Development and validation of a sensitive UHPLC-MS/MS method for the simultaneous analysis of tramadol, dextromethorphan chlorpheniramine and their major metabolites in human plasma in forensic context: application to pharmacokinetics.
The prerequisites for forensic confirmatory analysis by LC/MS/MS with respect to European Union guidelines are chromatographic separation, a minimum number of two MS/MS transitions to obtain the required identification points and predefined thresholds for the variability of the relative intensities of the MS/MS transitions (MRM transitions) in samples and reference standards. In the present study, a fast, sensitive and robust method to quantify tramadol, chlorpheniramine, dextromethorphan and their major metabolites, O-desmethyltramadol, dsmethyl-chlorpheniramine and dextrophan, respectively, in human plasma using ibuprofen as internal standard (IS) is described. The analytes and the IS were extracted from plasma by a liquid-liquid extraction method using ethyl acetate-diethyl-ether (1:1). Extracted samples were analyzed by ultra-high-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS). Chromatographic separation was performed by pumping the mobile phase containing acetonitrile, water and formic acid (89.2:11.7:0.1) for 2.0 min at a flow rate of 0.25 μL/min into a Hypersil-Gold C18 column, 20 × 2.0 mm (1.9 µm) from Thermoscientific, New York, USA. The calibration curve was linear for the six analytes. The intraday precision (RSD) and accuracy (RE) of the method were 3-9.8 and -1.7-4.5%, respectively. The analytical procedure herein described was used to assess the pharmacokinetics of the analytes in 24 healthy volunteers after a single oral dose containing 50 mg of tramadol hydrochloride, 3 mg chlorpheniramine maleate and 15 mg of dextromethorphan hydrobromide.


Yellow nail pigmentation following Depakote therapy.
Two months after being started on Depakote (divalproex sodium: Abbott Laboratories Inc., Abbott Park, Illinois), a 57-year-old female noticed the development of a transverse yellow band on all 20 proximal nails that eventually led to complete nail plate discoloration. Six to eight weeks after discontinuation of Depakote, normalization of her proximal nail plates was noted. Other anticonvulsants such as phenytoin and lithium have been documented to lead to nail pigmentation. Although several dermatologic reactions to Depakote have been described, we are not aware of any reported cases of nail discoloration secondary to Depakote. While our patient did have a history of renal disease with azotemia, we find it highly unlikely to be a contributing factor secondary to the fact that our patient's abnormality did not present similar to the nail abnormalities of renal disease. In conclusion, we found the temporal relationship between Depakote initiation/discontinuation and the nail discoloration to be highly indicative of Depakote as the source. Other anticonvulsants such as phenytoin and lithium have been documented to lead to nail pigmentation. Although several dermatologic reactions to Depakote have been described, we are not aware of any reported cases of nail discoloration secondary to Depakote. While our patient did have a history of renal disease with azotemia, we find it highly unlikely to be a contributing factor secondary to the fact that our patient's abnormality did not present similar to the nail abnormalities of renal disease. In conclusion, we found the temporal relationship between Depakote initiation/discontinuation and the nail discoloration to be highly indicative of Depakote as the source.


The Effectiveness and Safety of Mesenchymal Stem Cells in the Treatment of Osteoarthritis: A Systematic Review and Meta-analysis of 28 Randomized Controlled Trials.
To evaluate the effectiveness and safety of mesenchymal stem cells (MSCs) in the treatment of osteoarthritis (OA). Chinese databases (such as CNKI and SinoMed) and English databases (such as PubMed and Embase) were searched to collect randomized controlled trials (RCTs) of MSCs in the treatment of OA. The retrieval time is from inception to October 10, 2021. The literature was strictly selected according to the inclusion and exclusion criteria, data was extracted, and the quality was evaluated. RevMan 5.3 software was used for meta-analysis. STATA was used to evaluate publication bias. The registration number of this systematic review and meta-analysis is CRD42021277145. A total of 28 RCTs involving 1494 participants were included. The primary outcomes showed that MSCs may reduce WOMAC pain and VAS at the 3rd-month follow-up [WOMAC pain: -3.81 (-6.95, -0.68), P = 0.02. VAS: -1.11 (-1.53, -0.68), P < 0.00001], and the effect lasts for at least 12 months [WOMAC pain: -4.29 (-7.12, -1.47), P = 0.003. VAS: -1.77 (-2.43, -1.12), P < 0.00001]. MSCs may also reduce WOMAC stiffness and physical function at the 6th-month follow-up [WOMAC stiffness: -1.12 (-2.09, -0.14), P = 0.03. WOMAC physical function: -4.40 (-6.84, -1.96), P = 0.0004], and the effect lasts for at least 12 months [WOMAC stiffness: -0.99 (-1.95, -0.03), P = 0.04. WOMAC physical function: -3.26 (-5.91, -0.61), P = 0.02]. The improvement of WOMAC pain, VAS, WOMAC stiffness, and WOMAC physical function may be clinically significant. Meanwhile, after the MSC injection, Lequesne had been reduced compared with the control group [-4.49 (-8.21, -0.77), P = 0.002]. For adverse events, there is no significant difference in the safety of MSC injection and the control group [1.20 (0.97, 1.48), P = 0.09]. The quality of WOMAC physical function and adverse events were moderate. Based on current evidence, MSCs may be a safety therapy that have a good curative effect in the treatment of OA, the onset time is no later than 3 months, and the time to maintain the curative effect is no less than 12 months. However, these results should be generalized with caution due to the generally low quality of evidence and RCTs.


Dilute Au-Containing Ag Nanosponges as a Highly Active and Durable Electrocatalyst for Oxygen Reduction and Alcohol Oxidation Reactions.
Zero-dimensional nanoparticles (NPs) have been demonstrated as the promising class of catalysts for various chemical and electrochemical reactions. However, the emerging Au-Ag NP catalysts suffer from single functionality, limited activity enhancement, and unsatisfactory stability problems. Here, we report a facile kinetically controlled solution method to prepare a new class of Au-Ag nanoporous sponges (NSs) composed of three-dimensional networks without using additional stabilizing agents at room temperature. The unexpected shift of the d-band center in our Au-Ag NSs was observed for the first time in Au-Ag bimetallic systems, which effectively activates the Au-Ag NSs for electrochemical reactions. The robust electronic effect coupled with abundant accessible active sites from the hierarchically porous architecture make the bare Au-Ag NSs a superior multifunctional catalyst for oxygen reduction, ethylene glycol (EG) oxidation, and glucose oxidation reactions compared to the commercial Pt/C electrocatalyst in alkaline medium. The optimized AuAg3.2 NSs deliver a mass activity of 1.26 A mgAu-1 toward oxygen reduction reaction, which is ∼8.2 times as high as that of the Pt/C electrocatalyst, simultaneously showing outstanding stability with negligible activity decay after 10 000 cycles. For the anodic reactions, these AuAg3.2 NSs show extremely high activity and stability toward both EG and glucose catalytic oxidation reactions with a higher mass activity of 7.58 and 1.48 A mgAu-1, about 3- and 18.5-fold enhancement than Pt/C, respectively. This work provides important insights into the structural design, performance optimization, and cost reduction to promote the practical applications of liquid fuel cells.


Steroid cell tumor associated with primary amenorrhea and virilization.
A 22-year-old woman sought medical advice because of primary amenorrhea and virilization that was manifested by facial hirsutism, temporal balding, and clitorimegaly. Plasma steroid levels were determined at the time of initial assessment; androstenedione and testosterone were increased in comparison with normal values. Vaginal ultrasonography revealed the presence of a mass localized to the right ovary. The patient underwent oophorectomy, and pathologic examination of the surgical specimen led to the identification of a steroid cell tumor associated with a polycystic ovary. Tumor steroid-metabolizing enzymes were evaluated in vitro: 17alpha-hydroxylase, 3beta-hydroxysteroid dehydrogenase/ delta5-->4-isomerase, 17beta-hydroxysteroid oxidoreductase, and 5a-reductase, which are required for androgen synthesis, were present in the tumor tissue. Postoperatively, plasma androstenedione and testosterone levels returned to normal. This study demonstrated that the tumor was the source of the increased levels of androgen precursor and androgen in this woman; excess tumor-derived androgen may have been the trigger in the development of the polycystic ovary.


Hydrological Responses to Land-Use Change Scenarios under Constant and Changed Climatic Conditions.
This study quantified the hydrological responses to land-use change scenarios in the upper and middle Heihe River basin (HRB), northwest China, under constant and changed climatic conditions by combining a land-use/cover change model (dynamic conversion of land use and its effects, Dyna-CLUE) and a hydrological model (soil and water assessment tool, SWAT). Five land-use change scenarios, i.e., historical trend (HT), ecological protection (EP), strict ecological protection (SEP), economic development (ED), and rapid economic development (RED) scenarios, were established. Under constant climatic condition, hydrological variations are only induced by land-use changes in different scenarios. The changes in mean streamflow at the outlets of the upper and the middle HRB are not pronounced, although the different scenarios produce different outcomes. However, more pronounced changes are observed on a subbasin level. The frequency of extreme flood is projected to decrease under the SEP scenario, while under the other scenarios, no changes can be found. Two emission scenarios (A1B and B1) of three general circulation models (HadCM3, CGCM3, and CCSM3) were employed to generate future possible climatic conditions. Under changed climatic condition, hydrological variations are induced by the combination of land-use and climatic changes. The results indicate that the impacts of land-use changes become secondary when the changed climatic conditions have been considered. The frequencies of extreme flood and drought are projected to decrease and increase, respectively, under all climate scenarios. Although some agreements can be reached, pronounced difference of hydrological responses can be observed for different climate scenarios of different GCMs.


A decade of clinical research on clinical characteristics, medical treatments, and surgical treatments for individuals with craniofacial microsomia: What have we learned?
This article provides a review of a decade of clinical research studies on clinical features, medical interventions, and surgical interventions for individuals with craniofacial microsomia (CFM). We also provide recommendations for future clinical research. A systematic search of literature was conducted in Embase and PubMed/MEDLINE Ovid. All publications from 2010 to 2020 that included at least 10 individuals with CFM were considered relevant for this study. A total of 91 articles were included. In the past decade, many new studies on CFM have been published providing more insight on the diagnosis and management of patients with CFM. This review encompasses findings on the clinical difficulties patients with CFM encounter, including the craniofacial and extracraniofacial characteristics of patients with CFM and its related clinical consequences on breathing, feeding, speech, and hearing. A considerable number of large multicenter studies have been published in recent years, providing new insights in the clinical consequences of CFM. The phenotypic variety between patients with CFM makes patient-specific treatment tailored to individual needs essential. The research and development of clinical care standards might be challenging because of the heterogeneity of CFM. Future research on clinical and patient-reported outcomes can help identify optimal treatment strategies. Cooperation between craniofacial centers, using uniform registration and outcome measurement tools, could enhance research and future care for these patients. Level IV.


