Management of Oral Submucous Fibrosis with Injection of Hyaluronidase and Dexamethasone in Grade III Oral Submucous Fibrosis: A Retrospective Study.
Oral submucous fibrosis (OSMF) is a chronic debilitating and potentially malignant condition of the oral cavity. It is resistant and progressive affecting the entire oral cavity that sometimes causes a gradual reduction in mouth opening that may even extend up to the pharynx. Although the medical treatment is not completely systematized, optimal doses of its treatment with local injection of corticosteroids with hyaluronidase or placental extract is effective to some extent. However, a combination of steroids and topical hyaluronidase shows better long-term results than either agents used individually. To evaluate the efficacy of dexamethasone and hyaluronidase in the treatment of Grade III OSMF. A total of 28 patients diagnosed with OSMF were treated in Sri Rajiv Gandhi College of Dental Sciences for a time period of 9 months, by obtaining the patient's consent and with the approval of the institution's research ethical committee. They were treated by administering an intralesional injection of dexamethasone1.5 ml, hyaluronidase 1500 IU with 0.5 ml lignocaine HCL injected intralesionally biweekly for 4 weeks. Improvement in the patient's mouth opening with a net gain of 6 ± 2 mm (92%), the range being 4-8 mm. Definite reduction in burning sensation, painful ulceration and blanching of oral mucosa and patient followed up for an average of 9 months. Injection of hyaluronidase with dexamethasone is an effective method of managing Grade III OSMF and can possibly eliminate the morbidity associated with surgical management.


Citizenship as the exception to the rule: an addendum.
This addendum expands upon the arguments made in the author's 2020 essay, "Legal Personhood for Artificial Intelligence: Citizenship as the Exception to the Rule", in an effort to display the significance human augmentation technologies will have on (feasibly) inadvertently providing legal protections to artificial intelligence systems (AIS)-a topic only briefly addressed in that work. It will also further discuss the impacts popular media have on imprinting notions of computerised behaviour and its subsequent consequences on the attribution of legal protections to AIS and on speculative technological advancement that would aid the sophistication of AIS.


Promotion of hair growth by ginseng radix on cultured mouse vibrissal hair follicles.
A 70% methanol extract from red ginseng (steamed and dried roots of Panax ginseng C. A. Meyer, a kind of Ginseng Radix) had superior activity to that of white ginseng (peeled and dried root of P. ginseng, another kind of Ginseng Radix) in a hair growth promoting assay using mouse vibrissal follicles in organ culture. Of the major constituents of P. ginseng, ginsenoside-Rb(1) (G-Rb(1)) exhibited activity, but ginsenoside-Rg(1) (G-Rg(1)) and -Ro (G-Ro) were ineffective. Additionally, 20(S)-ginsenoside-Rg(3) (20(S)-G-Rg(3)) formed by the processing of red ginseng from the crude root of P. ginseng also showed hair growth promoting activity. These results indicate that Ginseng Radix possesses hair growth promoting activity, and its bioactive components are partially attributable to the ginseng saponin components mentioned above.


Isolated ileal-loop endorectal pull-through: a new approach in the management of complicated Hirschsprung's disease.
The isolated ileal-loop endorectal pull-through was performed on two patients with Hirschsprung's disease complicated by disuse atrophy of the distal colon. In both patients there was not only a short length of the proximal ganglionic colon, which could not be safely pulled down to the perineum, but also nonavailability of the distal aganglionic colon, which had to be resected for nonfunctioning disuse atrophy. This technique allowed a safe endorectal pull-through with primary anal anastomosis, and also prevented complications like frequent watery diarrhea, steatorrhea, malabsorption of vitamins A, D, and K, and pernicious anemia frequently observed following popular surgical procedures for long-segment and total colonic aganglionsis.


EMS communication system in Osaka, Japan.
Osaka prefecture, an industrial and commercial center in western Japan with a population of 7.4 million, is divided into 40 municipalities. Each municipality has an independent ambulance dispatching center to provide ambulances and rescue personnel information about availability of physicians and hospital beds in that municipality's receiving hospitals. An Emergency Medical Services Information Center (EMS-IC), equipped with a wireless network and memory devices, collects information on available specialits and vacant hospital beds every three hours from 300 hospitals and clinics in the whole prefecture and supplies them to physicians, ambulances, medical institutions, fire services headquarters, police departments, ambulance dispatching centers, medical societies and the Red Cross. EMS-IC can provide the name of the most appropriate medical institution to a running ambulance on request from rescue personnel. EMS-IC also stores information on bank blood and antiserum.


Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies.
Four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and the proton-pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600-mg loading/150-mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 micromol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively; and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively. The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.


Cytology in Barrett's esophagus.
Brush cytology is complementary to endoscopic biopsy and is recommended by some to be part of the routine endoscopic surveillance of patients with BE. Advantages of cytology include the ability to sample a greater area of involved epithelium, preferential exfoliation of the less cohesive dysplastic cells, simplicity, and lower cost. There are clear cytologic criteria for dysplasia, and biomarker studies can be performed on cytologic specimens. Despite these advantages, cytology is used by only 17% of gastroenterologists in the United States today. Limited data are available on the usefulness of cytology in the diagnosis and surveillance of BE. Cytology has good sensitivity for the detection of adenocarcinoma and HGD and good specificity for the detection of IM without dysplasia. Furthermore, cytology may detect abnormalities missed by biopsy. Cytology has problems in the detection of LGD, however. For cytology to become a useful surveillance option, its sensitivity for low-grade lesions must be improved. One potential way to accomplish this is to add biomarkers to routine cytologic specimens to define patients at increased risk of progression to cancer. If simple prognostic biomarkers could be developed and validated in histology and cytologic specimens, this would provide additional support for the utility of cytologic brushings in the surveillance of BE. Cytology could then conceivably accomplish the goals of improved efficiency, risk stratification, and decreased costs in BE surveillance programs.


Auditory-motor synchronization varies among individuals and is critically shaped by acoustic features.
The ability to synchronize body movements with quasi-regular auditory stimuli represents a fundamental trait in humans at the core of speech and music. Despite the long trajectory of the study of such ability, little attention has been paid to how acoustic features of the stimuli and individual differences can modulate auditory-motor synchrony. Here, by exploring auditory-motor synchronization abilities across different effectors and types of stimuli, we revealed that this capability is more restricted than previously assumed. While the general population can synchronize to sequences composed of the repetitions of the same acoustic unit, the synchrony in a subgroup of participants is impaired when the unit's identity varies across the sequence. In addition, synchronization in this group can be temporarily restored by being primed by a facilitator stimulus. Auditory-motor integration is stable across effectors, supporting the hypothesis of a central clock mechanism subserving the different articulators but critically shaped by the acoustic features of the stimulus and individual abilities.


Precision of Measurements Performed by a Cadre of Anthropometrists Trained for a Large Household Nutrition Survey in Ethiopia.
Well-trained anthropometrists are essential for the delivery of high-quality anthropometric data used to evaluate public health nutrition interventions. Scant data are currently available on the precision of data collected by large teams of anthropometrists employed for nutrition surveys in low-income country settings. The purpose of this study was to assess the precision of child midupper arm circumference (MUAC) and length/height measurements taken by fieldworkers training for nutrition survey deployment. Following 3 d of training, an anthropometry standardization exercise was conducted in small teams of trainees at 7 sites in the Amhara region of Ethiopia. In groups of 2-4, trainee anthropometrists (n = 79) each measured 16 children aged 6-47 mo (n = 336) twice for MUAC and length/height. Both intraobserver and interobserver precision were analyzed using technical error of measurement (TEM), relative TEM, coefficient of reliability (R), and repeatability metrics. Bland-Altman limits of agreement were calculated for intraobserver measurements. Intraobserver TEM was between 0.00 and 0.57 cm for MUAC (Bland-Altman 95% limits of agreement: -0.50 to 0.54 cm) and between 0.04 and 2.58 cm for length/height measurements (Bland-Altman 95% limits of agreement: -1.43 to 1.41 cm). Interobserver TEM was between 0.09 and 0.43 cm for MUAC and between 0.06 and 2.98 cm for length/height measurements. A high proportion of trainees achieved intraobserver R >0.95 (MUAC: 95%; length/height: 97%). Most teams also achieved interobserver R >0.95 (MUAC: 90%; length/height: 95%). Large numbers of anthropometrists (>75) in low-income settings can attain satisfactory precision in anthropometry following training and standardization. These protocols permit researchers to assess trainees, identify individuals who have not achieved the desired level of precision, and retrain or adjust roles prior to survey deployment.


Scabies.
Scabies is a mite infestation caused by Sarcoptes scabiei. Varieties of this organism can produce disease on 40 different species of animal, including humans. The organisms mature, burrow, and lay eggs. The newly hatched larvae mature and mate on the skin, causing itching and excoriated papules on humans, and mange, with crusts and oozing, on hair-bearing animals. Treatment with the gamma isomer of hexachlorobenzene or with pyrethrins is effective. Care must be taken that all infected or exposed individuals are treated. The role of fomites in the transmission of the disease is not clear. Most cases seem to be transmitted by close personal contact.


Association of TNFα-308, IFNγ+874, and IL10-1082 gene polymorphisms and the risk of non-small cell lung cancer in the population of the South Indian state of Telangana.
Cytokine-mediated inflammation is important in the pathogenesis of non-small cell lung cancer (NSCLC). Genetic polymorphisms in cytokine genes and their association with lung cancer in the Indian population have not been reported. For the first time, we analyzed genetic polymorphisms of TNFα -308, IFNγ +874, and IL10 -1082 genes in 246 NSCLC patients and 250 healthy controls in the South Indian population from Telangana using ARMS PCR. IFNγ+874 A/T and IL10-1082 G/G gene polymorphisms were found to be significantly associated with NSCLC with 1.56- and 1.68-fold disease risk, respectively. There was no association between the risk of NSCLC and TNFα-308 polymorphism. Gene polymorphisms stratified according to smoking revealed that IFNγ+874 A/T polymorphisms in smokers increased the disease risk by 2.91 fold. IL10-1082 G/G polymorphisms showed 2-fold increased risk among patients who were smokers when compared to the controls. However, there was no association between TNFα-308, IFNγ+874, and IL10-1082 gene polymorphism and the stage of the NSCLC patients. The overall risk associated with the combination of these polymorphisms indicated that the TNFα-308 G/A + IFNγ+874 A/T + IL10-1082 G/G genotype increased the risk by 1.5 fold. The results of our study indicate an association between cytokine gene polymorphisms and the risk of NSCLC in an Indian population.


