Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications.
Filamentous inclusions of alpha-synuclein protein are hallmarks of neurodegenerative diseases collectively known as synucleinopathies. Previous studies have shown that exposure to oxidative and nitrative species stabilizes alpha-synuclein filaments in vitro, and this stabilization may be due to dityrosine cross-linking. To test this hypothesis, we mutated tyrosine residues to phenylalanine and generated recombinant wild type and mutant alpha-synuclein proteins. alpha-Synuclein proteins lacking some or all tyrosine residues form fibrils to the same extent as the wild type protein. Tyrosine residues are not required for protein cross-linking or filament stabilization resulting from transition metal-mediated oxidation, because higher Mr SDS-resistant oligomers and filaments stable to chaotropic agents are detected using all Tyr --> Phe alpha-synuclein mutants. By contrast, cross-linking resulting from exposure to nitrating agents required the presence of one or more tyrosine residues. Furthermore, tyrosine cross-linking is involved in filament stabilization, because nitrating agent-exposed assembled wild type, but not mutant alpha-synuclein lacking all tyrosine residues, was stable to chaotropic treatment. In addition, the formation of stable alpha-synuclein inclusions in intact cells after exposure to oxidizing and nitrating species requires tyrosine residues. These findings demonstrate that nitrative and/or oxidative stress results in distinct mechanisms of alpha-synuclein protein modifications that can influence the formation of stable alpha-synuclein fibrils.


Serpinb1a Is Dispensable for the Development and Cytokine Response of Invariant Natural Killer T Cell Subsets.
Invariant natural killer T (iNKT) cells are innate-like T lymphocytes. They quickly respond to antigenic stimulation by producing copious amounts of cytokines and chemokines. iNKT precursors differentiate into three subsets iNKT1, iNKT2, and iNKT17 with specific cytokine production signatures. While key transcription factors drive subset differentiation, factors that regulate iNKT subset homeostasis remain incompletely defined. Transcriptomic analyses of thymic iNKT subsets indicate that Serpinb1a is one of the most specific transcripts for iNKT17 cells suggesting that iNKT cell maintenance and function may be regulated by Serpinb1a. Serpinb1a is a major survival factor in neutrophils and prevents cell death in a cell-autonomous manner. It also controls inflammation in models of bacterial and viral infection as well as in LPS-driven inflammation. Here, we examined the iNKT subsets in neutropenic Serpinb1a-/- mice as well as in Serpinb1a-/- mice with normal neutrophil counts due to transgenic re-expression of SERPINB1 in neutrophils. In steady state, we found no significant effect of Serpinb1a-deficiency on the proliferation and numbers of iNKT subsets in thymus, lymph nodes, lung, liver and spleen. Following systemic activation with α-galactosylceramide, the prototypic glycolipid agonist of iNKT cells, we observed similar serum levels of IFN-γ and IL-4 between genotypes. Moreover, splenic dendritic cells showed normal upregulation of maturation markers following iNKT cell activation with α-galactosylceramide. Finally, lung instillation of α-galactosylceramide induced a similar recruitment of neutrophils and production of iNKT-derived cytokines IL-17, IFN-γ, and IL-4 in wild-type and Serpinb1a-/- mice. Taken together, our results indicate that Serpinb1a, while dominantly expressed in iNKT17 cells, is not essential for iNKT cell homeostasis, subset differentiation and cytokine release.


CHRK1, a chitinase-related receptor-like kinase in tobacco.
A cDNA encoding a chitinase-related receptor-like kinase, designated CHRK1, was isolated from tobacco (Nicotiana tabacum). The C-terminal kinase domain (KD) of CHRK1 contained all of the conserved amino acids of serine/threonine protein kinases. The putative extracellular domain was closely related to the class V chitinase of tobacco and to microbial chitinases. CHRK1 mRNA accumulation was strongly stimulated by infection with fungal pathogen and tobacco mosaic virus. Amino acid-sequence analysis revealed that the chitinase-like domain of CHRK1 lacked the essential glutamic acid residue required for chitinase activity. The recombinant chitinase-like domain did not show any catalytic activity for either oligomeric or polymeric chitin substrates. The recombinant KD of CHRK1 exhibited autophosphorylation, but the mutant KD with a mutation in the essential ATP-binding site did not, suggesting that CHRK1 encoded a functional kinase. CHRK1 was detected in membrane fractions of tobacco BY2 cells. Furthermore, CHRK1-GFP fusion protein was localized in plasma membranes when it was expressed in animal cells. This is the first report of a new type of receptor-like kinase containing a chitinase-like sequence in the putative extracellular domain.


A neural encoder for earthquake rate forecasting.
Forecasting the timing of earthquakes is a long-standing challenge. Moreover, it is still debated how to formulate this problem in a useful manner, or to compare the predictive power of different models. Here, we develop a versatile neural encoder of earthquake catalogs, and apply it to the fundamental problem of earthquake rate prediction, in the spatio-temporal point process framework. The epidemic type aftershock sequence model (ETAS) effectively learns a small number of parameters to constrain the assumed functional forms for the space and time correlations of earthquake sequences (e.g., Omori-Utsu law). Here we introduce learned spatial and temporal embeddings for point process earthquake forecasting models that capture complex correlation structures. We demonstrate the generality of this neural representation as compared with ETAS model using train-test data splits and how it enables the incorporation additional geophysical information. In rate prediction tasks, the generalized model shows [Formula: see text] improvement in information gain per earthquake and the simultaneous learning of anisotropic spatial structures analogous to fault traces. The trained network can be also used to perform short-term prediction tasks, showing similar improvement while providing a 1000-fold reduction in run-time.


Structural insights into species-specific features of the ribosome from the human pathogen Mycobacterium tuberculosis.
Ribosomes from Mycobacterium tuberculosis (Mtb) possess species-specific ribosomal RNA (rRNA) expansion segments and ribosomal proteins (rProtein). Here, we present the near-atomic structures of the Mtb 50S ribosomal subunit and the complete Mtb 70S ribosome, solved by cryo-electron microscopy. Upon joining of the large and small ribosomal subunits, a 100-nt long expansion segment of the Mtb 23S rRNA, named H54a or the 'handle', switches interactions from with rRNA helix H68 and rProtein uL2 to with rProtein bS6, forming a new intersubunit bridge 'B9'. In Mtb 70S, bridge B9 is mostly maintained, leading to correlated motions among the handle, the L1 stalk and the small subunit in the rotated and non-rotated states. Two new protein densities were discovered near the decoding center and the peptidyl transferase center, respectively. These results provide a structural basis for studying translation in Mtb as well as developing new tuberculosis drugs.


Novel balloon application for rescue and realignment of a proximal end migrated pipeline flex embolization device into the aneurysmal sac: complication management.
The pipeline embolization device (PED) has become a routine firstline option for the treatment of an increasing population of intracranial aneurysms at many neurovascular centers. Intraprocedural complications during PED deployment, or complications associated with migration of the device, are rarely reported problems. Significant mismatch in luminal diameter between the inflow vessel and the outflow vessel or excessive dragging-stretching of the PED have been related to 'watermelon seed' or 'accordion' effects, respectively, resulting in stent migration. Here we present a novel balloon technique that was successfully used to realign an in situ flow diverting stent that had prolapsed into a large aneurysm. This represents a useful salvage technique and should be considered when encountering this potential complication.


Three Logistic Predictive Models for the Prediction of Mortality and Major Pulmonary Complications after Cardiac Surgery.
Background and Objectives: Pulmonary complications are a leading cause of morbidity after cardiac surgery. The aim of this study was to develop models to predict postoperative lung dysfunction and mortality. Materials and Methods: This was a single-center, observational, retrospective study. We retrospectively analyzed the data of 11,285 adult patients who underwent all types of cardiac surgery from 2003 to 2015. We developed logistic predictive models for in-hospital mortality, postoperative pulmonary complications occurring in the intensive care unit, and postoperative non-invasive mechanical ventilation when clinically indicated. Results: In the "preoperative model" predictors for mortality were advanced age (p < 0.001), New York Heart Association (NYHA) class (p < 0.001) and emergent surgery (p = 0.036); predictors for non-invasive mechanical ventilation were advanced age (p < 0.001), low ejection fraction (p = 0.023), higher body mass index (p < 0.001) and preoperative renal failure (p = 0.043); predictors for postoperative pulmonary complications were preoperative chronic obstructive pulmonary disease (p = 0.007), preoperative kidney injury (p < 0.001) and NYHA class (p = 0.033). In the "surgery model" predictors for mortality were intraoperative inotropes (p = 0.003) and intraoperative intra-aortic balloon pump (p < 0.001), which also predicted the incidence of postoperative pulmonary complications. There were no specific variables in the surgery model predicting the use of non-invasive mechanical ventilation. In the "intensive care unit model", predictors for mortality were postoperative kidney injury (p < 0.001), tracheostomy (p < 0.001), inotropes (p = 0.029) and PaO2/FiO2 ratio at discharge (p = 0.028); predictors for non-invasive mechanical ventilation were kidney injury (p < 0.001), inotropes (p < 0.001), blood transfusions (p < 0.001) and PaO2/FiO2 ratio at the discharge (p < 0.001). Conclusions: In this retrospective study, we identified the preoperative, intraoperative and postoperative characteristics associated with mortality and complications following cardiac surgery.


ELISPOT determination of interferon-gamma T-cell frequencies in patients with autoimmune sensorineural hearing loss.
Autoimmune sensorineural hearing loss (ASNHL) is the most common cause of sudden hearing loss in adults. Although the etiopathogenesis of this disease is unclear, it is widely believed that antibody and/or T-cell responses directed against inner ear-specific proteins may mediate ASNHL. Using the enzyme-linked immunospot (ELISPOT) assay, we have recently found that many patients with ASNHL have increased frequencies of peripheral blood T-cells capable of producing interferon (IFN)-gamma in response to a homogenate of human inner ear tissue. Our studies may ultimately lead to the identification of inner ear-specific autoimmune targets in ASNHL, and our ELISPOT approach may be particularly useful in supporting the diagnosis of this disease entity. In the current chapter we detail how to use the ELISPOT assay for measuring frequencies of IFN-gamma-producing T-cells in patients with ASNHL.


