Parameter estimation for discretely observed linear birth-and-death processes.

Birth-and-death processes are widely used to model the development of biological populations. Although they are relatively simple models, their parameters can be challenging to estimate, as the likelihood can become numerically unstable when data arise from the most common sampling schemes, such as annual population censuses. A further difficulty arises when the discrete observations are not equi-spaced, for example, when census data are unavailable for some years. We present two approaches to estimating the birth, death, and growth rates of a discretely observed linear birth-and-death process: via an embedded Galton-Watson process and by maximizing a saddlepoint approximation to the likelihood. We study asymptotic properties of the estimators, compare them on numerical examples, and apply the methodology to data on monitored populations.

Dimeric Proanthocyanidins on the Stability of Dentin and Adhesive Biointerfaces.

A dentin biomodification strategy with selective proanthocyanidin (PAC)-enriched extracts reinforces dentin and dentin-resin interfaces. Enrichment of the extracts according to the degree of polymerization allows exploration of bioactive principles of PACs and structure-activity relationships. This study investigated the sustained dentin matrix biomodification and dentin-resin bioadhesion of 2 fractions consisting exclusively of B-type PAC dimers with or without a single galloyl motif (specifically, DIMERG and DIMERNG) and their precursor material, enriched grape seed extract (e-GSE; Vitis vinifera). The biomodification potential was determined by long-term evaluation of the apparent modulus of elasticity and collagen solubility (hydroxyproline release). Chemical characterization of the dentin matrix was performed by attenuated total reflectance-Fourier-transform infrared spectroscopy. The bioadhesive properties were assessed by a microtensile bond strength test at different time points, and macro-hybrid layers were produced to verify the degree of conversion of the adhesive resin. Fractions consisting of DIMERG, DIMERNG, and their precursor, e-GSE, increased the modulus of elasticity at all time points and reduced collagen degradation. Specimens treated with DIMERNG remained stable throughout 12 mo of storage, whereas a significant drop in the modulus of elasticity was observed for the DIMERG and e-GSE groups at 6 mo. The fractions and precursor did not affect the degree of resin conversion at the hybrid layer. Changes in infrared resonances corresponding to collagen cross-links in the dentin matrix occurred for all treatments. Higher bond strength was observed for dentin treated with e-GSE as compared with DIMERG and DIMERNG; all biointerfaces remained stable after 12 mo. Nongalloylated PACs mediate stable dentin biomodification, which includes protective activity against collagen degradation and reinforcement of the anchoring dentin matrix. Collectively, PACs with a higher degree of oligomerization offer a robust bioadhesion between the hydrophilic dentin matrix and the hydrophobic adhesive.

Short-term effects of simulated microgravity on morphology and gene expression in human breast cancer cells.

INTRODUCTION: Microgravity has been shown to impose various effects on breast cancer cells. We exposed human breast cancer cells to simulated microgravity and studied morphology and alterations in gene expression. MATERIALS AND METHODS: Human breast cancer cells were exposed to simulated microgravity in a random positioning machine (RPM) for 24 h. Morphology was observed under light microscopy, and gene alteration was studied by qPCR. RESULTS: After 24 h, formation of three-dimensional structures (spheroids) occurred. BRCA1 expression was significantly increased (1.9×, p < 0.05) in the adherent cells under simulated microgravity compared to the control. Expression of KRAS was significantly decreased (0.6×, p < 0.05) in the adherent cells compared to the control. VCAM1 was significantly upregulated (6.6×, 2.0×, p < 0.05 each) in the adherent cells under simulated microgravity and in the spheroids. VIM expression was significantly downregulated (0.45×, 0.44×, p < 0.05 each) in the adherent cells under simulated microgravity and in the spheroids. There was no significant alteration in the expression of MAPK1, MMP13, PTEN, and TP53. CONCLUSIONS: Simulated microgravity induces spheroid formation in human breast cancer cells within 24 h and alters gene expression toward modified adhesion properties, enhanced cell repair, and phenotype preservation. Further insights into the underlying mechanisms could open up the way toward new therapies.

Likely Transiting Exocomets Detected By Kepler.

