Levodopa ONOFF-state freezing of gait: Defining the gait and non-motor phenotype.
Freezing in the levodopa-medicated-state (ON-state) is a debilitating feature of Parkinson's disease without treatment options. Studies detailing the distinguishing features between people with freezing of gait that improves with levodopa and those whose freezing continues even on levodopa are lacking. To characterize the gross motor, gait, and non-motor features of this phenotype. Instrumented continuous gait was collected in the levodopa-medicated-state in 105 patients: 43 non-freezers (no-FOG), 36 with freezing only OFF-levodopa (OFF-FOG) and 26 with freezing both ON- and OFF-levodopa (ONOFF-FOG). Evaluation of motor and non-motor disease features was undertaken using validated scales. A linear mixed model with age, sex, disease duration, and motor UPDRS scores as covariates was used to determine differences in spatiotemporal gait and non-motor disease features among the groups. Compared to OFF-FOG, the ONOFF-FOG group had greater disease severity (on the Unified Parkinson's disease Rating Scale) and worse cognition (on the Montreal Cognitive Assessment, Frontal Assessment Battery and Scales for Outcome in Parkinson's disease-Cognition scales) and quality of life (on the PDQ-39), but similar mood (on the Hamilton depression and anxiety scales) and sleep quality (on Epworth sleepiness scale and RBD questionnaire). For several gait features, differences between the ONOFF-OFF groups were at least as large and in the opposite direction as differences between OFF-no groups, controlling for disease severity. Variability in ONOFF-FOG was greater than in other groups. Using results from our study and others, a power analysis for a potential future study reveals sample sizes of at least 80 ONOFF and 80 OFF-FOG patients would be needed to detect clinically meaningful differences. Intra-patient variability in spatiotemporal gait features was much greater in ONOFF-FOG than in the other two groups. Our results suggest that multifactorial deficits may lead to ONOFF-FOG development.


Capturing primary ozonides for a syn-dihydroxylation of olefins.
Ozonolysis is a widely used and practical synthetic technique for the deconstructive oxidation of olefins using ozone. While there are numerous ozonolysis reactions that give a myriad of products and functionalities, almost all of them involve scission at the olefin double bond. Using ozone as a constructive reagent rather than a deconstructive one would open new domains of chemical reactivity and amplify molecular complexity in synthetic methodology. Here we report the use of primary ozonides as preparative synthetic intermediates for a safe and green olefin syn-dihydroxylation reaction. Furthermore, we have demonstrated this method using a continuous flow reactor that virtually eliminates peroxide accumulation and extended these applications towards the synthesis of pharmaceutically relevant small molecules such as guaifenesin, the active ingredient in Mucinex, and a precursor to ponesimod, a drug to treat multiple sclerosis.


Different expression of caspase-3 in rat hippocampal subregions during postnatal development.
Recent studies indicate that caspase-3 has distinct characteristics in postmitotic and neuronal progenitor apoptosis. Pyramidal neurons in CA1 and CA3 of the hippocampus become postmitotic during early postnatal development, whereas granule cells in the dentate gyrus (DG) undergo self-renewal throughout life. The distribution of caspase-3 in the hippocampal subfields during postnatal development is largely unknown. We used immunofluorescent staining for two isoforms of caspase-3 (an active 17 kDa isoform and an inactive 35 kDa precursor) and the Hoechst 33342 staining for nuclear chromatin to assess caspase-3 expression in the CA1, CA3, and DG of rat hippocampus during postnatal development. The expression of active caspase-3 reached a peak at P7 in CA1, at P2 in CA3, and then decreased with age. Whereas in DG, active caspase-3 expression increased slightly after P7, and remained at high levels for the rest of the investigated period. Procaspase-3 immunoreactivity was strong at P2 and decreased gradually to a basal plateau by P21 in the three regions examined. In addition, the number of apoptotic cells in the three regions all reached maximum levels at P7, and then decreased with age. These data indicate that there were specific spatio-temporal patterns of expression of active and precursor caspase-3 in the postnatally developing rat hippocampal subregions, and that the activation of caspase-3 in neuronal progenitor cells of DG and that in the postmitotic neurons of CA1 and CA3 may have distinct roles and mechanisms during postnatal development.


The Cytotoxicity and Genotoxicity of Particulate and Soluble Cobalt in Human Urothelial Cells.
Cobalt use is increasing particularly due to its use as one of the primary metals in cobalt-chromium-molybdenum (CoCrMo) metal-on-metal prosthetics. CoCrMo is a high-strength, wear-resistant alloy with reduced risk for prosthetic loosening and device fracture. More than 500,000 people receive hip implants each year in the USA which puts them at potential risk for exposure to metal ions and particles released by the prosthetic implants. Data show cobalt ions released from prosthetics reach the bloodstream and accumulate in the bladder. As patients with failed hip implants show increased urinary and blood cobalt levels, no studies have considered the effects of cobalt on human urothelial cells. Accordingly, we investigated the cytotoxic and genotoxic effects of particulate and soluble cobalt in urothelial cells. Exposure to both particulate and soluble cobalt resulted in a concentration-dependent increase in cytotoxicity, genotoxicity, and intracellular cobalt ions. Based on intracellular cobalt ion levels, we found, when compared to particulate cobalt, soluble cobalt was more cytotoxic, but induced similar levels of genotoxicity. Interestingly, at similar intracellular cobalt ion concentrations, soluble cobalt induced cell cycle arrest indicated by a lack of metaphases not observed after particulate cobalt treatment. These data indicate that cobalt compounds are cytotoxic and genotoxic to human urothelial cells and solubility may play a key role in cobalt-induced toxicity.


Cellular signalling in Trypanosoma cruzi: biphasic behaviour of inositol phosphate cycle components evoked by carbachol.
Stimulation of epimastigote forms of Trypanosma cruzi with carbachol resulted in a long-lasting response. The earlier phase for inositol phosphates was rapid and transient, peaking at 1 min with a return to basal levels by 6 min. In a second phase, these metabolite levels reached maximal values at 10-12 min, with a later declination to basal values at about 20 min. The inositol phosphate response was quenched by parasite treatment with atropine. The elevation in intracellular free calcium ([Ca(2+)]i) was transient, reaching the resting level at 87+/-8 s (n=48) of agonist addition. Myo-inositol 1,4,5-triphosphate (InsP(3)) production and [Ca(2+)]i mobilisation were carbachol dose-dependent. The maximally effective concentrations of agonist ranged between 1x10(-6) and 1x10(-5) M. The increase in carbachol concentration resulted in an evident attenuation of [Ca(2+)]i mobilisation and in [3H]InsP(3) levels. Pretreatment of the cells with 10 microM U73122, a phospholipase C (PLC) inhibitor, showed that both InsP(3) peaks triggered by carbachol were completely abolished, whereas there was not substantial change on the maximum elevation in [Ca(2+)]i. The first peak of InsP(3) and InsP(s) was completely abolished when the cells were incubated with phorbol 12-myristate 13-acetate ester (TPA) for 30 min before carbachol stimulation. A biphasic behaviour for PtdIns 4-kinase activity was demonstrated by changes in [32P]PtdInsP levels. The time-course of PtdIns4P 5-kinase activity showed a rapid, significant and transient decrease of [32P]PtdInsP(2) from 0 time to the third min. At the end of this time the polyphosphoinositide began to return towards control levels but, interestingly, after 5-6 min of stimulation there was a subsequent more important increase over control levels which peaked at 10 min. There was also a detectable increment of DAG at 1 min with a maximum at 3 min, this level remaining elevated until at least 10 min. Subsequently, these levels returned to the base line or even below it.


Ozone as an alternative decontamination process for N95 facemask and biosafety gowns.
COVID-19 pandemic created a global shortage of medical protective equipment. Here, we considered ozone (O3) a disinfectant alternative due to its potent oxidative activity against biological macromolecules. The O3 decontamination assays were done using SARS-CoV-2 obtained from patients to produce artificial contamination of N95 masks and biosecurity gowns. The quantification of SARS-CoV-2 was performed before and after exposing the samples to different ozone gas concentrations for times between 5 and 30 min. Viral loads as a function of the O3 exposure time were estimated from the data obtained by the RT-PCR technique. The genetic material of the virus was no longer detected for any tested concentrations after 15 min of O3 exposure, which means a disinfection Concentration-Time above 144 ppm min. Vibrational spectroscopies were used to follow the modifications of the polymeric fibers after the O3 treatment. The results indicate that the N95 masks could be safely reused after decontamination with treatments of 15 min at the established O3 doses for a maximum of 6 cycles.


Electrochemical Activation of Nitromethane to Construct Isoxazoline Aldoximes.
Activation of nitromethane to endow new reactivity is an interesting and meaningful but also challenging topic. Herein, we report an electrochemical activation of nitromethane to serve as both the heterocyclic skeleton and oxime sources for the construction of isoxazoline aldoximes. The isoxazoline aldoximes that are prepared by four steps with the reported strategy are synthesized in a single step from low-cost and readily available nitromethane and olefins with moderate to excellent yields under our electrochemical conditions. The reaction also takes advantage of high atom-economy and E-selectivity. Moreover, the mechanism is studied by control experiments, a kinetic isotope effect (KIE) study, cyclic voltammogram (CV) experiments, and density functional theory (DFT) calculations. The mechanistic results reveal that nitromethane may be activated under electrochemical conditions to deliver a 1,2,5-oxadiazole 2-oxide intermediate, which undergoes [3+2] cycloaddition with olefins to yield isoxazoline aldoximes.


The impact of domestic violence on women's mental health.
This longitudinal study aimed to establish a firmer scientific basis for recognition and treatment of post-traumatic psychiatric morbidity associated with domestic violence. The study used a sample of 335 women (mean age 45.5 years) recruited from the Royal Brisbane Hospital Emergency Department. This paper reports baseline data. The outcome measures of lifetime psychiatric diagnoses (DSM-111-R classification), showed that women who reported lifetime adult intimate abuse (n = 162) received significantly more diagnoses of generalised anxiety, dysthymia, depression, phobias, current harmful alcohol consumption and psychoactive drug dependence than those who reported no abuse ever (n = 173). Of the 191 women tested for lifetime post-traumatic stress disorder, those who reported lifetime abuse (n = 115) received significantly more diagnoses than those who reported no abuse (n = 76). Crude prevalence rates of psychiatric diagnoses for women who reported double abuse as child and adult were significantly higher than for women who reported adult intimate abuse only. Adjusted rates showed that doubly abused women had significantly greater risk of current harmful alcohol consumption and lifetime drug dependence than women who reported adult abuse only. A significant independent factor for lifetime psychiatric diagnoses was reporting abuse between a woman's parents. Measurement of the population attributable risk found that one-third of the psychiatric diagnoses were attributable to domestic violence.


