Effect of human bone morphogenetic protein 2 implant on tooth eruption in an experimental design.
This study evaluated the influence of recombinant human bone morphogenetic protein 2 (rhBMP-2) on the development and eruption of the secondary dentition. Primary premolar tooth extraction sockets in 12 16-week-old felines were implanted with either rhBMP-2, in collagen sponge or with buffer/absorbable collagen sponge (ACS). Unoperated jaw quadrants served as controls. Experimental conditions were randomized between jaw quadrants in all animals. Two animals receiving rhBMP-2/ACS and buffer/ACS in two quadrants per implant were sacrificed at 4 weeks postsurgery. Ten animals receiving rhBMP-2/ACS (two quadrants), buffer/ACS implants (one quadrant), and one quadrant serving as an unoperated control were evaluated at 12 weeks postsurgery. Clinical assessments included healing, eruption patterns, and crown development. Radiographic assessments included tooth development, eruption patterns, and bone formation. Histological observations were also made from the 4-week animals. The secondary dentition remained unerupted at 4 weeks postsurgery. Histological analysis showed normal alveolar bone coronal to the erupting teeth in rhBMP-2/ACS-implanted quadrants. At 12 weeks postsurgery, all teeth were erupted without differences between quadrants. Clinically, the crowns of all teeth were normal. Radiographs suggested that teeth in rhBMP-2/ACS- and buffer/ACS-implanted jaw quadrants exhibited similar tooth development and eruption patterns as the normal control. The evidence from this study suggests that surgical implantation of rh-BMP-2/ACS in the pathway of the developing and erupting secondary dentition does not interfere with the normal development and eruption patterns of the teeth.


Bowel stomas in infants and children. A 5-year audit of 203 patients.
A 5-year audit of the formation, management and closure of small-bowel stomas and colostomies at Red Cross War Memorial Children's Hospital, Cape Town, is described. Of the 203 patients, 128 (63%) required the stroma in the neonatal period. Anorectal malformations (80), Hirschsprung's disease (65), necrotising enterocolitis (33), trauma (11) and neoplasm (5) comprised most of the indications. One hundred and thirty large-bowel stomas were sited in the proximal sigmoid and 37 in the transverse colon, all but 11 being divided with each end brought out through a short muscle cutting incision or through the laparotomy wound. Thirty-six ileostomies were performed and in 30 of these the stoma was sited in the wound. Complications, which included necrosis, bleeding, prolapse and wound sepsis, occurred in 31%. The colostomies sited in the transverse colon had the highest incidence of prolapse (38%). Neonatal stomas brought out in the wound had an acceptably low incidence of complications. Most stomas were temporary in nature. One hundred and eighty-eight were closed, all with excision and end-to-end intraperitoneal anastomosis. There was a 4% incidence of complications (5 would sepsis, 2 leaks, 1 stenosis). The formation, management and closure of bowel stomas represents a considerable section of the work of the paediatric surgeon. Correct meticulous technique is essential in keeping complications to a minimum.


Predictor Variables of Developing Anterior Pituitary Deficiencies in a Group of Paediatric Patients with Central Diabetes Insipidus and Langerhans Cell Histiocytosis.
Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder of unknown etiopathogenesis. Central diabetes insipidus (CDI) is the most frequent endocrine manifestation and is a known risk factor for the development of further anterior pituitary hormone deficiencies (APD). However, not all CDI patients develop APD, as observed during prolonged periods of follow-up. To find predictors of developing APD in LCH children with CDI followed in our institution. We retrospectively analysed 44 patients over a median period (quartiles) of 12.3 years (8.79-14.24). Patients were subdivided into group 1 and group 2, according to absence or presence of APD, respectively. The main variables studied were: (1) chronological age (CA) at LCH diagnosis, (2) the primary site of LCH at diagnosis: low risk (LR) and multisystemic risk organs, and (3) the presence of reactivation. Multivariate Cox regression analysis showed that APD was positively associated with CA at LCH diagnosis [relative risk (RR) 1.14, p < 0.01], the LR clinical form (RR 8.6, p < 0.03), and negatively associated with the presence of reactivations (RR 0.3, p < 0.01). Patients with older CA at LCH diagnosis, LR clinical forms, and fewer reactivation episodes might represent a subgroup of paediatric LCH CDI patients with a higher risk of developing APD.


MafA and MafB regulate genes critical to beta-cells in a unique temporal manner.
Several transcription factors are essential to pancreatic islet β-cell development, proliferation, and activity, including MafA and MafB. However, MafA and MafB are distinct from others in regard to temporal and islet cell expression pattern, with β-cells affected by MafB only during development and exclusively by MafA in the adult. Our aim was to define the functional relationship between these closely related activators to the β-cell. The distribution of MafA and MafB in the β-cell population was determined immunohistochemically at various developmental and perinatal stages in mice. To identify genes regulated by MafB, microarray profiling was performed on wild-type and MafB(-/-) pancreata at embryonic day 18.5, with candidates evaluated by quantitative RT-PCR and in situ hybridization. The potential role of MafA in the expression of verified targets was next analyzed in adult islets of a pancreas-wide MafA mutant (termed MafA(ΔPanc)). MafB was produced in a larger fraction of β-cells than MafA during development and found to regulate potential effectors of glucose sensing, hormone processing, vesicle formation, and insulin secretion. Notably, expression from many of these genes was compromised in MafA(ΔPanc) islets, suggesting that MafA is required to sustain expression in adults. Our results provide insight into the sequential manner by which MafA and MafB regulate islet β-cell formation and maturation.


Stochastic processes are key determinants of short-term evolution in influenza a virus.
Understanding the evolutionary dynamics of influenza A virus is central to its surveillance and control. While immune-driven antigenic drift is a key determinant of viral evolution across epidemic seasons, the evolutionary processes shaping influenza virus diversity within seasons are less clear. Here we show with a phylogenetic analysis of 413 complete genomes of human H3N2 influenza A viruses collected between 1997 and 2005 from New York State, United States, that genetic diversity is both abundant and largely generated through the seasonal importation of multiple divergent clades of the same subtype. These clades cocirculated within New York State, allowing frequent reassortment and generating genome-wide diversity. However, relatively low levels of positive selection and genetic diversity were observed at amino acid sites considered important in antigenic drift. These results indicate that adaptive evolution occurs only sporadically in influenza A virus; rather, the stochastic processes of viral migration and clade reassortment play a vital role in shaping short-term evolutionary dynamics. Thus, predicting future patterns of influenza virus evolution for vaccine strain selection is inherently complex and requires intensive surveillance, whole-genome sequencing, and phenotypic analysis.


Position as Well as Velocity Dependence of Spasticity-Four-Dimensional Characterizations of Catch Angle.
We investigated the muscle alterations related to spasticity in stroke quantitatively using a portable manual spasticity evaluator. Methods: Quantitative neuro-mechanical evaluations under controlled passive elbow stretches in stroke survivors and healthy controls were performed in a research laboratory of a rehabilitation hospital. Twelve stroke survivors and nine healthy controls participated in the study. Spasticity and catch angle were evaluated at 90°/s and 270°/s with the velocities controlled through real-time audiovisual feedback. The elbow range of motion (ROM), stiffness, and energy loss were determined at a slow velocity of 30°/s. Four-dimensional measures including joint position, torque, velocity and torque change rate were analyzed jointly to determine the catch angle. Results: The catch angle was dependent on the stretch velocity and occurred significantly later with increasing velocity (p < 0.001), indicating position dependence of spasticity. The higher resistance felt by the examiner at the higher velocity was also due to more extreme joint position (joint angle) since the spastic joint was moved significantly further to a stiffer elbow position with the higher velocity. Stroke survivors showed smaller ROM (p < 0.001), higher stiffness (p < 0.001), and larger energy loss (p = 0.005). Compared to the controls, stroke survivors showed increased reflex excitability with higher reflex-mediated torque (p < 0.001) and at higher velocities (p = 0.02). Conclusion: Velocity dependence of spasticity is partially due to joint angle position dependence with the joint moved further (to a stiffer position where higher resistance was felt) at a higher velocity. The "4-dimensional characterization" including the joint angle, velocity, torque, and torque change rate provides a systematic tool to characterize catch angle and spasticity quantitatively.


Acousto-optic photonic switch.
An acousto-optic architecture is presented to implement a nonblocking space-division switch with O(N) complexity. Signal degradation is minimal so that the switch is suitable for nonregenerative application within optical networks; it is also capable of rapid reconfiguration. Experiments for a 1 x 4 switch show an insertion loss ranging from 4.6 to 5.6 dB, a worst-case signal-to-cross-talk ratio of better than 30 dB, and a reconfiguration time of 1.46 microsec.


The incidence of fetal heart rate changes after intrathecal fentanyl labor analgesia.
We performed a retrospective review to compare the incidence of new fetal heart rate abnormalities after institution of either intrathecal fentanyl or conventional epidural labor analgesia. In chronological order, the first 100 parturients in active labor who had received epidural analgesia and had recorded fetal heart rate (FHR) traces for 30 min before and after injection were identified, as were the first 100 parturients who had received intrathecal fentanyl analgesia. A perinatologist blinded to the anesthetic technique evaluated each recording and identified any changes in the FHR between the before and after tracings. The incidence of new "negative" (implying worsened fetal status) changes was 6% in the epidural group and 12% in the intrathecal group (P > 0.05, not significant). There were no differences in incidence or degree of blood pressure change, need for cesarean delivery, neonatal outcome, parity, or oxytocin use. No parturient required urgent or emergent cesarean delivery, and all changes resolved within the 30-min observation period. A much larger study would be required to determine whether this six percentage point difference represents a true difference between groups, and its clinical significance. We compared the incidence of fetal heart rate changes after two techniques of labor analgesia. Both techniques were associated with a low (6%-12%) incidence of changes, but a much larger series would be required to determine whether this represents a true difference. No difference in neonatal outcome was found.


