Proteome-wide analysis of human disease mutations in short linear motifs: neglected players in cancer?
Disease mutations are traditionally thought to impair protein functionality by disrupting the folded globular structure of proteins. However, 22% of human disease mutations occur in natively unstructured segments of proteins known as intrinsically disordered regions (IDRs). This therefore implicates defective IDR functionality in various human diseases including cancer. The functionality of IDRs is partly attributable to short linear motifs (SLiMs), but it remains an open question how much defects in SLiMs contribute to human diseases. A proteome-wide comparison of the distribution of missense mutations from disease and non-disease mutation datasets revealed that, in IDRs, disease mutations are more likely to occur within SLiMs than neutral missense mutations. Moreover, compared to neutral missense mutations, disease mutations more frequently impact functionally important residues of SLiMs, cause changes in the physicochemical properties of SLiMs, and disrupt more SLiM-mediated interactions. Analysis of these mutations resulted in a comprehensive list of experimentally validated or predicted SLiMs disrupted in disease. Furthermore, this in-depth analysis suggests that 'prostate cancer pathway' is particularly enriched for proteins with disease-related SLiMs. The contribution of mutations in SLiMs to disease may currently appear small when compared to mutations in globular domains. However, our analysis of mutations in predicted SLiMs suggests that this contribution might be more substantial. Therefore, when analysing the functional impact of mutations on proteins, SLiMs in proteins should not be neglected. Our results suggest that an increased focus on SLiMs in the coming decades will improve our understanding of human diseases and aid in the development of targeted treatments.


Acoustic obstructive sleep apnea detection.
Obstructive sleep apnea (OSA) is a common respiratory disorder during sleep, in which the airways are collapsed and impair the respiration. Apnea is s cessation of airflow to the lungs which lasts at least for 10s. The current gold standard method for OSA assessment is full night polysomnography (PSG); however, its high cost, inconvenience for patients and immobility have persuaded researchers to seek simple and portable devices to detect OSA. In this paper, we report on developing a new system for OSA detection and monitoring, which only requires two data channels: tracheal breathing sounds and the blood oxygen saturation level (S(a)O(2)). A fully automated method was developed that uses the energy of breathing sounds signals to segment the signals into sound and silent segments. Then, the sound segments are classified into breath, snore (if exists) and noise segments. The S(a)O(2) signal is analyzed to find the rises and drops in the S(a)O(2) signal. Finally, a fuzzy algorithm was developed to use this information and detect apnea and hypopnea events. The method was evaluated on the data of 40 patients simultaneously with full night PSG study, and the results were compared with those of the PSG. The results show high correlation (96%) between our system and PSG. Also, the method has been found to have sensitivity and specificity values of more than 90% in differentiating simple snorers from OSA patients.


Private volunteer medical organizations: how effective are they?
Religious and other secular organizations have been involved with medical missionary work in sub-Saharan Africa for centuries, especially in remote provinces and villages. In times past, most of these countries were under the control of foreign powers. Private volunteer organizations operated within a structured environment, which, perhaps, facilitated their mission and their ability to review and evaluate their effectiveness because of the tight control the colonial powers maintained over every facet of native life. However, the transition from colonialism to independence has resulted in a different environment in which healthcare is fragmented and a low priority in most countries because of financial constraints. The lack of standardization, vintage laboratory equipment, a manual medical record system, lack of a subsidized transportation system, infrequent postal service and the absence of phone systems in the remote provinces and villages make treatment and tracking of patients, monitoring therapy and measuring outcomes/results difficult. Therefore, judging the effectiveness of an initiative in remote district hospitals and village clinics can be difficult. This manuscript addresses some of these issues and provides solutions to some that have been effective for one organization.


Mechanisms underpinning inattention and hyperactivity: neurocognitive support for ADHD dimensionality.
Taxometric and behavioral genetic studies suggest that attention deficit hyperactivity disorder (ADHD) is best modeled as a dimension rather than a category. We extended these analyses by testing for the existence of putative ADHD-related deficits in basic information processing (BIP) and inhibitory-based executive function (IB-EF) in individuals in the subclinical and full clinical ranges. Consistent with the dimensional model, we predicted that ADHD-related deficits would be expressed across the full spectrum, with the degree of deficit linearly related to the severity of the clinical presentation. A total of 1547 children (aged 6-12 years) participated in the study. The Development and Well-Being Assessment (DAWBA) was used to classify children into groups according to levels of inattention and hyperactivity independently: (1) asymptomatic, (2) subthreshold minimal, (3) subthreshold moderate and (4) clinical ADHD. Neurocognitive performance was evaluated using a two-choice reaction time task (2C-RT) and a conflict control task (CCT). BIP and IB-EF measures were derived using a diffusion model (DM) for decomposition of reaction time (RT) and error data. Deficient BIP was found in subjects with minimal, moderate and full ADHD defined in terms of inattention (in both tasks) and hyperactivity/impulsivity dimensions (in the 2C-RT). The size of the deficit increased in a linear manner across increasingly severe presentations of ADHD. IB-EF was unrelated to ADHD. Deficits in BIP operate at subclinical and clinical levels of ADHD. The linear nature of this relationship provides support for a dimensional model of ADHD in which diagnostic thresholds are defined in terms of clinical and societal burden rather than representing discrete pathophysiological states.


NUCLEIC ACIDS: A NUCLEAR MAGNETIC RESONANCE STUDY.
Single-stranded nucleic acids in aqueous media exhibit proton magnetic resonance spectra with acceptable signal-noise ratios if multiple scans of the spectra are stored in and subsequently read out of a computer of average transients. Partial ordering of the adenine bases of polyadenylic acid in solution is reflected in contributions to the chemical shifts that are removed on "melting." More significantly, secondary structure such as occurs in complexes ofpolyA and polyU and in double-stranded DNA is manifested in proton magnetic resonance spectrabelow the "melting" temperature by severe resonance line broadening which results from anisotropic nuclear dipole-dipole interactions. The proton resonances are narrowed in and above the "melting" region, and measurement of integrated resonance intensities can give insight into quantitative aspects of hybridization, "melting," and other nucleic acid interactions.


Radiation Therapy for Aneurysmal Bone Cysts.
To evaluate the long-term effectiveness of radiation therapy (RT) as an adjuvant or alternative treatment for patients with aneurysmal bone cyst (ABC). The medical records of 12 patients who received RT at the University of Florida for ABC between 1964 and 2011 were reviewed and patients were contacted, when possible, for follow-up. Follow-up duration ranged from 3 to 36 years (median, 20.5 y). Patient age at the time of RT ranged from 3 to 23 years (mean, 12.75 y), with 7 females and 5 males. Four patients were treated for recurrent ABCs. Three patients were treated with surgical interventions (intralesional curettage, subtotal resection, or selective arterial embolization) before RT, and the rest received open biopsy only. The prescribed doses ranged from 20 to 60 Gy (mean, 30.15 Gy). Ten (83.3%) patients received between 1.5 and 2.0 Gy per fraction. All patients were doing well and free of any adverse reaction to RT as of the latest follow-up, including 1 who passed away from cardiac problems 34 years since completing RT and 3 who were lost to follow-up (at 16, 16, and 19 y) but were doing well at the last follow-up. RT continues to result in an excellent prognosis for patients with ABC who receive either RT alone or adjuvant RT after surgery.


Muscle synergies may improve optimization prediction of knee contact forces during walking.
The ability to predict patient-specific joint contact and muscle forces accurately could improve the treatment of walking-related disorders. Muscle synergy analysis, which decomposes a large number of muscle electromyographic (EMG) signals into a small number of synergy control signals, could reduce the dimensionality and thus redundancy of the muscle and contact force prediction process. This study investigated whether use of subject-specific synergy controls can improve optimization prediction of knee contact forces during walking. To generate the predictions, we performed mixed dynamic muscle force optimizations (i.e., inverse skeletal dynamics with forward muscle activation and contraction dynamics) using data collected from a subject implanted with a force-measuring knee replacement. Twelve optimization problems (three cases with four subcases each) that minimized the sum of squares of muscle excitations were formulated to investigate how synergy controls affect knee contact force predictions. The three cases were: (1) Calibrate+Match where muscle model parameter values were calibrated and experimental knee contact forces were simultaneously matched, (2) Precalibrate+Predict where experimental knee contact forces were predicted using precalibrated muscle model parameters values from the first case, and (3) Calibrate+Predict where muscle model parameter values were calibrated and experimental knee contact forces were simultaneously predicted, all while matching inverse dynamic loads at the hip, knee, and ankle. The four subcases used either 44 independent controls or five synergy controls with and without EMG shape tracking. For the Calibrate+Match case, all four subcases closely reproduced the measured medial and lateral knee contact forces (R2 ≥ 0.94, root-mean-square (RMS) error < 66 N), indicating sufficient model fidelity for contact force prediction. For the Precalibrate+Predict and Calibrate+Predict cases, synergy controls yielded better contact force predictions (0.61 < R2 < 0.90, 83 N < RMS error < 161 N) than did independent controls (-0.15 < R2 < 0.79, 124 N < RMS error < 343 N) for corresponding subcases. For independent controls, contact force predictions improved when precalibrated model parameter values or EMG shape tracking was used. For synergy controls, contact force predictions were relatively insensitive to how model parameter values were calibrated, while EMG shape tracking made lateral (but not medial) contact force predictions worse. For the subject and optimization cost function analyzed in this study, use of subject-specific synergy controls improved the accuracy of knee contact force predictions, especially for lateral contact force when EMG shape tracking was omitted, and reduced prediction sensitivity to uncertainties in muscle model parameter values.


Toward ecologically scaled landscape indices.
Nature conservation is increasingly based on a landscape approach rather than a species approach. Landscape planning that includes nature conservation goals requires integrated ecological tools. However, species differ widely in their response to landscape change. We propose a framework of ecologically scaled landscape indices that takes into account this variation. Our approach is based on a combination of field studies of spatially structured populations (metapopulations) and model simulations in artificial landscapes. From these, we seek generalities in the relationship among species features, landscape indices, and metapopulation viability. The concept of ecological species profiles is used to group species according to characteristics that are important in metapopulations' response to landscape change: individual area requirements as the dominant characteristic of extinction risk in landscape patches and dispersal distance as the main determinant of the ability to colonize patches. The ecological profiles and landscape indices are then integrated into two ecologically scaled landscape indices (ESLI): average patch carrying capacity and average patch connectivity. The field data show that the fraction of occupied habitat patches is correlated with the two ESLI. To put the ESLI into a perspective of metapopulation persistence, we determine the viability for six ecological profiles at different degrees of habitat fragmentation using a metapopulation model and computer-generated landscapes. The model results show that the fraction of occupied patches is a good indicator for metapopulation viability. We discuss how ecological profiles, ESLI, and the viability threshold can be applied for landscape planning and design in nature conservation.