Changes in efferent activities of the gastric vagus nerve by administration of glucose in the portal vein.
Injection of glucose in the portal vein, as well as in the left carotid artery, brought a transient decrease in efferent discharges of the gastric vagus nerve, whereas venous injection of regular insulin brought a gradual increase in the discharges.


Quantifying the impact of the Tokyo Olympics on COVID-19 cases using synthetic control methods.
This paper uses a synthetic control method (SCM) and a Ridge Augmented SCM to estimate the impact of holding the Tokyo Olympic games on the number of newly confirmed COVID-19 cases in Tokyo (Japan). Our analysis with these methods enables us to estimate the causal impact of the Tokyo Olympics on COVID-19 cases by constructing counterfactual COVID-19 cases for Tokyo (Japan) as the optimal weighted average of COVID-19 cases of OECD countries that are not affected by holding the Olympics through a data-driven approach. Based on reliable estimates obtained from different analytical settings, we find that, compared to the counterfactuals, holding the Tokyo Olympics significantly increased the daily average number of COVID-19 cases by 105 to 132 cases in Tokyo (47 to 65 cases in Japan as a whole) per million people. This result suggests that holding the Olympics likely led to the spread of COVID-19 infection in Tokyo (Japan).


Hypoplastic circumflex retroesophageal right-sided cervical aortic arch with unusual vascular arrangement and severe coarctation.
We report the case of a 12-year-old boy with a hypoplastic retroesophageal circumflex right-sided cervical aortic arch and coarctation. After the incidental finding of a heart murmur when the boy was 9 years old, cardiac magnetic resonance showed a right-sided cervical aortic arch, hypoplastic transverse arch, and separate origin of the left common carotid, right common carotid, right vertebral, and right subclavian arteries. The left subclavian artery arose from the proximal descending aorta next to the coarctation. An extra-anatomical ascending to descending aorta tube graft was inserted through a right lateral thoracotomy with good results.


Longitudinal analysis of the peripheral B cell repertoire reveals unique effects of immunization with a new influenza virus strain.
Despite the potential to produce antibodies that can neutralize different virus (heterotypic neutralization), there is no knowledge of why vaccination against influenza induces protection predominantly against the utilized viral strains (homotypic response). Identification of structural patterns of the B cell repertoire associated to heterotypic neutralization may contribute to identify relevant epitopes for a universal vaccine against influenza. Blood samples were collected from volunteers immunized with 2008/2009 trivalent inactivated vaccine (TIV), pandemic H1N1 (pdmH1N1) monovalent inactivated vaccine (MIV) and the 2014/2015 TIV. Neutralization was assessed by hemagglutination and microneutralization test. IgG V(H) amplicons derived from peripheral blood RNA from pre-immune and 7 days post vaccination were subjected to 454-Roche sequencing. Full reconstruction of the sampled repertoires was done with ImmunediveRsity. The TIV induced a predominantly homotypic neutralizing serologic response, while the 09 MIV induced a heterotypic neutralizing seroconversion in 17% of the individuals. Both the 08/09 and the 14/15 TIV were associated with a reduction in clonotypic diversity, whereas 09 MIV was the opposite. Moreover, TIV and MIV induced distinctive patterns of IGHV segment use that are consistent with B cell selection by conserved antigenic determinants shared by the pre-pandemic and the pandemic strains. However, low somatic hypermutation rates in IgG after 09 MIV immunization, but not after 08/09 and 14/15 TIV immunization were observed. Furthermore, no evidence of the original antigenic sin was found in the same individuals after vaccination with the three vaccines. Immunization with a new influenza virus strain (2009 pdmH1N1) induced unique effects in the peripheral B cell repertoire clonal structure, a stereotyped response involving distinctive IGHV segment use and low somatic hypermutation levels. These parameters were contrastingly different to those observed in response to pre-pandemic and post-pandemic vaccination, and may be the result of clonal selection of common antigenic determinants, as well as germinal center-independent responses that wane as the pandemic strain becomes seasonal. Our findings may contribute in the understanding of the structural and cellular basis required to develop a universal influenza vaccine.


A systematic review of the germicidal effectiveness of ultraviolet disinfection across high-touch surfaces in the immediate patient environment.
There is not yet a consensus regarding the in-use effectiveness of ultraviolet irradiation (UV-C) as a supplementary tool for terminal room disinfection. To summarize and evaluate literature detailing the germicidal effectiveness of UV-C disinfection on high-touch surfaces in the patient environment. A literature search was carried out utilizing PRISMA guidelines. Studies were included if intervention included UV-C after standard room disinfection in hospital rooms evaluated microbiologically by surface type. Twelve records met our criteria for inclusion. Studies predominantly focused on terminal disinfection of patient rooms, including five reports carried out in isolation rooms and three studies including operating room (OR) surfaces. Bedrails, remote controls, phones, tray tables, assist rails, floors, and toilets were the most commonly reported surfaces. Across study designs, surfaces, and room types, flat surfaces tended to showcase UV-C effectiveness best, particularly isolation room floors. In contrast, handheld surfaces (i.e., bed controls and assist bars) tended to show reduced efficacies (81-93%). In the OR, complex surfaces similarly demonstrated reduced UV-C effectiveness. Bathroom surfaces demonstrated 83% UV-C effectiveness overall, with surface characteristics uniquely impacted depending on the room type. Isolation room studies tended to include effectiveness comparison with standard treatment, reporting UV-C superiority most of the time. This review highlights the enhanced effectiveness of UV-C surface disinfection over standard protocols across various study designs and surfaces. However, surface and room characteristics do appear to play a role in the level of bacterial reduction.


Depression and PTSD among Houston Residents who Experienced Hurricane Harvey and COVID-19: Implications for Urban Areas Affected by Multiple Disasters.
Little is known about the combined impact of the COVID-19 pandemic and other major disasters on mental health. Hurricane Harvey hit the Gulf Coast in 2017, resulting in substantial costs, significant levels of displacement, and approximately 100 deaths, and was followed in 2020 by the COVID-19 pandemic. We randomly sampled 1167 Houstonians from 88 designated super-neighborhoods and surveyed them about their demographics, event-specific traumas and stressors, and symptoms of current depression and post-traumatic stress disorder (PTSD). We estimated the prevalence of depression (5.8%) and PTSD (12.6%) more than three years after Hurricane Harvey, and assessed the relative influence of event-specific stressors and traumas on current mental health. Overall, we observed evidence for two key findings that are salient for residents of urban environments in the context of multiple disasters. First, stressors were primary influences on depression, whereas both stressors and traumas influenced PTSD. Second, the influences of stressors and traumas on depression and PTSD symptoms faded with time.


Temperature-sensitive mutant of avian erythroblastosis virus suggests a block of differentiation as mechanism of leukaemogenesis.
A temperature sensitive mutant has been isolated for the first time from a replication defective acute leukaemia virus, AEV. In vivo, at 41 degrees C, the mutant shows a reduced leukaemogenic potential. In vitro, in erythroblasts transformed at 35 degrees C, haemoglobin synthesis can be induced by a shift to 41 degrees C. This indicates that the continuous expression of a viral gene product is necessary to maintain the undifferentiated state of the virus-transformed leukaemia cells.


Sex differences of ischemic stroke in young adults-A single-center Chinese cohort study.
Stroke at a young age is a societal challenge with a rising incidence. Our aim was to investigate sex differences in risk factors, etiology, and diagnostic process of ischemic stroke in Chinese young adults. We retrospectively recruited 411 consecutive patients with first-ever ischemic stroke who were 18 to 50 years of age (mean age, 38.2 ± 8.1 years, women 31.4%), admitted to Peking Union Medical College Hospital from 2007 to 2018. Sex differences in demographics, risk factors, etiology, and diagnostic testing were analyzed. Females were significantly younger than males (36.9 versus 38.7 years, P<0.05). Hypertension (43.0%), smoking (41.1%), hyperlipidemia (37.2%), and hyperhomocysteinemia (27.9%) were common risk factors, statistically higher among males than females (P<0.05). Stroke etiology showed a significant sex difference that large-artery atherosclerosis and small-vessel diseases were more common among males than females (48.6% versus 19.4%, P<0.001; 9.9% versus 3.1%, P<0.05, respectively). Stroke of other determined etiology was more common among females (50.4% versus 19.1%, P<0.001). Relevant abnormality rates were higher among females on screening for autoimmune diseases and thrombophilia (23.3% versus 11.1%, P<0.05 and 50.0% versus 16.7%, P<0.001, respectively). A high rate of the traditional stroke risk factors and etiological subtype of large artery atherosclerosis in males were found, as well as prominent sex differences in relevant diagnostic testing abnormality rates, providing useful information for developing sex-specific strategies in stroke evaluation and prevention in young adults.


Two groups of thermophilic amino acid aminotransferases exhibiting broad substrate specificities for the synthesis of phenylglycine derivatives.
Thirty two thermophilic amino acid aminotransferases (AATs) were expressed in Escherichia coli as soluble and active proteins. Based on their primary structures, the 32 AATs were divided into four phylogenetic groups (classes I, II, IV, and V). The substrate specificities of these AATs were examined, and 12 AATs were found capable of synthesizing ring-substituted phenylglycine derivatives such as hydroxyl-, methoxy-, and fluorophenylglycines. Eleven out of the 12 AATs were enzymes belonging to two phylogenetic groups namely, one subgroup of the class I family and the class IV family. AATs in these two groups may thus be useful for the synthesis of a variety of ring-substituted phenylglycine derivatives.


The power of predictions: An emerging paradigm for psychological research.
The last two decades of neuroscience research has produced a growing number of studies that suggest the various psychological phenomena are produced by predictive processes in the brain. When considered together, these studies form a coherent, neurobiologically-inspired research program for guiding psychological research about the mind and behavior. In this paper, we briefly consider the common assumptions and hypotheses that unify an emerging framework and discuss its ramifications, both for improving the replicability and robustness of psychological research and for innovating psychological theory by suggesting an alternative ontology of the human mind.