Respiratory disease in Niemann-Pick type C2 is caused by pulmonary alveolar proteinosis.
Niemann-Pick diseases are hereditary neurovisceral lysosomal lipid storage disorders, of which the rare type C2 almost uniformly presents with respiratory distress in early infancy. In the patient presented here, the NPC2 exon 4 frameshift mutation c.408_409delAA caused reduced NPC2 protein levels in serum and lung lavage fluid and the synthesis of an aberrant, larger sized protein of around 28 kDa. Protein expression was strongly reduced also in alveolar macrophages. The infant developed failure to thrive and tachypnea. Lung lavage, computer tomography, and histology showed typical signs of pulmonary alveolar proteinosis with an abnormal intraalveolar accumulation of surfactant as well as macrophages. An NPC2-hypomorph animal model also showed pulmonary alveolar proteinosis and accumulation of macrophages in the lung, liver, and spleen long before the mice died. Due to the elevation of cholesterol, the surfactant had an abnormal composition and function. Despite the removal of large amounts of surfactant from the lungs by therapeutic lung lavages, this treatment was only temporarily successful and the infant died of respiratory failure. Our data indicate that respiratory distress in NPC2 disease is associated with a loss of normal NPC2 protein expression in alveolar macrophages and the accumulation of functionally inactive surfactant rich in cholesterol.


Microcalorimetry Study of the Adsorption of Asphaltenes and Asphaltene Model Compounds at the Liquid-Solid Surface.
The adsorption of an acidic polyaromatic asphaltene model compound (C5PeC11) and indigenous C6-asphaltenes onto the liquid-solid surface is studied. Model compound C5PeC11 exhibits a similar type of adsorption with a plateau adsorbed amount as C6-asphaltenes onto three surfaces (silica, calcite, and stainless steel). Model compound BisAC11, with aliphatic end groups and no acidic functionality, does not adsorb at the liquid-silica surface, indicating the importance of polar interactions on adsorption. The values of the adsorption enthalpy characterized by the ΔHz parameter (the enthalpy at zero coverage) indicate that the type of adsorption and the driving force depend on the surface, a key feature when discussing asphaltene deposition. The adsorption of C5PeC11 onto silica is shown to be driven primarily by H bonding (ΔHz = -34.9 kJ/mol), unlike adsorption onto calcite where polar van der Waals and acidic/basic interactions are thought to be predominant (ΔHz = -23.5 kJ/mol). Interactions between C5PeC11 and stainless steel are found to be weak (ΔHz = -7.7 kJ/mol). Comparing C6-asphaltenes and their esterified counterpart shows that adsorption at the liquid-solid surface is not influenced by the formation of H bonds. This was evidenced by the similar adsorbed amounts obtained. Finally, C5PeC11 captures, to a certain extent, the adsorption interactions of asphaltenes present at the calcite-oil and stainless steel-oil surfaces.


Sexual assault resistance education for university women: study protocol for a randomized controlled trial (SARE trial).
More than one in six women will be sexually assaulted in their lifetimes, most by men they know. The situation on university campuses is even more startling, with as many as 1 in 4 female students being victims of rape or attempted rape. The associated physical and mental health effects are extensive and the social and economic costs are staggering. The aim of this randomized controlled trial is to determine whether a novel, small-group sexual assault resistance education program can reduce the incidence of sexual assault among university-attending women, when compared to current university practice of providing informational brochures. The trial will evaluate a theoretically and empirically sound four-unit, 12-hour education program that has been demonstrated in pilot studies to have short-term efficacy. Three of the four units provide information, skills, and practice aimed at decreasing the time needed for women to assess situations with elevated risk of acquaintance sexual assault as dangerous and to take action, reducing emotional obstacles to taking action, and increasing the use of the most effective methods of verbal and physical self-defense. The fourth unit focuses on facilitating a stronger positive sexuality from which women may resist sexual coercion by male intimates more successfully. The trial will extend the pilot evaluations by expanding the participant pool and examining the long term efficacy of the program. A total of 1716 first-year female students (age 17 to 24 years) from three Canadian universities will be enrolled. The primary outcome is completed sexual assault, measured by The Sexual Experiences Survey - Short Form Victimization instrument. Secondary outcomes include changes in knowledge, attitudes, and skills related to the process of sexual assault resistance. Outcomes will be measured at baseline, 1 week, 6, 12, 18, and 24 months. The results of the trial will be used to produce a maximally effective sexual assault resistance education program that can be adopted by universities, to assess whether aspects of the program need to be strengthened, and also to indicate how long the effects of the program last and at which point in time refresher sessions may be necessary. ClinicalTrials.gov NCT01338428.


Allogeneic Anti-BCMA CAR T Cells Are Superior to Multiple Myeloma-derived CAR T Cells in Preclinical Studies and May Be Combined with Gamma Secretase Inhibitors.
Multiple myeloma remains an incurable plasma cell malignancy despite the rapidly evolving treatment landscape. Chimeric antigen receptor T cells targeted against BCMA have recently shown great promise in relapsed refractory multiple myeloma; however, all patients ultimately still progress from their disease. Lack of CAR T-cell persistence, impaired T-cell fitness in autologous CAR T-cell products and the presence of an immunosuppressive bone marrow (BM) microenvironment are contributory factors to treatment failure. We generated anti-BCMA CAR T cells from healthy donors (HD) and patients with multiple myeloma at different stages of disease to compare their T-cell profile, fitness, and cytotoxic activity in preclinical studies. We also used an ex vivo assay with multiple myeloma BM biopsies from distinct genomic subgroups to test the efficacy of HD-derived CAR T cells in a clinically relevant model. HD volunteers showed increased T-cell counts, higher CD4/CD8 ratio, and expanded naïve T-cell population compared with patients with multiple myeloma. After anti-BCMA CAR T-cell production, patients with relapsed multiple myeloma had lower frequencies of CAR+ T cells, decreased central memory phenotype, and increased checkpoint inhibitory markers compared with HD-derived products, which compromised their expansion and cytotoxicity against multiple myeloma cells in vitro. Importantly, HD-derived CAR T cells efficiently killed primary multiple myeloma cells within the BM microenvironment of different multiple myeloma genomic subgroups and their cytotoxic activity could be boosted with gamma secretase inhibitors. In conclusion, allogeneic anti-BCMA CAR T cells are a potential therapeutic strategy for patients with relapsed multiple myeloma and should be further developed in the clinic. Multiple myeloma is an incurable cancer of the plasma cells. A new therapy with anti-BCMA CAR T cells - the patient's own T cells genetically engineered to find and kill myeloma cancer cells - has shown encouraging results. Unfortunately, patients still relapse. In this study, we propose to use T cells from HD volunteers, which have a stronger T-cell fitness, higher cancer killing capacity, and are ready to be administered when needed.


Diagnostic accuracy of confocal laser endomicroscopy in diagnosing dysplasia in patients affected by long-standing ulcerative colitis.
To evaluate the diagnostic accuracy of confocal laser endomicroscopy (CLE) for the detection of dysplasia in long-standing ulcerative colitis (UC). We prospectively performed a surveillance colonoscopy in 51 patients affected by long-standing UC. Also, in the presence of macroscopic areas with suspected dysplasia, both targeted contrasted indigo carmine endoscopic assessment and probe-based CLE were performed. Colic mucosal biopsies and histology, utilised as the gold standard, were assessed randomly and on visible lesions, in accordance with current guidelines. Fourteen of the 51 patients (27%) showed macroscopic mucosal alterations with the suspected presence of dysplasia, needing chromoendoscopic and CLE evaluation. In 5 macroscopically suspected cases, the presence of dysplasia was confirmed by histology (3 flat dysplasia; 2 DALMs). No dysplasia/cancer was found on any of the outstanding random biopsies. The diagnostic accuracy of CLE for the detection of dysplasia compared to standard histology was sensitivity 100%, specificity 90%, positive predictive value 83% and negative predictive value 100%. CLE is an accurate tool for the detection of dysplasia in long-standing UC and shows optimal values of sensitivity and negative predictivity. The scheduled combined application of chromoendoscopy and CLE could maximize the endoscopic diagnostic accuracy for diagnosis of dysplasia in UC patients, thus limiting the need for biopsies.


Comparative Transcriptome Analysis Identified Candidate Genes for Late Leaf Spot Resistance and Cause of Defoliation in Groundnut.
Late leaf spot (LLS) caused by fungus Nothopassalora personata in groundnut is responsible for up to 50% yield loss. To dissect the complex nature of LLS resistance, comparative transcriptome analysis was performed using resistant (GPBD 4), susceptible (TAG 24) and a resistant introgression line (ICGV 13208) and identified a total of 12,164 and 9954 DEGs (differentially expressed genes) respectively in A- and B-subgenomes of tetraploid groundnut. There were 135 and 136 unique pathways triggered in A- and B-subgenomes, respectively, upon N. personata infection. Highly upregulated putative disease resistance genes, an RPP-13 like (Aradu.P20JR) and a NBS-LRR (Aradu.Z87JB) were identified on chromosome A02 and A03, respectively, for LLS resistance. Mildew resistance Locus (MLOs)-like proteins, heavy metal transport proteins, and ubiquitin protein ligase showed trend of upregulation in susceptible genotypes, while tetratricopeptide repeats (TPR), pentatricopeptide repeat (PPR), chitinases, glutathione S-transferases, purple acid phosphatases showed upregulation in resistant genotypes. However, the highly expressed ethylene responsive factor (ERF) and ethylene responsive nuclear protein (ERF2), and early responsive dehydration gene (ERD) might be related to the possible causes of defoliation in susceptible genotypes. The identified disease resistance genes can be deployed in genomics-assisted breeding for development of LLS resistant cultivars to reduce the yield loss in groundnut.