Understanding When a Partner Is Not in the Mood: Sexual Communal Strength in Couples Transitioning to Parenthood.
Situations in which one partner is interested in having sex but the other partner is not "in the mood" are common in relationships. We extend previous work on sexual communal strength-the motivation to be responsive to a partner's sexual needs-to demonstrate that in addition to the motivation to meet a partner's need to have sex, the motivation to be understanding about a partner's need not to engage in sex is uniquely associated with sexual and relationship satisfaction. In Study 1, we adapted a measure of sexual communal strength for having sex (SCSS) to create a new measure of sexual communal strength for not having sex (SCSN). We demonstrated that SCSN is distinct from SCSS and associated with more positive and less negative responses to an imagined situation of sexual rejection. In Study 2, both SCSS and SCSN were uniquely associated with greater sexual and relationship satisfaction in couples transitioning to parenthood-a time when many couples experience changes to their sexual relationship. Having a partner who is higher in SCSN is associated with greater sexual satisfaction and relationship quality for new mothers but not new fathers, suggesting that during the transition to parenthood, it might be more important for women to have a partner who is understanding about their need not to engage in sex. The results suggest that the motivation to be understanding about a partner's need not to engage in sex may be an additional way that partners can show communal care in their sexual relationships.


Synthesis of some 3.4.5-trimethoxybenzyl derivatives of certain amino compounds likely to posses cns activity.
The condensation of 3.4.5-trimethoxybenzyl chloride with certain amines is described. Reacting the aralkyl chloride with 4-aminophenazone, 2-aminopyridine, piperidine, N-methylpiperazine, pyrrolidine and morpholine yielded the corresponding trimethoxybenzyl derivatives la--f. On the other hand, alpha-[3.4.5-trimethoxybenzamido]-glutarimide (2) was synthesized via the acylation of glutamic acid with trimethoxybenzoyl chloride, dehydration of the N-acyl derivative and finally imidation of the inner anhydride thus formed.


Allelism of SNQ1 and ATR1, genes of the yeast Saccharomyces cerevisiae required for controlling sensitivity to 4-nitroquinoline-N-oxide and aminotriazole.
SNQ1 gene function is required for the expression of resistance to 4NQO in wild-type yeast. The sequence of a 3.7 kb yeast DNA containing the gene SNQ1 was determined. The SNQ1 gene consists of an open reading frame of 1641 bp and encodes, according to the hydrophobicity analysis of the putative protein, a transmembrane protein of 547 amino acids. Homology searches in yeast genome databanks revealed a 100% sequence homology with gene ATR1 which controls resistance to aminotriazole in S. cerevisiae. Pre-treatment of wild-type yeast, but not of snq1-0::LEU2 disruption mutants, with sublethal doses of aminotriazole induced hyper-resistance to 4-nitroquinoline-N-oxide. Partial deletion of the nucleotide sequence coding for a putative ATP-binding site has no, or little, influence on resistance to 4NQO whereas total deletion of the region coding for this ATP-binding domain leads to 4NQO-sensitive null-mutants.


Adolescent chronic pain problems in the school setting: exploring the experiences and beliefs of selected school personnel through focus group methodology.
To systematically analyze school personnel's understanding of adolescent chronic pain problems and to learn how healthcare and school systems can collaborate more effectively to address these problems. Focus group methodology was employed in middle- and high-school settings. Five groups, comprised of 38 schoolteachers, administrators, school nurses, and guidance/mental health staff participated. Transcript analyses indicate that focus group members cited many challenges related to working with adolescents with pain in school (including high absence rates, wide individual variation in presentation of symptoms and impairment, the need to balance accommodations with school policies, attending to the needs of other students, and dealing with parents) and identified needs for more information about chronic pain problems and more guidance from healthcare professionals regarding how to manage pain symptoms and pain-related behaviors in the school setting. Results indicate that school personnel struggle when they encounter chronic pain problems in the school setting and feel inadequately educated about how to work effectively with students with chronic pain. Improved collaboration between healthcare and school systems is needed and could increase school success (i.e., the ability to attend school and to perform to the best of one's abilities) for adolescents with chronic pain disorders.


Anterior and medial thalamic lesions, discriminative avoidance learning, and cingulate cortical neuronal activity in rabbits.
Four groups of male albino rabbits were trained to perform a conditioned response (CR, stepping in an activity wheel) to an acoustic (pure tone) conditional stimulus (CS+). A 1.5-2.0 mA shock unconditional stimulus (US) delivered through the grid floor of the wheel was administered 5 s after CS+ onset, but stepping during the CS-US interval prevented the US. The rabbits were also trained to ignore a second tone (a negative conditional stimulus or CS-) of different auditory frequency than the CS+, that was presented in an irregular order on half of the conditioning trials but never followed by the US. One group had bilateral electrolytic lesions in the medial dorsal (MD) thalamic nucleus, a second group had combined bilateral lesions in the MD and the anterior thalamic nuclei, and a third group had no lesions. The fourth group was composed of rabbits with combined lesions that resulted in only partial damage in the anterior and MD nuclei. In all rabbits, multi-unit activity and field potentials were recorded from the cingulate cortical projection targets of the MD and anterior nuclei. The average rate of acquisition in rabbits with MD and partial lesions was not significantly different from that in controls, but the asymptotic performance in rabbits with lesions was significantly impaired, relative to that in controls. None of the rabbits that had the combined MD and anterior thalamic lesions reached the acquisition criterion. The average proportion of trials in which these rabbits performed avoidance responses during their final training sessions was 0.3, compared to 0.8 in controls. The unconditioned response was not significantly affected by the lesions, nor was there any indication that the lesions impaired the sensory processing of the CSs. These results and the massive training-induced neuronal discharges shown in past studies to occur in the limbic thalamic neurons indicate that these neurons are importantly involved in the circuitry that mediates discriminative avoidance conditioning in rabbits. The training-induced neuronal activity in cingulate cortex was dramatically attenuated in rabbits with lesions. Differences in the degree of this attenuation between lesion conditions and with respect to training stages were discussed in relation to a theoretical working model of limbic thalamic and cingulate cortical associative functions.


A tattoo granuloma with uveitis (TAGU) without sarcoidosis.
Tattooing is associated with a handful of potential complications. Short-term complications such as pain, pruritus, erythema, or swelling at the tattoo-site commonly occur from local skin trauma. Long-term complications tend to involve infections or immune-mediated reactions such as sarcoidosis. The sudden development of a papulonodular skin eruption affecting a particular pigment in a tattoo is often the initial manifestation of undiagnosed sarcoidosis in these patients. However, in a small number of individuals, the granulomatous change in the tattoo and uveitis occur in the absence of any evidence of sarcoidosis. A case is presented of a tattoo granuloma with uveitis (TAGU) without sarcoidosis.


Impact of Pregnancy on Ventricular Strain in Women with Repaired Tetralogy of Fallot.
Increasing numbers of women with repaired tetralogy of Fallot (rTOF) are reaching reproductive age and seek counseling regarding their cardiovascular risks related to pregnancy. Therefore, the aim of this study was to characterize changes in left ventricular (LV) strain in women with rTOF during pregnancy and in the postpartum period. Seventeen pregnancies in women with rTOF were included (mean age at repair = 3.2 years ± 5.5 years; mean age at delivery = 32.7 ± 4 years). Echocardiograms from three time periods were analyzed; baseline (prior to conception or in the first trimester), third trimester, and 4-6 weeks postpartum. Sixty-five percent of the patients had at least mild pulmonary regurgitation. Eight patients (47%) had undergone at least one pulmonary valve replacement. There were no changes in LV ejection fraction (EF) or circumferential strain across the three time periods. Significant differences were present in longitudinal strain within the three time points (p = 0.01). Postpartum strain decreased in magnitude compared to the third trimester value (- 17.7 ± 4.1 vs. - 21 ± 5, p-value = 0.003) but was not different when compared to baseline strain (- 17.7 ± 4.1 vs. - 19.4 ± 3.4; p-value = 0.15). In conclusion, in women with rTOF, changes in longitudinal strain were observed during pregnancy with a return to baseline after delivery; EF did not change. These findings provide evidence that pregnancy does not adversely impact LV mechanics in the short term in this potentially vulnerable patient population.


Evaluation of bioactive compounds from Ficus carica L. leaf extracts via high-performance thin-layer chromatography combined with effect-directed analysis.
This study compares different solvent systems with the use of spontaneous fermentation on the phytochemical composition of leaf extracts from a locally grown white variety of common fig (Ficus carica Linn.). The aim was to detect and identify bioactive compounds that are responsible for acetylcholinesterase (AChE), α-amylase and cyclooxygenase-1 (COX-1) enzyme inhibition, and compounds that exhibit antimicrobial activity. Bioactive zones in chromatograms were detected by combining High-performance thin-layer chromatography (HPTLC) with enzymatic and biological assays. A new experimental protocol for measuring the relative half-maximum inhibitory concentration (IC50) was designed to evaluate the potency of the extracts compared to the potency of known inhibitors. Although the IC50 of the fig leaf extract for α-amylase and AChE inhibition were significantly higher when compared to IC50 for acarbose and donepezil, the COX-1 inhibition by the extract (IC50 = 627 µg) was comparable to that of salicylic acid (IC50 = 557 µg), and antimicrobial activity of the extract (IC50 = 375-511 µg) was similar to ampicillin (IC50 = 495 µg). Four chromatographic zones exhibited bioactivity. Compounds from detected bioactive bands were provisionally identified by comparing the band positions to coeluted standards, and by Fourier transform infrared (FTIR) spectra from eluted zones. Flash chromatography was used to separate selected extract into fractions and isolate fractions that are rich in bioactive compounds for further characterisation with nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS) analysis. The main constituents identified were umbelliferon (zone 1), furocoumarins psoralen and bergapten (zone 2), different fatty acids (zone 3 and 4), and pentacyclic triterpenoids (calotropenyl acetate or lupeol) and stigmasterol (zone 4).


Effectiveness of Lung Transplantation in Patients With Interstitial Lung Diseases.
Interstitial lung diseases (ILDs) are a heterogeneous group of more than 200 diseases manifested by progressive exercise dyspnea, radiological lung changes, and ventilation restrictive disorders. ILDs are the second most common indication for lung transplantation (LTx). Our study group consisted of 139 patients who qualified for LTx at the Silesian Center for Heart Diseases between 2004 and 2018. Of the 139, 92 patients died while on the waiting list, and 47 patients underwent LTx. Medical records including laboratory test results, spirometry, and the 6-minute walk test (6MWT) were analyzed to determine eligibility for LTx. We also assessed quality of life post-LTx. Patients who qualified for LTx showed decreased values of parameters measured by spirometry (43.69 ± 19.05% of forced expiratory volume in the first second [FEV1] and 43.07 ± 20.55% of forced vital capacity [FVC] and severe desaturation during the 6MWT (SpO2 = 88.78% before 6-minute walk test and 73.23% after the test). After LTx, longer distances were achieved in the 6MWT (235.47 ± 159.57 m during qualification vs 533.2 ± 34.15 m 12 months after LTx) and increased values of spirometry. On average, patients had stopped working 6 years prior to LTx. There is no effective medical treatment for patients with end-stage ILDs. Therefore, lung transplantation is a lifesaving procedure for patients that also extends patients' lives and improves their quality of life.