Can sustainable development policy reduce carbon emissions? Empirical evidence from resource-based cities in China.
Resource-based cities (RBCs) have made outstanding contributions to China's social and economic development over recent decades. Nevertheless, with the worsening climate change and the exhausted resources, how to curb carbon emissions of RBCs to deliver their low-carbon transformation is becoming a problem plaguing the world. To facilitate the low-carbon transformation of RBCs, the Chinese government has formulated many policies, including the Sustainable Development Policy of National Resource-based Cities, 2013-2020 (SDPRC). However, the implementation of SDPRC has not yielded a clear environmental influence. Therefore, this study employs the Propensity Score Matching-Difference in Difference to investigate this influence based on the panel data of 285 prefecture-level cities from 2006 to 2017 while exploring the related heterogeneity and impact mechanisms. It is found that: (1) the implementation of SDPRC has significantly reduced carbon emissions and intensities of RBCs, with this effect becoming more conspicuous with the advancement of the policy. A robust test also verifies these findings. (2) Results from the heterogeneity test demonstrate that the implementation of SDPRC has imposed a suppressive effect on CO2 emissions in eastern, central, and western Chinese regions, especially pronounced in the latter two regions. Except for the growing cities, which are not significantly affected by the policy, the other three types of cities have seen a catalytic effect on CO2 emission reduction from the implementation of the policy, with the most significant impact observed in the declining cities. (3) Analyses of related mechanisms reveal that thanks to the implementation of SDPRC, RBCs suppress CO2 emissions mainly by optimizing their industrial structures and relieving their energy intensities. Finally, some policy recommendations are proposed based on the findings of this study to facilitate the low-carbon transformation of RBCs.


Renal clearance of theophylline and its major metabolites: age and urine flow dependency in paediatric patients.
The renal clearance of theophylline (TH) and its metabolites 1,3-dimethyluric acid (1,3-DMU), 3-methylxanthine (3-MX), and 1-methyluric acid (1-MU) has been studied in 10 children aged 8 months to 14 years. Individual renal clearances were calculated from serum levels and amounts excreted in urine after i.v. administration of the parent drug. The clearance of 1,3-DMU was found to depend both upon urine flow rate and age, which are interrelated. An effect of urinary pH was expected, but was not studied. Consistent age-dependent changes in the relative quantities of metabolites excreted were not observed.


DNA fingerprinting in birds.
Several regions of the human genome are highly variable in populations because the number of repeats in these regions of a short 'minisatellite' sequence varies at high frequency. Different minisatellites have a core sequence in common, however, and probes made up of tandem repeats of this core sequence detect many highly variable DNA fragments in several species including humans, cats, dogs and mice. The hypervariable sequences detected in this way are dispersed in the genome and their variability means that they can be used as a DNA 'fingerprint', providing a novel method for the identification of individuals, confirmation of biological relationships and human genetic analysis. We show here that human minisatellite-derived probes also detect highly variable regions in bird DNAs. Segregation analysis in a house sparrow family confirms that these regions comprise many mostly heterozygous dispersed loci and we conclude that house sparrow DNA fingerprints are analogous to those of humans. Fingerprint analysis identified one nestling, with fingerprint bands not present in the parent pair's fingerprints, which we conclude resulted from an extrapair copulation. Extrabond copulations have been described in many wild bird species, but their success and hence adaptive significance have rarely been quantifiable. DNA fingerprinting will be of great significance to studies of the sociobiology, demography and ecology of wild birds.


Factors influencing the choice of 5-HT3-receptor antagonist antiemetics: focus on elderly cancer patients.
With old age comes declining organ function, cognitive impairment, increased likelihood of comorbid conditions and multiple prescription and nonprescription pharmacotherapy. These issues are particularly relevant in elderly cancer patients, who commonly receive combination chemotherapy and supportive care agents along with radiation therapy and surgery. This situation can complicate medical care, particularly since over half of all cancers occur in those aged over 65 years. The 5-HT(3)-receptor antagonists as a class are highly effective antiemetics and are currently considered the gold standard for treatment of chemotherapy- and radiotherapy-induced nausea and vomiting. However, these agents do possess different pharmacologic properties, such as varying terminal half lives, routes of metabolism and selectivity for 5-HT(3) receptors. These differences may have an impact on efficacy (e.g., duration of action of the drug) safety (e.g., the risk of drug interactions and potential adverse effects), and simplicity of the dosing regimen. The focus of this review is on some of the pertinent issues of 5-HT(3) antagonists relating to elderly cancer patients.


Trichomoniasis and HIV interactions: a review.
To discuss the epidemiology of Trichomonas vaginalis (TV) and HIV co-infections, the role of TV in acquisition and transmission of HIV, special treatment considerations for TV among women with HIV and the prevention of TV among HIV-infected persons. Systematic review. Review of literature of EMBASE and PubMed databases from January 1990 to February 2013. Search keywords included TV, HIV co-infections, HIV acquisition, HIV transmission, HIV shedding, TV treatment, HIV and couples studies. We included studies of any design that contained the selected search words and were published during the specified time frame. We then searched the reference lists of included papers for additional papers and included these when relevant. There is strong evidence that TV increases both transmission and acquisition of HIV among women, and that successful treatment for TV can reduce HIV genital shedding. Single dose metronidazole (MTZ) should no longer be used for HIV+ women with TV given the high rates of asymptomatic bacterial vaginosis co-infections and other factors that may render MTZ less effective in HIV+ women. Prevention of TV among HIV+ persons is similar to among HIV, including promotion of condoms as well as regular screening and prompt treatment. There may be a role for expedited partner treatment for the prevention of repeat infections, but most repeat infections are clinical treatment failures. Diligence in screening and treating TV among both HIV- susceptible and HIV+ persons is an important public health strategy.


Discomfort caused by bonded lingual orthodontic appliances in adult patients as examined by retrospective questionnaire.
A retrospective questionnaire survey of 111 retention-period adult patients was performed to examine discomfort that may be caused by bonded lingual orthodontic appliances. Despite instructions to avoid or relieve the discomfort, 57% to 76% of patients complained of tongue soreness, difficulty in chewing fibrous food, difficulty in pronouncing the s and t sounds, and difficulty in tooth brushing after the bonding of lingual appliances; the levels were significantly higher than those undergoing edgewise labial treatment. Twenty percent to 44% of patients experienced high levels of the aforementioned discomfort. Although this discomfort decreased gradually with time, 20% to 46% of patients felt discomfort until after the removal of the lingual appliances. The ratio of tongue soreness and speech difficulty caused by upper lingual bracket application to lower lingual bracket application was almost equal. Rank correlation analyses revealed two things: the deeper the bite, the greater the level of tongue soreness, teeth pain and difficulty in chewing tough food; and the larger the overjet, the greater the level of tongue soreness.


Nuclear Phosphatidylinositol Signaling: Focus on Phosphatidylinositol Phosphate Kinases and Phospholipases C.
Phosphatidylinositol (PI) metabolism represents the core of a network of signaling pathways which modulate many cellular functions including cell proliferation, cell differentiation, apoptosis, and membrane trafficking. An array of kinases, phosphatases, and lipases acts on PI creating an important number of second messengers involved in different cellular processes. Although, commonly, PI signaling was described to take place at the plasma membrane, many evidences indicated the existence of a PI cycle residing in the nuclear compartment of eukaryotic cells. The discovery of this mechanism shed new light on many nuclear functions, such as gene transcription, DNA modifications, and RNA expression. As these two PI cycles take place independently of one another, understanding how nuclear lipid signaling functions and modulates nuclear output is fundamental in the study of many cellular processes. J. Cell. Physiol. 231: 1645-1655, 2016. © 2015 Wiley Periodicals, Inc.


Effectiveness of insulin therapy in people with Type 2 diabetes in the Hoorn Diabetes Care System.
To identify HbA1c trajectories after the start of insulin treatment and to identify clinically applicable predictors of the response to insulin therapy. The study population comprised 1203 people with Type 2 diabetes included in the Hoorn Diabetes Care System (n = 9849). Inclusion criteria were: age ≥ 40 years; initiation of insulin during follow-up after failure to reach HbA1c levels ≤ 53 mmol/mol (7%) with oral glucose-lowering agents; and a follow up ≥ 2 years after initiating insulin. Latent class growth modelling was used to identify trajectories of HbA1c . Subjects considered to be 'off target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during one-third or more of the follow-up time, and those considered to be 'on target' had HbA1c levels ≥ 53 mmol/mol (7.0%) during less than one-third of the follow-up time. Four HbA1c trajectories were identified. Most people (88.7%) were classified as having a stable HbA1c trajectory of ~57 mmol/mol (7.4%). Only 24.4% of the people were on target in response to insulin; this was associated with lower HbA1c levels and a higher age at the start of insulin treatment. Using latent class growth modelling, four HbA1c trajectories were identified. A quarter of the people starting insulin were on target. Low HbA1c levels and advanced age at the start of insulin therapy were associated with better response to insulin therapy. Initiating insulin earlier improves the likelihood of achieving and sustaining glycaemic control.


Intestinal adenomatosis in the pig: histochemical and electron microscopic studies of the mucosa.
Histochemical studies of normal and adenomatous intestinal mucosa of the pig showed the adenomatous epithelium to be deficient in enzymes normally found in mature absorptive cells. Electron microscopic studies confirmed that the adenomatous cells closely remsembled the crypt cells of normal mucosa.


Abrupt cessation of clonidine administration: a prospective study.
In 20 patients with mild to moderate hypertension, the effects of abrupt cessation of clonidine therapy on blood pressure, heart rate and catecholamine excretion were evaluated. In a double blind, crossover study, placebo was substituted for clonidine after 3 days of therapy and again after 30 days. The results demonstrated no instances of clinically significant symptoms or overshoot in blood pressure or heart rate. There was an overshoot in norepinephrine excretion that approached the upper limits of normal. Thus, a clinical withdrawal syndrome associated with abrupt cessation of clonidine was not seen in this study of patients without severe hypertension who were given the drug without a diuretic agent.


Fucoidin, a polysaccharide inhibiting leukocyte rolling, attenuates inflammatory responses in experimental pneumococcal meningitis in rats.
It is presumed that adjuvant therapy rather than new antibiotics will improve the prognosis of pneumococcal meningitis. We investigated the effect of fucoidin, a polysaccharide inhibiting leukocyte rolling, on inflammatory changes in experimental meningitis in rats. After induction of meningitis by pneumococcal cell wall components, regional cerebral blood flow and intracranial pressure increased over the observation period of 6 h. At the end of the experiments, cerebrospinal fluid pleocytosis and brain water content were higher in animals with meningitis than without. Fucoidin treatment in the meningitis group reduced all inflammatory changes, whereas fucoidin treatment of animals without meningitis increased blood white cell count, but had no effect on any other parameter. Our results confirm that selectins are involved in the early phase of pneumococcal meningitis and possibly are a target for adjunctive therapy.


