Expanding the neurodevelopmental phenotypes of individuals with de novo KMT2A variants.
De novo loss-of-function (LoF) variants in the KMT2A gene are associated with Wiedemann-Steiner Syndrome (WSS). Recently, de novo KMT2A variants have been identified in sequencing studies of cohorts of individuals with neurodevelopmental disorders (NDDs). However, most of these studies lack the detailed clinical information required to determine whether those individuals have isolated NDDs or WSS (i.e. syndromic NDDs). We performed thorough clinical and neurodevelopmental phenotyping on six individuals with de novo KMT2A variants. From these data, we found that all six patients met clinical criteria for WSS and we further define the neurodevelopmental phenotypes associated with KMT2A variants and WSS. In particular, we identified a subtype of Autism Spectrum Disorder (ASD) in five individuals, characterized by marked rigid, repetitive and inflexible behaviours, emotional dysregulation, externalizing behaviours, but relative social motivation. To further explore the clinical spectrum associated with KMT2A variants, we also conducted a meta-analysis of individuals with KMT2A variants reported in the published literature. We found that de novo LoF or missense variants in KMT2A were significantly more prevalent than predicted by a previously established statistical model of de novo mutation rate for KMT2A. Our genotype-phenotype findings better define the clinical spectrum associated with KMT2A variants and suggest that individuals with de novo LoF and missense variants likely have a clinically unrecognized diagnosis of WSS, rather than isolated NDD or ASD alone. This highlights the importance of a clinical genetic and neurodevelopmental assessment for individuals with such variants in KMT2A.


The 'wayfinding' experience of family carers who learn to manage technical health procedures at home: a grounded theory study.
With more care taking place in the home, family carers play an important role in supporting patients. Some family carers undertake technical health procedures generally managed by health professionals in hospital settings (e.g. managing a tracheostomy or enteral feeding). To explore how family carers learn to manage technical health procedures in order to help health professionals better understand and support this process. A grounded theory study using data from interviews with 26 New Zealand family carers who managed technical health procedures including nasogastric or gastrostomy feeding, stoma care, urinary catheterisation, tracheostomy management, intravenous therapy, diabetes management and complex wound dressings. Most (20 participants) were caring for their child and the remaining six for their spouse, parent or grandparent. Following grounded theory methods, each interview was coded soon after completion. Additional data were compared with existing material, and as analysis proceeded, initial codes were grouped into higher order concepts until a core concept was developed. Interviewing continued until no new ideas emerged and concepts were well defined. The core concept of 'wayfinding' indicates that the learning process for family carers is active, individualised and multi-influenced, developing over time as a response to lived experience. Health professional support was concentrated on the initial phase of carers' training, reducing and becoming more reactive as carers took responsibility for day-to-day management. Wayfinding involves self-navigation by carers, in contrast to patient navigator models which provide continuing professional assistance to patients receiving cancer or chronic care services. Wayfinding by carers raises questions about how carers should be best supported in their initial and ongoing learning as the management of these procedures changes over time.


Extraction of individual muscle mechanical action from endpoint force.
Most motor tasks require the simultaneous coordination of multiple muscles. That coordination is poorly understood in part because there is no noninvasive means of isolating a single muscle's contribution to the resultant endpoint force. The contribution of a single motor unit to isometric tasks can, however, be characterized using the spike-triggered averaging (STA) technique, applied to a single motor unit's spike train. We propose that a technique analogous to STA, which we call electromyogram (EMG)-weighted averaging (EWA), can be applied to surface EMGs to extract muscle mechanical action from the natural endpoint force fluctuations generated during steady isometric contraction. We demonstrate this technique on simultaneous recordings of fingertip force and surface EMG from the first dorsal interosseous (FDI) and extensor indicis (EI) of humans. The EWA direction was approximately the same across a wide range of fingertip force directions, and the average EWA direction was consistent with mechanical action direction of these muscles estimated from cadaveric and imaging data: the EWA directions were 193 +/- 2 degrees for the FDI and 71 +/- 5 degrees for the EI (95% confidence). EWA transient behavior also appears to capture temporal characteristics of muscle force fluctuations with peak force time and general waveform shape similar to that of the associated spike-triggered averages from single motor units. The EWA may provide a means of empirically characterizing the complex transformation between muscle force and endpoint force without the need for invasive electrode recordings or complex anatomical measurements of musculoskeletal geometry.


DNA methylation-based age prediction from various tissues and body fluids.
Aging is a natural and gradual process in human life. It is influenced by heredity, environment, lifestyle, and disease. DNA methylation varies with age, and the ability to predict the age of donor using DNA from evidence materials at a crime scene is of considerable value in forensic investigations. Recently, many studies have reported age prediction models based on DNA methylation from various tissues and body fluids. Those models seem to be very promising because of their high prediction accuracies. In this review, the changes of age-associated DNA methylation and the age prediction models for various tissues and body fluids were examined, and then the applicability of the DNA methylation-based age prediction method to the forensic investigations was discussed. This will improve the understandings about DNA methylation markers and their potential to be used as biomarkers in the forensic field, as well as the clinical field. [BMB Reports 2017; 50(11): 546-553].


Dysregulation of alternative splicing underlies synaptic defects in familial amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the degeneration of upper and lower motor neurons, progressive wasting and paralysis of voluntary muscles. A hallmark of ALS is the frequent nuclear loss and cytoplasmic accumulation of RNA binding proteins (RBPs) in motor neurons (MN), which leads to aberrant alternative splicing regulation. However, whether altered splicing patterns are also present in familial models of ALS without mutations in RBP-encoding genes has not been investigated yet. Herein, we found that altered splicing of synaptic genes is a common trait of familial ALS MNs. Similar deregulation was also observed in hSOD1G93A MN-like cells. In silico analysis identified the potential regulators of these pre-mRNAs, including the RBP Sam68. Immunofluorescence analysis and biochemical fractionation experiments revealed that Sam68 accumulates in the cytoplasmic insoluble ribonucleoprotein fraction of MN. Remarkably, the synaptic splicing events deregulated in ALS MNs were also affected in Sam68-/- spinal cords. Recombinant expression of Sam68 protein was sufficient to rescue these splicing changes in ALS hSOD1G93A MN-like cells. Hence, our study highlights an aberrant function of Sam68, which leads to splicing changes in synaptic genes and may contribute to the MN phenotype that characterizes ALS.


[Impact of the spraying of deltamethrin in a focus of leishmaniasis in Bolivia].
After one month of entomological observations to record pretreatment data, a sub Andean village of Yungas, Bolivia (alt. 1500 m) was sprayed at the beginning of the rainy season (January 1987). Houses were treated inside and outside with deltamethrin at 0.025 g/sq.m.; kennels, hen-houses and stacks of adobe were also sprayed in the same way. As a result of the treatment, Lutzomyia longipalpis, the local vector of visceral leishmaniasis, disappeared from houses and animal shelters for 9 and 10 months respectively. The impact of the treatment on the populations of Lu. nuneztovari and anglesi, the presumed vector of tegumentary leishmaniasis, was not obvious. As compared with pretreatment data, the rate of engorged females in houses decreased by two, and their density was also reduced. But these data are difficult to interpret due to the natural seasonal variation in density in this species. Moreover, the information from the control village did not correspond as expected. Lu. n. anglesi is a highly exophilic species in this area, a behaviour which could explain the limited impact of the treatment on this sandfly.


Detection of adeno-associated virus viremia in hematopoietic cell transplant recipients.
Adeno-associated virus (AAV) is widely considered to be nonpathogenic, but the clinical epidemiology of this virus is limited. By use of polymerase chain reaction assays, we investigated the incidence and clinical significance of AAV viremia in a population of consecutive recipients of a hematopoietic cell transplant (HCT). Four (2.8%) of 145 patients developed AAV viremia after HCT. Viremia was low level and transient in all patients. Two patients were admitted to the hospital and died in proximity to AAV viremia (<7 weeks between diagnosis and death); however, AAV was not detected in tissue specimens obtained at autopsy. Thus, AAV does not appear to play a pathogenic role in organ-specific illness, even in a highly immunocompromised population.


Low-threshold afferent signalling of viscous loads during voluntary movements of the human digits.
Humans can discriminate changes in load viscosity during voluntary contractions. The afferent signal origin is unknown. Microneurographic recordings from 83 single low-threshold afferents were made while participants performed triangular ramps either unloaded or with a viscous load. The neural discharges for each cycle were compared across load and velocity. Fifty-eight afferents did not respond. Afferents with sufficient activity were classified as ambiguous--discharges correlated to velocity and load (n=4), infinite viscosity--strong load and weak velocity signal (n=6), no viscosity--strong velocity and weak load signal (n=10) and those with neither (n=5). No single class of afferent provides a coherent signal of viscosity. These data suggest that the central nervous system compares the population response of different inputs to discriminate viscosity.


EVOLUTIONARY ORIGIN OF THE CYCLORRHAPHA (DIPTERA): TEST OF ALTERNATIVE MORPHOLOGICAL HYPOTHESES.
Abstract- The higher flies, infraorder Cyclorrhapha [=Muscomorpha (McAlpine, 1989)], have undergone enormous radiation since the Cretaceous (∼100 Myr). Rapid morphological evolution in cyclorrhaphans has made their phylogenetic placement with respect to more primitive clades a long-standing problem in dipteran systematics. Of the two most plausible hypotheses, one treats the Cyclorrhapha as sister group to the orthorrhaphous superfamily Empidoidea [=Empidiformia (Hennig, 1948), Orthogenya (Brauer, 1883)], while the other places them within the empidoids. The debate over cyclorrhaphan origin has heretofore focused on homology interpretations for a few character systems, particularly the male genitalia. We provide the first attempt to assemble and quantify all of the available morphological evidence. By cladistic analysis of these data under alternative codings of genitalic features reflecting opposing homology theories, and then excluding these features altogether, we sought to judge which genitalic theory is better supported by the evidence as a whole, and how much the debate matters to resolving cyclorrhaphan origins. Using the analog of a factorial design, we also measured the effect of alternative transformation series in several other controversial characters, of outgroup choice and of successive weighting. Under all manipulations, including both genitalic codings, the Cyclorrhapha originate within the Empidoidea, near the family Atelestidae. However, trees in which the Empidoidea are constrained to be monophyletic are only 1-6 steps longer (out of ∼150), a fit not significantly worse under a permutation test for monophyly. Adult morphological data may not suffice to settle either the placement of Cyclorrhapha or the debate over genitalic homology. Moreover, the issue of genitalic homology does not appear critical to that of cyclorrhaphan origin.


