Treatment intensification using long-acting insulin -predictors of future basal insulin supported oral therapy in the DIVE registry.
In patients with type-2 diabetes receiving oral antidiabetic drugs (OADs), the addition of insulin is frequently required to achieve sufficient control over blood glucose levels. It is, however, difficult to predict if, when and in which patients insulin therapy will be needed. We aimed to identify patient related variables associated with the addition of basal insulin to oral therapy resulting in a basal supported oral therapy (BOT). DIVE (DIabetes Versorgungs-Evaluation) is a prospective, observational, multi-centre diabetes registry established in Germany in 2011. For the present explorative analysis, 31,008 patients with type-2 diabetes prescribed at least one OAD were included. Patients who had previously received insulin and those over 90 years old were excluded. The event of interest was defined as the initiation of BOT during the observational period. Cause-specific Cox proportional hazards models based on a competing risk framework were applied for risk quantification. Multivariable adjusted hazard ratios demonstrated that longer diabetes duration, higher BMI, poorer glycaemic control, documentation of any micro- or macrovascular comorbidity, the presence of concomitant non-antidiabetic pharmacotherapies, and greater numbers of prescribed OADs increased the likelihood of BOT initiation. On the other hand BOT initiation was less likely in patients with older age and female gender. Analysing the likelihood of OAD termination without initiation of BOT provided supportive evidence for the variables predictive of BOT initiation. Analysis of the DIVE registry has resulted in the identification of a number of factors that may be predictive for the initiation of BOT for type-2 diabetes patients initially prescribed one or more OADs. Poor glycaemic control, the presence of vascular comorbidities and concomitant medications, and a greater number of OADs were all detected to increase the risk of a switch to BOT. Female gender and younger age showed protective properties. The close monitoring of patients displaying these characteristics may help to identify individuals who might benefit from early addition of insulin therapy to their oral treatment regimen.


Surgical outcome of the endoscopic endonasal approach for non-functioning giant pituitary adenoma.
Pituitary adenomas with extensive suprasellar extension are a therapeutic challenge. The efficacy and safety of the endoscopic endonasal approach for non-functioning giant pituitary adenoma was evaluated retrospectively. A total of 43 consecutive patients with pituitary adenomas with a suprasellar extension of >20mm underwent tumor resection with a purely endoscopic endonasal approach, and their surgical outcomes were analyzed. At surgery, irrespective of the size and shape of the adenoma, every effort was made to perform intracapsular resection under direct visual control using an angled-lens endoscope. Gross total removal was achieved in 20 out of 43 patients. Postoperatively, 42 patients showed varying improvement of both visual field defects and impaired visual acuity. In two patients who presented with gait disturbance and cognitive dysfunction due to obstructive hydrocephalus, these symptoms were completely resolved. There were no serious operative complications. The results indicate that intracapsular resection via the endoscopic approach can be a safe and effective treatment for giant pituitary adenomas.


Effect of derivatives of chrysophanol, a new type of potential antitumor agents of anthraquinone family, on growth and cell cycle of L1210 leukemic cells.
The new C-methyl modified derivatives of the anthraquinones chrysophanol and emodin, recently synthesized by us, are potentially bifunctional agents having the ability to intercalate to nucleic acids and also having alkylating properties. Two of these compounds, namely 3-(N,N-bis(2-chloroethyl)-amino)methyl-1,8-dihydroxy-9,10-anthraquinone (Compound 31.662) and its 1,8-di-O-methylated analog (Compound 31.655) have been presently tested on murine leukemic L1210 cells in vitro with respect to their cell cycle specificity. During the initial 24 h of treatment the cytostatic effects of the drugs predominated, manifesting as suppression of cell progression through S (especially through the early portion of S phase) and G2. After 24 h, the cytotoxic effects became apparent, and there was also the appearance of cells with doubled DNA content suggestive of either endoreduplication or impairment of cytokinesis; these cells at higher ploidy level were progressing through S and G2. The observed effects were time- and dose-dependent, occurring at 0.1-0.4 micrograms/ml concentration of 31.662 and 2.0-10.0 micrograms/ml of its methylated analog, either during continuous- or after a 4-h pulse-treatment. Modulation of the cell cycle by the studied drugs is similar to that generally caused by intercalators as well as alkylating agents. However, because no positive evidence of intercalation of the studied drugs to nucleic acids was found, it is possible that alkylation of DNA or other cell constituents may be the primary lesion(s) leading to perturbation of the cell cycle.


Proacrosin activation and acrosin release during the guinea pig acrosome reaction.
The kinetics of proacrosin activation and release from guinea pig spermatozoa during the nonsynchronous acrosome reaction were studied. Epididymal spermatozoa were incubated at 37 degrees C in a defined medium (pH 7.8) containing 1.7 mM Ca2+. After 195 min, 78% of the motile spermatozoa had undergone the acrosome reaction as determined by light microscopy. Acrosin and proacrosin levels in the spermatozoa and medium were measured at the beginning of the incubation period. Most of the total acrosin activity (78%) was associated with the spermatozoa, of which greater than 90% was in the form of proacrosin. Proacrosin represented a small, stable fraction (23%) of the total acrosin in the medium; it did not activate to acrosin while in the medium. After 195 min, a decrease in sperm-associated total acrosin (42%; p less than 0.05) was accompanied by an increase in the total acrosin level in the medium (115%; P less than 0.05). No change in the relative proacrosin content (percent of total acrosin) was evident in either medium or spermatozoa. Additional experiments quantified acrosin and proacrosin during the progression of the acrosome reaction. Both the loss of sperm-associated total acrosin and the increase in total acrosin levels in the medium were highly correlated with the fraction of acrosome-reacted spermatozoa (r = 0.954 and 0.922, respectively; P less than 0.001). However, the rate of acrosin appearance in the medium was only 60% (P less than 0.001) of the rate of acrosin loss from the spermatozoa. The fractional proacrosin content of spermatozoa (94%) and medium (31%) remained unchanged during the acrosome reaction (r = 0.15 and 0.30, respectively; P greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)


Stem cell-derived erythroid cells mediate long-term systemic protein delivery.
We demonstrate here the capacity of erythroid cells to mediate long-term, systemic and therapeutic protein delivery in vivo. By targeting human factor IX (hFIX) expression to late-stage erythropoiesis, we achieve long-term hFIX secretion at levels significantly higher (>tenfold) than those obtained with an archetypal ubiquitous promoter in a mouse model of hemophilia B. Erythroid cell-derived hFIX is biologically active, resulting in phenotypic correction of the bleeding disorder. In addition to achieving high expression levels and resistance to transcriptional silencing, red cell-mediated protein delivery offers multiple advantages including immune tolerance induction, reduction of the risk of insertional oncogenesis and relative ease of application by either engrafting transduced hematopoietic stem cells or transfusing ex vivo-generated, stem cell-derived erythroid cells.


Kernel principal components based cascade forest towards disease identification with human microbiota.
Numerous pieces of clinical evidence have shown that many phenotypic traits of human disease are related to their gut microbiome, i.e., inflammation, obesity, HIV, and diabetes. Through supervised classification, it is feasible to determine the human disease states by revealing the intestinal microbiota compositional information. However, the abundance matrix of microbiome data is so sparse, an interpretable deep model is crucial to further represent and mine the data for expansion, such as the deep forest model. What's more, overfitting can still exist in the original deep forest model when dealing with such "large p, small n" biology data. Feature reduction is considered to improve the ensemble forest model especially towards the disease identification in the human microbiota. In this work, we propose the kernel principal components based cascade forest method, so-called KPCCF, to classify the disease states of patients by using taxonomic profiles of the microbiome at the family level. In detail, the kernel principal components analysis method is first used to reduce the original dimension of human microbiota datasets. Besides, the processed data is fed into the cascade forest to preliminarily discriminate against the disease state of the samples. The proposed KPCCF algorithm can represent the small-scale and high-dimension human microbiota datasets with the sparse feature matrix. Systematic comparison experiments demonstrate that our method consistently outperforms the state-of-the-art methods with the comparative study on 4 datasets. Despite sharing some common characteristics, a one-size-fits-all solution does not exist in any space. The traditional depth model has limitations in the biological application of the unbalanced scale between small samples and high dimensions. KPCCF distinguishes from the standard deep forest model for its excellent performance in the microbiota field. Additionally, compared to other dimensionality reduction methods, the kernel principal components analysis method is more suitable for microbiota datasets.


Uterine tumor resembling ovarian sex-cord tumor: case report and review of the literature.
We report the clinicopathological characteristics, immunohistochemical features, ultrastructure, tissue source, differential diagnosis, treatment, and prognosis of a patient with a uterine tumor resembling ovarian sex-cord tumor (UTROSCT). A 40-year-old woman had a uterine myoma with enlargement for 2.5 years. An ultrasound examination showed a mixed echogenic mass at the posterior wall of the uterus and a dark cyst in the right adnexal area, which suggested a suspected uterine myoma with liquefaction and a suspected chocolate cyst. The patient underwent transabdominal tumor resection with removal of the right adnexal mass. Through postoperative pathological examination, the patient was diagnosed with UTROSCT. No recurrence was observed after a follow-up of 1 year. Although UTROSCT is usually benign, it can relapse or metastasize, and patients with UTROSCT need comprehensive diagnosis and treatment.


[New aspects of compression therapy].
In this review article the mechanisms of action of compression therapy are summarized and a survey of materials is presented together with some practical advice how and when these different devices should be applied. Some new experimental findings regarding the optimal dosage (= compression pressure) concerning an improvement of venous hemodynamics and a reduction of oedema are discussed. It is shown, that stiff, non-yielding material applied with adequate pressure provides hemodynamically superior effects compared to elastic material and that relatively low pressures reduce oedema. Compression over the calf is more important to increase the calf pump function compared to graduated compression. In patients with mixed, arterial-venous ulcers and an ABPI over 0.6 inelastic bandages not exceeding a sub-bandage pressure of 40 mmHg may increase the arterial flow and improve venous pumping function.


The cochlear ear horn: geometric origin of tonotopic variations in auditory signal processing.
While separating sounds into frequency components and subsequently converting them into patterns of neural firing, the mammalian cochlea processes signal components in ways that depend strongly on frequency. Indeed, both the temporal structure of the response to transient stimuli and the sharpness of frequency tuning differ dramatically between the apical and basal (i.e., the low- and high-frequency) regions of the cochlea. Although the mechanisms that give rise to these pronounced differences remain incompletely understood, they are generally attributed to tonotopic variations in the constituent hair cells or cytoarchitecture of the organ of Corti. As counterpoint to this view, we present a general acoustic treatment of the horn-like geometry of the cochlea, accompanied by a simple 3-D model to elucidate the theoretical predictions. We show that the main apical/basal functional differences can be accounted for by the known spatial gradients of cochlear dimensions, without the need to invoke mechanical specializations of the sensory tissue. Furthermore, our analysis demonstrates that through its functional resemblance to an ear horn (aka ear trumpet), the geometry of the cochlear duct manifests tapering symmetry, a felicitous design principle that may have evolved not only to aid the analysis of natural sounds but to enhance the sensitivity of hearing.