The identification and characteristics of sacral parasympathetic preganglionic neurones.
1. Sacral parasympathetic preganglionic neurones were identified by intracellular and extracellular micro-electrode recording of antidromic potentials in response to stimulation of the pelvic nerve or the second or third sacral ventral roots.2. The segmental distribution of autonomic neurones varied in different cats. In some cats they were mainly in S2 segment, in others in S3 and in the remainder, in both S2 and S3.3. The antidromic potentials showed initial segment-somadendritic (IS-SD) inflexions and delayed depolarizations and were slightly less prolonged than those of sympathetic neurones but more prolonged than those of spinal motoneurones. After-hyperpolarization was observed after the antidromic spike potential.4. The conduction velocities for sacral parasympathetic preganglionic fibres were less than 12.5 m/sec and thus were similar to those of sympathetic preganglionic fibres.5. Parasympathetic neurones were not excited by micro-electro-phoretically applied 5-hydroxytryptamine, noradrenaline or acetylcholine.


Drug-induced gingival hyperplasia in transplant recipients.
Gingival hyperplasia is a common occurrence in transplant recipients who are taking cyclosporine. This condition can be complicated when calcium channel blockers or phenytoin are added to the armamentarium of medications; it can be painful and may interfere with eating, speech, and appearance. Multiple mechanisms exist for gingival overgrowth. Prevention with appropriate oral hygiene appears important in controlling the inflammatory component and decreasing the severity of the overgrowth. Patients must be aware of the potential for the development of gingival hyperplasia and must follow up with regular professional cleanings. If the overgrowth persists, treatment options should be discussed between patients and their physician. Conversion from cyclosporine to tacrolimus, treatment with antibiotic therapy, and surgical excision or laser therapy are all potential therapies to consider.


Physiological selectivity and activity reduction of insecticides by rainfall to predatory wasps of Tuta absoluta.
In this study, we carried out three bioassays with nine used insecticides in tomato crops to identify their efficiency against tomato leaf miner Tuta absoluta, the physiological selectivity and the activity reduction of insecticides by three rain regimes to predatory wasps Protonectarina sylveirae and Polybia scutellaris. We assessed the mortality caused by the recommended doses of abamectin, beta-cyfluthrin, cartap, chlorfenapyr, etofenprox, methamidophos, permethrin, phenthoate and spinosad to T. absoluta and wasps at the moment of application. In addition, we evaluated the wasp mortality due to the insecticides for 30 days on plants that did not receive rain and on plants that received 4 or 125 mm of rain. Spinosad, cartap, chlorfenapyr, phenthoate, abamectin and methamidophos caused mortality higher than 90% to T. absoluta, whereas the pyrethroids beta-cyfluthrin, etofenprox and permethrin caused mortality between 8.5% and 46.25%. At the moment of application, all the insecticides were highly toxic to the wasps, causing mortality higher than 80%. In the absence of rain, all the insecticides continued to cause high mortality to the wasps for 30 days after the application. The toxicity of spinosad and methamidophos on both wasp species; beta-cyfluthrin on P. sylveirae and chlorfenapyr and abamectin on P. scutellaris, decreased when the plants received 4 mm of rain. In contrast, the other insecticides only showed reduced toxicity on the wasps when the plants received 125 mm of rain.


The emergence of sarcoptic mange in Australian wildlife: an unresolved debate.
Due to its suspected increase in host range and subsequent global diversification, Sarcoptes scabiei has important implications at a global scale for wildlife conservation and animal and human health. The introduction of this pathogen into new locations and hosts has been shown to produce high morbidity and mortality, a situation observed recently in Australian and North American wildlife.Of the seven native animal species in Australia known to be infested by S. scabiei, the bare-nosed wombat (Vombatus ursinus) suffers the greatest with significant population declines having been observed in New South Wales and Tasmania. The origins of sarcoptic mange in Australian native animals are poorly understood, with the most consistent conclusion being that mange was introduced by settlers and their dogs and subsequently becoming a major burden to native wildlife. Four studies exist addressing the origins of mange in Australia, but all Australian S. scabiei samples derive from only two of these studies. This review highlights this paucity of phylogenetic knowledge of S. scabiei within Australia, and suggests further research is needed to confidently determine the origin, or multiple origins, of this parasite.At the global scale, numerous genetic studies have attempted to reveal how the host species and host geographic location influence S. scabiei phylogenetics. This review includes an analysis of the global literature, revealing that inconsistent use of gene loci across studies significantly influences phylogenetic inference. Furthermore, by performing a contemporary analytical approach on existing data, it is apparent that (i) new S. scabiei samples, (ii) appropriate gene loci targets, and (iii) advanced phylogenetic approaches are necessary to more confidently comprehend the origins of mange in Australia. Advancing this field of research will aid in understanding the mechanisms of spillover for mange and other parasites globally.


Neuroradiology can predict the development of hand function in children with unilateral cerebral palsy.
Much variation is found in the development of hand function in children with unilateral cerebral palsy (CP). . To explore how anatomic brain abnormalities can be used to predict the development of hand function. A total of 32 children with unilateral CP (16 boys and 16 girls) were evaluated at least once a year by the Assisting Hand Assessment (AHA). The data collection covered an age range from 18 months to 8 years (mean time in study, 4 years and 6 months). Computerized tomography or magnetic resonance imaging of the brain were assessed for patterns of brain damage, including the location of gray and extent of white-matter damage. The children were divided into groups according to lesion characteristics, and a series of univariate models were analyzed with a nonlinear mixed-effects model. The rate and maximum limit of development were calculated. The highest predictive power of better development of hand function was the absence of a concurrent lesion to the basal ganglia and thalamus, independent of the basic type of brain lesion. This model predicted both the rate of increasing ability and hand function at age 8 years. Hand function was also predicted by the basic pattern of damage and by the extent of white-matter damage. The presence of unilateral or bilateral damage had no predictive value. Neuroradiological findings can be used to make a crude prediction of the future development of the use of the affected hand in young children with unilateral CP.


Adaptive changes after human immunodeficiency virus type 1 transmission.
Primary HIV-1 infection (PHI) is associated with a period of viremia, the resolution of which generally coincides with the development of both humoral and cellular immune responses. In this study replication-competent quasispecies were derived from virus isolated from an individual before and after seroconversion. Virus was also isolated from the presumed donor. Phenotypic and genotypic analysis of biological clones identified transmission of an R5/M-tropic phenotype. However, the ability of clones derived from the recipient to replicate in primary macrophages and PBMCs was restricted after transmission. This apparent selection process was supported by analysis of molecular clones derived from the isolated virus. Analysis of the ratio of synonymous and nonsynonymous substitutions predicted the existence of selective pressure soon after transmission, coincident with the development of HIV-1-specific antibodies. An Env trans-complementation assay demonstrated that the infectivity of a clone derived from the recipient after seroconversion was enhanced in the presence of a selected neutralizing antibody, indicating that the developing humoral immune response may have at least in part contributed to the selective pressure identified.


Discovery and Structural Optimization of 1,2,3,4-Tetrahydro-β-carbolines as Novel Reactive Oxygen Species Inducers for Controlling Intractable Plant Bacterial Diseases.
Nowadays, reactive oxygen species (ROS) have been acknowledged as promising bactericidal targets against pesticide-resistant bacteria. Herein, to further excavate more excellent ROS inducers, simple 1,2,3,4-tetrahydro-β-carboline derivatives containing a 3-aminopropanamide moiety were prepared and assessed for their antibacterial potency. Notably, three promising compounds displayed significant antibacterial potency. Compound I29 exhibits excellent in vitro bioactivity, with an EC50 value of 5.73 μg/mL, and admirable in vivo activities (protective activity of 55.74% and curative activity of 65.50%) toward Xanthomonas oryzae pv. oryzae. Compound I16 has good activity in vitro, with an EC50 of 3.43 μg/mL, and outstanding bioactivities in vivo (protective activity of 92.50% and curative activity of 59.68%) against Xanthomonas axonopodis pv. citri. Compound I6 shows excellent in vitro bioactivity (EC50 = 2.86 μg/mL) and significant protective activity (94.02%) for preventing Pseudomonas syringae pv. actinidiae. Antibacterial mechanism investigations indicate that these compounds disrupt the balance of the redox system to kill bacteria. These simple 1,2,3,4-tetrahydro-β-carboline derivatives are promising leads to the discovery of bactericidal agents.


Long-term outcome of epileptic dogs treated with implantable vagus nerve stimulators.
The long-term effect of implantable vagus nerve stimulators (VNS) on seizures has not been evaluated in epileptic dogs. Report seizure frequency in medication-resistant epileptic dogs before and after VNS implantation. Twelve client-owned dogs with idiopathic epilepsy and >1 seizure day per 3 weeks despite 3 months of appropriate use of 2 antiseizure medications and seizure diaries maintained 6 months before and >12 months after VNS implantation. Uncontrolled, open-label, before and after study. Mean monthly seizures and inter-seizure periods obtained from contemporaneous seizure diaries in the 6 months before implantation were compared with 0 to 6 months, 7 to 12 months, and subsequent 12-month periods after implantation. The number of dogs with >50% decrease in seizure frequency, >3 times increase in inter-ictal period interval, and seizure freedom for >3 months at the time of death or last follow-up were recorded. Five of 12 dogs were euthanized <12 months after implantation. All 7 remaining dogs showed >50% decrease in seizure frequency until last follow-up, starting at a median of 37 to 48 months after implantation (range, 0-6 to 61-72 months) and a >3-fold increase in mean inter-seizure interval starting a median of 25 to 36 months after implantation (range, 0-6 months to 49-60 months), 3/7 dogs were seizure-free at death or last follow-up. Monthly seizure frequencies decreased and inter-seizure intervals increased in all dogs 2 to 3 years after VNS implantation, but a high proportion were euthanized before this time point. Prospective clinical trials are required to establish causality and the magnitude of this association.


