Role of Tc-99m pertechnetate for remnant scintigraphy, post-thyroidectomy, and serum thyroglobulin and antithyroglobulin antibody levels in the patients with differentiated thyroid cancer.
Postoperative scanning may help to identify patients with differentiated thyroid cancer (DTC); however, low dose I-131 can lead to stunning and suboptimal response to ablative therapy. The aim of this retrospective study is to compare postablative I-131 scintigraphy with post-thyroidectomy Tc-99m pertechnetate scintigraphy, serum thyroglobulin (Tg) and antithyroglobulin antibody (TgAb) levels in patients with DTC. Patients who had undergone surgical thyroidectomy for DTC were evaluated retrospectively. All patients had undergone Tc-99m pertechnetate and postablative I-131 scans. Serum Tg and TgAb levels were measured in all subjects. Preablative pertechnetate scans of the thyroid bed were viewed blindly and then directly compared with postablative I-131 scans and Tc-99m pertechnetate scintigraphy was compared with serum Tg and TgAb levels. One hundred and seventy-four patients (146 women, 28 men) with a mean age of 48.7 ± 13.1 (range 12-84) years who had undergone surgical thyroidectomy for DTC were evaluated retrospectively. Of 174 patients, 6 (3%) had negative I-131 and also Tc-99m pertechnetate scintigraphy results. Of the remaining 168 positive I-131 scans, 131 (75%) were positive in at least one site on the pertechnetate scan, 19 (11%) were considered to have equivocal uptake and 18 (11%) were negative. For the per-site analysis, pertechnetate sites were considered to be accurately determined if they showed concordant uptake at sites that correlated precisely with those seen on the postablation I-131 scans. There were a total of 356 positive foci on I-131 scans. Of these, 273 foci (77%) were unequivocally positive on pertechnetate scintigraphy, 41 (11%) showed equivocal uptake and 42 (12%) foci could not be detected. There were statistically significant differences (p < 0.0001) between the negative and positive foci in terms of Tg levels on pertechnetate sites. A positive pertechnetate scan is, therefore, sufficient to guide progression to I-131 ablation in most patients. Pertechnetate scintigraphy may be of particular benefit if it is considered desirable to avoid use of I-131 in post-thyroidectomy remnant imaging. Tg level is an important parameter in the detection of remnant thyroid tissue in patients with DTC.


Detection of primary cytotoxic T lymphocytes specific for the envelope glycoprotein of HIV-1 by deletion of the env amino-terminal signal sequence.
A heterogenous population of envelope glycoprotein-specific cytotoxic effector cells are found in the peripheral blood of individuals infected with HIV-1, and in many cases env-specific lysis is not restricted by MHC molecules and is not blocked by antibody to CD3 (Rivière, Y. et al., J. Virol. 1989, 63:2270). In order to detect env-specific cytotoxic T lymphocytes (CTL) in fresh peripheral blood mononuclear cells of HIV-1-infected donors, a mutant env gene with deletion of the amino-terminal signal sequence was inserted into vaccinia virus. This deletion of the amino-terminal signal sequence was inserted into vaccinia virus. This deletion results in synthesis of an envelope protein that is not glycosylated and not expressed at the surface of infected cells. Target cells infected with this recombinant vaccinia virus are not lysed by antibody-mediated cellular cytotoxicity, but they are recognized by secondary CTL. Comparing lysis of target cells expressing gp160 of HIV-1 and the signal peptide deletion mutant, primary env-specific CTL were detected in some individuals infected with HIV-1.


Endosomal proteolysis of insulin-like growth factor-I at its C-terminal D-domain by cathepsin B.
IGF-I is degraded within the endosomal apparatus as a consequence of receptor-mediated endocytosis. However, the nature of the responsible protease and the position of the cleavage sites in the IGF-I molecule remain undefined. In vitro proteolysis of IGF-I using an endosomal lysate required an acidic pH and was sensitive to CA074, an inhibitor of the cathepsin B enzyme. By nondenaturing immunoprecipitation, the acidic IGF-I-degrading activity was attributed to the luminal species of endosomal cathepsin B with apparent molecular masses of 32- and 28-kDa. The cathepsin B precursor, procathepsin B, was processed in vitro within isolated endosomes at pH 5 or at 7 in the presence of ATP, the substrate of the vacuolar H(+)-ATPase. The rate of IGF-I hydrolysis using an endosomal lysate or pure cathepsin B was found to be optimal at pH 5-6 and moderate at pH 4 and 7. Competition studies revealed that EGF and IGF-I share a common binding site on the cathepsin B enzyme, with native IGF-I displaying the lowest affinity for the protease (IC50 approximately 1.5 microM). Hydrolysates of IGF-I generated at low pH by endosomal IGF-I-degrading activity and analyzed by reverse-phase HPLC and mass spectrometry revealed cleavage sites at Lys68-Ser69, Ala67-Lys68, Pro66-Ala67 and Lys65-Pro66 within the C-terminal D-domain of IGF-I. Treatment of human HepG2 hepatoma cells with the cathepsin B proinhibitor CA074-Me reduced, in vivo, the intracellular degradation of internalized [125I]IGF-I and, in vitro, the degradation of exogenous [125I]IGF-I incubated with the cell-lysates at pH 5. Inhibitors of cathepsin B and pro-cathepsin B processing, which abolish endosomal proteolysis of IGF-I and alter tumor cell growth and IGF-I receptor signalling, merit investigation as antimetastatic drugs.


The Role of Sulfadiazine for the Treatment of Refractory Intracranial Infection.
Sulfadiazine (SD) is a classic antibiotic for intracranial infection. Due to the medical market policy, SD has not been chosen as an essential drug in all the hospitals in China. However, its therapeutic effect is definite and cannot be substituted. The aim of this study was to evaluate the therapeutic and economic value of SD compared to other popular antibiotics in patients with refractory intracranial infection. A retrospective single-center study was performed from January 2011 until December 2012. Thirteen patients diagnosed with refractory intracranial infection were treated with SD. The clinical effects were reviewed. Treatment was successful for 12 of the patients (cure rate=92.3%). One patient died of secondary epilepsy, respiratory complications, and multiple organ failure. Only one patient was allergic to SD, and there were no drug-related liver or kidney side effects. SD is a safe, effective, and economical antibiotic, and is used by our neurosurgical department. It should be offered as an option for the patients with refractory intracranial infection, especially for patients with lower ability to pay.


Determination of 2,5-hexanedione, a metabolite of n-hexane, in urine: evaluation and application of three analytical methods.
Three methods for the determination of 2,5-hexanedione (2,5-HD) in urine were compared in order to assess their applicability for toxicokinetic studies and biological monitoring of occupational exposure to n-hexane. Two of them were based on derivatization, followed by gas chromatography and electron-capture detection. Of these two, one is a modification of the other, already published, method. The third one involves direct extraction of 2,5-HD followed by gas chromatography and flame-ionization detection. To determine 2,5-HD in urine of workers occupationally exposed to n-hexane, the most straightforward method, direct extraction of 2,5-HD from urine, has been proven to be the most suitable. However, in case of very low concentrations of 2,5-HD in urine, or analysis of small samples of blood, e.g. in kinetic studies, it is necessary to use a more sensitive procedure. The sensitivity of the methods based on the derivatization of 2,5-HD followed by electron-capture detection, was, as expected, much higher in terms of analytical reliability. By using these methods, however, precautions are necessary to avoid a matrix effect.


The molecular nature of 1,25-(OH)2-D3-induced calcium-binding protein biosynthesis in the rat.
Exogenous 1,25-(OH)2-D3, administered to vitamin D-replete animals on a high calcium diet, induces biosynthesis of the duodenal, cytosolic calcium-binding protein (CaBP) in less than 2 h. This process can be blocked by simultaneously administered cycloheximide, but not by actinomycin D. In vitamin D-replete animals on a low Ca diet, on the other hand, 1,25-(OH)2-D3 administration leads to new CaBP synthesis only after about 7 h; this process can be blocked by actinomycin D. In vitamin D-deficient animals on a high calcium diet who have no CaBP, treatment with 1,25-(OH)2-D3 induces CaBP formation in congruent to 8 h; this process is known to be blocked by actinomycin D. Thus in D-replete animals on a low calcium diet and in D-deficient animals, CaBP biosynthesis proceeds by a transcriptional route, whereas in D-replete animals on a high calcium diet the rapid response appears to be posttranscriptional. This finding points to the possibility of a more rapid regulatory action of vitamin D than previously reported and how vitamin D might function in the D-replete state.


Synthesis of thermosensitive magnetic nanocarrier for controlled sorafenib delivery.
Allyl glycidyl ether/N-isopropylacrylamide-grafted magnetic nanoparticles were prepared using silica-coated magnetic nanoparticles as a substrate for radical copolymerization of allyl glycidyl ether and N-isopropylacrylamide. Chitosan was coupled with the prepared nanoparticles by opening the epoxy ring of the allyl glycidyl ether. The thermosensitive magnetic nanocarrier (TSMNC) obtained can be applied as a potent drug carrier. The TSMNC structure was characterized using Fourier transform infrared spectroscopy, X-ray diffraction, thermogravimetric analysis, differential scanning calorimetry, vibrating sample magnetometer, and elemental analysis. Its morphology and size were investigated using field emission scanning electron microscopy, transmission electron microscopy and dynamic light scattering. The feasibility of employing the TSMNC for adsorption and in vitro controlled release of the chemotherapeutic agent sorafenib was tested. The effect of the adsorption parameters of pH, temperature, and loading time of sorafenib onto TSMNC was evaluated. The adsorption data was fitted to the Langmuir and Freundlich isotherms and the relevant parameters derived. The drug release profile indicated that 88% of the adsorbed drug was released within 35h at 45°C and drug release was Fickian diffusion-controlled. The results confirmed that the TSMNC has a high adsorption capacity at low temperature and good controlled release in a slow rate at a high temperature and could be developed for further application as a drug nanocarrier.


Autologous transplantation of intestine-isolated glia cells improves neuropathology and restores cognitive deficits in β amyloid-induced neurodegeneration.
Alzheimer's disease (AD) is characterized by chronic deposition of β-amyloid (Aβ) in the brain, progressive neurodegeneration and consequent cognitive and behavioral deficits that typify the disease. Astrocytes are pivotal in this process because they are activated in the attempt to digest Aβ which starts a neuroinflammatory response that further contributes to neurodegeneration. The intestine is a good source of astrocytes-like cells-referred to as enteric glial cells (EGCs). Here we show that the autologous transplantation of EGCs into the brain of Aβ-injected rats arrested the development of the disease after their engraftment. Transplanted EGCs showed anti-amyloidogenic activity, embanked Aβ-induced neuroinflammation and neurodegeneration, and released neutrophic factors. The overall result was the amelioration of the pathological hallmarks and the cognitive and behavioral deficits typical of Aβ-associated disease. Our data indicate that autologous EGCs transplantation may provide an efficient alternative for applications in cell-replacement therapies to treat neurodegeneration in AD.


