Cleidocranial dysplasia presenting with retained deciduous teeth in a 15-year-old girl: a case report.
Cleidocranial dysplasia is a rare congenital defect of autosomal dominant inheritance caused by mutations in the Cbfa1 gene, also called Runx2, located on the short arm of chromosome 6. It primarily affects bones which undergo intramembranous ossification. This condition is of clinical significance to dentistry due to the involvement of the facial bones, altered eruption patterns and multiple supernumerary teeth. Our patient, a 15-year-old Indian girl, presented with the typical features of prolonged retention of deciduous dentition and delayed eruption of permanent teeth, that is, mandibular prognathism along with other skeletal abnormalities like shrugged shoulder and the absence of clavicles. A multidisciplinary approach was followed, comprising orthodontic, surgical and pedodontic teams for management. Successful treatment of such a case lies in a holistic approach that takes care of all aspects, including the primary pathology, the deformity itself and even the psychological angle.


Immunocytochemical evidence for direct synaptic connections between corticotrophin-releasing factor (CRF) and gonadotrophin-releasing hormone (GnRH)-containing neurons in the preoptic area of the rat.
Electron microscopic double-label immunostaining with peroxidase and avidin-ferritin was used to study connections between corticotrophin-releasing factor (CRF) and gonadotrophin-releasing hormone (GnRH) immunoreactive elements in the medial preoptic area of the rat. Synaptic contacts were observed between CRF-immunoreactive axon terminals and the dendrites of GnRH-immunopositive neurons. These results suggest that the inhibitory effects of stress-induced CRF release on reproductive function may involve a direct CRF input to the GnRH-producing cells.


Can hospital discharge diagnoses be used for surveillance of surgical-site infections?
The aim of this study was to assess the data quality of postoperative infections in a hospital discharge registry in the Emilia-Romagna region of Italy. Data from a prospective regional study of postoperative infections in 6158 patients from 31 of the 36 public hospitals of the region were compared with data from the regional hospital discharge registry, using different classes of ICD-9-CM codes. The sensitivity of the hospital discharge database for postoperative surgical infections was 10% when ICD-9-CM codes directly indicative of postoperative infectious complications were used. When non-specific codes of postoperative complications, not necessarily of infectious origin, were added, the sensitivity reached 21%. At present, the hospital discharge registry is not suited for surveillance of hospital-acquired infection.


Rates of colpopexy and colporrhaphy at the time of hysterectomy for prolapse.
It has been shown that addressing apical support at the time of hysterectomy for pelvic organ prolapse (POP) reduces recurrence and reoperation rates. In fact, national guidelines consider hysterectomy alone to be inadequate treatment for POP. Despite this, anterior and posterior colporrhaphy are frequently performed without a colpopexy procedure and hysterectomy alone is often utilized for treatment of prolapse. The objectives of this study were to: (1) determine rates of concomitant procedures for POP in hysterectomies performed with POP as an indication, (2) identify factors associated with performance of a colpopexy at the time of hysterectomy for POP, and (3) identify the influence of surgical complexity on perioperative complication rates. This is a retrospective cohort study of hysterectomies performed for POP from Jan. 1, 2013, through May 7, 2014, in a statewide surgical quality database. Patients were stratified based on procedures performed: hysterectomy alone, hysterectomy with colporrhaphy and without apical suspension, and hysterectomy with colpopexy with or without colporrhaphy. Demographics, medical history and intraoperative care, and perioperative care were compared between the groups. Multivariable logistic regression models were created to identify factors independently associated with use of colpopexy and factors associated with increased rates of postoperative complications. POP was an indication in 1557 hysterectomies. Most hysterectomies were vaginal (59.6%), followed by laparoscopic or robotic (34.1%), and abdominal (6.2%). Hysterectomy alone was performed in 43.1% (95% confidence interval [CI], 40.6-45.6) of cases, 32.8% (95% CI, 30.4-35.1) had a colporrhaphy without colpopexy, and 24.1% (95% CI, 22-26.3) had a colpopexy with or without colporrhaphy. Use of colpopexy was independently associated with patient age >40 years, POP as the only indication for surgery (odd ratio [OR], 1.6; 95% CI, 1.185-2.230), laparoscopic surgery (OR, 3.2; 95% CI, 2.860-5.153), and a surgeon specializing in urogynecology (OR, 8.2; 95% CI, 5.156-12.923). The overall perioperative complication rate was 6.6%, with the majority being considered minor. Complications were more likely when the procedure was performed with an abdominal approach (OR, 2.3; 95% CI, 1.088-4.686), with the use of a colpopexy procedure (OR, 3.1; 95% CI, 1.840-5.194), and by a surgeon specializing in urogynecology (OR, 2.2; 95% CI, 1.144-4.315). Colpopexy and colporrhaphy may be underutilized and are potential targets for quality improvement. Performance of additional procedures at the time of hysterectomy increased the rate of perioperative complications. Long-term consequences of these surgical practices deserve additional study.


A role for deficits in GABAergic neurosteroids and their metabolites with NMDA receptor antagonist activity in the pathophysiology of posttraumatic stress disorder.
Trauma-focused psychotherapies show general efficacy in post-traumatic stress disorder (PTSD), although outcomes vary substantially among individuals with PTSD and many patients do not achieve clinically meaningful symptom improvement. Several factors may contribute to poor treatment response, including genetic or environmental (e.g., stress) effects on neurobiological factors involved in learning and memory processes critical to PTSD recovery. In this review, we discuss the relationship between deficient GABAergic neurosteroid metabolites of progesterone, allopregnanolone (Allo) and pregnanolone (PA), and PTSD symptoms in men and women or PTSD-like behavioral abnormalities observed in male rodent models of PTSD. We also review the role and molecular underpinnings of learning and memory processes relevant to PTSD recovery, including extinction, extinction retention, reconsolidation of reactivated aversive memories and episodic non-aversive memory. We then discuss preclinical and clinical research that supports a role in these learning and memory processes for GABAergic neurosteroids and sulfated metabolites of Allo and PA that allosterically antagonize NMDA receptor function. Studies supporting the possible therapeutic impact of appropriately timed, acutely administered Allo or Allo analogs to facilitate extinction retention and/or block reconsolidation of aversive memories are also reviewed. Finally, we discuss important future directions for research in this area. Examining the varied and composite effects in PTSD of these metabolites of progesterone, as well as neuroactive derivatives of other parent steroids produced in the brain and the periphery, will likely enable a broadening of targets for treatment development. Defining contributions of these neuroactive steroids to common PTSD-comorbid psychiatric and medical conditions, as well as subpopulation-specific underlying dysfunctional physiological processes such as hypothalamic-pituitary-adrenal axis and immune system dysregulation, may also enable development of more effective multisystem precision medicines to prevent and treat the broader, polymorbid sequelae of extreme and chronic stress.


Wilms tumor, misdiagnosed preoperatively: a review of 19 National Wilms Tumor Study I cases.
This study establishes the difficulty in making specific diagnoses in children with retroperitoneal tumors when only excretory urograms are used in diagnosis. Complementary use of excretory urography and ultrasonography should make the number of preoperative errors less by separating cases of Wilms tumor from those with cystic disease. This investigation underscores the hazards inherent in the use of preoperative irradiation and chemotherapy, since some children with benign disease are likely to receive inappropriate therapy.


Chemotaxis of leukocytes from peripheral blood of patients with juvenile rheumatoid arthritis (JRA).
Spontaneous and stimulated migration of leukocytes from peripheral blood was studied in 15 patients with JRA and 15 controls. Cells from both groups showed equal migratory ability. However, in the presence of the activated serum of the JRA patients, there was a significant decrease in migration of leukocytes from JRA patients and from controls, suggesting the existence of a serum factor responsible for this chemotactic impairment. The effect of washing on the migration of these cells was also studied. A significant decrease could be observed in the spontaneous and stimulated migration of washed cells from both JRA patients and controls.


The provision of home health services through health maintenance organizations: the role of the physician.
The authors report the results of a comprehensive national study of the provision of home health care (HHC) through health maintenance organizations (HMOs), funded by a 1987 grant from the National Center for Health Services Research. The initial study included a literature review, interviews of 125 HHC providers and researchers, case studies of 6 HMOs, and a survey of 103 HMOs with Medicare contracts (as of March 1988). Upon discovery of controversy over the role of the HMO physician, the authors conducted an additional substudy of 30 primary care physicians. The article focuses on findings concerning the HMO physician in HHC and the implications for physicians generally, in light of what the larger study and additional data (January 1989-January 1990) show about HMO development and home health care.


Necator americanus: maintenance through one hundred generations in golden hamsters (Mesocricetus auratus). II. Morphological development of the adult and its comparison with humans.
Through 100 passages, the human hookworm Necator americanus was adapted to the golden hamster, Mesocricetus auratus, without either the requirement for exogenous steroids or other immunosuppressive agents, nor the requirement to infect hamsters as pups. Adult N. americanus recovered from infected hamsters were morphologically similar to those from infected humans in Sichuan Province, China, although they were smaller and the females produced fewer eggs. The natural history and kinetics of N. americanus infection was different in female and male hamsters. Female hamsters supported low intensity infections that lasted for approximately two months. In contrast, the peak intensity of infection in male hamsters was high, but this situation lasted less than for 4 weeks at which time many of the hookworms were expelled. However, even after the major parasite expulsion, the total number of hookworms consistently remained higher in chronically infected male hamsters compared with female hamsters. The hamster model of N. americanus is potentially useful for studying the development of new anthelminthic drugs and vaccines.


Runx2 is required for the proliferation of osteoblast progenitors and induces proliferation by regulating Fgfr2 and Fgfr3.
Runx2 and Sp7 are essential transcription factors for osteoblast differentiation. However, the molecular mechanisms responsible for the proliferation of osteoblast progenitors remain unclear. The early onset of Runx2 expression caused limb defects through the Fgfr1-3 regulation by Runx2. To investigate the physiological role of Runx2 in the regulation of Fgfr1-3, we compared osteoblast progenitors in Sp7-/- and Runx2-/- mice. Osteoblast progenitors accumulated and actively proliferated in calvariae and mandibles of Sp7-/- but not of Runx2-/- mice, and the number of osteoblast progenitors and their proliferation were dependent on the gene dosage of Runx2 in Sp7-/- background. The expression of Fgfr2 and Fgfr3, which were responsible for the proliferation of osteoblast progenitors, was severely reduced in Runx2-/- but not in Sp7-/- calvariae. Runx2 directly regulated Fgfr2 and Fgfr3, increased the proliferation of osteoblast progenitors, and augmented the FGF2-induced proliferation. The proliferation of Sp7-/- osteoblast progenitors was enhanced and strongly augmented by FGF2, and Runx2 knockdown reduced the FGF2-induced proliferation. Fgfr inhibitor AZD4547 abrogated all of the enhanced proliferation. These results indicate that Runx2 is required for the proliferation of osteoblast progenitors and induces proliferation, at least partly, by regulating Fgfr2 and Fgfr3 expression.


