Differential expression of full-length telomerase reverse transcriptase mRNA and telomerase activity between normal and malignant renal tissues.
Activation of telomerase, a key event during immortalization and malignant transformation, requires expression of the telomerase reverse transcriptase (hTERT). Consistently, lack of telomerase activity and hTERT expression occurs in most normal human somatic cells. However, it has been observed that both normal and cancerous renal tissues express hTERT whereas only the latter exhibits telomerase activity. The mechanism underlying the dissociation between hTERT expression and telomerase activity is unclear. In the present study, we examined telomerase activity and alternative splicing of hTERT transcripts in renal cell carcinoma (RCC) specimens and adjacent normal tissues from 33 patients with RCC. Telomerase activity was detectable in 27 of 33 (82%) RCC samples but none in their normal counterparts. Thirty-two of 33 tumors expressed overall hTERT mRNA and 27 of them contained full-length hTERT transcripts, all with telomerase activity. Although 42% (14 of 33) of normal renal samples expressed hTERT mRNA, none of them had full-length hTERT transcripts, coinciding with lack of telomerase activity. The presence of full-length hTERT mRNA and telomerase activity was significantly associated with c-MYC induction. In tumors, absence of full-length hTERT mRNA or telomerase activity defines a subgroup of nonmetastatic, early-stage RCCs. Taken together, telomerase repression in normal renal tissues is attributed to the absence of full-length hTERT transcripts, whereas telomerase activation is achieved via induction of or switch to expression of full-length hTERT mRNA during the oncogenic process of kidneys, and associated with aggressive RCCs.


Direct Anthropometry of Repaired Bilateral Complete Cleft Lip: A Long-Term Assessment.
Repair of bilateral complete cleft lip requires more than following a design in a textbook. The operative strategy should incorporate knowledge of anticipated nasolabial changes with growth. Direct nasolabial anthropometry was recorded in 174 children with bilateral complete cleft lip before and immediately after primary repair. Serial measurements were taken in 66 Caucasian patients between the ages of 6 months and 15 years and compared to Farkas' normal values. Data for upper philtral width were unavailable; therefore, this dimension was measured in 454 nonsyndromic Caucasian male and female subjects aged 1 year to adulthood. Rates and types of revision were also documented. Inter-medial canthal width stayed above the mean and within normal limits throughout puberty. Interalar width was initially narrowed and hovered in the high normal range throughout adolescence. Columellar height and nasal projection were constructed slightly long and paralleled normal growth. Available cutaneous philtral length was used in the primary repair; however, this dimension remained short. The philtrum was made narrow and matched normal values throughout adolescence. Normal inferior/superior philtral width ratio was 1.60 for female subjects and 1.59 for male subjects. A full median tubercle was built at primary repair but, sometimes in late childhood, necessitated secondary augmentation with a dermal graft in 31 of 174 patients (18 percent), usually performed in late childhood or adolescence. Serial anthropometry documented postoperative changes in nasolabial dimensions compared to normal growth curves. Repair of bilateral complete cleft lip requires primary correction of nasal and labial features based on their differential growth, with special attention to nasal width, philtral height and proportions, and size of the median tubercle. Therapeutic, IV.


Improvement of fatigue after vitamin D supplementation in kidney transplant recipients.
Low serum levels of vitamin D have been associated with fatigue in both healthy and clinical populations. Our aim was to evaluate the effect of vitamin D supplementation on fatigue in kidney transplant recipients (KTRs). In total, 137 patients after kidney transplant and 119 age- and sex-matched healthy volunteers were recruited. Serum levels of 25-hydroxyvitamin D (25(OH)D) were measured by competitive protein-binding assay. Fatigue was assessed using the subscale fatigue of the Checklist Individual Strength (CIS). Of all KTRs, 60 patients without initial vitamin D3 supplementation were started on vitamin D3 supplementation (cholecalciferol) 800 IU/d, with a follow-up examination after 3.0 to 9.0 months (mean, 6 months). Fatigue was found in 40.1% of KTRs. Serum 25(OH)D levels were inversely and independently associated with CIS scores in KTRs (P = .002). In the 60 patients who received vitamin D3 supplementation, 25(OH)D was overall increased at follow-up with 18.5% (P = .004) and CIS scores improved with 10.0% (P = .007). As vitamin D has beneficial effects on fatigue scores in KTRs, we suggest monitoring this parameter in KTRs and supplementation with vitamin D3 when vitamin D levels are low.


Detailed investigations of phase transitions and magnetic structure in Fe(III), Mn(II), Co(II) and Ni(II) 3,4,5-trihydroxybenzoate (gallate) dihydrates by neutron and X-ray diffraction.
The effect of cation valency on the complex structures of divalent and trivalent transition metal gallates has been examined using a combination of neutron and synchrotron X-ray powder diffraction, single-crystal X-ray diffraction and XANES spectroscopy. In the divalent frameworks, M(C(7)H(4)O(5))·2H(2)O (M = Mn, Co and Ni), it was found that charge balance was achieved via the presence of protons on the meta-hydroxyl groups. It was also established that these compounds undergo a discontinuous phase transition at lower temperatures, which is driven by the position of the extra-framework water molecules in these materials. By contrast, in the trivalent Fe gallate, Fe(C(7)H(3)O(5))·2H(2)O, it was found that the stronger bonding between the meta-hydroxy oxygen and the cations leads to a weakening of the bond between this oxygen and its proton. This is turn is thought to lead to stronger hydrogen bonding with the extra-framework water. The lattice water is disordered in the Fe(III) case, which prevents the phase transition found in the M(II) gallates. Refinement against the neutron diffraction patterns also revealed that the relatively mild microwave synthesis of gallate frameworks in D(2)O led to an extensive deuteration of the ortho-hydrogen sites on the aromatic ring, which may suggest a more versatile method of deuterating aromatic organics. The antiferromagnetic structure of Co gallate has also been determined.


Oxidized titanium implants in reconstructive jaw surgery.
Rehabilitation with implant-supported bridges in patients with insufficient bone volumes may require bone reconstructive procedures in conjunction with or prior to implant placement. Clinical follow-up studies using turned titanium and bone grafts have demonstrated higher failure rates than when used in nongrafted patients. Improved bone integration has been demonstrated for oxidized titanium implants; however, their clinical performance in bone reconstruction situations is not known. This study was performed to analyze the survival and stability of oxidized titanium implants placed in patients subjected to reconstructive jaw surgery at one clinic. Two hundred oxidized titanium implants (Mk III, TiUnite, Nobel Biocare AB, Göteborg, Sweden) were placed in 47 patients in conjunction with or secondary to six different reconstructive procedures owing to insufficient bone volume. In all six groups, implant stability was assessed by resonance frequency analysis and manually checked for rotation stability at implant insertion, at the time of abutment connection, and after a minimum of 12 months of loading of the prosthetic construction. Periapical radiographs were taken after a minimum of 12 months of loading (mean 21 months) for evaluation of the marginal bone levels. The mean clinical follow-up period was 30 months. Of the 200 implants, 199 were considered osseointegrated at the time of abutment surgery. At the 12-month postloading follow-up, another two implants were considered not stable. Three implants (1.5%) were ranked as unsuccessful. Clinical experience with 200 consecutive oxidized implants in various reconstruction situations shows a successful outcome, with only three failures (1.5%) during a mean follow-up period of 30 months.


Population risk prediction models for incident heart failure: a systematic review.
The prevalence of heart failure is expected to significantly rise unless high-risk patients are effectively screened and appropriate, cost-effective prevention interventions are implemented. We performed a systematic review to evaluate the prediction characteristics of the published heart failure risk prediction models as of August 2014 using MEDLINE and EMBASE databases. Eligible studies reported the development, validation, or impact assessment of a model. Two investigators performed independent review to extract data on study design and characteristics, risk predictors, discrimination, calibration, and reclassification ability of models, as well as validation and impact analysis. We included 13 publications reporting on 28 heart failure risk prediction models. Models had acceptable-to-good discriminatory ability (c-statistics, >0.70) in the derivation sample. Calibration was less commonly assessed, but was acceptable when it was. Only 2 models were externally validated more than once, displaying modest-to-acceptable discrimination (c-statistics, 0.61-0.79). When assessed, novel blood and imaging markers modestly improved risk prediction. One model assessed the prediction properties in race-based subgroups, whereas 2 models evaluated sex-based subgroups. Impact analysis found none of the models recommended for use in any clinical practice guideline. Incident heart failure risk prediction remains at an early stage. The discrimination ability of current models is acceptable in derivation data sets but most models have not been externally validated. It remains unclear which models are cost-effective and best suit population screening needs. The effects of models on clinical and preventative care requires further study.


The neuroendocrinology of social isolation.
Social isolation has been recognized as a major risk factor for morbidity and mortality in humans for more than a quarter of a century. Although the focus of research has been on objective social roles and health behavior, the brain is the key organ for forming, monitoring, maintaining, repairing, and replacing salutary connections with others. Accordingly, population-based longitudinal research indicates that perceived social isolation (loneliness) is a risk factor for morbidity and mortality independent of objective social isolation and health behavior. Human and animal investigations of neuroendocrine stress mechanisms that may be involved suggest that (a) chronic social isolation increases the activation of the hypothalamic pituitary adrenocortical axis, and (b) these effects are more dependent on the disruption of a social bond between a significant pair than objective isolation per se. The relational factors and neuroendocrine, neurobiological, and genetic mechanisms that may contribute to the association between perceived isolation and mortality are reviewed.


Fabrication and performance of a miniaturized 64-element high-frequency endoscopic phased array.
We have developed a 40-MHz, 64-element phased-array transducer packaged in a 2.5 x 3.1 mm endoscopic form factor. The array is a forward-looking semi-kerfed design based on a 0.68Pb(Mg(1/3)Nb(2/3))O(3) - 0.32PbTiO3 (PMN-32%PT) single-crystal wafer with an element-to-element pitch of 38 µm. To achieve a miniaturized form factor, a novel technique of wire bonding the array elements to a polyimide flexible circuit board oriented parallel to the forward looking ultrasound beam and perpendicular to the array was developed. A technique of partially dicing into the back of the array was also implemented to improve the directivity of the array elements. The array was fabricated with a single-layer P(VDF-TrFE)-copolymer matching layer and a polymethylpentene (TPX) lens for passive elevation focusing to a depth of 7 mm. The two-way -6-dB pulse bandwidth was measured to be 55% and the average electromechanical coupling (k(eff)) for the individual elements was measured to be 0.62. The one-way -6-dB directivities from several array elements were measured to be ±20°, which was shown to be an improvement over an identical kerfless array. The -3-dB elevation focus resulting from the TPX lens was measured to be 152 µm at the focal depth, and the focused lateral resolution was measured to be 80 µm at a steering angle of 0°. To generate beam profiles and images, the probe was connected to a commercial ultrasound imaging platform which was reprogrammed to allow for phased array transmit beamforming and receive data collection. The collected RF data were then processed offline using a numerical computing script to generate sector images. The radiation pattern for the beamformed transmit pulse was collected along with images of wire phantoms in water and tissue-equivalent medium with a dynamic range of 60 dB. Finally, ex vivo tissue images were generated of porcine brain tissue.


