Synthesis, Electrochemical and Photochemical Properties of Sulfanyl Porphyrazine with Ferrocenyl Substituents.
Ferrocene is useful in modern organometallic chemistry due to its versatile applications in material sciences, catalysis, medicinal chemistry, and diagnostic applications. The ferrocene moiety can potentially serve many purposes in therapeutics and diagnostics. In the course of this study, (6-bromo-1-oxohexyl)ferrocene was combined with dimercaptomaleonitrile sodium salt to yield a novel maleonitrile derivative. Subsequently, this compound was subjected to an autocyclotetramerization reaction using the Linstead conditions in order to obtain an octaferrocenyl-substituted magnesium(II) sulfanyl porphyrazine. Following that, both compounds-the maleonitrile derivative and the porphyrazine derivative-were subjected to physicochemical characterization using UV-Vis, ES-TOF, MALDI-TOF, and one-dimensional and two-dimensional NMR spectroscopy. Moreover, the sulfanyl porphyrazine was subjected to various photophysical studies, including optical absorption and emission measurements, as well as the evaluation of its photochemical properties. Values of singlet oxygen generation quantum yields were obtained in different organic solvents. The electrochemical properties of the synthesized compounds were studied using cyclic voltammetry. According to the electrochemical results, the presence of electron-withdrawing oxohexyl groups attached to ferrocene afforded significantly more positive oxidation potentials of the ferrocene-based redox process up to 0.34 V vs. Fc+/Fc.


Physiological modulation of BiP activity by trans-protomer engagement of the interdomain linker.
DnaK/Hsp70 chaperones form oligomers of poorly understood structure and functional significance. Site-specific proteolysis and crosslinking were used to probe the architecture of oligomers formed by the endoplasmic reticulum (ER) Hsp70, BiP. These were found to consist of adjacent protomers engaging the interdomain linker of one molecule in the substrate binding site of another, attenuating the chaperone function of oligomeric BiP. Native gel electrophoresis revealed a rapidly-modulated reciprocal relationship between the burden of unfolded proteins and BiP oligomers and slower equilibration between oligomers and inactive, covalently-modified BiP. Lumenal ER calcium depletion caused rapid oligomerization of mammalian BiP and a coincidental diminution in substrate binding, pointing to the relative inertness of the oligomers. Thus, equilibration between inactive oligomers and active monomeric BiP is poised to buffer fluctuations in ER unfolded protein load on a rapid timescale attainable neither by inter-conversion of active and covalently-modified BiP nor by the conventional unfolded protein response.


Pediatric neurology training in Canada: current status and future directions.
Child neurology training in Canada has changed considerably over time, with increasing requirements for standardized teaching of the fundamentals of child neurology and the CanMEDS competencies. We sought to determine the current status of child neurology training in Canada as well future directions for training. A web-based survey was sent to program directors (PD's) of active pediatric neurology training programs. General questions about the programs were asked, as well as about success at the Royal College of Physicians and Surgeons of Canada (RCPSC) exam, breakdown of rotations, views on CanMEDS roles and questions on the future of pediatric neurology. 9/9 PD's completed the survey. 96.5% of all trainees successfully passed their RCPSC exam from 2001-2006. Breakdowns of the number and type of rotations for each year of training were provided. All CanMEDS roles were deemed to be important by PD's and programs have developed unique strategies to teach and assess these roles.92.6% of trainees chose to go into academic practice, with the most popular subspecialty being epilepsy. All PD's favour joint training sessions particularly for neurogenetics and neuromuscular disease. Overall, PD's suggest recruitment for future child neurologists at the medical student level but are divided as to whether we are currently training too few or too many child neurologists. This survey provides a view of the current state of pediatric neurology training in Canada and suggestions for further development of post-graduate training. In particular, attention should be given to joint educational programs as well as urgently assessing the manpower needs of child neurologists.


[Studies on establishment and maintenance of persistent infection with measles virus in NC-37 cell. III. Role of interferon in establishment and maintenance of persistent infection (author's transl)].
Human lymphoblastoid cell, NC-37, persistently infected with measles virus could always produce interferon in culture medium. Persistently infected cells were sensitive to interferon and acquired antiviral state, but normally yielded infectious progeny virus in culture fluid. Sensitivity of measles virus to interferon was studied because measles virus continued to replicate in these persistently infected cell. Attenuated and SSPE viruses which established persistent infection were relatively resistant to antiviral effect of interferon while wild strain had a sensitivity. Interferon produced endogenously in these persistently infected cells did not play an important role in maintenance of persistent infection caused by the suppression of virus replication. As it was found that persistently infected cell treated with interferon as high as 10(4) units/ml was significantly decreased virus yield in parallel with hemadsorption, it is suggested that endogenous measles virus which has been replicate in persistently infected cell might be also sensitive to high titer of interferon. NC-37 cell pretreated with interferon (10(3) units/ml) was infected with wild strain of measles virus. The treated cell led to decrease approximately 30% of virus yield and hemadsorption at the time when maximum yield was obtained in control cell, and that cell death reduced one week, but persistent infection could not be established.


Heritability of pubertal timing: detailed evaluation of specific milestones in healthy boys and girls.
Pubertal timing is highly heritable. Observational studies were inconclusive concerning a potential sex-specific difference in the parental contribution, while genome-wide association studies highlighted a heterogeneity in the genetic architecture of pubertal timing between sexes. Our objectives were to evaluate the association of timing of pubertal milestones in offspring with parental pubertal timing and to identify the genetic basis of the heterogeneity. (1.) Population-based mixed cross-sectional/longitudinal cohort (2006-2014, COPENHAGEN Puberty Study) comprising 1381 healthy Danish children including their parents. (2.) UK Biobank-based summary statistics of genetic data on timing of menarche (n = 188 644), voice-break (n = 154 459) and facial hair (n = 161 470). (1.) Participants underwent clinical examination(s) including blood sampling. Parental pubertal timing was obtained by questionnaire. Timing of milestones were analyzed using SAS-lifereg. (2.) Genetic correlations between pubertal outcomes were estimated using LD Score regression. Genetic heterogeneity was analyzed using METAL. We observed significant associations of relative parental pubertal timing with timing of pubertal milestones in offspring of concordant sex, that is, fathers/sons (e.g. testicular enlargement: P = 0.004, β = 0.34 years per relative category) and mothers/daughters (e.g. thelarche: P < 0.001, β = 0.45 years per relative category). Fewer milestones were associated with relative parental pubertal timing in offspring of discordant sex compared to concordant sex. Large-scale genetic data highlight both moderate to strong genetic correlations between timing of menarche, voice-break and facial hair. Out of 434 lead single-nucleotide polymorphisms significantly associated with at least one outcome, 39 exhibited a significant genetic heterogeneity between sexes (P < 1.15 × 10-4). Our results highlight a distinct genetic heterogeneity of pubertal timing between sexes.


Spectral element method for band structures of three-dimensional anisotropic photonic crystals.
A spectral element method (SEM) is introduced for accurate calculation of band structures of three-dimensional anisotropic photonic crystals. The method is based on the finite-element framework with curvilinear hexahedral elements. Gauss-Lobatto-Legendre polynomials are used to construct the basis functions. In order to suppress spurious modes, mixed-order vector basis functions are employed and the Bloch periodic boundary condition is imposed into the basis functions with tangential components at the boundary by multiplying a Bloch phase factor. The fields and coordinates in the curvilinear hexahedral elements are mapped to the reference domain by covariant mapping, which preserves the continuity of tangential components of the field. Numerical results show that the SEM has exponential convergence for both square-lattice and triangular-lattice photonic crystals. The sampling density as small as 3.4 points per wavelength can achieve accuracy as high as 99.9%. The band structures of several modified woodpile photonic crystals are calculated by using the SEM.


Peripheral activities during EMR use in emergency care: a case study.
We report on how the use of electronic medical record (EMR) systems in an emergency department (ED) contributes to peripheral physician activities and in turn, how these peripheral activities can lead to challenges in the patient care process. Through a qualitative research study, we identify three prominent peripheral activities that affect the continuity of care: (1) transition between multiple artifacts, (2) movement between multiple locations and (3) transition of information between multiple care providers. We discuss how the peripheral activities can introduce new errors and create bottlenecks in patient flow, consequently affecting both clinical and organizational goals. We highlight the importance of integrating EMR applications with the model of practice in the ED.


Mortality, complications and loss of pulmonary function after pneumonectomy vs. sleeve lobectomy in patients younger and older than 70 years.
Retrospective single institution analysis of all patients undergoing sleeve lobectomy or pneumonectomy between 2000 and 2005. Seventy-eight patients underwent pneumonectomy (65 patients <70 years, 13 patients >70 years) and 69 sleeve lobectomy (50 patients <70 years, 19 patients >70 years). Pre-existing co-morbidity, surgical indication and induction therapy was similarly distributed between treatment by age-groups. In patients <70 years, pneumonectomy and sleeve lobectomy resulted in a 30-day mortality of 3% vs. 0 and an overall complication rate of 26% vs. 44%, respectively. In patients >70 years, pneumonectomy and sleeve lobectomy resulted in a 30-day mortality of 15% vs. 0 and an overall complication rate of 23% vs. 32%. In both age groups, pneumonectomy was associated with more airway complications (NS) and a significantly higher postoperative loss of FEV(1) than sleeve lobectomy (P<0.0001, P<0.03). Age per se did not influence the loss of FEV(1) and DLCO for a given type of resection. Sleeve lobectomy may have a therapeutic advantage over pneumonectomy in the postoperative course of elderly patients.


Chronic cerebrospinal venous insufficiency and multiple sclerosis.
Chronic cerebrospinal venous insufficiency has recently been proposed to be etiologic to multiple sclerosis. Independent investigation into this theory during the past 2 years has not succeeded in verifying this relationship. A critical analysis of the scientific methods used in the original studies of chronic cerebrospinal venous insufficiency in multiple sclerosis reveals several methodological problems with regard to potential bias and confounding. The current evidence calls into question whether chronic cerebrospinal venous insufficiency in multiple sclerosis exists at all.


