Androgens modulate autophagy and cell death via regulation of the endoplasmic reticulum chaperone glucose-regulated protein 78/BiP in prostate cancer cells.
Pro-survival signalling mediated by the androgen receptor (AR) is implicated as a key contributor to prostate carcinogenesis. As prostate tumours are characterized by nutrient-poor, hypoxic and acidified microenvironments, one mechanism whereby AR signalling may contribute to survival is by promoting adaptation to cellular stress. Here we have identified a novel role for AR in the inhibition of autophagy induced by serum withdrawal. This blockade is attributed to AR-mediated upregulation of the endoplasmic reticulum (ER) chaperone glucose-regulated protein 78/BiP (Grp78/BiP), and occurs independently of ER stress response pathway activation. Interestingly, AR activation did not affect serum starvation-induced mammalian target of rapamycin inhibition, illustrating that the adaptive role for androgens lies not in the ability to modulate nutrient sensing, but in the promotion of ER stability. Finally, we show that the adaptive advantage conferred by AR-mediated Grp78/BiP upregulation is temporary, as upon chronic serum starvation, AR activation delayed but did not suppress the onset of autophagy and cell death. This study reveals a novel mechanism whereby maintained AR signalling promotes temporary adaptation to cellular stress and in turn may contribute to the evasion of prostate tumour cell death.


Full clinical recovery after topical acyclovir treatment of Epstein-Barr virus associated cutaneous B-cell lymphoma in patient with mycosis fungoides.
Primary cutaneous T- and B-cell lymphomas are a heterogeneous group of diseases with varied clinical presentations and prognosis. The use of new molecular, histological, and clinical criteria has improved their recognition. Cutaneous B-cell and T-cell lymphomas are seldom found together in the same patient. Here we report a rare case of mycosis fungoides variant of a cutaneous T-cell lymphoma (CTCL) which later developed Epstein-Barr virus (EBV) associated cutaneous B-cell lymphoproliferative disorder. The patient initially presented with generalized erythroderma, extensive plaques, and axillary lymphadenopathy. Histopathology and immunophenotyping of her tumor from the right breast nodule revealed a T-cell lymphoma consistent with mycosis fungoides. She was initially treated with pentostatin, followed by topical mechlorethamine and topical steroids. After progression of her mycosis fungoides with worsening diffuse skin lesions on this regimen, her treatments were changed to oral bexarotene with an initial partial response followed by stable disease. Three years from her initial presentation, she developed ulcerated cauliflower-like nodules on her forehead. Biopsy of these lesions revealed EBV-positive large- and medium-sized pleomorphic B-cells consistent with EBV-driven B-cell lymphoproliferative disorder. She was treated with topical acyclovir cream on the involved skin areas while continuing with oral bexarotene for mycosis fungoides. Skin lesions gradually diminished and totally disappeared after four weeks of topical acyclovir treatment. Bexarotene treatment was continued for another year until the mycosis fungoides progressed and became wide spread causing her death four and a half years after the initial diagnosis. The coexistence of two cutaneous non-Hodgkin lymphomas of different lineage in the same patient and the complete clinical response of EBV-related B-cell cutaneous component to topical acyclovir makes this rare case particularly interesting.


Muscarinic receptors in canine colonic circular smooth muscle. II. Signal transduction pathways.
We have, in the accompanying work, demonstrated the coexistence of M2 and M3 muscarinic receptors in the circular smooth muscle of canine colon. In the present study, the effects of muscarinic receptor stimulation on phosphoinositide turnover and adenylate cyclase activity were examined. In myo-[3H]inositol-labeled circular smooth muscle strips, carbachol caused a concentration-dependent (EC50 = 5 microM) increase in [3H]inositol phosphate production. The more M3 receptor-selective muscarinic antagonist pirenzepine (KB = 53 nM) was approximately 60 times more potent than the more M2-selective agent AF-DX 116 (KB = 3 microM) in blocking carbachol-elicited accumulation of [3H]inositol phosphates. The carbachol-stimulated increase in [3H]inositol phosphate accumulation was not affected by pretreatment of the tissue with pertussis toxin (200 ng/ml, 3 hr). Within the first minute, carbachol (100 microM) caused a rapid and transient increase of [3H]inositol 1,4,5-trisphosphate production that oscillated continuously in the presence of agonist (120 min). The accumulation of [3H]inositol 1,3,4-trisphosphate was also extremely rapid, reaching a peak at 15 sec. The accumulation of [3H]inositol monophosphate was delayed and progressively increased over 30 min. [3H]inositol 1,3,4,5-tetrakisphosphate, although not detectable in the first minute, accumulated to significant levels over 30 min in the presence of agonist. Addition of carbachol in the adenylate cyclase assay caused inhibition of forskolin-stimulated [32P]cAMP production and blocked forskolin-stimulated cAMP accumulation in the intact tissue. The inhibitory effects of carbachol on adenylate cyclase were blocked by atropine, AF-DX 116, and 4-diphenylacetoxy-N-methylpiperidine methobromide but were unaffected by the more M3-selective agent pirenzepine (1 microM). Pretreatment of tissues with pertussis toxin completely eliminated M2 receptor-mediated inhibition of adenylate cyclase activity, without altering inositol 1,4,5-trisphosphate accumulation. We conclude that muscarinic receptor stimulation of inositol trisphosphate production is mediated by the M3 receptor coupled to a pertussis toxin-insensitive GTP-binding protein and results in the rapid formation of inositol tetrakisphosphate, whereas inhibition of adenylate cyclase activity is mediated by the M2 subtype of muscarinic receptor coupled to the pertussis toxin-sensitive GTP-binding protein Gi.


Treatment of systemic sclerosis-associated digital ulcers: recommendations of the Turkish Society for Rheumatology.
Digital ulcers (DUs) are associated with a significant burden in systemic sclerosis (SSc) by leading to severe pain, physical disability, and reduced quality of life. This effort aimed to develop recommendations of the Turkish Society for Rheumatology (TRD) on the management of DUs associated with SSc. In the first meeting held in December 2020 with the participation of a task force consisting of 23 rheumatologists the scope of the recommendations and research questions were determined. A systematic literature review was conducted by 5 fellows and results were presented to the task force during the second meeting. The Oxford system was used to determine the level of evidence. The preliminary recommendations were discussed, modified, and voted by the task force and then by members of TRD via e-mail invitation allowing personalised access to a web-based questionnaire [SurveyMonkey®]. A total of 23 recommendations under 7 main headings were formulated covering non-pharmacological measures for the prevention of DUs and pharmacological treatments including vasodilators, anti-aggregants, antibiotics, wound care, pain control, and interventions including sympathectomy, botulinum toxin, and surgery. Risk factors, poor prognostic factors, prevention of DU and adverse effects of medical treatments were reported as 4 overarching principles. These evidence-based recommendations for the management of SSc-associated DUs were developed to provide a useful guide to all physicians who are involved in the care of patients with SSc, as well as to point out unmet needs in this field.


A descriptive, correlational study of patient satisfaction, provider satisfaction, and provider workload at an army medical center.
Strong national interest in health care delivery systems and a highly competitive marketplace have mandated that military hospital commanders be increasingly aware of organizational performance. Historically, one variable that has been used to assess such performance is patient satisfaction with the care received. The purpose of this study was to measure patient satisfaction at a major military medical center and to assess how patient satisfaction correlated with the variables of provider satisfaction and nurse/patient ratio. One hundred eighty-eight patients completed the LaMonica-Oberst Patient Satisfaction Scale. Data analysis revealed that, although overall patient satisfaction was high, it was significantly higher on the intensive care units and in other areas where the nurse/patient ratio was high. Interestingly, there was no correlation between the staff's perceptions of their work environment and patient satisfaction. Findings from this study serve to highlight the continued need for a low nurse/patient ratio and are suggestive of the need for refinement of patient satisfaction survey tools available at present.


Refractive status in eyes with inhomogeneous or irregular pupils.
In some eyes, aberrometric measurements of the refractive error can differ by more than 1 diopter from standard subjective refraction. We aim to understand the reasons for these discrepancies and to study the role of both amplitude (irregular or inhomogeneous pupil transmission) and phase (aberrations) of the wavefront. The spherical equivalent was measured by different subjective, objective, and aberrometric methods in a population of 177 eyes. We first analyzed the degree of correlation between the outcomes of the different methods. Then we analyzed cases showing the highest discrepancies (>1 diopter) between subjective and aberrometric spherical equivalent. The refractive error sensing method was generalized and applied here to include the effect of inhomogeneous pupil transmittance (Stiles-Crawford effect) and irregular pupil shapes on refractive error. Objective and aberrometric methods showed a strong correlation with subjective methods (R > 0.89 in all cases). However, individual data points may show large discrepancies. Several eyes with discrepancies of 1 D or even 2 D usually presented higher values of higher-order aberration (mainly coma and/or spherical aberration) than average, which may cause these eyes to have a natural bifocal (or even multifocal) optical performance. Refractive error sensing analysis suggests that this multifocal performance could explain the high objective-subjective discrepancies found in these eyes. Nevertheless, the Stiles-Crawford effect (or irregular pupils) can substantially modify the energy distribution, tending to minimize multifocal effects, thus minimizing discrepancies between aberrometric and subjective refraction. Discrepancies between aberrometric and subjective refraction may appear in aberrated eyes when aberrometric methods ignore the impact of the wavefront amplitude (inhomogeneous or irregular pupil transmittance.) The generalized refractive error sensing proposed here seems promising and able to provide a reliable clinical refraction in monofocal and multifocal eyes.


Anitschkow nuclear changes in postmortem pericardial scrapings.
To document the presence of Anitschkow nuclear changes (ANC) in pericardial mesothelium at autopsy after the incidental finding of ANC in pericardial scrapings from a fatal case of overwhelming sepsis. Fourteen, nonconsecutive autopsy cases were studied. Using the edge of a scalpel, the visceral pericardium from the left ventricle was scraped, and the sample was smeared onto glass slides, fixed in 95% ethanol, Papanicolaou stained and evaluated for the presence of ANC. Histologic correlation was also performed. ANC were observed in pericardial mesothelial cells in 6 of 14 cases. Sepsis was the cause of death in three. Fatal cardiac arrhythmia, T-cell lymphoma and fulminant hepatic necrosis were found in the remaining cases. While readily seen in cytologic preparations, ANC were found focally in only one case examined histologically. Postmortem cytologic evaluation provides information relevant to the autopsy. In this study, ANC were very clearly seen in six pericardial scrapings. Clinical correlation supports the current theory that ANC represent a nonspecific reactive cell change.