Early Diagnosis and Monitoring of Neurodegenerative Langerhans Cell Histiocytosis.
Neurodegenerative Langerhans Cell Histiocytosis (ND-LCH) is a rare, unpredictable consequence that may devastate the quality of life of patients cured from LCH. We prospectively applied a multidisciplinary diagnostic work-up to early identify and follow-up patients with ND-LCH, with the ultimate goal of better determining the appropriate time for starting therapy. We studied 27 children and young adults with either ND-LCH verified by structural magnetic resonance imaging (MRI) (group 1) or specific risk factors for (diabetes insipidus, craniofacial bone lesions), but no evidence of, neurodegenerative MRI changes (group 2). All patients underwent clinical, neurophysiological and MRI studies. Seventeen patients had MRI alterations typical for ND-LCH. Nine showed neurological impairment but only three were symptomatic; 11 had abnormal somatosensory evoked potentials (SEPs), and five had abnormal brainstem auditory evoked potentials (BAEPs). MR spectroscopy (MRS) showed reduced cerebellar NAA/Cr ratio in nine patients. SEPs showed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for predicting ND-LCH of 70.6% (95%CI, 44.0%-89.7%), 100% (69.2%-100%), 100% (73.5%-100%), and 66.7% (38.4%-88.2%), respectively. Repeated investigations in group 1 revealed increasingly abnormal EP parameters, or neurological examination, or both, in nine of fifteen patients while MRI remained unchanged in all but one patient. A targeted MRI study should be performed in all patients with risk factors for ND-LCH for early identification of demyelination. The combined use of SEPs and careful neurological evaluation may represent a valuable, low-cost, well-tolerated and easily available methodology to monitor patients from pre-symptomatic to symptomatic stages. We suggest a multidisciplinary protocol including clinical, MRS, and neurophysiological investigations to identify a population target for future therapeutic trials.


Parental epigenetic control of embryogenesis: a balance between inheritance and reprogramming?
At fertilization, fusion of two differentiated gametes forms the zygote that is capable of forming all of the varied cell lineages of an organism. It is widely thought that the acquisition of totipotency involves extensive epigenetic reprogramming of the germline state into an embryonic state. However, recent data argue that this reprogramming is incomplete and that substantial epigenetic information passes from one generation to the next. In this review we summarize the changes in chromatin states that take place during mammalian gametogenesis and examine the evidence that early mammalian embryogenesis may be affected by inheritance of epigenetic information from the parental generation.


The Role of Intravitreal Anti-VEGF Agents in Rabbit Eye Model of Open-Globe Injury.
To evaluate the effects of intravitreal anti-VEGF agents in a rabbit model of open-globe injury (OGI). OGI was induced in the right eyes of 75 Belgian rabbits by making 5 mm circumferential incision placed 6 mm behind the limbus. The rabbits were divided into 4 groups: control (n = 5), OGI group (n = 40), and intravitreal Ranibizumab and Conbercept (n = 15 each). Ranibizumab or Conbercept was injected into the vitreous at 0.5 hours, 3 days, or 7 days. Vitreous fluid was collected, and levels of growth factors and cytokines were measured by enzyme-linked immunosorbent assay (ELISA). On day 28 after OGI, B scan examination and histological examination were performed to evaluate intravitreal proliferation and formation of epiretinal fibrosis. Vitreous levels of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-β), and plasminogen activator inhibitor-1 (PAI-1) were significantly increased in rabbit eyes after OGI. Compared to eyes in OGI group, anti-VEGF treatments significantly reduced these growth factors and cytokines. Among the 7 eyes examined from each group for intravitreal proliferative changes, they were found in 7 of 7 (100%) in OGI group and were decreased by Ranibizumab and Conbercept to 5 of 7 (71.4%) and 4 of 7 (57.1%), respectively. Both Ranibizumab and Conbercept inhibited epiretinal scar formation at the wound site, with Conbercept showing the greatest effect (maximal length of scar (L), L OGI = 503 ± 82.44 μm, L Ranibizumab = 355 ± 43.66 μm, and L Conbercept = 250.33 ± 36.02 μm). Anti-VEGF treatments after OGI significantly attenuated the upregulation of growth factors and cytokines in the vitreous and prevented intravitreal proliferation and epiretinal scar formation and thus may protect against the development of posttraumatic complications such as proliferative vitreoretinopathy (PVR).


A prospective study of psychotic symptoms in dementia sufferers: psychosis in dementia.
Eighty-seven out of a clinical cohort of 124 patients with Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev.) dementia were followed up at monthly intervals for 1 year. Psychotic symptoms were assessed using the Burns's Symptom Checklist, and cognitive functioning was evaluated with the CAMCOG. The annual incidence rate of psychotic symptoms was 47%, although many of the incident symptoms lasted less than 3 months. Fifty-three percent of patients with psychosis experienced resolution of their symptoms. Patients either experienced brief or persistent psychotic disorders, with few having an intermediary course. Persistent psychosis was significantly associated with a 3-month duration of symptoms at baseline. Neuroleptics did not significantly influence the course of psychotic symptoms.


[Marchiafava-Bignami disease in Uruguay].
Marchiafava-Bignami disease (MBD) is a rare complication of chronic alcoholism characterized by demyelination and necrosis of the corpus callosum that usually has a poor prognosis. It has an extensive clinical spectrum presentation and can presently be diagnosed in vivo with the computed tomography (CT) and magnetic resonance imaging (MRI). We describe two cases of MBD disease with fatal outcome that presented with acute onset coma. Impairment of consciousness, hypertonia, and frontal release signs were the dominant clinical signs. One of the patients had optic neuropathy and the other had neuropsychiatric symptoms before onset of coma and pellagra-like skin lesion. The CT scan and MRI showed lesions of the white matter that were fundamentally in the corpus callosum. The possibility of the existence of MBD should be investigated in all patients with chronic alcoholism who have prolonged confusional syndrome, stupor or coma. A prodromal stage with neuropsychiatric symptoms should be thoroughly investigated with a neuropsychological exploration including interhemispheric disconnection signs. Careful attention should be given to the corpus callosum in the image for the diagnosis of this probably underdiagnosed disease.


A method for MRI guidance of intercostal high intensity focused ultrasound ablation in the liver.
High intensity focused ultrasound (HIFU) is a promising method for the noninvasive treatment of liver tumors. However, the presence of ribs in the HIFU beam path remains problematic since it may lead to adverse effects (skin burns) by absorption and reflection of the incident beam at or near the bone surface. This article presents a method based on magnetic resonance (MR) imaging for identification of the ribs in the HIFU beam, and for selection of the transducer elements to deactivate. The ribs are visualized on anatomical images acquired prior to heating and manually segmented. The resulting regions of interest surrounding the ribs are projected onto the transducer surface by ray tracing from the focal point. The transducer elements in the "shadow" of the ribs are then deactivated. The method was validated ex vivo and in vivo in pig liver during breathing under multislice real-time MR thermometry, using the proton resonance frequency shift method. Ex vivo and in vivo temperature data showed that the temperature increase near the ribs was substantial when HIFU sonications were performed with all elements active, whereas the temperature was reduced with deactivation of the transducer elements located in front of the ribs. The temperature at the focal point was similar with and without deactivation of the transducer elements, indicative of no loss of heat efficiency with the proposed technique. This method is simple, rapid, and reliable, and enables intercostal HIFU ablation while sparing ribs and their surrounding tissues.


Recruitment of septin cytoskeletal proteins by botulinum toxin A protease determines its remarkable stability.
Proteolytic cleavage of synaptosomal-associated protein 25 by the light chain of botulinum neurotoxin type A (LCA) results in a blockade of neurotransmitter release that persists for several months in motor neurons. The L428A/L429A mutation in LCA is known to significantly shorten both the proteolytic and neuroparalytic effects of the neurotoxin in mice. To elucidate the cellular mechanism for LCA longevity, we studied the effects of L428A/L429A mutation on the interactome, localization and stability of LCA expressed in cultured neuronal cells. Mass spectrometry analysis of the LCA interactome showed that the mutation prevented the interaction of LCA with septins. The wild-type LCA was concentrated in plasma-membrane-associated clusters, colocalizing with septins-2 and septin-7, which accumulated in these clusters only in the presence of LCA. The L428A/L429A mutation decreased co-clustering of LCA and septins and accelerated proteasomal and non-proteasomal degradation of LCA. Similarly, the impairment of septin oligomerization by forchlorfenuron or silencing of septin-2 prevented LCA interaction and clustering with septins and increased LCA degradation. Therefore, the dileucine-mediated LCA-septin co-clustering is crucial for the long-lasting stabilization of LCA-related proteolytic and presumably neuroparalytic activity.


Efficacy and safety of saxagliptin for the treatment of type 2 diabetes mellitus.
Saxagliptin, a member of the dipeptidyl peptidase-4 inhibitor (DPP-4i) class of drugs, was approved by the FDA for the treatment of type 2 diabetes (T2D) in 2009, and has been in clinical use for more than a decade. Since the drug was first launched, much real-world evidence has also been accumulated. The efficacy and safety of saxagliptin, especially its cardiovascular safety, are of particular interest. This review provides an overview of the safety and efficacy of saxagliptin based on observational studies, pharmacovigilance, and meta-analyses. In addition, with the findings of recent cardiovascular outcome trials (CVOTs), the authors discuss, herein, the efficacious use of saxagliptin. Saxagliptin exhibits a moderate glucose-lowering effect and is well tolerated by patients with T2D. SAVOR-TIMI 53, a CVOT of saxagliptin, reported neutral effects of saxagliptin in respect of the cardiovascular outcomes, but did raise a concern about the risk of heart failure. Conversely, recent CVOTs on sodium-glucose co-transporter-2 inhibitors (SGLT2i) have shown a favorably reduced risk of heart failure with these drugs. Also, DPP-4is decrease the serum glucagon level, whereas the SGLT2is increase it. Given the characteristics of the two classes of drugs, combined therapy with the two might be a promising option.


