Fractional CO₂ vaginal laser for the genitourinary syndrome of menopause in breast cancer survivors.
Adjuvant chemotherapy and endocrine therapy can induce early iatrogenic menopause or worsen pre-existing menopausal symptoms in breast cancer survivors (BCS). The second most frequent menopausal symptom after hot flushes is the genitourinary syndrome (GSM). Since hormone replacement therapy is contraindicated in BCS, vaginal laser might represent a new nonhormonal option for GSM. This study aims at evaluating the effectiveness of the fractional CO₂ vaginal laser for GSM in BCS compared with healthy women. This is a retrospective study on 135 postmenopausal women (45 BCS and 90 healthy women) who underwent fractional CO2 laser for GSM. Objective (VHI and VVHI) and subjective outcomes (VAS for dyspareunia and vaginal dryness and a pain questionnaire) were evaluated at baseline visit and at every follow-up visit. Subjective and objective parameters improved significantly in both groups after laser therapy. The improvement was progressive and long-lasting up to 12 months after the end of the treatment. No severe adverse events were observed during the treatment. Fractional CO₂ vaginal laser induces a significant and long-lasting improvement on GSM symptoms in BCS. However, this improvement is slower than in healthy women undergoing the same treatment. Laser therapy turns out to be safe and well-tolerated.


Gossypiboma of the leg: MR imaging characteristics. A case report.
We report a 22-year-old man with a solid mass in the right proximal leg, which was furned out to be a gossypiboma. MR imaging revealed a well-defined mass lesion that showed intermediate signal intensity at T1-weighted imaging (T1WI) and slightly high signal intensity at T2-weighted imaging (T2WI). Wavy, low-signal-intensity stripes were visible within the fluid-filled central cavity. At surgical exploration, a sponge, retained after previous knee surgery, was discovered, and it was found that a granuloma had developed. Pathologic examination revealed granulomatous inflammation, with lymphocyte and giant cell infiltration. The presence of wavy, low-signal-intensity gauze fibers at T2WI may be a characteristic MR appearance of gossypiboma.


Erratum: Real-Time Monitoring of Neurocritical Patients with Diffuse Optical Spectroscopies.
An erratum was issued for: Real-Time Monitoring of Neurocritical Patients with Diffuse Optical Spectroscopies. The Authors section was updated from: Rodrigo Menezes Forti1,2 Marilise Katsurayama2,3 Lenise Valler2,3 Andrés Quiroga1,2 Luiz Simioni1 Julien Menko4 Antonio L. E. Falcão3 Li Min Li2,5 Rickson C. Mesquita1,2 1Institute of Physics, University of Campinas 2Brazilian Institute of Neuroscience and Neurotechnology 3Clinical Hospital, University of Campinas 4Department of Emergency Medicine, Albert Einstein College of Medicine 5School of Medical Sciences, University of Campinas to: Rodrigo Menezes Forti1,2 Marilise Katsurayama2,3 Giovani Grisotti Martins1 Lenise Valler2,3 Andrés Quiroga1,2 Luiz Simioni1 Julien Menko4 Antonio L. E. Falcão3 Li Min Li2,5 Rickson C. Mesquita1,2 1Institute of Physics, University of Campinas 2Brazilian Institute of Neuroscience and Neurotechnology 3Clinical Hospital, University of Campinas 4Department of Emergency Medicine, Albert Einstein College of Medicine 5School of Medical Sciences, University of Campinas.


Cultural safety in telehealth consultations with Indigenous people: A scoping review of global literature.
Telehealth has become increasingly routine within healthcare and has potential to reduce barriers to care, including for Indigenous populations. However, it is crucial for practitioners to first ensure that their telehealth practice is culturally safe. This review aims to describe the attributes of culturally safe telehealth consultations for Indigenous people as well as strategies that could promote cultural safety. A scoping review was conducted on key features of cultural safety in telehealth for Indigenous people using the Johanna Briggs Institute (JBI) guidelines and PRISMA-ScR checklist. Five electronic databases were searched, and additional literature was identified through handsearching. A total of 649 articles were screened resulting in 17 articles included in the review. The central themes related to the provision of culturally safe telehealth refer to attributes of the practitioner: cultural and community knowledge, communication skills and the building and maintenance of patient-provider relationships. These practitioner attributes are modified and shaped by external environmental factors: technology, the availability of support staff and the telehealth setting. This review identified practitioner-led features which enhance cultural safety but also recognised the structural factors that can contribute, both positively and negatively, to the cultural safety of a telehealth interaction. For some individuals, telehealth is not a comfortable or acceptable form of care. However, if strategies are undertaken to make telehealth more culturally safe, it has the potential to increase opportunities for access to care and thus contribute towards reducing health inequalities faced by Indigenous peoples.


Antioxidant Activities and Total Phenolic Content of Aqueous Extract of Pleurotus ostreatus (Cultivated Oyster Mushroom).
Pleurotus ostreatus better known as oyster mushroom is widely cultivated and consumed as food in Malaysia. The present study aims to assess the antioxidative potential and total phenolic content of P. ostreatus aqueous extract. The antioxidant activities were evaluated against DPPH and ABTS radical-scavenging activity, ferric-reducing antioxidant power (FRAP) and β-carotene-linoleate bleaching assay, and the Folin-Ciocalteu method for total phenolic content (TPC). The DPPH and ABTS radical-scavenging activity was found to be 63.20% and 87.29% respectively; antioxidant activity using FRAP at 1.45 mM FE/100g and β-carotenelinoleate bleaching assay was 83.51%, while the TPC was found to be 798.55 mg GAE/100g. These antioxidant activities were compared to synthetic antioxidant, BHA and ascorbic acid. Ascorbic acid showed highest scavenging effects on DPPH and ABTS radical, followed by P. ostreatus and BHA (at maximum safety limit). The ferric reducing power of P. ostreatus was significantly higher than BHA and ascorbic acid. The antioxidant activity as assessed in β-carotene-linoleate bleaching assay was found to be higher in BHA compared to P. ostreatus. The aqueous extract of P. ostreatus was found to respond differently in antioxidant assays. The antioxidative activity of the aqueous extract of P. ostreatus correlated with its total phenolic content. Generally, the antioxidant activities of P. ostreatus' aqueous extract are comparable to that of BHA and ascorbic acid to a certain extent.


[Health problems and childhood causes of death in Spain 1900-1935].
Referring to risk model used in epidemiology, the research proposed the use of a holistic framework for the understanding and explain the relations that existed between health levels and causes of death in Spanish children between 1900 and 1935. In the first place, to analyse the evolution of some of the main causes of infant deaths. Secondly, will attempt to explain some of the main trends in infant mortality through the analysis of certain disease frameworks, including both primary or etiological elements and together with socio-economic and cultural context. In the opinion of Spanish hygienists and paediatricians of the period, these disease frameworks (feeding practices, popular attitudes to children's health, as in the case of teething, etc.) were responsible for the high levels of infant morbidity and mortality.


The effects of RNA interference mediated VEGF gene silencing on biological behavior of renal cell carcinoma and transplanted renal tumor in nude mice.
This study was to explore the effects of RNA interference mediated vascular endothelial growth factor (VEGF) gene silencing on biological behavior of renal cell carcinoma (RCC), transplanted renal tumor and angiogenesis in nude mice. The specific siRNA sequence targeting VEGF were designed and synthesized to construct hVEGF-siRNA plasmid which was transfected into RCC 786-O cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used for the detection of VEGF gene expression and western blot was adopted for the examination of VEGF protein expression. The 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to detect cell growth as well as cell migration and invasion. The transplanted renal tumor models in nude mice were established, and the growth condition of nude mice, and VEGF protein expression in transplanted tumor slices and the microvessel density (MVD) were detected. The expression level of VEGF mRNA in VEGF-siRNA group was significant lower than that in the control group and negative group, suggesting that establishment of plasmid specifically inhibited the expression of VEGF gene The expression level of VEGF protein in VEGF-siRNA group was significant lower than that in the control group and negative group. VEGF gene silencing has the significant inhibition effects on proliferation, migration and invasion of RCC 786-O cells. The tumor weight, VEGF protein positive rate and MVD in VEGF-siRNA group were significant lower than those in negative group and blank group. The VEGF gene silencing could inhibit the cell proliferation, migration and invasion of RCC 786-O cells; inhibition of VEGF protein expression could prevent transplanted RCC growth and tumor angiogenesis.


A Comparative Study of the Effect of Low-Dose Epinephrine and Ketamine on Rapid-Sequence Endotracheal Intubation by the Priming Dose Method of Cisatracurium in Patients under General Anesthesia.
Low-dose ephedrine and ketamine may accelerate the onset time of action of neuromuscular blocking agents. We studied the effect of ephedrine and ketamine and cisatracurium priming on endotracheal intubation conditions and the onset time of action of cisatracurium. The study was a double-blind clinical trial performed on American Society of Anesthesiologists (ASA) class 1 and 2 patients, who were candidates for general anesthesia. In total, 120 patients were entered into the study and were divided into 4 groups, E, K, E + K, and N. The first group was given 70 mcg/kg ephedrine (E group), the second group was given 0.5 ml/kg ketamine (K group), the third group was given the same amount of ketamine plus ephedrine (E + K group), and the fourth group was given the same volume of normal saline (control group); a single dose of 0.1 mg/kg cisatracurium was given, and intubating conditions were evaluated at 60 seconds after cisatracurium administration. The mean Cooper score based on the response to laryngoscopy, the position of the vocal cords, and the movement of the diaphragm of patients in the control group with a mean of 2.53 ± 1.07 was significantly lower than in the three groups of E, K, and E + K with the means of 4.47. 1.17, 4.53 ± 1.14, and 7.63 ± 1.42, respectively (P value < 0.001). In the (E + K) group, it was significantly higher than in the two other drugs alone (P value < 0.001). The two groups of E and K alone were not significantly different from each other (P value = 0.997). The means of hemodynamic parameters were not significantly different in any of the groups (P value > 0.05). According to the results of the present study, the use of low-dose ephedrine and ketamine alone can improve intubation conditions. In addition, the combined use of these drugs not only had any Positive effect on patients' hemodynamic parameters but also greatly improved intubation conditions.


Development of ultraviolet-reflecting butterfly scales: How to make an interference filter.
Light and electron microscope studies of development of the ultraviolet-reflecting scales of male Colias eurytheme butterflies show that basic developmental processes are similar to those of other scales. The ridges form between bundles of microfilaments and as they form they buckle to produce the lamellae seen in the adult scales. There is evidence that the buckling may be purely in response to mechanical stress and that some of the bundles of microfilaments may produce such stresses.