A case report and literature review of daptomycin-induced liver injury.
Daptomycin is a lipopeptide antimicrobial used to treat gram positive organisms including multi-drug resistant infections. It has been shown to occasionally cause abnormalities in liver function but more commonly is associated with elevations in serum creatinine phosphokinase (CK) (Hair and Keam, 2007) [1]. We describe a case where a patient being treated for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia with daptomycin developed asymptomatic elevated transaminases without evidence of multiorgan failure, hyperbilirubinemia or elevation of CK levels. Other etiologies for liver injury were considered and ruled out, and after daptomycin was discontinued, the transaminases returned to normal levels. We also provide a review of other cases to date documenting possible cases of daptomycin-induced liver injury.


Redox signaling and modulation in ageing.
In spite of considerable progress that has been reached in understanding how reactive oxygen species (ROS) interact with its cellular targets, several important challenges regarding regulatory effects of redox signaling mechanisms remain to be addressed enough in aging and age-related disorders. Redox signaling is precisely regulated in different tissues and subcellular locations. It modulates the homeostatic balance of many regulatory facilities such as cell cycle, circadian rhythms, adapting the external environments, etc. The newly proposed term "adaptive redox homeostasis" describes the transient increase in ROS buffering capacity in response to amplified ROS formation rate within a physiological range. Redox-dependent second messengers are generated in subcellular locations according to a specific set of rules and regulations. Their appearance depends on cellular needs in response to variations in external and internal stimulus. The intensity and magnitude of ROS signaling determines its downstream effects. This issue includes review and research papers in the context of redox signaling mechanisms and related redox-regulatory interventions, aiming to guide for understanding the degenerative processes of biological ageing and alleviating possible prevention approaches for age-related complications.


High-risk ovarian cancer based on 126-gene expression signature is uniquely characterized by downregulation of antigen presentation pathway.
High-grade serous ovarian cancers are heterogeneous not only in terms of clinical outcome but also at the molecular level. Our aim was to establish a novel risk classification system based on a gene expression signature for predicting overall survival, leading to suggesting novel therapeutic strategies for high-risk patients. In this large-scale cross-platform study of six microarray data sets consisting of 1,054 ovarian cancer patients, we developed a gene expression signature for predicting overall survival by applying elastic net and 10-fold cross-validation to a Japanese data set A (n = 260) and evaluated the signature in five other data sets. Subsequently, we investigated differences in the biological characteristics between high- and low-risk ovarian cancer groups. An elastic net analysis identified a 126-gene expression signature for predicting overall survival in patients with ovarian cancer using the Japanese data set A (multivariate analysis, P = 4 × 10(-20)). We validated its predictive ability with five other data sets using multivariate analysis (Tothill's data set, P = 1 × 10(-5); Bonome's data set, P = 0.0033; Dressman's data set, P = 0.0016; TCGA data set, P = 0.0027; Japanese data set B, P = 0.021). Through gene ontology and pathway analyses, we identified a significant reduction in expression of immune-response-related genes, especially on the antigen presentation pathway, in high-risk ovarian cancer patients. This risk classification based on the 126-gene expression signature is an accurate predictor of clinical outcome in patients with advanced stage high-grade serous ovarian cancer and has the potential to develop new therapeutic strategies for high-grade serous ovarian cancer patients.


Effects of muscarinic receptor type 3 knockout on mouse islet secretory responses.
The impact of muscarinic type 3 receptor knockout (M3KO) on the cholinergic regulation of insulin secretion and phospholipase C (PLC) activation was determined. Islets isolated from control, wild-type mice or heterozygotes responded with comparable insulin secretory responses to 15 mM glucose. This response was markedly amplified by the inclusion of 10 microM carbachol. While 15 mM glucose-induced release remained similar to wild-type and heterozygote responses in M3KO mice, the stimulatory impact of carbachol was abolished. Stimulation with 15 mM glucose plus 50 microM carbachol increased fractional efflux rates of myo-[2-3H]inositol from control wild-type and heterozygote islets but not from M3KO islets. Fed plasma insulin levels of M3KO mice were reduced 68% when compared to values obtained from combined wild-type and heterozygote animals. These studies support the conclusion that the M3 receptor in islets is coupled to PLC activation and insulin secretion and that cholinergic stimulation of the islets may play an important role in the regulation of plasma insulin levels.


Comparison of sodium fluorescein and intraoperative ultrasonography in brain tumor resection.
Various intraoperative neuroimaging modalities are available to the neurosurgeon during brain tumor surgery. There remains no consensus on which modalities are superior. This retrospective, single-center cohort study directly compares sodium fluorescein (SF) and intraoperative ultrasonography (IOUS) as intraoperative imaging modalities in a sample of patients with glioblastoma isocitrate dehydrogenase 1 wildtype (GBM). Adult patients with GBM who underwent surgical resection using SF or IOUS guidance between 2010 and 2020 were included. Primary outcomes included extent of resection (EOR), post-operative residual tumor volume, gross total resection (GTR) rate, false negative assessments, and the incidence of new post-operative neurologic deficits. Additionally, pre-and post-test probabilities were calculated to assess each modality's ability to identify residual tumor. 98 patients met inclusion criteria (34 SF and 64 IOUS). Mean EOR was significantly higher for SF (94 ± 11 %) when compared to IOUS (87 ± 20 %; p = 0.032). Mean post-operative residual tumor was significantly higher for IOUS (197 ± 358 mm2) when compared to SF (81 ± 161mm2; p = 0.038). GTR was more frequent with SF (62 % vs 46 %, p = 0.12). False negative assessments for residual tumor were more common with IOUS (22 % vs 15 %, p = 0.53). One patient in each group suffered a new neurologic deficit post-operatively (p = 0.58). Sensitivity, specificity, positive predictive value, and negative predictive value were 62 %, 100 %, 100 %, and 81 % for SF and 59 %, 100 %, 100 %, and 67 % for IOUS, respectively. Taken together, SF may be superior to IOUS in maximizing EOR in patients with GBM, however, both modalities appear to have good efficacy.


Probing a Spin Transfer Controlled Magnetic Nanowire with a Single Nitrogen-Vacancy Spin in Bulk Diamond.
The point-like nature and exquisite magnetic field sensitivity of the nitrogen vacancy (NV) center in diamond can provide information about the inner workings of magnetic nanocircuits in complement with traditional transport techniques. Here, we use a single NV in bulk diamond to probe the stray field of a ferromagnetic nanowire controlled by spin transfer (ST) torques. We first report an unambiguous measurement of ST tuned, parametrically driven, large-amplitude magnetic oscillations. At the same time, we demonstrate that such magnetic oscillations alone can directly drive NV spin transitions, providing a potential new means of control. Finally, we use the NV as a local noise thermometer, observing strong ST damping of the stray field noise, consistent with magnetic cooling from room temperature to ∼150 K.


Combining synchrotron X-ray diffraction, mechanistic modeling and machine learning for in situ subsurface temperature quantification during laser melting.
Laser melting, such as that encountered during additive manufacturing, produces extreme gradients of temperature in both space and time, which in turn influence microstructural development in the material. Qualification and model validation of the process itself and the resulting material necessitate the ability to characterize these temperature fields. However, well established means to directly probe the material temperature below the surface of an alloy while it is being processed are limited. To address this gap in characterization capabilities, a novel means is presented to extract subsurface temperature-distribution metrics, with uncertainty, from in situ synchrotron X-ray diffraction measurements to provide quantitative temperature evolution data during laser melting. Temperature-distribution metrics are determined using Gaussian process regression supervised machine-learning surrogate models trained with a combination of mechanistic modeling (heat transfer and fluid flow) and X-ray diffraction simulation. The trained surrogate model uncertainties are found to range from 5 to 15% depending on the metric and current temperature. The surrogate models are then applied to experimental data to extract temperature metrics from an Inconel 625 nickel superalloy wall specimen during laser melting. The maximum temperatures of the solid phase in the diffraction volume through melting and cooling are found to reach the solidus temperature as expected, with the mean and minimum temperatures found to be several hundred degrees less. The extracted temperature metrics near melting are determined to be more accurate because of the lower relative levels of mechanical elastic strains. However, uncertainties for temperature metrics during cooling are increased due to the effects of thermomechanical stress.


PI3K Inhibitors in Advanced Breast Cancer: The Past, The Present, New Challenges and Future Perspectives.
Breast cancer is the leading cause of death in the female population and despite significant efforts made in diagnostic approaches and treatment strategies adopted for advanced breast cancer, the disease still remains incurable. Therefore, development of more effective systemic treatments constitutes a crucial need. Recently, several clinical trials were performed to find innovative predictive biomarkers and to improve the outcome of metastatic breast cancer through innovative therapeutic algorithms. In the pathogenesis of breast cancer, the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB/AKT)-mammalian target of rapamycin (mTOR) axis is a key regulator of cell proliferation, growth, survival, metabolism, and motility, making it an interest and therapeutic target. Nevertheless, the PI3K/AKT/mTOR cascade includes a complex network of biological events, needing more sophisticated approaches for their use in cancer treatment. In this review, we described the rationale for targeting the PI3K pathway, the development of PI3K inhibitors and the future treatment directions of different breast cancer subtypes in the metastatic setting.


Intestinal hypomotility in systemic sclerosis: a histological study into the sequence of events.
The pathogenesis of intestinal involvement in systemic sclerosis (SSc) is thought to be a sequential process (vascular, neuronal, and consecutive muscular impairment), but understanding of the underlying histological changes and how they translate to symptoms, is still lacking. Therefore, we systematically investigated histological characteristics of SSc in the intestines, compared to controls. Autopsy material from the small bowel and colon was used for histological semiquantitative evaluation of the vasculature, enteric nervous system, interstitial cells of Cajal (ICC), and muscle layers, using a combination of histochemical and immunohistochemical stainings, according to guidelines of the Gastro 2009 International Working Group. Vascular changes were most frequently encountered, represented by intima fibrosis in both arteries and small vessels, and represented by venous dilatation. Second, generalized fibrosis of the circular muscle layer was significantly more found in SSc patients than in controls. Third, reduction of submucosal nerve fibers and myenteric neurons was shown in the colon of four SSc patients, which may explain severe symptoms of intestinal dysmotility. The density of myenteric ICC network was decreased in the small bowel of SSc patients. The postulated sequential processes of intestinal involvement in SSc could not be supported by our histological evaluation. The interpatient diversity suggests that parallel processes occur, explaining the variety of histological features and clinical symptoms. Key Points • Histological analysis showed vascular changes, fibrosis in the muscularis propria, and reduction of the ENS and ICC network in the intestines of SSc patients. • Pathophysiological mechanisms leading to intestinal dysmotility in SSc may be parallel rather than sequential. • The interpatient diversity suggests parallel pathophysiological processes, explaining the variety of histological features and clinical symptoms.


