates, elastic taping, and control (wait list) groups. Pilates training was performed for 6 weeks, twice a week and 60 minutes per session. In elastic taping group, in addition to Pilates training, elastic taping was applied to the upper back twice a week for 6 weeks with the aim of postural correction. In order to evaluate the postural control before and after the training, Berg Balance Scale, Trunk Impairment Scale, the tests of NeuroCom Balance Master performance test device as Limits of stability (LOS), Sit-to Stand, Walk Across and Tandem Walking Tests were performed. The data of 20 patients (6 male in Pilates group, 2 female and 6 male in elastic taping group, 3 female and 3 male in control group) were analyzed. Reaction times in LOS test decreased significantly and walking speed in Walk Across test increased significantly after 6 weeks in Pilates and elastic taping groups. In elastic taping group, the postural sways of Tandem Walk test were decreased significantly and, the rising index in Sit-to-Stand test increased significantly after 6 weeks (Wilcoxon Test, p<0.05). We believe that Pilates is a feasible rehabilitation strategy for PD, and it has a remedial effect on the dynamic balance and postural control for these patients. We also think that elastic taping could be applied for supporting the right posture.


A New Framework to Implement Model-Informed Dosing in Clinical Guidelines: Piperacillin and Amikacin as Proof of Concept.
Background: Modeling and simulation is increasingly used to study pediatric pharmacokinetics, but clinical implementation of age-appropriate doses lags behind. Therefore, we aimed to develop model-informed doses using published pharmacokinetic data and a decision framework to adjust dosing guidelines based on these doses, using piperacillin and amikacin in critically ill children as proof of concept. Methods: Piperacillin and amikacin pharmacokinetic models in critically ill children were extracted from literature. Concentration-time profiles were simulated for various dosing regimens for a virtual PICU patient dataset, including the current DPF dose and doses proposed in the studied publications. Probability of target attainment (PTA) was compared between the different dosing regimens. Next, updated dosing recommendations for the DPF were proposed, and evaluated using a new framework based on PK study quality and benefit-risk analysis of clinical implementation. Results: Three studies for piperacillin (critically ill children) and one for amikacin (critically ill pediatric burn patients) were included. Simulated concentration-time profiles were performed for a virtual dataset of 307 critically ill pediatric patients, age range 0.1-17.9 y. PTA for unbound piperacillin trough concentrations >16 mg/L was >90% only for continuous infusion regimens of 400 mg/kg/day vs. 9.7% for the current DPF dose (80 mg/kg/6 h, 30 min infusion). Amikacin PTA was >90% with 20 mg/kg/d, higher than the PTA of the DPF dose of 15 mg/kg/d (63.5%). Using our new decision framework, altered DPF doses were proposed for piperacillin (better PTA with loading dose plus continuous infusion), but not for amikacin (studied and target population were not comparable and risk for toxicity with higher dose). Conclusions: We show the feasibility to develop model-informed dosing guidelines for clinical implementation using existing pharmacokinetic data. This approach could complement literature and consensus-based dosing guidelines for off-label drugs in the absence of stronger evidence to support pediatricians in daily practice.


Phenotypic characteristics of pediatric inflammatory bowel disease in Japan: results from a multicenter registry.
There are few published registry studies from Asia on pediatric inflammatory bowel disease (IBD). Registry network data enable comparisons among ethnic groups. This study examined the characteristics of IBD in Japanese children and compared them with those in European children. This was a cross-sectional multicenter registry study of newly diagnosed Japanese pediatric IBD patients. The Paris classification was used to categorize IBD features, and results were compared with published EUROKIDS data. A total of 265 pediatric IBD patients were initially registered, with 22 later excluded for having incomplete demographic data. For the analysis, 91 Crohn's disease (CD), 146 ulcerative colitis (UC), and 6 IBD-unclassified cases were eligible. For age at diagnosis, 20.9% of CD, 21.9% of UC, and 83.3% of IBD-unclassified cases were diagnosed before age 10 years. For CD location, 18.7%, 13.2%, 64.8%, 47.3%, and 20.9% were classified as involving L1 (ileocecum), L2 (colon), L3 (ileocolon), L4a (esophagus/stomach/duodenum), and L4b (jejunum/proximal ileum), respectively. For UC extent, 76% were classified as E4 (pancolitis). For CD behavior, B1 (non-stricturing/non-penetrating), B2 (stricturing), B3 (penetrating), and B2B3 were seen in 83.5%, 11.0%, 3.3%, and 2.2%, respectively. A comparison between Japanese and European children showed less L2 involvement (13.2% vs. 27.3%, P< 0.01) but more L4a (47.3% vs. 29.6%, P< 0.01) and L3 (64.8% vs. 52.7%, P< 0.05) involvement in Japanese CD children. Pediatric perianal CD was more prevalent in Japanese children (34.1% vs. 9.7%, P< 0.01). Upper gastrointestinal and perianal CD lesions are more common in Japanese children than in European children.


Molecular recognition at crystal interfaces.
Nucleation, growth, and dissolution of crystals have been studied by stereochemical approach involving molecular recognition at interfaces. A methodology is described for using ;;tailor-made'' additives designed to interact stereospecifically with crystal surfaces during growth and dissolution. This procedure was instrumental in controlling crystal morphology and in revising the concept of the structure and symmetry of solid solutions. Consequently, it was applied to the transformation of centrosymmetric single crystals into solid solutions with polar arrangement displaying second-harmonic generation and to the performance of asymmetric synthesis of guest molecules inside centrosymmetric host crystals. The method has led to a discovery of a new ;;relay'' mechanism explaining the effect of solvent on crystal growth. Finally, it allowed for the design of auxiliary molecules that act as promoters or inhibitors of crystal nucleation that can be used to resolve enantiomers and crystallize desired polymorphs.


The separation of the alpha-chains of collagen by free-flow electrophoresis.
1. The separation of the alpha-components of codfish-skin and calf-skin collagen from the higher-molecular-weight components was accomplished by gel filtration with Bio-Gel P-300 resin in 5m-lithium chloride and at pH7.4. 2. From this fraction three distinct alpha-components, corresponding to the alpha1-, alpha2- and alpha3- chains of collagen, were isolated by free-flow electrophoresis in 6m-urea at 4 degrees . At the temperatures and pH values used there was no detectable degradation of the alpha-chains.


Where is toxicology headed in the future?
Herbert Remmer was a pioneer in the study of the phenomenon of enzyme induction. He was also a leading figure, if not the foremost, in the development of the discipline of toxicology in Germany during his tenure as Professor of Toxicology at the University of Tübingen. Included here are some brief thoughts about where toxicology came from, where it is today, and what the future is. Toxicology is at a crossroads today, at an interface between basic science and applied projects. From its past as a descriptive discipline, it has incorporated a medley of concepts and technology from basic science. The usefulness of many approaches is now being evaluated. The hope is that toxicology will be able to be much more predictive in the future; a great need exists in the pharmaceutical industry. The shape of academic toxicology is also changing.