Clinicians' views on learning in brain injury rehabilitation.
To determine clinicians' views on learning ability in brain injury rehabilitation. Online survey. An online survey was sent to physicians, psychologists and therapists of three Dutch organizations for neuropsychology or rehabilitation. The survey enquired (1) whether clinicians take learning ability into account; (2) about factors influencing learning ability; and (3) about assessment tools used to assess learning ability. Thirty-seven physicians, 83 psychologists and 43 therapists completed the online survey. In total, 93% of respondents reported that they take learning ability into account when making a prognosis. The most frequently mentioned factors influencing learning ability were cognition, awareness of deficits and motivation. Learning ability was mainly determined by means of cognitive and memory tests and observations during therapy. This study demonstrates that a patient's learning ability may be influenced by not only cognition but also by motivation and awareness of deficits. Structured and standardized assessment of these factors may be suggested for standard use in clinical practice. More research is needed about the influence these factors have on the learning process.


A live attenuated BCG vaccine overexpressing multistage antigens Ag85B and HspX provides superior protection against Mycobacterium tuberculosis infection.
Tuberculosis (TB) remains one of the most menacing infectious diseases, although attenuated Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine has been widely used to protect children against primary TB. There are increasing evidences that rapid growing and dormant Mycobacterium tuberculosis (M. tuberculosis) coexist in vivo after infection. However, BCG vaccine only elicits cell-mediated immune responses to secretory antigens expressed by rapid growing pathogen. BCG vaccine is thus unable to thwart the reactivation of latent tuberculosis infection (LTBI), and its protection wanes over age after neonatal immunization. In order to extend its ability for a durable protection, a novel recombinant BCG (rBCG) strain, named rBCG::XB, was constructed by overexpressing immunodominant multistage antigens of Ag85B and HspX, which are expressed by both rapid replicating and dormant M. tuberculosis. Long-term protective effect and immunogenicity of rBCG::XB were compared with the parental BCG in vaccinated C57BL/6 mice. Our results demonstrated that rBCG::XB provided the stronger and long-lasting protection against M. tuberculosis H37Rv intranasal infection than BCG. The rBCG::XB not only elicited the more durable multistage antigen-specific CD4(+)Th1-biased immune responses and specific polyfunctional CD4(+)T cells but also augmented the CD8(+) CTL effects against Ag85B in vivo. In particular, higher levels of CD4(+) TEM and CD8(+) TCM cells, dominated by IL2(+) CD4(+) and CD8(+) TCM cells, were obtained in the spleen of rBCG::XB vaccinated mice. Therefore, our findings indicate that rBCG::XB is a promising candidate to improve the efficacy of BCG.


Ocular and extraocular roles of neuropsin in vertebrates.
The ability to detect and adapt to different levels of ambient light is critical for animal survival. Light detection is the basis of vision, but light also regulates eye development and drives several non-image-forming functions, including synchronizing circadian rhythms to the daily light/dark cycle, restricting pupils in response to changes in light intensity, and modulating mood in response to light. Until the early 2000s, these functions were thought to be solely mediated by ocular photoreceptors. However, neuropsin (OPN5), a UV-sensitive opsin, has been receiving growing attention, as new methods have revealed previously unappreciated functions of OPN5. In fact, OPN5-mediated extraocular and deep-brain photoreception have recently been described for the first time in mammals. This review aims to synthesize current knowledge of the properties and functions of OPN5 across vertebrates.


A comparison of hydrophilic interaction liquid chromatography and capillary electrophoresis for the metabolomics analysis of human serum.
Cationic, anionic, zwitterionic and, partially polar metabolites are very important constituents of blood serum. Several of these metabolites underpin the core metabolism of cells (e.g., Krebs cycle, urea cycle, proteins synthesis, etc.), while others might be considered ancillary but still important to grasp the status of any organism through blood serum analysis. Due to its wide chemical diversity, modern metabolomics analysis of serum is still struggling to provide a complete and comprehensive picture of the polar metabolome, due to the limitations of each specific analytical method. In this study, two metabolomics-based analytical methods using the most successful techniques for polar compounds separation in human serum samples, namely hydrophilic interaction liquid chromatography (HILIC) and capillary electrophoresis (CE), are evaluated, both coupled to a high-resolution time-of-flight mass spectrometer via electrospray ionization (ESI-Q-TOF-MS). The performance of the two methods have been compared using five terms of comparison, three of which are specific to metabolomics, such as (1) compounds' detectability (2) Pezzatti score (Pezzatti et al. 2018), (3) intra-day precision (repeatability), (4) ease of automatic analysis of the data (through a common deconvolution alignment and extrapolation software, MS-DIAL, and (5) time & cost analysis. From this study, HILIC-MS proved to be a better tool for polar metabolome analysis, while CE-MS helped identify some interesting variables that gave it interest in completing metabolome coverage in metabolomics studies. Finally, in this framework, MS-DIAL demonstrates for the first time its ability to process CE data for metabolomics, although it is not designed for it.


Left atrial appendage closure with amplatzer septal occluder in patients with atrial fibrillation: CT-based morphologic considerations.
This study analyzed left atrial appendage (LAA) dimensions measured by computed tomography (CT) scan to define optimal selection of Amplatzer septal occluders for LAA closure. Patients with atrial fibrillation and contraindications to anticoagulation have limited options for LAA closure until approval of dedicated closure devices. Off-label use of available cardiac devices represents one option. All consecutive patients undergoing LAA occlusion with an Amplatzer device who had undergone CT scanning were included. Numerous dimensions of the LAA were measured in order to optimally select a device that would simultaneously provide good anchoring and good sealing of the LAA. Of 11 eligible patients, 8 had successful Amplatzer deployment. In all successful cases, the putative "left atrial" disc was well matched to the "landing zone" of the LAA, proving good anchoring. The proximal (putative "right atrial") disc was sized to cover the LAA orifice. The failed cases shed light on procedural variables. LAA occlusion with an Amplatzer device is a viable option for patients with atrial fibrillation and contraindications to anticoagulation. Careful attention to LAA dimensions as measured on CT scan assists in optimizing device selection.


Interactions of Ro 15-4513 with diazepam, sodium pentobarbital and ethanol in a holeboard test.
Ro 15-4513 (1.5 mg/kg) decreased the exploratory activity of mice in a holeboard test. This effect was reversed by diazepam (1 mg/kg), ethanol (1 g/kg) and sodium pentobarbital (15 mg/kg). Higher doses of these three agents reduced the number of exploratory head-dips, and Ro 15-4513 antagonised these effects. These observations are consistent with the suggestion that Ro 15-4513 is a partial inverse agonist at benzodiazepine receptors and acts by reducing the efficacy of GABA. Ro 15-4513's interaction with ethanol in the holeboard closely resembled its interaction with the barbiturate.


Hemodynamics of idiopathic paroxysmal atrial fibrillation.
The hemodynamics of induced atrial fibrillation (AF) was investigated in 15 patients (ages 58 +/- 11 years) with paroxysmal AF presenting without organic heart disease or hypertension. A hemodynamic study was performed both during sinus rhythm and after the induction of AF. The mean heart rate increased from 73 +/- 11 to 128 +/- 18 beats/min (P < 0.001) after AF. Systolic and mean aortic pressures did not significantly change, and diastolic aortic pressure increased (78 +/- 11 vs 89 +/- 12 mmHg, P < 0.01). Left ventricular end-diastolic pressure decreased during AF (9 +/- 3 vs 6 +/- 2.6 mmHg, P < 0.005), whereas mean pulmonary wedge pressure increased (8 +/- 2 vs 12 +/- 4 mmHg, P < 0.001). Systolic pulmonary arterial pressure did not show significant variations, and there was a slight but statistically significant increase in the diastolic and mean pulmonary arterial pressures (P < 0.01). The right ventricular end-diastolic pressure decreased during AF (5.6 +/- 2 vs 3.8 +/- 2 mmHg, P < 0.01), whereas mean right atrial pressure showed a trend toward an increase. Stroke volume markedly decreased (P < 0.001) while the cardiac index did not significantly change. Systemic vascular resistance, pulmonary arteriolar resistance, and the arteriovenous O2 difference showed no significant variations after the induction of AF. These results suggest that in subjects without organic heart disease, paroxysmal AF is well tolerated hemodynamically, and the rise in the atrial pressures during AF is not related to an increase in the ventricular end-diastolic pressure.


Clinical outcomes of two minimally invasive transforaminal lumbar interbody fusion (TLIF) for lumbar degenerative diseases.
There are two modified TLIF, including MIS-TLIF and TLIF through Wiltse approach (W-TLIF). Although both of the two minimally invasive surgical procedures can be effective in the treatment for lumbar degenerative diseases, no comparative analysis has been made so far regarding their clinical outcomes. To compare the clinical outcomes of MIS-TLIF and W-TLIF for the treatment for single-segment degenerative lumbar diseases. Ninety-seven patients with single-segment degenerative lumbar disorders were included in this study. Forty-seven underwent MIS-TLIF surgery (group A). For group B, fifty patients underwent W-TLIF. The Japanese Orthopedic Association (JOA) score, the visual analog scale (VAS) of low back pain (LBP) and leg pain, MRI score and atrophy rate of CSA, interbody fusion rate were assessed during the postoperative follow-up. Incision length, blood loss, operative time, CPK, and postoperative incision pain VAS were better in group A (P < 0.05). The seconds of intraoperative fluoroscopy in groups A and B were 76 ± 9 and 7 ± 2, respectively (P < 0.05). In group B, The blood loss and CPK at L5-S1 were significantly higher than those at L4-5. Postoperative JOA scores, VAS of leg pain, and fusion rate were statistically the same between the two groups. VAS of LBP, MRI score, and atrophy rate of CSA was better in group A than in group B (P < 0.05). Both methods are effective in the treatment for lumbar degenerative disease. MIS-TLIF has less blood loss, shorter surgical incision, and less lower postoperative back pain, while W-TLIF is less expensive for hospital stay with lower exposure to X-rays.