Phantom erectile penis after sex reassignment surgery.
Between January 2001 and December 2007, we performed vaginoplasty as sex reassignment surgery in a total of 14 male-to-female transsexual (MTFTS) patients [1]. Several complications occurred such as partial flap necrosis, rectovaginal fistula formation and hypersensitivity of the neoclitoris. Just after the operation, some patients feel that their penises still exist, but by several weeks postoperatively, this sensation has disappeared. Herein we report a case of MTFTS in whom the sensation of a phantom erectile penis persisted for much longer.


Epidural analgesia and liver resection: postoperative coagulation disorders and epidural catheter removal.
The aim of this study was to quantify the duration and severity of postoperative coagulopathy in order to establish the optimal time for epidural catheter removal. In a 2-year retrospective study, 140 consecutive patients underwent major liver resection. Epidural catheters were present in 123 patients (87.9%). Resections were: 33 (26.8%) right hepatectomy (with or without left metastasectomy), 9 (7.3%) left hemihepatectomy (with or without right metastasectomy), 37 (30.1%) trisectionectomy (extended hemihepatectomy) and 44 (35.8%) non-anatomical metastasectomy. Surgery was quantified by segments resected (4 [range: 1-7]). Vascular inflow occlusion was used in 65.6%. Ischaemic time was 26.5 min (range: 0-104 min). Platelet count fell postoperatively and was lowest on day 2 (205±72 10(9) L(-1)). There was a significant increase in prothrombin time, activated partial thromboplastin time and International Normalised Ratio (INR) postoperatively, peaking on day 2 (21.5±5.6 s, 37.9±5.8 s and 1.9±0.5, respectively). Changes persisted beyond day 6. Epidural catheters were removed on day 5 (1-11), with a protocol criterion of INR <1.2. Actual INR on day 5 was 1.49±0.36. Despite this, no epidural or spinal haematoma was recorded.


Commissurorraphy in the Dog.
Commissurorraphy is a surgical procedure designed to move the lip commissure rostrally. This procedure may be helpful as a unilateral procedure in cases of unilateral mandibulectomy to support tongue function and improve esthetics. Bilateral commissurorraphy is utilized in cases of radical bilateral mandibulectomy and as a salvage procedure for support of bilateral mandibular fractures in cases where rigid surgical fixation is not feasible. Dehiscence is the most likely complication of commissurorraphy. Tension can be reduced at the rostral extent of the incision by utilizing mattress sutures, intravenous fluid tubing, and/or buttons to prevent tearing through sutures.


[Menthol in the control of bladder activity: A review].
Menthol is a natural compound, of which the known effects on human physiology are manifold (a feeling of freshness, decongestant, bowel antispasmodic). Its implication in vesico-sphincteral physiopathology has been studied since the nineties. Literature review of the previous studies having implied menthol in pelvi-perineal physiology through the articles indexed on the Pubmed database, with keywords menthol, menthol and bladder, menthol and toxicity, and TRPM8. Only articles in English were selected. Of the 30 articles that were included, most demonstrated the existence of a micturition reflex to menthol and cold, mediated by the C-type nerve to the spine through activation of TRPM8 urothelial receptors. More recent experiments paradoxically showed an inhibitory effect of menthol on detrusor contractility, independently of TRPM8, when muscle tissue is directly exposed to the compound. However, similar effects of targeted cutaneous exposure or urothelial exposure on detrusorian function have also been demonstrated through TRPM8. This receptor also appears to be involved in interstitial cystitis and idiopathic detrusor overactivity. Lastly, the potential toxicity of menthol appears negligible. Most of the referenced studies are related to animal experiments. Of the three studies that implied humans, only one elucidates some therapeutic applications. It seems that menthol and its receptors are involved in vesico-sphincteral physiopathology and could provide therapeutic potential in detrusorian overactivity and interstitial cystitis with reduced toxicity.


Signaling pathways predisposing to chronic kidney disease progression.
The loss of functional nephrons after kidney injury triggers the compensatory growth of the remaining ones to allow functional adaptation. However, in some cases, these compensatory events activate signaling pathways that lead to pathological alterations and chronic kidney disease. Little is known about the identity of these pathways and how they lead to the development of renal lesions. Here, we combined mouse strains that differently react to nephron reduction with molecular and temporal genome-wide transcriptome studies to elucidate the molecular mechanisms involved in these events. We demonstrated that nephron reduction led to 2 waves of cell proliferation: the first one occurred during the compensatory growth regardless of the genetic background, whereas the second one occurred, after a quiescent phase, exclusively in the sensitive strain and accompanied the development of renal lesions. Similarly, clustering by coinertia analysis revealed the existence of 2 waves of gene expression. Interestingly, we identified type I interferon (IFN) response as an early (first-wave) and specific signature of the sensitive (FVB/N) mice. Activation of type I IFN response was associated with G1/S cell cycle arrest, which correlated with p21 nuclear translocation. Remarkably, the transient induction of type I IFN response by poly(I:C) injections during the compensatory growth resulted in renal lesions in otherwise-resistant C57BL6 mice. Collectively, these results suggest that the early molecular and cellular events occurring after nephron reduction determine the risk of developing late renal lesions and point to type I IFN response as a crucial event of the deterioration process.


Characterization of deep sub-wavelength nanowells by imaging the photon state scattering spectra.
Optical-matter interactions and photon scattering in a sub-wavelength space are of great interest in many applications, such as nanopore-based gene sequencing and molecule characterization. Previous studies show that spatial distribution features of the scattering photon states are highly sensitive to the dielectric and structural properties of the nanopore array and matter contained on or within them, as a result of the complex optical-matter interaction in a confined system. In this paper, we report a method for shape characterization of subwavelength nanowells using photon state spatial distribution spectra in the scattering near field. Far-field parametric images of the near-field optical scattering from sub-wavelength nanowell arrays on a SiN substrate were obtained experimentally. Finite-difference time-domain simulations were used to interpret the experimental results. The rich features of the parametric images originating from the interaction of the photons and the nanowells were analyzed to recover the size of the nanowells. Experiments on nanoholes modified with Shp2 proteins were also performed. Results show that the scattering distribution of modified nanoholes exhibits significant differences compared to empty nanoholes. This work highlights the potential of utilizing the photon status scattering of nanowells for molecular characterization or other virus detection applications.


Mesenchymal Stem Cells Isolated from the Anterior Cruciate Ligament: Characterization and Comparison of Cells from Young and Old Donors.
Mesenchymal stem cells (MSCs) isolated from the anterior cruciate ligament (ACL) share multiple characteristics of bone marrow-derived mesenchymal stem cells (BMSCs), allowing their use for regenerative therapies. Injuries to the ACL can affect people of all ages. This study assesses whether the regenerative potential of ACL-derived MSCs (ACL-MSCs) from old donors is as high as the potential of ACL-MSCs from young donors. ACL-MSCs were isolated from ACL tissues obtained from young and old donors at the time of ACL reconstruction or arthroplasty. Proliferative capacity, multilineage differentiation potential (chondrogenic, osteogenic, and adipogenic lineages), and transcriptome-wide gene expression were assessed and compared between young and old donors. BMSCs of middle-aged donors served as an additional comparator. No substantial differences between ACL-MSCs from young and old donors were observed in their proliferative capacity and multilineage differentiation potential. The latter did not substantially differ between both ACL-MSC groups and BMSCs. Differential expression of genes related to the cytoskeleton and to protein dephosphorylation amongst other pathways was detected between ACL-MSCs from young and old donors. Regenerative potential of ACL-MSCs from old donors was not substantially lower than that from young donors, suggesting that regenerative therapies of ACL tears are feasible in both age groups. In vivo studies of the effect of age on the efficacy of such therapies are needed.


AIMp1 Potentiates TH1 Polarization and Is Critical for Effective Antitumor and Antiviral Immunity.
Dendritic cells (DCs) must integrate a broad array of environmental cues to exact control over downstream immune responses including TH polarization. The multienzyme aminoacyl-tRNA synthetase complex component AIMp1/p43 responds to cellular stress and exerts pro-inflammatory functions; however, a role for DC-expressed AIMp1 in TH polarization has not previously been shown. Here, we demonstrate that the absence of AIMp1 in bone marrow-derived DC (BMDC) significantly impairs cytokine and costimulatory molecule expression, p38 MAPK signaling, and TH1 polarization of cocultured T-cells while significantly dysregulating immune-related gene expression. These deficits resulted in significantly compromised BMDC vaccine-mediated protection against melanoma. AIMp1 within the host was also critical for innate and adaptive antiviral immunity against influenza virus infection in vivo. Cancer patients with AIMp1 expression levels in the highest tertiles exhibited a 70% survival advantage at 15-year postdiagnosis as determined by bioinformatics analysis of nearly 9,000 primary human tumor samples in The Cancer Genome Atlas database. These data establish the importance of AIMp1 for the effective governance of antitumor and antiviral immune responses.


Reverse midpalmar island flap transfer for fingertip reconstruction.
Significant soft tissue defects of the fingertip with exposure of tendon or bone represent a challenging problem when homodigital or heterodigital artery island flaps are not available. In an attempt to resolve this problem, 15 patients with fingertip injuries involving palmar skin defects or amputation were treated with a vascularized flap transfer from the midpalmar area. A 2.5 x 1.5 to 4.5 x 2 cm flap from the radial or distal aspect of the midpalm, pedicled on the terminal branch of the superficial palmar arch or common/proper palmar digital artery and vein, was transferred in a retrograde fashion to cover the skin and soft tissue defects of the finger. All the flaps survived without complications. Moving two-point discrimination in the flap averaged 6 mm in patients who underwent sensory flap transfer. We concluded that vascularized skin flaps from the radial or distal aspects of the midpalm offer a good alternative option for the reconstruction of fingertip palmar skin and soft tissue defects.