Nine undescribed oxidized ergosterols from the endophytic fungus Penicillium herquei and their cytotoxic activity.
A chemical investigation of the EtOAc extract of the endophytic fungus Penicillium herquei led to the isolation of nine undescribed oxidized ergosterols, penicisterols A-I (1-9), along with ten known analogs (10-19). Their structures and absolute configurations were elucidated by a combination of spectroscopic data analysis, quantum-chemical electronic circular dichroism (ECD) calculations and comparisons, [Rh2(OCOCF3)4]-induced ECD experiments, DFT-calculated 13C chemical shifts and DP4+ probability analysis. Compound 1 was a rare example of ergosterol in which the bond between C-8 and C-9 was cleaved to form an enol ether. Moreover, compound 2 possessed a rare (2,5-dioxo-4-imidazolidinyl)-carbamic acid ester group substituted at C-3. All undescribed oxidized ergosterols (1-9) were evaluated for their cytotoxic activity against five cancer cell lines including 4T1 (mouse breast carcinoma), A549 (human pulmonary carcinoma), HCT-116 (human colorectal carcinoma), HeLa (human cervical carcinoma) and Hepg2 (human hepatoma carcinoma) cells. Compounds 2 and 3 displayed moderate cytotoxic activity against 4T1, A549 and HeLa cells, with IC50 values ranging from 17.22 to 31.35 μM.


The effect of nitric-oxide-related supplements on human performance.
Nitric oxide (NO) has led a revolution in physiology and pharmacology research during the last two decades. This labile molecule plays an important role in many functions in the body regulating vasodilatation, blood flow, mitochondrial respiration and platelet function. Currently, it is known that NO synthesis occurs via at least two physiological pathways: NO synthase (NOS) dependent and NOS independent. In the former, L-arginine is the main precursor. It is widely recognized that this amino acid is oxidized to NO by the action of the NOS enzymes. Additionally, L-citrulline has been indicated to be a secondary NO donor in the NOS-dependent pathway, since it can be converted to L-arginine. Nitrate and nitrite are the main substrates to produce NO via the NOS-independent pathway. These anions can be reduced in vivo to NO and other bioactive nitrogen oxides. Other molecules, such as the dietary supplement glycine propionyl-L-carnitine (GPLC), have also been suggested to increase levels of NO, although the physiological mechanisms remain to be elucidated. The interest in all these molecules has increased in many fields of research. In relation with exercise physiology, it has been suggested that an increase in NO production may enhance oxygen and nutrient delivery to active muscles, thus improving tolerance to physical exercise and recovery mechanisms. Several studies using NO donors have assessed this hypothesis in a healthy, trained population. However, the conclusions from these studies showed several discrepancies. While some reported that dietary supplementation with NO donors induced benefits in exercise performance, others did not find any positive effect. In this regard, training status of the subjects seems to be an important factor linked to the ergogenic effect of NO supplementation. Studies involving untrained or moderately trained healthy subjects showed that NO donors could improve tolerance to aerobic and anaerobic exercise. However, when highly trained subjects were supplemented, no positive effect on performance was indicated. In addition, all this evidence is mainly based on a young male population. Further research in elderly and female subjects is needed to determine whether NO supplements can induce benefit in exercise capacity when the NO metabolism is impaired by age and/or estrogen status.


Identification and functional characterization of cereblon as a binding protein for large-conductance calcium-activated potassium channel in rat brain.
Large-conductance Ca2+-activated K+ (BK(Ca)) channels are activated by membrane depolarization and modulated by intracellular Ca2+. Here, we report the direct interaction of cereblon (CRBN) with the cytosolic carboxy-terminus of the BK(Ca) channel alpha subunit (Slo). Rat CRBN contained the N-terminal domain of the Lon protease, a 'regulators of G protein-signaling' (RGS)-like domain, a leucine zipper (LZ) motif, and four putative protein kinase C (PKC) phosphorylation sites. RNA messages of rat cereblon (rCRBN) were widely distributed in different tissues with especially high-levels of expression in the brain. Direct association of rCRBN with the BK(Ca) channel was confirmed by immunoprecipitation in brain lysate, and the two proteins were co-localized in cultured rat hippocampal neurons. Ionic currents evoked by the rSlo channel were dramatically suppressed upon coexpression of rCRBN. rCRBN decreased the formation of the tetrameric rSlo complex thus reducing the surface expression of functional channels. Therefore, we suggest that CRBN may play an important role in assembly and surface expression of functional BK(Ca) channels by direct interaction with the cytosolic C-terminus of its alpha-subunit.


Hypoimmune induced pluripotent stem cells survive long term in fully immunocompetent, allogeneic rhesus macaques.
Genetic engineering of allogeneic cell therapeutics that fully prevents rejection by a recipient's immune system would abolish the requirement for immunosuppressive drugs or encapsulation and support large-scale manufacturing of off-the-shelf cell products. Previously, we generated mouse and human hypoimmune pluripotent (HIP) stem cells by depleting HLA class I and II molecules and overexpressing CD47 (B2M-/-CIITA-/-CD47+). To determine whether this strategy is successful in non-human primates, we engineered rhesus macaque HIP cells and transplanted them intramuscularly into four allogeneic rhesus macaques. The HIP cells survived unrestricted for 16 weeks in fully immunocompetent allogeneic recipients and differentiated into several lineages, whereas allogeneic wild-type cells were vigorously rejected. We also differentiated human HIP cells into endocrinologically active pancreatic islet cells and showed that they survived in immunocompetent, allogeneic diabetic humanized mice for 4 weeks and ameliorated diabetes. HIP-edited primary rhesus macaque islets survived for 40 weeks in an allogeneic rhesus macaque recipient without immunosuppression, whereas unedited islets were quickly rejected.


Phase 1/2 study of sorafenib added to cladribine, high-dose cytarabine, G-CSF, and mitoxantrone in untreated AML.
The multikinase inhibitor sorafenib improves event-free survival (EFS) when used with 7 + 3 in adults with newly-diagnosed acute myeloid leukemia (AML), irrespective of the FLT3-mutation status. Here, we evaluated adding sorafenib to cladribine, high-dose cytarabine, granulocyte colony-stimulating factor, and mitoxantrone (CLAG-M) in a phase 1/2 trial of 81 adults aged ≤60 years with newly diagnosed AML. Forty-six patients were treated in phase 1 with escalating doses of sorafenib and mitoxantrone. No maximum tolerated dose was reached, and a regimen including mitoxantrone 18 mg/m2 per day and sorafenib 400 mg twice daily was declared the recommended phase 2 dose (RP2D). Among 41 patients treated at RP2D, a measurable residual disease-negative complete remission (MRD- CR) rate of 83% was obtained. Four-week mortality was 2%. One-year overall survival (OS) and EFS were 80% and 76%, without differences in MRD- CR rates, OS, or EFS between patients with or without FLT3-mutated disease. Comparing outcomes using CLAG-M/sorafenib with those of a matched cohort of 76 patients treated with CLAG-M alone, multivariable-adjusted survival estimates were improved for 41 patients receiving CLAG-M/sorafenib at RP2D (OS: hazard ratio,0.24 [95% confidence interval, 0.07-0.82]; P = .023; EFS: hazard ratio, 0.16 [95% confidence interval, 0.05-0.53]; P = .003). Benefit was limited to patients with intermediate-risk disease (univariate analysis: P = .01 for OS; P = .02 for EFS). These data suggest that CLAG-M/sorafenib is safe and improves OS and EFS relative to CLAG-M alone, with benefits primarily in patients with intermediate-risk disease. The trial was registered at www.clinicaltrials.gov as #NCT02728050.


[The effect of high temperature on the frequency of nondisjunction and loss of sex chromosomes in females of Drosophila melanogaster strain I(1)ts403 with a defect in the heat shock protein system].
High temperature (37 degrees C) induces sex chromosome non-disjunction and loss in Drosophila melanogaster females l(1)ts403 with the defect in heat-shock protein system. The same temperature has no effect on the females from the T line and other earlier studied lines.


How to increase your funding chances: common pitfalls in medical grant applications.
This commentary identifies 16 items to consider when trying to achieve success with grant applications.


A role for Th17 cells in the immunopathogenesis of atopic dermatitis?
Atopic dermatitis (AD) is a common inflammatory skin disease. Both epidermal barrier dysfunction and immunodysregulation are suggested to influence the pathogenesis of AD. AD has been considered a paradigmatic T helper cell (Th) 2-mediated disease, with a switch to a Th1 cell environment during the chronic phase of the disease. Previously unreported findings now suggest a possible role for Th17 cells as well.


Transfer of natural radionuclides from hay and silage to cow's milk in the vicinity of a former uranium mine.
After the closure of the former Žirovski Vrh uranium mine in Slovenia, mining and milling wastes were deposited on two waste piles, which are located close to the mine. These wastes contain elevated levels of natural radionuclides from the uranium decay chain. Due to different migration processes (erosion, aerial deposition, through groundwater), these radionuclides can be transported via fodder into cow's milk, which is an important foodstuff for Slovenian people. Therefore, natural radionuclides were analysed in the transfer food chain from soil to cow's fodder and cow's milk. After sampling, (238)U, (234)U, (230)Th, (226)Ra, (210)Pb and (210)Po were determined using radiochemical separation methods and alpha spectrometry or proportional counting. Hay and silage to milk concentration ratios (kg dry weight L(-1)) were calculated and were 0.260 for (238)U, 0.255 for (230)Th, 0.070 for (226)Ra, 0.021 for (210)Pb and 0.019 for (210)Po. The calculated annual ingestion dose due to milk consumption for the natural radionuclides analysed was 9 μSv/year for adults and 389 μSv/year for infants with the highest contribution of (210)Po (51% for adults and 63% for infants) and (210)Pb (36% for adults and 24% for infants). This study provides new data quantifying the transfer of natural radionuclides to milk, which is a parameter for which there have been very few previously reported values.