Black, White, and Hispanic Children's Health and Function 2-13 Months After Sibling Intensive Care Unit Death.
To describe children's anxiety, depression, behaviors, and school performance at 2-13 months after sibling neonatal/pediatric intensive care unit (NICU/PICU) or emergency department (ED) death and compare these outcomes by child age, sex, race/ethnicity, whether the child saw their sibling in the NICU/PICU/ED, and attended the sibling's funeral. Children in 71 families were recruited for this longitudinal study from 4 children's hospitals and 14 other Florida hospitals. Children rated anxiety (Spence Children's Anxiety Scale) and depression (Children's Depression Inventory); parents rated child behaviors (Child Behavior Checklist) and reported school performance (detentions, suspensions, requested parent-teacher meetings) at 2, 4, 6, and 13 months post-sibling death. Analyses included repeated measures-ANOVA, t-tests, and 1-way ANOVA. In total, 132 children and 96 parents participated. More children were female (58%), black (50%), and school-age (72%). Of the children, 43% had elevated anxiety and 6% had elevated depression over 13 months post-sibling death. Child-rated anxiety was higher for girls and black vs white children. Child-rated anxiety and depression were lower if they saw their sibling in the NICU/PICU/ED before and/or after the death, and/or attended the funeral. Teens were more withdrawn than school-age children at all time points. Children who did not see their deceased sibling in the NICU/PICU/ED after death had more requests for parent-teacher conferences. Children's anxiety was more common than depression, especially in girls and black children. Children who saw their siblings in the NICU/PICU/ED before/after death and/or attended funeral services had lower anxiety and depression over the first 13 months after sibling death.


DNA methylation profiles of human active and inactive X chromosomes.
X-chromosome inactivation (XCI) is a dosage compensation mechanism that silences the majority of genes on one X chromosome in each female cell. To characterize epigenetic changes that accompany this process, we measured DNA methylation levels in 45,X patients carrying a single active X chromosome (X(a)), and in normal females, who carry one X(a) and one inactive X (X(i)). Methylated DNA was immunoprecipitated and hybridized to high-density oligonucleotide arrays covering the X chromosome, generating epigenetic profiles of active and inactive X chromosomes. We observed that XCI is accompanied by changes in DNA methylation specifically at CpG islands (CGIs). While the majority of CGIs show increased methylation levels on the X(i), XCI actually results in significant reductions in methylation at 7% of CGIs. Both intra- and inter-genic CGIs undergo epigenetic modification, with the biggest increase in methylation occurring at the promoters of genes silenced by XCI. In contrast, genes escaping XCI generally have low levels of promoter methylation, while genes that show inter-individual variation in silencing show intermediate increases in methylation. Thus, promoter methylation and susceptibility to XCI are correlated. We also observed a global correlation between CGI methylation and the evolutionary age of X-chromosome strata, and that genes escaping XCI show increased methylation within gene bodies. We used our epigenetic map to predict 26 novel genes escaping XCI, and searched for parent-of-origin-specific methylation differences, but found no evidence to support imprinting on the human X chromosome. Our study provides a detailed analysis of the epigenetic profile of active and inactive X chromosomes.


Nicotine derived from the electronic cigarette improves time-based prospective memory in abstinent smokers.
It is well established that nicotine improves, and deprivation impairs, cognitive performance and mood in smokers. Prospective memory (PM), remembering to execute a delayed intention at a given time point, is under-explored in smokers. Whilst a handful of studies have shown improved PM with nicotine, the effects of nicotine delivered via the electronic cigarette (e-cigarette) have not been investigated. This study explores whether, by comparison with placebo, nicotine delivered via the e-cigarette can improve PM, tobacco withdrawal symptoms and desire to smoke in abstinent smokers. Twenty smokers, abstinent for 8-10 h, each completed two experimental sessions under nicotine (18 mg) and placebo (0 mg) e-cigarette conditions. Participants completed a single-item desire-to-smoke scale and the Mood and Physical Symptoms Scale. PM was measured using the Cambridge Prospective Memory Test. Compared with placebo, the nicotine e-cigarette reduced the desire to smoke and tobacco withdrawal symptoms, and improved time-based but not event-based PM. There was a moderate, marginally significant negative correlation between PM performance during abstinence and nicotine dependence. This is the first study to show that nicotine derived via e-cigarette can improve PM in abstinent smokers, suggesting efficient nicotine delivery. The finding that the effect of nicotine was restricted to time-based rather than event-based PM is consistent with the view that nicotine acts to improve performance on strategic (effortful) rather than automatic processing. These findings add to the growing body of evidence that the e-cigarette can replace some of the effects of nicotine derived from tobacco smoking, thus highlighting its potential for smoking cessation.


Use of subgroup-specific hematopoietic stem cell collection efficiencies to improve truncation calculations for large-volume leukapheresis procedures.
A critical component of optimizing peripheral blood (PB) hematopoietic stem cell (HSC) collections is accurately determining the processed blood volume required to collect the targeted number of HSCs. Fundamental to most truncation equations employed to determine this volume is the procedure's estimated collection efficiency (CE), which is typically applied uniformly across all HSC collections. Few studies have explored the utility of using different CEs in subpopulations of donors that have substantially different CEs than the institutional average. Initial procedures from 343 autologous and 179 allogeneic HSC collections performed from 2018 to 2021 were retrospectively analyzed. Predictive equations were developed to determine theoretical truncation rates in various donor subgroups. Quantitative variables (pre-procedure cell counts) and qualitative variables (relatedness to recipient, gender, method of venous access, and mobilization strategy) were found to significantly impact CE. However, much of the variability in CE between donors could not be explained by the variables assessed. Analyses of procedures with high pre-collection PB cell counts identified lower CE values for these donors' truncation equations which still allow truncation but minimize risk of collecting less CD34+ cells than requested. Individualized CE does not substantially improve truncation volume calculations over use of a fixed CE and adds complexity to these calculations. The optimal fixed CE varies between autologous and allogeneic donors, and donors with high pre-collection PB cell counts in either of these groups. This model will be clinically validated and continuously refined through analysis of future HSC collections.


Prion-like properties of Tau protein: the importance of extracellular Tau as a therapeutic target.
Work over the past 4 years indicates that multiple proteins associated with neurodegenerative diseases, especially Tau and α-synuclein, can propagate aggregates between cells in a prion-like manner. This means that once an aggregate is formed it can escape the cell of origin, contact a connected cell, enter the cell, and induce further aggregation via templated conformational change. The prion model predicts a key role for extracellular protein aggregates in mediating progression of disease. This suggests new therapeutic approaches based on blocking neuronal uptake of protein aggregates and promoting their clearance. This will likely include therapeutic antibodies or small molecules, both of which can be developed and optimized in vitro prior to preclinical studies.