Enzyme-triggered hydrogelation via self-assembly of alternating peptides.
α-Chymotrypsin catalyzed oligomerization of the "dipeptide lego" KL-ethyl ester (OEt) in aqueous media triggers a rapid sol-gel transition due to formation of alternating (KL)x. Resulting mixed chain oligomers, at alkaline pH, self-assemble into β-sheets. Thereafter, intermolecular backbone hydrogen bonding between peptides causes formation of physically entangled nanofibrillar networks.


Is the Infection of the SARS-CoV-2 Delta Variant Associated With the Outcomes of COVID-19 Patients?
Background: Severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) Delta variant (B.1.617.2) has been responsible for the current increase in Coronavirus disease 2019 (COVID-19) infectivity rate worldwide. We compared the impact of the Delta variant and non-Delta variant on the COVID-19 outcomes in patients from Yogyakarta and Central Java provinces, Indonesia. Methods: In this cross-sectional study, we ascertained 161 patients, 69 with the Delta variant and 92 with the non-Delta variant. The Illumina MiSeq next-generation sequencer was used to perform the whole-genome sequences of SARS-CoV-2. Results: The mean age of patients with the Delta variant and the non-Delta variant was 27.3 ± 20.0 and 43.0 ± 20.9 (p = 3 × 10-6). The patients with Delta variant consisted of 23 males and 46 females, while the patients with the non-Delta variant involved 56 males and 36 females (p = 0.001). The Ct value of the Delta variant (18.4 ± 2.9) was significantly lower than that of the non-Delta variant (19.5 ± 3.8) (p = 0.043). There was no significant difference in the hospitalization and mortality of patients with Delta and non-Delta variants (p = 0.80 and 0.29, respectively). None of the prognostic factors were associated with the hospitalization, except diabetes with an OR of 3.6 (95% CI = 1.02-12.5; p = 0.036). Moreover, the patients with the following factors have been associated with higher mortality rate than the patients without the factors: age ≥65 years, obesity, diabetes, hypertension, and cardiovascular disease with the OR of 11 (95% CI = 3.4-36; p = 8 × 10-5), 27 (95% CI = 6.1-118; p = 1 × 10-5), 15.6 (95% CI = 5.3-46; p = 6 × 10-7), 12 (95% CI = 4-35.3; p = 1.2 × 10-5), and 6.8 (95% CI = 2.1-22.1; p = 0.003), respectively. Multivariate analysis showed that age ≥65 years, obesity, diabetes, and hypertension were the strong prognostic factors for the mortality of COVID-19 patients with the OR of 3.6 (95% CI = 0.58-21.9; p = 0.028), 16.6 (95% CI = 2.5-107.1; p = 0.003), 5.5 (95% CI = 1.3-23.7; p = 0.021), and 5.8 (95% CI = 1.02-32.8; p = 0.047), respectively. Conclusions: We show that the patients infected by the SARS-CoV-2 Delta variant have a lower Ct value than the patients infected by the non-Delta variant, implying that the Delta variant has a higher viral load, which might cause a more transmissible virus among humans. However, the Delta variant does not affect the COVID-19 outcomes in our patients. Our study also confirms that older age and comorbidity increase the mortality rate of patients with COVID-19.


In vivo leptin infusion impairs insulin and leptin signalling in liver and hypothalamus.
Leptin resistance contributes to the pathogenesis of common obesity related metabolic diseases, including insulin resistance. However, the relationship between leptin and insulin resistance is not clearly established. Here, we show that induced hyperleptinemia by leptin infusion alters insulin signalling in rat liver. Leptin infusion clearly reduced the insulin or leptin dependent IRS-1/IRS-2 association to p85 regulatory subunit of PI 3-kinase. Leptin infusion also abolished STAT-3 phosphorylation in response to insulin or leptin and similar results were obtained for MAP-kinase phosphorylation. Hypothalamic leptin resistance was also induced by leptin infusion since leptin was unable to induce STAT-3 phosphorylation. These results provide evidence that induced hyperleptinemia can contribute to the onset of insulin resistance at least at the hepatic level.


Immunological study of a cellular 35K phosphorylated polypeptide detected in Rous sarcoma virus transformed cells.
We have immunoprecipitated a phosphoprotein of 35K daltons (35K) common to RSV-transformed chick embryo fibroblasts (CEF) and rodent cells. The phosphorylation of this antigen depends on the expression of the v-src gene and contains phosphotyrosine. The pre-existing 35K protein, of CEF infected de novo, was further shown to become phosphorylated shortly after the appearance of active pp60v-src, and about 1 day before morphological transformation. The experiments with RSV-transformed rodent cells have shown that the 35K phosphoprotein is associated with the cellular framework. Another phosphoprotein of 37K was found in the RSV-transformed rodent cells, but not in the transformed CEF. However, this protein was not phosphorylated at tyrosine residues and its phosphorylation persisted, at the restrictive temperature, in cells transformed by a ts mutant of RSV.


A rare cause of odynophagia and dysphagia: oesophageal lichen planus.
We report a case of oesophageal lichen planus, a rare entity which causes dysphagia and odynophagia, mainly in adult females.


Double-blind, placebo-controlled, dose-ranging study of new recombinant hypoallergenic Bet v 1 in an environmental exposure chamber.
Recombinant allergens offer a tool for improving specific immunotherapy (SIT). To find the optimal dose of a new hypoallergenic folding variant of recombinant Bet v 1 (rBet v 1-FV) as SIT for patients with birch pollen allergy. Before SIT, thirty-seven adult patients were exposed for eight hours in an environmental exposure chamber (EEC) to birch pollen at an average concentration of 3500 ± 500 grains/m(3) , then randomized to four maintenance dose groups of rBet v 1-FV and one placebo group: 20 μg (n = 7), 80 μg (n = 8), 160 μg (n = 7), 320 μg (n = 8), and placebo (n = 7). Patients were treated for 10 weeks with weekly injections and then re-exposed in the EEC. The optimal dose for SIT was assessed using efficacy results from the EEC, IgG responses, and tolerability. Thirty-six patients were evaluable for efficacy assessment. The total symptom score significantly decreased in all active groups compared with placebo (-18.8% for placebo patients; -71.9%, P = 0.0022 for 20 μg; -75.6%, P = 0.0007 for 80 μg; -81.8%, P = 0.0009 for 160 μg; -78.3%, P = 0.0003 for 320 μg). IgG1 increased significantly in all active groups compared to placebo. All four active doses were well tolerated, no serious adverse event occurred; two Grade II reactions, according to EAACI classification, were observed, one in each of the 160- and 320-μg groups. Considering efficacy, immunological response, and tolerability, a maintenance dose of 80 μg of rBet v 1-FV appears to be the ideal dose for allergen immunotherapy in birch pollen allergic patients.


Use of Administrative Data for the Identificationof Laboratory-Confirmed Influenza Infection: The Validity ofInfluenza-Specific ICD-9 Codes.
We used Pediatric Health Information System data and laboratory records from 3 children's hospitals to determine whether administrative data accurately identify children with laboratory-confirmed influenza. Among 23 282 inpatients, diagnosis codes for influenza detected 73% of laboratory-confirmed influenza cases, whereas <1% of patients without a diagnosis code had laboratory-confirmed influenza.


Prediction of total volatile basic nitrogen contents using wavelet features from visible/near-infrared hyperspectral images of prawn (Metapenaeus ensis).
A visible/near-infrared hyperspectral imaging (HSI) system (400-1000 nm) coupled with wavelet analysis was used to determine the total volatile basic nitrogen (TVB-N) contents of prawns during cold storage. Spectral information was denoised by conducting wavelet analysis and uninformative variable elimination (UVE) algorithm, and then three wavelet features (energy, entropy and modulus maxima) were extracted. Quantitative models were established between the wavelet features and the reference TVB-N contents by using three regression algorithms. As a result, the LS-SVM model with modulus maxima features was considered as the best model for determining the TVB-N contents of prawns, with an excellent RP(2) of 0.9547, RMSEP=0.7213 mg N/100g and RPD=4.799. Finally, an image processing algorithm was developed for generating a TVB-N distribution map. This study demonstrated the possibility of applying the HSI imaging system in combination with wavelet analysis to the monitoring of TVB-N values in prawns.


Hidden pathologies associated with (and concealed by) early gestational isolated fetal hydrothorax.
Isolated fetal hydrothorax is an uncommon finding on routine prenatal ultrasound and is associated with a variable prognosis. We believe this is the first report of a patient whose antenatal hydrothorax was associated with both congenital diaphragmatic hernia and congenital pulmonary lymphangiectasia. This rare combination caused significant problems in diagnosis and subsequent treatment.


Dynamics of glucose concentration during the initiation of ketogenic diet treatment in children with refractory epilepsy: Results of continuous glucose monitoring.
The ketogenic diet (KD) is a diet low in carbohydrates and rich in fats which has long been used to treat refractory epilepsy. The metabolic changes related to the KD may increase the risk of hypoglycemia, especially during the first days. The study focused on the impact of KD initiation on glycemia in non-diabetic patients with refractory epilepsy. The subjects were 10 pediatric patients (6 boys, mean age 6.1 ± 2.4 years), treated for intractable epilepsy. Blinded continuous glucose monitoring system (CGM) Dexcom G4 was used. Patients started on their regular diet in the first 36 hours of monitoring, followed by an increase in lipids intake and a gradual reduction of carbohydrates (relations 1:1; 2:1; 3:1; 3.5:1). We analyzed changes in glycemia during fat: nonfat ratio changes using a generalized linear model. The mean monitored time per person was 6 days, 10 hours and 44 minutes. The mean ± SD glycemia for the regular diet was 4.84 ± 0.20 mmol/L, for the carbohydrates/fat ratio of 1:1 it was 4.03 ± 0.16, for the ratio of 2:1 it was 3.57 ± 0.10, for the ratio 3:1 it was 3.39 ± 0.13 and for the final ratio of 3.5:1 it was 2.79 ± 0.06 mmol/L (P < 0.001). The portions of time spent in glycemia ≤3.5 mmol/L (≤2.5 mmol/L respectively) were: on the normal diet 0.88% (0.31%) of the monitored period, during 1:1 KD ratio 1.92% (0.95%), during 2:1 ratio 3.18% (1.02%), and during 3:1 and 3.5:1 ratios 13.64% (2.36%) of the monitored time (P < 0.05). Continuous glucose monitoring system shows the dynamic of glucose concentration in ketogenic diet treatment initiation. It may be a useful tool to control the effects of this diet on glucose metabolism, especially in hypoglycemia detection.