Triacontanol priming as a smart strategy to attenuate lead toxicity in Brassica oleracea L.
The most prevalent heavy metal pollutant in the environment is lead (Pb). Lead potentially contribute 10% of overall heavy metal contamination. Lead uptake by plants has been found to have an impact on their metabolic functions, photosynthetic activity, growth, and productivity. The current experiment was conducted to investigate the impact of triacontanol (Tria) for attenuating Pb stress in Brassica oleracea var. italic (broccoli). Three different Tria concentrations (10, 20 and 30 µmol L-1) were used to prime broccoli seeds. Growth of broccoli was reduced when exposed to Pb-driven toxicity. Additionally, Pb had a deleterious impact on the protein quantity, stomatal conductance, transpiration and photosynthetic rate. Nevertheless, plants grown from seeds primed with Tria2 (20 µmol L-1 Tria) exhibited improved morphological characteristics, uptake of mineral content (Mn+2, Zn+2, K+1, Na+1) along with biomass production. There was 1.6-fold increase in photosynthetic rate, the phenol (1.3 folds), and DPPH activity (1.2 folds) in seed primed with Tria2. Additionally, plants treated with Tria2 demonstrated enhanced MTI and gas exchange characteristics that improves plant stress tolerance under Pb stress. Seed priming with Tria can be used to increase plant tolerance to Pb stress as evidenced by the improved growth and biochemical characteristics of broccoli seedlings.


Percutaneous cardiopulmonary bypass and innovations in clinical counterpulsation.
This report points out the progress that has been made with cardiac support devices since they were first clinically applied in the mid-1960s. Advances in technology have allowed the development of PBY. Innovatively applied modifications of existing support systems have allowed patient survival when conventional systems could not be utilized. Continued refinements in design, materials, and power sources will allow circulatory assistance to progress as an extremely useful clinical tool for the treatment of patients with acute and chronic ventricular failure.


Genetics of genetics in Drosophila: P elements serving the study of homologous recombination, gene conversion and targeting.
P-element induced double strand break repair in Drosophila can be used for studying the mechanisms of homologous recombination in higher eucaryotes as well as for targeting and converting genes in their original chromosomal environment. So far studies on the molecular mechanisms of recombination were mainly possible in fungi. Even though gene targeting through homologous recombination is becoming a routine instrument in the mouse the underlying molecular events are by no means clear. The genetics of Drosophila provides a powerful tool to study the basics of gene targeting and gene conversion events in higher eucaryotes.


In situ precipitation of hydrous ferric oxide (HFO) for remediation of subsurface iodine contamination.
A practical approach for in situ hydrous ferric oxide (HFO) precipitation was developed for iodine immobilization under field-scale conditions at the Hanford Site. A series of 1D meter-long bench-top column experiments packed with Hanford sediments was conducted with a single acidic ferric solution (0.1 M, pH = 1.5) injection. Because carbonate and clay minerals are widely present in sediments, self-pH buffering of the injected acidic ferric solution occurred due to mineral dissolution, leading to HFO precipitation under a neutral condition. Up to ~12 mg/g Fe as HFO successfully precipitated and evenly distributed in the column sediments, and the remobilization of the neoformed HFO precipitates was limited (≤ ~3.16 wt% after over 100 pore volumes (pv) of flushing). The transport of iodate (IO3-) in the HFO-amended sediments was strongly retarded through both adsorption and co-precipitation processes. However, reversible adsorption of iodine on HFO was observed, which might limit its application to slow-moving groundwater systems.


Regulation of the SK3 channel by microRNA-499--potential role in atrial fibrillation.
MicroRNAs are important regulators of gene expression, including those involving electrical remodeling in atrial fibrillation (AF). Recently, KCNN3, the gene that encodes the small-conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF. To evaluate the changes in atrial myocardial microRNAs in patients with permanent AF and to determine the role of microRNA on the regulation of cardiac SK3 expression. Atrial tissue obtained during cardiac surgery from patients (4 sinus rhythm and 4 permanent AF) was analyzed by using microRNA arrays. Potential targets of microRNAs were predicted by using software programs. The effects of specific microRNAs on target gene expression were evaluated in HL-1 cells from a continuously proliferating mouse hyperplastic atrial cardiomyocyte cell line. Interactions between microRNAs and targets were further evaluated by using luciferase reporter assay and by using Argonaute pull-down assay. Twenty-one microRNAs showed significant (>2-fold) changes in AF. MicroRNA 499 (miR-499) was upregulated by 2.33-fold (P < .01) in AF atria, whereas SK3 protein expression was downregulated by 46% (P < .05). Transfection of miR-499 mimic in HL-1 cells resulted in the downregulation of SK3 protein expression, while that of miR-499 inhibitor upregulated SK3 expression. Binding of miR-499 to the 3' untranslated region of KCNN3 was confirmed by luciferase reporter assay and by the increased presence of SK3 mRNA in Argonaute pulled-down microRNA-induced silencing complexes after transfection with miR-499. Atrial miR-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.


Leukemia specific antigens: FOCMA and immune surveillance.
In cats, horizontally transmitted viruses cause leukemia and lymphoma under natural conditions. As with other retroviruses, feline leukemia virus (FeLV) contains products of 3 major genes; the virus core gag gene products, the polymerase, and the virus envelope glycoprotein. When cells are transformed in vitro by the related feline sarcoma virus (FeSV), an additional protein, FOCMA is expressed at the cell membrane. FOCMA, which is FeSV-coded, is transformation and/or tumor specific and expressed regardless of whether or not the cells make virus or contain virus structural antigens. Lymphoid leukemia cells also express FOCMA, both when FeLV is used to induce the disease in laboratory cats and when the tumors occur under natural conditions. FOCMA is expressed on both T and B lymphoid leukemia cells, but not expressed on non-malignant lymphoid cells, even when they are infected with FeLV. About one-third of the naturally occurring lymphoid tumors of cats lack detectable FeLV proteins and varying portions of the FeLV provirus. Despite this, they regularly express FOCMA, which is the target of an immuno-surveillance response that functions effectively under most conditions. FOCMA thus provides a useful model for antigens that might be expressed in "virus-negative" leukemias of man.


Value of routine immediate postoperative brain computerized tomography in pediatric neurosurgical patients.
Routine immediate postoperative brain CT (RIPO CT) has advantages and disadvantages. The present study was performed to know the extent of gain by RIPO CT in the aspect of immediate postoperative patient care in pediatric patient population and according to the disease entity and surgical procedure. We reviewed 910 cases of pediatric brain surgery performed from January 2008 to March 2010 who had RIPO CT. The value of each examination was graded according to the impact of the CT findings on the decision making processes on postoperative patient care or on the understanding of postoperative patient's status: level I (urgent surgical procedures are necessary), level II (high level of attention should be paid because of possible urgent surgical procedure in near future), level III (RIPO CT is useful for understanding of postoperative change of patient's status), and level IV (no significant gain). The number of patients in each level was evaluated, and proportions of levels according to disease entity and surgical procedure were compared. In total, the proportion of each level of I to IV was 0.4%, 4.9%, 3.5%, and 91.2%, respectively. The group of brain tumors, especially those who have malignant or highly vascular tumors, showed significantly higher value of RIPO CT. Cases of traumatic epidural hematoma and intracerebral hemorrhage revealed significantly high proportion of level II although no case underwent reoperation. The results of present study may be useful for making policy of "selective" application of immediate postoperative brain CT according to the patient conditions. Also the use of immediate postoperative brain CT can be decided in individual cases by considering disease entity and surgical procedure.


The cluster Ir4 and its interaction with a hydrogen impurity. A density functional study.
To contribute to the understanding of how iridium particles act as catalysts for hydrogenation and dehydrogenation of hydrocarbons, we have determined structures and binding energies of various isomers of Ir(4) as well as HIr(4) on the basis of relativistic density functional theory. The most stable isomer of Ir(4) showed a square planar structure with eight unpaired electrons. The tetrahedral structure, experimentally suggested for supported species, was calculated 49 kJ mol(-1) less stable. Hydrogen coordinates preferentially to a single Ir center of the planar cluster with a binding energy of up to 88 kJ mol(-1) with respect to the atom in the H(2) molecule. Terminal interaction of hydrogen with an Ir(4) tetrahedron causes the cluster to open to a butterfly structure. We calculated terminal binding of hydrogen at different Ir(4) isomers to be more stable than bridge coordination, at variance with earlier studies.


Detection of extracellular factor-positive Streptococcus suis serotype 2 strains in tonsillar swabs of live sows by PCR.
In this study, the sensitivity (Se) and specificity (Sp) of a PCR for the detection of EF-positive Streptococcus suis serotype 2 strains in tonsillar swabs of live sows were assessed. We sampled 471 sows originating from four farrow-to-finish farms by tonsillar swabbing and collected their tonsils after slaughter. On these specimens, a PCR, a bacterial examination (BE) or both were performed for the detection of EF-positive S. suis serotype 2 strains. Swab-PCR, Tonsil-PCR and Tonsil-BE were regarded as three integral tests. A Bayesian approach was used to calculate the Se and Sp of the tests. Se and Sp for Swab-PCR were 0.63 (95% credibility interval <0.52, 0.74>) and 0.96 (<0.92, 0.99>), respectively. Values for Se and Sp of Tonsil-PCR amounted to 0.88 (<0.75, 0.96>) and 0.94 (<0.87, 0.99>), respectively. For Tonsil-BE, Se was 0.65 (<0.51, 0.76>) and Sp was 0.97 (<0.91, 0.99>). Repetition of the swabbing procedure after 10 min resulted in a higher Se 0.85 (<0.67, 0.96>) than the Se of the first-Swab-PCR. Repetition of the PCR on the same sample did not result in any significant changes in the outcome of the analysis.


A Young Patient with Undiagnosed Polycythemia-Paraganglioma Syndrome: A Case Report.
BACKGROUND Erythrocytosis results from primary or secondary causes and is characterized by an increased red blood cell count. Secondary erythrocytosis is a result of an underlying cause outside the bone marrow and is often mediated by erythropoietin. Paragangliomas are rare tumors characterized by increased release of catecholamines with symptoms such as hypertension, hematuria, headache, sweating, and post-micturition syncope. Polycythemia-paraganglioma syndrome (PPS) is exceedingly rare, and reports in the literature are limited. CASE REPORT A 14-year-old female patient presented to our clinic with sweating, palpitations, and palmar erythema. The patient's history was significant for uninvestigated hypertension diagnosed at the age of 9. There was no history of smoking or illicit drug use. Blood investigations revealed an elevated hemoglobin level of 18.5 g/dL and a hematocrit of 57.5%. Whole-genome sequencing found no mutations, excluding polycythemia vera from the differential diagnosis. Computed tomography (CT) revealed 2 lesions compatible with urinary bladder paragangliomas and retroperitoneal lesions, likely representing metastatic lymphadenopathy. Whole-body gallium-68 DOTATATE PET/CT scan demonstrated significant tracer uptake within the necrotic retroperitoneal lymph nodes. However, evaluation of the bladder lesion was limited due to physiological urinary excretion of the tracer. A 24-hour urine collection demonstrated high normetanephrine levels of 24 µmol/L. These findings confirmed the diagnosis of PPS. CONCLUSIONS PPS is largely associated with HIF2A mutations. This article describes the case of a young PPS patient and highlights the importance of considering neoplasms in the differential diagnosis of hypertension in young patients. Further, it is crucial to conduct clinical investigations on young hypertensive patients to exclude underlying causes such as renal diseases, coarctation of the aorta, and neuroendocrine disorders.


