Alterations of the enteric nervous system in neonatal necrotizing enterocolitis revealed by whole-mount immunohistochemistry.
Pathology reports on neonatal necrotizing enterocolitis (NNEC) rarely consider its effects on the enteric nervous system (ENS). Thus, the aim of this study has been to perform a two-dimensional assessment of neuropathologic lesions within the three ganglionated plexuses of the intestinal wall by means of whole-mount immunohistochemistry. Resected segments of ileum and colon affected by acute NNEC were submitted to immunohistochemical procedures using antibodies against neuronal (protein gene product 9.5) and glial (protein S-100, glial fibrillary acidic protein) proteins. Examination of the myenteric plexus and external submucosal plexus revealed a noticeable reduction in glial cells concomitant with the gradual deterioration of nerve cells, both findings predominating in the antimesenteric intestinal circumference, where ischemic lesions tend to appear first. The most severe damage of nervous tissue was observed in the plexus submucosus internus dependent on the depth of mucosal injury. The destroyed ganglia appeared like "empty baskets" (residual tangles) and housed deteriorated nerve and glial cells. Taking the anatomy of the intestinal vascular blood supply into consideration, the characteristic topography of neuropathologic lesions gives further support to an ischemic event within the cascade of different pathogenetic factors culminating in NNEC. Moreover, the demonstrated alterations of the ENS and their potential adverse effects on intestinal motility and neuroimmunologic interactions may contribute to the complex pathogenesis of NNEC, which remains a field of further investigation.


Ypk1, the yeast orthologue of the human serum- and glucocorticoid-induced kinase, is required for efficient uptake of fatty acids.
Fatty acids constitute an important energy source for various tissues. The mechanisms that mediate and control uptake of free fatty acids from the circulation, however, are poorly understood. Here we show that efficient fatty-acid uptake by yeast cells requires the protein kinase Ypk1, the orthologue of the human serum- and glucocorticoid-induced kinase Sgk1. ypk1Delta mutant cells fail to grow under conditions that render cells auxotrophic for fatty acids, show a reduced uptake of radiolabelled or fluorescently labelled fatty acids, lack the facilitated component of the uptake activity, and have elevated levels of fatty acids in a bovine serum albumin (BSA) back-extractable compartment. Efficient fatty-acid uptake and/or incorporation requires the protein-kinase activity of Ypk1, because a kinase-dead point-mutant allele of YPK1 is defective in this process. This function of Ypk1 in fatty-acid uptake and/or incorporation is functionally conserved, because expression of the human Sgk1 kinase rescues ypk1Delta mutant yeast. These observations suggest that Ypk1 and possibly the human Sgk1 kinase affect fatty-acid uptake and thus energy homeostasis through regulating endocytosis. Consistent with such a proposition, mutations that block early steps of endocytosis display reduced levels of fatty-acid uptake.


A clinical study of radiation cataract formation in adult life following gamma irradiation of the lens in early childhood.
To analyse long term effects on the lens of radium irradiation during infancy. An infant cohort (n = 20, median age 6 months) treated for skin haemangioma with one or two radium-226 needles located at or within the orbital rim was examined 30 to 45 years after gamma radiation. Detailed information about the treatment procedure was available for all cases. Subcapsular opacities were graded semiquantitatively according to a scale based on extent and density of the opacities. A high prevalence of light to moderate posterior, subcapsular, and cortical cataract formation was found in the lenses on the treated side irradiated with a mean dose ranging from approximately 1 to 8 Gy. The cataract formation increased as a function of dose. The presence of subcapsular punctate opacities and vacuoles in the lenses on the untreated side receiving irradiation of an estimated dose varying around 0.1 Gy indicates a higher sensitivity than expected. The growing lens during infancy is sensitive to radium irradiation at doses lower than those previously stated. The eye lens seems suitable for studies of effects of low dose radiation since damaged cells are retained in the lens for a lifetime.