Free and bound cortisol in plasma and saliva during ACTH challenge in dairy cows and horses.
Cortisol levels reflect hypothalamic-pituitary-adrenocortical (HPA) axis activity. While most plasma cortisol is supposed to be bound to the soluble corticosteroid-binding globulin (CBG), only free cortisol (FC) actively regulates metabolic and immunological processes. We aimed to establish a multispecies suitable method to assess FC in cows and horses which in combination with total cortisol (TC) allows interpreting proportional changes of cortisol in saliva as well as in blood in response to a standardized HPA axis activation via ACTH. We further investigated if the ratios of cortisol fractions as obtained at basal levels in healthy horses (herbivorous and monogastric) and dairy cows (herbivorous and ruminant) change during HPA axis activation, and to which extent saliva cortisol (SC) is representative for alterations in plasma FC and adrenal cortex reactivity. However, it was not the objective of the present study to directly compare the two species. Dosages of ACTH applied in cows and horses were based on published data. Synthetic ACTH was intravenously administered to eight dairy cows (0.16 µg/kg BW) and five horses (1 µg/kg BW). Blood and saliva were collected every 30 min for 3 h from a jugular vein catheter, and analyzed for TC and SC, the ratio of free cortisol (rFC), and the concentration of FC (cFC) in plasma. During the entire sampling period of the ACTH test, plasma TC was paralleled by blood cFC, rFC, and SC in both cows and horses. All cortisol fractions increased within 30 min of ACTH administration compared to basal values (0 min, P < 0.05). Peak TC concentration reached 63.2 ± 9.6 ng/mL and 73.2 ± 11.8 ng/mL in bovine and equine plasma, respectively. Peak values of rFC averaged 17.9 ± 4.5% in cows and 19.2 ± 7.8% in horses. The ratio of SC to cFC in horses remained similar during the ACTH challenge suggesting that SC is recruited from plasma FC. However, SC increased less compared to plasma TC and FC during HPA axis activation in cows. In conclusion, the short-term activation of the HPA axis caused not only an elevation of TC, but also a similar increase of rFC in both species. SC closely reflected changes of FC in horses, but less accurately in cows. The concomitant evaluation of changes among cortisol fractions might give further indications on adaptation mechanisms in glucocorticoid regulation as well as differentiate cortisol-related health disorders.


Effects of low-dose oral contraceptives on blood coagulation.
A study has been performed on the effect of Norinyl-1 and Ortho-Novin, two low-dose oral contraceptives, on blood-clotting factors. Ortho-Novin contains twice the amount of hormone as Norinyl-1. It was therefore possible to observe whether any changes detected were related to the dose of oestrogen-progestin combination. The women were tested in parallel with matched normal female controls and a group in the third trimester of pregnancy. Significant rises in factor VII and X levels were found with both low-dose preparations from the third month onwards. There was no difference between patients on Norinyl-1 and Ortho-Novin, and hence the clotting changes do not appear to be dose-dependent. The long-term effects on clotting factors of these low-dose oral contraceptive preparations remain to be investigated.


Oxygen electrode syringe as an instrument for determining oxygen-hemoglobin dissociation curves.
A new instrument is described which simplifies the measurement of the oxygen-hemoglobin dissociation curve, using small volumes of blood. An oxygen electrode, as the plunger of a syringe accommodating increasing volumes of blood at predetermined levels of saturation with oxygen, measures the amount of dissolved oxygen in the plasma, which is proportional to the gas tension.


Glutathione in spermatozoa and seminal plasma of infertile men.
Glutathione has a central role in the defence against oxidative damage; however, the data on glutathione concentrations in the semen of infertile men are limited. To expand this knowledge the glutathione content of the ejaculates and blood plasmas of 77 infertile men and 11 controls were analysed. The concentrations of total glutathione were assessed in spermatozoa, seminal plasma and blood plasma using a coupled spectrophotometric assay. In the spermatozoa of patients with oligozoospermia the glutathione concentrations (2.57+/-0.96 nmol/10[8] spermatozoa; mean +/- SD) were significantly lower than in the controls (3.49+/-0.87 nmol/10[8] spermatozoa; P +/- 0.03). The glutathione content of spermatozoa from patients with normozoospermia showed large variations (3.04+/-1.37 nmol/10[8] spermatozoa). An association between the intracellular glutathione content and the ability to penetrate bovine cervical mucus was observed (r = 0.2, P = 0.04). The intracellular glutathione concentrations correlated with the glutathione levels in seminal plasma (r = 0.46, P < 0.0001). There was no correlation between glutathione concentrations in blood plasma and those in seminal plasma or in spermatozoa. The glutathione concentrations in seminal plasmas did not differ between the different groups, however, correlated with the serum follicle stimulating hormone concentrations (r = 0.53, P = 0.005). This study demonstrated that intracellular glutathione levels of spermatozoa are decreased in certain populations of infertile men.


[Determination of captopril plus its disulfide metabolites in human plasma].
A new and sensitive HPLC method has been developed for the determination of captopril plus its disulfide metabolites (total captopril) in human plasma. Captopril disulfides and the drug covalently bound to protein were reduced with sodium borohydride to captopril. After liquid-liquid extraction, captopril was treated with o-phthalaldehyde in the presence of D-phenylalanine. The fluorescent derivative of captopril was measured by HPLC using a C-18 reversed phase column with fluorescence detection at the excitation and emission wavelengths of 235 nm and 440 nm, respectively. The mobile phase consisted of a methanol-acetonitrile-phosphate buffer (0.02 mol.L-1, pH 6.4) mixture (30:30:135, v/v), and was set at a flow rate of 1 ml.min-1. The linear range of the assay was between 5 ng.ml-1 (lower limit of quantitation) and 300 ng.ml-1 for total captopril in plasma. The method was successfully applied to determine plasma concentrations of captopril plus its disulfide metabolites in hypertensive patients and was demonstrated to be suitable for the therapeutic drug monitoring.


Uncoupling of VEGF with endothelial NO as a potential mechanism for abnormal angiogenesis in the diabetic nephropathy.
Abnormal angiogenesis is a well characterized complication in diabetic retinopathy and is now recognized as a feature of diabetic nephropathy. The primary growth factor driving the increased angiogenesis in diabetic retinopathy and nephropathy is vascular endothelial growth factor (VEGF). While VEGF is considered an important growth factor for maintaining glomerular capillary integrity and function, increased action of VEGF in diabetic renal disease may carry adverse consequences. Studies by our group suggest that the effects of VEGF are amplified in the setting of endothelial dysfunction and low nitric oxide (NO) levels, which are a common feature in the diabetic state. The lack of NO may amplify the effects of VEGF to induce inflammation (via effects on the macrophage) and may lead to dysregulation of the vasculature, exacerbating features of diabetic renal disease. In this review, we summarize how an "uncoupling" of the VEGF-NO axis may contribute to the pathology of the diabetic kidney.


Ophthalmic features of Joubert syndrome.
Joubert syndrome (Online Mendelian Inheritance in Man 213300) is a rare autosomal recessive congenital malformation of the brainstem and cerebellar vermis. Diagnosis is based on characteristic clinical features (e.g., hypotonia, episodic hyperpnea, developmental delay, progressive ataxia) and is confirmed by distinctive neuroradiologic findings (e.g., the "molar tooth" sign). Variable ophthalmic features have been mentioned in prior reports; however, most do not detail eye findings and the few that do were before the publication of suggested diagnostic criteria. The objective of the current study is to describe the ophthalmic phenotype in a cohort of patients with Joubert syndrome for whom the diagnosis was made using current diagnostic criteria. Prospective case series. Eight children diagnosed clinically with radiologic confirmation. Ophthalmic examination and visual electrophysiology. Ocular and oculomotor examination (as allowed by patient cooperation), electroretinography, flash visual-evoked potential (fVEP). Patients' ages ranged from 7 months to 10 years. Saccadic dysfunction was observed in all cooperative patients (6/6); compensatory head thrusts or turns were present in all except the youngest patient (7 months of age). Most patients (5/8) had primary-position nystagmus (see-saw in 3/5). Abnormal pursuit (3/7) and a dystrophic retinal appearance (3/8) were also seen. One patient had bilateral asymmetric ptosis with unilateral lid elevation during ipsilateral abduction. Electroretinography findings were normal for all 8 patients. Seven patients underwent fVEP; 6 were abnormal (asymmetric) and one was not interpretable because of study artifact. Ophthalmologists should be aware that saccadic dysfunction (typically with head thrusts) and primary position nystagmus (typically see-saw) in a developmentally delayed child suggest the diagnosis of Joubert syndrome, especially if a dystrophic retinal appearance is also present. Our findings of asymmetric fVEPs and see-saw nystagmus suggest an abnormality in optic nerve decussation, consistent with the concept that impaired axonal guidance occurs in patients with Joubert syndrome. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Functional roles of presynaptic GABA(A) receptors on glycinergic nerve terminals in the rat spinal cord.
GABA(A) receptor-mediated presynaptic depolarization is believed to induce presynaptic inhibition of excitatory synaptic transmission. We report here the functional roles of presynaptic GABA(A) receptors in glycinergic transmission of the rat spinal cord. In mechanically dissociated rat sacral dorsal commissural nucleus (SDCN) neurons attached with native glycinergic and GABAergic nerve terminals, glycinergic spontaneous inhibitory postsynaptic currents (sIPSCs) were isolated from a mixture of both glycinergic and GABAergic sIPSCs by perfusing the SDCN nerve cell body with ATP-free internal solution. Under such experimental conditions, exogenously applied muscimol (0.5 microM) depolarized glycinergic presynaptic nerve terminals and significantly increased glycinergic sIPSC frequency to 542.7 +/- 47.3 % of the control without affecting the mean current amplitude. The facilitatory effect of muscimol on sIPSC frequency was completely blocked by bicuculline (10 microM) or SR95531 (10 microM), selective GABA(A) receptor antagonists. This muscimol-induced presynaptic depolarization was due to a higher intraterminal Cl(-) concentration, which is maintained by a bumetanide-sensitive Na-K-Cl cotransporter. On the contrary, when electrically evoked, this muscimol-induced presynaptic depolarization was found to decrease the action potential-dependent glycine release evoked by focal stimulation of a single terminal. The results suggest that GABA(A) receptor-mediated presynaptic depolarization has two functional roles: (1) presynaptic inhibition of action potential-driven glycinergic transmission, and (2) presynaptic facilitation of spontaneous glycinergic transmission.