The Efficient Synthesis of Benzannulated Seven-Membered O-Heterocycles via the Intramolecular Ring-Opening Cyclization of Cyclopropanes.
An efficient and practical approach for the synthesis of substituted benzannulated seven-membered O-heterocycles from cyclopropane derivatives is described. The transformation proceeds via Lewis acid mediated ring opening of cyclopropanes followed by a concomitant 7-endo-tet cyclization to furnish the 4-benzoyl-3,4-dihydrobenzo[b]oxepin-5(2H)-one derivatives in excellent yields (up to 92%). This potentially general method is featured by its high atom economy, broad substrate scope, and mild reaction conditions. Moreover, the representative products exhibited selective antifungal activity in vitro against the fungus Cryptococcus neoformans. Therefore, the present reaction will be useful for the development of novel antifungal therapeutic reagents.


A novel ABA-induced transcript factor from Millettia pinnata, MpAITR1, enhances salt and drought tolerance through ABA signaling in transgenic Arabidopsis.
Abiotic stress, such as salt and drought stress, seriously limits plant growth and crop yield. Abscisic acid (ABA) is essential in regulating plant responses to abiotic stress via signal perception, transduction, and transcriptional regulation. Pongamia (Millettia pinnata) is a kind of semi-mangrove plant with strong stress tolerance and can grow in fresh and sea water. However, the molecular mechanism of the ABA signaling pathway mediating the environmental tolerance of Pongamia is still scarce so far. AITR (ABA-Induced Transcription Repressor) was a recently identified small conserved family of transcription factor in angiosperms, which played controversial roles in response to abiotic stresses in different species. Here, we identified an ABA-induced gene, MpAITR1, which encoded a nucleus localization transcriptional factor in Pongamia. MpAITR1 was highly induced by ABA and salt treatments in roots and leaves. Heterologous expression of MpAITR1 in Arabidopsis increased sensitivity to ABA, moreover, enhanced tolerance to salt and drought stress. The expression levels of some ABA-responsive and stress-responsive genes were altered in transgenic plants compared to wild-type plants under the ABA, salt, and drought stress, which was consistent with the stress-tolerant phenotype of transgenic plants. These results reveal that MpAITR1 positively modulates ABA signaling pathways and enhances the tolerance to salt and drought stress by regulating downstream target genes. Taken together, MpAITR1 from the semi-mangrove plant Pongamia serves as a potential candidate for stress-tolerant crop breeding.


[Application status and analysis of Fu's subcutaneous needling in the treatment of peripheral facial paralysis].
This paper summarizes the status of application and research of Fu's subcutaneous needling for peripheral facial paralysis, and the characteristics of different stages of peripheral facial paralysis treated with Fu's subcutaneous needling are analyzed from the aspects of intervention timing, protocol design, needle insertion point, sweeping and reperfusion activity, tube retaining time and acupuncture frequency. It is found that there are no norms and standards in sweeping and reperfusion, tube retention and acupuncture frequency in clinical application,and the exploration of staged treatment is insufficient in the research. In the future, it is necessary to form standardized operation to promote clinical promotion, and improve the research on treatment rules and mechanism according to the characteristics of disease stage.


Basic pH-induced modification of excitation-energy dynamics in fucoxanthin chlorophyll a/c-binding proteins isolated from a pinguiophyte, Glossomastix chrysoplasta.
Photosynthetic organisms have diversified light-harvesting complexes (LHCs) to collect solar energy efficiently, leading to an acquisition of their ecological niches. Herein we report on biochemical and spectroscopic characterizations of fucoxanthin chlorophyll a/c-binding protein (FCP) complexes isolated from a marine pinguiophyte Glossomastix chrysoplasta. The pinguiophyte FCP showed one subunit band in SDS-PAGE and one protein-complex band with a molecular weight at around 66 kDa in clear-native PAGE. By HPLC analysis, the FCP possesses chlorophylls a and c, fucoxanthin, and violaxanthin. To clarify excitation-energy-relaxation processes in the FCP, we measured time-resolved fluorescence spectra at 77 K of the FCP adapted to pH 5.0, 6.5, and 8.0. Fluorescence curves measured at pH 5.0 and 8.0 showed shorter lifetime components compared with those at pH 6.5. The rapid decay components at pH 5.0 and 8.0 are unveiled by fluorescence decay-associated (FDA) spectra; fluorescence decays occur in the 270 and 160-ps FDA spectra only at pH 5.0 and 8.0, respectively. In addition, energy-transfer pathways with time constants of tens of picoseconds are altered under the basic pH condition but not the acidic pH condition. These findings provide novel insights into pH-dependent energy-transfer and energy-quenching machinery in not only FCP family but also photosynthetic LHCs.


Utility of novel viral and immune markers in predicting HBV treatment endpoints: A systematic review of treatment discontinuation studies.
Antivirals represent the mainstay of chronic hepatitis B treatment given their efficacy and tolerability, but rates of functional cure remain low during long-term therapy. Treatment discontinuation has emerged as a strategy to maintain partial cure and achieve functional cure in select patient groups. We aimed to evaluate how data from treatment discontinuation studies exploring novel viral and/or immune markers could be applied to the functional cure program. Treatment discontinuation studies evaluating novel viral and/or immune markers were identified by a systematic search of the PubMed database through to October 30, 2022. Data extraction focused on information regarding novel markers, including identified cut-off levels, timing of measurement, and associated effect on study outcomes of virological relapse, clinical relapse, and HBsAg seroclearance. From a search of 4,492 citations, 33 studies comprising a minimum of 2,986 unique patients met the inclusion criteria. Novel viral markers, HBcrAg and HBV RNA, were demonstrated across most studies to be helpful in predicting off-therapy partial cure, with emerging evidence to support a link with functional cure. From novel immune marker studies, we observed that treatment discontinuation has the potential to trigger immune restoration, which may be associated with a transient virological relapse. To this end, these studies support the combination of virus-directing agents with immunomodulator therapies to induce two key steps underlying functional cure: viral antigen load reduction and restoration of the host immune response. Patients with a favourable profile of novel viral and immune markers stand to benefit from a trial of antiviral treatment discontinuation alongside novel virus-directing agents with the aim of achieving functional cure without excessive risk of severe clinical relapse. Select patients with chronic hepatitis B undergoing nucleoside analogue therapy may benefit from a trial of treatment discontinuation, aiming to maintain partial cure and/or achieve functional cure. We propose a profile of novel viral and immune markers to identify patients who are likely to achieve these goals without excessive risk of hepatic decompensation. Furthermore, treatment discontinuation may also be considered as a therapeutic strategy to trigger immune restoration, which may increase the chance of functional cure when used in conjunction with novel virus-directing agents.


Age factor relevant to the development of radiation pneumonitis in radiotherapy of lung cancer.
The significance of age factor for the development of radiation pneumonitis is evaluated in 62 patients with lung cancer between 1977 and 1985. The younger group consists of those less than 70 years old and the elderly group of those 70 years old or more. Radiation doses ranged from 1.5 to 2 Gy, 3 to 5 times per week, therefore the delivered doses were converted to nominal single doses (rets dose). Severe radiation pneumonitis was more often observed in the elderly than in the younger regardless of radiation field size and chemotherapy (n.s.). The onset of radiation pneumonitis occurred earlier in a field size of 90 sq cm or more than in that of less than 90 sq cm in both age groups; there was no significant difference between the two age groups in each field size. The pneumonitis was more frequently noted with increasing rets dose in both age groups (n.s.) regardless of field size and chemotherapy. It is concluded that there is no significant difference in the development of radiation pneumonitis between the younger group and the elderly group, but the pneumonitis is inclined to be more severe in the latter.


Risk factors for pathologic gambling and other compulsions among Parkinson's disease patients taking dopamine agonists.
Three hundred patients with Parkinson's disease taking dopamine agonists were surveyed for the presence of compulsions. Fifty-eight reported active compulsions which had developed after initiation of dopamine agonists. These included 25 with sexual compulsions and 28 with self-described compulsive gambling, of whom 17 met criteria for pathologic gambling. Males were over-represented. Patients with any compulsion and those with pathologic gambling were about 6 years younger than those without compulsions. These behavioral problems were not associated with an individual dopamine agonist, nor dose or duration, nor concomitant levodopa. Follow-up of the pathologic gamblers 1 year after intervention, which was cessation of the dopamine agonist in most cases, found ongoing but controlled gambling in five and complete cessation within 4 months in the remainder.


Histological alterations in the hepatic tissues of Al2O3 nanoparticles exposed freshwater fish Oreochromis mossambicus.
Adverse effects of nanoparticles on aquatic environment and organisms have drawn much special attention to many researches. Aluminium oxide nanoparticles (Al2O3-NPs) have potential uses in varied fields and are seen entering into the ecosystem. Their potential toxicity to the freshwater fish is not much studied. Hence this study was framed to investigate the effect Al2O3 NPs on freshwater fish Oreochromis mossambicus in terms of sub lethal toxicity, histological changes and hepato somatic index (HSI) under laboratory conditions. Fishes were exposed to varying concentrations of Al2O3 NPs for 96hr. LC50 value was found to be in between 235 and 245ppm. The findings of the present work showed that the NPs were accumulated in the fish liver and caused major histological anomalies such as structural alterations in the portal vein, necrotic hepatocytes, vacuolation, aggregation of blood cells and melanomacrophages. Significant histological alterations were observed in the highest concentration. Our results evidenced that the Al2O3 NPs in the aquatic environment affects the health condition of the fishes.