Verification of the efficacy of topical sirolimus gel for systemic rare vascular malformations: a pilot study.
Numerous clinical trials of sirolimus, an inhibitor of mechanistic/mammalian target of rapamycin complex 1, for the treatment of vascular malformations have been conducted. However, aside from lymphatic malformations, the efficacy of sirolimus for venous and capillary malformations has not been established. Moreover, no generalized venous or capillary malformations have been treated with topical sirolimus. To evaluate the safety and efficacy of topical sirolimus for venous and capillary malformations and to compare the efficacy of topical and systemic sirolimus therapy, an open-label single-arm pilot study with 0.2% sirolimus gel was conducted from July 19, 2019, to January 30, 2020, in four patients diagnosed with different vascular malformations (blue rubber bleb nevus syndrome, common venous malformation, phakomatosis pigmentovascularis type IVb, and angiokeratoma in Fabry disease). The primary endpoint was the safety evaluation of sirolimus gel. The main secondary endpoint was the improvement rate evaluated by the Central Judgment Committee at 12 weeks using photographs. No adverse events were observed. Blood sirolimus was not detected in any patient. Two patients (50%) had mild improvement, and the remaining two patients (50%) showed no change after 12 weeks of treatment. Blue rubber bleb nevus syndrome, a generalized venous malformation, showed the greatest response. In conclusion, 0.2% sirolimus gel was found to be as clinically effective as systemic sirolimus treatment in patients with venous and capillary malformations and more effective for early active lesions, even systemic venous malformations.


Queen Execution, Diploid Males, and Selection For and Against Polyandry in the Brazilian Stingless Bee Scaptotrigona depilis.
Female mating frequency varies. Determining the causes of this variation is an active research area. We tested the hypothesis that in stingless bees, Meliponini, single mating is due to the execution of queens that make a matched mating at the complementary sex determination locus and have diploid male offspring. We studied the Brazilian species Scaptotrigona depilis. We made up 70 test colonies so that 50% (single matched mating), 25% (double mating), 12.5% (quadruple mating), or 0% (single nonmatched mating) of the emerging brood were diploid males. Queen execution following diploid male emergence was equal and high in colonies producing 50% (77% executed) and 25% (75%) diploid males versus equal and low in colonies producing 12.5% (7%) and 0% (0%) diploid males. These results show that queens that mate with two males with similar paternity suffer an increased chance of being executed, which selects against double mating. However, double mating with unequal paternity (e.g., 25∶75), which occasionally occurs in S. depilis, is selectively neutral. Single mating and double mating with unequal paternity form one adaptive peak. The results show a second adaptive peak at quadruple mating. However, this is inaccessible via gradual evolutionary change in a selective landscape with reduced fitness at double mating.


Functional intervention following cardiac surgery to prevent postoperative delirium in older patients (FEEL WELL study).
Postoperative delirium is a common complication in patients after cardiac surgery, especially in older patients, and can manifest as a disturbance of attention and consciousness. It can lead to increased postoperative morbidity, prolonged need for care, and mortality. The presented study investigates whether the occurrence of postoperative delirium after cardiac surgery can be prevented by a multisensory stimulation. It was conducted as a prospective, randomized, controlled, non-pharmacological intervention study in the years 2021 and 2022 at the University Hospital Bonn in Germany. A total of 186 patients over 65 years with elective cardiac surgery were enrolled. Patients were randomized either to the intervention or control group. In both groups, postoperative delirium was assessed with the 3-min diagnostic interview for confusion assessment method on the first 5 days after surgery and pain was assessed using the Numeric Rating Scale. Multisensory stimulation was performed 20 min a day for the first three postoperative days in the intervention group. The incidence of postoperative delirium was 22.6% in the intervention group and 49.5% in the control group (p < 0.001). Duration of postoperative delirium was significantly shorter in the intervention group (p < 0.001). Stay in the intensive care unit was significantly longer in the control group (p = 0.006). In the regression model non-intervention, high pain scores, advanced age, and prolonged mechanical ventilation were associated with postoperative delirium (p = 0.007; p = 0.032; p = 0.006; p = 0.006, respectively). Results of the study imply that a multisensory stimulation done on the first 3 days after planned cardiac surgery can reduce the incidence and duration of postoperative delirium in older patients. Influence of the treatment on the incidence of delirium in other patient groups, the length of stay in the intensive care unit, and patients´ postoperative pain should be confirmed in further clinical studies. DRKS, DRKS00026909. Registered 28 October 2021, Retrospectively registered, https://drks.de/search/de/trial/DRKS00026909 .


Rho0 production and possible modification in Au+Au and p+p collisions at square root [sNN] = 200 GeV.
We report results on rho(770)(0)-->pi(+)pi(-) production at midrapidity in p+p and peripheral Au+Au collisions at sqrt[s(NN)]=200 GeV. This is the first direct measurement of rho(770)(0)-->pi(+)pi(-) in heavy-ion collisions. The measured rho(0) peak in the invariant mass distribution is shifted by approximately 40 MeV/c(2) in minimum bias p+p interactions and approximately 70 MeV/c(2) in peripheral Au+Au collisions. The rho(0) mass shift is dependent on transverse momentum and multiplicity. The modification of the rho(0) meson mass, width, and shape due to phase space and dynamical effects are discussed.


Teachers victimizing students: Contributions of student-to-teacher victimization, peer victimization, school safety, and school climate in Chile.
Although most of the school violence literature is focused on peer victimization, interest is growing in teachers being victimized by their students. However, there is far less interest in students being victimized by their teachers, patterns of mutual victimization, and how they are associated with other school factors. Using the conceptual framework of school violence in evolving contexts, the present study examined teacher-to-student victimization in Chile and tested, for the first time, the associations of student-to-teacher victimization, peer victimization, school safety, classroom climate, and school climate at the individual and school levels. The sample consisted of 50,344 students (51.6% female) in Grades 5-8 in 431 schools in Chilean public-funded schools. Findings indicated that verbal types of teacher-student mutual victimization were more prevalent than physical and sexual victimization. Teacher-to-student victimization was higher among male and younger students. Multilevel analyses showed that student-to-teacher victimization, school safety, classroom climate, and school climate were associated with teacher-to-student victimization. We discuss the need for whole-school approaches that enhance social and academic support from teachers to reduce mutual forms of victimization and suggest a public health approach that places the school in the center. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Quality indicators for multiple sclerosis.
Determining whether persons with multiple sclerosis (MS) receive appropriate, comprehensive healthcare requires tools for measuring quality. The objective of this study was to develop quality indicators for the care of persons with MS. We used a modified version of the RAND/UCLA Appropriateness Method in a two-stage process to identify relevant MS care domains and to assess the validity of indicators within high-ranking care domains. Based on a literature review, interviews with persons with MS, and discussions with MS providers, 25 MS symptom domains and 14 general health domains of MS care were identified. A multidisciplinary panel of 15 stakeholders of MS care, including 4 persons with MS, rated these 39 domains in a two-round modified Delphi process. The research team performed an expanded literature review for 26 highly ranked domains to draft 86 MS care indicators. Through another two-round modified Delphi process, a second panel of 18 stakeholders rated these indicators using a nine-point response scale. Indicators with a median rating in the highest tertile were considered valid. Among the most highly rated MS care domains were appropriateness and timeliness of the diagnostic work-up, bladder dysfunction, cognition dysfunction, depression, disease-modifying agent usage, fatigue, integration of care, and spasticity. Of the 86 preliminary indicators, 76 were rated highly enough to meet predetermined thresholds for validity. Following a widely accepted methodology, we developed a comprehensive set of quality indicators for MS care that can be used to assess quality of care and guide the design of interventions to improve care among persons with MS.