Extended release drug delivery strategies in psychiatry: theory to practice.
An overview of the emerging field of long-term delivery strategies for improved convenience and adherence with psychiatric medications is provided. This review is motivated by the hypothesis that adherence to treatment is an important determinant of clinical outcomes in a wide range of settings and is particularly important in psychiatry practice where patients require treatment for months or years and premature discontinuation can have serious consequences for patient health and quality of life. The author reviews the relevant literature and highlights several approaches to providing improved access to continuous medication through new and innovative delivery strategies ranging from days to annual intervals.Benefits and Disadvantages: Several solutions to the problem of discontinuous access to pharmacotherapy are being developed in the form of new, long-acting drug-delivery systems, which gradually release medication over a period of several days or weeks with a single application. Long-acting formulations of psychiatric medications offer a number of potential benefits in comparison with conventional immediate-release agents, including improved safety and effectiveness. Potential limitations to using long-acting formulations may include pain and discomfort at the injection site, perceived inconvenience of a new treatment method, preference for oral medications, and length of time to titrate down to the lowest effective dose. The introduction of new, long-acting drug formulations could provide significant improvements in clinical outcomes and patient satisfaction for many patients, including those with affective disorders, schizophrenia, and alcohol dependence. Switching from oral administration to these new agents requires careful monitoring to reach the optimal dose, and patient concerns regarding the use of new delivery methods must be addressed. Long-acting formulations are not intended to be a sole form of treatment, and the use of psychotherapy as an adjunct form of treatment is still required. Controlled clinical trials of these new formulations have only recently been completed, offering clinicians a new option in their treatment regimens; however, as technologies improve, several new formulations are likely to enter clinical trials during the next few years. Psychiatrists will need to become acquainted with these technologies and educate their patients about them so they may work together to determine the most effective treatment option.


The degree of mineralization of bone tissue measured by computerized quantitative contact microradiography.
Strength of bones depends on bone matrix volume (BMV), bone microarchitecture, but also bone mineralization, and we have recently shown in osteoporotic patients treated with alendronate that fracture risk and bone mineral density (BMD) were changed without modifications of BMV or bone microarchitecture. Mineralization of bone matrix implies two successive steps: a rapid primary mineralization on the calcification front followed by a slow process of secondary mineralization progressively adding about one-half of the mineral content on bone matrix. These two steps are clearly illustrated by microradiographs of compact and cancellous bone tissue from transiliac human biopsies. Our working hypothesis is based on the impact of changes in bone remodeling rate on the degree of mineralization of bone, i.e., on the BMD measured at the tissue level. Contact quantitative microradiography using a computerized microdensitometric method, is described and allows the measurement of the mean degree of mineralization of bone (MDMB). This parameter may be quantitatively evaluated by exposing an aluminum calibration step-wedge and a plane-parallel calcified tissue section simultaneously to the same beam of X-rays, then determining, from the resulting microradiograph, the thickness of aluminum that produces the same X-ray absorption as a given region of the bone tissue section. To be used as a control group, iliac bone samples were taken at necropsy from 43 subjects (30 women aged 48.4 +/- 3.7 years and 13 men aged 66.0 +/- 4.4 years) who died suddenly showing no apparent bone disease. A control MDMB, which does not change with age, and a control distribution of these values are thus established. These control values are necessary for interpreting the changes in MDMB observed in bone conditions untreated or treated.


Transient blindness following mild head trauma. Criteria for a benign outcome.
A series of seven children in Hawaii experienced transient cortical blindness following mild head trauma. All children, ages 3 through 8, recovered fully. The most prominent clinical feature was initial restlessness and agitation following relatively mild head trauma without significant loss of consciousness (LOC). One child may have experienced this several times. The clinical features associated with a benign outcome in this syndrome include: pediatric age group, mild head trauma, brief or no LOC, onset of blindness occurring within hours of the head injury, absent optokinetic nystagmus, duration of blindness less than 24 hours, agitation and restlessness, absence of skull fracture or visible cerebral injury on CT scan, absence of other neurological deficits, and EEG findings that initially show posterior slowing with subsequent normalization. Transiently fixed and dilated pupils have been described in these patients but should be viewed cautiously by clinicians in making this diagnosis, since cortical blindness is defined by sparing of the pupils. This syndrome may be underdiagnosed, since it may not be obvious that the child is blind unless the diagnosis is considered.


Determining the Effect of Amino Acids on the Allergenic Activity of Pollen Extracts.
The diagnosis and treatment of allergic diseases require high quality pollen allergen extracts for reliable test results and effective treatments. The quality of the pollen allergen extracts is influenced by pharmacologically inert ingredients, such as stabilizers which are added to prevent the degradation of the allergenic activity. This study was conducted to develop a stabilizer formulation in order to protect the allergenic activity of the pollen's extracts. Pine and orchard grass pollen allergen extracts were incubated for 40 days at 37 °C. The effects of chemicals were examined via inhibition ELISA on days 7, 14, 21, 28, and 40 to evaluate the ability of the pollen allergen extracts to inhibit specific IgE in the sera of sensitized patients. Our findings showed that the pine pollen and orchard grass allergen extracts treated with Lys/Glu had the best stabilizing effect resulting in a 97% IgE inhibition following the 40 days of incubation. In the non-treatment group, the IgE inhibition decreased to 23% at the end of the 40 days. The orchard grass pollen allergen extracts receiving no treatment decreased to 12% IgE inhibition following the 40-day incubation. Amino acids are able to act as an effective stabilizer for pollen allergen extracts and prevent the degradation of their activity over time. Particularly applying Lys/ Glu in pollen allergenic extracts can protect allergenic activity and potency of the pollen extracts to inhibit specific IgE in human sera.


Humor Affects Fairness Considerations in the Gain and Loss Contexts.
Human decision-making behaviors in social contexts are largely driven by fairness considerations. The dual-process model suggests that in addition to cognitive processes, emotion contributes to economic decision-making. Although humor, as an effective emotional regulation strategy to induce positive emotion, may influence an individual's emotional state and decision-making behavior, previous studies have not examined how humor modulates fairness-related responses in the gain and loss contexts simultaneously. This study uses the Ultimatum Game (UG) in gain and loss contexts to explore this issue. The results show, in the gain context, viewing humorous pictures compared to humorless pictures increased acceptance rates and this effect was moderated by the offer size. However, we did not find the same effect in the loss context. These findings indicate that humor's affection for fairness considerations may depend on the context and provide insight into the finite power of humor in human sociality, cooperation and norm compliance.


Effects of Strength Training and Anabolic Steroid in the Peripheral Nerve and Skeletal Muscle Morphology of Aged Rats.
Thirty male 20-month-old Wistar rats were divided into groups: IC-initial control (n = 6), FC-final control (n = 6), AC-anabolic hormone control (n = 6), ST-strength trained (n = 6) and STA-strength trained with anabolic hormone (n = 6). All groups were submitted to adaptation, familiarization and maximum load carrying test (MLCT). Strength training (6-8×/session with loads of 50%-100% MLCT, 3×/week and pause of 120 s) was performed in ladder climbing (LC) for 15 weeks. The administration of testosterone propionate (TP) was performed 2×/week (10 mg/kg) in animals in the AC and STA groups. After the experimental period, animals were euthanized and the tibial nerve and plantaris muscle removed and prepared for electron transmission and histochemistry. To compare the groups we used one-way ANOVA (post hoc Bonferroni), student's t-tests for pre vs. post (dependent and independent variables) comparisons and significance level set at p ≤ 0.05. The following significant results were found: (a) aging decreased the number of myelinated axon fibers; (b) use of isolated TP increased the diameter of myelinated fibers, along with increased thickness of myelin sheath; (c) ST increased area of myelinated and unmyelinated fibers, together with the myelin sheath. These changes made it possible to increase the area occupied by myelinated fibers keeping their quantity and also reduce the interstitial space; and (d) association of anabolic steroid and ST increased the area of unmyelinated axons and thickness of the myelin sheath. Compared to ST, both strategies have similar results. However, Schwann cells increased significantly only in this strategy.


Cytomegalovirus and polyomavirus BK posttransplant.
Virus replication and progression to disease in transplant patients is determined by patient-, graft- and virus-specific factors. This complex interaction is modulated by the net state of immunosuppression and its impact on virus-specific cellular immunity. Due to the increasing potency of immunosuppressive regimens, graft rejections have decreased, but susceptibility to infections has increased. Therefore, cytomegalovirus (CMV) remains the most important viral pathogen posttransplant despite availability of effective antiviral drugs and validated strategies for prophylactic, preemptive and therapeutic intervention. CMV replication can affect almost every organ system, with frequent recurrences and increasing rates of antiviral resistance. Together with indirect long-term effects, CMV significantly reduces graft and patient survival after solid organ and hematopoietic stem cell transplantation. The human polyomavirus called BK virus (BKV), on the other hand, only recently surfaced as pathogen with organ tropism largely limited to the reno-urinary tract, manifesting as polyomavirus-associated nephropathy in kidney transplant and hemorrhagic cystitis in hematopoetic stem cell transplant patients. No licensed anti-polyoma viral drugs are available, and treatment relies mainly on improving immune functions to regain control over BKV replication. In this review, we discuss diagnostic and therapeutic aspects of CMV and BKV replication and disease posttransplantation.


Effectiveness of an aggressive antibiotic regimen for chemoembolization in patients with previous biliary intervention.
Liver abscess occurs in most patients with biliary stents or bypass undergoing chemoembolization despite the use of standard prophylactic antibiotics. The present study was conducted to investigate the efficacy of an aggressive prophylactic regimen to prevent abscess in such patients. Between November 2002 and July 2005, 16 chemoembolization procedures were performed in seven patients who had undergone biliary intervention. Prophylaxis was initiated with levofloxacin 500 mg daily and metronidazole 500 mg twice daily 2 days before chemoembolization and continued for 2 weeks after discharge. A bowel preparation regimen was given with neomycin 1 g plus erythromycin base 1 g orally at 1 p.m., 2 p.m., and 11 p. m. the day before chemoembolization. With the Fisher exact test, the incidence of infectious complications was compared with previously reported data for patients with and without earlier biliary intervention who had received standard prophylaxis. Liver abscess occurred in two of seven patients after two of 16 procedures. Previously reported incidences were six of seven patients (P=.103) and six of 14 procedures (P=.101) among patients with previous biliary intervention receiving standard prophylaxis and one of 150 patients (P=.005) and one of 383 procedures (P=.004) among patients with no previous biliary intervention. There was a trend toward a lower rate of abscess formation among patients at high risk who received more aggressive antibiotic prophylaxis, but the difference did not reach statistical significance. The rate of infection remained significantly higher than among patients without previous biliary intervention.