In vivo use of a nanoknife for axon microsurgery.
Microfabricated devices with nanoscale features have been proposed as new microinstrumentation for cellular and subcellular surgical procedures, but their effectiveness in vivo has yet to be demonstrated. In this study, we examined the in vivo use of 10 to 100 microm-long nanoknives with cutting edges of 20 nm in radius of curvature during peripheral nerve surgery. Peripheral nerves from anesthetized mice were isolated on a rudimentary microplatform with stimulation microelectrodes, and the nanoknives were positioned by a standard micromanipulator. The surgical field was viewed through a research microscope system with brightfield and fluorescence capabilities. Using this assembly, the nanoknife effectively made small, 50 to 100 microm-long incisions in nerve tissue in vivo. This microfabricated device was also robust enough to make repeated incisions to progressively pare down the nerve as documented visually and by the accompanying incremental diminution of evoked motor responses recorded from target muscle. Furthermore, this nanoknife also enabled the surgeon to perform procedures at an unprecedented small scale such as the cutting and isolation of a small segment from a single constituent axon in a peripheral nerve in vivo. Lastly, the nanoknife material (silicon nitride) did not elicit any acute neurotoxicity as evidenced by the robust growth of axons and neurons on this material in vitro. Together, these demonstrations support the concept that microdevices deployed in a neurosurgical environment in vivo can enable novel procedures at an unprecedented small scale. These devices are potentially the vanguard of a new family of microscale instrumentation that can extend surgical procedures down to the cellular scale and beyond.


[Lipoma of spermatic cord; report of a case].
To report an additional case of lipoma of the spermatic cord, an uncommon, silent tumor. A case of lipoma of the spermatic cord is described. The patient had presented with an enlarged scrotum with no symptoms. The literature on lipoma of the spermatic cord is briefly reviewed, with special reference to its diagnosis, forms of presentation and treatment. US evaluation demonstrated a mass adhered to the epididymis. An epididymal tumor was suspected and surgical exploration by the inguinal approach was performed. Lipoma is the most common tumor of the spermatic cord. Its etiology is unknown. It frequently appears in the fourth and fifth decades of life and usually involves the left hemiscrotum. It is silent and is detected by enlargement of the scrotum. The diagnosis is histological supported by US, which offers a reliability of 80%-100%. Treatment is by surgery in all cases.


Substantial enhancement of energy storage capability in polymer nanocomposites by encapsulation of BaTiO3 NWs with variable shell thickness.
Dielectric polymer nanocomposites have received keen interest due to their potential application in energy storage. Nevertheless, the large contrast in dielectric constant between the polymer and nanofillers usually results in a significant decrease of breakdown strength of the nanocomposites, which is unfavorable for enhancing energy storage capability. Herein, BaTiO3 nanowires (NWs) encapsulated by TiO2 shells of variable thickness were utilized to fabricate dielectric polymer nanocomposites. Compared with nanocomposites with bare BaTiO3 NWs, significantly enhanced energy storage capability was achieved for nanocomposites with TiO2 encapsulated BaTiO3 NWs. For instance, an ultrahigh energy density of 9.53 J cm-3 at 440 MV m-1 could be obtained for nanocomposites comprising core-shell structured nanowires, much higher than that of nanocomposites with 5 wt% raw ones (5.60 J cm-3 at 360 MV m-1). The discharged energy density of the proposed nanocomposites with 5 wt% mTiO2@BaTiO3-1 NWs at 440 MV m-1 seems to rival or exceed those of some previously reported nanocomposites (mostly comprising core-shell structured nanofillers). More notably, this study revealed that the energy storage capability of the nanocomposites can be tailored by the TiO2 shell thickness. Finite element simulations were employed to analyze the electric field distribution in the nanocomposites. The enhanced energy storage capability should be mainly attributed to the smoother gradient of dielectric constant between the nanofillers and polymer matrix, which alleviated the electric field concentration and leakage current in the polymer matrix. The methods and results herein offer a feasible approach to construct high-energy-density polymer nanocomposites with core-shell structured nanowires.


[Vertebrogenic dysphagia in diffuse idiopathic skeletal hyperostosis (Forestier's disease)].
Swallowing disorders can be caused by morphologic changes of the cervical spine such as diffuse idiopathic skeletal hyperostosis. The paper describes current concepts of this clinical entity also known as Forestier's disease. The symptomatology, radiographic features and treatment are discussed. Particular interest is focused on dysphagia. The diagnosis is exclusively radiographic. Cervical osteophytes can be detected in 20-30% of the population in asymptomatic patients. Therefore, the attribution of the presence of osteophytic deformities of the barium column to dysphagia should not be made unless objective evidence of impairment of pharyngeal function such as abnormal posterior pharyngeal wall motion is proven by dynamic imaging means. The therapeutic approach depends on the extent of dysphagic complaints. Indications for surgery are failure to respond to conservative management (anti-inflammatory drugs, concomitant antibiotics, dietary nutrition). The anterolateral extrapharyngeal approach is commonly preferred.


[Deep infiltrating endometriosis: anatomical distribution and surgical treatment].
To evaluate the anatomical distribution of deep infiltrating endometriosis (DIE) lesions in a sample of women from the South of Brazil. A prospective study was conducted on women undergoing surgical treatment for DIE from January 2010 to January 2012. The lesions were classified according to eight main locations, from least serious to worst: round ligament, anterior uterine serosa/vesicouterine peitoneal reflection, utero-sacral ligament, retrocervical area, vagina, bladder, intestine, ureter. The number and location of the DIE lesions were studied for each patient according to the above-mentioned criteria and also according to uni- or multifocality. The statistical analysis was performed using Statistica version 8.0. The values p<0.05 were considered statistically significant. During the study period, a total of 143 women presented 577 DIE lesions: uterosacral ligament (n=239; 41.4%), retrocervical (n=91; 15.7%), vagina (n=50; 8.7%), round ligament (n=50; 8,7%), vesico-uterine septum (n=41; 7.1%), bladder (n=12; 2.1%), and intestine (n=83; 14.4%), ureter (n=11; 1.9%). Multifocal disease was observed in the majority of patients (p<0.0001), and the mean number of DIE lesions per patient was 4. Ovarian endometrioma was present in 57 women (39.9%). Sixty-five patients (45.4%) presented intestinal infiltration on histological examination. A total of 83 DIE intestinal lesions were distributed as follows: appendix (n=7), cecum (n=1) and rectosigmoid (n=75). The mean number of intestinal lesions per patient was 1.3. DIE has a multifocal pattern of distribution, a fact of fundamental importance for the definition of the complete surgical treatment of the disease.


[Analysis of antibiotic use based on case histories].
Type and dose of antibiotics, length and purpose of therapy was retrospectively collected from case histories of the 2230 patients who were discharged from a district general hospital between January 1 and 31, 1995. The suitability of each antibiotic for its stated purpose was compared with the current therapeutic recommendations, guidelines and literature. 24.6% of patients received antibiotics. 83.9% of the 728 courses was monotherapy, 16.1% was combined therapy. 82.7% of the 852 prescriptions was empiric, 7.5% directed against an identified microorganism and 9.8% was prophylactic. 596 microbiological samples of 272 (49.5%) patients were sent to the laboratory. Infections of lower and upper airways, urinary tracts, wounds and abdominal organs were most frequently diagnosed. Majority of utilized antibiotics were broad spectrum beta lactams. 5.3% of patients suffered from hospital acquired infections. 23.8% of prescriptions were determined as unnecessary. Problems of inappropriate antibacterial spectrum (11.0% of prescriptions), negligence of pharmacokinetics (6.1%), long duration of therapy (7.2%) and underdosing (6.1%) were also frequent. Authors emphasize the importance of the monitoring drug utilisation, the introduction of hospital diagnostic and therapeutic protocols in order to improve the antibiotic usage.


Is the periodontal status a risk factor for the development of psoriasis?
Psoriasis is a common, chronic, inflammatory, and hyperproliperative skin disease. It has been known that the infectious agents play a role in triggering and exacerbation of the disease. Periodontal diseases are chronic inflammatory gum diseases initiated by microorganisms in dental plaques. This study intended to determine the role of periodontal diseases, as chronic infective foci in psoriasis. A total of 76 patients, who applied to Faculty of Medicine, Department of Dermatology, İnönü University, diagnosed as psoriasis and a control group consisting of 76 dermatologic patients without any systemic disease at similar age and gender were included the study. The dental examinations of the subjects were done by the Community Periodontal Index of Treatment Needs index system, using a periodontal probe. Significant difference was identified between the patients with psoriasis and control group, in terms of CPI (Community Periodontal Index), oral hygiene habits, frequency of tooth brushing and flossing (P = 0.01, P = 0.001, P = 0.01, P = 0.05, respectively). A positive correlation between the severities of psoriasis and dental disease was determined, but this difference was not statistically significant (P = 0.204). The periodontal disease may affect psoriasis as a chronic infectious focus and probably through proinflammatory cytokines. In order to clarify the exact role of periodontal disease in psoriasis, the issue should be studied in larger series with serum cytokine levels.


Cascade enzymatic reactions for efficient carbon sequestration.
Thermochemical processes developed for carbon capture and storage (CCS) offer high carbon capture capacities, but are generally hampered by low energy efficiency. Reversible cascade enzyme reactions are examined in this work for energy-efficient carbon sequestration. By integrating the reactions of two key enzymes of RTCA cycle, isocitrate dehydrogenase and aconitase, we demonstrate that intensified carbon capture can be realized through such cascade enzymatic reactions. Experiments show that enhanced thermodynamic driving force for carbon conversion can be attained via pH control under ambient conditions, and that the cascade reactions have the potential to capture 0.5 mol carbon at pH 6 for each mole of substrate applied. Overall it manifests that the carbon capture capacity of biocatalytic reactions, in addition to be energy efficient, can also be ultimately intensified to approach those realized with chemical absorbents such as MEA.