Use of At-Home COVID-19 Tests - United States, August 23, 2021-March 12, 2022.
COVID-19 testing provides information regarding exposure and transmission risks, guides preventative measures (e.g., if and when to start and end isolation and quarantine), identifies opportunities for appropriate treatments, and helps assess disease prevalence (1). At-home rapid COVID-19 antigen tests (at-home tests) are a convenient and accessible alternative to laboratory-based diagnostic nucleic acid amplification tests (NAATs) for SARS-CoV-2, the virus that causes COVID-19 (2-4). With the emergence of the SARS-CoV-2 B.1.617.2 (Delta) and B.1.1.529 (Omicron) variants in 2021, demand for at-home tests increased† (5). At-home tests are commonly used for school- or employer-mandated testing and for confirmation of SARS-CoV-2 infection in a COVID-19-like illness or following exposure (6). Mandated COVID-19 reporting requirements omit at-home tests, and there are no standard processes for test takers or manufacturers to share results with appropriate health officials (2). Therefore, with increased COVID-19 at-home test use, laboratory-based reporting systems might increasingly underreport the actual incidence of infection. Data from a cross-sectional, nonprobability-based online survey (August 23, 2021-March 12, 2022) of U.S. adults aged ≥18 years were used to estimate self-reported at-home test use over time, and by demographic characteristics, geography, symptoms/syndromes, and reasons for testing. From the Delta-predominant period (August 23-December 11, 2021) to the Omicron-predominant period (December 19, 2021-March 12, 2022)§ (7), at-home test use among respondents with self-reported COVID-19-like illness¶ more than tripled from 5.7% to 20.1%. The two most commonly reported reasons for testing among persons who used an at-home test were COVID-19 exposure (39.4%) and COVID-19-like symptoms (28.9%). At-home test use differed by race (e.g., self-identified as White [5.9%] versus self-identified as Black [2.8%]), age (adults aged 30-39 years [6.4%] versus adults aged ≥75 years [3.6%]), household income (>$150,000 [9.5%] versus $50,000-$74,999 [4.7%]), education (postgraduate degree [8.4%] versus high school or less [3.5%]), and geography (New England division [9.6%] versus West South Central division [3.7%]). COVID-19 testing, including at-home tests, along with prevention measures, such as quarantine and isolation when warranted, wearing a well-fitted mask when recommended after a positive test or known exposure, and staying up to date with vaccination,** can help reduce the spread of COVID-19. Further, providing reliable and low-cost or free at-home test kits to underserved populations with otherwise limited access to COVID-19 testing could assist with continued prevention efforts.


In vitro generation of HIV type 1 subtype C isolates resistant to enfuvirtide.
Enfuvirtide (ENF) is the first in a new class of antiretroviral agents targeting the fusion process of the viral life cycle. ENF is a synthetic 36-amino acid peptide that binds to the HR-1 region of gp41 preventing fusion of viral and cellular membranes. With the introduction of ENF there are now four classes of antiretrovirals each with distinct and different resistance pathways. Resistance to ENF among subtype B HIV-1 isolates is associated with amino acid changes mainly in the HR-1 region, although other regions of envelope have also been implicated. To determine whether subtype C viruses developed resistance mutations similar to subtype B viruses, 11 subtype C and 4 subtype B viruses were passaged in the presence of increasing concentrations of ENF. The subtype C isolates showed varying levels of replication at 1 microg/ml ENF by day 18, but by day 29 all replicated efficiently at 10 microg/ml ENF. All subtype C isolates showed evidence of genotypic changes in gp41 HR-1 following exposure to ENF that included G36S/E/D, I37T, V38M/A/L/E, N/S42D, N43K, L45R/M, and A50T/V. Three subtype C viruses had compensatory changes in the HR-2 region, which corresponds to the ENF sequence, and two isolates had changes in the V3 region. Mutational patterns among the four subtype B viruses were similar to those for subtype C and those previously published in the literature. These data indicate that in vitro resistance to ENF develops rapidly among HIV-1 subtype C isolates. In general, mutational patterns for subtype C were similar to those described for subtype B, suggesting that the mechanism of action for ENF is similar for HIV-1 subtype B and C isolates.


Equation to estimate visceral adipose tissue volume based on anthropometry for workplace health checkup in Japanese abdominally obese men.
The purpose of this study was to develop a new equation model for predicting abdominal visceral adipose tissue (VAT) volume using anthropometric values for workplace health checkup and to clarify the association between metabolic risk factors and measured and predicted VAT volumes. Two hundred sixty male workers (200 for derivation group and 60 for validation group) participated in the cross-sectional study. The anthropometric variables and VAT volume were measured with 24 consecutive magnetic resonance images. Measurements in the validation group also included metabolic risk factors, i.e. blood pressure, HDL cholesterol, triglyceride, fasting glucose and HbA1c. Using multiple regression analyses for the derivation group, we determined the best prediction equation for abdominal VAT volume with a variance of 47% as follows: 47.03 age+117.79 BMI+74.18 waist circumference -8,792.7. In our validation group, the correlation coefficient between the measured and predicted VAT volumes was 0.74 (p<0.01). Furthermore, blood pressure, fasting glucose and HbA1c correlated with both measured and predicted VAT volumes. This study suggests that the equation model has potential to assess VAT accumulation levels in workers health checkup where CT and MRI are not available.


The importance of the propagule-sediment-tide "power balance" for revegetation at the coastal frontier.
Revegetation of pioneer plants is a critical phase in community establishment for mudflats in seriously degraded coastal wetlands. We tested a hypothesis of the importance of a "power balance" among propagule resilience and sedimentary and tidal disturbances for vegetation reestablishment. Our experiment used three types of propagules (seeds, seedlings, and corms) of native Scirpus species in the fringing flats with similar tidal flows and varying sedimentary intensities in the Yangtze Estuary. Regardless of the initial planting densities, the seed germination rate was extremely low in the field situation. Although the incubated seedlings were planted directly on the bare flat, the wave movement easily flushed the seedlings, even at the site with moderate sedimentary accretion. Failure of the revegetation practice using the seed and seedling materials indicated that the combined "growing and anchoring power" of young seedlings and "stabilizing power" of the sediment were insufficient to withstand the "dislodging power" of the tidal energy. In contrast, the planting approach with underground propagules (corms) proved to be feasible for vegetation establishment at the sites with moderate and low-level sedimentary intensities. The successful practice improved the tipping point of plant survival and tussock formation could be surpassed when the combined growing and anchoring power of seedlings that developed from corms with the stabilizing power of the sediment was greater than the dislodging power of the wave energy. However, at the site with high-level sedimentary intensity, the excessive sediment converted to the burying stress power as seedlings developed from the corms, revealing a burial threshold for seedling survival. The risk of seedling establishment was high when the burying stress power of the sediment far outweighed the combination of the growing power of the seedlings and the sediment removal power of the tidal current and surpassed the tipping point of vegetation die-off. Additionally, we checked the practice cost of the different approaches to ensure a highly cost-effective revegetation planning based on site suitability. This study highlights that understanding of the propagule-sediment-tide power balance offers a tool for improvement of the revegetation and management of site-specific sedimentary and hydrological environments for many degraded coastal ecosystems.


Phylogenomics of 2,4-Diacetylphloroglucinol-Producing Pseudomonas and Novel Antiglycation Endophytes from Piper auritum.
2,4-Diacetylphloroglucinol (DAPG) (1) is a phenolic polyketide produced by some plant-associated Pseudomonas species, with many biological activities and ecological functions. Here, we aimed at reconstructing the natural history of DAPG using phylogenomics focused at its biosynthetic gene cluster or phl genes. In addition to around 1500 publically available genomes, we obtained and analyzed the sequences of nine novel Pseudomonas endophytes isolated from the antidiabetic medicinal plant Piper auritum. We found that 29 organisms belonging to six Pseudomonas species contain the phl genes at different frequencies depending on the species. The evolution of the phl genes was then reconstructed, leading to at least two clades postulated to correlate with the known chemical diversity surrounding DAPG biosynthesis. Moreover, two of the newly obtained Pseudomonas endophytes with high antiglycation activity were shown to exert their inhibitory activity against the formation of advanced glycation end-products via DAPG and related congeners. Its isomer, 5-hydroxyferulic acid (2), detected during bioactivity-guided fractionation, together with other DAPG congeners, were found to enhance the detected inhibitory activity. This report provides evidence of a link between the evolution and chemical diversity of DAPG and congeners.


Proton Radiotherapy for Patients With Oligometastatic Breast Cancer Involving the Sternum.
A subset of metastatic breast cancer patients present with oligometastatic disease involving the sternum. Given the proximity to traditional target structures, a proton radiation field can be expanded to include this region, providing definitive therapy for patients who are otherwise metastatic. We evaluated the feasibility and outcomes of a small series of patients who received comprehensive nodal irradiation inclusive of an isolated sternal metastasis using proton pencil beam scanning. Four patients with a diagnosis of metastatic breast cancer with an isolated metastasis to the sternum received multimodality therapy with curative intent and then underwent adjuvant pencil beam scanning with definitive treatment to the sternum. Dosimetric parameters and treatment outcomes were evaluated. With respect to treatment coverage, proton therapy was able to deliver comprehensive target structure coverage while maintaining modest doses to the organs at risk compared with photon techniques. At a median follow-up of 28 months from diagnosis, none of the patients have experienced relapse within the radiation portal or developed additional sites of metastatic disease. Pencil beam scanning for oligometastatic breast cancer with isolated sternal lesions appears feasible without undue normal tissue exposure. Current treatment outcomes appear promising.


NMR and gas chromatography studies of lyophilized human brain tumors.
1H HR MAS (high resolution magic angle spinning) NMR is a promising tool in the in vitro characterisation of brain tumors. Brain tissue samples were collected from patients with intracranial tumors during surgery, frozen and lyophilized. The analysis of solid samples was performed by high-speed rotation (33 kHz) H MAS NMR. The most intense resonances arise from lipids (methylene mid-chain and methyl carbons of fatty acids). 1H MAS spectra obtained from the same histological type of brain tumors are similar; spectra of glioblastomas were different from those of meningiomas. 1H and 13C NMR solution spectra of lipid extracts confirmed the presence of aliphatic chains fatty acids and cholesterol as major constituents. Biochemical information on liberated fatty acid composition was obtained by gas-chromatography (GC). The glioma content of the linoleic acid (18:2n6) was found to be greater, whereas the level of docosahexaenoic acid (22:6n3) was significantly reduced.