Focal Therapy in Primary Localised Prostate Cancer: The European Association of Urology Position in 2018.
Radical treatment of localised prostate cancer is recognised to be an unnecessary intervention or overtreatment in many men. Consequently, there has been a rapid uptake in the use of focal ablative therapies. However, there are several biological and practical concerns about such approaches as they have yet to be proved as robust treatment options. In particular, the multifocal nature of prostate cancer argues against unifocal treatment, while limitations in imaging can preclude the accurate identification of the number, location, and extent of prostate cancer foci. To date, a number of ablative options have reported results on mainly low-risk disease. Most series are relatively immature, with a lack of consistent follow-up, and the morbidity of retreatment is often not considered. The authors consider focal therapy to be an investigational modality, and encourage prospective recording of outcomes and recruitment of suitable patients. Focal therapy of prostate cancer is the targeted destruction of cancer within a specific part of the prostate gland, sparing the rest of the prostate and nearby tissue. This procedure could potentially reduce side effects when compared with established standard treatments, such as surgery or radiotherapy, which treat the entire prostate. Studies show that for most men with low-risk cancer, active surveillance is the preferred treatment option. However, the available data regarding all forms of focal therapy are still poor and inconclusive. Consequently, due to both the lack of clear results associated with focal therapy and the difficulties in detecting all cancerous areas of the prostate, focal therapy should be considered an investigational modality only.


Immune-mediated mechanisms of atherosclerosis and implications for the clinic.
A large body of evidence supports the inflammatory hypothesis of atherosclerosis, and both innate and adaptive immune responses play important roles in all disease stages. Areas covered: Here, we review our understanding of the role of the immune response in atherosclerosis, focusing on the pathways currently amenable to therapeutic modulation. We also discuss the advantages or undesirable effects that may be foreseen from targeting the immune response in patients at high cardiovascular risk, suggesting new avenues for research. Expert commentary: There is an extraordinary opportunity to directly test the inflammatory hypothesis of atherosclerosis in the clinic using currently available therapeutics. However, a more balanced interpretation of the experimental and translational data is needed, which may help address and identify in more detail the appropriate settings where an immune pathway can be targeted with minimal risk.


Anthelmintic efficacy of pumpkin seed (Cucurbita pepo Linnaeus, 1753) on ostrich gastrointestinal nematodes in a semiarid region of Paraíba State, Brazil.
The aim of this study was to verify the in vivo effectiveness of pumpkin seed (Curcubita pepo Linnaeus, 1753) in naturally infected ostriches in the Cariri zone, semiarid region of Paraíba State, Brazil. Forty-eight ostriches were used, African Black breed, of 14 to 36 months old, naturally infected by gastrointestinal nematodes. These animals were divided into four groups of 12 ostriches. Group 1 consists of animals treated with 0.5 g/kg live weight (l. w.) of pumpkin seed meal; group 2 received 1 g/kg l. w. of pumpkin seed meal; group 3 was treated with Albendazole 5 %, at the dosage of 1 mL/10 kg l. w.; and Group 4 was the control group and do not received treatment. Groups 1 and 2 received the treatment for three consecutive days, orally, at intervals of 7 days, totaling nine administrations. The Albendazole 5 % was administered one time, at the beginning of the experiment, according to the manufacturer's recommendations. The groups treated with pumpkin seed showed a significant decrease in egg counts per gram of feces (EPG), wherein group 2 (1 g/kg l. w.) was the most effective. The control and drug groups showed no reduction in EPG. The results of the present study demonstrate that the administration of pumpkin seed was effective in controlling gastrointestinal helminths in naturally infected ostriches.


Inactivation of the maize transposable element Activator (Ac) is associated with its DNA modification.
The Activator (Ac) element at the waxy locus (wx-m7 allele) has the ability to undergo changes in its genetic activity and cycles between an active and inactive phase. Comparison of active Ac elements at several loci and the inactive Ac at wx-m7 by Southern blot analysis revealed that the inactive Ac sequence was not susceptible to digestion by the methylation sensitive enzyme PvuII while active elements were susceptible to PvuII digestion. Restriction digest comparisons between the clones of the active and inactive Ac elements were indistinguishable. Further analyses with the enzymes SstII and the methylation sensitive and insensitive isoschizomers EcoRII and BstNI showed the inactive Ac sequence was methylated at these sites, whereas the active Ac was hypomethylated. Although the active Ac at the wx-m7 allele in different genetic backgrounds showed differences in the Ac DNA modification pattern, at least a fraction of genomic DNA contained Ac sequences that were unmethylated at all of the internal sites we assayed. These data may suggest a role for DNA modification in the ability of Ac to transpose from the waxy locus and to destabilize unlinked Ds elements.


Allicin protects against cisplatin-induced vestibular dysfunction by inhibiting the apoptotic pathway.
Cisplatin is an anticancer drug that causes the impairment of inner ear function as side effects, including hearing loss and balance dysfunction. The purpose of this study was to investigate the effects of allicin against cisplatin-induced vestibular dysfunction in mice and to make clear the mechanism underlying the protective effects of allicin on oto-vestibulotoxicity. Mice intraperitoneally injected with cisplatin exhibited vestibular dysfunction in swimming test, which agreed with impairment in vestibule. However, these impairments were significantly prevented by pre-treatment with allicin. Allicin markedly reduced cisplatin-activated expression of cleaved-caspase-3 in hair cells and vascular layer cells of utricule, saccule and ampulla, but also decreased AIF nuclear translocation of hair cells in utricule, saccule and ampulla. These results showed that allicin played an effective role in protecting vestibular dysfunction induced by cisplatin via inhibiting caspase-dependent and caspase-independent apoptotic pathways. Therefore, allicin may be useful in preventing oto-vestibulotoxicity mediated by cisplatin.


[Advancement of maggot including living body to treat chronic infected wounds].
Human has used maggot to treat diseases for thousands of years. In recent years, with abuse of antibiotic and the rising incidence of antibiotic resistance, maggot therapy, as a surgical alternative, is mainly applied to treat chronic infected wounds on account of its low cost, efficacy and safety. Its mechanisms are disinfection, bio-debridement and enhancement of tissue regeneration. Maggot therapy which serves as a kind of biological therapy is promising. However, living maggot therapy could result in inevitable complications, so that we should apply traditional Chinese medicine theory to investigate and develop new delivery method of maggot. The review summarizes the past and present of maggot therapy.


The interpretation of perioperative lactate abnormalities in patients undergoing cardiac surgery.
Hyperlactataemia and lactic acidosis are commonly encountered during and after cardiac surgery. Perioperative lactate production increases in the myocardium, skeletal muscle, lungs and in the splanchnic circulation during cardiopulmonary bypass. Hyperlactataemia has a bimodal distribution in the perioperative period. An early increase in lactate levels, arising intraoperatively or soon after intensive care unit admission, is a familiar and concerning finding for most clinicians. It is highly suggestive of tissue ischaemia and is associated with a prolonged intensive care unit stay, a prolonged requirement for respiratory and cardiovascular support and increased postoperative mortality. Its presence should prompt a thorough search for potential causes of tissue hypoxia. In contrast, late-onset hyperlactataemia, a less well recognised complication, occurs 4 to 24 hours after completion of surgery and is typically associated with preserved cardiac output and oxygen delivery. Risk factors for late-onset hyperlactataemia include hyperglycaemia, long cardiopulmonary bypass time and elevated endogenous catecholamines. Although patients with this complication may have a longer duration of ventilation and intensive care unit length of stay than those with normolactataemia, an association with increased mortality has not been demonstrated. The discovery of late-onset hyperlactataemia should not delay the postoperative progress of an otherwise stable patient following cardiac surgery.


E-cigarette use is associated with susceptibility to tobacco use among Australian young adults.
Calls have been made to relax current Australian regulations related to e-cigarettes to increase the accessibility of the devices for smoking cessation purposes. However, e-cigarettes have been found to increase risk of initiation of conventional cigarette smoking, especially among young adults. To assist in guiding the development of policy in Australia, the present study examined whether e-cigarette use among Australian young adults who have never smoked a tobacco cigarette is associated with susceptibility to future tobacco cigarette use. An online web panel provider recruited 519 never smokers aged 18-25 years (55% female; average age = 21.21 years, SD = 2.32). Respondents completed an online survey that assessed their curiosity about tobacco smoking, willingness and intentions to smoke, and a number of individual and social factors. Cross-sectional regression analyses were conducted to assess the association between e-cigarette use and susceptibility to tobacco cigarette use while controlling for multiple covariates. Curiosity about tobacco smoking, willingness to smoke, and intentions to smoke were significantly higher among users of e-cigarettes than never users. The relationship between e-cigarette use and susceptibility to future tobacco cigarette use remained significant after controlling for numerous covariates. E-cigarette use, even just one or two puffs, has the potential to increase susceptibility to tobacco cigarette use among Australian young adults. Findings suggest that increasing the availability of e-cigarettes by relaxing current strict regulations surrounding their sale may have unintended consequences.


Does declared surgeon specialist interest influence the outcome of emergency laparotomy?
In the UK, general surgeons must demonstrate competency in emergency general surgery before obtaining a certificate of completion of training. Subsequently, many consultants develop focused elective specialist interests which may not mirror the breadth of procedures encountered during emergency practice. Recent National Emergency Laparotomy Audit analysis found that declared surgeon special interest impacted emergency laparotomy outcomes, which has implications for emergency general surgery service configuration. We sought to establish whether local declared surgeon special interest impacts emergency laparotomy outcomes. Adult patients having emergency laparotomy were identified from our prospective National Emergency Laparotomy Audit database from May 2016 to May 2019 and categorised as colorectal or oesophagogastric according to operative procedure. Outcomes included 30-day mortality, return to theatre and length of stay. Binomial logistic regression was used to identify any association between declared consultant specialist interest and outcomes. Of 600 laparotomies, 358 (58.6%) were classifiable as specialist procedures: 287 (80%) colorectal and 71 (20%) oesophagogastric. Discordance between declared specialty and operation undertaken occurred in 25% of procedures. For colorectal emergency laparotomy, there was an increased risk of 30-day mortality when performed by a non-colorectal consultant (unadjusted odds ratio 2.34; 95% confidence interval 1.10-5.00; p = 0.003); however, when adjusted for confounders within multivariate analysis declared surgeon specialty had no impact on mortality, return to theatre or length of stay. Surgeon-declared specialty does not impact emergency laparotomy outcomes in this cohort of undifferentiated emergency laparotomies. This may reflect the on-call structure at Birmingham Heartlands Hospital, where a colorectal and oesophagogastric consultant are paired on call and provide cross-cover when needed.