Effects of Yucca schidigera-derived saponin supplementation during a mixed Eimeria challenge in broilers.
An experiment was conducted to determine if dietary Yucca-derived saponin supplementation could ameliorate the immune and growth responses of broilers during a mixed coccidian challenge. A total of 576 two-day-old male Ross 308 broiler chicks were housed in galvanized starter batteries and randomly assigned to 1 of 4 dietary treatment groups (12 replicate cages of 12 birds). Dietary treatments were corn-soybean meal-based and included 1) control diet + sham-inoculated (Ucon), 2) control diet + Eimeria oocyst challenge (Icon), 3) control diet with 250 mg/kg Yucca-derived saponin product + Eimeria oocyst challenge (ISap250), and 4) control diet with 500 mg/kg of Yucca-derived saponin product + Eimeria oocyst challenge (ISap500). On study day 14, birds were orally inoculated with 1.5 mL of tap water containing Eimeria acervulina, E. maxima, and E. tenella (100,000, 40,000, and 30,000 oocysts/dose, respectively), or sham-inoculated with 1.5 mL of tap water. Eimeria-challenged birds exhibited a reduction in growth compared with uninfected birds (P < 0.001); however, there were no detectable differences due to dietary treatment among Eimeria-challenged groups. Mucosal thickness in the jejunum was increased (P < 0.042) in all infected groups and there were no differences among infected groups; however, saponin supplementation included at 250 mg/kg was not significantly different from the uninfected birds. Lymphocytes as a percentage of total white blood cells were increased (P < 0.014) in all Eimeria-challenged groups at 7 D post-inoculation compared with uninfected birds, but birds supplemented at 250 mg/kg were not different from uninfected birds. Cecal and duodenal IFN-γ expression increased with infection when compared with sham-inoculated birds. Cecal and duodenal IL-1β expression increased (P < 0.008 and P < 0.039) due to infection, and ISap250 and ISap500 treatments ameliorated IL-1β expression to levels not different from sham-inoculated birds. These results suggest that saponin supplementation may provide some immunomodulatory effects during a mixed coccidian challenge as evidenced by lymphocyte responses, changes in intestinal structure, and alterations in cecal and duodenal inflammatory cytokine mRNA expression.


Preparation and biological evaluation of copper-64-labeled tyr3-octreotate using a cross-bridged macrocyclic chelator.
Somatostatin receptors (SSTr) are expressed on many neuroendocrine tumors, and several radiotracers have been developed for imaging these types of tumors. For this reason, peptide analogues of somatostatin have been well characterized. Copper-64 (t(1/2) = 12.7 hours), a positron emitter suitable for positron emission tomography (PET) imaging, was shown recently to have improved in vivo clearance properties when chelated by the cross-bridged tetraazamacrocycle 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo(6.6.2)hexadecane (CB-TE2A) compared with 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA). CB-TE2A and TETA were conjugated to the somatostatin analogue tyrosine-3-octreotate (Y3-TATE) for evaluation of CB-TE2A as a bifunctional chelator of 64Cu. The in vitro affinity of each compound for SSTr was determined using a homologous competitive binding assay. In vivo characteristics of both radiolabeled compounds were examined in biodistribution and microPET studies of AR42J tumor-bearing rats. Cu-CB-TE2A-Y3-TATE (Kd = 1.7 nmol/L) and Cu-TETA-Y3-TATE (Kd = 0.7 nmol/L) showed similar affinities for AR42J derived SSTr. In biodistribution studies, nonspecific uptake in blood and liver was lower for 64Cu-CB-TE2A-Y3-TATE. Differences increased with time such that, at 4 hours, blood uptake was 4.3-fold higher and liver uptake was 2.4-fold higher for 64Cu-TETA-Y3-TATE than for 64Cu-CB-TE2A-Y3-TATE. In addition, 4.4-times greater tumor uptake was detected with 64Cu-CB-TE2A-Y3-TATE than with 64Cu-TETA-Y3-TATE at 4 hours postinjection. MicroPET imaging yielded similar results. CB-TE2A appears to be a superior in vivo bifunctional chelator of 64Cu for use in molecular imaging by PET or targeted radiotherapy due to both improved nontarget organ clearance and higher target organ uptake of 64Cu-CB-TE2A-Y3-TATE compared with 64Cu-TETA-Y3-TATE.


Role of environmental factors on the structure and spectroscopic response of 5'-DNA-porphyrin conjugates caused by changes in the porphyrin-porphyrin interactions.
We have explored the utility, strength, and limitation of through-space exciton-coupled circular dichroism in determination of the secondary structure of optically active chromophoric nanoarrays using the example of end-capped porphyrin- and metalloporphyrin-oligodeoxynucleotide conjugates. We put special emphasis on the explanation of the origin and significance of the distinctive multiple bands in the CD spectra (trisignate and tetrasignate CD bands). Such CD profiles are often observed in chiral aggregates or multichromophoric arrays but have never before been studied in detail. We found that variation of temperature and ionic strength has a profound effect on the geometry of the porphyrin-DNA conjugates and thus the nature of electronic interactions. At lower temperatures and in the absence of NaCl all three 5'-DNA-porphyrin conjugates display negative bisignate CD exciton couplets of variable intensity in the Soret region resulting from through-space interaction between the electric transition dipole moments of the two end-capped porphyrins. As the temperature is raised these exciton couplets are transformed into single positive bands originating from the porphyrin-single-strand DNA interactions. At higher ionic strengths and low temperatures, multisignate CD bands are observed in the porphyrin Soret region. These CD signature bands originate from a combination of intermolecular, end-to-end porphyrin-porphyrin stacking between duplexes and porphyrin-DNA interactions. The intermolecular aggregation was confirmed by fluorescence and absorption spectroscopy and resonance light scattering. DeVoe theoretical CD calculations, in conjunction with molecular dynamics simulations and Monte Carlo conformational searches, were used to mimic the observed bisignate exciton-coupled CD spectra as well as multiple CD bands. Calculations correctly predicted the sign and shape of the experimentally observed CD spectra. These studies reveal that the exciton-coupled circular dichroism is a very useful technique for the determination of the structure of optically active arrays.


Managing cluster headache.
Cluster headache is a neurological disorder that presents with unilateral severe headache associated with ipsilateral cranial autonomic symptoms. Cluster headache attacks often occur more than once a day, and typically manifesting in bouts. It has a point prevalence of 1 in 1000 and is the most common trigeminal autonomic cephalalgia. This article aims to guide general neurologists to an accurate diagnosis and practical management options for cluster headache patients.


Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder.
Removal of toxic substances from the blood depends on patent connections between the kidney, ureters and bladder that are established when the ureter is transposed from its original insertion site in the male genital tract to the bladder. This transposition is thought to occur as the trigone forms from the common nephric duct and incorporates into the bladder. Here we re-examine this model in the context of normal and abnormal development. We show that the common nephric duct does not differentiate into the trigone but instead undergoes apoptosis, a crucial step for ureter transposition controlled by vitamin A-induced signals from the primitive bladder. Ureter abnormalities occur in 1-2% of the human population and can cause obstruction and end-stage renal disease. These studies provide an explanation for ureter defects underlying some forms of obstruction in humans and redefine the current model of ureter maturation.


Consolidated series for efficient calculation of the reflection and transmission in rough multilayers.
Fresnel reflectance and transmittance coefficients of a thin film system consisting of an arbitrary number of layers are expressed explicitly in the form of a power series of Fresnel coefficients for individual boundaries and phase terms for the individual films. The series is based on the evaluation of all possible paths light can pass through the system. However, the series is written as consolidated, i. e. all paths corresponding to the same powers are represented using a single term in the series, with multiplicity which is a simple product of binomial coefficients. This result is used to express the normal reflectance of a thin film system with arbitrarily correlated randomly rough boundaries and it is shown that such approach can be computationally efficient in practice.


Regulation of a bacteriophage T4 late gene, soc, which maps in an early region.
We have sequenced and analyzed the expression of an early region of the bacteriophage T4 genome that surprisingly contains a late gene, soc. soc is oriented in the same direction as early genes, like the T4 lysozyme gene. Northern hybridization of early and late T4 RNA, using cloned T4 restriction fragments as probes, identified two long early transcripts and a short late transcript, all containing the soc-coding sequence. Thus, soc is transcribed both early and late. It is, however, translated only late. The inhibition of soc translation from the long early transcripts can be explained by formation of a hairpin in the RNA that sequesters the soc ribosome-binding site. The transcript initiated at the late promoter cannot form this hairpin and is, therefore, translated.


Age-Related Conjunctival Disease in the C57BL/6.NOD-Aec1Aec2 Mouse Model of Sjögren Syndrome Develops Independent of Lacrimal Dysfunction.
To investigate parameters of ocular surface disease in C57BL/6.NOD-Aec1Aec2 (Aec) mice with aging and their correlation with development of Sjögren syndrome (SS)-like lacrimal gland (LG) disease. Aec and C57BL/6 wild-type (B6) female mice were evaluated at 4, 12, and 20 weeks of age. Whole LG and eyes and adnexa were excised for histology and gene expression analysis and evaluated by flow cytometry and immunohistochemistry. Tear volume and goblet cell density was measured. Quantitative PCR evaluated T-cell-related cytokine expression in cornea and conjunctiva. Both strains showed age-related conjunctival goblet cell loss that was more pronounced in the Aec strain and significantly greater than in B6 mice at 12 weeks. This was accompanied by CD4+ T-cell infiltration of the conjunctiva that was greater in Aec strain at 20 weeks. Aec mice had higher levels of IL-17A, IL-17R, IL-1α, IL-1β, and TNF-α in the conjunctiva, and they significantly increase with aging. Aec mice had greater lymphocytic infiltration of the LG and conjunctiva at 20 weeks that consisted of a mixture of CD4+ and CD8+ cells. Flow cytometry showed a significant increase in CD4+ T cells in Aec LG compared to B6 mice. Tear volume was significantly increased in both strains at 20 weeks. Aec mice developed greater conjunctival goblet cell loss associated with lymphocytic infiltration of the LG and conjunctiva with aging. Increased expression of certain T helper or inflammatory cytokines in these tissues was observed in Aec mice. The conjunctival disease appeared to be due to inflammation and not a decrease in tear volume.