We present the first good evidence for exocomet transits of a host star in continuum light in data from the Kepler mission. The Kepler star in question, KIC 3542116, is of spectral type F2V and is quite bright at Kp = 10. The transits have a distinct asymmetric shape with a steeper ingress and slower egress that can be ascribed to objects with a trailing dust tail passing over the stellar disk. There are three deeper transits with depths of ≃ 0.1% that last for about a day, and three that are several times more shallow and of shorter duration. The transits were found via an exhaustive visual search of the entire Kepler photometric data set, which we describe in some detail. We review the methods we use to validate the Kepler data showing the comet transits, and rule out instrumental artefacts as sources of the signals. We fit the transits with a simple dust-tail model, and find that a transverse comet speed of ∼35-50 km s-1 and a minimum amount of dust present in the tail of ∼ 1016 g are required to explain the larger transits. For a dust replenishment time of ∼10 days, and a comet lifetime of only ∼300 days, this implies a total cometary mass of ≳ 3 × 1017 g, or about the mass of Halley's comet. We also discuss the number of comets and orbital geometry that would be necessary to explain the six transits detected over the four years of Kepler prime-field observations. Finally, we also report the discovery of a single comet-shaped transit in KIC 11084727 with very similar transit and host-star properties.

Long-term evaluation of the stability of dentin matrix following treatments with aqueous solutions of titanium tetrafluoride at different concentrations.

OBJECTIVE: The purpose of this study was to investigate the effects of aqueous solutions of different concentrations of titanium tetrafluoride (TiF4) on dentin matrix stability up to six months. DESIGN: Dentin specimens prepared from fifteen nonerupted molars were demineralized and randomly distributed into groups: 2.5% TiF4, 4% TiF4, 1000 ppm NaF, and control (distilled water). The modulus of elasticity (ME) and dry masses of the dentin matrix were determined at baseline, and up to 6 months following treatment. Collagen solubilization was estimated by hydroxyproline (HYP) quantification in the simulated body fluid used to store the dentin specimens. RESULTS: The 2.5% TiF4 group presented higher ME immediately after treatment, and at 3 and 6 months storage, whereas 4% TiF4 showed higher means at 3 and 6 months (p < 0.001). No significant differences were observed among the groups over time (p = 0.9325). However, the 2.5% TiF4 group showed significantly higher ME than the control group, immediately after treatment. All the groups presented significantly higher mass change immediately, compared with 3 and 6 months (p < 0.0001). Except for the 4% TiF4 group, HYP release was higher in the first quarter (p = 0.0152), when no significant differences were found among the groups. In the second quarter, the means were significantly higher in the 2.5% TiF4 and 4% TiF4 groups. The group treated with 2.5% TiF4 had a statistically higher HYP release than the control group. CONCLUSION: An aqueous solution of 2.5% TiF4 increases the immediate stiffness values, but does not stabilize the collagenous dentin matrix.

Vitamin D effects on monocytes' CCL-2, IL6 and CD14 transcription in Addison's disease and HLA susceptibility.

Addison's disease is a rare autoimmune disorder leading to adrenal insufficiency and life-long glucocorticoid dependency. Vitamin D receptor (VDR) polymorphisms and vitamin D deficiency predispose to Addison's disease. Aim of the current study was, to investigate potential anti-inflammatory vitamin D effects on monocytes in Addison's disease, focusing on inflammatory CCL-2 and IL6, as well on monocyte CD14 markers. Addison's disease is genetically linked to distinct HLA susceptibility alleles. Therefore we analyzed, whether HLA genotypes differed for vitamin D effects on monocyte markers. CD14+ monocytes were isolated from Addison's disease patients (AD, n=13) and healthy controls (HC, n=15) and stimulated with 1,25-dihydroxyvitamin D3 and IL1ß as an inflammatory stimulant. Cells were processed for mRNA expression of CCL-2, IL6 and CD14 and DNA samples were genotyped for major histocompatibility class (MHC) class II-encoded HLA- DQA1-DQB1 haplotypes. We found a downregulation of CCL-2 after vitamin D treatment in IL1ß-stimulated monocytes both from AD patients and HC (AD p<0.001; HC p<0.0001). CD14 expression however, was upregulated in both HC and AD patients after vitamin D treatment (p<0.001, respectively). HC showed higher CD14 transcription level than AD patients after vitamin D treatment (p=0.04). Compared to IL1ß-induced inflammation, HC have increased CD14 levels after vitamin D treatment (p<0.001), whereas the IL1ß-induced CD14 expression of AD patients' monocytes did not change after vitamin D treatment (p=0.8). AD patients carrying HLA high-risk haplotypes showed an increased CCL-2 expression after IL1ß-induced inflammation compared to intermediate-risk HLA carriers (p=0.05). Also HC monocytes' CD14 transcription after IL1ß and vitamin D co-stimulation differed according to HLA risk profile. We show that vitamin D can exert anti-inflammatory effects on AD patients' monocytes which may be modulated by HLA risk genotypes.