Correlation between NF-κB signal pathway-mediated caspase-4 activation and Kawasaki disease.
The aim of the study was to investigate the role and mechanisms of action of nuclear factor-κB (NF-κB)-mediated caspase-4 activation in the induction of inflammatory cytokines during Kawasaki disease (KD) and coronary artery endothelial cell injury. Peripheral blood mononuclear cells (PBMCs) were isolated from KD patients and healthy controls and cultured. Double antibody sandwich enzyme-linked immunosorbent assay (ELISA) was applied to detect tumor necrosis factor (TNF)-α levels in activated PBMC-conditioned culture media. To establish a culture model for human coronary artery endothelial cells (HCAECs), we employed KD patient-origin PBMC culture-conditioned media to induce HCAEC transformation and detected the nuclear activation of NF-κB p65 and intracellular caspase-4 protein concentrations using western blot analysis. We also investigated the nuclear transfer of NF-κB p65 using immunofluorescence, as well as HCAEC interleukin (IL)-6 and IL-1β secretion using ELISA. Finally, we investigated HCAEC apoptosis using using Annexin V/PI double staining. After PBMCs were stimulated in vitro, TNF-α secretion was significantly higher in the KD group versus controls (P<0.01). HCAEC cells treated with supernatant conditioned by cells from KD patients showed a significant elevation of NF-κB p65 and caspase-4 protein expression versus HCAEC cells treated with supernatant conditioned by control cells (P<0.01). Similarly, IL-6 and IL-1β secretion, as well as apoptotic rate, were significantly elevated (P<0.01). SN50, an NF-κB inhibitor, significantly attenuated caspase-4 expression, secretion of IL-6, IL-1β, and TNF-α, as well as HCAEC apoptosis in cells treated with KD patient PBMC-conditioned media. NF-κB can induce the generation of various inflammatory factors including IL-6 and IL-1β, mediate the expression of caspase-4 in HCAEC cells, and affect apoptosis and injury of HCAEC cells. Therefore, the expression of caspase-4, mediated by NF-κB signal pathway, plays a critical role in KD.


Atypical glycolysis in Clostridium thermocellum.
Cofactor specificities of glycolytic enzymes in Clostridium thermocellum were studied with cellobiose-grown cells from batch cultures. Intracellular glucose was phosphorylated by glucokinase using GTP rather than ATP. Although phosphofructokinase typically uses ATP as a phosphoryl donor, we found only pyrophosphate (PPi)-linked activity. Phosphoglycerate kinase used both GDP and ADP as phosphoryl acceptors. In agreement with the absence of a pyruvate kinase sequence in the C. thermocellum genome, no activity of this enzyme could be detected. Also, the annotated pyruvate phosphate dikinase (ppdk) is not crucial for the generation of pyruvate from phosphoenolpyruvate (PEP), as deletion of the ppdk gene did not substantially change cellobiose fermentation. Instead pyruvate formation is likely to proceed via a malate shunt with GDP-linked PEP carboxykinase, NADH-linked malate dehydrogenase, and NADP-linked malic enzyme. High activities of these enzymes were detected in extracts of cellobiose-grown cells. Our results thus show that GTP is consumed while both GTP and ATP are produced in glycolysis of C. thermocellum. The requirement for PPi in this pathway can be satisfied only to a small extent by biosynthetic reactions, in contrast to what is generally assumed for a PPi-dependent glycolysis in anaerobic heterotrophs. Metabolic network analysis showed that most of the required PPi must be generated via ATP or GTP hydrolysis exclusive of that which happens during biosynthesis. Experimental proof for the necessity of an alternative mechanism of PPi generation was obtained by studying the glycolysis in washed-cell suspensions in which biosynthesis was absent. Under these conditions, cells still fermented cellobiose to ethanol.


A Glutamatergic Spine Model to Enable Multi-Scale Modeling of Nonlinear Calcium Dynamics.
In synapses, calcium is required for modulating synaptic transmission, plasticity, synaptogenesis, and synaptic pruning. The regulation of calcium dynamics within neurons involves cellular mechanisms such as synaptically activated channels and pumps, calcium buffers, and calcium sequestrating organelles. Many experimental studies tend to focus on only one or a small number of these mechanisms, as technical limitations make it difficult to observe all features at once. Computational modeling enables incorporation of many of these properties together, allowing for more complete and integrated studies. However, the scale of existing detailed models is often limited to synaptic and dendritic compartments as the computational burden rapidly increases when these models are integrated in cellular or network level simulations. In this article we present a computational model of calcium dynamics at the postsynaptic spine of a CA1 pyramidal neuron, as well as a methodology that enables its implementation in multi-scale, large-scale simulations. We first present a mechanistic model that includes individually validated models of various components involved in the regulation of calcium at the spine. We validated our mechanistic model by comparing simulated calcium levels to experimental data found in the literature. We performed additional simulations with the mechanistic model to determine how the simulated calcium activity varies with respect to presynaptic-postsynaptic stimulation intervals and spine distance from the soma. We then developed an input-output (IO) model that complements the mechanistic calcium model and provide a computationally efficient representation for use in larger scale modeling studies; we show the performance of the IO model compared to the mechanistic model in terms of accuracy and speed. The models presented here help achieve two objectives. First, the mechanistic model provides a comprehensive platform to describe spine calcium dynamics based on individual contributing factors. Second, the IO model is trained on the main dynamical features of the mechanistic model and enables nonlinear spine calcium modeling on the cell and network level simulation scales. Utilizing both model representations provide a multi-level perspective on calcium dynamics, originating from the molecular interactions at spines and propagating the effects to higher levels of activity involved in network behavior.


Sleep-disordered breathing and heart failure: a vicious cycle of cardiovascular risk.
Sleep-disordered breathing (SDB) represents an important cardiovascular risk factor that is still often underestimated and not always optimally treated. Such breathing disorders can induce several harmful effects on the heart, also favoring the development of arrhythmias, ischemic heart disease, and left ventricular remodeling. Obstructive sleep apnea syndrome (OSA) is more frequent in heart failure patients than in the general population, promoting the worsening of left ventricular dysfunction. Both sleep apnea and heart failure have common clinical manifestations but also similar neurohormonal characteristics, both contributing to the development and progression of heart failure and resulting in increased mortality. The pathophysiological mechanisms underlying left ventricular dysfunction associated with SDB will be analyzed, and the potential therapeutic effects of gliflozins on OSA in heart failure patients will be discussed.


[Vasculitis and granulomatosis in the respiratory tract].
Lately new aspects of diseases have been described in long known forms of pulmonary vasculitis and granulomatosis like Wegener's granulomatosis (WG), sarcoidosis (SA), exogenous allergic alveolitis and the Churg-Strauss syndrome. In WG it is clinically important to distinguish between two different phases of disease - the early initial phase with localized inflammation and granuloma formation and the later generalized form of disease where an involvement of virtually every organ system can occur. Recently autoantibodies (antineutrophil cytoplasmic antibodies) have been discovered which are highly specific for WG and additionally are helpful to determine the activity of the disease. With respect to both findings and more recent experience with various therapeutic regimes a therapy considering the phase and activity of disease is recommended. In SA the analysis of the bronchoalveolar lavage has not only led to a immunodiagnostic concept but also given immunopathogenic insights. In contrast to former ideas the SA is not the consequence of an anergic state but more likely of an increased activity of the immune system which is hinted at by the finding of activated CD4-positive lymphocytes in the interstitial tissue and lavage fluid. In exogenous allergic alveolitis new disease concepts are arising from the better understanding of the triggering agents which can now be better analysed.


Low Back Pain in Medical Students and Professors During the Pandemic: Retrospective Cohort Study.
Objective This study aimed to determine the prevalence of low back pain before and during the pandemic, comparing both periods. Methods A questionnaire was administered, containing questions about the presence of low back pain, sociodemographic characteristics and environmental factors that could be related to such pain. Results Among the 978 responses obtained, the prevalence of low back pain during the pandemic was 69.94%, which represented a significant increase over values from the pre-pandemic period (57.37%). A high prevalence of low back pain was found between all groups, especially among women. Some factors were associated with the incidence of low back pain, such as having previously diagnosed spinal problems and sedentary lifestyle. Conclusions The prevalence of low back pain increased significantly during the pandemic in the studied groups.


Tip-enhanced Raman imaging: an emergent tool for probing biology at the nanoscale.
Typically limited by the diffraction of light, most optical spectroscopy methods cannot provide the spatial resolution necessary to characterize specimens at the nanoscale. An emerging exception to this rule is tip-enhanced Raman spectroscopy (TERS), which overcomes the diffraction limit through electromagnetic field localization at the end of a sharp metallic tip. As demonstrated by the Zenobi group in this issue of ACS Nano, TER imaging is an analytical technique capable of providing high-resolution chemical maps of biological samples. In this Perspective, we highlight recent advances and future applications of TER imaging as a technique for interrogating biology at the nanoscale.


Importance of the midwife in the first-time mother's experience of childbirth.
The aim of this study was to examine factors related to how the first-time mother experiences childbirth. The data were collected by questionnaire in a sample of 326 first-time mothers in Tampere University hospital in Finland. The multivariate method used was a stepwise regression analysis. The most important predictors for the nature of the childbirth experience were the characteristics of the midwife, such as empathy, friendliness, tenderness, calmness and lack of hurry; the attitude of the child's father toward the pregnancy; the duration of delivery; and the mother's age and marital status. The more positive the experience the mother had of the attending midwife caring for her, the more positively she experienced childbirth. The positive attitude of the child's father toward the pregnancy and a short duration of delivery were also predictors for a positive childbirth experience. Young and unmarried mothers also had more positive experiences of childbirth. On the basis of the research results, we can state that positive childbirth experiences of first-time mothers are enhanced by the positive characteristics and professional skills of the attending midwife, positive attitude of the spouse/child's father toward the pregnancy, and a short duration of delivery.