Stability and bioactivity of thrombin binding aptamers modified with D-/L-isothymidine in the loop regions.
Thrombin binding aptamer (TBA) is a 15-mer single-strand DNA that was identified by SELEX screening technology. It adopts a chair-type antiparallel G-quadruplex and can specifically interact with thrombin, thus inhibiting blood coagulation. Isonucleoside (isoNA) is a type of nucleoside isomer in which the base is shifted to 2′-positions of the glycosyl group, endowed with the ability to modulate local conformation of nucleotides, and L-isoNA could alter the conformation more due to the inversion of glycosyl configuration. Incorporation of L-isothymidine (L-isoT) at T3, T9, T12 positions and D-isoT at the T7 position in TBA's loop regions promoted the formation of G-quadruplex, resulting in enhanced affinity with thrombin and an increased anticoagulant effect. Computer simulation indicated that TBA-12L showed the strongest binding with thrombin, which was consistent with experimental results. The bioactivity of double isoNA incorporated TBA with D-IsoT at T7 and L-IsoT at T12 was comparable to that of TBA-12L, suggesting that the T12 of TBA was very important in interaction with thrombin. Our study also suggested that TBA might interact with two thrombin molecules through the TT loops (T3T4, T12T13) and TGT loop, but the second bonding did not show additional biological effects.


Enzymic hydrolysis of sphingomyelin in the presence of bile salts.
Sphingomyelin in mixed dispersion with bile salts was hydrolysed by the solubilized sphingomyelinase of rat brain lysosomes. In parallel studies, physical properties of these dispersions were determined. The kinetic curves that described the rate of hydrolysis as a function of increasing concentrations of bile salt were multiphasic. A region of very low activity was followed by an ascending portion, a peak, a descending portion, a trough and a second ascending portion. The positions of the initiation points, peaks and troughs were found to be a function of the respective ratios of the bile salt to sphingomyelin for the detergent sodium taurodeoxycholate, but of the absolute concentration of the detergent for sodium taurocholate. Turbidity studies suggested that hydrolysis of sphingomyelin begins at a bile salt concentration that solubilizes the lipid and incorporates it into a mixed micelle with the detergent. Ultracentrifugation studies suggested that the sizes of the mixed aggregates of detergent and lipid were a function of the ratio of taurodeoxycholate to sphingomyelin, but of the absolute concentration of the bile salt, for sodium taurocholate.


[An analysis of the effect of tobacco on glucose metabolism].
The nicotine contained in tobacco smoke produces an elevation of the plasmatic catecholamines which, in turn, may be the cause of the increase in basal glycemia by several mechanisms. The aim of this study was to investigate the relation between cigarette consumption and the increase in glucose in smokers and non smokers. Basal glycemia and glucosylate hemoglobin (HbA1c) were determined in 74 males, 38 smokers and 36 non smokers who were consulted and included in the prevention activities program of the center. Significantly greater fasting glycemia was found in smokers than in nonsmokers. However, upon analyzing the values of glucosylate hemoglobin no significant differences were observed between the two groups. These data suggest that nicotine contained in tobacco smoke produces a transitory hyperglycemia.


Methyl jasmonate reduces grain yield by mediating stress signals to alter spikelet development in rice.
Jasmonic acid (JA) is involved in plant development and the defense response. Transgenic overexpression of the Arabidopsis (Arabidopsis thaliana) jasmonic acid carboxyl methyltransferase gene (AtJMT) linked to the Ubi1 promoter increased levels of methyl jasmonate (MeJA) by 6-fold in young panicles. Grain yield was greatly reduced in Ubi1:AtJMT plants due to a lower numbers of spikelets and lower filling rates than were observed for nontransgenic (NT) controls. Ubi1:AtJMT plants had altered numbers of spikelet organs, including the lemma/palea, lodicule, anther, and pistil. The loss of grain yield and alteration in spikelet organ numbers were reproduced by treating NT plants with exogenous MeJA, indicating that increased levels of MeJA in Ubi1:AtJMT panicles inhibited spikelet development. Interestingly, MeJA levels were increased by 19-fold in young NT panicles upon exposure to drought conditions, resulting in a loss of grain yield that was similar to that observed in Ubi1:AtJMT plants. Levels of abscisic acid (ABA) were increased by 1.9- and 1.4-fold in Ubi1:AtJMT and drought-treated NT panicles, respectively. The ABA increase in Ubi1:AtJMT panicles grown in nondrought conditions suggests that MeJA, rather than drought stress, induces ABA biosynthesis under drought conditions. Using microarray and quantitative polymerase chain reaction analyses, we identified seven genes that were regulated in both Ubi1:AtJMT and drought-treated NT panicles. Two genes, OsJMT1 and OsSDR (for short-chain alcohol dehydrogenase), are involved in MeJA and ABA biosynthesis, respectively, in rice (Oryza sativa). Overall, our results suggest that plants produce MeJA during drought stress, which in turn stimulates the production of ABA, together leading to a loss of grain yield.


Variables associated with 7-day, 30-day, and 1-year fatality after ischemic stroke.
Seven-day, 30-day, and 1-year case-fatality indicators have been used to compare stroke care among hospitals, provinces, and countries and to implement quality improvement strategies. However, limited information is available concerning variables associated with stroke case fatality at these different points in time. We sought to identify and compare variables associated with 7-day, 30-day, and 1-year stroke fatality. This was a cohort study of consecutive patients with acute ischemic stroke admitted to 11 stroke centers in Ontario, Canada, between July 2003 and March 2005 and captured in the Registry of the Canadian Stroke Network (RCSN). The RCSN database was linked to administrative databases to capture all deaths occurring within 7, 30, and 365 days of hospital admission for ischemic stroke. Logistic regression was used to determine variables associated with stroke fatality at each time point. Outcome measures were all-location mortality within 7 days, 30 days, and 1 year of hospital admission. Our cohort included 3631 patients admitted with ischemic stroke. Seven-day case fatality was 6.9% (249/3631), 30-day case fatality was 12.6% (457/3631), and 1-year case fatality was 23.6% (856/3631). In the multivariable analyses, stroke severity, neurologic deterioration during hospitalization, nonuse of antithrombotics during hospital admission, and lack of assessment by a stroke team were the most consistent predictors of case fatality at 7 days, 30 days, and 1 year after stroke. Physician experience in stroke management was inversely associated with 7-day and 30-day mortality, whereas age, comorbid illness, and pneumonia during hospital admission were associated with 30-day and 1-year mortality. Stroke severity and certain processes of care were associated with case fatality at 7 days, 30 days, and 1 year after stroke. This information may be useful for comparing risk-adjusted case-fatality rates among hospitals and for implementing strategies to improve the processes and quality of care in the acute phase of stroke.


Utilization, Safety, and Technical Performance of a Telemedicine System for Prehospital Emergency Care: Observational Study.
As a consequence of increasing emergency medical service (EMS) missions requiring an EMS physician on site, we had implemented a unique prehospital telemedical emergency service as a new structural component to the conventional physician-based EMS in Germany. We sought to assess the utilization, safety, and technical performance of this telemedical emergency service. We conducted a retrospective analysis of all primary emergency missions with telemedical consultation of an EMS physician in the City of Aachen (250,000 inhabitants) during the first 3 operational years of our tele-EMS system. Main outcome measures were the number of teleconsultations, number of complications, and number of transmission malfunctions during teleconsultations. The data of 6265 patients were analyzed. The number of teleconsultations increased during the run-in period of four quarters toward full routine operation from 152 to 420 missions per quarter. When fully operational, around the clock, and providing teleconsultations to 11 mobile ambulances, the number of teleconsultations further increased by 25.9 per quarter (95% CI 9.1-42.6; P=.009). Only 6 of 6265 patients (0.10%; 95% CI 0.04%-0.21%) experienced adverse events, all of them not inherent in the system of teleconsultations. Technical malfunctions of single transmission components occurred from as low as 0.3% (95% CI 0.2%-0.5%) during two-way voice communications to as high as 1.9% (95% CI 1.6%-2.3%) during real-time vital data transmissions. Complete system failures occurred in only 0.3% (95% CI 0.2%-0.6%) of all teleconsultations. The Aachen prehospital EMS is a frequently used, safe, and technically reliable system to provide medical care for emergency patients without an EMS physician physically present. Noninferiority of the tele-EMS physician compared with an on-site EMS physician needs to be demonstrated in a randomized trial.


Adjuvant polyarthritis. VI. Effect of oxonate-induced hyperuricemia on the development of acute inflammation, immune response and adjuvant arthritis.
In humans, there is a negative correlation between gout and rheumatoid arthritis. Similarly, rats rendered hyperuricemic by an oxonate diet appeared resistant to develop adjuvant arthritis. These animals exhibited a normal inflammatory response to a subplantar injection of carrageenin and normal humoral and cell-mediated immune responses to a sensitizing dose of EL4 cells. However, unlike that of normal animals, the cell-mediated immune system of the oxonate-treated rats was found to be unable to respond to adjuvant stimulation, which may be the basis for their resistance to develop adjuvant disease.


Nifedipine, captopril, metoprolol and nifedipine with metoprolol in hypertensive crisis in non-intensive care setting.
In 102 cases of severe hypertension (DBP > or = 115 mm Hg), with or without acute complications, efficacy and safety of SL Nifedipine 10 mg (NIF), SL Captopril 25 mg (CAP), IV Metoprolol 15 mg (MET) and SL NIF + IV MET were studied in an inpatient trial. Maximum mean percent reduction in SBP was 13.3, 9.7, 15.7 and 19.9 and in DBP was 21.2, 13.9, 12.5 and 20.4 with NIF, CAP, MET and NIF + MET respectively. A safe DBP of < or = 110 mm Hg (Kaplan) was achieved in 90, 61, 72.2 and 95.2 percent of patients. A statistically significant fall in DBP was observed at 5 minutes with all regimens except CAP which was at 15 minutes. Mild side effects observed were palpitations and flushing (NIF n = 4), taste disturbances (CAP n = 3), heaviness of head (CAP n = 1) and giddiness (MET n = 2, NIF + MET n = 2). The trial data suggest that hypertensive crisis can be managed, without intensive care facility, with all four regimens; this implies significant cost containment.


Disability rights and empowerment: Reflections on AJCP research and a call to action.
People living with physical, sensory, intellectual, and/or developmental disabilities experience complex social, environmental, political, and cultural challenges along with stigma and marginalization in education, employment, and community life. These multiple and complex barriers often hinder their full and effective participation in society. In this reflection, we curated articles on physical, sensory, intellectual, and/or developmental disabilities published in the American Journal of Community Psychology from 1973 to 2022. We reviewed titles and abstracts to identify themes that grouped manuscripts in relevant community psychology core concepts and values. From our analysis, five themes emerged: (a) promoting empowerment and advocacy; (b) promoting organizations and settings that support people with disabilities; (c) including people with disabilities in knowledge production; (d) promoting social justice in disability research, and (e) promoting support networks of families of people with disabilities. We conclude this reflection with a discussion of recommendations for future research, practice, and a call to action.