HIV post-exposure prophylaxis provided at an urban paediatric emergency department to female adolescents after sexual assault.
In 1998, the New York State Department of Health released guidelines governing the provision of HIV post-exposure prophylaxis (HIV PEP) after adolescent and adult sexual assault. This study sought to examine the extent of HIV PEP provision in a New York City paediatric emergency department (ED) after the release of these guidelines. Using logs of the sexual assault and violence intervention advocacy programme, the authors identified patients who had been evaluated for sexual assault in the hospital's paediatric ED from January 1999 to December 2000. These patients' medical records were reviewed retrospectively for details of their sexual assault and the medical treatment they received in the paediatric ED. Of 25 patients identified from the hospital's affiliated sexual assault and violence intervention advocacy programme logs, 14 female adolescents had received HIV PEP. Each patient had suffered forced vaginal intercourse. Sixty four per cent of the survivors knew their assailant, but none knew his HIV status. No patients received HIV PEP within the optimal one hour prescription time, but no patient presented within the one hour window. Eighty six per cent presented >12 hours and 42% >24 hours after assault. HIV PEP was ordered an average of 218 minutes after the patient presented to the ED. Patients received drugs an average of 58 minutes after they were ordered. All but one patient received a three drug regimen. This study advocates improved efforts to expedite HIV PEP provision in the ED, such as educating ED practitioners on its proper use, and making HIV PEP drugs available for direct dispense from the ED.


Can Our Fingers Alone Raise Us Up to the Sky? Analysis of the Digit Ratio Association with Success in Olympic Wrestling.
The aim of this study is to analyse the contribution of the second to fourth digit ratio (2D:4D) to success in wrestling. A total of 180 elite wrestlers who participated in the 2011 Spanish Wrestling Championship took part in this study (132 men, 23.6 +/- 6.1 years old; 48 women, 21.7 +/- 4.9 years old). Prior to competition, wrestlers were interviewed about their years of training experience and their hands were scanned. 2D:4D was calculated using computer-assisted image analysis. A multinomial logistic regression coefficient to calculate odd ratios (OR's) and 95% confidence intervals (CI's) were established to determine the contribution of digit ratio and training experience to success in Olympic wrestling. Additionally, mean and median analyses were calculated between males and females, and between successful and non-successful wrestlers in order to establish differences in 2D:4D and training experience between these groups. There were no differences between successful and non-successful wrestlers in 2D:4D (p=0.87 for right hand, and p=0.46 for left hand), whereas having high training experience supposed an increase up to 4.38,(1.70-11.01) times more likely to be successful. Our results suggest that 2D:4D fails in predicting wrestling success, whereas training background is a good predictor of competition prowess in highly trained wrestlers.


Factors causing rickets in institutionalised handicapped children on anticonvulsant therapy.
An epidemiological study on vitamin D-dependent rickets was carried out in severely handicapped institutionalised children on long-term anticonvulsant therapy. Nine (10%) of 94 patients had overt rickets on the basis of roentgenological bone changes and biochemical indices, but 46 patients in hospital without medication, and 50 epileptic patients attending an outpatient clinic and taking anticonvulsants had no sign of rickets. Causative factors for the development of rickets were evaluated. Administration of anticonvulsive drugs depressed the serum 25-hydroxyvitamin D (25-OHD) level, but this was not the major factor in the development of rickets. Vitamin D intake seemed to be about average in these patients and its supplementation increased their serum 25-OHD level. This serum 25-OHD level was not maintained by supplemental vitamin D, unless the children were exposed to sunlight. These results indicate that although several factors--such as anticonvulsants, low vitamin D intake, and inactivity--are concerned in the development of rickets, the main cause is lack of sun in institutionalised handicapped children.


Enhanced immune-modulatory effects of thalidomide and dexamethasone co-treatment on T cell subsets.
Thalidomide (TM) has been reported to have anti-cancer and anti-inflammatory properties, and dexamethasone (DX) is known to reduce inflammation and inhibit production of inflammatory cytokines. Many studies have reported that combinatorial therapy with TM and DX is clinically used to treat multiple myeloma and lupus nephritis, but the mechanism responsible for its effects has not been elucidated. In this study, we determined that TM and DX co-treatment had an enhanced immune-modulatory effect on T cells through regulating the expression of co-stimulatory molecules. Splenic naive T cells from C57BL/6 mice were sort-purified and cultured for CD4+ T cell proliferation and regulatory T (Treg) cell conversion in the presence of TM and/or DX. Following incubation with the drugs, cells were collected and OX40, 4-1BB, and glucocorticoid-induced tumour necrosis factor receptor-related protein (GITR) expression was quantified by flow cytometry. TM (1 or 10 μm) decreased CD4+ T cell proliferation in a dose-dependent manner, whereas TM/DX (0·1 or 1 nm) co-treatment further decreased proliferation. Treg cell populations were preserved following drug treatment. Furthermore, expression of co-stimulatory molecules decreased upon TM/DX co-treatment in effector T (Teff) cells and was preserved in Treg cells. Splenic CD4+ T cells isolated from TM- and DX-treated mice exhibited the same patterns of Teff and Treg cell populations as observed in vitro. Considering the selective effect of TM on different T cell subsets, we suggest that TM may play an immunomodulatory role and that TM/DX combinatorial treatment could further enhance these immunomodulatory effects by regulating GITR, OX40, and 4-1BB expression in CD4+ T cells.


Early intravenous administration of nutritional support (IVANS) in metastatic gastric cancer patients at nutritional risk, undergoing first-line chemotherapy: study protocol of a pragmatic, randomized, multicenter, clinical trial.
Malnutrition is common in cancer patients, particularly in those affected by gastrointestinal malignancies, and negatively affects treatment tolerance, survival, functional status, and quality of life (QoL). Nutritional support, including supplemental parenteral nutrition (SPN), has been recommended at the earliest opportunity in malnourished cancer patients. The limited available evidence on the efficacy of SPN in gastrointestinal cancer patients is positive, particularly with regards to QoL, body composition, and energy intake, but the evidence on survival is still scanty. Furthermore, studies regarding the early administration of SPN in combination with nutritional counseling from the beginning of first-line chemotherapy (CT) are lacking. We hypothesize that early systematic SPN in combination with nutritional counseling (NC), compared with NC alone, can benefit patients with previously untreated metastatic gastric cancer at nutritional risk undergoing first-line CT. The aim of this pragmatic, multicenter, randomized (1:1), parallel-group, open-label, controlled clinical trial is to evaluate the efficacy in terms of survival, weight maintenance, body composition, QoL and feasibility of cancer therapy of early systematic SNP. This is in combination with NC, compared with NC alone, in treatment-naïve metastatic gastric cancer patients at nutritional risk undergoing first-line CT. Malnutrition in oncology remains an overlooked problem. Although the importance of SPN in gastrointestinal cancer patients has been acknowledged, no studies have yet evaluated the efficacy of early SPN in metastatic gastric patients undergoing CT. The present study, which guarantees the early provision of nutritional assessment and support to all the enrolled patients in accordance with the recent guidelines and recommendations, could represent one of the first proofs of the clinical effectiveness of early intensive nutritional support in cancer patients undergoing CT. This study could stimulate further large randomized trials in different cancer types, potentially resulting in the improvement of supportive care quality. This study is registered on ClinicalTrials.gov: NCT03949907.


[The combined treatment of patients with chronic nonspecific salpingo-oophoritis using a low-frequency magnetic field and iodobromine water].
The studies of 116 females with chronic nonspecific salpingo-oophoritis demonstrate that combination of low-frequency magnetic field with iodine-bromine water effectively corrects immunological indices, i.e. improves T- and B-cell immunity, production of IgM and IgA, proportion of immunoregulatory subpopulations of T-lymphocytes.


Highly sensitive iridium(iii) complex-based phosphorescent probe for thiophenol detection.
A cyclometalated iridium(iii) complex (Ir-DNBS) was designed and synthesized as a high-performance phosphorescent thiophenol probe. Ir-DNBS displays a distinct phosphorescence "off-on" response toward thiophenol with high selectivity, high sensitivity (detection limit: 2.5 nM) and fast response (10 min). It is noteworthy that the signaling phosphore of Ir-DNBS possesses relatively high photoluminescence quantum efficiency (ΦPL = 0.21) together with relatively long lifetime (τ = 2.07 μs), indicative of its potential in achieving high temporal resolution. Ir-DNBS is also applicable to the detection of thiophenol in actual water samples with high recovery rate. Photophysical and spectral characterization results revealed that the probing mechanism of Ir-DNBS toward thiophenol lies in the thiolate-mediated cleavage reaction, resulting in suppressed photo-induced excited state electron transfer process in the reaction product.


The effect of acclimation to hypoxia and sustained exercise on subsequent hypoxia tolerance and swimming performance in goldfish (Carassius auratus).
The objective of this study was to determine whether acclimation to hypoxia and sustained exercise would increase hypoxia tolerance (as indicated by a decrease in critical oxygen tension, P(crit)) and swimming performance in goldfish (Carassius auratus), and to investigate the relationship between changes in performance and gill remodelling and tissue metabolic capacity. Goldfish were acclimated to either hypoxia (48 h at 0.3 mg O(2) l(-1)) or sustained exercise (48 h at 70% of critical swimming speed, U(crit)) and then P(crit) and U(crit) were determined in normoxia (10 mg O(2) l(-1)) and hypoxia (1 mg O(2) l(-1)) and compared with values from control fish. Acclimation to both hypoxia and sustained exercise improved hypoxia tolerance (P(crit) was reduced by 49% and 39%, respectively), which was associated with an increase in lamellar surface area (71% and 43%, respectively) and an increase in blood [Hb] (26% in both groups). Exercise acclimation also resulted in a decrease in routine ( ). Acclimation to both hypoxia and sustained exercise resulted in a significant increase in U(crit) in hypoxia (18% and 17%, respectively), which was associated with an increase in maximal O(2) consumption rate at U(crit) ( ; 35% and 39%, respectively). While hypoxia acclimation resulted in an increase in U(crit) in normoxia, acclimation to sustained exercise did not improve subsequent swimming performance in normoxia. This lack of improvement was possibly due to depleted oxidizable substrates during exercise acclimation.