Abdominal ultrasound examination of the first-trimester fetus.
The first-trimester fetus can now be comprehensively studied with ultrasound. Various biometric measurements correlate well with gestational age, such as crown-rump length (r2 = 0.938) and cranial apex to ear diameter (r2 = 0.983). On the other hand, yolk sac diameter (r2 = 0.129) and abdominal perimeter (r2 = 0.58) correlate poorly with gestational age. By 10 weeks' gestation, kidneys can be visualized in 60% of cases; 98% will be seen at 11 weeks; and 100% of cases will be visible by 12 weeks. The bladder appears later, and by 12 weeks' gestation this organ can be identified in 50% of cases. It is likely that renal agenesis can be diagnosed (or excluded) reliably in the first trimester. With improving technology, prenatal diagnosis of some fetal anomalies is now possible in the first trimester.


Is natural infection with M. tuberculosis protective against cancer?
In order to investigate the effect of natural infection with M. tuberculosis on cancer incidence, a case-control study was undertaken on 108 recently diagnosed cancer cases (all sites) and 317 controls. After removal of cancer cases or controls considered immunoincompetent (25% and 17% respectively), the remaining subjects were tested by intradermal injection of tuberculin (5 I.U.). Results were compared separately for each sex. It was observed that the proportion of tuberculin-negative subjects was higher in cancer patients than in controls within each sex (males 31.3% vs 20.1%, females: 59.2% vs 37.3%) the difference in females being statistically significant (p less than 0.02). Odds ratio for negative tuberculin test was 1.80 and 2.44 for males and females respectively. The results are discussed on the basis of cell-mediated immunity produced by infection with M. tuberculosis and its relations with tumor growth.


Peptides from aminoacyl-tRNA synthetases can cure the defects due to mutations in mt tRNA genes.
Recent results from several laboratories have confirmed that human and yeast leucyl- and valyl-tRNA synthetases can rescue the respiratory defects due to mutations in mitochondrial tRNA genes. In this report we show that this effect cannot be ascribed to the catalytic activity per se and that isolated domains of aminoacyl-tRNA synthetases and even short peptides thereof have suppressing effects.


Computerized tomography: a method to study cross-sectional muscle area in nutritional evaluation.
We have compared two ways of determining cross-sectional muscle area in patients undergoing total parenteral nutrition, namely, computerised tomography and anthropometric measurements. There was a poor correlation between the two methods of determining cross-sectional limb area. The cross-sectional area increased in all patients considered on clinical grounds to have improved during the course of treatment.


Experimental occlusion of two small coronary arteries in the same heart. A new validation method for infarct size manipulation.
A method for the evaluation of interventions aimed at manipulation of infarct size is described. This method has 2 advantages over other methods: 1. Two small-to-medium sized coronary branches of the same heart are occluded and reperfused in sequence. Thereby a "control-infarct" can be compared with a "test-infarct", both within the same heart. 2. The amount of infarcted tissue in both areas is quantitated by using the p-NBT method. A condition of the method is that the areas of perfusion of both arteries are equal. Infarct size is always expressed as a percentage of the perfusion area of the occluded artery. Validation experiments with simultaneous occlusion and reperfusion of both arteries resulted in infarcts of equal size. Validation experiments with regard to the p-NBT method showed that reperfusion accelerates the washout of dehydrogenases from infarcted tissue which allows early and precise diagnosis of infarcts after relatively short occlusion- and reperfusion periods.


Diagnostic marker signature for esophageal cancer from transcriptome analysis.
Esophageal cancer is often diagnosed at an advanced stage. Diagnostic markers are needed for achieving a cure in esophageal cancer detecting and treating tumor cells earlier. In patients with locally advanced squamous cell carcinoma of the esophagus (ESCC), we profiled the gene expression of ESCC compared to corresponding normal biopsies for diagnostic markers by genome microarrays. Profiling of gene expression identified 4844 genes differentially expressed, 2122 upregulated and 2722 downregulated in ESCC. Twenty-three overexpressed candidates with best scores from significance analysis have been selected for further analysis by TaqMan low-density array-technique using a validation cohort of 40 patients. The verification rate was 100 % for ESCC. Twenty-two markers were additionally overexpressed in adenocarcinoma of the esophagus (EAC). The markers significantly overexpressed already in earlier tumor stages (pT1-2) of both histological subtypes (n = 19) have been clustered in a "diagnostic signature": PLA2G7, PRAME, MMP1, MMP3, MMP12, LIlRB2, TREM2, CHST2, IGFBP2, IGFBP7, KCNJ8, EMILIN2, CTHRC1, EMR2, WDR72, LPCAT1, COL4A2, CCL4, and SNX10. The marker signature will be translated to clinical practice to prove its diagnostic impact. This diagnostic signature may contribute to the earlier detection of tumor cells, with the aim to complement clinical techniques resulting in the development of better detection of concepts of esophageal cancer for earlier therapy and more favorite prognosis.


Success rate of infrazygomatic crest mini-implants used for en-masse retraction of maxillary anterior teeth in first premolar extraction cases: A three-dimensional comparative prospective clinical trial between adolescents and young adults.
The purpose of this study was to compare the success rate of infrazygomatic mini-implants between adolescents and young adults. A total of 60 subjects of different age groups ie, (group I [adolescents]: 12-18 years, mean age: 14.9 ± 2.9 years; group II [young adults]: 19-25 years, mean age = 21.9 ± 3.1 years) were assessed in the study. En-masse retraction of maxillary anterior teeth was carried out with extraction of upper first premolars with infrazygomatic crest (IZC) mini-implants as anchorage units. Clinical parameters such as success rate, soft tissue thickness, maximum insertion torque, maximum removal torque, pain response, soft tissue response, and cone-beam computed tomography parameters such as embedded angulation, penetration depth, thickness of bone on buccal and palatal aspect of mini-implant, and peri-implant bone density were evaluated. The success rate of IZC mini-implants in adolescents was found to be 96.6% and 98.3% in young adults respectively. There was no significant difference in success rate between the two groups. Intergroup comparison showed a significant difference (P < 0.05) in terms of maximum insertion torque, maximum removal torque, soft tissue thickness, cortical bone thickness, and peri-implant bone density values. Comparison between right and left side revealed a significant difference (P < 0.05) with regards to soft tissue response, soft tissue thickness, total bone thickness, cortical bone thickness, and peri-implant bone density. There was no significant difference in the success rate of IZC mini-implants between adolescents and young adults. Thus, the use of IZC mini-implants can be recommended in adolescents for successful orthodontic treatment.


Identification of a locus modifying the electrophoretic mobility of malate dehydrogenase isozymes in incense-cedar (Calocedrus decurrens), and its implications for population studies.
Using megagametophyte (maternal haploid) and embryo (diploid) tissues of incense-cedar seeds, the expression of one of three malate dehydrogenase (MDH) loci was found to be influenced by a second, unlinked, modifier locus. Whereas alleles of the affected structural locus are codominant, the modifier alleles show dominance. The action of the modifier, limited to 1 of 28 structural loci examined, results in a shift of electrophoretic mobility detectable in conventional starch gels. Both the structural and the modifier MDH loci are polymorphic in all populations surveyed. Studies of genetic variation in natural populations made without rigorous genetic analysis may not detect such modification. By misinterpreting the genetic basis of enzyme phenotypes, such undetected modification can result in overestimates of genetic diversity in natural populations and can cause an apparent excess of homozygotes relative to expectations. These effects on allele and genotype frequency estimates are dependent on the levels of polymorphism at both the structural and the modifier loci. Using procedures common to many surveys of electrophoretic variation, the frequency of a recessive modifier allele could be as high as 0.3 before being detected.


Retrograde Type A Aortic Dissection 48 Hours after TEVAR in a Patient with a Delayed Diagnosis of Vascular Ehlers-Danlos Syndrome.
We report a case of a fatal retrograde Type A aortic dissection following thoracic endovascular aortic repair (TEVAR). The patient was diagnosed with vascular Ehlers-Danlos syndrome (vEDS) only postoperatively, which is a relative contraindication for TEVAR. The patient had no major or minor criteria for vEDS. This case report emphasizes pitfalls of TEVAR in patients with a connective tissue disorder.


Identification of TyeA residues required to interact with YopN and to regulate Yop secretion.
The secretion of Yops via the Yersinia type III secretion system (T3SS) is controlled, in part, by a cytoplasmic YopN/TyeA complex. This complex is required to prevent Yop secretion in the presence of extracellular calcium and prior to contact between the bacterium and a eukaryotic cell. In this study we utilized site-directed mutagenesis to analyze the role of specific TyeA regions and residues in the regulation of Yop secretion. We identified two spatially distinct, surface-exposed regions of the TyeA molecule that were required to regulate Yop secretion. One region, identified by residues M51, F55 and P56, was required for TyeA to interact with YopN. A second region, identified by residues R19, W20 and D25 was not involved in the interaction of TyeA with YopN, but may be required for the YopN/TyeA complex to interact with the T3S apparatus in a manner that blocks Yop secretion.


Removal of fipronil by advanced oxidative processes using sulfite activated by cobalt immobilized on silica.
Sulfite auto-oxidation catalyzed by cobalt complexed with ammonia deposited on silica (CoNSi) was used to generate sulfate radicals. The material was characterized by ATR-FTIR, suggesting that the silica structure did not change, and SEM-EDS, indicating an uniform dispersion of cobalt across the material surface according with XRD results. BET analysis provided information on a mesoporous material (type IV isotherm) with regular morphology (H1 hysteresis). The DSC analysis showed that CoNSi is thermally stable under the studied conditions. Quantitative analysis of Fipronil (FIP) was performed by HPLC-DAD, where the applied method was selective and linear. The Box-Behnken experimental design (BBD) method was used to define the best condition for removing the analyte in water. It was found that in 60 min, 76% removal of 1.8 mg L-1 of FIP was reached by adding 0.30 g of the material and 0.30 g of the sulfite in a solution under stirring, aeration, pH 8.0, and room temperature and protected from radiation. However, analysis of cobalt leaching into the solution by FAAS showed a small amount of the metal (0.44 mg L-1) informing that the synthesis of the material must be improved.