Active straight leg raising (ASLR) competence improves with reverse-ASLR exercises and not repeating ASLR exercises.
In the Functional Movement Screen (FMS), a subgroup of those with a score of 1 due to limitations in the active straight leg raising (ASLR) but not in the passive straight leg raising is considered to have a stability or motor control dysfunction (SMCD). The FMS proposes the use of the movements in a reverse pattern to improve FMS scores. The aim of this study was to investigate whether the reverse pattern of the ASLR (reverse-ASLR) was more effective than repeating the ASLR to improve the FMS score in participants with the FMS ASLR score of 1 due to the SMCD (ASLR-1-SMCD). A two-armed randomized controlled trial was conducted in individuals with the ASLR-1-SMCD. The intervention was either the reverse-ASLR or the ASLR exercise on both sides at home for a month followed by a 1-month wait-and-see interval, wherein the primary outcome measure was the right FMS ASLR score. Forty participants were randomized to the ASLR exercise group (n=20) or the reverse-ASLR exercise group (n=20). The Fisher exact test demonstrated a statistically significant difference (P=0.020) in the proportion of those with FMS ASLR score improvement to a score of 2 (ASLR exercise group, one; reverse-ASLR exercise group, eight) at follow-up 1, but no significance (P=0.106) at follow-up 2 (ASLR exercise group, none; reverse-ASLR exercise group, four). This study indicated that the reverse-ASLR exercise was more effective than repeating the ASLR exercise in order to improve the ASLR score among individuals with the ASLR-1-SMCD.


[Pituitary prolactinoma with severe erectile dysfunction as the initial symptom: diagnosis and treatment of 4 cases].
Pituitary prolactinoma with severe erectile dysfunction (ED) as the initial symptom is often misdiagnosed. This article explores the diagnosis and treatment of severe ED caused by pituitary prolactinoma. We retrospectively analyzed the diagnosis and treatment of 4 cases of pituitary prolactinoma with severe ED (IIEF-5 score 5 - 7) as the initial clinical symptom confirmed by MRI. The 4 cases of pituitary prolactinoma-induced severe ED, with serum prolactin 10 times above the maximum normal level, were misdiagnosed for 2 years. All failed to respond to the PDE5 inhibitor therapy, and then 3 of them underwent transnasal hypophysectomy. Twenty-four months of follow-up found the level of prolactin restored to normal in 1 case (IIEF-5 = 19), and reduced to 600 and 768 IU/L respectively (IIEF-5 = 15) in the other 2. Then administration of the PDE5 inhibitor was followed, which produced satisfactory efficacy. One case was treated with oral bromocriptine, which restored the prolactin level to normal at 12 months (IIEF-5 > 21). Prolactin detection and brain MRI can help to confirm pituitary prolactinoma with severe ED at the onset. As for its treatment, in case of an extremely high level of prolactin, simple administration of the PDE5 inhibitor is ineffective. When the prolactin level is reduced after surgery or medication, the symptom of ED can be improved and, in case of no obvious relief, administration of the PDE5 inhibitor can be followed, which may achieve satisfactory results.


TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression.
Chronic kidney disease (CKD) is associated with persistent low-grade inflammation and immunosuppression. In this study we tested the role of Toll-like receptor 4, the main receptor for endotoxin (LPS), in a mouse model of renal fibrosis and in a model of progressive CKD that better resembles the human disease. C3HeJ (TLR4 mutant) mice have a missense point mutation in the TLR4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR4 mutant mice developed less interstititial fibrosis in comparison to wild-type (WT) mice. Furthermore, 4 weeks after 5/6 nephrectomy with continuous low-dose angiotensin II infusion, C3HeOuJ (TLR4 WT) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR4 mutant mice were significantly protected from CKD progression. TLR4 WT mice also developed low-grade systemic inflammation, splenocyte apoptosis and increased expression of the immune inhibitory receptor PD-1 in the spleen, which were not observed in TLR4 mutant mice. In vitro, endotoxin (LPS) directly upregulated NLRP3 inflammasome expression in renal epithelial cells via TLR4. In summary, TLR4 contributes to renal fibrosis and CKD progression, at least in part, via inflammasome activation in renal epithelial cells, and may also participate in the dysregulated immune response that is associated with CKD.


Onset of decoherence: six-wave mixing measurements of vibrational decoherence on the excited electronic state of I2 in solid argon.
Pump-probe, four-wave, and six-wave mixing measurements of I2 isolated in solid argon are used to provide a clear experimental measure for the onset of vibrational quantum decoherence on the excited electronic state. The electronically resonant, six-wave mixing measurements bypass the rapid electronic dephasing, and measure the quantum cross-correlation between two packets launched on the B-state. The vibrational quantum coherence survives one period of motion, 400 fs, during which approximately 2000 cm(-1) of energy is transferred to the lattice. The decoherence occurs during the second cycle of motion, while classically coherent motion measured via pump-probe spectroscopy using the same electronic resonances continues for approximately 15 periods. This is contrasted with vibrational dephasing on the ground electronic surface, which lasts for 10(2) periods, as measured through time-resolved coherent anti-Stokes Raman scattering. The measurements and observables are discussed through time-circuit diagrams, and a mechanistic description of decoherence is derived through semiclassical analysis and simulations that reproduce the experiments.


Non-Conjugated Polymer Dots with Crosslink-Enhanced Emission in the Absence of Fluorophore Units.
A new type of fluorescent material is presented, which is called non-conjugated polymer dots (NCPDs). The NCPDs only possess sub-fluorophores (which are groups such as C=O, C=N, N=O) instead of typical conjugated fluorophore groups, and thus these materials should not have strong photoluminescence (PL) in the usual sense. Nevertheless, the PL of these sub-fluorophores can be enhanced by chemical crosslinking or physical immobilization of polymer chains, which is named the crosslink-enhanced emission (CEE) effect. The significant advances achieved by us and other groups on both experimental and theoretical aspects are discussed, and the covalent-bond CEE, rigidity-aggregated CEE, or supramolecular CEE in NCPDs is elaborated. Moreover, synthetic strategies, unique optical properties, and the promise of NCPDs in bio-related fields, such as bioimaging and drug delivery, are systematically discussed.


Adverse Events Associated With Bioabsorbable Nasal Implants: A MAUDE Database Analysis.
Bioabsorbable implants (eg, Latera) have recently been approved for addressing nasal valve collapse. The purpose of this study is to summarize adverse events and treatment sequelae associated with bioabsorbable nasal implants queried in the Manufacturer and User Facility Device Experience (MAUDE) database. Of the 26 device reports entered between March 2017 and April 2022, the most frequently reported complications included abscess (n = 13) and implant protrusion (n = 5). Other common symptoms reported greater than 1-year postimplantation included facial pain/discomfort (n = 3) and failure to absorb (n = 3). Management of adverse events included treatment with antibiotics (n = 9), steroid injections (n = 4), and explantation (n = 20). In 3 reports, adverse reactions required a biopsy of adjacent tissue for pathologic analysis. These findings suggest that further research is required to assess the potential long-term complications and optimize the management of bioabsorbable nasal implants. Furthermore, standardized reporting templates may improve the utility of the MAUDE database.


Is early response by (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography a predictor of long-term outcome in patients with metastatic colorectal cancer?
Identify in advance responder patients to chemotherapy in metastatic colorectal cancer (CRC) would allow prompt interruption of ineffective therapies in non-responder patients. Hence, predictive markers are sought in numerous trials to detect responder patients, including tumor shrinkage measured by imaging methods. Usually, Response Evaluation Criteria in Solid Tumors (RECIST) is used to evaluate tumor response in metastatic CRC, but these criteria are questionable with use of biological agents associated to chemotherapy. Our aim was correlate early metabolic response by (18)F-2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography ((18)FDG-PET-CT) with long-term outcome in metastatic CRC in first-line therapy. We prospectively evaluated 36 patients with metastatic CRC in first-line treatment with 5-fluorouracil, leucovorin (folinic acid), oxaliplatin (FOLFOX) or 5-fluorouracil, leucovorin (folinic acid), irinotecan (FOLFIRI) associated with cetuximab or bevacizumab. (18)FDG-PET-CT was performed at baseline and after two cycles of chemotherapy. The early metabolic response [standardized uptake value (SUV)] was measured to identify responder and non-responder patients and correlated with overall survival (OS) and progression-free survival (PFS). Median age was 58.5 years (range, 41-74 years). PFS was 15.5 months for responder and 13.3 months for non-responder (P=0.42), OS was 55.7 months for responder and not reached for non-responder. There was no correlation between delta-SUV and clinical and pathological variables analyzed. In the subgroup of patients who did not undergo resection of metastasis (45%), PFS was higher for responders (15.3×6.8 months, P=0.02). According to our findings, early response by (18)FDG-PET-CT was not a predictor of long-term outcome for patients with metastatic CRC treated in the first-line chemotherapy with a monoclonal antibody.


Cytological features of diffuse and circumscribed gliomas.
The current World Health Organization classification of gliomas is based on morphological, genetic, and molecular parameters. In this review, we intend to present the most relevant cytological features of these tumours, with a particular focus on their analysis during intraoperative studies. Rapid diagnosis is required in this context, and at present it is not possible to evaluate the genetic or molecular profile of a tumour intraoperatively. New terminology and diagnostic parameters have been introduced, but the essence of intraoperative recognition remains the same. The main challenge in astrocytoma IDH-mutant, grade 2 is recognising the tissue as neoplastic. Since glioma grades 3 and 4 are assigned based on histological and genetic variables that are not necessarily measurable on cytology, the term high-grade glioma is often used for intraoperative diagnosis. Oligodendroglioma, IDH-mutant and 1p/19q-codeleted shows peculiar cytological findings as well as the common subtypes of glioblastoma IDH-wildtype (giant cell, epithelioid, gliosarcoma and small cell). Many of the paediatric-type-diffuse gliomas have been described very recently and there are no cytological reports of proven cases. Finally, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, subependymal giant cell astrocytoma, chordoid glioma, and astroblastoma MN1-altered constitute the group of circumscribed astrocytic gliomas. They are remarkable entities that the pathologist must be able to recognise since most are low-grade neoplasms that can show atypical morphological features.


Intracavitary radiotherapy boosting for nasopharynx cancer.
Intracavitary radiotherapy is conceptually an attractive method of boosting dose to nasopharynx cancer whilst sparing sensitive normal tissues. A high dose rate (HDR) microselectron can be used to deliver a brachytherapy boost conveniently, safely, comfortably and effectively. Following external radiotherapy a single outpatient treatment has been given to patients using the remote afterloading system of sources placed in modified paediatric endotracheal tubes. This has been associated with good primary control and no evidence of serious morbidity in eight patients. The main limitation of this method is restriction of its utilization to small volume primary disease.