[Inhibitory effects of serotonin and sodium ascorbate on the oxidative aggregation of lipoproteins].
Milk lipoproteins (MLPs) are structurally and biochemically similar to blood lipoproteins, which allow the former to be used as model objects for studying the properties of the latter. The results of turbidimetric measurements showed a change in the light scattering from MLP suspensions upon contact with Fe3+ ions in the free from or in chelate complexes with o-phenanthroline and EDTA. No such effect was observed for Fe2+ ions. The effect of Cu2+ ions (in microscopic amounts) was similar to that of Fe3+, while Ca2+ and Mg2+ produce no effect. It was found that 1,1-azabicyclohexanecarbonitrile-2-methylpropionamidine dihydrochloride (an azoinitiator capable of spontaneous decomposition with the formation of peroxide radicals in an oxygen containing-medium) introduced into an MLP suspension produces the same effect as Fe3+ and Cu2+ ions. Study of the particle size distribution in a microcapillary by the method of impedance measurements showed that a change in the light scattering from the suspension is caused by the MLP aggregation. The action of aggregation factors upon the MLPs led to their oxidation, as indicated by accumulation of the TBA-active products. The ability of copper ions to oxidize MLPs agrees with the data reported on the copper-ion-induced oxidation of blood lipoproteins, which was observed in studying a relationship between this oxidation and clinical manifestations of atherosclerosis. Thus, pronounced oxidation of both milk an blood lipoproteins in the presence of microscopic amounts of copper ions is indicative of a similarity of these processes. The process of lipoprotein aggregation induced by various oxidizing agents is inhibited by sodium ascorbate and serotonin. At the same time, beta-naphthol (an antioxidant soluble in lipids) does not affect the aggregation process. It is suggested that the oxidative aggregation of lipoproteins mag be related to the problem of atherogenesis and thrombogenesis.


Threat to occupational status control and cardiovascular risk.
Individuals exposed to chronically stressful social contexts were show n to suffer from increased cardiovascular risk. High effort at work in combination with low reward, and especially with low control over one's occupational status, defines one such stressful social context. In this study an association between high effort, low occupational status control and hypertension as well as the co-manifestation of hypertension and elevated atherogenic lipids [coronary high risk (CHR) status] is explored in a group of 179 middle-aged (48.5+/-6.5 years) male managers. After adjustment for relevant covariates, logistic regression analysis showed independent effects of indicators of high extrinsic effort [time pressure: odds radio (OR)=5.31 95% confidence intervals (95%-C1): 1.10-25.57; severe problems: OR = 4.64 95% Cl: 1.37-15.68] and of low status control (forced job change: OR = 3.92 95% Cl: 1.29-11.92) on CHR. Similar, but less powerful effects were observed with respect to the criterion of hypertension. In conclusion, our findings indicate that effort-reward imbalance at work, and especially threatened status control, defines an independent psychosocial risk constellation with relevance to cardiovascular disease.


Biochemical characteristics and biological properties of Annurca apple cider.
Our work aimed to investigate the phenolic composition and antioxidant capacity of the de-alcoholized extract of cider obtained from the Annurca apple (Malus domestica var. Annurca). The antimicrobial effect of the extract against different pathogens, including Chronobacter sakazakii, was also examined. The extract's potential anti-quorum-sensing (AQS) activity was assessed using the test microorganism Chromobacterium violaceum. Biochemical analysis of the extract using ultra-performance liquid chromatography revealed catechin and caffeic acid as the most abundant polyphenols present, which represented about 35.5% and 36.6% of the total phenolics identified, respectively. An antioxidant capacity was also found (50% effective concentraiton=10 μL). The extract exhibited clear antimicrobial activity against all strains used in the experiments. Escherichia coli and Bacillus cereus were the most sensitive bacteria to the antimicrobial activity. The extract also inhibited the growth of the emergent pathogen strain C. sakazakii. The AQS activity of apple cider is reported here for the first time. In conclusion, our results demonstrate some biological properties of the apple cider and contribute to reinforcing the potential of the apple and its derivatives as functional components of the diet.


The effect of age on the pharmacokinetics of oxprenolol.
The pharmacokinetics of oxprenolol have been studied in young and healthy elderly volunteers. Drug concentrations in plasma and urine have been measured after a single 80-mg dose of oxprenolol and again after repeated administration (80 mg twice daily) for a period of 1 week. It has been shown that multiple dosing does not result in oxprenolol accumulation in either group and that age has no effect on the pharmacokinetics of this drug.


Correlates and economic outcomes of proton pump inhibitor use by routes in intensive care unit patients.
Objectives were to evaluate correlates, and economic outcomes of proton pump inhibitor (PPI) use by route in the intensive care unit from an institutional-payer perspective. A 13-month retrospective study of electronic medical records was conducted of 534 adult (≥19 year-old) intensive care unit patients receiving a PPI (39% enteral-only, 34% parenteral-only, 27% both-route) in a Midwest USA academic medical center. Possible cost-savings with sensitivity analysis were estimated as differences in drug costs (US dollars) between switch eligible parenteral and alternate enteral-PPI medication doses. In multivariate logistic-regression of switch criteria (any oral-medication, orogastric-tube, nothing by oral route), significant correlate for enteral versus parenteral PPI-use was any oral-medication use but not orogastric-tube. Using enteral esomeprazole/lansoprazole instead of parenteral (esomeprazole/pantoprazole) PPI (in 37% i.e. 696 of 1895 switch-eligible doses) would have saved US$2384.17 or US$3564.86, respectively. By switching eligible patients on oral-medications or on orogastric-tube from parenteral- to enteral-PPI, institutions can realize significant drug cost-savings.


Phase-matching and mitigation of four-wave mixing in fibers with positive gain.
We present a theoretical study of four-wave mixing interactions in fibers in the presence of gain. In contrast to passive fibers, positive gain at the pump wavelength leads to constructive generation of the signal and idler waves, even in the case of large phase-mismatch, so that FWM processes can be very efficient even in isotropic single-mode fibers with normal dispersion. We also propose simple ways to mitigate these parametric interactions by applying a controlled variation of the phase-mismatch along the fiber. These concepts apply to all optical amplifiers.


Extracorporeal membrane oxygenation for the management of respiratory failure due to ANCA-associated vasculitis.
We present here two patients whose near fatal respiratory distress was caused by pulmonary hemorrhage, and who were treated successfully by extracorporeal membrane oxygenation (ECMO). The underlying disease was anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis. They were initially treated with methylprednisolone pulse therapy along with cyclophosphamide. However, their respiratory failure progressed with a low PaO2/FiO2 ratio (< 100 mmHg) despite mechanical ventilation, and ECMO was initiated. After several days, the pulmonary hemorrhage subsided, and the patients were weaned successfully from ECMO. We suggest that ECMO may be used to manage life-threatening pulmonary hemorrhage in patients suffering from ANCA-associated systemic vasculitis.


Human motor augmentation with an extra robotic arm without functional interference.
Extra robotic arms (XRAs) are gaining interest in neuroscience and robotics, offering potential tools for daily activities. However, this compelling opportunity poses new challenges for sensorimotor control strategies and human-machine interfaces (HMIs). A key unsolved challenge is allowing users to proficiently control XRAs without hindering their existing functions. To address this, we propose a pipeline to identify suitable HMIs given a defined task to accomplish with the XRA. Following such a scheme, we assessed a multimodal motor HMI based on gaze detection and diaphragmatic respiration in a purposely designed modular neurorobotic platform integrating virtual reality and a bilateral upper limb exoskeleton. Our results show that the proposed HMI does not interfere with speaking or visual exploration and that it can be used to control an extra virtual arm independently from the biological ones or in coordination with them. Participants showed significant improvements in performance with daily training and retention of learning, with no further improvements when artificial haptic feedback was provided. As a final proof of concept, naïve and experienced participants used a simplified version of the HMI to control a wearable XRA. Our analysis indicates how the presented HMI can be effectively used to control XRAs. The observation that experienced users achieved a success rate 22.2% higher than that of naïve users, combined with the result that naïve users showed average success rates of 74% when they first engaged with the system, endorses the viability of both the virtual reality-based testing and training and the proposed pipeline.


Cross-Regional Research in Demographic Impact on Safety Consciousness and Safety Citizenship Behavior of Construction Workers: A Comparative Study between Mainland China and Hong Kong.
The construction industry has rapidly developed with continuous prosperity in Hong Kong and Mainland China, although accidents still occur with unacceptable frequency and severity. For promoting the safety issue of workers in construction industry, safety citizenship behavior (SCB) and safety consciousness (SC) were considered two influential constructs and further studied with integration of sociodemographic theories by scholars. However, no study has compared the SC and SCB of construction workers in terms of the demographic influence between Mainland China and Hong Kong. To fill this research gap, this study investigated the territorial difference between these two regions by conducting a cross-sectional questionnaire survey with recruitment of 253 Mainland construction workers and 256 Hong Kong construction workers. Significant similarities and differences of SC and SCB performance were revealed in terms of the workers with different genders, education levels, weekly working hours, and ages. This study provides insights into the comparison of demographic influence on SC and SCB of construction workers between Hong Kong and Mainland China, which is unique as it can yield useful managerial knowledge relevant to the personal safety of targeted groups of construction workers with particular demographic characteristics in both regions and contribute the implementation of safety interventions in line with the specific distinction in the territorial aspect.


Resolving sub-diffraction limit encounters in nanoparticle tracking using live cell plasmon coupling microscopy.
We use plasmon coupling between individual gold nanoparticle labels to monitor subdiffraction limit distances in live cell nanoparticle tracking experiments. While the resolving power of our optical microscope is limited to approximately 500 nm, we improve this by more than an order of magnitude by detecting plasmon coupling between individual gold nanoparticle labels using a ratiometric detection scheme. We apply this plasmon coupling microscopy to resolve the interparticle separations during individual encounters of gold nanoparticle labeled fibronectin-integrin complexes in living HeLa cells.