Biostability of the Proanthocyanidins-Dentin Complex and Adhesion Studies.

Oligomeric proanthocyanidins (OPACs) are potent and renewable natural bioactives possible to be refined into chemically standardized mixtures for biological applications. Herein, we found that multiscale interactions of OPACs with the dentin matrix create tight biointerfaces with hydrophobic methacrylate adhesives on wet surfaces. An enriched mixture of OPACs, with a known phytochemical profile, was produced from grape seed crude extract ( Vitis vinifera; enriched grape seed extract [e-GSE]) and applied to dentin matrices to determine changes to the mechanical properties and biodegradability of the dentin matrix and favorable resin adhesion mechanisms. Methods included a 3-point flexural test, quantification of hydroxyproline (collagen solubilization), static and dynamic nanomechanical analyses, resin-dentin microtensile bond strength, and micropermeability at the adhesive interface. The e-GSE-modified dentin matrix exhibited remarkably low collagen solubilization and sustained the bulk elastic properties over 12 mo. Tan δ findings reveal a more elastic-like behavior of the e-GSE-modified dentin matrix, which was not affected by H-bond destabilization by urea. Dentin-methacrylate biointerfaces with robust and stable adhesion were created on e-GSE-primed dentin surfaces, leading to a dramatic decrease of the interfacial permeability. Standardized OPAC mixtures provide a new mechanism of adhesion to type I collagen-rich tissues that does not rely on hydrophilic monomers. The bioadhesion mechanism involves physicochemical modifications to the dentin matrix, reduced tissue biodegradation, and bridging to methacrylate resins.

Effect of Bioactive Primers on Bacterial-Induced Secondary Caries at the Tooth-Resin Interface.

Secondary caries at the tooth-resin interface is the primary reason for replacement of resin composite restorations. The tooth-resin interface is formed by the interlocking of resin material with hydroxyapatite crystals in enamel and collagen mesh structure in dentin. Efforts to strengthen the tooth-resin interface have identified chemical agents with dentin collagen cross-linking potential and antimicrobial activities. The purpose of the present study was to assess protective effects of bioactive primer against secondary caries development around enamel and dentin margins of class V restorations, using an in vitro bacterial caries model. Class V composite restorations were prepared on 60 bovine teeth (n=15) with pretreatment of the cavity walls with control buffer solution, an enriched fraction of grape seed extract (e-GSE), 1-ethyl-3-(3-dimethyl aminopropyl)-carbodiimide/N-hydroxysuccinimide, or chlorhexidine digluconate. After incubating specimens in a bacterial model with Streptococcus mutans for four days, dentin and enamel were assessed by fluorescence microscopy. Results revealed that only the naturally occurring product, e-GSE, significantly inhibited the development of secondary caries immediately adjacent to the dentin-resin interface, as indicated by the caries inhibition zone. No inhibitory effects were observed in enamel margins. The results suggest that the incorporation of e-GSE into components of the adhesive system may inhibit secondary caries and potentially contribute to the protection of highly vulnerable dentin-resin margins.

Endocrine Control of Exaggerated Trait Growth in Rhinoceros Beetles.