Progesterone as a possible tumor marker for "nonendocrine" ovarian malignant tumors.
Fifty-one postmenopausal or oophorectomized women with cancer of the ovary were studied. The histologic types were IC, IIC, IIIC, V, and FIGO Stages I-IV. Their tumor volumes were evaluated once a month using bimanual recto-vaginal palpation under anesthesia. Blood samples were drawn for progesterone radioimmunoassay at monthly intervals for 4 months. The plasma levels were compared with those of a control group of postmenopausal women and a control group of fertile women in the follicular phase of the menstrual cycle. The results show a relationship between tumor volume and plasma progesterone level. Histologic type and FIGO stage seem to be less important. During chemotherapy the plasma progesterone value decreased with the reduction in tumor volume. Women bilaterally oophorectomized and radically operated showed a lower plasma progesterone level than both the control groups, which indicates significant progesterone production in the postmenopausal ovary. The results suggest that progesterone may be used as a tumor marker in "nonendocrine" ovarian tumors.


GINS2 facilitates epithelial-to-mesenchymal transition in non-small-cell lung cancer through modulating PI3K/Akt and MEK/ERK signaling.
Non-small-cell lung cancer (NSCLC) is a cancer with high morbidity and mortality. We aimed to define the effect of Go-Ichi-Ni-San complex subuint 2 (GINS2) acting on NSCLC. The expressions of GINS2 in NSCLC tissues and cells were detected using real-time quantitative polymerase chain reaction, western blot, and immunohistochemistry (IHC). The relationship between GINS2 expression and NSCLC prognosis or clinicopathologic features was analyzed through statistical analysis. The overexpressed or downexpressed plasmids of GINS2 were transfected into NSCLC cell lines, and then cell proliferation, invasion, and migration viability were, respectively, determined by Cell Counting Kit-8 assay, transwell, and wound healing assay. The epithelial-mesenchymal transition (EMT) was observed and the EMT-related proteins were measured using IHC and western blot. The function of GINS2 in vivo was assessed by mice model. The related proteins of mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) pathways were evaluated using western blot. GINS2 expression was upregulated in NSCLC tissues and cell lines, and its high expression was correlated with the poor prognosis and several clinicopathologic features, such as TMN stages (tumor size, lymph node, and metastasis) and clinical stages. GINS2 enhanced NSCLC cell proliferation, migration, and invasion viability in vivo and in vitro. GINS2 also promoted NSCLC cells EMT. In addition, GINS2 could regulate phosphorylated proteins of PI3K p85, Akt, MEK, and ERK expressions, it revealed that GINS2 effected on PI3K/Akt and MEK/ERK pathways. GINS2 promoted cell proliferation, migration, invasion, and EMT via modulating PI3K/Akt and MEK/ERK signaling pathways. It might be a target in NSCLC treatment.


Plasmodium berghei: gluconeogenesis in the infected mouse liver studied by 13C nuclear magnetic resonance.
Using 13C nuclear magnetic resonance, we have compared the gluconeogenic activity of perfused livers isolated from normal starved mice and mice highly parasitized with Plasmodium berghei, using [2-13C]pyruvate as substrate. In both types of livers, 13C labeling of glucose carbons occurred in positions 1, 2, 5, and 6. The equal proportions of [1,6-13C]- and [2,5-13C]glucose in livers from malarial and normal mice suggests that pyruvate enters the gluconeogenic pathway directly and, to an equal extent, via the tricarboxylic acid cycle. The normalized signal heights indicated that at a given time after the addition of [2-13C]pyruvate the degree of 13C labeling in glucose carbons was reduced in livers from malarial animals, when compared to livers from normal animals. During the course of the perfusion experiment, the [2-13C]lactate resonance signal was always more intense from livers of malarial animals than from normal animals. A reduced activity of hepatic gluconeogenesis in malarial animals was further confirmed by a separate set of perfusion experiments which showed a 56% reduction of the measured rate of glucose production in livers from malarial animals, with respect to that of normal animals. A lowered NAD/NADH ratio in livers from malarial animals would explain the increased proportion of lactate observed in the spectra and be related to a decreased gluconeogenic rate. A more reduced oxidoreduction level in the hepatocytes of a malarial animal would result from a defect in the oxidative phosphorylation activity of mitochondria.


Biomarkers of intravenous immunoglobulin resistance and coronary artery lesions in Kawasaki disease.
Currently, there are no reliable indicators for predicting intravenous immunoglobulin resistance and coronary artery lesions in the early stage of Kawasaki disease. A total of 300 patients with Kawasaki disease were studied retrospectively. Laboratory data were compared between the intravenous immunoglobulin resistant (29 patients) and responsive groups, and between the groups with coronary artery lesions (48 patients) and without coronary artery lesions. The intravenous immunoglobulin resistant group had significantly higher D-dimer, globulin, interleukin-6 and serum ferritin levels in comparison to the intravenous immunoglobulin responder group. D-dimer level had a sensitivity of 87.0% and a specificity of 56.3% for predicting intravenous immunoglobulin resistance at a cutoff point of 1.09 mg/L. Globulin had a sensitivity of 62.1% and a specificity of 82.3% for predicting intravenous immunoglobulin resistance at a cutoff point of 34.7 g/L. Serum ferritin level had a sensitivity of 42.9% and a specificity of 88.8% for predicting intravenous immunoglobulin resistance at a cutoff point of 269.7 ng/mL. The patients with coronary artery lesions had higher D-dimer and tumor necrosis factor-α level. D-dimer level had a sensitivity of 50% and a specificity of 78.6% for predicting coronary artery lesions at a cutoff point of 1.84 mg/L. Based on analysis by multivariate logistic regression, serum ferritin and globulin were independent risks for intravenous immunoglobulin resistance, D-dimer was independent risk for coronary artery lesions. Elevated serum ferritin, globulin and D-dimer levels are significantly associated with intravenous immunoglobulin resistance in Kawasaki disease. Moreover, serum D-dimer is significantly increased in Kawasaki disease with coronary artery lesions.


New Insights into the Surgical Management of Breast Cancer.
William Halstead is considered by many as the father of modern breast surgery. He popularized the notion that breast cancer progresses in an orderly fashion and that appropriately timed radical surgery can interrupt this progression to save lives. This view dominated for nearly 100 years and still persists to one extent or another in the minds of physicians and patients alike. Rapid advances in breast cancer biology have highlighted the heterogeneity of breast cancer and paradigm-shifting clinical trials have successfully challenged prevailing wisdom to effect a seed change in breast cancer surgery. Advances in radiation and systemic therapies permit more limited surgery for most patients. Recurrence rates of all kinds are on the decline; yet, paradoxically, use of bilateral mastectomy is increasing.


Designing new antitubercular isoniazid derivatives with improved reactivity and membrane trafficking abilities.
Isoniazid (INH) is one of the two most effective first-line antitubercular drugs and is still used at the present time as a scaffold for developing new compounds to fight TB. In a previous study, we have observed that an INH derivative, an hydrazide N'-substituted with a C10acyl chain, was able to counterbalance its smaller reactivity with a higher membrane permeability. This resulted in an improved performance against the most prevalent Mycobacterium tuberculosis (Mtb) resistant strain (S315T), compared to INH. In this work, we have designed two new series of INH derivatives (alkyl hydrazides and hydrazones) with promising in silico properties, namely membrane permeabilities and spontaneous IN* radical formation. The kinetics, cytotoxicity, and biological activity evaluations confirmed the in silico predictions regarding the very high reactivity of the alkyl hydrazides. The hydrazones, on the other hand, showed very similar behavior compared to INH, particularly in biological tests that take longer to complete, indicating that these compounds are being hydrolyzed back to INH. Despite their improved membrane permeabilities, the reactivities of these two series are too high, impairing their overall performance. Nevertheless, the systematic data gathered about these compounds have showed us the need to find a balance between lipophilicity and reactivity, which is paramount to devise better INH-based derivatives aimed at circumventing Mtb resistance.


Experimental Observation of a Peculiar Effect in Saturated Electron Paramagnetic Resonance Spectra Undergoing Spin Exchange. Magnetic Polariton?
We report the experimental observation of a spectral manifestation of a magnetic polariton that was theoretically predicted last year. This unprecedented manifestation is demonstrated not only for 15N-enriched peroxylamine disulfonate, a radical that adheres strictly to the assumptions of the theory, but also for a radical, 4-oxo-2,2,6,6-tetramethylpiperidine-d16;1-15N-1-oxyl, that departs somewhat from the assumptions, as well as the Galvinoxyl radical that represents a severe departure. The magnetic polariton is likely to be of interest to physical chemists in other fields because of the intrinsic advantage of a finite basis set in developing theories.


Pulsed dye laser and non-ablative wrinkle reduction.
Non-ablative wrinkle reduction is currently an issue, which is being widely discussed in the literature and at academic meetings worldwide. We present the findings of our randomized within patient controlled clinical trial into periorbital wrinkle reduction with a 595 nm pulsed dye laser. Twenty-six volunteers, 25 female and 1 male were enrolled into our study. The study was set up as a randomized within patient controlled clinical trial. Subjects received one treatment to the periorbital wrinkles around one eye, using the other as the control. They were then observed at 3 and 6 months post treatment. They then received three treatments spaced 4 weeks apart and were again observed at 3 and 6 months. The author and one blinded assessor reviewed them independently. At the end of the trial a panel of three blinded assessors scored photographs of the subjects independently. The Fitzpatrick wrinkle score was used to score the subjects. All data was subjected to statistical analysis using non-parametric t-tests. Statistical analysis revealed no significant differences in the wrinkle scores of the patients upon completion of the trial protocols. The 595 nm pulsed dye laser set at 0.5 millisecond pulse width is not an effective means of achieving sub-purpuric non-ablative periorbital wrinkle reduction.


