Live imaging of cell protrusive activity, and extracellular matrix assembly and remodeling during morphogenesis in the frog, Xenopus laevis.
Cell motility and matrix assembly have traditionally been studied in isolation because of a lack of suitable model systems in which both can be observed simultaneously. With embryonic tissues from the gastrulating frog Xenopus laevis we observe stages of fibronectin fibrillogenesis coincident with protrusive activity in the overlying cells. Using live confocal time-lapse images collected from Cy3-tagged fibronectin and plasma membrane tethered green fluorescent protein, we describe the movement and the elaboration of a complex fibrillar network undergoing topological rearrangements of fibrils on the surface of an embryonic tissue. Discrete processes of annealing, polymerization, stretching, breaking, and recoiling are recorded. Elaboration and maintenance of the complex topology of the extracellular matrix appears to require filamentous actin. These findings support a mechanical-model in which cell tractive forces elaborate the complex topological fibrillar network and are part of a homeostatic mechanism for the regulation of the extracellular matrix.


Community trait overdispersion due to trophic interactions: concerns for assembly process inference.
The expected link between competitive exclusion and community trait overdispersion has been used to infer competition in local communities, and trait clustering has been interpreted as habitat filtering. Such community assembly process inference has received criticism for ignoring trophic interactions, as competition and trophic interactions might create similar trait patterns. While other theoretical studies have generally demonstrated the importance of predation for coexistence, ours provides the first quantitative demonstration of such effects on assembly process inference, using a trait-based ecological model to simulate the assembly of a competitive primary consumer community with and without the influence of trophic interactions. We quantified and contrasted trait dispersion/clustering of the competitive communities with the absence and presence of secondary consumers. Trophic interactions most often decreased trait clustering (i.e. increased dispersion) in the competitive communities due to evenly distributed invasions of secondary consumers and subsequent competitor extinctions over trait space. Furthermore, effects of trophic interactions were somewhat dependent on model parameters and clustering metric. These effects create considerable problems for process inference from trait distributions; one potential solution is to use more process-based and inclusive models in inference.


Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis.
Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals. GLDN encodes gliomedin, a secreted cell adhesion molecule involved in the formation of the nodes of Ranvier. Transmission electron microscopy of the sciatic nerve from one of the affected individuals showed a marked lengthening defect of the nodes. The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay. The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na+ channels at developing nodes. These results indicate a major role of gliomedin in node formation and the development of the peripheral nervous system in humans. These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies.


Contemporary Evaluation and Management of Parathyroid Carcinoma.
Parathyroid carcinoma is a rare malignancy, representing 0.005% of all cancers and 0.5%-1% of all parathyroid disorders. Parathyroid carcinoma occurs equally in males and females, as opposed to primary hyperparathyroidism, which has a female predominance. Patients with parathyroid carcinoma present with symptoms of hypercalcemia, similar to those with benign primary hyperparathyroidism. Parathyroid carcinoma should be suspected when calcium or parathyroid hormone levels are high. Because of the difficulty of discerning parathyroid carcinoma from adenoma preoperatively, the diagnosis of carcinoma is often made only after parathyroidectomy. The goals of surgery are resection with negative margins because surgery represents the only opportunity for cure. Adjuvant therapy with chemotherapy or external beam radiation has not been proven to affect disease-free or overall survival for these patients. Recurrence is common, with reoperation recommended for resectable recurrent disease. Palliation with calcimimetic pharmacotherapy can aid with management of symptomatic hypercalcemia in recurrent or persistent disease after parathyroidectomy. Ultimately, patients succumb to sequelae of hypercalcemia rather than tumor burden.


New approach for the design of an optical square pulse generator.
What is believed to be a new approach for the design and analysis of a reconfigurable optical square pulse generator using the concept of temporal optical integration and the digital signal processing method is presented. The reconfigurable square pulse generator is synthesized using compact active semiconductor-based waveguide technology, and it consists simply of the cascade of a tunable microring resonator (or a tunable all-pole filter) and a tunable asymmetrical Mach-Zehnder interferometer (or a tunable all-zero filter). The reconfigurable generator can convert an input picosecond pulse (i.e., soliton or Gaussian pulse) into an optical square pulse. The pulse width of the generated square pulse can be adjusted by controlling the time delay of a variable delay element in the tunable all-zero filter. The reconfigurable generator can convert an input picosecond pulse train into return-to-zero (RZ) and non-return-to-zero (NRZ) signals with square pulse shapes. The repetition rates of the generated RZ and NRZ signals can be varied by adjusting the bit period of the input picosecond pulse train, the input pulse width, and the time delay of the variable delay element. The effect of the deviation of the parameter values on the generator performance is also studied.


Upregulation of anticoagulant proteins, protein S and tissue factor pathway inhibitor, in the mouse myocardium with cardio-specific TNF-α overexpression.
Heart failure (HF) has been recognized as a hypercoagulable state. However, the natural anticoagulation systems in the failing heart have not been studied. Recent experimental and clinical data have indicated that not only the thrombomodulin (TM)/protein C (PC) pathway but also the protein S (PS)/tissue factor pathway inhibitor (TFPI) system function as potent natural anticoagulants. To investigate the balance between procoagulant and anticoagulant activities in the failing heart, we measured the cardiac expression of tissue factor (TF), type 1 plasminogen activator inhibitor (PAI-1), TM, PC, PS, and TFPI by RT-PCR and/or Western blot analysis in male transgenic (TG) mice with heart-specific overexpression of TNF-α. Both procoagulant (TF and PAI-1) and anticoagulant (PS and TFPI) factors were upregulated in the myocardium of 24-wk-old TG (end-stage HF) but not in that of 4-wk-old TG (early decompensated HF) compared with the wild-type mice. Both factors were also upregulated in the infarcted myocardium at 3 days after coronary ligation in the wild-type mice. The expression of TM was downregulated in the TG heart, and PC was not detected in the hearts. The transcript levels of PS orphan receptors, Mer and Tyro3, but not Axl, were significantly upregulated in the TG heart. Double immunohistochemical staining revealed that myocardial infiltrating CD3-positive T cells may produce PS in the TG myocardium. In conclusion, the PS/TFPI was upregulated in the myocardium of a different etiological model of HF, thus suggesting a role for the PS/TFPI system in the protection of the failing heart under both inflammatory and hypercoagulable states.


Detection of Mild Cognitive Impairment with MEG Functional Connectivity Using Wavelet-Based Neuromarkers.
Studies on developing effective neuromarkers based on magnetoencephalographic (MEG) signals have been drawing increasing attention in the neuroscience community. This study explores the idea of using source-based magnitude-squared spectral coherence as a spatial indicator for effective regions of interest (ROIs) localization, subsequently discriminating the participants with mild cognitive impairment (MCI) from a group of age-matched healthy control (HC) elderly participants. We found that the cortical regions could be divided into two distinctive groups based on their coherence indices. Compared to HC, some ROIs showed increased connectivity (hyper-connected ROIs) for MCI participants, whereas the remaining ROIs demonstrated reduced connectivity (hypo-connected ROIs). Based on these findings, a series of wavelet-based source-level neuromarkers for MCI detection are proposed and explored, with respect to the two distinctive ROI groups. It was found that the neuromarkers extracted from the hyper-connected ROIs performed significantly better for MCI detection than those from the hypo-connected ROIs. The neuromarkers were classified using support vector machine (SVM) and k-NN classifiers and evaluated through Monte Carlo cross-validation. An average recognition rate of 93.83% was obtained using source-reconstructed signals from the hyper-connected ROI group. To better conform to clinical practice settings, a leave-one-out cross-validation (LOOCV) approach was also employed to ensure that the data for testing was from a participant that the classifier has never seen. Using LOOCV, we found the best average classification accuracy was reduced to 83.80% using the same set of neuromarkers obtained from the ROI group with functional hyper-connections. This performance surpassed the results reported using wavelet-based features by approximately 15%. Overall, our work suggests that (1) certain ROIs are particularly effective for MCI detection, especially when multi-resolution wavelet biomarkers are employed for such diagnosis; (2) there exists a significant performance difference in system evaluation between research-based experimental design and clinically accepted evaluation standards.


Goal-setting in geriatric rehabilitation: Can the nursing profession meet patients' needs? A narrative review.
To provide an overview of patients' needs concerning goal-setting, and indications of how those needs can be met by nurses. A narrative review. Pubmed and Cinahl were searched through March 1, 2020 for: patients' experiences concerning goal-setting and the role of nursing in rehabilitation. Additional articles were found through snowballing. A total of 22 articles were reviewed on patients' experiences, and 12 on the nursing role. Patients need to be prepared for collaborating in goal-setting and to receive an explanation about their part in that process. The multiplicity of disciplines may cloud patients' understanding of the process. The nurse's planning of the rehabilitation process should be aimed at resolving this issue. Goals need to be meaningful, and patients need support in attaining them. The interpretive, integrative, and consoling functions of Kirkevold's nursing role are suitable to meet these needs. Both the literature about patients' needs regarding goal-setting and the nursing role make clear that the way nurses work in rehabilitation can gain in clarity. Strengthening the role of nurses will improve the goal-setting process for patients. Interprofessional collaboration, clear work procedures, continuity of care, time and trust, and the physical environment all are important to reinforce this role.