Recombinant IL 2 but not recombinant interferon-gamma stimulates both proliferation and IgM secretion in a Ly-1+ clone of neoplastic murine B cells (BCL1).
We have used a lymphokine-responsive clone (3B3) of B leukemia cells (BCL1) to examine the effects of several recombinant and purified lymphokines. Cells from BCL1-3B3 were induced to secrete IgM in the presence of recombinant interleukin 2 (rIL 2) (10 to 50 U/ml); a concomitant increase in proliferation was observed. Recombinant interferon-gamma (rIFN-gamma) was a potent inhibitor of proliferation. In addition, rIFN-gamma did not induce an increase in IgM secretion and, when added to rIL 2-stimulated BCL1-3B3 cells, completely blocked IgM secretion at a concentration of 10 U/ml. Purified and recombinant IL 1 (rIL 1) had no significant effect on differentiation either alone or in combination with rIL 2 and/or rIFN-gamma. However, rIL 1 was able to synergize with rIL 2 in enhancing the proliferation of BCL1-3B3. The ability of cells to respond to rIL 2 was limited to the in vitro (Ly-1+) clones of BCL1 cells since the in vivo derived (Ly-1-) BCL1 cells did not differentiate in response to IL 2. Consistent with their functional response to rIL 2, cells from the in vitro clone (3B3) are IL 2-receptor-positive (IL-2R+) and the in vivo derived BCL1 cells are IL-2R-. A second set of neoplastic B cell clones derived from the AKR 225 lymphoma did not respond to rIL 2 even though they expressed receptors for IL 2 and could be induced by T cell supernatant to secrete IgM, thus indicating that expression of IL 2R is not the sole requirement for IL 2 responsiveness. The monoclonal anti-IL 2R antibody (7D4) mimicked IL 2 in its ability to stimulate differentiation of BCL1-3B3 cells. These data suggest that rIL 2 and the monoclonal anti-IL-2R antibody are capable of inducing a differentiative response in the Ly-1+ BCL1-3B3 cells that is functionally equivalent to the response evoked by the previously described lymphokine B cell differentiation factor for IgM (BCDF mu). Thus, two distinct lymphokines appear to be providing a similar signal to a clonal neoplastic B cell population. Furthermore, rIL 2 is capable of providing both a proliferative and a differentiative signal.


Impact of Cancer Awareness Drive on Generating Understanding and Improving Screening Practices for Breast Cancer: a Study on College Teachers in India
Background: Breast cancer is the most common cancer among women in India and most present at advanced stage. Although early detection is the only way to reduce morbidity and mortality, people have a very low awareness about breast cancer signs and symptoms and screening practices. The purpose of this study was to assess the level of awareness and impact of awareness programs in adoption of safe practices in prevention and early detection. Methods: This assessment was part of a pink chain campaign on cancer awareness. During events from 2011 to 2015 at various women colleges in different parts in India, a pre-test of knowledge related to breast cancer was followed by an awareness program. Post-tests using the same questionnaire were conducted at the end of the interactive sessions, at 6 months and after1 year. Results: A total of 872 out of 985 teachers participated in the study (overall response rate of 88.5 %). Mean age of the study population was 41.6 years (range 28-59 yrs). There was a significant increase in level of knowledge regarding breast cancer at 6 months and this was sustained at 1 year. Adoption of breast self-examination (BSE) was significantly more frequent in comparison to CBE and mammography. Magazines and newspapers were sources for knowledge regarding screening tests for breast cancer for more than 60% of teachers. Regarding post-awareness at 6 months and 1 year, there was a significant change in alcohol and smoking habits. Major reasons came out to be ignorance (83%) at the start of the campaign which was changed to lack of time (37.7%), lethargic attitude (32.2 %) and lack of time (31.5 %) at 6 months and same at 1 year also. Conclusions: With our awareness program there was a significant increase in level of knowledge regarding breast cancer at 6 months and this was sustained at 1 year. Adoption of BSE was significantly greater in comparison to CBE, mammography. To inculcate safe lifestyle practices in people, awareness programmes such as pink chain campaigns should be conducted more widely and frequently.


The social determinants and starting and sustaining quit attempts in a national sample of Aboriginal and Torres Strait Islander smokers.
To assess whether social, economic and demographic measures are associated with initiating and sustaining quit attempts in a national sample of Aboriginal and Torres Strait Islander smokers. We analysed data from 759 adults who reported smoking at least weekly in the Talking About The Smokes baseline survey (April 2012 - October 2013) and completed a follow up survey a year later (August 2013 - August 2014). Almost none of the standard baseline socioeconomic indicators predicted making or sustaining quit attempts. However, becoming employed was associated with making quit attempts (OR 1.88) and both becoming employed (OR 3.03) and moving to purchase a home (OR 2.34) were both positively associated with sustaining abstinence of one month or more. More smokers who had insufficient money for food or essentials because of money spent on cigarettes had made a quit attempt (OR 1.47) and sustained abstinence of one month or more (OR 1.74). Disadvantage does not seem to have pervasive negative effects on quitting. We should be more optimistic in our tobacco control activities with the most disadvantaged among Aboriginal and Torres Strait Islander smokers. Increasing personal empowerment (e.g. getting a job) may lead to at least short-term improvements in quitting.


Work and sick leave among patients with early inflammatory joint conditions.
To study the occurrence of sick leave and to identify work characteristics related to sick leave in patients with early inflammatory joint conditions. Patients with inflammatory joint conditions present for <12 months were included in this cross-sectional study. Approximately 85% of patients satisfying the criteria participated. Data collection included demographics, clinical characteristics, pain, physical functioning and mental health (Short Form 36), fatigue, and behavioral coping (Coping of Rheumatic Stressors questionnaire). Work characteristics included physical load, psychosocial load, job control, and support at work. Outcome was defined as sick leave for >2 weeks during the past 6 months. Multiple logistic regression analysis was conducted. Sick leave was reported by 54 (26%) of 210 employed patients, with 75% of the sick leave periods attributed to joint conditions. Of these 210 patients, 23% were classified as having rheumatoid arthritis (RA), 35% as having non-RA arthritis, and 42% as having inflammatory joint conditions without synovitis. Pain, poor physical functioning, and passive behavioral coping were related to increased sick leave, whereas diagnostic group was not. Low job control, i.e., low control over planning and pacing of activities within the job, was associated with increased sick leave (odds ratio [OR] 2.74), whereas being a supervisor (OR 0.21) and clerical work (OR 0.45) were related to reduced sick leave. Substantial sick leave in the past 6 months was reported by 26% of patients with early inflammatory joint conditions. Pain, functional limitations, and fewer opportunities to determine one's work activities were associated with the occurrence of sick leave.


A circular RNA derived from MMP9 facilitates oral squamous cell carcinoma metastasis through regulation of MMP9 mRNA stability.
Emerging evidence demonstrates that dysregulation of circular RNA is linked to tumorigenesis and aggressive progression. However, its role in oral squamous cell carcinoma remains largely uncharacterized. In this study, we identified a novel metastasis-associated circular RNA, circular matrix metalloproteinase 9 (hsa_circ_0001162, a circular RNA derived from matrix metalloproteinase 9), which was remarkably upregulated in oral squamous cell carcinoma and positively correlated with matrix metalloproteinase 9 expression. Patients with high circular matrix metalloproteinase 9 expression were prone to lymph node metastasis and an advanced TNM stage. Importantly, circular matrix metalloproteinase 9 was identified as an efficacious diagnostic and prognostic biomarker for oral squamous cell carcinoma patients. Functional experiments showed that depletion of circular matrix metalloproteinase 9 weakened the migratory and invasive capabilities of oral squamous cell carcinoma cells in vitro as well as inhibited lung metastasis in vivo. Regarding the mechanism, circular matrix metalloproteinase 9 could simultaneously interact with AUF1 and miR-149 to block the inhibitory effect of AUF1 and miR-149 on matrix metalloproteinase 9 3'-untranslated region, resulting in enhanced matrix metalloproteinase 9 messenger RNA stability, thereby facilitating oral squamous cell carcinoma metastasis. Collectively, our data indicate that circular matrix metalloproteinase 9 acts as a metastasis-promoting gene in oral squamous cell carcinoma through regulating the messenger RNA stability of its parental gene. Therapeutic targeting of circular matrix metalloproteinase 9 may be a promising treatment intervention for metastatic oral squamous cell carcinoma patients.


Plasmonic Optical Imaging of Gold Nanorods Localization in Small Animals.
Gold nanoparticles (GNP) have been intensively investigated for applications in cancer imaging and therapy. Most imaging studies focused on microscopic imaging. Their potential as optical imaging probes for whole body small animal imaging has rarely been explored. Taking advantage of their surface plasmon resonance (SPR) properties, we aim to develop a noninvasive diffuse optical imaging method to map the distribution of a special type of GNP, gold nanorods (GNR), in small animals. We developed an integrated dual-modality imaging system capable of both x-ray computed tomography (XCT) and diffuse optical tomography (DOT). XCT provides the animal anatomy and contour required for DOT; DOT maps the distribution of GNR in the animal. This SPR enhanced optical imaging (SPROI) technique was investigated using simulation, phantom and mouse experiments. The distribution of GNR at various concentrations (0.1-100 nM, or 3.5 ug/g-3.5 mg/g) was successfully reconstructed from centimeter-scaled volumes. SPROI detected GNR at 18 μg/g concentration in the mouse breast tumor, and is 3 orders more sensitive than x-ray imaging. This study demonstrated the high sensitivity of SPROI in mapping GNR distributions in small animals. It does not require additional imaging tags other than GNR themselves. SPROI can be used to detect tumors targeted by GNR via passive targeting based on enhanced permeability and retention or via active targeting using biologically conjugated ligands.


Multiple antigen peptide containing B and T cell epitopes of F1 antigen of Yersinia pestis showed enhanced Th1 immune response in murine model.
Yersinia pestis is a facultative bacterium that can survive and proliferate inside host macrophages and cause bubonic, pneumonic and systemic infection. Apart from humoral response, cell-mediated protection plays a major role in combating the disease. Fraction 1 capsular antigen (F1-Ag) of Y. pestis has long been exploited as a vaccine candidate. In this study, F1-multiple antigenic peptide (F1-MAP or MAP)-specific cell-mediated and cytokine responses were studied in murine model. MAP consisting of three B and one T cell epitopes of F1-antigen with one palmitoyl residue was synthesized using Fmoc chemistry. Mice were immunized with different formulations of MAP in poly DL-lactide-co-glycolide (PLGA) microspheres. F1-MAP with CpG oligodeoxynucleotide (CpG-ODN) as an adjuvant showed enhanced in vitro T cell proliferation and Th1 (IL-2, IFN-γ and TNF-α) and Th17 (IL-17A) cytokine secretion. Similar formulation also showed significantly higher numbers of cytokine (IL-2, IFN-γ)-secreting cells. Moreover, F1-MAP with CpG formulation showed significantly high (P < 0.001) percentage of CD4(+) IFN-γ(+) cells as compared to CD8(+) IFN-γ(+) cells, and also more (CD4- IFN-γ)(+) cells secrete perforin and granzyme as compared to (CD8- IFN-γ)(+) showing Th1 response. Thus, the study highlights the importance of Th1 cytokine and existence of CD4(+) and CD8(+) immune response. This study proposes a new perspective for the development of vaccination strategies for Y. pestis that trigger T cell immune response.