Total Synthesis of (+)-Euphorikanin A via an Atropospecific Cascade.
A total synthesis of the ingenane-derived diterpenoid (+)-euphorikanin A is described. Key to the strategy is a stereocontrolled one-pot sequence consisting of transannular aldol addition reaction, hemiketal formation, and subsequent semipinacol rearrangement that efficiently leads to the complete euphorikanin skeleton. Atroposelective ring-closing olefin metathesis proved critical for the stereospecific cascade, leading to formation of a (Z)-bicyclo[7.4.1]tetradecenone core. An additional salient feature of the route is pyrolysis of a bis-methylxanthate to cleanly furnish the natural product.


Molecular analysis and pathogenesis of the feline aplastic anemia retrovirus, feline leukemia virus C-Sarma.
We describe the molecular cloning of an anemogenic feline leukemia virus (FeLV), FeLV-C-Sarma, from the productively infected human rhabdomyosarcoma cell line RD(FeLV-C-S). Molecularly cloned FeLV-C-S proviral DNA yielded infectious virus (mcFeLV-C-S) after transfection of mammalian cells, and virus interference studies using transfection-derived virus demonstrated that our clone encodes FeLV belonging to the C subgroup. mcFeLV-C-S did not induce viremia in eight 8-week-old outbred specific-pathogen-free (SPF) cats. It did, however, induce viremia and a rapid, fatal aplastic anemia due to profound suppression of erythroid stem cell growth in 9 of 10 inoculated newborn, SPF cats within 3 to 8 weeks (21 to 58 days) postinoculation. Thus, the genome of mcFeLV-C-S encodes the determinants responsible for the genetically dominant induction of irreversible erythroid aplasia in outbred cats. A potential clue to the pathogenic determinants of this virus comes from previous work indicating that all FeLV isolates belonging to the C subgroup, an envelop-gene-determined property, and only those belonging to the C subgroup, are potent, consistent inducers of aplastic anemia in cats. To approach the molecular mechanism underlying the induction of this disease, we first determined the nucleotide sequence of the envelope genes and 3' long terminal repeat of FeLV-C-S and compared it with that of FeLV-B-Gardner-Arnstein (mcFeLV-B-GA), a subgroup-B feline leukemia virus that consistently induces a different disease, myelodysplastic anemia, in neonatal SPF cats. Our analysis revealed that the p15E genes and long terminal repeats of the two FeLV strains are highly homologous, whereas there are major differences in the gp70 proteins, including five regions of significant amino acid differences and apparent sequence substitution. Some of these changes are also reflected in predicted glycosylation sites; the gp70 protein of FeLV-B-GA has 11 potential glycosylation sites, only 8 of which are present in FeLV-C-S.


Neurocognitive Test Performance and Concussion-Like Symptom Reporting Among Adolescent Athletes With Self-Reported Autism on Preseason Assessments.
To examine baseline neurocognitive functioning and symptom reporting among adolescents with self-reported autism. Participants in this cross-sectional, observational study were 60,751 adolescents who completed preseason testing. There were 425 students (0.7%) who self-reported an autism spectrum disorder (ASD) diagnosis. Cognitive functioning was measured by Immediate Post-Concussion Assessment and Cognitive Testing and symptom ratings were obtained from the Post-Concussion Symptom Scale. Groups differed significantly across all neurocognitive composites (p values <.002); effect size magnitudes for most differences were small, though among boys a noteworthy difference on visual memory and among girls differences on verbal memory and visual motor speed composites were noted. Among boys, the ASD group endorsed 21 of the 22 symptoms at a greater rate. Among girls, the ASD group endorsed 11 of the 22 symptoms at a greater rate. Some examples of symptoms that were endorsed at a higher rate among adolescents with self-reported autism were sensitivity to noise (girls: odds ratio, OR = 4.38; boys: OR = 4.99), numbness or tingling (girls: OR = 3.67; boys: OR = 3.25), difficulty remembering (girls: OR = 2.01; boys: OR = 2.49), difficulty concentrating (girls: OR = 1.82; boys: OR = 2.40), sensitivity to light (girls: OR = 1.82; boys: OR = 1.76), sadness (girls: OR = 1.72; boys: OR = 2.56), nervousness (girls: OR = 1.80; boys: OR = 2.27), and feeling more emotional (girls: OR = 1.79; boys: OR = 2.84). Students with self-reported autism participating in organized sports likely experience a low degree of functional impairment, on average. If they sustain a concussion, their clinical management should be more intensive to maximize the likelihood of swift and favorable recovery.


Effect of some clinically used proteolytic enzymes on inflammation in rats.
The study was designed to investigate the role of three proteolytic enzymes viz., chymotrypsin, trypsin and serratiopeptidase on hind paw edema and cotton pellet induced granuloma and their possible interactions with aspirin in albino rats. Animals were treated with proteolytic enzymes alone in three different doses or aspirin or in combination with subantiinflammatory dose of aspirin or saline, 30 min before injection of 0.1ml 1% carrageenan. Paw volume was measured before and 3 h after the injection of carrageenan. Chymotrypsin, (5, 18 and 36 mg/kg), trypsin (1.44, 2.88 and 5.76 mg/kg) and serratiopeptidase (0.45, 0.9 and 2.70 mg/kg) were showed dose dependent antiinflammatory activity in acute model of inflammation. Serratiopeptidase showed better antiinflammatory activity on carrageenan induced inflammation than other two proteolytic enzymes and aspirin. However, chymotrypsin and serratiopeptidase were found to be more effective than aspirin in subacute model of inflammation. Chymotrypsin, trypsin and serratiopeptidase possess antiinflammatory activity and exhibit synergistic effect with aspirin in both acute and subacute models of inflammation in rats.


Excess weight, arterial pressure and physical activity in commuting to school: correlations.
The prevalence of obesity and elevated arterial pressure (AP) has increased in children and adolescents, whereas physical activity has decreased. To identify and correlate excess weight, body fat and elevated AP among active and passive students with the way they commute to school. One thousand five hundred and seventy students aged 7 to 12 years participated in the study conducted in João Pessoa, state of Paraíba. Students completed a questionnaire about the way they commuted to school (active = walking/biking or passive = by car/motorcycle/bus) and the time spent traveling to school. Excess weight was determined by BMI > or =25 kg/m(2), excess body fat as > or =85th percentile for tricipital fold measurement, and high AP as > or =90th percentile. Chi-square test and Poisson's regression were used for the analysis. Active commuting was associated with a lower prevalence of excess weight and body fat as compared to passive commuting (p<0.05). The prevalence ratio (PR) of excess weight was associated with excess body fat (Male: PR= 6.45 95%CI= 4.55-9.14; Female: PR= 4.10 95%CI= 3.09-5.45), elevated SAP [Systolic Arterial Pressure] (Male: PR= 1.99 95%CI= 1.30-3.06; Female: PR= 2.09 95%CI= 1.45-3.01), and elevated DAP [Diastolic Arterial Pressure] in girls (PR = 1.96 95%CI= 1.41-2.75). No association with active commuting was observed (p>0.05) Passive commuting to school showed a correlation with excess weight and body fat but not with elevated AP. Excess weight was associated with excessive body fat and elevated AP. Excess weight should be prevented as a way to avoid fat accumulation and AP elevation.


[Docetaxel as a component in the combined therapy of locally advanced squamous cell carcinoma of the glottis and oral cavity].
Two modalities of chemoradiotherapy for locally advanced squamous cell cancer of oro-hypopharynx and oral cavity were compared in the treatment of 34 patients. Five-year survival after cisplatin, 5-FU, taxotere, and carboplatin plus irradiation with TTD of 68-72 Gy (group 1) was 59.5% versus 13.8% without taxotere (group 2). Relapse was in 9 cases (60%) (4 - group 1 and 5 - group 2). Post-therapeutic complication stage III-IV was 57.8% (group 1) and 48% (group 2).


Self-assembly of diclofenac prodrug into nanomicelles for enhancing the anti-inflammatory activity.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for the treatment of various types of inflammatory conditions. Diclofenac is a very common NSAID that is utilized to relieve pain and reduce fever and, most importantly, inflammation. However, it suffers from low water solubility and a low dissolution profile. Therefore, we aim to develop a new drug delivery system based on the synthesis of amphiphilic structures that are capable of self assembling into nano-micelles which will be a water-soluble delivery system for the diclofenac. The amphiphilic structure consists of a hydrophilic moiety of triethylene glycol (TEG), polyethylene glycol PEG 400, or PEG 600 linked with the hydrophobic drug diclofenac through an ester linkage. The diclofenac derivatives were successfully synthesized as confirmed by nuclear magnetic resonance. Moreover, the formation of the micellar structure of the synthesized amphiphilic derivatives was confirmed by atomic force microscopy obtaining a spherical shape of the micelles with average diameters of 200 nm for Dic-PEG400-Dic, and 110 nm for Dic-PEG600-Dic. The critical micelle concentration has been determined as 2.7 × 10-3 mg mL-1 for Dic-PEG400-Dic, and 1 × 10-4 mg mL-1 for Dic-PEG600-Dic. The in vitro diclofenac release profile by esterase enzyme was conducted and showed almost complete conversion to free diclofenac within 35 h in the case of Dic-PEG400-Dic micelles and more than 85% of Dic-PEG600-Dic micelles. Then the anti-inflammatory activity was determined by testing the TNF-α production in LPS-stimulated Balb/c mice. Diclofenac micelles significantly suppressed TNF-α production after a 5 mg kg-1 dose was given. The developed micelles showed TNF-α inhibition up to 87.4% and 84% after 48 hours of treatment in the case of Dic-PEG400-Dic and Dic-PEG600-Dic micelles respectively in comparison to 42.3% in the case of diclofenac alone. Dic-PEG400-Dic micelles showed the most potent anti-inflammatory activity with improved TNF-α suppression through time progress. Therefore, the developed nano-micelles provide a facile synthetic approach to enhance diclofenac water solubility, improve the anti-inflammatory effect and achieve a sustained release profile to get better patient compliance.