Digital Health Intervention to Increase Health Knowledge Related to Diseases of High Public Health Concern in Iringa, Tanzania: Protocol for a Mixed Methods Study.
Traditionally, health promotion and health education have been provided to communities in the global south in the form of leaflets or orally by health care workers. Digital health interventions (DHIs) such as digital health messages accessed by smartphones have the potential to reach more people at a lower cost and to contribute to strengthening of health care systems. The DHI in this study focuses on disseminating digital health education regarding 3 disease complexes of high public health concern: HIV/AIDS, tuberculosis, and Taenia solium (neuro)cysticercosis or taeniasis, a parasitic zoonotic disease that requires a One Health approach. The DHI presents the participants with animated health videos (animations) and provides access to information spots (InfoSpots) with a free-of-charge digital health platform containing messages about health to rural Tanzanian communities. The objective of this study is to measure the effect of the DHI on health knowledge uptake and retention over time in the rural communities. This is a mixed methods study including a nonrandomized controlled trial and qualitative interviews conducted in rural Tanzania. A health platform containing digital health messages for the communities was developed prior to the study. The health messages consist of text, pictures, quizzes, and animations of everyday stories, aimed at disease prevention and early treatment. The baseline and immediate postintervention assessments were completed in Iringa, Tanzania in May 2019. The participants were interviewed by enumerators and completed questionnaires regarding health knowledge. Participants in the intervention group were exposed to 3 different health animations once on a tablet device. The participants' health knowledge was assessed again immediately after the exposure. The first follow-up survey was undertaken in August 2019. The InfoSpots with the digital health platform were thereafter launched in the intervention villages in November 2019. Qualitative interviews were undertaken in February 2020. The second follow-up was completed in June 2020. A total of 600 participants have been enrolled in the trial. We will assess (1) the difference in knowledge scores between baseline and the immediate postintervention assessments in the intervention group and (2) the difference in knowledge scores between the intervention and control groups at baseline, 3 and 6 months post-DHI rollout. Since a randomized design did not prove feasible, potential confounders (eg, age, gender, education, and time of exposure) may be introduced, and results will be adjusted. Data analysis for the 35 qualitative interviews is currently ongoing, and perspectives and experiences related to use and nonuse of the InfoSpots are being explored. The data have been collected, and the analysis is ongoing in this digital health study, aimed at evaluating the effects of a DHI based on relevant health messages. The publications of results can be expected this year. ClinicalTrials.gov NCT03808597; https://clinicaltrials.gov/ct2/show/NCT03808597. RR1-10.2196/25128.


Hydroxytyrosol from olive fruits prevents blue-light-induced damage in human keratinocytes and fibroblasts.
Skin aging is a complex biological process influenced by a combination of endogenous or intrinsic and exogenous or extrinsic factors due to environmental damage. The primary environmental factor that causes human skin aging is the ultraviolet irradiation from the sun. Recently, it was established that the long-term exposure to light-emitting-diode-generated blue light (LED-BL) from electronic devices seems to have a relevant implication in the molecular mechanisms of premature photoaging. BL irradiation induces changes in the synthesis of various skin structures through DNA damage and overproduction of reactive oxygen species (ROS), matrix metalloproteinase-1 and -12, which are responsible for the loss of the main components of the extracellular matrix of skin like collagen type I and elastin. In the current study, using human keratinocytes and fibroblasts exposed to specific LED-BL radiation doses (45 and 15 J/cm 2 ), we produced an in vitro model of skin photoaging. We verified that, compared with untreated controls, the treatment with LED-BL irradiation results in the alteration of metalloprotease-1 (collagenase), metalloprotease-12 (elastase), 8-dihydroxy-2'-deoxyguanosine, proliferating cell nuclear antigen, and collagen type I. Moreover, we showed that the photoaging prevention is possible via the use of hydroxytyrosol extracted from olive fruits, well known for antioxidant properties. Our results demonstrated that hydroxytyrosol protects keratinocytes and fibroblasts from LED-BL-induced damage. Thus, hydroxytyrosol might be proposed as an encouraging candidate for the prevention of BL-induced premature photoaging.


A kinetic study of the in vivo incorporation of 65ZN into the rat hippocampus.
Previous autoradiographical studies utilizing 65Zn demonstrated an apparent concentration of 65Zn in the mossy fiber boutons of the hippocampus. To examine the speciation of the 65Zn pool found in this neuronal pathway, we investigated the in vivo incorporation of systemic 65Zn into rat hippocampus compared with other brain regions. We were especially interested in kinetically assessing the zinc associated with three previously identified cytosolic zinc-binding species found in the hippocampus. The hypothesis that two of these cytosolic zinc-binding species, a metallothionein-like protein and a putative zinc-glutathione complex, may be responsible for the sequestration of zinc in the hippocampus was tested. It was confirmed that the t 1/2 of hippocampal zinc is longer than other brain regions that were studied. Furthermore, we observed that 65Zn is incorporated into three cytosolic zinc-binding species in the hippocampus as resolved using Ultrogel AcA 34 gel permeation chromatography. One of these species, the putative zinc-glutathione complex, accumulates zinc more slowly than the other species. The data suggest that the putative zinc-glutathione complex may represent an important 65Zn pool in the hippocampus. This finding is in accordance with out hypothesis that a zinc-binding species, specifically, the putative zinc-glutathione complex, may be responsible for the sequestration of zinc in the hippocampal mossy boutons.


A Case Series of Acute Kidney Injury During Anti-tuberculosis Treatment.
Objective The standard anti-tuberculosis (TB) regimen occasionally causes acute kidney injury (AKI). The major etiology is rifampicin-induced acute interstitial nephritis. However, the standard management of AKI induced by anti-TB drugs has yet to be established. Methods We retrospectively reviewed patients with TB who developed AKI after starting standard anti-TB treatment between 2006 and 2016 at a single TB center. The clinical characteristics and the management are described. Results Among 1,430 patients with active TB, 15 (1.01%) developed AKI. The mean age (standard deviation) was 61 years (18). The median (interquartile range) time to AKI development was 45 days (21-54 days). The median serum creatinine level before anti-TB treatment was 0.7 mg/dL (0.5-1.4 mg/dL), whereas the median peak serum creatinine level after AKI onset was 4.0 mg/dL (3.08-5.12 mg/dL). Five patients (33.3%) were pathologically confirmed as having acute interstitial nephritis (AIN), and 7 patients (46.7%) had a clinical diagnosis of the disease. All anti-TB drugs were stopped, and steroids were administered to 5 (100%) patients with pathologically confirmed AIN and 3 (42.8%) patients with clinically diagnosed AIN. The renal function was normalized in 12 patients (80.0%) after restarting anti-TB treatment without rifampicin (n=12) or isoniazid (n=1). Two patients died due to severe renal failure after restarting rifampicin. Conclusion Rifampicin is the leading cause of AKI. Levofloxacin may be an alternative to rifampicin thanks to its safety and potency. Restarting anti-TB treatment without rifampicin and short-term steroid administration may be a feasible management for AKI.


Comparison of oral cefpodoxime proxetil and penicillin V potassium in the treatment of group A streptococcal pharyngitis/tonsillitis. The Cefpodoxime Pharyngitis Study Group.
Ninety-three patients with a diagnosis of acute pharyngitis/tonsillitis due to Streptococcus pyogenes were randomly assigned to receive 100 mg of cefpodoxime proxetil orally with food every 12 hours or 250 mg of penicillin V potassium orally on an empty stomach every six hours. Treatment efficacy was evaluated in 30 cefpodoxime-treated and 33 penicillin-treated patients. After 10 days of treatment, S pyogenes was eradicated from the throat culture in 29 of the 30 cefpodoxime-treated patients and in 30 of the 33 penicillin-treated patients. Twenty days after treatment termination, infection recurred in one patient of each treatment group. Clinical cure or improvement was found in 97% of the patients in each group. Adverse medical events occurred in nine of the 48 cefpodoxime-treated patients and in four of the 45 penicillin-treated patients; these were probably related to the study drug in seven and two patients, respectively. The most common adverse events were nausea (in three cefpodoxime and one penicillin patient) and diarrhea (in three and two). No patient showed colitis related to Clostridium difficile. No clinically significant abnormal laboratory test results were found in either treatment group. It is concluded that cefpodoxime proxetil is as effective and safe as penicillin V potassium in the treatment of pharyngitis due to S pyogenes.


Decreased sensitivity to changes in the concentration of metal ions as the basis for the hyperactivity of DtxR(E175K).
The metal-ion-activated diphtheria toxin repressor (DtxR) is responsible for the regulation of virulence and other genes in Corynebacterium diphtheriae. A single point mutation in DtxR, DtxR(E175K), causes this mutant repressor to have a hyperactive phenotype. Mice infected with Mycobacterium tuberculosis transformed with plasmids carrying this mutant gene show reduced signs of the tuberculosis infection. Corynebacterial DtxR is able to complement mycobacterial IdeR and vice versa. To date, an explanation for the hyperactivity of DtxR(E175K) has remained elusive. In an attempt to address this issue, we have solved the first crystal structure of DtxR(E175K) and characterized this mutant using circular dichroism, isothermal titration calorimetry, and other biochemical techniques. The results show that although DtxR(E175K) and the wild type have similar secondary structures, DtxR(E175K) gains additional thermostability upon activation with metal ions, which may lead to this mutant requiring a lower concentration of metal ions to reach the same levels of thermostability as the wild-type protein. The E175K mutation causes binding site 1 to retain metal ion bound at all times, which can only be removed by incubation with an ion chelator. The crystal structure of DtxR(E175K) shows an empty binding site 2 without evidence of oxidation of Cys102. The association constant for this low-affinity binding site of DtxR(E175K) obtained from calorimetric titration with Ni(II) is K(a)=7.6+/-0.5x10(4), which is very similar to the reported value for the wild-type repressor, K(a)=6.3x10(4). Both the wild type and DtxR(E175K) require the same amount of metal ion to produce a shift in the electrophoretic mobility shift assay, but unlike the wild type, DtxR(E175K) binding to its cognate DNA [tox promoter-operator (toxPO)] does not require metal-ion supplementation in the running buffer. In the timescale of these experiments, the Mn(II)-DtxR(E175K)-toxPO complex is insensitive to changes in the environmental cation concentrations. In addition to Mn(II), Ni(II), Co(II), Cd(II), and Zn(II) are able to sustain the hyperactive phenotype. These results demonstrate a prominent role of binding site 1 in the activation of DtxR and support the hypothesis that DtxR(E175K) attenuates the expression of virulence due to the decreased ability of the Me(II)-DtxR(E175K)-toxPO complex to dissociate at low concentrations of metal ions.