The battle against biofilm infections: juglone loaded nanoparticles as an anticandidal agent.
In this study, juglone nanoparticles were prepared by single emulsion solvent evaporation method and their effect against Candida albicans biofilm was investigated in comparison with the free juglone and Fluconazole by performing XTT, crystal violet, standard plate count, confocal microscopy and membrane depolarization analyses. Juglone nanoparticles and free juglone were found to inhibit biofilm formation and pre-established biofilms (98-100%) at all doses tested, whereas Fluconazole did not cause a significant inhibition, even at the highest dose applied, especially against pre-established biofilms. Membrane depolarization analysis showed that free juglone and juglone loaded nanoparticles were effective on C. albicans membrane structure and have fluorescence quenching effect on DiSC3(5). It is extremely important that the antibiofilm activity of the juglone nanoparticles is similar to that of the juglone used at the same concentration, since similar effect is provided by using less active substance due to controlled release. Accordingly, it can easily be said that juglone loaded nanoparticles are much more effective in the formation and elimination of C. albicans biofilm than the free juglone and Fluconazole.


A functional scale for spinal and bulbar muscular atrophy: Cross-sectional and longitudinal study.
We aimed to develop, validate, and evaluate a disease-specific outcome measure for SBMA: the Spinal and Bulbar Muscular Atrophy Functional Rating Scale (SBMAFRS). We examined the Japanese version (SBMAFRS-J) in 80 Japanese SBMA subjects to evaluate its validity and reliability. We then assessed this scale longitudinally in 41 additional SBMA subjects. The English version (SBMAFRS-E) was also tested in 15 US subjects. The total score of the SBMAFRS-J was distributed normally without an extreme ceiling or floor effect. For SBMAFRS-J, the high intra- and inter-rater agreement was confirmed (intra-class correlation coefficients [ICCs] 0.910 and 0.797, respectively), and internal consistency was satisfactory (Cronbach's alpha 0.700-0.822). In addition, SBMAFRS-J demonstrated concurrent, convergent, and discriminant validity, except for the respiratory subscale. The inter-rater reliability and internal consistency of SBMAFRS-E were also satisfactory. Longitudinally, SBMAFRS-J showed a higher sensitivity to disease progression than the existing clinical measures. In conclusion, we developed and validated a disease-specific functional rating scale for SBMA in both Japanese and English versions, although it needs to be re-assessed in interventional studies with a larger sample size including English speaking subjects.


Dynamics and the failure of transition state theory in alkene hydroboration.
Transition state theory fails to accurately predict the selectivity in an example where it is ubiquitously invoked, hydroboration. The hydroboration of terminal alkenes with BH(3) is moderately regioselective, affording an 88:12-90:10 ratio of anti-Markovnikov/Markovnikov adducts. High-level ab initio calculations predict too large of an energy difference between anti-Markovnikov and Markovnikov transition structures to account for the observed product ratio, and consideration of calculational error, solvent, tunneling, and entropy effects does not resolve the discrepancy. Trajectory studies, however, predict well the experimental selectivity. The decreased selectivity versus transition state theory arises from the excess energy generated as the BH(3) interacts with the alkene, and the observed selectivity is proposed to result from a combination of low selectivity in direct trajectories, moderate RRKM selectivity, and high selectivity after thermal equilibration.


Oral targeted therapies in the treatment of pulmonary arterial hypertension: a meta-analysis of clinical trials.
Oral targeted therapies have been widely used in the treatment of pulmonary arterial hypertension (PAH). Many new oral agents emerge for PAH in recent years. In this study, we performed a meta-analysis to evaluate the efficacy and safety of oral targeted therapies in PAH, focusing on overall survival improvement. Randomized controlled trials of oral targeted therapies in patients with PAH published through September 2013 were identified by searching the Cochrane Library, EMBASE, and PUBMED databases. We calculated risk ratios for dichotomous data and weighted mean differences with 95% confidence intervals for continuous data. 18 trials with a total of 4363 subjects were indentified in the meta-analysis. Analysis by drug class revealed that phosphodiesterase type 5 inhibitors (PDE-5Is) were associated with a statically significant reduction in mortality (RR 0.22; 95% CI 0.07-0.71, p = 0.011), while other drugs only showed a trend toward reducing mortality. Compared with placebo, endothelin receptor antagonists (ERAs), PDE-5Is and riociguat significantly reduced clinical worsening, ameliorated WHO function class, and increased the 6-min walk distance. However, oral prostanoids only showed a mild effect on 6-min walk distance (19.88 m; 95% CI 10.12-29.64, p = 0.000), and did not have any effect on reducing mortality and clinical worsening. Moreover, oral prostanoids significantly increased the incidence of withdrawal due to adverse effects (RR 3.41; 95% CI 2.06-5.63, p = 0.000). This meta-analysis suggests that all oral agents confer a therapeutic benefit. Of these, only PDE-5Is has a proven survival benefit. ERAs and riociguat are efficient in reducing clinical worsening, and ameliorating exercise capacity. Oral prostanoids have the significant adverse effects and weak therapeutic effects.


Minimal Important Difference in Voice Handicap Index-10.
The minimal important difference (MID) on patient-reported outcome measures can indicate how much of a change on that scale is meaningful. To use an anchor-based approach to estimate MID in the Voice Handicap Index-10 (VHI-10) total score. In this cohort study, a volunteer sample of adult patients visiting the voice clinic at the University of Minnesota from April 7, 2013, through July 3, 2016, completed the VHI-10 (range, 0-40, with higher scores indicating greater voice-related handicap) at baseline and 2 weeks later in conjunction with a global rating of change. An anchor-based approach was used to identify an MID. The association between the global change score and change in VHI-10 score was analyzed using Pearson rank correlation. A distribution-based method was used to corroborate the findings. Global rating of change on the VHI-10. Of the 273 participants, 183 (67.0%) were women and 90 (33.0%) were men (mean [SD] age, 54.3 [15.6] years); 259 (94.9%) were white. Participants had a variety of voice disorders, most commonly muscle tension dysphonia, irritable larynx, benign vocal fold lesions, and motion abnormalities. Among patients reporting no change on the global change score, the mean (SD) change in VHI-10 score was 1 (5). Among those reporting a small change, the mean (SD) change in VHI-10 was also 1 (5). Among those reporting a moderate change in voice symptoms, the mean (SD) change in VHI-10 score was 6 (8). Among those with a large change, the mean (SD) change in VHI-10 score was 9 (13). The correlation between the global change score and the change in VHI-10 score was 0.32 (95% CI, 0.12-0.49). Distribution-based analyses identified effect sizes comparable to those of the anchor-based categories. These findings suggest that a difference of 6 on the VHI-10 may represent an MID. This difference was associated with a moderate change on the global rating scale, and the small-change and no-change categories were indistinguishable. Given the lack of differentiation between small and no change and the modest correlation between the global change score and change in the VHI-10 score, additional studies are needed.


Expression, localization, and function of the carnitine transporter octn2 (slc22a5) in human placenta.
L-carnitine is assumed to play an important role in fetal development, and there is evidence that carnitine is transported across the placenta. The protein involved in this transfer, however, has not been identified on a molecular level. We therefore characterized localization and function of the carnitine transporter OCTN2 in human placenta. Significant expression of OCTN2 mRNA was detected in human placenta applying real-time polymerase chain reaction technology. Confocal immunofluorescence microscopy using an antibody directed against the carboxy terminus of OCTN2 protein revealed that it is predominantly expressed in the apical membrane of syncytiotrophoblasts. This was confirmed by the costaining of organic anion-transporting polypeptide B and MRP2, which are known to be expressed mainly in the basal and apical syncytiotrophoblasts membrane, respectively. To further support this finding, we performed transport studies using basal and apical placenta membrane vesicles. We could demonstrate that the carnitine uptake into the apical vesicles was about eight times higher compared with the basal ones. Moreover, this uptake was sodium- and pH-dependent with an apparent K(m) value of 21 muM and inhibited by verapamil, which is in line with published data for recombinant OCTN2. Finally, experiments using trophoblasts in cell culture revealed that expression of OCTN2 paralleled human choriogonadotropin production and thus is modulated by cellular differentiation. In summary, we show expression and function of OCTN2 in human placenta. Moreover, several lines of evidence indicate that OCTN2 is localized in the apical membrane of syncytiotrophoblasts, thereby suggesting a major role in the uptake of carnitine during fetal development.


Chemical and morphologic alterations of rabbit bone induced by adriamycin.
Long term, low dose administration of adriamycin (ADR) to young growing rabbits resulted in significant alterations in bone structure and chemistry. Morphologic changes were most pronounced at epiphyseal and metaphyseal areas of long bones. Epiphyseal cartilage plates were thin and there was derangement of growth zones. Areas of primary and secondary spongiosa were deficient in trabeculae, osteoblasts and osteoclasts. Analysis of femora, humeri and lumbar vertebrae from ADR-treated rabbits revealed increased water and fat content and significant decreases in bone density compared to age-matched controls. Cortices of long bones were roentgenographically thin and contained large irregular spaces evident microscopically. Evaluation of bone ash from ADR treated rabbits revealed significant increases in the percentage of calcium and phosphorus, although Ca/P ratios were not different from controls. Results of in vitro studies indicate that ADR binds readily to nondemineralized, but not demineralized, fresh cortical bone powder. The findings of decreased bone density, histopathologic alterations, and a paucity of osteogenic cells in ADR treated rabbits are interpreted as retardation of bone maturation. It is suggested that ADR affects adversely both the organic and inorganic fractions of bone. Due to its unique characteristics of cytostatic action, binding to metal cations and orange-red fluorescence, ADR is a novel chemical agent that may be useful in experimental bone studies.