HOW INFECTION SHAPED HISTORY: LESSONS FROM THE IRISH FAMINE.
Human history has been profoundly affected by infection throughout the millennia. In most cases, the impact has been a direct consequence of infection in humans. However, in the 1840s, a plant infection - potato blight, caused by the fungus Phytopthera infestans - showed us how an environmental catastrophe in a vulnerable community can profoundly affect human history. Before the visitation of potato blight, the population of Ireland was the most rapidly growing in Europe in the early 1840s. Yet between 1845 and 1850, Ireland's population fell by over one-third - with 3 million people disappearing from the island - half through death and half through emigration. This directly led to a subsequent diaspora of almost 80 million people, many destined for residence in the Americas. The diaspora carried enormous consequences for the social, economic, and political development of the US. Today, lessons from the Irish famine remain poignant and relevant. Social science maps the dimensions of a disaster dependent on the size of its impact and the relative vulnerability of the society which experiences the disaster. Ireland's vulnerability was in terms of its overall poverty and its dependence on the potato as a subsistence crop. However, a critical factor in the disaster was the political structure in which it occurred - where governance was unwilling and unable to respond to the needs of the population.


Beneficial effects of olive oil and Mediterranean diet on cancer physio-pathology and incidence.
Virgin olive oil is a characteristic component and the main source of fat of the Mediterranean diet. It is a mix of high-value health compounds, including monounsaturated fatty acids (mainly oleic acid), simple phenols (such as hydroxytyrosol and tyrosol), secoiridoids (such as oleuropein, oleocanthal), flavonoids, and terpenoids (such as squalene). Olive oil consumption has been shown to improve different aspects of human health and has been associated with a lower risk of cancer. However, the underlying cellular mechanisms involved in such effects are still poorly defined, but seem to be related to a promotion of apoptosis, modulation of epigenetic patterns, blockade of cell cycle, and angiogenesis regulation. The aim of this review is to update the current associations of cancer risk with the Mediterranean diet, olive oil consumption and its main components. In addition, the identification of key olive oil components involved in anticarcinogenic mechanisms and pathways according to experimental models is also addressed.


Organization of a comprehensive anesthesiology oral practice examination program: planning, structure, startup, administration, growth, and evaluation.
To describe the planning, structure, startup, administration, growth, and evaluation of a comprehensive oral practice examination (OPE) program. Midwest U.S. anesthesiology residency training program. Committee planning involved consideration of formal and frequency of administration, timing for best resident and faculty availability, communication, forms design, clerical support, record keeping, and quality monitoring. OPE format was deliberately constructed to resemble that used by the American Board of Anesthesiology (ABA) to enhance resident familiarity with ABA style oral examination. Quality improvement tools consisted of regular examiner and examinee inservice sessions, liaison with ABA associate examiners, and review of examinee exit questionnaires. A set of OPE databases was constructed to facilitate quality monitoring and educational research efforts. A semiannual administration schedule on three to four consecutive Mondays optimally accommodated resident rotations and faculty work schedules. Continued administration of the OPE program required ongoing construction of a pool of guided case-oriented questions, selection of appropriate questions based on examinee training exposure, examination calendar publication, and scheduling of recurring examiner and examinee activities. Important issues that required action by the governing committee were examination timing, conflict with clinical demands, use of OPE results, and procurement of training resources. The OPE program grew from 56 examinations in the first year to 120 exams by year 3. It was perceived positively by the majority of residents. There were 90.2% of exit questionnaires that acknowledged specific learning about oral examination technique, while only 0.3% indicated lack of meaningful information exchange. Fewer than 10% of responses indicated misleading questions or badgering by examiners. Resident preparedness increased with repeat OPE exposure. A comprehensive mock oral examination program was successfully planned, initiated, and developed. It is well accepted by residents and faculty. Its inception was associated with an increase in resident preparedness. Now in its tenth year of existence it continues to be an asset and essential component of our training program.


Complete republication: Epidemiology of tuberculosis in the EU/EEA in 2010 - Monitoring the progress towards tuberculosis elimination.
The 2012 combined tuberculosis (TB) surveillance and monitoring report for the European Union and European Economic Area identifies a mean annual decline in TB notification rate by 4.4% from 2006 to 2010. Culture confirmation for new pulmonary cases and drug susceptibility testing have increased to 65.6% and 70.8%, but remain under their targets of 80% and 100%, respectively. Reporting of treatment outcome and coinfection with human immunodeficiency virus also remain suboptimal. Strengthened control practices are needed to allow progress towards TB elimination.


Robust Superlubricity and Moiré Lattice's Size Dependence on Friction between Graphdiyne Layers.
Structural superlubricity is a fascinating physical phenomenon that plays a significant role in many scientific and technological fields. Here, we report the robust superlubricating state achieved on the interface of relatively rotated graphdiyne (GDY) bilayers; such an interface with ultralow friction is formed at nearly arbitrary rotation angles and sustained at temperatures up to 300 K. We also identified the reverse correlation between the friction coefficient and size of the Moiré lattice formed on the surface of the incommensurate stacked GDY bilayers, particularly in a small size range. Our investigations show that the ultralow friction and the reduction of the friction coefficient with the increase in size of the Moiré lattice are closely related to the interfacial energetics and charge density as well as the atomic arrangement. Our findings enable the development of a new solid lubricant with novel superlubricating properties, which facilitate precise modulation of the friction at the interface between two incommensurate contacting crystalline surfaces.


MAP2, synaptophysin immunostaining in rat brain and behavioral modifications after cerebral postischemic reperfusion.
Plasticity in the central nervous system after cerebral ischemia is a controversial issue; focal cerebral ischemia produces an area of infarction that is surrounded by neurons that may respond to nearby damage by creating new synapses. In the present study the expression of the postsynaptic microtubule-associated protein 2 (MAP2) and the presynaptic marker protein, synaptophysin, was investigated by immunocytochemical techniques in the CA1 sector of hippocampus and in cerebellum of rats made ischemic by bilateral clamping of common carotid arteries and reperfused for 7 and 30 days. In addition, ischemia-induced behavioral alterations were also evaluated after 7 and 30 days of reperfusion. The present study demonstrates a decreased postsynaptic MAP2 immunoreactivity, representative of neuronal loss, particularly in CA1 sector of hippocampus and in cerebellum of ischemic rats reperfused for 7 days. After 30 days of reperfusion, MAP2 immunostaining was similar to control. In the same brain sections an increased presynaptic synaptophysin immunoreactivity has been observed only after 30 days of reperfusion. These data suggest compensatory regenerative changes associated with synaptic remodelling and are supported by behavioral recovery observed under the same experimental conditions.


Surgical treatment of vaginal vault prolapse: a historic summary and review of outcomes.
This study aimed to review the history of surgical treatment of vaginal vault prolapse, its current treatments, and its outcomes. A PubMed search was conducted using the following terms: vaginal vault prolapse, apical prolapse, surgical treatments, culdoplasty, uterosacral ligament fixation, and sacral colpopexy. Vaginal vault prolapse is a common condition with many surgical treatment options. Surgical principles and treatment of this condition dates back to the 19th century. Native tissue repairs such as McCall culdoplasty, uterosacral ligament fixation, and sacrospinous fixation have high overall success rates with restoring apical anatomy. Sacral colpopexy also has excellent success rates when mesh is needed to augment repairs. There are many options for the treatment of vaginal vault prolapse. Modifications have been made to the original procedures; however, the basic principles are still applicable and include attaching the vaginal apex to level 1 support.


Reduced temperature alters Pseudomonas exotoxin A entry into the mouse LM cell.
The movement of Pseudomonas exotoxin A (PE) into the cytoplasm of mouse LM fibroblasts was followed by using inhibition of protein synthesis as a biochemical index of toxin activity; biotinyl-PE and avidin-gold colloids were used for electron microscopy. At 37 degrees C both specific antitoxin and pronase-trypsin protected cells against PE toxicity when added within seconds of warming cells, whereas methylamine was protective when added during the first 7 min of endocytosis. Lowering the temperature to 19 degrees C afforded protection when the temperature transition was accomplished within 15 min of the original endocytic event. These data suggest that PE enters an acidic compartment before reaching a step blocked by shifting cells from 37 to 19 degrees C. PE expressed toxicity for LM cells at 19 degrees C, but at a concentration 1 order of magnitude higher than that required at 37 degrees C. At 19 degrees C, antitoxin or trypsin-pronase protection was rapidly ablated. In contrast cells were fully protected by methylamine for 90 min. Using electron microscopy we demonstrated that toxin moved normally (30 s) to coated areas at 19 degrees C, but remained at this site for up to 20 min before being internalized. The majority of the toxin internalized at 19 degrees C remained in endosomes or in Golgi-associated vesicles and was not delivered to lysosomes. The results suggest that, under physiological conditions (37 degrees C), PE rapidly enters cells through coated areas, moves to an acidic compartment (i.e., the endosome), and then probably to the Golgi region en route to lysosomes. The evidence suggests that movement of toxin from endosomes or Golgi vesicles to lysosomes is blocked at 19 degrees C. We hypothesize that the active form of PE enters the cytosol, where it expresses its toxicity during fusion of Golgi-derived, toxin-laden vesicles with lysosomes.