Juvenile hormone (JH) is a key insect growth regulator frequently involved in modulating phenotypically plastic traits such as caste determination in eusocial species, wing polymorphisms in aphids, and mandible size in stag beetles. The jaw morphology of stag beetles is sexually-dimorphic and condition-dependent; males have larger jaws than females and those developing under optimum conditions are larger in overall body size and have disproportionately larger jaws than males raised under poor conditions. We have previously shown that large males have higher JH titers than small males during development, and ectopic application of fenoxycarb (JH analog) to small males can induce mandibular growth similar to that of larger males. What remains unknown is whether JH regulates condition-dependent trait growth in other insects with extreme sexually selected structures. In this study, we tested the hypothesis that JH mediates the condition-dependent expression of the elaborate horns of the Asian rhinoceros beetle, Trypoxylus dichotomus. The sexually dimorphic head horn of this beetle is sensitive to nutritional state during larval development. Like stag beetles, male rhinoceros beetles receiving copious food produce disproportionately large horns for their body size compared with males under restricted diets. We show that JH titers are correlated with body size during the late feeding and early prepupal periods, but this correlation disappears by the late prepupal period, the period of maximum horn growth. While ectopic application of fenoxycarb during the third larval instar significantly delayed pupation, it had no effect on adult horn size relative to body size. Fenoxycarb application to late prepupae also had at most a marginal effect on relative horn size. We discuss our results in context of other endocrine signals of condition-dependent trait exaggeration and suggest that different beetle lineages may have co-opted different physiological signaling mechanisms to achieve heightened nutrient-sensitive weapon growth.

Anoctamin 6 is localized in the primary cilium of renal tubular cells and is involved in apoptosis-dependent cyst lumen formation.

Primary cilia are antenna-like structures projected from the apical surface of various mammalian cells including renal tubular cells. Functional or structural defects of the cilium lead to systemic disorders comprising polycystic kidneys as a key feature. Here we show that anoctamin 6 (ANO6), a member of the anoctamin chloride channel family, is localized in the primary cilium of renal epithelial cells in vitro and in vivo. ANO6 was not essential for cilia formation and had no effect on in vitro cyst expansion. However, knockdown of ANO6 impaired cyst lumen formation of MDCK cells in three-dimensional culture. In the absence of ANO6, apoptosis was reduced and epithelial cells were incompletely removed from the center of cell aggregates, which form in the early phase of cystogenesis. In line with these data, we show that ANO6 is highly expressed in apoptotic cyst epithelial cells of human polycystic kidneys. These data identify ANO6 as a cilium-associated protein and suggest its functional relevance in cyst formation.

Bcl-2 inhibition to overcome memory cell barriers in transplantation.

Memory T cells (Tm) represent a major barrier for immunosuppression and tolerance induction after solid organ transplantation. Taking into consideration the critical role of the intrinsic apoptosis pathway in the generation and maintenance of Tm, we developed a new concept to deplete alloreactive Tm by targeting Bcl-2 proteins. The small-molecule Bcl-2/Bcl-XL inhibitor ABT-737 efficiently induced apoptosis in alloreactive Tm in vitro and in vivo and prolonged skin graft survival in sensitized recipients. A short course of ABT-737 induction therapy prevented Tm-mediated resistance in a donor-specific transfusion model and allowed mixed chimerism induction across Tm barriers. Since Bcl-2 inhibitors yielded encouraging safety results in cancer trials, this novel approach might represent a substantial advance to prevent allograft rejection and induce tolerance in sensitized recipients.

A strong magnetic field around the supermassive black hole at the centre of the Galaxy.

Earth's nearest candidate supermassive black hole lies at the centre of the Milky Way. Its electromagnetic emission is thought to be powered by radiatively inefficient accretion of gas from its environment, which is a standard mode of energy supply for most galactic nuclei. X-ray measurements have already resolved a tenuous hot gas component from which the black hole can be fed. The magnetization of the gas, however, which is a crucial parameter determining the structure of the accretion flow, remains unknown. Strong magnetic fields can influence the dynamics of accretion, remove angular momentum from the infalling gas, expel matter through relativistic jets and lead to synchrotron emission such as that previously observed. Here we report multi-frequency radio measurements of a newly discovered pulsar close to the Galactic Centre and show that the pulsar's unusually large Faraday rotation (the rotation of the plane of polarization of the emission in the presence of an external magnetic field) indicates that there is a dynamically important magnetic field near the black hole. If this field is accreted down to the event horizon it provides enough magnetic flux to explain the observed emission--from radio to X-ray wavelengths--from the black hole.