Effect of cardio-metabolic risk factors on all-cause mortality among HIV patients on antiretroviral therapy in Malawi: A prospective cohort study.
Cardiovascular disease (CVD) risk among people living with HIV is elevated due to persistent inflammation, hypertension and diabetes comorbidity, lifestyle factors and exposure to antiretroviral therapy (ART). Data from Africa on how CVD risk affects morbidity and mortality among ART patients are lacking. We explored the effect of CVD risk factors and the Framingham Risk Score (FRS) on medium-term ART outcomes. A prospective cohort study of standardized ART outcomes (Dead, Alive on ART, stopped ART, Defaulted and Transferred out) was conducted from July 2014-December 2016 among patients on ART at a rural and an urban HIV clinic in Zomba district, Malawi. The primary outcome was Dead. Active defaulter tracing was not done and patients who transferred out and defaulted were excluded from the analysis. At enrolment, hypertension, diabetes and dyslipidemia were diagnosed, lifestyle data collected and the FRS was determined. Cox-regression analysis was used to determine independent risk factors for the outcome Dead. Of 933 patients enrolled, median age was 42 years (IQR: 35-50), 72% were female, 24% had hypertension, 4% had diabetes and 15.8% had elevated total cholesterol. The median follow up time was 2.4 years. Twenty (2.1%) patients died, 50 (5.4%) defaulted, 63 (6.8%) transferred out and 800 (85.7%) were alive on ART care (81.7% urban vs. 89.9% rural). In multivariable survival analysis, male gender (aHR = 3.28; 95%CI: 1.33-8.07, p = 0.01) and total/HDL cholesterol ratio (aHR = 5.77, 95%CI: 1.21-27.32; p = 0.03) were significantly associated with mortality. There was no significant association between mortality and hypertension, body mass index, central obesity, diabetes, FRS, physical inactivity, smoking at enrolment, ART regimen and WHO disease stage. Medium-term all-cause mortality among ART patients was associated with male gender and elevated total/HDL cholesterol ratio.


Exploring Injured Persons' Experiences of Engaging and Using Lawyers in Road Traffic Injury Compensation Claims.
Legal services can play a critical role in facilitating claimant access to entitlements and shaping claimant experiences and outcomes in compensation settings. However, much remains unknown about claimants' goals in engaging legal services, experiences of using legal services, and satisfaction with legal advisers. Drawing on semi-structured interviews with claimants in the road traffic injury compensation scheme in the State of Victoria, Australia, this article identified that most claimants engaged legal services to access entitlements when they struggled to do so alone. Claimants often had little understanding of the activities performed by their lawyers: despite this, most viewed legal service use as valuable or worthwhile in terms of outcomes achieved. Claimants' experiences and levels of satisfaction were coloured by the quantity and quality of communication between themselves and their legal representatives. The findings highlight opportunities for schemes, lawyers, and legal profession regulators to increase the responsiveness of services to claimants' needs.


GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits.
Cortical networks are composed of glutamatergic excitatory projection neurons and local GABAergic inhibitory interneurons that gate signal flow and sculpt network dynamics. Although they represent a minority of the total neocortical neuronal population, GABAergic interneurons are highly heterogeneous, forming functional classes based on their morphological, electrophysiological, and molecular features, as well as connectivity and in vivo patterns of activity. Here we review our current understanding of neocortical interneuron diversity and the properties that distinguish cell types. We then discuss how the involvement of multiple cell types, each with a specific set of cellular properties, plays a crucial role in diversifying and increasing the computational power of a relatively small number of simple circuit motifs forming cortical networks. We illustrate how recent advances in the field have shed light onto the mechanisms by which GABAergic inhibition contributes to network operations.


How does adjuvant chemotherapy affect menopausal symptoms, sexual function, and quality of life after breast cancer?
The aim of the study was to determine the association between adjuvant chemotherapy for breast cancer and menopausal symptoms, sexual function, and quality of life. Participants attended a menopause clinic with a dedicated service for cancer survivors at a large tertiary women's hospital. Information about breast cancer treatments including adjuvant chemotherapy was collected from medical records. Menopausal symptoms were recorded with the Greene Climacteric Scale and Functional Assessment of Cancer Therapy, Breast Cancer, and Endocrine Symptom Subscales. Sexual symptoms were recorded using Fallowfield's Sexual Activity Questionnaire. Quality of life was measured with Functional Assessment of Cancer Therapy scales. The severity of vasomotor, psychological, or sexual symptoms (apart from pain) did not differ between those who had received adjuvant chemotherapy (n = 339) and other breast cancer survivors (n = 465). After adjustment for current age, time since menopause, and current use of antiestrogen endocrine therapy, the risk of "severe pain" with sexual intercourse was twice as common after chemotherapy (31.6% vs 20.0%, odds ratio [OR] 2.18, 95% CI 1.25-3.79). Those treated with chemotherapy were more likely to report "severe problems" with physical well-being (OR 1.92, 95% CI 1.12-3.28) and lower breast cancer-specific quality of life (OR 1.89 95% CI 1.13-3.18), but did not differ in other quality of life measures. In this large study of breast cancer patients presenting to a specialty menopause clinic, previous chemotherapy was not associated with current vasomotor or psychological symptoms. Severe pain with intercourse was significantly more common in those treated with adjuvant chemotherapy.


The effect of an antimicrobial mouthwash on dental plaque and gingivitis in yound adults.
The effectiveness of an antimicrobial mouthwash (alexidine, 2-ethylhexyl bisbiguanidine dihydrochloride) in preventing plaque and gingivitis was evaluated in 45 young male adults. In a study using a double-blind cross-over design, subjects received a thorough prophylaxis and refrained from all routine oral hygiene for 2 weeks. During this period, subjects rinsed twice daily with either a treatment (alexidine) or placebo mouthwash. Plaque and gingivitis were assessed on selected teeth on days 2, 7 and 14. The characteristics of plaque that were recorded include: surface area score, dry weight and differential counts of microorganisms. After the 14th day, subjects resumed their regular oral hygiene practices for 3 weeks before starting the second experimental period. Aftter a second prophylaxis, the treatment and placebo groups from the first 2 weeks were crossed over and the procedures followed previously were repeated during the sixth and seventh weeks. The alexidine mouthwash was statistically and clinically effective in decreasing plaque scores and plaque weight, and statistically but not clinically effective in decreasing gingivitis scores. No systemic side effects were observed, but an asymptomatic brown tongue stain was observed in about half of the subjects. There was no evidence to suggest that alexidine disturbed the relative composition of the microorganisms in plague, but there was a suggestion that it decreased the number of microorganisms almost 2-fold when compared with the placebo group.


Noise monitoring and adverse health effects in residents in different functional areas of Luzhou, China.
The purpose of the study was to investigate the noise pollution situation and the resulting adverse effect on residents' health in Luzhou, China, to provide data for noise pollution prevention policies and interventions. Four different functional areas (commercial, construction, residential, and transportation hub areas) were chosen to monitor noise level for 3 months. The survey was performed by questionnaire on the spot on randomly selected individuals; it collected data on the impact of noise on residents' health (quality of sleep, high blood pressure, subjective feeling of nervous system damage, and attention) as well as the knowledge of noise-induced health damage, the degree of adaptation to noise, and their solutions. The noise levels of residential, commercial, transportation, and construction areas exceeded the national standards (P < .001). Sleep quality, prevalence of hypertension, and attention in transportation hub areas were significantly different from those in the other 3 areas (P < .05); only 24.46% of people knew the health hazards associated with noise; 64.57% of residents have adapted to the current noise environment. Most of them have to close the doors and windows to reduce noise. The noise pollution situation in Luzhou, China, is serious, especially the traffic noise pollution. Residents pay less attention to it and adopt single measures to reduce the noise. We should work toward the prevention and control of traffic noise and improve the residents' awareness to reduce the adverse health effects of noise.


Exploring the relationship between thumb-sucking and psychopathology.
Studied the relationship between chronic thumb-sucking and behavior problems reflective of psychopathology. Compared scores on the Child Behavior Checklist (CBCL) and Eyberg Child Behavior Inventory (ECBI) for matched samples of thumb-sucking, referred, and nonreferred children. Mean scores for the thumb-sucking and nonreferred samples were equivalent and were significantly lower than scores for the referred sample. Comparing scores for older children (8-14 years) and younger children (4-7 years) did not produce a significant interaction. Correlating measures of thumb-sucking severity with ECBI and CBCL scores produced only 8 (of 42) significant correlations and a mean correlation of only .09. Collectively our results provide little support for the theoretically derived notion that thumb-sucking is necessarily a symptom of psychopathology.


Fatal rupture of a mycotic aneurysm of the right coronary artery post pneumococcal sepsis.
Aneurysms of the coronary arteries are rare and mycotic coronary aneurysms are even rarer. We report a unique, yet unfortunately autopsy-proven fatal case of a ruptured atherosclerotic mycotic aneurysm of the right coronary artery with streptococcus pneumoniae in a non-immunocompromised patient resulting in cor tamponade and death.


[The heart in sarcoidosis].
This paper discusses the problems of cardiac sarcoidosis in patients with respiratory diseases. Emphasis is placed on the difficulty of diagnosing minimal and atypical lesions, the value of thallium scintigraphy and therapeutic problems.


[VUV spectral properties of (Y, Gd) Al3 (BO3)4: Tb].
(Y, Gd)A13 (BO3)4 doped with Ce and Tb were prepared by solid state reaction. The structure, VUV excitation properties, excitation were studied. (Y,Gd)Al3 (BO3)4 belongs to trigonal crystal system with thespace group of R32, and the crystal structure does not change as Tb3+ and Ce3+ ions are doped to the crystal lattice. The host absorption band of (Y,Gd)Al3 (BO3)4:Tb moves to longer wavelength as Gd3+ mol concentration increases. The energy transfer between Gd3+ and Tb3+ is very effective, and the samples with high Gd3+ mol concentrations have high radiant efficiencies. It was found that the luminescence of Tb3+ is quenched by Ce3+ in (Y,Gd)Al3(BO3)4:Ce, Tb under VUV excitation.