Development of Corynebacterium glutamicum as a monoterpene production platform.
Monoterpenes are commonly known for their role in the flavors and fragrances industry and are also gaining attention for other uses like insect repellant and as potential renewable fuels for aviation. Corynebacterium glutamicum, a Generally Recognized as Safe microbe, has been a choice organism in industry for the annual million ton-scale bioproduction of amino acids for more than 50 years; however, efforts to produce monoterpenes in C. glutamicum have remained relatively limited. In this study, we report a further expansion of the C. glutamicum biosynthetic repertoire through the development and optimization of a mevalonate-based monoterpene platform. In the course of our plasmid design iterations, we increased flux through the mevalonate-based bypass pathway, measuring isoprenol production as a proxy for monoterpene precursor abundance and demonstrating the highest reported titers in C. glutamicum to date at 1504.6 mg/L. Our designs also evaluated the effects of backbone, promoter, and GPP synthase homolog origin on monoterpene product titers. Monoterpene production was further improved by disrupting competing pathways for isoprenoid precursor supply and by implementing a biphasic production system to prevent volatilization. With this platform, we achieved 321.1 mg/L of geranoids, 723.6 mg/L of 1,8-cineole, and 227.8 mg/L of linalool. Furthermore, we determined that C. glutamicum first oxidizes geraniol through an aldehyde intermediate before it is asymmetrically reduced to citronellol. Additionally, we demonstrate that the aldehyde reductase, AdhC, possesses additional substrate promiscuity for acyclic monoterpene aldehydes.


Occurrence of Side Effects in Treatment-Resistant Depression: Role of Clinical, Socio-Demographic and Environmental Characteristics.
Introduction: Treatment-resistant depression (TRD) is a disabling psychiatric condition characterized by the failure of two antidepressants (ADs). Since the occurrence of side effects (SEs) appears to be one of the main determinants of early discontinuation of pharmacological treatments contributing to a pseudo-resistance, the purpose of this study was to determine the parameters associated with the occurrence of SEs under ADs in a cohort of patients with TRD. Methods: An observational, cross-sectional, multicentre study was carried out using data from the French network of Expert Centers for TRD. For the 108 patients enrolled in the study, the statistical analyses focused on the overall occurrence and on the profile of the SEs (9 categories, 32 items). Results: SEs were influenced by age and sex and were positively associated with the intensity of anxious, depressive and suicidal symptoms, a history of childhood trauma (sexual abuse, emotional abuse and neglect), and negatively associated with self-esteem, and assessment of overall functioning. Conclusion: Using variables accessible in common practice, these results fall within the dynamic of a more tailored approach to medicine that could allow, through integrated pharmacological management, the continuation of antidepressant treatments, and therefore limit the risk of therapeutic failure.


[The impact of the working conditions on morbidity in workers in jobs hazardous for vibration and noise in aviation enterprises].
A comprehensive evaluation of particular features of labour conditions of those workers engaged in assembling--riveting in Kiev plants of aircraft industry was done as was that of early morbidity patterns among them. A whole complex of hygienic investigations was carried out, involving those designed to study labour conditions, pathopsychological testing of 103 assemblers--fitters, analysis of quality of changes in the vegetative nervous system, level of constitutional and reactive anxiety, routine clinical and instrumental examination. There has been disclosed high level of vegetative dysfunctions during the early stage unspecific disorders presenting as psychovegetative syndrome, vegetative-vascular-trophic syndrome, cerebral angiodystonic syndrome. It is suggested that the above syndromes be regarded as early unspecific signs of development of vibronoise pathology during the early stages of its development. It is recommended that quality of the vegetative nervous system should be considered in advising the workers on the choice of vocations in which health hazards from exposure to vibration and noise exist.


Polyneuropathy: a poetic diagnosis.
A 60-year-old woman presented with subacute progressive lower extremity weakness. This was associated with a 40lb weight loss and fevers. She was previously healthy, aside from renal transplantation 9 years earlier for end stage renal disease resulting from IgA nephropathy. On examination, she had clubbing, a single lymph node in the right cervical chain, and objective findings of lower extremity weakness with lower motor neuron findings. Investigations revealed a thrombocytosis and elevated CSF protein. Electromyographic evidence of diffuse polyradiculopathy with demyelination was documented. On imaging, she had a large lytic/sclerotic lesion in the right scapula measuring 8 cm, a pericardial effusion, and borderline splenomegaly. Pathological assessment of the excised lymph node revealed Castleman-like changes; biopsy of the right scapular lesion revealed λ-restricted plasma cells, in the absence of a monoclonal protein in the bone marrow or periphery. A diagnosis of POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) with plasmacytoma was established; a post-transplant lymphoproliferative disorder was suspected.


Hepatitis C, mental health and equity of access to antiviral therapy: a systematic narrative review.
Access to hepatitis C (hereafter HCV) antiviral therapy has commonly excluded populations with mental health and substance use disorders because they were considered as having contraindications to treatment, particularly due to the neuropsychiatric effects of interferon that can occur in some patients. In this review we examined access to HCV interferon antiviral therapy by populations with mental health and substance use problems to identify the evidence and reasons for exclusion. We searched the following major electronic databases for relevant articles: PsycINFO, Medline, CINAHL, Scopus, Google Scholar. The inclusion criteria comprised studies of adults aged 18 years and older, peer-reviewed articles, date range of (2002-2012) to include articles since the introduction of pegylated interferon with ribarvirin, and English language. The exclusion criteria included articles about HCV populations with medical co-morbidities, such as hepatitis B (hereafter HBV) and human immunodeficiency virus (hereafter HIV), because the clinical treatment, pathways and psychosocial morbidity differ from populations with only HCV. We identified 182 articles, and of these 13 met the eligibility criteria. Using an approach of systematic narrative review we identified major themes in the literature. Three main themes were identified including: (1) pre-treatment and preparation for antiviral therapy, (2) adherence and treatment completion, and (3) clinical outcomes. Each of these themes was critically discussed in terms of access by patients with mental health and substance use co-morbidities demonstrating that current research evidence clearly demonstrates that people with HCV, mental health and substance use co-morbidities have similar clinical outcomes to those without these co-morbidities. While research evidence is largely supportive of increased access to interferon by people with HCV, mental health and substance use co-morbidities, there is substantial further work required to translate evidence into clinical practice. Further to this, we conclude that a reconsideration of the appropriateness of the tertiary health service model of care for interferon management is required and exploration of the potential for increased HCV care in primary health care settings.


Identification of spike protein residues of murine coronavirus responsible for receptor-binding activity by use of soluble receptor-resistant mutants.
We previously demonstrated by site-directed mutagenesis analysis that the amino acid residues at positions 62 and 214 to 216 in the N-terminal region of mouse hepatitis virus (MHV) spike (S) protein are important for receptor-binding activity (H. Suzuki and F. Taguchi, J. Virol. 70:2632-2636, 1996). To further identify the residues responsible for the activity, we isolated the mutant viruses that were not neutralized with the soluble form of MHV receptor proteins, since such mutants were expected to have mutations in amino acids responsible for receptor-binding activity. Five soluble-receptor-resistant (srr) mutants isolated had mutations in a single amino acid at three different positions: one was at position 65 (Leu to His) (srr11) in the S1 subunit and three were at position 1114 (Leu to Phe) (srr3, srr4, and srr7) and one was at position 1163 (Cys to Phe) (srr18) in the S2 subunit. The receptor-binding activity examined by a virus overlay protein blot assay and by a coimmunoprecipitation assay showed that srr11 S protein had extremely reduced binding activity, while the srr7 and srr18 proteins had binding activity similar to that of wild-type cl-2 protein. However, when cell surface receptors were used for the binding assay, all srr mutants showed activity similar to that of the wild type or only slightly reduced activity. These results, together with our previous observations, suggest that amino acids located at positions 62 to 65 of S1, a region conserved among the MHV strains examined, are important for receptor-binding activity. We also discuss the mechanism by which srr mutants with a mutation in S2 showed high resistance to neutralization by a soluble receptor, despite their sufficient level of binding to soluble receptors.


Tuning the Fluorometric Sensing of Phosphate on UiO-66-NH2(Zr, Ce, Hf) Metal Nodes.
Metal-organic frameworks (MOFs) with intrinsic luminescent properties, modular structure, and tunable electronic properties, provide unique opportunities for designing target-specific molecular sensors by systematically choosing their constituent building blocks. We report a simple one-step MOF-based sensing platform for phosphate (P) detection that combines the luminescent properties of 2-aminoterephthalic acid (ATA) with the affinity of rationally selected nodes in UiO-66-NH2 to bind with P. This MOF possesses an electron-donating amine group that controls the light-harvesting characteristics of the linkers. Substituting Zr6 node with Ce6 or Hf6 results in a series of isostructural MOFs with distinct optical properties that are nonexistent in the unsubstituted MOF. We have utilized these MOFs to quantitatively measure P, using its ability to bind strongly to metal nodes inhibiting the LMCT process and altering the linker's photon emission. Using this system, detection limits of 4.5, 7.2 and 10.5 μM were obtained for the UiO-66-NH2(Ce), UiO-66-NH2, and UiO-66-NH2(Hf) respectively, adopting a straightforward single step procedure. These results demonstrate that the selection of metal nodes in a series of isostructural MOFs can be used to modulate their electronic properties and create sensing probes possessing the desired characteristics needed for the detection of environmental contaminants.


Nuclear entry of activated MAPK is restricted in primary ovarian and mammary epithelial cells.
The MAPK/ERK1/2 serine kinases are primary mediators of the Ras mitogenic signaling pathway. Phosphorylation by MEK activates MAPK/ERK in the cytoplasm, and phospho-ERK is thought to enter the nucleus readily to modulate transcription. Here, however, we observe that in primary cultures of breast and ovarian epithelial cells, phosphorylation and activation of ERK1/2 are disassociated from nuclear translocalization and transcription of downstream targets, such as c-Fos, suggesting that nuclear translocation is limited in primary cells. Accordingly, in import assays in vitro, primary cells showed a lower import activity for ERK1/2 than cancer cells, in which activated MAPK readily translocated into the nucleus and activated c-Fos expression. Primary cells express lower levels of nuclear pore complex proteins and the nuclear transport factors, importin B1 and importin 7, which may explain the limiting ERK1/2 import found in primary cells. Additionally, reduction in expression of nucleoporin 153 by siRNA targeting reduced ERK1/2 nuclear activity in cancer cells. ERK1/2 activation is dissociated from nuclear entry, which is a rate limiting step in primary cells and in vivo, and the restriction of nuclear entry is disrupted in transformed cells by the increased expression of nuclear pores and/or nuclear transport factors.