Prevalence, incidence and natural history of dyspepsia and functional dyspepsia.
Estimates of the prevalence of dyspepsia in the community have varied between studies. This is, in large part, because of differences in the definitions used. Roughly speaking, 15-20% of the general population will report recurrent upper abdominal pain over the course of a year. Most of these people do not have endoscopic abnormalities and thus meet the criteria for functional dyspepsia. These symptoms appear to come and go, which makes determination of the incidence of dyspepsia quite difficult. Most studies have not distinguished whether the onset of symptoms represents recurrence or de novo symptoms. Approximately 5-10% of the population will develop symptoms of dyspepsia in a given year, and 50% of people with dyspepsia will lose their symptoms the following year. Regardless of the exact figures, all studies have demonstrated dyspepsia to be exceedingly common in the community.


Contact sensitivity to DNCB in normal and cell-mediated-immunity deficient chickens: in vivo detection and correlation with lymphocyte transformation and graft-versus-host reaction.
Optimum conditions for the contact sensitivity (CS) test using 2,4-dinitrochlorobenzene (DNCB) were sensitization with 0.25 ml of a DNCB solution (10 mg/ml) and challenge with one-tenth of this dose two weeks later. This produced reaction in terms of skin thickness which could be easily observed and measured. The cutaneous hypersensitivity developed slowly, reaching its maximum manifestation after 24 h of challenge and gradually declining thereafter. The development of a skin reaction was typical of delayed type hypersensitivity and was characterized histopathologically by congestion, oedema, mononuclear and heterophilic cell infiltration in the dermal layer and lymphocytic perivascular cuffing. The efficiency of the CS test was compared with that of the lymphocyte transformation (LT) test and graft-versus-host (GvH) reaction for monitoring cell-mediated immunity (CMI) in normal and CMI deficient chickens. CMI deficient chickens were prepared by neonatal thymectomy and inoculation of antithymocyte serum. The CMI response of deficient chickens was significantly less (p less than 0.01) as determined by all three tests. The percentage decrease in response to mount GvH, CS and LT was 88.9, 58.3 and 74.6, respectively. All the tests were found to be equally effective in assessing CMI response in chickens as determined by comparing the means of their performances.


[Allergic and non-allergic hypersensitivity to non-opioid analgesics, antipyretics and nonsteroidal anti-inflammatory drugs in children: epidemiology, clinical aspects, pathophysiology, diagnosis and prevention].
Non-opioid analgesics, antipyretics and nonsteroidal anti-inflammatory drugs are widely used, but suspected allergic reactions to these drugs are rare, especially in children. Most frequent reactions are cutaneous (urticaria, angioedema) and respiratory (rhinitis, asthma). Other reactions (anaphylaxis, potentially harmful toxidermias) are rare. In a few patients, reactions may result from a specific (allergic) hypersensitivity, with positive responses in prick and intradermal tests (anaphylaxis, immediate urticaria and/or angioedema) and in intradermal and patch tests (non-immediate reactions). However, most reactions result from a non-specific (non-allergic) hypersensitivity (intolerance), with a frequent cross-reactivity between the various families of analgesics, antipyretics and nonsteroidal anti-inflammatory drugs, including paracetamol. Based on a convincing clinical history and/or positive responses in challenge tests, intolerance to non-opioid analgesics, antipyretics and nonsteroidal anti-inflammatory drugs has been diagnosed in 13 to 50% of the patients with allergic-like reactions to these drugs. Risk factors are a personal atopy and age. Prevention is based on administration of other (families of) analgesics, antipyretics and nonsteroidal anti-inflammatory drugs in patients with allergic hypersensitivity to these drugs. In patients with non-allergic hypersensitivity, prevention is based on administration of drugs with a low cyclo-oxygenase-1 inhibitory activity (if tolerated). Desensitization is efficient in patients with respiratory reactions, but does not work in patients with mucocutaneous reactions and anaphylaxis.


Q-value customized versus wavefront-optimized ablation in femtosecond laser-assisted LASIK for myopia and myopic astigmatism: a prospective contralateral comparative study.
Corneal refractive surgery for myopia results in an oblate shift with increased postoperative aberrations inversely affecting the quality of vision. Aspheric ablation profiles have been introduced to minimize such a problem. The aim of this study was to compare changes in corneal asphericity, central and mid-peripheral pachymetry between the Q-value customized and the wavefront-optimized (WFO) ablation profiles. A prospective, comparative non-randomized fellow eye study was conducted. Eighty eyes of 40 eligible patients underwent femtosecond laser-assisted laser in situ keratomileusis for myopia and myopic astigmatism. In each patient, the more myopic eye was included in the custom-Q ablation experimental group and the other less myopic eye was included in the WFO control group. For the custom-Q group, the target asphericity was set to the preoperative Q-value. Corneal asphericity, central and mid-peripheral pachymetric changes and the root mean square of corneal higher-order aberrations (RMSh) were assessed 6 months following surgery. Visual and refractive outcomes were also evaluated in both platforms 6 months postoperatively. The mean preoperative refractive spherical equivalent was significantly more myopic in the custom-Q group than in the WFO group (P = 0.001). The mean Q-value changed from - 0.2 ± 0.1 to 0.6 ± 0.7 and from - 0.2 ± 0.1 to 0.4 ± 0.5 in the custom-Q and WFO groups, respectively. The oblate shift in corneal asphericity was not significantly different between both treatment groups (P = 0.094). The mean ablation depth at the pupillary center was significantly greater in the custom-Q group (P = 0.011), while there was no significant difference at the mid-peripheral pachymetry (P = 0.256). The RMSh significantly increased in both treatment profiles (P < 0.001) with no significant difference between the two groups (P = 0.06). The uncorrected distance visual acuity (UDVA) and the manifest refraction spherical equivalents (MRSE) significantly improved in both treatment groups (P < 0.001). The custom-Q treatment profile with target asphericity set at the preoperative Q-value achieved comparable outcomes vs. the WFO profile in terms of postoperative corneal asphericity and mid-peripheral pachymetry despite the greater amount of ablation, the smaller optical zone, and the resulting increase in postoperative corneal flattening in the custom-Q group. Trial registration (Clinicaltrials.gov): NCT04738903, 4 February 2021- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04738903.


Plasma free and sulfate conjugated catecholamine levels during acute physiological stimulation in man.
The responses of plasma free and sulfate-conjugated catecholamines to acute physiological stimulation was examined in normal male subjects. Catecholamines were measured with a sensitive radioenzymatic assay incorporating simultaneous hydrolysis of sulfate conjugates and O-methylation of free norepinephrine and epinephrine. Following 20 minutes recumbency after venepuncture 30 +/- 3% of norepinephrine and 16 +/- 5% of epinephrine was in thr free form. Free catecholamines generally increased during standing, cold immersion and isometric handgrip, but sulfates did not change. Bicycle ergometry markedly increased free catecholamines which rapidly returned to basal levels at the end of exercise. In contrast, sulfated norepinephrine decreased substantially with exercise in all subjects but returned to basal levels 3 minutes after stopping exercise. Epinephrine sulfate varied considerably between subjects but showed a similar, although smaller, fall with exercise. Thus, during physiological stimulation, which caused increases in free norepinephrine and epinephrine levels in plasma, the only consistent change in sulfated catecholamines was a marked fall in norepinephrine sulfate after bicycle exercise. This may indicate saturation of sulfotransferase activity, substrate inhibition or impaired tissue conjugation.


[The biology of prions, a response to the enigma of spongiform encephalopathies of sheep and humans].
Prions are small proteinaceous infectious particles without nucleic acids. The prion protein arise from a cellular protein by a post-transduction event and constitute amyloid deposits. Prions are the agent of animal and human spongiform encephalopathies which evolve on simultaneous infectious and genetic dependence in the absence of a detectable immune response.


Profiling of polar ionogenic metabolites in Polish wines by capillary electrophoresis-mass spectrometry.
The composition of wine is determined by a complex interaction between environmental factors, genetic factors (i.e., grape varieties), and winemaking practices (including technology and storage). Metabolomics using NMR spectroscopy, GC-MS, and/or LC-MS has shown to be a useful approach for assessing the origin, authenticity, and quality of various wines. Nonetheless, the use of additional analytical techniques with complementary separation mechanisms may aid in the deeper understanding of wine's metabolic processes. In this study, we demonstrate that CE-MS is a very suitable approach for the efficient profiling of polar ionogenic metabolites in wines. Without using any sample preparation or derivatization, wine was analyzed using a 10-min CE-MS workflow with interday RSD values for 31 polar and charged metabolites below 3.8% and 23% for migration times and peak areas, respectively. The utility of this workflow for the global profiling of polar ionogenic metabolites in wine was evaluated by analyzing different cool-climate Polish wine samples.


Sediment quality of Ergene River Basin: bio-ecological risk assessment of toxic metals.
Ergene River Basin is located in the north-west part of Marmara Region of Turkey. There are many industrial enterprises on its basin and as well as the majority of these facilities are located on the upstream of the basin. Therefore, Ergene River is one of the rare river ecosystems that are contaminated almost from the source area.The aim of this investigation was to assess the sediment contamination of Ergene River Basin including Meriç and Ergene Rivers and 10 significant tributaries of the system by investigating total of 25 macro- and micro-element concentrations. Sediments were sampled in spring season (rainy) of 2018 from 21 stations and element accumulations were investigated by using an ICP-MS.The investigated macro- and micro-elements in terms of concentration levels in abiotic components of the basin and the investigated basin components in terms of sediment quality characteristics were classified by using cluster analysis (CA). Biological Risk Index (mERM-Q) and Potential Ecological Risk Index (RI) were also applied to detected data to make an assessment of biological and ecological risks of toxic elements on the system.As a result of elemental CA, four statistically significant clusters were formed, which were named as "most intense elements", "moderate intense elements", "moderate rare elements", and "rarest elements". As a result of locational CA, three statistically significant clusters were formed, which were named as "low contaminated zone", "moderate contaminated zone", and "high contaminated zone". As a result of mERM-Q, chromium was determined as the most risky element, and as a result of RI, cadmium was determined as the most risky element for the sediments of Ergene River Basin.


Congenital synostosis between the fourth and fifth metacarpal bones.
Congenital synostosis between the fourth and fifth metacarpals is a rare congenital anomaly. This article reports the clinical features, hand pattern profiles, and dermatoglyphics of 14 patients with congenital synostosis between their fourth and fifth metacarpals. Surgical procedures are discussed.