Prenatal diagnosis for methylmalonic acidemia and inborn errors of vitamin B12 metabolism and transport.
Vitamin B12 (cobalamin) is an essential cofactor for two enzymes: methionine synthase (MS), which requires methylcobalamin (MeCbl), and methylmalonyl-CoA mutase (MUT), which requires adenosylcobalamin (AdoCbl). A number of individually rare inborn errors of cobalamin metabolism are known and are distinguished by complementation analysis (mut, cblA-cblH). From 1984 to 2005, we have performed prenatal diagnosis for 117 high-risk pregnancies. We identified a total of 21 affected pregnancies (18%): cblA, 2/8; cblB, 0/5; cblC, 10/52; cblE, 2/3; cblF, 0/5; cblG, 0/5; transcobalamin deficiency, 0/2; methylmalonyl-CoA mutase (mut) deficiency, 7/30; and unclassified MMA, 0/7. Studies were performed on amniotic fluid, cultured chorionic villus cells (CCVC), cultured amniocytes (CA), or various combinations of these three types of sample. Analyses done include propionate and methyltetrahydrofolate incorporation into protein and cobalamin cofactor levels (CA: 92%, CCVC: 18%), amniotic fluid metabolite measurement either by gas chromatography/mass spectrometry (GC/MS) or by liquid chromatography-tandem mass spectrometry (LC-MS/MS) (49%), and direct mutation analysis (5%). There was one false negative CCVC result in a pregnancy at risk for cblC and one false positive CCVC in a pregnancy at risk for mutase deficiency. One unaffected pregnancy at risk for an unclassified form of MMA and another unaffected pregnancy at risk for cblC, had higher than control MMA amniotic fluid levels. Our experience suggests that prenatal diagnosis for these disorders should be done by application of two independent methods, and that CA studies appear more reliable than CCVC studies.


[A scheme for solution of hospital's data backup system].
In this paper, the implementation scheme for a hospital's data backup and recovery is introduced. It analyzes the goal of system design: to build a centralized, policy-based administration, automatic and high efficient data backup system.


Cotton remains from archeological sites in central coastal peru.
Cotton remains from four archeological sites in central coastal Peru, representing a time sequence from about 2500 to 1000 B.C., were compared with similar materials obtained from living wild and cultivated forms of Gossypium barbadense L. The comparison revealed that the archeological cotton samples were primitive forms of Gossypium barbadense, differing little from present-day wild forms of the same species. Although not the earliest cottons recorded for the New World, they appear to represent the earliest stages of cotton domestication yet recorded.


Myocardial Injury in Patients With Sepsis and Its Association With Long-Term Outcome.
Sepsis is frequently complicated by the release of cardiac troponin, but the clinical significance of this myocardial injury remains unclear. We studied the associations between troponin release during sepsis and 1-year outcomes. We enrolled consecutive patients with sepsis in 2 Dutch intensive care units between 2011 and 2013. Subjects with a clinically apparent cause of troponin release were excluded. High-sensitivity cardiac troponin I (hs-cTnI) concentration in plasma was measured daily during the first 4 intensive care unit days, and multivariable Cox regression analysis was used to model its association with 1-year mortality while adjusting for confounding. In addition, we studied cardiovascular morbidity occurring during the first year after hospital discharge. Among 1258 patients presenting with sepsis, 1124 (89%) were eligible for study inclusion. Hs-cTnI concentrations were elevated in 673 (60%) subjects on day 1, and 755 (67%) ever had elevated levels in the first 4 days. Cox regression analysis revealed that high hs-cTnI concentrations were associated with increased death rates during the first 14 days (adjusted hazard ratio, 1.72; 95% confidence interval, 1.14-2.59 and hazard ratio, 1.70; 95% confidence interval, 1.10-2.62 for hs-cTnI concentrations of 100-500 and >500 ng/L, respectively) but not thereafter. Furthermore, elevated hs-cTnI levels were associated with the development of cardiovascular disease among 200 hospital survivors who were analyzed for this end point (adjusted subdistribution hazard ratio, 1.25; 95% confidence interval, 1.04-1.50). Myocardial injury occurs in the majority of patients with sepsis and is independently associated with early-but not late-mortality, as well as postdischarge cardiovascular morbidity.


Potential of Mitochondria-Targeted Antioxidants to Prevent Oxidative Stress in Pancreatic β-cells.
Pancreatic β-cells are vulnerable to oxidative stress due to their low content of redox buffers, such as glutathione, but possess a rich content of thioredoxin, peroxiredoxin, and other proteins capable of redox relay, transferring redox signaling. Consequently, it may be predicted that cytosolic antioxidants could interfere with the cytosolic redox signaling and should not be recommended for any potential therapy. In contrast, mitochondrial matrix-targeted antioxidants could prevent the primary oxidative stress arising from the primary superoxide sources within the mitochondrial matrix, such as at the flavin (IF) and ubiquinone (IQ) sites of superoxide formation within respiratory chain complex I and the outer ubiquinone site (IIIQ) of complex III. Therefore, using time-resolved confocal fluorescence monitoring with MitoSOX Red, we investigated various effects of mitochondria-targeted antioxidants in model pancreatic β-cells (insulinoma INS-1E cells) and pancreatic islets. Both SkQ1 (a mitochondria-targeted plastoquinone) and a suppressor of complex III site Q electron leak (S3QEL) prevented superoxide production released to the mitochondrial matrix in INS-1E cells with stimulatory glucose, where SkQ1 also exhibited an antioxidant role for UCP2-silenced cells. SkQ1 acted similarly at nonstimulatory glucose but not in UCP2-silenced cells. Thus, UCP2 can facilitate the antioxidant mechanism based on SkQ1+ fatty acid anion- pairing. The elevated superoxide formation induced by antimycin A was largely prevented by S3QEL, and that induced by rotenone was decreased by SkQ1 and S3QEL and slightly by S1QEL, acting at complex I site Q. Similar results were obtained with the MitoB probe, for the LC-MS-based assessment of the 4 hr accumulation of reactive oxygen species within the mitochondrial matrix but for isolated pancreatic islets. For 2 hr INS-1E incubations, some samples were influenced by the cell death during the experiment. Due to the frequent dependency of antioxidant effects on metabolic modes, we suggest a potential use of mitochondria-targeted antioxidants for the treatment of prediabetic states after cautious nutrition-controlled tests. Their targeted delivery might eventually attenuate the vicious spiral leading to type 2 diabetes.


The neuromuscular blockade produced by pure alkaloid, mitragynine and methanol extract of kratom leaves (Mitragyna speciosa Korth.).
The effects of pure alkaloid, mitragynine and a methanolic extract of kratom leaves were investigated on neuromuscular junction and compound nerve action potential. Wistar rats were killed by cervical dislocation and decapitated. The phrenic nerve-hemidiaphragms, hemidiaphragms and sciatic nerve were isolated. Kratom methanolic extract present at 0.1-1 mg/mL and mitragynine (0.0156 mg/mL) decreased the muscle twitch on the isolated phrenic nerve-hemidiaphragm and hemidiaphragm preparation. Muscle relaxation caused by kratom extract (1 mg/mL) was greater than the effect of mitragynine. Pancuronium and succinylcholine potentiated the effect of kratom extract. It also had a direct relaxation effect on the hemidiaphragm muscle. The muscle relaxation caused by kratom extract was not antagonized by neostigmine, tetraethylammonium and calcium chloride. High concentrations of kratom extract (10-40 mg/mL) and mitragynine (2 mg/mL) blocked the nerve conduction, amplitude and duration of compound nerve action potential. The mechanism of action of kratom extract might not act as a competitive antagonist of acetylcholine yet its dominant effect was at the neuromuscular junction and not at the skeletal muscle or somatic nerve.


Extranuclear steroid receptors: nature and actions.
Rapid effects of steroid hormones result from the actions of specific receptors localized most often to the plasma membrane. Fast-acting membrane-initiated steroid signaling (MISS) leads to the modification of existing proteins and cell behaviors. Rapid steroid-triggered signaling through calcium, amine release, and kinase activation also impacts the regulation of gene expression by steroids, sometimes requiring integration with nuclear steroid receptor function. In this and other ways, the integration of all steroid actions in the cell coordinates outcomes such as cell fate, proliferation, differentiation, and migration. The nature of the receptors is of intense interest, and significant data suggest that extranuclear and nuclear steroid receptor pools are the same proteins. Insights regarding the structural determinants for membrane localization and function, as well as the nature of interactions with G proteins and other signaling molecules in confined areas of the membrane, have led to a fuller understanding of how steroid receptors effect rapid actions. Increasingly, the relevance of rapid signaling for the in vivo functions of steroid hormones has been established. Examples include steroid effects on reproductive organ development and function, cardiovascular responsiveness, and cancer biology. However, although great strides have been made, much remains to be understood concerning the integration of extranuclear and nuclear receptor functions to organ biology. In this review, we highlight the significant progress that has been made in these areas.


The preservation of good medicine is dependent on information.
BASIS FOR THE ARGUMENT. Virtually all physicians feel a growing loss of control in their private practices and a sense of disillusionment with today's medicine. In the good ole days of modern medicine, medicine was a profession and a physician had a special bond with his patient and his community. In a constructive sense, a physician had power which was used to practice good medicine and provided part of the basis for a satisfying practice. As modern medicine evolved, the complexity of the science and the cost of technology forced new, non-physician players into the process of providing patient care. Over time, costs seemed to become the predominant theme and medicine became a business. One fact is certain, that as a result of this process, physicians lost power. Less provable, but widely believed, is that patient care suffered. There is also a growing concern that clinical outcomes are less than optimal and that health care services are more costly than they need to be because of wide variations in the diagnostic and treatment processes.


Biliary tract emergencies.
Gallstones are responsible for the majority of biliary tract emergencies and will be the main focus of this article. Gallstones present with features related to the site of the calculi and are therefore considered separately. Cholecystolithiasis refers to gallstones confined to the gallbladder, whereas choledocholithiasis refers to gallstones within the common bile duct.


Maternal characteristics and immunization status of children in North Central of Nigeria.
Routine immunization coverage in Nigeria is one of the lowest national coverage rates in the world. The objective of this study was to compare the mother' characteristics and the child's Immunization status in some selected rural and urban communities in the North central part of Nigeria. A descriptive cross sectional study, using a multistage sampling technique to select 600 respondent women with an index child between 0-12 months. Mean age of rural respondents was 31.40±7.21 years and 32.72+6.77 years among urban respondents, though there was no statistically significant difference in age between the 2 locations (p-0.762). One hundred and ninetyseven (65.7%) and 241(80.3%) of rural and urban respondents respectively were aware of immunization, the difference was statistically significant (p-0.016). knowledge in urban areas was better than among rural respondents. There was statistically significant association between respondents age, employment status, mothers' educational status and the child's immunization status (P<0.05), while variables like parity, age at marriage, marital status, No of children, household income and place of index were not statistically associated with immunization status as P>0.05. More than half 179(59.7%) of rural and 207(69.0%) of urban had good practice of immunization though the difference was not statistically significant (p-0.165). The immunization coverage in urban community was better than that of the rural community. The result of this study has clearly indicated that mothers in Nigeria have improved on taking their children for immunization in both rural and urban area compared to previous reports.