Probability-based 3D k-space sorting for motion robust 4D-MRI.
Current 4D-MRI techniques are prone to breathing-variation-induced motion artifacts. This study developed a novel method for motion-robust multi-cycle 4D-MRI using probability-based multi-cycle sorting to overcome this deficiency. The main cycles were first extracted from the breathing signal. 3D k-space data were then sorted using a result-driven method for each main cycle. The new method was tested on a 4D-extended cardiac-torso (XCAT) phantom with a patient and an artificially generated breathing curve. For comparison, the k-space data were sorted using conventional phase sorting to generate single-cycle 4D-MRI images. Signal-to-noise ratio (SNR) of tumor and liver, tumor volume consistency, and average intensity projection (AIP) accuracy were compared between the two methods. The original phantom images were used as references for the evaluation. The new method showed improved tumor-to-liver SNR and tumor volume consistency as compared to 3D k-space phase sorting in both the simulated artificial and real patient breathing signals. For the artificial breathing cycles, the average tumor-to-liver SNR and standard deviation (SD) of tumor volume were 2.53 and 3.80% for cycle 1, 2.24 and 6.16% for cycle 2 of probability-based sorting as compared to 1.47 and 21.83% obtained using the phase sorting method; for the patient breathing curve, values of 1.99 and 2.71%, 1.97 and 3.29%, 1.88 and 4.16% were observed for cycle 1, cycle 2 and cycle 3 of probability-based sorting, versus 1.44 and 7.20% for phase sorting method. Furthermore, the AIP accuracy was improved in the probability-based sorting approach when compared to phase sorting, with the average intensity difference per voxel reduced from 0.39 to 0.15 for the artificial curve, and from 0.46 to 0.21 for the patient curve. We demonstrated the feasibility of probability-based 3D k-space sorting for motion-robust multi-cycle 4D-MRI reconstruction with breathing variation induced motion artifact reduction compared with conventional 2D image sorting and 3D phase sorting methods. This new technique can potentially improve the accuracy of radiation treatment guidance for mobile targets.


[Development of carnosine eyedrops and assessing their efficacy in corneal diseases].
Stable eye drops of 5% carnosine have been developed. Trials of the drug on mice, rats, rabbits, and dogs showed it to be well tolerated at both total and local levels. In animals the eye drops did not affect the diameter of the pupil, nor did they increase the intraocular pressure. Clinical trials were carried out in 109 patients. Carnosine eye drops exerted a good therapeutic effect in corneal erosion, trophic keratitis, postherpetic epitheliopathy, primary and secondary corneal dystrophy, and bullous keratopathy. Used in combined treatment, the eye drops accelerated healing of corneal ulcers in herpesvirus and bacterial infection or dry keratoconjunctivitis. The Pharmacological Committee of the Ministry of Health and Medical Industry of the Russian Federation permitted 5% carnosine eye drops for medical use.


Breastfeeding Outcomes After Oxytocin Use During Childbirth: An Integrative Review.
Despite widespread use of exogenous synthetic oxytocin during the birth process, few studies have examined the effect of this drug on breastfeeding. Based on neuroscience research, endogenous oxytocin may be altered or manipulated by exogenous administration or by blocking normal function of the hormone or receptor. Women commonly cite insufficient milk production as their reason for early supplementation, jeopardizing breastfeeding goals. Researchers need to consider the role of birth-related medications and interventions on the production of milk. This article examines the literature on the role of exogenous oxytocin on breastfeeding in humans. Using the method described by Whittemore and Knafl, this integrative review of literature included broad search criteria within the PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane, and Scopus databases. Studies published in English associating a breastfeeding outcome in relation to oxytocin use during the birth process were included. Twenty-six studies from 1978 to 2015 met the criteria. Studies were analyzed according to the purpose of the research, measures and methods used, results, and confounding variables. The 26 studies reported 34 measures of breastfeeding. Outcomes included initiation and duration of breastfeeding, infant behavior, and physiologic markers of lactation. Timing of administration of oxytocin varied. Some studies reported on low-risk birth, while others included higher-risk experiences. Fifty percent of the results (17 of 34 measures) demonstrated an association between exogenous oxytocin and less optimal breastfeeding outcomes, while 8 of 34 measures (23%) reported no association. The remaining 9 measures (26%) had mixed findings. Breastfeeding intentions, parity, birth setting, obstetric risk, and indications for oxytocin use were inconsistently controlled among the studies. Research on breastfeeding and lactation following exogenous oxytocin exposure is limited by few studies and heterogeneous methods. Despite the limitations, researchers and clinicians may benefit from awareness of this body of literature. Continued investigation is recommended given the prevalence of oxytocin use in clinical practice.


Treatment for methaqualone dependence in adults.
Methaqualone is a potent quinazoline, a class of sedative-hypnotics, that has a high potential for abuse. While the oral use of methaqualone (Quaalude, Mandrax) has waned in western countries since the mid-late 1980's, the practice of smoking methaqualone is a serious public health problem in South Africa, other parts of Africa and India. In the context of diminishing resources devoted to substance abuse treatment in regions affected by methaqualone abuse, it would be desirable to base treatment on the best evidence available. This review aimed to provide health care workers, policy-makers and consumers with the necessary information to make decisions regarding effective treatment of this highly dependence-producing drug. To compare the effectiveness of any type of pharmacological or behavioural treatment administered in either an in-patient or out-patient setting compared with either a placebo or no treatment or a waiting list, or with another form of treatment administered in either an in- or out-patient setting. The authors searched the following databases: Cochrane Drugs and Alcohol Group'Register of Trials (February 2004); Cochrane Central Register of Controlled Trials (CENTRAL-The Cochrane Library, Issue 2, 2004); MEDLINE (OVID - January 1966 to february 2004), PsycInfo (OVID - January 1967 to february 2004). Relevant conference proceedings and reference lists of relevant articles were hand-searched. Broad internet searches were conducted and contact made with experts in the field. All randomised controlled trials and quasi-randomised trials of the effectiveness of treatment programmes (in- or out-patient) for methaqualone dependence and abuse were considered for inclusion in this review. The authors independently assessed study eligibility and quality. No studies were found that met the inclusion criteria. To date, no randomized controlled trials appear to have been conducted. Consequently, the effectiveness of inpatient versus outpatient treatment, psychosocial treatment versus no treatment, and pharmacological treatments versus placebo for methaqualone abuse or dependence has yet to be established.


Clinical and molecular features of Hürthle cell carcinoma of the thyroid.
Hürthle cell cancer (HCC) of the thyroid remains the subject of controversy with respect to natural course, treatment, and follow-up. The objective of the study was to evaluate the clinical and molecular features associated with outcome in HCC. The study was a review of 173 HCC cases treated at Mayo Clinic over 11 years with a median 5.8-year follow-up. None of the patients with minimally invasive histology had persistent disease, clinical recurrence, or disease-related death. Male gender and TNM stage were independently associated with increased risk of clinical recurrence or death in widely invasive patients. The 5-year cumulative probability of clinical recurrence or death was higher in patients with TNM stage III-IV (females, 74%; males, 91%) compared with patients with TNM stage I-II (females, 0%; males, 17%). Pulmonary metastases were best identified by computed tomography, whereas radioactive iodine scans were positive in only two of 27 cases. Thyroglobulin was detectable in patients with clinical disease, with the notable exception of five patients with distant metastases. The common TERT C228T promoter mutation was detected in both widely invasive and minimally invasive tumors. TERT mRNA was below the limit of detection in all samples. Widely invasive HCC with TNM stage III-IV is aggressive, with low probability of recurrence-free survival. Males have worse outcomes than females. Minimally invasive HCC appears to be considerably less aggressive. Radioactive iodine scan performs poorly in detecting distant disease. Although the TERT gene is mutated in HCC, the role of this mutation remains to be demonstrated.


BCAS2 regulates oocyte meiotic prophase I by participating in mRNA alternative splicing.
Oocyte meiotic prophase I (MI) is an important event in female reproduction. Breast cancer amplified sequence 2 (BCAS2) is a component of the spliceosome. Previous reports have shown that BCAS2 is critical in male germ cell meiosis, oocyte development, and early embryo genome integrity. However, the role of BCAS2 in oocyte meiosis has not been reported. We used Stra8-GFPCre mice to knock out Bcas2 in oocytes during the pachytene phase. The results of fertility tests showed that Bcas2 conditional knockout (cKO) in oocytes results in infertility in female mice. Morphological analysis showed that the number of primordial follicles in the ovaries of 2-month-old (M) mice was significantly reduced and that follicle development was blocked. Further analysis showed that the number of primordial follicles decreased and that follicle development was slowed in 7-day postpartum (dpp) ovaries. Moreover, primordial follicles undergo apoptosis, and DNA damage cannot be repaired in primary follicle oocytes. Meiosis was abnormal; some oocytes could not reach the diplotene stage, and more oocytes could not develop to the dictyotene stage. Alternative splicing (AS) analysis revealed abnormal AS of deleted in azoospermia like (Dazl) and diaphanous related formin 2 (Diaph2) oogenesis-related genes in cKO mouse ovaries, and the process of AS was involved by CDC5L and PRP19.


Surgical Therapy of Congenital Nevi in the First Year of Life-Psychological Impact on Parents.
The birth of a child with a congenital melanocytic nevus (CMN) can lead to distress in the parents. Surgical treatment of CMN can begin in infancy. To provide insight into the perspective of parents of children with CMN regarding their experienced psychological burden and motivation to undergo surgery as well as their satisfaction. Retrospective analysis of patient data of infants (< 1 year of age), who were surgically treated by power stretching for CMN using subcutaneous infiltration anesthesia (SIA) from 01/01/2020 to 08/31/2021. To evaluate the parent's motivation and psychological burden during the surgical treatment of their child, a questionnaire was designed to interview them in a standardized telephone-based interview. Out of 45 interviewed parents, 62.2% indicated "severe" or "very severe" distress at the time of their child's birth. Distress was mostly reduced by information about diagnosis and treatment (n = 34) and treatment-progress (n = 27). Stigmatization was experienced by 35.6% of parents. 84,5% of parents were highly satisfied with early initiation of surgical therapy. 69% felt "very satisfied" or "satisfied" with the outcome of surgery. Motivation for surgical therapy was concern about malignant transformation of the, possible stigmatization of the child due to the nevus, while most of the parents (73.3%) mentioned both. Surgical treatment of CMN by power stretching in SIA in infancy is associated with high levels of satisfaction among the children's parents. Early initiation of surgical therapy and education about the diagnosis can reduce the psychological burden of the parents and can prevent psychosocial problems in affected children.


Impaired facial emotion recognition in patients with ventromedial prefrontal hypoperfusion.
Empathy refers to our ability to recognize and share emotions by another human being. Impairment may underlie many of the emotional deficits commonly associated with a range of neuropsychiatric and neurological conditions. The prefrontal cortex (PFC) has long been implicated in these processes, but the specific contribution of subregions of the PFC remain unclear. Studies regarding the role of subregions of the prefrontal cortex such as the ventromedial prefrontal cortex (vmPFC)-in facial emotion recognition have yielded inconsistent results. The present study aimed to investigate the capacity to recognize nonverbal emotional facial expressions in a group of patients with the following: (a) perfusion deficits in the vmPFC (vmPFC group; N = 13), (b) hypoperfusions sparing the vmPFC (nonvmPFC group; N = 12), and in (c) a control group of healthy volunteers (control group; N = 17). Regions of hypoperfusion were identified by means of Single Photon Emission Computed Tomography (SPECT). Participants were asked to recognize facial expressions of the 7 basic emotions (happiness, fear, surprise, anger, disgust, sadness, or neutral). Detection of facial expressions of fear, disgust, and surprise was affected after functional disruption of the vmPFC. The present study confirms the role of the vmPFC in recognizing emotional facial expressions.