[The RBE of 0.85 MeV neutrons on guinea pig mortality].
A comparative study was made of the death rate of guinea pigs after neutron (0.85 MeV) and 137Cs-gamma-radiation (0.66 MeV); LD50/30 were 1.58 and 3.44 Gy respectively. CRBE of neutrons was 2.2 as determined by median lethal dose values for guinea pigs.


Expression of oestrogen receptor alpha and beta in cultured human ovarian surface epithelial cells.
Ovarian surface epithelial (OSE) cells participate in the formation of the ovarian cortex and are potential targets of oestrogen action. Oestrogens typically act through nuclear oestrogen receptors (ER) of which there are two known subtypes: ERalpha and ERbeta. In view of the potential importance of oestrogen as a local regulator of OSE cell function, we screened for ERalpha and ERbeta mRNA in primary OSE cell cultures by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, and used freshly isolated granulosa cells (GC) and granulosa-lutein cells (GLC) as positive controls. OSE cells, scraped from the ovarian surface of women undergoing laparotomy for benign gynaecological conditions, were cultured for up to 21 days to obtain enough cells for mRNA extraction. GC were obtained from spontaneously cyclic women undergoing total hysterectomy; while GLC were obtained from follicular aspirates of gonadotrophin-stimulated in-vitro fertilization patients. Total RNA (1 microg) was reverse transcribed into single-stranded cDNA for PCR (30 cycles) using primers selected to give specific ERalpha and ERbeta products. The ERalpha and ERbeta PCR products, authenticated by cloning and sequencing, were both weakly detectable by Southern analysis in cultured OSE cells and readily detectable in GC and GLC. These results show that cultured human OSE express both ERalpha and ERbeta mRNA, consistent with a role for oestrogen in the regulation of OSE cell function in vivo.


Trauma and violent offending among adolescents: a birth cohort study.
Earlier studies, based on data collected among juvenile court clients or prisoners, suggest that there is an association between trauma and adolescent-onset offending. However, there is a lack of large-scale data on juvenile violence and clinical mental health observations with unselected participants, and a risk-factor-oriented research combining multiple variables affecting violent behaviour. We analyse the effect of trauma on violent offending using longitudinal register-linkage population data. The study is based on administrative data on all Finnish children born between 1986 and 2000, linked with their biological and adoptive parents (N=913 675). The data include annually updated demographic and socioeconomic information from Statistics Finland, hospital discharge and specialised outpatient service records as well as the data from all suspected criminal offences known to the police (1996-2017). We measured trauma diagnosis at age 12-14 and followed participants for subsequent violent criminality from age 15 to 17. The population average estimates, taking into account observed substance abuse and other mental health diagnoses, shows that trauma-related disorders (adjustment problems, post-traumatic stress disorder and acute stress disorder) were associated with violent offending. The same was true in sibling fixed effect models, which take into account genetic and environmental confounding shared by siblings. These results suggest that severe stress related to traumatic or strong negative life changes in adolescence is a risk factor for violent behaviour.


Cardiac rehabilitation: health characteristics and socio-economic status among those who do not attend.
Cardiac rehabilitation (CR) is well documented, in randomised trials, to reduce mortality risk after myocardial infarction (MI). Selection of healthy patients for CR is a relatively unexplored problem. Our aims were to identify predictors of CR-attendance and to describe the prognosis as concerns mortality, re-admission and invasive treatment among CR-attendees as compared to CR-non-attendees. From a cohort of 138 290 persons aged 30-69 years, we identified consecutive MI patients, between 1 April 2000 and 31 March 2002. There were 206 MI patients, who survived until admission, and among the 200 who survived 30 days, 145 (72.5%) attended a comprehensive CR programme. Data were obtained from patient charts and from Danish population registers, and as a result we had no non-participation for the study. The 2-year mortality proportions for patients surviving the first 30 days of admission were 2.8 and 21.8% among CR-attendees and CR-non-attendees, respectively (P < 0.0001). Among CR-non-attendees, there was a smaller fraction having an invasive treatment performed as compared with CR-attendees. By multiple logistic regression controlling for age and sex, CR-attendance was associated with chest pain, whereas CR-non-attendance was associated with low gross income, single living and inverted T-wave in the electrocardiogram. CR attendance rate was 72.5%. Non-attendees have a higher mortality risk, which in part may be attributed to selection of healthy patients. Non-attendees are older and more likely to have atypical symptoms at admission, a low socioeconomic status and to live alone. Special attention is needed to improve CR attendance among such patients.