Pre-cancerous (DNA and chromosomal) lesions in professional sports.
Exhaustive exercises may become detrimental, causing disturbance of intracellular oxidant-antioxidant balance and damage to macromolecules, leading to genomic instability when DNA/chromosomes get damaged. As these are precancerous lesions, cancer occurrence is probable. Because professional sports requires high-intensity training and increasing physical demand, there may occur cellular genomic instability. To evaluate genetic damage at DNA and chromosomal levels in hockey and baseball-soft ball players and compare with levels in age- and sex-matched sedentary controls. Players professionally active in their sport from 3 to 11 years on a daily training session of 4h/day were contacted during their camps, and the study was approved by the Institutional Ethics Committee. All participants were healthy individuals, not on any medication and were not taking any supplements. Genetic damage using the single cell gel electrophoresis assay and buccal micronucleus cytome assay of 56 individuals (36 players and 20 controls) was evaluated. Student's t -test, ANOVA, Pearson correlation and linear regression and Chi-square analysis were performed. Players had significantly elevated levels of genetic damage. There were no gender differences and also no significant difference in the genetic damage incurred in both sports types. However, the extent of DNA migration in hockey players was higher. Significantly increased genomic instability in players of both sports was observed. Both repaired and repairable genetic damage cells were observed in different tissues of the same subject. The presence of such genetic damage implies that these players are at an individual risk from cancer- and age-related diseases.


Embryology of the lower genitourinary tract.
The urinary and genital systems are closely related in their development so that dividing them into separate divisions is often artificial. The lower urinary system begins as a cloaca. The urorectal septum then divides the cloaca into a ventral urogenital sinus and a dorsal hindgut. The ureteral bud forms off the mesonephric duct. The male and female genital systems are the same until the gonad assumes characteristics of the testis or ovary in the eighth week of gestation. It is not until the eleventh or twelfth week that the external genitalia assume specific sexual characteristics. Anomalies of the urethra and bladder can vary from a severe epispadias-exstrophy complex to a minimal Type I urethral valve. Ureteral anomalies include duplications, ectopia, and ureteroceles. An undescended testis is probably the most common anomaly in the male genital tract. Female genital anomalies can include a variety of uterine duplication anomalies. Gonadal abnormalities are often created by a chromosomal defect and are ultimately reflected by abnormal sexual differentiation.


Altered serum creatine kinase level and cardiac function in ischemia-reperfusion injury during percutaneous coronary intervention.
Myocardial ischemia-reperfusion injury (MIRI) resulting from primary percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) is considered harmful to the patient, but its clinical significance remains unclear. This study explored the relationship of cardiac function examined by echocardiography and serum creatine kinase (CK) and CK-MB levels with MIRI in a cohort of Chinese AMI patients. We retrospectively analysed the clinical and angiographic data in 228 AMI patients in whom the infarct-related artery (IRA) was successfully recanalized by primary PCI. Cardiac function was evaluated by use of echocardiography before discharge from hospital. The in-hospital mortality rate in the MIRI group was 13.4% (16/119), which was significantly higher than the 4.6% (5/109) mortality rate in the non-MIRI group (P=0.021). The median of peak serum CK level was remarkably lower in the suppression-type MIRI group than in the non-MIRI group. There were no significant differences in the peak serum CK or CK-MB levels between the irritation-type MIRI group and the non-MIRI group. The peak CK and CK-MB levels were significantly higher in the no-reflow-type MIRI group than in the non-MIRI group. Left ventricular ejection fraction in the no-reflow-type MIRI group was significantly lower than in the non-MIRI group; left ventricular end-diastolic volume was significantly higher than in the irritation-type MIRI subgroup; and left ventricular end-systolic volume was greater than that in non-MIRI group and suppression-type MIRI group. MIRI (especially the no-reflow type) may lead to acute hemodynamic disorders and increase the mortality rate. However, suppression- and irritation-type MIRI may imply the existence of surviving myocardium.


Myocardial responses to alpha-adrenoceptor stimulation with methoxamine hydrochloride in lambs.
This study was undertaken to evaluate the effects of methoxamine on left ventricular performance, coronary blood flow (CBF), and myocardial oxygen consumption (MVO2) in lambs. Measurement of maximum rate of rise of left ventricular pressure (LV dP/dtmax), left ventricular end-diastolic pressure (LVEDP), CBF, and MVO2 were made in nine lambs using a hemodynamically controlled preparation. The lambs were given atropine sulfate (1 mg), tetraethylammonium chloride (100 mg), and practolol (4 mg/kg) to provide parasympathetic, ganglionic, and beta-adrenergic blockades. Aortic pressure and blood flow and heart rate were held constant in each lamb. Dose-related increases in LV dP/dtmax and decreases in LVEDP were observed after progressively larger doses of methoxamine ranging from 0.4 to 6.0 mg/kg were given. These positive inotropic responses were eliminated by giving phentolamine (2 mg/kg). CBF, myocardial O2 extraction, and MVO2 did not change significantly. A positive inotropic action of methoxamine was also demonstrated in five additional animals by obtaining ventricular function curves. Initially the mean stroke volume at LVEDP 10 cmH2O (SV10) was 4.11 +/- 0.16 (SE) ml. This value increased to 5.09 +/- 0.28 ml after methoxamine (P less than 0.01). After phentolamine, SV 10 fell to 4.37 +/- 0.08 ml (P less than 0.05). These observations support the hypothesis that alpha-adrenergic receptors are present and mediate a substantial positive inotropic action on neonatal lamb myocardium.


[Serum anti endomysial and anti transglutaminase antibodies in patients with connective tissue diseases].
The detection of anti-transglutaminase IgA (tTG) and anti-endomysial (EMA) is used for screening of celiac disease (CD) with a sensitivity and specificity of 90 and 99% respectively. There is an association between CD and connective tissue diseases (CTD). To report the frequency of IgA tTG and EMA in patients with a definite diagnosis of CTD and inflammatory arthropathies (IA). One hundred forty nine patients, aged 19 to 86 years (133 females) with CTD and IA were studied. tTG were determined by ELISA and EMA by indirect immunofluorescence. Eight participants had at least one positive antibody (5.4%, confidence intervals (CI) = 1.8-9), six had both (4.0% CI = 0.9-7.2) and two had only tTG positive. An intestinal biopsy was performed in four of these participants, finding a marked villous atrophy in three and partial atrophy in one. Five percent of this group of patients with CTD or IA had positive antibodies for CD.


Sex differences in tibial adaptations to arduous training: An observational cohort study.
Military training increases tibial density and size, but it is unknown if men and women adapt similarly to the same arduous training. Seventy-seven men and 57 women not using hormonal contraceptives completed this study. Tibial volumetric bone mineral density (vBMD) and geometry were measured by peripheral quantitative computed tomography (4%, 14%, 38%, and 66% sites) at the start (week 1) and end (week 14) of British Army basic training. Training increased trabecular vBMD (4% site in men; 4% and 14% sites in women), cortical vBMD (38% site), total area (14% and 38% sites), trabecular area (14% site), cortical area and thickness (14%, 38%, and 66% sites), periosteal perimeter (14%, 38%, and 66% sites), and all indices of estimated strength (14%, 38%, and 66% sites); and, decreased endosteal perimeter (66% site) in men and women (all p ≤ 0.045). The increase in trabecular vBMD (4% and 14% sites) was greater in women and the increases in cortical area and strength (38% site) were greater in men (sex × time interactions, all p ≤ 0.047). P1NP increased and βCTX and sclerostin decreased during training in men and women, consistent with adaptive bone formation. PTH decreased in men but increased in women. Arduous weight-bearing activity increased the density and size of the tibia after 14 weeks. Women experienced similar tibial adaptations as men, however, a greater increase in trabecular vBMD in women compared with men could be due to higher loading at this skeletal site in women, whereas the small increase in cortical area could be due to inhibitory effects of oestradiol.


[Clinically predictive factors of Gleason score upgrading in patients after radical prostatectomy].
To assess the discrepancy between preoperative needle biopsy (NB) Gleason score and pathological specimen Gleason score (GS) after radical prostatectomy, and to explore the risk factors of postoperative upgrading of GS. We retrospectively evaluated 160 patients who suffered from biopsy proved prostatic carcinoma and performed radical prostatectomy. Age of the patients was 57-82 years, with the average age of 71.6; prebiopsy prostate specific antigen (PSA) was 0.31-40.32 μg/L,with the average PSA of 11.29 μg/L; body mass index (BMI) was 16.41-32.04 kg/m2, with the average BMI of 23.63 kg/m2; prostate volume (PV) was 9.52-148.46 mL, with the average PV of 40.19 mL. All the patients included in the study had complete information for clinical variables, including age, BMI, prebiopsy PSA level, PV, number of biopsy cores obtained, percentage, clinical stage, and biopsy GS. Grading of NB Gleason score was compared with their corresponding radical prostatectomy specimens, and the discrepancy between the NB and prostatectomy specimens GS assessed. Upgrading was defined as any increase in the pathological GS over that of the biopsy GS as a total sum of primary and secondary grades or a change in the order of primary and secondary grades towards higher ones. Univariable and multivariable Logistic regression analyses were used to identify predictors of pathological grading changes. Of the 160 patients, the specimen GS was upgraded in 49 (30.6%) patients and remained with no change in 82 (51.3%) patients. Univariate and multivariate regression analysis showed that prostate volume and biopsy GS were independent predictors with postoperative upgrading of GS. Age, BMI, PSA before needle biopsy, clinical stage and needle number showed no statistical significance (P>0.05). Lower biopsy GS and smaller prostate volume are increased risks for clinically upgrading of GS after radical prostatectomy. This fact should be kept in mind when deciding on therapy decisions for patients with prostate cancer.