Membrane Distillation-Crystallization for Sustainable Carbon Utilization and Storage.
Anthropogenic greenhouse gas emissions from power plants can be limited using postcombustion carbon dioxide capture by amine-based solvents. However, sustainable strategies for the simultaneous utilization and storage of carbon dioxide are limited. In this study, membrane distillation-crystallization is used to facilitate the controllable production of carbonate minerals directly from carbon dioxide-loaded amine solutions and waste materials such as fly ash residues and waste brines from desalination. To identify the most suitable conditions for carbon mineralization, we vary the membrane type, operating conditions, and system configuration. Feed solutions with 30 wt % monoethanolamine are loaded with 5-15% CO2 and heated to 40-50 °C before being dosed with 0.18 M Ca2+ and Mg2+. Membranes with lower surface energy and greater roughness are found to more rapidly promote mineralization due to up to 20% greater vapor flux. Lower operating temperature improves membrane wetting tolerance by 96.2% but simultaneously reduces crystal growth rate by 48.3%. Sweeping gas membrane distillation demonstrates a 71.6% reduction in the mineralization rate and a marginal improvement (37.5%) on membrane wetting tolerance. Mineral identity and growth characteristics are presented, and the analysis is extended to explore the potential improvements for carbon mineralization as well as the feasibility of future implementation.


Two genes controlling the expression of extended globoglycolipids in mouse kidney are closely linked to each other on chromosome 19.
The gene (Gsl-5) controlling the expression of GL-Y (Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-6(Gal beta 1-3)Gb4Cer) in mouse kidney was suggested to be located near Ea-4 on mouse chromosome 19 by the results of glycolipid analysis of BXD/Ty recombinant inbred strains (Sekine et al. [1987] J. Biochem. 101, 563-568). In this study, Gsl-5 was mapped on mouse chromosome 19. Among 133 backcross progeny produced on mating between DBA/2 mice and (WHT/Ht x DBA/2)F1 mice, 10 recombinants between Lyt-1 and Gsl-5 were detected, indicating that Gsl-5 is located at 7.5 +/- 2.3 centimorgans (cM) from Lyt-1. While among 154 backcross progeny produced on mating between DBA/2 and (DBA/2 x Mus musculus castaneus)F1 mice, 39 recombinants between Got-1 and Gsl-5 were obtained, indicating that the distance between Got-1 and Gsl-5 is 25.3 +/- 3.5 cM and that Gsl-5 is telomeric to Lyt-1. In the latter mating experiment, we detected 3 recombinants between Gsl-5 and the gene (Gsl-6) controlling the expression of the Z1 ganglioside (NeuGc alpha 2-3Gal beta 1-3Gb4Cer) among the 154 backcross mice. These results indicate that these two genes, Gsl-5 and Gsl-6, are closely linked to each other, being 1.9 +/- 1.1 cM apart. This is the report of evidence that two genes controlling the expression of carbohydrates in glycoconjugates are closely linked and the first to suggest that some genes controlling the expression of carbohydrates may be clustered.(ABSTRACT TRUNCATED AT 250 WORDS)


The Possible Role of Anti-Neu5Gc as an Obstacle in Xenotransplantation.
Seventy to ninety percentage of preformed xenoreactive antibodies in human serum bind to the galactose-α(1,3)-galactose Gal epitope, and the creation of Gal knockout (KO) pigs has eliminated hyperacute rejection as a barrier to xenotransplantation. Now other glycan antigens are barriers to move ahead with xenotransplantation, and the N-glycolyl neuraminic acid, Neu5Gc (or Hanganutziu-Deicher antigen), is also a major pig xenoantigen. Humans have anti-Neu5Gc antibodies. Several data indicate a strong immunogenicity of Neu5Gc in humans that may contribute to an important part in antibody-dependent injury to pig xenografts. Pig islets express Neu5Gc, which reacted with diet-derived human antibodies and mice deleted for Neu5Gc reject pancreatic islets from wild-type counterpart. However, Neu5Gc positive heart were not rejected in Neu5Gc KO mice indicating that the role of Neu5Gc-specific antibodies has to be nuanced and depend of the graft situation parameters (organ/tissue, recipient, implication of other glycan antigens). Recently generated Gal/Neu5Gc KO pigs eliminate the expression of Gal and Neu5Gc, and improve the crossmatch of humans with the pig. This review summarizes the current and recent experimental and (pre)clinical data on the Neu5Gc immunogenicity and emphasize of the potential impact of anti-Neu5Gc antibodies in limiting xenotransplantation in humans.


Current strategies in whole-brain radiation therapy for brain metastases.
Whole-brain radiation therapy (WBRT) has been the primary treatment for patients with brain metastases for more than 50 years and provides effective palliative relief in most patients. Although advancements in radiotherapeutic technique continue to improve local and locoregional control, median survival for patients treated with WBRT monotherapy remains fixed at approximately 4 to 6 months. Key issues in the use of WBRT include optimizing its efficacy when it is used in conjunction with surgery, radiosurgery, radiosensitizers, and new chemotherapeutic agents. These multimodal approaches to brain metastases have resulted in significant increases in the median survival time in many patients. Radiosurgery is part of a continuing effort to improve the effects of radiation therapy, especially in brain metastases. The optimal combination of WBRT and radiosurgery remains to be elucidated, including appropriate timing or sequence and use in conjunction with other modalities. Newer radiosensitizing agents (e.g., efaproxiral [RSR-13] and motexafin gadolinium) have shown promise in the treatment of brain tumors, especially in specific patient subsets. Recently developed systemic chemotherapy agents, such as temozolomide, which crosses the blood-brain barrier, have a synergistic effect on brain metastases when used in conjunction with radiation. In addition, the use of interstitial chemotherapy agents provides highly focused local chemotherapy in the brain without increasing systemic toxicity; carmustine polymer wafer, in combination with WBRT, has shown promising results in treating brain metastases.


Rapid determination of thiamine, riboflavin, pyridoxine, and niacinamide in infant formulas by liquid chromatography.
A simplified, simultaneous determination of vitamins B1, B2, B3, and B6 in supplemented infant formulas was developed from a single deproteinized sample extract, with analysis by reversed-phase, ion-pair chromatography with an acidified methanol-water mobile phase. The dioctylsulfosuccinate counter-ion facilitates unique retention of the pyridine-based vitamins (niacinamide and pyridoxine) and allows for concurrent measurement of both the pyridoxal and riboflavin 5'-phosphate endogenous components of milk. Other naturally occurring undetected vitamin congeners have minimal analytical significance. UV detection is used for niacinamide, and programmed fluorescence detection is used for riboflavin and the B6 vitamins. Thiamine is routinely determined sequentially under modified elution conditions.


Auricular Neuromodulation for Mass Vagus Nerve Stimulation: Insights From SOS COVID-19 a Multicentric, Randomized, Controlled, Double-Blind French Pilot Study.
Importance: An exacerbated inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is believed to be one of the major causes of the morbidity and mortality of the coronavirus disease 2019 (COVID-19). Neuromodulation therapy, based on vagus nerve stimulation, was recently hypothesized to control both the SARS-CoV-2 replication and the ensuing inflammation likely through the inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells pathway and could improve the clinical outcomes as an adjunct treatment. We proposed to test it by the stimulation of the auricular branch of the vagus nerve, i.e., auricular neuromodulation (AN), a non-invasive procedure through the insertion of semipermanent needles on the ears. Objective: The aim of this study was to assess the effect of AN on the clinical outcomes in patients affected by COVID-19. Design, Setting, and Participants: A multicenter, randomized, placebo-controlled, double-blind clinical trial included 31 patients with respiratory failure due to COVID-19 requiring hospitalization. Within 72 h after admission, patients received either AN (n = 14) or sham neuromodulation (SN, n = 15) in addition to the conventional treatments. Main Outcome and Measures: The primary endpoint of the study was the rate of a clinical benefit conferred by AN at Day 14 (D14) as assessed by a 7-point Clinical Progression Scale. The secondary endpoint of the study was the impact of AN on the rate of transfer to the intensive care unit (ICU) and on the survival rate at D14. Results: The AN procedure was well-tolerated without any reported side effects but with no significant improvement for the measures of both primary (p > 0.3) and secondary (p > 0.05) endpoints at the interim analysis. None of the AN-treated patients died but one in the SN group did (81 years). Two AN-treated patients (73 and 79 years, respectively) and one SN-treated patient (59 years) were transferred to ICU. Remarkably, AN-treated patients were older with more representation by males than in the SN arm (i.e., the median age of 75 vs. 65 years, 79% male vs. 47%). Conclusion: The AN procedure, which was used within 72 h after the admission of patients with COVID-19, was safe and could be successfully implemented during the first two waves of COVID-19 in France. Nevertheless, AN did not significantly improve the outcome of the patients in our small preliminary study. It is pertinent to explore further to validate AN as the non-invasive mass vagal stimulation solution for the forthcoming pandemics. Clinical Trial Registration: [https://clinicaltrials.gov/], identifier [NCT04341415].


Project Access-New Haven: improving access to specialty care for patients without insurance.
Poor access to specialty care among uninsured adults threatens the delivery of quality health care and may contribute to the misuse and overuse of emergency departments and hospitals. We sought to improve access to specialty care through a program called Project Access-New Haven (PA-NH),which engages specialty physicians and hospitals to volunteer in a coordinated-care model for the uninsured. Patient navigators guide patients through the health-care network and help to alleviate administrative obstacles. Project Access-New Haven has been operational since August 2010. With >200 specialty physicians volunteering and strong commitments from local hospitals, comprehensive specialty care has been provided to 78 patients. Average wait-time for appointments is 17 days. PA-NH provides timely medical care and patient navigation foruninsured patientswith specialty-care needs. In the process, more physicians are participating in the care of vulnerable populations. Further data are needed to assess the potential cost-savings of PA-NH.