Detection of foot-and-mouth disease virus in nasal swabs of asymptomatic cattle by RT-PCR within 24 hours.
A method for extracting RNA from animal-derived materials that provides foot-and-mouth disease viral template suitable for Tth polymerase-dependent synthesis of cDNA and subsequent PCR is described. Viral genomes were detected in less than 24 h. Nasal swabs that can be easily and repeatedly collected, proved suitable for virus detection by PCR, even during the asymptomatic stages of infection.


Phototherapy treatment of psoriasis today.
The use of the various forms of phototherapy remains an essential treatment option for psoriasis vulgaris. Expertise concerning the mechanisms involved with the actions of therapeutic ultraviolet light and the proper delivery of office-based treatments resides within the specialty of dermatology. New therapies for the treatment of moderate to severe psoriasis will soon become available which have specific actions on the cutaneous immune system. A better understanding of the known mechanisms of action for ultraviolet light therapy makes it appropriate to include this area of treatment with new biologic agents. Photochemotherapy and various forms for delivery of narrow band ultraviolet B can be used as treatments, either as monotherapy or in combination with other agents, to effectively treat moderate and severe psoriasis.


Parameters of optic nerve electrical stimulation affecting neuroprotection of axotomized retinal ganglion cells in adult rats.
We previously showed the enhancement of survival of retinal ganglion cells (RGCs) by electrical stimulation (ES) of the optic nerve (ON) stump in adult rats. To elucidate the mechanisms underlying the survival enhancement, we determined whether the neuroprotective effect of ES is affected by the following parameters: stimulation time, frequency of current pulses and starting of ES. ES for 10min immediately after ON transection was not effective in increasing the number of surviving RGCs 7 days after the transection, but that for 30min was effective. ES at 20Hz was the most effective, when applied just after axotomy. When the starting of ES to the ON was shifted either 3h after or 4h before the axotomy, the neuroprotective effect of ES was not observed. These results suggest that the electrical activation of RGCs and/or the transected ON interfere with early events after axotomy that leads to RGC death.


Fibres of intermediate type 1C and 2C are found continuously in mdx soleus muscle up to 52 weeks.
The mdx mutant is a murine homologous model of Duchenne muscular dystrophy (DMD). Fibre types determined by the myosin-ATPase technique in soleus muscles were compared in C57BL/10 control and mdx mice from 3 to 52 weeks of age. The control strain continuously presented 70% of type 2 fibres whereas the mdx strain showed an increase to 80% at 6 weeks and a subsequent decline. In mdx muscles, necrosis which begins at 3 weeks of age did not affect specifically one type of fibre. Type grouping was never observed when muscle regeneration occurred. Fibres of intermediate type (1C and 2C) were found continuously up to 52 weeks of age in the mdx mutant. The foci of small immature regenerating fibres were of type 2C but never 1C. A few mature fibres were either of type 2C or 1C. We suggest that the presence of intermediate type fibres could result from the co-expression of type 1 and 2 myosin heavy chains, indicating a transition from type 2 to type 1 in regenerating fibres.


Effect of iron overload on spontaneous and xenobiotic-induced lipid peroxidation in vivo.
To study the effect of iron-overload on hepatic lipid peroxidation, two rat models of haemochromatosis were employed: in the first model resembling secondary haemochromatosis, repeated i.p. injections with Fe-dextran led to an accumulation of Fe in Kupffer cells, while in the second model resembling hereditary haemochromatosis, iron was located mainly in periportal hepatocytes after feeding on a diet containing 3.5% Fe-fumarate for 3 weeks. In both models, total hepatic iron content was elevated four- to fivefold over controls. In vivo lipid peroxidation (ethane exhalation) was enhanced only in the second model, indicating that the hepatocytes are the main targets of Fe-induced lipid peroxidation. Low hepatotoxicity was observed in the second model. Additional treatment of the rats with hepatotoxic agents led to different results: with ethanol and bromobenzene, lipid peroxidation was only evident in both models of iron-overload, while paracetamol-induced lipid peroxidation was seen only in Fe-fumarate-fed rats. CCl4-induced lipid peroxidation was strongly enhanced in both models of haemochromatosis. Hepatotoxicity was enhanced by iron overload only in the case of CCl4-treated, Fe-fumarate-fed rats. The activities of phase I and phase II enzymes of xenobiotic metabolism were not markedly altered in livers of iron-overloaded rats. This implies that neither the bioactivation nor the detoxification of the agents studied were affected in experimental haemochromatosis.


gamma-Butyrobetaine hydroxylase and the protective role of glutathione peroxidase.
The selenoenzyme glutathione peroxidase in the presence of GSH effectively replaced catalase in the in vitro assay for gamma-butyrobetaine hydroxylase. Quantitatively, glutathione peroxidase was an order of magnitude more efficient than catalase, with maximal activity at less than 0.1 microM glutathione peroxidase in a standard reaction. Glutathione peroxidase prevented the loss of gamma-butyrobetaine hydroxylase during preliminary incubation with ferrous ions but without other substrates as well as in the course of the reaction. Regardless of whether glutathione peroxidase or catalase was present in the assay, the ascorbate concentrations needed to achieve half-maximal rates were similar (about 1 mM). Phosphate stimulated the rate of L-carnitine synthesis. Ferrous ion saturation indicated a pronounced effect of phosphate on the maximal velocity of the enzyme-catalyzed reaction, but its mechanism of action remains to be elucidated. Based on the subcellular distribution of gamma-butyrobetaine hydroxylase, catalase, and glutathione peroxidase, the role of glutathione peroxidase assumes importance. However, initial studies indicated that the assayable activity of liver gamma-butyrobetaine hydroxylase and L-carnitine concentrations in liver, blood plasma, and muscle were not significantly altered in selenium-deficient rats.


Movement artefact removal from NIRS signal using multi-channel IMU data.
The non-invasive nature of near-infrared spectroscopy (NIRS) makes it a widely accepted method for blood oxygenation measurement in various parts of the human body. One of the main challenges in this method lies in the successful removal of movement artefacts in the detected signal. In this respect, multi-channel inertia measurement unit (IMU) containing accelerometer, gyroscope and magnetometer can be used for better modelling of movement artefact than using accelerometer only, which as a result, movement artefact can be more accurately removed. A wearable two-channel continuous wave NIRS system, incorporating an IMU sensor which contain accelerometer, gyroscope and magnetometer in it, was developed to record NIRS signal along with the simultaneous recording of movement artefacts related signal using the IMU. Four healthy subjects volunteered in the recording of the NIRS signals. During the recording from the first two subject, movement artefacts were simulated in one of the NIRS channels by tapping the photodiode sensor nearby. The corresponding IMU data for the simulated movement artefacts were used to estimate the artefacts in the corrupted signal by autoregressive with exogenous input method and subtracted from the corrupted signal to remove the artefacts in the NIRS signal. Signal-to-noise ratio (SNR) improvement was used to evaluate the performance of the movement artefacts removal process. The performance of the movement artefacts estimation and removal were compared using accelerometer only, accelerometer and gyroscope, and accelerometer, gyroscope and magnetometer data from IMU sensor to estimate the artefact in NIRS reading. For the remaining two subjects the NIRS signal was recorded by natural movement artefacts impact and the results of artefacts removal was compared using accelerometer only, accelerometer and gyroscope, and accelerometer, gyroscope and magnetometer data from IMU sensor to estimate the artefact in NIRS reading. The quantitative and qualitative results revealed that the SNR improvement increases with the number of IMU channels used in the artefacts estimation, and there were approximately 5-11 dB increase in SNR when nine channel IMU data were used rather than using only three channel accelerometer data only. The artefact removal from natural movements also demonstrated that the combination of gyroscope and magnetometer sensors with accelerometer provided better estimation and removal of the movement artefacts, which was revealed by the minimal change of the HbO2 and Hb level before, during and after movement artefacts occurred in the NIRS signal. The movement artefacts in NIRS can be more accurately estimated and removed by using accelerometer, gyroscope and magnetograph signals from an integrated IMU sensor than using accelerometer signal only.


Fire and Darkness: On the Assessment and Management of Bipolar Disorder.
Bipolar disorder is characterized by recurrent mood episodes, affecting 1% to 2% of the population. Although its defining features are manic and hypomanic episodes, its course is dominated by depressive syndromes. Diagnosis can be challenging owing to symptom overlap with other disorders. Management goals include early and complete remission of acute episodes and the prevention of relapse between episodes. We present an overview of bipolar disorder and its subtypes, including algorithms and suggestions for screening, assessment, and treatment.


[Construction of eukaryotic expression vector of siRNA specific to bcr/abl fusion gene].
To construct eukaryotic expression vector of siRNA specific to bcr/abl and to initially investigate the effect of recombinant plasmid on bcr/abl and P210 protein expression in K562 cells. siRNA (small interfering RNA) was designed according to the Tuschl's principle of RNAi-based medicine, and was converted into cDNA coding expression of shRNA (small hairpin RNAs)of siRNA for bcr/abl fusion gene. The cDNA was synthesized and inserted into plasmid pTER. The pTER117 and pTER363 of recombinant plasmid being eukaryotic expression vector was controlled by the H1 promoter of RNA polymerase III, identified by the restriction map and the sequence analysis, and transfected into K562 cells by Lipofectamine. Expression of bcr/abl mRNA was assayed by RT-PCR; expression of P210 protein was detected by immunohistochemistry. The pTER117 and pTER363 of recombinant plasmid identified by the restriction map and the sequence analysis completely coincided with the designs. 24 hours after transfection in K562 cells, the recombinant plasmid could down regulate the expression of the bcr/abl mRNA and bcr/abl protein(P210) in K562 cells. The siRNA eukaryotic expression vector against bcr/abl mRNA has been successfully conctructed, and it effectively inhibits the expression of bcr/abl in K562 cells.


Change blindness in simulated driving in individuals with homonymous visual field loss.
Individuals with homonymous visual field loss (HVFL) fail to perceive visual information that falls within the blind portions of their visual field. This places additional burden on memory to represent information in their blind visual field, which may make visual changes in the scene more difficult to detect. Failing to detect changes could have serious implications in the context of driving. A change blindness driving simulator experiment was conducted with individuals with HVFL (n = 17) and in those with normal vision (NV; n = 16) where changes (pedestrians appearing) were triggered based on the driver's gaze location. Gaze was used to ensure that the location of the change was visible before and after the change occurred. There were wide individual differences in both vision groups, ranging from no change blindness to more than 33% of events. Those with HVFL had more change blindness than those with NV (16.7% vs. 6.3%, p < 0.001) and more change blindness to pedestrians appearing in their blind than seeing hemifield (34.6% vs. 10.4%, p < 0.001). Further, there was more change blindness for events appearing in the seeing hemifield for those with HVFL than normal vision (p = 0.023). These results suggest that individuals with HVFL may be more susceptible to failures of awareness, such as change blindness, than individuals with normal vision. Increased risk for failures of awareness may result in motor vehicle crashes where the driver fails to notice the other road user (looked-but-failed-to-see incidents).