Simultaneous whole-cell recordings from photoreceptors and second-order neurons in an amphibian retinal slice preparation.
One of the central tasks in retinal neuroscience is to understand the circuitry of retinal neurons and how those connections are responsible for shaping the signals transmitted to the brain. Photons are detected in the retina by rod and cone photoreceptors, which convert that energy into an electrical signal, transmitting it to other retinal neurons, where it is processed and communicated to central targets in the brain via the optic nerve. Important early insights into retinal circuitry and visual processing came from the histological studies of Cajal and, later, from electrophysiological recordings of the spiking activity of retinal ganglion cells--the output cells of the retina. A detailed understanding of visual processing in the retina requires an understanding of the signaling at each step in the pathway from photoreceptor to retinal ganglion cell. However, many retinal cell types are buried deep in the tissue and therefore relatively inaccessible for electrophysiological recording. This limitation can be overcome by working with vertical slices, in which cells residing within each of the retinal layers are clearly visible and accessible for electrophysiological recording. Here, we describe a method for making vertical sections of retinas from larval tiger salamanders (Ambystoma tigrinum). While this preparation was originally developed for recordings with sharp microelectrodes, we describe a method for dual whole-cell voltage clamp recordings from photoreceptors and second-order horizontal and bipolar cells in which we manipulate the photoreceptor's membrane potential while simultaneously recording post-synaptic responses in horizontal or bipolar cells. The photoreceptors of the tiger salamander are considerably larger than those of mammalian species, making this an ideal preparation in which to undertake this technically challenging experimental approach. These experiments are described with an eye toward probing the signaling properties of the synaptic ribbon--a specialized synaptic structure found in only a handful of neurons, including rod and cone photoreceptors, that is well suited for maintaining a high rate of tonic neurotransmitter release--and how it contributes to the unique signaling properties of this first retinal synapse.


Autoantibody repertoire to Ro/SSA and La/SSB antigens in patients with primary and secondary Sjögren's syndrome.
Autoimmune diseases are characterized serologically by the presence of antibodies to specific autoantigens. Antibodies to the two antigens Ro/SSA and La/SSB are found in patients with primary (pSS) and secondary Sjögren's syndrome (sSS). To explore if differences in the fine specificity of these autoantibodies could be distinguished in sera from patients with primary (n = 17) and secondary (n = 20) Sjögren's syndrome, sera were analysed by immunoblotting and ELISA using recombinant antigens and synthetic peptides. Minor differences were detected when the frequencies of the Ro 60 kD, Ro 52 kD and La autoantibody specificities to full-length proteins in the pSS and sSS groups were compared. However, when reactivity to different parts of the Ro 60 kD antigen was analysed, including recombinant fragments encompassing amino acid (aa) 1-134, aa 181-320 and aa 397-525, only two sera, both from pSS patients, reacted to the aminoterminal fragment aa 1-134, and 3/4 sera that reacted with the carboxyterminal aa 397-525 fragment derived from sSS patients. Of all the anti-Ro 60 kD positive sera, 80% reacted with the middle fragment encompassing aa residues 181-320. The fine specificity of the autoantibodies reacting with this 181-320 aa region was further mapped with synthetic peptides, and a peptide (VSLVCEKLCNEKLLKKARIH) recognized by 8 out of 16 sera from both pSS and sSS patients was identified.


Functional and structural conservation in the mechanosensitive channel MscL implicates elements crucial for mechanosensation.
mscL encodes a channel in Escherichia coli that is opened by membrane stretch force, probably serving as an osmotic gauge. Sequences more or less similar to mscL are found in other bacteria, but the degree of conserved function has been unclear. We subcloned and expressed these putative homologues in E. coli and examined their products under patch clamp. Here, we show that each indeed encodes a conserved mechanosensitive channel activity, consistent with the interpretation that this is an important and primary function of the protein in a wide range of bacteria. Although similar, channels of different bacteria differ in kinetics and their degree of mechanosensitivity. Comparison of the primary sequence of these proteins reveals two highly conserved regions, corresponding to domains previously shown to be important for the function of the wild-type E. coli channel, and a C-terminal region that is not conserved in all species. This structural conservation is providing insight into regions of this molecule that are vital to its role as a mechanosensitive channel and may have broader implications for the understanding of other mechanosensitive systems.


Tensile bond strength of fluorosed Kenyan teeth using the acid etch technique.
Tensile bond strength tests were performed on 120 enamel specimens equally distributed over 'normal' American, 'normal' Kenyan and fluorosed Kenyan teeth. The mean tensile bond strength for American teeth was 59.08 +/- 15.81 kg/cm2, for normal Kenyan teeth 41.52 +/- 14.64 kg/cm2 and for fluorosed Kenyan teeth prior to removing the surface layer 49.20 +/- 17.67 kg/cm2. There was an increase in the adhesive bond strength for fluorosed teeth after first grinding and polishing with a green stone followed by pumice (58.84 +/- 20.65 kg/cm2). The coefficients of variation were 27% for fluorosed Kenyan teeth prior to grinding and 35% after grinding. The tested etching times varied from 60 to 150 s. The normal Kenyan teeth had the lowest tensile bond strength. This may have been due to the inability to etch adequately these teeth in 60 s. The increase in tensile bond strength indicates removal of the surface layer of fluorosed enamel by grinding then acid etching may improve the bond strength.


EUS-guided Choledochoduodenostomy Versus Hepaticogastrostomy: A Systematic Review and Meta-analysis.
Endoscopic ultrasound-guided biliary drainage (EUS-BD) has emerged as an alternative in cases of endoscopic retrograde cholangiopancreatography (ERCP) failure. Two types of EUS-BD methods for achieving biliary drainage when ERCP fails are choledochoduodenostomy (CDS) or hepaticogastrostomy (HGS). However, there is no consensus if one approach is better than the other. Therefore, we conducted a systematic review and meta-analysis to evaluate these 2 main EUS-BD methods. We searched MEDLINE, Embase, Scopus, Cochrane database, LILACS from inception through April 8, 2017, using the following search terms in various combinations: biliary drainage, biliary stent, transluminal biliary drainage, choledochoduodenostomy, hepaticogastrostomy, endoscopic ultrasound-guided biliary drainage. We selected studies comparing CDS and HGS in patients with malignant biliary obstruction with ERCP failure. Pooled odds ratio (OR) were calculated for technical success, clinical success, and adverse events and difference of means calculated for duration of procedure and survival after procedure. A total of 10 studies with 434 patients were included in the meta-analysis: 208 underwent biliary drainage via HGS and the remaining 226 via CDS. The technical success for CDS and HGS was 94.1% and 93.7%, respectively, pooled OR=0.96 [95% confidence interval (CI)=0.39-2.33, I=0%]. Clinical success was 88.5% in CDS and 84.5% in HGS, pooled OR=0.76 (95% CI=0.42-1.35, I=17%). There was no difference for adverse events OR=0.97 (95% CI=0.60-1.56), I=37%. CDS was about 2 minutes faster with a pooled difference in means of was -2.69 (95% CI=-4.44 to -0.95). EUS-CDS and EUS-HGS have equal efficacy and safety, and are both associated with a very high technical and clinical success. The choice of approach may be selected based on patient anatomy.


Characteristics of patients with type 2 diabetes mellitus in two rural, medically underserved communities.
In the state of Hawai'i, Native Hawaiians and Filipinos suffer from increased disparities, compared to other groups, in diabetes prevalence and adverse health outcomes that are exacerbated by challenges to health care access among rural communities. To address the limited literature describing rural, underserved patients with diabetes in Hawai'i, this paper aims to characterize two rural communities that are located on Moloka'i and Lana'i in federally-designated medically underserved areas and that are served by a single Native Hawaiian health care system entitled Na Pu'uwai. Descriptive analyses examining associations between variables were performed using the baseline demographic information, clinical measures, and questionnaire responses collected from 40 adult study participants with diabetes. The data revealed that the study participants had a high prevalence of insulin use (60%); a HbA1c level greater than or equal to 9% (55%); a high-fat diet (73%); and comorbidities, including hyperlipidemia (85%), hypertension (83%), and obesity (70%). Furthermore, among the participants, the mean SF-12v2™ General Health Perceptions Score was significantly lower for participants with uncontrolled diabetes compared to those with controlled diabetes (P = .02); however, this association was not statistically significant in the multivariable regression model that adjusted for age and number of diabetes medications. Based on these results, the participants appear to belong to a high-risk group with a complicated manifestation of diabetes. This study adds to the growing body of literature demonstrating disparities in diabetes among rural, minority, and underserved communities, highlighting the need for further investigation, development, and implementation of strategies for reaching these vulnerable populations.


Orientation-Dependent Exciton-Plasmon Coupling in Embedded Organic/Metal Nanowire Heterostructures.
The excitation of surface plasmons by optical emitters based on exciton-plasmon coupling is important for plasmonic devices with active optical properties. It has been theoretically demonstrated that the orientation of exciton dipole can significantly influence the coupling strength, yet systematic study of the coupling process in nanostructures is still hindered by the lack of proper material systems. In this work, we have experimentally investigated the orientation-dependent exciton-plasmon coupling in a rationally designed organic/metal nanowire heterostructure system. The heterostructures were prepared by inserting silver nanowires into crystalline organic waveguides during the self-assembly of dye molecules. Structures with different exciton orientations exhibited varying coupling efficiencies. The near-field exciton-plasmon coupling facilitates the design of nanophotonic devices based on the directional surface plasmon polariton propagations.


Association between serum concentration of 25-hydroxyvitamin D and the risk of hip arthroplasty for osteoarthritis: result from a prospective cohort study.
There is ongoing debate regarding the optimal serum concentrations of 25-hydroxy-vitamin D for musculoskeletal health, including osteoarthritis (OA). The aim of this prospective cohort study was to determine whether serum 25-hydroxy-vitamin D concentrations were associated with the risk of hip arthroplasty for OA. This study examined 9135 participants from the Australian Diabetes, Obesity and Lifestyle Study who had serum 25-hydroxy-vitamin D measured in 1999-2000 and were aged ≥40 years at the commencement of arthroplasty data collection. The incidence of hip arthroplasty for OA during 2002-2011 was determined by linking cohort records to the Australian Orthopaedic Association National Joint Replacement Registry. Over an average 9.1 (standard deviation (SD) 2.7) years of follow-up, 201 hip arthroplasties for OA were identified (males n = 90; females n = 111). In males, a one-standard-deviation increase in 25-hydroxy-vitamin D was associated with a 25% increased incidence (HR 1.25, 95% CI 1.02-1.56), with a dose response relationship evident by quartiles of 25-hydroxy-vitamin D concentration (P for trend 0.04). These results were independent of age, body mass index (BMI), ethnicity, smoking status, physical activity, season of blood collection, latitude, hypertension and diabetes, area level disadvantage or after excluding those with extreme low 25-hydroxy-vitamin D concentrations. No significant association was observed in women (HR 1.10, 95% CI 0.87, 1.39). Increasing serum 25-hydroxy-vitamin D concentrations were associated with an increased risk of hip arthroplasty for OA in males, while no significant association was observed in females. The mechanism for the association warrants further investigation.