Dopaminergic and glutamatergic signaling crosstalk in Huntington's disease neurodegeneration: the role of p25/cyclin-dependent kinase 5.
Altered glutamatergic and dopaminergic signaling has been proposed as contributing to the specific striatal cell death observed in Huntington's disease (HD). However, the precise mechanisms by which mutant huntingtin sensitize striatal cells to dopamine and glutamate inputs remain unclear. Here, we demonstrate in knock-in HD striatal cells that mutant huntingtin enhances dopamine-mediated striatal cell death via dopamine D(1) receptors. Moreover, we show that NMDA receptors specifically potentiate the vulnerability of mutant huntingtin striatal cells to dopamine toxicity as pretreatment with NMDA increased D(1)R-induced cell death in mutant but not wild-type cells. As potential underlying mechanism of increased striatal vulnerability, we identified aberrant cyclin-dependent kinase 5 (Cdk5) activation. We demonstrate that enhanced Cdk5 phosphorylation and increased calpain-mediated conversion of the Cdk5 activator p35 into p25 may account for the deregulation of Cdk5 associated to dopamine and glutamate receptor activation in knock-in HD striatal cells. Moreover, supporting a detrimental role of Cdk5 in striatal cell death, neuronal loss can be widely prevented by roscovitine, a potent Cdk5 inhibitor. Significantly, reduced Cdk5 expression together with enhanced Cdk5 phosphorylation and p25 accumulation also occurs in the striatum of mutant Hdh(Q111) mice and HD human brain suggesting the relevance of deregulated Cdk5 pathway in HD pathology. These findings provide new insights into the molecular mechanisms underlying the selective vulnerability of striatal cells in HD and identify p25/Cdk5 as an important mediator of dopamine and glutamate neurotoxicity associated to HD.


Nonhistone protein acetylation as cancer therapy targets.
Acetylation and deacetylation are counteracting, post-translational modifications that affect a large number of histone and nonhistone proteins. The significance of histone acetylation in the modification of chromatin structure and dynamics, and thereby gene transcription regulation, has been well recognized. A steadily growing number of nonhistone proteins have been identified as acetylation targets and reversible lysine acetylation in these proteins plays an important role(s) in the regulation of mRNA stability, protein localization and degradation, and protein-protein and protein-DNA interactions. The recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery is a key element in the dynamic regulation of genes controlling cellular proliferation, differentiation and apoptosis. Many nonhistone proteins targeted by acetylation are the products of oncogenes or tumor-suppressor genes and are directly involved in tumorigenesis, tumor progression and metastasis. Aberrant activity of HDACs has been documented in several types of cancers and HDAC inhibitors (HDACi) have been employed for therapeutic purposes. Here we review the published literature in this field and provide updated information on the regulation and function of nonhistone protein acetylation. While concentrating on the molecular mechanism and pathways involved in the addition and removal of the acetyl moiety, therapeutic modalities of HDACi are also discussed.


Classification of European mtDNAs from an analysis of three European populations.
Mitochondrial DNA (mtDNA) sequence variation was examined in Finns, Swedes and Tuscans by PCR amplification and restriction analysis. About 99% of the mtDNAs were subsumed within 10 mtDNA haplogroups (H, I, J, K, M, T, U, V, W, and X) suggesting that the identified haplogroups could encompass virtually all European mtDNAs. Because both hypervariable segments of the mtDNA control region were previously sequenced in the Tuscan samples, the mtDNA haplogroups and control region sequences could be compared. Using a combination of haplogroup-specific restriction site changes and control region nucleotide substitutions, the distribution of the haplogroups was surveyed through the published restriction site polymorphism and control region sequence data of Caucasoids. This supported the conclusion that most haplogroups observed in Europe are Caucasoid-specific, and that at least some of them occur at varying frequencies in different Caucasoid populations. The classification of almost all European mtDNA variation in a number of well defined haplogroups could provide additional insights about the origin and relationships of Caucasoid populations and the process of human colonization of Europe, and is valuable for the definition of the role played by mtDNA backgrounds in the expression of pathological mtDNA mutations.


Clarithromycin Dose-Dependently Stabilizes Rat Peritoneal Mast Cells.
Macrolides, such as clarithromycin, have antiallergic properties. Since exocytosis in mast cells is detected electrophysiologically via changes in membrane capacitance (Cm), the absence of such changes due to the drug indicates its mast cell-stabilizing effect. Employing the whole-cell patch clamp technique in rat peritoneal mast cells, we examined the effects of clarithromycin on Cm during exocytosis. Using a water-soluble fluorescent dye, we also examined its effect on deformation of the plasma membrane. Clarithromycin (10 and 100 μM) significantly inhibited degranulation from mast cells and almost totally suppressed the GTP-x03B3;-S-induced increase in Cm. It washed out the trapping of the dye on the surface of mast cells. This study provides for the first time electrophysiological evidence that clarithromycin dose-dependently inhibits the process of exocytosis. The mast cell-stabilizing action of clarithromycin may be attributable to its counteractive effect on plasma membrane deformation induced by exocytosis.


Cardiac looping and the vertebrate left-right axis: antagonism of left-sided Vg1 activity by a right-sided ALK2-dependent BMP pathway.
The rightward looping of the primary heart tube is dependent upon upstream patterning events that establish the vertebrate left-right axis. In Xenopus, a left-sided Vg1 signaling pathway has been implicated in instructing cells to adopt a 'left-sided identity'; however, it is not known whether 'right-sided identity' is acquired by a default pathway or by antagonism of Vg1 signaling. Here, we propose that an antagonistic, BMP/ALK2/Smad-mediated signaling pathway is active on the right side of the Xenopus embryo. Truncated ALK2 receptor expression on the right side of the blastula elicits heart reversals and altered nodal expression. Consistent with these findings, constitutively active ALK2 (CA-ALK2) receptor expression on the left side of the blastula also elicits heart reversals and altered nodal expression. Coexpression of CA-ALK2 with mature Vg1 ligand results in predominantly left-sided nodal expression patterns and normal heart looping, demonstrating that the ALK2 pathway can 'rescue' left-right reversals that otherwise occur following right-sided misexpression of mature Vg1 ligand alone. Results with chimeric precursor proteins indicate that the mature domain of BMP ligands can mimic the ability of the ALK2 signaling pathway to antagonize the Vg1 pathway. Consistent with the observed antagonism between BMP and Vg1 ligands, left-sided ectopic expression of Xolloid results in heart reversals. Moreover, ectopic expression of Smad1 or Smad7 identified two downstream modulators of the BMP/ALK2 signaling pathway that also can regulate cardiac orientation. Collectively, these results define a BMP/ALK2-mediated pathway on the right side of the Xenopus embryo and, moreover, suggest that left-right patterning preceding cardiac morphogenesis involves the activation of two distinct and antagonistic, left- and right-sided TGF(beta)-related signaling pathways.