Characterization of a proteolipid complex of aminoacyl-tRNA synthetases and transfer RNA from rat liver.
A high molecular weight complex containing aminoacyl-tRNA synthetases, peptidyl acetyltransferase, lipids and tRNA has been isolated from the 250,000 x g postmitochondrial supernatant from rat liver cells. Aminoacyl-tRNA synthetase activity directed towards arginine, aspartate, glutamine, glutamate, glycine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, and tyrosine is present. An endogenous pool of aminoacyladenylates is indicated by an ATP-32PPi exchange catalyzed by the native complex, which shows a dramatic increase after addition of ATP. Lysine is the only amino acid which greatly increases the exchange rate catalyzed by the native complex in vitro, whereas components of the denatured complex activate all the 13 amino acids in the presence of ATP. Six of the eight lipid fractions were glycolipids; cholesterol and cholesterol esters were absent. The extracted RNA has many characteristics of tRNA. These findings provide evidence for the organization of aminoacyl-tRNA synthetases in a complex with peptidyl acetyltransferase that also contains lipids and tRNA and that can be readily isolated from the cytosol of rat liver cells.


Trap Location and Premises Condition Influences on Aedes aegypti (Diptera: Culicidae) Catches Using Biogents Sentinel Traps During a 'Rear and Release' Program: Implications for Designing Surveillance Programs.
As the incidence of arboviral diseases such as dengue, Zika, chikungunya, and yellow fever increases globally, controlling their primary vector, Aedes aegypti (L.) (Diptera: Culicidae), is of greater importance than ever before. Mosquito control programs rely heavily on effective adult surveillance to ensure methodological efficacy. The Biogents Sentinel (BGS) trap is the gold standard for surveilling adult Aedes mosquitoes and is commonly deployed worldwide, including during modern 'rear and release' programs. Despite its extensive use, few studies have directly assessed environmental characteristics that affect BGS trap catches, let alone how these influences change during 'rear and release' programs. We assessed male and female Ae. aegypti spatial stability, as well as premises condition and trap location influences on BGS trap catches, as part of Debug Innisfail 'rear and release' program in northern Australia. We found similar trends in spatial stability of male and female mosquitoes at both weekly and monthly resolutions. From surveillance in locations where no males were released, reduced catches were found at premises that contained somewhat damaged houses and unscreened properties. In addition, when traps were located in areas that were unsheltered, more than 10 m from commonly used sitting areas or more visually complex catches were also negatively affected. In locations where males were released, we found that traps in treatment sites, relative to control sites, displayed increased catches in heavily shaded premises and were inconsistently influenced by differences in house sets and building materials. Such findings have valuable implications for a range of Ae. aegypti surveillance programs.


Energy cost of walking and gait instability in healthy 65- and 80-yr-olds.
This study tested whether the lower economy of walking in healthy elderly subjects is due to greater gait instability. We compared the energy cost of walking and gait instability (assessed by stride to stride changes in the stride time) in octogenarians (G80, n = 10), 65-yr-olds (G65, n = 10), and young controls (G25, n = 10) walking on a treadmill at six different speeds. The energy cost of walking was higher for G80 than for G25 across the different walking speeds (P < 0.05). Stride time variability at preferred walking speed was significantly greater in G80 (2.31 +/- 0.68%) and G65 (1.93 +/- 0.39%) compared with G25 (1.40 +/- 0.30%; P < 0.05). There was no significant correlation between gait instability and energy cost of walking at preferred walking speed. These findings demonstrated greater energy expenditure in healthy elderly subjects while walking and increased gait instability. However, no relationship was noted between these two variables. The increase in energy cost is probably multifactorial, and our results suggest that gait instability is probably not the main contributing factor in this population. We thus concluded that other mechanisms, such as the energy expenditure associated with walking movements and related to mechanical work, or neuromuscular factors, are more likely involved in the higher cost of walking in elderly people.


Chronic treatment with novel nanoformulated micelles of rapamycin, Rapatar, protects diabetic heart against ischaemia/reperfusion injury.
Enhanced mammalian target of rapamycin (mTOR) signalling contributes to the pathogenesis of diabetes and plays a critical role in myocardial ischaemia/reperfusion (I/R) injury. Rapatar is a novel nanoformulated micellar of rapamycin, a putative inhibitor of mTOR that has been rationally designed to increase water solubility of rapamycin to facilitate p.o. administration and enhance bioavailability. We examined the effect of Rapatar on the metabolic status and protection against myocardial I/R injury in type 2 diabetic mice. Adult male db/db mice were treated daily for 10 weeks with Rapatar (0.75 mg·kg-1 ·day-1 , p.o.) or vehicle. Isolated hearts were connected to a Langendorff perfusion system and subjected to global ischaemia (30 min) and reperfusion (1 h). Rapatar reduced fasting plasma glucose and triglyceride levels, prevented the gain in body weight and also improved glucose tolerance and insulin sensitivity in db/db mice compared with control. Cardiac function was improved following Rapatar treatment in db/db mice. Myocardial infarct size was reduced in Rapatar-treated mice with improved post-ischaemic rate-force product. Western blot analyses demonstrated a significant inhibition of phosphorylation of ribosomal protein S6 (downstream target of mTORC1), but not Akt (Ser473 , target of mTORC2) following chronic treatment with Rapatar. Rapatar also induced phosphorylation of AMPK, STAT3, ERK1/2 and glycogen synthase kinase 3β, without interfering with phosphorylation of p38. Our studies indicate that chronic treatment with Rapatar improves metabolic status and cardiac function with a reduction of infarct size following myocardial I/R injury in diabetic mice.


A matrix approach to human class II histocompatibility antigens: reactions of four monoclonal antibodies with the products of nine haplotypes.
Three putative HLA-DC-specific monoclonal antibodies, Genox 3.53, BT3/4 and anti-Leu-10, and the HLA-DR-specific antibody, L243, were compared. Their interactions with molecules from homozygous cell lines expressing DR types 1 through 9 were studied. Indirect radioimmunoassays on 29 cell lines demonstrated that Genox 3.53 reactivity correlated with DR1, 2, 6; BT3/4 reactivity correlated with DR 1, 2, 4, 6, 8; and anti-Leu-10 reactivity correlated with DR1,2,4,5,6,8, and 9. In addition, one of six DR3-positive cells and three DR7, DRw10-positive cells reacted with anti-Leu-10 and one of two DR9-positive cells reacted with BT3/4. Binding studies with soluble antigen and competitive radioimmunoassays demonstrated that all three antibodies reacted with the DC1 molecule. Preincubation with BT3/4 blocked anti-Leu-10 binding; Genox 3.53 and L243 did not. Genox 3.53 and L243 were only blocked by themselves. Serial immunoprecipitation showed anti-Leu-10 reacted with non-HLA-DR molecules from cells expressing DR types 1-6, 8 and 9. However, the molecules precipitated by anti-Leu-10 were characteristic class II major histocompatibility complex (MHC) molecules. Their alpha and beta chains were of lower apparent molecular weight than the DR chains in all haplotypes. They also comigrated with the DC1 molecule precipitated by Genox 3.53. Serial immunoprecipitation also showed that anti-Leu-10 removed all Genox 3.53 reactive molecules from cell lysates, but Genox 3.53 removed only a subset of anti-Leu-10 reactive molecules. These studies show Genox 3.53, BT3/4, and anti-Leu-10 react exclusively with class II MHC molecules that are not HLA-DR, and most likely define different polymorphisms of DC molecules, the human equivalent of mouse I-A products.


Durability of the Prostatic Urethral Lift: 2-Year Results of the L.I.F.T. Study.
For a therapy to become an important part of a provider armamentarium it must be safer or better than existing therapies and be durable. The prostatic urethral lift offers rapid improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia with minimal side effects. We report 2-year results of a multicenter, randomized, blinded trial of the prostatic urethral lift. A total of 206 men 50 years old or older with an AUA-SI of 13 or greater, a peak flow rate of 12 ml per second or less and a 30 to 80 cc prostate were randomized 2:1 between the prostatic urethral lift and sham treatment. The prostatic urethral lift is performed by placing permanent transprostatic implants to lift apart the prostate lobes and reduce urethral obstruction. Sham treatment entailed rigid cystoscopy, a blinding screen and sounds that mimicked those of the prostatic urethral lift procedure. Patients were assessed for lower urinary tract symptoms, peak flow rate, quality of life and sexual function. The prostatic urethral lift reduced the AUA-SI 88% more than sham treatment (-11.1 vs -5.9, p = 0.003). Patients with the prostatic urethral lift experienced an AUA-SI reduction from 22.1 at baseline to 18.0 (-17%), 11.1 (-50%), 11.4 (-48%) and 12.5 (-42%) at 2 weeks, 3 months, and 1 and 2 years, respectively (p <0.0001). The peak flow rate was increased 4.2 ml per second at 3 months and 2 years (p <0.0001). By 2 years only 7.5% of patients required additional intervention for lower urinary tract symptoms. Adverse events were typically mild and transient. Encrustation did not develop on implants properly placed in the prostate. There was no occurrence of de novo sustained ejaculatory or erectile dysfunction. The prostatic urethral lift preserves sexual function and provides rapid improvement in symptoms, flow and quality of life that are sustained to 2 years.


MicroRNAs: A novel potential biomarker for diagnosis and therapy in patients with non-small cell lung cancer.
Lung cancer is still one of the most serious causes of cancer-related deaths all over the world. MicroRNAs (miRNAs) are defined as small non-coding RNAs which could play a pivotal role in post-transcriptional regulation of gene expression. Increasing evidence demonstrated dysregulation of miRNA expression associates with the development and progression of NSCLC. To emphasize a variety of tissue-specific miRNAs, circulating miRNAs and miRNA-derived exosomes could be used as potential diagnostic and therapeutic biomarkers in NSCLC patients. In the current review, we paid attention to the significant discoveries of preclinical and clinical studies, which performed on tissue-specific miRNA, circulating miRNA and exosomal miRNA. The related studies were obtained through a systematic search of Pubmed, Web of Science, Embase. A variety of tissue-specific miRNAs and circulating miRNAs with high sensitivity and specificity which could be used as potential diagnostic and therapeutic biomarkers in NSCLC patients. In addition, we emphasize that the miRNA-derived exosomes become novel diagnostic biomarkers potentially in these patients with NSCLC. MiRNAs have emerged as non-coding RNAs, which have potential to be candidates for the diagnosis and therapy of NSCLC.