Procyanidins can interact with Caco-2 cell membrane lipid rafts: involvement of cholesterol.
Large procyanidins (more than three subunits) are not absorbed at the gastrointestinal tract but could exert local effects through their interactions with membranes. We previously showed that hexameric procyanidins (Hex), although not entering cells, interact with membranes modulating cell signaling and fate. This paper investigated if Hex, as an example of large procyanidins, can selectively interact with lipid rafts which could in part explain its biological actions. This mechanism was studied in both synthetic membranes (liposomes) and Caco-2 cells. Hex promoted Caco-2 cell membrane rigidification and dehydration, effects that were abolished upon cholesterol depletion with methyl-β-cyclodextrin (MCD). Hex prevented lipid raft structure disruption induced by cholesterol depletion/redistribution by MCD or sodium deoxycholate. Supporting the involvement of cholesterol-Hex bonding in Hex interaction with lipid rafts, the absence of cholesterol markedly decreased the capacity of Hex to prevent deoxycholate- and Triton X-100-mediated disruption of lipid raft-like liposomes. Stressing the functional relevance of this interaction, Hex mitigated lipid raft-associated activation of the extracellular signal-regulated kinases (ERK) 1/2. Results support the capacity of a large procyanidin (Hex) to interact with membrane lipid rafts mainly through Hex-cholesterol bondings. Procyanidin-lipid raft interactions can in part explain the capacity of large procyanidins to modulate cell physiology.


Mild glycine encephalopathy (NKH) in a large kindred due to a silent exonic GLDC splice mutation.
Classic neonatal-onset glycine encephalopathy (GE) is devastating and life threatening. Milder, later onset variants have been reported but were usually sporadic and incompletely defined. To determine the clinical and biochemical phenotype and molecular basis of mild GE in nine children from a consanguineous Israeli Bedouin kindred. Genomic DNA was screened for GLDC, AMT, and GCSH gene mutations. GLDC expression in lymphoblasts was studied by Northern blot and reverse transcriptase PCR analysis. Clinical features included hypotonia, abnormal movements, convulsions, and moderate mental retardation with relative sparing of gross motor function, activities of daily living skills, and receptive language. Aggression and irritability were prominent. CSF-to-plasma glycine ratio was mildly to moderately elevated. All nine patients were homozygous and their parents heterozygous for a novel, translationally silent GLDC exon 22 transversion c.2607C>A. Lymphoblast GLDC mRNA levels were considerably reduced. Three aberrantly spliced cDNA species were identified: exon 22 and exon 22 to 23 skipping, and insertion of an 87-base pair cryptic exon. Homozygosity for c.2607C>A was also identified in an unrelated but haplotypically identical patient with an unusually favorable outcome despite severe neonatal-onset GE. Mutation analysis enabled prenatal diagnosis of three unaffected and one affected pregnancies. The mutation in this kindred led to missplicing and reduced GLDC (glycine decarboxylase) expression. The 4 to 6% of normally spliced GLDC mRNA in the patients may account for their relatively favorable clinical outcome compared with patients with classic glycine encephalopathy.


Magnetic circular dichroism studies of iron(ii) binding to human calprotectin.
Calprotectin (CP) is an abundant metal-chelating protein involved in host defense, and the ability of human CP to bind Fe(ii) in a calcium-dependent manner was recently discovered. In the present study, near-infrared magnetic circular dichroism spectroscopy is employed to investigate the nature of Fe(ii) coordination at the two transition-metal-binding sites of CP that are a His3Asp motif (site 1) and a His6 motif (site 2). Upon the addition of sub-stoichiometric Fe(ii), a six-coordinate (6C) Fe(ii) center associated with site 2 is preferentially formed in the presence of excess Ca(ii). This site exhibits an exceptionally large ligand field (10Dq = 11 045 cm-1) for a non-heme Fe(ii) protein. Analysis of CP variants lacking residues of the His6 motif supports that CP coordinates Fe(ii) at site 2 by employing six His ligands. In the presence of greater than one equiv. of Fe(ii) or upon mutation of the His6 motif, the metal ion also binds at site 1 of CP to form a five-coordinate (5C) Fe(ii)-His3Asp motif that was previously unidentified in this system. Notably, the introduction of His-to-Ala mutations at the His6 motif results in a mixture of 6C (site 2) and 5C (site 1) signals in the presence of sub-stoichiometric Fe(ii). These results are consistent with a reduced Fe(ii)-binding affinity of site 2 as more weakly coordinating water-derived ligands complete the 6C site. In the absence of Ca(ii), both sites 1 and 2 are occupied upon addition of sub-stoichiometric Fe(ii), and a stronger ligand field is observed for the 5C site. These spectroscopic studies provide further evaluation of a unique non-heme Fe(ii)-His6 site for metalloproteins and support the notion that Ca(ii) ions influence the Fe(ii)-binding properties of CP.


A high-performance renewable thermosetting resin derived from eugenol.
A renewable bisphenol, 4,4'-(butane-1,4-diyl)bis(2-methoxyphenol), was synthesized on a preparative scale by a solvent-free, Ru-catalyzed olefin metathesis coupling reaction of eugenol followed by hydrogenation. After purification, the bisphenol was converted to a new bis(cyanate) ester by standard techniques. The bisphenol and cyanate ester were characterized rigorously by NMR spectroscopy and single-crystal X-ray diffraction studies. After complete cure, the cyanate ester exhibited thermal stability in excess of 350 °C and a glass transition temperature (Tg ) of 186 °C. As a result of the four-carbon chain between the aromatic rings, the thermoset displayed a water uptake of only 1.8% after a four day immersion in 85 °C water. The wet Tg of the material (167 °C) was only 19 °C lower than the dry Tg , and the material showed no significant degradation as a result of the water treatment. These results suggest that this resin is well suited for maritime environments and provide further evidence that full-performance resins can be generated from sustainable feedstocks.


Parental education predicts corticostriatal functionality in adulthood.
Socioeconomic disadvantage experienced in early development predicts ill health in adulthood. However, the neurobiological pathways linking early disadvantage to adult health remain unclear. Lower parental education-a presumptive indicator of early socioeconomic disadvantage-predicts health-impairing adult behaviors, including tobacco and alcohol dependencies. These behaviors depend, in part, on the functionality of corticostriatal brain systems that 1) show developmental plasticity and early vulnerability, 2) process reward-related information, and 3) regulate impulsive decisions and actions. Hence, corticostriatal functionality in adulthood may covary directly with indicators of early socioeconomic disadvantage, particularly lower parental education. Here, we tested the covariation between parental education and corticostriatal activation and connectivity in 76 adults without confounding clinical syndromes. Corticostriatal activation and connectivity were assessed during the processing of stimuli signaling monetary gains (positive feedback [PF]) and losses (negative feedback). After accounting for participants' own education and other explanatory factors, lower parental education predicted reduced activation in anterior cingulate and dorsomedial prefrontal cortices during PF, along with reduced connectivity between these cortices and orbitofrontal and striatal areas implicated in reward processing and impulse regulation. In speculation, adult alterations in corticostriatal functionality may represent facets of a neurobiological endophenotype linked to socioeconomic conditions of early development.


Usefulness of ultrasound guidance for central venous catheterisation in patients with end-stage renal disease.
Renal replacement therapy often requires the insertion of a central venous catheter. The procedure is invasive and can lead to a number of complications. To minimise the risk of such complications, ultrasonography is used. The aim of the present study was to assess the usefulness of ultrasound-assisted vs. traditional method of location of anatomical orientation points for the placement of central venous catheters. . The prospective and randomised study was carried out, which included 135 patients requiring central venous catheterisation. Patients were allocated into two groups: group I (without ultrasound) - 70 patients and group II (ultrasound guidance) - 65 patients. In the latter, the procedure was performed in 38 cases due to technical problems. The following parameters were compared: age, patient's condition, results of blood clotting tests, and selected renal function parameters. Moreover, the mode of procedure (emergent, scheduled), factors directly affecting the efficacy of catheter insertion and complications (use of anticoagulants, anatomical variants, sites of access, number of cannulation attempts) were analysed. RESULTS. Ultrasound was significantly more commonly used during emergent cannulation procedures (P = 0.002), in the elderly (P = 0.001) and unconscious patients (P = 0.001). Moreover, it was more frequently applied in patients undergoing anticoagulation (P = 0.01) and during the insertion of access through the subclavian and femoral vein (P = 0.013). The percentage of successful first attempt cannulation was higher in ultrasound-guided cases (P = 0.013). There were no significant intergroup differences in the incidence of early complications (P = 0.269). The study findings did not demonstrate significant differences in the incidence of early complications during cannulation with and without ultrasound guidance. The first attempt success rate was found to be significantly higher in cases of ultrasound-assisted central venous catheterisation.


Nonsuicidal self-injury in an American Indian reservation community: results from the White Mountain Apache surveillance system, 2007-2008.
To describe characteristics and correlates of nonsuicidal self-injury (NSSI) among the White Mountain Apache Tribe. NSSI has not been studied before in American Indian samples despite associated risks for suicide, which disproportionately affect American Indian youth. Apache case managers collected data through a tribally mandated surveillance system. Data from 2007 and 2008 (N = 182) were examined for rates, methods, precipitants, functions, past history of self-injury and service use, by age and gender. The rate of NSSI among all ages was 600 in 100,000, with individuals 10 to 14 years old disproportionately affected at a rate of 3,000 in 100,000. More females (65%) reported NSSI, and cutting was the preferred method (98%) for both genders combined. Most frequently reported precipitants were peer pressure/copying, conflict with boy/girlfriend and "depression." A substantial proportion (22%) was intoxicated/high at the time. More reported the function of NSSI was to "effect internal state" (45%) than "effect circumstances" (15%). More than one-third (39%) received ED treatment and referrals for aftercare (36%). Of those referred, only 30% followed up with services. Most (79%) reported past NSSI; 30% reported past suicidal ideation and 25% attempts. NSSI is a significant, largely unaddressed mental health problem among the White Mountain Apache Tribe and likely other reservation communities, especially as NSSI could serve as a precursor to suicide in this population. Interestingly, another self-destructive behavior, severe substance use, was reported to the surveillance system by Apaches and described in terms similar to NSSI, an important preliminary finding worth further exploration.