Bispectral index in calves anesthetized with xylazine, midazolam, ketamine, isoflurane and subjected to continuous rate infusion of lidocaine.
To assess the bispectral index (BIS) and recovery in calves anesthetized with xylazine, midazolam, ketamine and isoflurane and subjected to CRI of lidocaine. Xilazine was administered followed by ketamine and midazolam, orotracheal intubation and maintenance on isoflurane using mechanical ventilation. Lidocaine (2 mg kg(-1) bolus) or saline (0.9%) was administered i.v. followed by a CRI (100 µg kg(-1) minute(-1)) of lidocaine (L) or saline (C). Were recorded BIS, heart rate (HR), mean arterial pressure (MAP) and rectal temperature (RT) before administration of premedication (TB) and 15 minutes after (TX), before administering lidocaine (T0) and 20, 40, 60 and 80 minutes after the start of the CRI . Time do sternal recumbency (SRE) and standing (ST) and plasma lidocaine concentration also evaluated. In both treatments BIS decreased significantly at all times compared to TB. TX was higher than the subsequent times. HR decreased from baseline at all times and decreased from T40 in L compared to C. SRE was higher in L compared to C. Bispectral index values were consistent with the degree of hypnosis of the animals. Lidocaine did not potentiate isoflurane anesthesia assessed by BIS in unstimulated calves anesthetized with constant E´Iso. Lidocaine increased the time to sternal recumbency.


Representation of mRNA sequences in normal and SV40 transformed human diploid fibroblasts.
The representation of mRNA sequences in normal and SV40-transformed WI-38 human diploid fibroblasts was examined. Variations in the hybridization of polysomal RNAs to 3H-labeled DNAs complementary to poly A+ mRNA of normal and SV40-transformed cells suggest differences in the mRNA populations. a comparison of the representation of histone RNA sequences of normal and SV40-transformed human diploid cells did not reveal significant differences.


Efficient Synthesis of α-Haloboronic Esters via Cu-Catalyzed Atom Transfer Radical Addition.
The synthesis of α-haloboronic esters via atom transfer radical addition (ATRA) is constrained due to its limited range of compatible substrates or the need to manipulate the olefin coupling partners. Herein, we present a novel approach for their synthesis via Cu-catalyzed ATRA to vinyl boronic esters. The catalyst is proposed to mediate a traditionally inefficient halogen atom transfer of the α-boryl radical intermediate, thus significantly expanding the range of participating substrates relative to established methods. The forty-eight examples illustrate that a wide range of radical precursors, including primary, secondary, and tertiary alkyl halides, readily add across both unsubstituted and α-substituted vinyl pinacol boronic esters. Further, a one-pot, two-step protocol is presented for direct access to an array of α-functionalized products. Finally, the synthetic utility of this methodology is demonstrated in the synthesis of an ixazomib analogue.


Pharmacokinetics of melphalan in isolated perfusion of the limbs.
The pharmacokinetics of melphalan (L-phenylalanine mustard) in isolated perfusion treatment of patients with melanoma in the limbs have been studied at standardized pseudo-physiological perfusion conditions. Perfused tissue volumes ranged from 2.1 to 16 liters as measured by water displacement. A fixed dose of 10 mg of the drug per liter of perfused tissue was applied. The resulting variation in total melphalan dosage gave rise to varying drug concentrations in the perfusate as the extracorporeal system was operated with a fixed volume of priming fluid. Perfusion with melphalan was applied for 60 min. Concentrations of intact drug were assayed by high-performance liquid chromatography. The melphalan concentrations vs. time for each patient were fitted to a biexponential equation using a nonlinear least-squares computer program. Mean half-lives of 4.7 +/- 0.3 and 53.0 +/- 1.6 min were obtained for the alpha and beta phase, respectively. The hybrid constant alpha remained virtually constant with increasing dose (i.e., increasing drug concentration) and beta also appeared independent of dose levels. With increasing tissue volume plasma clearance was found to diminish per unit of tissue volume. This phenomenon, and a levelling off of the steady-state distribution volume with increasing volume of perfused tissue, are discussed in terms of a possibly restricted transfer of drug from intravascular to the extracellular space and of the possibility of saturation of cellular uptake systems in the bulk of the limb tissues.


[The effectiveness of glass bead sterilizer in the dental practice].
Although it is not FDA-approved as inter-patients sterilization measure, in Israel, glass bead sterilizer is still a common method for chair-side sterilization of small dental hand instruments, especially endodontic files. Studies from the 1950-1970s achieved sterilization by the bead sterilizer within few seconds. Nevertheless, there are no current evidence-based instructions for using this sterilizer. The study was designed to evaluate the effectiveness of this method in sterilization of endodontic files, according to current microbiologic knowledge. Standard endodontic k-files (#15, 50, 80) were sterilized in a steam autoclave and then soaked in Actinomyces israelii, Eikenella corrodens or Bacillus cereus [0.5 MacFarland] media for 10 sec. After drying, the files were placed in 225 degrees C or 250 degrees C-heated glass bead sterilizers for 0, 15, 30 or 60 sec. After appropriate incubation for 10 d, morphologic and biochemical examinations were performed to reveal bacterial growth. Files that have been contaminated with A. israelii were sterilized within 30 sec, whereas B. cereus and E. corrodens-contaminated files needed 60 sec for sterilization. The use in bead sterilizer has to be limited only for sterilization of intra-appointment purpose. However, it seems that the common method of using bead sterilizer for sterilization time of few seconds is not effective. In order to eliminate spore-forming bacteria, like B. cereus, by bead sterilizer, the sterilization time has to be at least 60 sec. More research is needed, however, for establishing the effectiveness of the bead sterilizer for viral infection control and for other dental instruments.


Development of a capillary electrophoresis method based on magnetic solid-phase extraction using Pt-Co-MWCNTs-COOH as magnetic adsorbents for simultaneous and sensitive detection of eight biogenic amines in foods.
Biogenic amines (BAs) in high concentrations are toxic and may cause a series of health symptoms. A sensitive measurement of BAs levels is essential for human health. Capillary electrophoresis (CE) has emerged for the separation of eight BAs due to simple sample preparation and highly efficient separation. However, an important drawback for CE is low sensitivity. Magnetic solid-phase extraction (MSPE) has entered our field of vision owning to its brief operation and low solvent consumption. Hence, MSPE as the pre-treatment has great potential to improve CE sensitivity for the analysis of BAs in complex food. Results showed that the Pt-Co-MWCNTs-COOH possessed strong magnetism, good reusability, and high adsorptive ability toward eight biogenic amines based on the hydrogen bonding between the -COOH of Pt-Co-MWCNTs-COOH and -NH2 groups of BAs. Using it as an adsorbent, a magnetic solid-phase extraction coupled with capillary electrophoresis (MSPE-CE) method was developed to effectively extract and sensitively analyze eight BAs. Under optimal conditions, the MSPE-CE method has wide linearities (10.0-1000.0 μg L-1 ) and low limits of detection (1.0-6.1 μg L-1 ). The accuracy of the developed method yielded recovery values from 82.07% to 102.58%. Meanwhile, the BAs contents in two samples were analyzed using the MSPE-CE method, with the results consistent with those detected by a high-performance liquid chromatography method. Given those advantages, the established MSPE-CE method promises the practical guidance of monitoring a variety of BAs and provides a foundation for the detection of other food hazards. This article is protected by copyright. All rights reserved.


"A new deal for the drug addict": the Addiction Research Center, Lexington, Kentucky.
This article describes the social organization of knowledge production in the formative moments of the substance abuse research enterprise. It describes the institutional arrangements and material conditions of a U.S. Public Health Service laboratory that was housed in a facility run jointly with the federal Bureau of Prisons. The Addiction Research Center (ARC) in Lexington, Kentucky, was dedicated to elucidating the basic underlying mechanisms of drug addiction. The ARC was housed on the rural campus of a prison-hospital called "Narco," one of two "narcotics farms" in Lexington, Kentucky, and Fort Worth, Texas. For its studies on drug effects, the ARC had access to a pool of drug-experienced human subjects drawn from the ranks of convicted felons. Given their unparalleled access to human subjects, the scientists who worked at the ARC made conceptual contributions still acknowledged today. Based on archival work as well as dozens of oral history interviews with individuals who began their research careers at Lexington, the article presents an analytic, intellectual history of the early work of Abraham Wikler, whose lifelong pursuit of the underlying mechanisms of opiate addiction led him to hypothesize the role of conditioning in relapse, as an exemplar of the kind of scientific research that depended on closely listening to and observing "post-addicts," as subject participants were called.


Phospholipase C-related catalytically inactive protein participates in the autophagic elimination of Staphylococcus aureus infecting mouse embryonic fibroblasts.
Autophagy is an intrinsic host defense system that recognizes and eliminates invading bacterial pathogens. We have identified microtubule-associated protein 1 light chain 3 (LC3), a hallmark of autophagy, as a binding partner of phospholipase C-related catalytically inactive protein (PRIP) that was originally identified as an inositol trisphosphate-binding protein. Here, we investigated the involvement of PRIP in the autophagic elimination of Staphylococcus aureus in infected mouse embryonic fibroblasts (MEFs). We observed significantly more LC3-positive autophagosome-like vacuoles enclosing an increased number of S. aureus cells in PRIP-deficient MEFs than control MEFs, 3 h and 4.5 h post infection, suggesting that S. aureus proliferates in LC3-positive autophagosome-like vacuoles in PRIP-deficient MEFs. We performed autophagic flux analysis using an mRFP-GFP-tagged LC3 plasmid and found that autophagosome maturation is significantly inhibited in PRIP-deficient MEFs. Furthermore, acidification of autophagosomes was significantly inhibited in PRIP-deficient MEFs compared to the wild-type MEFs, as determined by LysoTracker staining and time-lapse image analysis performed using mRFP-GFP-tagged LC3. Taken together, our data show that PRIP is required for the fusion of S. aureus-containing autophagosome-like vacuoles with lysosomes, indicating that PRIP is a novel modulator in the regulation of the innate immune system in non-professional phagocytic host cells.


FSGS permeability factor-associated nephrotic syndrome: remission after oral galactose therapy.
Some cases of nephrotic syndrome in focal and segmental glomerulosclerosis (FSGS) are associated with a circulating factor, the FSGS permeability factor (FSPF). Galactose has a high affinity for FSPF, and experimental data suggest that it could reduce its activity. We describe the case of a 48-year-old male with a nephrotic syndrome found to be resistant to corticosteroids, immunosuppression and plasmaphaeresis. The patient was given oral galactose as a last resort treatment, which was followed by a remission of his nephrotic syndrome that correlated with a reduction of FSPF activity. This case is the first report of a long-standing remission of an FSPF-associated nephrotic syndrome on oral galactose therapy.