Glycobiology in the cytosol: the bitter side of a sweet world.
Progress in glycobiology has undergone explosive growth over the past decade with more of the researchers now realizing the importance of glycan chains in various inter- and intracellular processes. However, there is still an area of glycobiology awaiting exploration. This is especially the case for the field of "glycobiology in the cytosol" which remains rather poorly understood. Yet evidence is accumulating to demonstrate that the glycoconjugates and their recognition molecules (i.e. lectins) are often present in this subcellular compartment.


Decreased gene expression of human beta-defensin-1 in the development of squamous cell carcinoma of the oral cavity.
The aim of this study was to investigate the gene expression of human beta-defensin-1, -2, -3 (hBD-1, -2, -3), interleukin-1beta, tumour necrosis factor-alpha and cyclooxygenase-2 in oral squamous cell carcinoma (OSCC) compared to benign and premalignant lesions as well as healthy controls. Biopsies of healthy gingiva (n=5), irritation fibroma (n=5), leukoplakia (n=5) and OSCC (n=5) were obtained during routine surgical procedures. RNA was extracted according to standard protocols and transcripts of hBD-1, -2, -3, interleukin-1beta, tumour necrosis factor-alpha and cyclooxygenase-2 were analysed by real-time polymerase chain reaction. The expression of hBD-1 was reduced in all lesions (5-fold in irritation fibroma and 2.5-fold in leukoplakia), but most significantly (50-fold) in OSCC. hBD-1 appears to play a role in the development of OSCC. The loss of its function might contribute to the malignant progression of these tumours.


Apoptosis induced by N6-substituted derivatives of adenosine is related to intracellular accumulation of corresponding mononucleotides in HL-60 cells.
The in vitro induction of apoptosis by N6-substituted derivatives of adenosine and adenine was investigated in HL-60 cells. Using reversed phase HPLC/MS analysis we demonstrated that both N6-substituted derivatives of adenosine and adenine are phosphorylated within cells to the monophosphate level. While N6-substituted derivatives of adenosine were phosphorylated by adenosine kinase and corresponding mononucleotides were produced in large quantities, N6-substituted derivatives of adenine were converted into the corresponding mononucleotides via the phosphoribosyl transferase pathway, which yielded 50-100 times lower amounts of the mononucleotides than the adenosine kinase pathway. Accordingly, N6-substituted derivatives of adenine were relatively inefficient inductors of apoptosis at the concentrations applied. Inhibitors of adenosine kinase that abrogated the formation of monophosphates from N6-substituted derivatives of adenosine completely prevented cells from going into apoptosis. These results consistently support the idea that pro-apoptotic effects of N6-substituted derivatives of adenosine are related to their intracellular conversion into corresponding mononucleotides which eventually trigger apoptosis when accumulated beyond certain level. Intracellular accumulation of mononucleotides derived from the corresponding N6-substituted derivatives of adenosine led to a rapid decrease in ATP production and consequently to apoptosis induction. Nevertheless, the detailed mechanism is unknown and must be further elucidated. Apoptosis, induced by N6-substituted derivatives of adenosine, was accompanied by a distinct caspase-3 activation. However, a broad spectrum caspase inhibitor, z-VAD-fmk, failed to prevent cells from death, thereby indicating that caspases alone were not mediators of cell death.


Effects of IP3R2 Receptor Deletion in the Ischemic Mouse Retina.
Glial cells in the diseased nervous system undergo a process known as reactive gliosis. Gliosis of retinal Müller glial cells is characterized by an upregulation of glial fibrillary acidic protein and frequently by a reduction of inward K(+) current amplitudes. Purinergic signaling is assumed to be involved in gliotic processes. As previously shown, lack of the nucleotide receptor P2Y1 leads to an altered regulation of K(+) currents in Müller cells of the ischemic retina. Here, we asked first whether this effect is mediated by the IP3 receptor subtype 2 (IP3R2) known as the major downstream signaling target of P2Y1 in Müller cells. The second question was whether lack of IP3R2 affects neuronal survival in the control and ischemic retina. Ischemia was induced in wild type and IP3R2-deficient (IP 3 R2 (-/-)) mice by transient elevation of the intraocular pressure. Immunostaining and TUNEL labelling were used to quantify neuronal cell loss. The downregulation of inward K(+) currents in Müller cells from ischemic IP 3 R2 (-/-) retinae was less strong than in wild type animals. The reduction of the number of cells in the ganglion cell layer and of calretinin- and calbindin-positive cells 7 days after ischemia was similar in wild type and IP 3 R2 (-/-) mice. However, IP3R2 deficiency led to an increased number of TUNEL-positive cells in the outer nuclear layer at 1 day and to an enhanced postischemic loss of photoreceptors 7 days after ischemia. This implies that IP3R2 is involved in some but not all aspects of signaling in Müller cells after an ischemic insult.


Being watched by a humanoid robot and a human: Effects on affect-related psychophysiological responses.
Eye contact with a humanoid robot has been shown to evoke similar affect and affiliation related psychophysiological responses as eye contact with another human. In this pre-registered study, we investigated whether these effects are dependent on the experience of being "watched". Psychophysiological responses (SCR, zygomatic and corrugator facial EMG, frontal EEG asymmetry) to a humanoid robot's or a human model's direct vs. averted gaze were measured while manipulating the participants' belief of whether the robot/human model could see them or not. The results showed greater autonomic arousal responses and facial responses related to positive affect both to the robot's and the human model's direct vs. averted gaze, regardless of the belief condition. The belief condition influenced the overall magnitude of these responses to both stimulus models, however, to a lesser extent for the robot than for the human model. For the frontal EEG asymmetry, the effect of gaze direction was non-significant in both belief conditions. The results lend further support for the importance of eye contact in human-robot interaction and provide insights into people's implicit attributions of humanoid robots' mental capacities.


Impact of high glucose and transforming growth factor-β on bioenergetic profiles in podocytes.
Diabetic nephropathy is the most common cause of chronic renal failure in industrialized countries. Depletion of podocytes plays an important role in the progression of diabetic glomerulopathy. Various factors in the diabetic milieu lead to serious podocyte stress driving the cells toward cell cycle arrest (p27(Kip1)), hypertrophy, detachment, and apoptosis. Mitochondria are responsible for oxidative phosphorylation and energy supply in podocytes. Recent studies indicated that mitochondrial dysfunction is a key factor in diabetic nephropathy. In the present study, we investigated metabolic profiles of podocytes under diabetic conditions. We examined oxygen consumption rates (OCRs) and oxidative phosphorylation complex activities in murine podocytes. Cells were exposed to high glucose for 48 hours, cultured for 10 passages under high-glucose conditions (30 mmol/L), or incubated with transforming growth factor-β (5 ng/mL) for 24 hours. After prolonged exposure to high glucose, podocytes showed a significantly increased OCR at baseline and also a higher OCR after addition of oligomycin, indicating significant changes in mitochondrial energy metabolism. Higher OCRs after inhibition of respiration by rotenone also indicated changes in nonmitochondrial respiration. Podocytes stimulated with a proapoptotic concentration of transforming growth factor-β displayed similar bioenergetic profiles, even with decreased citrate synthase activity. In all tested conditions, we found a higher cellular nicotinamide adenine dinucleotide content and changes in activities of respiratory chain complexes. In summary, we provide for the first time evidence that key factors of the diabetic milieu induce changes in glucose metabolism and mitochondrial function in podocytes.


Arthroscopic pullout repair of a complete radial tear of the tibial attachment site of the medial meniscus posterior horn.
We developed an effective arthroscopic pullout technique for repairing complete radial tears of the tibial attachment site of the medial meniscus posterior horn (MMPH). In our technique, the torn meniscus is reattached to the tibial plateau immediately medial or anteromedial to the posterior cruciate ligament (PCL) using two No. 2 Ethibond sutures (Ethicon, Somerville, NJ). After a complete radial tear of the tibial attachment site of the MMPH and its reparability were confirmed, using a Caspari suture loaded with a suture shuttle, one No. 2 Ethibond suture is placed through the meniscus, through the red-red zone, 3 to 5 mm medial to the torn edge of the MMPH, and the other is passed through the meniscocapsular junction 3 to 5 mm medial to the torn edge of the meniscus. Then, a tibial tunnel, 5-mm in diameter, is made from the anteromedial aspect of the proximal tibia to the previously prepared tibial plateau, immediately medial or anteromedial to the PCL, and the two No. 2 Ethibond sutures are pulled out through the tibial tunnel and then fixed to the proximal tibia using a 3.5-mm cortical screw and washer. Firm reattachment of the torn meniscus was confirmed arthroscopically.


Simultaneous aerobic removal of phosphorus and nitrogen by a novel salt-tolerant phosphate-accumulating organism and the application potential in treatment of domestic sewage and aquaculture sewage.
Phosphorus (P) and nitrogen (N) pollution are the worldwide challenging problem. In the present study, a new salt-tolerant phosphate-accumulating organism (PAO) was isolated and identified as Bacillus subtilis GHSP10. Strain GHSP10 did not produce hemolysin and showed high susceptibility to antibiotics. The favorable phosphorus removal C/N ratios, P/N ratios, temperature, salinities, pH values and shaking speeds of strain GHSP10 were 10-20, 0.1-0.2, 28 °C, 0-3%, 7.5-8.5 and 100-250 r/min. Besides, strain GHSP10 could conduct heterotrophic nitrification-aerobic denitrification and the maximal removal efficiencies of ammonium, nitrite and nitrate were 99.52%, 81.10% and 95.84% respectively. Moreover, the phosphorus removal process of strain GHSP10 was achieved under entirely aerobic conditions, and glycogen and poly-β-hydroxybutyrate could provide energy source for the phosphorus removal process of strain GHSP10. The amplification of ppk, hao, napA, narG, nirK genes as well as the expression of polyphosphate kinase helped to reveal the removal pathways of phosphorus and nitrogen, providing theoretical support for the phosphorus removal, nitrification and aerobic denitrification abilities of strain GHSP10. Furthermore, efficient removal of phosphorus and nitrogen from both domestic sewage and aquaculture sewage could be accomplished by strain GHSP10. This study may provide a hopeful candidate strain for simultaneous removal of phosphorus and nitrogen pollution from both freshwater sewage and saline sewage.