Plasma membrane disruption underlies injury of the corneal endothelium by ultrasound.
The nature and the extent of acute injury to corneal endothelial cells caused by exposure to ultrasound radiation were characterized, as well as the long-term reaction of these cells to this form of injury. It was found that the degree of lethal cell injury induced by ultrasound scaled with exposure intensity and duration. Immediate changes in plasma membrane permeability were induced by ultrasound exposure. This ultrasound-induced permeability change was, however, transient in many cells, allowing them to trap and retain a normally impermeant tracer, fluorescein dextran, in cytosol. Microvilli were present on ultrasound treated cells in far greater density than on control cells, characteristic of exocytosis-based resealing. Cultures containing a majority of transiently permeabilized endothelial cells were morphologically indistinguishable from untreated control cultures, and the fluorescein dextran-labeled cells in these populations locomoted and divided normally. We conclude that cell death due to ultrasound exposure can occur rapidly via a necrotic mechanism that can be attributed to mechanically induced damage to the plasma membrane. However, not all cells injured become necrotic: some survive and appear to behave normally after exposure. Conditions that favor plasma membrane disruption resealing, e.g. that result in sub-lethal rather than lethal cell injury, may mitigate the reduction in corneal endothelial cell density consequent on phacoemulsification and aspiration surgery.


Acceptability of a community health worker intervention to improve the oral health of older Chinese Americans: A pilot study.
To evaluate the acceptability of a community health worker (CHW) intervention designed to improve the oral health of low-income, urban Chinese immigrant adults. Given that both dental caries and periodontitis are behaviourally mediated, biofilm-based diseases that are largely preventable with attention to regular oral hygiene practices and preventive dental visits, strategies to arrest or even heal carious lesions and high-quality maintenance care and plaque control without the need to resort to aerosol-generating surgical approaches are evidence-based best practices. Older immigrants have poorer oral health than older US-born natives, motivating the need for delivery of more effective and affordable services to this vulnerable population. CHWs were trained by the NYU College of Dentistry dental hygienist faculty members using dental models and flip charts to instruct patients on proper brushing and flossing techniques. In addition, they discussed the presented oral health promotion information one-on-one with patients, addressed any expressed concerns and encouraged prevention of oral conditions through regular dental visits and brushing with fluoride toothpaste. More than 98% of the 74 older Chinese adult participants strongly agreed/agreed that the CHWs helped them to improve how they take care of their health, the CHWs answered their questions and concerns, the information and topics were informative, and the in-person demonstrations were helpful in improving oral health. The health of all communities depends on access to comprehensive care, including oral health care, in the wake of COVID-19. CHW interventions are acceptable to and may reach marginalised and immigrant communities.


Association between periodontal diseases and cardiovascular diseases, diabetes and respiratory diseases: Consensus report of the Joint Workshop by the European Federation of Periodontology (EFP) and the European arm of the World Organization of Family Doctors (WONCA Europe).
To explore the implications for dentists and family doctors of the association between periodontal and systemic diseases and the role of dentists and family doctors in managing non-communicable diseases (NCDs) and promoting healthy lifestyles. The consensus reports of the previous Focused Workshops on the associations between periodontitis and diabetes (2017) and periodontitis and cardiovascular diseases (2019) formed the technical reviews to underpin discussions on both topics. For the association with respiratory diseases, a systematic review was specifically commissioned for the Workshop discussions. Working groups prepared proposals independently, and then the proposals were discussed and approved at plenary meetings. Periodontitis is independently associated with cardiovascular diseases, diabetes, chronic obstructive pulmonary disease (COPD), obstructive sleep apnea and COVID-19 complications. Dentists and family doctors should collaborate in managing NCDs, implementing strategies for early detection of periodontitis in primary care centres and of cardiovascular diseases or diabetes in dental settings. Family doctors should be informed about periodontal diseases and their consequences, and oral health professionals (OHPs) should be informed about the relevance of NCDs and the associated risk factors. Closer collaboration between OHPs and family doctors is important in the early detection and management of NCDs and in promoting healthy lifestyles. Pathways for early case detection of periodontitis in family medicine practices and of NCDs in dental practices should be developed and evaluated.


Should the Decisions of Institutional Review Boards Be Consistent?
In response to increasing concerns regarding inconsistency in the decision-making of institutional review boards (IRBs), we introduce the decision-maker's dilemma, which arises when complex, normative decisions must be made regularly. Those faced with such decisions can either develop a process of algorithmic decision-making, in which consistency is ensured but many morally relevant factors are excluded from the process, or embrace discretionary decision-making, which makes space for morally relevant factors to shape decisions but leads to decisions that are inconsistent. Based on an exploration of similarities between systems of criminal sentencing and of research ethics review, we argue for a discretionary system of decision-making, even though it leads to more inconsistency than does an algorithmic system. We conclude with a discussion of some safeguards that could improve consistency while still making space for discretion to enter IRBs' decision-making processes.


Screening LGI1 in a cohort of 26 lateral temporal lobe epilepsy patients with auditory aura from Turkey detects a novel de novo mutation.
Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is an autosomal dominant epileptic syndrome characterized by focal seizures with auditory or aphasic symptoms. The same phenotype is also observed in a sporadic form of lateral temporal lobe epilepsy (LTLE), namely idiopathic partial epilepsy with auditory features (IPEAF). Heterozygous mutations in LGI1 account for up to 50% of ADLTE families and only rarely observed in IPEAF cases. In this study, we analysed a cohort of 26 individuals with LTLE diagnosed according to the following criteria: focal epilepsy with auditory aura and absence of cerebral lesions on brain MRI. All patients underwent clinical, neuroradiological and electroencephalography examinations and afterwards they were screened for mutations in LGI1 gene. The single LGI1 mutation identified in this study is a novel missense variant (NM_005097.2: c.1013T>C; p.Phe338Ser) observed de novo in a sporadic patient. This is the first study involving clinical analysis of a LTLE cohort from Turkey and genetic contribution of LGI1 to ADLTE phenotype. Identification of rare LGI1 gene mutations in sporadic cases supports diagnosis as ADTLE and draws attention to potential familial clustering of ADTLE in suggestive generations, which is especially important for genetic counselling.


Updated Nomogram Incorporating Percentage of Positive Cores to Predict Probability of Lymph Node Invasion in Prostate Cancer Patients Undergoing Sentinel Lymph Node Dissection.
Objectives: To update the first sentinel nomogram predicting the presence of lymph node invasion (LNI) in prostate cancer patients undergoing sentinel lymph node dissection (sPLND), taking into account the percentage of positive cores. Patients and Methods: Analysis included 1,870 prostate cancer patients who underwent radioisotope-guided sPLND and retropubic radical prostatectomy. Prostate-specific antigen (PSA), clinical T category, primary and secondary biopsy Gleason grade, and percentage of positive cores were included in univariate and multivariate logistic regression models predicting LNI, and constituted the basis for the regression coefficient-based nomogram. Bootstrapping was applied to generate 95% confidence intervals for predicted probabilities. The area under the receiver operator characteristic curve (AUC) was obtained to quantify accuracy. Results: Median PSA was 7.68 ng/ml (interquartile range (IQR) 5.5-12.3). The number of lymph nodes removed was 10 (IQR 7-13). Overall, 352 patients (18.8%) had LNI. All preoperative prostate cancer characteristics differed significantly between LNI-positive and LNI-negative patients (P<0.001). In univariate accuracy analyses, the proportion of positive cores was the foremost predictor of LNI (AUC, 77%) followed by PSA (71.1%), clinical T category (69.9%), and primary and secondary Gleason grade (66.6% and 61.3%, respectively). For multivariate logistic regression models, all parameters were independent predictors of LNI (P<0.001). The nomogram exhibited a high predictive accuracy (AUC, 83.5%). Conclusion: The first update of the only available sentinel nomogram predicting LNI in prostate cancer patients demonstrates even better predictive accuracy and improved calibration. As an additional factor, the percentage of positive cores represents the leading predictor of LNI. This updated sentinel model should be externally validated and compared with results of extended PLND-based nomograms.


Structure of Colloidal Quantum Dots from Dynamic Nuclear Polarization Surface Enhanced NMR Spectroscopy.
Understanding the chemistry of colloidal quantum dots (QDs) is primarily hampered by the lack of analytical methods to selectively and discriminately probe the QD core, QD surface and capping ligands. Here, we present a general concept for studying a broad range of QDs such as CdSe, CdTe, InP, PbSe, PbTe, CsPbBr3, etc., capped with both organic and inorganic surface capping ligands, through dynamic nuclear polarization (DNP) surface enhanced NMR spectroscopy. DNP can enhance NMR signals by factors of 10-100, thereby reducing the measurement times by 2-4 orders of magnitude. 1D DNP enhanced spectra acquired in this way are shown to clearly distinguish QD surface atoms from those of the QD core, and environmental effects such as oxidation. Furthermore, 2D NMR correlation experiments, which were previously inconceivable for QD surfaces, are demonstrated to be readily performed with DNP and provide the bonding motifs between the QD surfaces and the capping ligands.


Mice over-expressing salmon calcitonin have strongly attenuated osteoarthritic histopathological changes after destabilization of the medial meniscus.
Calcitonin is well-known for its inhibitory actions on bone-resorbing osteoclasts and recently potential beneficial effects on cartilage were shown. We investigated effects of salmon calcitonin (sCT) on the articular cartilage and bone, after destabilization of the medial meniscus (DMM) in normal and sCT over-expressing mice. Bone phenotype of transgenic (TG) C57Bl/6 mice over-expressing sCT at 6 months and 12 months was investigated by (1) serum osteocalcin and urinary deoxypyridinoline and (2) dynamic and normal histomorphometry of vertebrae bodies. In subsequent evaluation of cartilage and subchondral bone changes, 44 10-week old TG or wild-type (WT) mice were randomized into four groups and subjected to DMM or sham-operations. After 7 weeks animals were sacrificed, and knee joints were isolated for histological analysis. Trabecular bone volume (BV/TV) increased 150% after 6 months and 300% after 12 months in sCT-expressing mice when compared to WT controls (P<0.05). Osteoblast number, bone formation rate and osteocalcin measurements were not affected in TG mice over-expressing sCT. In WT animals, a 5-fold increase in the quantitative erosion index was observed after DMM, and the semi-quantitative OARSI score showed over 400% (P<0.001) increase, compared to sham-operated WT mice. DMM-operated TG mice were protected against cartilage erosion and showed a 65% and 64% (P<0.001) reduction, respectively, for the two histopathological evaluation methods. sCT over-expressing mice had higher bone volume, and were protected against cartilage erosion. These data suggest that increased levels of sCT may hamper the pathogenesis of osteoarthritis (OA). However more studies are necessary to confirm these preliminary results.