Effects of IL-4, IL-5, and IL-6 on growth and immunoglobulin production of Epstein-Barr virus-infected human B cells.
In the present study we investigated whether interleukin-4 (IL-4), IL-5, and IL-6 could enhance the efficiency of Epstein-Barr virus (EBV) transformation for the generation of specific human monoclonal antibody (HuMAb)-producing B-cell lines directed against erythrocyte Rhesus(D) antigen. In newly EBV-infected B cells, IL-4 and IL-6 caused a comparable enhancement of proliferation and of total IgG and IgA production. IL-6 showed a much stronger effect than IL-4 on IgM production, whereas IL-4 was unique in inducing IgE production. No stimulatory effects of IL-5 on either growth or Ig production were observed. Although addition of IL-6 resulted during the early phase after EBV infection in high numbers of Ag-specific antibody-producing wells, this did not result in an increased number of stable HuMAb-secreting cell lines. When the effects of cytokines were tested on established polyclonal EBV B cells, in a high cell density culture system, only IL-6 was able to enhance Ig secretion, while no effect could be demonstrated on proliferation. These studies substantiate that IL-6 is an important regulator of proliferation and Ig production, and that it acts at distinct stages after EBV infection, but does not increase the final overall recovery of Ag-specific EBV B-cell lines.


Semiological and psychiatric characteristics of children with psychogenic nonepileptic seizures: Gender-related differences.
To compare semiological characteristics, precipitating stress factors and psychiatric diagnoses of girls and boys with psychogenic nonepileptic seizures (PNESs). We retrospectively reviewed medical records of children diagnosed with PNES and who also underwent psychiatric evaluation. Sixty-two children (44 girls, 18 boys), aged 11-18 years (mean age 14.19 ± 1.96 years) were included. Diagnosis of PNES was established by any of the following: (1) observation of the seizure by a neurologist and routine EEG, (2) evaluation of amateur video records of the typical seizure and routine EEG, or (3) video-EEG monitoring. Psychiatric examinations of patients were performed using the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present and Lifetime Version (KSADS-PL). Tremor was the most prevalent ictal motor sign in both girls and boys. Atonic falls and longer episodes were significantly more frequent in girls than boys. Tonic-clonic-like movements of the extremities were significantly more prevalent in boys than girls. No gender-specific differences were observed in the rates of semiological types. Academic underachievement was the most prevalent precipitating stressor for boys, and was significantly more prevalent in boys than girls. The rate of major depression was significantly higher in girls than boys. The most prominent diagnosis in boys was attention deficit/hyperactivity disorder, and this was significantly more prevalent than in girls. PNES in males of juvenile age may be a distinct entity from that in girls with different semiological and psychogenic correlates. Consideration of these gender-related differences may be beneficial for the early recognition and treatment of PNES.


Mucoepidermoid carcinoma expleomorphic adenoma of the submandibular gland.
We described a rare case of carcinoma expleomorphic adenoma in which mucoepidermoid carcinoma arise from a previous incompletely excised pleomorphic adenoma of the submandibular gland. The tumor was surgically resected along with a modified radical neck dissection and postoperative radiotherapy. The patient remained disease free 3 years after the last operation. The pathology showed concurrent presence of Warthin's tumor in the specimen. The concurrent presence of mucoepidermoid carcinoma, pleomorphic adenoma, and synchronous Warthin's tumor make this case unique, and such a combination associated with the submandibular gland has not been documented in the literature before.


[Microelectrode-guided posteroventral pallidotomy for Parkinson's disease: clinical study of 100 cases].
To evaluate the outcome of posteroventral pallidotomy (PVP) for Parkinson's disease (PD). The data from 100 patients with PD receiving PVP were retrospectively analyzed with UPDRS. PVP significantly improved PD symptoms. Several typical symptoms were improved:tremor in 72% patients, rigidity 81%, akinesia 71%, gait 60%, balance 64% and off state 75%. PVP improves Parkinsonian symptoms, and is superior to classical thalamotomy. Microelectrode recording is essential to surgical results and avoidance of severe complication.


Metal Organic Frameworks Combining CoFe2O4 Magnetic Nanoparticles as Highly Efficient SERS Sensing Platform for Ultrasensitive Detection of N-Terminal Pro-Brain Natriuretic Peptide.
N-terminal pro-brain natriuretic peptide (NT-proBNP) has been demonstrated to be a sensitive and specific biomarker for heart failure (HF). Surface-enhanced Raman spectroscopy (SERS) technology can be used to accurately detect NT-proBNP at an early stage for its advantages of high sensitivity, less wastage and time consumption. In this work, we have demonstrated a new SERS-based immunosensor for ultrasensitive analysis of NT-proBNP by using metal-organic frameworks (MOFs)@Au tetrapods (AuTPs) immobilized toluidine blue as SERS tag. Here, MOFs@AuTPs complexes were utilized to immobilize antibody and Raman probe for their excellent characteristics of high porosity, large surface area, and good biocompatibility which can obviously enhance the fixing amount of biomolecule. To simplify the experimental operation and improve the uniformity of the substrate, Au nanoparticles functionalized CoFe2O4 magnetic nanospheres (CoFe2O4@AuNPs) were further prepared to assemble primary antibody. Through sandwiched antibody-antigen interactions, the immunosensor can produce a strong SERS signal to detect NT-proBNP fast and effectively. With such design, the proposed immunosensor can achieve a large dynamic range of 6 orders of magnitude from 1 fg mL(-1) to 1 ng mL(-1) with a detection limit of 0.75 fg mL(-1). And this newly designed amplification strategy holds high probability for ultrasensitive immunoassay of NT-proBNP.


Salinity and nutrient modulate soil bacterial communities in the coastal wetland of the Yellow River Delta, China.
The Yellow River Delta is the largest and youngest estuarine and coastal wetland in China and is experiencing the most active interactions of seawater and freshwater in the world. Bacteria played multifaceted influence on soil biogeochemical processes, and it was necessary to investigate the intermodulation between the soil factors and bacterial communities. Soil samples were collected at sites with different salinity degree, vegetations, and interference. The sequences of bacilli were tested using 16S rRNA sequencing method and operational taxonomic units were classified with 97% similarity. The soil was highly salinized and oligotrophic, and the wetland was nitrogen-restricted. Redundancy analysis suggested that factors related with seawater erosion were principal to drive the changes of soil bacterial communities and then the nutrient level and human disturbance. A broader implication was that, in the early succession stages of the coastal ecosystem, seawater erosion was the key driver of the variations of marine oligotrophic bacterial communities, while the increasing nutrient availability may enhance in the abundance of the riverine copiotrophs in the late stages. This study provided new insights on the characteristics of soil bacterial communities in estuarine and coastal wetlands.


Influence of environmental variability and Emiliania huxleyi ecotypes on alkenone-derived temperature reconstructions in the subantarctic Southern Ocean.
Long-chain unsaturated alkenones produced by haptophyte algae are widely used as paleotemperature indicators. The unsaturation relationship to temperature is linear at mid-latitudes, however, non-linear responses detected in subpolar regions of both hemispheres have suggested complicating factors in these environments. To assess the influence of biotic and abiotic factors in alkenone production and preservation in the Subantarctic Zone, alkenone fluxes were quantified in three vertically-moored sediment traps deployed at the SOTS observatory (140°E, 47°S) during a year. Alkenone fluxes were compared with coccolithophore assemblages, satellite measurements and surface-water properties obtained by sensors at SOTS. Alkenone-based temperature reconstructions generally mirrored the seasonal variations of SSTs, except for late winter when significant deviations were observed (3-10 °C). Annual flux-weighted averages in the 3800 m trap returned alkenone-derived temperatures ~1.5 °C warmer than those derived from the 1000 m trap, a distortion attributed to surface production and signal preservation during its transit through the water column. Notably, changes in the relative abundance of E. huxleyi var. huxleyi were positively correlated with temperature deviations between the alkenone-derived temperatures and in situ SSTs (r = 0.6 and 0.7 at 1000 and 2000 m, respectively), while E. huxleyi var. aurorae, displayed an opposite trend. Our results suggest that E. huxleyi var. aurorae produces a higher proportion of C37:3 relative to C37:2 compared to its counterparts. Therefore, the dominance of var. aurorae south of the Subtropical Front could be at least partially responsible for the less accurate alkenone-based SST reconstructions in the Southern Ocean using global calibrations. However, the observed correlations were largely influenced by the samples collected during winter, a period characterized by low particle fluxes and slow sinking rates. Thus, it is likely that other factors such as selective degradation of the most unsaturated alkenones could also account for the deviations of the alkenone paleothermometer.


Evaluating competence and confidence using simulation technology.
This article discusses the role of simulation training in educating nurses and reducing clinical errors and describes a research project designed to determine the effectiveness of deliberate practice and simulation technology.


Thin filament near-neighbour regulatory unit interactions affect rabbit skeletal muscle steady-state force-Ca(2+) relations.
The role of cooperative interactions between individual structural regulatory units (SUs) of thin filaments (7 actin monomers : 1 tropomyosin : 1 troponin complex) on steady-state Ca(2+)-activated force was studied. Native troponin C (TnC) was extracted from single, de-membranated rabbit psoas fibres and replaced by mixtures of purified rabbit skeletal TnC (sTnC) and recombinant rabbit sTnC (D27A, D63A), which contains mutations that disrupt Ca(2+) coordination at N-terminal sites I and II (xxsTnC). Control experiments in fibres indicated that, in the absence of Ca(2+), both sTnC and xxsTnC bind with similar apparent affinity to sTnC-extracted thin filaments. Endogenous sTnC-extracted fibres reconstituted with 100 % xxsTnC did not develop Ca(2+)-activated force. In fibres reconstituted with mixtures of sTnC and xxsTnC, maximal Ca(2+)-activated force increased in a greater than linear manner with the fraction of sTnC. This suggests that Ca(2+) binding to functional Tn can spread activation beyond the seven actins of an SU into neighbouring units, and the data suggest that this functional unit (FU) size is up to 10-12 actins. As the number of FUs was decreased, Ca(2+) sensitivity of force (pCa(50)) decreased proportionally. The slope of the force-pCa relation (the Hill coefficient, n(H)) also decreased when the reconstitution mixture contained < 50 % sTnC. With 15 % sTnC in the reconstitution mixture, n(H) was reduced to 1.7 +/- 0.2, compared with 3.8 +/- 0.1 in fibres reconstituted with 100 % sTnC, indicating that most of the cooperative thin filament activation was eliminated. The results suggest that cooperative activation of skeletal muscle fibres occurs primarily through spread of activation to near-neighbour FUs along the thin filament (via head-to-tail tropomyosin interactions).