In vivo anticancer, anti-inflammatory, and toxicity studies of mixed-ligand Cu(II) complexes of dien and its Schiff dibases with heterocyclic aldehydes and 2-amino-2-thiazoline. Crystal structure of [Cu(dien)(Br)(2a-2tzn)](Br)(H(2)O).
A new series of complexes of the type [Cu(dien)(2a-2tzn)Y(2)] and [Cu(dienXX)(2a-2tzn)Y(2)], where dien=diethylenetriamine and dienXX=Schiff dibase of diethylenetriamine formed with 2-furaldehyde (dienOO), 2-thiophenecarboxaldehyde (dienSS), or pyrrol-2-carboxaldehyde (dienNN); Y=Cl, Br or NO(3); and 2a-2tzn=2-amino-2-thiazoline, were synthesized and their structure established by C, H, N and Cu analysis; IR and electronic spectra; magnetic susceptibility; and molar conductivity. The isolated complexes are monomers, paramagnetic, and electrolytes of types 1:1 or 1:2. In both types of solid state complexes, [Cu(dien)(2a-2tzn)Y(2)] and [Cu(dienXX)(2a-2tzn)Y(2)], dien and its Schiff dibases are bonded to Cu(II) in a tridentate fashion through 3N atoms. The coordination sphere is completed by the endocyclic nitrogen of the thiazoline moiety and by two Cl, Br, or NO(3) groups with distorted octahedral geometry. The proposed structure of these compounds was supported by X-ray analysis of [Cu(dien)(Br)(2a-2tzn)](Br)(H(2)O). The coordination polyhedron around the copper atom can be described as a distorted square pyramid [Cu(dien)(Br)(2a-2tzn)](+). Its basal plane is occupied by the four nitrogen atoms of the dien and thiazoline ligands with Cu-N distances ranging between 1.996(6) and 2.032(3)A, and the axial position is occupied by one of the two bromine atoms (Br1) with a Cu1-Br1 bond distance of 2.782(1)A. The second bromine atom (Br2) is 4.694(2)A from the copper atom, which exists as a discrete anion and is responsible for the cationic nature of the complex. Results regarding toxicity, antitumor, and anti-inflammatory activities of the investigated compounds are promising and allow the selection of a lead compound for further biological studies.


Extended X-ray absorption fine structure spectroscopy measurements and ab initio molecular dynamics simulations reveal the hydration structure of the radium(II) ion.
Radium is refocused from the viewpoint of an environmental pollutant and cancer therapy using alpha particles, where it mainly exists as a hydrated ion. We investigated the radium hydration structure and the dynamics of water molecules by extended X-ray absorption fine structure (EXAFS) spectroscopy and ab initio molecular dynamics (AIMD) simulation. The EXAFS experiment showed that the coordination number and average distance between radium ion and the oxygen atoms in the first hydration shell are 9.2 ± 1.9 and 2.87 ± 0.06 Å, respectively. They are consistent with those obtained from the AIMD simulations, 8.4 and 2.88 Å. The AIMD simulations also revealed that the water molecules in the first hydration shell of radium are less structured and more mobile than those of barium, which is an analogous element of radium. Our results indicate that radium can be more labile than barium in terms of interactions with water.


A role for computer simulation in solving the riddles of autoreceptor-mediated regulation of GABA release.
The autoreceptor-mediated control of GABA release was simulated on a personal computer using commercially available software (STELLA/ITHINK). The experimental data to be matched were taken from previous publications. A basic model was able to fairly accurately reproduce frequency dependencies of GABA release in the presence and absence of uptake inhibition as well as concentration-response curves for changes in release produced by the agonist, (-)-baclofen, or by relatively low concentrations of the antagonists, phaclofen and CGP 35348. Obvious mismatch was observed at high concentrations of a potent antagonist, at a stimulation frequency of 2 Hz. Whereas the experimental data indicate a 3-fold increase in release as compared to controls, simulation predicts a 7-fold increase. By adaptation of the model, simulation data were obtained indicating that this mismatch was not due to (a) the autoreceptor occurring as two subtypes with different affinities for antagonists, (b) the occurrence of an agonist and antagonist state of the autoreceptor, with the latter prevailing at low synaptic concentrations of endogenous GABA, and (c) overruling of uptake inhibition by markedly elevated synaptic GABA concentrations. On the other hand, a simple restriction of the amount of transmitter able to be released per time unit produced much better matching data. A refined model assuming a restricted replacement capacity for exocytotically emptied synaptic vesicles at their docking sites gave similar results. As a consequence, we shall attempt to address this possibility experimentally. Simulation can never prove a case in the positive sense. It can, however, help to exclude ill-matching solutions of a problem and to prioritize among possible ones, which then must be experimentally addressed. We found simulation with this user-friendly software extraordinarily useful, also and not least because it necessitates and stimulates very intense dealing with a subject.


Different postnatal development of cells expressing mRNA encoding neurotensin receptor.
In situ hybridization histochemistry revealed three different ontogenetic patterns of localized expression of the high-affinity type of neurotensin receptor mRNA in the developing rat brain: one comprises sites which showed transient expression of neurotensin receptor mRNA during the first postnatal week, the expression greatly decreasing thereafter (type I); another comprises sites at which there is a gradual increase in neurotensin receptor mRNA after birth, as there is in cell number and intensity, with advancing age, followed by a plateau (type II); the third comprises sites at which there is much expression of neurotensin receptor mRNA already at birth, and a slight decrease thereafter (type III). The cerebral cortex, except retrosplenial and entorhinal cortices, and the anterior dorsal thalamic nucleus exhibit the type I pattern, while the horizontal and vertical limbs of the diagonal band of Broca, magnocellular preoptic nucleus, substantia innominata, ventral part of the suprachiasmatic nucleus, medial habenular nucleus, ventral tegmental area and substantia nigra pars compacta exhibit the type II pattern. The tenia tecta, retrosplenial and entorhinal cortices exhibit the type III pattern. One of the most striking findings in this study was that the entire neocortex and most of the limbic cortex exhibit the type I pattern, i.e. neurotensin receptor mRNA is expressed transiently long before a neuronal network is established there. This suggests that neurotensin plays an important role in cortical development, other than its reported transmitter-like role in the adult.


Deficits in autonomic indices of emotion regulation and reward processing associated with prescription opioid use and misuse.
Prescription opioid misuse and high-dose opioid use may result in allostatic dysregulation of hedonic brain circuitry, leading to reduced emotion regulation capacity. In particular, opioid misuse may blunt the ability to experience and upregulate positive affect from natural rewards. The purpose of this study was to examine associations between opioid use/misuse and autonomic indices of emotion regulation capability in a sample of chronic pain patients receiving prescription opioid pharmacotherapy. Chronic pain patients taking long-term opioid analgesics (N = 40) completed an emotion regulation task while heart rate variability (HRV) was recorded, and also completed self-report measures of opioid misuse, craving, pain severity, and emotional distress. Based on a validated cut-point on the Current Opioid Misuse Measure, participants were grouped as opioid misusers or non-misusers. Opioid misuse status and morphine equivalent daily dose (MEDD) were examined as predictors of HRV and self-reports of emotion regulation. Opioid misusers exhibited significantly less HRV during positive and negative emotion regulation, and significantly less positive effect, than non-misusers, after controlling for confounders including pain severity and emotional distress. MEDD was inversely associated with positive emotion regulation efficacy. Findings implicate the presence of reward processing deficits among chronic pain patients with opioid-misusing behaviors, and opioid dosage was associated with deficient emotion regulation, suggesting the presence of compromised top-down cognitive control over bottom-up hedonic processes. Emotion regulation among opioid misusers may represent an important treatment target.


Testicular dysfunction after cyclophosphamide-vincristine-procarbazine-prednisolone chemotherapy for advanced Hodgkin's disease. A long-term follow-up study.
Gonadal functions were evaluated in 92 male patients after treatment for advanced Hodgkin's disease. The patients received six to ten cycles of cyclophosphamide, vincristine, procarbazine, and prednisolone (COPP) chemotherapy. All patients were in remission and were followed for 1 to 17 years (median, 6). Testicular atrophy was noticed in 89 (96.7%) patients. All patients remained azoospermic during the period of follow-up. The testosterone levels did not differ before and after treatment. The follicle stimulating hormone levels rose from pretreatment values (mean +/- standard deviation) of 179.27 +/- 21.99 ng/ml to 578.79 +/- 102.36 ng/ml after the treatment; the rise was significant (P less than 0.001). The luteinizing hormone levels rose from pretreatment values of 106.96 +/- 20.37 ng/ml to 127.37 +/- 32.19 ng/ml after treatment; the rise was significant (P less than 0.05). Testicular biopsy specimens in 19 patients showed germinal aplasia in all cases. It is concluded that six or more cycles of COPP chemotherapy for advanced Hodgkin's disease in men leads to permanent sterility.


The intraprostatic spiral: a new device for insertion with the patient under local anesthesia and with ultrasonic guidance with 3 months of followup.
Acute or chronic urinary retention (median retention volume 1,000 ml.) was relieved successfully in 41 of 45 consecutive patients by insertion of an intraprostatic spiral with the patient under local anesthesia and with ultrasonic guidance. Insertion guided by ultrasound was successful in 35 patients (77 per cent). In 6 patients the spiral was inserted via the traditional endoscopic technique. During 3 months of followup the spiral remained in situ in 27 patients and in 6 it was repositioned. These 33 patients had free voiding with a median maximum flow rate of 13.6 ml. per second. Residual urine volume 1 month after insertion of the spiral was low (median 27 ml.). In 8 patients the spiral was removed during the observation period due to urinary incontinence or retention. The intraprostatic spiral is a favorable alternative to an indwelling catheter in patients awaiting an operation and in those with a high operative risk.


Clinical course of drug-induced hypersensitivity syndrome treated without systemic corticosteroids.
Drug-induced hypersensitivity syndrome (DIHS) is a severe reaction to drugs which characteristically occurs after a long latency period. In addition, human herpes virus 6 (HHV-6) reactivation is a characteristic finding in DIHS, which has been known to be related to disease severity. Because DIHS has generally been treated by systemic corticosteroids, the natural clinical course is not clear. Data for patients with both DIHS and HHV-6 reactivation were retrospectively collected from four hospitals. Data were collected on 12 patients ranging in age from 21 to 76 years (median, 65.5). All cases had been suspected of DIHS at their initial visit, and the elevation of serum anti-HHV-6 antibody had been confirmed (4-256 times: median; 32). The culprit drugs were carbamazepine (6), salazosulfapyridine (4), mexiletine (1) and zonisamide (1). The period of latency from the first administration of the drug ranged from 15 to 50 days (median, 30). All patients were treated conservatively for DIHS without systemic corticosteroids. The peaks of the patients' symptoms and laboratory findings were as follows (days from the onset of skin lesions): fever, 4-16 (median, 10.5); liver abnormality, 3-22 (median, 7.5); leukocytosis, 7-20 (median, 9). All patients recovered without pneumonia, myocarditis, nephritis or other systemic disease, from 7 to 37 days (median, 18) after withdrawal of the drug and from 11 to 44 days (median, 21) after the onset of skin lesions. It might be unnecessary to give systemic corticosteroids immediately to all patients suspected of having DIHS.