Clinical potential, safety, and tolerability of arbaclofen in the treatment of autism spectrum disorder.
Autism spectrum disorder (ASD) is a behaviorally defined disorder which has increased in prevalence over the last two decades. Despite decades of research, no effective treatment is currently available. Animal models, as well as other lines of evidence, point to abnormalities in the balance of cortical excitation to inhibition in individuals with ASD, with this imbalance resulting in an overall increase in cortical excitation. To reduce cortical excitatory glutamate pathways, arbaclofen, a selective agonist of the gamma aminobutyric acid receptor type B, has been developed. This article reviews the evidence for this treatment for ASD using a systematic review methodology. Overall, a systematic search of the literature revealed 148 relevant references with the majority of these being review papers or news items that mentioned the potential promise of arbaclofen. Five original studies were identified, four of which used STX209, a form of arbaclofen developed by Seaside Therapeutics, Inc., and one which used R-baclofen. In an animal model, treatment of Fragile X, a genetic disease with ASD features, demonstrated a reversal of behavioral, neurological, and neuropathological features associated with the disease. One double-blind, placebo-controlled study treated children and adults with Fragile X. Results from this study were promising, with signs of improvement in social function, especially in the most severely socially impaired. Two studies, one open-label and one double-blind, placebo-controlled, were conducted in children, adolescents, and young adults with ASD. These studies suggested some improvements in socialization, although the effects were limited and may have been driven by individuals with ASD that were higher-functioning. These studies and others that have used arbaclofen for the treatment of gastroesophageal reflux suggest that arbaclofen is safe and well-tolerated. Clearly, further clinical studies are needed in order to refine the symptoms and characteristics of children with ASD that are best treated with arbaclofen.


Phase-sensitive optical low-coherence reflectometry technique applied to the characterization of photonic crystal fiber properties.
Localized measurements of group-velocity dispersion and birefringence of photonic crystal fibers are achieved with a phase-sensitive optical low-coherence reflectometry technique. This technique is efficient for fiber samples no longer than 1 m. Theoretical simulations are in good agreement with experimental results. As a result, the stress-induced birefringence proves to be at most 1 order of magnitude below the geometrical-shape birefringence.


Signal and Texture Features from T2 Maps for the Prediction of Mild Cognitive Impairment to Alzheimer's Disease Progression.
Early detection of Alzheimer's disease (AD) is crucial to preserve cognitive functions and provide the opportunity for patients to enter clinical trials. In recent years, some studies have reported that features related to the signal and texture of MRI images can be an effective biomarker of AD. To test these claims, a study was conducted using T2 maps, a sequence not previously studied, of 40 patients with mild cognitive impairment (MCI) from the Alzheimer's Disease Neuroimaging Initiative database, who either progressed to AD (18) or remained stable (22). From these maps, the mean value and absolute difference of 37 signal and texture imaging features for 40 contralateral pairs of regions were measured. We used seven machine learning methods to analyze whether, by adding these imaging features to the neuropsychological studies currently used for diagnosis, we could more accurately identify patients who will progress to AD. The predictive models improved with the addition of signal and texture features. Additionally, features related to the signal and texture of the images were much more relevant than volumetric ones. Our results suggest that contralateral signal and texture features should be further investigated as potential biomarkers for the prediction of AD.


A new Newton's law of cooling?
Several physiologists confuse Fourier's law of animal heat flow with Newton's law of cooling. A critique of this error in 1932 remained ineffective. In 1969 Molnar tested Newton's cooling law. In 1971 Strunk found Newtonian cooling unrealistic for animals. Unfortunately, he called the Fourier formulation of animal heat flow, requiring post-Newtonian observations, a "contemporary Newtonian law of cooling."


Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner.
Mutations of the alpha1A calcium channel subunit have been shown to cause such human neurological diseases as familial hemiplegic migraine, episodic ataxia-2, and spinocerebellar ataxia 6 and also to cause the murine neurological phenotypes of tottering and leaner. The leaner phenotype is recessive and characterized by ataxia with cortical spike and wave discharges (similar to absence epilepsy in humans) and a gradual degeneration of cerebellar Purkinje and granule cells. The mutation responsible is a single-base substitution that produces truncation of the normal open reading frame beyond repeat IV and expression of a novel C-terminal sequence. Here, we have used whole-cell recordings to determine whether the leaner mutation alters calcium channel currents in cerebellar Purkinje cells, both because these cells are profoundly affected in leaner mice and because they normally express high levels of alpha1A. In Purkinje cells from normal mice, 82% of the whole-cell current was blocked by 100 nM omega-agatoxin-IVA. In Purkinje cells from homozygous leaner mice, this omega-agatoxin-IVA-sensitive current was 65% smaller than in control cells. Although attenuated, the omega-agatoxin-IVA-sensitive current in homozygous leaner cells had properties indistinguishable from that of normal Purkinje neurons. Additionally, the omega-agatoxin-IVA-insensitive current was unaffected in homozygous leaner mice. Thus, the leaner mutation selectively reduces P-type currents in Purkinje cells, and the alpha1A subunit and P-type current appear to be essential for normal cerebellar function.


Human Milk Retains Important Immunologic Properties After Defatting.
In neonatal chylothorax, thoracic lymphatic drainage is ineffective. The resultant effusions often require drainage, leading to a loss of immune components. Affected infants can be managed with formula or defatted human milk feedings low in long-chain triglycerides to decrease lymph production. We hypothesized that there is no significant difference in the immunological profile or antibacterial effect of full-fat and defatted human milk. Milk from lactating mothers was divided into 1 aliquot that was defatted via centrifugation with the full-fat aliquot as control. Macronutrient content was analyzed with mid-infrared spectroscopy. Flow cytometry was used to measure immune cell populations. Lactoferrin, lysozyme, immunoglobulin (Ig)A, and IgG values were determined using enzyme-linked immunosorbent assay. The antibacterial properties were determined by inoculating paired full-fat and defatted milk samples with Escherichia coli or Streptococcus pneumoniae bacteria and performing colony counts. Compared with full-fat milk, defatted milk demonstrated decreased total energy and fat and increased carbohydrate concentrations. Defatted milk demonstrated a significant decrease in all immune cell populations. There was no difference in IgA, IgG, lysozyme, or lactoferrin concentrations. Both aliquots demonstrated equivalent growth inhibition of E. coli and S. pneumoniae. Unexpectedly, defatted human milk contained significantly less leukocytes than full-fat milk. IgA, IgG, lysozyme, and lactoferrin concentrations were preserved. The ability of defatted milk to inhibit bacterial growth was unaffected, suggesting that the antibacterial benefits of human milk remain after the defatting process. Further investigation regarding the clinical effect of leukocyte loss in defatted milk is warranted.


Development of an animal model of acetabular fractures.
A closed intraarticular fracture is a complex injury that consists of a physical disruption of the subchondral bone and articular surface, and an impaction injury to the articular surface that occurs at the time of the fracture. Few experimental models have been able to incorporate the elements of displaced articular fractures and blunt impaction injury to the articular surface. This work details the initial stages of an attempt to develop such model. Using a model of a dorsal wall fracture of the acetabulum in a goat, we have developed a bench-top method for assessing articular contact stress. Additionally, preliminary in vivo survival data are presented.


Tissue responses to hexyl 5-aminolevulinate-induced photodynamic treatment in syngeneic orthotopic rat bladder cancer model: possible pathways of action.
Orthotopic bladder cancer model in rats mimics human bladder cancer with respect to urothelial tumorigenesis and progression. Utilizing this model at pT1 (superficial stage), we analyze the tissue responses to hexyl 5-aminolevulinate-induced photodynamic therapy (HAL-PDT). In comparison to untreated rats, HAL-PDT causes little change in tumor-free rat bladder but induces inflammatory changes with increased lymphocytes and mononuclear cell infiltration in rat bladders with tumor. Immunohistochemistry reveals that HAL-PDT is without effect on proliferating cell nuclear antigen expression within the tumor and increases caspase-3 expression in both normal urothelium and the tumor. Transmission electron microscopy reveals severe mitochondrial damage, formations of apoptotic bodies, vacuoles, and lipofuscin bodies, but no microvillus-formed niches in HAL-PDT-treated bladder cancer rats. Bioinformatics analysis of the gene expression profile indicates an activation of T-cell receptor signaling pathway in bladder cancer rats without PDT. HAL-PDT increases the expression of CD3 and CD45RA in the tumor (determined by immunohistochemistry). We suggest that pathways of action of HAL-PDT may include, at least, activations of mitochondrial apoptosis and autophagy, breakdown of cancer stem cell niches, and importantly, enhancement of T-cell activation.


Insights from new cestodes of the crocodile shark, Pseudocarcharias kamoharai (Lamniformes: Pseudocarchariidae), prompt expansion of Scyphyophyllidum and formal synonymization of seven phyllobothriidean genera - at last!
Three new cestode species are described from the crocodile shark (Pseudocarcharias kamoharai) in Ecuador. All three were examined with light and scanning electron microscopy. The unique combination of morphological features in one of the new species prompted formal investigation of the non-monophyly of Paraorygmatobothrium relative to the morphologically similar genera Doliobothrium, Guidus, Marsupiobothrium, Nandocestus, Orectolobicestus, Ruhnkecestus and Scyphophyllidium. Sequence data generated for part of the 28S rDNA gene were subjected to maximum likelihood (ML) analysis. The resulting tree led to the synonymization of six of these seven genera with Scyphophyllidium, and transfer of their species to the latter genus. With the new species, the number of described members of Scyphophyllidium is now 45. The diagnosis of Scyphophyllidium is revised to accommodate these species. In addition, to expedite future descriptions, eight categories of Scyphophyllidium species are circumscribed, based largely on bothridial features. Scyphophyllidium timvickiorum n. sp. is a category 1 species. Beyond being the smallest category 1 species, it bears, rather than lacks, apical suckers and lacks, rather than bears, strobilar scutes. The two other new species are members of Clistobothrium. Clistobothrium amyae n. sp. differs from its congeners in bothridial shape, elongate cephalic peduncle and tiny size. Clistobothrium gabywalterorum n. sp. differs from the two of its congeners that also possess foliose bothridia in overall size and testis number. Despite their substantial morphological differences, the ML tree indicates they are sister taxa. Both are unique among their congeners in possessing cephalic peduncle spinitriches. The diagnosis of Clistobothrium is revised accordingly.