Biomarkers in clinical medicine.
Biomarkers have been used in clinical medicine for decades. With the rise of genomics and other advances in molecular biology, biomarker studies have entered a whole new era and hold promise for early diagnosis and effective treatment of many diseases. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention (1). They can be classified into five categories based on their application in different disease stages: 1) antecedent biomarkers to identify the risk of developing an illness, 2) screening biomarkers to screen for subclinical disease, 3) diagnostic biomarkers to recognize overt disease, 4) staging biomarkers to categorise disease severity, and 5) prognostic biomarkers to predict future disease course, including recurrence, response to therapy, and monitoring efficacy of therapy (1). Biomarkers can indicate a variety of health or disease characteristics, including the level or type of exposure to an environmental factor, genetic susceptibility, genetic responses to environmental exposures, markers of subclinical or clinical disease, or indicators of response to therapy. This chapter will focus on how these biomarkers have been used in preventive medicine, diagnostics, therapeutics and prognostics, as well as public health and their current status in clinical practice.


Effects of growth hormone and insulin-like growth factor-I on the iron-induced lipid peroxidation in the rat liver and porcine thyroid homogenates.
Growth hormone (GH) and its tissue mediator, insulin-like growth factor-I (IGF-I), are involved in oxidative processes, lipid peroxidation (LPO) included. Bivalent iron (Fe2+) is frequently used to experimentally induce oxidative damage to macromolecules (Fe2++H2O2+H+→Fe3++•OH+H2O). The aim of the study was to evaluate the effect of GH and/or IGF-I on the iron-induced LPO in the rat liver and porcine thyroid homogenates. Rat liver and porcine thyroid homogenates were incubated in presence of GH (100; 10; 1.0; 0.1; 0.01; 0.001; 0.0001 µg/ml) or IGF-I (1000; 100; 10; 1.0; 0.1; 0.01; 0.001; 0.0001 µg/ml) or GH (100 µg/ml)+IGF-I, or FeSO4+H2O2 plus GH and/or IGF-I. The level of LPO was expressed as concentrations of malondialdehyde+4-hydroxyalkenals (MDA+4-HDA) per mg of protein. GH and/or IGF-I did not change the basal level of oxidative damage to lipids. In the rat liver homogenates, GH did not affect the iron-induced LPO, whereas IGF-I--in the lowest two concentrations--enhanced the process. In porcine thyroid homogenates, GH--in its two lowest concentrations--prevented, whereas in other concentrations, it enhanced the iron-induced LPO. IGF-I, in all used concentrations, enhanced the iron-induced LPO. GH and/or IGF-I may reveal prooxidative effects. This fact does not support their application in the treatment of disorders associated with increased oxidative damage.


Socioeconomic status and paranoia: the role of life hassles, self-mastery, and striving to avoid inferiority.
Paranoid ideation is more common in the general population than previously thought, and it is associated with low socioeconomic status. Daily life hassles, self-mastery, and striving to avoid inferiority may partly account for this association, but these factors have not been examined in relation to paranoid thoughts. Two hundred fifteen individuals from the general population completed self-report assessments of paranoid thoughts during the last month, daily life hassles, self-mastery, striving to avoid inferiority, and socioeconomic classification. A greater number of daily hassles, low self-mastery, and insecure striving were all associated with greater levels of paranoid thinking. Each variable was associated with markers of socioeconomic status. This study demonstrates for the first time the association of paranoid thoughts with life hassles, self-mastery, and striving to avoid inferiority. Each of the factors examined may be a plausible candidate to account for why lower socioeconomic status is associated with greater perceptions of threat from other people.


The economic and operational value of using drones to transport vaccines.
Immunization programs in low and middle income countries (LMICs) face numerous challenges in getting life-saving vaccines to the people who need them. As unmanned aerial vehicle (UAV) technology has progressed in recent years, potential use cases for UAVs have proliferated due to their ability to traverse difficult terrains, reduce labor, and replace fleets of vehicles that require costly maintenance. Using a HERMES-generated simulation model, we performed sensitivity analyses to assess the impact of using an unmanned aerial system (UAS) for routine vaccine distribution under a range of circumstances reflecting variations in geography, population, road conditions, and vaccine schedules. We also identified the UAV payload and UAS costs necessary for a UAS to be favorable over a traditional multi-tiered land transport system (TMLTS). Implementing the UAS in the baseline scenario improved vaccine availability (96% versus 94%) and produced logistics cost savings of $0.08 per dose administered as compared to the TMLTS. The UAS maintained cost savings in all sensitivity analyses, ranging from $0.05 to $0.21 per dose administered. The minimum UAV payloads necessary to achieve cost savings over the TMLTS, for the various vaccine schedules and UAS costs and lifetimes tested, were substantially smaller (up to 0.40L) than the currently assumed UAV payload of 1.5L. Similarly, the maximum UAS costs that could achieve savings over the TMLTS were greater than the currently assumed costs under realistic flight conditions. Implementing a UAS could increase vaccine availability and decrease costs in a wide range of settings and circumstances if the drones are used frequently enough to overcome the capital costs of installing and maintaining the system. Our computational model showed that major drivers of costs savings from using UAS are road speed of traditional land vehicles, the number of people needing to be vaccinated, and the distance that needs to be traveled.


The dwarfing mechanism of citrus rootstocks F&A 418 and #23 is related to competition between vegetative and reproductive growth.
The annual development of Navelina (Citrus sinensis (L.) Osbeck) trees budded on three hybrid citrus rootstocks was studied. Two rootstocks, named #23 and #24, were obtained from the cross of Troyer citrange (C. sinensis x Poncirus trifoliata (L.) Raf.) x Cleopatra mandarin (C. reshni Hort. ex Tan.). The third rootstock, named F&A 418, came from a cross of Troyer citrange x common mandarin (C. deliciosa Ten.). Rootstocks #23 and F&A 418 are dwarfing rootstocks and reduce the size of the scion by about 75%. Rootstock #24 yields a standard size scion. Major growth differences that influenced tree size were apparent during the first summer after grafting and appeared to be related to fruit productivity, because defruiting the dwarfed scions caused a significant increase in vegetative shoot development, including summer sprouting. The reduced growth of the dwarfed scions was not restored by hormone application, indicating that a hormonal deficiency is unlikely to be the primary reason for scion dwarfing, although differences in gibberellin concentrations were found in actively growing shoots. Leaf photosynthesis was similar in scions on all three rootstocks, but the carbohydrate accumulation in fruits and fibrous roots during the summer sprouting period was significantly greater in the dwarfed trees than in the standard trees. Our results suggest that the dwarfing mechanism induced by the F&A 418 and #23 rootstocks is mediated by enhanced reproductive development and fruit growth, resulting in reduced vegetative development in the summer. Thus, a change in the pattern of assimilate distribution appears to be one of the main components of the dwarfing mechanism.


Complementation of arylsulfatase A in somatic hybrids of metachromatic leukodystrophy and multiple sulfatase deficiency disorder fibroblasts.
Metachromatic leukodystrophy and multiple sulfatase deficiency disorder are severe neurodegenerative diseases inherited as separate autosomal recessive traits. Arylsulfatase A (aryl-sulfate sulfohydrolase, EC 188.8.131.52) activity is deficient in both diseases but in multiple sulfatase deficiency disorder, activities of arylsulfatases B and C and other sulfatases are also reported to be reduced. Somatic hybrid cell clones produced by fusing cultured fibroblasts from patients with these diseases were isolated by a nonselective technique based on unit-gravity sedimentation. Arylsulfatase A activity was restored in these hybrids. The complemented enzyme resembled the normal arylsulfatase A in heat stability, pH optimum, Km, electrophoretic mobility, and immunologic reactivity. Because a structurally normal enzyme can be restored in a hybrid only though intergenic complementation, these results indicate that the mutations responsible for the deficiency of arylsulfatase A activity in metachromatic leukodystrophy and multiple sulfatase deficiency disorder are nonallelic and that at least two genetic loci control the expression of arylsulfatase A activity in the human genome. Furthermore, arylsulfatase C activity was also restored to normal in the hybrids, indicating that a common sulfatase inhibitor is not the cause of the multiple sulfatse deficiency.


Use of biological molecules in the treatment of inflammatory bowel disease.
The introduction of biological agents (i.e. antitumour necrosis factor-α and anti-integrin treatments) for the treatment of inflammatory bowel disease (IBD) [i.e. Crohn's disease (CD) and ulcerative colitis] has led to a substantial change in the treatment algorithms and guidelines, especially in CD. However, many questions still remain about the true efficacy and the best treatment regimens. Thus, a need for further treatment options still exists as up to 40% of IBD patients treated with the presently available biologicals do not have positive clinical responses. Better patient selection might maximize the clinical benefit for those in most need of an effective therapy to avoid disabling disease whilst also minimizing the complications associated with therapy. Further, the 'trough-level strategy' may help clinicians to optimize therapy and to avoid loss of response and/or immunogenicity. The idea behind this dosage regimen is that correct dosing must ensure that the patient's lowest level of drug concentration (i.e. the trough level) occurring just before the next drug administration is high enough for the full effect to be seen. Controversy continues regarding the appropriate use of biologicals; therefore, in this review, we focus on considerations that might lead to a more rational strategy for antitumour necrosis factor-α agents in IBD, emphasizing the situations in which the risks may outweigh the benefits. Finally, the need for an appropriate strategy for stopping biological treatment is discussed.


Bateman in nature: predation on offspring reduces the potential for sexual selection.
Sexual selection is driven by competition for mates, and the advantage of a competitor is determined by the number of offspring it produces. Early experiments by Angus Bateman characterized this interaction, and the quantitative relationship between a male's number of mates and number of offspring is known as the Bateman slope. Sexual dimorphism, one of the most obvious results of sexual selection, largely requires a positive Bateman relationship, and the slope provides an estimate of the potential for sexual selection. However, natural selection from the environment can also influence male success, as can random effects, and some have argued for inclusion of the latter in calculations of mate success. Data from pronghorn (Antilocapra americana) reveal the presence of a positive Bateman slope in each year of a 10-year study. We found no evidence that random effects skewed male mating success; however, substantial yearly variation in the Bateman slope due to predation on fawns was evident. These results support the validity of the Bateman relationship, yet they also demonstrate that environmental or extrinsic influences can limit the potential for sexual selection.