Minor psychiatric disorders and syncope: the role of psychopathology in the expression of vasovagal reflex.
A high prevalence of minor psychiatric disorders (MPDs) has been reported in patients with vasovagal syncope (VVS). However, the relationship between the psychiatric substrate and syncope remains unclear. In order to test the hypothesis that MPDs may predispose to VVS, we assessed the prevalence of syncope, the response to head-up tilt test (HUTT) and the efficacy of psychiatric drug treatment in reducing syncopal episodes, in patients with recently diagnosed MPDs. The response to HUTT was compared with that in an equal number of matched (a) patients with VVS and (b) healthy controls. A high rate of patients with MPDs (58%) had a positive HUTT. Additionally, 45% had a history of syncope; among them, the rate of positive HUTT was identical to that in the VVS group (83%). Following psychiatric drug treatment, the number of patients with syncope decreased in the MPD group (6/67 from 30/67, p < 0.01). Psychiatric symptoms and quality of life were also improved. The number of syncopal spells decreased equally in the MPD and VVS groups (0.6 +/- 0.5 from 2.5 +/- 1.4, p < 0.01, and 0.7 +/- 0.5 from 2.7 +/- 1.3, p < 0.01, respectively). A high proportion of patients with MPDs experience syncope, associated with a high rate of positive HUTT, comparable to that observed in VVS. Psychiatric treatment results in the improvement of syncopal and psychiatric symptoms. These findings suggest involvement of co-occurring MPDs in the pathogenesis of VVS. Therefore, the diagnosis and treatment of MPDs, when present, may be crucial for the effective therapy of vasovagal syndrome.


Updated results of a randomized, double-blind, multicenter sham-controlled trial of microwave thermotherapy with the Dornier Urowave in patients with symptomatic benign prostatic hyperplasia. Urowave Investigators Group.
A total of 220 patients with clinical benign prostatic hyperplasia (BPH), an AUA symptom index (AUA SI) of > 13 points, and a peak flow rate of < 12 ml/s were randomly assigned to either active or sham treatment. All treatments were conducted as an outpatient procedure without general anesthesia. Sham-treated patients underwent a simulated 60-min treatment with an indwelling treatment catheter. Patients were followed at 1 week and at 1, 3, and 6 months. The treatments were well tolerated. The AUA SI dropped from 23.6 to 12.6 points at 6 months (P < 0.05) in the active group and from 23.9 to 17.9 points in the sham-treated group (P < 0.05 for the difference between groups). There was a significant difference between the groups at 6 months (P < 0.001). Similar and statistically significant changes occurred regarding the AUA bother index and the quality of life scores. Statistically significant improvements were also noted for the peak flow rate (from 7.7 to 10.6 ml/s at 6 months for the active group and from 8.1 to 9.6 ml/s for the sham-treated group; P < 0.05 for the difference between groups) and for the average flow rate. An improvement in the AUA SI of > 30% was achieved by 72% versus 40% (active versus sham) and an improvement of > 50% was accomplished by 48% versus 21% of the respective patients. Actively treated patients reported more dysuria, urgency, and ejaculatory dysfunction following treatment than did sham-treated patients. Urinary retention occurred in 5.4% of patients. The Dornier Urowave is better in improving symptoms, bother, quality of life, and flow rates than is a sham treatment in patients with symptomatic BPH. The treatments can be given on an outpatient basis with local anesthesia. Adverse events are in general transient and mild in nature. This device compares favorably with other second-generation devices. Extended follow-up is necessary to document the long-term durability of these improvements.


[Action of ketoprofen on hepatic lysosomes in the rat].
Evidence for the stabilizing effect of ketoprofen on the lysosomal membrane is presented. Ketoprofen was as potent as indomethacin in stabilizing lysosomes subjected to changes in osmotic pressure. This effect was more marked in rats with adjuvant arthritis than in normal animals.


[An ultrastructural study of the optic papilla in experimental hypotony].
The ultrastructures of the optic papilla at different intervals during experimental hypotony in rabbits were studied by transmission electron microscopy, with the results that after 14 days the axons of optic nerve fibers showed signs of degeneration; after 21 days there appeared marked pathological changes, and after 30 days there were serious irreversible pathological changes. These findings suggest that clinical hypotony, such as occurs after glaucoma operations particularly, should be duly attended to.


[Effect of adaptation to periodic hypoxia on bioelectric activity of cardiomyocytes and cardiac resistance to contractive and arrhythmogenic effects of excessive calcium].
The experiments with isolated hearts from the rats adaptive to a periodic exposure to hypoxia in the barochamber revealed a significant decrease in the contractile and arrhythmogenic effects of high Ca2+ concentrations. With low sodium solution, the contracture and the resting potential depression of cardiomyocytes in the cardiac papillary muscles turned to be less pronounced during adaptation. Increasing the concentration of Ca2+ in the washing solution resulted in lower resting potential, amplitude and duration of the action potential; hypoxic adaptation prevented the changes to a great extent. Whether the changes found may contribute to the anti-arrhythmic effect of periodic hypoxic adaptation is discussed in the paper.


Leukaemia mortality in relation to magnetic field exposure: findings from a study of United Kingdom electricity generation and transmission workers, 1973-97.
To investigate whether risks of leukaemia are related to occupational exposure to magnetic fields. The mortality experienced by a cohort of 83 997 employees of the former Central Electricity Generating Board of England and Wales was investigated for the period 1973-97. All employees were employed for at least 6 months with some employment in the period 1973-82. Computerised work histories were available for 79 972 study subjects for the period 1971-93. Detailed calculations were performed by others to enable a novel assessment to be made of exposures to magnetic fields. Two analytical approaches were used, indirect standardisation (n=83 997) and Poisson regression (n=79 972). Based on serial mortalities for England and Wales, the standardised mortality ratio of 84 for all leukaemias (observed 111, expected 132.3) was similar to that of 83 for all causes (observed 14 845, expected 17 918). No significant positive trends were found for the risks of various types of leukaemia (chronic lymphatic leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, all leukaemia) either with lifetime cumulative exposure to magnetic fields or with such exposures received in the most recent 5 years. There are no discernible excess risks of leukaemia as a consequence of occupational exposure to magnetic fields in United Kingdom electricity generation and transmission workers.


Microbiological evaluation of protected environments during patient occupancy.
Microbiological monitoring has been conducted in two life island (LI) units and two laminar airflow (LAF) rooms while they were occupied by patients undergoing cancer chemotherapy. There were only 5 organisms per 1,000 ft(3) of air sampled in LAF rooms, 31 organisms in LI units, and over 3,000 organisms in regular hospital rooms. None of the floor samples obtained from hospital rooms was sterile, compared to over 70% in LAF rooms. The rate of deposition of organisms onto settling plates was one organism per 4.5 hr in LAF rooms compared to one organism per 0.08 hr in hospital rooms. Potential pathogens were isolated much more frequently from environmental samples obtained from hospital rooms than from LI units or LAF rooms. Two sites of persistent contamination arose in the LAF rooms: the vinyl tile flooring and the water supply system. Over half of the potential pathogens cultured from the protected environment units were cultured initially from the patients who occupied the units.


Short-term transport of glyphosate with erosion in Chinese loess soil--a flume experiment.
Repeated applications of glyphosate may contaminate the soil and water and threaten their quality both within the environmental system and beyond it through water erosion related processes and leaching. In this study, we focused on the transport of glyphosate and its metabolite aminomethylphosphonic acid (AMPA) related to soil erosion at two slope gradients (10 and 20°), two rates of pesticide with a formulation of glyphosate (Roundup®) application (360 and 720 mg m(-2)), and a rain intensity of 1.0 mm min(-1) for 1 h on bare soil in hydraulic flumes. Runoff and erosion rate were significantly different within slope gradients (p<0.05) while suspended load concentration was relatively constant after 15 min of rainfall. The glyphosate and AMPA concentration in the runoff and suspended load gradually decreased. Significant power and exponent function relationship were observed between rainfall duration and the concentration of glyphosate and AMPA (p<0.01) in runoff and suspended load, respectively. Meanwhile, glyphosate and AMPA content in the eroded material depended more on the initial rate of application than on the slope gradients. The transport rate of glyphosate by runoff and suspended load was approximately 14% of the applied amount, and the chemicals were mainly transported in the suspended load. The glyphosate and AMPA content in the flume soil at the end of the experiment decreased significantly with depth (p<0.05), and approximately 72, 2, and 3% of the applied glyphosate (including AMPA) remained in the 0-2, 2-5, and 5-10 cm soil layers, respectively. The risk of contamination in deep soil and the groundwater was thus low, but 5% of the initial application did reach the 2-10 cm soil layer. The risk of contamination of surface water through runoff and sedimentation, however, can be considerable, especially in regions where rain-induced soil erosion is common.


Cellular microparticles for tumor targeting delivery: from bench to bedside.
Within the past few years, cell derived microparticles (MPs) have emerged as a highly potent natural drug delivery system for tumor therapy. We and others have engineered different cells to obtain eleven kinds of MPs, which efficiently delivered antitumor agents to recipient cells and achieved ideal treatment outcomes in a great number of rodent tumor models. More significantly, autologous tumor cell derived MPs packaging chemotherapeutic drugs were demonstrated to be safe and tolerable and accomplished decent objective clinical response in lung cancer patients in clinical settings, leading to their approval as a novel biotherapy for treating malignancies in China. In this feature article, we review MP mediated tumor targeting delivery. The impact of tumor cell derived MPs on tumor progression and metastasis will be briefly summarized. Different means to prepare, label and characterize MPs will be introduced. Advantages and limitations of distinctive cargo encapsulation strategies will be outlined and compared. Tumor cell MP mediated in vivo transport processes will be reviewed comprehensively. Representative MPs shed by platelets, endothelial cells, macrophages, and dendritic cells will be selected to showcase their advantages in tumor targeting delivery. Multifarious therapeutic agents, including chemotherapeutic drugs, oncolytic adenovirus, nucleic acids, antigens, antibodies, to name a few, have been transported to their targets for corresponding cancer therapies. Current challenges and future opportunities on translating MPs for tumor targeting delivery will be provided in the end.