Virulence genes in verocytotoxigenic Escherichia coli strains isolated from humans and cattle.
Verocytotoxigenic Escherichia coli (VTEC) causing diarrhoea, haemorrhagic colitis and haemolytic-uremic syndrome usually have additional traits such as the adhesin intimin and a large plasmid that seems to increase virulence. There are, however, isolates of VTEC causing serious symptoms that do not harbour these traits. In the present study we have used PCR with primers detecting adhesin genes other than eaeA, namely fimA, papC, sfaD/sfaE and daaE. We have also used PCR to detect the genes hlyA and iutA that besides the plasmid-borne gene E-hly possibly support the bacterial access to iron. The aim of the study was to identify and compare the presence of virulence genes in VTEC isolates of human and cattle origin. The main finding was that the absence of E-hly might be compensated for by the gene iutA coding for aerobactin or hlyA coding for alpha-haemolysin as 94% of the human VTEC isolates had at least one of these genes. Interestingly, only 45% of VTEC isolated from cattle had any of these genes. We propose that this might be the reason for the relatively low incidence of symptomatic VTEC infections among humans in relation to the high number of VTEC among cattle.


[Finite element modeling and simulation of the human tympanic membrane].
Besides a knowledge of material properties geometric properties are needed to investigate the mechanical behavior of the human eardrum. Although the geometry of the eardrum has been examined methodically, its composition has been described in the literature. The true surface geometry of a cadaver specimen of the human eardrum was examined under a laser-scanning microscope. Forty points (85 parameters) depicted the surface of this cadaver specimen and formed the basis for a finite shell model. Furthermore, the coupling with the malleus and its suspension was simulated. Additional geometric and material parameters were chosen from the available literature. Both static behavior and the influence of a parameter variation to modal behavior of the finite element model were tested. ANSYS 5.1 software was used for this study.


Etiology and treatment of social anxiety: a commentary.
Substantial advances in our understanding of the etiology and treatment of performance anxiety have occurred during the past decade. It has become clear that the development of efficient and effective treatments cannot be divorced from knowledge of the specific form of psychopathology being treated and that treatments must be tailored to this psychopathology. After describing a current model of the etiology of performance anxiety and social phobia, this commentary notes the common factors present across the rich and diverse set of articles in this issue describing treatments from different approaches and different theoretical orientations. To the extent that these common factors are important mechanisms of action, it is possible that the future will introduce more unified and more effective, efficient, and theoretically informed treatment for performance anxiety as well as the potential for preventive techniques.


Chronic cough - occupational considerations.
Chronic cough is a common symptom in a wide range of respiratory conditions, and may also occur as a result of upper airway or gastro-esophageal problems. Whilst chronic cough of any cause may be exacerbated by work, in some cases it has a direct occupational cause, resulting from a harmful acute or chronic workplace exposure. Such occupational conditions may only be suspected by taking a detailed occupational history, and directly asking employed patients whether their cough improves away from work. Early and accurate diagnosis, linked with tailored drug therapy, modification of workplace exposures, and expert compensation advice is likely to offer the best outcome for this group of patients.


Prevalence, patterns of treatment, and control of hypertension in predialysis patients with chronic kidney disease.
Data on the prevalence, treatment and control of hypertension in patients with advanced chronic kidney disease (CKD) are limited. This study aimed to examine the above factors in a cohort of predialysis patients. During a period of 4 months, we recorded information on blood pressure (BP), comorbidities, medications and related parameters of patients followed up in the Low-Clearance Clinic of our Department. Control rates of hypertension were calculated at two thresholds: <130/80 and <140/90 mm Hg. Univariate and multiple linear regression analyses were employed to assess factors associated with BP control. In the population studied [n = 238, males 58.4%, age 66.21 ± 4.2 years (mean ± SD), estimated glomerular filtration rate 14.5 ± 4.8 ml/min/1.73 m(2)], the prevalence of hypertension was 95.0%. Treatment rate among hypertensives was at 99.1%. On average, 3.04 ± 1.32 antihypertensive drugs were used, ranging from 1 to 7 agents. BP control rates at the <130/80 and <140/90 mm Hg thresholds were 26.5% and 48.2%, respectively. The systolic goal was achieved in 31.0% and 50.4%, whereas the diastolic goal was achieved in 67.7% and 91.2% of patients, respectively. In multivariate analysis, only black race was independently and inversely related with hypertension control (β = -0.187, p = 0.030). No specific antihypertensive class showed independent associations with control. Hypertension is highly prevalent in predialysis CKD patients. An almost universal treatment, employing a multi-agent regime, can help towards improved rates of control. Systolic BP is the main barrier to successful control and black race is associated with poorer control rates.


Distinct displacements of the optic radiation based on tumor location revealed using preoperative diffusion tensor imaging.
OBJECT Visual field defects (VFDs) due to optic radiation (OR) injury are a common complication of temporal lobe surgery. The authors analyzed whether preoperative visualization of the optic tract would reduce this complication by influencing the surgeon's decisions about surgical approaches. The authors also determined whether white matter shifts caused by temporal lobe tumors would follow predetermined patterns based on the tumor's topography. METHODS One hundred thirteen patients with intraaxial tumors of the temporal lobe underwent preoperative diffusion tensor imaging (DTI) fiber tracking. In 54 of those patients, both pre- and postoperative VFDs were documented using computerized perimetry. Brainlab's iPlan 2.5 navigation software was used for tumor reconstruction and fiber visualization after the fusion of DTI studies with their respective magnetization-prepared rapid gradient-echo (MP-RAGE) images. The tracking algorithm was as follows: minimum fiber length 100 mm, fractional anisotropy threshold 0.1. The lateral geniculate body and the calcarine cortex were employed as tract seeding points. Shifts of the OR caused by tumor were visualized in comparison with the fiber tracking of the patient's healthy hemisphere. RESULTS Temporal tumors produced a dislocation of the OR but no apparent fiber destruction. The shift of white matter tracts followed fixed patterns dependent on tumor location: Temporolateral tumors resulted in a medial fiber shift, and thus a lateral transcortical approach is recommended. Temporopolar tumors led to a posterior shift, always including Meyer's loop; therefore, a pterional transcortical approach is recommended. Temporomesial tumors produced a lateral and superior shift; thus, a transsylvian-transcisternal approach will result in maximum sparing of the fibers. Temporocentric tumors also induced a lateral fiber shift. For those tumors, a transsylvian-transopercular approach is recommended. Tumors of the fusiform gyrus generated a superior (and lateral) shift; consequently, a subtemporal approach is recommended to avoid white matter injury. In applying the approaches recommended above, new or worsened VFDs occurred in 4% of the patient cohort. Total neurological and surgical morbidity were less than 10%. In 90% of patients, gross-total resection was accomplished. CONCLUSIONS Preoperative visualization of the OR may help in avoiding postoperative VFDs.


Inactivation of horse liver alcohol dehydrogenase by modification of cysteine residue 174 with 3-bromopropionic acid.
Horse liver alcohol dehydrogenase is inactivated with Michaelis kinetics at pH 7 and 25 degrees C by 3-bromopropionic acid. In the absence of NAD+, the Ki is 2 mM, and the pseudo bimolecular rate constant (k3/Ki) is 0.03 M-1 s-1; in the presence of 1 mM NAD+, Ki is 2.3 mM, and k3/Ki is 0.006 M-1 s-1. 3-Bromopropionic acid is a competitive inhibitor, Ki of 0.4 mM, against ethanol as a substrate. Inactivation was prevented in the ternary complexes with NAD+ X pyrazole and NADH X isobutyramide, was retarded by NAD+, NADH, or bipyridine, and was almost unaffected by imidazole and AMP. Carboxyethylated enzyme did not detectably (as observed spectrophotometrically) bind bipyridine, NAD+, or NADH. Enzyme was inactivated with radioactive 3-bromopropionic acid, aminoethylated, and digested with trypsin and chymotrypsin. Analysis of the labeled peptides showed that Cys-174 was predominantly modified. In the presence of 1 mM NAD+, the reaction was much less specific. The interaction of the carboxyl group of 3-bromopropionic acid with the guanidino group of Arg-369 probably facilitates the selective reaction with Cys-174, which is ligated to the zinc at the active site. Carboxyethylation apparently inactivates by interfering with the proper binding of the pyrophosphate of the coenzyme to the enzyme.


Foot and ankle biomechanics in walking and running. A review.
The biomechanics of the foot and ankle are initially discussed, as a series of isolated joints and segments, and subsequently as an integrated unit during the functional activities of walking and running. The kinematics and kinetics of the foot and ankle during the three major components of stance phase are reviewed. The first component, between foot contact and foot flat, is characterized primarily by force absorption. The portion of the gait cycle between foot flat and heel off is associated with controlled forward progression of the center of mass and maximum mobility of the transverse tarsal joint. In the third phase, supination of the foot results in increased rigidity of the transverse tarsal joint, and therefore improved force transmission. The controversy regarding the function of the triceps surae during this phase of the gait cycle is discussed.


[René Allendy, or the evolution of a misunderstanding].
The publication of the correspondence between Sigmund Freud and René Laforgue clarifies the conditions of the development of psychoanalysis in France. Freud's cautiousness towards French psychoanalysts is immediately apparent. It rests on what Freud perceives as a lack of respect for the founding principles of his work. The misunderstanding between Vienna and Paris is immediate, profound and enduring. The evolution of this misunderstanding, its transmission, and its effects, will be depicted by studying the work and the practice of René Allendy.


Emergence of leadership in a robotic fish group under diverging individual personality traits.
Variations of individual's personality traits have been identified before as one of the possible mechanisms for the emergence of leadership in an interactive collective, which may lead to benefits for the group as a whole. Complementing the large number of existing literatures on using simulation models to study leadership, we use biomimetic robotic fish to gain insight into how the fish's behaviours evolve under the influence of the physical hydrodynamics. In particular, we focus in this paper on understanding how robotic fish's personality traits affect the emergence of an effective leading fish in repeated robotic foraging tasks when the robotic fish's strategies, to push or not to push the obstacle in its foraging path, are updated over time following an evolutionary game set-up. We further show that the robotic fish's personality traits diverge when the group carries out difficult foraging tasks in our experiments, and self-organization takes place to help the group to adapt to the level of difficulties of the tasks without inter-individual communication.