Pharmaceutical Drugs of Uncertain Value, Lifecycle Regulation at the US Food and Drug Administration, and Institutional Incumbency.
Policy Points The US Food and Drug Administration (FDA) has in recent years allowed onto the market several drugs with limited evidence of safety and effectiveness, provided that manufacturers agree to carry out additional studies while the drugs are in clinical use. Studies suggest that these postmarketing requirements (PMRs) frequently lack transparency, are subject to delays, and fail to answer the questions of greatest clinical importance. Yet, none of the literature speaks directly to the challenges that the FDA-as a regulatory institution-encounters in enforcing PMRs. Through a series of interviews with FDA leadership, this article analyzes and situates those challenges in the midst of political threats to the FDA's public health mandate. Modern pharmaceutical regulation is premised on a rigorous examination of a drug's safety and effectiveness prior to its lawful sale. However, since the 1990s, the US Food and Drug Administration (FDA) has gradually shifted to a model of "lifecycle" regulation that increasingly relies on postmarketing requirements (PMRs) to encourage studies of drug safety and effectiveness following regulatory approval. This article examines the range of legal, institutional, and political challenges that FDA faces in the context of lifecycle regulation. Document-based legal and policy analysis was combined with a set of semistructured interviews of current and former FDA officials (n = 23) in order to explore the implications of the FDA's use of PMRs. The median interview time per official was 61 minutes, with a range of 24 to 227 minutes. All of the officials interviewed occupied positions of leadership and influence within the FDA, such as directors of an FDA center or office, key legal counsel on agency-wide policy initiatives, and the commissioner of the FDA. Insufficient resources and coordination within the FDA, inadequate legal authorities, and the political economy of withdrawing an approved indication in the face of opposition from companies and patients all contribute to the observed shortcomings in the FDA's use and enforcement of PMRs. Further, the FDA is fully aware of these challenges, yet is seemingly resigned to and resistant to criticism of its use of PMRs. This study of the FDA's shift toward lifecycle regulation reveals not simply an agency in transition, but rather an agency on guard against a set of larger political threats to its mandate. This can be characterized as a state of institutional incumbency in which the agency is engaged in an effort to reproduce key features of the regulatory system-in concert with regulated industries and others-while simultaneously sanctioning significant changes to the regulatory standards the FDA has long applied, to the detriment of public health.


Rural health education.
Thirty-five health sciences students and four mentors, including myself, were participating in a 'Country Week' rural health experience in the catchment area of the Murchison River in the midwest of Western Australia. The Murchison, once a gold mining centre, now has a population of about 2500, many of whom live on sheep and cattle stations.


Low salt mimics effects of dark pulses on circadian pacemaker in cultured chick pineal cells.
Chick pineal cells in static culture display a persistent photosensitive circadian rhythm of melatonin production and release. Pulses of white light or darkness, in otherwise constant red light, induce phase shifts in subsequent cycles whose magnitude and direction depend on the phase at which the pulse is given. Such "phase-dependent phase shifts" are mediated by effects on the underlying pacemaker. We reported previously that inhibiting the Na-K-ATPase with ouabain or salt solutions lacking potassium evokes phase shifts with the same phase dependence as those induced by pulses of darkness. One of the consequences of inhibiting the sodium pump is cell swelling. To test the relevance of this effect, we exposed chick pineal cells to pulses of medium containing reduced concentrations of NaCl, which should cause cell swelling. These hypotonic solutions induced phase shifts in the melatonin rhythm with the same phase dependence as those caused by pulses of ouabain or darkness. The size of the phase shifts varied with degree of dilution, and phase shifting was prevented by replacement of NaCl. In view of previous results showing that hypertonic media mimicked the phase-shifting effects of light, these results suggest that cell swelling may mediate the darklike effects of ouabain on the circadian pacemaker in chick pineal cells.


Characterization of the hexaploid oat Avena byzantina cv. Kanota monosomic series using C-banding and RFLPs.
The establishment of a C-banded karyotype of hexaploid oat (Avena spp., 2n = 6x = 42) has facilitated the cytological characterization of a monosomic series in 'Kanota', an A. byzantina (C. Koch) cultivar. The 'Kanota' series of monosomics analyzed in this study consists of only 12 of the 21 different chromosome-deficient lines possible plus potential translocated segments of two or three additional chromosomes. These findings were confirmed by RFLP mapping data from studies in which oat probes were assigned to syntenic groups using the 'Kanota' set of monosomic lines. Among the remaining nine monosomic lines analyzed, eight are missing chromosomes represented in the set of 12 unique lines and one line, monosomic K13, is missing a chromosome from the unique set of 12 that possesses a cytologically detectable translocation. This same translocation, involving chromosomes 7C and 14, is found in 5 of the 21 'Kanota' monosomics. The incompleteness of the set of 'Kanota' monosomics might be due to (i) difficulty in identifying individual oat chromosomes without C-banding, (ii) plant genotypic and phenotypic variability in the original source population of the 'Kanota' monosomics, and (or) (iii) a high frequency of monosomic shifts in progency of the original 'Kanota' monosomic lines.


Childhood soft tissue sarcoma: a 20-year experience.
To evaluate the disease-free and overall survival of pediatric patients with nonrhabdomyosarcoma soft-tissue sarcomas. We retrospectively analyzed the records of 67 pediatric patients with a diagnosis of nonrhabdomyosarcoma soft tissue sarcoma treated with curative intent between 1970 and 1992. Median follow-up time for the 52 survivors was 120 months (range, 7 to 277 months). Fifty-nine patients received external beam radiotherapy, in a median dose of 5400 cGy (range, 1800 to 6660 cGy.) All patients underwent an initial surgical procedure. Eighteen patients had gross residual disease, and 15 had gross total excision with microscopic residual disease or positive margins. Adjuvant chemotherapy was administered to 44 patients (65%). The actuarial 10-year freedom from progression or recurrence and overall survival rates were 76% and 75%, and the 20-year rates were the same. Of 18 patients with gross residual disease, 9 (50%) had local progression and 6 died of local-only disease. By contrast, only one patient with microscopic residual disease who received postoperative radiotherapy had a local recurrence. The disease-free survival rate also correlated with histologic grade. As with adult soft tissue sarcomas, gross residual disease predicts local failure. Our results suggest that pediatric patients with soft tissue sarcomas treated with surgery and postoperative radiotherapy generally have a favorable overall survival rate.


Migrainous infarction: a rare and often overlooked diagnosis.
Migraine is a neurological entity and a well-known independent risk factor for cerebral infarction, which mostly afflicts the young female population. Researching focal neurological signs in this subset of the population with the diagnosis of a neurological ischemic event should always take into account the migraine as the etiology or as an associated factor. The etiology of central nervous system (CNS) ischemia is considerable. Migraine, although rare, also may be included in this vast etiological range, which is called migrainous infarction. In this setting, the diagnostic criteria required for this diagnosis is extensive. Herein, we present the case of a female adolescent who submitted to the emergency facility complaining of diplopia, dysarthria, and imbalance, which started concomitantly with a migrainous crisis with aura-a challenging clinical case that required extensive research to address all possible differential diagnoses.


Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation.
Adenosine receptors and β-adrenoceptors are G-protein-coupled receptors (GPCRs) that activate intracellular G proteins on binding the agonists adenosine or noradrenaline, respectively. GPCRs have similar structures consisting of seven transmembrane helices that contain well-conserved sequence motifs, indicating that they are probably activated by a common mechanism. Recent structures of β-adrenoceptors highlight residues in transmembrane region 5 that initially bind specifically to agonists rather than to antagonists, indicating that these residues have an important role in agonist-induced activation of receptors. Here we present two crystal structures of the thermostabilized human adenosine A(2A) receptor (A(2A)R-GL31) bound to its endogenous agonist adenosine and the synthetic agonist NECA. The structures represent an intermediate conformation between the inactive and active states, because they share all the features of GPCRs that are thought to be in a fully activated state, except that the cytoplasmic end of transmembrane helix 6 partially occludes the G-protein-binding site. The adenine substituent of the agonists binds in a similar fashion to the chemically related region of the inverse agonist ZM241385 (ref. 8). Both agonists contain a ribose group, not found in ZM241385, which extends deep into the ligand-binding pocket where it makes polar interactions with conserved residues in H7 (Ser 277(7.42) and His 278(7.43); superscripts refer to Ballesteros-Weinstein numbering) and non-polar interactions with residues in H3. In contrast, the inverse agonist ZM241385 does not interact with any of these residues and comparison with the agonist-bound structures indicates that ZM241385 sterically prevents the conformational change in H5 and therefore it acts as an inverse agonist. Comparison of the agonist-bound structures of A(2A)R with the agonist-bound structures of β-adrenoceptors indicates that the contraction of the ligand-binding pocket caused by the inward motion of helices 3, 5 and 7 may be a common feature in the activation of all GPCRs.


Structures and Biosynthesis of Caryoynencins, Unstable Bacterial Polyynes from Pseudomonas protegens Recombinant Expressing the cayG Gene.
Bacteria in certain genera can produce "bacterial polyynes" that contain a conjugated C≡C bond starting from a terminal alkyne. Protegenin A is a derivative of octadecanoic acid that contains an ene-tetrayne moiety. It was discovered in Pseudomonas protegens Cab57 and exhibits strong antioomycete and moderate antifungal activity. By introducing cayG, a cytochrome P450 gene from Burkholderia caryophylli, into P. protegens Cab57, protegenin A was converted into more complex polyynes, caryoynencins A-E. A purification method that minimized the degradation and isomerization of caryoynencins was established. For the first time, as far as we know, the 1H and 13C{1H} NMR signals of caryoynencins were completely assigned by analyzing the NMR data of the isolated compounds and protegenin A enriched with [1-13C]- or [2-13C]-acetate. Through the structural analysis of caryoynencins D/E and bioconversion experiments, we observed that CayG constructs the allyl alcohol moiety of caryoynencins A-C through sequential hydroxylation, dehydration, and hydroxylation. The recombinant strain exhibited a stronger antioomycete activity compared to the wild-type strain. This paper proposes a stable purification and structural determination method for various bacterial polyynes, and P. protegens Cab57 holds promise as an engineering host for the production of biologically active polyynes.