Triose Kinase Controls the Lipogenic Potential of Fructose and Dietary Tolerance.
The surge in fructose consumption is a major factor behind the rapid rise of nonalcoholic fatty liver disease in modern society. Through flux and genetic analyses, we demonstrate that fructose is catabolized at a much higher rate than glucose, and triose kinase (TK) couples fructolysis with lipogenesis metabolically and transcriptionally. In the absence of TK, fructose oxidation is accelerated through the activation of aldehyde dehydrogenase (ALDH) and serine biosynthesis, accompanied by increased oxidative stress and fructose aversion. TK is also required by the endogenous fructolysis pathway to drive lipogenesis and hepatic triglyceride accumulation under high-fat diet and leptin-deficient conditions. Intriguingly, a nonsynonymous TK allele (rs2260655_A) segregated during human migration out of Africa behaves as TK null for its inability to rescue fructose toxicity and increase hepatic triglyceride accumulation. Therefore, we posit TK as a metabolic switch controlling the lipogenic potential of fructose and its dietary tolerance.


Reed warblers migrating through Portugal: climatic influence on stopover ecology over the last decade.
The arrival and breeding dates of small migrant birds have advanced throughout Europe. This study evaluates the hypothesis of a faster migration along the migratory route, which should lead to a decrease in stopover duration in staging areas over the last decades. Several climatic predictors were analysed as proxies to understand the stopover ecology of reed warbler Acrocephalus scirpaceus migrating through Central Portugal. The minimum stopover duration of migratory reed warblers decreased significantly over the last decade during both the spring and autumn migrations. Warmer conditions en route should increase food availability, increasing the body condition of departing birds and the quality of departing sites en route to Portugal, such that migrants will reduce the stopover duration at Portuguese reedbeds.


Murine and human interleukin 2 can substitute for the thymus in immune responses to TNP-Ficoll in Xenopus laevis, the South African clawed toad.
Extirpation of the thymuses of Xenopus laevis abrogates the capacity to respond to trinitrophenol (TNP)-Ficoll regardless of the age of the animal. This thymus requirement can be substituted for by a variety of treatments which stimulate thymus-derived (T)cell activity in the periphery, such as the rejection of allogeneic skin grafts, immunologic challenge with thymus-dependent immunogens, (e.g., heterologous erythrocytes), or plant-derived lectins (e.g., concanavalin A). Here we report that interleukin 2 (IL-2), a T-cell-produced hormone of mammalian origin also substitutes for this thymus requirement in thymectomized toads.


Site-Directed and Random Mutagenesis in Porphyromonas gingivalis: Construction of Fimbriae-Related-Gene Mutant.
Porphyromonas gingivalis, an etiological agent of chronic periodontitis, is an asaccharolytic anaerobic gram-negative coccobacillus. Genetic approaches greatly facilitate research on organisms at the molecular level. Although with some challenges, the use of genetic techniques (such as constructing knockout mutants) in P. gingivalis are feasible. In this chapter, we describe detailed methods for site-directed and random mutagenesis through the construction of fimbriae-related gene mutants of P. gingivalis.


"It's got its own life, and you can't contain it": A qualitative study of patient and health professional experiences of diabetes care.
To explore the perspectives of patients and health professionals on facilitators and barriers to care in a diabetes clinic in urban South Africa. Although much attention has been given to the science behind diabetes management, a qualitative approach to exploring experiences, facilitators and barriers to care may have considerable value in understanding and improving diabetes care. We conducted a qualitative study in the context of a 3-year collaboration at a diabetes clinic. The present study formed part of the preparatory phase to the larger project. Linguistically and culturally matched research assistants collected data over a period of 18 months. Methods included interviews, focus groups, ethnographic observations and informal discussions with 38 patients and health professionals. Data from each participant group were transcribed, translated and analysed using reflexive thematic analysis principles and thereafter triangulated. The Standards for Reporting Qualitative Research checklist was followed. Initial findings suggest that factors can be classified into three overarching themes: relationships, health systems and the interplay between disease and the lifeworld. System resource pressures, the nuances of team interactions and a complex healthcare site may adversely affect care, even at sites where there are elements of good practice. The collective psychosocial experience of patients appears to conflict with the biomedical approach to diabetes management. The all-consuming nature of the disease, together with contextual and systemic factors, plays a significant role in influencing experiences of care. While systemic and contextual influences on experiences of diabetes care may be difficult to modify, our study suggests a need to focus on ways of enhancing relationships within the clinic and seeking to understand the lifeworld of the patient.


Identification of long non-protein coding RNAs in chicken skeletal muscle using next generation sequencing.
Vertebrate genomes encode thousands of non-coding RNAs including short non-coding RNAs (such as microRNAs) and long non-coding RNAs (lncRNAs). Chicken (Gallus gallus) is an important model organism for developmental biology, and the recently assembled genome sequences for chicken will facilitate the understanding of the functional roles of non-coding RNA genes during development. The present study concerns the first systematic identification of lncRNAs using RNA-Seq to sample the transcriptome during chicken muscle development. A computational approach was used to identify 281 new intergenic lncRNAs in the chicken genome. Novel lncRNAs in general are less conserved than protein-coding genes and slightly more conserved than random non-coding sequences. The present study has provided an initial chicken lncRNA catalog and greatly increased the number of chicken ncRNAs in the non-protein coding RNA database. Furthermore, the computational pipeline presented in the current work will be useful for characterizing lncRNAs obtained from deep sequencing data.


STAT3-miR-17/20 signalling axis plays a critical role in attenuating myocardial infarction following rapamycin treatment in diabetic mice.
Deregulation of mTOR (mammalian target of rapamycin) signalling occurs in diabetes, which exacerbates injury following myocardial infarction (MI). We therefore investigated the infarct-limiting effect of chronic treatment with rapamycin (RAPA, mTOR inhibitor) in diabetic mice following myocardial ischaemia/reperfusion (I/R) injury and delineated the potential protective mechanism. Adult male diabetic (db/db) or wild-type (WT) (C57) mice were treated with RAPA (0.25 mg/kg/day, intraperitoneal) or vehicle (5% DMSO) for 28 days. The hearts from treated mice were subjected to global I/R in Langendorff mode. Cardiomyocytes, isolated from treated mice, were subjected to simulated ischaemia/reoxygenation (SI/RO) to assess necrosis and apoptosis. Myocardial infarct size was increased in diabetic heart following I/R as compared to WT. Likewise, enhanced necrosis and apoptosis were observed in isolated cardiomyocytes of diabetic mice following SI/RO. Treatment with RAPA reduced infarct size as well as cardiomyocyte necrosis and apoptosis of diabetes and WT mice. RAPA increased STAT3 phosphorylation and miRNA-17/20a expression in diabetic hearts. In addition, RAPA restored AKT phosphorylation (target of mTORC2) but suppressed S6 phosphorylation (target of mTORC1) following I/R injury. RAPA-induced cardioprotection against I/R injury as well as the induction of miR-17/20a and AKT phosphorylation were abolished in cardiac-specific STAT3-deficient diabetic mice, without alteration of S6 phosphorylation. The infarct-limiting effect of RAPA was obliterated in cardiac-specific miRNA-17-92-deficient diabetic mice. The post-I/R restoration of phosphorylation of STAT3 and AKT with RAPA were also abolished in miRNA-17-92-deficient diabetic mice. Additionally, RAPA suppressed the pro-apoptotic prolyl hydroxylase (Egln3/PHD3), a target of miRNA-17/20a in diabetic hearts, which was abrogated in miRNA-17-92-deficient diabetic mice. Induction of STAT3-miRNA-17-92 signalling axis plays a critical role in attenuating MI in RAPA-treated diabetic mice. Our study indicates that chronic treatment with RAPA might be a promising pharmacological intervention for attenuating MI and improving prognosis in diabetic patients.


Factors associated with non-invasive mechanical ventilation failure in patients with hematological neoplasia and their association with outcomes.
The usefulness of non-invasive mechanical ventilation (NIMV) in oncohematological patients is still a matter of debate. To analyze the rate of noninvasive ventilation failure and the main characteristics associated with this endpoint in oncohematological patients with acute respiratory failure (ARF). A ventilatory support protocol was developed and implemented before the onset of the study. According to the PaO2/FiO2 (P/F) ratio and clinical judgment, patients received supplementary oxygen therapy, NIMV, or invasive mechanical ventilation (IMV). Eighty-two patients were included, average age between 52.1 ± 16 years old; 44 (53.6%) were male. The tested protocol was followed in 95.1% of cases. Six patients (7.3%) received IMV, 59 (89.7%) received NIMV, and 17 (20.7%) received oxygen therapy. ICU mortality rates were significantly higher in the IMV (83.3%) than in the NIMV (49.2%) and oxygen therapy (5.9%) groups (P < 0.001). Among the 59 patients who initially received NIMV, 30 (50.8%) had to eventually be intubated. Higher SOFA score at baseline (1.35 [95% CI = 1.12-2.10], P = 0.007), higher respiratory rate (RR) (1.10 [95% CI = 1.00-1.22], P = 0.048), and sepsis on admission (16.9 [95% CI = 1.93-149.26], P = 0.011) were independently associated with the need of orotracheal intubation among patients initially treated with NIMV. Moreover, NIMV failure was independently associated with ICU (P < 0.001) and hospital mortality (P = 0.049), and mortality between 6 months and 1 year (P < 0.001). The implementation of a NIMV protocol is feasible in patients with hematological neoplasia admitted to the ICU, even though its benefits still remain to be demonstrated. NIMV failure was associated with higher SOFA and RR and more frequent sepsis, and it was also related to poor prognosis.


Geranylated flavonoids displaying SARS-CoV papain-like protease inhibition from the fruits of Paulownia tomentosa.
SARS-CoV papain-like protease (PLpro) is an important antiviral target due to its key roles in SARS virus replication. The MeOH extracts of the fruits of the Paulownia tree yielded many small molecules capable of targeting PLpro. Five of these compounds were new geranylated flavonoids, tomentin A, tomentin B, tomentin C, tomentin D, tomentin E (1-5). Structure analysis of new compounds (1-5) by NMR showed that they all contain a 3,4-dihydro-2H-pyran moiety. This chemotype is very rare and is derived from cyclization of a geranyl group with a phenol functionality. Most compounds (1-12) inhibited PLpro in a dose dependent manner with IC50's raging between 5.0 and 14.4 μM. All new compounds having the dihydro-2H-pyran group showed better inhibition than their parent compounds (1 vs 11, 2 vs 9, 4 vs 12, 5 vs 6). In kinetic studies, 1-12 emerged to be reversible, mixed inhibitors.