Acupuncture for soft tissue shoulder disorders: a series of 201 cases.
A retrospective observational study was performed on shoulder pain cases seen in a community general practice. Two hundred and one patients were treated with acupuncture (on distant points plus local shoulder points), moxibustion and auriculotherapy. Data was retrieved from records over a three-year period to assess the effect of acupuncture and moxibustion on pain, mobility and disability, and to compare perceived efficacy rates with published reports from Chinese acupuncturists. Using a four-point outcome scale in this series of 201 patients the study found: one patient (0.5%) reported no improvement, 12 (6%) simple improvement, 68 (33.8%) remarkable improvement, and 120 (59.7%) clinical resolution. Only two patients left the programme. In conclusion, treatment of soft tissue shoulder disorders with acupuncture and moxibustion in this series seems to have good clinical results in diminishing symptoms, shortening disease duration time and improving functional ability, even in long-lasting disease (up to 10 years). A combination of distant points plus local points, moxibustion and auriculotherapy seems to increase effectiveness, reduce the number of sessions per patient, and increase the time between sessions, suiting the needs of patients and those of a busy National Health Service clinic. The authors report results similar to those reported by Chinese acupuncturists when using similar diagnostic procedures, techniques, outcome measures and patients. This case series is the first step towards conducting a randomised controlled trial (RCT) of acupuncture efficacy in shoulder pain. Such trials are needed to confirm the perceived efficacy of acupuncture from observational studies.


Appraising the evidence for avoiding lotions or topical agents prior to radiation therapy.
This project aimed to determine whether avoiding the use of lotions or topical agents for four hours prior to radiation therapy is supported by evidence. A comprehensive literature review, interviews with clinical experts, benchmarking with international cancer centers, and consultation with professional nursing organizations were conducted. Results showed limited evidence as well as variation in practice.


Free-induction-decay magnetic field imaging with a microfabricated Cs vapor cell.
Magnetic field imaging is a valuable resource for signal source localization and characterization. This work reports an optically pumped magnetometer (OPM) based on the free-induction-decay (FID) protocol, that implements microfabricated cesium (Cs) vapor cell technology to visualize the magnetic field distributions resulting from various magnetic sources placed close to the cell. The slow diffusion of Cs atoms in the presence of a nitrogen (N2) buffer gas enables spatially independent measurements to be made within the same vapor cell by translating a 175 μm diameter probe beam over the sensing area. For example, the OPM was used to record temporal and spatial information to reconstruct magnetic field distributions in one and two dimensions. The optimal magnetometer sensitivity was estimated to be 0.43 pT/H z within a Nyquist limited bandwidth of 500 Hz. Furthermore, the sensor's dynamic range exceeds the Earth's field of approximately 50 μT, which provides a framework for magnetic field imaging in unshielded environments.


Conformational analysis of the biologically active cyclic analog of beta-casomorphin H-Tyr-cyclo[D-OrnPheProGly].
A biologically active analog of beta-casomorphin, H-Tyr-cyclo[D-OrnPheProGly], was studied by theoretical conformational analysis. Random sampling was used to search the conformational space of allowed dihedral angles. Among 53 low-energy conformers with different folding of the peptide cyclic moiety, only those were selected which correspond to the low-energy area of the model linear tripeptide Ac-D-AlaAlaPro-NHMe. This peptide was used as the main chain "template" for the D-OrnPheProGly fragment of the studied cyclopeptide molecule. Only 15 conformers were chosen as potentially biologically active structures. The conformational possibilities of the Phe residue were constrained to the combined (A + G) region of the Ala residue phi,psi-map for linear peptides.


Accentuated Paralimbic and Reduced Mesolimbic D2/3-Impulsivity Associations in Parkinson's Disease.
Impulsivity is a behavioral trait that is elevated in many neuropsychiatric disorders. Parkinson's disease (PD) patients can exhibit a specific pattern of reward-seeking impulsive-compulsive behaviors (ICBs), as well as more subtle changes to generalized trait impulsivity. Prior studies in healthy controls (HCs) suggest that trait impulsivity is regulated by D2/3 autoreceptors in mesocorticolimbic circuits. While altered D2/3 binding is noted in ICB+ PD patients, there is limited prior assessment of the trait impulsivity-D2/3 relationship in PD, and no prior direct comparison with patterns in HCs. We examined 54 PD (36 M; 18 F) and 31 sex- and age-matched HC (21 M; 10 F) subjects using [18F]fallypride, a high-affinity D2/3 receptor ligand, to measure striatal and extrastriatal D2/3 nondisplaceable binding potential (BPND). Subcortical and cortical assessment exclusively used ROI or exploratory-voxelwise methods, respectively. All completed the Barratt Impulsiveness Scale, a measure of trait impulsivity. Subcortical ROI analyses indicated a negative relationship between trait impulsivity and D2/3 BPND in the ventral striatum and amygdala of HCs but not in PD. By contrast, voxelwise methods demonstrated a positive trait impulsivity-D2/3 BPND correlation in ventral frontal olfactocentric-paralimbic cortex of subjects with PD but not HCs. Subscale analysis also highlighted different aspects of impulsivity, with significant interactions between group and motor impulsivity in the ventral striatum, and attentional impulsivity in the amygdala and frontal paralimbic cortex. These results suggest that dopamine functioning in distinct regions of the mesocorticolimbic circuit influence aspects of impulsivity, with the relative importance of regional dopamine functions shifting in the neuropharmacological context of PD.SIGNIFICANCE STATEMENT The biological determinants of impulsivity have broad clinical relevance, from addiction to neurodegenerative disorders. Here, we address biomolecular distinctions in Parkinson's disease. This is the first study to evaluate a large cohort of Parkinson's disease patients and age-matched healthy controls with a measure of trait impulsivity and concurrent [18F]fallypride PET, a method that allows quantification of D2/3 receptors throughout the mesocorticolimbic network. We demonstrate widespread differences in the trait impulsivity-dopamine relationship, including (1) loss of subcortical relationships present in the healthy brain and (2) emergence of a new relationship in a limbic cortical area. This illustrates the loss of mechanisms of behavioral regulation present in the healthy brain while suggesting a potential compensatory response and target for future investigation.


Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders.
KCNN2 encodes the small conductance calcium-activated potassium channel 2 (SK2). Rodent models with spontaneous Kcnn2 mutations show abnormal gait and locomotor activity, tremor and memory deficits, but human disorders related to KCNN2 variants are largely unknown. Using exome sequencing, we identified a de novo KCNN2 frameshift deletion in a patient with learning disabilities, cerebellar ataxia and white matter abnormalities on brain MRI. This discovery prompted us to collect data from nine additional patients with de novo KCNN2 variants (one nonsense, one splice site, six missense variants and one in-frame deletion) and one family with a missense variant inherited from the affected mother. We investigated the functional impact of six selected variants on SK2 channel function using the patch-clamp technique. All variants tested but one, which was reclassified to uncertain significance, led to a loss-of-function of SK2 channels. Patients with KCNN2 variants had motor and language developmental delay, intellectual disability often associated with early-onset movement disorders comprising cerebellar ataxia and/or extrapyramidal symptoms. Altogether, our findings provide evidence that heterozygous variants, likely causing a haploinsufficiency of the KCNN2 gene, lead to novel autosomal dominant neurodevelopmental movement disorders mirroring phenotypes previously described in rodents.


The Fcgamma receptor genotype as a risk factor for generalized early-onset periodontitis in Japanese patients.
Genetic polymorphisms of immunoglobulin G (IgG) Fc receptors (FcgammaR) were recently shown to be associated with recurrence rates of adult periodontitis (AP). The purpose of this study was to evaluate whether FcgammaR polymorphisms are also associated with generalized early-onset periodontitis (G-EOP) in Japanese patients. Thirty-eight Japanese patients with G-EOP and 83 Japanese patients with AP were identified according to established clinical criteria, including measurements of probing depth, clinical attachment level, and alveolar bone level. FcgammaR genotypes for 3 bi-allelic polymorphisms were determined in these G-EOP and AP patients and 104 race-matched healthy controls by means of allele-specific polymerase chain reactions. There was a significant difference in the distribution of FcgammaRIIIb genotypes between G-EOP patients and healthy controls (P = 0.02). Additionally, a significant over-representation of FcgammaRIIIb-NA2 allele was observed in G-EOP patients as compared to AP patients and controls (P= 0.02, P= 0.009, respectively). Moreover, we found a strong association between G-EOP and the composite genotype comprising FcgammaRIIIb-NA2 and FcgammaRIIIa-158F (G-EOP versus controls: odds ratio 2.4, 95% CI 1.0-6.0, chi2 = 4.13, P= 0.04). This study indicates that the FcgammaRIIIb-NA2 allele and possibly FcgammaRIIIa-158F could be associated with susceptibility to G-EOP in Japanese patients.


A simple hydrophobicity-based approach to predict the toxicity of unknown organic micropollutant mixtures in marine water.
In this study, we propose a simple hydrophobicity-based approach to predict the toxicity of mixtures of marine organic micropollutants. Fifty mixtures were chosen, comprising individual chemicals randomly chosen from three halogenated benzenes, three phenols, two petroleum hydrocarbons, three polychlorinated biphenyls (PCBs), four organochlorine pesticides (OCPs) and two herbicides, with the intention of simulating the mixtures of organic micropollutants that may exist in some marine waters. The hydrophobicity of the mixtures was quantified by measuring the C(18)-Empore(TM) disk/water partition coefficients (K(MD)). A K(MD)-based approach was proposed to describe their toxicity to Photobacterium phosphoreum, and the application of this approach to another 10 related mixtures proved its predictive capability, as indicated by the consistency between the predicted and observed toxicities (r(2)=0.905, SE=0.101, and F=76.325 at P<0.001). This predictive capability convinces us that the K(MD)-based approach provides a general approach to predicting the toxicity of mixtures of organic micropollutants in marine water.


[Free energy linearity principle in enzymatic catalysis and thermodynamic principles of specificity].
It was demonstrated that the free energy linearity principle, i.e. relationship between the kinetics and thermodynamics of enzymatic reactions, can be applied to enzymatic hydrolysis of specific substrates of chymotrypsin, thus suggesting that the substrate binding energy can be utilized for decreasing the activation barrier of the reaction. The literary data support the applicability of the free energy linearity principle to enzymatic reactions catalyzed by some hydrolytic enzymes.