Hazardous, harmful, and dependent alcohol use in healthcare professionals: a systematic review and meta-analysis.
Healthcare professionals work in high-pressured and demanding environments, which has been linked to the use of alcohol as a coping strategy. This international review aimed (i) to determine the pooled prevalence of hazardous, harmful, dependent, and frequent binge drinking in healthcare professionals, and (ii) to explore factors associated with variation in these outcomes. Scopus, MEDLINE, and PsycINFO were searched from 2003 to 17th November 2022, for studies reporting a prevalence estimate for any outcome among healthcare professionals. Random-effects meta-analyses determined pooled prevalence estimates. Sub-group analyses were conducted, stratifying the meta-analyses by pandemic period vs pre-pandemic period. Meta-regressions explored factors that were associated with variation in the outcomes. PROSPERO (CRD42020173119). After screening 9,108 records, 64 studies were identified as eligible. The pooled prevalence was 19.98% [95% Confidence Intervals [CI]: 16.05-24.23%] for hazardous alcohol use (K = 52), 3.17% [95% CI: 0.95-6.58%] for harmful drinking (K = 8), 14.59% [95% CI: 7.16-25.05%] for dependent drinking (K = 7), and 17.71% [95% CI: 8.34-29.63%] for frequent binge drinking (K = 11). The prevalence of hazardous drinking was greater during the pandemic (28.19%) compared with pre-pandemic estimates (17.95%), though this was not statistically significant (p = 0.049). Studies including all hospital staff (32.04%) showed higher prevalence estimates for hazardous drinking compared with studies of doctors (16.78%) and nurses (27.02%). Approximately one fifth of healthcare professionals drink to hazardous levels, with higher prevalence estimates observed during the COVID-19 pandemic. It may be that healthcare professionals used alcohol to cope with the additional trauma and stressors. Further research is needed to investigate whether this is sustained in the post-pandemic period.


Involvement of single unit activity in inferotemporal and perirhinal cortices in recognition memory of visual objects in the macaque.
Recognizing objects from the past is a vitally important ability for everyday live. The studies of brain mechanisms responsible for visual recognition memory suggest that the modulation of single unit activity in the inferotemporal and perirhinal cortices could be an important part of the neuronal substrate of recognition memory. In this review, I will describe Stimulus Specific Adaptation (SSA)--the reduction in neuronal response to previously viewed objects. The experimental tasks in which SSA is observed will be presented, along with the possibility that SSA may be enhanced by saccadic exploration of visual scene. Next, I will demonstrate that under special circumstances (partially split-brain preparation) monkeys could recognize the re-presentation of visual images without the concomitant appearance of SSA. The most promising alternative candidate for neuronal mechanism involved in recognition memory is delay activity--an increased frequency of cell firing in the time between the initial presentation of an image and its subsequent re-presentation. In order to determine if delay activity is important for recognition we have started to investigate the effects on recognition memory of disrupting delay activity by electrical stimulation. Preliminary results indicate a positive correlation between a reduction in delay activity and a decrease in recognition performance.


Bridging cyanides from cyanoiron metalloligands to redox-active dinitrosyl iron units.
Cyanide, as an ambidentate ligand, plays a pivotal role in providing a simple diatomic building-block motif for controlled metal aggregation (M-CN-M'). Specifically, the inherent hard-soft nature of the cyanide ligand, i.e., hard-nitrogen and soft-carbon centers, is due to electronic handles for binding Lewis acids following the hard-soft acid-base principle. Studies by Holm and Karlin showed structural and electronic requirements for cyanide-bridged (por)FeIII-CN-CuII/I (por = porphyrin) molecular assemblies as biomimetics for cyanide-inhibited terminal quinol oxidases and cytochrome-C oxidase. The dinitrosyliron unit (DNIU) that exists in two redox states, {Fe(NO)2}9 and {Fe(NO)2}10, draws attention as an electronic analogy of CuII and CuI, d9 and d10, respectively. In similar controlled aggregations, L-type [(η5-C5R5)Fe(dppe)(CN)] (dppe = diphenyl phosphinoethane; R = H and Me) have been used as N-donor, μ-cyanoiron metalloligands to stabilize the DNIU in two redox states. Two bimetallic [(η5-C5R5)(dppe)FeII-CN-{Fe(NO)2}9(sIMes)][BF4] complexes, Fe-1 (R = H) and Fe*-1 (R = CH3), showed dissimilar FeIIC[triple bond, length as m-dash]N-{Fe(NO)2}9 angular bends due to the electronic donor properties of the [(η5-C5R5)Fe(dppe)(CN)] μ-cyanoiron metalloligand. A trimetallic [(η5-C5Me5)(dppe)FeII-CN]2-{Fe(NO)2}10 complex, Fe*-2, engaged two bridging μ-cyanoiron metalloligands to stabilize the {Fe(NO)2}10 unit. The lability of the FeII-CN-{Fe(NO)2}9/10 bond was probed by suitable X-type (Na+SPh-) and L-type (PMe3) ligands. Treatment of Fe-1 and Fe*-1 with PMe3 accounted for a reduction-induced substitution at the DNIU, releasing [(η5-C5R5)Fe(dppe)(CN)] and N-heterocyclic carbene, and generating (PMe3)2Fe(NO)2 as the reduced {Fe(NO)2}10 product.


NGF inhibits M/KCNQ currents and selectively alters neuronal excitability in subsets of sympathetic neurons depending on their M/KCNQ current background.
M/KCNQ currents play a critical role in the determination of neuronal excitability. Many neurotransmitters and peptides modulate M/KCNQ current and neuronal excitability through their G protein-coupled receptors. Nerve growth factor (NGF) activates its receptor, a member of receptor tyrosine kinase (RTK) superfamily, and crucially modulates neuronal cell survival, proliferation, and differentiation. In this study, we studied the effect of NGF on the neuronal (rat superior cervical ganglion, SCG) M/KCNQ currents and excitability. As reported before, subpopulation SCG neurons with distinct firing properties could be classified into tonic, phasic-1, and phasic-2 neurons. NGF inhibited M/KCNQ currents by similar proportion in all three classes of SCG neurons but increased the excitability only significantly in tonic SCG neurons. The effect of NGF on excitability correlated with a smaller M-current density in tonic neurons. The present study indicates that NGF is an M/KCNQ channel modulator and the characteristic modulation of the neuronal excitability by NGF may have important physiological implications.


Tracking of Cardiorespiratory Fitness from Childhood to Mid-adulthood.
High cardiorespiratory fitness (CRF) in adulthood is important for survival from major chronic diseases and preserving good health. We examined how childhood CRF tracks, or persists, into adulthood. Among a cohort of 748 school children followed over 34 years, we found child CRF correlated with young- (r = 0.30) and mid-adulthood (r = 0.16) CRF.


Standardising joint assessment in rheumatoid arthritis.
Evaluating joint involvement in rheumatoid arthritis in a key clinical assessment. We investigated the extent of variation in measurement of joint swelling and tenderness and evaluated the impact of training to standardise methods. Eight observers (medical and nursing staff) examined eight rheumatoid patients for joint swelling and tenderness before and after training in clinical methods. The EULAR handbook for joint evaluation was used for training and assessments were based on the 28 joint count. There was extensive variability in both numbers of swollen and tender joints. Coefficients of variation for articular indices recorded by the 8 observers in individual patients were often high (up to a maximum of 204%), indicating considerable differences between observers. Training had an impact on the assessment of the numbers of swollen joints which increased by a mean of 32% (P < 0.05) and the number of tender joints which increased by 41% (p < 0.01). Training had only a limited impact on the variation among observers in determining the number of swollen and number of tender joints. After training, the mean coefficients of variation were still 59% for swollen joints and 65% for tender joints. These results highlight the extent of variation in clinical assessment of rheumatoid arthritis and show the advantages of training. It leads to increased sensitivity of measurement. Standardisation appears essential for clinical studies.


Determination of Sites Involved, HIV Co-Infection & Utility of Diagnostic Modalities in EPTB.
Tuberculosis remains a major global public health problem and an on-going epidemic. Though the chief objectives of the Revised National Tuberculosis Control Programme (RNTCP) in detecting and curing the infectious pulmonary cases is well taken, there has been a steady rise in the number of Extra Pulmonary Tuberculosis (EPTB) cases as documented in several studies. EPTB which usually constitutes around 15%-20% of the total TB cases is now being increasingly reported due to a combination of better diagnostic facilities, and the HIV pandemic. Though several studies have shown increasing prevalence of EPTB, only few studies are available, especially in the Indian scenario, that study the pattern and risk factors. Hence, this retrospective observational study was undertaken to determine the sites of the involvement, HIV co-infection and usefulness of various diagnostic modalities in EPTB affecting patients attending a medical college DOTS clinic. One hundred ten EPTB patients referred to the DOTS clinics of the TB & Chest department from the period Dec 2010- Mar 2012 were included in the study. The diagnosis of EPTB was established by combined clinical, microbiological, histopathological &/or imaging modalities. Their medical records were assessed to determine the age distribution, gender and anatomical sites of involvement. The presence of co-morbid conditions like smoking history, alcoholism, diabetic and HIV status were noted. BCG status and Mantoux test readings were recorded. The different diagnostic tests used in confirming EPTB at different sites were recorded. Chest x-ray was analysed for all patients to assess coexisting pulmonary involvement. All patients were followed to assess the outcome of treatment. The mean age of patients was 34.4. The male to female ratio was 58:52 showing a slight male predominance. The most common site of involvement was lymph node followed by pleural effusion and abdominal TB. The prevalence of lymph node TB was noted to be higher in female patients as compared to other sites of EPTB. Mantoux test was positive in 57 (51.8%) patients. HIV co-infection was noted in only 3 (2.7%) patients. Concomitant pulmonary involvement was seen in 19 (17.3%) patients. Lymph node was the most common site involvement showing a significant female preponderance followed by pleural effusion and abdominal TB. The rates of HIV co-infection and diabetes mellitus were 2.7% and 20% respectively. The most useful diagnostic modality was tissue sampling followed by imaging. Mantoux test is not unequivocal for the diagnosis of EPTB.


Effects of trypsin inhibitor and particle size of expeller-extracted soybean meal on broiler live performance and weight of gizzard and pancreas.
Soybean meal (SBM) is a co-product that remains after the oil is removed from whole soybeans by either solvent extraction or mechanically pressing soybeans using an expeller. Expeller-extracted soybean meal (ESBM) contains more fat and less protein than solvent-extracted soybean meal (SSBM), but has higher trypsin inhibitors (TI) that limit its inclusion in poultry diets. We hypothesized that increasing the particle size of ESBM could enhance chick tolerance to dietary TI. The experiment consisted of a 2 × 6 factorial arrangement of 2 ESBM particle sizes (coarse, 1,300 µm, and fine, 530 µm) and 6 TI levels (6, 9, 12, 15, 18, and 21 TIU/mg). A total of 672 male broiler chicks was randomly assigned among the 12 treatment combinations with 8 replicates per combination. The birds were provided with 1 kg/bird of starter diet in a crumble form. The pancreas and gizzard were excised and weighed at 16 d of age and organ weights relative to BW calculated. Feed consumption, BW, and feed conversion ratio (FCR) were determined at 7 and 14 d of age. Increasing TI level produced a quadratic effect (P < 0.01) on BW and FCR at 14 d of age. The best performance was obtained when chicks were fed diets containing ESBM at intermediate TI levels. Increasing the particle size of the ESBM from 530 to 1,300 µm improved BW and feed intake (P < 0.01) without affecting FCR. The relative weight of the pancreas increased linearly as TI level increased (P < 0.001). The results of this study indicated that chicks performed better when fed coarse ESBM at an intermediate TI level.