Subcortical contributions to the sense of body ownership.
The sense of body ownership (i.e., the feeling that our body or its parts belong to us) plays a key role in bodily self-consciousness and is believed to stem from multisensory integration. The development of experimental paradigms that allow the controlled manipulation of body ownership in laboratory settings, such as the rubber hand illusion, provide an effective tool to investigate the malleability of the sense of body ownership and the boundaries distinguishing self and other. Neuroimaging studies on body ownership converge on the involvement of several cortical regions, including the premotor cortex and posterior parietal cortex. However, relatively less attention has been paid to subcortical structures that may also contribute to body ownership perception, such as the cerebellum and putamen. Here, on the basis of neuroimaging and neuropsychological observations, we provide an overview of relevant subcortical regions and consider their potential role in generating and maintaining a sense of ownership over the body. We also suggest novel avenues for future research targeting the role of subcortical regions in making sense of the body as our own.


Hepatocyte growth factor promotes proliferation and neuronal differentiation of neural stem cells from mouse embryos.
Hepatocyte growth factor (HGF), originally cloned as a hepatocyte mitogen, has recently been reported to exhibit neurotrophic activity in addition to being expressed in different parts of the nervous system. At present, the effects of HGF on neural stem cells (NSCs) are not known. In this study, we first report the promoting effect of HGF on the proliferation of neurospheres and neuronal differentiation of NSCs. Medium containing only HGF was capable of inducing neurosphere formation. Addition of HGF to medium containing fibroblast growth factor 2 or epidermal growth factor increased both the size and number of newly formed neurospheres. More neurons were also obtained when HGF was added in differentiation medium. In contrast, neurosphere numbers were reduced after repeated subculture by mechanical dissociation, suggesting that HGF-formed neurospheres comprised predominantly progenitor cells committed to neuronal or glial lines. Together, these results suggest that HGF promotes proliferation of neurospheres and neuronal differentiation of NSCs derived from mouse embyos.


Pico145 inhibits TRPC4-mediated mICAT and postprandial small intestinal motility.
In intestinal smooth muscle cells, receptor-operated TRPC4 are responsible for the majority of muscarinic receptor cation current (mICAT), which initiates cholinergic excitation-contraction coupling. Our aim was to examine the effects of the TRPC4 inhibitor Pico145 on mICAT and Ca2+ signalling in mouse ileal myocytes, and on intestinal motility. Ileal myocytes freshly isolated from two month-old male BALB/c mice were used for patch-clamp recordings of whole-cell currents and for intracellular Ca2+ imaging using Fura-2. Functional assessment of Pico145's effects was carried out by standard in vitro tensiometry, ex vivo video recordings and in vivo postprandial intestinal transit measurements using carmine red. Carbachol (50 µM)-induced mICAT was strongly inhibited by Pico145 starting from 1 pM. The IC50 value for the inhibitory effect of Pico145 on this current evoked by intracellularly applied GTPγS (200 µM), and thus lacking desensitisation, was found to be 3.1 pM, while carbachol-induced intracellular Ca2+ rises were inhibited with IC50 of 2.7 pM. In contrast, the current activated by direct TRPC4 agonist (-)-englerin A was less sensitive to the action of Pico145 that caused only ∼43 % current inhibition at 100 pM. The inhibitory effect developed rather slowly and it was potentiated by membrane depolarisation. In functional assays, Pico145 produced concentration-dependent suppression of both spontaneous and carbachol-evoked intestinal smooth muscle contractions and delayed postprandial intestinal transit. Thus, Pico145 is a potent GI-active small-molecule which completely inhibits mICAT at picomolar concentrations and which is as effective as trpc4 gene deficiency in in vivo intestinal motility tests.


Long-wavelength optical properties of a plasmonic crystal.
The optical properties of a plasmonic crystal composed of gold nanorod particles have been studied. Because of the strong coupling between the incident light and vibrations of free electrons, the long-wavelength optical properties such as the dielectric abnormality and polariton excitation etc., which were suggested originally in ionic crystals, can also be present in the plasmonic crystal. The results show that the plasmonic and ionic lattices may share a common physics.


Force transducers for the evaluation of labial, lingual, and mandibular motor impairments.
Three transducers were developed for evaluating lip, tongue, and jaw muscle force control in individuals with motor speech disorders. The rationale for the development of these transducers was based upon the hypothesized need for clinical assessment of the individual motor subsystems of the speech production mechanism. To provide an indication of the utility of these devices, exemplary force control data from adults with Parkinson's disease and spastic cerebral palsy are provided. Observations of differential force control impairment in the labial, lingual, and mandibular subsystems of these dysarthric individuals supported the rationale for this development. Observations were made also concerning the utility of these nonspeech measures for predicting speech motor dysfunction.


Current treatment options to prevent perinatal transmission of herpes simplex virus.
Neonatal herpes is a potentially devastating consequence of perinatal transmission of the herpes simplex virus (HSV), with significant morbidity and mortality. Treatment options are available, but must begin early in disease with manifestations that are often protean. Thus, preventive measures need to be optimised. Antiviral suppression in late pregnancy of women with a history of recurrent genital herpes will decrease symptomatic recurrence at delivery and appears to reduce caesarian section rates. However, primary HSV Type 2 and primary HSV Type 1 episodes have the highest neonatal transmission rates and thus, effective prevention may require the identification and suppression of the discordant partner. Significant experience has been gained with the use of acyclovir in pregnancy and it is recommended for both episodic and suppressive therapy in pregnant women. Its use has been demonstrated to be cost-effective in suppressive therapy, although issues regarding compliance and the potential for neonatal neutropenia need to be addressed. The more conveniently dosed prodrugs valacyclovir and famciclovir are being evaluated for use in pregnancy.


Electrosurgery: short-circuit between education and practice.
Introduction: Electrosurgery is used in 80% of surgical procedures. The technique allows surgeons to skilfully dissect tissues and achieve haemostasis. Since improper use of electrosurgery can lead to serious adverse events, training is required to potentially reduce the number and severity of these events. In this study we evaluate education and training in electrosurgery for surgical residents. Material and methods: Residents from six surgical subspecialties in the Netherlands were invited to anonymously complete a digital questionnaire about training, supervision and adverse events regarding electrosurgery. Results: Of the 197 respondents, 69% had received some form of training; mostly a single theoretical lecture. The feeling of competence in theory and practical skills was positively rated by 39% and 71%, respectively. Moreover, 35% judged the theoretical knowledge of their supervisors as insufficient and 65% changed their electrosurgical application technique to the preference of the supervisor. 30% of the residents had encountered a serious adverse event (e.g., burn wounds) related to the application of electrosurgery. Conclusions: The training of residents in theoretical aspects of electrosurgery is limited. Residents are not satisfied with the acquired theoretical knowledge of themselves and of their supervisors. Since adverse events related to electrosurgery occur frequently, more extensive education for both residents and their supervisors is needed to enhance patient safety.


Spontaneous Pneumothorax in a Young Female With Lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare disorder of abnormal proliferation of smooth muscle-like cells which results in the formation of thin-walled cysts and progressive lung destruction. It commonly presents with progressive dyspnea that is often associated with a history of pneumothorax or chylothorax particularly among females of reproductive age. In this report, we present a case of hydropneumothorax as the initial presentation of LAM in a 33-year-old woman, a rather rare presentation. We also discuss the pathogenetic mechanisms, the diagnosis, and treatment strategies using mTOR inhibitors like sirolimus.


TRAP-5' stem loop interaction increases the efficiency of transcription termination in the Bacillus subtilis trpEDCFBA operon leader region.
TRAP regulates expression of the Bacillus subtilis trpEDCFBA operon by a transcription attenuation mechanism in which tryptophan-activated TRAP binds to 11 (G/U)AG repeats in the nascent trp leader transcript. Bound TRAP blocks formation of an antiterminator structure and allows formation of an overlapping intrinsic terminator upstream of the trp operon structural genes. A 5' stem-loop (5'SL) structure located upstream of the triplet repeat region also interacts with TRAP. TRAP-5'SL RNA interaction participates in the transcription attenuation mechanism by preferentially increasing the affinity of TRAP for the nascent trp leader transcript during the early stages of transcription, when only a few triplet repeats have been synthesized. Footprinting assays indicated that the 5'SL contacts TRAP through two discrete groups of single-stranded nucleotides that lie in the hairpin loop and in an internal loop. Filter binding and in vivo expression assays of 5'SL mutants established that G7, A8, and A9 from the internal loop, and A19 and G20 from the hairpin loop are critical for proper 5'SL function. These nucleotides are conserved among certain other 5'SL-containing organisms. Single-round transcription results indicated that the 5'SL increases the termination efficiency when transcription is fast; however, the influence of the 5'SL was lost when transcription was slowed by reducing the ribonucleoside triphosphate concentration. Since there is a limited amount of time for TRAP to bind to the nascent transcript and promote termination, our data suggest that the contribution of TRAP-5'SL interaction increases the rate of TRAP binding, which, in turn, increases the efficiency of transcription termination.


Hepatic resection for hepatocellular carcinoma in end-stage renal disease patients: two decades of experience at Chang Gung Memorial Hospital.
Hepatocellular carcinoma (HCC) is a common disease in Taiwan. The prevalence of viral hepatitis infection and the subsequent development of HCC are well known to be higher in patients with end-stage renal disease (ESRD) requiring hemodialysis (HD) or peritoneal dialysis (PD) than among the general population. However, information on hepatic resection for ESRD-HCC patients is limited. The clinical features of 26 ESRD-HCC patients who underwent hepatic resection from 1982 to 2001 were retrospectively reviewed. Meanwhile, the clinicopathological features and the outcome of 1 198 HCC patients without ESRD undergoing hepatic resection were used for comparison. Of 1 224 surgically resected HCC patients, 26 (4.2%) were ESRD-HCC. Univariate analysis revealed more associated disease, more physical signs of anemia and postoperative complications, lower hemoglobin, platelet, alpha-fetoprotein, elevated blood urea nitrogen (BUN) and creatinine levels, smaller tumors, lower HBsAg positivity, higher HCV positivity, and longer hospital stays in the ESRD-HCC group compared with the HCC group. Furthermore, multivariate stepwise logistic regression analysis revealed that elevated BUN and creatinine levels were the only two independently significant factors in the patients in the ESRD-HCC group. Overall and disease-free survival rates were similar between the ESRD-HCC and HCC groups. Elevated BUN and creatinine were the only two main independent factors differentiating ESRD-HCC from HCC patients. ESRD should not be a contraindication of hepatic resection in HCC patients; however, careful operative techniques and perioperative care are crucial to achieving lower morbidity and mortality. Comparable overall survival and disease-free survival can be achieved in selected ESRD-HCC patients undergoing hepatic resection when compared with conventional HCC patients.