A single residue contributes to the difference between Kir4.1 and Kir1.1 channels in pH sensitivity, rectification and single channel conductance.
Kir1.1 and Kir4.1 channels may be involved in the maintenance of pH and K+ homeostasis in renal epithelial cells and CO2 chemoreception in brainstem neurons. To understand the molecular determinants for their characteristic differences, the structure-function relationship was studied using site-directed mutagenesis. According to previous studies, Glu158 in Kir4.1 is likely to be the major rectification controller. This was confirmed in both Kir1.1 and Kir4.1. Mutation of Gly210, the second potential rectification controller, to glutamate did not show any additional effect on the inward rectification. More interestingly, we found that Glu158 in Kir4.1 was also an important residue contributing to single channel conductance and pH sensitivity. The E158N Kir4.1 mutant had a unitary conductance of 35 pS and a midpoint pH for channel inhibition (pKa) value of 6.72, both of which were almost identical to those of the wild-type (WT) Kir1.1. Flickering channel activity was clearly seen in the E158N mutant at positive membrane potentials, which is typical in the WT Kir1.1 but absent in the WT Kir4.1. Reverse mutation in Kir1.1 (N171E) reduced the unitary conductance to 27 pS (23 pS in WT Kir4.1). However, the pH sensitivity of this mutant did not show a marked difference from the WT Kir1.1. Therefore, it is possible that a residue(s) in addition to Asn171 is also involved. Thus we studied several other residues in both M2 and H5 regions. We found that joint mutations of Val140 and Asn171 to residues seen in Kir4.1 greatly reduced the pH sensitivity (pKa 6. 08). The V140T mutation in Kir1.1 led to a unitary conductance of approximately 70 pS, and the G210E mutation in Kir4.1 caused a decrease in pH sensitivity of 0.4 pH units. These results indicate that the pore-forming sequences are targets for modulations of multiple channel-biophysical properties and demonstrate a site contributing to rectification, unitary conductance and proton sensitivity in these Kir channels.


Multidisciplinary rehabilitation for fibromyalgia and musculoskeletal pain in working age adults.
Non-malignant musculoskeletal pain is an increasing problem in western countries. Fibromyalgia syndrome is an increasing recognised chronic musculoskeletal disorder. The objective of this systematic review was to determine the effectiveness of multidisciplinary rehabilitation for fibromyalgia and widespread musculoskeletal pain among working age adults. An electronic search was conducted and included Medline from 1966, PsycLIT from 1967 and EMBASE from 1980 to April 1998. The Cochrane Musculoskeletal Group Trials Register was searched as well as, the Cochrane Controlled Trials Register (CCTR). The references of identified articles and reviews were checked, studies published in the Finnish medical database Medic from 1978 to 1998 screened and the Science Citation Index searched. Content experts were also contacted for additional or unpublished studies. From all references found in our original search, we selected all randomized controlled trials (RCTs) and clinical controlled trials (CCTs). Trials had to assess the effectiveness of multidisciplinary rehabilitation for patients suffering from fibromyalgia and widespread musculoskeletal pain among working age adults. The rehabilitation program was required to be multidisciplinary; that is, it had to consist of a physician's consultation, plus a psychological, social or vocational intervention, or a combination of both. Four reviewers independently selected the RCTs and CCTs that met the specified inclusion criteria. Two experts in the field of rehabilitation evaluated the relevance and applicability of the findings of the selected studies to actual clinical use. Two other reviewers extracted the data and assessed the main results and the methodological quality of the studies using standardized forms. Finally, a qualitative analysis was performed to evaluate the level of scientific evidence for the effectiveness of multidisciplinary rehabilitation. After screening 1808 abstracts, and the references of 65 reviews, we found only seven relevant studies (1050 patients) that met our inclusion criteria. None of these were considered, methodologically, a high quality randomized controlled trial. Four of the included RCTs on fibromyalgia were graded low quality and suggest no quantifiable benefits. The three included RCTs on widespread musculoskeletal pain showed that based on limited evidence, overall, no evidence of efficacy was observed. However, behavioral treatment and stress management appear to be important components. Education combined with physical training showed some positive effects in long term follow up. We conclude that there appears to be little scientific evidence for the effectiveness of multidisciplinary rehabilitation for these musculoskeletal disorders. However, multidisciplinary rehabilitation is a commonly used intervention for chronic musculoskeletal disorders, which cause much personal suffering and substantial economic loss to the society. There is a need for high quality trials in this field.


Retinoids can be classified according to their effects on vitamin A metabolism in HeLa cells.
Although retinoids may exert their action via binding to nuclear retinoic acid receptors (RARs), other mechanisms of action are not excluded. For example, the anti-acne drug, isotretinoin, lacks affinity for the receptors, but is a very potent inhibitor of endogenous vitamin A metabolism in human epidermal cells. To further extend this observation, we studied the effect of 12 different retinoids on the metabolism of [3H]retinol ([3H]ROH) in HeLa cells, previously shown to produce constant levels of 3,4-didehydroretinol (ddROH). The cells were cultured in the presence of the unlabeled retiniods for 20 h, followed by 4 h incubation with [3H]ROH. The accumulation of [3H]ROH and [3H]ddROH in cellular extracts was analysed by HPLC. Addition of 10(-10) to 10(-5) M of four naturally occurring isomers of retinoic acid caused a 4- to 6-fold increase in [3H]ROH accumulation and an 80% decrease in [3H]ddROH. Addition of synthetic retinoids with a terminal carboxyl (CD270, CD271, CD367 and Ro 13-7410) decreased the [3H]ddROH accumulation with about 70%, but hardly at all affected the accumulation of [3H]ROH. We conclude that cultured HeLa cells appear to be useful for screening retinoids for their effects on vitamin A metabolism showing that a terminal carboxylic acid is a prerequisite for any major effects on metabolism to occur. Whether this effect is due to interaction with RARs or to competitive inhibition of vitamin-A-metabolizing enzymes demands to be studied.


Canonical Wnt signaling controls proliferation of retinal stem/progenitor cells in postembryonic Xenopus eyes.
Vertebrate retinal stem cells, which reside quiescently within the ciliary margin, may offer a possibility for treatment of degenerative retinopathies. The highly proliferative retinal precursor cells in Xenopus eyes are confined to the most peripheral region, called the ciliary marginal zone (CMZ). Although the canonical Wnt pathway has been implicated in the developing retina of different species, little is known about its involvement in postembryonic retinas. Using a green fluorescent protein-based Wnt-responsive reporter, we show that in transgenic Xenopus tadpoles, the canonical Wnt signaling is activated in the postembryonic CMZ. To further investigate the functional implications of this, we generated transgenic, hormone-inducible canonical Wnt pathway activating and repressing systems, which are directed to specifically intersect at the nuclear endpoint of transcriptional Wnt target gene activation. We found that postembryonic induction of the canonical Wnt pathway in transgenic retinas resulted in increased proliferation in the CMZ compartment. This is most likely due to delayed cell cycle exit, as inferred from a pulse-chase experiment on 5-bromo-2'-deoxyuridine-labeled retinal precursors. Conversely, repression of the canonical Wnt pathway inhibited proliferation of CMZ cells. Neither activation nor repression of the Wnt pathway affected the differentiated cells in the central retina. We conclude that even at postembryonic stages, the canonical Wnt signaling pathway continues to have a major function in promoting proliferation and maintaining retinal stem cells. These findings may contribute to the eventual design of vertebrate, stem cell-based retinal therapies. Disclosure of potential conflicts of interest is found at the end of this article.


Heparin-binding proteins are involved in thrombin time variability in normal and patient plasmas.
The ability of plasma proteins to neutralize the anticoagulant activity of heparin was studied using a thrombin time assay with 20 normal adult and 207 patient plasma samples. The thrombin times of normal adult plasmas spiked with the same amount of heparin were found to vary significantly, and this variability was attributed to differences in heparin-binding proteins among individuals. This possibility was investigated by determining thrombin times for a variety of plasma samples following proteolytic digestion. A study of patient pooled plasma showed that incubation with a protease increased the thrombin time from 23 s to > 300 s, suggesting that the anticoagulant activity of heparin could be neutralized by plasma proteins and released with proteolytic digestion. Incubation of the digested plasma with heparinase I returned the thrombin time almost to control values. In addition, patients who received prior heparin injections had different responses to similar dosages of heparin, as indicated by differences in thrombin times. Thus, the anticoagulant activity of heparin may be affected by the balance between free heparin and protein-bound heparin in plasma.


Japanese clinical practice guidelines for congenital biliary dilatation.
Until now, there have been no practical clinical guidelines for congenital biliary dilatation (CBD). In this review article, the Japanese Study Group on Congenital Biliary Dilatation (JSCBD) propose to establish clinical practice guidelines for CBD. Because the evidence-based literature is relatively small, we decided to create guidelines based on the consensus of experts, using the medical literature for reference. A total of 20 clinical questions (CQs) were considered by the members of the editorial committee responsible for the guidelines. The CQs included the distinct aspects of CBD: (1) Concepts and Pathology (three CQs); (2) Diagnosis (six CQs); (3) Pancreaticobiliary Complications (three CQs); Treatments and Prognosis (eight CQs). Each statements and comments for CQs were made by the guidelines committee members. CQs were finally approved after review by members of the editorial committee and the guidelines evaluation board of CBD. These guidelines were created to provide assistance in the clinical practice of CBD management; their contents focus on clinical utility, and they include general information on CBD to make this disease more widely recognized.