Third trimester chemotherapy and neonatal hematopoiesis.
An 18-year-old woman with severe pancytopenia secondary to chemotherapy given in the third trimester of pregnancy and who delivered an infant with normal peripheral blood counts is reported. The literature is reviewed, and recommendations for the method of delivery in this setting are discussed.


Role of the Toll‑like receptor 3 signaling pathway in the neuroprotective effect of sevoflurane pre‑conditioning during cardiopulmonary bypass in rats.
The aim of the present study was to explore the roles and possible molecular mechanism of the alleviating effect of sevoflurane pre‑treatment on the extracorporeal circulation and to investigate the possible involvement of the Toll‑like receptor (TLR3) signaling pathway. A total of 64 male Sprague Dawley rats were randomly divided into three groups: The sham operation group (H group; n=8), cardiopulmonary bypass (CPB) group (C group; n=24) and sevoflurane pre‑conditioning group (S group; n=32). The C group was subjected to tracheal intubation and mechanical ventilation, vessel puncture and catheter placement in the right femoral artery and right internal jugular vein, while no CPB was performed in the H group. The S group was pre‑treated with 2.4% sevoflurane for 1 h prior to establishing the CPB model. The CPB in the C and S groups was performed for 1 h. Blood of the rats was analyzed and clinical parameters were detected prior to, during and at various time‑points after CPB. In addition, eight rats from the C and S groups each were sacrificed at these time‑points and brain tissue samples were analyzed. The levels of the brain damage‑specific protein S100‑β as well as IL‑6 and IFN‑β in the serum were detected by ELISA; furthermore, the expression levels of TLR3 and TIR‑domain‑containing adapter‑inducing interferon‑β (TRIF) in the left hippocampus were assessed by ELISA and/or western blot analysis. The right hippocampus was assessed for neuronal apoptosis by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. The mean arterial pressure, heart rate and hematocrit were significantly decreased following CPB (P<0.05), while there was no significant changes in any other clinical parameters. The serum levels of S100‑β and IL‑6 in the C group were significantly increased compared with those in the H group (P<0.05), which was attenuated by sevoflurane‑pre‑treatment. Compared with the H group, the serum levels of IFN‑β as well as hippocampal protein levels of TLR3 and TRIF were significantly increased in the C group during and after CPB (P<0.05), which was markedly aggravated in the S group (P<0.05). The number of apoptotic hippocampal neurons, although being generally low, was significantly increased in the C group compared with that in the H group (P<0.05), while apoptosis was significantly attenuated by sevoflurane‑pre‑treatment (P<0.05). The present study therefore concluded that 2.4% sevoflurane pre‑treatment has a protective effect on the rat brain against CPB‑induced injury, which may be mediated via the TLR3 signaling pathway through upregulating the expression levels of anti‑inflammatory and downregulating pro‑inflammatory proteins.


Contact urticaria provoked by balsam of Peru.
Six patients with chronic urticaria are described in whom immediate type hypersensitivity to balsam of Peru was proven by patch test.


In vitro effects of penicillin and telithromycin on the expression of Streptococcus pneumoniae capsule.
To evaluate the effects of subinhibitory concentrations of penicillin and telithromycin on capsular formation by Streptococcus pneumoniae. A total of 60 isolates of S. pneumoniae, 20 susceptible, 20 intermediately resistant and 20 resistant to penicillin, were studied. All isolates were susceptible to telithromycin. All isolates were capsulate when grown without antibiotics. Encapsulation was lower after incubation with telithromycin as compared with penicillin in isolates susceptible to penicillin (20% versus 75%), in those intermediately resistant to penicillin (25% versus 95%) and in isolates fully resistant to penicillin (15% versus 100%) (P < 0.01). Telithromycin appears to be superior to penicillin in reducing the expression of the capsule by S. pneumoniae.


The "relief effect": a sociobiological model for neurotic distress and large-group therapy.
The author discusses the new discipline of sociobiology. He develops the hypothesis that relief of neurotic distress may be associated with experiencing social affiliation and presents data that demonstrate a decline in neurotic symptom intensity in individuals who joined a cohesive religious sect. Anthropological and ethological evidence for the adaptive value of this "relief effect" provides a basis for the evolution of this trait. The author proposes a corresponding model for psychotherapy in large groups.


Frequency control of cell cycle oscillators.
The cell cycle oscillator, based on a core negative feedback loop and modified extensively by positive feedback, cycles with a frequency that is regulated by environmental and developmental programs to encompass a wide range of cell cycle times. We discuss how positive feedback allows frequency tuning, how size and morphogenetic checkpoints regulate oscillator frequency, and how extrinsic oscillators such as the circadian clock gate cell cycle frequency. The master cell cycle regulatory oscillator in turn controls the frequency of peripheral oscillators controlling essential events. A recently proposed phase-locking model accounts for this coupling.


In vitro inhibitory activities of essential oils from two Korean thymus species against antibiotic-resistant pathogens.
The in vitro inhibitory activities of essential oils from Thymus magnus and T. quinquecostatus as well as their main constituents were evaluated against susceptible and resistant species of Streptococcus pneumoniae, Staphylococcus aureus, Salmonella enteritidis, and Salmonella typhimurium. Notably, the essential oil fraction of T. magnus and its main components displayed significant inhibitory action against both antibiotic-susceptible and resistant strains of S. pneumoniae, S. aureus, and S. typhimurium with minimum inhibitory concentrations (MICs) ranging from 0.125 to 8 mg/mL. The differential MIC values imply that the oil fraction and its main components exhibit distinct patterns of activity against the tested bacterial species. Moreover, the disk diffusion test revealed that the inhibitory activities of oil fraction and components were dose-dependent. Data from the checkerboard titer test confirmed synergism between the antibiotic, norfloxacin, and T. magnus oil or thymol, particularly against the resistant strains of S. aureus.


The Psychosocial Effects of the COVID-19 Pandemic on Youth Living with HIV in Western Kenya.
The objective of this study was to assess psychosocial effects of COVID-19 among adolescents living with HIV (ALHIV) in Kenya and to assess the feasibility of conducting behavioral surveys by phone. We adapted our protocol to administer telephone rather than in-person follow-up surveys and included questions about COVID-19. The majority of participants (99%) reported having heard of COVID-19; 23% reported no longer being able to go outside, 17% reported that they could no longer go to their regular clinic for medical care, and 3% reported that they could no longer get medication refills. PHQ-9 screening identified 9% (n = 45) with mild depression symptoms, and 1% (n = 3) with moderate-to-severe depression symptoms. Young adults 20-24 years old had more mild to severe depressive symptoms than the younger age groups (p < 0.001). Offering remote peer-support or mental health care, continuing to offer differentiated care services, and considering financial support will support the health and well-being of ALHIV.


Fast embedding methods for clustering tens of thousands of sequences.
Most sequence clustering methods require a full distance matrix to be computed between all pairs of sequences. This requires computer memory and time proportional to N(2) for N sequences. For small N or say up to 10000 or so, this can be accomplished in reasonable times for sequences of moderate length. For very large N, however, this becomes increasingly prohibitive. In this paper, we have tested variations on a class of published embedding methods that have been designed for clustering large numbers of complex objects where the individual distance calculations are expensive. These methods involve embedding the sequences in a space where the similarities within a set of sequences can be closely approximated without having to compute all pair-wise distances. We show how this approach greatly reduces computation time and memory requirements for clustering large numbers of sequences and demonstrate the quality of the clusterings by benchmarking them as guide trees for multiple alignments. Source code is available on request from the authors.


An ongoing burden: chlamydial infections among young American Indian women.
Studies conducted in the 1980s, when there was limited chlamydia screening, showed high positivity, 23%-30%, among American Indian women. In the 1990 s, chlamydia screening and treatment programs were implemented in a variety of settings serving American Indian women including Indian Health Service (IHS) clinics. Yet, a 2000-2001 national survey documented a chlamydia prevalence of 13.3% among young American Indian women, five times higher than the prevalence among whites. The purpose of this analysis was to determine the chlamydia positivity and risk factors for chlamydia among women screened in Indian Health Service (IHS) clinics participating in the National Infertility Prevention Program in 2003. Data were analyzed from 11,485 chlamydia tests performed among women universally screened in 23 IHS clinics in three states (Montana, North Dakota, South Dakota). Sexual risk history and clinical data were collected in the Montana IHS clinics and used to assess risk factors for chlamydial infection in a multivariate logistic regression model. Chlamydia positivity was highest among 15-19 year old women screened in IHS clinics (state range: 15.3%-18.6%). Positivity decreased with age but remained high even among women aged 30-34 years. Young age and having had multiple or new sex partners in the last 90 days were associated with an increased risk of chlamydia; however, chlamydia positivity was greater than 6.7% for women with no known risk factors. A greater emphasis on chlamydia screening and treatment should be a component of any program whose goal is to improve the reproductive health of American Indian women.


Magnetic resonance imaging verification of a multi-compartment perfusion model for a chromatography gel phantom.
A model of MRI signal intensity was developed for chromatography column phantoms containing Sephadex gels, which were used to simulate tissue perfusion and the exchange of protons between extravascular and intravascular tissue compartments. Computer simulations of two-compartment and three-compartment models were compared in experiments that used two chromatography columns. One column contained a Sephadex G-25 gel that had a smaller pore size and a slower rate of exchange between extrabead and intrabead compartments than did a second column, which contained a G-50 gel with a larger pore size. In both columns the beads were of approximately the same size to simulate the same ratio of intrabead volume to extrabead volume. Slice-selective spin-echo experiments were performed with the columns oriented parallel to each other in a 1.5 T imager and parallel to the magnetic field, with water flowing through each column perpendicular to the slice at mean flow velocities ranging between 0 and 0.66 mm/s. The results of the experiments agreed with computer simulations, which showed that the MRI signal intensity in the perfused columns is a function of the rate of exchange between extrabead and intrabead compartments. The exchange process modifies the transit time of protons passing through an excited region. The simulations also showed that both two-compartment and three-compartment models could be used to fit the experimental data. Experiments with chromatography gel columns are a preliminary investigation into the potential of using MRI to measure the exchange between extravascular and intravascular compartments of endogenous protons during blood perfusion of biological tissue.