Genetic analyses of a seasonal interval timer.
Seasonal clocks (e.g., circannual clocks, seasonal interval timers) permit anticipation of regularly occurring environmental events by timing the onset of seasonal transitions in reproduction, metabolism, and behavior. Implicit in the concept that seasonal clocks reflect adaptations to the local environment is the unexamined assumption that heritable genetic variance exists in the critical features of such clocks, namely, their temporal properties. These experiments quantified the intraspecific variance in, and heritability of, the photorefractoriness interval timer in Siberian hamsters (Phodopus sungorus), a seasonal clock that provides temporal information to mechanisms that regulate seasonal transitions in body weight. Twenty-seven families consisting of 54 parents and 109 offspring were raised in a long-day photoperiod and transferred as adults to an inhibitory photoperiod (continuous darkness; DD). Weekly body weight measurements permitted specification of the interval of responsiveness to DD, a reflection of the duration of the interval timer, in each individual. Body weights of males and females decreased after exposure to DD, but 3 to 5 months later, somatic recrudescence occurred, indicative of photorefractoriness to DD. The interval timer was approximately 5 weeks longer and twice as variable in females relative to males. Analyses of variance of full siblings revealed an overall intraclass correlation of 0.71 +/- 0.04 (0.51 +/- 0.10 for male offspring and 0.80 +/- 0.06 for female offspring), suggesting a significant family resemblance in the duration of interval timers. Parent-offspring regression analyses yielded an overall heritability estimate of 0.61 +/- 0.2; h(2) estimates from parent-offspring regression analyses were significant for female offspring (0.91 +/- 0.4) but not for male offspring (0.35 +/- 0.2), indicating strong additive genetic components for this trait, primarily in females. In nature, individual differences, both within and between sexes, in the timekeeping properties of seasonal interval timers, and a strong heritable basis thereof, would provide ample substrate for selection to rapidly influence seasonal clocks. Balancing selection in environments where the onset of spring conditions varies from year to year could maintain genetic variance in interval timers and yield interval timers tuned to the local environment.


Toxicological studies of deltamethrin.
Deltamethrin [( S]-alpha-cyano-3-phenoxybenzyl-cis-(1R,3R)-3-(2,2-dibromovinyl+ ++) (2,2-dimethyl-cyclopropane-carboxylate], is the most potent insecticide known at the present time. But it is also one of the most toxic pyrethroids for vertebrates. The toxicity study of deltamethrin was performed on mice and rats, and on anaesthetized dogs, the administration route being either oral or intravenous. The oral LD50 of deltamethrin suspended in 10% gum-arabic solution was 5.54 +/- 1.29 g/kg p.o. in male mice and 3.45 +/- 1.27 g/kg p.o. in female mice. In rats and anaesthetized dogs, deltamethrin at high concentrations by the oral route engendered neither mortality nor signs of intoxication. When dissolved in glycerol formal and given intravenously, the LD50 of deltamethrin was as low as 3.44 +/- 0.67 mg/kg in anaesthetized dogs. Values obtained for the toxicity of deltamethrin varied not only with the animal species and sex involved, but also with the administration routes and solvents used. Administered orally, it was 100 times less toxic when suspended in gum-arabic solution than dissolved in oil or organic solvent. Whatever the animal species, sex, administration routes and solvents employed, the poisoning symptoms of deltamethrin are identical, i.e. salivation, ataxia and choreoathetotic movements with rolling convulsions, appearing within 7 h after administration. No cellular alteration was detectable by means of optical microscopy of excised organs.


Multiple Grouped Scalp Nodules in a Middle-Aged Man: A Rare Case of Angiolymphoid Hyperplasia with Eosinophilia.
An otherwise healthy man in his 50s presented complaining of pruritic lesions on the left side of his scalp. The lesions had slowly been growing in size over the preceding 30 years. They would occasionally bleed, and this is what ultimately prompted him to seek medical advice. Physical examination revealed multiple aggregated and soft, flesh-colored nodules on the left posterior auricular area of the scalp (Figure 1). No appreciable clinical lymphadenopathy was identified on examination. A shave biopsy of one of the nodules was performed for diagnostic clarification.


Trigeminal Nerve White Matter Fiber Abnormalities in Primary Trigeminal Neuralgia: A Diffusion Spectrum Imaging Study.
Diffusion spectrum imaging (DSI) was used to quantitatively study the changes in the trigeminal cistern segment in patients with trigeminal neuralgia (TN) and to further explore the value of acquiring DSI data from patients with TN. To achieve high-resolution fiber tracking, 60 patients with TN and 35 healthy controls (HCs) were scanned with conventional magnetic resonance imaging (MRI) and DSI. The patients and the members of the control group were compared within and between groups. The correlations between quantitative parameters of DSI and the visual analog scale (VAS), and symptom duration and responsible vessel types were analyzed. Compared with unaffected side of patients in the TN group, the affected side showed significantly decreased quantitative anisotropy (QA) (p < 0.001), fractional anisotropy (FA) (p = 0.001), and general FA (GFA) (p < 0.001). The unaffected side exhibited significantly decreased QA (p + 0.001), FA (p = 0.001), and GFA (p < 0.001) and significantly increased axial diffusivity (AD) (p = 0.036) compared with the affected side of patients in the TN group and the average values of HCs. There were significantly decreased QA (p = 0.046) and FA (p = 0.008) between the unaffected side of patients and the average values of HCs. GFA can evidently distinguish arteries, veins, and features of unaffected side in TN patients. Using high-resolution fiber tracking technology, DSI can provide quantitative information that can be used to detect the integrity of trigeminal white matter in patients with TN and can improve the understanding of the disease mechanism.


Dietary Glycemic Index and Glycemic Load Are Positively Associated with Oxidative Stress among Premenopausal Women.
Diets with a high glycemic index (GI) and glycemic load (GL) have been hypothesized to increase oxidative stress, but the limited human studies are inconsistent. The aim of this cross-sectional study was to investigate associations between dietary GI, GL, and carbohydrate intake and oxidative stress, as measured by F2-isoprostanes (F2-IsoPs). Concentrations of F2-IsoP and its metabolite (15-F2t-IsoP-M) were measured in urine samples collected at enrollment from 866 premenopausal women (aged 35-54 y) participating in the Sister Study. Total carbohydrate intake and dietary GI and GL were assessed using a validated food frequency questionnaire. Urinary F2-IsoP and 15-F2t-IsoP-M concentrations were compared across quintiles of carbohydrate intake, GI, and GL using multivariable linear regression models. Urinary F2-IsoP concentrations were positively associated with dietary GI (P-trend = 0.023), and both F2-IsoP and 15-F2t-IsoP-M concentrations were positively associated with GL (F2-IsoP: P-trend < 0.001; 15-F2t-IsoP-M: P-trend < 0.001) and total carbohydrate intake (F2-IsoP: P-trend = 0.012; 15-F2t-IsoP-M: P-trend < 0.001). Stratified analyses suggested that a positive association between GI and urinary 15-F2t-IsoP-M concentrations was present among women with a body mass index [BMI (in kg/m2)] ≥30.0, but not among those with a BMI of <25.0 or 25.0-29.9 (P-interaction = 0.01). Our cross-sectional analyses in a sample of premenopausal women support hypothesized relations between high dietary GI and GL and oxidative stress, as assessed by urinary F2-IsoP and 15-F2t-IsoP-M concentrations. Given potential associations between oxidative stress and the development of cardiovascular disease and type 2 diabetes, our findings may have important implications for reducing chronic disease risk.


Structure and thermodynamics of carbon and carbon/silicon precursors to nanostructures.
The structures at the Hartree-Fock level, as well as the energetics, are reported for the unsaturated system C(36)H(16), its Si-doped analogue C(32)Si(4)H(16), and several smaller, unsaturated fragments. Structural effects on the electronic distribution are discussed in terms of a localized orbital energy decomposition. The standard heats of formation are calculated based on homodesmic and isodesmic reactions and the G2(MP2,SVP) method with a valence double-zeta plus polarization basis. The origin of the observed explosion of the all-carbon system (C(36)H(16)) to form carbon nanotubes was investigated by exploring a possible initial reactive channel (dimerization), which could lead to the formation of the observed onion-type nanostructures.


Clinicopathological features of 50 mismatch repair (MMR)-deficient endometrial carcinomas, tested by immunohistochemistry: A single institutional feasibility study, India.
There are few comprehensive studies from Asia on clinicopathologic features of mismatch repair (MMR)-deficient endometrial carcinomas, including rarely from our country. One hundred and four cases of endometrial carcinomas were tested for four MMR proteins by immunohistochemistry. Among 50 MMR-deficient (MMRd) tumors(48%), age-range was 27-68 years(median = 53) and tumor size(n = 34) varied from 1.2-10 cm(average = 4.6). Lower uterine segment(LUS) was involved in 21/31 cases(67.7%). Histopathologically, all cases were endometrioid adenocarcinomas(EMACs), of FIGO grade 2(low-grade)(18 cases) and 3(high-grade)(32 cases), displaying de-differentiated, undifferentiated and lymphoepithelioma(LE)-like patterns, in 24 cases(48%). Tumor infiltration ≥ half of myometrium was seen in 30/44 cases (68.1%); lymphovascular emboli in 19/43 cases(44.1%); and lymph node metastasis in 7/22(31.8%) cases. Uncommonly, clear cell component(n = 2) and focal neuroendocrine differentiation (n = 2) were observed. Immunohistochemically, tumor cells showed paired loss of MLH1 and PMS2 in 33(66%) and MSH2 and MSH6 in 14(28%) cases, along with loss of MSH2 and PMS2, in two and a single case, respectively. Nine patients(18%) were treated for another cancer and 9/33(27.2%) disclosed familial history of cancer. MSH2 was the most frequently lost MMR protein in those cases. Additionally, tumor cells displayed ER positivity in 41/50 cases(82%), PR in 38/41cases(92.6%) and wild-type p53 staining in 24/28 cases(85.7%). Tumor with LE-pattern showed PDLI immunoexpression. Certain clinicopathologic features suggestive for MMRd associated ECs, such as relatively large-sized tumors, involving LUS; especially high-grade, infiltrative EMACs, with undifferentiated/de-differentiated, and LE-like patterns; showing deep muscle invasion, frequent PR immunoexpression and invariably, wild-type p53 immunostaining can be useful in screening cases of Lynch syndrome. This constitutes the first report on these tumors from our country.