Using the ventrogluteal site for intramuscular injections.
Traditionally, the dorsogluteal site has been the site preferred by nurses for the administration of medication via intramuscular injection. However, there is evidence to support the use of the ventrogluteal site. It was recently advocated as the site of choice in a respected nursing manual. This article discusses the use of the ventrogluteal site, the intramuscular injection technique, and issues associated with teaching it.


[The mechanism of OC-STAMP overexpression induced actin cytoskeleton remodeling in promoting epithelial-mesenchymal transition in the alveolar type Ⅱ epithelial cell].
Objective: To explore the mechanism of osteoclast stimulatory transmembrane protein (OC-STAMP) overexpression on epithelial-mesenchymal transition (EMT) . Methods: In April 2021, mice alveolar type Ⅱ epithelial cells MLE-12 were divided into five groups: overexpression control group (NC group), Ocstamp overexpression group (over-Ocstamp group), Fasudil intervention group (over-Ocstamp+Fasudil group), silence control group (si-NC group), Ocstamp silence group (si-Ocstamp group). The protein expressions of OC-STAMP, epithelial marker protein-E-cadherin (E-cad), interstitial marker protein-α-smooth muscle actin (α-SMA), Ras homolog gene family member A (RhoA), Rho GDP dissociation inhibitor α (Rho GDIα), Rho-associated protein kinase (ROCK), phosphate myosin phosphatase (p-MYPT) were examined by Western blotting and Immunocytochemical staining. The filamentous actin (F-actin) was detected by Phalloidin method. t test was used to compare the relative expression of each protein between the two groups. Results: Western blotting and Immunocytochemical staining showed that compared with the NC group, the expression level of E-cad was down-regulated, while the expression levels of α-SMA, Rho GDIα, RhoA, ROCK, p-MYPT were increased, and F-actin expression was enhanced in the over-Ocstamp group. The differences were statistically significant (P<0.05). There were no significant differences in E-cad and α-SMA protein expression in si-Ocstamp group compared with si-NC group (P>0.05). Compared with over-Ocstamp group, the expression level of E-cad protein in over-Ocstamp+Fasudil group was up-regulated, the expression levels of α-SMA, Rho GDIα, RhoA, ROCK and p-MYPT protein were decreased, and F-actin expression was weakened, with statistical significance (P<0.05) . Conclusion: OC-STAMP overexpression in alveolar type Ⅱ epithelial cells may induce actin cytoskeleton remodeling through activation of Rho GDIα/RhoA/ROCK signaling pathway, thus promoting EMT.


Vegetables, fruits and phytoestrogens in the prevention of diseases.
The intake of 400-600 g/d of fruits and vegetables is associated with reduced incidence of many common forms of cancer, and diets rich in plant foods are also associated with a reduced risk of heart disease and many chronic diseases of ageing. These foods contain phytochemicals that have anti-cancer and anti-inflammatory properties which confer many health benefits. Many phytochemicals are colourful, and recommending a wide array of colourful fruits and vegetables is an easy way to communicate increased diversity of intake to the consumer. For example, red foods contain lycopene, the pigment in tomatoes, which is localized in the prostate gland and may be involved in maintaining prostate health, and which has also been linked with a decreased risk of cardiovascular disease. Green foods, including broccoli, Brussels sprouts and kale, contain glucosinolates which have also been associated with a decreased risk of cancer. Garlic and other white-green foods in the onion family contain allyl sulphides which may inhibit cancer cell growth. Other bioactive substances in green tea and soybeans have health benefits as well. Consumers are advised to ingest one serving of each of the seven colour groups daily, putting this recommendation within the United States National Cancer Institute and American Institute for Cancer Research guidelines of five to nine servings per day. Grouping plant foods by colour provides simplification, but it is also important as a method to help consumers make wise food choices and promote health.


Effect of high-intensity interval training on muscle remodeling in rheumatoid arthritis compared to prediabetes.
Sarcopenic obesity, associated with greater risk of cardiovascular disease (CVD) and mortality in rheumatoid arthritis (RA), may be related to dysregulated muscle remodeling. To determine whether exercise training could improve remodeling, we measured changes in inter-relationships of plasma galectin-3, skeletal muscle cytokines, and muscle myostatin in patients with RA and prediabetes before and after a high-intensity interval training (HIIT) program. Previously sedentary persons with either RA (n = 12) or prediabetes (n = 9) completed a 10-week supervised HIIT program. At baseline and after training, participants underwent body composition (Bod Pod®) and cardiopulmonary exercise testing, plasma collection, and vastus lateralis biopsies. Plasma galectin-3, muscle cytokines, muscle interleukin-1 beta (mIL-1β), mIL-6, mIL-8, muscle tumor necrosis factor-alpha (mTNF-α), mIL-10, and muscle myostatin were measured via enzyme-linked immunosorbent assays. An independent cohort of patients with RA (n = 47) and age-, gender-, and body mass index (BMI)-matched non-RA controls (n = 23) were used for additional analyses of galectin-3 inter-relationships. Exercise training did not reduce mean concentration of galectin-3, muscle cytokines, or muscle myostatin in persons with either RA or prediabetes. However, training-induced alterations varied among individuals and were associated with cardiorespiratory fitness and body composition changes. Improved cardiorespiratory fitness (increased absolute peak maximal oxygen consumption, or VO2) correlated with reductions in galectin-3 (r = -0.57, P = 0.05 in RA; r = -0.48, P = 0.23 in prediabetes). Training-induced improvements in body composition were related to reductions in muscle IL-6 and TNF-α (r < -0.60 and P <0.05 for all). However, the association between increased lean mass and decreased muscle IL-6 association was stronger in prediabetes compared with RA (Fisher r-to-z P = 0.0004); in prediabetes but not RA, lean mass increases occurred in conjunction with reductions in muscle myostatin (r = -0.92; P <0.05; Fisher r-to-z P = 0.026). Subjects who received TNF inhibitors (n = 4) or hydroxychloroquine (n = 4) did not improve body composition with exercise training. Exercise responses in muscle myostatin, cytokines, and body composition were significantly greater in prediabetes than in RA, consistent with impaired muscle remodeling in RA. To maximize physiologic improvements with exercise training in RA, a better understanding is needed of skeletal muscle and physiologic responses to exercise training and their modulation by RA disease-specific features or pharmacologic agents or both. ClinicalTrials.gov Identifier: NCT02528344 . Registered on August 19, 2015.