Rhodamine functionalized conducting polymers for dual intention: electrochemical sensing and fluorescence imaging of cells.
We report here the electrochemical co-polymerization of two functional monomers, one containing fluorescent rhodamine dye (RF) and the other monomer having amine groups (RD), onto electroactive Indium Tin Oxide (ITO) glass. After one step preparation of these surfaces, a three peptide called ArginylGlysylAspartic acid (RGD) was immobilized via EDC chemistry by using amine groups (P(RF-co-RD)/RGD) of the co-polymer, for further use in various bio-applications such as cell adhesion and imaging as well as electrochemical cell sensing. The resultant RGD bound and also fluorescent platforms were utilized as targeted adhesion materials towards integrin avb3 receptor positive (U87-MG) cells and the selectivity was checked by using HaCaT cells as a control. Finally, electrochemical measurements were carried out to characterize step by step surface modification and detection of cell attachment. As a result, P(RF-co-RD)/RGD is a promising material for multi-purpose uses, such as fluorescence imaging without the need for an additional dye for cell visualization and as a targeted adhesion and electrochemical cell sensing platform.


Electrostatic Contribution to 19F Chemical Shifts in Fluorotryptophans in Proteins.
DFT calculations indicate that the 19F chemical shifts of aromatic rings containing single fluorine substituents are sensitive to the electric fields and electric field gradients at the position of the fluorine atom. The present work explores whether long-range structure restraints can be gained from changes in 19F chemical shifts following mutations of charged to uncharged residues. 19F chemical shifts of fluorotryptophan residues were measured in two different proteins, GB1 and the NT* domain, following mutations of single asparagine residues to aspartic acid. Four different versions of fluorotryptophan were investigated, including 4-, 5-, 6-, and 7-fluorotryptophan, which were simultaneously installed by cell-free protein synthesis using 4-, 5-, 6-, and 7-fluoroindole as precursors for the tryptophan synthase present in the S30 extract. For comparison, the 1H chemical shifts of the corresponding nonfluorinated protein mutants produced with 13C-labeled tryptophan were also measured. The results show that the 19F chemical shifts respond more sensitively to the charge mutations than the 1H chemical shifts in the nonfluorinated references, but the chemical shift changes were much smaller than predicted by DFT calculations of fluoroindoles in the electric field of a partial charge in vacuum, indicating comprehensive dielectric shielding by water and protein. No straightforward correlation with the location of the charge mutation could be established.


Soyasaponins Ab and Bb prevent scopolamine-induced memory impairment in mice without the inhibition of acetylcholinesterase.
Soy (Glycine max, family Leguminosae), which contains isoflavones and saponins as main constituents, is known to exhibit memory-enhancing effects. Therefore, to investigate the role of soyasaponins in memory impairments, we isolated soyasaponins Ab (SA) and Bb (SB) from soybean and measured their protective effects against scopolamine-induced memory impairment in mice. SA and SB significantly prevented scopolamine-induced memory impairment in passive avoidance and Y-maze tasks. Compared to SA, SB rescued memory impairment more potently. Treatment with SB (10 mg/kg, p.o.) protected memory impairment in passive avoidance and Y-maze tasks to 97% (F = 68.10, P < 0.05) and 78% (F = 35.57, P < 0.05) of untreated normal control level, respectively. SA and SB (10 mg/kg) also rescued scopolamine-induced memory impairment in Morris water maze task (F = 14.51, P < 0.05). In addition, soyasaponins preserved brain-derived neurotrophic factor (BNDF) expression (F = 33.69, P < 0.05) and cAMP response element-binding (CREB) protein phosphorylation (F = 91.62, P < 0.05) in the hippocampus of scopolamine-treated mice. However, SA and SB did not inhibit acetylcholinesterase in vitro and ex vivo. On the basis of these findings, we suggest that soybean, particularly soyasaponins, may protect memory impairment by increasing BDNF expression and CREB phosphorylation.


Temperature regulation of young coypus (Myocastor coypus) in air and water.
Coypus (Myocastor coypus Molina) have recently colonized temperate regions of Europe in large numbers, originating from populations indigenous to subtropical regions of South America. Observations of coypu behavior in the wild and in enclosures under a temperate climate showed a preference for close proximity to water and frequent swimming bouts. Little change was observed in the semiaquatic habit in winter, despite high mortality during this period, particularly among young and adult male coypus. Evidence for constraints on thermal adaptation was sought from measurements in a thermostatic chamber of the resting metabolic rate (RMR) of young coypus caught from wild populations in France and of the body (Tb) and skin (Tsk) temperatures as a function of ambient temperature (Ta). A light heterothermic response with deep Tb falling by 0.8 degree C and stabilizing at a new level of 36.7 degrees C was observed in water and air at Ta below the lower critical temperatures. In common with other semiaquatic mammals, RMR (2.94 W/kg) was high relative to terrestrial mammals of equivalent body mass. Minimal thermal conductance was 0.10 W.kg-1.degree C-1 in air for Ta between -10 and +20 degrees C, and conductance varied in water from 0.24 to 1.18 W.kg-1.degrees C-1 for Ta between 5 and 35 degrees C. The physiological adaptations to cold and particularly the high insulative value of the fur (80-90% of the insulation) help to explain the successful extension of the coypu's range to temperate regions. Energetic costs were nevertheless high in cold water, suggesting that social factors may be implicated in severe winter mortality, particularly dominance hierarchy regulating the persistent use of water bodies even under freezing conditions.


Hemifacial Microsomia : Clinicoradiological Insight and Report of a Case.
Hemifacial microsomia is a congenital malformation characterized by deficiency in the amount of hard and soft tissue on one side of the face. It is primarily a syndrome of the first branchial arch, involving underdevelopment of the temporomandibular joint, masticatory muscles, mandibular ramus, ear and, occasionally, defects in facial nerve and muscles. The clinical and radiological manifestations of a 14-year-old male patient having hemifacial microsomia is highlighted in this article to enhance our knowledge and diagnostic skill of this rare entity. This case illustrates that early diagnosis and intervention in a patient with hemifacial microsomia is quintessential for proper functioning and esthetics of the orofacial structures, which will lead to a better prognosis.


Resonantly guided modes in microstructured optical fibers with a circular array of high-index rods.
A microstructured optical fiber with a new type of waveguiding mechanism is proposed. The fiber consists of a circular rod array of high index material (n=3.48) embedded in a low index background (n=1.44). The rod array exhibits guided-mode resonance (GMR) for cylindrical waves arriving from inside the array, and thus functions as a highly reflective circular wall. Through finite-difference time-domain (FDTD) simulations, we confirmed light confinement and guidance near the GMR wavelength. Basic optical characteristics such as dispersion relations, loss spectra, and mode field profiles were calculated.


Public Health Workforce Self-Identified Training Needs by Jurisdiction and Job Type.
Ensuring adequate and appropriate training of the workforce is a crucial priority for governmental public health. This is particularly important, given the diverse backgrounds of the public health workforce; the vast majority (approximately 83%) do not have formal training in public health, and those that do have formal training in public health have limited training in management and other essential organizational skills. The purpose of this article is to identify training needs among public health workers in specific job types and settings. This cross section study used 2014 data from the Public Health Workforce Interests and Needs Survey. Qualitative analyses were used to code open-ended responses to questions about training needs. Needs are stratified across job types and jurisdiction. Eight main themes or skill areas were identified with the largest proportion indicating a need for management/leadership skills (28.2%). The second most frequent need was communication skills (21.3%). Across the 9 job types examined, general management skills were either the first or second training need for 7 job types. Among individuals who already have leadership/management positions, budgeting was the most common training need. Findings from this study can inform targeted strategies to address training needs for specific types of employees. Such strategies can influence the efficiency and effectiveness of public health efforts and employee satisfaction. As new public health frameworks-like Public Health 3.0 and the Chief Health Strategist-are advanced nationally, it is necessary to ensure that the workforce has the skills and abilities to implement these frameworks.


Biotechnology and Consumer Decision-Making.
Society is facing major challenges in climate change, health care and overall quality of life. Scientific advances to address these areas continue to grow, with overwhelming evidence that the application of highly tested forms of biotechnology is safe and effective. Despite scientific consensus in these areas, consumers appear reluctant to support their use. Research that helps to understand consumer decision-making and the public's resistance to biotechnologies such as vaccines, fluoridated water programs and genetically engineered food, will provide great social value. This article is forward-thinking in that it suggests that important research in behavioral decision-making, specifically affect and ambiguity, can be used to help consumers make informed choices about major applications of biotechnology. This article highlights some of the most controversial examples: vaccinations, genetically engineered food, rbST treated dairy cows, fluoridated water, and embryonic stem cell research. In many of these areas, consumers perceive the risks as high, but the experts calculate the risks as low. Four major thematic approaches are proposed to create a roadmap for policymakers to consider for policy design and implementation in controversial areas of biotechnology. This article articulates future directions for studies that implement decision-making research to allow consumers to appropriately assign risk to their options and make informed decisions.


A powerful test of parent-of-origin effects for quantitative traits using haplotypes.
Imprinting is an epigenetic phenomenon where the same alleles have unequal transcriptions and thus contribute differently to a trait depending on their parent of origin. This mechanism has been found to affect a variety of human disorders. Although various methods for testing parent-of-origin effects have been proposed in linkage analysis settings, only a few are available for association analysis and they are usually restricted to small families and particular study designs. In this study, we develop a powerful maximum likelihood test to evaluate the parent-of-origin effects of SNPs on quantitative phenotypes in general family studies. Our method incorporates haplotype distribution to take advantage of inter-marker LD information in genome-wide association studies (GWAS). Our method also accommodates missing genotypes that often occur in genetic studies. Our simulation studies with various minor allele frequencies, LD structures, family sizes, and missing schemes have uniformly shown that using the new method significantly improves the power of detecting imprinted genes compared with the method using the SNP at the testing locus only. Our simulations suggest that the most efficient strategy to investigate parent-of-origin effects is to recruit one parent and as many offspring as possible under practical constraints. As a demonstration, we applied our method to a dataset from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to test the parent-of-origin effects of the SNPs within the PPARGC1A, MTP and FABP2 genes on diabetes-related phenotypes, and found that several SNPs in the MTP gene show parent-of-origin effects on insulin and glucose levels.