Dynamic vocal cord behavior and stridor during emergence from general anesthesia in small children with supraglottic airway.
Stridor during emergence from anesthesia is not rare in children managed with supraglottic airway (SGA). However, we know little about the mechanisms of stridor and behavior of the vocal cords (VC). This study aimed to clarify patterns of VC movement and laryngeal airway maintenance function during recovery from anesthesia in children with SGA. This is a secondary analysis of data collected from an observational study involving 27 anesthetized children. Using a multi-panel recording system, endoscopic VC image, vital sign monitor, multi-channel tracings of respiratory variables and respiratory sound and patient's view were simultaneously captured in one monitor. Inspiratory and expiratory VC angles formed by lines connecting anterior and posterior commissures were measured at the first spontaneous breath and the breath one minute after the first breath. VC narrowing and dilation were assessed by differences of VC angles. Inspiratory VC narrowing (median (IQR): 5.3 (2.7, 9.1) degree at the first breath) and dilation (- 2.7 (- 3.8, - 1.7) degree at the first breath) were observed in 15 and 12 out of 27 children, respectively. The former group achieved greater tidal volume compared to the latter in one minute. Five children (19%) temporarily developed stridor-like sound from outside with inspiratory VC narrowing. The stridor-like sound was captured by microphones attached to the neck and anesthesia circuit, but was not evident from the chest. Laryngeal narrowing occurs in half of the children with SGA during emergence from anesthesia, and temporal stridor-like sound is relatively common. UMIN (University Hospital Information Network) Clinical Registry: UMIN000025058 ( https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000028697 ).


[Quantitative evaluation of CT-MRI images of various tumors with expansive or infiltrative growth pattern].
To investigate quantitatively the proliferation of tumors in characteristic of either expansive or infiltrative growth pattern. The CT/MRI images of 34 tumor patients with 6 different pathological types were adopted to undergo quantitative evaluation of the growth pattern of these tumors. Three key parameters, fractal dimension (Df) of the border between the tumor and neighboring tissues, degree of heterogeneity (H), and clumsiness (C) inside the tumor, were computed numerically. The Df values of the infiltrative tumors were higher than those of the expansive tumors, thus revealing the more evident complexity and openness of the border of infiltrative tumor. Heterogeneity and clumsiness existed within both expansive and infiltrative tumors. The clumsiness derived from heterogeneity and they were correlated positively with each other. The growth coefficient of clumsiness of the expansive tumor was greater than that of the infiltrative tumor. The method to analyze the fractal dimension of tumor border, and degrees of heterogeneity and clumsiness within a tumor presented in this paper gives some enlightenment to the fundamental research in characterizing tumor growth and shows practical value in clinical diagnosis of tumor, and may be of benefit to the quantitative evaluation of radiological images and computer-aided diagnosis.


Auditory temporal edge detection in human auditory cortex.
Auditory objects are detected if they differ acoustically from the ongoing background. In simple cases, the appearance or disappearance of an object involves a transition in power, or frequency content, of the ongoing sound. However, it is more realistic that the background and object possess substantial non-stationary statistics, and the task is then to detect a transition in the pattern of ongoing statistics. How does the system detect and process such transitions? We use magnetoencephalography (MEG) to measure early auditory cortical responses to transitions between constant tones, regularly alternating, and randomly alternating tone-pip sequences. Such transitions embody key characteristics of natural auditory temporal edges. Our data demonstrate that the temporal dynamics and response polarity of the neural temporal-edge-detection processes depend in specific ways on the generalized nature of the edge (the context preceding and following the transition) and suggest that distinct neural substrates in core and non-core auditory cortex are recruited depending on the kind of computation (discovery of a violation of regularity, vs. the detection of a new regularity) required to extract the edge from the ongoing fluctuating input entering a listener's ears.


Immunocytochemistry of the cell nucleus.
This electron microscopic review addresses in situ immunocytochemistry of the mammalian cell nucleus with special reference to the use of autoantibodies, which are the major source of antinuclear antibodies. The localization of many key nuclear antigens is documented and immunocytochemical data are related to the major functional processes of transcription and processing of RNA and to replication of DNA.


Secondary signals mediated by GPIIb/IIIa in thrombin-activated platelets.
We have previously found that stimulation of aequorin-loaded platelets by thrombin produced a two-peaked increase in intracellular free calcium concentration ([Ca2+]i), and the development of the second peak of [Ca2+]i was closely related with the aggregation. In this report, we studied the interrelationship between the GPIIb/IIIa complex, aggregation, cytoskeletons and [Ca2+]i of platelets. The pretreatment of the platelets with dihydrocytochalasin B (4 microM), an actin polymerization inhibitor, did not inhibit aggregation and TXB2 production, but did inhibit both actin polymerization and the second peak of [Ca2+]i increase induced by thrombin, suggesting that actin polymerization and the second peak of [Ca2+]i are interrelated. GRGDSP (100 microM), a synthetic anti-adhesive peptide, has already been reported to inhibit platelet aggregation and the second peak of [Ca2+]i induced by thrombin. It also inhibited actin polymerization and TXB2 production, suggesting that aggregation was important for not only the generation of the second peak of [Ca2+]i but also for actin polymerization and TXB2 production. PGI2 (5 nM) did not abolish but only delayed aggregation, TXB2 production, actin polymerization and the second peak of [Ca2+]i increase. These findings suggest that the secondary signals are caused by aggregation (fibrinogen-binding to the GPIIb/IIIa) in thrombin-aggregated platelets, which results in the TXA2 production and the secondary peak of [Ca2+]i increase, and the latter was dependent on actin polymerization.


2-Deoxyglucose stimulates the release of insulin and somatostatin from the perfused catfish pancreas.
Glucokinase was proposed to function as a glucose sensor in pancreatic B-cells, acting possibly as a pacemaker of the rate of glycolysis. Glucose, mannose, and 2-deoxyglucose are good substrates of glucokinase which are easily taken up into B-cells. Glucose and mannose are well-known stimuli of insulin release in mammals and fish. I report here that 2-deoxyglucose is also a strong stimulus of insulin and somatostatin release from the in vitro perfused pancreas (i.e., splenic Brockmann body) of channel catfish (Ictalurus punctatus). This is surprising because the product of the glucokinase-catalyzed phosphorylation of 2-deoxyglucose. 2-deoxyglucose-6-phosphate, cannot be metabolized further at an appreciable rate. 3-O-Methylglucose, which does not bind appreciably to mammalian glucokinase, stimulated neither insulin nor somatostatin release. Glucosamine, which binds tightly to glucokinase but is phosphorylated only at a very low rate, did not stimulate insulin release either, but did cause a small amount of somatostatin to be released. The results suggest that glucose-activated glucokinase itself may serve as a signal molecule in glucose recognition by B- and D-cells.


Febrile ulceronecrotic Mucha-Habermann disease in a 34-month-old boy: a case report and review of the literature.
We report a case of febrile ulceronecrotic Mucha-Habermann disease (FUMHD) in a 34-month-old boy. Our patient had a history of biopsy-proven pityriasis lichenoides et varioliformis acuta (PLEVA) since age 2. At 34 months, his skin lesions rapidly progressed to ulceration and necrosis in the setting of high fever. Skin biopsy revealed an intense lichenoid infiltrate with parakeratosis at the edges of areas of epidermal necrosis consistent with FUMHD, which is the severe variant of PLEVA. Despite initial treatment with prednisolone, his disease progressed to involve more than 50% of his body surface area. In addition to corticosteroids, he was treated with intravenous immunoglobulin, dapsone, and acyclovir, without complete resolution of disease. Methotrexate successfully cleared his skin disease and systemic symptoms. This patient highlights the exceptional response of FUMHD to methotrexate. Based on our review of the literature, this also represents the youngest reported case of FUMHD.


Desensitisation of cultured glial cells to epidermal growth factor by receptor down-regulation.
Epidermal growth factor (EGF), which can be purified from the mouse submaxillary gland or from pregnant human urine, is a potent multiplication-stimulating factor for several types of cultured cells, including human fibroblasts and glial cells. The molecule binds with high affinity and saturation kinetics to a cell-surface receptor, is subsequently internalised and finally degraded. The binding event is accompanied by a reduction in the number of EGF receptors. This phenomenon--'receptor down-regulation'--has been demonstrated with several hormones and may be a general principle for the modulation of binding groups on the outer cell surface. Further, it has been proposed that receptor loss acts to regulate the cellular response to the binding ligand. The present study provides direct experimental support for this hypothesis. It demonstrates that down-regulation of EGF receptors on glial cells causes desensitisation of the mitogenic response of these cells to subsequent stimulation with EGF.


RNA-based biomarkers for the diagnosis, prognosis, and therapeutic response monitoring of prostate cancer.
Prostate cancer (CaP) is the most common malignant neoplasm of the urinary tract. The current recommendations for CaP diagnosis rely on the prostate-specific antigen levels and a digital rectal examination for anatomical abnormalities. However, these diagnostic tools are not highly sensitive. In particular, prostate-specific antigen has a low positive predictive value (approximately 30%). Thus, there is a need to develop biomarkers to improve the early clinical detection of CaP. Several novel technologies enable the identification of biomarkers from diverse sources, including the urine, serum, and prostate tissues. Furthermore, advances in genomic techniques have enabled the analysis of novel biomarkers, such as deoxyribonucleic acids (DNAs), ribonucleic acids (RNAs), proteins, and circulating tumor cells. Previous studies have demonstrated that RNAs are potential diagnostic biomarkers for various cancers using high-throughput sequencing analysis. The sensitivity and specificity of RNA biomarkers are higher than those of protein biomarkers. Polymerase chain reaction enables the amplification of trace levels of RNAs with high sensitivity and specificity. RNA biomarkers provide dynamic insights into cellular states and regulatory processes when compared with DNA biomarkers. Additionally, multiple copies of various RNAs in a cell provide more information than DNA. The levels of specific RNAs in CaP tissues are upregulated when compared with those in non-cancerous tissues. Additionally, RNAs can be easily isolated from various body fluids. Thus, RNAs are potential non-invasive biomarkers for CaP. Moreover, the analysis of RNA levels adjusted for each stage of CaP enables the determination of prognostic individualized therapy for aggressive or progressive CaP. This review focused on the diagnostic and prognostic values of RNAs for CaP.