The long-term impact of oxaliplatin chemotherapy on rodent cognition and peripheral neuropathy.
Chemotherapy treatment is associated with cognitive dysfunction in cancer survivors after treatment completion. The duration of these impairments is unclear. Therefore this paper aims to evaluate the lasting impact of varying doses of the chemotherapy oxaliplatin (OX) on cognition and peripheral neuropathy. In Experiment 1 rats were treated once a week for 3 weeks with either physiological saline (control) or 6 mg/kg OX i.p. and were assessed for peripheral neuropathy, using von Frey filaments, and cognitive function, using novel object and location recognition, up to 2 weeks after treatment completion. For Experiment 2 rats received 3 weekly i.p. injections of either physiological saline (control), 0.6 mg/kg, 2mg/kg or 6 mg/kg OX and assessed for peripheral neuropathy and cognitive function up to 11 months after treatment completion. Systemic OX treatment induced lasting effects on cognitive function at 11 months after treatment, and peripheral neuropathy at 1 month after treatment and these were dose dependent; higher doses of OX resulted in worse cognitive outcomes and more severe peripheral neuropathy.


The role of asymmetric dimethylarginine (ADMA) in COVID-19: association with respiratory failure and predictive role for outcome.
We aimed to assess the potential role of Asymmetric dimethylarginine (ADMA) in conditioning respiratory function and pulmonary vasoregulation during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) infection. Within 72 h from admission, samples from 90 COVID-19 patients were assessed for ADMA, SDMA, L-arginine concentrations. In addition to classical statistics, patients were also clustered by a machine learning approach according to similar features. Multivariable analysis showed that C-reactive protein (OR 1.012), serum ADMA (OR 4.652), white blood cells (OR = 1.118) and SOFA (OR = 1.495) were significantly associated with negative outcomes. Machine learning-based clustering showed three distinct clusters: (1) patients with low severity not requiring invasive mechanical ventilation (IMV), (2) patients with moderate severity and respiratory failure whilst not requiring IMV, and (3) patients with highest severity requiring IMV. Serum ADMA concentration was significantly associated with disease severity and need for IMV although less pulmonary vasodilation was observed by CT scan. High serum levels of ADMA are indicative of high disease severity and requirement of mechanical ventilation. Serum ADMA at the time of hospital admission may therefore help to identify COVID-19 patients at high risk of deterioration and negative outcome.


Another angiogenic gene linked to amyotrophic lateral sclerosis.
A new study by Greenway and colleagues links mutations in the angiogenin gene to patients with amyotrophic lateral sclerosis (ALS)--a progressive and fatal motoneuron disease. This is an unexpected finding because angiogenin was originally identified as a molecule involved in the formation of blood vessels (angiogenesis). Angiogenin bears striking similarity to vascular endothelial growth factor (VEGF), which is the prototypic angiogenic factor that has recently emerged as a molecule with important neuroprotective activities. Besides VEGF, angiogenin is the second so-called angiogenic factor implicated in ALS, raising the question of whether additional angiogenic factors might have a role in ALS. Overall, these findings identify angiogenin as a novel candidate gene in the pathogenesis of ALS--a discovery that ultimately might lead to the development of new therapeutic strategies.


Particulate arsenic trioxide induces higher DNA damage and reactive oxygen species than soluble arsenite in lung epithelial cells.
Environmental arsenic exposure is associated with lung cancer. Arsenic is the first substance known to cause lung cancer by two distinct routes, ingestion and inhalation, in the forms of soluble arsenite and particulate arsenic trioxide, respectively. In comparison to significant progresses in research on mechanisms for lung carcinogenesis of arsenic ingestion, inhalation arsenic exposure route in particulate form and its lung carcinogenic mechanisms are relatively under-investigated. Fundamentally, it remains unclear whether particulate arsenic exposure is in a dissolved form and whether particulate exposure yields higher damage. Utilizing dynamic laser scattering, particulate arsenic trioxide exposure in cellular system was confirmed to be in particulate form instead of dissolved form. Using immunofluorescence, particulate arsenic trioxide was demonstrated to generate dramatically higher oxidative DNA damage and strand break, as well as significantly higher superoxide, in lung epithelial cell lines such as BEAS-2B, HSAEC1-KT, and SAE, comparing to soluble arsenite exposure at similar or lower concentration. This study demonstrated that particulate arsenic trioxide exposure yields higher damage in lung epithelial cells, and indicated that inhalation route of particulate arsenic exposure plays an important role in lung carcinogenesis.


Risk factors for surgical-site infections after radical gastrectomy for gastric cancer: a study in China.
About 10% of patients get a surgical-site infection (SSI) after radical gastrectomy for gastric cancer, but SSI remains controversial among surgeons. The aim of this study was to explore the risk factors for SSIs after radical gastrectomy in patients with gastric cancer to guide clinical therapies and reduce the incidence of SSI. The study was a retrospective cohort study in patients who underwent radical gastrectomy for gastric cancer. SSI was defined in accordance with the National Nosocomial Infection Surveillance System. We evaluated patient-related and peri-operative variables that could be risk factors for SSIs. The Chi-squared test and logistic regression analysis were used to assess the association between these risk factors and SSI. Among the 590 patients, 386 were men and 204 were women. The mean age was 56.6 (28-82) years and 14.2% (84/590) of these patients had an SSI. Among them, incisional SSI was observed in 23 patients (3.9%) and organ/space SSI in 61 patients (10.3%). Multivariate logistic regression analysis identified sex (odds ratios [ORs] = 2.548, and 95% confidence interval [CI]: 1.268-5.122, P = 0.009), total gastrectomy (OR = 2.327, 95% CI: 1.352-4.004, P = 0.002), albumin level (day 3 after surgery) <30 g/L (OR = 1.868, 95% CI: 1.066-3.274, P = 0.029), and post-operative total parenteral nutrition (OR = 2.318, 95% CI: 1.026-5.237, P = 0.043) as independent risk factors for SSI. SSI was common among patients after radical gastrectomy for gastric cancer. The method supporting post-operative nutrition and the duration of prophylactic antibiotics may be important modifiable influencing factors for SSI.


Budd-Chiari syndrome caused by membranous obstruction of the inferior vena cava associated with coeliac disease.
Ten cases of Budd-Chiari syndrome associated with coeliac disease have been reported in the literature, most of them in North African subjects. Supporting this association, we report a new case in a young Spanish Caucasian man in whom the cause of the syndrome was the membranous obstruction of the inferior vena cava, an infrequent cause of Budd-Chiari syndrome in Western countries. A percutaneous balloon angioplasty was performed, with satisfactory outcome.


HIV-1 assembly: viral glycoproteins segregate quantally to lipid rafts that associate individually with HIV-1 capsids and virions.
HIV-1 assembly depends on its structural protein, Gag, which after synthesis on ribosomes, traffics to the late endosome/plasma membrane, associates with HIV Env glycoprotein, and forms infectious virions. While Env and Gag migrate to lipid microdomains, their stoichiometry and specificity of interaction are unknown. Pseudotyped viral particles can be made with one viral core surrounded by heterologous envelope proteins. Taking advantage of this property, we analyzed the association of HIV Env and Ebola glycoprotein (GP), with HIV-1 Gag coexpressed in the same cell. Though both viral glycoproteins were expressed, each associated independently with Gag, giving rise to distinct virion populations, each with a single glycoprotein type. Confocal imaging demonstrated that Env and GP localized to distinct lipid raft microdomains within the same cell where they associated with different virions. Thus, a single Gag particle associates "quantally" with one lipid raft, containing homogeneous trimeric viral envelope proteins, to assemble functional virions.


Dynamic Invasive Hemodynamic Congestion Profile Impacts Acute Myocardial Infarction Complicated by Cardiogenic Shock Outcomes: A Real-World Single-Center Study.
Cardiogenic shock (CS) commonly complicates the management of acute myocardial infarction (AMI), and it results in high mortality rates. Pulmonary artery catheter (PAC) monitoring can be valuable for personalizing critical-care interventions. We hypothesized that patients with AMI-CS experiencing persistent congestion measures during the first 24 hours of the PAC installment would exhibit worse in-hospital survival rates. We studied 295 patients with AMI-CS between January 2006 and December 2021. The first 24-hour PAC-derived hemodynamic measures were divided by the congestion profiling and the proposed 2022 Cardiovascular Angiography and Interventions (SCAI) classification. Biventricular congestion was the most common profile and was associated with the highest patient mortality rates at all time points (mean 56.6%). A persistent congestive profile was associated with increased mortality rates (hazard ratio [HR] = 1.85; P = 0.002) compared with patients who achieved decongestive profiles. Patients with SCAI stages D/E had higher levels of right atrial pressure (RAP): 14-15 mmHg) and pulmonary capillary wedge pressure (PCWP): 18-20 mmHg) compared with stage C (RAP, 10-11 mmHg, mean difference 3-5 mmHg; P < 0.001; PCWP 14-17 mmHg; mean difference 1.56-4 mmHg; P = 0.011). In SCAI stages D/E, the pulmonary artery pulsatility index (0.8-1.19) was lower than in those with grade C (1.29-1.63; mean difference 0.21-0.73; P < 0.001). Continuous congestion profiling using the SCAI classification matched the grade of hemodynamic severity and the increased risk of in-hospital death. Early decongestion appears to be an important prognostic and therapeutic goal in patients with AMI-CS and warrants further study.


[Granulomatous inflammation of the orbit as a complication of stem cells injection (case study)].
The article present a case report of orbital granulomatous inflammation after a retrobulbar injection of allogenous stem cells. Experimental treatment resulted in an orbital tumor that required surgical excision. Lymphogranulomatous inflammation with a secondary abscess was verified by morphological and immunohistochemical analyses. This case demonstrates the possible dangerous complications of the "off-label" therapy amid the rising popularity of stem cells treatment.


Vaccination of BALB/c mice with an avirulent Mycoplasma pneumoniae P30 mutant results in disease exacerbation upon challenge with a virulent strain.
Mycoplasma pneumoniae is a significant human respiratory pathogen that causes high morbidity worldwide. No vaccine to prevent M. pneumoniae infection currently exists, since the mechanisms of pathogenesis are poorly understood. To this end, we constructed a P30 cytadhesin mutant (P-130) with a drastically reduced capacity for binding to erythrocytes and an inability to glide on glass substrates. This mutant was determined to be avirulent and cannot survive in the lungs of BALB/c mice. We also ascertained that the previously identified P30 gliding motility mutant II-3R is avirulent and also cannot be recovered from the lungs of mice after infection. Mutant P130 was then assessed for its efficacy as a live attenuated vaccine candidate in mice after challenge with wild-type M. pneumoniae. After vaccination with the P-130 P30 mutant, mice showed evidence of exacerbated disease upon subsequent challenge with the wild-type strain PI1428, which appears to be driven by a Th17 response and corresponding eosinophilia. Our results are in accordance with other reports of vaccine-induced disease exacerbation in rodents and emphasize the need to better understand the basic mechanisms of M. pneumoniae pathogenesis.