N-substituted benzenesulfonamide compounds: DNA binding properties and molecular docking studies.
Benzenesulfonamide-based imine compounds 5-8 were prepared and screened for their binding properties to the FSdsDNA. The structures of synthesized compounds were elucidated by the spectroscopic and analytical methods. Compounds 5-8 were screened for their interactions with the FSdsDNA. Compound 8 showed the highest binding affinity to the FSdsDNA with intrinsic binding constant of 3.10 × 104 M-1. The compounds caused the quenching of the DNA-EB emission indicating displacement of EB (ethidium bromide) from the FSdsDNA. Finally, the binding interactions between the DNA and binder molecules 5-8 were examined by the molecular docking studies. The compounds locate approximately same region of the minor groove of DNA via hydrogen bonding contacts between the sulfonamide oxygen atoms and the DG10/DG16 nucleotides of DNA.Communicated by Ramaswamy H. Sarma.


Patterns of CDKN2A gene loss in sequential oral epithelial dysplasias and carcinomas.
The CDKN2A gene locus encodes two different proteins derived from alternative splicing. p16 (exons 1alpha, 2, and 3) acts as a G1 cell cycle regulator, and p14ARF (exons 1beta, 2, and 3) acts to modulate MDM2-mediated degradation of p53. Inactivation of p16 is a common finding in many cancers; however, there is little data on CDKN2A gene abnormalities in oral precancer. In this longitudinal study, we examined changes in the CDKN2A gene locus in sequential epithelial dysplasias and oral carcinomas from 11 patients. Genomic DNA was extracted from laser-microdissected lesional tissue, and exons 1alpha, 1beta, and 2 were analyzed by duplex PCR. Immunohistochemistry was done to identify p16 and p14ARF protein expression. Two adjacent polymorphic microsatellite markers were used for allelotyping. Homozygous deletion of exon 1alpha was identified in 2 of 17 (12%) precancerous lesions. Loss of either exon 1alpha, exon 2, or both was seen in seven of nine (78%) carcinomas. In five of these carcinomas, there was loss of only exon 1alpha. No case showed deletion of exon 1beta. In 5 of 11 patients, microsatellite markers showed differing patterns of allelic imbalance in the precancerous lesions and the subsequent carcinoma, suggesting a complex genetic pattern of progression from dysplasia to carcinoma. We conclude that during oral carcinogenesis homozygous deletion of exon 1alpha of the CDKN2A gene is common but that deletion of exon 2 and 1beta is less frequent. Moreover, our results suggest that the progression from oral precancer to cancer, in some cases, is more complex genetically than predicted by linear models of carcinogenesis.


Embodied spatial transformations: "body analogy" for the mental rotation of objects.
The cognitive advantage of imagined spatial transformations of the human body over that of more unfamiliar objects (e.g., Shepard-Metzler [S-M] cubes) is an issue for validating motor theories of visual perception. In 6 experiments, the authors show that providing S-M cubes with body characteristics (e.g., by adding a head to S-M cubes to evoke a posture) facilitates the mapping of the cognitive coordinate system of one's body onto the abstract shape. In turn, this spatial embodiment improves object shape matching. Thanks to the increased cohesiveness of human posture in people's body schema, imagined transformations of the body operate in a less piecemeal fashion as compared with objects (S-M cubes or swing-arm desk lamps) under a similar spatial configuration, provided that the pose can be embodied. If the pose cannot be emulated (covert imitation) by the sensorimotor system, the facilitation due to motoric embodiment will also be disrupted.


Fetal alcohol programming of hypothalamic proopiomelanocortin system by epigenetic mechanisms and later life vulnerability to stress.
Hypothalamic proopiomelanocortin (POMC) neurons, one of the major regulators of the hypothalamic-pituitary-adrenal (HPA) axis, immune functions, and energy homeostasis, are vulnerable to the adverse effects of fetal alcohol exposure (FAE). These effects are manifested in POMC neurons by a decrease in Pomc gene expression, a decrement in the levels of its derived peptide β-endorphin and a dysregulation of the stress response in the adult offspring. The HPA axis is a major neuroendocrine system with pivotal physiological functions and mode of regulation. This system has been shown to be perturbed by prenatal alcohol exposure. It has been demonstrated that the perturbation of the HPA axis by FAE is long-lasting and is linked to molecular, neurophysiological, and behavioral changes in exposed individuals. Recently, we showed that the dysregulation of the POMC system function by FAE is induced by epigenetic mechanisms such as hypermethylation of Pomc gene promoter and an alteration in histone marks in POMC neurons. This developmental programming of the POMC system by FAE altered the transcriptome in POMC neurons and induced a hyperresponse to stress in adulthood. These long-lasting epigenetic changes influenced subsequent generations via the male germline. We also demonstrated that the epigenetic programming of the POMC system by FAE was reversed in adulthood with the application of the inhibitors of DNA methylation or histone modifications. Thus, prenatal environmental influences, such as alcohol exposure, could epigenetically modulate POMC neuronal circuits and function to shape adult behavioral patterns. Identifying specific epigenetic factors in hypothalamic POMC neurons that are modulated by fetal alcohol and target Pomc gene could be potentially useful for the development of new therapeutic approaches to treat stress-related diseases in patients with fetal alcohol spectrum disorders.


Traumatic diaphragmatic hernia.
The records of 36 patients with traumatic diaphragmatic hernia (TDH) were reviewed. In 14, acute hernias were diagnosed, but the diagnosis was made one month to 15 years after injury in 22 patients with chronic hernia. Seven acute TDHs were due to blunt and seven to penetrating trauma. Four chronic TDHs were due to blunt and 18 to penetrating trauma. Chest pain, abdominal pain, or dyspnea occurred in each acute case and in 18 of 22 chronic cases. Plain chest roentgenograms were abnormal in 33 of 36 cases. Pleural effusion or abnormal diaphragmatic contour were common abnormal findings. Supradiaphragmatic bowel, pathognomonic of TDH, was evident in seven acute and eight chronic hernias. Celiotomy was routinely employed in acute hernias, celiotomy or thoracotomy in chronic hernias. There were three deaths, two with associated CNS injury and one with chronic pulmonary disease.


Geometrically Interlocking Space-Filling Tiling Based on Fabric Weaves.
In this article, we introduce a framework for the geometric design and fabrication of a family of geometrically interlocking space-filling shapes, which we call woven tiles. Our framework is based on a unique combination of (1) Voronoi partitioning of space using curve segments as the Voronoi sites and (2) the design of these curve segments based on weave patterns closed under symmetry operations. The underlying weave geometry provides an interlocking property to the tiles and the closure property under symmetry operations ensure single tile can fill space. In order to demonstrate this general framework, we focus on specific symmetry operations induced by fabric weaving patterns. We specifically showcase the design and fabrication of woven tiles on flat and curved domains by using the most common 2-fold fabrics, namely, plain, twill, and satin weaves. We further evaluate and compare the mechanical behavior of the so created woven tiles through finite element analysis.


Strategies to Increase Flu Vaccination Coverage among Healthcare Workers: A 4 Years Study in a Large Italian Teaching Hospital.
Flu vaccination is recommended among healthcare workers (HCWs). The low vaccination coverage registered in our hospital among HCWs called for new engaging approaches to improve flu vaccination coverage. The aim of this study was to evaluate the efficacy of different strategies implemented during the last four years (2015-2019). A quasi-experimental study was conducted, involving almost 4000 HCWs each year. Starting from the 2015-2016 campaign, new evidence-based strategies were progressively implemented. At the end of each campaign, an evaluation of the vaccination coverage rate reached was performed. Moreover, during the last three campaigns, differences in coverage among job category, wards involved or not in on-site vaccination (OSV) intervention, age classes and gender were analyzed. An increasing flu vaccination coverage rate was registered, from 6% in 2015-2016 to almost 22% at the end of 2018-2019. The overall number of vaccinated HCWs increased, especially at younger ages. OSV strategy always leads to better results, and physicians always show a higher vaccination coverage than nurses and other HCWs. The implemented strategies were effective in achieving higher flu vaccination coverage among HCWs in our hospital and therefore can be considered valuable examples of good prevention practices in hospital settings.


Downregulation of immunodetectable atrial connexin40 in a canine model of chronic left ventricular myocardial infarction: implications to atrial fibrillation.
The substrate(s) for atrial fibrillation associated with chronic left ventricular myocardial infarction remain poorly defined. Since atrial connexin40 has a rapid turnover rate and may cause atrial fibrillation, we hypothesized that chronic left ventricular myocardial infarction downregulates atrial Connexin40 and increases atrial fibrillation vulnerability. The left anterior descending coronary artery was occluded distal to the first diagonal branch in five dogs and studied 7 weeks later. Five dogs with no left anterior descending coronary artery occlusion served as control. Vulnerability to atrial fibrillation was tested by burst atrial stimulation (50 milliseconds for 3 seconds). Atrial fibrillation was induced in all myocardial infarction dogs, lasting from 20 seconds to several minutes. In contrast, only rapid repetitive activity and short-lasting atrial fibrillation (< 5 seconds) could be induced in control dogs. The mean refractory periods of epicardial RA and LA appendages were not significantly different in the two groups. Mean left ventricular myocardial infarction size was 17 +/- 4% of the left ventricle. Histologic analyses showed no signs of atrial ischemic injury or interstitial fibrosis in either group. Atrial myocyte diameter measured at the level of the nuclei of longitudinally sectioned myocytes was not significantly different in the two groups (10.1 +/- 1.2 microm vs. 10.2 +/- 1.2 microm; P = 0.3). Atrial Connexin40 (both left and right atria) in the left ventricular myocardial infarction group was highly heterogeneous and had significantly smaller total area stained than in the control (0.48 +/- 0.09% vs. 0.82 +/- 0.13%; P < 0.01). Chronic left ventricular myocardial infarction downregulates immunodetectable atrial Connexin40, a property that might contribute to the increased atrial fibrillation vulnerability in this model.