Nonneoplastic intracranial cysts and cystic lesions.
This article reviews the gamut of cystic lesions, unrelated to neoplastic disease, that are found in the brain, subarachnoid space, and ventricles. The utility of MRI in diagnosing these entities is shown.


Using government data to understand the use and availability of medicines for hypertension and diabetes: lessons from Peru.
Regular measurement of the availability and use of key medicines for non-communicable diseases allows the tracking of progress to achieve equitable access to medicines. Using a country-level public sector monitoring system for medicine supply, we aim to evaluate the availability and use of losartan 50 mg tablets and metformin 850 mg tablets between 2015 and 2020 investigating the impact of different policy changes and the COVID-19 pandemic. Data from the Peruvian National System of Medicine Supply were analyzed using an interrupted time series analysis with known and unknown structural breaks. The outcomes assessed were medicine use (monthly doses dispensed at facilities over time) and medicine availability (proportion of facilities that reported having the medicine available). The use of losartan and metformin at the primary level of care had a linear increasing trend over the period of analysis. In secondary and tertiary levels of care, there were no increases but some significant level and trend changes of doses dispensed at different times between 2017 to 2019, but none were related to the change of procurement procedures. At all levels of care, the COVID-19 onset in April 2020 caused an abrupt drop in doses dispensed especially at the primary level. Regarding availability, we found an increasing linear trend in the primary level of care for both medicines. In secondary and tertiary levels of care, the availability fluctuated between 40 and 95%. The onset of the COVID-19 pandemic did not significantly impact medicine availability, except for losartan in the tertiary level of care. The availability and proper dispensing of first-line medicines for hypertension and diabetes is an essential factor for sustainable and equitable treatment. Health care systems need to be prepared for forecasting the increasing demand of medicines for chronic diseases, but also to maintain effective medicine supply chains during humanitarian crisis like pandemics.


Metadensity: a background-aware python pipeline for summarizing CLIP signals on various transcriptomic sites.
Cross-linking and immunoprecipitation (CLIP) is a technology to map the binding sites of RNA-binding proteins (RBPs). The region where an RBP binds within RNA is often indicative of its molecular function in RNA processing. As an example, the binding sites of splicing factors are found within or proximal to alternatively spliced exons. To better reveal the function of RBPs, we developed a tool to visualize the distribution of CLIP signals around various transcript features. Here, we present Metadensity (https://github.com/YeoLab/Metadensity), a software that allows users to generate metagene plots. Metadensity allows users to input features such as branchpoints and preserves the near-nucleotide resolution of CLIP technologies by not scaling the features by length. Metadensity normalizes immunoprecipitated libraries with background controls, such as size-matched inputs, then windowing in various user-defined features. Finally, the signals are averaged across a provided set of transcripts. Metadensity is available at https://github.com/YeoLab/Metadensity, with example notebooks at https://metadensity.readthedocs.io/en/latest/tutorial.html. Supplementary data are available at Bioinformatics Advances online.


Development of Electron Energy Loss Spectroscopy in the Biological Sciences.
The high sensitivity of electron energy loss spectroscopy (EELS) for detecting light elements at the nanoscale makes it a valuable technique for application to biological systems. In particular, EELS provides quantitative information about elemental distributions within subcellular compartments, specific atoms bound to individual macromolecular assemblies, and the composition of bionanoparticles. The EELS data can be acquired either in the fixed beam energy-filtered transmission electron microscope (EFTEM) or in the scanning transmission electron microscope (STEM), and recent progress in the development of both approaches has greatly expanded the range of applications for EELS analysis. Near single atom sensitivity is now achievable for certain elements bound to isolated macromolecules, and it becomes possible to obtain three-dimensional compositional distributions from sectioned cells through EFTEM tomography.


Parameters affecting in vitro bond strength of composites to enamel and dentin.
In vitro tensile bond strengths of Photo Clearfil Bright (PB) and Clearfil Photo Posterior (CP) with Clearfil Photo Bond to human enamel and dentin were determined by a truncated cone bond test. Parameters tested were: four substrates (etched enamel; unetched dentin, D1; dentin conditioned with 10% polyacrylic acid, D2; and dentin etched with phosphoric acid, D3); two techniques (bonding agent prepolymerized, and bonding agent and composite polymerized together); and two storage times in 37 degrees C water (one day and one week). Bond strengths of PB and CP to enamel ranged from 15 to 25 MN/m2 and 19 to 24 MN/m2, respectively. Bond strengths of PB to dentin ranged from 10.2 to 13.6 MN/m2 for D1, 8.2 to 10.5 MN/m2 for D2, and 5.5 to 7.8 MN/m2 for D3. Bond strengths of CP to dentin ranged from 7.6 to 12.3 MN/m2 for D1, 6.8 to 9.5 MN/m2 for D2, and 4.6 to 6.7 MN/m2 for D3. Bond strengths were higher to enamel than to dentin. The highest bond strengths to dentin were to unetched dentin, followed by conditioned dentin, and then etched dentin. Polymerization techniques and storage times did not affect the bond strengths.


Pesticides Hazardous Hotspots: Empirical Evidences from North India.
The pesticide use in Indian agriculture showed a declining trend in the late 1990s and early 2000s. Since 2007, pesticide use gained an upward trend. To study the pesticide use pattern and identify pesticide hotspots, we collected data from a sample of 1201 apple, rice, vegetable, and cotton growers from the temperate Kashmir Valley, subtropical Jammu, and Punjab. Our study provided some interesting empirical results: prophylactic pesticide applications in apple crop making it a pesticide guzzler [25.2 kg of active ingredient (ai)/ha] with use of riskiest carcinogen pesticides (9 kg of a.i/ha) and field use environmental impact quotient (FEIQ) (620.4/ha) being the highest, the Kashmir Valley is the "pesticide hottest spot", followed by cotton and rice areas of Punjab and vegetable cultivation in Jammu subtropics. Pesticides banned for use in vegetables, such as monocrotophos were also applied by farmers in vegetable crops. However, rice areas in Kashmir and Jammu were only treated with herbicides. The protective measures taken by farmers while mixing and applying pesticides were primitive, resulting in localized mild/moderate pesticide poisoning besides loss of consciousness. We also found that the official data on the pesticide use are underreported and hence unreliable. Our study shows that neither the pesticide use by mass nor the pesticide use frequency, in combination or alone, is the robust indicator to measure the pesticide hazardous hotspots; besides these, FEIQ and less hazardous pesticides that are not probable or possible carcinogen should be rather used in conjunction.


The lodgepole × jack pine hybrid zone in Alberta, Canada: a stepping stone for the mountain pine beetle on its journey East across the boreal forest?
Historical data show that outbreaks of the tree killing mountain pine beetle are often preceded by periods of drought. Global climate change impacts drought frequency and severity and is implicated in the range expansion of the mountain pine beetle into formerly unsuitable habitats. Its expanded range has recently reached the lodgepole × jack pine hybrid zone in central Alberta, Canada, which could act as a transition from its historical lodgepole pine host to a jack pine host present in the boreal forest. This field study tested the effects of water limitation on chemical defenses of mature trees against mountain pine beetle-associated microorganisms and on beetle brood success in lodgepole × jack pine hybrid trees. Tree chemical defenses as measured by monoterpene emission from tree boles and monoterpene concentration in needles were greater in trees that experienced water deficit compared to well-watered trees. Myrcene was identified as specific defensive compound, since it significantly increased upon inoculation with dead mountain pine beetles. Beetles reared in bolts from trees that experienced water deficit emerged with a higher fat content, demonstrating for the first time experimentally that drought conditions benefit mountain pine beetles. Further, our study demonstrated that volatile chemical emission from tree boles and phloem chemistry place the hybrid tree chemotype in-between lodgepole pine and jack pine, which might facilitate the host shift from lodgepole pine to jack pine.


The Brain Trauma Foundation. The American Association of Neurological Surgeons. The Joint Section on Neurotrauma and Critical Care. Age.
Age is a strong factor influencing both mortality and morbidity. Despite some contradictions, most literature supports children faring better than adults who have severe brain injury. The significant influence of age upon outcome is not explained by the increased frequency of systemic complications or intracerebral hematomas with age. Increasing age is a strong independent factor in prognosis, with a significant increase in poor outcome above 60 years of age.


Electron diffraction studies of human erythrocyte membrane and its lipid extracts. Effects of hydration, temperature and hydrolysis.
The organization of lipid molecules in individual human erythrocyte ghost membranes and single bilayers of their total lipid extracts were studied by low-dose electron diffraction in a controlled environment. The highest onset temperature (Ts) at which diffraction rings corresponding to a gel state appeared, were found to be in the range of -2 to -4 degrees C for both the whole ghost membrane and bilayers of its total lipid extracts. The onsets were abolished by dehydration before separated crystallizations of cholesterol and phospholipid occurred. Ts increased as a result of free fatty acids accumulation in membranes after phospholipase A2 treatment or storage.


Transcriptome Analysis of Schwann Cells at Various Stages of Myelination Implicates Chromatin Regulator Sin3A in Control of Myelination Identity.
Enhancing remyelination after injury is of utmost importance for optimizing the recovery of nerve function. While the formation of myelin by Schwann cells (SCs) is critical for the function of the peripheral nervous system, the temporal dynamics and regulatory mechanisms that control the progress of the SC lineage through myelination require further elucidation. Here, using in vitro co-culture models, gene expression profiling of laser capture-microdissected SCs at various stages of myelination, and multilevel bioinformatic analysis, we demonstrated that SCs exhibit three distinct transcriptional characteristics during myelination: the immature, promyelinating, and myelinating states. We showed that suppressor interacting 3a (Sin3A) and 16 other transcription factors and chromatin regulators play important roles in the progress of myelination. Sin3A knockdown in the sciatic nerve or specifically in SCs reduced or delayed the myelination of regenerating axons in a rat crushed sciatic nerve model, while overexpression of Sin3A greatly promoted the remyelination of axons. Further, in vitro experiments revealed that Sin3A silencing inhibited SC migration and differentiation at the promyelination stage and promoted SC proliferation at the immature stage. In addition, SC differentiation and maturation may be regulated by the Sin3A/histone deacetylase2 (HDAC2) complex functionally cooperating with Sox10, as demonstrated by rescue assays. Together, these results complement the recent genome and proteome analyses of SCs during peripheral nerve myelin formation. The results also reveal a key role of Sin3A-dependent chromatin organization in promoting myelinogenic programs and SC differentiation to control peripheral myelination and repair. These findings may inform new treatments for enhancing remyelination and nerve regeneration.


Effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and CYP3A activity in hypercholeresterolemic patients.
Variability of response to statins has been related to polymorphisms in genes involved in cholesterol homeostasis and statin metabolism, such as CYP3A4 and CYP3A5. We investigated the effects of atorvastatin on CYP3A4 and CYP3A5 mRNA expression in mononuclear cells and on CYP3A activity and their interactions with common variants. Unrelated individuals (n=121) with hypercholesterolemia (HC) were treated with atorvastatin (10 mg/day/4 weeks). Ninety-two normolipidemic (NL) subjects were selected as a control group. Genotype analysis of CYP3A4*1B (rs2740574), CYP3A4*22 (rs35599367), CYP3A5*3C (rs776746), and CYP3A5*1D (rs15524) and mRNA levels in peripheral blood mononuclear cells (PBMCs) were estimated. CYP3A activity was phenotyped by the urinary cortisol to 6-beta-hydroxy-cortisol ratio. LDL cholesterol reduction in response to atorvastatin was positively correlated with change in CYP3A4 (R(2)=0.039, p=0.037) and CYP3A5 (R(2)=0.047, p=0.019) mRNA levels and negatively correlated with CYP3A activity (R(2)=0.071, p=0.022). CYP3A5*3C (AGT haplotype) was associated to lower basal CYP3A5 mRNA expression in HC (p<0.045), however none of the haplotype groups impacted treatment. It is likely that cholesterolemia status changes promoted by atorvastatin play a role in regulating CYP3A4 and CYP3A5 mRNA expression in PBMCs, as well as CYP3A activity. CYP3A5*3C (AGT haplotype) also contributes for the variability of CYP3A5 mRNA levels in PBMCs.


Bayesian Time-Series Models in Single Case Experimental Designs: A Tutorial for Trauma Researchers.
Single-case experimental designs (SCEDs) involve obtaining repeated measures from one or a few participants before, during, and, sometimes, after treatment implementation. Because they are cost-, time-, and resource-efficient and can provide robust causal evidence for more large-scale research, SCEDs are gaining popularity in trauma treatment research. However, sophisticated techniques to analyze SCED data remain underutilized. Herein, we discuss the utility of SCED data for trauma research, provide recommendations for addressing challenges specific to SCED approaches, and introduce a tutorial for two Bayesian models-the Bayesian interrupted time-series (BITS) model and the Bayesian unknown change-point (BUCP) model-that can be used to analyze the typically small sample, autocorrelated, SCED data. Software codes are provided for the ease of guiding readers in estimating these models. Analyses of a dataset from a published article as well as a trauma-specific simulated dataset are used to illustrate the models and demonstrate the interpretation of the results. We further discuss the implications of using such small-sample data-analytic techniques for SCEDs specific to trauma research.


Observation on the changes of clinical symptoms, blood and brain copper deposition in Wilson disease patients treated with dimercaptosuccinic acid for 2 years.
To compare the clinical symptoms, brain copper deposition changes of Meso-2,3-dimercaptosuccinic acid (DMSA) and penicillamine therapy in patients with Wilson disease (WD) within 2 years. 68 drug-naive patients with WD were enrolled. 10 WD patients treated with zinc gluconate alone were used as the control group. Neurological symptoms were scored using the modified Young Scale. Liver function tests, copper indices and sensitive weighted imaging (SWI) examination were collected. The values of corrected phase (CP) were collected. WD patients were treated with DPA (group 1) or DMSA (group 2) for two years, and followed up every 2 months. The ratio of neurological improvement in group 2 was higher than that in group 1 (P = 0.029). Higher rate of neurologic worsening was noticed in patients treated with DPA vs DMSA (P = 0.039). The post-treatment neurological score of DMSA group was lower than that of Zn group (P = 0.037). Hepatic function in 63.3% of patients was stable, while 16.7% was improved, and 20% was deteriorated, after DMSA therapy. Urinary copper levels were lower 1 month (p = 0.032), 4 months (p = 0.041), 12 months (p = 0.037) after initiation of treatment in group 2 than in group 1. At the first year of treatment, the CP values in globus pallidus and substantia nigra in group 2 were higher than those in group 1 (P = 0.034,0.039). At the second year of treatment, the CP values of substantia nigra in group 2 were higher (P = 0.041). Discontinuation was more common in patients on DPA therapy (P = 0 0.032). DMSA could remove metal from brain tissue faster than DPA. DMSA is effective for neurologic symptoms, while the outcome for hepatic symptoms is not entirely satisfactory. DMSA therapy is better tolerated than DPA.


Understanding Bench Press Biomechanics-Training Expertise and Sex Affect Lifting Technique and Net Joint Moments.
Mausehund, L and Krosshaug, T. Understanding bench press biomechanics-Training expertise and sex affect lifting technique and net joint moments. J Strength Cond Res 37(1): 9-17, 2023-The purpose of this study was to compare normalized net joint moments (NJMs), moment arms, and muscle activity in the bench press exercise between powerlifters and recreationally strength-trained lifters and between women and men. Thirty-four healthy adults, including 12 powerlifters (6 women and 6 men) and 22 recreational lifters (9 women and 13 men), performed a 6-8 repetition maximum set of the bench press, while elbow and shoulder NJMs and moment arms and electromyographic (EMG) activity of 6 upper extremity muscles were recorded. The results showed that training expertise and sex affected bench press technique substantially. Powerlifters applied a different bar path which impacted joint kinematics to a greater extent and joint kinetics to a lesser extent. Specifically, powerlifters had lower normalized peak elbow NJMs and shorter joint ROMs than recreational lifters ( p ≤ 0.05), yet no differences in normalized shoulder NJMs and muscle activity were observed. Women showed lower normalized mean shoulder NJMs, higher normalized peak elbow NJMs, and higher mean elbow to shoulder NJM ratios than men ( p ≤ 0.05). The muscle activity of the long head of the triceps brachii and the elbow to shoulder EMG ratio were higher, yet muscle activity of the sternocostal and abdominal head of the pectoralis major was lower for female than for male subjects ( p ≤ 0.05). In conclusion, powerlifters and men are more shoulder dominant when performing the bench press than recreational lifters and women, respectively. These findings will have implications for resistance training program design, expected training adaptations and bench press performance.


Unimpaired Neuropsychological Performance and Enhanced Memory Recall in Patients with Sbma: A Large Sample Comparative Study.
Peculiar cognitive profile of patients with SBMA has been described by fragmented literature. Our retrospective study reports the neuropsychological evaluations of a large cohort of patients in order to contribute towards the understanding of this field. We consider 64 neuropsychological evaluations assessing mnesic, linguistic and executive functions collected from 2013 to 2015 in patients attending at Motor Neuron Disease Centre of University of Padova. The battery consisted in: Digit Span forwards and backwards, Prose Memory test, Phonemic Verbal fluency and Trail making tests. ANCOVA statistics were employed to compare tests scores results with those obtained from a sample of healthy control subjects. Multiple linear regressions were used to study the effect on cognitive performance of CAG-repeat expansion, the degree of androgen insensitivity and their interaction to cognitive performance. Statistical analyses did not reveal altered scores in any neuropsychological tests among those adopted. Interestingly, patients performed significantly better in the Prose Memory test's score. No relevant associations were found with genetic, hormonal or clinical patients' profile. Results inconsistent with previous studies have been interpreted according to the phenomenon of somatic mosaicism. We suggest a testosterone-related and the mood state-dependant perspectives as two possible interpretations of the enhanced performances in the Prose Memory test. Further studies employing more datailed tests batteries are encouraged.


The role of working memory in achievement goal pursuit.
The present research examined the role of working memory in the pursuit of qualitatively different achievement goals. Pursuit of a mastery-approach goal entails a focus on developing self-referential competence while a performance-approach goal entails a focus on demonstrating normative competence. Across two experiments it was found that, when working memory is loaded, individuals pursuing a mastery-approach goal experienced larger performance decrements than individuals pursuing a performance-approach goal or those in a no-goal control. It was also found that reliance upon working memory intensive strategies (explicit strategies) was more evident for those in a mastery-approach condition, whereas reliance upon less working memory intensive strategies (implicit strategies) was more evident for those in the performance-approach condition. Results suggest that a motivated focus on developing self-referential skill relies heavily on working memory, facilitated by the use of deliberative, 'step-by-step' strategies during goal pursuit. Conversely, a focus on demonstrating normative skill depends less on working memory, facilitated by the use of more heuristic 'short-cut' strategies during goal pursuit. These findings show, for the first time, that working memory plays an important, but selective, role in achievement goal pursuit.


Biodiversity of Trichoderma (Hypocreaceae) in Southern Europe and Macaronesia.
The first large-scale survey of sexual and asexual Trichoderma morphs collected from plant and fungal materials conducted in Southern Europe and Macaronesia including a few collections from French islands east of Africa yielded more than 650 specimens identified to the species level. Routine sequencing of tef1 revealed a genetic variation among these isolates that exceeds previous experience and ca. 90 species were recognized, of which 74 are named and 17 species newly described. Aphysiostroma stercorarium is combined in Trichoderma. For the first time a sexual morph is described for T. hamatum. The hitherto most complete phylogenetic tree is presented for the entire genus Trichoderma, based on rpb2 sequences. For the first time also a genus-wide phylogenetic tree based on acl1 sequences is shown. Detailed phylogenetic analyses using tef1 sequences are presented in four separate trees representing major clades of Trichoderma. Discussions involve species composition of clades and ecological and biogeographic considerations including distribution of species.


Tumour selective targeting of cell cycle kinases for cancer treatment.
The deregulation of the cell cycle and checkpoint machinery in cancer presents a highly attractive therapeutic strategy. We review here the strategies used to exploit the dysregulated cell cycle, both through targeting kinases required for cell cycle progression, and checkpoint kinases to inappropriately force cells through the cell cycle. Appropriate control of the cell cycle is critical for proliferating normal cells, and we discuss the importance of defining tumour specific vulnerabilities that could be targeted with cell cycle kinase inhibitors. Recent studies have shown that ER-positive breast cancers rely on CDK4 to promote proliferation. TP53 mutant cancer cell lines are sensitive to WEE1 and CHK1 inhibitors in combination with chemotherapy, while PTEN-deficient aneuploid cancer cell lines are sensitive to TTK inhibitors.