Changes in the activities of the enzymes of urea synthesis caused by dexamethasone and dibutyryladenosine 3':5'-cyclic monophosphate in foetal rat liver maintained in organ culture.
Liver explants from 19-day foetal rats were maintained in organ culture, in a defined medium, for up to 48h. Both 6-N,2'-O-dibutyryl cyclic AMP, in the presence of theophylline, and dexamethasone caused an increase in the activities of carbamoyl phosphate synthase, argininosuccinate synthetase, argininosuccinate lyase and arginase. These increases could be abolished by simultaneously incubating the explants with cycloheximide. No change in the activity of ornithine transcarbamoylase was found with either hormone. Previous work has shown that injection of corticosteroids into 19.5-day foetal rats in utero did not cause an increase in the arginine synthetase system. Present results suggest that this lack of effect is not due to any incompetence of the foetal rat liver at this stage to respond to this agent. The observations on ornithine transcarbamoylase activity suggest that this enzyme is induced in the liver of the perinatal rat by neither corticosteroids nor hormones acting via cyclic AMP, and it may be that all the enzymes of the urea cycle are induced physiologically by an agent or agents as yet unidentified.


New therapeutic approaches to cognitive impairment.
Therapeutic approaches to the cognitive impairment of dementia are making their way into clinical practice. Clinical pharmacologic approaches toward improvement of cognitive symptoms are discussed, with an emphasis on cholinergic approaches, since they currently appear most promising and since several cholinesterase inhibitors may soon be available for prescribing. As more knowledge is gained about dosing, side effects, and mechanisms of action, these drugs can be prescribed more efficiently. Current research approaches to slowing the rate of cognitive decline are discussed, including the use of antioxidants, monoamine oxidase-B inhibitors, and cholinesterase inhibitors. Drugs that improve cognition may also have effects on behavioral symptoms, severe dementia, and non-Alzheimer's dementia. Evidence suggests that some dementia patients may be particularly responsive to intervention and that other medications may enhance response. Psychosocial interventions may also contribute to prolonging the time to institutionalization.


Mental health interventions for healthcare workers during the first wave of COVID-19 pandemic in Spain.
In order to reduce distress associated with working with COVID-19 patients, several psychological intervention programmes for healthcare workers have been developed in Spain. We aimed to describe the main characteristics and components of these programmes for healthcare workers treating COVID-19 patients in Spanish hospitals. An online survey was designed to evaluate the main characteristics of psychological intervention programmes for healthcare workers during the first wave of COVID-19 pandemic. Valid responses were received from 36 hospitals. Most of these programmes offered both in-person and online therapy. The most common aim of these interventions was emotional regulation, which was treated by psychoeducational and cognitive-behavioural techniques in individual interventions. Group interventions mainly used psychoeducation and mindfulness. Only half of the teams that offered in-person interventions received training in the proper use of personal protective equipment. Several hospitals in Spain have developed mental health interventions for healthcare workers during the COVID-19 pandemic, deploying a wide range of therapeutic modalities and techniques. The rapid implementation of these programmes during the pandemic suggests that safety may not have received sufficient attention. The planning and development of interventions for healthcare workers during pandemics merits greater attention by national and regional authorities and institutions.