Organoruthenium(II) complexes attenuate stress in Caenorhabditis elegans through regulating antioxidant machinery.
The 1:1 stoichiometric reactions of 3-methoxy salicylaldehyde-4(N)-substituted thiosemicarbazones (H2L1-4) with [RuCpCl(PPh3)2] was carried out in methanol. The obtained complexes (1-4) were characterized by analytical, IR, absorption and 1H NMR spectroscopic studies. The structures of ligand [H2-3MSal-etsc] (H2L3) and complex [RuCp(Msal-etsc) (PPh3)] (3), were characterized by single crystal X-ray diffraction studies. The interaction of the ruthenium(II) complexes (1-4) with calfthymus DNA (CT-DNA) has been explored by absorption and emission titration methods. Based on the observations, an intercalative binding mode of DNA has been proposed. The protein binding abilities of the new complexes were monitored by quenching the tryptophan and tyrosine residues of BSA, as model protein. From the studies, it was found that the new ruthenium metallacycles exhibited better affinity than their precursors. The free radical scavenging assay suggests that all complexes effectively scavenged the DPPH radicals as compared to that of standard control ascorbic acid and scavenging activities of complexes are in the order of 4 > 2 > 3 > 1. In addition, ruthenium(II) complexes (2-4) also exhibited an excellent in vivo antioxidant activity as it was able to increase the survival of worms exposed to lethal oxidative and thermal stresses possibly through reducing the intracellular ROS levels. It was interesting to note that complexes 2-4 failed to increase the lifespan of mev-1 mutant worms having shortened lifespan due to the over production of free radicals. This data confirmed that complexes 2-4 conferred stress resistance in C. elegans, but they also require an endogenous detoxification mechanism for doing so. The genetic and reporter gene expression analysis revealed that complexes 2-4 maintained the intracellular redox status and offered stress protection through transactivation of antioxidant defence machinery genes gst-4 and sod-3 which are directly regulated by SKN-1 and DAF-16 transcription factors, respectively. Altogether, our results suggested that complexes 2-4 might play a crucial role in stress modulation and they perhaps exert almost similar effects in higher models, which is an important issue to be validated in future.


"I wouldn't have joined if it wasn't online": understanding older people's engagement with teleyoga classes for fall prevention.
Yoga-based exercise is a promising strategy for promoting healthy ageing, with the potential to reduce falls and increase physical, cognitive and psychological wellbeing. Teleyoga (real-time yoga provided via interactive videoconferencing) can deliver yoga programs at scale, potentially reducing costs, increasing convenience, and reaching people who cannot attend studio-based classes. But better understanding of how older people perceive and engage with teleyoga is needed to optimise its design, implementation and promotion. This study built on a previous realist process evaluation of the SAGE yoga trial which is testing the effect of a yoga-based exercise program on falls among 700 community-dwelling people aged 60 + years. In this second phase of evaluation we conducted focus groups with participants who had completed the SAGE program online and with the yoga instructors who were delivering it. We also conducted interviews with participants who had withdrawn from the trial. Six program theories developed in the earlier evaluation provided a framework for data analysis, supplemented by inductive coding and an analytical workshop. Participants described physical and psychological benefits from the SAGE teleyoga program. While noting that teleyoga cannot facilitate hands-on correction or the same quality of observation or interaction as studio classes, participants were highly appreciative of their yoga instructors' strategies for optimising visibility, instruction, social connection and therapeutic alliance, and for adapting to constrained home environments. Some participants argued that teleyoga was superior to studio classes due to its accessibility and convenience, its lower exposure to potential embarrassment about physical appearance or capabilities, and a reduced sense of peer competition and distraction. Our program theories applied across studio and online modes of delivery. Teleyoga increases accessibility for people in diverse locations and circumstances; it provides a psychologically safer space which combats self-consciousness and unwanted competitiveness; it may enhance embodiment and mindfulness for some; and it has the potential to be offered relatively cheaply at scale which could support free or reduced price classes for people on low incomes and pensions, thereby encouraging a wider population to engage in yoga for healthy ageing and fall prevention.


The Influence of Age on Eye Movements during Reading in Early Elementary School Children.
Eye movement disorders have been observed in many eye diseases, such as amblyopia and developmental dyslexia. The detection of pathological eye movement behaviour is difficult and requires more data for comparison. Therefore, the main purpose of this study was to evaluate the influence of age, school level, gender, and mother tongue on eye movements while reading. One hundred and twenty-seven normally sighted children aged 7 - 12 were recruited from grades 2 - 5. The children were asked to read aloud two texts of The New International Reading Speed Text (IReST) of similar difficulty. Eye movements while reading were recorded by eyetracking technology (SMI RED 250, SensoMotoric Instruments, Teltow, Germany). The eye movement parameters were obtained from 118 children, and reading speed (words/minute), number of saccades, number of fixations, reading errors, and influence of school grade were analyzed. We showed a significant influence of age in all eye movement parameters. The main finding of this study is that younger children performed more saccades, a higher number of fixations per word, and more reading errors while taking more time to read the text than older children in higher grades. In early grades, non-native German speakers read more slowly and performed more saccades and fixations, but no more differences were seen by grade 5. Overall, there was no significant influence of gender or school system on reading parameters. This study highlights the need for an age-appropriate normative database for eye movements during reading.


Orbital oedema: an unusual presentation of Noonan's syndrome.
We report a 52-year-old man who presented with severe chronic bilateral orbital oedema, and dysmorphic features characteristic of Noonan's syndrome. No recognized cause of the orbital oedema was found. This is the first report of late-onset orbital oedema in association with Noonan's syndrome, a condition known to be associated with widespread lymphatic hypoplasia and ectasia.


Streptococcus anginosus: a stealthy villain in deep odontogenic abscesses.
Odontogenic infections (OIs) occasionally spread to deep facial and neck tissues. Our study aimed to explore the role of Streptococcus anginous group (SAG) in these severe OIs. A retrospective study of patients aged ≥ 18 years who required hospital care for acute OI was conducted. We analysed data of OI microbial samples and recorded findings of SAG and other pathogens. These findings were compared with data regarding patients' prehospital status and variables of infection severity. In total, 290 patients were included in the analyses. The most common (49%) bacterial finding was SAG. Other common findings were Streptococcus viridans and Prevotella species, Parvimonas micra, and Fusobacterium nucleatum. Infection severity variables were strongly associated with SAG occurrence. Treatment in an intensive care unit was significantly more common in patients with SAG than in patients without SAG (p < 0.001). In addition, SAG patients expressed higher levels of C-reactive protein (p = 0.001) and white blood cell counts (p < 0.001), and their hospital stays were longer than those of non-SAG patients (p = 0.001). SAG is a typical finding in severe OIs. Clinical features of SAG-related OIs are more challenging than in other OIs. Early detection of SAG, followed by comprehensive infection care with prompt and careful surgical treatment, is necessary due to the aggressive behaviour of this dangerous pathogen.


The development and initial validation of the Earthquake Fear Scale: Its links to personality traits, psychological distress, harmony in life, and mental wellbeing.
Unexpected and unpredictable earthquakes may have a negative impact on people's mental health. The earthquake fear experienced by individuals causes psychological problems. This article is made up of three different studies that look at earthquake fear. The seven item Earthquake Fear Scale (EFS) was confirmed in Study I (N = 407) utilising confirmatory factor analysis. In addition, Item Response Analysis was done, and it was found that all of the items showed a good degree of discrimination. The reliability of the EFS has been proven with different reliability coefficients. In Study II (N = 505), both correlation and network analysis were carried out, and earthquake fear was found to be significantly associated with depression, anxiety, stress, and mental wellbeing. Moreover, neuroticism and conscientiousness, two of the big five personality traits, are significantly associated with earthquake fear. In Study III (N = 382), it was revealed that psychological distress and harmony in life play a serial and fully mediating role in the link between earthquake fear and mental wellbeing. The psychological influence of earthquake fear is emphasised in this pioneering and comprehensive study on earthquake fear.


LH-RH binding to purified pituitary plasma membranes: absence of adenylate cyclase activation.
Purified bovine pituitary plasma membranes possess two specific LH-RH binding sites. The high affinity site (2.5 X 10(9) l/mol) has low capacity (9 X 10(-15) mol/mg membrane protein) while the low affinity site 6.1 X 10(5) l/mol) has a much higher capacity (1.1 X 10(-10) mol/mg). Specific LH-RH binding to plasma membranes is increased 8.5-fold during purification from homogenate whilst adenylate cyclase activity is enriched 7--8-fold. Distribution of specific LH-RH binding to sucrose density gradient interface fractions parallels that of adenylate cyclase activity. Mg2+ and Ca2+ inhibit specific [125I]LH-RH binding at micromolar concentrations. Synthetic LH-RH, up to 250 microgram/ml, failed to stimulate adenylase cyclase activity of the purified bovine membranes. Using a crude 10,800 g rat pituitary membrane preparation, LH-RH similarly failed to activate adenylate cyclase even in the presence of guanyl nucleotides. These data confirm the presence of LH-RH receptor sites on pituitary plasma membranes and suggest that LH-RH-induced gonadotrophin release may be mediated by mechanisms other than activation of adenylate cyclase.


Development, evaluation and application of 3D QSAR Pharmacophore model in the discovery of potential human renin inhibitors.
Renin has become an attractive target in controlling hypertension because of the high specificity towards its only substrate, angiotensinogen. The conversion of angiotensinogen to angiotensin I is the first and rate-limiting step of renin-angiotensin system and thus designing inhibitors to block this step is focused in this study. Ligand-based quantitative pharmacophore modeling methodology was used in identifying the important molecular chemical features present in the set of already known active compounds and the missing features from the set of inactive compounds. A training set containing 18 compounds including active and inactive compounds with a substantial degree of diversity was used in developing the pharmacophore models. A test set containing 93 compounds, Fischer randomization, and leave-one-out methods were used in the validation of the pharmacophore model. Database screening was performed using the best pharmacophore model as a 3D structural query. Molecular docking and density functional theory calculations were used to select the hit compounds with strong molecular interactions and favorable electronic features. The best quantitative pharmacophore model selected was made of one hydrophobic, one hydrogen bond donor, and two hydrogen bond acceptor features with high a correlation value of 0.944. Upon validation using an external test set of 93 compounds, Fischer randomization, and leave-one-out methods, this model was used in database screening to identify chemical compounds containing the identified pharmacophoric features. Molecular docking and density functional theory studies have confirmed that the identified hits possess the essential binding characteristics and electronic properties of potent inhibitors. A quantitative pharmacophore model of predictive ability was developed with essential molecular features of a potent renin inhibitor. Using this pharmacophore model, two potential inhibitory leads were identified to be used in designing novel and future renin inhibitors as antihypertensive drugs.


Autobiographical memory in depression: an fMRI study.
Depression is associated with three distinct alterations in memory functioning: mood-congruent recall, over-generality, and intrusive memories. These concern the autobiographical memory system, yet no previous studies have examined the neural correlates of autobiographical memory function in depression. In the present study we used functional magnetic resonance imaging (fMRI) to assess depressed and control participants during an autobiographical memory task. In their first visit to the laboratory, participants wrote a narrative account of a distressing event. Participants were scanned during the second visit while they viewed old items from their narrative and new words or phrases in a recognition memory task. Activity common to both groups during the successful identification of personal emotional memories was observed in regions previously associated with autobiographical memory retrieval. Reduced activity in the depressed group was observed in three regions of the prefrontal cortex associated with cognitive, emotional, and memory inhibition. These results are consistent with a failure by depressed individuals to inhibit task-irrelevant information during an autobiographical memory task.