Infrared Spectroscopy of Fluorenyl Cations at Cryogenic Temperatures.
The notion of (anti)aromaticity is a successful concept in chemistry to explain the structure and stability of polycyclic hydrocarbons. Cyclopentadienyl and fluorenyl cations are among the most studied classical antiaromatic systems. In this work, fluorenyl cations are investigated by high-resolution gas-phase infrared spectroscopy in helium droplets. Bare fluorenyl cations are generated in the gas phase by electrospray ionization. After mass-to-charge selection, ions are captured in ultracold helium nanodroplets and probed by infrared spectroscopy using a widely tunable free-electron laser in the 600-1700 cm-1 range. The highly resolved cryogenic infrared spectra confirm, in combination with DFT computations, that all cations are present in their singlet states.


Modulating quorum sensing by antiactivation: TraM interacts with TraR to inhibit activation of Ti plasmid conjugal transfer genes.
Conjugal transfer of the Ti plasmid pTiC58 is regulated by a quorum-sensing system involving the transcriptional activator TraR and the acyl homoserine lactone autoinducer N-(3-oxo-octanoyl)-L-homoserine lactone (AAI). Activation of tra gene expression by TraR and AAI is inhibited by TraM, an 11 kDa protein also coded for by the Ti plasmid. Previous studies suggested that TraM interferes with TraR activity by directly interacting with the activator protein. Using the yeast two-hybrid system, constructs of Saccharomyces cerevisiae containing a fusion of traR to the B42 domain of the prey plasmid pJG4.5 and a fusion of traM to the lexA gene of the bait plasmid pEG202 produced beta-galactosidase and grew on medium lacking leucine, both phenotypes indicative of an interaction between the two proteins. Early termination mutants and substitution mutants mapping to the C-terminus of TraM were isolated by screening for alleles unable to interfere with TraR activity in Agrobacterium tumefaciens. These mutants all failed to interact with the TraR fusion in the two-hybrid system. An N-terminal deletion mutant of TraM lacking the first 27 residues weakly interacted with TraR in the two-hybrid system whereas deletions of 48 amino acids or more abolished the interaction. As assessed by Western blot analysis, the mutant fusion proteins were produced at levels indistinguishable from that of the wild-type TraM in the yeast tester strain. Mutants of TraR that were not inhibited by TraM in A. tumefaciens were isolated and fell into two classes. In the first, the mutation resulted in increased expression of wild-type TraR. In the second, a proline residue at position 176 was changed to serine (P176 --> S) or to leucine (P176 --> L). The P176 --> S mutant interacted with wild-type TraM, but at a detectably lower level, in the two-hybrid assay. Mutants of TraR with N-terminal deletions as large as 105 amino acids interfered with the ability of TraM to inhibit wild-type TraR in A. tumefaciens. Two-hybrid assays indicated that these mutants, as well as a C-terminal 49 residue fragment of TraR, can interact with TraM. We conclude that TraM and TraR interact in vivo and that this interaction is responsible for inhibition of TraR-mediated activation. We also conclude that the two proteins interact with each other through domains located at their respective C-termini.


12-lipoxygenase promotes obesity-induced oxidative stress in pancreatic islets.
High-fat diets lead to obesity, inflammation, and dysglycemia. 12-Lipoxygenase (12-LO) is activated by high-fat diets and catalyzes the oxygenation of cellular arachidonic acid to form proinflammatory intermediates. We hypothesized that 12-LO in the pancreatic islet is sufficient to cause dysglycemia in the setting of high-fat feeding. To test this, we generated pancreas-specific 12-LO knockout mice and studied their metabolic and molecular adaptations to high-fat diets. Whereas knockout mice and control littermates displayed identical weight gain, body fat distribution, and macrophage infiltration into fat, knockout mice exhibited greater adaptive islet hyperplasia, improved insulin secretion, and complete protection from dysglycemia. At the molecular level, 12-LO deletion resulted in increases in islet antioxidant enzymes Sod1 and Gpx1 in response to high-fat feeding. The absence or inhibition of 12-LO led to increases in nuclear Nrf2, a transcription factor responsible for activation of genes encoding antioxidant enzymes. Our data reveal a novel pathway in which islet 12-LO suppresses antioxidant enzymes and prevents the adaptive islet responses in the setting of high-fat diets.


Kavalactone metabolism in rat liver microsomes.
The specific CYP enzymes involved in kavalactone (KLT) metabolism and their kinetics have not been fully examined. This study used rat liver microsomes (RLM) to determine kavain (KA), methysticin (MTS) and desmethoxyyangonin (DMY) enzyme kinetic parameters, to elucidate the major CYP450 isoforms involved in KLT metabolism and to examine gender differences in KLT metabolism. Formation of the major KLT metabolites was first-order, consistent with classic enzyme kinetics. In both male and female RLM, clotrimazole (CLO) was the most potent inhibitor of KA and MTS metabolism. This suggests CYP3A1/3A23 (females) and CYP3A2 (males) are the main isoenzymes involved in the metabolism of these KLTs in rats, while the roles of CYP1A2, -2 C6, -2 C9, -2E1 and -3A4 are limited. Desmethoxyyangonin metabolism was equally inhibited by cimetidine (CIM) and CLO in females, and CIM and nortriptyline in males. This implies that DMY metabolism involves CYP2C6 and CYP2C11 in males, and CPY2C12 in females. CYP3A1/3A23 may also be involved in females.


Quantification of bacterial fluorescence using independent calibrants.
Fluorescent reporters are commonly used to quantify activities or properties of both natural and engineered cells. Fluorescence is still typically reported only in arbitrary or normalized units, however, rather than in units defined using an independent calibrant, which is problematic for scientific reproducibility and even more so when it comes to effective engineering. In this paper, we report an interlaboratory study showing that simple, low-cost unit calibration protocols can remedy this situation, producing comparable units and dramatic improvements in precision over both arbitrary and normalized units. Participants at 92 institutions around the world measured fluorescence from E. coli transformed with three engineered test plasmids, plus positive and negative controls, using simple, low-cost unit calibration protocols designed for use with a plate reader and/or flow cytometer. In addition to providing comparable units, use of an independent calibrant allows quantitative use of positive and negative controls to identify likely instances of protocol failure. The use of independent calibrants thus allows order of magnitude improvements in precision, narrowing the 95% confidence interval of measurements in our study up to 600-fold compared to normalized units.


The influence of sheep age group on the seasonal prevalence of oestrosis in the island of Majorca.
Oestrosis is highly prevalent in Mediterranean countries. Understanding the life cycle of Oestrus ovis is crucial to design effective control measures of this myiasis, largely based on the use of macrocyclic lactones. We carried out a survey of ovine oestrosis in the island of Majorca (Spain) and found that 46.03% of animals were infested in a 13-month period. Interestingly, we found significant differences in oestrosis prevalences in winter and autumn when separating the animals by group of age (P<0.001). Pearson correlation analysis showed that prevalence in lambs younger than 4 months was significantly affected by changes in air temperature (P<0.05), but this association was not significant in adult sheep (P=0.081). Chronic infestations or unsystematic treatments may explain confusing results in adult sheep. Observing the evolution of the disease in young lambs, we determined that the hypobiotic period took place from October to February and the beginning of fly activity occurred between May and June. Interannual variations in oestrosis prevalence indicate the need of monitoring the disease to establish the appropriate timing of treatments. We hypothesize that lambs are better indicators of the seasonality of oestrosis than their older counterparts. Furthermore, we propose that observing O. ovis infestations in young lambs can be used as an efficient early warning system of fly activity, to be applied in future control programs.