Depression, body image and quality of life in acne scars.
Acne scars commonly occur in almost 95% of adolescents having acne. Depression and the psychosocial impact of acne have been studied by previous researchers but there are few studies on acne scar patients. To study the prevalence of depression, body image, and quality of life in patients with acne scars and the correlation of depression with body image and quality of life. Around 81 patients above 18 years of age clinically diagnosed as having different grades of acne by a dermatologist were assessed for depression using Becks Depression Inventory, Body image concern inventory, and Dermatology Life Quality Index and included in the study after being informed consent. The mean duration of acne was 6.03 ± 2.9 years, and acne scar was 2.88 ± 1.2 years. Nearly 93% of our sample had an equal preponderance of Grade 1 and Grade 2 acne scars. 31 (38.27%) patients had clinical depression with a total mean BDI score of 16.8 ± 9.7. 15 (18.5%) and 7 (8.6%) patients had moderate and severe depression respectively. Only 5 (6.17%) patients reported significant body image disturbances. All patients reported a very large effect on the quality of life due to flaws in facial appearance leading to feelings of embarrassment and impairment in sexual activities. Depression was significantly associated with grade 1 and 2 scars, body image disturbances, and quality of life. There is a high prevalence of depression in patients with acne scarring which needs to be detected and treated. Liaison with a psychiatrist would improve the outcome.


The role of a department of physiological (clinical) measurement in the UK National Health Service.
The relatively new concept of a centralized department of physiological measurement, and the ways in which such a department interacts with related hospital departments within the framework of the National Health Service, are be borne in mind when setting up such a department are outlined and, finally, discussed. A variety of structural and functional considerations which are to the author describes his own department in the light of these considerations.


Arsenic Dispensing Powder Promotes Erythropoiesis in Myelodysplastic Syndromes via Downregulation of HIF1A and Upregulation of GATA Factors.
Traditional Chinese Medicine (TCM) is a practical medicine based on thousands of years of medical practice in China. Arsenic dispensing powder (ADP) has been used as a treatment for MDS patients with a superior efficacy on anemia at Xiyuan Hospital of China Academy of Chinese Medical Sciences. In this study, we retrospectively analyzed MDS patients that received ADP treatment in the past 9 years and confirmed that ADP improves patients' anemia and prolongs overall survival in intermediate-risk MDS patients. Then, we used the MDS transgenic mice model and cell line to explore the drug mechanism. In normal and MDS cells, ADP does not show cellular toxicity but promotes differentiation. In mouse MDS models, we observed that ADP showed significant efficacy on promoting erythropoiesis. In the BFU-E and CFU-E assays, ADP could promote erythropoiesis not only in normal clones but also in MDS clones. Mechanistically, we found that ADP could downregulate HIF1A in MDS clones through upregulation of VHL, P53 and MDM2, which is involved in two parallel pathways to downregulate HIF1A. We also confirmed that ADP upregulates GATA factors in normal clones. Thus, our clinical and experimental studies indicate that ADP is a promising drug to promote erythropoiesis in both MDS and normal clones with a superior outcome than current regular therapies. ADP promotes erythropoiesis in myelodysplastic syndromes via downregulation of HIF1A and upregulation of GATA factors.


Prevalence of normal serum amylase levels in patients with acute alcoholic pancreatitis.
Acute alcoholic pancreatitis is uncommonly diagnosed when the serum amylase level is normal. We defined acute alcoholic pancreatitis as a clinical syndrome in which hyperamylasemia was not a necessary component and sought support for the diagnosis by ultrasonography and computed tomography of the pancreas. In 68 episodes of acute alcoholic pancreatitis identified in a one-year period, the serum amylase level was normal at the time of hospital admission in 32%. In 40 episodes, we performed ultrasonography and computed tomography within 48 hr of admission. The diagnosis was supported by ultrasonography in 43%, by computed tomography in 68%. Ultrasonography and computed tomography supported the diagnosis as frequently in patients with normal serum amylase levels as in patients with hyperamylasemia. We conclude that patients with acute alcoholic pancreatitis frequently have normal serum amylase levels. The widespread clinical practice of relying solely on hyperamylasemia to establish the diagnosis of acute alcoholic pancreatitis is unjustified and should be abandoned.