[Painless myocardial ischemia in patient with extensive constrictive atherosclerosis of coronary arteries].
We describe in this article a clinical case of a patient with arterial hypertension, painless myocardial ischemia and extensive constrictive atherosclerosis of coronary arteries. Coronary heart disease (painless ischemia) was suspected basing on results of transesophageal electrostimulation coupled with stress echocardiography and was confirmed by coronary angiography. This description is followed by discussion of possibilities of different instrumental methods in diagnostics of painless ischemia, classification of painless ischemia, treatment, and prognosis.


Age, body mass index, and menstrual cycle influence young women's heart rate variability --a multivariable analysis.
Heart rate variability (HRV) in women has been related independently to endogenous sex hormones, hormone replacement therapy, menopause, menstrual cycle, body mass index (BMI), and physical conditioning. However, the joint influence of all these factors has not been reported. The present study describes the relation between circadian variation HRV and assesses its association with BMI, age, and menstrual cycle in healthy young women. A multivariable analysis was performed to estimate the predictive variables involved in SDNN, pNN50, and rMSSD profile, using the classification and regression tree (CART) and the logistic regression models. It was found that the first predictive variable was age, which divided women in two groups: >29.5 years old and <29.5 years old. In the case of the SDNN, the second predictive variable was BMI; the highest values were observed in women younger than 23 years old, with a BMI less than 19.82 kg/m2 and during the follicular phase of her menstrual cycle. For pNN50 and rMSSD the second predictive variable was menstrual cycle for women younger than 29.5 years old. Thus, in this group of women, age was a major determinant of cardiac autonomic nervous modulation followed by the BMI. HRV may be better understood using a multivariable analysis that could mimic physiological conditions.


Dally-like protein sequesters multiple Wnt ligands in the Drosophila germarium.
Cells in multicellular organisms rely on secreted ligands for development and morphogenesis. Several mechanisms modulate the availability and distribution of secreted ligands, determining their ability to signal locally and at long range from their source. One of these mechanisms is Dally-like protein (Dlp), a cell-surface glypican that exhibits biphasic functions in Drosophila wing discs, promoting Wg signaling at long-range from Wg source cells and inhibiting Wg signaling near source cells. In the germarium at the tip of the ovary, Dlp promotes long-range distribution of Wg from cap cells to follicle stem cells. However, the germarium also expresses other Wnts - Wnt2, Wnt4, and Wnt6 - that function locally in escort cells to promote oogenesis. Whether and how local functions of these Wnts are regulated remains unknown. Here we show that the dlp overexpression phenotype is multifaceted and phenocopies multiple Wnt loss-of-function phenotypes. Each aspect of dlp overexpression phenotype is suppressed by co-expression of individual Wnts, and the suppression pattern exhibited by each Wnt suggests that Wnts have functional specificity in the germarium. Further, dlp knockdown phenocopies Wnt gain-of-function phenotypes. Together these data show that Dlp inhibits the functions of each Wnt. All four Wnts co-immunoprecipitate with Dlp in S2R+ cells, suggesting that in the germarium, Dlp sequesters Wnts to inhibit local paracrine Wnt signaling. Our results indicate that Dlp modulates the availability of multiple extracellular Wnts for local paracrine Wnt signaling in the germarium.


Workers' compensation issues in home care.
Workers' compensation expenses can add up quickly for home care agencies, where employees are in and out of patients' homes all day, often with no supervision or with no help in transferring patients or heavy equipment. Simple precautions and proper training and followup can greatly reduce this financial burden.


Normal-Tension Glaucoma Masqueraders: Detection Using Optical Coherence Tomography.
Optical coherence tomography (OCT) has become an important tool in the diagnosis and management of glaucoma; however, there can be overlap in the OCT findings between glaucoma and other diseases. We describe the clinical examination finings and interpretation of OCT imaging that led to the diagnosis of glaucoma masqueraders in a clinical case series. Four adult patients seen in the glaucoma clinic at the Duke Eye Center were included in a retrospective observational case series. Clinical presentation, history, examination, and testing (visual fields, scanning laser ophthalmoscopy, and spectral-domain OCT imaging) were reviewed. We report a case series of 4 patients and their spectral-domain OCT findings with retinal disease or nonglaucomatous optic neuropathy, who presented for evaluation of suspected or previously diagnosed normal-tension glaucoma. The first patient showed marked diffuse retinal nerve fiber layer (RNFL) and macular thinning on OCT due to cancer-associated retinopathy. The second patient, who demonstrated deep focal inferotemporal RNFL loss with a corresponding arc of macular thinning on OCT, had a previous branch retinal artery occlusion. The third patient's OCT showed global RNFL and macular thinning from optic nerve hypoplasia. The last patient had bilateral, symmetric superior and temporal RNFL thinning on OCT with corresponding inferior arcuate defects, consistent with superior segmental optic nerve hypoplasia. In light of the clinical context and examination, optic nerve and macular OCT can be beneficial in distinguishing between glaucoma and glaucoma mimics.


A physical map of the human genome.
The human genome is by far the largest genome to be sequenced, and its size and complexity present many challenges for sequence assembly. The International Human Genome Sequencing Consortium constructed a map of the whole genome to enable the selection of clones for sequencing and for the accurate assembly of the genome sequence. Here we report the construction of the whole-genome bacterial artificial chromosome (BAC) map and its integration with previous landmark maps and information from mapping efforts focused on specific chromosomal regions. We also describe the integration of sequence data with the map.


Role of optical spectroscopy using endogenous contrasts in clinical cancer diagnosis.
Optical spectroscopy has been intensively studied for cancer management in the past two decades. This review paper first introduces the background of optical spectroscopy for cancer management, which includes the advantages of optical techniques compared to other established techniques, the principle of optical spectroscopy and the typical setup of instrumentation. Then the recent progress in optical spectroscopy for cancer diagnosis in the following organs is reviewed: the brain, breast, cervix, lung, stomach, colon, prostate and the skin. Reviewed papers were selected from the PubMed database with keywords combining the terms of individual optical spectroscopy techniques and cancers. The primary focus is on the in vivo applications of optical spectroscopy in clinical studies. Ex vivo studies are also included for some organs to highlight special applications or when there are few in vivo results in the literature. Practical considerations of applying optical spectroscopy in clinical settings such as the speed, cost, complexity of operation, accuracy and clinical value are discussed. A few commercially available clinical instruments that are based on optical spectroscopy techniques are presented. Finally several technical challenges and standard issues are discussed and firm conclusions are made.


Hyperoside mediates protection from diabetes kidney disease by regulating ROS-ERK signaling pathway and pyroptosis.
Renal tubular injury is a key factor in the progression of diabetic kidney disease to end-stage renal disease. Hyperoside, a natural flavonol glycoside in various plants, is a potentially effective drug for the clinical treatment of diabetic kidney disease. However, the specific mechanisms remain unknown. Therefore, this study will explore the effect and mechanism of hyperoside on renal tubulointerstitium in diabetic kidney disease. db/db mouse (C57BL/KsJ) is a model of type 2 diabetes resulting from Leptin receptor point mutations, with the appearance of diabetic kidney disease. Therefore, db/db mice were used for in vivo experimental studies. In vitro, human renal tubular epithelial cells were incubated with bovine serum albumin to simulate the injury of renal tubular epithelial cells caused by excessive albumin in primary urine. The experimental results showed that hyperoside could improve kidney function and reduce kidney tissue damage in mice, and could inhibit oxidative stress, extracellularly regulated protein kinases 1/2 signaling activation, and pyroptosis in human renal tubular epithelial cells. Therefore, hyperoside inhibited oxidative stress by regulating the activation of the extracellularly regulated protein kinases 1/2/mitogen-activated protein kinase signaling pathway, thereby alleviating proteinuria-induced pyroptosis in renal tubular epithelial cells. This study provides novel evidence that could facilitate the clinical application of hyperoside in diabetic kidney disease treatment.


The pancreas responds to remote damage and systemic stress by secretion of the pancreatic secretory proteins PSP/regI and PAP/regIII.
In patients with infection and sepsis serum levels of Pancreatic Stone protein/regenerating protein I (PSP) are highly elevated. The origin of PSP during these conditions is presumably the pancreas, however, an intestinal origin cannot be excluded. Similarly, pancreatitis-associated protein (PAP) was identified in the pancreas. These proteins were also localized in intestinal organs. Here we aim to elucidate the bio-distribution of PSP and PAP in animal models of sepsis and in healthy humans. PSP and PAP responded to remote lesions in rats although the pancreatic response was much more pronounced than the intestinal. Tissue distribution of PSP demonstrated a 100-fold higher content in the pancreas compared to any other organ while PAP was most abundant in the small intestine. Both proteins responded to CLP or sham operation in the pancreas. PSP also increased in the intestine during CLP. The distribution of PSP and PAP in human tissue mirrored the distribution in the murine models. Distribution of PSP and PAP was visualized by immunohistochemistry. Rats and mice underwent midline laparotomies followed by mobilization of tissue and incision of the pancreatic duct or duodenum. Standard cecum-ligation-puncture (CLP) procedures or sham laparotomies were performed. Human tissue extracts were analyzed for PSP and PAP. The pancreas reacts to remote lesions and septic insults in mice and rats with increased PSP synthesis, while PAP is selectively responsive to septic events. Furthermore, our results suggest that serum PSP in septic patients is predominantly derived through an acute phase response of the pancreas.