Invasiveness of Salmonella typhimurium in HEp-2 cell cultures pre-infected with Mycoplasma hominis and Mycoplasma orale.
The influence of mycoplasma infection on the in vitro invasiveness of S. typhimurium in HEp-2 cell cultures has been tested. Two strains of arginine-utilizing mycoplasma species Mycoplasma hominis and M. orale both seemed to inhibit the bacterial in vitro invasiveness. Both the ratio of infected cells and the number of intracellular bacteria per cell were reduced in the mycoplasma-infected cultures.


Allopregnanolone and depression and anxiety symptoms across the peripartum: an exploratory study.
Recent research has implicated allopregnanolone (ALLO), a neuroactive steroid and metabolite of progesterone, in perinatal mood and anxiety symptoms. We sought to add to the limited literature examining ALLO and mood and anxiety at multiple time points across the peripartum. We measured mood and anxiety symptoms and ALLO levels by ELISA at the second and third trimester (T2 and T3) and week 6 postpartum (W6) in N = 73 women with prior histories of mood and/or anxiety disorders and N = 38 healthy controls. Analytic methods included multivariate and logistic regressions with linear mixed effect models. Among all participants (N = 111), higher ALLO levels at W6 were associated with higher depression and anxiety scores: each one unit increase in log ALLO at W6 was associated with a 2.54 point increase on the Edinburgh Postnatal Depression Scale (EPDS) (95% CI: 0.73 to 4.33) and an 8.0 point increase on the Perinatal Anxiety Screening Scale (PASS) (95% CI: 3.82 to 12.6). In addition, the nature of the relationship between log ALLO level and psychological measures changed across time; from T2 to W6 for EPDS, β = 3.73 (95% CI:1.16, 6.30), p = 0.0045; for PASS β = 9.78 (95% CI:3.77, 15.79), p = 0.0014); from T3 to W6, for (EPDS, β = 2.52 (95% CI:0.08, 4.96), p = 0.043; for PASS β = 7.33 (95% CI:1.63, 13.02), p = 0.018). The relationship of log ALLO to mood and anxiety symptoms was the same among women with and without psychiatric histories. Our exploratory findings indicate that the relationship between ALLO and mood and anxiety symptoms may change across the peripartum.


Application of adipose-derived stem cells in photoaging: basic science and literature review.
Photoaging is mainly induced by continuous exposure to sun light, causing multiple unwanted skin characters and accelerating skin aging. Adipose-derived stem cells(ADSCs) are promising in supporting skin repair because of their significant antioxidant capacity and strong proliferation, differentiation, and migration ability, as well as their enriched secretome containing various growth factors and cytokines. The identification of the mechanisms by which ADSCs perform these functions for photoaging has great potential to explore therapeutic applications and combat skin aging. We also review the basic mechanisms of UV-induced skin aging and recent improvement in pre-clinical applications of ADSCs associated with photoaging. Results showed that ADSCs are potential to address photoaging problem and might treat skin cancer. Compared with ADSCs alone, the secretome-based approaches and different preconditionings of ADSCs are more promising to overcome the current limitations and enhance the anti-photoaging capacity.


Enzymatic assay for total plasma Cys.
Patients with vascular disease and end-stage renal disease have significantly higher concentrations of plasma total Cys (tCys) than do healthy individuals. Described here is a nonradioactive, precise, rapid and sensitive enzymatic colorimetric assay for tCys in plasma samples and is homogeneous in that it avoids separation methods. The tCys assay uses only the recombinant enzymes methionine alpha,gamma-lyase (rMETase) and S-adenosylhomocysteine hydrolase (rSAHH) cloned from Pseudomonas putida and Trichomonas vaginalis, respectively. The rSAHH traps homocysteine and the rMETase thereby produces H(2)S exclusively from Cys. The reaction product, H(2)S, is measured colorimetrically following its reaction with N,N-dibutylphenylenediamine (DBPDA). The procedure takes 3-4 h to complete.


Influence of acetylcholine on binding of 4-[125I]iododexetimide to muscarinic brain receptors.
The distribution of nicotinic and muscarinic cholinergic receptors in the human brain in vivo has been successfully characterized using radiolabeled tracers and emission tomography. The effect of acetylcholine release into the synaptic cleft on receptor binding of these tracers has not yet been investigated. The present study examined the influence of acetylcholine on binding of 4-[125I]iododexetimide to muscarinic cholinergic receptors of porcine brain synaptosomes in vitro. 4-Iododexetimide is a subtype-unspecific muscarinic receptor antagonist with high affinity. Acetylcholine competed with 4-[125I]iododexetimide in a dose-dependent manner. A concentration of 500 microM acetylcholine inhibited 50% of total specific 4-[125I]iododexetimide binding to synaptosomes when both substances were given simultaneously. An 800 microM acetylcholine solution reduced total specific 4-[125I]iododexetimide binding by about 35%, when acetylcholine was given 60 min after incubation of synaptosomes with 4-[125I]iododexetimide. Variations in the synaptic acetylcholine concentration might influence muscarinic cholinergic receptor imaging in vivo using 4-[123I]iododexetimide. Conversely, 4-[123I]iododexetimide might be an appropriate molecule to investigate alterations of acetylcholine release into the synaptic cleft in vivo using single photon emission computed tomography.


Relation of Elevated Serum Uric Acid Level to Endothelial Dysfunction in Patients with Acute Coronary Syndrome.
Serum uric acid (SUA) level is known to have a prognostic value in patients with acute coronary syndrome (ACS). Endothelial function plays an important role in the development of cardiovascular disease. Although relation between SUA level and endothelial function has been previously studied in various populations, it is partially understood in patients with ACS. A total of 55 patients with ACS with measurements of SUA level and reactive hyperemia index (RHI) to evaluate endothelial function were included. They were classified into three groups according to the tertiles of SUA level. The tertiles of SUA level were as follows: low tertile, ≤ 5.2 mg/dl; intermediate tertile, 5.3 to 6.5 mg/dl; and high tertile, ≥ 6.6 mg/dl. Mean SUA level and RHI were 5.8±1.5 mg/dl and 1.88±0.58. There was a significant negative correlation between SUA level and RHI (r=-0.41, p=0.002). RHI was stepwisely observed in favor of the higher tertile groups (2.14±0.74 vs. 1.84±0.45 vs. 1.67±0.38, p=0.04). Multivariate analysis showed elevated SUA level as an independent predictor of reduced RHI. Elevated SUA level was significantly associated with endothelial dysfunction in patients with ACS, possibly leading to subsequent poor outcomes following ACS.


Is the ovary in an inguinal hernia 'descended' like a testis or not?
How testes descend through the inguinal canal is well described, but how the ovaries appear inside an inguinal hernia remains controversial. We reviewed the literature to determine whether ovarian 'descent' has been described. The English literature from 1950 to 2014 was reviewed via PubMed, Medline and Web of Science to identify papers describing an ovary in the hernia sac: reports were examined to find whether the ovary prolapsed or 'descended', and the anatomy of its supporting ligaments, cranial suspensory ligament (CSL) and round ligament (female gubernaculum, RL). In forty reports of >7140 inguinal herniotomies and/or imaging studies in females the hernia contains an ovary in 15-20%, often with the ipsilateral fallopian tube. The RL and ovary were aligned along the same path as testicular descent only rarely in Müllerian anomalies with an isolated uterine horn preceding the ovary into the sac. The ligament usually found inside the hernia sac was the CSL, not the RL. The high frequency of incarcerated ovary, along with the close proximity of the CSL to the internal ring in females is consistent with a sliding hernia pulling the CSL (and ovary) into the hernia sac, not ovarian 'descent' by traction on the RL.


Increased frequency of T cells expressing IL-10 in Alzheimer disease but not in late-onset depression patients.
Higher risk of dementia is expected for patients with late onset depression (LOD) history. The IL-10 polymorphisms are associated with Alzheimer disease (AD). On the other hand, there is no study associating IL-10 polymorphisms to LOD. This study aimed to investigate the -1082G/A polymorphism association in LOD, AD patients and controls and also the peripheral expression of IL-10 in CD4+ T cells. It was done in a case-control study comparing immune system phenotype and genetic polymorphism association among control individuals, LOD and AD patients. Participants were 569 subjects composed the genetics sample (249 AD, 222 LOD and 98 controls) from a tertiary medical center based on Belo Horizonte, Brazil. Flow cytometry analysis was performed in 55 people (22 AD patients, 11 LOD patients and 22 controls). A real time PCR for IL-10 SNP (rs 1800896) through genotyping analysis and flow cytometry evaluation of CD4+ T cells expressing IL-10 was done. An increased CD4+ T cells expressing IL-10 were detected only in the AD group. There was no difference detected in allele or genotype analysis for IL-10 polymorphism among LOD, AD patients or controls. IL-10 might have a role in the modulation of immune response in AD patients, however it is not presented in LOD population.


Antimycobacterial substances from Phaeosphaeria sp BCC8292.
Eleven substances including naphthalenones, naphthoquinones, unsymmetrical naphthoquinone dimers and a chlorinated diphenyl ether, three of which are new, have been isolated from the fungus Phaeosphaeria sp. The absolute stereochemistry of naphthalenones has been determined by the Mosher and exciton chirality methods. The biological activity of these compounds against Mycobacterium tuberculosis and cytotoxicity against KB, BCA, NCI-H 187 and Vero cell lines were evaluated.


Shifts in tonic accommodation after near work are related to refractive errors in children.
A link between changes in tonic accommodation (TA) produced by sustained near work and the development of adult-onset myopia has been suggested in studies of young adults. Measures of TA before and after near work have been lacking in children of school age, which is the most susceptible period for the development and progression of juvenile-onset myopia. In the present study accommodation was measured in 87 children, aged 7 to 16 years, before and after 15 minutes of video game playing. All children were refracted before testing and wore optical correction during measures of accommodation with a Canon R1 autorefractor. Most children showed initial values of TA (far focus minus dark focus) between 0.0 and 1.0 D, with a mean of 0.68 D. Grouped by refractive status, the myopic children initially showed 0.30 D of TA, while the emmetropic children showed 0.75 D and the hyperopic children showed 0.94 D. After playing the video game, TA of the myopes increased by 1.15 D, compared to smaller increases for the emmetropes (0.68 D) and hyperopes (0.24 D). Comparable values have been obtained from young adults. These results indicate that the smallest initial values of TA and the largest inward shifts in TA are found during the period of acquisition and progression of myopia, regardless of age.