Shifts along the parasite-mutualist continuum are opposed by fundamental trade-offs.
Theory suggests that symbionts can readily evolve more parasitic or mutualistic strategies with respect to hosts. However, many symbionts have stable interactions with hosts that improve nutrient assimilation or confer protection from pathogens. We explored the potential for evolution of increased parasitism or decreased parasitism and mutualism in a natural gut symbiosis between larvae of Plutella xylostella and the microbe Enterobacter cloacae. We focused on interactions with the pathogen, Bacillus thuringiensis: selecting for parasitism in terms of facilitating pathogen infection, or increased mutualism in terms of host protection. Selection for parasitism led to symbionts increasing pathogen-induced mortality but reduced their competitive ability with pathogens and their in vitro growth rates. Symbionts did not evolve to confer protection from pathogens. However, several lineages evolved reduced parasitism, primarily in terms of moderating impacts on host growth, potentially because prudence pays dividends through increased host size. Overall, the evolution of increased parasitism was achievable but was opposed by trade-offs likely to reduce fitness. The evolution of protection may not have occurred because suppressing growth of B. thuringiensis in the gut might provide only weak protection or because evolution towards protective interactions was opposed by the loss of competitive fitness in symbionts.


Undifferentiated (embryonal) sarcoma of the liver in childhood: results of a retrospective Italian study.
The clinical features and the treatment of undifferentiated (embryonal) sarcoma of the liver in 8 patients younger than 19 years old were analyzed. All these cases were registered in the retrospective multicentric study on childhood malignant tumors of the liver, conducted between 1983 and 1985 by the Italian Association of Pediatric Hematology Oncology. The age of the patients ranged from 94 to 190 months (median = 113.5 months); all children were males. An abdominal mass was the common presenting features. Abnormalities in hemogram and common liver tests were rarely reported. Angiography revealed various degrees of vascularization in these tumors. Two patients achieved a surgical complete remission (CR) at diagnosis; one patient achieved surgical CR after primary chemotherapy with vincristine, adriamycin, cyclophosphamide and 5-fluorouracil, which reduced the tumor volume and permitted surgical resection. Two of these patients are still in CR at 14 and 60 months after diagnosis; the third patient died of liver failure without evidence of recurrence 6 months after diagnosis. All of the other patients, who never achieved CR, died of disease. One was lost to follow-up, and one surgical death occurred. Reports of childhood undifferentiated sarcoma are reviewed.


Evaluation of continuous-infusion gallium nitrate and hydroxyurea in combination for the treatment of refractory non-Hodgkin's lymphoma.
Based on preclinical studies demonstrating synergy between gallium and hydroxyurea, we evaluated the efficacy and toxicity of continuous intravenous gallium nitrate in combination with oral hydroxyurea in patients with refractory non-Hodgkin's lymphoma. Fourteen patients, median age 64 years (range 53-89), with stage III or IV low- or intermediate-grade lymphoma were treated with gallium nitrate and hydroxyurea in combination for 7 days at four different dose levels: (a) gallium nitrate, 200 mg/m2/day; hydroxyurea, 500 mg/day; (b) gallium nitrate, 250 mg/m2/day; hydroxyurea, 1,000 mg/day; (c) gallium nitrate, 300 mg/m2/day; hydroxyurea, 1,000 mg/day; and (d) gallium nitrate, 350 mg/m2/day, hydroxyurea, 1,000 mg/day. All patients had progressive disease and had been heavily pretreated. Six of 14 patients had objective tumor regression following treatment (one complete response, one near-complete response, and four partial responses) with a median duration of response of 7 weeks (range 3-38 weeks). An additional four patients had minor responses. Responses occurred at all dose levels and in both low- and intermediate-grade histologic subtypes. The predominant toxicities encountered were anemia and reversible nephrotoxicity. Combination gallium nitrate and hydroxyurea has significant activity in lymphoma and is well tolerated even by elderly patients. Because of the lack of cross-resistance to other drugs and the potential synergistic antineoplastic activity, gallium nitrate and hydroxyurea should be further evaluated in combination with other chemotherapeutic agents.