Lower exposure rates of partially absorbable mesh compared to nonabsorbable mesh for cystocele treatment: 3-year follow-up of a prospective randomized trial.

INTRODUCTION AND HYPOTHESIS: In surgery for pelvic organ prolapse (POP) the use of alloplastic meshes has become common. Among possible complications, mesh exposure is the most frequent problem. It is hypothesized that exposure rates are correlated to mesh weight and the amount of foreign material. Therefore, we conducted a prospective open-label randomized multicenter trial comparing a conventional polypropylene mesh (PP) with a partially absorbable polypropylene mesh (PA) for cystocele treatment. METHODS: A total of 200 patients with POP > stage I were randomized either to a conventional or a partially absorbable mesh. Exposure rates were observed after 3, 12, and 36 months and correlated to mesh material, patient characteristics, intraoperative data, and treatment centers. Furthermore, management of mesh exposure, satisfaction with surgery, and postoperative pain were evaluated. RESULTS: At all follow-up intervals mesh exposure rate was smaller in the group of the partially absorbable mesh (3 months PP 11.3 % vs PA 3.2 %, p=0.0492; 12 months 6.6 % vs 6.3 %; 36 months 7.5 % vs 3.4 %). Over the course of time, mesh exposure was observed in 27 patients, with surgical intervention necessary in 11 patients. The rate of recurrent POP was higher (p>0.05) in patients with the partially absorbable mesh. The majority of patients were fully satisfied with the operation (52.8 %) and had no pelvic floor pain (67.5 %). CONCLUSION: In this prospective, randomized trial with a long-term follow-up there was a low exposure rate in both treatment groups with a trend toward fewer exposures in the group of the partially absorbable mesh.

Treatment of intraarticular middle phalanx fractures using the Ligamentotaxor®.

BACKGROUND: We evaluated the outcome of intraarticular middle phalanx fractures after dynamic treatment with the Ligamentotaxor® system. MATERIALS AND METHODS: Ten consecutive patients (seven male, three female; mean age 52 years) with intraarticular middle phalanx fractures were treated with the Ligamentotaxor® between 2009 and 2011. Proximal interphalangeal joint mobility, grip strength and 'Disabilities of the Arm, Shoulder and Hand' (DASH) score were evaluated in a 15-month follow-up. The reconstitution of the intraarticular space was measured immediately after trauma, at 6 weeks and at 15 months by radiograph control. The severity of the trauma was classified according to AO. RESULTS: We found B1 30 %, C1 (Seno I + II) 50 % and C3 (Seno III-V) 20 %. In 60 % of the cases, fractures were localized on the middle base of the fifth digit, in 20 % on the third digit and in 20 % on the index finger. The dynamic treatment lasted 7 weeks; patients were exposed to full workload after 9 weeks. The mean flexion mobility after 15 months reached 73° (range 60-100°), and the extension deficit was 13° (range 0-20°) on average. Grip strength attained 71.3 % (range 60-87 %) of the contralateral side. Initial x-ray after trauma compared to the x-ray after 15 months showed an intraarticular space reconstitution average of 0.5 mm (range 0.1-0.9 mm) anterior-posterior and 0.6 mm (range 0.1-1 mm) lateral. Patients evaluated their outcome with an average of 14.6 points (range 3.3-26.7) using the DASH score. CONCLUSION: Good results can be obtained with the Ligamentotaxor®. We recommend it for the dynamic treatment of intraarticular middle phalanx finger fractures. Larger series and long-term results are needed.

Resistance to ABT-737 in activated T lymphocytes: molecular mechanisms and reversibility by inhibition of the calcineurin-NFAT pathway.