Comparative studies on the modes of action of the antirhinovirus agents Ro 09-0410, Ro 09-0179, RMI-15,731, 4',6-dichloroflavan, and enviroxime.
Modes of action of five antirhinovirus agents were compared. Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 were active preferentially against human rhinovirus. Serotypes of the virus varied in their susceptibility to these three agents, whereas Ro 09-0179 and enviroxime showed activity against all the serotypes of the virus tested to date. Ro 09-0410, RMI-15,731, and 4',6-dichloroflavan inactivated the virus directly, although 4',6-dichloroflavan did so only slightly. Inactivation by 4',6-dichloroflavan and RMI-15,731 was associated with the binding of the agents to the virus, since the infectivity, reduced by exposure to the agents, was restored to the original level by extraction of the agents with chloroform. The binding of [3H]Ro 09-0410 to human rhinovirus type 2 was inhibited by unlabeled Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 but not by Ro 09-0179 or enviroxime. Furthermore, subtypes resistant to both 4',6-dichloroflavan and RMI-15,731 showed cross-resistance to Ro 09-0410 and vice versa. On the other hand, sublines resistant to these three agents were not cross-resistant to Ro 09-0179 or enviroxime. These results indicate (i) that Ro 09-0410, 4',6-dichloroflavan, and RMI-15,731 exert their activities through the same mode of action, namely, binding to or interaction with some specific site on the viral capsid protein, and (ii) that the binding or interaction sites for these three agents are either the same or very close to each other.


Quercetin Decreases Corneal Haze In Vivo and Influences Gene Expression of TGF-Beta Mediators In Vitro.
We have previously reported the flavonoid, quercetin, as a metabolic regulator and inhibitor of myofibroblast differentiation in vitro. Our current study evaluated the effects of topical application of quercetin on corneal scar development using two different animal models followed by RNA analysis in vitro. Wild-type C57BL/6J mice were anesthetized and the corneal epithelium and stroma were manually debrided, followed by quercetin (0.5, 1, 5, or 50 mM) or vehicle application. Corneal scarring was assessed for 3 weeks by slit lamp imaging and clinically scored. In a separate animal study, six New Zealand White rabbits underwent lamellar keratectomy surgery, followed by treatment with 5 mM quercetin or vehicle twice daily for three days. Stromal backscattering was assessed at week 3 by in vivo confocal microscopy. In mice, a single dose of 5 mM quercetin reduced corneal scar formation. In rabbits, stromal backscattering was substantially lower in two out of three animals in the quercetin-treated group. In vitro studies of human corneal fibroblasts showed that quercetin modulated select factors of the transforming growth factor-β (TGF-β) signaling pathway. These results provide evidence that quercetin may inhibit corneal scarring. Further studies in a larger cohort are required to validate the efficacy and safety of quercetin for clinical applications.


Dispersions of nanoclays of different shapes into aqueous and solid biopolymeric matrices. Extended physicochemical study.
Dispersions of nanofillers into aqueous and solid biopolymeric matrices were studied from the physicochemical viewpoint. This work was carried out based on the idea that the combination of biopolymers, derived from renewable resources, and nanofiller, environmentally friendly, may form a new generation of nanomaterials with excellent and unique properties at low cost. To this purpose, two pectins with different degrees of methyl esterification and nanoclays like halloysite and laponite RD were selected. The thermodynamic and structural studies on the aqueous mixtures of pectin and nanoclay were able to discriminate the interactions, which control the adsorption of pectin onto the filler and the aggregation of both pectin and clay particles. The gained insights were useful to interpret the mesoscopic structure of the nanocomposites (prepared from the aqueous mixtures by means of the casting method) evidenced by SEM, thermal stability, tensile properties, and transparency investigations. The attained knowledge represents a basic point for designing new hybrid nanostructures in both the aqueous and the solid phase for specific purposes.


[Classification of temporomandibular joint disorders].
The classification of TMD is hindered by limited knowledge of the cause and natural progression of these disorders. However, advancement in our knowledge must be conducted and is dependent upon an accepted taxonomy and correspondent criteria. The presented criteria are an attempt to improve clarity of definitions and operationalize the criteria. These criteria are intended for use by the clinician in the daily practice of diagnosing and treating TMD. They are to be used with good clinical judgement in the evaluation of individual patients suffering from TMD.


Maternal zinc supplementation during pregnancy affects autonomic function of Peruvian children assessed at 54 months of age.
Maternal prenatal zinc supplementation improved fetal autonomic regulation in a nutrient-deficient population in Peru. To evaluate whether differences in autonomic regulation existed in early childhood, we studied 165 children from a zinc supplementation trial (80% of original sample) as part of a comprehensive evaluation at age 54 mo. Electrocardiogram (ECG) data were collected from the children at rest and while they underwent a cognitive testing battery following a standardized protocol. Of these, 79 were born to mothers receiving 25 mg/d zinc in addition to 60 mg/d iron and 250 μg/d folic acid during pregnancy, and 86 were born to mothers receiving iron and folic acid only. Derived cardiac measures included heart period (HP), range, HP variability (HPV), mean square of successive differences (MSSD), and a measure of vagal tone (V). Children in the zinc supplementation group had greater HP (i.e. slower heart rate), greater range, higher time-independent (HPV) and time-dependent (MSSD) variability in HP, and higher V (P < 0.05) during baseline. Analyses conducted across the cognitive testing period revealed similar effects of prenatal zinc supplementation on cardiac patterns. Concurrent child zinc plasma concentration was also associated with longer HP, greater variability, and marginally higher range and V (P < 0.10). Differences in cardiac patterns due to prenatal zinc supplementation were detectable in children at 54 mo of age during conditions of both rest and challenge, indicating that supplementing zinc-deficient pregnant women has beneficial long-term consequences for neural development associated with autonomic regulation.


Toad Poisoning: Clinical Characteristics and Outcomes.
This study was performed to describe the clinical characteristics and outcomes of patients with toad poisoning in Thailand. We carried out a retrospective study of patients with toad poisoning from the Ramathibodi Poison Center Toxic Exposure Surveillance System during a 5-year period (2012-2016). We studied 36 patients poisoned by toad toxin. The median age was 31 years. Most patients were male (66.7%) and had ingested toad meat (50%). The most common presentation was gastrointestinal (GI) symptoms with a median onset of 2 h after ingestion. Twelve patients presented with bradycardia; seven presented with shock and one with cardiac arrest. In the initial EKGs of all patients, the most common abnormality was sinus bradycardia.Two patients developed cardiac arrest early during management in the emergency room (within 15 minutes after ER arrival or within 4.5 h after ingestion). During admission, one patient developed sinus bradycardia, and two developed bradyarrhythmia; however, all three were stable. No tachyarrhythmias such as ventricular tachycardia were detected in any patient. Some patients (11.1%) presented with hyperkalemia. Serum digoxin was detected in five of seven patients tested, ranging from 0.43 to >8 ng/mL. Most patients (75%) were admitted to the hospital; the median duration of hospitalization was 2 d (range 0.5-5 d). The overall mortality rate was 8.3%, and all three patients that died ate toad meat and/or eggs and developed cardiac arrest. All patients received supportive with/without symptomatic care including GI decontamination, inotropic drugs, cardiac pacing, and management of hyperkalemia. One patient received intravenous calcium for hyperkalemia but did not develop dysrhythmia after calcium administration. One patient received digoxin-specific antibody fragments (DsFab), after which he clinically improved and was discharged. Toad poisoning commonly caused GI symptoms and bradycardia. However, in severe cases, death occurred. Tachyarrhythmia was not observed. Supportive, symptomatic care might be the main therapies for this poisoning, especially if DsFab is not available.


Paediatric Strategy Forum for medicinal product development of chimeric antigen receptor T-cells in children and adolescents with cancer: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.
The seventh multi-stakeholder Paediatric Strategy Forum focused on chimeric antigen receptor (CAR) T-cells for children and adolescents with cancer. The development of CAR T-cells for patients with haematological malignancies, especially B-cell precursor acute lymphoblastic leukaemia (BCP-ALL), has been spectacular. However, currently, there are scientific, clinical and logistical challenges for use of CAR T-cells in BCP-ALL and other paediatric malignancies, particularly in acute myeloid leukaemia (AML), lymphomas and solid tumours. The aims of the Forum were to summarise the current landscape of CAR T-cell therapy development in paediatrics, too identify current challenges and future directions, with consideration of other immune effector modalities and ascertain the best strategies to accelerate their development and availability to children. Although the effect is of limited duration in about half of the patients, anti-CD19 CAR T-cells produce high response rates in relapsed/refractory BCP-ALL and this has highlighted previously unknown mechanisms of relapse. CAR T-cell treatment as first- or second-line therapy could also potentially benefit patients whose disease has high-risk features associated with relapse and failure of conventional therapies. Identifying patients with very early and early relapse in whom CAR T-cell therapy may replace haematopoietic stem cell transplantation and be definitive therapy versus those in whom it provides a more effective bridge to haematopoietic stem cell transplantation is a very high priority. Development of approaches to improve persistence, either by improving T cell fitness or using more humanised/fully humanised products and co-targeting of multiple antigens to prevent antigen escape, could potentially further optimise therapy. Many differences exist between paediatric B-cell non-Hodgkin lymphomas (B-NHL) and BCP-ALL. In view of the very small patient numbers with relapsed lymphoma, careful prioritisation is needed to evaluate CAR T-cells in children with Burkitt lymphoma, primary mediastinal B cell lymphoma and other NHL subtypes. Combination trials of alternative targets to CD19 (CD20 or CD22) should also be explored as a priority to improve efficacy in this population. Development of CD30 CAR T-cell immunotherapy strategies in patients with relapsed/refractory Hodgkin lymphoma will likely be most efficiently accomplished by joint paediatric and adult trials. CAR T-cell approaches are early in development for AML and T-ALL, given the unique challenges of successful immunotherapy actualisation in these diseases. At this time, CD33 and CD123 appear to be the most universal targets in AML and CD7 in T-ALL. The results of ongoing or planned first-in-human studies are required to facilitate further understanding. There are promising early results in solid tumours, particularly with GD2 targeting cell therapies in neuroblastoma and central nervous system gliomas that represent significant unmet clinical needs. Further understanding of biology is critical to success. The comparative benefits of autologous versus allogeneic CAR T-cells, T-cells engineered with T cell receptors T-cells engineered with T cell receptor fusion constructs, CAR Natural Killer (NK)-cell products, bispecific T-cell engager antibodies and antibody-drug conjugates require evaluation in paediatric malignancies. Early and proactive academia and multi-company engagement are mandatory to advance cellular immunotherapies in paediatric oncology. Regulatory advice should be sought very early in the design and preparation of clinical trials of innovative medicines, for which regulatory approval may ultimately be sought. Aligning strategic, scientific, regulatory, health technology and funding requirements from the inception of a clinical trial is especially important as these are very expensive therapies. The model for drug development for cell therapy in paediatric oncology could also involve a 'later stage handoff' to industry after early development in academic hands. Finally, and very importantly, strategies must evolve to ensure appropriate ease of access for children who need and could potentially benefit from these therapies.