Cell position within human pluripotent stem cell colonies determines apical specialization via an actin cytoskeleton-based mechanism.
Human pluripotent stem cells (hPSCs) grow as colonies with epithelial-like features including cell polarity and position-dependent features that contribute to symmetry breaking during development. Our study provides evidence that hPSC colonies exhibit position-dependent differences in apical structures and functions. With this apical difference, edge cells were preferentially labeled with amphipathic dyes, which enabled separation of edge and center cells by fluorescence-activated cell sorting. Transcriptome comparison between center and edge cells showed differential expression of genes related to apicobasal polarization, cell migration, and endocytosis. Accordingly, different kinematics and mechanical dynamics were found between center and edge cells, and perturbed actin dynamics disrupted the position-dependent apical polarity. In addition, our dye-labeling approach could be utilized to sort out a certain cell population in differentiated micropatterned colonies. In summary, hPSC colonies have position-dependent differences in apical structures and properties, and actin dynamics appear to play an important role in the establishment of this position-dependent cell polarity.


[Sport and physical activity].
A regular sport activity involves physical and psychological benefits helping to improve the quality of life at any age. This aspect is even more important in the developing age, when the sport takes on a role of training and education. In this context, instances directed to allow adolescent and young adults with heart disease to practice sports seem justified, and they're becoming more pressing since when the diagnostic and therapeutic advances, especially in cardiac surgery and in interventional hemodynamics, allow an increasing number of patients, previously allocated to physical inactivity, to lead an active lifestyle. However, we have to keep in mind that congenital heart disease population is varied, not only by the nature of the malformation, but also because in the same cardiopathy you can find subjects in "natural history" or after surgery and, between them, subjects treated with several techniques and different outcomes. This justifies the need for a close collaboration between sports doctors, cardiologists and heart surgeons, particularly in the management of the most difficult and delicate problems.


[The heart and rheumatoid arthritis. Prospective study of 100 cases].
We studied one hundred consecutive patients with rheumatoid arthritis from the cardiological point of view through non invasive methods to detect the frequency of cardiovascular complications. Seventy three (73%) were females and twenty seven (27%) males. Mean age, 48.6 years. Mean age of presentation of the disease, 34.2 years. Mean age of duration of the illness, 21.8 years. Fifty seven per cent had some type of cardiopulmonary complication. Clinically 52 per cent referred some type of cardiopulmonary symptoms. The physical examination was abnormal in 27 per cent. Rheumatoid factor (Waaler-Rose) was positive in 82 per cent. The cardiac X ray series was abnormal in 33 per cent, the resting electrocardiogram in 48 per cent and the M mode echocardiogram in 52 per cent of the cases. The complications detected were: pericardial effusion (21%); pleural effusion (9%); pulmonary fibrosis (6%) which represents a higher incidence of previously reported in the literature; congestive heart failure (10%); valvular lesion (9%) among those are included six patients with valvular heart disease of non detectable etiology; ischemic heart disease (8%); myocarditis (6%); rythm disturbances (22%) and conduction defects (20%) including a 46 year old female patient who developed a complete AV block during an exacerbation of her illness, requiring the insertion of definitive pacemaker. Our results showed that some of the detected lesions are in part more frequent and severe than those reported in the literature, probably due to, that on one hand their search was intentional and on the other, our group was constituted by with severe and long standing rheumatoid arthritis.


Hyperexpression of Integrin α5β1 Promotes Resistance of MCF-7 Human Breast Carcinoma Cells to Doxorubicin via ERK Protein Kinase Down-regulation.
In MCF-7 human breast carcinoma cells, α5β1 integrin hyperexpression, which was accomplished by transduction of a full-length α5 integrin cDNA, increased by about 50-70% the number of cells, survived during 48-72 h cell treatment with doxorubicin. Up-regulation of α5β1 reduced the level of the apoptogenic p53 protein and p21 cell cycle inhibitor, but enhanced the activity of Akt and mTOR protein kinases. In addition to these findings, we observed a significant decrease in the activity of both isoforms of phosphokinase Erk1/2, which is known to play a key role in cell viability pathways, including pathways alleviating stress damages caused by distinct antitumor drugs. Diminished Erk activity accompanying the rise of drug resistance can be explained by an "atypical" function of this kinase, which, in the cells studied, promotes an enhanced rather than reduced sensitivity to doxorubicin. To verify this suggestion, the effect of a specific Erk inhibitor, PD98059, on the resistance to doxorubicin of control and α5 cDNA-transduced MCF-7 cells was investigated. The data showed that suppression of Erk activity increased the resistance of control cells (transduced with an "empty" vector) to a level higher than that demonstrated by the α5 cDNA-transduced cells. The highest level of resistance was observed in α5β1-trancduced cells treated with PD98059. Akt and mTOR kinase inhibitors had little if any effect on doxorubicin resistance of α5 cDNA-transduced MCF-7 cells. The data show for the first time that integrin α5β1 can stimulate drug resistance of tumor cells through a mechanism based on the inhibition of protein kinase Erk. From a more general view, the results of this investigation suggest that signal protein kinases can perform in tumor cells "non-canonical" functions, opposite to those, which are the basis for using kinase inhibitors in targeted cancer therapy. It follows that if a protein kinase is supposed to be used as a target for such therapy, it is important to explore its features in the particular tumor prior to the onset of treatment.


Cognitive impairment in relapsing-remitting multiple sclerosis can be predicted by imaging performed several years earlier.
Cognitive deficits in multiple sclerosis (MS) are common and correlate with contemporary MRI brain abnormalities, particularly atrophy, but the ability of imaging early in the disease to predict later cognitive impairment remains to be determined. Thirty relapsing-remitting MS patients recruited within three years of the onset of the disease, and in whom MRI had been performed at baseline and a year later, were assessed neuropsychologically five years later. Imaging parameters accounting for significant variance in cognitive performance were identified using multiple regressions, once confounding variables were controlled. Patients performed significantly worse than expected on tests of attention/speed of information processing and half of them had experienced some decline in IQ in relation to premorbid estimates. The rate of global brain atrophy in the first year of the study accounted for significant variance in the overall cognitive performance, and in memory and attention/speed of information processing. Poor performance on attention tests was associated with high T1-weighted lesion volume and reduced magnetization transfer ratio (MTR) in normal-appearing white matter (NAWM). These results suggest that neuroaxonal loss was identified early in the disease, and its rate of progression, predicted cognitive impairment later in the disease. Neuroaxonal loss is likely to affect commissural and association fibres that subserve the cognitive processes impaired in MS.


Agonist interactions with cardiac muscarinic receptors. Effects of Mg2+, guanine nucleotides, and monovalent cations.
Analysis of [3H]quinuclidinyl benzilate/acetylcholine competition curves indicated that the agonist acetylcholine bound with three different affinities to chick heart muscarinic receptors. The estimated KD values for acetylcholine were 2.7, 240, and 4000 nM. Mg2+ increased and guanosine 5'-(beta, gamma-imino)triphosphate (Gpp(NH)p) decreased the proportion of the receptors in the highest affinity state without altering the KD values. Monovalent cations increased the KD values of the three affinity states and obscured the detection of the highest affinity state. The nature of the three affinity states and the sites of action of Mg2+, guanine nucleotides, and monovalent cations were probed with three experimental protocols. Treatments with N-ethylmaleimide or pertussis toxin eliminated both the highest affinity state and the sensitivity to Gpp(NH)p. In contrast, partial effects of Mg2+ were retained after either of these treatments. The effects of monovalent cations on the affinity of the receptor for agonists were unaffected by both treatments. Solubilization of the receptors with digitonin-cholate yielded preparations displaying only the low affinity state for agonist. Agonist binding to the solubilized receptors was insensitive to Mg2+ and guanine nucleotides but retained sensitivity to monovalent cations. The results indicate that chick heart muscarinic receptors can exist in vitro in three agonist affinity states and that the entire population of receptors can be interconverted from one state to another by Mg2+ and guanine nucleotides. Guanine nucleotides presumably act via the inhibitory guanine nucleotide-binding regulatory (Ni) protein, whereas there appear to be at least two distinct sites of action of Mg2+. One site is associated with Ni. Another is distinguishable from Ni but does not appear to be on the receptor itself. The effect of monovalent cations on the interaction of agonists with cardiac muscarinic receptors is qualitatively different and mediated at distinct sites from the effects of Mg2+ and guanine nucleotides.


How Many Participants Do We Have to Include in Properly Powered Experiments? A Tutorial of Power Analysis with Reference Tables.
Given that an effect size of d = .4 is a good first estimate of the smallest effect size of interest in psychological research, we already need over 50 participants for a simple comparison of two within-participants conditions if we want to run a study with 80% power. This is more than current practice. In addition, as soon as a between-groups variable or an interaction is involved, numbers of 100, 200, and even more participants are needed. As long as we do not accept these facts, we will keep on running underpowered studies with unclear results. Addressing the issue requires a change in the way research is evaluated by supervisors, examiners, reviewers, and editors. The present paper describes reference numbers needed for the designs most often used by psychologists, including single-variable between-groups and repeated-measures designs with two and three levels, two-factor designs involving two repeated-measures variables or one between-groups variable and one repeated-measures variable (split-plot design). The numbers are given for the traditional, frequentist analysis with p < .05 and Bayesian analysis with BF > 10. These numbers provide researchers with a standard to determine (and justify) the sample size of an upcoming study. The article also describes how researchers can improve the power of their study by including multiple observations per condition per participant.


3D printed multi-compartment capsular devices for two-pulse oral drug delivery.
In the drug delivery area, versatile therapeutic systems intended to yield customized combinations of drugs, drug doses and release kinetics have drawn increasing attention, especially because of the advantages that personalized pharmaceutical treatments would offer. In this respect, a previously proposed capsular device able to control the release performance based on its design and composition, which could extemporaneously be filled, was improved to include multiple separate compartments so that differing active ingredients or formulations may be conveyed. The compartments, which may differ in thickness and composition, resulted from assembly of two hollow halves through a joint also acting as a partition. The systems were manufactured by fused deposition modeling (FDM) 3D printing, which holds special potential for product personalization, and injection molding (IM) that would enable production on a larger scale. Through combination of compartments having wall thickness of 600 or 1200μm, composed of promptly soluble, swellable/erodible or enteric soluble polymers, devices showing two-pulse release patterns, consistent with the nature of the starting materials, were obtained. Systems fabricated using the two techniques exhibited comparable performance, thus proving the prototyping ability of FDM versus IM.