Identification of key genes and pathways associated with cholangiocarcinoma development based on weighted gene correlation network analysis.
As the most frequently occurred tumor in biliary tract, cholangiocarcinoma (CCA) is mainly characterized by its late diagnosis and poor outcome. It is therefore urgent to identify specific genes and pathways associated with its progression and prognosis. The differentially expressed genes in The Cancer Genome Atlas were analyzed to build the co-expression network by Weighted gene co-expression network analysis (WGCNA). Gene ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted for the selected genes. Module-clinical trait relationships were analyzed to explore the association with clinicopathological parameters. Log-rank tests and cox regression were used to identify the prognosis-related genes. The most related modules with CCA development were tan module containing 181 genes and salmon module with 148 genes. GO analysis suggested enrichment terms of digestion, hormone transport and secretion, epithelial cell proliferation, signal release, fibroblast activation, response to acid chemical, wnt, Nicotinamide adenine dinucleotide phosphate metabolism. KEGG analysis demonstrated 15 significantly altered pathways including glutathione metabolism, wnt, central carbon metabolism, mTOR, pancreatic secretion, protein digestion, axon guidance, retinol metabolism, insulin secretion, salivary secretion, fat digestion. Key genes of SOX2, KIT, PRSS56, WNT9A, SLC4A4, PRRG4, PANX2, PIR, RASSF8, MFSD4A, INS, RNF39, IL1R2, CST1, and PPP3CA might be potential prognostic markers for CCA, of which RNF39 and PRSS56 also showed significant correlation with clinical stage. Differentially expressed genes and key modules contributing to CCA development were identified by WGCNA. Our results offer novel insights into the characteristics in the etiology, prognosis, and treatment of CCA.


A procedure for comparing the ecological status and transformation measures in an anthropized coastal area.
The overall vitality and quality of the coastline can be improved through ecological transformation; ecological status assessment can scientifically guide this modification by putting forward a transformation plan for the coastline. This study took the Shenzhen Bay area between Hong Kong and Shenzhen as the study area to build an index system and combined it with quantitative and qualitative methods by designing the code of data processing, calculation, and analysis through the MATLAB platform, with the goal being to put forward the directions and suggestions for coastline transformation based on the analysis of results. The results and conclusions are as follows: (1) The key aspects of the ecological transformation of the Shenzhen Bay Coastline are water quality, coastal wetland restoration, landscape diversity, beach stability, and infrastructure improvement. (2) Actions to promote these aspects include overall shoreline control of water pollution, cultural landscape implantations, the improvement of existing infrastructure, and the restoration of selected beach sand regions, mangrove wetlands, and eroded shorelines. Suggestion includes the critical support which comes from the public needs for information acquisition and science education, in addition with the policy and management, all should be formulated into the transformation plan. The index system can be applied to other regions at home and abroad, and the results and conclusions based on the index system could also provide criteria for planning the ecological transformation process.


Role of Dendritic Cells in Inflammation.
From the first manuscript describing "A Novel Cell Type in Peripheral Lymphoid Organs of Mice" [...].


Cultivating quality: implementing standardized reporting and safety checklists.
Developing processes to create a culture of safety. It's estimated that as many as 98,000 hospitalized patients lose their lives each year in the United States because of medical errors that could have been prevented. While standardized reporting and safety checklists have been shown to improve communication and patient safety, implementation of these tools in hospitals remains challenging. To implement standardized nurse-to-nurse reporting along with safety checklists at Mission Hospital, a 522-bed facility in Mission Viejo, California, using Lewin's change theory and Knowles's adult learning theory. Nurses were tested to assess their knowledge of the standardized nurse-to-physician reporting method called SBAR (Situation, Background, Assessment, Recommendation), their understanding of the concept of the nurse-to-nurse reporting method called SBAP (Situation, Background, Assessment, Plan), and the use of safety checklists. Then, after viewing a 22-minute educational video, they were retested. A total of 482 nurses completed the pretest and posttest. On the pretest, the nurses' mean score was 15.935 points (SD, 3.529) out of 20. On the posttest, the mean score was 18.94 (SD, 1.53) out of 20. A Wilcoxon matched-pairs signed-rank test was performed; the two-tailed P value was < 0.001. The application of Lewin's change theory and Knowles's adult learning theory was successful in the process of implementing standardized nurse-to-nurse reporting and safety checklists at Mission Hospital.


Correction to: Can We Accurately Predict Cost Effectiveness Without Access to Overall Survival Data? The Case Study of Nivolumab in Combination with Ipilimumab for the Treatment of Patients with Advanced Melanoma in England.
The second Key Point for Decision Makers, which reads.


Infarction of the right hemisphere in a patient with antiphospholipid antibody syndrome.
Hemicraniectomy as a surgical treatment for intracranial pressure following large ischemic lesions is widely practiced in selected patients. The antiphospholipid antibody syndrome (APS), a disorder characterized by recurrent arterial and venous thrombosis, is a very rare cause of space occupying ischemic lesions. We present a case of a 35 year old female diagnosed with APS who initially presented with small ischemic lesions and within days developed a massive near-total infarction of the right hemisphere. Because of central nervous system, skin and systemic manifestations Sneddon's syndrome and catastrophic antiphospholipid antibody syndrome (CAPS) remained a possible diagnoses. Sneddon's syndrome is a non-inflammatory occlusive arteriopathy of small and medium size arteries predominantly of the skin and brain, whereas the catastrophic antiphospholipid antibody syndrome is characterized by acute multi-organ system thrombosis of small and large vessels. In addition to the diagnostic criteria for APS a heterozygous factor V Leiden mutation was found in this patient, which may be a contributing risk factor for cerebral ischemia. When considering invasive decompressive procedures the neurosurgeon has to be aware of the poor prognosis of some forms of APS with systemic manifestations.


Chemical probing reveals insights into the signaling mechanism of inflammasome activation.
Caspase-1-mediated IL-1β production is generally controlled by two pathways. Toll-like receptors (TLRs) recognize pathogen-derived products and induce NF-κB-dependent pro-IL-1β transcription; NOD-like receptors (NLRs) assemble caspase-1-activating inflammasome complexes that sense bacterial products/danger signals. Through a targeted chemical screen, we identify bromoxone, a marine natural product, as a specific and potent inhibitor of the caspase-1 pathway. Bromoxone is effective over diverse inflammatory stimuli including TLR ligands plus ATP/nigericin, cytosolic DNA, flagellin and Bacillus anthracis lethal toxin. Bromoxone also efficiently suppresses caspase-1 activation triggered by several types of bacterial infection. Bromoxone acts upstream or at the level of the inflammasome in a transcription-independent manner. Bromoxone also inhibits pro-IL-1β expression by targeting components upstream of IKK in the TLR-NF-κB pathway. The unique dual activities of bromoxone are shared by the known TAK1 inhibitor that specifically blocks Nalp3 inflammasome activation. Hinted from the mechanistic and pharmacological properties of bromoxone, we further discover that several known NF-κB inhibitors that act upstream of IKK, but not those targeting IKK or IKK downstream, are potent blockers of different NLRs-mediated caspase-1 activation. Our study uncovers a possible non-transcriptional molecular link between the NLR (Nalp3)-mediated inflammasome pathway and TLR-NF-κB signaling, and suggests a potential strategy to develop new anti-inflammatory drugs.


Priority setting in breast reconstructive surgery: A DELPHI consensus.
Breast reconstructive surgery is often performed following breast cancer treatment to restore the natural appearance of the breast. Despite various research performed in this field, there is a discrepancy between the research question that is considered crucial jointly by patients, carers and healthcare professionals and the research performed. The Breast Reconstruction Priority Setting Partnership was formed to determine the top research priorities in all aspects of breast reconstructive surgery. The Priority Setting Partnership (PSP) was conducted in line with James Lind Alliance (JLA) principles involving patients and clinicians. An online survey was conducted to gather uncertainties related to breast reconstruction by involving patients, carers and clinicians. Following this, a modified Delphi consensus process was performed to identify the top 10 research priorities. A total of 239 unique research uncertainties were identified via the online survey, which involved 100 participants. A review of literature established that 58 of these uncertainties did not have a high-quality systematic review, prompting the need for more in-depth research. A further 28 research uncertainties were obtained by performing a literature search. Of the final 86 unique questions, the Delphi panel achieved consensus on the top ten research priorities. Recommendations to address these research priorities have been put forward based on current evidence. This study involved patients, carers and healthcare professionals to establish the top 10 priority areas for research in breast reconstructive surgery. Recommendations have been put forward on the necessary future research that is required to address these uncertainties.


The antibiotic minocycline prevents methamphetamine-induced rewarding effects in mice.
Repeated use of methamphetamine (METH) causes dependence in humans, and to date, there are no effective medication treatments for METH addiction. We previously reported that the antibiotic minocycline attenuated behavioral abnormalities (hyperactivity and behavioral sensitization) and dopaminergic neurotoxicity in mice and monkeys, after the administration of METH. In this study, we examined the effect of minocycline on METH-induced rewarding effects in mice using the conditioned place preference (CPP) paradigm. Minocycline (40 mg/kg, IP) significantly attenuated METH (1.0 mg/kg, SC)-induced place preference in mice. In vivo microdialysis experiments using free-moving mice, showed that minocycline (40 mg/kg, IP) significantly attenuated the increased extracellular dopamine (DA) levels within the nucleus accumbens, typically seen after the administration of METH (1.0 mg/kg, SC). These findings suggest that minocycline may block METH-induced rewarding effects by down regulating extracellular DA levels in the nucleus accumbens of mice. This would make minocycline a potential therapeutic drug for the treatment of METH induced disorders.


Thermoregulation, plasma catecholamine and metabolite levels during submaximal work in individuals susceptible to malignant hyperpyrexia.
Measurements of body temperature, respiratory gas exchange, sweat evaporation rate and circulating levels of catecholamines, lactate, pyruvate, free fatty acids and glucose were made in seven patients susceptible to malignant hyperpyrexia (MHS) and in seven control subjects during 2 h of treadmill walking at 40% of maximum oxygen consumption. These studies took place in an ambient temperature of 22 degrees C. The MHS patients displayed the same thermoregulatory, plasma catecholamine and metabolic responses as the control subjects. The results of the present study suggest that non-competitive, low-intensity, steady-state exercise need not be contraindicated for MHS patients.