Ruptured breast implant removal because of patient anxiety in the absence of breast implant-associated anaplastic large cell lymphoma.
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) has been regarded as a long-term problem after silicone breast implantations. We report a case in which BIA-ALCL and breast cancer were not detected preoperatively, with subsequent removal of a ruptured breast implant. A 52-year-old woman had silicone breast implants on both sides for breast augmentation 15 years ago. Right axillary lymphadenopathy and intracapsular ruptures were noted by magnetic resonance imaging. Right axillary lymph node biopsy was performed at our department of breast surgery. Flow cytometry for BIA-ALCL was also performed using the exudate around the implant. The results were negative for breast cancer and BIA-ALCL. However, taking into consideration exacerbation of breast implant rupture and the patient's anxiety about BIA-ALCL, ruptured bilateral implants were removed by total capsulectomy. The postoperative course was uneventful 1 year after the operation, and her anxiety was dispelled despite her breast deformity. Appropriate explantation and periodic examination may be required to prevent excessive anxiety.


Reassessment of the toxicity of Hypericum perforatum (St John's wort) for cattle.
To investigate the clinical effect of administering sufficient Hypericum perforatum to cattle to deliver quadruple the reported oral toxic dose. Thirty-six yearling Hereford (n = 18) and Angus (n = 18) steers. A series of six experiments was conducted, each using 12 animals in a 2 x 2 factorial design, with two breeds of cattle (Hereford, Angus) and two dose levels of hypericin, 1.5 mg/kg (treated group) and 0 mg/kg (control group). Each set of 12 steers was used in duplicate experiments, with all animals alternated between treated and control groups. Treated groups received finely milled H. perforatum administered orally in gelatin capsules to provide 1.5 mg hypericin/kg body weight. All cattle were then exposed to direct sunlight for 5 h per day for 5 successive days. Rectal temperatures were measured immediately before and at the end of each sunlight exposure session. Rectal temperature above 40 degrees C, together with some other clinical sign of hypericin poisoning, was considered indicative of intoxication. No animals developed a rectal temperature above 40 degrees C or other clinical signs of hypericin poisoning. While the reported bovine oral toxic dose of 3 g dried plant/kg body weight, for flowering stage, presumed narrow leaved biotype, H. perforatum, is probably correct, the corresponding dose for hypericin of 0.37 mg/kg is incorrect. Based on its known concentration in this plant the toxic dose of hypericin for partially pigmented Hereford-cross cattle is estimated at about 10.5 mg/kg body weight and more than this for fully pigmented cattle. This would imply that cattle of the former type should be about three and a half times better protected against H. perforatum toxicity than are unpigmented, wool protected, Merino sheep. Cattle, particularly if fully pigmented, may have a role in grazing management to control H. perforatum.


Comparison of chest HRCT severity score in PCR positive and PCR negative clinically suspected COVID-19 Patients.
The limitations and false-negative results of Real-time Polymerase chain reaction (RT PCR) in diagnosing COVID-19 infection demand the need for imaging modalities such as chest HRCT to improve the diagnostic accuracy and assess the severity of the infection. The study aimed to compare the chest HRCT severity scores in RT-PCR positive and negative cases of COVID-19. This cross-sectional study included 50 clinically suspected COVID-19 patients. Chest HRCT and PCR testing of all 50 patients were done and the chest HRCT severity scores for each lung and bronchopulmonary segments were compared in patients with positive and negative PCR results. Chi-square and Mann Whitney U test were used to assess differences among study variables. Chest HRCT severity score was more in PCR negative patients than in those with PCR positive results. However, the difference was not significant (p=0.11). There was a significant association in severity scores of the anterior basal segment of the left lung (p=0.022) and posterior segment upper lobe of right lung (p=0.035) with PCR results. This association was insignificant for other bronchopulmonary segments (p>0.05). CR negativity does not rule out infection in clinically suspected COVID-19 patients. The use of chest HRCT helps to determine the extent of lung damage in clinically suspected patients irrespective of PCR results. Guidelines that consider clinical symptoms, chest HRCT severity score and PCR results for a confirmed diagnosis of COVID-19 in suspected patients are needed.


Tenascin is an ubiquitous extracellular matrix protein of human renal interstitium in normal and pathologic conditions.
Tenascin, a large oligomeric glycoprotein, is a recent addition to a list of increasing extracellular matrix proteins. Previous studies have documented the strong expression of tenascin in embryonic kidney and in both normal and abnormal mature glomeruli implicating an important role of this extracellular matrix protein in nephrogenesis and glomerular scarring. Whether tenascin plays any role in interstitial fibrosis, a common final pathway of tubulointerstitial nephritis, is no known; on the other hand, a detailed knowledge of the structural components of interstitial fibrosis is essential for further studies on other fundamental aspects of this biologically and clinically important process. In this study, the expression of tenascin in the renal interstitium was immunohistochemically evaluated in 208 renal specimens during normal kidney (23 cases), acute tubular necrosis (8), acute tubulointerstitial nephritis (8), chronic primary tubulointerstitial nephritis (30), tubulointerstitial nephritis secondary to glomerular diseases of mild (46) and severe (55) degree, ischemic damage (24), and rejection (14). It was found that in normal kidney tenascin expression was limited to the medullary interstitium. In kidney with tubulointerstitial nephritis, tenascin was ubiquitously and constantly expressed in any areas with tubulointerstitial damage regardless of diagnosis, etiology, the cortical vs. medullary location of the lesions, stage of the fibrogenetic process, density of fibroblasts, or severity of interstitial inflammation in the affected areas. Indeed, strong tenascin expression was seen in areas where there was only interstitial edema or inflammation as judged by routine light microscopic preparations. In summary, this study systematically documents tenascin as a novel extracellular matrix protein selectively expressed in the medullary interstitium in normal kidney, and ubiquitously present in areas with interstitial fibrosis.


The importance of positive bacterial cultures of specimens obtained during clean orthopaedic operations.
Microbiological cultures of specimens of tissue and of fluids from the wound in forty patients who had had consecutive clean, elective orthopaedic operations (excluding total joint replacements) and had not received antibiotics preoperatively were analyzed. Of the forty patients, twenty-three (58 per cent) had a positive culture on at least one of the media that were used and seventeen (43 per cent) had negative cultures. Of the forty specimens that were obtained from swabbing of the wound, eight (20 per cent) were positive on culture, compared with twenty (50 per cent) that were obtained from biopsy of tissue. Of these twenty-eight positive cultures, thirteen (46 per cent) were on routine blood-agar plates and fifteen (54 per cent), in broth only. Of the thirty-three bacterial organisms that were identified in the twenty-eight positive cultures of the wound, nineteen (58 per cent) were coagulase-negative Staphylococcus; eight (24 per cent), Propionibacterium acnes; two (6 per cent), Peptostreptococcus; and four (12 per cent), miscellaneous organisms. In all of the positive cultures on the blood-agar plates, except in those showing Propionibacterium acnes, there were five colonies or fewer. One patient had a clinical infection with Staphylococcus aureus that developed later, but the initial cultures of the wound had been positive for Staphylococcus epidermidis only. None of the bacteria that grew on culture were Staphylococcus aureus or the less common pathogenic gram-negative bacteria, such as Escherichia coli, Pseudomonas, or Klebsiella.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical experience with the delay phenomenon in autologous breast reconstruction with the deep inferior epigastric artery perforator flap.
The delay phenomenon has been used for breast reconstruction with pedicled flaps but has not been widely reported with free flaps. Our goals were to (1) describe our operative technique for vascular delay of deep inferior epigastric artery perforator (DIEP) flaps when a large percentage of the contralateral hemiabdomen would be needed for added volume of a breast reconstruction, (2) document any clinical improvement in flap vascularization after the delay period, and (3) develop a patient selection algorithm for this procedure. From August 2008 through July 2009, six patients at The Johns Hopkins Breast Center underwent autologous breast reconstruction with vascularly delayed DIEP flaps, a technique that preserves lateral skin bridges to the flap. This technique was used based on preoperative three-dimensional computed tomography angiograms showing potential vascular compromise. We assessed length of delay, flap weight, length of stay, and outcome. Transfer delay averaged 15.8 ± 4.1 days from the original surgery. Transferred flap weight averaged 620.2 ± 156.7 g. The flaps in all six patients developed adequate arterial inflow and/or venous drainage on reassessment at final transfer. Preoperative screening with three-dimensional computed tomography angiography of the abdominal wall and modification of the flap harvest technique, including use of the clamp test to establish need for delay, were thought to be paramount for patient selection. In a very select group of patients undergoing breast reconstruction whose DIEP flaps showed vascular compromise before detachment, the delay phenomenon successfully enhanced vascularity and prevented fat necrosis.


Management of early acute renal failure: focus on post-injury prevention.
In this review, we describe our current understanding of various aspects of secondary renal injury and its prevention. Secondary renal injury indicates any injury to the kidney, which occurs after an initial event has already triggered injury to the organ. Analysis of the literature reveals several important fields of possible intervention. First, blood pressure is considered important and hypotension is associated with renal injury. Avoiding hypotension is an important mechanism of renal protection from secondary injury. Similarly, a low cardiac output state should be promptly treated or prevented. Adequate volume resuscitation is also considered important although strong direct evidence for this intervention is not available. There is insufficient evidence to suggest that any drug can specifically increase renal blood flow in man independent of an effect on blood pressure or cardiac output. Specific kidney protective approaches have not yet been identified. Intensive insulin therapy possibly delivers renal protection and deserves further investigation. Modulation of the stress response appears attractive in experimental models but it has not been shown effective in man. Ischemic preconditioning is a useful strategy for renal protection in the experimental setting. An understanding of the mechanisms involved in ischemic preconditioning might assist in developing novel and effective interventions in man. The pillars of protection from secondary renal injury are similar to those needed to protect the kidney from primary injury: maintenance of adequate intravascular volume, cardiac output, and arterial blood pressure. Novel protective strategies such as intensive insulin therapy require further investigation.