Fabrication of highly uniform conductive polypyrrole nanowires with DNA template.
Deoxyribonucleic acid (DNA) is considered as one of the alternative materials for electronic device applications; however, DNA has critical limitation to electronic device applications due to its low electrical conductivity and unreliability. Therefore, it is required for electronic devices to prepare the well defined conductive polymer nanowires with DNA as a template. Polypyrrole (PPy) is an attractive polymer due to its high conductivity and environmental stability in bulk; although it is well known that ammonium persulfate (APS) used for the polymerization of pyrrole causes the deformation of DNA molecules. We minimized the damage of immobilized DNA strands on (3-aminopropyl) triethoxysilane (APTES) modified silicon wafer during APS polymerization. Atomic force microscopy (AFM) images from different APS treatment times and from using the vortex process obviously showed the effect on the synthesis of individual and continuous polypyrrole nanowires (PPy NWs). The PPy NWs at various pyrrole concentrations had similar height; however, the higher concentration gave more residues. Fourier transform-infrared spectroscopy (FT-IR) spectroscopy provided the strong evidence that PPy NWs were successfully synthesized on the DNA strands.


Restoration of serotonin neuronal firing following long-term administration of bupropion but not paroxetine in olfactory bulbectomized rats.
Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine. Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats. Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30 mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin(1A) receptors; paroxetine (10 mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin(1A) receptors. The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin(1A) receptors in hippocampus.


Secretory Expression of Different C-terminal Truncated HCV E1 Proteins in Mammalian Cells and Characterization of the Expressed Products.
Three fragments of the HCV envelope 1 (E1) with different C-terminal truncation at aa310, aa325, aa340 were cloned into the mammalian expression vector pSecTagB. An epitope in the hepatitis B surface antigen, preS1(21--47), were genetically engineered onto the N-terminus of the recombinant protein and used as an affinity tag for detection and purification. The resulting pSec-preS1-E1t310, pSec-preS1-E1t325 and pSec-preS1-E1t340 were transiently expressed in the HeLa cells and the antigenicity, secretory efficiency and glycosylation type of the recombinant E1 proteins were compared. All of the three recombinant proteins could be detected by both preS1 monoclonal antibody and E1 polyclonal antiserum. The expression products were secreted and highly mannose-type glycosylated, with S1E1t325 being secreted, indicating the influence of the hydrophobic regions on the secretion of the E1 protein. Three CHO cell lines expressing the proteins, S1E1t310, S1E1t325 and S1E1t340, were established and the CHO/pSecS1E1t325 was chosen for further study. The secreted S1E1t325 could be enriched from cell culture medium by the preS1 antibody-coupled Sepharose. The glycosylation analysis indicated the lack of complex glycogen even after the E1 was secreted via Golgi complexes. The established stable cell lines and anti-preS1 affinity method could be utilized to enrich and purify the HCV E1 expressed in mammalian cells, and may be used for further characterization of this protein.


Neural blastocyst complementation enables mouse forebrain organogenesis.
Genetically modified mice are commonly generated by the microinjection of pluripotent embryonic stem (ES) cells into wild-type host blastocysts1, producing chimeric progeny that require breeding for germline transmission and homozygosity of modified alleles. As an alternative approach and to facilitate studies of the immune system, we previously developed RAG2-deficient blastocyst complementation2. Because RAG2-deficient mice cannot undergo V(D)J recombination, they do not develop B or T lineage cells beyond the progenitor stage2: injecting RAG2-sufficient donor ES cells into RAG2-deficient blastocysts generates somatic chimaeras in which all mature lymphocytes derive from donor ES cells. This enables analysis, in mature lymphocytes, of the functions of genes that are required more generally for mouse development3. Blastocyst complementation has been extended to pancreas organogenesis4, and used to generate several other tissues or organs5-10, but an equivalent approach for brain organogenesis has not yet been achieved. Here we describe neural blastocyst complementation (NBC), which can be used to study the development and function of specific forebrain regions. NBC involves targeted ablation, mediated by diphtheria toxin subunit A, of host-derived dorsal telencephalic progenitors during development. This ablation creates a vacant forebrain niche in host embryos that results in agenesis of the cerebral cortex and hippocampus. Injection of donor ES cells into blastocysts with forebrain-specific targeting of diphtheria toxin subunit A enables donor-derived dorsal telencephalic progenitors to populate the vacant niche in the host embryos, giving rise to neocortices and hippocampi that are morphologically and neurologically normal with respect to learning and memory formation. Moreover, doublecortin-deficient ES cells-generated via a CRISPR-Cas9 approach-produced NBC chimaeras that faithfully recapitulated the phenotype of conventional, germline doublecortin-deficient mice. We conclude that NBC is a rapid and efficient approach to generate complex mouse models for studying forebrain functions; this approach could more broadly facilitate organogenesis based on blastocyst complementation.


Possible anatomic structures causing entrapment neuropathies of the median nerve: an anatomic study.
This study aimed at identifying the anatomic structures which may be responsible for entrapment neuropathies of the median nerve. Thirty upper extremities of 15 formalin fixed adult cadavers were dissected from the axilla to the distal forearm under Zeiss Opmi 9--FC microscope. We encountered seven different anatomic structures that may compress the median nerve. These structures are the brachialis muscle, Struther's ligament, the bicipital aponeurosis, pronator teres, flexor digitorum superficialis, the accessory head of plexor pollicis longus (Gantzer's muscle) and vascular structures. The supracondylar process, which we did not encounter in our dissection, has been reported as another cause. Based on our dissection findings and on literature, the median nerve can be compressed by seven different structures from the axilla to the distal forearm. Knowledge of the course of the median nerve and its relations with the adjacent anatomic structures facilitates determination of the exact cause of entrapment and allows for a safe surgery.


[Giant cell tumors of the pancreas. Clinical presentation].
The authors report the case of a large tumor located at the tail of pancreas. Despite extensive surgery and absence of synchronous metastasis, death occurred after a short period of survival. The authors stress the lack of major clinical features of carcinoma of left pancreas and outline the high malignancy of giant cell type.


Improving neutralization potency and breadth by combining broadly reactive HIV-1 antibodies targeting major neutralization epitopes.
The isolation of broadly neutralizing HIV-1 monoclonal antibodies (MAbs) to distinct epitopes on the viral envelope glycoprotein (Env) provides the potential to use combinations of MAbs for prevention and treatment of HIV-1 infection. Since many of these MAbs have been isolated in the last few years, the potency and breadth of MAb combinations have not been well characterized. In two parallel experiments, we examined the in vitro neutralizing activities of double-, triple-, and quadruple-MAb combinations targeting four distinct epitopes, including the CD4-binding site, the V1V2-glycan region, the V3-glycan supersite, and the gp41 membrane-proximal external region (MPER), using a panel of 125 Env-pseudotyped viruses. All MAb combinations showed substantially improved neutralization breadth compared to the corresponding single MAbs, while the neutralization potency of individual MAbs was maintained. At a 50% inhibitory concentration (IC50) cutoff of 1 μg/ml per antibody, double-MAb combinations neutralized 89 to 98% of viruses, and triple combinations neutralized 98 to 100%. Overall, the improvement of neutralization breadth was closely predicted by an additive-effect model and explained by complementary neutralization profiles of antibodies recognizing distinct epitopes. Subtle but consistent favorable interactions were observed in some MAb combinations, whereas less favorable interactions were observed on a small subset of viruses that are highly sensitive to V3-glycan MAbs. These data demonstrate favorable in vitro combinations of broadly neutralizing HIV-1 MAbs and suggest that such combinations could have utility for HIV-1 prevention and treatment. Over the last 5 years, numerous broadly reactive HIV-1-neutralizing MAbs have been isolated from B cells of HIV-1-infected donors. Each of these MAbs binds to one of the major vulnerable sites (epitopes) on the surface of the viral envelope glycoprotein. Since antibodies to distinct viral epitopes could theoretically act together to provide greater potency and breadth of virus neutralization, we tested physical mixtures of double, triple, and quadruple combinations of neutralizing MAbs targeting four major epitopes on HIV-1 Env. When tested together, antibody combinations showed substantially improved neutralization breadth compared to single MAbs. This improvement could be explained by the complementary neutralization profiles of individual MAbs. We further demonstrated that each antibody maintained its full neutralization potency when used in combination with other MAbs. These data provide a rationale for clinical use of antibody-based combinations for HIV-1 prevention and therapy.


Injectable hydrogels of optimized acellular nerve for injection in the injured spinal cord.
Spinal cord injury (SCI) affects a quarter million individuals in the United States, and there is currently no clinical treatment. Both fresh and acellular peripheral nerve grafts can induce spinal axon regeneration and support functional recovery in experimental injury models. Nonetheless, a scaffold that can be injected into a spinal contusion would be far less invasive to apply. We aimed to develop the first injectable acellular nerve graft for promoting repair after contusion SCI. We report a method to enzymatically solubilize optimized acellular (OA) nerve-a decellularized peripheral nerve graft developed in our laboratory and currently used clinically-to obtain an injectable solution that undergoes thermal gelation under physiological conditions. We quantified multiple physical and compositional properties of this novel material as well as tested its efficacy at acute and chronic time points following cervical contusion SCI. This injectable optimized acellular (iOA) nerve graft retains native chemical cues such as collagens and glycosaminoglycans. By varying hydrogel concentration, the rheological properties and compressive modulus of iOA were similar to that previous reported for rat central nervous tissue. iOA solution was compatible with rat Schwann cells in culture, and hydrogel injection into a rat cervical contusion model significantly reduced the ratio of M1:M2 macrophages after one week, favoring regenerative phenotypes (p < 0.05). Furthermore, while iOA treatment did not affect locomotor or respiratory recovery over an eight week period, the percentage of axonal coverage increased at the distal tissue interface (p < 0.05), suggesting enhanced axonal extension within this region. Our data indicate that this novel injectable form of acellular nerve grafts is amenable for use after contusion SCI and may bolster a simultaneous therapy by acutely modulating the inflammatory milieu and supporting axonal growth.