Self-propelled worm-like filaments: spontaneous spiral formation, structure, and dynamics.
Worm-like filaments that are propelled homogeneously along their tangent vector are studied by Brownian dynamics simulations. Systems in two dimensions are investigated, corresponding to filaments adsorbed to interfaces or surfaces. A large parameter space covering weak and strong propulsion, as well as flexible and stiff filaments is explored. For strongly propelled and flexible filaments, the free-swimming filaments spontaneously form stable spirals. The propulsion force has a strong impact on dynamic properties, such as the rotational and translational mean square displacement and the rate of conformational sampling. In particular, when the active self-propulsion dominates thermal diffusion, but is too weak for spiral formation, the rotational diffusion coefficient has an activity-induced contribution given by v(c)/ξ(P), where v(c) is the contour velocity and ξ(P) the persistence length. In contrast, structural properties are hardly affected by the activity of the system, as long as no spirals form. The model mimics common features of biological systems, such as microtubules and actin filaments on motility assays or slender bacteria, and artificially designed microswimmers.


Construction of Activity-based Anorexia Mouse Models.
Anorexia nervosa (AN) is a psychiatric disorder mainly characterized by extreme hypophagia, severe body weight loss, hyperactivity, and hypothermia. Currently, AN has the highest mortality rate among psychiatric illnesses. Despite decades of research, there is no effective cure for AN nor is there a clear understanding of its etiology. Since a complex interaction between genetic, environmental, social, and cultural factors underlines this disorder, the development of a suitable animal model has been difficult so far. Here, we present our protocol that couples a loss-of-function mouse model to the activity-based anorexia model (ABA), which involves self-imposed starvation in response to exposure to food restriction and exercise. We provide insights into a neural circuit that drives survival in AN and, in contrast to previous protocols, propose a model that mimics the conditions that mainly promote AN in humans, such as increased incidence during adolescence, onset preceded by negative energy balance, and increased compulsive exercise. This protocol will be useful for future studies that aim to identify neuronal populations or brain circuits that promote the onset or long-term maintenance of this devastating eating disorder.


Parametrization and Benchmark of Long-Range Corrected DFTB2 for Organic Molecules.
We present the parametrization and benchmark of long-range corrected second-order density functional tight binding (DFTB), LC-DFTB2, for organic and biological molecules. The LC-DFTB2 model not only improves fundamental orbital energy gaps but also ameliorates the DFT self-interaction error and overpolarization problem, and further improves charge-transfer excited states significantly. Electronic parameters for the construction of the DFTB2 Hamiltonian as well as repulsive potentials were optimized for molecules containing C, H, N, and O chemical elements. We use a semiautomatic parametrization scheme based on a genetic algorithm. With the new parameters, LC-DFTB2 describes geometries and vibrational frequencies of organic molecules similarly well as third-order DFTB3/3OB, the de facto standard parametrization based on a GGA functional. LC-DFTB2 performs well also for atomization and reaction energies, however, slightly less satisfactorily than DFTB3/3OB.


Intratracheal oxygen administration increases FIO2 and PaO2 compared with intranasal administration in healthy, standing horses.
To evaluate the efficacy of 2 different oxygen delivery strategies-intranasal and tracheal insufflation-on the inspired fraction of oxygen (FIO2) in standing horses and to determine the time needed for arterial oxygen partial pressure (PaO2) equilibration. 6 healthy adult horses. In this blinded, randomized crossover design study, horses were randomly assigned to receive oxygen via nasal cannula (group N) or transcutaneous tracheal catheter (group T). After placement of venous and arterial catheters, FIO2 was measured through a catheter placed into the distal portion of the trachea. After baseline measurements were obtained, horses received oxygen at up to 25 mL/kg/min for 1 hour via either intranasal or intratracheal catheter. The FIO2 and PaO2 were recorded at 5, 10, 15, 20, 25, 30, 45, and 60 minutes during and 5, 10, 15, 20, and 30 minutes after oxygen insufflation. Data were analyzed by use of a 2-way repeated measures ANOVA with Tukey-Kramer post hoc testing for pairwise comparisons (P < 0.05). During oxygen administration, FIO2 and PaO2 increased significantly when compared with baseline, resulting in significantly higher values for group T (37.7 ± 2.4%; 214.6 ± 18 mm Hg) than for group N (34.3 ± 3.9%; 184.1 ± 11 mm Hg). The equilibration time was less than 10 minutes. Intratracheal oxygen administration resulted in better oxygenation than nasal insufflation and should therefore be considered in standing horses that are experiencing severe respiratory compromise. The equilibration between FIO2 and PaO2 is rapid in adult horses.