The association of stroke and coronary heart disease: a population study.
In a 20-year population-based study (1960 through 1979), we estimated the cumulative probability of (1) the occurrence of stroke after a diagnosis of angina pectoris, (2) the occurrence of stroke after a diagnosis of myocardial infarction, and (3) the occurrence of myocardial infarction or sudden unexpected death after a diagnosis of cerebral infarction. In patients in whom angina had been diagnosed, no significant difference was noted between the observed and the expected probability of stroke throughout 10 years of follow-up. In patients with a diagnosis of myocardial infarction, a significant difference was noted between observed and expected probabilities of stroke at 1 month and at 2 months. This early excess in probability of stroke was especially pronounced in the subgroup of patients with transmural myocardial infarction but not evident in those with subendocardial myocardial infarction. Among patients with a diagnosis of cerebral infarction, the difference between observed and expected probabilities of myocardial infarction or sudden unexpected death was not significant until 5 years after the cerebral infarction and showed no change thereafter.


Draft Genome Sequence of Enterobacter mori AYS9, a Potential Plant Growth-Promoting Rhizobacterium.
Here, we report the draft genome sequence of Enterobacter mori AYS9, a rhizobacterium isolated from the rhizosphere of sorghum plants in South Africa. The genome sequence comprised 4,852,175 bp and exhibited a GC content of 55.5% and 4,567 genes, with 4,453 coding sequences, 3 rRNAs, 64 tRNAs, and 1 CRISPR.


Assessment of the abiotic transformation of 17β-estradiol in the presence of vegetable matter--II: the role of molecular oxygen.
This study characterizes the effect of oxygen in the abiotic transformation of estrogens when they are contacted with a surrogate of the vegetable wastes found in sewage. 17β-Estradiol (E2) and 17β-(14)C(4)-estradiol ((14)C-E2) were utilized as model compounds. Batch experiments were run under both oxic and anoxic conditions. In order to accomplish an accurate mass balance of the target estrogen, two analyses were performed simultaneously: first, radioactivity counting, and second, quantitation of E2 and (14)C-E2, as well as their transformation product estrone and (14)C(4)-estrone, by Liquid Chromatography tandem Mass Spectrometry. Under oxic conditions, the total concentration of (14)C-E2 was found to decrease by 78% in 72 h (15% and 7% remained in the liquid and solid phases, respectively). Conversely, when the estrogens were contacted with the synthetic influent under anoxic conditions, E2 was quantitatively recovered after 72 h (70% and 22% in aqueous and solid matrices, correspondingly). These results suggest that when the concentration of dissolved oxygen is null or limited, catalysis through an oxidative coupling mechanism is halted. Moreover, it was confirmed that the catalytic reaction occurred solely in the presence of the solid phase of the model vegetable matter.


Efficacy and Safety of Naftifine HCl Cream 2% in the Treatment of Pediatric Subjects With Tinea Corporis.
Tinea corporis is fungal infection of body surfaces other than the feet, groin, scalp, or beard. Naftifine hydrochloride is a topical antifungal of the allylamine class used to treat tinea corporis, displaying fungicidal activity and clinically significant anti-bacterial and anti-inflammatory effects.
 To evaluate the efficacy and safety of two-weeks once daily application of naftifine cream 2% in the treatment of tinea corporis among pediatric subjects.
 At baseline, 231 subjects were randomly assigned 1:1 to naftifine cream 2% (n=116) and vehicle (n=115). Treatment effect consisting of mycologic determination (KOH and dermatophyte cultures) and scoring of clinical symptom severity was evaluated at baseline, week 2 (end of treatment) and week 3. Efficacy was analyzed in 181 subjects (n=88, naftifine; n=93, vehicle) with a positive baseline dermatophyte culture and KOH for whom week 3 assessments were available. Safety was evaluated by adverse events (AE) and laboratory values in 231 subjects (n=116, naftifine; n=115, vehicle).
 Children with tinea corporis treated with naftifine cream 2% demonstrated significantly greater improvements from baseline over vehicle for mycological cure (P<0.0001) and treatment effectiveness (P=0.003) as early as 2 weeks (end of treatment). Response rates continued to increase post-treatment and were the highest 1-week after completion of the therapy (P=0.003 for complete cure; and P<0.001 for mycological cure and treatment effectiveness). Treatment related adverse events were minimal.
 Treatment with naftifine cream 2% applied once daily for two weeks was well-tolerated and was effective in treating tinea corporis in children. Further improvement was observed 1-week after treatment completion for all key outcome measures (complete cure, mycological cure, treatment effectiveness, clinical cure, and clinical success) and clinical signs and symptoms (erythema, induration, and pruritus).

 J Drugs Dermatol. 2016;15(6):743-748.


Interpretation of drug risk and benefit: individual and population perspectives.
To provide pharmacists with the necessary nomenclature and tools to interpret the medical literature on drug risks and benefits. Primary articles were identified by MEDLINE search (1990-December 2003) and through secondary sources. All of the articles identified from the data sources were evaluated, and all information from secondary sources deemed relevant was included. Articles in the primary and secondary literature were reviewed. The articles show that measurement of drug risks and benefits is consistently reported with similar terminology. However, the interpretation and subsequent balancing of risks and benefits can be difficult. All drugs have concomitant risks and benefits. The medical literature documents those risks and benefits and it is this medical evidence that is typically used to make drug therapy decisions. Pharmacists who either manage individual patients or populations of patients (pharmacy benefit managers) may interpret this medical evidence more clearly by understanding the implications of various statistical methods used in studies.


Effect of yoga intervention on biochemical, oxidative stress markers, inflammatory markers and sleep quality among subjects with type 2 diabetes in South India: Results from the SATYAM project.
The aim of this study was to investigate the effect of yoga intervention on the biochemical, oxidative stress markers and inflammatory markers and sleep quality among subjects with type 2 diabetes. Subjects with type 2 diabetes attending a tertiary care centre for diabetes during Feb 2017 to Oct 2019 in Chennai, India were randomly assigned to two different groups. Group1(non-Yoga) (n = 150) was advised on simple physical exercises whereas group2(Yoga) (n = 150) was trained and advised to do yogasanas with static loosening exercises for 50 min for 5 days in a week. Both the groups were followed up for a period of 3 months. Anthropometric, biochemical, oxidative stress markers, inflammatory markers and sleep quality were assessed at baseline and after follow up. There was a significant reduction in BMI, blood glucose levels, HbA1c, lipid levels, IL6, TNFα and TBARS in Yoga group as compared to non-Yoga group. There was marked improvement in the levels of Adiponectin, PTGIS and sleep quality among subjects practising yogasanas. Regular practice of yogasanas improved glycaemic control, oxidative stress, inflammatory response and sleep quality among subjects with type 2 diabetes. Hence, Yogasanas can be used as an adjuvant therapy for managing type 2 diabetes.


Noradrenaline release in rats during prolonged cold-stress and repeated swim-stress.
1 Plasma noradrenaline concentration in rats was measured during prolonged cold-stress and repeated swim-stress. 2 Cold exposure for 6 h caused a rise in plasma noradrenaline which reached a peak at 4 h. 3 Administration of desmethylimipramine and normetanephrine to block neuronal and extra-neuronal uptake of noradrenaline raised plasma noradrenaline concentration without changing the pattern of the response to cold exposure. 4 Repeated cold exposure on subsequent days produced no change in the pattern of plasma noradrenaline concentration. 5 Five successive 1-min swims at 30-min intervals caused a rise in plasma noradrenaline concentration which was maximal after the third swim. 6 It is suggested that prolonged and repeated activation of sympathetic nerve terminals leads to a decline in noradrenaline release.


Hyperapobetalipoproteinemia in a kindred with familial combined hyperlipidemia and familial hypercholesterolemia.
A child showed a type IIb lipoprotein pattern and triglyceride-enriched cutaneous xanthomas before 1 year of age. The proband and 9 of 18 relatives had elevated plasma levels of low density lipoprotein (LDL) B protein; of these nine relatives, four had elevated LDL of increased density while five had elevated LDL of normal density. Compared with normal LDL, LDL of increased density had less cholesteryl ester and free cholesterol, more apolipoprotein B and triglyceride, and a lower molecular weight and flotation rate (Sf degrees). Patients with LDL of increased density had higher mean plasma levels of triglycerides, very low density lipoproteins, and intermediate density lipoproteins, but lower levels of high density lipoproteins than those with elevated LDL of normal density. Multiple lipoprotein patterns in the father's family suggested the presence of familial combined hyperlipidemia (FCH). The mother of the proband and two of her relatives had type IIa lipoprotein patterns and tendon xanthomas, compatible with familial hypercholesterolemia (FH). High affinity binding, internalization, and degradation of 125I LDL in cultured fibroblasts from the proband and his mother were reduced two- to threefold compared with normal cells, while LDL receptor activity in the proband's father was normal. This unusual proband has apparently inherited both FCH and FH.


L-theanine exuded from Camellia sinensis roots regulates element cycling in soil by shaping the rhizosphere microbiome assembly.
Root exudate metabolites are a key medium for the interaction between plants and soil microbiota. L-theanine is a unique non-protein amino acid critical for the flavor and potential health benefits of tea products; however, its biological function in tea plants is not well understood. As L-theanine is mainly synthesized in the roots of tea plants, we hypothesized that L-theanine could affect the function of the rhizosphere microbiota by modulating microbial assembly. In the present study, L-theanine was detected in the exudates of tea plant roots using liquid chromatography-mass spectrometry. Additionally, 16S rRNA gene sequencing revealed that L-theanine significantly altered the structure of the rhizosphere microbiota and selectively shaped rhizosphere microbial assembly. Moreover, metagenomic data showed that L-theanine affected the abundance of genes encoding element cycling in soil. Interestingly, the denitrification and complete nitrification pathways were significantly inhibited by L-theanine by decreasing the narH, napA, and napB genes abundance. These findings provide new insights into the biological function of L-theanine, as well as the implications of interactions between tea plant root exudates and the rhizosphere microbiome.


Design, synthesis and biological evaluation of bivalent ligands against A(1)-D(1) receptor heteromers.
To design and synthesize bivalent ligands for adenosine A1-dopamine D1 receptor heteromers (A1-D1R), and evaluate their pharmacological activities. Bivalent ligands and their corresponding A1R monovalent ligands were designed and synthesized. The affinities of the bivalent ligands for A1R and D1R in rat brain membrane preparation were examined using radiolabeled binding assays. To demonstrate the formation of A1-D1R, fluorescence resonance energy transfer (FRET) was conducted in HEK293 cells transfected with D1-CFP and A1-YFP. Molecular modeling was used to analyze the possible mode of protein-protein and protein-ligand interactions. Two bivalent ligands for A1R and D1R (20a, 20b), as well as the corresponding A1R monovalent ligands (21a, 21b) were synthesized. In radiolabeled binding assays, the bivalent ligands showed affinities for A1R 10-100 times higher than those of the corresponding monovalent ligands. In FRET experiments, the bivalent ligands significantly increased the heterodimerization of A1R and D1R compared with the corresponding monovalent ligands. A heterodimer model with the interface of helixes 3, 4, 5 of A1R and helixes 1, 6, 7 from D1R was established with molecular modeling. The distance between the two ligand binding sites in the heterodimer model was approximately 48.4 Å, which was shorter than the length of the bivalent ligands. This study demonstrates the existence of A1-D1R in situ and a simultaneous interaction of bivalent ligands with both the receptors.