Paclitaxel (Taxol) induces cumulative mild neurotoxicity.
Paclitaxel (Taxol), a new antineoplastic drug, has been reported to be neurotoxic at doses above 200 mg/m2 per course. It is uncertain whether neurotoxicity is related to cumulative amounts of paclitaxel. Neuropathy was prospectively assessed in 18 patients with breast cancer, receiving between two and eight courses of 135 or 175 mg/m2 of paclitaxel. Vibratory perception thresholds (VPT) and tendon reflex scores were proportionally related to the corresponding cumulative amounts of paclitaxel (P = 0.002; P = 0.0003). The amounts of paclitaxel administered between the first and last assessments (175-1225 mg/m2) were related to concomitant changes in VPT (P = 0.034). Paclitaxel had no clear neurotoxic threshold; if present, it lies below 540 mg/m2. Rather, VPT appeared to increase 0.1 micron per 400 mg/m2 over the entire range of 175-1225 mg/m2 of paclitaxel. Clinical neuropathy prevailed in 0/8 patients at screening and in 5/10 patients at the final assessment (P = 0.029). Neuropathy never exceeded grade 1. Thus, although neurotoxicity of paclitaxel is frequent and cumulative, it remains mild or subclinical up to at least 1400 mg/m2 administered over eight cycles.


Ankle arthroplasty in a patient with bleeding diathesis and the mid-term clinical outcome of the case.
The purpose of this report was to present the case of a patient with bleeding diathesis on whom we performed ankle arthroplasty for the first time. A 29-year old male patient with bleeding diathesis, who had been treated and followed up over a long period, underwent ankle arthroplasty because of osteoarthritis of the ankle. The patient was prepared for surgery by the haematology department in accordance with the guidelines for surgical preparation, diagnosis and management of haemophilia. After ankle arthroplasty was performed, the preoperative and two-year postoperative clinical outcomes were evaluated using a subjective foot score and Maryland foot score. Preoperative factor VIII levels were raised to the target level of haemostasis prior to the surgical procedure. The factor VIII levels were maintained within the normal range up to postoperative day 14. The subjective foot score of the patient was 40 preoperatively and 85 postoperatively, whereas their Maryland foot scores were 33 preoperatively and 90 postoperatively. Both scoring systems indicate an excellent clinical outcome. As observed, the early and mid-term functional outcomes are promising for patients with bleeding diathesis who undergo ankle arthroplasty.


Nontoxic membrane translocation peptide from protamine, low molecular weight protamine (LMWP), for enhanced intracellular protein delivery: in vitro and in vivo study.
Naturally derived, nontoxic peptides from protamine by the authors, termed low molecular weight protamines (LMWPs), possess high arginine content and carry significant sequence similarity to that of TAT, by far the most potent protein transduction domain peptide. Therefore, it was hypothesized that these LMWPs would also inherit the similar translocation activity across the cell membrane, which enables any impermeable species to be transduced into the cells. LMWPs were prepared by enzymatic digestion of protamine, examined their capability of transducing an impermeable protein toxin into the tumor cells by chemical conjugation, and determined cytotoxicity of transduced protein toxin (e.g., gelonin) against cancer cell lines and a tumor-bearing mouse. In vitro results showed that LMWPs could indeed translocate themselves into several mammalian cell lines as efficiently as TAT, thereby transducing impermeable gelonin into the cells by chemical conjugation. In vivo studies further confirmed that LMWP could carry an impermeable gelonin across the tumor mass and subsequently inhibit the tumor growth. In conclusion, the presence of equivalent cell translocation potency, absence of toxicity of peptide itself, and the suitability for low-cost production by simple enzymatic digestion could expand the range of clinical applications of LMWPs, including medical imaging and gene/protein therapies.


Second allogeneic hematopoietic SCT for relapsed ALL in children.
A second SCT is generally accepted as the only potentially curative approach for ALL patients that relapse after SCT, but the role of second SCT for pediatric ALL is not fully understood. We performed a retrospective analysis of 171 pediatric patients who received a second allo-SCT for relapsed ALL after allo-SCT. OS at 2 years was 29.4 ± 3.7%, the cumulative incidence of relapse was 44.1 ± 4.0% and non-relapse mortality was 18.8 ± 3.5%. Relapse occurred faster after the second SCT than after the first SCT (117 days vs 164 days, P=0.04). Younger age (9 years or less), late relapse (180 days or more after first SCT), CR at the second SCT, and myeloablative conditioning were found to be related to longer survival. Neither acute GVHD nor the type of donor influenced the outcome of second SCT. Multivariate analysis showed that younger age and late relapse were associated with better outcomes. Our analysis suggests that second SCT for relapsed pediatric ALL is an appropriate treatment option for patients that have achieved CR, which is associated with late relapse after the first SCT.


Correlation between Argus II array-retina distance and electrical thresholds of stimulation is improved by measuring the entire array.
To describe two methods of measuring Argus II array-retina distance and to correlate array-retina distance to electrode stimulation thresholds. This was a case series of eight patients implanted with the Argus II. Spectral domain-optical coherence tomography array-retina distance was measured by two methods and correlated to corresponding electrode thresholds: (1) array-retina distance at each array corner and the largest array-retina distance and (2) using manual optical coherence tomography segmentation, the average array-retina distance was determined for each group of four electrodes. Patients 1-5 and 6-8 were analyzed separately due to a different threshold programming software. The Spearman's rank coefficient between array-retina distance and thresholds was -0.006 (p = 0.98) for patients 1-5, and 0.16 (p = 0.59) for patients 6-8 with the first method. The Spearman's rank coefficient was 0.25 (p < 0.001) for patients 1-5 and 0.36 (p < 0.001) for patients 6-8 with the second method. There is a positive correlation between array-retina distance and threshold measurements when measuring the entire array but not when using a faster measurement method of four corners and largest array-retina distance.


Examining Unilateral and Bilateral Exercises through the Load-velocity Relationship.
This study aimed to examine the load-velocity (L-V) relationship in the bench-press (BP) and leg-press (LP) exercises performed unilaterally, and compared this unilateral L-V relationship with the bilateral variants. Nineteen men (age=23.5±2.1 years) completed two incremental tests in BP and LP, performed bilaterally and unilaterally, across two sessions with a 48-hour rest period. We found a close relationship between medium propulsive velocity (MPV) and %1RM in unilateral BP (R2 =0.97, SEE=0.06 m·s-1) and LP (R2=0.96, SEE=0.06 m·s-1). No significant differences were observed between the preferred and non-preferred sides in the L-V relationship for either exercise. Additionally, higher velocities were achieved in unilateral exercises compared to bilateral exercises, particularly with light and moderate loads (30-70%1RM) in BP (p<0.05) and with light loads (30-45%1RM) in LP (p<0.05). Close L-V relationships were observed in unilateral exercises, without differences in the L-V relationships between preferred and non-preferred sides despite the interlimb asymmetries in the absolute strength values. Interestingly, lower velocities were observed at light loads (~30-45% 1RM) for bilateral compared to unilateral exercises, which could be explained by different strength deficits for these exercises.


Serum Cingulin levels are increased in children with autism spectrum disorder.
Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders in which the underlying pathogenesis and etiologic factors are not fully understood. The blood brain barrier (BBB) plays a critical role in central nervous system defense by limiting access to circulating solutes, macromolecules, and cells that can negatively affect neuronal activity. The loss of BBB integrity is likely to be seen as a common pathologic finding for many psychiatric disorders such as schizophrenia, ASD, and mood disorders. In this study, we aimed to investigate whether serum Cingulin levels are associated with ASD. A total of 40 treatment-naive children with ASD and 40 healthy controls were included in the present study. The Schedule for Affective Disorders and Schizophrenia for School-Aged Children, Present and Lifetime Version-DSM-5 (K-SADS-PL-DSM-5) has been used to screen healthy controls for psychiatric disorders by a psychiatrist after a physical examination by a paediatrician. The clinical severity of the ASD symptoms has been assessed by the Childhood Autism Rating Scale (CARS). Venous blood samples were collected and serum Cingulin levels were measured. When the ASD and control groups were compared, CARS and Cingulin values of the patient group were statistically higher than the healthy group. There is a statistically positive correlation between CARS and Cingulin values. To the best of our knowledge, this study is a first in the literature conducted about the serum Cingulin levels, which is a component of BBB, among patients with ASD. Our findings demonstrate that serum Cingulin levels are meaningfully higher in ASD group compared to the healthy control group. It has been also indicated that there has been a meaningful relationship between serum Cingulin levels and ASD symptom severity.


Degradation of double-walled polymer microspheres of PLLA and P(CPP:SA)20:80. II. In vivo degradation.
Double-walled (DW) polymer microspheres with a core of poly(1,3-bis-(p-carboxyphenoxy propane)-co-(sebacic anhydride)20:80 (P(CPP:SA)20:80) and an external coat of poly(L-lactic acid) (PLLA) were implanted subcutaneously and intramuscularly and were allowed to degrade for up to 6 months. The tissue surrounding the implant was fixed and sectioned for histological evaluation by light and scanning electron microscopy. The remaining polymer was extracted with chloroform and analyzed by gel permeation chromatography (G PC), Fourier-transform infrared (FTIR) spectroscopy, and differential scanning calorimetry (DSC). The inner core of the more hydrolytically labile P(CPP:SA)20:80 degraded first, becoming more granular over time. The PLLA coating showed no changes morphologically. The DW microspheres induced a stronger inflammatory response during the first week than did the SW PLLA microspheres, but this resolved by the second week. The SW PLLA microspheres showed no changes by SEM or optical microscopy. No differences in degradation were seen between samples implanted subcutaneously and those implanted intramuscularly. In vivo degradation was correlated to the results of an in vitro degradation study published as the first paper in this two paper series.


Nutrition, weight gain and eating behavior in pregnancy: a review of experimental evidence for long-term effects on the risk of obesity in offspring.
Obesity has reached near epidemic proportions in the developed world. As reproductive age women are a part of this trend, the effect of maternal obesity on the developing fetus must be investigated. In this review, we evaluated the experimental evidence relating maternal nutritional status and eating behavior before and during pregnancy on the risk of obesity in the offspring. The studies were compiled and selected based on their methodologies, study design and relevance. The analyzed studies were compiled to quantify, if possible, the relationship between maternal and offspring weight. Descriptive and observational studies were also included if they were seminal in the field. Based on the current data, maternal obesity is a critical factor exacerbating multigenerational obesity. Mechanistic studies, mainly in animals, have identified potential areas for intervention which might limit transmission of adverse risk factors for obesity from mothers to infants during pregnancy.