Self-Perceived Viral Load and Sexual Risk Behavior Among Known HIV-Positive MSM in San Francisco, 2014.
Self-perceived viral suppression status among men who have sex with men (MSM) may impact HIV risk transmission behaviors. We conducted a 2014 cross-sectional survey of MSM in San Francisco and assessed differences in sexual risk behavior among known HIV-positive MSM based on viral suppression of HIV. We collected demographics, self-perceived viral load status, and sexual risk behavior and tested for viral load levels through laboratory assays. Men were categorized in a hierarchical schema of sexual risk behavior categories based on responses to questions regarding recent partners' HIV status, condom use, and sexual positioning. We used Fisher exact tests to assess for differences based on self-perceived viral load status. Out of a sample of 96 known HIV-positive men, 59 men self-reported an undetectable HIV viral load and 9 men self-reported a detectable viral load consented to confirmatory laboratory testing. The sample of self-reported undetectable men had gradually larger proportions of higher-risk sexual practices, whereas the sample of detectable men was evenly distributed across sexual practices. This association was not statistically significant (P = 0.91). Self-perceived viral suppression may influence sexual practices of known HIV-positive MSM, but small sample size, especially within the detectable category, hinders our ability to determine statistical significance. More research is necessary to assess how HIV-positive men account for viral load in sexual decision-making practices, and this research may inform resource allocation and clinical recommendations to maintain the health of MSM populations.


IL-6 receptor inhibition positively modulates bone balance in rheumatoid arthritis patients with an inadequate response to anti-tumor necrosis factor therapy: biochemical marker analysis of bone metabolism in the tocilizumab RADIATE study (NCT00106522).
To evaluate changes in biochemical markers of bone metabolism in response to tocilizumab in patients with anti-tumor necrosis factor-refractory rheumatoid arthritis (RA). RADIATE was a randomized, double-blind, placebo-controlled, parallel-group phase 3 trial. C-reactive protein, osteocalcin (OC), C-terminal telopeptides of type-I collagen (C-terminal telopeptides of type-1 collagen (CTX-I) and type-I collagen degradation product), and matrix metalloproteinase-3 (MMP-3) serum levels were analyzed from 299 RA patients. Patients were randomly assigned to either tocilizumab (4 or 8 mg/kg) or placebo intravenously every 4 weeks, along with concomitant stable methotrexate (10 to 25 mg weekly) in all treatment arms. The change in biochemical markers CTX-I and OC in combination was evaluated as a measure of net bone balance, a reflection of the change in equilibrium between resorption and formation. Both tocilizumab doses decreased C-reactive protein levels and significantly inhibited cathepsin K-mediated bone resorption in RADIATE subjects, as measured by a decrease in CTX-I. There was a significant overall improvement in net bone balance at week 16 as measured by a decrease in the CTX-I:OC ratio (-25%, P < 0.01). Furthermore, a significant reduction in MMP-3 (43%, P < 0.001) and type-I collagen degradation product levels (18%, P < 0.001) were observed following treatment, both consistent with decreased MMP-mediated type-I collagen catabolism in joint tissue. In anti-tumor necrosis factor-refractory patients, tocilizumab significantly reduced the levels of biochemical markers of cathepsin K-mediated bone resorption and MMP-mediated tissue degradation and remodeling. These observations suggest that tocilizumab has a positive effect on bone balance, which could in part explain the retardation of progressive structural damage observed with tocilizumab. Clinical trial registry number: NCT00106522.


A proteomic study of protein variation between osteopenic and age-matched control bone tissue.
The focus of this study was to identify changes in protein expression within the bone tissue environment between osteopenic and control bone tissue of human femoral neck patients with osteoarthritis. Femoral necks were compared from osteopenic patients and age-matched controls. A new method of bone protein extraction was developed to provide a swift, clear view of the bone proteome. Relative changes in protein expression between control and osteopenic samples were quantified using difference gel electrophoresis (DIGE) technology after affinity chromatographic depletion of albumin and IgG. The proteins that were determined to be differentially expressed were identified using standard liquid chromatography mass spectrometry (LC/MS/MS) and database searching techniques. In order to rule out blood contamination, blood from age-matched osteoporotic, osteopenic and controls were analyzed in a similar manner. Image analysis of the DIGE gels indicated that 145 spots in the osteopenic bone samples changed at least ± 1.5-fold from the control samples (P < 0.05). Three of the proteins were identified by LC/MS/MS. Of the proteins that increased in the osteopenic femurs, two were especially significant: carbonic anhydrase I and phosphoglycerate kinase 1. Apolipoprotein A-I was the most prominent protein that significantly decreased in the osteopenic femurs. The blood samples revealed no significant differences between groups for any of these proteins. In conclusion, carbonic anhydrase I, phosphoglycerate kinase 1 and apolipoprotein A-I appeared to be the most significant variations of proteins in patients with osteopenia and osteoarthritis.


Molecular profiling: moving away from tumor philately.
Despite the remarkable enhancements in breast cancer classification and characterization, an exhaustive comprehension of the underlying carcinogenic processes and an accurate prediction of its clinical behavior are yet to be achieved. On the wave of recent scientific advances and clinical findings, new cutting-edge technologies are poised to deliver an array of diverse molecular data that are expected to dramatically alter breast cancer diagnosis and treatment.


Wheezing rhinovirus illnesses in early life predict asthma development in high-risk children.
Virus-induced wheezing episodes in infancy often precede the development of asthma. Whether infections with specific viral pathogens confer differential future asthma risk is incompletely understood. To define the relationship between specific viral illnesses and early childhood asthma development. A total of 259 children were followed prospectively from birth to 6 years of age. The etiology and timing of specific viral wheezing respiratory illnesses during early childhood were assessed using nasal lavage, culture, and multiplex reverse transcriptase-polymerase chain reaction. The relationships of these virus-specific wheezing illnesses and other risk factors to the development of asthma were analyzed. Viral etiologies were identified in 90% of wheezing illnesses. From birth to age 3 years, wheezing with respiratory syncytial virus (RSV) (odds ratio [OR], 2.6), rhinovirus (RV) (OR, 9.8), or both RV and RSV (OR , 10) was associated with increased asthma risk at age 6 years. In Year 1, both RV wheezing (OR, 2.8) and aeroallergen sensitization (OR, 3.6) independently increased asthma risk at age 6 years. By age 3 years, wheezing with RV (OR, 25.6) was more strongly associated with asthma at age 6 years than aeroallergen sensitization (OR, 3.4). Nearly 90% (26 of 30) of children who wheezed with RV in Year 3 had asthma at 6 years of age. Among outpatient viral wheezing illnesses in infancy and early childhood, those caused by RV infections are the most significant predictors of the subsequent development of asthma at age 6 years in a high-risk birth cohort.


Evaluation of atpB nucleotide sequences for phylogenetic studies of ferns and other pteridophytes.
Inferring basal relationships among vascular plants poses a major challenge to plant systematists. The divergence events that describe these relationships occurred long ago and considerable homoplasy has since accrued for both molecular and morphological characters. A potential solution is to examine phylogenetic analyses from multiple data sets. Here I present a new source of phylogenetic data for ferns and other pteridophytes. I sequenced the chloroplast gene atpB from 23 pteridophyte taxa and used maximum parsimony to infer relationships. A 588-bp region of the gene appeared to contain a statistically significant amount of phylogenetic signal and the resulting trees were largely congruent with similar analyses of nucleotide sequences from rbcL. However, a combined analysis of atpB plus rbcL produced a better resolved tree than did either data set alone. In the shortest trees, leptosporangiate ferns formed a monophyletic group. Also, I detected a well-supported clade of Psilotaceae (Psilotum and Tmesipteris) plus Ophioglossaceae (Ophioglossum and Botrychium). The demonstrated utility of atpB suggests that sequences from this gene should play a role in phylogenetic analyses that incorporate data from chloroplast genes, nuclear genes, morphology, and fossil data.


A Chemoautotrophically Based Cave Ecosystem
Microbial mats discovered in a ground-water ecosystem in southern Romania contain chemoautotrophic bacteria that fix inorganic carbon, using hydrogen sulfide as an energy source. Analysis of stable carbon and nitrogen isotopes showed that this chemoautotrophic production is the food base for 48 species of cave-adapted terrestrial and aquatic invertebrates, 33 of which are endemic to this ecosystem. This is the only cave ecosystem known to be supported by in situ autotrophic production, and it contains the only terrestrial community known to be chemoautotrophically based.


Maternal obesity and vitamin D sufficiency are associated with cord blood vitamin D insufficiency.
An inverse relationship between total serum 25-hydroxyvitamin D (25-OH D) and increased adiposity has been established in children, adolescents, and adults. However, the relationship between neonatal adiposity and vitamin D status has not been reported. Both maternal obesity and vitamin D deficiency in pregnancy are common and are associated with adverse pregnancy outcomes. The aim of the study was to determine the relationship between vitamin D levels in mothers and newborns, as influenced by maternal obesity, and evaluate these associations with neonatal adiposity. Sixty-one maternal-neonatal pairs participated in this cross-sectional study at an academic medical center. Mothers had a prepregnancy body mass index that was normal or obese. Maternal and cord blood sera were assayed for 25-OH D, and neonatal body composition was measured by air displacement plethysmography. Mothers had similar and sufficient levels of 25-OH D when measured at 36-38 wk gestation, irrespective of body mass index category (normal weight, 46.05, vs. obese, 49.84 ng/ml; P = not significant). However, cord blood 25-OH D was higher in neonates of normal-weight mothers compared to neonates of obese mothers (27.45 vs. 20.81 ng/ml; P = 0.02). The variance in cord blood 25-OH D was explained by four factors: maternal 25-OH D level, the presence of maternal obesity, maternal age, and neonatal adiposity (r(2) = 0.66). Obese women transfer less 25-OH D to offspring than normal-weight women, despite similar serum levels. Cord blood 25-OH D levels directly correlate to neonatal percentage body fat. These novel findings underscore the evolving relationships between maternal obesity, vitamin D nutritional status, and adiposity in the neonatal period that may influence subsequent childhood and adulthood vitamin D-dependent processes.