Retrograde melting in the system mg-fe-si-o.
Under certain limits of oxygen fugacity and temperature in the system Mg-Fe-Si-O the crystalline assemblage of olivine, tridymite, and metallic iron will produce liquid with cooling. Changes in composition, accompanying changes in temperature, of the olivine phase cause exothermic oxidation of the metallic iron, providing enough heat to produce liquid.


Seasonal variation in the incidence rate of tuberculous meningitis is associated with sunshine hours.
Tuberculous meningitis (TBM) is a severe complication of tuberculosis and occurs mainly during early childhood. The incidence rate of TBM varies with season, and serum vitamin D levels, which are dependent on sunlight, might play a role. We studied the association between TBM incidence rate and hours of sunshine in Cape Town, South Africa and found a significant association between the incidence rate of TBM and hours of sunshine 3 months earlier (incidence rate ratio per 100 sunshine hours 0·69, 95% confidence interval 0·54-0·88, P = 0·002). The association supports the hypothesis that vitamin D might play a role in the pathophysiology of TBM. Further prospective studies in which vitamin D status is measured are necessary to determine causality.


[Diagnosis of primary chronic rheumatic carditis in adults].
The authors maintain that in some cases one can note the so-called primar chronic rheumatic carditis, or apparently primary rheumatic carditis. Streptococcal infections can be held responsible for the eventuality of a sub-clinical evolution of rheumatism, and there which develops as a clinical form of latent rheumatism, and there is the possibility of ulterior development of valvular cardiopathy without a clear history of acute rheumatic fever in the antecedents. One of the groups subjects with maximal exposure to repeated streptococcic infection is represented by the teaching personnel working permanently in school or pre-school children collectivities or with teen-agers, which are both carriers and disseminators of the rheumatogenic streptococcal infection. Of a total of 50 cases of apparently primary chronic valvular cardiopathies that have been followed by the ASCAR personnel, 48 had tonsillary infections in their antecedents, 8 had arthralgia and 4 cases were detected by chance. In school collectivities at high risk prophylaxis with penicillin should be mandatory, both for the students and for the teaching personnel.


Optical time-stretch confocal microscopy at 1 μm.
We demonstrate optical time-stretch confocal microscopy in the 1 μm spectral window for high-speed and high-resolution cellular imaging. In contrast to the prior demonstrations of time-stretch imaging, which all operated in the telecommunication band, the present work extends the utility of this imaging modality to a wavelength regime (~1 μm), which is well known to be the optimal diagnostic window in biophotonics. This imaging technique enables us to image the nasopharyngeal epithelial cells with cellular resolution (<2 μm), at a line scan rate of 10 MHz, and with a field of view as wide as ~0.44 mm × 0.1 mm. We also theoretically and experimentally characterized the system performance. As the low-loss dispersive fibers for the time-stretch process as well as other essential optical components for enhancing the imaging sensitivity are commonly available at 1 μm, time-stretch confocal microscopy in this wavelength range could usher in realizing high-speed cell imaging with an unprecedented throughput.