Family impact of child oral and oro-facial conditions.
The aim of this study was to develop and evaluate the Family Impact Scale, a measure of the family impact of child oral and oro-facial disorders. This formed one component of the Child Oral Health Quality of Life Instrument. The scale was developed using a process described by Guyatt et al. (1987) and Juniper et al. (1996). An item pool was developed using a review of existing child health status and family impact questionnaires, interviews with 41 parents-caregivers of children with paedodontic, orthodontic and oro-facial conditions and discussions with dental specialists. The resulting pool of 21 items was used in an item impact study in which 93 parents-caregivers provided data on the frequency and importance of these items. The 14 items identified most frequently or rated the most important were selected for the final questionnaire. The discriminant and construct validity and internal consistency reliability of this 14-item scale were assessed in a study of 266 parents-caregivers from the three clinical groups. Seventy-nine of these participants completed a second copy of the questionnaire to facilitate assessment of test-retest reliability. Family Impact Scale scores ranged from 0 to 33, indicating that the measure was sensitive to variations in family impact. Floor effects were minimal with only 10.2% of subjects having a score of zero and there were no ceiling effects, that is, subjects with maximum scores. Almost three-quarters of parents-caregivers reported some family impact 'sometimes' or 'often/everyday' over the previous 3 months. Impact on parental or family activities of this frequency was reported by 53.0%, impact on parental emotions by 44.0%, conflict in the family by 31.6% and financial difficulties by 31.2%. The measure and its component items were reasonably good at discriminating between the three clinical groups included in the study and showed good construct validity. It had excellent internal consistency reliability with a Cronbach's alpha of 0.83 and was reproducible for parent-caregivers who reported that their child's condition was stable (ICC = 0.80). The study provides some data to suggest that child oral and oro-facial conditions have a pervasive impact on the family. The Family Impact Scale had good technical properties. Its evaluative properties need to be tested in longitudinal studies.


THE FREQUENCY OF RISK FACTORS ON TRENDS OF PANCREATIC CANCER IN KOSOVO.
The aim of this paper is to analyze different factors that influence the trends of pancreatic cancer mortality and morbidity of patients treated at the UCCK of Kosovo. Within this study, we have evaluated pancreatic cancer risk factors, durability and lethality regarding Kosovan patients who have been diagnosed and treated within Kosovo. The study in question is that of retrospective research traversing the period of 2011-2015. This retrospective research study includes 362 patients recently diagnosed with pancreatic cancer, 2011-2015 at the University Clinical Center of Kosovo in Pristina. The main important factors included in this study are: age, sex and risk factors that altogether have considerable influence in incidence of pancreatic cancer. The imaging diagnostics are performed with the use of 2D ECHO Phillips, MSCT Sensation 64 and 6 and 1.5T MRI Symphony Siemens that are situated in the Radiologic Clinic of UCCK. The statistic data were obtained from NIPH of Kosovo and Agency of Statistics of Kosovo. Out of the total number of the 362 patients diagnosed with pancreatic cancer, the mortality in all age groups was higher at male patients-61.6 % of cases (n=223) with the highest number found at 51-60 years age group. The 38.4 % (n= 139) were female patients with the highest incidence frequency at F 61-70 years age group. The F/M ratio is 1:1.6. The "plane" nicotine users were found at 34 % (n=123) while the joined, nicotine/alcohol addiction was detected at 26 % (n= 94). The 18.5% (n=67) have had established diagnose of the diabetes mellitus tip II and 9.6 % (n=35) have undergone the medical treatment of the gastroduodenal peptic ulcerations. The total number of deaths is 310 (85.6%) and there are only 52 patients (14.4%) still alive. The mortality rate of the pancreatic cancer in Kosovo was 17.2 in 100.000 residents while the morbidity rate was 2.8 in 100.000 residents. This retrospective research study intends to present the role of the risk factor, that influence the mortality and morbidity of the pancreatic cancer in Kosovo and finally, to compare these results with similar studies abroad with aim to prevent the pancreatic cancer. The analyses of the obtained statistical data shows that the nicotine addiction play important role in incidence of the pancreatic cancer as well as alcohol addiction, presence of the diseases such are diabetes mellitus tip II and gastroduodenal peptic ulcers.


Tumor cell-derived extracellular vesicles for breast cancer specific delivery of therapeutic P53.
Breast cancer has consistently had the highest incidence among women in the world. Tumor cell-derived extracellular vesicles (EV) have been leveraged as drug carriers for cancer treatment. Herein, we developed an efficient theranostic platform for breast cancer-specific delivery of lipophilic triphenylphosphonium (TPP)-modified therapeutic recombinant P53 proteins (TPP/P53) by breast cancer cell-derived EVs. We observed that the EVs were routinely captured by their patent cells, so when, TPP/P53 was loaded into the EVs (TPP/P53@EVs), TPP/P53 was targeted to the mitochondria of breast cancer cells, where it caused signal amplification and induced the death of breast cancer cells. Our findings demonstrated that the TPP/P53@EVs showed good tumor-targeting capability and efficiently destroyed the tumor tissues without any obvious toxicity in vivo. Therefore, our TPP/P53@EVs might provide a "drug-free" strategy for future applications in breast cancer therapy.


Activation of N2O reduction by the fully reduced micro4-sulfide bridged tetranuclear Cu Z cluster in nitrous oxide reductase.
The tetranuclear CuZ cluster catalyzes the two-electron reduction of N2O to N2 and H2O in the enzyme nitrous oxide reductase. This study shows that the fully reduced 4CuI form of the cluster correlates with the catalytic activity of the enzyme. This is the first demonstration that the S = 1/2 form of CuZ can be further reduced. Complementary DFT calculations support the experimental findings and demonstrate that N2O binding in a bent mu-1,3-bridging mode to the 4CuI form is most efficient due to strong back-bonding from two reduced copper atoms. This back-donation activates N2O for electrophilic attack by a proton.


Effects of a cross-training exercise program in persons with osteoarthritis of the knee a randomized controlled trial.
This study was designed to evaluate, by means of a randomized controlled trial, the effects of a physical activity program incorporating aerobic, strength, and stretching exercises in individuals with osteoarthritis of the knee. We randomly assigned 137 volunteers ages >/=50 to an experimental group or a control group. The experimental group participated in three 1-hour sessions of supervised exercises per week over a 3-month period. The control participants were instructed to continue their usual daily activities, and they attended 1-hour education sessions twice a month. The effectiveness of the program was evaluated using repeated measurements of parameters related to self-reported health status, physical capacity, and joint tenderness.After 3 months, significantly greater improvements were observed in the experimental group than the control group in terms of: arthritis pain (p = 0.02), ability to walk and bend (p = 0.03), aerobic capacity (p < 0.0001), hamstring and low back flexibility (p = 0.003), quadriceps and hamstring strength (p <0.01), and the perception of changes relating to osteoarthritis of the knee and general condition (p < 0.0001). However, no significant differences were observed between the groups in isokinetic strength of the quadriceps (all p's >== 0.05), joint tenderness (p = 0.18), and health perception (p = 0.7). The overall results suggest that this program is effective for older persons with osteoarthritis of the knee and that it could contribute to maintaining their independence and improving their quality of life.


Ultrastructural analysis, zinc transporters, glucose transporters and hormones expression in New world primate (Callithrix jacchus) and human pancreatic islets.
The New world primates (NWP) Callithrix jacchus separated from man approximately 50 million years ago and is a potential alternative small non-human primate model for diabetes research. Ultrastructure, and gene expression of pancreatic islets and the recently described diabetes auto antigenic zinc transporters families in human, NWP and pig pancreas were studied. Morphologically NWP islets were larger than pig islets and similar in size to human islets. NWP islets alpha cells had high dense core surrounded by a limiting membrane, beta cells by the mixed morphology of the granule core, and delta cells by moderate opaque core. Antibody staining for insulin, glucagon, somatostatin and Glucagon-like peptide-1 (GLP-1) showed that the distribution pattern of the different cell types within islets was comparable to pig and human islets. In all three species protein expression of zinc transporter ZnT8 was detected in most of the insulin producing beta cells whereas Zip14 expression was widely expressed in alpha and beta cells. In both human and NWP little or no expression of Glut2 was observed compared to Glut1 and glucokinase at the protein level, however the messenger RNA level of Glut2 was greater than Glut1 and glucokinase. In contrast all three glucose transporters were expressed in pig islets at the protein level. The expression of Zip14 in islets is reported for the first time. In conclusion NWP pancreatic islets express comparable islet cell types and distribution to humans and pigs. Importantly, marmosets have a similar glucose transporter profile to humans, making this non-endangered primate species a useful animal model for pancreatic biology.


Fully conjugated azacorannulene dimer as large diaza[80]fullerene fragment.
A fully conjugated azacorannulene dimer with a large π-surface (76π system) was successfully synthesized from a fully conjugated bifunctional polycyclic aromatic azomethine ylide. This molecule represents an example of diaza[80]fullerene (C78N2) fragment molecule bearing two internal nitrogen atoms. X-ray crystallography analysis shows its boat-shaped structure with two terminal azacorannulenes bent in the same direction. The molecular shape leads to unique selective association with a dumbbell-shaped C60 dimer (C120) over C60 through shape recognition. Owing to its large π-surface and a narrow HOMO-LUMO gap, the azacorannulene dimer exhibits red fluorescence with a quantum yield of up to 31%. The utilization of the fully conjugated bifunctional azomethine ylide is a powerful method for the bottom-up synthesis of large multiazafullerene fragments, providing a step towards the selective total synthesis of multiazafullerenes.