Effects of different feeding levels during three short periods of gestation on gilt and litter performance, nutrient digestibility, and energy homeostasis in gilts.
The present study investigated the effects of different feeding levels during 3 short periods of gestation on gilt and litter performance, apparent total tract digestibility (ATTD) of energy and nutrients, and energy homeostasis in gilts. A total of 18 gilts were allotted to 1 of 3 dietary treatments using a completely randomized design. All gilts were fed 1 common corn-soybean meal-based diet with the amount of 1.0 × maintenance energy intake (100 × BW (BW) kcal ME/d) throughout gestation except 3 periods of 7 d when dietary treatments were imposed on d 27, d 55, and d 83 of gestation. During the 3 short periods, gilts were fed 1 of 3 different feeding levels: 0.5, 1.0, and 2.0 × maintenance energy level (0.5M, 1.0M, and 2.0M, respectively). Results showed that gilts on 2.0M feeding level had higher ( < 0.05) weight gain from d 27 to 109 of gestation (37.05 vs. 15.34 kg) and greater ( < 0.05) BW change, average daily gain, and gain to feed ratio during gestation periods 1 (d 27-34) and 3 (d 83-90) when compared with gilts on 0.5M feeding level. No differences ( > 0.10) in litter performance were observed among the 3 feeding levels. Additionally, the slopes of BW change in response to feeding levels in period 1 were 4.32 kg/0.5M change from 0.5M to 1.0M feeding level and 3.72 kg/0.5M change from 1.0M to 2.0M feeding level, respectively. There were quadratic ( < 0.05) effects of feeding levels on ATTD of dry matter and gross energy during periods 1 and 2 (d 55-62). Furthermore, fasting plasma concentrations of acyl ghrelin and nonesterified fatty acid (NEFA) in period 1 were greater ( < 0.01) in gilts on 0.5M feeding level than those on 2.0M feeding level. In conclusion, increasing feeding levels during 3 short periods increased primiparous sow performance during these short periods but did not affect litter performance. ATTD of energy and nutrients, and BW change efficiency were maximized for gilts on 1.0 M feeding level. The data also indicated that sows on the lowest feeding level were exposed to negative energy balance as evidenced by the higher plasma acyl ghrelin and NEFA concentrations.


One-pool model for Ca2+ oscillations involving Ca2+ and inositol 1,4,5-trisphosphate as co-agonists for Ca2+ release.
Experimental observations indicate that Ca(2+)-induced Ca2+ release (CICR) may underlie Ca2+ oscillations in a variety of cells. In its original version, a theoretical model for signal-induced Ca2+ oscillations based on CICR assumed the existence of two types of pools, one sensitive to inositol 1,4,5-trisphosphate (IP3) and the other one sensitive to Ca2+. Recent experiments indicate that Ca2+ channels may sometimes be sensitive to both IP3 and Ca2+. Such a regulation may be viewed as Ca(2+)-sensitized IP3-induced Ca2+ release or, alternatively, as a form of IP3-sensitized CICR. We show that sustained oscillations can still occur in a one-pool model, provided that the same Ca2+ channels are sensitive to both Ca2+ and IP3 behaving as co-agonists. This model and the two-pool model based on CICR both account for a number of experimental observations but differ in some respects. Thus, while in the two-pool model the latency and period of Ca2+ oscillations are of the same order of magnitude and correlate in a roughly linear manner, latency in the one-pool model is always brief and remains much shorter than the period of oscillations. Moreover, the first Ca2+ spike is much larger than the following ones in the one-pool model. These distinctive properties might provide an explanation for the differences in Ca2+ oscillations observed in various cell types.


Detection of human-induced environmental disturbances in a show cave.
We investigated the effects of human-induced disruption in a subterranean stable environment containing valuable Palaeolithic paintings and engravings (Ardales Cave, Southern Spain) using a double analytical approach. An environmental monitoring system was installed in the cave to record temperature, relative humidity, carbon dioxide (CO(2)) and radon ((222)Rn) concentrations in air. In the same stations, an aerobiological sampling was conducted to quantify the level of airborne microorganisms. The combination of different methods allowed us to detect the extent of human-induced changes, confirming that these can be very hazardous in certain cave areas that should be apparently outside the scope of human disturbances, either by their remoteness to the visitor entrance or by being briefly visited. The detection of evident anomalies in the environmental parameters and airborne microorganism concentration in the cave area housing the high density of paintings and engravings helps to control human disturbances and supports the direct application of this double approach for cave management purposes.


Making Use of Your Assets: Clinical Use of EOD Radiography in the Forward-Deployed Setting.
Ultrasonography is currently the primary means of imaging for forward surgical teams/forward resuscitative surgical teams (FSTs/FRSTs). As FSTs/FRSTs are pushed farther forward into more austere environments, access to other imaging modalities may be limited, potentially affecting resources. On a recent deployment, the 126th FRST was able to use radiography equipment from a co-located explosive ordnance disposal (EOD) team to assist in the diagnosis and treatment of medical and surgical patients, thereby saving time and resources. We provide three case examples in which using EOD radiography assisted in clinical decision making. Although the safety profile has not been assessed for clinical use in humans, EOD radiography can be a useful technique to aid in time-sensitive decision making in resource-constrained operational areas.


3D printing of a high protein yoghurt-based gel: Effect of protein enrichment and gelatine on physical and sensory properties.
The potential application of 3D printing technology in creating protein-rich desserts with multisensory design was investigated. Yoghurt-gel inks were formulated by varying the concentration of gelatine and whey protein isolate (WPI). Assessment of rheological and textural properties prior to printing, showed that an increase of gelatine concentration from 7.5 to 12.5% w/w increased the yield stress, storage modulus, loss modulus, firmness, and resilience of yoghurt gels. Addition of 12% WPI reduced these effects; creating softer gels with reduced resilience. However, these gels showed stable shape after printing, especially in formulations with higher gelatine concentrations. The changes in textural properties caused by the extrusion process need to be considered when designing yoghurt gels, as a significant reduction in firmness and resilience and an increase in adhesiveness were observed after 3D printing. The more stable and well-shaped 3D printed yoghurt gels were obtained by the combined effect of WPI and gelatine which provided a good balance of appearance, taste, flavour, and mouthfeel attributes evaluated by a trained sensory panel. A consumer study performed with thirty healthy adults showed the potential to improve sensory acceptance through the creation of multisensory layered design.


Management of emergencies in general practice: role of general practitioners.
Management of emergencies is an integral part of primary care. Being first contact care providers general practitioners may encounter any type of emergency. Acute attacks of asthma, myocardial infarction, anaphylactic shock, hypoglycemic coma, convulsions, head injuries and trauma are some of the common emergencies encountered by GPs. Updated knowledge, communication and procedural skills, trained paramedical staff, necessary equipment and medications and appropriate practice organization are vital to provide optimum care which may even save lives of patients. The wide range of problems and the rarity of the problems make it difficult for primary care doctors to be updated and competent in providing emergency care. Some of the emergencies can be managed completely at a general practice while others should be referred to hospital after initial management. The extent to which a patient should be managed may be determined by the degree of severity of the condition, expertise of the doctor and distance to the nearest hospital. Apart from pharmacological management, explanation about the condition and the need for admission and appropriate advice on care prior to admission are also vital components of management. Writing an appropriate referral, arranging transport facilities, informing the hospital about the referral are also important steps in the process as these measures could prevent crucial delays. Emergency care is a responsibility of primary care doctors and they should be knowledgeable and skilled and organize their practices to provide prompt and effective management whenever the need arises.


Patterns of spontaneous purkinje cell complex spike activity in the awake rat.
The olivocerebellar system is known to generate periodic synchronous discharges that result in synchronous (to within 1 msec) climbing fiber activation of Purkinje cells (complex spikes) organized in parasagittally oriented strips. These results have been obtained primarily in anesthetized animals, and so the question remains whether the olivocerebellar system generates such patterns in the awake animal. To this end, multiple electrode recordings of crus 2a complex spike activity were obtained in awake rats conditioned to execute tongue movements in response to a tone. After removal of all movement- and tone-related activity, the remaining data were examined to characterize spontaneous complex spike activity in the alert animal. Spontaneous complex spikes occurred at an average firing rate of 1 Hz and a clear approximately 10 Hz rhythmicity. Analysis of the autocorrelograms using a rhythm index indicated that the large majority of Purkinje cells displayed rhythmicity, similar to that in the anesthetized preparation. In addition, the patterns of synchronous complex spike activity were also similar to those observed in the anesthetized preparation (i.e., simultaneous activity was found predominantly among Purkinje cells located within the same parasagittally oriented strip of cortex). The results provide unequivocal evidence that the olivocerebellar system is capable of generating periodic patterns of synchronous activity in the awake animal. These findings support the extrapolation of previous results obtained in the anesthetized preparation to the waking state and are consistent with the timing hypothesis concerning the role of the olivocerebellar system in motor coordination.


Efficacy of postoperative prophylactic antibiotics in reducing permanent pacemaker infections.
Despite limited evidence, postoperative prophylactic antibiotics are often used in the setting of permanent pacemaker implantation or replacement. The aim of this study is to investigate the efficacy of postoperative antibiotics. Postoperative prophylactic antibiotics may be not clinically useful. We recruited 367 consecutive patients undergoing permanent pacemaker implantation or generator replacement at a tertiary referral center. Baseline demographics, clinical characteristics, and procedure information were collected, and all patients received preoperative prophylactic antibiotics. Postoperative prophylactic antibiotics were administered at the discretion of the treating physician, and all patients were seen in follow-up every 3 to 6 months for an average follow-up period of 16 months. The primary endpoint was device-related infection. A total of 110 patients were treated with preoperative antibiotics only (group 1), whereas 257 patients received both preoperative and postoperative antibiotics (group 2). After a mean follow-up period of 16 months, 1 patient in group 1 (0.9%) and 4 patients in group 2 (1.5%) experienced a device-related infection. There was no significant difference in the rate of infection between the 2 groups (P = 0.624). In the univariate analysis, only the age (60 ± 11 vs 75 ± 12 years, P < 0.001) was significantly different between the infected and noninfected groups. In the multivariate analysis, younger age was an independent risk factor for infective complications (odds ratio = 1.08, P = 0.016). Patients treated with preoperative and postoperative antibiotics had a similar rate of infection as those treated with preoperative antibiotics alone. Further studies are needed to confirm these preliminary findings.


[The synergy of radiology and CAD/CAM].
For treatment planning purposes, data acquired with cone-beam computer tomography and data from other three-dimensional imaging techniques can be combined in a single dataset. With the aid of this combined dataset extensive treatment planning and prosthetic solutions can be realised. The planning and production of the definitive prosthetic solution can then be accomplished using computer-aided design and computer-aided manufacturing technologies. These technological developments are expected to play an increasingly significant role for chair-side solutions.