Central retinal artery pressure and carotid artery stenosis.
The central retinal artery (CRA), which can be non-invasively examined with ophthalmoscopy, may be regarded as an extracranial part of the cerebrovascular system. Assessment of CRA pressure may be of help in assessing the impediment of the intracranial blood circulation in patients with a carotid artery stenosis (CAS). The aim of this study was to explore the potential associations between diastolic central retinal artery pressure (diastCRAP) and CAS. The prospective longitudinal clinical observational study included patients with CAS and a control group without CAS. diastCRAP was assessed using ophthalmodynamometry. The study group consisted of 95 patients with CAS (50 of whom had >75%CAS and underwent surgery; the surgical study group) and a control group of 64 individuals without CAS. In all study participants, a lower diastCRAP was significantly associated with a higher degree of CAS (P<0.001). Multivariate analysis indicated that a higher CAS degree was significantly (correlation coefficient: r=0.75) associated with a higher brachial diastolic blood pressure (P<0.001) and lower diastCRAP (P<0.001). Within the surgical study group at the baseline of the study, diastCRAP was significantly lower at the surgical side than at the contralateral side (P=0.02). The diastCRAP on the surgical side increased significantly (P<0.001) after surgery. In the surgical study group at baseline, diastCRAP on the surgical side was not significantly associated with brachial diastolic blood pressure (P=0.22), whereas after surgery, diastCRAP was significantly associated with brachial diastolic blood pressure (P=0.001). DiastCRAP was found to be significantly and linearly correlated with the degree of CAS in intra-individual inter-eye, inter-individual and intra-individual follow-up comparisons. The strong and linear association between diastCRAP and the degree of CAS suggest that diastCRAP should be explored further for use as an indicator of cerebrovascular status.


[The latitude-zonal and spatial-successional trends in the distribution of yeasts].
The distribution of yeasts in natural habitats is analyzed in the different nature zones of the former USSR (from tundra to desert) using the results of long-term research. Yeast community structure is changing in parallel to different stages of plant debris decay as well as to latitude-zonal gradient. These changes are not fluctuating but trend ones. As mineralization of plant debris proceeds the availability of sugars decreases and habitat become more extremal for yeasts which are typical saccharolytics. It causes decrease in species abundance and species diversity. At the same time in zonal gradient the most significant changes take place in the relative abundance of dominant species, genera or higher taxonomic groups. The thermotolerant species occurred more often in the southern regions while psychrophilic species dominate in the north. Soil yeast communities become more polytrophic in the north latitudes where mineralization of organic matter is rather low. Species inhabiting climatic pessimum areas usually form chlamidospores.


The Projective Consciousness Model: Projective Geometry at the Core of Consciousness and the Integration of Perception, Imagination, Motivation, Emotion, Social Cognition and Action.
Consciousness has been described as acting as a global workspace that integrates perception, imagination, emotion and action programming for adaptive decision making. The mechanisms of this workspace and their relationships to the phenomenology of consciousness need to be further specified. Much research in this area has focused on the neural correlates of consciousness, but, arguably, computational modeling can better be used toward this aim. According to the Projective Consciousness Model (PCM), consciousness is structured as a viewpoint-organized, internal space, relying on 3D projective geometry and governed by the action of the Projective Group as part of a process of active inference. The geometry induces a group-structured subjective perspective on an encoded world model, enabling adaptive perspective taking in agents. Here, we review and discuss the PCM. We emphasize the role of projective mechanisms in perception and the appraisal of affective and epistemic values as tied to the motivation of action, under an optimization process of Free Energy minimization, or more generally stochastic optimal control. We discuss how these mechanisms enable us to model and simulate group-structured drives in the context of social cognition and to understand the mechanisms underpinning empathy, emotion expression and regulation, and approach-avoidance behaviors. We review previous results, drawing on applications in robotics and virtual humans. We briefly discuss future axes of research relating to applications of the model to simulation- and model-based behavioral science, geometrically structured artificial neural networks, the relevance of the approach for explainable AI and human-machine interactions, and the study of the neural correlates of consciousness.


Assessment of the InSiGHT Interpretation Criteria for the Clinical Classification of 24 MLH1 and MSH2 Gene Variants.
Pathogenicity assessment of DNA variants in disease genes to explain their clinical consequences is an integral component of diagnostic molecular testing. The International Society for Gastrointestinal Hereditary Tumors (InSiGHT) has developed specific criteria for the interpretation of mismatch repair (MMR) gene variants. Here, we performed a systematic investigation of 24 MLH1 and MSH2 variants. The assessments were done by analyzing population frequency, segregation, tumor molecular characteristics, RNA effects, protein expression levels, and in vitro MMR activity. Classifications were confirmed for 15 variants and changed for three, and for the first time determined for six novel variants. Overall, based on our results, we propose the introduction of some refinements to the InSiGHT classification rules. The proposed changes have the advantage of homogenizing the InSIGHT interpretation criteria with those set out by the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium for the BRCA1/BRCA2 genes. We also observed that the addition of only few clinical data was sufficient to obtain a more stable classification for variants considered as "likely pathogenic" or "likely nonpathogenic." This shows the importance of obtaining as many as possible points of evidence for variant interpretation, especially from the clinical setting.


Metabolic regulation of aldose reductase activity by nitric oxide donors.
Regulation of aldose reductase (AR), a member of the aldo-keto reductase superfamily, by nitric oxide (NO) donors was examined. Incubation of human recombinant AR with S-nitrosoglutathione (GSNO) led to inactivation of the enzyme and the formation of an AR-glutathione adduct. In contrast, incubation with S-nitroso-N-acetyl penicillamine (SNAP) or N-(beta-D-glucopyranosyl)-SNAP (GlycoSNAP) led to an increase in enzyme activity which was accompanied by the direct nitrosation of the enzyme and the formation of a mixed disulfide with the NO-donor. To examine in vivo modification, red blood cells (RBC) and rat aortic vascular smooth muscle cells (VSMC) were incubated with 1 mM GSNO or SNAP. Exposure of VSMC to SNAP and GSNO for 2 h at 37 degrees C led to approximately 71% decrease in the enzyme activity with DL-glyceraldehyde as the substrate. Similarly, exposure of RBC in 5 mM glucose to NO-donors for 30 min at room temperature, followed by increasing the glucose concentration to 40 mM, resulted in >75% decrease in the formation of sorbitol. These investigations indicate that NO and/or its bioactive metabolites can regulate cellular AR, leading to either activation (by nitrosation) or inactivation (by S-thiolation).