Alternating arginine-modulated substrate specificity in an engineered tyrosine aminotransferase.
Mutation of six residues of Escherichia coli aspartate aminotransferase results in substantial acquisition of the transamination properties of tyrosine amino-transferase without loss of aspartate transaminase activity. X-ray crystallographic analysis of key inhibitor complexes of the hexamutant reveals the structural basis for this substrate selectivity. It appears that tyrosine aminotransferase achieves nearly equal affinities for a wide range of amino acids by an unusual conformational switch. An active-site arginine residue either shifts its position to electrostatically interact with charged substrates or moves aside to allow access of aromatic ligands.


Molecular and Biochemical Assessment of Gene Therapy in the Canine Model of Duchenne Muscular Dystrophy.
Mutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD), a progressive muscle-wasting disease. Adeno-associated virus (AAV) mediated gene replacement, and CRISPR/Cas9-mediated genome editing hold the potential to treat DMD. Molecular and biochemical analyses are essential to determine gene transfer efficiency and therapeutic efficacy. In this chapter, we present a series of methods routinely used in our laboratory to extract and quantify DNA, RNA, and protein in gene therapy studies performed in the canine DMD model.


Occipital approach for treatment of arteriovenous malformation of the vertebral artery by balloon occlusion.
The successful treatment of a congenital vertebral fistula with the balloon catheter occlusion technique is reported. A new approach is presented (the occipital approach), based upon the pathological enlargement of the second intervertebral space anastomosis between occipital and vertebral arteries.


Synthesis of Anthracene-Based Cyclic π-Clusters and Elucidation of their Properties Originating from Congested Aromatic Planes.
Synthesis and properties of anthracene-based cyclic π-clusters which possess two and four anthracene units are discussed. The optimal cyclization conditions were determined based on a nickel(0)-mediated reaction that afforded a cyclic anthracene dimer as the major product. Bringing two anthracene planes in close proximity in a face-to-face manner resulted in red-shifted absorption owing to the narrowing of the HOMO-LUMO gap. The cyclic anthracene dimer exhibits multi-stimuli responsiveness due to high π-congestion. For example, photoirradiation on the anthracene dimer affords its photoisomer having C-C bonds that are longer than 1.65 Å, which can undergo thermal reversion under gentle heating. This enabled mechanochromism of the photoisomer (colorless) to the original anthracene dimer (red). Photoisomerization was also observed in the crystalline state, accompanied by crystal jumping or collapsing, that is, the photosalient effect.


SATB2 in Neoplasms of Lung, Pancreatobiliary, and Gastrointestinal Origins.
Special AT-rich binding protein 2 (SATB2) immunohistochemistry (IHC) has high sensitivity and specificity for colorectal adenocarcinoma (CRC), but data on its expression in specific subsets of pulmonary, gastric, small bowel, and pancreatobiliary adenocarcinomas (ADCAs) are relatively limited or discordant. We assessed SATB2 expression in a large cohort of ADCAs from these sites to determine its reliability in distinguishing CRC from them. SATB2 IHC was performed on 335 neoplasms, including 40 lung ADCAs, 165 pancreatobiliary neoplasms (34 intraductal papillary mucinous neoplasms [IPMNs], 19 pancreatic ADCAs, 112 cholangiocarcinomas [CCs]), and 35 gastric, 13 small bowel, 36 ampullary (AMP), and 46 CRC ADCAs. The cases were evaluated for positivity (defined as ≥5% nuclear staining), and an H-score was calculated based on the percentage of SATB2+ cells and staining intensity. Analysis was performed to determine the optimal H-score threshold to separate CRC and non-CRC. SATB2 was positive in 3% of lung, 2% of CC, 17% of gastric, 38% of small bowel, and 6% of AMP ADCAs. All pancreatic ADCA/IPMNs were negative, and 87% CRCs were positive. SATB2 is not entirely specific for colorectal origin and can be expressed in a subset of gastrointestinal ADCAs. It is most useful in the differential of CRC vs lung and pancreatobiliary ADCAs.


[Polymorphism of human MDR1 gene in the Siberian and central Asian populations].
The multidrug resistance gene (MDR1, ABCB1) encodes transmembrane P-glycoprotein an ATP-dependent transporter, which is involved in elimination of drugs, xenobiotics, peptides from a cell. It is expressed in such organs as a brain, kidneys, a liver, a gastroenteric tract. It is supposed, that this protein may take part in formation of individual resistance to action of adverse factors of an environment, such as toxic substances, xenobiotics and infectious diseases. A number of polymorphisms in MDR1 gene is associated with a expression level and functioning of the gene, as well as with the ability to eliminate drugs and with the resistance to various neurodegeneration and gastroenteric tract diseases. In this study the frequencies of five single nucleotide polymorphisms (SNPs) (3435C/T, 2677G/T/A, 1236C/T, +139C/T and -1G/A), located in MDR1 gene, frequencies of haplotypes, the genetic differentiation and linkage disequilibrium pattern in populations of Russians, Tuvinians, northern and southern Kirghizes are described. Significant genetic differences were found between populations of Russians and northern Kirghizes, and also between Tuvinians and northern Kirghizes. The linkage disequilibrium pattern is characterized by high population specificity.


Glycan microarrays.
Glycan microarrays are presentations of multiple glycans or glycoconjugates printed on a single slide for screening with glycan-binding proteins (GBPs), which include lectins, antibodies, bacteria, and viruses. Glycans derivatized with functional groups can be immobilized onto appropriately activated glass slides to generate glycan microarrays where each glycan is printed at similar concentrations. Here we describe a method for fluorescently and functionally derivatizing free reducing glycans, printing microarrays, and interrogating the microarrays with GBPs.


Visualization of neuromuscular junctions over periods of several months in living mice.
Identified neuromuscular junctions were followed in the sternomastoid muscle of living mice for several months by repeated staining with the fluorescent dye 4-(4-diethylaminostyryl)-N-methylpyridinium iodide (4-Di-2-ASP; Magrassi et al., 1987). Overall terminal growth occurred at many endplates; however, the branching pattern of presynaptic arbors was largely unchanged, even after several months. The absence of significant remodeling over time was not a result of dye-staining, since sprouting was readily induced at residual motor endings by partial denervation. We conclude that--apart from overall growth--most neuromuscular junctions in the adult mouse are stable over intervals that represent a significant fraction of the animal's lifetime.


Population ecology and life history of the diurnal skink Morethia boulengeri in arid Australia.
The life history and population ecology of the skink Morethia boulengeri were studied from September 1985 to May 1987 in populations in a riverine woodland habitat and at an abandoned homestead in Kinchega National Park. The population dynamics and life histories of the two populations were remarkably similar. Yearly mortality (including emigration) ranged from 0.84-0.89. The yearly emigration rate was 0.01-0.03. Size-and body-condition-dependent mortality could be demonstrated for the population in riverine woodland. Average spring time densities were similar in both study sites but varied between years and ranged from 421-1823 individuals/ha. M. boulengeri females laid on average 2.8 eggs per clutch and usually produced three clutches per year. Egg mass was significantly correlated with female snout-vent-length, but relative clutch mass and egg size were not. All surviving juveniles reproduced for the first time in their first year. Some activity occurred throughout the year. Preferred body temperatures decreased in the cooler months. The data fit demographic models of life history evolution.


Regional, Socioeconomic, and Dietary Risk Factors for Vitamin B-12 Deficiency Differ from Those for Folate Deficiency in Cameroonian Women and Children.
Representative data on folate and vitamin B-12 dietary intake and status in low-income countries are rare, despite the widespread adoption of folic acid fortification. The purpose of this study was to evaluate folate and vitamin B-12 intake, status, and risk factors for deficiency before implementation of a national fortification program in Cameroon. A nationally representative cross-sectional cluster survey was conducted in 3 ecologic zones of Cameroon (South, North, and the 2 largest cities, Yaoundé/Douala), and information on dietary intake was collected from 10 households in each of 30 randomly selected clusters per zone. In a subset of women and their 12- to 59-mo-old children (n = 396 pairs), plasma folate and vitamin B-12, as well as breast milk vitamin B-12, were analyzed. Vitamin B-12 and folate dietary intake patterns and plasma concentrations were similar for women and children. In the subsample, 18% and 29% of women and 8% and 30% of children were vitamin B-12 (≤ 221 pmol/L) and folate (< 10 nmol/L) deficient, respectively. Mean dietary folate ranged from 351 μg dietary folate equivalents/d in the North to 246 μg dietary folate equivalents/d in Yaoundé/Douala; plasma folate was negatively associated with socioeconomic status (P = 0.001). Plasma vitamin B-12 deficiency was similar in the South and North, 29% and 40%, respectively, but was only 11% in Yaoundé/Douala, and was positively associated with socioeconomic status. Mean breast milk vitamin B-12 was statistically significantly lower in the North (101 pmol/L) than in the South (296 pmol/L) or Yaoundé/Douala (349 pmol/L). Folate intake and status are inadequate among women and young children in Yaoundé/Douala, whereas low vitamin B-12 intake and status are more common in poor and rural areas, especially in the North. Different strategies may be needed to control deficiency of these nutrients in different regions of Cameroon.


Ultrasonic studies of lipid bilayer. Phase transition in synthetic phosphatidylcholine liposomes.
The ultrasonic velocity at 3 MHz and the density in the nonsonicated and sonicated liposomes of dipalmitoylphosphatidylcholine have been measured in the temperature range from 0 degrees C to 55 degrees C. The results indicate that nonsonicated multilamellar vesicles undergo a weak first order transition which is analogous to the nematic-isotropic transition of liquid crystals. A sharp change in the ultrasonic velocity associated with the first order transition disappears when the multilamellar vesicles are sonicated. The bulk modulus of the lipid bilayer calculated from the ultrasonic velocity and the density of sonicated liposomes has a value of 3.0 X 10(10) dyne/cm2 at 20 degrees C, reaches a minimum value of 2.1 X 10(10) dyne/cm2 at its transition temperature and increases slightly to 2.2 X 10(10) dyne/cm2 at 50 degrees C.