Preterm birth and/or low birth weight are associated with periodontal disease and the increased placental immunohistochemical expression of inflammatory markers.
The objective of this study was to determine whether gynecological and periodontal clinical parameters and the immunohistochemical expression in placental chorionic villi of the markers cyclooxygenase-2 (COX-2), interleukin (IL)-1β, vascular endothelial growth factor receptor 1 (VEGFR1), podoplanin, and Heat Shock Protein 70 (HSP70) are associated with preterm birth (PB) and/or low birth weight (LBW) neonates. An observational case-control study was performed in 130 puerperal women: mothers of PB/LBW neonates (cases, n=65) and mothers of full-term normal-weight neonates (controls, n=65). Data were gathered from all participants on socio-demographic, gynecological, and periodontal variables and on placental immunohistochemical COX-2, IL-1β, VEGFR1, podoplanin, and HSP70 expression. Among the 42 women with mild/moderate periodontitis or gingivitis, the studied periodontal variables were significantly worse and the placental COX-2 (p=0.043), HSP70 (p=0.001), IL-1β (p=0.001), VEGFR1 (p=0.032), and podoplanin (p=0.058) expressions were significantly higher in the cases than in the controls. In comparison to the mothers without periodontitis, only COX-2 (p=0.026) and VEGFR1 (p=0.005) expressions were significantly increased in those with the disease. Increased COX-2 values were detected in the women with a history of genitourinary infection (p=0.036), premature rupture of membrane (p=0.012), or drug treatment (p=0.050). The etiology of preterm birth and/or low birth weight is multifactorial and involves consumption habits, social-health factors, and infectious episodes. These adverse pregnancy outcomes were associated with periodontitis and the increased placental expression of IL-1β, COX-2, VEGFR1, and HSP70.


Adenosine acts through A2 receptors to inhibit IL-2-induced tyrosine phosphorylation of STAT5 in T lymphocytes: role of cyclic adenosine 3',5'-monophosphate and phosphatases.
Adenosine is a purine nucleoside with immunosuppressive activity that acts through cell surface receptors (A(1), A(2a), A(2b), A(3)) on responsive cells such as T lymphocytes. IL-2 is a major T cell growth and survival factor that is responsible for inducing Jak1, Jak3, and STAT5 phosphorylation, as well as causing STAT5 to translocate to the nucleus and bind regulatory elements in the genome. In this study, we show that adenosine suppressed IL-2-dependent proliferation of CTLL-2 T cells by inhibiting STAT5a/b tyrosine phosphorylation that is associated with IL-2R signaling without affecting IL-2-induced phosphorylation of Jak1 or Jak3. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reversed by the protein tyrosine phosphatase inhibitors sodium orthovanadate and bpV(phen). Adenosine dramatically increased Src homology region 2 domain-containing phosphatase-2 (SHP-2) tyrosine phosphorylation and its association with STAT5 in IL-2-stimulated CTLL-2 T cells, implicating SHP-2 in adenosine-induced STAT5a/b dephosphorylation. The inhibitory effect of adenosine on IL-2-induced STAT5a/b tyrosine phosphorylation was reproduced by A(2) receptor agonists and was blocked by selective A(2a) and A(2b) receptor antagonists, indicating that adenosine was mediating its effect through A(2) receptors. Inhibition of STAT5a/b phosphorylation was reproduced with cell-permeable 8-bromo-cAMP or forskolin-induced activation of adenylyl cyclase, and blocked by the cAMP/protein kinase A inhibitor Rp-cAMP. Forskolin and 8-bromo-cAMP also induced SHP-2 tyrosine phosphorylation. Collectively, these findings suggest that adenosine acts through A(2) receptors and associated cAMP/protein kinase A-dependent signaling pathways to activate SHP-2 and cause STAT5 dephosphorylation that results in reduced IL-2R signaling in T cells.


Progression of hepatitis C infection in a renal transplant recipient: a case report.
We present a patient with hepatitis C virus (HCV) infection who developed chronic active hepatitis (CAH) after renal transplantation. Alpha-interferon (a-IF) therapy was administered in view of deteriorating liver biochemistry. Liver histology at this stage showed features suggestive of chronic active hepatitis (CAH). The patient had stable graft function. Therapy with a-IF resulted in noticeable biochemical response within two weeks of commencement. An episode of steroid resistant renal allograft rejection occurred after 10 weeks of a-IF therapy which responded well to anti-lymphocyte globulin. Since then, the CAH has gradually progressed on to the development of cirrhotic changes and hepato-cellular carcinoma after 10 years following transplantation. Our case indicates that liver disease in anti-HCV positive patients can follow a serious course following renal transplantation.


Herbal dewormer fails to control gastrointestinal nematodes in goats.
Gastrointestinal nematode (GIN) parasitism is the most important disease of small ruminants. Control is usually based on the use of chemical anthelmintics (dewormers); but these are prohibited from use in organic livestock, and the effectiveness of chemical anthelmintics in conventional operations is limited by high levels of anthelmintic resistance. Consequently, herbal dewormers are increasing in popularity as an alternative to chemical dewormers for GIN control. However, the effectiveness of herbal dewormers remains unproven. The objective of this study was to examine the effectiveness of a commercially available herbal dewormer to control GIN in goats. Lactating (n=16) and young (n=8) dairy goats grazed poor quality mixed grass pastures between March and July 2006 at the Heifer International Ranch in Perryville, AR. Goats were supplemented with grass hay and concentrate. Goats were untreated or administered herbal dewormer (n=12/treatment) according to manufacturer recommendations. FAMACHA scores (1=red or healthy; 5=severely anemic) were determined and fecal samples collected for fecal egg count (FEC) determination every 14 days between Days 0 (day of first herbal treatment) and 112. FAMACHA scores in the herbal treated group were greater than in the untreated control group (P<0.005), indicating a higher level of anemia. FEC were greater for herbal treated goats on Pasture A compared with B by Day 42, but similar among groups thereafter. FEC (P<0.03) and FAMACHA scores (P<0.001) were greater in lactating than in non-lactating goats. Herbal dewormer treatment yielded no measurable health benefits indicating that the herbal dewormer failed to control GIN in these goats.


Comprehensive circular RNA profiling reveals the regulatory role of circRNA_0007694 in papillary thyroid carcinoma.
The present study aimed to identify differentially expressed circRNAs in thyroid cancer and verify their potential functions. Next-generation sequencing was used to identify differentially expressed circRNAs between papillary thyroid carcinoma (PTC) tissues and paired pericarcinomatous tissues. Polymerase chain reaction and Sanger sequencing methods successfully identified hsa_circ_0007694. A hsa_circ_0007694 over-expression vector was prepared to determine the effect of this circRNA on proliferation, migration, invasion, apoptosis, and the cell cycle in PTC cells. An in vivo animal assay was conducted by injecting PTC cells into the chests of mice. Further, RNA-seq was performed, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, to verify the regulatory mechanism of hsa_circ_0007694. Western blotting was used to verify the genes thought to be involved in the hsa_circ_0007694 regulatory pathways based on KEGG analysis. We identified a circRNA, hsa_circ_0007694 that was down-regulated in PTC tissues compared to pericarcinomatous tissues. Over-expression of hsa_circ_0007694 promoted apoptosis and inhibited proliferation, migration, and invasion in PTC cells in vitro, and decreased tumor growth in vivo. Transcriptome sequence analysis suggested 129 differentially expressed genes between PTC tissue and paired pericarcinomatous tissue. KEGG analysis and western blotting indicated that the PI3K/AKT/mTOR and Wnt signaling networks are most likely to be related to hsa_circ_0007694 in thyroid cancer. The circRNA hsa_circ_0007694 is down-regulated in PTC and is therefore a potential therapeutic target.


Integration of reinforcement learning to realize functional variability of microfluidic systems.
In this article, we present a proof-of-concept for microfluidic systems with high functional variability using reinforcement learning. By mathematically defining the objective of tasks, we demonstrate that the system can autonomously learn to behave according to its objectives. We applied Q-learning to a peristaltic micropump and showed that two different tasks can be performed on the same platform: adjusting the flow rate of the pump and manipulating the position of the particles. First, we performed typical micropumping with flow rate control. In this task, the system is rewarded according to the deviation between the average flow rate generated by the micropump and the target value. Therefore, the objective of the system is to maintain the target flow rate via an operation of the pump. Next, we demonstrate the micromanipulation of a small object (microbead) on the same platform. The objective was to manipulate the microbead position to the target area, and the system was rewarded for the success of the task. These results confirmed that the system learned to control the flow rate and manipulate the microbead to any randomly chosen target position. In particular, the manipulation technique is a new technology that does not require the use of structures such as wells or weirs. Therefore, this concept not only adds flexibility to the system but also contributes to the development of novel control methods to realize highly versatile microfluidic systems.


Diagnostic procedures for small pulmonary nodules detected by mass-screening.
A retrospective study was performed to evaluate the diagnostic procedures performed in small peripheral pulmonary nodules that were detected at mass screening. The medical records were reviewed of patients who had peripheral pulmonary nodules < or =20 mm detected by mass screening between 1995 and 2007. A total of 41.7% of patients were diagnosed based on pathological findings of specimens obtained by bronchoscopic procedures (bronchoscopy group), while the remainder were diagnosed using specimens obtained by surgical biopsy (surgery group). The median diameter of lung tumors in the bronchoscopy group was 20 mm, while that in the surgery group was 15 mm. Of patients with lung cancer in the bronchoscopy group 22.9% had tumors < or =15 mm, however, 63.8% of patients in the surgery group had tumors < or =15 mm. Pulmonary nodules < or =15 mm in diameter found in specimens obtained by bronchoscopic procedures should be diagnosed by surgical biopsy.