Glycosylation as a criterion for defining subpopulations of fast-transported proteins.
The role carbohydrate residues may play in the sorting of newly synthesized fast-transported proteins during the initiation of fast axonal transport has been examined by identifying individual fast-transported glycoproteins that contain either or both fucose and galactose. [3H]Fucose or [3H]galactose was incorporated together with [35S]methionine in vitro in bullfrog dorsal root ganglia. Fast-transported proteins that accumulated proximal to a ligature on the spinal nerve were separated via two-dimensional gel electrophoresis, and 92 gel spots were analyzed quantitatively for the presence of 35S and 3H. Of these spots, 56 (61%) contained either or both fucose and galactose. Glycomoieties were generally associated with families of charged spots whose isoelectric points could be altered with neuraminidase treatment. Single spots tended to be unglycosylated and were unaffected by neuraminidase. The prevalence of glycoproteins was considerably greater in the higher-molecular weight range. Of the 55 spots analyzed with molecular weight greater than approximately 35,000 daltons, 89% were glycosylated, whereas only 19% of the 37 spots with lower molecular weight contained sugar moieties. When considered in light of previous studies in which similar subpopulations have been described, the current findings suggest that the presence or absence of glycomoieties may represent another criterion by which proteins are sorted during the initiation of fast axonal transport.


Research applications and implications of adenosine in diseased airways.
Adenosine, when given by inhalation, initiates the narrowing of airways in subjects with asthma or chronic obstructive pulmonary disease (COPD). The underlying mechanism of this narrowing appears to involve the stimulation of specific mast cell surface adenosine receptors with the subsequent release of mediators and contraction of airway smooth muscle. Although methacholine and histamine have become gold standards as bronchial provocants used to quantify bronchial hyperresponsiveness, the airways response to the indirect stimulus adenosine more closely reflects bronchial inflammation. This distinctive feature of adenosine could be exploited to enable superior diagnostic discrimination between asthma and COPD, allow better monitoring of disease activity and progression, and improve the individual adjustment of long-term asthma management with topical glucocorticosteroids. In this article, we review recent developments in this area of rapidly evolving clinical research, focusing on the putative role of adenosine as a mediator of airway inflammation and as a useful bronchoprovocant in several clinical and research applications.


Expression of the Robo4 receptor in endothelial cells is regulated by two AP-1 protein complexes.
Roundabout4 (Robo4) is an endothelial cell-specific gene that plays an important role in endothelial cell stability. We previously identified a 3-kb Robo4 promoter and demonstrated the importance of its proximal region in regulating Robo4 gene expression. To investigate the role of the upstream promoter in Robo4 gene regulation, we searched evolutionarily conserved promoter regions by phylogenetic footprinting and identified three conserved promoter regions. The most upstream region included a conserved AP-1 binding motif at position -2875. A mutation in the AP-1 motif significantly decreased Robo4 promoter activity in a transient reporter assay. An electrophoretic mobility shift assay and a chromatin immunoprecipitation assay demonstrated binding of a c-Jun/c-Jun complex and a c-Jun/Fra-1 complex to the AP-1 motif. Knockdown experiments using siRNA revealed that both c-Jun/c-Jun and c-Jun/Fra-1 complexes regulate Robo4 gene expression, and that the c-Jun/c-Jun complex is essential for maximum promoter activation. Collectively, these results indicate that AP-1 complexes regulate Robo4 gene expression in endothelial cells.


A central nervous system keratan sulfate proteoglycan: localization to boundaries in the neonatal rat brain.
During the development of the central nervous system (CNS), adhesive molecules promote the formation of axonal pathways and appropriate neuronal connections by facilitating cellular interactions. In addition to the interactions that bring neurons together, recent evidence suggests inhibition of neuronal interactions also plays a role by restricting axons to their appropriate pathways and forming boundaries between functional units of the developing CNS. The present study describes the distribution of a recently identified large keratan sulfate proteoglycan, ABAKAN, in the postnatal day 14 (P14) and adult rat brain. In the adult brain ABAKAN appears to be relatively evenly distributed throughout the CNS, while at P14 this proteoglycan is found at high concentrations between different functional units of the neonatal brain. For example, ABAKAN appears to separate different cortical areas and mark the boundaries between thalamic nuclei. In vitro assays demonstrate that this keratan sulfate proteoglycan is a potent inhibitor of neurite growth. The distribution of ABAKAN at P14 and the effects of this keratan sulfate proteoglycan on neurite growth suggest that ABAKAN functions as a molecular barrier to axonal growth in the developing rat brain.


Expression and function of CB1 receptor in the rat striatum: localization and effects on D1 and D2 dopamine receptor-mediated motor behaviors.
Cannabinoid CB1 receptors are densely expressed on striatal projection neurons expressing dopamine D1 or D2 receptors. However, the specific neuronal distribution of CB1 receptors within the striatum is not known. Previous research has established that the endocannabinoid system controls facilitation of behavior by dopamine D2 receptors, but it is not clear if endocannabinoids also modulate D1 receptor-mediated motor behavior. In the present study, we show that cannabinoid CB1 receptor mRNA is present in striatonigral neurons expressing substance P and dopamine D1 receptors, as well as in striatopallidal neurons expressing enkephalin and dopamine D2 receptors. We explored the functional relevance of the interaction between dopamine D1 and D2 receptors and cannabinoid CB1 receptors with behavioral pharmacology experiments. Potentiation of endogenous cannabinoid signaling by the uptake blocker AM404 blocked dopamine D1 receptor-mediated grooming and D2 receptor-mediated oral stereotypies. In addition, contralateral turning induced by unilateral intrastriatal infusion of D1 receptor agonists is counteracted by AM404 and potentiated by the cannabinoid antagonist SR141716A. These results indicate that the endocannabinoid system negatively modulates D1 receptor-mediated behaviors in addition to its previously described effect on dopamine D2 receptor-mediated behaviors. The effect of AM404 on grooming behavior was absent in dopamine D1 receptor knockout mice, demonstrating its dependence on D1 receptors. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D1 and D2 receptor-mediated behaviors, a finding that may contribute to our understanding of basal ganglia motor disorders.


Electron-transfer-dominated non-radical activation of peroxydisulfate for efficient removal of chlorophenol contaminants by one-pot synthesized nitrogen and sulfur codoped mesoporous carbon.
Synergistic adsorption and oxidative degradation (via persulfate activation) on metal-free carbonaceous materials are expected to be environmentally friendly and highly efficient approach toward contaminants removal. Herein, nitrogen and sulfur codoped mesoporous carbon (NSDMC) were firstly synthesized via co-carbonization of calcium citrate and thiourea without any templates. NSDMC samples exhibit remarkably enhanced adsorption capacity and oxidative degradation (by activating PDS) for chlorophenols elimination. Increased SBET and introduced N-containing functional groups are beneficial for chlorophenols adsorption, PDS accessibility and successive activation. Doped sulfur species (especially for thiophenic S) can enhance the electron-transport performance of NSDMC, further promoting PDS activation and chlorophenols degradation. It can be ascribed to the synergistic effect of N and S codoping. NSDMC-30 (containing 5.83 at.% nitrogen and 2.15 at.% sulfur, and possessing SBET of 1935.9 m2 g-1) exhibits the optimal adsorption and catalytic oxidation capability for 4-CP removal. Degradation rate constant of NSDMC-30 is 0.125 min-1, which is 3.0 times and 7.8 times higher than nitrogen-doped MC and pristine MC, respectively. Radicals quenching experiments and EPR tests demonstrate that non-radical pathways play dominant role for PDS activation and chlorophenols degradation. Based on the influences of catalyst loading, initial 4-CP concentration, and PDS dosage on degradation kinetics of 4-CP, the pre-adsorption is unveiled to be the critical step determining oxidation rate of chlorophenols. More importantly, the results of in-situ Raman and electrochemical tests show that the surface-confined and activated PDS complex (carbon-PDS*) and continuous electron transfer from co-adsorbed 4-CP are mainly responsible for the oxidative degradation of chlorophenols. The intermediate products and TOC removal indicate that chlorophenols can be efficiently degraded and mineralized by as-synthesized NSDMC via activating PDS. Besides, the present NSDMC/PDS system is also applicable for purification of actual polluted water samples. This work provides in-depth knowledge of carbon-driven nonradical process for PDS activation and contaminants remediation.


Influence of variation in semiflexed knee positioning during image acquisition on separate quantitative radiographic parameters of osteoarthritis, measured by Knee Images Digital Analysis.
The clinical application of quantitative measurement of separate radiographic parameters of knee osteoarthritis (OA) might be hampered by a lack of reproducible semiflexed joint positioning during acquisition of radiographs. The influence of systematic variations in knee positioning on measurement of separate quantitative radiographic parameters was studied. Five components of knee position during radiographic acquisition (beam height, lower and upper leg extension, internal rotation, and lateral shift) were systematically varied within a clinically relevant range, using three cadaver legs. The influence of these variations on the measurement of the separate quantitative radiographic parameters by Knee Images Digital Analysis (KIDA) was evaluated. Significant changes were validated in vivo. Changes were compared with differences during 2-year follow-up in a radiographic progression cohort of early OA. Systematic variation in upper and lower leg extension induced changes in the measurement of joint space width (JSW). Lower leg extension also influenced osteophyte area and eminence height measurement. Also bone density measurement was influenced by variation in all five position components. Variations were of clinical relevance compared with 2-year differences in knees with radiographic progression, and were confirmed in vivo. Variations in semiflexed knee positioning, which are considered to occur easily during image acquisition in trials and clinical practice despite standardization, are of significant influence on the quantitative measurement of most separate radiographic parameters of OA using KIDA. The additional value of quantitative measurement might improve significantly by better standardization during radiographic acquisition; with radiography still being the gold standard for structure-modification in OA.


Bacteremia with esophageal dilation.
Antibiotic prophylaxis has been recommended for selected patients undergoing esophageal stricture dilation because of a reported high rate of bacteremia. The aim of this study was to determine the rate of bacteremia after esophageal dilatation in a large series and the source of the organisms recovered. Blood cultures and oral temperatures were obtained before esophageal dilation and at 5 and 30 minutes after dilation. Dilators were cultured immediately before dilation. Procedural data collected included type of dilation, number of passes, and presence of malignancy. Of 100 procedures in 86 patients undergoing esophageal dilation, 22 (22%) were associated with a positive post-dilation blood culture. Bacteremia was more frequent with dilation of malignant strictures compared with benign strictures (9 of 17 [52.9%] vs. 13 of 83 [15.7%], respectively, p = 0.002) and with passage of multiple dilators compared with passage of a single dilator (16 of 46 [34.8%] versus 6 of 54 [11.1%], respectively, p = 0.007). Bacterial isolates from 22 positive blood cultures matched those from a dilator in only one episode (4.5%). The rate of bacteremia after esophageal dilation is 22% and is associated with dilation of malignant strictures or passage of multiple dilators. Organisms cultured from the blood are not transmitted from the dilator.