Influence of deoxynivalenol on NF-kappaB activation and IL-8 secretion in human intestinal Caco-2 cells.
Deoxynivalenol (DON) is the most prevalent trichothecene mycotoxin in crops in Europe and North America. In human intestinal Caco-2 cells, DON activates the mitogen-activated protein kinases (MAPKs). We hypothesized a link between DON ingestion and intestinal inflammation, and used Caco-2 cells to assess the effects of DON, at plausible intestinal concentrations (250-10,000 ng/ml), on inflammatory mediators acting downstream the MAPKs cascade i.e. activation of nuclear factor-kappaB (NF-kappaB) and interleukin-8 (IL-8) secretion. In addition, Caco-2 cells were co-exposed to pro-inflammatory stimuli in order to mimic an inflamed intestinal epithelium. Dose-dependent increases in NF-kappaB activity and IL-8 secretion were observed, reaching 1.4- and 7.6-fold, respectively using DON at 10 microg/ml. Phosphorylation of inhibitor-kappaB (IkappaB) increased (1.6-fold) at DON levels <0.5 microg/ml. Exposure of Caco-2 cells to pro-inflammatory agents, i.e. 25 ng/ml interleukin-1beta, 100 ng/ml tumor necrosis factor-alpha or 10 microg/ml lipopolysaccharides, activated NF-kappaB and increased IL-8 secretion. Synergistic interactions between these stimuli and DON were observed. These data show that DON induces NF-kappaB activation and IL-8 secretion dose-dependently in Caco-2 cells, and this effect was accentuated upon pro-inflammatory stimulation, suggesting DON exposure could cause or exacerbate intestinal inflammation.


Relationships between dopamine infusions and intracranial hemodynamics in patients with raised intracranial pressure.
Dopamine, 1-10 micrograms/kg body weight/min was infused in 6 patients suffering from cerebrovascular diseases with elevated intracranial pressure and a critical cerebral perfusion pressure. Dopamine decreased intracranial pressure in 3 and increased it moderately in the other 3 patients. In all patients, the dopamine-induced rise of mean arterial pressure led to an increase of cerebral perfusion pressure. Transcranial Doppler ultrasonographic recordings of the middle cerebral artery in patients whose intracranial pressure declined revealed a decrease of the pathologically elevated cerebrovascular resistance, and an augmentation of cerebral blood supply. In conclusion, dopamine infusions may improve cerebral hemodynamics in some patients with severe brain edema. Such patients can be identified by intracranial pressure and Doppler monitoring.


Enzymes of the Entner-Doudoroff and pyruvate decarboxylation pathways in Zymomonas mobilis wild-type CP4 and mutant strains grown in continuous culture.
The osmotolerant Zymomonas mobilis strain suc40, (containing plasmid pDS3154-inaZ), which is capable of producing simultaneously ethanol and ice nuclei protein, was cultivated in a chemically defined complete sucrose medium, as well as in a sugar beet molasses medium in continuous culture. The strain exhibited the normal Monod's relationship between biomass and dilution rate, and between growth substrate concentration and dilution rate. Specific activities of a number of enzymes that appear to control important steps in the metabolic flux of the Entner-Doudoroff and pyruvate decarboxylation pathways were investigated over a range of growth rates in steady state cultures. With the exception of glucose-6-phosphate dehydrogenase and gluconate kinase, all of the enzymes exhibited a very similar pattern for the wild type Z. mobilis CP4 and for the osmotolerant mutants, independent of the media used; the enzyme patterns remained relatively constant over the studied growth range. The specific activity of glucose-6-phosphate dehydrogenase was increased 2-fold by decreasing dilution rate in sugar beet molasses. The specific activity of gluconate kinase was 2-fold lower at medium growth rates compared with that at either low or high growth rates. Pyruvate kinase, pyruvate decarboxylase and alcohol dehydrogenase activities were significantly higher compared with those of the enzymes governing the early steps of the Entner-Doudoroff pathway. The present study, which was designed to determine the behaviour of important enzymes in sucrose metabolism of Z. mobilis suc40/pDS3154-inaZ grown in continuous culture showed that the microorganism required regulation of specific enzyme activities at the transcriptional level when sugar beet molasses were used as the growth medium.


Functional role of growth/differentiation factor 5 in chondrogenesis of limb mesenchymal cells.
Growth/Differentiation Factor 5 (GDF5) plays an important role in limb mesenchymal cell condensation and chondrogenesis. Here we demonstrate, using high density cultures of chick embryonic limb mesenchyme, that GDF5 misexpression increased condensation of chondroprogenitor cells and enhanced chondrogenic differentiation. These effects were observed in the absence of altered cellular viability or biosynthetic activity, suggesting that GDF5 action might be directed at the level of cellular adhesion or cell-cell communication. GDF5- enhanced condensation occurred independent of cell density or N-cadherin mediated adhesion and signaling, but was inhibited upon interference of gap junction mediated communication. p38 MAP kinase signaling was required for the GDF5 effect on chondrocyte differentiation, but not for mesenchymal condensation. These findings suggest gap junction involvement in the action of GDF5 in developmental chondrogenesis.


Effective plasma concentrations of antiarrhythmic drugs against sustained halothane-adrenaline arrhythmia in dogs.
We determined the minimum effective plasma concentrations of several antiarrhythmic agents against canine halothane-adrenaline arrhythmia. Sustained ventricular tachycardia was produced by continuous adrenaline infusion at rates of 1.5 to 4 micrograms/kg/min under 1.5% halothane anesthesia. Procainamide, 20 mg/kg, produced ventricular fibrillation in three of nine dogs. Disopyramide, 3 mg/kg, suppressed the arrhythmia in nine of 11 dogs at a minimum effective plasma concentration of 4.2 micrograms/ml, but produced ventricular fibrillation in the remaining two dogs. Phenytoin, 5 mg/kg, was effective at a minimum concentration of 12 micrograms/ml. Lidocaine, 10 mg/kg, suppressed the arrhythmia at a minimum concentration of 15 micrograms/ml, which is much higher than the human toxic plasma level. These drugs may have suppressed the adrenaline arrhythmia by inhibiting the sodium channel, because their effective concentrations were very close to membrane-stabilizing concentrations in vitro. Small doses of 30 micrograms/kg propranolol and 0.1 mg/kg N-696, two beta-blockers, and 0.1 mg/kg verapamil, a calcium channel blocker, yielding a concentration of 0.03 micrograms/ml, suppressed the arrhythmia, probably by indirectly or directly blocking the calcium channel.


[Identification of a novel AGPAT2 variant in a Chinese patient with congenital generalized lipodystrophy type 1].
To explore the genetic basis for an infant with congenital generalized lipodystrophy. Peripheral blood samples of the child and her parents were collected for the extraction of genomic DNA. All exons and flanking sequences of the AGPAT2 gene were subjected to Sanger sequencing. The child was found to harbor compound heterozygous c.792_805delGGAGAACGGGGCCA (p.Gln264Hisfs*208) and c.335C>T (p.P112L) variants in exons 6 and 3 of the AGPAT2 gene, which were respectively inherited from her mother and father. c.792_805delGGAGAACGGGGCCA (p.Gln264Hisfs*208) was previously unreported, while c.335C>T (p.P112L) was known to be pathogenic. The compound heterozygous variants of the AGPAT2 gene probably underlie the disease in this child.


Ribosomal RNA in Mauthner axon: implications for a protein synthesizing machinery in the myelinated axon.
RNA was extracted from myelin-free Mauthner axons of the goldfish on a microscale and fractionated by microelectrophoresis. Microextracts showed the presence of nominal 26 SE, 18 SE, 5 SE and 4 SE components, which co-migrated with rRNA from fish brain. In addition, a non-ribosomal 15 SE component was present in axon microextracts, but not in RNA extracts of fish brain or of myelin sheath from Mauthner axon, indicating an unusual enrichment of a putative mRNA class. Evidence was presented to support the contention that axonal rRNA was not due to contamination from the myelin sheath. Possible reasons for the lack of ultrastructural evidence for axoplasmic ribosomes are discussed.


Association between admission heart rate and major adverse cardiovascular events in acute myocardial infarction participants with different left ventricular ejection fraction.
This study intended to investigate the independent effect of admission heart rate (HR) on the risk of major adverse cardiovascular events (MACEs) in acute myocardial infarction (AMI) patients with different left ventricular ejection fraction (LVEF) levels. The study was a secondary analysis of the Acute Coronary Syndrome Quality Improvement in Kerela Trial. The relationship between admission HR and 30-day adverse outcomes in AMI patients with different LVEF levels was detected using a Logistic regression model. Interaction tests were used to compare the effects of different subgroups on HR and MACEs. Our study enrolled 18,819 patients. In both partially and fully adjusted models (Model1 and Model2), the risk of MACEs was highest in patients with HR ≥ 120 (OR: 1.62, 95%CI: (1.16, 2.26), P = 0.004, Model1; OR: 1.46, 95%CI: (1.00, 2.12), P = 0.047, Model2). There was a significant interaction between LVEF and HR (P for interaction = 0.003). Meanwhile, the trend test for this association showed that HR was positively and significantly associated with the MACEs in LVEF≥40% group (OR (95%CI): 1.27 (1.12, 1.45), P < 0.001). However, in LVEF<40% group, the trend test was not statistically significant (OR (95%CI): 1.09 (0.93, 1.29), P = 0.269). This study found that elevated admission HR was associated with a significantly higher risk for MACEs in patients admitted with AMI. Elevated admission HR was significantly associated with the risk of MACEs in AMI patients without low LVEF but not those with low LVEF (<40%). LVEF levels should be considered when evaluating the association between admission HR and the prognosis of AMI patients in the future.