Surgical strategies for the treatment of deformity-associated cervical spondylotic stretch myelopathy: a case series with technically nuanced illustrative operative videos.
The aim of this study was to elucidate the vital role of anterior-only osteotomies for rigid cervical kyphosis causing stretch myelopathy by using illustrative cases and high-definition intraoperative videos. The authors describe 4 select patients who underwent anterior-only osteotomies within a 2-year time frame and demonstrate the nuances of each case with unique operative videos. Outcomes for each of the cases demonstrated marked improvement in cervical spine alignment relative to preoperative conditions. Postoperative CT scans and upright radiographs for case 1 at 8 months demonstrated complete reduction of the kyphotic deformity and restoration of the C2 slope. In case 2, the 2-year postoperative radiographs showed significant realignment of the cervical spine, and the patient made significant neurological improvement since the operation, specifically in hand dexterity, balance, neck pain, and the ability to comfortably achieve and maintain a horizontal gaze. For case 3, postoperative upright radiographs revealed marked improvement in the patient's cervical sagittal alignment. The 4-month follow-up was also notable for substantial improvement in postural neck pain, bilateral upper extremity strength, and continued improvements in dexterity. Case 4 also demonstrated an excellent outcome with unkinking of the patient's spinal cord and correction of her sagittal plane deformity, as shown on her 5-month postoperative upright radiographs. Deformity-associated cervical spondylotic stretch myelopathy often leads to devastating neurological decline and can significantly decrease quality of life. Carefully selected cases of circumferentially rigid cervical kyphosis can be successfully corrected with anterior-only osteotomies followed by posterior fixation while avoiding back-front-back operations.


Stability of bovine adrenal medulla cells in culture.
The functional stability of primary cultures of adrenal medulla cells was investigated. Isolated cells were prepared by treatment of bovine adrenal glands with collagenase followed by purification on Percoll density gradients and were maintained in Dulbecco's medium containing 10% fetal calf serum. Within 12 h after plating on plastic culture dishes, the cells became firmly attached and exhibited good survival for periods of time up to 3 weeks, as indicated by their morphology using light and electron microscopy, by maintenance of their content of catecholamines, tyrosine hydroxylase, dopamine-beta-hydroxylase, and phenylethanolamine N-methyltransferase, and their ability to respond to secretagogues. During the first 10 days to 2 weeks in culture there was little or no change in any of these parameters. During the 3rd week there were progressive losses of catecholamine and enzyme activities and increased vacuolization of medullary cells. The cells synthesized protein and RNA with no apparent loss in activities over the period studied, but did not incorporate [3H]thymidine into PCA-precipitable material. The cells responded to secretagogues and secretory antagonists similarly to isolated perfused adrenal glands. The studies described here demonstrate that primary cultures of adrenal medulla cells provide an excellent experimental system for obtaining more detailed information on stimulus-secretion coupling and other functional aspects of the adrenal medulla.


Moderation effects of loneliness between fatalism and wellbeing during the COVID-19 pandemic.
The COVID-19 pandemic has put more than just our physical health at risk. Due to containment measures, people have become increasingly isolated and have drastically reduced their daily social interactions. Many studies have already shown the negative effects of these measures, including fatalism. However, research linking fatalism during COVID-19 to well-being indicators is still limited. The goal of this study is to examine the relationship between COVID-19-related fatalism and well-being indicators, as well as the role of loneliness in moderating this relationship. Data was collected from 1,036 adults in Peru through an online survey that included the Quality-of-Life Index, the Fatalism Facing COVID-19 Scale, the Loneliness Scale, and the Mood Assessment Scale. Three models were tested using linear regression and ordinary least squares with bias-corrected bootstrapping. The results indicate that fatalism has a negative impact on quality of life and a positive effect on negative affect, and loneliness moderates both relationships, supporting the conclusion that fatalism exacerbates the effect of well-being indicators and negative affect.


Finite element analysis predictions in the canine lumbar spine are useful and correlate with ex vivo biomechanical studies.
To verify the validity of finite element analysis (FEA) predictions obtained from a canine lumbar segment model in comparison with experimental biomechanical testing results from the same subjects. 6 healthy beagle dogs were euthanized for other purposes. The L1-2 and L5-6 segments were harvested from euthanized animals and subjected to rotation tests and compression tests, respectively, using both ex vivo mechanical testing and FEA. For each method, we recorded the maximum torque value and angle of vertebral body rotation at rupture observed in rotation tests, as well as the maximum stress value and displacement of the vertebral body endplate at rupture measured from compression tests. We then calculated Pearson's correlation coefficient to determine correlations between the angle of gyration and displacement at rupture determined by mechanical testing and FEA. The study started on March 26, 2021, and ended on March 18, 2023. For the rotation test, correlation coefficients for the maximum torque and rotation angle of the vertebral body at rupture were r = 0.92 and 0.96, respectively. For the compression test, correlation coefficients for the maximum stress and displacement of the vertebral body endplate at rupture were r = 0.73 and 0.94, respectively. All results showed strong correlations between the FEA predictions and ex vivo mechanical test results. These findings suggest that FEA predictions are sufficiently reliable for ex vivo mechanical test results for biomechanical studies of canine lumbar segment models.


A number-needed-to-treat analysis of the use of respiratory syncytial virus immune globulin to prevent hospitalization.
To estimate how many infants in selected high-risk subgroups would require treatment with respiratory syncytial virus immune globulin (RSV-IG) to avoid 1 hospital admission and to determine whether this is economically justified. Cost-benefit analysis. Data from 3 randomized controlled trials of RSV-IG are used to estimate the number needed to treat to prevent 1 hospital admission for respiratory syncytial virus infection. The threshold number needed to treat is computed according to a formula incorporating costs and benefits of RSV-IG prophylaxis. Estimates of the willingness to pay were obtained from a sample of 39 health care providers (35 physicians and 4 nurses). The number needed to treat to prevent 1 hospital admission for respiratory syncytial virus infection. The threshold number needed to treat that would balance costs with benefits. More than 16 (95% confidence interval, 12.5-23.8) infants would need to be treated with RSV-IG to avoid 1 hospital admission for respiratory syncytial virus infection, ranging from 63 for premature infants without chronic lung disease to 12 (confidence interval, 6.3-100.0) for infants with bronchopulmonary dysplasia. A sensitivity analysis of the costs and values of hospital admission for respiratory syncytial virus infection and RSV-IG treatment resulted in a weak recommendation against the treatment of infants with bronchopulmonary dysplasia and strong recommendations that the costs and risks of RSV-IG treatment outweigh the benefits for the combined sample of infants and premature infants without lung disease. The number-needed-to-treat procedures offer a method to assess evidence of treatment effects and decision rules for whether to accept treatment recommendations. Under plausible assumptions, treatment with RSV-IG is not recommended for infants without lung disease. Institutions can examine cost and benefit assumptions that best fit their own practice setting.


Endothelial FAK is required for tumour angiogenesis.
Focal adhesion kinase (FAK) is a cytoplasmic tyrosine kinase that plays a fundamental role in integrin and growth factor mediated signalling and is an important player in cell migration and proliferation, processes vital for angiogenesis. However, the role of FAK in adult pathological angiogenesis is unknown. We have generated endothelial-specific tamoxifen-inducible FAK knockout mice by crossing FAK-floxed (FAKfl/fl) mice with the platelet derived growth factor b (Pdgfb)-iCreER mice. Tamoxifen-treatment of Pdgfb-iCreER;FAKfl/fl mice results in FAK deletion in adult endothelial cells (ECs) without any adverse effects. Importantly however, endothelial FAK-deletion in adult mice inhibited tumour growth and reduced tumour angiogenesis. Furthermore, in in vivo angiogenic assays FAK deletion impairs vascular endothelial growth factor (VEGF)-induced neovascularization. In addition, in vitro deletion of FAK in ECs resulted in reduced VEGF-stimulated Akt phosphorylation and correlating reduced cellular proliferation as well as increased cell death. Our data suggest that FAK is required for adult pathological angiogenesis and validates FAK as a possible target for anti-angiogenic therapies.


Disentangling multidimensional femtosecond spectra of excitons by pulse shaping with coherent control.
Sequences of carefully timed and shaped optical pulses provide femtosecond snapshots of molecular structure as well as electronic and vibrational dynamical processes, in analogy with multidimensional NMR. We apply a genetic learning algorithm towards the design of pulse sequences which simplify the multidimensional signals by controlling the relative intensities of various peaks. Numerical simulations demonstrate how poorly resolved weak features may be amplified and observed by using optimized optical pulses, specifically shaped to achieve a desired spectroscopic target.


Evaluation of Etest strips for rapid susceptibility testing of Mycobacterium tuberculosis.
In this study, our objective was to evaluate Etest strips containing exponential gradients of isoniazid (INH), rifampin (RIF), and streptomycin (STR) for susceptibility testing of Mycobacterium tuberculosis. M. tuberculosis isolates were tested for antimicrobial susceptibilities by the standard proportion method using Löwenstein-Jensen (LJ) medium and by the Etest. The MICs determined by the Etest were obtained at 5, 7, or 10 days. In some strains with Etest-discrepant results, radiometric susceptibility testing (BACTEC) was performed to determine a consensus result. M. tuberculosis concordance between the two methods was 97% (86 of 89 isolates) for RIF, 96% for INH (84 of 87 isolates), and 80% (61 of 76 isolates) for STR. Most of the MICs determined by the Etest were easy to interpret and readable within 5 days. Results correlated well with those obtained by the LJ proportion and BACTEC methods for INH and RIF. However, a high proportion of false-sensitive and false-resistant results were observed, most often for STR. We also observed that variations in the inoculum size of M. tuberculosis isolates affected the MICs to a substantial degree. These discrepancies, along with the expense of the media, the Etest strips, and the specialized equipment required (CO2 incubator), make this method less useful in developing countries.


Pleiotropic roles of TGFβ/Smad signaling in the progression of chronic liver disease.
A wide range of pathophysiological changes are involved in the progression of chronic liver disease (CLD). The multifunctional cytokine transforming growth factor β (TGFβ) can cross talk with other signaling pathways and mediate nearly every aspect of cell physiology from growth to differentiation and cell death. TGFβ can maintain immune response homeostasis and mediate wound-healing responses. Additionally, not only can TGFβ prevent the occurrence of hepatocarcinoma by regulating the proliferation of hepatic progenitor cells, TGFβ can also play important roles in blunting inflammation by interfering with tumor inhibition response generated by inflammatory mediators. The TGFβ/Smad signaling pathway is an important response that is mediated by TGFβ. This pathway also plays multiple functions in the progression of chronic liver disease. The pleiotropic effects of TGFβ and TGFβ/Smad signaling create challenges in the treatment of CLD under conditions that might interfere with the TGFβ signaling pathway. Detailed understanding of the pleiotropic roles of TGFβ signaling in CLD might assist in the selection of more accurate therapeutic approaches, and in the targeting of the right type of cell in the development of treatment strategies, and ultimately in achieving the desired therapeutic effects.