Optimisation and production of alpha amylase from thermophilic Bacillus spp. and its application in food waste biodegradation.
This study employed Bacillus spp. with α-amylase production isolated from Malaysian hot spring for domestic kitchen food waste treatment contained grains, vegetables, chicken and tuna that mimic the food waste discharge from domestic kitchens in Malaysian household. Results showed that Bacillus licheniformis HULUB1 and Bacillus subtilis SUNGB2 possess excellent amylolytic properties. Highest α-amylase activity was obtained when both isolates were cultivated at pH 6.0 and 65 °C with concentrations of 18.15 U/mL for HULUB1 and 22.14 U/mL for SUNGB2. Stability of α-amylase with significant levels of enzyme activity were recorded at 55-85 °C and pH 5.0-9.0. The extracted mixed α-amylase of HULUB1 and SUNGB2 showed greatest reduction were achieved at day 12 with 45% ± 0.03 solid content at 65 °C. While the mixed culture of HULUB1 and SUNGB2 displayed an enhanced effect on the food waste contents reduction with 43% ± 0.02 solid content at 45 °C after day 12. The findings showed that the combination of the two Bacillus spp. isolates possessed degradation of food wastes at faster rate than α-amylase. It was also pointed out that the standard food waste (SFW) and the treatment process assimilated for this study was suitable for the growth of Bacillus spp.


Cost-Effective Smartphone-Based Articulable Endoscope Systems for Developing Countries: Instrument Validation Study.
Endoscopes are widely used for visualizing the respiratory tract, urinary tract, uterus, and gastrointestinal tracts. Despite high demand, people in underdeveloped and developing countries cannot obtain proper access to endoscopy. Moreover, commercially available endoscopes are mostly nonarticulable as well as not actively controlled, limiting their use. Articulating endoscopes are required for some diagnosis procedures, due to their ability to image wide areas of internal organs. Furthermore, actively controlled articulating endoscopes are less likely to harm the lumen than rigid endoscopes because they can avoid contact with endothelial tissues. The study aimed to demonstrate the feasibility and acceptability of smartphone-based wide-field articulable endoscope system for minimally invasive clinical applications in developing and less developed countries. A thin articulable endoscope system that can be attached to and actively controlled by a smartphone was designed and constructed. The system consists of a flexible endoscopic probe with a continuum mechanism, 4 motor modules for articulation, a microprocessor for controlling the motor with a smartphone, and a homebuilt app for streaming, capturing, adjusting images and video, and controlling the motor module with a joystick-like user interface. The smartphone and motor module are connected via an integrated C-type On-The-Go (OTG) USB hub. We tested the device in several human-organ phantoms to evaluate the usability and utility of the smartphone-based articulating endoscope system. The resolution (960 × 720 pixels) of the device was found to be acceptable for medical diagnosis. The maximum bending angle of 110° was designed. The distance from the base of the articulating module to the tip of the endoscope was 45 mm. The angle of the virtual arc was 40.0°, for a curvature of 0.013. The finest articulation resolution was 8.9°. The articulating module succeeded in imaging all 8 octants of a spherical target, as well as all 4 quadrants of the indices marked in human phantoms. The portable wide-field endoscope was successfully controlled using a smartphone, yielding clear images with a resolution of 960 × 720 pixels at realistic focal distances. Actively and precisely controlled articulating movements have resulted in minimally invasive monitoring in the narrow space of internal organs providing a wide-area view. We found our smartphone-based active articulated endoscope to be suitable for point-of-care applications in developing and less developed countries.


miR-497-5p/SALL4 axis promotes stemness phenotype of choriocarcinoma and forms a feedback loop with DNMT-mediated epigenetic regulation.
Choriocarcinoma stem-like cells (CSLCs) might be at the origin of choriocarcinoma development associated with drug resistance or relapse. Spalt-like transcription factor 4 (SALL4), which is considered to be a stemness-related gene, can be regulated by miRNAs. In this study, SALL4 result is associated with progression-free survival of choriocarcinoma patients and CSLC's stemness characteristics. In addition, it could be downregulated by miR-497-5p by direct binding. miR-497-5p silencing by hypermethylation promoted malignant CSLC phenotype in vitro and in vivo. Furthermore, increased DNA methyltransferases (DNMTs) by SALL4 upregulation inhibited miR-497-5p expression via hypermethylation promotion. SALL4 appeared to be a key factor in promoting stemness phenotype of choriocarcinoma. Silencing miR-497-5p and SALL4 promotes choriocarcinoma progression and forms a feedback loop with DNMT-mediated epigenetic regulation, playing a crucial role in stemness maintenance in choriocarcinoma.


The association between race and neighborhood socioeconomic status in younger Black and White adults with chronic pain.
Both race and socioeconomic status (SES) contribute to disparities. We assessed the relative roles of neighborhood socioeconomic status (nSES) and race in the chronic pain experience for young adults (<50 years old). Data from a tertiary care pain center was matched to 2000 US Census data to examine the role of race and nSES on chronic pain and its sequelae in 3,730 adults (9.7% black, 61% female) 18 to 49 years old (37 ± 8 years). Blacks had significantly more pain and disability and lived in lower SES neighborhoods. Living in a lower SES neighborhood was associated with increased sensory, affective, and "other" pain, pain-related disability, and mood disorders. Race was independently associated with affective and "other" pain on the McGill Pain Questionnaire scales, and both disability factors. Racial disparities in sensory pain and mood disorders were mediated by nSES. In every case, race and neighborhood SES played important roles in the outcomes for chronic pain. Age was related to both disability outcomes. Gender was associated with voluntary disability and mood disorders, with men displaying worse outcomes. Important racial- and SES-related variability in pain related outcomes in young adults with chronic pain were defined. Black race was associated with neighborhood SES, and black race plays an important role in pain outcomes beyond neighborhood SES.


Discrimination and quantification of cocaine and adulterants in seized drug samples by infrared spectroscopy and PLSR.
Middle infrared spectroscopy and multivariate analysis have been applied for the development of methods to perform both quantitative and qualitative analysis of real drug samples seized by the Brazilian Police Federal (BPF). Currently, quantification of cocaine and determination of adulterants in seizures is performed using gas chromatography with flame ionization detection. However, this technique requires a relatively complex sample preparation, higher time of analysis, the destruction of sample and a high cost. In this context, this paper presents a simpler method to quantify cocaine and its major adulterants in seized materials. Out of 375 seizures, taken within a time frame of 2009-2013. A total of 1085 samples were analyzed of which 500 were selected for the calibration set and 585 for the validation set. Cocaine concentration in seized samples was determined by using middle infrared spectroscopy and partial least squares regression (PLSR), obtaining an average prediction error of 3.0% (w/w), precision of 2.0 and 11.8% (w/w) of minimum detectable cocaine concentration in a range varying from 24.2 to 99.9% (w/w). Results indicate that the developed method is able to discriminate between cocaine hydrochloride and free base samples, to quantify cocaine content as well as to estimate the concentration of main adulterants phenacetin, benzocaine, caffeine, lidocaine and aminopyrine.


Capillary electrophoresis separation of the new anti-AIDS agents 9-(2-phosphonylmethoxyethyl)adenine and 9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine in mixtures with some monoribonucleotides or the most common deoxynucleotides.
The present work describes an electrophoretic method for the separation and determination of the new antivirals, 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(2-phosphonylmethoxyethyl)-2,9-diaminopurine (PMEDAP) in model mixtures with some monoribonucleotide isomers (3'-AMP, 2'-CMP, 3'-CMP, 3'-GMP, 2'-GMP, 3'-UMP, 5'-GMP, and 5'-UMP) or with the most common deoxynucleotides (dCMP, dCDP, dCTP, dTMP, dTDP, dTTP, dGMP, dGDP, dGTP, dAMP, dADP, dATP). A fused-silica capillary tube, 75 microm ID, 67.8 cm total length (60.3 cm length to the detector), with detection at 210 nm was employed. A hydrodynamic injection for 10 s (1.5 psi vacuum) was utilized to introduce the sample, and 30 kV voltage was applied for the separation. The complete separation of PMEA and PMEDAP from the mononucleotide isomers and deoxynucleotide mixtures is possible in less that 10 min and 25 min, respectively, using 20 mM borate buffer, pH 9.9, with the addition of 10 mM beta-cyclodextrin. Efficiencies of more than 120 000 and resolution higher than 1.9 were reached for each of the compounds studied. This capillary electrophoretic procedure opens the possibility for future determination of PMEA and PMEDAP in cell pool samples.


Bovine arthritides. Classification, diagnosis, prognosis, and treatment.
Bovine arthritides are an important aspect of food animal practice, and a good understanding of these conditions allows the practitioner to develop effective treatment regimens. This article discusses the complexities of joint diseases and the problems associated with their diagnoses and treatments.


Bedside ultrasound of acute adrenal hemorrhage.
Most complications from traumatic isolated adrenal hemorrhage are thought to be minor and do not require specific treatment. However, there are often additional intraabdominal organ injuries, such as liver and ipsilateral kidney, associated with adrenal injury. It is, therefore, important to identify these injuries as early as possible, preferably on initial assessment. We describe a case of a 43-year-old man who presented to the emergency department after sustaining blunt force trauma to the flank during a soccer match and was subsequently diagnosed with acute adrenal injury by use of bedside ultrasonography.


An analysis of nursing students' ethical conflicts in a hospital.
Education can be taken as a key factor in transmission of a value tradition in healthcare. In professional and educational contexts, transmission of values appears to be a kind of guarantee for an occupational group's professional identity, awareness and ethical integrity. Given the positives of such transmission of value traditions, one can also pay attention to conflicts between the professional tradition and individuals who are brought into that tradition. How does mediation of value tradition in healthcare education appear out of the students' perspective based on their own narratives? Students' texts were analysed through a combination of contrastive discourse analysis and sociohistorical description and then evaluated from an ethical perspective. Data were collected from the annual electronic feedback given by students after their clinical practice at a University Hospital. Organizational approval was received. Information about the voluntary nature of participation was a part of the feedback tool. The analysis points to the fact that there is a definite theme in the students' experiences that both the previous research has neglected and that stands in conflict with the current tradition of healthcare education in Finland. That theme can be summarized in the experience of 'losing one's identity', and it is expressed in a request to experience of 'losing one's identity' and it is expressed in a request to have a right to 'use one's own name' also as a healthcare professional. Being addressed by one's name is to make the person directly involved and responsible, realizing that that person's perspective is of importance to the way the world is. We argue that this theme (my name) is of ethical importance and could have empowering potentiality when used in an ethically sound way.