Investigating the "Rule of W," a mnemonic for teaching on postoperative complications.
To identify the timing and relative frequency of common postoperative complications in a contemporary, diverse surgical population and develop a mnemonic for teaching and clinical decision support. We enrolled a cohort of general and vascular surgical patients undergoing elective, inpatient surgery in the American College of Surgeons National Surgical Quality Improvement Program database between 2005 and 2011. Index complications were noted by postoperative day (POD). Timing and incidence were compared within each day. Among 614,525 patients, 51,173 (9.88%) experienced the following index complications over 30 days: pneumonia (n = 5947), urinary tract infection (n = 9459), superficial surgical site infection (sSSI) (n = 20,460), deep/organ space surgical site infection (dSSI) infection (n = 11,847), venous thromboembolism (n = 4478), kidney injury (n = 2620), and myocardial infarction (n = 1813). Median time to complication differed significantly for index complications (p < 0.0001). On POD 0, the most common complication was myocardial infarction (incidence 4.26/10,000 patient days; 95% CI: 3.75-4.78). On POD 1 and 2, pneumonia was the most common complication, with peak incidence on POD 2 (20.36; 95% CI: 19.22-21.51). On POD 3, pneumonia (16.3; 95% CI: 15.27-17.33) and urinary tract infection (15.5; 95% CI: 14.49-16.51) were significantly more common than other complications. On POD 4, the most common complication was sSSI (16.24; 95% CI: 15.20-17.28). From POD 5 to POD 30, sSSI and dSSI were the 2 most common complications. Risk of venous thromboembolism declined only slightly through POD 30. We propose a mnemonic for postoperative complication timing and frequency, independent of fever, as follows: Waves (myocardial infarction), Wind (pneumonia), Water (urinary tract), Wound (sSSI and dSSI), and Walking (venous thromboembolism) in the order of likelihood.


Mirroring Tool: The Simplest Computer-Aided Simulation Technology?
The aims of this study were to present our experience in the use of the mirroring tool in computer-aided simulation (CAS) as well as to describe its diversified uses and indications systematically. Between 2006 and 2012, 144 patients underwent preoperative CAS with mirroring tool developed by our department called Accu-Navi System. Various mirroring methods were performed and classified systemically. The outcome was evaluated thru its performance intraoperatively and the results postoperatively. The optimal preoperative plans were achieved for all 144 patients using the mirroring tool. This provided the surgeon with accurate surgical information preoperatively and intraoperatively. There were 138 operations performed based on the preoperative plan. The duration of the operations was significantly shortened with improved surgical accuracy and safety. The mean discrepancy was confirmed to be less than 1.0 mm by comparing postoperative computed tomography with the preoperative plan. Postoperative esthetics improved remarkably along with patients' satisfaction without complications thru long-term follow-up evaluations. The mirroring tool with its many uses can be a valuable CAS procedure for craniofacial surgery.


Nitrogen metabolism of beef steers fed endophyte-free tall fescue hay: effects of ruminally protected methionine supplementation.
Level of nitrogen (N) intake and ruminally protected methionine supplementation were evaluated in eight Angus growing steers (initial BW 253+/-21 kg, final BW 296+/-21 kg) in a replicated 4+/-4 Latin square design. The steers were fed two endophyte-free tall fescue (Festuca arundinacea) hays that contained 2.2 (LO) or 2.8% (HI) of DM as N and were either supplemented or not with ruminally protected methionine (10 g metabolizable methionine/d). Diets were fed to provide adequate energy for 0.5 kg ADG and sufficient protein for maintenance (LO), or protein to support 0.5 kg ADG (HI). Following at least 14 d of adjustment, N balance was measured for 6 d. Isotopic urea was infused (15N15N-urea, 0.164 mmol urea N/h) via a jugular catheter for 56 h and urine was collected from 48 to 56 h to measure urea kinetics. Jugular blood was collected during the balance trial, and serum was analyzed for serum urea N (SUN). By design, daily N intake was greater (P < 0.05) for HI (112 g) than for LO (89 g). Compared with LO, steers when fed HI had greater (P < 0.05) daily DMI (4,217 vs 4,151 g), fecal N (34.4 vs 31.2 g), N digested (77.1 vs 57.7 g), urine N (48.3 vs 37.5 g), urine urea N excretion (34.6 vs 24.8 g), and N retained (29.8 vs 21.1 g). When fed HI steers also had higher (P < 0.05) urine urea N concentration (276 vs 219 mM), SUN (8.7 vs 6.7 mM), N digestibility (69.1 vs 64.9%), percentage of urinary N present as urea (71.5 vs 66.7%, P < 0.053), and rate of urea N production (59.6 vs 49.2 g/d) but lower (P < 0.05) percentage of urea N produced that was returned to the ornithine cycle (15.03 vs 19.2 1%) than when fed LO. Methionine supplementation decreased daily urine N (41.2 vs 44.6 g, P = 0.10) and increased both the amount of N retained daily (27.9 vs 23.7 g, P < 0.089) and the percentage of N digested that was retained (40.4 vs 34.6%, P < 0.094). In summary, supplemental methionine met a specific dietary limitation by increasing the amount of digested N that was retained by the steers.


Silver nanoparticle monolayer-to-bilayer transition at the air/water interface as studied by the GISAXS technique: application of a new paracrystal model.
An original diffraction model for the analysis of grazing-incidence small-angle X-ray scattering (GISAXS) from the nanoparticle Langmuir films was developed. This model relies on the concept of the 2D hexagonal paracrystal and employs the distorted-wave Born approximation that is relevant for GISAXS measurements at the air/water interface when the angle of incidence is close to the critical value. The model comprises the cases of the close-packed nanoparticle monolayer and bilayer with the AB-type layer stacking. In this way, both the lateral (along the interface) and vertical (normal to the interface) correlations of the nanoparticle positions can be analyzed. The model was applied to an in situ GISAXS study of the formation of a silver nanoparticle Langmuir film during compression at the air/water interface in the Langmuir-Blodgett trough. Spherical nanoparticles of 5.8 ± 0.6 nm diameter were employed. Different compression stages starting from the submonolayer up to the monolayer collapse via bilayer formation were analyzed in terms of the mean lateral interparticle distance, degree of paracrystal disorder, interlayer distance, vertical disorder, and layer-stacking type in the bilayer as well as the ratio between the monolayer and bilayer coverage in the final film. The model developed is applicable to any nanoparticle Langmuir film formed at the air/liquid interface to extract structural parameters on the nanoscale. The particular results obtained have direct implications on the preparation of silver plasmonic templates with "hot spots" for surface-enhanced Raman scattering.


Computed tomography scanning findings associated with rapid expansion of abdominal aortic aneurysms.
Early repair of abdominal aortic aneurysms (AAA) is particularly appropriate for those that are most likely to expand. Our aim was to define features on computed tomography (CT) scanning associated with subsequent rapid aneurysm expansion. We reviewed CT scans of 80 patients with AAA (> 3.0 cm) who underwent CT scanning of the abdomen and pelvis two times, at least 6 months apart, between 1986 and 1992. The aneurysms initially measured 4.4 +/- 0.6 cm, and the mean interval between obtaining scans was 22 +/- 12 months. Clinical variables assessed included age, sex, medical risk factors, underlying cardiovascular and pulmonary diseases, and administration of beta blockers and lipid-lowering agents. Computer-aided measurements on each CT scan section included the maximal and minimal diameters and area of the aneurysm. Dimensions of the luminal thrombus and the arc of aneurysm wall covered by thrombus (TARC). Maximal aneurysm dimensions were related to juxtarenal aortic and second lumbar vertebral body dimensions. Mean aneurysm expansion was 0.26 +/- 0.25 cm/yr. CT scanning variables that correlated significantly with rate of expansion included the mean TARC (r = 0.43, p < 0.001), thrombus volume fraction (r = 0.37, p < 0.001), TARC on the largest aneurysm cross section (r = 0.34, p < 0.01), and thrombus area fraction (r = 0.30, p < 0.01). Rapid expansion (> 0.5 cm/yr) occurred in 15 (19%) aneurysms. The two predictors for rapid expansion on logistic regression analysis were mean TARC (p < 0.005) and the presence of carotid artery disease (p < 0.05). An increased AAA thrombus load is associated with a higher likelihood of rapid expansion and should weigh in favor of early surgical repair.


Structural approaches to the study of oligosaccharides in glycoprotein quality control.
High-mannose-type oligosaccharides have been shown to play important roles in protein quality control. Several intracellular proteins, such as lectins, chaperones and glycan-processing enzymes, are involved in this process. These include calnexin/calreticulin, UDP-glucose:glycoprotein glucosyltransferase (UGGT), cargo receptors (such as VIP36 and ERGIC-53), mannosidase-like proteins (e.g. EDEM and Htm1p) and ubiquitin ligase (Fbs). They are thought to recognize high-mannose-type glycans with subtly different structures, although the precise specificities are yet to be clarified. In order to gain a clear understanding of these protein-carbohydrate interactions, comprehensive synthesis of high-mannose-type glycans was conducted. In addition, two approaches to the synthesis of artificial glycoproteins with homogeneous oligosaccharides were investigated. Furthermore, a novel substrate of UGGT was discovered.


The cell biology of alpha-synuclein: a sticky problem?
Parkinson's disease (PD) is the most common neurodegenerative motor disorder, marked by chronic progressive loss of neurons in the substantia nigra, thereby damaging purposeful control of movement. For decades, it was believed that PD was caused solely by environmental causes. However, the discovery of genetic factors involved in PD has revolutionized our attempts to understand the disease's pathology. PD now appears to be more polygenetic than previously thought and is most likely caused by a complex interaction of genetic risks and environmental exposures. The first gene found to be mutated in PD encodes for the presynaptic protein alpha-synuclein, which is also a major component of Lewy bodies and Lewy neurites, the neuropathological hallmarks of the disease. While these findings provide a classic example of how rare genetic mutations in disease can point to important pathways in idiopathic disease pathologies, much of the study of alpha-synuclein has focused on understanding how this protein undergoes the transition from an unfolded monomer to amorphous aggregates or Lewy body-like filaments rather than addressing what its fundamental function might be. Since alterations in synuclein function may predispose to the disease pathology of PD, regardless of the presence of genetic mutations, a more thorough understanding of the cellular regulation and function of alpha-synuclein may be of crucial importance to our understanding of this degenerating disorder.