Microencapsulation of cells, including islets, within stable ultra-thin membranes of maleimide-conjugated PEG-lipid with multifunctional crosslinkers.
The encapsulation of islets of Langerhans (islets) and insulin-secreting cells within a semi-permeable membrane has been suggested as a safe and simple technique for islet transplantation to attenuate early graft loss and avoid immunosuppressive therapy. The total volume of these implants tends, however, to increase upon encapsulation of the islets and cells within the polymer membrane, limiting transport between encapsulated cells and the surrounding tissue. Ultra-thin membranes could potentially overcome these diffusion limitations to provide for clinically applicable implants. Here we propose a method to encapsulate islets and cells within a stable ultra-thin polymer membrane using poly(ethylene glycol)-conjugated phospholipid bearing a maleimide group (Mal-PEG-lipids) and multiple interactive polymers (e.g., 4-arm PEG-Mal and 8-arm PEG-SH). When Mal-PEG-lipids were added to islet and cell suspensions, spontaneous incorporation into a cell surface occurred from the micelles at an equilibrium state. The addition of 4-arm PEG-Mal and 8-arm PEG-SH to the mixture induced a substantial increase in the membrane thickness because a number of Mal-PEG-lipid micelles were involved in the membrane formation at the micrometer level. No appreciable increase in islet volume was observed after microencapsulation by this method. Microencapsulation of islets with the polymer membranes, which showed semi-permeability, did not impair insulin release in response to glucose stimulation, even after 7 days. The polymer membrane structure surrounding the islets and cells was well maintained for at least 30 days. In addition, the membrane formed showed much lower thrombogenicity and inhibited complement activation upon exposure to human whole blood and serum.


Three new species of Chromis (Teleostei, Pomacentridae) from mesophotic coral ecosystems of the Philippines.
Three new species of Chromis (Perciformes, Pomacentridae) from the Philippines, collected between 75-150 m depth, are described by a combination of morphological features and their coloration. Chromisgunting sp. n. was found in Batangas and Oriental Mindoro, and differs from its congeners in body depth (2.1-2.2 in SL), and color of adults, light brown, with a silver area on the anterior end and a bilateral black margin along the exterior side of the tail. It is most similar to C.scotochiloptera, with a 5.3% genetic divergence in COI. Chromishangganan sp. n. was found around Lubang Island. Body depth (1.9-2.0 in SL) and adult coloration (yellowish with dark black outer margins on dorsal and anal fins) also separate this species from its congeners. It is most similar to C.pembae, with a 2.5% genetic divergence. Chromisbowesi sp. n. was found in Batangas, and also differs from its congeners by the combination of body depth (1.5-1.6 in SL), and color of adults (brownish grey in the dorsal side to whitish on the ventral side, with alternating dark and light stripes in the sides of body). It is most similar to C.earina, with a 3.6% genetic divergence in COI.


A Prospective Comparison of Standard Technique, Doppler Ultrasonography, and Pressure Waveform Analysis for Confirming Intraosseous Catheter Placement.
Purpose: Intraosseous (IO) catheters allow healthcare workers to rapidly administer fluids and medications to critically ill patients when intravenous access is inadequate or unable to be obtained. An improperly placed IO catheter can lead to delays in care, as well as serious complications such as limb necrosis. Methods: In this single-center, prospective, observational study, we compared 2 established methods of confirming proper IO catheter placement to a novel pressure waveform analysis technique in which the IO catheter is attached to a standard pressure transducer. Attaching a pressure transducer to a properly placed IO catheter produces a pulsatile waveform. Misplacement of the IO catheter produces a flatline waveform. Results: Of 42 IO catheters, 8 (19%) were incorrectly placed per the waveform analysis technique. Compared to the pressure waveform analysis technique, the standard method and the power Doppler method incorrectly classified 4/8 (50%) and 5/8 (62.5%) of the misplaced catheters, respectively. The standard method had a higher positive predictive value for detecting incorrectly placed IO catheters than the power Doppler method (100% vs 63%, respectively). Blinded reviewers demonstrated better agreement using the pressure waveform analysis technique than using power Doppler (k = 0.77 vs k = 0.58, respectively). Conclusion: The standard and power Doppler ultrasonography techniques identify incorrectly placed IO catheters sub-optimally. The pressure waveform analysis technique is more accurate than the standard of care and has superior interrater agreement compared to the ultrasound method of confirmation. With more than 500 000 IO catheters placed in the United States each year, this novel technique may improve overall IO safety. Trial Registration Number: NCT03908879.


Discontinuation of imatinib in Japanese patients with chronic myeloid leukemia.
It was recently recognized that some chronic myeloid leukemia patients with a complete molecular response could sustain that response after discontinuation of imatinib. To characterize the clinical outcomes and profiles of chronic phase chronic myeloid leukemia patients who could discontinue imatinib, we conducted a nationwide survey in Japan. Among 3,242 imatinib-treated chronic myeloid leukemia patients, we identified 50 who had discontinued imatinib for at least six months; of these we analyzed 43. Molecular recurrence was detected in 19 patients, and a complete molecular response rate was estimated to be 47% following imatinib discontinuation. Based on multivariate regression analysis, imatinib dose intensity and prior interferon-α administration were independently predictive of molecular recurrence within 12 months. The depth of the molecular response should be a factor influencing long-term sustained complete molecular response after discontinuation of imatinib. Additionally, an immunological mechanism modified by interferon-α might control chronic myeloid leukemia stem cells.


Distinct catecholaminergic pathways projecting to hippocampal CA1 transmit contrasting signals during behavior and learning.
Neuromodulatory inputs to the hippocampus play pivotal roles in modulating synaptic plasticity, shaping neuronal activity, and influencing learning and memory. Recently it has been shown that the main sources of catecholamines to the hippocampus, ventral tegmental area (VTA) and locus coeruleus (LC), may have overlapping release of neurotransmitters and effects on the hippocampus. Therefore, to dissect the impacts of both VTA and LC circuits on hippocampal function, a thorough examination of how these pathways might differentially operate during behavior and learning is necessary. We therefore utilized 2-photon microscopy to functionally image the activity of VTA and LC axons within the CA1 region of the dorsal hippocampus in head-fixed male mice navigating linear paths within virtual reality (VR) environments. We found that within familiar environments some VTA axons and the vast majority of LC axons showed a correlation with the animals' running speed. However, as mice approached previously learned rewarded locations, a large majority of VTA axons exhibited a gradual ramping-up of activity, peaking at the reward location. In contrast, LC axons displayed a pre-movement signal predictive of the animal's transition from immobility to movement. Interestingly, a marked divergence emerged following a switch from the familiar to novel VR environments. Many LC axons showed large increases in activity that remained elevated for over a minute, while the previously observed VTA axon ramping-to-reward dynamics disappeared during the same period. In conclusion, these findings highlight distinct roles of VTA and LC catecholaminergic inputs in the dorsal CA1 hippocampal region. These inputs encode unique information, likely contributing to differential modulation of hippocampal activity during behavior and learning.


Clinical experience with chronomodulated infusional 5-fluorouracil chemoradiotherapy for pancreatic adenocarcinoma.
To evaluate retrospectively the efficacy and chronic toxicities of concurrent radiotherapy and chronomodulated infusion 5-fluorouracil (5-FU) in patients with pancreatic adenocarcinoma. Twenty-eight patients with pancreatic adenocarcinoma were treated between January 1997 and May 2000 with 5-FU chronomodulated chemoradiotherapy. Chronomodulated delivery of chemotherapy was chosen on the basis of a lower toxicity profile in the treatment of GI malignancies. The median age was 64 years. Of the 28 patients, 12 were men and 16 were women. Eight patients had unresectable disease and 20 were treated after pancreatic resection. The median radiation dose was 50.4 Gy given in 28 fractions. The median field length and width was 10.6 cm and 10.9 cm, respectively. Concurrent chemotherapy with 5-FU was administered 5 d/wk, with a median total dose of 8.4 g/m2 (300 mg/m2/d). Chronomodulated 5-FU delivery consisted of a low basal infusion for 16 h followed by an 8-h escalating-deescalating infusion peaking at 10 pm. Survival and recurrence data were evaluated using Kaplan-Meier actuarial analysis. Toxicities were recorded using the Radiation Therapy Oncology Group grading system. The median follow-up for all patients was 26 months (range, 4-68 months). The median overall survival for the 20 patients treated postoperatively was 34 months, with a 3- and 5-year actuarial survival rate of 40% and 21%, respectively. If the 3 patients with carcinoma of the ampulla were removed from the data set, the mean overall survival in the resected patients was 34 months, with a 3-year and 5-year actuarial survival rate of 40% and 17%, respectively. The 8 unresectable patients had a median overall survival of 14 months, and none lived past 2 years. No patient experienced Grade 3 or 4 hematologic toxicity or weight loss. Five patients had nausea and dehydration requiring i.v. fluids; only one (4%) was hospitalized. Four patients required a dose reduction of 5-FU, one for nausea, one for a transient ischemic attack, one for an infection, and one because of myocardial infarction. Seven resected patients, four of whom had no evidence of disease, developed diabetes mellitus 1-2 years after radiotherapy. Chronomodulated 5-FU administration, based on the concept of chronotolerance, has relatively low acute toxicity. Our median survival rate was greater than that after most chemoradiotherapy programs that result in more acute toxicity. Additional study is warranted to evaluate chronomodulated radiosensitizing chemotherapy schedules in prospective trials and with attention to late effects after radiotherapy, including diabetes mellitus.


Rapid Prototyping of a Cyclic Olefin Copolymer Microfluidic Device for Automated Oocyte Culturing.
Assisted reproductive technology (ART) can benefit from the features of microfluidic technologies, such as the automation of time-consuming labor-intensive procedures, the possibility to mimic in vivo environments, and the miniaturization of the required equipment. To date, most of the proposed approaches are based on polydimethylsiloxane (PDMS) as platform substrate material due to its widespread use in academia, despite certain disadvantages, such as the elevated cost of mass production. Herein, we present a rapid fabrication process for a cyclic olefin copolymer (COC) monolithic microfluidic device combining hot embossing-using a low-temperature cofired ceramic (LTCC) master-and micromilling. The microfluidic device was suitable for trapping and maturation of bovine oocytes, which were further studied to determine their ability to be fertilized. Furthermore, another COC microfluidic device was fabricated to store sperm and assess its quality parameters over time. The study herein presented demonstrates a good biocompatibility of the COC when working with gametes, and it exhibits certain advantages, such as the nonabsorption of small molecules, gas impermeability, and low fabrication costs, all at the prototyping and mass production scale, thus taking a step further toward fully automated microfluidic devices in ART.