Deconstructing Timbre into 5 Physiological Parameters: Vocal Mode, Amount of Metal, Degree of Density, Size of Larynx, and Sound Coloring.
Timbre has been related to adjustment at the source as well as adjustments in resonance, including laryngeal height and hypopharynx area and volume. However, it is often presented in vocal pedagogy as solely related to resonance. Very little data is available on the laryngeal adjustments at both source and resonance involved in achieving various timbres across a variety of phonation types. To systematically assess the independent laryngeal adjustments at the source and independent laryngeal adjustments in the vocal tract necessary to obtain the lightest and darkest timbral extremes for four different phonation types. Twenty-one professional singers produced a sustained vowel "EH" as in "stay" in each of the four phonation types ("UH" as in "hungry" for one type), varying the sound coloring to the lightest and darkest of their ability without altering pitch, vowel, or loudness. The singers were observed using laryngostroboscopy and electroglottography. A systematic assessment protocol covering 31 laryngeal gestures was developed based on previous research for objectively classifying changes in laryngeal setups. Darkening and lightening the sound color involved altering the size of the vocal tract space related to lowering/raising the larynx, widening/closing the piriform sinuses, increasing/decreasing the distance between stylopharyngeus and palatopharyngeus, increasing/decreasing anterior-posterior narrowing (and the resulting view of the vocal folds), medialising/retracting ventricular folds, and altering supraglottic funnel depth. The phonation types did not show equal ability to be colored. Female singers exhibited less coloring variation compared to the males. Classical singing exhibited both lightening and darkening colouring features. The singers were able to produce a variety of different timbral expressions within each of the investigated four phonation types by coloring the sustained note darker or lighter using laryngeal adjustments. Timbre is deconstructed as a perceptual artefact defined by (1) the choice of vocal mode, (2) the amount of metallic character, (3) the degree of density in the note, (4) the chosen sound color, and (5) the natural size of the larynx and vocal tract.


Simulated shift work during pregnancy does not impair progeny metabolic outcomes in sheep.
Maternal shift work increases the risk of pregnancy complications, although its effects on progeny health after birth are not clear. We evaluated the impact of a simulated shift work protocol for one-third, two-thirds or all of pregnancy on the metabolic health of sheep progeny. Simulated shift work had no effect on growth, body size, body composition or glucose tolerance in pre-pubertal or young adult progeny. Glucose-stimulated insulin secretion was reduced in adult female progeny and insulin sensitivity was increased in adult female singleton progeny. The results of the present study do not support the hypothesis that maternal shift work exposure impairs metabolic health of progeny in altricial species. Disrupted maternal circadian rhythms, such as those experienced during shift work, are associated with impaired progeny metabolism in rodents. The effects of disrupted maternal circadian rhythms on progeny metabolism have not been assessed in altricial, non-litter bearing species. We therefore assessed postnatal growth from birth to adulthood, as well as body composition, glucose tolerance, insulin secretion and insulin sensitivity, in pre-pubertal and young adult progeny of sheep exposed to control conditions (CON: 10 males, 10 females) or to a simulated shift work (SSW) protocol for the first one-third (SSW0-7: 11 males, 9 females), the first two-thirds (SSW0-14: 8 males, 11 females) or all (SSW0-21: 8 males, 13 females) of pregnancy. Progeny growth did not differ between maternal treatments. In pre-pubertal progeny (12-14 weeks of age), adiposity, glucose tolerance and insulin secretion during an i.v. glucose tolerance test and insulin sensitivity did not differ between maternal treatments. Similarly, in young adult progeny (12-14 months of age), food intake, adiposity and glucose tolerance did not differ between maternal treatments. At this age, however, insulin secretion in response to a glucose bolus was 30% lower in female progeny in the combined SSW groups compared to control females (P = 0.031), and insulin sensitivity of SSW0-21 singleton females was 236% compared to that of CON singleton female progeny (P = 0.025). At least in this model, maternal SSW does not impair progeny metabolic health, with some evidence of greater insulin action in female young adult progeny.


Rapid ultrasensitive detection of hexavalent chromium in soil and groundwater by a microProbing imaging platform.
Rapid detection methods are needed to investigate the environmental quality risk of soil and groundwater in contaminated lands. Currently there is lack of rapid detection methods to sensitively and accurately analyze contaminations of hexavalent chromium in soil due to the challenge of complex sample pretreatment or expensive instrumentation. Here we report a rapid accurate detection platform for quantifying hexavalent chromium in soil and groundwater with ultrasensitivity. The platform consists of a novel sensor of microProbing beads and a portable microscope. Each microProbing bead was a nanoliter reactor to selectively sequestrate Cr (VI) with the enrichment factor up to 150 ×. The microProbing beads presented the signal uniformity of ~97% for the statistical colorimetric imaging analysis. Combined with a miniaturized microscope, the microProbing beads allowed for detecting aqueous Cr (VI) and soluble Cr (VI) in soil within 45 min. The platform achieved high sensitivity with the detection limits of 0.003 ppb for aqueous Cr (VI) and 0.07 ppm for soil Cr (VI). It accurately detected soil and groundwater samples from a chromium contaminated land in Yangtze River Basin of China. The consistency to the laboratory standard methods was achieved with the low cost of ~0.20 US dollar per test. The microProbing imaging platform with the operational simplicity and device portability is highly promising for the field analysis of Cr (VI) in contaminated lands.


Salidroside ameliorates acetaminophen-induced acute liver injury through the inhibition of endoplasmic reticulum stress-mediated ferroptosis by activating the AMPK/SIRT1 pathway.
Acetaminophen (APAP) overdose has long been considered a major cause of drug-induced liver injury. Ferroptosis is a type of programmed cell death mediated by iron-dependent lipid peroxidation. Endoplasmic reticulum (ER) stress is a systemic response triggered by the accumulation of unfolded or misfolded proteins in the ER. Ferroptosis and ER stress have been proven to contribute to the progression of APAP-induced acute liver injury (ALI). It was reported that salidroside protects against APAP-induced ALI, but the potential mechanism remain unknown. In this study, male C57BL/6 J mice were intraperitoneally (i.p.) injected APAP (500 mg/kg) to induce an ALI model. Salidroside was i.p. injected at a dose of 100 mg/kg 2 h prior to APAP administration. Mice were sacrificed 12 h after APAP injection and the liver and serum of the mice were obtained for histological and biochemistry analysis. AML12 cells were used in in vitro assays. The results indicated that salidroside mitigated glutathione degradation via inhibiting cation transport regulator homolog 1 (CHAC1) to attenuate ferroptosis, and simultaneously suppressing PERK-eIF2α-ATF4 axis-mediated ER stress, thus alleviating APAP-induced ALI. However, PERK activator CCT020312 and overexpression of ATF4 inhibited the protective function of salidroside on CHAC1-mediated ferroptosis. Besides this, activation of the AMPK/SIRT1 signaling pathway by salidroside was demonstrated to have a protective effect against APAP-induced ALI. Interestingly, selective inhibition of SIRT1 ameliorated the protective effects of salidroside on ER stress and ferroptosis. Overall, salidroside plays a significant part in the mitigation of APAP-induced ALI by activating the AMPK/SIRT1 signaling to inhibit ER stress-mediated ferroptosis in the ATF4-CHAC1 axis.


Advanced squamous cell carcinoma involving both upper and lower lips and oral commissure with simultaneous reconstruction by local flap: a case report.
Squamous cell carcinoma is one of the most common malignant tumors of the skin and oral mucosa. However, squamous cell carcinoma involving near total upper and lower lip and oral commissure is rarely seen in the English literature. Simultaneous reconstruction of the upper and lower lips has been inconclusive and presents a challenge to the surgeon. We report such a case and outline our simultaneous reconstruction with local flaps. To the best of our knowledge this has never been reported. A 73-year-old Thai woman presented with a large rapidly growing squamous cell carcinoma involving the upper lip, lower lip, left oral commissure and left cheek. En bloc resection of upper lip, lower lip, left oral commissure and buccal region was performed. Left radical neck dissection and right modified neck dissection were performed. Reconstruction of the upper lip with a left nasolabial-cheek cervicofacial rotational-advancement flap and right cheek advancement with perialar crescent flap was performed. The lower lip was reconstructed with bilateral labiomental advancement flaps. Squamous cell carcinoma can grow rapidly and spread along the orbicularis oris muscle and across the oral commissure to the opposite lip. In advanced cancer, multimodal treatment is necessary. No gold standard in the reconstruction of both upper and lower lips has been established. We report the case of an advanced squamous cell carcinoma involving both the upper lip, lower lip, left oral commissure and buccal area and simultaneous reconstruction with local flap coverage that, to the best of our knowledge, has never been reported.


Experimental simulation of quantum tunneling in small systems.
It is well known that quantum computers are superior to classical computers in efficiently simulating quantum systems. Here we report the first experimental simulation of quantum tunneling through potential barriers, a widespread phenomenon of a unique quantum nature, via NMR techniques. Our experiment is based on a digital particle simulation algorithm and requires very few spin-1/2 nuclei without the need of ancillary qubits. The occurrence of quantum tunneling through a barrier, together with the oscillation of the state in potential wells, are clearly observed through the experimental results. This experiment has clearly demonstrated the possibility to observe and study profound physical phenomena within even the reach of small quantum computers.


[Hip joint operations in routine patient management--determinants of quality of life].
The study was conducted in co-operation with a German sickness fund to identify determinants of health related quality of life (HRQL) after hip surgery in routine health care. In 9/97 all beneficiaries (age 40-75 years), which were treated in hospital for osteoarthrosis (n = 1352), were sent a questionnaire on average 5.2 months (t1), postoperatively. The standardized questionnaire contained a.o. items about pre- and postoperative subjective assessment of disease specific symptoms (Lequesne-Index), complications, comorbidity, health related quality of life (SF-36). The response rate at t1 was 67.8%. Patients with hip surgery (n = 390) were sent a second questionnaire 17.2 months (t2) postoperatively. At t2 data from 293 patients were available for analysis. Patients (57.6% male) were on average 61 years of age and 61.2% reported no co-morbidity. 88.4% received total hip replacement. 30.3% of patients reported at least one complication. HRQL in patients after hip surgery is significantly impaired in six of the eight SF-36 subscales compared to the German norms at t1 and t2. From t1 to t2 substantial improvements appear in the SF-36 subscales physical functioning, role physical and bodily pain (p < 0.001). Major determinants of HRQL are comorbidity (if yes: less improvement) and attendance of inpatient rehabilitation (if yes: more improvement). In routine healthcare HRQL after hip surgery is determined by patient characteristics and postoperative rehabilitation. Inspite of substantial improvements patients did not (yet) reach the level of the reference population.