Investigation of an outbreak of Salmonella enteritidis gastroenteritis associated with consumption of eggs in a restaurant chain in Maryland.
Salmonella enteritidis ser. enteritidis was isolated from patrons and employees of three restaurants in a restaurant chain in Maryland during August and September 1985. Isolates from all three restaurants had identical plasmid profiles; this profile was present in 13 of 40 randomly selected S. enteritidis isolates received by the Maryland state health department laboratory during a comparable time period. The outbreak in one restaurant resulted in at least 71 illnesses, with 17 persons known to have been hospitalized. Scrambled eggs served on a "breakfast bar" were implicated as the vehicle of transmission in this restaurant, with eggs a possible vehicle in another of the three restaurants. The data point out the risks associated with improper handling of eggs in food service establishments, provide further evidence for the observed association between S. enteritidis and eggs in the northeastern United States, and demonstrate the utility of plasmid analysis in investigation of outbreaks involving common Salmonella serotypes.


Group dynamic practices applied to health education.
The application of group dynamic techniques as pedagogical tools transforms the classroom into a laboratory for living. In such an environment, concepts relative to man's behavior are not only explained but learned experimentally through the interactive process. Through utilization of this model, the health educator can provide an opportunity for different groups at school to learn about each other's values as well as appreciate their differences. Coping with peer pressure, shyness, others' feelings and defense mechanisms become a part of the learning process. The difficulties of responsible decision making can be periodically examined. Personal expression by a wide range of students is at best difficult to accomplish, and the use of materials and media as motivational devices can not be viewed as ends in themselves. They need to be utilized with regard to a functional analysis of the group dynamic process. Such an analysis should include the teacher's own biases, communication patterns, student roles, reasons for resistance and awareness of sub groups. After making a diagnosis of the system, the teacher is then in a position to orchestrate class behavior through a variety of strategic moves. Such moves include recreating communication channels, controlling stress levels, manipulating seating and modeling desirable behaviors. By incorporating aspects of therapeutic techniques into his/her teaching style, the teacher must not only be knowledgeable but astute and inventive as well.


Lymphocyte predominant Hodgkin's disease nodular subtype with coexistent "large cell lymphoma". Histological progression or composite malignancy?
Nodular lymphocyte predominant (NLP) Hodgkin's disease (NLP HD) has been recently suggested to be of B-cell derivation on the basis of phenotypic and morphologic findings. Consistent with this view, there are sporadic case reports of coexisting NLP HD and large cell lymphoma (LCL). We describe a compilation of seven unique cases of NLP HD selected from the NIH case consultation files in which lymphohistiocytic mononuclear variant cells (L&H) became clustered into increasingly large aggregates. In areas of the same tumor mass, large confluent sheets of these cells resembled LCL. In contrast to what would be expected for LCL, all patients had localized disease clinically, and six of seven achieved long-term disease-free survival following radiation therapy or chemotherapy (two cases) for HD. None of the patients developed disseminated LCL. Also notable was a high frequency of axillary lymph node involvement (five of seven) and the high rate of occurrence in blacks (six of seven). Immunophenotypic (in two cases) and molecular genetic analysis (in one case) was suggestive of B-cell derivation for the proliferating cells. These findings also raise the possibility that some so-called large cell lymphomas may actually represent histologically progressed NLP HD, and that such cases might be associated with a favorable prognosis comparable to that seen in NLP HD.


Puroindolines: the molecular genetic basis of wheat grain hardness.
The variation in grain hardness is the single most important trait that determines end-use quality of wheat. Grain texture classification is based primarily on either the resistance of kernels to crushing or the particle size distribution of ground grain or flour. Recently, the molecular genetic basis of grain hardness has become known, and it is the focus of this review. The puroindoline proteins a and b form the molecular basis of wheat grain hardness or texture. When both puroindolines are in their 'functional' wild state, grain texture is soft. When either one of the puroindolines is absent or altered by mutation, then the result is hard texture. In the case of durum wheat which lacks puroindolines, the texture is very hard. Puroindolines represent the molecular-genetic basis of the Hardness locus on chromosome 5DS and the soft (Ha) and hard (ha) alleles present in hexaploid bread wheat varieties. To date, seven discrete hardness alleles have been described for wheat. All involve puroindoline a or b and have been designated Pina-D1b and Pinb-D1b through Pinb-D1g. A direct role of a related protein, grain softness protein (as currently defined), in wheat grain texture has yet to be demonstrated.


A 30-year experience with bone graft epiphysiodesis in the treatment of slipped capital femoral epiphysis.
A retrospective review was carried out of all cases treated by bone graft epiphysiodesis for slipped capital femoral epiphysis at Children's Hospital Medical Center of Akron between the years 1950 and 1980. Only those cases followed for a minimum of 1 year following treatment were included in the review and evaluated as to their status of avascular necrosis, acute cartilage necrosis, or other complications attendant to the surgical approach. One hundred seventy-six patients representing 207 hips underwent bone graft epiphysiodesis over this 30-year period. One hundred fifty-nine patients representing 185 hips were followed a minimum of 1 year and were included in this study. There were 25 cases of acute slipping representing 26 hips and 134 patients representing 159 hips involved with the chronic slipping process. In the acute group of patients representing 26 hips, there were two cases of avascular necrosis and one case of acute cartilage necrosis. In the chronic group of 159 hips, there were four cases of reslipping, one due to graft resorption, one due to placement of the graft short the growth plate, and two that went on to acute slipping. All cases were salvaged with good results. There was one case of avascular necrosis in the chronic group; not a single case of acute cartilage necrosis was encountered. Owing to the rapid nature of growth plate closure following bone graft epiphysiodesis, the avoidance of hardware removal or pin penetration, and the extremely low incidence of overall complications, we suggest that bone graft epiphysiodesis is at least as good as multiple pin fixation in the treatment of slipped capital femoral epiphysis.


[Operative management of spontaneous kidney transplant rupture. Personal experiences and literature review].
Spontaneous rupture of the cadaver kidney is not rare in the early post-transplant period. In the literature the rupture complication rate varies between 0.3% and 8.5%. in our series 4.2% (12 of 285) of transplanted kidneys ruptured spontaneously. All transplant ruptures occurred as an early complication within 6 weeks postoperatively in the clinical setting of oliguria. In 8 of 12 patients we tried to preserve the graft by covering it with dehydrated solvent-dried human dura that is then sutured in place. In these cases surgical repair resulted in diuresis and restoration of normal graft function with long-term survival. This study emphasizes the possibility and necessity of conservation and repair of the ruptured allograft.


Immunosurveillance and survivin-specific T-cell immunity in children with high-risk neuroblastoma.
Tumor immunosurveillance influences oncogenesis and tumor growth, but it remains controversial whether clinical failure of immunosurveillance is a result of lymphocyte dysfunction or tumor escape. In this study, our goal was to characterize the physiology of tumor immunosurveillance in children with high-risk neuroblastoma (HR-NBL). Immunohistopathologic studies were carried out on 26 tumor samples from a cohort of HR-NBL patients diagnosed at Children's Hospital of Philadelphia for the 2-year period from May 2003 to May 2005. Blood from nine HLA-A2+ patients in this cohort was analyzed for T cells specific for the antiapoptotic protein survivin. Survivin protein was expressed by 26 of 26 tumors. In HLA-A2+ patients, circulating cytotoxic T lymphocytes (CTLs) specific for survivin were detected by peptide/major histocompatibility complex tetramer analysis in the blood of eight of nine children with HR-NBL at the time of diagnosis. Rather than being selectively rendered anergic in vivo, circulating survivin-specific CTLs were highly functional as shown by cytotoxicity and interferon gamma enzyme-linked immunospot assays in six of nine patients. Survivin-specific CD107a mobilization by T cells was found in five of five patients. By immunohistochemistry, tumor-infiltrating T cells were few or absent in 26 of 26 tumors. Children with HR-NBL harbor robust cellular immune responses to the universal tumor antigen survivin at the time of diagnosis, but intratumoral T cells are strikingly rare, suggesting a failure of cellular immunosurveillance. Efforts to develop novel therapies that increase T-cell trafficking into tumor nests are warranted.


Information-criterion based selection of models for community noise annoyance.
Statistical evidence for various models relating day-night sound level (DNL) to community noise annoyance is assessed with the Akaike information criterion. In particular, community-specific adjustments such as the community tolerance level (CTL, the DNL at which 50% of survey respondents are highly annoyed) and community tolerance spread (CTS, the difference between the DNL at which 90% and 10% are highly annoyed) are considered. The results strongly support models characterizing annoyance on a community-by-community basis, rather than with complete pooling and analysis of all available surveys. The most likely model was found to be a 2-parameter logistic model, with CTL and CTS fit independently to survey data from each community.


Effects of diabetes and difluoromethylornithine treatment on hyperplasia, activity of MAP-kinase, and activity and association with cyclin B of p34cdc2 kinase in rat jejunal mucosa.
The different signal transduction pathways of rapidly proliferating cells of the intestine are not clearly understood. We report here a possible signaling pathway that involves regulation of activity of two closely related kinases, MAP-K (mitogen-activated protein kinase) and p34cdc2 kinase, during hyperplasia of diabetic jejunal mucosa. Our aim was to investigate the activity and phosphorylation of MAP-K and activity and association of p34cdc2 kinase with cyclin B during diabetes-induced jejunal mucosal hyperplasia in vivo. We studied untreated and difluoromethylornithine (DFMO) treated control rats and rats with streptozotocin-induced type I diabetes. Assays were done 10 days after the induction of diabetes. In diabetic rats there was jejunal hyperplasia as indicated by increases in the jejunal mucosal weight/cm and DNA content as well as increased activities of MAP-K and p34cdc2 kinase and association of the latter with cyclin B as compared to corresponding values in control rats. Administration of DFMO, an irreversible inhibitor of the proliferation-associated enzyme ornithine decarboxylase (ODC), prevented diabetes-I induced jejunal hyperplasia and decreased all of the above enzymic parameters in both diabetic and control rats. In our previous in vivo study, DFMO administration also blocked diabetic jejunal hyperplasia and in addition decreased ornithine decarboxylase and tyrosine kinase activities jejunal and tyrosine phosphorylation of proteins. Thus the jejunal mucosal hyperplasia found in diabetes appears to involve activation of signal transduction pathways involving tyrosine kinases, MAP-K, p34cdc2 kinase, and cyclin B.