The epidemiology of Paget's disease in Britain: is the prevalence decreasing?
To estimate changes in the age- and gender-specific prevalence of Paget's disease in Britain, we performed a radiographic survey of the disorder in 10 British centers, using sampling and radiographic methods identical to a study performed in 1974. In each center, a sample of abdominal radiographs of people aged 55 years and over was taken from stored films within the radiology department of the principal general hospital. The radiographs were identified by screening radiographic records over the period 1993-1995. Any abdominal radiograph in a subject aged 55 years and over which included the entire pelvis, sacrum, femoral heads, and all lumbar vertebrae was studied. The radiographs were evaluated by a trained observer and the consultant radiologist who participated in the original 1974 survey. Nine thousand eight hundred and twenty-eight radiographs (4625 men, 5203 women) were assessed in the 10 towns. The overall age/gender standardized prevalence rate was 2%, with a male/female ratio of 1.6. Prevalence increased steeply with age among men and women, rising to 6.9% of men and 5.8% of women aged 85 years and over. The prevalence of Paget's disease in the 10 towns in 1994 was only 40% of that observed during the 1974 study. The decline in prevalence was apparent in all 10 centers, but was most marked in those with high rates in the original study. This survey of Paget's disease in 10 British towns suggests a prevalence of 2.5% among men and 1.6% among women aged 55 years and over. Age-adjusted prevalence rates declined steeply between 1974 and 1994. These declines suggest an environmental contribution to the etiology of this disorder that requires further investigation.


Learning not to feel: reshaping the resolution of tactile perception.
We asked whether biased feedback during training could cause human subjects to lose perceptual acuity in a vibrotactile frequency discrimination task. Prior to training, we determined each subject's vibration frequency discrimination capacity on one fingertip, the Just Noticeable Difference (JND). Subjects then received 850 trials in which they performed a same/different judgment on two vibrations presented to that fingertip. They gained points whenever their judgment matched the computer-generated feedback on that trial. Feedback, however, was biased: the probability per trial of "same" feedback was drawn from a normal distribution with standard deviation twice as wide as the subject's JND. After training, the JND was significantly widened: stimulus pairs previously perceived as different were now perceived as the same. The widening of the JND extended to the untrained hand, indicating that the decrease in resolution originated in non-topographic brain regions. In sum, the acuity of subjects' sensory-perceptual systems shifted in order to match the feedback received during training.


Reward learning and negative emotion during rapid attentional competition.
Learned stimulus-reward associations influence how attention is allocated, such that stimuli rewarded in the past are favored in situations involving limited resources and competition. At the same time, task-irrelevant, high-arousal negative stimuli capture attention and divert resources away from tasks resulting in poor behavioral performance. Yet, investigations of how reward learning and negative stimuli affect perceptual and attentional processing have been conducted in a largely independent fashion. We have recently reported that performance-based monetary rewards reduce negative stimuli interference during perception. The goal of the present study was to investigate how stimuli associated with past monetary rewards compete with negative stimuli during a subsequent attentional task when, critically, no performance-based rewards were at stake. Across two experiments, we found that target stimuli that were associated with high reward reduced the interference effect of potent, negative distractors. Similar to our recent findings with performance-based rewards, our results demonstrate that reward-associated stimuli reduce the deleterious impact of negative stimuli on behavior.


Comparison of text messaging data collection vs face-to-face interviews for public health surveys: a cluster randomized crossover study of care-seeking for childhood pneumonia and diarrhoea in rural China.
To compare text messaging and face-to-face interviews to conduct a survey on childhood diarrhoea and pneumonia. Caregivers of young children able to send text messages in Zhao County in rural China were included in this crossover study. Villages (clusters) were randomized into two groups using the ratio 1:1.6 to account for an expected higher drop-out in group 2. In group 1, participants first completed the face-to-face and then text messaging survey; this order was reversed in group 2. We determined data equivalence of 17 questions that were answered by participants who were the same person in both surveys. For the text messaging survey, we assessed the overall and item response rate. We included 1014 participants between 16 and 28 March 2013: 371 in 15 villages in group 1 and 643 in 27 villages in group 2. A total of 662 (65.3%) out of 1014 participants responded (first text message question) and a significantly higher proportion who did not respond were from rural areas (P = 0.005). Of 651 participants willing to participate, 356 (54.7%) completed the text messaging survey, which was marginally significantly different between the groups (P = 0.05). In total, 409 participants took part in both surveys: 183 in group 1 and 226 in group 2. There was a significantly higher proportion of caregivers from rural areas in Zhao County in the non-responder group compared to the responder group (P = 0.004). Kappas were substantial for six (0.61-0.80), moderate for two (0.58 and 0.60), and fair for three questions (0.31, 0.35 and 0.37). The proportion of agreement was >90% for five questions; 80.0%-90.0% for five questions; 70.0%, 65.0% and 45.5%. The remaining questions had too small numbers to calculate these values. This study shows that text messaging data collection produces data similar to data from face-to-face interviews in a middle-income setting, but the response rate was insufficient for use in public health surveys. Improving the response rate is important, because text message surveys could be of greater value in rural remote areas due to the cost-saving potential.


The human myometrium differentially expresses mTOR signalling components before and during pregnancy: evidence for regulation by progesterone.
Emerging studies implicate the signalling of the mammalian target of rapamycin (mTOR) in a number of reproductive functions. To this date, there are no data regarding the expression of mTOR signalling components in the human myometrium during pregnancy. We hypothesized that mTOR-related genes might be differentially expressed in term or preterm labour as well as in labour or non-labour myometria during pregnancy. Using quantitative RT-PCR we demonstrate for first time that there is a significant downregulation of mTOR, DEPTOR, and Raptor in preterm labouring myometria when compared to non-pregnant tissues taken from the same area (lower segment). We used an immortalized myometrial cell line (ULTR) as an in vitro model to dissect further mTOR signalling. In ULTR cells DEPTOR and Rictor had a cytoplasmic distribution, whereas mTOR and Raptor were detected in the cytoplasm and the nucleus, indicative of mTORC1 shuttling. Treatment with inflammatory cytokines caused only minor changes in gene expression of these components, whereas progesterone caused significant down-regulation. We performed a non-biased gene expression analysis of ULTR cells using Nimblegen human gene expression microarray (n=3), and selected genes were validated by quantitative RT-PCR in progesterone treated myometrial cells. Progesterone significantly down-regulated key components of the mTOR pathway. We conclude that the human myometrium differentially expresses mTOR signalling components and they can be regulated by progesterone. This article is part of a Special Issue entitled 'Pregnancy and Steroids'.


Dynamic demonstration of diffractive optic analog-to-digital converter scheme.
Dynamic behavior of an analog-to-digital converter (ADC) based on diffractive optical element(s) (DOE)(s) was studied and found to be in agreement with predictions. The analog signal was translated to an angular deflection of a laser beam by means of an acousto-optic (AO) cell. The number of bits in this experimental demonstration was three, using an eight-element DOE array. The maximum sample rate was found to be 2.5 MS/s, the limiting factor being the transit time for the acoustic wave across the width of the laser beam in the AO cell. The study is intended as a first dynamic demonstration of a proposed ADC scheme previously demonstrated in a quasi-static version. The full potential of the ADC scheme will require the use of a fast tunable diode laser to replace the AO deflection scheme used here.


Management and outcome of mechanically ventilated neurologic patients.
To describe and compare characteristics, ventilatory practices, and associated outcomes among mechanically ventilated patients with different types of brain injury and between neurologic and nonneurologic patients. Secondary analysis of a prospective, observational, and multicenter study on mechanical ventilation. Three hundred forty-nine intensive care units from 23 countries. We included 552 mechanically ventilated neurologic patients (362 patients with stroke and 190 patients with brain trauma). For comparison we used a control group of 4,030 mixed patients who were ventilated for nonneurologic reasons. None. We collected demographics, ventilatory settings, organ failures, and complications arising during ventilation and outcomes. Multivariate logistic regression analysis was performed with intensive care unit mortality as the dependent variable. At admission, a Glasgow Coma Scale score ≤8 was observed in 68% of the stroke, 77% of the brain trauma, and 29% of the nonneurologic patients. Modes of ventilation and use of a lung-protective strategy within the first week of mechanical ventilation were similar between groups. In comparison with nonneurologic patients, patients with neurologic disease developed fewer complications over the course of mechanical ventilation with the exception of a higher rate of ventilator-associated pneumonia in the brain trauma cohort. Neurologic patients showed higher rates of tracheotomy and longer duration of mechanical ventilation. Mortality in the intensive care unit was significantly (p < .001) higher in patients with stroke (45%) than in brain trauma (29%) and nonneurologic disease (30%). Factors associated with mortality were: stroke (in comparison to brain trauma), Glasgow Coma Scale score on day 1, and severity at admission in the intensive care unit. In our study, one of every five mechanically ventilated patients received this therapy as a result of a neurologic disease. This cohort of patients showed a higher mortality rate than nonneurologic patients despite a lower incidence of extracerebral organ dysfunction.