Combination of compositional data analysis and machine learning approaches to identify sources and geochemical associations of potentially toxic elements in soil and assess the associated human health risk in a mining city.
Mining activities change the chemical composition of the environment and have negative reflection on people's health and there is no single measure to deal with adverse consequences of mining activities, as each case is specific and needs to be understood and mitigated in a unique way. In this study, the combination of compositional data analysis (CoDA), k-means algorithm, hierarchical cluster analysis applied to reveal the geochemical associations of potentially toxic elements (PTE) in soil of Alaverdi city (Armenia) (Ti, Fe, Ba, Mn, Co, V, Pb, Zn, Cu, Cr, Mo, As). Additionally, to assess PTE-induced health risk, two commonly used approaches were used. The obtained results show that the combination of CoDA and machine learning algorithms allow to identify and describe three geochemical associations of the studied elements: the natural, manmade and hybrid. Moreover, the revealed geochemical associations were linked to the natural pattern of distribution of the element concentrations including the influence of the natural mineralization of the parent rocks, as well as the emission from the copper smelter and urban management related activities. The health risk assessment using the US EPA method demonstrated that the observed contents of studied elements are posing a non-carcinogenic risk to children in the entire territory of the city. In the case of adults, the non-carcinogenic risk was identified in areas situated close to the copper smelter. The Summary pollution index (Zc) values were in line with the results of the US EPA method and indicated that the main residential part of the city was under the hazardous pollution level suggesting the possibility of increase in the overall incidence of diseases among frequently ill individuals, children with chronic diseases and functional disorders of vascular system. The obtained results indicated the need for further in-depth studies with special focus on the synergic effect of PTE.


Differential regulation of cytochrome P450 genes associated with biosynthesis and detoxification in bifenthrin-resistant populations of navel orangewom (Amyelois transitella).
Pyrethroid resistance was first reported in 2013 for the navel orangeworm, Amyelois transitella, but the genetic underpinnings of pyrethroid resistance are unknown. We investigated the role of cytochrome P450 monooxygenases (P450s) belonging to the CYP3 and CYP4 clans using colonies derived from individuals collected in 2016 from almond orchards in two counties. One colony (ALM) originated from an almond orchard in Madera County with no reported pyrethroid resistance and the second colony (R347) originated from the same Kern County orchard where pyrethroid resistance was first reported. We used high-throughput quantitative real-time PCR (qRT-PCR) analyses of 65 P450s in the CYP3 and CYP4 clans of A. transitella to identify P450s induced by bifenthrin and associated with pyrethroid resistance. Nine P450s were constitutively overexpressed in R347 compared to ALM, including CYP6AE54 (11.7-fold), belonging to a subfamily associated with metabolic pesticide detoxification in Lepidoptera and CYP4G89 (33-fold) belonging to a subfamily associated with cuticular hydrocarbon (CHC) synthesis and resistance via reduced pesticide penetrance. Cuticular hydrocarbons analysis revealed that R347 produced twice as many total CHCs in the egg and adult stages as ALM. Topical toxicity bioassays for R347 determined that egg mortality was reduced at low bifenthrin concentrations and larval mortality was reduced at high concentrations of bifenthrin compared to ALM. Our discovery of both changes in metabolism and production of CHCs for R347 have implications for the possible decreased efficacy of other classes of insecticide used to control this insect. The threat of widespread pyrethroid resistance combined with the potential for cross-resistance to develop through the mechanism of reduced penetrance warrants developing management strategies that facilitate insecticide passage across the cuticle.


Enhancing Psychological Sexual Health of People With Spinal Cord Injury and Their Partners in an Italian Unipolar Spinal Unit: A Pilot Data Study.
Like the slogan of the American Consortium for Spinal Cord Medicine says, "No injury, no matter how serious, can take away your ability to have a relationship, experience love, and experience the attraction between two people." However, people with spinal cord injury (SCI) have to fight with their own and societal attitudes and stereotypes that limit sexuality to the physiological functions of genitalia, phallocentric primacy of sexual pleasure, and sexual attractiveness of perfect bodies. The scope of the present study is to evaluate the impacts of a psychoeducational intervention in a personal growth group on the sexual life of seven people with SCI and four of their partners particularly their sexual interest and satisfaction, depression, and anxiety. Due to the small samples size, nonparametric statistical tests were used to compare pre- and post-outcome measures for all participants: patients and the partners group. Possible effects of gender were also considered. The effectiveness of the psychoeducational intervention was clearly apparent, showing a high effect size in improving sexual interest and satisfaction, and the opportunity and ability to enjoy sexuality. A reduction of anxiety was also observed for all participants, although it may not have been related to the psychoeducational intervention. Moreover, the intervention significantly improved the opportunity and ability to enjoy sexuality for the partner and patient group. No effect was found on depression. This was the first initiative in Italy aiming to address the sexual life and not only to cure the sexual dysfunction of people with SCI. The positive, clear evidence of the validity of the Love & Life project's intervention bodes well for new psychoeducational initiatives that in Italy meet the sexual needs of people with SCI and their partners, providing adequate education and psychological support, involving partners, and creating a space to talk among peers.


Cytochrome P450 2E1-deficient MRL+/+ mice are less susceptible to trichloroethene-mediated autoimmunity: Involvement of oxidative stress-responsive signaling pathways.
Reactive trichloroethene (TCE) metabolites and oxidative stress are involved in TCE-mediated autoimmunity, as evident from our earlier studies in MRL+/+ mice. However, molecular mechanisms underlying the autoimmunity remain largely unknown. Cytochrome P450 2E1 (CYP2E1), the major enzyme responsible for TCE metabolism, could contribute to TCE-induced toxic response through free radical generation. The current study was, therefore, aimed to further evaluate the significance of TCE metabolism leading to oxidative stress and autoimmune response by using MRL+/+ mice that lack CYP2E1. The Cyp2e1-null MRL+/+ mice were generated by backcrossing Cyp2e1-null mice (B6N; 129S4-Cyp2e1) to MRL +/+ mice. Female MRL+/+ and Cyp2e1-null MRL+/+ mice were given TCE (10 mmol/kg, i.p., every 4th day) for 6 weeks; their respective controls received corn oil only. TCE treatment in MRL+/+ mice induced oxidative stress, evident from significantly increased serum malondiadelhyde (MDA)-protein adducts, their antibodies and reduced liver GSH levels. TCE treatment also modulated Nrf2 pathway with decreased Nrf2 and HO-1, and elevated NF-κB (p65) expression in the liver. TCE exposure also led to increases in serum antinuclear antibodies (ANA) and anti-double stranded DNA antibodies (anti-dsDNA). Although TCE treatment in Cyp2e1-null MRL+/+ mice also led to increases in serum MDA-protein adducts and their antibodies, changes in liver GSH, Nrf2, HO-1 and NF-κB along with increases in serum ANA, anti-dsDNA, the alterations in the oxidative stress and autoimmunity markers in these mice were less pronounced compared to those in MRL+/+ mice. These findings support the contribution of CYP2E1-mediated TCE metabolism in autoimmune response and an important role of Nrf2 pathway in TCE-mediated autoimmunity.


Comparative in-vitro activities of teicoplanin, vancomycin, coumermycin and ciprofloxacin, alone and in combination with rifampicin or LM 427, against Staphylococcus aureus.
The bactericidal interactions in vitro of two antibiotics active at the cell wall (teicoplanin and vancomycin) or two inhibitors of DNA gyrase (coumermycin and ciprofloxacin) combined with two inhibitors of protein synthesis (rifampicin and LM 427) were assessed against five Staphylococcus aureus strains. The S. aureus isolates included two oxacillin-sensitive and three oxacillin-resistant strains. The concentrations tested covered the range usually obtained in the serum with recommended doses. Coumermycin + rifampicin or LM 427, and ciprofloxacin + rifampicin or LM 427 were antagonistic when the concentration of either drug was higher than the MIC, and additive when sub-MIC concentrations were tested. Teicoplanin or vancomycin + rifampicin or LM 427 produced variable results. Of the synergic combinations, 14 of 15 included teicoplanin. Of the antagonistic combinations, 20 of 33 included LM 427. Antagonism with LM 427 was due to the higher intrinsic activity of LM 427 alone than teicoplanin, vancomycin or rifampicin. Teicoplanin (20 mg/l) + rifampicin or LM 427 (1 mg/l) was synergic (9/10).


Conformation of alpha zeins in solid state by Fourier transform IR.
The major maize storage proteins (alpha zeins) are deposited as an insoluble mass in the protein bodies of the endosperm. Because they are insoluble in water, most structural studies are performed in alcohol solutions. To solve the question raised by several authors about denaturation of the alpha zein structure by alcohol, we analyze the secondary structure of alpha zeins prepared with and without solubilization in alcohol (corn gluten meal and protein bodies with high concentrations of alpha zeins and traces of beta zeins). The secondary structures of alpha zeins are analyzed in the solid state by Fourier transform IR spectroscopy (FTIR) in KBr pellets and solid-state 13C-NMR spectroscopy. The proportion of secondary structures obtained by FTIR of alpha zeins prepared with and without solubilization in alcohol yield almost identical proportions of alpha helices and beta sheets. The proportion of alpha helices (43%) agrees with that measured by circular dichroism in an alcohol solution. However, the proportion of beta sheets (28%) is higher than the one measured by the same technique. Gluten and protein body samples with high beta zein content showed higher beta sheet and lower alpha helix proportions than that obtained for alpha zein preparations. The solid-state 13C-NMR spectra show the carbonyl peak for the alpha zeins at delta 176 and for the sample rich in beta zeins at delta 172, which demonstrates the presence of a high content of alpha helices and beta sheets, respectively. These results indicate that alcohol solubilization does not affect the conformation of alpha zeins, validating the secondary structure measurements in solution.