[Evaluation of minerals contents in daily food rations of low physically active women].
The aim of the paper was to assess the minerals contents in daily food rations of low physically active women. The data on minerals intake were collected using 24-hour recall and diet history questionnaire. The intake of Ca, Fe, K, Zn and Mg was very low; Ca--47.9% of recommended level, Fe--65% of recommended level, K, Zn and Mg from 55% to 68% of recommended level. The study showed unsatisfactory low consumption of milk and dairy products, cereal products, vegetables and fruits, which are rich source of minerals.


Ranitidine in reflux oesophagitis. A double-blind placebo-controlled study.
This study was designed to assess the effect of ranitidine on patients with symptomatic oesophageal reflux. In a double-blind comparative trial in 46 patients a twice daily dose of 150 mg ranitidine was compared with placebo. Relief of pain, endoscopic healing and histological improvement were significantly better in those treated with ranitidine. Thus, ranitidine is of value in the management of patients with reflux oesophagitis and may prevent the development of peptic stricture.


Dynamic control of surface energy and topography of microstructured conducting polymer films.
Microstructured polymer surfaces, including conducting and insulating polymers, have been prepared to achieve electrochemical control of the surface energy and topography. The reported surface switches include pillar- and mesh-like surface patterns of polypyrrole (PPy), poly(3,4-ethylene-dioxythiophene) (PEDOT), and photoresists. The structures have been evaluated by contact angle measurements and optical and scanning electron microscopy to determine the surfaces characteristics. These microstructured polymer surface switches can be electrochemically modified from dewetting to wetting conditions, with a maximum associated change of the water contact angle from 129 degrees to 44 degrees . This contact angle switching was observed for samples in which dynamic control of the surface topography and surface tension was coupled. Control of topography was achieved with a dynamic height-switching range of more than 3 mum. In addition, dynamic control of anisotropic wetting is reported. Our experiments were carried out under conditions that are suitable for a biointerface, implying potential application in biotechnology and cell science. In particular, switching of the energy, chemistry, and topography of the surface, along with their associated orientation, are interesting features for dynamic (electronic) control of the seeding and proliferation for living cells. The technology reported promises for electronically controlled cell-growth within Petri dishes, well plates, and other cell-hosting tools.


Overview of panic and social anxiety disorders.
Panic disorder and social anxiety disorder are often-overlooked but debilitating disorders that share some common symptoms and treatments. Patients with panic disorder experience unexpected panic attacks and then worry about having more attacks. Those with social anxiety disorder fear doing or saying something embarrassing in social situations. The prevalence of these conditions is about 3% for panic disorder and 13% for social anxiety disorder in the United States and is higher in women than in men. Both disorders are thought to have a familial link and to be related to dysregulation of neurotransmitter systems. Panic and social anxiety disorders are often comorbid with other psychiatric disorders. Medication treatment and/or cognitive-behavioral therapy might need to be continued over the long term to prevent relapse.


The effect of pregnancy and lactation on bone mineral density in fluoride-exposed rats.
Fluoride increases metabolic turnover of the bone in favour of bone formation. Excessive intake of fluoride may lead to pathological changes in teeth and bones: dental and skeletal fluorosis. In this study, we investigated the effect of pregnancy and lactation on bone mineral density (BMD) in fluoride-exposed rats. Female Wistar rats were given commercially available spring water with 100 ppm fluoride (N = 8), or without addition (N = 8) for 18 weeks. At 16 weeks of age, four female rats and one male rat were kept in a cage for 5 days; all females were successfully impregnated. BMD was measured at 16 weeks of age, on the first day postpartum, and at the end of lactation. Spinal BMD was significantly higher in fluoride-exposed rats than control (P < 0.05), but there were no differences in femoral BMD (P = 0.670). During pregnancy, spinal BMD and femoral BMD were not significantly changed in fluoride-exposed rats, whereas BMD of the spine was significantly decreased in the control rats (P = 0.013), but not in the femur. During lactation, BMD was significantly decreased at the two regions compared to initial values (P < 0.05) in both groups. This study shows that pregnancy has no effect on bone, but lactation has a decreasing effect on BMD in fluoride-exposed rats.


Developmental trajectory of subtle motor signs in attention-deficit/hyperactivity disorder: A longitudinal study from childhood to adolescence.
This study examined the developmental trajectory of neurodevelopmental motor signs among boys and girls with attention-deficit/hyperactivity disorder (ADHD) and typically-developing (TD) children. Seventy children with ADHD and 48 TD children, aged 8-17 years, were evaluated on at least two time-points using the Physical and Neurological Assessment of Subtle Signs (PANESS). Age-related changes in subtle motor signs (overflow, dysrhythmia, speed) were modeled using linear mixed-effects models to compare the developmental trajectories among four subgroups (ADHD girls and boys and TD girls and boys). Across visits, both boys and girls with ADHD showed greater overflow, dysrhythmia, and slower speed on repetitive motor tasks compared to TD peers; whereas, only girls with ADHD were slower on sequential motor tasks than TD girls. Developmental trajectory analyses revealed a greater reduction in overflow with age among boys with ADHD than TD boys; whereas, trajectories did not differ among girls with and without ADHD, or among boys and girls with ADHD. For dysrhythmia and speed, there were no trajectory differences between the subgroups, with all groups showing similar reductions with age. Children with ADHD show developmental trajectories of subtle motor signs that are consistent with those of TD children, with one clear exception: Boys with ADHD show more significant reductions in overflow from childhood to adolescence than do their TD peers. Our findings affirm the presence of subtle motor signs in children with ADHD and suggest that some of these signs, particularly motor overflow in boys, resolve through adolescence while dysrhythmia and slow speed, may persist.


Neural correlates of cognitive impairment in posterior cortical atrophy.
With the prospect of disease-modifying drugs that will target the physiopathological process of Alzheimer's disease, it is now crucial to increase the understanding of the atypical focal presentations of Alzheimer's disease, such as posterior cortical atrophy. This study aimed to (i) characterize the brain perfusion profile in posterior cortical atrophy using regions of interest and a voxel-based approach; (ii) study the influence of the disease duration on the clinical and imaging profiles; and (iii) explore the correlations between brain perfusion and cognitive deficits. Thirty-nine patients with posterior cortical atrophy underwent a specific battery of neuropsychological tests, mainly targeting visuospatial functions, and a brain perfusion scintigraphy with 99mTc-ethyl cysteinate dimer. The imaging analysis included a comparison with a group of 24 patients with Alzheimer's disease, matched for age, disease duration and Mini-Mental State Examination, and 24 healthy controls. The single-photon emission computed tomography profile in patients with posterior cortical atrophy was characterized by extensive and severe hypoperfusion in the occipital, parietal, posterior temporal cortices and in a smaller cortical area corresponding to the frontal eye fields (Brodmann areas 6/8). Compared with patients with Alzheimer's disease, the group with posterior cortical atrophy showed more severe occipitoparietal hypoperfusion and higher perfusion in the frontal, anterior cingulate and mesiotemporal regions. When considering the disease duration, the functional changes began and remained centred on the posterior lobes, even in the late stage. Correlation analyses of brain perfusion and neuropsychological scores in posterior cortical atrophy highlighted the prominent role of left inferior parietal damage in acalculia, Gerstmann's syndrome, left-right indistinction and limb apraxia, whereas damage to the bilateral dorsal occipitoparietal regions appeared to be involved in Bálint's syndrome. Our findings provide new insight into the natural history of functional changes according to disease duration and highlight the role of parietal and occipital cortices in the cognitive syndromes that characterize the posterior cortical atrophy.


Ns1 is a key protein in the vaccine composition to protect Ifnar(-/-) mice against infection with multiple serotypes of African horse sickness virus.
African horse sickness virus (AHSV) belongs to the genus Orbivirus. We have now engineered naked DNAs and recombinant modified vaccinia virus Ankara (rMVA) expressing VP2 and NS1 proteins from AHSV-4. IFNAR((-/-)) mice inoculated with DNA/rMVA-VP2,-NS1 from AHSV-4 in an heterologous prime-boost vaccination strategy generated significant levels of neutralizing antibodies specific of AHSV-4. In addition, vaccination stimulated specific T cell responses against the virus. The vaccine elicited partial protection against an homologous AHSV-4 infection and induced cross-protection against the heterologous AHSV-9. Similarly, IFNAR((-/-)) mice vaccinated with an homologous prime-boost strategy with rMVA-VP2-NS1 from AHSV-4 developed neutralizing antibodies and protective immunity against AHSV-4. Furthermore, the levels of immunity were very high since none of vaccinated animals presented viraemia when they were challenged against the homologous AHSV-4 and very low levels when they were challenged against the heterologous virus AHSV-9. These data suggest that the immunization with rMVA/rMVA was more efficient in protection against a virulent challenge with AHSV-4 and both strategies, DNA/rMVA and rMVA/rMVA, protected against the infection with AHSV-9. The inclusion of the protein NS1 in the vaccine formulations targeting AHSV generates promising multiserotype vaccines.


Egg-derived bioactive peptides with ACE-inhibitory properties: a literature update.
Egg proteins contain a wide set of peptide sequences which have an impact on cardiovascular health. Their modes-of-action involve, among others, the inhibition of angiotensin-converting enzyme (ACE) and antioxidant and anti-inflammatory properties. In this review, we focus particularly on ACE-inhibition and discuss recent findings in: (i) production methods for egg protein-derived ACE-inhibitory peptides, (ii) in vitro functionality of these peptides, (iii) their intestinal digestion and absorption in order to reach the target tissue, (iv) the impact of ACE-inhibitory egg-derived peptides in vivo and (v) future perspectives for the implementation of egg-derived ACE-inhibitory peptides as functional foods.


What do parents think about enrolling their premature babies in several research studies?
To investigate parents' opinions about enrolling their premature baby into several research studies in the few days after birth. A questionnaire was given to parents of premature babies in the neonatal intensive care unit who had been invited to join several studies (two to seven). All 50 mothers and 42 of 48 fathers completed the questionnaire independently; 28% had been asked to join two studies, 32% three, 24% four, 14% five, and 2% six studies. There were 61 babies with mean (SD) gestational age 26.9 (1.6) weeks and birth weight 877 (249) g. Nearly three quarters (71%) of the parents thought it was very good for their baby to be in a hospital that was carrying out a lot of research. Most (93%) thought that their baby would get the same or better care in a study. Only 15% thought their baby was too small for research studies. Almost all (98%) wanted to be involved in the decision about their baby joining a study. Only 22% were worried about the number of studies; 10% would not enroll their baby in any studies, but 74% were willing for their baby to join two or more studies, and 10% would enroll in all the studies. Most (94%) believed that their baby's participation would improve care of future babies. Most of these parents were willing to join several studies. The majority were not worried about their baby participating in the studies. The profession needs to be aware that parents are supportive of neonatal research and participation in multiple studies.