Dynamic regulation of the intrinsic apoptosis pathway controls central and peripheral lymphocyte deletion, and may interfere with the pro-apoptotic potency of B-cell lymphoma 2 inhibitors such as ABT-737. By following a T-cell receptor (TCR) transgenic population of alloantigen-specific T cells, we found that sensitivity to ABT-737 radically changed during the course of allo-specific immune responses. Particularly, activated T cells were fully resistant to ABT-737 during the first days after antigen recognition. This phenomenon was caused by a TCR-calcineurin-nuclear factor of activated T cells-dependent upregulation of A1, and was therefore prevented by cyclosporine A (CsA). As a result, exposure to ABT-737 after alloantigen recognition induced selection of alloreactive T cells in vivo, whereas in combination with low-dose CsA, ABT-737 efficiently depleted alloreactive T cells in murine host-versus-graft and graft-versus-host models. Thus, ABT-737 resistance is not a prerogative of neoplastic cells, but it physiologically occurs in T cells after antigen recognition. Reversibility of this process by calcineurin inhibitors opens new pharmacological opportunities to modulate this process in the context of cancer, autoimmunity and transplantation.

Oral magnesium supplementation reduces insulin resistance in non-diabetic subjects - a double-blind, placebo-controlled, randomized trial.

The incidence of insulin resistance and metabolic syndrome correlates with the availability of magnesium (Mg). We studied the effect of oral Mg supplementation on insulin sensitivity and other characteristics of the metabolic syndrome in normomagnesemic, overweight, insulin resistant, non-diabetic subjects. Subjects were tested for eligibility using oral glucose tolerance test (OGTT) and subsequently randomized to receive either Mg-aspartate-hydrochloride (n = 27) or placebo (n = 25) for 6 months. As trial endpoints, several indices of insulin sensitivity, plasma glucose, serum insulin, blood pressure and lipid profile were determined. Mg supplementation resulted in a significant improvement of fasting plasma glucose and some insulin sensitivity indices (ISIs) compared to placebo. Blood pressure and lipid profile did not show significant changes. The results provide significant evidence that oral Mg supplementation improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects emphasizing the need for an early optimization of Mg status to prevent insulin resistance and subsequently type 2 diabetes.

Four-digit replantation in a mentally retarded person: a case report.

This report describes a case where 4 digits were replanted in a mentally retarded patient with a history of smoking and the inability to follow postoperative arrangements.

[Limited portal carpal tunnel release. An alternative to classic open release?]. / Die minimal-invasive Karpaltunnelspaltung. Eine Alternative zur klassischen offenen Spaltung?

The aim of this study was to determine the significance of limited portal carpal tunnel release compared to the classic open approach. We present a retrospective comparative clinical trial including 161 patients (105 open release and 56 limited portal release). Special interest was directed towards postoperative functionality, disorders and quality of life. Significant advantages could be demonstrated for the limited portal carpal tunnel release: rapid ability to return to work as well as to routine tasks of daily living and high patient satisfaction. In the hands of trained surgeons, limited portal carpal tunnel release represents a rewarding alternative to the classic open release.

Bony remodelling in unilateral dermatomal cavernous haemangiomatosis of the arm.

We report a case of a massive unilateral dermatomal cavernous haemangioma (UDCH) affecting the left arm and adjacent neck in the region of the C4-C8 dermatomes, with associated bony remodelling. To our knowledge, this is the first report of the rare condition UDCH with bony abnormalities.

Script-driven imagery of self-injurious behavior in patients with borderline personality disorder: a pilot FMRI study.

OBJECTIVE: Self-injurious behavior (SIB) is one of the most distinctive features of borderline personality disorder (BPD) and related to impulsivity and emotional dysregulation. METHOD: Female patients with BPD (n = 11) and healthy controls (n = 10) underwent functional magnetic resonance imaging while listening to a standardized script describing an act of self-injury. Experimental sections of the script were contrasted to the neutral baseline section and group-specific brain activities were compared. RESULTS: While imagining the reactions to a situation triggering SIB, patients with BPD showed significantly less activation in the orbitofrontal cortex compared with controls. Furthermore, only patients with BPD showed increased activity in the dorsolateral prefrontal cortex during this section and a decrease in the mid-cingulate while imagining the self-injurious act itself. CONCLUSION: This pattern of activation preliminary suggests an association with diminished emotion regulation, impulse control as well as with response selection and reappraisal during the imagination of SIB.