Relation of androgen receptor gene polymorphism to bone mineral density and fracture risk in early postmenopausal women during a 5-year randomized hormone replacement therapy trial.
In women, the influence of androgens on bone health is not clear. It has been suggested that the androgen receptor (AR) genotype is associated with bone mineral density and serum androgen levels in pre- and perimenopausal women, but the association between AR genotype, bone mineral density, and fracture risk has not been studied in postmenopausal women. Therefore, we studied whether AR polymorphism affects bone mineral density, bone mineral density change, or fracture risk in a 5-year randomized hormone replacement therapy (HRT) trial on 331 early postmenopausal women (mean baseline age, 52.7 +/- 2.3 years). The participants consisted of two treatment groups: the HRT group (n = 151) received a sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU + 93 mg calcium as lactate/day, and the non-HRT group (n = 180) received 93 mg calcium alone or in combination with vitamin D3, 100-300 IU/day for 5 years. Bone mineral density was measured from lumbar spine and proximal femur (DXA) before and after the 5-year trial. All new symptomatic, radiographically defined fractures were recorded during the follow-up. The length of CAG repeat in exon 1 of AR gene was evaluated after polymerase chain reaction (PCR) amplification. The subjects were divided into three repeat groups according to AR alleles. None of the baseline characteristics were associated with AR gene polymorphism and HRT treatment. The polymorphism did not influence the calculated annual changes of lumbar or femoral neck bone mineral density during the 5-year follow-up in the HRT (p = 0.926 and 0.146, respectively) or non-HRT (p = 0.818 and 0.917, respectively) groups. In all, 28 women sustained 33 fractures during the follow-up. Thus, the numbers of fractures were limited. The AR repeat length variation was not significantly associated with fracture risk in the HRT or non-HRT groups (p = 0.632 and 0.459, respectively; Cox proportional hazards model). In conclusion, AR gene polymorphism was not associated with baseline bone mineral density, 5-year bone mineral density change, or fracture risk in early postmenopausal Finnish women.


Biosynthesis and processing of the type II insulin-like growth factor receptor in H-35 hepatoma cells.
The biosynthesis and post-translational processing of the insulin-like growth factor II (IGF-II) receptor has been studied in H-35 hepatoma cells using a specific polyclonal anti-receptor immunoglobulin preparation. Cells were pulse-labeled with [35S]methionine followed by incubation with excess unlabeled methionine (chase). Gel electrophoresis of the immunoadsorbed receptors shows that the receptor is first synthesized as a 245-kDa precursor which is transformed to the mature 250-kDa form with a half-time of about 2 h. The 245-kDa precursor could also be labeled biosynthetically with [3H]mannose, only one-half of which was ultimately found associated with the 250-kDa product. Neuraminidase converts the 250-kDa receptor species to a 245-kDa form. Whereas the 250-kDa receptor is insensitive to detectable cleavage by endoglycosidase H, digestion of the 245-kDa species with this enzyme produces a 232-kDa form. A similar 232-kDa receptor species accumulates in H-35 cells incubated with tunicamycin (2 micrograms/ml). This tunicamycin-induced aglyco-receptor is not further processed to the 250-kDa form. Monensin (50 nM) blocks receptor processing at the 245-kDa stage. Endoglycosidase H treatment of the monensin-induced 245-kDa species indicates that this is a mixture of partially processed precursors having equivalent Mr. No evidence was obtained for the presence of O-linked oligosaccharides on the IGF-II receptor. The IGF-II binding activity of the three different biosynthetic forms of the receptor was assessed by affinity cross-linking of 125I-IGF-II to the receptors using disuccinimidyl suberate. Both the mature 250-kDa receptor and the neuraminidase-digested 245-kDa form specifically bound 125-I-IGF-II. However, the 232-kDa aglyco-receptor had no detectable IGF-II binding activity using this method. In summary, these studies show: 1) that the H-35 cell IGF-II receptor is synthesized first as a 245-kDa precursor having 4-6 high-mannose oligosaccharide side chains, 2) processing of the receptor oligosaccharides by mannose removal and terminal sialylation converts the 245-kDa precursor to the 250-kDa mature product which has been previously identified as the functional receptor in the plasma membrane, 3) the apparent molecular mass of the receptor in the absence of N-glycosylation is 232-kDa, and 4) glycosylation of the IGF-II receptor is required for the acquisition of IGF-II binding activity.


A mathematically modelled cytogel cortex exhibits periodic Ca++-modulated contraction cycles seen in Physarum shuttle streaming.
If each of many cells of an embryo (or different zones in a single cell) possess identical active cytogel machinery, having the 'right' mechanochemical response properties, then the collective interaction among those identical participants leads automatically to the globally coherent tissue deformations seen in embryogenesis, and to shuttle streaming in the plasmodial slime mould Physarum polycephalum. Biologically plausible, and experimentally verifiable hypotheses are proposed concerning how the tension generated by a strand of cytogel is determined by the deformation it suffers and by the concentration of a contraction trigger chemical, Ca2+, whose kinetics involve coupling to mechanical strain. The consequences of these hypotheses, deduced by solving the appropriate differential equation systems numerically, and displayed in computer-animated films, closely imitate diverse tissue deformation events seen in developing embryos. The same hypotheses on cytogel behaviour are used to model a thick-walled Physarum vein segment, and two such segments are set up to be able to pump endoplasm back and forth between them. Under certain conditions, this model exhibits spontaneous rhythmic mechanochemical oscillations, many features of which correlate well with shuttle streaming in Physarum. Small gradual variations of parameters, presumably under genetic control, are shown to cause abrupt and biologically interesting bifurcations of the qualitative behaviour of the model.


H. pylori stimulates gastrin release from canine antral cells in primary culture.
Patients chronically infected with Helicobacter pylori are known to have hypergastrinemia. Previous studies have demonstrated the stimulation of gastrin from isolated G cells by monocytes and cytokines. The aim of this study was to determine if H. pylori can directly stimulate gastrin secretion. The secretion of gastrin from canine G cells in 48-h primary cultures was investigated using either live H. pylori bacteria or various bacterial extracts from three well-characterized strains. Whole bacterial sonic extracts and water-extracted surface proteins, but not PBS extracts, from strains 43579 (CagA+/VacA+), 60190 (CagA+/VacA+), and 60190:v1 (CagA+/VacA-) significantly stimulated gastrin release. Controls demonstrated that gastrin stimulation by the sonic extracts was not due to a direct toxic effect on G cells. We conclude that H. pylori produces a soluble factor(s), which can directly stimulate gastrin release in enriched canine G cell cultures. This stimulatory effect may play an important role in the H. pylori-associated hypergastrinemia and subsequent development of peptic ulcer disease.


[Endoscopic Treatment for Esophageal Cancer].
Esophageal cancer incidence rate per 100,000 is 4.7 in 2013, which accounts for 1.1% of the total cancer incidence in Korea. Superficial esophageal squamous cell carcinoma is frequently detected in persons undergoing upper endoscopy for gastrointestinal symptoms or for gastric cancer screening. Esophagectomy with lymph node dissection is the standard treatment for esophageal cancer. However, given the considerable morbidity and mortality of esophagectomy, endoscopic resection has become the standard of care for most cases of superficial esophageal squamous cell carcinoma without metastasis. In addition, endoscopic submucosal dissection has increased the cure rate, even when the tumor is large, compared to endoscopic mucosal resection. Thus, endoscopic submucosal dissection is the treatment of choice for superficial esophageal squamous cell carcinoma with a negligible risk of lymph node metastasis. Endoscopic resection is usually associated with a low risk of morbidity and no mortality, and has also shown favorable long-term outcomes. However, the long-term risk of metastasis remains after endoscopic resection, which varies according to the characteristics of tumor. This review describes the indication and outcomes of endoscopic resection, complications of endoscopic resection, and management after treatment.


[Infectious keratitis after penetrating keratoplasty].
To investigate the prevalence of microbial keratitis, predisposing risk factors, the spectrum of pathogens and the prognosis for graft survival and visual outcome in patients who developed microbial keratitis following penetrating keratoplasty (PK). and methods: We reviewed 16 cases (15 patients) of microbial keratitis after PK. In all cases, corneal scrapings were obtained and microbiologically analyzed. Efficacy of treatment was evaluated by anatomical (clarity of graft) and visual recovery. Principal indications for PK were pseudophakic bullous keratopathy (50%) and microbial keratitis in the previous graft (25%). Sixty-three per cent of infections occurred within 1 year of PK. Principal predisposing risk factors were suture-related problems (44%) and microbial keratitis in the previous graft (25%). All of the scrapings were positive according to the microbiological evaluation with gram-positive cocci (64%), gram-positive rods (12%), fungi (18%), and Acanthamoeba (6%). We found 1 case of polymicrobial infection. Best visual and anatomical results were observed in nonadvanced cases and/or these treated early. After medical and surgical treatments, 8 patients (50%) had a clear graft and 10 patients (63%) had visual acuity less than 20/200. Postoperative control of risk factors and early recognition of infectious complications may decrease the incidence of severe microbial keratitis after PK.


Serum alpha-fetoprotein measurement in predicting clinical outcome related to autologous cytokine-induced killer cells in patients with hepatocellular carcinoma undergone minimally invasive therapy.
In patients with hepatocellular carcinoma (HCC) receiving potentially curative minimally invasive therapy, autologous cytokine-induced killer (CIK) cells were used to reduce recurrence. In this study we observed the changes in serum alpha-fetoprotein (AFP) after the treatment with CIK cells to explore if AFP could serve as a marker for predicting immunotherapeutic clinical outcome. A total of 122 patients with HCC and elevated AFP (>25 ng/mL) received a curative treatment of transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation (RFA) at the Sun Yat-sen University Cancer Center. Of these patients, 83 patients without residual tumor or extrahepatic metastasis and with AFP level less than 1.5 times the normal range (AFP<37.5 ng/mL) were randomly assigned to the study group (n=42) and the control group (n=41). In the study group, CIK cells were transfused intravenously or via common hepatic arteries every week for at least 4 times, and the T-lymphocyte subset data before and after CIK cell infusions was examined by flow cytometry. All the two groups of patients were screened by tomography every 2 months to observe tumor recurrence. Serum AFP was collected at baseline and at different time points after treatment in parallel with radiologic response and clinical outcome. Two patients in the control group were lost to follow-up after treatment. After CIK cell infusions, the downtrend of the AFP level was observed in the study group and not in the control group. There was a significant difference in the level of AFP between different time points after CIK infusions in both groups. The 1-year recurrence rate was 7.14% for the study group and 23.1% for the control group (P=0.044). In subgroup analysis, for patients with a slightly high level of AFP (25 ng/mL<AFP<37.5 ng/mL) after curative TACE plus RFA treatment, the 1-year recurrence rate was 28.57% for the study group and 80% for the control group. The time to recurrence in the study group was also longer than that in the control group (mean 10.2 months vs. 6.8 months). After CIK cell infusions, the percent of CD3+CD4+ T cells and CD4+ /CD8+ T cells increased from 28.1+/-5.9% and 0.9+/-0.3% to 32.7+/-3.6% and 1.2+/-0.2% (P<0.001 and=0.004, respectively), while the percent of CD3+CD8+ T cells decreased from 32.9+/-8.4% to 28.8+/-2.2% (P=0.046). Also the percentage of patients with hepatitis B virus (HBV)-DNA content less than 1x10(3) copies/mL was 73.5% in the study group and 9.1% in the control group. CIK cells transfusion may reduce the level of serum AFP and anti-HBV and decrease the 1-year recurrence rate of patients with HCC after curative TACE plus RFA. Serum AFP decrease after CIK cell treatment may serve as a useful marker for predicting immunotherapy clinical outcome in patients with HCC undergone curative minimally invasive therapy.