Ultrasonographic verification of hepatic hydatidosis in a female dromedary camel: a case report.
This report describes for the first time, the antemortem diagnosis of hydatidosis in dromedary camel based on the WHO informal working groups on echinococcosis guidelines of echinococcosis classification. The case was admitted at the University Veterinary Hospital, Qassim University, Saudi Arabia, with a history of progressive weight loss and decreased appetite for the past 4 months. Alterations in hematobiochemical parameters included leukopenia, neutropenia, decreased hematocrit percent, red blood cells count and hemoglobin concentration, hypoproteinemia, hypoalbuminemia, hyperglobulinemia, hyperglycemia and azotemia. Ultrasonographically, multiple cysts were imaged within the hepatic tissue containing anechoic fluid and fibrin tags. Ultrasound-guided aspiration of a cyst revealed a clear non-turbid fluid. Ultrasonographic diagnostic is recommended for the work-up of cystic lesions of camel liver suspected to be due to Echinococcus granulosus.


Lymphomatoid papulosis associated with plaque-stage and granulomatous mycosis fungoides.
A 47-year-old black man had typical papulonodular lesions of lymphomatoid papulosis (LyP) with concurrent plaque-stage mycosis fungoides (MF). Both diagnoses were confirmed histologically. This supports the concept that LyP is part of the spectrum of cutaneous T-cell lymphoproliferative disorders. The patient also had a large nodule and a deeply infiltrated plaque, each of which exhibited a deep granulomatous reaction. These were interpreted as representing granulomatous MF. Clinically, there was an evolution from a predominance of LyP lesions to a predominance of MF plaques. Topical carmustine therapy resulted in a substantial decrease in the number and size of both LyP and MF lesions. Both lesion types involuted with hypopigmentation.


Nanoparticle albumin-bound (NAB) technology is a promising method for anti-cancer drug delivery.
Albumin is a versatile drug carrier in anti-cancer drug delivery system and it also has an actively targeting capacity to tumors. Recently, nanoparticle albumin-bound (nab) paclitaxel (nab-paclitaxel; Abraxane) has been approved in 2006 for use in patients with metastatic breast cancer who have failed in the combination chemotherapy, and so the nab-technology has attracted much interest in the anti-cancer drug delivery system. The details about the preparation, characterization and evaluation of nab-paclitaxel (ABI-007) are discussed. The pharmacokinetics, pharmacodynamics and the clinical trials of ABI-007 are also reviewed. Furthermore, the recent applications of nab-technology in the anti-cancer drug delivery systems are summarized by virtue of the patents pertaining to nab-technology. To sum up, nab-technology has a great potential of being applied extensively in the field of anti-cancer agents delivery in the future in order to acquire the good safety and better therapeutical effect.


Intraperitoneal administration of cisplatin via an in situ cross-linkable hyaluronic acid-based hydrogel for peritoneal dissemination of gastric cancer.
To develop a drug-delivery system for the prolonged retention of intraperitoneally (i.p.) administered cisplatin (CDDP) to deliver intraperitoneal chemotherapy against peritoneal carcinomatosis effectively. CDDP was encapsulated inside an in situ cross-linkable hyaluronic acid (HA)-based hydrogel. The gelation and degradation kinetics of the hydrogel and the release kinetics of CDDP were investigated in vitro, and the antitumor effect was investigated in a mouse model of peritoneal dissemination of human gastric cancer. The gelation time varied according to the concentration of two polymers: HA-adipic dihydrazide and HA-aldehyde. CDDP was released from the hydrogel for more than 4 days. A cell proliferation assay showed that the polymers themselves were not cytotoxic toward MKN45P, a human gastric cancer cell line. By mixing the two polymers in the peritoneum, in situ gelation was achieved. The weight of peritoneal nodules decreased in the hydrogel-conjugated CDDP group, whereas no significant antitumor effect was observed in the free CDDP group. In situ cross-linkable HA hydrogels represent a promising biomaterial to prolong the retention and sustain the release of intraperitoneally administered CDDP in the peritoneal cavity and to enhance its antitumor effects against peritoneal dissemination.


Psychosocial differences associated with body weight among female adolescents: the importance of body image.
To determine whether overweight female adolescents differ from normal and underweight female adolescents with respect to a set of psychosocial factors, while controlling for body image. Female participants of the National Longitudinal Study of Adolescent Health (n = 3197) were selected for analysis. Multivariate Analysis of Variance (MANOVA) was used to test whether overweight subjects differed from normal and underweight subjects with respect to measures of depression, self-esteem, trouble in school, school connectedness, family connectedness, sense of community, autonomy, protective factors, and grades. Stepdown F-tests and discriminant function coefficients provided information regarding the strength of specific factors in contributing to overall differences. MANOVA revealed significant differences between groups on the combined set of psychosocial factors. Self-esteem defined the difference in a positive direction while grades defined the difference inversely. When controlling for body image, multidimensional group differences were still evident; however, self-esteem was no longer a significant contributing variable. While overweight female adolescents seem to suffer from low self-esteem, it may be explained by body image. Efforts should be directed toward encouraging and supporting healthy eating patterns and physical activity while encouraging students to recognize personal strengths not related to physique.


Traffic-related exposures, airway function, inflammation, and respiratory symptoms in children.
Traffic-related emissions have been associated with respiratory symptoms in some studies. However, there is limited information on how traffic-related emissions relate to lung function and airway inflammation. To determine the differential association of traffic-related exposures with exhaled nitric oxide (NO) and lung volumes and symptoms in children with and without asthma. We performed a longitudinal study of 200 children from ages 6 to 12 years of whom half had physician-diagnosed asthma. Two-week NO(2) and 48-hour average levels of elemental carbon and particulate matter of less than 2.5 microm (PM(2.5)) were measured at participating schools. Road and traffic densities were determined at schools and at each participant's house. In children with asthma, an interquartile increase in road density within the 50-, 100-, and 200-m home buffer areas was associated with increased exhaled NO (50 m: 28%; P = 0.03; 95% confidence interval [CI], 3-60; 100 m: 27%; P = 0.005; 95% CI, 8-49; 200 m: 17%, P = 0.09, 95% CI, -2 to 40), and reduced FEV(1) (50 m: -0.091 L; P = 0.038; 95% CI, -0.174 to -0.007; 100 m: -0.072 L, P = -0.028, 95% CI, -0.134 to -0.009; 200 m: -0.106 L, P = 0.002, 95% CI, -0.171 to -0.041]). Exposure to NO(2) at schools was marginally associated with reduced FEV(1) (-0.020; P = 0.060; 95% CI, -0.042 to 0.001). We did not observe significant associations with PM(2.5) or elemental carbon on exhaled NO. We did not observe significant reductions in lung volumes or changes in exhaled NO among healthy children. Vehicular traffic exposures are associated with increased levels of exhaled NO and reduced lung volumes in children with asthma.