Unichromophoric platinum-acetylides that contain pentiptycene scaffolds: torsion-induced dual emission and steric shielding of dynamic quenching.
The effect of the rigid bulky pentiptycene scaffolds on the photoluminescence, redox properties, and oxygen sensing behavior of unichromophoric Pt-acetylides is reported. When the pentiptycene groups are near the Pt(PBu3)2 center, the Pt-acetylides display both blue fluorescence and green phosphorescence with long phosphorescence lifetimes (90-202 μs) in THF. Their phosphorescence intensity is highly sensitive to molecular oxygen, and the emission color depends on the concentration of not only oxygen but also the complexes, which allows a feasible determination of oxygen in the range of 1-5% air volume. The dynamic quenching rate constants decrease linearly with increasing the number of pentiptycene groups, revealing the steric shielding effect of the peripheral rings of pentiptycene. A dependence of oxidation potential on the number of pentiptycene groups also revealed the steric shielding effect on the electron transfer between the complexes and the electrode. In a PMMA matrix, the dual emissive properties are diminished due to increased phosphorescence and decreased fluorescence intensity, and the phosphorescence lifetimes are significantly increased (up to ∼700 μs), leading to an "on-off" optical response to oxygen concentration. Both the dual emissive properties and long-lived triplet excitons are attributed to diminished spin-orbit couplings caused by twisting and steric shielding of the π-conjugated backbone around the Pt center.


Changes in conformational equilibria regulate the activity of the Dcp2 decapping enzyme.
Crystal structures of enzymes are indispensable to understanding their mechanisms on a molecular level. It, however, remains challenging to determine which structures are adopted in solution, especially for dynamic complexes. Here, we study the bilobed decapping enzyme Dcp2 that removes the 5' cap structure from eukaryotic mRNA and thereby efficiently terminates gene expression. The numerous Dcp2 structures can be grouped into six states where the domain orientation between the catalytic and regulatory domains significantly differs. Despite this wealth of structural information it is not possible to correlate these states with the catalytic cycle or the activity of the enzyme. Using methyl transverse relaxation-optimized NMR spectroscopy, we demonstrate that only three of the six domain orientations are present in solution, where Dcp2 adopts an open, a closed, or a catalytically active state. We show how mRNA substrate and the activator proteins Dcp1 and Edc1 influence the dynamic equilibria between these states and how this modulates catalytic activity. Importantly, the active state of the complex is only stably formed in the presence of both activators and the mRNA substrate or the m7GDP decapping product, which we rationalize based on a crystal structure of the Dcp1:Dcp2:Edc1:m7GDP complex. Interestingly, we find that the activating mechanisms in Dcp2 also result in a shift of the substrate specificity from bacterial to eukaryotic mRNA.


Apoptosis in medfly hemocytes is regulated during pupariation through FAK, Src, ERK, PI-3K p85a, and Akt survival signaling.
Focal adhesion kinase (FAK) and its downstream signaling targets are implicated in the process of apoptosis induced by external stimuli, in several mammalian systems. In this report, we demonstrate, that medfly (Ceratitis capitata) hemocytes do undergo apoptosis during larval development. In particular, we show using Western blot, ELISA and flow cytometry analysis, that FAK expression silencing in transfected by FAK double-stranded RNA (dsRNA) hemocytes, enhances twofold hemocyte apoptosis, by signaling through Src, MEK/ERK, and PI-3K/Akt signaling pathways. FAK expression silencing, in response to FAK dsRNA treatment, blocks partially the phosphorylation of its downstream targets. Pre-incubation of hemocytes, with specific inhibitors of FAK downstream signaling molecules, demonstrated that all these inhibitors reduced hemocyte viability and enhanced the magnitude of apoptosis about threefold. This data suggest that these pathways contribute to hemocyte survival and/or death during development. The expression and phosphorylation of FAK, Src, PI-3K p85a, Akt, and ERK signaling molecules appear to be dependent upon developmental stages. The expression and phosphorylation of the above signaling molecules, in annexin-positive and annexin-negative hemocytes is also distinct. The maximum expression and phosphorylation of FAK, Src, PI-3K p85a, Akt, and ERK appeared in annexin-positive hemocytes, in both early and late apoptotic hemocytes. The novel aspect of this report is based on the fact that hemocytes attempt to suppress apoptosis, by increasing the expression/phosphorylation of FAK and, hence its downstream targets signaling molecules Src, ERK, PI-3K p85a, and Akt. Evidently, the basic survival pathways among insects and mammals appear to remain unchanged, during evolution.


Active learning and relevance vector machine in efficient estimate of basin stability for large-scale dynamic networks.
The interconnectivity between constituent nodes gives rise to cascading failure in most dynamic networks, such as a traffic jam in transportation networks and a sweeping blackout in power grid systems. Basin stability (BS) has recently garnered tremendous traction to quantify the reliability of such dynamical systems. In power grid networks, it quantifies the capability of the grid to regain the synchronous state after being perturbated. It is noted that detection of the most vulnerable node or generator with the lowest BS or N-1 reliability is critical toward the optimal decision making on maintenance. However, the conventional estimation of BS relies on the Monte Carlo (MC) method to separate the stable and unstable dynamics originated from the perturbation, which incurs immense computational cost particularly for large-scale networks. As the BS estimate is in essence a classification problem, we investigate the relevance vector machine and active learning to locate the boundary of stable dynamics or the basin of attraction in an efficient manner. This novel approach eschews the large number of sampling points in the MC method and reduces over 95% of the simulation cost in the assessment of N-1 reliability of power grid networks.


Height Prediction From Ulna Length of Critically Ill Patients.
Ulna length (UL) has been used in mathematical formulas to predict the body height of healthy and sick individuals. However, the evaluation of its use with patients admitted to intensive care units (ICU) is scarce. The objective of this study was to develop a mathematical equation to estimate critically ill patients' height using the UL measure and to evaluate its agreement with measured standing height. This cross-sectional study was performed at the ICU of a tertiary hospital in Brazil. A total of 100 patients aged ≥18 years who had their body height measured before ICU admission were enrolled. The equation was developed through multiple linear regression, and its agreement was assessed through paired Student's t test and Bland-Altman plot. The following formula was obtained: height in cm = 153.492 - (7.97 × sex [sex: male = 1, female = 2]) + (0.974 × UL [in cm]). The difference between means of measured height (MH) and height estimated from UL was not significant (166.26 ± 8.75 cm and 166.30 ± 5.29 cm, respectively, P = .96), and a significant correlation (r = 0.624, P < .001) was detected. In the Bland-Altman analysis, UL was in agreement with MH; however, there was a significant bias (P < .001) suggesting that it may be disproportional and dependent on the average's height value. The mathematical equation for height estimation using UL developed in this study matched the MH of critically ill patients. However, we suggest more studies for its validation.


IFN Regulatory Factor 2 Inhibits Expression of Glycolytic Genes and Lipopolysaccharide-Induced Proinflammatory Responses in Macrophages.
Rapid initiation and timely resolution of inflammatory response in macrophages are synergistic events that are known to be equally critical to optimal host defense against pathogen infections. However, the regulation of these processes, in particular by a specific cellular metabolic program, has not been well understood. In this study, we found that IFN regulatory factor 2 (IRF2) underwent an early degradation in a proteasome-mediated pathway in LPS-treated mouse macrophages, followed by a later recovery of the expression via transactivation. We showed that IRF2 was anti-inflammatory in that knockdown of this protein promoted the production of LPS-induced proinflammatory mediators. Mechanistically, although IRF2 apparently did not target the proximal cytoplasmic signaling events upon LPS engagements, it inhibited HIF-1α-dependent expression of glycolytic genes and thereby cellular glycolysis, sequential events necessary for the IRF2 anti-inflammatory activity. We found that macrophages in endotoxin tolerant state demonstrated deficiency in LPS-augmented glycolysis, which was likely caused by failed downregulation of IRF2 and the ensuing upregulation of the glycolytic genes in these cells. In contrast to observations with LPS, knockdown of IRF2 decreased IL-4-induced macrophage alternative activation. The pro-IL-4 activity of IRF2 was dependent on KLF4, a key mediator of the alternative activation, which was transcriptionally induced by IRF2. In conclusion, our data suggest that IRF2 is an important regulator of the proinflammatory response in macrophages by controlling HIF-1α-dependent glycolytic gene expression and glycolysis. This study also indicates IRF2 as a novel therapeutic target to treat inflammatory disorders associated with dysregulations of macrophage activations.


Health-related quality of life in long-term breast cancer survivors: nationwide survey in Denmark.
To investigate health-related quality of life (HRQOL) in a nationally representative sample of long-term breast cancer survivors (BCS) in Denmark. An age-stratified random sample of 2,000 female BCS > or = 5 years after primary surgery without recurrence was drawn from the Danish Breast Cancer Cooperative Group register, which is representative regarding long-term BCS in Denmark, and compared with 3,104 women of the nationally representative Danish Health and Morbidity Survey 2000. The Short Form-36 questionnaire assessed HRQOL and its association with BCS' sociodemography, type of surgery, systemic therapy, radiotherapy, time since operation, receptor status, and low/high risk protocol. The response rate was 79%. BCS tended to rate HRQOL better than the general female population. BCS reported significantly less "bodily pain" (P < 0.0001), better "general health" (P < 0.0001), but worse "mental health" (P < 0.0001). Age interacted significantly with four other subscales (P < 0.05): Younger BCS reported worse HRQOL than equally aged women of the general population, while older BCS reported better HRQOL. Poor HRQOL was significantly associated with being single (all subscales: P < 0.05), short education (all subscales: P < 0.05, except "social function"), and high body mass index ("physical function", "role physical": P < 0.05). Breast cancer (low/high risk, receptor status) and treatment did not affect HRQOL. HRQOL was similar between BCS and women of the general population. Potential long-term effects of breast cancer (low/high risk, receptor status) and treatment did not seem to impact HRQOL. However, predictors for worse HRQOL in BCS were being single, and having a short education.