Lithium in drinking water and the incidence of bipolar disorder: A nation-wide population-based study.
Animal data suggest that subtherapeutic doses, including micro doses, of lithium may influence mood, and lithium levels in drinking water have been found to correlate with the rate of suicide. It has never been investigated whether consumption of lithium may prevent the development of bipolar disorder (primary prophylaxis). In a nation-wide population-based study, we investigated whether long-term exposure to micro levels of lithium in drinking water correlates with the incidence of bipolar disorder in the general population, hypothesizing an inverse association in which higher long-term lithium exposure is associated with lower incidences of bipolar disorder. We included longitudinal individual geographical data on municipality of residence, data from drinking water lithium measurements and time-specific data from all cases with a hospital contact with a diagnosis of mania/bipolar disorder from 1995 to 2013 (N=14 820) and 10 age- and gender-matched controls from the Danish population (N= 140 311). Average drinking water lithium exposure was estimated for all study individuals. The median of the average lithium exposure did not differ between cases with a diagnosis of mania/bipolar disorder (12.7 μg/L; interquartile range [IQR]: 7.9-15.5 μg/L) and controls (12.5 μg/L; IQR: 7.6-15.7 μg/L; P=.2). Further, the incidence rate ratio of mania/bipolar disorder did not decrease with higher long-term lithium exposure, overall, or within age categories (0-40, 41-60 and 61-100 years of age). Higher long-term lithium exposure from drinking water was not associated with a lower incidence of bipolar disorder. The association should be investigated in areas with higher lithium levels than in Denmark.


First and recurrent pediatric urinary tract infections: do they have different antibiotic susceptibilities?
Antibiotic susceptibility studies in children rarely differentiate between first and recurrent urinary tract infections (UTI), although the latter, frequently associated with underlying urinary tract anomalies and antibiotic prophylaxis, are more likely to be associated with higher antibiotic resistance of uropathogens as a result. We investigated whether antibiotic resistance was different between first and recurrent UTIs in 250 episodes (145 first and 105 recurrent) in 154 children (2 months to 12 years of age) with culture proven UTI. According to univariate analysis, resistance to cefuroxime and gentamicin was significantly lower in recurrences. This association remained statistically significant in the multivariable analysis, with adjusted odds ratio OR of 0.8 for cefuroxime (p=0.04) and for gentamicin (p=0.003) after adjusting for the role of confounding factors. The risk of resistance to other antibiotics was otherwise similar for first and recurrent UTIs.


Nucleotide polymorphism and copy number variant detection using exome capture and next-generation sequencing in the polyploid grass Panicum virgatum.
Switchgrass (Panicum virgatum) is a polyploid, outcrossing grass species native to North America and has recently been recognized as a potential biofuel feedstock crop. Significant phenotypic variation including ploidy is present across the two primary ecotypes of switchgrass, referred to as upland and lowland switchgrass. The tetraploid switchgrass genome is approximately 1400 Mbp, split between two subgenomes, with significant repetitive sequence content limiting the efficiency of re-sequencing approaches for determining genome diversity. To characterize genetic diversity in upland and lowland switchgrass as a first step in linking genotype to phenotype, we designed an exome capture probe set based on transcript assemblies that represent approximately 50 Mb of annotated switchgrass exome sequences. We then evaluated and optimized the probe set using solid phase comparative genome hybridization and liquid phase exome capture followed by next-generation sequencing. Using the optimized probe set, we assessed variation in the exomes of eight switchgrass genotypes representing tetraploid lowland and octoploid upland cultivars to benchmark our exome capture probe set design. We identified ample variation in the switchgrass genome including 1,395,501 single nucleotide polymorphisms (SNPs), 8173 putative copy number variants and 3336 presence/absence variants. While the majority of the SNPs (84%) detected was bi-allelic, a substantial number was tri-allelic with limited occurrence of tetra-allelic polymorphisms consistent with the heterozygous and polyploid nature of the switchgrass genome. Collectively, these data demonstrate the efficacy of exome capture for discovery of genome variation in a polyploid species with a large, repetitive and heterozygous genome.


[Characteristics of carbohydrate metabolism in the rat liver in thiamine deficiency].
Thiamine deficiency in rats induced by oxythiamine is accompanied by an increase in the free NADP+/NADPH ratio in liver tissue, which results in multifold stimulation of the metabolite flux in the oxidation branch of the pentose cycle. The increase in the intracellular concentrations of isocitrate and alpha-ketoglutarate with a simultaneous decrease of malate in the liver of vitamin-deficient rats points to the inhibition of alpha-ketoglutarate dehydrogenase responsible for the anomalous metabolism under conditions of thiamine deficiency. The decrease of the functional activity of the tricarboxylic acid cycle is concomitant with the activation of conversions in the oxidation branch of the pentose cycle, glucuronate and glycolytic pathways of carbohydrate metabolism, which is directed at eliminating the energy deficiency in rats with B1-hypovitaminosis.


Inflammaging (inflammation + aging): A driving force for human aging based on an evolutionarily antagonistic pleiotropy theory?
Aging, and especially human aging, can be explained by the emerging concept of parainflammation-driven inflammaging, i.e. a combination of inflammation and aging. Inflammaging posits that aging either physiologically or pathologically can be driven by the pro-inflammatory cytokines and substances produced by the innate immune system. Animals must maintain homeostasis as they age despite incessant attack from both intrinsic and extrinsic stimuli/antigens. These potentially harmful pro-inflammatory signals at a later stage of life may act antagonistically to the beneficial role they had in an earlier stage of life, like serving as developmental engines for body system formation. The concept of inflammaging is based on an antagonistic pleiotropy theory programmed during evolution. Clinical trials including caloric restriction, sirtuin activators, and p38 MAPK inhibitors against both pathological aging such as metabolic syndrome, diabetes mellitus, rheumatoid arthritis, and Werner syndrome and physiological aging have been proposed.


Can Breast Implants Induce Breast Cancer Immunosurveillance? An Analysis of Antibody Response to Breast Cancer Antigen following Implant Placement.
Women with cosmetic breast implants have significantly lower rates of subsequent breast cancer than the general population (relative risk, 0.63; 95 percent CI, 0.56 to 0.71). The authors hypothesize that breast implant-induced local inflammation stimulates immunosurveillance recognition of breast tumor antigen. Sera were collected from two cohorts of healthy women: women with long-term breast implants (i.e., breast implants for >6 months) and breast implant-naive women. Antibody responses to breast tumor antigens were tested by enzyme-linked immunosorbent assay and compared between cohorts by unpaired t test. Of the implant-naive cohort, nine women underwent breast augmentation, and antibody responses before and after implant placement were compared by paired t test. Sera were collected from 104 women: 36 (34.6 percent) long-term breast implants and 68 (65.4 percent) implant-naive women. Women with long-term breast implants had higher antibody responses than implant-naive women to mammaglobin-A (optical density at 450 nm, 0.33 versus 0.22; p = 0.003) and mucin-1 (optical density at 450 nm, 0.42 versus 0.34; p = 0.02). There was no difference in antibody responses to breast cancer susceptibility gene 2, carcinoembryonic antigen, human epidermal growth factor receptor-2, or tetanus. Nine women with longitudinal samples preoperatively and 1 month postoperatively demonstrated significantly elevated antibody responses following implant placement to mammaglobin-A (mean difference, 0.13; p = 0.0002) and mucin-1 (mean difference 0.08; p = 0.02). There was no difference in postimplant responses to other breast tumor antigens, or tetanus. Women with long-term breast implants have higher antibody recognition of mammaglobin-A and mucin-1. This study provides the first evidence of implant-related immune responses to breast cancer antigens. Therapeutic, V.


Trabecular morphometry by fractal signature analysis is a novel marker of osteoarthritis progression.
To evaluate the effectiveness of using subchondral bone texture observed on a radiograph taken at baseline to predict progression of knee osteoarthritis (OA) over a 3-year period. A total of 138 participants in the Prediction of Osteoarthritis Progression study were evaluated at baseline and after 3 years. Fractal signature analysis (FSA) of the medial subchondral tibial plateau was performed on fixed flexion radiographs of 248 nonreplaced knees, using a commercially available software tool. OA progression was defined as a change in joint space narrowing (JSN) or osteophyte formation of 1 grade according to a standardized knee atlas. Statistical analysis of fractal signatures was performed using a new model based on correlating the overall shape of a fractal dimension curve with radius. Fractal signature of the medial tibial plateau at baseline was predictive of medial knee JSN progression (area under the curve [AUC] 0.75, of a receiver operating characteristic curve) but was not predictive of osteophyte formation or progression of JSN in the lateral compartment. Traditional covariates (age, sex, body mass index, knee pain), general bone mineral content, and joint space width at baseline were no more effective than random variables for predicting OA progression (AUC 0.52-0.58). The predictive model with maximum effectiveness combined fractal signature at baseline, knee alignment, traditional covariates, and bone mineral content (AUC 0.79). We identified a prognostic marker of OA that is readily extracted from a plain radiograph using FSA. Although the method needs to be validated in a second cohort, our results indicate that the global shape approach to analyzing these data is a potentially efficient means of identifying individuals at risk of knee OA progression.


Computer-assisted detection of mammographic masses: a template matching scheme based on mutual information.
The purpose of this study was to develop a knowledge-based scheme for the detection of masses on digitized screening mammograms. The computer-assisted detection (CAD) scheme utilizes a knowledge databank of mammographic regions of interest (ROIs) with known ground truth. Each ROI in the databank serves as a template. The CAD system follows a template matching approach with mutual information as the similarity metric to determine if a query mammographic ROI depicts a true mass. Based on their information content, all similar ROIs in the databank are retrieved and rank-ordered. Then, a decision index is calculated based on the query's best matches. The decision index effectively combines the similarity indices and ground truth of the best-matched templates into a prediction regarding the presence of a mass in the query mammographic ROI. The system was developed and evaluated using a database of 1465 ROIs extracted from the Digital Database for Screening Mammography. There were 809 ROIs with confirmed masses (455 malignant and 354 benign) and 656 normal ROIs. CAD performance was assessed using a leave-one-out sampling scheme and Receiver Operating Characteristics analysis. Depending on the formulation of the decision index, CAD performance as high as A(zeta) = 0.87 +/- 0.01 was achieved. The CAD detection rate was consistent for both malignant and benign masses. In addition, the impact of certain implementation parameters on the detection accuracy and speed of the proposed CAD scheme was studied in more detail.