[Myocardial noncompaction: two cases and review].
Myocardial noncompaction (MN) is a rare form of cardiomyopathy due to an arrest in endomyocardial embryogenesis. It is characterized by multiple prominent trabeculations with deep intertrabecular recesses in ventricular walls. The disease usually affects the left ventricle and may cause cardiac failure, arrhythmias, and systemic embolism. We would like to present two rare cases of MN with a poor long-term prognosis. The first case is an unique case in the literature having bioprosthetic valve implantation and associated with a recovery of heart failure after the operation, the second case is another interesting case because of the association of A-V complete block, and multiple structural cardiac abnormalities.


[Optimizing history taking for evaluating the risk of venous thromboembolism: the OPTIMEV study].
Venous thromboembolism (VTE) is a frequent disease and remains a major cause of mortality and morbidity among our patients. During the 20 past years, clinical description, diagnostic tools, and treatment have changed dramatically. Most published data describing risk factors for VTE no longer apply to the patients seen in daily practice. We present here the rationale, aims, and methodology of the OPTIMEV Study (OPTimisation de l'Interrogatoire pour la Maladie thromboEmbolique Veineuse). Risk factors for VTE are numerous, complex and interactions between them and their clinical importance is difficult to measure (table I). For example, odds ratios for VTE recurrence vary greatly across longitudinal studies. We searched the National Library of Medecine (PubMed) and the Amedeo website using the following keywords: "venous thromboembolism", "pulmonary embolism", "deep vein thrombosis", "risk factors". We selected 84 relevant articles published between 1972 and 2005. Based on this literature analysis, we identified the following major risk factors: VTE recurrence, surgery, cancer, immobilization, age, biological factors. For these factors, data are lacking and some questions are proposed. The broad objective of the study is to better evaluate clinical risk factors that fit today's practice against VTE. Specific aims are: 1) to determine whether risk factors are different between proximal and distal deep vein thrombosis (DVT); 2) to develop and prospectively validate a new prediction rule for outpatients. The primary hypothesis is that careful assessment of VTE recurrence, adequate surgical thromboprophylaxis, cancer staging, and varicose vein stratification according to the CEAP classification, is mandatory for accurate evaluation of thromboembolic disease risk. We conducted a multicenter, prospective, cohort study of 10000 patients. Enrollees are inpatients and outpatients presenting with a clinical suspicion of VTE in Emergency Departments and outpatient clinics in France. 4173 patients have been enrolled at this time (Figure 2). All eligible patients are enrolled during a selected period of time through different seasons. Data are collected by physicians in charge of the patients using an electronic case recording form. Collected data include baseline characteristics, risk factors, results of diagnostic investigations. Outcome measures obtained through telephone interview at 3 and 12 months include cancer diagnosis, VTE recurrence, haemorrhagic events, treatments, death. Univariate and multivariate analysis will be performed using multilevel logistic regression. The study organization is performed by the Centre d'Investigation Clinique de Grenoble and is sponsored by the French Society of Vascular Medicine. First results, to be published in 2006, will allow development of new prediction rules for VTE diagnosis.


[Acute paraplegia. A rare complication of aortic dissection].
A 67 year-old normotensive woman had a syncope followed by shock and remained anuric after hemodynamic stabilization. Paraplegia and paresis of the right upper limb, as well as signs of ischemia of the distal lower limbs were noted. The possibility of acute aortic dissection was raised and confirmed by computed tomography. The paraplegia was attributed to an ischemic infarction of the spinal cord. The patient died on the fourth hospital day due to a pericardial temponade. This rare and not well recognized complication of aortic dissection is briefly reviewed.


Co-designing electronics with microfluidics for more sustainable cooling.
Thermal management is one of the main challenges for the future of electronics1-5. With the ever-increasing rate of data generation and communication, as well as the constant push to reduce the size and costs of industrial converter systems, the power density of electronics has risen6. Consequently, cooling, with its enormous energy and water consumption, has an increasingly large environmental impact7,8, and new technologies are needed to extract the heat in a more sustainable way-that is, requiring less water and energy9. Embedding liquid cooling directly inside the chip is a promising approach for more efficient thermal management5,10,11. However, even in state-of-the-art approaches, the electronics and cooling are treated separately, leaving the full energy-saving potential of embedded cooling untapped. Here we show that by co-designing microfluidics and electronics within the same semiconductor substrate we can produce a monolithically integrated manifold microchannel cooling structure with efficiency beyond what is currently available. Our results show that heat fluxes exceeding 1.7 kilowatts per square centimetre can be extracted using only 0.57 watts per square centimetre of pumping power. We observed an unprecedented coefficient of performance (exceeding 10,000) for single-phase water-cooling of heat fluxes exceeding 1 kilowatt per square centimetre, corresponding to a 50-fold increase compared to straight microchannels, as well as a very high average Nusselt number of 16. The proposed cooling technology should enable further miniaturization of electronics, potentially extending Moore's law and greatly reducing the energy consumption in cooling of electronics. Furthermore, by removing the need for large external heat sinks, this approach should enable the realization of very compact power converters integrated on a single chip.


[Anemia with aplastic anemia, paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes].
This review discusses aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH) and the myelodysplastic syndrome (MDS, all diseases associated with severe anemia. Anemia in AA and MDS is mainly due to defective or lacking eryhtropoiesis in the case of PNH mostly due to hemolysis. Management by transfusions, the use of growth factors and iron chelation is being discussed as are more specific treatment approaches directed against the underlying disease.


Carnosol: a phenolic diterpene with cancer chemopreventive potential.
Cancer is an unbeaten health challenge for the humankind. After striving for decades to find a cancer cure, attention has now been shifted to reduce the morbidity and mortality from cancer by halting the course of tumor development. Numerous bioactive phytochemicals, especially those present in edible and non-edible plant species, have been reported to reduce the risk of many cancers. Multiple lines of evidence suggest that carnosol, a phenolic diterpene present in rosemary (Rosmarinus officinalis L.), holds the promise of preventing certain types of cancer. A remarkable progress has been made in delineating the biochemical mechanisms underlying the chemopreventive effects of carnosol. Results from in vitro cell culture studies as well as animal model experiments have revealed that carnosol inhibits experimentally induced carcinogenesis and exhibits potent anti-oxidative, anti-inflammatory, antiproliferative and apoptosis inducing properties. Moreover, carnosol enhances the sensitivity of chemoresistant cancer cells to chemotherapeutic agents. The purpose of this review is to shed light on the detailed mechanistic aspects of cancer chemoprevention with carnosol.


Surrogate markers in AIDS and cancer trials.
There is significant need for rapid yet reliable evaluation of promising new interventions for the treatment of patients with cancer or HIV infection. Considerable attention has been given to identifying replacement or 'surrogate' endpoints for the true clinical efficacy endpoints, in order to reduce the cost, size and duration of clinical trials. We discuss issues which affect the validity of surrogate markers. The reliability of the CD4 lymphocyte count marker is carefully considered in clinical trials of anti-retroviral agents in HIV infected individuals. The nature of surrogate markers and their reliability is discussed in cancer prevention, screening and treatment trials. Some suggested uses of marker information are also considered.


Encapsulation of MSCs and GDNF in an Injectable Nanoreinforced Supramolecular Hydrogel for Brain Tissue Engineering.
The co-administration of glial cell line-derived neurotrophic factor (GDNF) and mesenchymal stem cells (MSCs) in hydrogels (HGs) has emerged as a powerful strategy to enhance the efficient integration of transplanted cells in Parkinson's disease (PD). This strategy could be improved by controlling the cellular microenvironment and biomolecule release and better mimicking the complex properties of the brain tissue. Here, we develop and characterize a drug delivery system for brain repair where MSCs and GDNF are included in a nanoparticle-modified supramolecular guest-host HA HG. In this system, the nanoparticles act as both carriers for the GDNF and active physical crosslinkers of the HG. The multifunctional HG is mechanically compatible with brain tissue and easily injectable. It also protects GDNF from degradation and achieves its controlled release over time. The cytocompatibility studies show that the developed biomaterial provides a friendly environment for MSCs and presents good compatibility with PC12 cells. Finally, using RNA-sequencing (RNA-seq), we investigated how the three-dimensional (3D) environment, provided by the nanostructured HG, impacted the encapsulated cells. The transcriptome analysis supports the beneficial effect of including MSCs in the nanoreinforced HG. An enhancement in the anti-inflammatory effect of MSCs was observed, as well as a differentiation of the MSCs toward a neuron-like cell type. In summary, the suitable strength, excellent self-healing properties, good biocompatibility, and ability to boost MSC regenerative potential make this nanoreinforced HG a good candidate for drug and cell administration to the brain.


Study on Early Onset Melanoma and Germ-Line Mutation in CDKN2A among Patients in Imam Khomeini Hospital Complex.
Malignant melanoma is a highly lethal melanocytic neoplasia with different predisposing factors. The genetic background in familial cases is an important issue in finding at risk family members. CDKN2A is one of these predisposing genes which have been estimated to be involved in germ line mutation in approximately 5-10% of familial melanoma cases. An inclusion criteria for familial melanoma was prepared according to the literature, and the age of onset was considered as a single criteria for selection. A total number of 322 melanoma cases were investigated regarding the criteria, among which 20 patients were chosen (<40 years). DNA was extracted from Formalin Fixed Paraffin Embed of normal tissues and DNA sequencing was performed for all coding sequences of CDKN2A (p16). One of the cases showed a pathogenic mutation in codon 108, exon 2(322G >C; Asp108His). Further analysis of his offspring indicated no mutation in the next generation. As far as the authors of the present study are concerned, this was the first report on this germ-line mutation with mentioned amino acid alteration in the melanoma. Screening the CDKN2A gene for possible mutation could prevent the incidence of familial cases in at risk members.<br />.