Paeonol Attenuates Quorum-Sensing Regulated Virulence and Biofilm Formation in Pseudomonas aeruginosa.
With the prevalence of multidrug-resistant bacteria and clinical -acquired pathogenic infections, the development of quorum-sensing (QS) interfering agents is one of the most potential strategies to combat bacterial infections and antibiotic resistance. Chinese herbal medicines constitute a valuable bank of resources for the identification of QS inhibitors. Accordingly, in this research, some compounds were tested for QS inhibition using indicator strains. Paeonol is a phenolic compound, which can effectively reduce the production of violacein without affecting its growth in Chromobacterium violaceum ATCC 12472, indicating its excellent anti-QS activity. This study assessed the anti-biofilm activity of paeonol against Gram-negative pathogens and investigated the effect of paeonol on QS-regulated virulence factors in Pseudomonas aeruginosa. A Caenorhabditis elegans infection model was used to explore the anti-infection ability of paeonol in vivo. Paeonol exhibited an effective anti-biofilm activity against Gram-negative bacteria. The ability of paeonol to interfere with the AHL-mediated quorum sensing systems of P. aeruginosa was determined, found that it could attenuate biofilm formation, and synthesis of pyocyanin, protease, elastase, motility, and AHL signaling molecule in a concentration- and time-dependent manner. Moreover, paeonol could significantly downregulate the transcription level of the QS-related genes of P. aeruginosa including lasI/R, rhlI/R, pqs/mvfR, as well as mediated its virulence factors, lasA, lasB, rhlA, rhlC, phzA, phzM, phzH, and phzS. In vivo studies revealed that paeonol could reduce the pathogenicity of P. aeruginosa and enhance the survival rate of C. elegans, showing a moderate protective effect on C. elegans. Collectively, these findings suggest that paeonol attenuates bacterial virulence and infection of P. aeruginosa and that further research elucidating the anti-QS mechanism of this compound in vivo is warranted.


Low-cost fiber Bragg grating vibroacoustic sensor for voice and heartbeat detection.
A fiber Bragg grating (FBG) vibroacoustic sensor exploiting an intensity-based interrogation principle is presented. The optical system is complemented by signal processing techniques that allow disturbances to be mitigated and improve the spectral estimation. The sensor is capable of performing frequency analysis of sounds up to 3 kHz, with top sensitivity in the 100-500 Hz frequency range, and of dynamically tracking pulsed phenomena that induce a strain to the FBG. The sensor has been applied to the detection of voice, showing a great intelligibility of the speech despite the low-quality environment, and to the monitoring of the heartbeat rate from the wrist.


Invited Commentary: The Contribution to the Field of Nutritional Epidemiology of the Landmark 1985 Publication by Willett et al.
The semiquantitative food frequency questionnaire (FFQ) has been the primary source of dietary exposure data in epidemiology for decades. Although frequency instruments had been evaluated before the 1985 publication "Reproducibility and Validity of a Semiquantitative Food Frequency Questionnaire" by Willett et al. (Am J Epidemiol. 1985;122(1):51-65), that paper was the prototype for the development and validation of what was then a highly innovative method for collecting dietary data. This approach was adopted in nearly all subsequent cohort studies of diet and disease. The paper also catalyzed an extended scientific discourse regarding methods for validation, energy adjustment, and measurement error. It is now well established that data from FFQs and other self-reported dietary assessment instruments have both value and error and that this error should be considered in the analysis and interpretation of findings, including sensitivity analyses in which adjustment for measurement error is explored. Advances in technology make it feasible to consider collecting multiple granular short-term instruments such as recalls or records over time in addition to FFQs among all participants in large cohort studies; both provide valuable information. Without a doubt, the 1985 publication by Willett et al. provided the foundation that propelled the field of nutritional epidemiology forward, and it continues to be relevant today.


Advancements in pharmacotherapy options for treating diabetes in children and adolescents.
This study compares diabetes management between pediatric and adult patients and identifies treatment challenges and gaps. We searched PubMed and Clinicaltrails.gov databases for studies published from 2001 to 2023 on diabetes management in different age groups. Research shows children have lower insulin sensitivity, clearance, and β cell function than adults. The US FDA only allows insulin, metformin, and liraglutide as antidiabetic medication options for children. However, some off-label drugs, like meglitinides, sulfonylureas, and alogliptin, have demonstrated positive results in treating certain types of diabetes caused by gene mutations. It's crucial to adopt personalized and precise approaches to managing diabetes in pediatrics, which vary from those used for adult patients. New studies support the classification of type 2 diabetes into several subtypes based on age, BMI, glycemia, homeostasis model estimates, varying insulin resistance, different rates of complications, and islet autoantibodies. With this insight, prevention, treatment, and precision medicine of diabetes might be changed. More research is necessary to assess the safety and efficacy of different antidiabetic drugs and improve diabetes treatment for children and adolescents.


Amyloid PET imaging in clinical practice.
Amyloid positron emission tomography (PET) imaging enables in vivo detection of brain Aβ deposition, one of the neuropathological hallmarks of Alzheimer's disease. There is increasing evidence to support its clinical utility, with major studies showing that amyloid PET imaging improves diagnostic accuracy, increases diagnostic certainty and results in therapeutic changes. The Amyloid Imaging Taskforce has developed appropriate use criteria to guide clinicians by predefining certain scenarios where amyloid PET would be justified. This review provides a practical guide on how and when to use amyloid PET, based on the available research and our own experience. We discuss its three main appropriate indications and illustrate these with clinical cases. We stress the importance of a multidisciplinary approach when deciding who might benefit from amyloid PET imaging. Finally, we highlight some practical points and common pitfalls in its interpretation.


Positive ecological effects of wind farms on vegetation in China's Gobi desert.
With the rapid development of wind power, there are increasing concerns about the negative ecological effects of its construction and operation. However, previous studies have mainly focused on the effects of wind farms on flying fauna (i.e., birds and bats) or climate change separately from communities or ecosystems, and little attention has been paid to vegetation during wind farm operation. Furthermore, few studies have referred to vulnerable ecosystems with low biomass and biodiversity. In this research, a field study was conducted to investigate the effects of wind farms on the individual traits, community structures and ecosystem functions of Gobi Desert ecosystems. The effects were measured by comparing interfering areas (IAs, located between 40 m and 90 m in the downstream direction of the wind turbine) with non-interfering areas (NIAs, located over 200 m from the wind turbine matrixes). The results showed that (1) plant individuals in IAs were less stressed and in better physiological states than those in NIAs; (2) for community structures, IA plants tended to be shorter and denser and had a higher coverage condition than that of NIA plants; and (3) ecosystem functions in IAs were significantly improved due to the existence of shrubs and higher biomass. Meanwhile, significant correlations were identified between the wind wake caused by the large spinning blades and the community structures. Constructing wind turbines in the Gobi Desert is a win-win strategy that both contributes to the growth of desert vegetation with a favourable microclimate and sufficiently utilizes wind power to produce clean energy.


Guidance on water intake effectively improves urinary frequency in patients with nocturia.
To evaluate how guidance on water-intake impacts the degree of nocturia. A total of 67 male patients were enrolled in the present study. Patients were asked to adjust their water and food intakes so that their 24-h urine production/bodyweight would be equal or lower than 30 mL/kg. One month after the treatment, the therapeutic gain from and adverse effects of fluid restriction were examined by comparing the pretreatment and post-treatment value of various parameters. Overall, 65 eligible patients were evaluated. In 44 patients (67%), the frequency of nocturia was improved to one or more times. The change in frequency of nocturia showed a positive correlation with the change in nocturnal urine volume. The change in nocturnal urine volume showed a positive correlation with the changes in 24-h urine production/bodyweight, 24-h drinking volume and daytime drinking volume. The changes in 24-h urine production/bodyweight and daytime drinking volume were independent factors influencing therapeutic effect. None of the participants reported any adverse event. In patients with a 24-h urine production/bodyweight equal or higher than 30 mL/kg, guidance on water intake might be considered effective and safe as a lifestyle therapy. Water restriction should be carried out not only in the evening, but also during daytime.


Neurocognitive Effects of Cocoa and Red-Berries Consumption in Healthy Adults.
In recent decades, the elderly population has increased at higher rates than any other population group, resulting in an increase in age-related diseases such as neurodegenerative and cognitive impairment. To address this global health problem, it is necessary to search for new dietary strategies that can prevent the main neurocognitive problems associated with the ageing process. Therefore, the aim of the present study was to analyze the effect of cocoa flavanols and red berry anthocyanins on brain-derived neurotrophic factor (BDNF) and nerve growth factor receptor (NGF-R) and to stablish the possible improvement in cognitive performance by using a battery of neurocognitive tests that included the Verbal Learning Test Spain-Complutense, the Spatial Recall Test 10/36 BRB-N, the Wechsler Adult Intelligence Scale III and IV, the STROOP Task and the Tower of London Test. A randomized, double-blind, parallel-group study was performed in 60 healthy volunteers between 50 and 75 years old who consumed a cocoa powder, a red berries mixture or a combination of both for 12 weeks. After the intervention, we observed a reduction in the time needed to start (p = 0.031) and finish (p = 0.018) the neurocognitive test known as the Tower of London in all groups, but the decrease in time to finish the task was more pronounced in the intervention with the combination of cocoa-red berries group. We failed to show any significant difference in BDNF and NGF-R sera levels. However we found a negative correlation between BDNF and the number of movements required to finish the TOL in women (p = 0.044). In conclusion, our study showed an improvement in executive function, without any change in neurotrofin levels, for all intervention arms.


Two different microarray technologies for preimplantation genetic diagnosis and screening, due to reciprocal translocation imbalances, demonstrate equivalent euploidy and clinical pregnancy rates.
To compare single nucleotide polymorphism (SNP) and comparative genomic hybridization (aCGH) microarray platforms to evaluate embryos for parental translocation imbalances and aneuploidy. A retrospective review of preimplantation genetic diagnosis and screening (PGD/PGS) results of 498 embryos from 63 couples undergoing 75 in vitro fertilization cycles due to parental carriers of a reciprocal translocation. There was no significant difference between SNP and aCGH microarrays when comparing the prevalence of embryos that were euploid with no translocation imbalance, euploidy with a parental translocation imbalance or aneuploid with or without the parental chromosome imbalance. The clinical pregnancy rates were also equivalent for SNP (60 %) versus aCGH (65 %) microarrays. Of 498 diagnosed embryos, 45 % (226/498) were chromosomally normal without translocation errors or aneuploidy, 22 % (112/498) were euploid but had a parentally derived unbalanced chromosomal segregant, 8 % (42/498) harbored both a translocation imbalance and aneuploidy and 24 % (118/498) of embryos were genetically balanced for the parental reciprocal translocation but were aneuploid for other chromosomes. The overall clinical pregnancy rate per IVF cycle following SNP or aCGH microarray analysis was 61 % and was higher if the biopsy was done on blastocysts (65 %) versus cleavage stage embryos (59 %), although not statistically significant. SNP or aCGH microarray technologies demonstrate equivalent clinical findings that maximize the pregnancy potential in patients with known parental reciprocal chromosomal translocations.