The case for intervention bias in the practice of medicine.
Bias is an inclination to present or hold a partial perspective at the expense of possibly equal or more valid alternatives. In this paper, we present a series of conditional arguments to prove that intervention bias exists in the practice of medicine. We then explore its potential causes, consequences, and criticisms. We use the term to describe the bias on the part of physicians and the medical community to intervene, whether it is with drugs, diagnostic tests, non-invasive procedures, or surgeries, when not intervening would be a reasonable alternative. The recognition of intervention bias in medicine is critically important given today's emphasis on providing high-value care and reducing unnecessary and potentially harmful interventions.


Nurse telephone screening of new Medicare HMO members: a pilot program.
Members newly enrolled in an HMO and covered under a Medicare risk contract were screened over the telephone by a registered nurse within their first month of membership to assess whether screening could lead to early intervention and later reduce utilization of health care services. This pilot study screened 36 patients (mean age = 71 years) constituting 25.2% of the new Medicare members during the period of study. Health care encounters were tracked for the first 6 months of membership. A historical comparison group included 32 patients (mean age = 72.6 years) who had enrolled 1 year earlier. A retrospective chart review determined the number of health care encounters during the comparison group's first 6 months of membership. Episodes of health care service utilization were fewer among the screening group than among the comparison group in all areas studied. This pilot study suggests the potential benefit of screening and early intervention by health care providers.


An EMA study of VCV coarticulatory direction.
This study addresses three issues that are relevant to coarticulation theory in speech production: whether the degree of articulatory constraint model (DAC model) accounts for patterns of the directionality of tongue dorsum coarticulatory influences; the extent to which those patterns in tongue dorsum coarticulatory direction are similar to those for the tongue tip; and whether speech motor control and phonemic planning use a fixed or a context-dependent temporal window. Tongue dorsum and tongue tip movement data on vowel-to-vowel coarticulation are reported for Catalan VCV sequences with vowels /i/, /a/, and /u/, and consonants /p/, /n/, dark /l/, /s/, /S/, alveolopalatal /n/ and /k/. Electromidsagittal articulometry recordings were carried out for three speakers using the Carstens articulograph. Trajectory data are presented for the vertical dimension for the tongue dorsum, and for the horizontal dimension for tongue dorsum and tip. In agreement with predictions of the DAC model, results show that directionality patterns of tongue dorsum coarticulation can be accounted for to a large extent based on the articulatory requirements on consonantal production. While dorsals exhibit analogous trends in coarticulatory direction for all articulators and articulatory dimensions, this is mostly so for the tongue dorsum and tip along the horizontal dimension in the case of lingual fricatives and apicolaminal consonants. This finding results from different articulatory strategies: while dorsal consonants are implemented through homogeneous tongue body activation, the tongue tip and tongue dorsum act more independently for more anterior consonantal productions. Discontinuous coarticulatory effects reported in the present investigation suggest that phonemic planning is adaptative rather than context independent.


Role of Nigella sativa and a number of its antioxidant constituents towards azoxymethane-induced genotoxic effects and colon cancer in rats.
This study examined the chemopreventive effect of Nigella sativa and some of its antioxidant constituents on a number of colon cancer biomarkers in rats induced with azoxymethane (AOM). Sixty male Sprague-Dawley rats were randomly assigned into ten subgroups: vehicle (1-5) and experimental (6-10). The rats in each group were fed one of the following diets: basal diet, (200 mg/kg) Nigella sativa, (0.2 mg/kg) selenium, (1.2 mg/kg) all-trans-retinol plus (100 mg/kg) DL-alpha-tocopherol and (10 mg/kg) thymoquinone, respectively. Only rats in subgroups 6-10 were injected with AOM (15 mg/kg) once per week for 2 weeks. Both groups were fed their respective diets for 5 weeks. Then they were killed and examined for colonic aberrant crypt foci (ACF). Our result showed that only vitamin supplementation was effective on ACF. Nigella sativa revealed inhibitory effects only on DNA damage (day 34) in the AOM-treated rat group. Alternatively, selenium, thymoquinone and vitamins inhibited the MDA content in the liver. Although the exact mechanisms involved in the protective role of Nigella sativa against the initiation of colon carcinogenesis are not clearly understood, the results suggest that its inhibitory effects might depend on the combined competitive inhibition of various antioxidant constituents of this plant.


Phylodynamics reveals the role of human travel and contact tracing in controlling the first wave of COVID-19 in four island nations.
New Zealand, Australia, Iceland, and Taiwan all saw success in controlling their first waves of Coronavirus Disease 2019 (COVID-19). As islands, they make excellent case studies for exploring the effects of international travel and human movement on the spread of COVID-19. We employed a range of robust phylodynamic methods and genome subsampling strategies to infer the epidemiological history of Severe acute respiratory syndrome coronavirus 2 in these four countries. We compared these results to transmission clusters identified by the New Zealand Ministry of Health by contact tracing strategies. We estimated the effective reproduction number of COVID-19 as 1-1.4 during early stages of the pandemic and show that it declined below 1 as human movement was restricted. We also showed that this disease was introduced many times into each country and that introductions slowed down markedly following the reduction of international travel in mid-March 2020. Finally, we confirmed that New Zealand transmission clusters identified via standard health surveillance strategies largely agree with those defined by genomic data. We have demonstrated how the use of genomic data and computational biology methods can assist health officials in characterising the epidemiology of viral epidemics and for contact tracing.


Temporary occlusion of middle cerebral artery by macroembolism in carotid surgery.
Two patients are presented who during carotid endarterectomy (CEA) temporarily showed an obstruction of the middle cerebral artery (MCA) mainstem by a macroembolus resulting in cerebral ischaemia. Both cases are unusual examples of CEA and selected from a cohort of more than 1,500 operations. During surgery with general anaesthesia, brain function was monitored with computerized electroencephalography (EEG) and transcranial Doppler (TCD) ultrasonography. The simultaneous use of EEG and TCD monitoring allowed us to witness the development of intraoperative cerebral ischaemia and to relate these events to a temporary occlusion of the MCA mainstem by a macroembolus. This is the first life report that describes obstruction of a cerebral artery by arterial embolism resulting in cerebral ischaemia.


Risk of Cataract in Intermediate Uveitis.
To determine the incidence of and predictive factors for cataract in intermediate uveitis. Retrospective cohort study. Patients were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study, in which medical records were reviewed to determine demographic and clinical data of every eye/patient at every visit at 5 participating US tertiary care uveitis centers. The primary outcome was development of vision-compromising cataract as defined by a decrease in visual acuity to 20/40 or less, or requiring cataract surgery. Survival analysis assessed visually defined cataract to avoid bias due to timing of surgery vis-à-vis inflammatory status. Among 2,190 eyes of 1,302 patients with intermediate uveitis, the cumulative incidence of cataract formation was 7.6% by 1 year (95% confidence interval [CI] = 6.2%-9.1%), increasing to 36.6% by 10 years (95% CI = 31.2%-41.6%). Increased cataract risk was observed in eyes with concurrent anterior uveitis causing posterior synechiae (hazard ratio = 2.68, 95% CI = 2.00-3.59, P < .001), and in eyes with epiretinal membrane formation (hazard ratio = 1.54, 95% CI = 1.15-2.07, P = .004). Higher dose corticosteroid therapy was associated with significantly higher incidence of cataract, especially time-updated use of topical corticosteroids ≥2 times/d or ≥4 periocular corticosteroid injections. Low-dose corticosteroid medications (oral prednisone 7.5 mg daily or less, or topical corticosteroid drops <2 times/d) were not associated with increased cataract risk. Our study found that the incidence of clinically important cataract in intermediate uveitis is moderate. The risk is higher with markers of severity and with higher doses of corticosteroid medications, the latter being potentially modifiable.


Treatment of pulmonary hypertension in patients with connective tissue disease and interstitial lung disease.
Pulmonary hypertension (PH) in patients with connective tissue disease (CTD) can occur in isolation or concomitantly with interstitial lung disease (ILD). Targeted therapies for PH can mitigate clinical deterioration in CTD patients with isolated PH; however, the effect of these therapies in CTD patients with PH and ILD (CTD-PH-ILD) are poorly characterized. To investigate outcomes following long-term treatment of PH in patients with CTD-PH-ILD.    A retrospective evaluation of 13 CTD-PH-ILD patients who were treated with bosentan, sildenafil or bosentan plus sildenafil, was conducted. Immunosuppressants were prescribed as indicated. Patients underwent pulmonary function testing and assessment of 6 min walk distance at the time of treatment initiation and during follow-up. Patients were followed until time of death, lung transplantation or the end of the study. Kaplan-Meier estimates of survival were calculated and log-rank testing was used to analyze survival differences according to CTD subtype. Thirteen patients (seven with systemic sclerosis [SSc], four with overlap syndrome, and two with rheumatoid arthritis) were followed for a mean (± SD) duration of 33.8±21.7 months. The survival estimate at a median duration of 34 months was 85%; two patients with SSc died. Mortality rates were greater among patients with SSc versus other CTD subtypes (P=0.04). No changes from baseline to follow-up in mean forced vital capacity or exercise capacity, and no treatment-related toxicity, were observed. Treatment using PH-specific therapies in patients with CTD, PH and ILD was well tolerated. Further studies to investigate the efficacy of PH-specific therapies in CTD-PH-ILD patients are warranted.


Inhibition of restriction in Streptomyces clavuligerus by heat treatment.
Inefficient transformation of Streptomyces clavuligerus protoplasts by DNA from the plasmid pIJ702, isolated from S. lividans, was attributed to restriction in view of the observation that efficient transformation was observed using modified pIJ702 (isolated from S. clavuligerus). The restriction system could be partially inhibited by treating protoplasts at 45 degrees C prior to transformation. This treatment increased the transformation frequencies of pIJ702 DNA by 100-fold and was used to introduce other plasmids into S. clavuligerus.