Can motor volition be extracted from the spinal cord?
Spinal cord injury (SCI) results in the partial or complete loss of movement and sensation below the level of injury. In individuals with cervical level SCI, there is a great need for voluntary command generation for environmental control, self-mobility, or computer access to improve their independence and quality of life. Brain-computer interfacing is one way of generating these voluntary command signals. As an alternative, this study investigates the feasibility of utilizing descending signals in the dorsolateral spinal cord tracts above the point of injury as a means of generating volitional motor control signals. In this work, adult male rats were implanted with a 15-channel microelectrode array (MEA) in the dorsolateral funiculus of the cervical spinal cord to record multi-unit activity from the descending pathways while the animals performed a reach-to-grasp task. Mean signal amplitudes and signal-to-noise ratios during the behavior was monitored and quantified for recording periods up to 3 months post-implant. One-way analysis of variance (ANOVA) and Tukey's post-hoc analysis was used to investigate signal amplitude stability during the study period. Multiple linear regression was employed to reconstruct the forelimb kinematics, i.e. the hand position, elbow angle, and hand velocity from the spinal cord signals. The percentage of electrodes with stable signal amplitudes (p-value < 0.05) were 50% in R1, 100% in R2, 72% in R3, and 85% in R4. Forelimb kinematics was reconstructed with correlations of R² > 0.7 using tap-delayed principal components of the spinal cord signals. This study demonstrated that chronic recordings up to 3-months can be made from the descending tracts of the rat spinal cord with relatively small changes in signal characteristics over time and that the forelimb kinematics can be reconstructed with the recorded signals. Multi-unit recording technique may prove to be a viable alternative to single neuron recording methods for reading the information encoded by neuronal populations in the spinal cord.


Oximetry alone versus portable polygraphy for sleep apnea screening before bariatric surgery.
Screening for obstructive sleep apnea (OSA) is recommended as part of the preoperative assessment of obese patients scheduled for bariatric surgery. The objective of this study was to compare the sensitivity of oximetry alone versus portable polygraphy in the preoperative screening for OSA. Polygraphy (type III portable monitor) and oximetry data recorded as part of the preoperative assessment before bariatric surgery from 68 consecutive patients were reviewed. We compared the sensitivity of 3% or 4% desaturation index (oximetry alone) with the apnea-hypopnea index (AHI; polygraphy) to diagnose OSA and classify the patients as normal (<10 events per hour), mild to moderate (10-30 events per hour), or severe (>30 events per hour). Using AHI, the prevalence of OSA (AHI > 10 per hour) was 57.4%: 16.2% of the patients were classified as severe, 41.2% as mild to moderate, and 42.6% as normal. Using 3% desaturation index, 22.1% were classified as severe, 47.1% as mild to moderate, and 30.9% as normal. With 4% desaturation index, 17.6% were classified as severe, 32.4% as mild, and 50% as normal. Overall, 3% desaturation index compared to AHI yielded a 95% negative predictive value to rule out OSA (AHI > 10 per hour) and a 100% sensitivity (0.73 positive predictive value) to detect severe OSA (AHI > 30 per hour). Using oximetry with 3% desaturation index as a screening tool for OSA could allow us to rule out significant OSA in almost a third of the patients and to detect patients with severe OSA. This cheap and widely available technique could accelerate preoperative work-up of these patients.


Overexpression of lunatic fringe does not affect epithelial cell differentiation in the developing mouse lung.
The Notch/Notch-ligand pathway regulates cell fate decisions and patterning in various tissues. Several of its components are expressed in the developing lung, suggesting that this pathway is important for airway cellular patterning. Fringe proteins, which modulate Notch signaling, are crucial for defining morphogenic borders in several organs. Their role in controlling cellular differentiation along anterior-posterior axis of the airways is unknown. Herein, we report the temporal-spatial expression patterns of Lunatic fringe (Lfng) and Notch-regulated basic helix-loop-helix factors, Hes1 and Mash-1, during murine lung development. Lfng was only expressed during early development in epithelial cells lining the larger airways. Those epithelial cells also expressed Hes1, but at later gestation Hes1 expression was confined to epithelium lining the terminal bronchioles. Mash-1 displayed a very characteristic expression pattern. It followed neural crest migration in the early lung, whereas at later stages Mash-1 was expressed in lung neuroendocrine cells. To clarify whether Lfng influences airway cell differentiation, Lfng was overexpressed in distal epithelial cells of the developing mouse lung. Overexpression of Lfng did not affect spatial or temporal expression of Hes1 and Mash-1. Neuroendocrine CGRP and protein gene product 9.5 expression was not altered by Lfng overexpression. Expression of proximal ciliated (beta-tubulin IV), nonciliated (CCSP), and distal epithelial cell (SP-C, T1alpha) markers also was not influenced by Lfng excess. Overexpression of Lfng had no effect on mesenchymal cell marker (alpha-sma, vWF, PECAM-1) expression. Collectively, the data suggest that Lunatic fringe does not play a significant role in determining cell fate in fetal airway epithelium.


Lycopene intake and the risk of erectile dysfunction in US adults: NHANES 2001-2004.
Erectile dysfunction is a condition with a high incidence among adult men. Lycopene has been shown to lower blood glucose and reduce weight in diabetic patients because of its antioxidant and anti-inflammatory properties. However, the association between lycopene and the incidence of erectile dysfunction is unclear. The aim of this study was to examine the dietary lycopene intake and its association with erectile dysfunction risk in the US population. We investigated the lycopene intake of adult participants with complete information on clinical variables from the National Health and Nutrition Examination Survey between 2001 and 2004. Dose-response curve analysis was applied to explore the association between lycopene intake and erectile dysfunction. Logistic regression models were used to adjust for confounders. Different ethnicities, body mass index level, hypertension status, diabetes status, and smoking status were analyzed as subgroups. Propensity score matching was employed to eliminate the effects of potential confounders to confirm the reliability of the results. A total of 3265 participants with lycopene consumption data were included in our study, including 931 individuals with erectile dysfunction and 2334 without erectile dysfunction during National Health and Nutrition Examination Survey 2001-2004. We found more consumption of lycopene in the non-erectile dysfunction group than in the erectile dysfunction group. Dose-response curve analysis revealed a significant negative association between lycopene intake and erectile dysfunction prevalence. After adjusting for age, race, cigarette smoking, body mass index, annual family income, education, physical activity, hypertension, diabetes, depression, and testosterone level, we found that increased lycopene intake reduced the odds ratio of erectile dysfunction. Low lycopene intake was positively related to erectile dysfunction in almost all subgroups, especially in Mexican American, non-Hispanic white, body mass index <25, hypertension positive, diabetes mellitus negative, and smoke negative. Furthermore, the results were confirmed in the 1:1 matched group. Our national data suggest that lower dietary lycopene intake is positively associated with an increased risk of erectile dysfunction in US men.


Embedded optical waveguides fabricated in SF10 glass by low-repetition-rate ultrafast laser.
Symmetric embedded waveguides were fabricated in heavy metal oxide SF10 glass using slit-shaped infrared femtosecond laser writing in the low-repetition frequency regime. The impact of the writing parameters on the waveguide formation in the transverse writing scheme was systemically studied. Results indicate that efficient waveguides can be inscribed in a wide parameter space ranging from 500 fs to 1.5 ps pulse duration, 0.7-4.2 μJ pulse energy, and 5 μm/s to 640 μm/s scan speed and pointing out the robustness of the photoinscription process. The refractive index profile reconstructed from the measured near field pattern goes up to 10(-3). In addition, propagation losses of the waveguides are tolerable, with the lowest propagation loss estimated at 0.7 dB/cm. With a 5 μm/s scan speed and 3.5 μJ pulse energy in a high-dose regime, few-mode guiding was achieved in the waveguide at 800 nm signal injection wavelength. This is due to a combination of increased refractive index in the core of the trace and the appearance of a depressed cladding.


Functional plasticity in the immature striate cortex of the monkey shown by the [14C]deoxyglucose method.
Autoradiographic representation of the local rates of cerebral glucose utilization and local cerebral functional activity by means of the [14C]deoxyglucose technique reveals the existence of the ocular dominance columns in the striate cortex of the monkey in the first day of life. In contrast to the stability of these columns in more mature brain, monocular deprivation for 3 months from the first day of life results in their complete disappearance and a reversion of the autoradiographic pattern to that seen in animals with normal binocular vision. These results are consistent with a reorganization of the representation of the visual fields of the two eyes in the striate cortex and provide additional evidence of the plasticity of the striate cortex of the monkey in early life.


Roles of replication fork-interacting and Chk1-activating domains from Claspin in a DNA replication checkpoint response.
Claspin is essential for the ATR-dependent activation of Chk1 in Xenopus egg extracts containing incompletely replicated DNA. Claspin associates with replication forks upon origin unwinding. We show that Claspin contains a replication fork-interacting domain (RFID, residues 265-605) that associates with Cdc45, DNA polymerase epsilon, replication protein A, and two replication factor C complexes on chromatin. The RFID contains two basic patches (BP1 and BP2) at amino acids 265-331 and 470-600, respectively. Deletion of either BP1 or BP2 compromises optimal binding of Claspin to chromatin. Absence of BP1 has no effect on the ability of Claspin to mediate activation of Chk1. By contrast, removal of BP2 causes a large reduction in the Chk1-activating potency of Claspin. We also find that Claspin contains a small Chk1-activating domain (residues 776-905) that does not bind stably to chromatin, but it is fully effective at high concentrations for mediating activation of Chk1. These results indicate that stable retention of Claspin on chromatin is not necessary for activation of Chk1. Instead, our findings suggest that only transient interaction of Claspin with replication forks potentiates its Chk1-activating function. Another implication of this work is that stable binding of Claspin to chromatin may play a role in other functions besides the activation of Chk1.