Gene expression signature of atypical breast hyperplasia and regulation by SFRP1.
Atypical breast hyperplasias (AH) have a 10-year risk of progression to invasive cancer estimated at 4-7%, with the overall risk of developing breast cancer increased by ~ 4-fold. AH lesions are estrogen receptor alpha positive (ERα+) and represent risk indicators and/or precursor lesions to low grade ERα+ tumors. Therefore, molecular profiles of AH lesions offer insights into the earliest changes in the breast epithelium, rendering it susceptible to oncogenic transformation. In this study, women were selected who were diagnosed with ductal or lobular AH, but no breast cancer prior to or within the 2-year follow-up. Paired AH and histologically normal benign (HNB) tissues from patients were microdissected. RNA was isolated, amplified linearly, labeled, and hybridized to whole transcriptome microarrays to determine gene expression profiles. Genes that were differentially expressed between AH and HNB were identified using a paired analysis. Gene expression signatures distinguishing AH and HNB were defined using AGNES and PAM methods. Regulation of gene networks was investigated using breast epithelial cell lines, explant cultures of normal breast tissue and mouse tissues. A 99-gene signature discriminated the histologically normal and AH tissues in 81% of the cases. Network analysis identified coordinated alterations in signaling through ERα, epidermal growth factor receptors, and androgen receptor which were associated with the development of both lobular and ductal AH. Decreased expression of SFRP1 was also consistently lower in AH. Knockdown of SFRP1 in 76N-Tert cells resulted altered expression of 13 genes similarly to that observed in AH. An SFRP1-regulated network was also observed in tissues from mice lacking Sfrp1. Re-expression of SFRP1 in MCF7 cells provided further support for the SFRP1-regulated network. Treatment of breast explant cultures with rSFRP1 dampened estrogen-induced progesterone receptor levels. The alterations in gene expression were observed in both ductal and lobular AH suggesting shared underlying mechanisms predisposing to AH. Loss of SFRP1 expression is a significant regulator of AH transcriptional profiles driving previously unidentified changes affecting responses to estrogen and possibly other pathways. The gene signature and pathways provide insights into alterations contributing to AH breast lesions.


Bortezomib, doxorubicin, and dexamethasone combination therapy followed by thalidomide and dexamethasone consolidation as a salvage treatment for relapsed or refractory multiple myeloma: analysis of efficacy and safety.
We conducted a phase 2 study with bortezomib, doxorubicin, and dexamethasone (PAD) followed by thalidomide and dexamethasone (TD) in patients with relapsed multiple myeloma (MM). Forty patients were enrolled between November 2005 and October 2007, with follow-up continuing until January 2009. Efficacy could be assessed in 37 patients. The overall response rate to PAD followed by TD was 83.6%: complete response 51.4%, near-complete response 13.4%, very good partial remission 5.4%, and partial response 13.4%. The median follow-up was 27 months (range 13-39). The median progression-free survival (PFS) from the start of treatment was 18 months (95% CI, 9.7-26.2 months), with a 1-year PFS rate of 56.9% and 3-year PFS rate of 25.7%. Median overall survival was 35.1 months (95% CI, 18.5-51.7), with a 1-year survival rate of 75% and 3-year survival rate of 27.3%. One hundred seventy-eight PAD cycles (median 6, range 1-6) in 38 patients were assessable for safety. The most common hematologic toxicity was thrombocytopenia, with grade 3-4 in 35.8%. Sensory neuropathy occurred at grade 2 in 26.3% and grade 3 in 10.3%. Two hundred TD treatment cycles (median 4, range 0-12 cycles) were administered. Most adverse events were of mild degree and manageable. PAD followed by TD in patients with relapsed MM is very effective and tolerable.


Situational Analysis of Low-density Lipoprotein Cholesterol Control and the Use of Statin Therapy in Diabetes Patients Treated in Community Hospitals in Nanjing, China.
Comprehensive management of diabetes should include management of its comorbid conditions, especially cardiovascular complications, which are the leading cause of morbidity and mortality among patients with diabetes. Dyslipidemia is a comorbid condition of diabetes and a risk factor for cardiovascular complications. Therefore, lipid level management is a key of managing patients with diabetes successfully. However, it is not clear that how well dyslipidemia is managed in patients with diabetes in local Chinese health-care communities. This study aimed to assess how well low-density lipoprotein cholesterol (LDL-C) was managed in Nanjing community hospitals, China. We reviewed clinical records of 7364 diabetic patients who were treated in eleven community hospitals in Nanjing from October 2005 to October 2014. Information regarding LDL-C level, cardiovascular risk factors, and use of lipid-lowering agents were collected. In patients without history of cardiovascular disease (CVD), 92.1% had one or more CVD risk factors, and the most common CVD risk factor was dyslipidemia. The overall average LDL-C level was 2.80 ± 0.88 mmol/L, which was 2.62 ± 0.90 mmol/L and 2.82 ± 0.87 mmol/L in patients with and without CVD history respectively. Only 38% of all patients met the target goal and 37.3% of patients who took lipid-lowering agents met target goal. Overall, 24.5% of all patients were on lipid-lowering medication, and 36.3% of patients with a CVD history and 20.9% of patients without CVD history took statins for LDL-C management. The mean statin dosage was 13.9 ± 8.9 mg. Only a small portion of patients achieved target LDL-C level, and the rate of using statins to control LDL-C was low. Managing LDL-C with statins in patients with diabetes should be promoted, especially in patients without a CVD history and with one or more CVD risk factors.


[Development of Lyophilization Procedure Ensuring Survival of Bifidobacteria and Preservation of Their Probiotic Potential upon Long-Term Storage].
Survival of bifidobacteria and preservation of their morphological characteristics after 12-month storage of lyophilized cells was studied for the strains of Bifidobacterium bifidum and B. animalis isolated and maintained in the microbial collection of the Department of Microbiology, Moscow State University. A combined approach to pre-lyophilization treatment of microorganisms and subsequent storage was developed in order to improve cell survival. Compared to the standard cryoprotector concentrations, sucrose and glucose (5% and higher) in skim milk, as well as freezing at ‒70°C with subsequent storage at the same temperature resulted in improved survival of bifidobacteria. Under such conditions, the number of viable cells (CFU) after 12 months of storage was two to three orders of magnitude higher than in the case of the standard lyophilization procedure. Investigation of dynamics of resistance of reactivated clones to such gastrointestinal stress factors as gastric juice and bile acids revealed preservation of these properties at all storage modes. However, since the number of surviving cells decreased during storage according to the standard procedure, the number of stress-affected cells was correspondingly lower. Reactivated cultures exhibited high resistance to oxygen, with survival decreasing to 35% of the initial level.


Combining in vitro and in silico approaches to evaluate the multifunctional profile of rosmarinic acid from Blechnum brasiliense on targets related to neurodegeneration.
Natural products are important sources of chemical diversity leading to unique scaffolds that can be exploited in the discovery of new drug candidates or chemical probes. In this context, chemical and biological investigation of ferns and lycophytes occurring in Brazil is an approach adopted by our research group aiming at discovering bioactive molecules acting on neurodegeneration targets. In the present study, rosmarinic acid (RA) isolated from Blechnum brasiliense showed an in vitro multifunctional profile characterized by antioxidant effects, and monoamine oxidases (MAO-A and MAO-B) and catechol-O-methyl transferase (COMT) inhibition. RA showed antioxidant effects against hydroxyl (HO(•)) and nitric oxide (NO) radicals (IC50 of 29.4 and 140 μM, respectively), and inhibition of lipid peroxidation (IC50 of 19.6 μM). In addition, RA inhibited MAO-A, MAO-B and COMT enzymes with IC50 values of 50.1, 184.6 and 26.7 μM, respectively. The MAO-A modulation showed a non-time-dependent profile, suggesting a reversible mechanism of inhibition. Structural insights on RA interactions with MAO-A and COMT were investigated by molecular docking. Finally, RA (up to 5 mM) demonstrated no cytotoxicity on polymorphonuclear rat cells. Taken together, our results suggest that RA may be exploited as a template for the development of new antioxidant molecules possessing additional MAO and COMT inhibition effects to be further investigated on in vitro and in vivo models of neurodegenerative diseases.


L-cysteine efflux in erythrocytes as a function of human age: correlation with reduced glutathione and total anti-oxidant potential.
Thiol compounds such as cysteine (Cys) and reduced glutathione (GSH) play an important role in human aging and age-related diseases. In erythrocytes, GSH is synthesized by glutamic acid, cysteine, and glycine, but the rate of GSH synthesis is determined only by the availability of L-cysteine. Cysteine supplementation has been shown to ameliorate several parameters that are known to degenerate during human aging. We have studied L-cysteine efflux in vitro in human erythrocytes as a function of age by suspending cells in solution containing 10 mM L-cysteine for uptake; later cells were re-suspended in phosphate-buffered saline (PBS)-glucose to allow efflux. Change in the free sulfhydryl (-SH) concentration was then measured to calculate the rate of efflux. The GSH/oxidized glutathione (GSSG) ratio was taken as a control to study the oxidation/reduction state of the erythrocyte. The total anti-oxidant potential of plasma was measured in terms of ferric reducing ability of plasma (FRAP) values. We have shown a significant (p<0.0001) decline in the efflux of L-cysteine in erythrocytes during human aging, and the GSH/GSSG ratio decreases as a function of human age. The decline in L-cysteine efflux during aging correlates with the decrease in GSH and the FRAP value. This finding may help to explain the shift in the redox status and low GSH concentration that might determine the rate of L-cysteine efflux observed in erythrocytes and an important factor in the development of oxidative stress in erythrocytes during aging.


Strings on a Violin: Location Dependence of Frequency Tuning in Active Dendrites.
Strings on a violin are tuned to generate distinct sound frequencies in a manner that is firmly dependent on finger location along the fingerboard. Sound frequencies emerging from different violins could be very different based on their architecture, the nature of strings and their tuning. Analogously, active neuronal dendrites, dendrites endowed with active channel conductances, are tuned to distinct input frequencies in a manner that is dependent on the dendritic location of the synaptic inputs. Further, disparate channel expression profiles and differences in morphological characteristics could result in dendrites on different neurons of the same subtype tuned to distinct frequency ranges. Alternately, similar location-dependence along dendritic structures could be achieved through disparate combinations of channel profiles and morphological characteristics, leading to degeneracy in active dendritic spectral tuning. Akin to strings on a violin being tuned to different frequencies than those on a viola or a cello, different neuronal subtypes exhibit distinct channel profiles and disparate morphological characteristics endowing each neuronal subtype with unique location-dependent frequency selectivity. Finally, similar to the tunability of musical instruments to elicit distinct location-dependent sounds, neuronal frequency selectivity and its location-dependence are tunable through activity-dependent plasticity of ion channels and morphology. In this morceau, we explore the origins of neuronal frequency selectivity, and survey the literature on the mechanisms behind the emergence of location-dependence in distinct forms of frequency tuning. As a coda to this composition, we present some future directions for this exciting convergence of biophysical mechanisms that endow a neuron with frequency multiplexing capabilities.