Estrogen treatment improves spatial learning in APP + PS1 mice but does not affect beta amyloid accumulation and plaque formation.
We investigated the effects of ovariectomy (OVX) and 17 beta-estradiol (0.18 mg per pellet) treatment on spatial learning and memory, hippocampal beta amyloid (A beta) levels, and amyloid plaque counts in double transgenic mice (A/P) carrying mutated amyloid precursor protein (APPswe) and presenilin-1 (PS1-A246E). After OVX at 3 months of age, the mice received estrogen treatment for the last 3 months of their lifetime before they were killed at 6, 9, or 12 months of age. Estrogen treatment in A/P OVX mice increased the number of correct choices in a position discrimination task in the T-maze, and slightly improved their performance in a win-stay task (1/8 arms baited) in the radial arm maze (RAM). However, estrogen treatment did not reverse the A beta-dependent cognitive deficits of A/P mice in the water maze (WM) spatial navigation task. Furthermore, ovariectomy or estrogen treatment in OVX and sham-operated A/P mice had no effect on hippocampal amyloid accumulation. These results show that the estrogen treatment in a transgenic mouse model of Alzheimer's disease (AD) improves performance in the same learning and memory tasks as in the normal C57BL/6J mice. However, the estrogen effects in these mice appeared to be unrelated to A beta-induced cognitive deficits. Our results do not support the idea that estrogen treatment decreases the risk or alleviates the symptoms of Alzheimer's disease by inhibiting the accumulation of A beta or formation of amyloid plaques.


Dissociable contributions of motor-execution and action-observation to intramanual transfer.
We examined the hypothesis that different processes and representations are associated with the learning of a movement sequence through motor-execution and action-observation. Following a pre-test in which participants attempted to achieve an absolute, and relative, time goal in a sequential goal-directed aiming movement, participants received either physical or observational practice with feedback. Post-test performance indicated that motor-execution and action-observation participants learned equally well. Participants then transferred to conditions where the gain between the limb movements and their visual consequences were manipulated. Under both bigger and smaller transfer conditions, motor-execution and action-observation participants exhibited similar intramanual transfer of absolute timing. However, participants in the action-observation group exhibited superior transfer of relative timing than the motor-execution group. These findings suggest that learning via action-observation is underpinned by a visual-spatial representation, while learning via motor-execution depends more on specific force-time planning (feed forward) and afferent processing associated with sensorimotor feedback. These behavioural effects are discussed with reference to neural processes associated with striatum, cerebellum and motor cortical regions (pre-motor cortex; SMA; pre-SMA).


An on-site health home for homeless men in addiction recovery.
Patients with comorbid substance abuse, mental health disorders, and chronic health conditions face difficult challenges when attempting to access health care. A large gospel rescue mission developed an onsite wellness center, based on an integrated, embedded practice health home model, to promote health care access among homeless men in addiction recovery. The center model integrated primary care with behavioral health, specialty care referrals, and wellness services to address the multifaceted needs of the population. Standardized health care performance measures and resident and staff feedback support the effectiveness of the model in promoting improved health care access and treatment adherence. Future directions for program expansion include infrastructure development, expanded community outreach, and evaluation of effectiveness of the onsite health home through systematic program evaluation and research.


Knowledge, Attitudes, and Practices of Artisanal and Small-Scale Miners regarding Tuberculosis, Human Immunodeficiency Virus, and Silicosis in Zimbabwe.
In Zimbabwe, artisanal and small-scale miners (ASMs) have a high prevalence of tuberculosis (TB), human immunodeficiency virus (HIV), and silicosis. Previous studies on ASMs utilised programme data, and it was not possible to understand reasons for the high prevalence of these comorbidities. We conducted a cross-sectional study to investigate the knowledge, attitudes, and practices of ASMs regarding TB, HIV, and silicosis. We enrolled a convenience sample of 652 ASMs. Their mean (standard deviation) age was 34.2 (10.8) years. There were 602 (92%) men and over 75% had attained secondary education. A total of 504 (80%) of the ASMs knew that TB is a curable disease, and 564 (87%) knew that they were at higher risk of TB than the general population. However, they were less likely to know that HIV increases the risk of TB disease, 340 (52%), with only 226 (35%) who perceived the risk of TB infection to be high among ASMs. Only 564 (59%) were aware that silica dust causes permanent and incurable lung diseases. Six hundred and twenty (97%) showed a positive attitude towards healthcare when they were sick, and 97% were willing to use special respirators to prevent dust inhalation. On practices, only 159 (30%) reported consistent use of either cloth or respirators to prevent dust inhalation. Three hundred and five (49%) ASMs reported consistent use of condoms outside their homes and 323 (50%) reported use of water to suppress dust. Only 480 (75%) of ASMs sought healthcare services when sick. ASMs cited challenges of accessing healthcare services due to lack of money to pay for healthcare (50%), long distances to clinics (17%), and the shortage of medicines at clinics (11%). Effective control of TB, silicosis, and HIV among ASMs requires addressing the identified knowledge gaps and barriers that are faced by ASMs in accessing personal protective equipment and healthcare services. This will require multisector collaboration and the involvement of ASMs in co-designing a package of healthcare services that are tailored for them.


Upper limb joint kinematics using wearable magnetic and inertial measurement units: an anatomical calibration procedure based on bony landmark identification.
The estimate of a consistent and clinically meaningful joint kinematics using wearable inertial and magnetic sensors requires a sensor-to-segment coordinate system calibration. State-of-the-art calibration procedures for the upper limb are based on functional movements and/or pre-determined postures, which are difficult to implement in subjects that have impaired mobility or are bedridden in acute units. The aim of this study was to develop and validate an alternative calibration procedure based on the direct identification of palpable anatomical landmarks (ALs) for an inertial and magnetic sensor-based upper limb movement analysis protocol. The proposed calibration procedure provides an estimate of three-dimensional shoulder/elbow angular kinematics and the linear trajectory of the wrist according to the standards proposed by the International Society of Biomechanics. The validity of the method was assessed against a camera-based optoelectronic system during uniaxial joint rotations and a reach-to-grasp task. Joint angular kinematics was found as characterised by a low-biased range of motion (<-2.6°), a low root mean square deviation (RMSD) (<4.4°) and a high waveform similarity coefficient (R2 > 0.995) with respect to the gold standard. Except for the cranio-caudal direction, the linear trajectory of the wrist was characterised by a low-biased range of motion (<11 mm) together with a low RMSD (8 mm) and high waveform similarity (R2 > 0.968). The proposed method enabled the estimation of reliable joint kinematics without requiring any active involvement of the patient during the calibration procedure, complying with the metrological standards and requirements of clinical movement analysis.


Countermeasures for sleep loss and deprivation.
Sleep deprivation is ubiquitous and carries profound consequences in terms of personal and public health and safety. There is no substitute for a good night's sleep. Sleep that is optimal in quality and quantity for individuals, factoring in their age and personal sleep requirements, will minimize sleep debt and maximize daytime performance. Therefore, setting aside an adequate amount of time for sleep should be a priority; sleep should not be sacrificed at the expense of other activities of daily living. Nevertheless, there are certain therapeutic countermeasures available for individuals who are unable to obtain adequate sleep because of medical or sleep-related conditions (eg, narcolepsy, obstructive sleep apnea) when excessive daytime sleepiness is the main feature of the condition, or residual sleepiness despite treatment for the main conditions is present. These therapeutic countermeasures may also be considered in situations in which occupational constraints (eg, rotating shift work, military duty) dictate that constant or heightened vigilance is important or critical to work performance, crucial decision making, and/or survival. Exploration of the causes of sleep loss or deprivation, whether it is voluntary, or work or family induced, and/or the effects of a medical or sleep disorder, is a necessary first step in the evaluation of a patient who has significant daytime fatigue or sleepiness. Wake-promoting substances and medications such as caffeine, modafinil, methylphenidate, and dextroamphetamine may be considered in situations in which sleep loss is unavoidable or persists despite treatment of an underlying disorder that is characterized by or associated with daytime fatigue or sleepiness.


Astrocyte membrane structure: changes after circulatory arrest.
Membranes of the astrocytic processes investing small blood vessels and the surface of the brain contain numerous arrays of orthogonally packed particles as revealed by the freeze-fracture technique. The structure of these particle arrays, which we have termed "assemblies," is the same whether tissue is prepared for freeze-fracture by conventional fixation or by quick excision and rapid freezing. However, assemblies are progressively replaced by amorphous clumps and then disappear as the interval between decapitation and rapid freezing increases. Nearly normal numbers of assemblies may be maintained in cerebellar slices in vitro, but there too they disappear at low PO2 or in the presence of dinitrophenol. No other neuronal or glial membrane specialization exhibits a comparable lability.


Role of brain nitric oxide in (+/-)3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity in rats.
The role of nitric oxide (NO) in the long-term serotoninergic neurotoxicity induced by (+/-)3,4-methylenedioxymethamphetamine (MDMA) in rats was investigiated. Pretreatment with Nomega-nitro-L-arginine (L-NOARG) (10 mg kg-1), a nitric oxide synthase (NOS) inhibitor, partially protected against long-term serotonin (5-HT) depletion induced by MDMA (40 mg kg-1) in frontal cortex and parietal cortex, but not in other brain regions examined. Brain NOS activities in these two regions were significantly elevated at 6 h after MDMA administration. Moreover, L-NOARG pretreatment caused significant inhibition of brain NOS activity but did not affect the acute 5-HT and dopamine (DA) changes or the hyperthermia induced by MDMA. These results suggest that it is the NOS inhibitory properties of L-NOARG, rather than its effects on the acute monoamine changes or the hyperthermia induced by MDMA, that are responsible for the prevention of neurotoxicity. The regional differences on the protection of L-NOARG and on the activation of NOS by MDMA indicate the unequal role that NO may play in MDMA-induced neurotoxicity in different brain regions.


Injury and Liability Associated With Spine Surgery.
Although spine surgery is associated with significant morbidity, the anesthesia liability profile for spine surgery is not known. We examined claims for spine procedures in the Anesthesia Closed Claims Project database to evaluate patterns of injury and liability. A retrospective cohort study was performed. Inclusion criteria were anesthesia claims provided for surgical procedures in 2000 to 2014. We compared mechanisms of injury for cervical spine to thoracic or lumbar spine procedures using χ and the Fisher exact test. Univariate and multivariate logistic regression analyses were used to determine factors associated with permanent disabling injury in spine surgery claims. The 207 spine procedure (73% thoracic/lumbar; 27% cervical) claims comprised >10% of claims. Permanent disabling injuries to nerves, the spinal cord, and the eyes or visual pathways were more common with spine procedures than in nonspine procedures. Hemorrhage and positioning injuries were more common in thoracic/lumbar spine claims, whereas difficult intubation was more common in cervical spine claims. Multiple logistic regression demonstrated prone positioning (odds ratio=3.50; 95% confidence interval, 1.30-9.43) and surgical duration of ≥4 hours increased the odds of severe permanent injury in spine claims (odds ratio=2.73; 95% confidence interval, 1.11-6.72). Anesthesia claims related to spine surgery were associated with severe permanent disability primarily from nerve and eye injuries. Prone positioning and surgical duration of ≥4 hours were associated with permanent disabling injuries. Attention to positioning, resuscitation during blood loss, and reducing length of surgery may reduce these complications.