Post-stroke administration of omega-3 polyunsaturated fatty acids promotes neurovascular restoration after ischemic stroke in mice: Efficacy declines with aging.
Post-stroke treatment with omega-3 polyunsaturated fatty acids (n-3 PUFAs) may be a promising therapy in young animals but this has not been tested in aged subjects, a population at most risk of ischemic stroke. Herein we examined the therapeutic efficacy of n-3 PUFAs after distal middle cerebral artery occlusion (dMCAO) in young (10-12 weeks old) and aged (18 months old) mice. Post-ischemic mice were randomly assigned to 4 groups that received: 1) regular food with low content of n-3 PUFAs, 2) intraperitoneal docosahexaenoic acid (DHA, a major component of n-3 PUFAs) injections, 3) Fish oil (FO, containing high concentration of n-3 PUFAs) dietary supplement, or 4) combined treatment with DHA and FO dietary supplement. Long-term neurorestoration induced by n-3 PUFA post-stroke administration and its underlying mechanism(s) were analyzed up to 35 days after dMCAO. Aged mice showed more severe neurological deficits than young mice after dMCAO with histological lesions extended to the striatum. Notably, post-stroke treatment with combined DHA injections and FO dietary supplementation was more effective in reducing brain injury and improving sensorimotor function in aged mice than either treatment alone, albeit to a lesser extent than in the young mice. Unlike the improvement in spatial cognitive function observed in young mice, the combined treatment regimen failed to improve cognitive function in aged mice. The reduction in stroke-induced neurological deficits with n-3 PUFA post-treatment was associated with enhanced angiogenesis, oligodendrogenesis, neuron survival and white matter restoration. Together, these results indicate that the neurological benefits of n-3 PUFA administration after stroke extend to older animals and are associated with improved neuronal survival and brain remodeling, therefore suggesting that post-stroke administration of n-3 PUFAs is a viable clinically relevant treatment option against stroke.


Poor Nutritional Status Is Associated with Arrhythmic Events on 24-Hour Holter Recording.
Malnutrition is associated with cardiovascular disease morbidity and mortality. Arrhythmias may be the cardiac consequences of malnutrition. The objective of the study was to evaluate the association between prognostic nutritional index (PNI), Controlling Nutritional Status (CONUT) score, and arrhythmic events on 24-h electrocardiography (ECG) Holter recording in patients without manifested arrhythmia. In this retrospective analysis of 477 patients who underwent 24-h ECG Holter monitoring, PNI and CONUT score were calculated and patients were divided into tertiles according to PNI and into three groups according to CONUT score; 0: normal, 1-2: mild risk of malnutrition, ≥3: moderate-severe risk of malnutrition. Arrhythmic events were compared between PNI tertiles and CONUT score groups. Total number of premature atrial contractions, premature ventricular contractions (PVCs), PVC burden, and incidence of paroxysmal atrial fibrillation (PAF) were significantly higher in patients within the lowest PNI tertile. Total number of PVCs, PVC burden, and incidence of PAF were significantly higher in patients with CONUT score ≥3. The cut-off value for PNI to predict the presence of PVC was defined as 39.41 using ROC curve analysis. The area under the curve was 0.650 (p < 0.001). Multivariate analysis showed that PNI was independent predictor of the presence of PVC and PAF. Also, CONUT score was independent predictor of the presence of PVC and PAF. Incidence of nonsustained ventricular tachycardia did not differ between PNI tertiles or CONUT score groups. Poor nutritional status, assessed by PNI and CONUT score, is associated with arrhythmic events on 24-h ECG Holter recording in patients without manifested arrhythmia.


Far-field super-resolution ghost imaging with a deep neural network constraint.
Ghost imaging (GI) facilitates image acquisition under low-light conditions by single-pixel measurements and thus has great potential in applications in various fields ranging from biomedical imaging to remote sensing. However, GI usually requires a large amount of single-pixel samplings in order to reconstruct a high-resolution image, imposing a practical limit for its applications. Here we propose a far-field super-resolution GI technique that incorporates the physical model for GI image formation into a deep neural network. The resulting hybrid neural network does not need to pre-train on any dataset, and allows the reconstruction of a far-field image with the resolution beyond the diffraction limit. Furthermore, the physical model imposes a constraint to the network output, making it effectively interpretable. We experimentally demonstrate the proposed GI technique by imaging a flying drone, and show that it outperforms some other widespread GI techniques in terms of both spatial resolution and sampling ratio. We believe that this study provides a new framework for GI, and paves a way for its practical applications.


Vascular cognitive impairment in India: Challenges and opportunities for prevention and treatment.
The burden of vascular contribution to cognitive impairment and dementia is substantially high in India. There are approximately 5.3 million dementia patients in India and nearly 40% are estimated to be due to vascular dementia. Several factors pose unique challenges to reducing the burden of vascular dementia and vascular cognitive impairment (VCI) in India. Wide heterogeneity in vascular risk factor profile, diversity in socioeconomic, ethnic and dietary factors, as well as regional and rural-urban differences impact uniform implementation of preventive and therapeutic strategies. There is limited evidence on the natural history of vascular disease from longitudinal cohorts in India. Additionally, the lack of advanced brain imaging and genetic information pose challenges to understanding pathophysiology and treatment response to VCI in India. Efforts are now being made to implement programmes to reduce cardiovascular risk and VCI at the population level. Cognitive and functional measures appropriate to the diverse linguistic and educational context have been developed to diagnose VCI across India. Multicentric clinical and research cohorts of stroke are also being established. Filling research gaps and developing intervention strategies for the Indian context are crucial to address the growing burden of VCI.


Binding of two distamycin A molecules in the minor groove of an alternating B-DNA duplex.
Here we report the 1.8A X-ray structure of a 2:1 drug-DNA complex between distamycin A and an alternating B-DNA octamer duplex d(ICICICIC)2. The two distamycin A molecules are bound side by side with dyad symmetry in an antiparallel orientation in the expanded minor groove. The amides of each drug molecule are hydrogen bonded to the minor groove base atoms of only one DNA strand. The complex not only shows binding of two drug molecules, but the DNA duplex also exhibits striking low-high alternations in the helical twist angles, the sugar puckering and the phosphate conformations, providing the basis for a new model for an alternating B-DNA with a dinucleotide repeat.


DNase VII of human placenta. Mechanism studies.
The mechanism of the human placental DNase VII, described previously (Hollis, G. F., and Grossman, L. (1981) J. Biol. Chem. 256, 8074-8079) has been investigated in further detail. The enzyme initiates exonucleolytic hydrolysis from the 3'-end of DNA in a nonprocessive, or distributive, manner, regardless of whether the carbohydrate moiety associated with the 3'-terminal nucleotide contains H or OH at its 2' and 3' positions. DNase VII does not have associated RNase H activity; however, it is capable of removing 3'-terminal ribonucleotides. The enzyme also can hydrolyze DNA containing a terminal nucleotide lacking a purine or pyrimidine as well as termini containing noncomplementary nucleotides. DNase VII activity is product-inhibited by deoxynucleoside 5'-monophosphates. From kinetic studies, the mononucleotide deoxyadenylic acid is a noncompetitive inhibitor with a Ki = 0.3 mM. The resemblance of DNase VII to the 3'----5' exonuclease activity of Escherichia coli DNA polymerase I and its possible role in excision repair and proofreading are discussed.


A foreign body in the floor of the mouth.
A case of unusual presentation of foreign body in the floor of mouth is reported. The patient presented with a history and clinical findings of sublingual ranula. Marsupialisation and sublingual sialadenectomy was planned. After marsupialisation, a foreign body (spray cover) was found between the lumen of the submandibular duct and the ranula.


NMR investigation of the copper(II)-carnosine complex in water solution.
The predominant species in water solution of excess carnosine and Cu2+ ions was characterized by measuring 13C and 1H spin-lattice and spin-spin relaxation rates. Four peptide molecules were calculated to be coordinated to the metal through the imidazole nitrogen. Evaluation of ion-proton distances demonstrated that metal complexation does not involve severe changes in conformation of the peptide.


Comparison in dark hydrogen fermentation followed by photo hydrogen fermentation and methanogenesis between protein and carbohydrate compositions in Nannochloropsis oceanica biomass.
The thermodynamic comparison in dark fermentation between amino acids and reducing sugars released from Nannochloropsis oceanica biomass are investigated for the first time. The total utilisation efficiencies of amino acids and reducing sugars are both about 95% in dark fermentation. But the consumption time of most amino acids is about 2 times as long as that of most reducing sugars in dark fermentation. A three-stage method comprising dark fermentation, photofermentation and methanogenesis is proposed to improve hydrogen and energy yields from N. oceanica biomass. Overall, the maximum hydrogen yield of 183.9 ml/g-total volatile solids (TVS) and the methane yield of 161.3 ml/g-TVS are achieved from N. oceanica biomass through the three-stage method. The total energy yield of hydrogen and methane from microalgae biomass through the three-stage method is 1.7 and 1.3 times higher than those through the two-stage (dark fermentation and methanogenesis) and single-stage (methanogenesis) methods, respectively.


Impact of site-directed mutant luciferase on quantitative green and orange/red emission intensities in firefly bioluminescence.
Firefly bioluminescence has attracted great interest because of its high quantum yield and intriguing modifiable colours. Modifications to the structure of the enzyme luciferase can change the emission colour of firefly bioluminescence, and the mechanism of the colour change has been intensively studied by biochemists, structural biologists, optical physicists, and quantum-chemistry theorists. Here, we report on the quantitative spectra of firefly bioluminescence catalysed by wild-type and four site-directed mutant luciferases. While the mutation caused different emission spectra, the spectra differed only in the intensity of the green component (λmax ~ 560 nm). In contrast, the orange (λmax ~ 610 nm) and red (λmax ~ 650 nm) components present in all the spectra were almost unaffected by the modifications to the luciferases and changes in pH. Our results reveal that the intensity of the green component is the unique factor that is influenced by the luciferase structure and other reaction conditions.


Methodological validation of an existing telemetry system for QT evaluation in conscious guinea pigs.
Guinea pigs are suitable for in vivo QT assessment of newly discovered drugs at the pre-clinical stage because of the ease with which these animals can be handled, the lower amount of compound required for testing, and the similarity of the ion channels between the guinea pig heart and the human. Our purpose was to provide detailed methodological information on an existing telemetry recording system for use in evaluating QT interval prolongation in guinea pigs. Hartley guinea pigs weighing 400-700 g were used to investigate the appropriate configuration of electrodes to record defined T-waves and the influence of the surgical implantation of a transmitter on the QT interval, as well as to determine the appropriate formula for QT correction. In addition, the validity of using telemetry-monitored guinea pigs was tested by using compounds with (positive references) or without (vehicles) a QT-prolonging effect. A lead with the negative pole placed between the scapulas and the positive pole positioned close to the sternum was found to be the most appropriate to obtain well-defined T-waves. The period for recovery from transmitter implantation was estimated to be at least 1 week. The best-fit formula for our telemetry guinea pig model was a modified Bazett's formula. QTc was prolonged significantly in guinea pigs given positive references, and the QTc was unaffected when the animals were given vehicles. We believe that the information provided herein will be a quite helpful guide for researchers to evaluate the QT interval reliably and reproducibly in this telemetry guinea pig model.