Contrasting Modulatory Effects from the Dorsal and Ventral Premotor Cortex on Primary Motor Cortex Outputs.
The dorsal and ventral premotor cortices (PMd and PMv, respectively) each take part in unique aspects for the planning and execution of hand movements. These premotor areas are components of complex anatomical networks that include the primary motor cortex (M1) of both hemispheres. One way that PMd and PMv could play distinct roles in hand movements is by modulating the outputs of M1 differently. However, patterns of effects from PMd and PMv on the outputs of M1 have not been compared systematically. Our goals were to study how PMd within the same (i.e., ipsilateral or iPMd) and in the opposite hemisphere (i.e., contralateral or cPMd) can shape M1 outputs and then compare these effects with those induced by PMv. We used paired-pulse protocols with intracortical microstimulation techniques in sedated female cebus monkeys while recording EMG signals from intrinsic hand and forearm muscles. A conditioning stimulus was delivered in iPMd or cPMd concurrently or before a test stimulus in M1. The patterns of modulatory effects from PMd were compared with those from PMv collected in the same animals. Striking differences were revealed. Conditioning stimulation in iPMd induced more frequent and powerful inhibitory effects on M1 outputs compared with iPMv. In the opposite hemisphere, cPMd conditioning induced more frequent and powerful facilitatory effects than cPMv. These contrasting patterns of modulatory effects could allow PMd and PMv to play distinct functions for the control of hand movements and predispose them to undertake different, perhaps somewhat opposite, roles in motor recovery after brain injury.SIGNIFICANCE STATEMENT The dorsal and ventral premotor cortices (PMd and PMv, respectively) are two specialized areas involved in the control of hand movements in primates. One way that PMd and PMv could participate in hand movements is by modulating or shaping the primary motor cortex (M1) outputs to hand muscles. Here, we studied the patterns of modulation from PMd within the same and in the opposite hemisphere on the outputs of M1 and compared them with those from PMv. We found that PMd and PMv have strikingly different effects on M1 outputs. These contrasting patterns of modulation provide a substrate that may allow PMd and PMv to carry distinct functions for the preparation and execution of hand movements and for recovery after brain injury.


Transcatheter aortic valve implantation for the treatment of severe symptomatic aortic stenosis in patients at very high or prohibitive surgical risk: acute and late outcomes of the multicenter Canadian experience.
The aim of this study was: 1) to evaluate the acute and late outcomes of a transcatheter aortic valve implantation (TAVI) program including both the transfemoral (TF) and transapical (TA) approaches; and 2) to determine the results of TAVI in patients deemed inoperable because of either porcelain aorta or frailty. Very few data exist on the results of a comprehensive TAVI program including both TA and TF approaches for the treatment of severe aortic stenosis in patients at very high or prohibitive surgical risk. Consecutive patients who underwent TAVI with the Edwards valve (Edwards Lifesciences, Inc., Irvine, California) between January 2005 and June 2009 in 6 Canadian centers were included. A total of 345 procedures (TF: 168, TA: 177) were performed in 339 patients. The predicted surgical mortality (Society of Thoracic Surgeons risk score) was 9.8 +/- 6.4%. The procedural success rate was 93.3%, and 30-day mortality was 10.4% (TF: 9.5%, TA: 11.3%). After a median follow-up of 8 months (25th to 75th interquartile range: 3 to 14 months) the mortality rate was 22.1%. The predictors of cumulative late mortality were peri-procedural sepsis (hazard ratio [HR]: 3.49, 95% confidence interval [CI]: 1.48 to 8.28) or need for hemodynamic support (HR: 2.58, 95% CI: 1.11 to 6), pulmonary hypertension (PH) (HR: 1.88, 95% CI: 1.17 to 3), chronic kidney disease (CKD) (HR: 2.30, 95% CI: 1.38 to 3.84), and chronic obstructive pulmonary disease (COPD) (HR: 1.75, 95% CI: 1.09 to 2.83). Patients with either porcelain aorta (18%) or frailty (25%) exhibited acute outcomes similar to the rest of the study population, and porcelain aorta patients tended to have a better survival rate at 1-year follow-up. A TAVI program including both TF and TA approaches was associated with comparable mortality as predicted by surgical risk calculators for the treatment of patients at very high or prohibitive surgical risk, including porcelain aorta and frail patients. Baseline (PH, COPD, CKD) and peri-procedural (hemodynamic support, sepsis) factors but not the approach determined worse outcomes.


Senescent remodeling of the innate and adaptive immune system in the elderly men with prostate cancer.
Despite years of intensive investigation that has been made in understanding prostate cancer, it remains a major cause of death in men worldwide. Prostate cancer emerges from multiple alterations that induce changes in expression patterns of genes and proteins that function in networks controlling critical cellular events. Based on the exponential aging of the population and the increasing life expectancy in industrialized Western countries, prostate cancer in the elderly men is becoming a disease of increasing significance. Aging is a progressive degenerative process strictly integrated with inflammation. Several theories have been proposed that attempt to define the role of chronic inflammation in aging including redox stress, mitochondrial damage, immunosenescence, and epigenetic modifications. Here, we review the innate and adaptive immune systems and their senescent remodeling in elderly men with prostate cancer.


[Possible mechanisms regulating the entry of normal and neoplastic cells into the DNA synthesis phase].
Literature data concerning some aspects in the regulation of the entry of normal and neoplastic cells into the phase of DNA synthesis are reviewed. Basing on the analysis of data reported by different authors, a hypothetical model is suggested for regulation of cell passing from G- to S-period. The main chain in the regulation is the constitutive synthesis of protein-repressor which blocks the expression of genes whose products are necessary for replication ("replication genes"). The repressor inactivation is achieved by growth factors through protein kinases. A comparison is made between the transcriptional mechanisms in eukaryotic and prokaryotic cells. Four hypothetic types of genes have been isolated responsible for regulation of progression of the cell to phase S. The role of quantitative and/or qualitative changes in the products of these genes in neoplastic transformation is discussed.


[Chronic lymphatic leukemia. Immunophenotyping as an aid to correct diagnosis].
The purpose of the study was to examine the validity of the primary diagnosis in chronic lymphocytic leukemia based on clinical and morphological criteria, and to examine the role of immune phenotyping for correct diagnosis in an unselected population-based group of patients. Over a 2-year period leukemic cells from 222 of 235 patients in Norway with a recent clinical diagnosis of chronic lymphocytic leukemia (CLL) were immune phenotyped in order to find cases erroneously diagnosed as CLL. Median age was 72.5 years, and the ratio of men to women was 1.47. At the time of diagnosis, 77% of the patients were in Binet stage A and 23% in stage B or C. Immune phenotyping, in some patients followed by lymph node or bone marrow biopsy, showed a different diagnosis in 11 (5%) of 222 patients: prolymphocytic leukemia, four patients (three B-cell and one T-cell); morbus Waldenstrøm, one patient; T-cell CLL, one patient; hairy cell leukemia, one patient; mycosis fungoides, one patient; mantle cell lymphoma, one patient; monocytoid B-cell lymphoma, one patient and immunoblastic lymphoma one patient. In eight of these 11 patients, the clinical features or morphology, or both, were atypical for CLL, but this was not recognized at the time of diagnosis. Thus, immune phenotyping is valuable for correct diagnosis in a small subgroup of patients with chronic B- or T-cell leukemia, and it is essential in patients with modest lymphocytosis (lymphocytes < 10. 10(9)/1).


Decision making in de novo Parkinson's disease.
The aim is to study decision making in patients with de novo Parkinson's disease (PD). Recent studies reported that medicated patients with PD have poor performances compared with age-matched healthy controls in decision making tasks, specially in the Iowa Gambling Task. Two principal causal hypotheses have been proposed to explain this phenomenon: the overdosing effects of dopaminergic therapy on the orbital frontostriatal circuit that is involved in reward processing, or an amygdala dysfunction, as suggested by similar Skin Conductance Responses of patients with PD and amygdala-damaged patients while performing this task. The assessment of decision making with the Iowa Gambling Task was conducted in 30 nondemented and nondepressed patients with de novo PD and in 25 age-matched healthy controls. No statistically significant difference emerged between performances of de novo PD patients and performances of healthy controls. De novo PD patients have performances in the Iowa Gambling Task similar to those of age-matched healthy controls, suggesting that difficulties in decision making emerge, at least in de novo PD patients, by dopaminergic overstimulation of the orbital frontostriatal circuits.


Nitric oxide synthase and changes in oxidative stress levels in embryonic kidney observed in a rabbit model of intrauterine growth restriction.
This work aimed to study the effect of uteroplacental circulation restriction on endothelial kidney damage in a fetal rabbit model. New Zealand rabbits were subjected to 40% to 50% of uteroplacental artery ligation at day 25 of pregnancy. After 5 days, surviving fetuses were harvested by cesarean section. The gene and protein expressions of selected enzymes associated with nitric oxide production and oxidative stress were analyzed in fetal kidney homogenates. The placenta weight (6.06 ± 0.27, p < 0.0319) and fetal body (19.90 ± 1.03, p < 0.0001) were significantly reduced in the uteroplacental circulation restriction group. The kidneys from restricted fetuses presented a mild vascular congestion and glomerular capillary congestion, without inflammation or hypertrophy. We found endothelial nitric oxide synthase phosphorylation inhibition (0.23 ± 0.13, p < 0.012) and arginase-2 (0.29 ± 0.14, p < 0.023) protein induction in fetal kidneys of the circulation restriction group. Finally, the kidneys from circulation-restricted fetuses showed increased inducible nitric oxide synthase messenger RNA (mRNA) (2.68 ± 0.24, p < 0.01) and reduced heme oxygenase-1 mRNA (23 ± 1.3, p < 0.003), with increased reactive oxygen species (1.69 ± 0.09, p < 0.001) and nitrotyrosine protein (1.74 ± 0.28, p < 0.003) levels, without changes in Nox mRNA. We describe significant deregulation of vascular activity and oxidative damage in kidneys of fetal rabbits that have been exposed to restriction of the uterine circulation. © 2016 John Wiley & Sons, Ltd.