Implementation of surveillance of invasive mosquitoes in Belgium according to the ECDC guidelines.
In 2012, the new guidelines for the surveillance of IMS in Europe, produced by the European Centre for Disease Prevention and Control (ECDC), were tested in Belgium. This study aimed at (1) testing the usefulness and applicability in the field of the ECDC guidelines for the surveillance of IMS in Europe and (2) surveying IMS throughout Belgium. First, the scenarios, which Belgium is facing, were identified according to the ECDC guidelines. Second, the surveillance strategy and the methods were identified based on the guidelines and adjusted to the Belgium context. Two areas colonised by IMS and 20 potential points of entry (PoE) were selected. Mosquito Magnet Liberty Plus (CO2-baited) traps (23) and oviposition traps (147) were set-up, and larval sampling was performed monthly or bi-monthly from July till October 2012. Finally, the costs and workload of the surveillance activities were compared to the estimates provided by the ECDC guidelines. Surveillance at 20 potential PoE (complying with scenario 1) revealed that no new IMS were established in Belgium. Surveillance at two sites colonised by IMS (scenario 2) indicated that although control measures have drastically reduced the Ae. j. japonicus population this species is still present. Furthermore, Ae. koreicus is permanently established. For both scenarios, the problems encountered are discussed and recommendations are given. In addition, the actual workload was lower than the estimated workload, while the actual costs were higher than the estimated ones. The ECDC guidelines are helpful, applicable and efficient to implement surveillance of IMS in Belgium. Recommendations were customised to the local context (political demands, salary and investment costs, and existing expertise). The workload and costs related to the preparatory phase (i.e., planning, contacts with the PoE, writing a protocol) were found to be missing in the cost evaluation suggested in the guidelines. Updates on the occurrence of IMS in Belgium and the related risk for disease agents they can transmit will only be available once a structured and permanent surveillance system is implemented.


Generation of a Magoh conditional allele in mice.
Magoh encodes a core component of the exon junction complex (EJC), which binds mRNA and regulates mRNA metabolism. Magoh is highly expressed in proliferative tissues during development. EJC components have been implicated in several developmental disorders including TAR syndrome, Richieri-Costa-Pereira syndrome, and intellectual disability. Existing germline null Magoh mice are embryonic lethal as homozygotes and perinatal lethal as heterozygotes, precluding detailed analysis of embryonic and postnatal functions. Here, we report the generation of a new genetic tool to dissect temporal and tissue-specific roles for Magoh in development and adult homeostasis. This Magoh conditional allele has two loxP sites flanking the second exon. Ubiquitous Cre-mediated deletion of the floxed allele in a heterozygous mouse (Magoh(del/+) ) causes 50% reduction of both Magoh mRNA and protein. Magoh(del/+) mice exhibit both microcephaly and hypopigmentation, thus phenocopying germline haploinsufficient Magoh mice. Using Emx1-Cre, we further show that conditional Magoh deletion in neural progenitors during embryonic development also causes microcephaly. We anticipate this novel conditional allele will be a valuable tool for assessing tissue-specific roles for Magoh in mammalian development and postnatal processes.


Design of Experiments for Optimizing Ultrasound-Assisted Extraction of Bioactive Compounds from Plant-Based Sources.
Plant-based materials are an important source of bioactive compounds (BC) with interesting industrial applications. Therefore, adequate experimental strategies for maximizing their recovery yield are required. Among all procedures for extracting BC (maceration, Soxhlet, hydro-distillation, pulsed-electric field, enzyme, microwave, high hydrostatic pressure, and supercritical fluids), the ultrasound-assisted extraction (UAE) highlighted as an advanced, cost-efficient, eco-friendly, and sustainable alternative for recovering BC (polyphenols, flavonoids, anthocyanins, and carotenoids) from plant sources with higher yields. However, the UAE efficiency is influenced by several factors, including operational variables and extraction process (frequency, amplitude, ultrasonic power, pulse cycle, type of solvent, extraction time, solvent-to-solid ratio, pH, particle size, and temperature) that exert an impact on the molecular structures of targeted molecules, leading to variations in their biological properties. In this context, a diverse design of experiments (DOEs), including full or fractional factorial, Plackett-Burman, Box-Behnken, Central composite, Taguchi, Mixture, D-optimal, and Doehlert have been investigated alone and in combination to optimize the UAE of BC from plant-based materials, using the response surface methodology and mathematical models in a simple or multi-factorial/multi-response approach. The present review summarizes the advantages and limitations of the most common DOEs investigated to optimize the UAE of bioactive compounds from plant-based materials.


Oral Health-Related Quality of Life among Adolescents in the First 6 Months of Fixed Orthodontic Therapy.
Clarification on disabilities that may arise during orthodontic treatment allows patients to have more realistic expectations. This prospective study assessed the impact of fixed orthodontic therapy on adolescents' quality of life over 6 months. A total of 78 adolescents aged 11-17 years were included. Quality of life was measured using the Child Perceptions Questionnaire (CPQ11-14, short form) at five moments: before treatment (T0), one week (T1), one month (T2), three months (T3), and six months (T4) after treatment initiation. Multiple and pairwise comparisons were conducted for CPQ11-14 scores (Friedman and Wilcoxon test; effect size). Changes in the quality of life were assessed as mean differences (T0-T1 and T0-T4) in total and domain scores (Kruskal-Wallis and Mann-Whitney test) (α = 5%). Significant differences were observed between T0 and T4 in the oral symptoms' domain (p < 0.001), and between T0 and T1, T2, T3, and T4 for emotional well-being (p < 0.001 for all). Significant differences in impact were also found between T0 and T2, T3, and T4 with regard to social well-being (p = 0.004, =0.049, and <0.001, respectively). Orthodontic therapy positively impacted the emotional and social aspects of adolescents' quality of life. Negative effects were primarily related to pain, mouth sores, and difficulty biting or chewing. Understanding the symptoms and feelings of orthodontic patients aids professionals in decision-making.


Ocular manifestations of central nervous system lymphoma.
Primary intraocular lymphoma (PIOL) is a variant of primary central nervous system lymphoma in which lymphoma cells are initially present only in the eyes without evidence of disease in the brain or cerebrospinal fluid. Patients with PIOL are typically older adults who present with blurred vision and floaters. The ophthalmic examination characteristically shows a cellular infiltrate in the vitreous with or without the presence of subretinal infiltrates. Diagnostic evaluation for PIOL includes neuroimaging, cytologic examination of the cerebrospinal fluid, and a diagnostic vitrectomy with special handling of the vitreous specimen, if the former is nondiagnostic. Molecular and cytokine analyses are useful adjuncts to cytology for the diagnosis of PIOL. Recent molecular studies demonstrating viral DNA in the ocular lymphoma cells suggest a role for infectious agents in the pathogenesis of PIOL. To date, the best mode for treatment of PIOL or recurrent primary central nervous system lymphoma involving only the eyes remains undefined.


Convergence in hearing-related genes between echolocating birds and mammals.
Echolocation, the detection of objects by means of sound waves, has evolved independently in diverse animals. Echolocators include not only mammals such as toothed whales and yangochiropteran and rhinolophoid bats but also Rousettus fruit bats, as well as two bird lineages, oilbirds and swiftlets. In whales and yangochiropteran and rhinolophoid bats, positive selection and molecular convergence has been documented in key hearing-related genes, such as prestin (SLC26A5), but few studies have examined these loci in other echolocators. Here, we examine patterns of selection and convergence in echolocation-related genes in echolocating birds and Rousettus bats. Fewer of these loci were under selection in Rousettus or birds compared with classically recognized echolocators, and elevated convergence (compared to outgroups) was not evident across this gene set. In certain genes, however, we detected convergent substitutions with potential functional relevance, including convergence between Rousettus and classic echolocators in prestin at a site known to affect hair cell electromotility. We also detected convergence between Yangochiroptera, Rhinolophidea, and oilbirds in TMC1, an important mechanosensory transduction channel in vertebrate hair cells, and observed an amino acid change at the same site within the pore domain. Our results suggest that although most proteins implicated in echolocation in specialized mammals may not have been recruited in birds or Rousettus fruit bats, certain hearing-related loci may have undergone convergent functional changes. Investigating adaptations in diverse echolocators will deepen our understanding of this unusual sensory modality.


Lack of pharmacodynamic interactions between quinidine and digoxin in isolated atrial muscle of guinea pig heart.
Quinidine has been reported to have no effect on the positive inotropic action of digoxin observed in isolated cardiac muscle preparations. This is surprising because quinidine has been shown to reduce Na+ influx in cardiac muscle. The conditions which increase Na+ influx stimulate the glycoside binding to Na+- and K+-activated Mg++-dependent ATP phosphohydrolase (Na+,K+-ATPase), and therefore quinidine may be expected to have an opposite effect. Thus, the effects of quinidine on cardiac muscle and its possible interactions with digoxin were re-evaluated using electrically paced left atrial muscle preparations of guinea pig heart. Quinidine caused a frequency- and concentration-dependent decrease in maximal upstroke velocity and amplitude of the action potential without altering resting membrane potential. In addition, quinidine prolonged action potential duration markedly in a frequency-dependent manner. Despite action potential prolongation, the alkaloid reduced net Na+ influx as determined by a decrease in steady-state ouabain-sensitive 86Rb+ uptake. Under these conditions, however, quinidine failed to reduce the rate of onset or the maximal positive inotropic effect of digoxin; or did it reduce digoxin binding to Na+,K+- ATPase in beating atrial muscle preparations. Benzocaine, which reduced net Na+ influx without increasing the action potential duration, also failed to affect the peak inotropic effect of digoxin or the glycoside binding. Quinidine had no direct effects on glycoside binding to isolated cardiac Na+,K+-ATPase. Moreover, [3H]ouabain binding to isolated enzyme was relatively insensitive to changes in Na+ concentrations between 1 and 8 mM although binding was stimulated clearly by Na+ above 8 mM. These results indicate that quinidine, at therapeutic concentrations, does not interact pharmacodynamically with digoxin in isolated cardiac muscle.