Lipid peroxidation by activated platelets: a possible link between thrombosis and atherogenesis.
Generation of reactive oxygen species (ROS) by platelets was detected by a cyano-tetrazolium dye (CTC) which forms fluorescent formazan on the cell surface upon reduction. Fluorescence was quantitated by a densitometric device. Resting platelets in plasma produced significant fluorescence (P < 0.0001), and addition of thrombin enhanced the fluorescence of the coagulated platelet mass even further (by 2 h, a 6- and 8-fold increase over fluorescence of platelet-free plasma was measured, respectively). Blood containing CTC was perfused through a glass capillary tubing and the action of shear forces resulted in the formation of an occlusive platelet thrombus. Such thrombi (formed either from whole blood or platelet-rich plasma) were intensely fluorescent, indicating formation of ROS in the platelet mass (a 10- and 8-fold increase in fluorescence over coagulated plasma, respectively). Lipid peroxide content of resting platelets in platelet-rich plasma was doubled over 24 h storage, while addition of thrombin caused a 7.4-fold increase (P < 0.0001) of lipid peroxides in the retracted platelet-rich plasma-clot. Transition metal chelator and antioxidant prevented lipid peroxidation by platelets in response to thrombin. Thrombin activation of (washed) platelets in plasma-free medium caused only 1.4-fold increase in oxidation of added low density lipoprotein (LDL). In contrast, thrombin activation of platelets suspended in de-lipidated autologous plasma resulted in a 5.25-fold increase (P < 0.0001) in LDL oxidation. Generation of ROS and lipid peroxides by platelets can be an important mechanism through which thrombotic events contribute to atherogenesis.


Histiocytic lymphoma cell lines: immunologic and cytogenetic studies.
Cell lines were established from 15 patients with diffuse histiocytic lymphoma (DHL) of the intermediate grade, diffuse large cell (class G), and high-grade, large cell immunoblastic (class H) types. Immunologic studies indicated that 11 of the 15 DHL cell lines were B cell in origin, 2 were histiocytic, and 2 were null cell. Cytogenetic studies revealed 1 hypodiploid, 11 hyperdiploid, and 3 near-tetraploid cell lines. Chromosome #7 was trisomic in 3 lines, chromosomes #12 in 4 lines, and chromosome #13 in 3 lines. Chromosome #2 was monosomic in 3 lines, chromosome #8 was monosomic in 5 lines, chromosome #14 in 4 lines, and chromosome #22 in 6 cell lines. This is of special interest, as chromosomes #2, #8, #14, and #22 are clearly concerned with rearrangements in Burkitt's lymphoma and immunoglobulin expression. The most common rearrangement in the DHL cell lines involved chromosome #14 at band 14q32. However, in contrast to Burkitt's lymphoma, the pattern of translocation in DHL is between chromosome #14 and usually chromosome #11 or chromosome #18. The 14;18 translocation is not restricted to patients with low-grade follicular, small cleaved cell lymphomas, as has been reported. The 14q+ chromosome is characteristic of lymphoid malignancies in general. It is due, invariably, to a translocation with the breakpoint in band 14q32, which is the locus of the immunoglobulin heavy chain genes. We propose that in each translocation, for example, chromosomes #11 or #18, an oncogene may be transposed onto chromosome #14, and that each 14q+ translocation in DHL represents an event that transposes an oncogene from another chromosome to chromosome #14.


Promiscuous enzymatic activity-aided multiple-pathway network design for metabolic flux rearrangement in hydroxytyrosol biosynthesis.
Genetic diversity is a result of evolution, enabling multiple ways for one particular physiological activity. Here, we introduce this strategy into bioengineering. We design two hydroxytyrosol biosynthetic pathways using tyrosine as substrate. We show that the synthetic capacity is significantly improved when two pathways work simultaneously comparing to each individual pathway. Next, we engineer flavin-dependent monooxygenase HpaBC for tyrosol hydroxylase, tyramine hydroxylase, and promiscuous hydroxylase active on both tyrosol and tyramine using directed divergent evolution strategy. Then, the mutant HpaBCs are employed to catalyze two missing steps in the hydroxytyrosol biosynthetic pathways designed above. Our results demonstrate that the promiscuous tyrosol/tyramine hydroxylase can minimize the cell metabolic burden induced by protein overexpression and allow the biosynthetic carbon flow to be divided between two pathways. Thus, the efficiency of the hydroxytyrosol biosynthesis is significantly improved by rearranging the metabolic flux among multiple pathways.


Effect of using calcium-silicate and silicone based root canal sealers in bulk or with main core material on bond strength.
The purpose of this study was to assess the push-out bond strength of calcium-silicate and silicone based root canal sealers in bulk and with main cone. Roots (n=48) randomly divided into 4 groups (n=12) according to the obturation protocol; (1) iRoot SP in bulk; (2) iRoot SP with gutta-percha; (3) GuttaFlow Bioseal in bulk; (4) GuttaFlow Bioseal with gutta-percha. Six horizontal sections were obtained from each root (n=72). Effect of sealers on bond strength was statistically significant (P<0.05). Highest mean value was obtained in iRoot-Bulk group and lowest in GuttaFlow Bioseal-GP group. Both iRoot SP groups had significantly higher bond strength values than both GuttaFlow Bioseal groups (P<0.05). There was no significant difference between iRoot-GP and iRoot-Bulk groups (P=0.603) also GuttaFlow Bioseal-GP and GuttaFlow Bioseal-Bulk groups (P=0.684). Based on findings, using calcium silicate-based sealer in bulk can be also suitable in clinical practice.


A skin chamber technique as a human model for studies of aseptic inflammatory reactions.
Using a combination of induced skin blistering and collection chambers permits dynamic studies of the aseptic inflammatory reaction in humans. Blisters filled with interstitial fluid can be generated by applying negative pressure to normal skin for up to 2 h. The blisters are subsequently denuded to form superficial "skin windows" that are well defined with regard to area and depth. The denuded areas are covered with a separate collection chamber filled with a suitable medium and left for 18-24 h. During this period, neutrophils and inflammatory agents accumulate in the chamber medium, and sequential events in the inflammatory process can be studied by repeated sampling. Inactive medium or isolated peripheral blood cells from the same individual can be used as controls for both cellular functions and the pro-/anti-inflammatory mediators that are generated or released.


Infection Control in the Dental Office.
The goal of an infection control program is to provide a safe working environment for dental health care personnel and their patients. Practitioners can achieve this by adopting measures that reduce health care-associated infections among patients and occupational exposures among dental health care personnel. It is crucial for all dental practitioners to be up to date on current Centers for Disease Control and Prevention guidelines, equipment, and techniques for proper infection control. Continuous evaluation of infection control practices is important. Patients and dental providers should be confident that oral health care can be delivered and received in a safe manner.


Inhibitory connections of ipsilateral semicircular canal afferents onto Renshaw cells in the lumbar spinal cord of the cat.
1. In intercollicularly decerebrate cats, the excitability of lumbar spinal Renshaw cells (tested by single shocks to ventral roots and deafferented muscle nerves) decreased for 600-1000 ms after conditioning electrical stimulation of ipsilateral semicircular canal nerves. 2. Conditioning stimulation of posterior canal afferents and combined stimulation of anterior and lateral canal afferents were equally effective in causing inhibition of Renshaw cells. No significant differences were observed for Renshaw cells excitable from hind-limb flexor or extensor nerves. 3. Inhibition appeared when one to five stimuli were applied to the canal afferents and arrived at the spinal segmental level 11-15 ms after the onset of conditioning stimulation. 4. Evidence is adduced to suggest that the inhibitory effects on Renshaw cells following stimulation of semicircular canal afferents were mediated directly, i.e. they were not caused by alterations of motoneurone activity. 5. Excitation of Renshaw cells due to stimulation of the canal afferents was rarely observed; it could not be excluded that it was secondary to motoneurone discharges. 6. It is suggested that vestibular inhibition of Renshaw cells ensure a high gain of hind-limb alpha-motoneurones during postural adjustments following a massive disturbance of body equilibrium.


Colour polymorphism in the salt-marsh isopod, Sphaeroma rugicauda; Evidence for stable equilibrium frequencies.
If morph frequencies in a polymorphic population are maintained at stable equilibria, then if the frequencies are perturbed they should return to their equilibrium values. Artificial populations of the isopod were set up in cages on the salt-marsh with varying frequencies of the "pattern" morph. The cages were left undisturbed for five months over the breeding season. In the control cages the initial frequency of pattern (0.15) was the same as in the natural population. At the end of the experiment the frequency had not changed significantly, and was not significantly different from the frequency of pattern in the natural population (at the end of the experiment). High frequency cages started with pattern at a frequency of 0.5, showed significant decreases in frequency towards the control values, from which they were not significantly different by the end of the experiment. The average frequency in low frequency cages (started with pattern at 0.06) rose only slighly and was still significantly lower than the average control frequency by the end of the experiment. It is suggested that in these cages the restoring force may have been opposed by random processes, since pattern was lost entirely from some of the cages. The results indicate that the polymorphism is at a stable equilibrium, although the nature of the restoring forces were not identified.


Defining 'relative' androgen deficiency in aging men: how should testosterone be measured and what are the relationships between androgen levels and physical, sexual and emotional health?
In men, bioavailable and free testosterone levels decline by about 1.0 and 1.2% per year, respectively, after the age of 40. The definition of clinically relevant androgen deficiency in the aging male remains uncertain. Clinical features common to both aging and androgen deficiency include decreased muscle mass and strength, and increased fatigue, increased fat mass, loss of libido, erectile dysfunction, impaired cognitive function and depression. It is, however, difficult to separate the effect on plasma testosterone of concomitant disease, compared with the effects of a decrease in testosterone levels alone. Testosterone supplementation has been shown to be effective in improving many of the clinical features of androgen deficiency in the older male, and is safe, at least in the short term. The maximum benefit occurs in those men with the lowest testosterone levels.


Antimonial treatment of hamsters infected with Leishmania (Viannia) panamensis: assessment of parasitological cure with different therapeutic schedules.
The objective of the study was to establish the effective dose and route of administration of Glucantime for treating hamsters infected with Leishmania (Viannia) panamensis and to use this method to test new treatment regimens to attain clinical and parasitological cure. In the first experiments animals were inoculated subcutaneously in the hind foot with 5 x 10(6) promastigotes of L. panamensis (HOM/COL/84/1099) from a 6 d culture. One month after inoculation, Glucantime was administered intramuscularly (i.m.) at 20, 40 or 60 mg/kg/d for 20 d to groups of hamsters. Only 60 mg/kg/d resulted in both clinical improvement and parasite elimination from the skin and draining lymph node. In the second set of experiments, i.m., local and combined antimonial regimens were compared. The local regimen, of 4 intralesional (i.l.) injections of 4 mg of antimony at 5 d intervals, and the combined regimen (i.m. and i.l.), were more efficient at clearing parasites than the systemic (i.m.) schedule, especially when a low dosage of Glucantime (30 mg/kg/d x 20 d) was used. The results suggest that combining local treatment and low systemic dosages of antimonials results in clearance of L. panamensis.