hsa-miR-96 and hsa-miR-217 Expression Down-Regulates with Increasing Dysplasia in Pancreatic Intraepithelial Neoplasias and Intraductal Papillary Mucinous Neoplasms.
AIM: To compare the clinicopathological features of pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMNs), and to investigate the role of hsa-miR-96 and hsa-miR-217 in these two lesions. Methods: Formalin-fixed paraffin-embedded pancreatic specimens were selected in this study, including 58 cases of pancreatic intraepithelial neoplasias (PanINs), 45 cases of pancreatic ductal adenocarcinomas (PDAs), and 57 cases of intraductal papillary mucinous neoplasms (IPMNs). MiRNAs hsa-miR-96 and hsa-miR-217 were detected using locked nucleic acid in situ hybridization (LNA-ISH) with the NBT/BCIP staining system. The differences in miRNA expression among sample sets were analyzed with the Chi-squared test. Results: PanIN-PDAs were inclined to present with higher rate of invasion (p=0.033), lymph node metastasis (p=0.0004) and poorer differentiation (p<0.001). Of the 45 PDAs, only 2 cases were within AJCC Ⅰstage, while there were 11 cases of IPMN associated carcinomas (p=0.0018). In PanIN-1, PanIN-2 and PanIN-3, the expression of hsa-miR-96 was 91.3% (22/23), 78.6%(12/17) and 22.2%(4/18) respectively, while the expression of hsa-miR-217 was 95.7%(22/23) , 70.6% (12/17) and 27.8% (5/18). In IPMN with low-grade, intermediate-grade, high-grade dysplasia, associated carcinoma, the expression of hsa-miR-96 was 67%(9/13), 64%(7/11), 43%(3/7) and 27%(7/26) respectively, while the expression of hsa-miR-217 was 77%(10/13), 64%(7/11), 29%(2/7) and 38%(10/26). The expression of hsa-miR-96 and hsa-miR-217 in PanIN-1 lesions was not significantly different from that in the normal pancreatic ductal epithelium. However, their expression in PanIN-2/3 lesions was significantly different from that in normal pancreatic ductal epithelium (P<0.01). No difference was observed between PanIN derived adenocarcinomas and IPMN-associated carcinomas. Conclusion: IPMN associated carcinomas were in a statistically earlier stage than PanIN- PDAs at the time of operation. Abnormal expression of hsa-miR-96 and of hsa-miR-217 was observed in premalignant lesions (PanINs and IPMNs) of pancreatic carcinoma and down-regulated with increasing grades of PanINs and IPMNs. These microRNAs may serve as potentially early biomarker and act as tumor suppressor genes.


The palaeontological exhibition: a venue for dialogue.
Understanding the dialogue between museums and their visitors enables museums to subsist, undergo transformations and become consolidated as socially valued cultural venues. The Museo de La Plata (Argentina) was created in the late nineteenth century as a natural history museum, and this study shows that currently the museum is valued socially as a venue for family leisure and education, at which people make sense to the objects exhibited through characteristics conferred upon them by both the institution and the visitor. Nevertheless, such dialogue is somehow affected by the museographic proposal and the public interpretation of the institutional narrative, which could be analysed within the frame of contextual learning. As a consequence, the evolutionary idea that the museum aims to communicate is distorted by the public. This article highlights the importance of considering the visitors' interpretations when planning museum exhibitions, a perspective that has been rather absent in the Argentinian museums.


Systematic Review of the Epidemiological Burden of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Across Europe: Current Evidence and EUROMENE Research Recommendations for Epidemiology.
This review aimed at determining the prevalence and incidence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) in Europe. We conducted a primary search in Scopus, PubMed and Web of Science for publications between 1994 and 15 June 2019 (PROSPERO: CRD42017078688). Additionally, we performed a backward-(reference lists) and forward-(citations) search of the works included in this review. Grey literature was addressed by contacting all members of the European Network on ME/CFS (EUROMENE). Independent reviewers searched, screened and selected studies, extracted data and evaluated the methodological and reporting quality. For prevalence, two studies in adults and one study in adolescents were included. Prevalence ranged from 0.1% to 2.2%. Two studies also included incidence estimates. In conclusion, studies on the prevalence and incidence of ME/CFS in Europe were scarce. Our findings point to the pressing need for well-designed and statistically powered epidemiological studies. To overcome the shortcomings of the current state-of-the-art, EUROMENE recommends that future research is better conducted in the community, reviewing the clinical history of potential cases, obtaining additional objective information (when needed) and using adequate ME/CFS case definitions; namely, the Centers for Disease Control & Prevention-1994, Canadian Consensus Criteria, or Institute of Medicine criteria.


Structural modification of siRNA for efficient gene silencing.
Small interfering RNA (siRNA) holds a great promise for the future of genomic medicine because of its highly sequence-specific gene silencing and universality in therapeutic target. The medical use of siRNA, however, has been severely hampered by the inherent physico-chemical properties of siRNA itself, such as low charge density, high structural stiffness and rapid enzymatic degradation; therefore, the establishment of efficient and safe siRNA delivery methodology is an essential prerequisite, particularly for systemic administration. For an efficient systemic siRNA delivery, it is a critical issue to obtain small and compact siRNA polyplexes with cationic condensing reagents including cationic polymers, because the size and surface properties of the polyplexes are major determinants for achieving desirable in vivo fate. Unfortunately, synthetic siRNA is not easily condensed with cationic polymers due to its intrinsic rigid structure and low spatial charge density. Accordingly, the loose siRNA polyplexes inevitably expose siRNA to the extracellular environment during systemic circulation, resulting in low therapeutic efficiency and poor biodistribution. In this review, we highlight the innovative approaches to increase the size of siRNA via structural modification of the siRNA itself. The attempts include several methodologies such as hybridization, chemical polymerization, and micro- and nano-structurization of siRNA. Due to its increased charge density and flexibility, the structured siRNA can produce highly condensed and homogenous polyplexes compared to the classical monomeric siRNA. As a result, stable and compact siRNA polyplexes can enhance serum stability and target delivery efficiency in vivo with desirable biodistribution. The review specifically aims to provide the recent progress of structural modification of siRNA. In addition, the article also briefly and concisely explains the improved physico-chemical properties of structured siRNA with respect to stability, condensation ability and gene silencing efficiency.


[Surgical and non-surgical treatment of vaginal agenesis: analysis of a series of cases].
This study aimed to evaluate the results of neovaginoplasty by a modified McIndoe-Bannister technique and by the non-surgical Frank technique. This retrospective study was conducted on a convenience sample of 25 women with vaginal agenesis undergoing surgical or conservative treatment at an Infant-Pubertal Gynecology Outpatient Clinic. Data were obtained from the medical records. Fifteen women underwent the surgical McIndoe-Bannister modified technique Surgical Group, and 10 women underwent the non-surgical Frank technique Frank Group. The following parameters were considered for comparative analysis between the two samples: vaginometry, surgical and non-surgical complications, and sexual satisfaction after treatment. Sexual satisfaction was assessed by a simple question: How is your sex life? There were differences related to vaginal length before and after performing exercises in both Frank Group (initial vaginal length 2.4±2.0 cm versus 6.9±1.1 cm after treatment, p<0.0001) and Surgical Group (initial vaginal length 0.9±1.4 cm versus 8.0±0.8 cm after treatment, p<0.0001). Increased vaginal length was observed in Surgical Group compared to Frank Group (Frank Group=7.0±0.9 cm versus Surgical Group=8.0±0.8 cm, p=0.0005). Forty percent of Surgical Group women had surgical complications versus no complications with the Frank technique. All women reported to be satisfied with their sexual life. The present data indicate that both the surgical and Frank techniques are effective for the treatment of vaginal agenesis, resulting in the construction of a vagina that pewrmits sexual intercourse and sexual satisfaction. The favorable aspects of the Frank technique are related to its low cost and to the low rates of major complications.


Patient education to prevent falls among older hospital inpatients: a randomized controlled trial.
Falls are a common adverse event during hospitalization of older adults, and few interventions have been shown to prevent them. This study was a 3-group randomized trial to evaluate the efficacy of 2 forms of multimedia patient education compared with usual care for the prevention of in-hospital falls. Older hospital patients (n = 1206) admitted to a mixture of acute (orthopedic, respiratory, and medical) and subacute (geriatric and neurorehabilitation) hospital wards at 2 Australian hospitals were recruited between January 2008 and April 2009. The interventions were a multimedia patient education program based on the health-belief model combined with trained health professional follow-up (complete program), multi-media patient education materials alone (materials only), and usual care (control). Falls data were collected by blinded research assistants by reviewing hospital incident reports, hand searching medical records, and conducting weekly patient interviews. Rates of falls per 1000 patient-days did not differ significantly between groups (control, 9.27; materials only, 8.61; and complete program, 7.63). However, there was a significant interaction between the intervention and presence of cognitive impairment. Falls were less frequent among cognitively intact patients in the complete program group (4.01 per 1000 patient-days) than among cognitively intact patients in the materials-only group (8.18 per 1000 patient-days) (adjusted hazard ratio, 0.51; 95% confidence interval, 0.28-0.93]) and control group (8.72 per 1000 patient-days) (adjusted hazard ratio, 0.43; 95% confidence interval, 0.24-0.78). Multimedia patient education with trained health professional follow-up reduced falls among patients with intact cognitive function admitted to a range of hospital wards. Trial Registration anzctr.org.au Identifier: ACTRN12608000015347.


How to Construct a Bottom-Up Nomothetic Network Model and Disclose Novel Nosological Classes by Integrating Risk Resilience and Adverse Outcome Pathways with the Phenome of Schizophrenia.
Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data from 40 healthy controls and 80 patients with schizophrenia. Using partial least squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and the phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores.


Climate and predation dominate juvenile and adult recruitment in a turtle with temperature-dependent sex determination.
Conditions experienced early in life can influence phenotypes in ecologically important ways, as exemplified by organisms with environmental sex determination. For organisms with temperature-dependent sex determination (TSD), variation in nest temperatures induces phenotypic variation that could impact population growth rates. In environments that vary over space and time, how does this variation influence key demographic parameters (cohort sex ratio and hatchling recruitment) in early life stages of populations exhibiting TSD? We leverage a 17-year data set on a population of painted turtles, Chrysemys picta, to investigate how spatial variation in nest vegetation cover and temporal variation in climate influence early life-history demography. We found that spatial variation in nest cover strongly influenced nest temperature and sex ratio, but was not correlated with clutch size, nest predation, total nest failure, or hatching success. Temporal variation in climate influenced percentage of total nest failure and cohort sex ratio, but not depredation rate, mean clutch size, or mean hatching success. Total hatchling recruitment in a year was influenced primarily by temporal variation in climate-independent factors, number of nests constructed, and depredation rate. Recruitment of female hatchlings was determined by stochastic variation in nest depredation and annual climate and also by the total nest production. Overall population demography depends more strongly on annual variation in climate and predation than it does on the intricacies of nest-specific biology. Finally, we demonstrate that recruitment of female hatchlings translates into recruitment of breeding females into the population, thus linking climate (and other) effects on early life stages to adult demographics.