The efficacy of anakinra compared to standard care of treatment for COVID-19: a meta-analysis.
As SARS-CoV-2 continues to spread worldwide, this study brings to light the link that anakinra, a recombinant IL-1 receptor antagonist, has in averting grave clinical outcomes. The objectives of this meta-analysis are to investigate the effects of anakinra in interventional groups compared to control/standard of care groups on mortality along with the provision of a prevalence estimate of the variables associated with death (C-reactive protein-CRP, ferritin, acute respiratory distress syndrome-ARDS). According to the PRISMA 2020 statement guidelines, a systematic search was conducted from December 19, 2020, until December 10, 2021, with keywords including COVID-19, coronavirus, SARS-CoV-2, anakinra, mortality, across the following databases: PubMed/MEDLINE, Scopus, Web of Science, CINAHL Plus, and Cochrane. A random-effects model was applied using RevMan 5.4 for all statistical analyses. The meta-analysis pooled in 1297 participants with 565 (43.6%) patients in the anakinra group. When comparing to the control/standard of care group, the anakinra group had a much lower risk of death (RR = 0.47. 95% CI = 0.37-0.59, Z = 6.44; P < 0.001). In addition to the risk of death being reduced by around 50% in the interventional group, prognostic indicators such as CRP and ferritin were improved with fewer occurrences of severe ARDS. Patients with COVID-19 pneumonia may be treated with anakinra as a safe and viable treatment modality to defer adverse outcomes such as a death in the 28-day period. Despite an auspicious premise, our findings must be used with caution as adequately powered randomized, placebo-controlled trials are required to corroborate these findings.


New legal requirements for submission of product information to poisons centres in EU member states.
In the past eight years, the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) has been intensively involved in a European Commission led process to develop EU legislation on the information of hazardous products that companies have to notify to EU Poisons Centres (or equivalent "appointed bodies"). As a result of this process, the Commission adopted Regulation (EU) No 2017/542, amending the CLP Regulation by adding an Annex on harmonised product submission requirements. Harmonised mixture information requirements: Detailed and consistent information on the composition of the hazardous product will become available to EU Poisons Centres (PC). The information will be submitted by companies to PCs (or equivalent "appointed bodies") using a web-based software application or in-house software. Two new important features are introduced. Firstly, to be able to rapidly identify the product formula, a Unique Formula Identifier (UFI) on the product label links to the submitted information. Secondly, for better comparability of reports on poisonings between EU member states, a harmonised Product Categorisation System will specify the intended use of a product. Rapid product identification and availability of detailed composition information will lead to timely and adequate medical intervention. This may lead to considerable reduction in healthcare costs. Additionally, for companies trading across the EU, costs of submission of this information will be reduced significantly. Next steps: From 2017, an implementation period has started, consisting of a three-year period for stakeholders to implement the new requirements, followed by a gradual applicability for consumer products (2020), professional products (2021) and industrial use-only products (2024). Technical tools to generate the electronic format and the UFI together with guidance documents are expected to be made available by the end of 2017 by the European Chemicals Agency (ECHA). Guidance on interpretation of legal text and ECHA helpdesk support are planned to be ready at the end of 2018.


Excess all-cause mortality in the evaluation of a screening trial to account for selective participation.
In addition to disease-specific mortality, a randomized controlled cancer screening trial may be evaluated in terms of excess mortality, in which case no patient-specific information on causes of death is needed. We studied the effect of not accounting for attendance on the calculated excess mortality in a prostate cancer screening trial. The numerator of the excess mortality rate related to prostate cancer diagnoses in each study arm equals the excess number of deaths observed in the cancer patients. The estimation of the expected number of deaths in the absence of the prostate cancer diagnoses has to account for the self-selection of those participating in the trial, particularly if the proportion of non-participants is substantial. The European prostate cancer screening trial (ERSPC). In the screening arm, non-attendees had roughly twice the mortality rate of attendees. Approximately twice as many cancers were detected in the screening arm compared with the control arm, primarily in attendees. Unless attendance is properly accounted for, the expected mortality of prostate cancer patients in the screening arm is overestimated by 0.9-3.6 deaths per 1000 person-years. Attendees have a lower all-cause mortality rate (are healthier) and a higher probability of a prostate cancer diagnosis than non-attendees and the men randomized to the control arm. If attendance is not accounted for, the excess mortality and the between-arm excess mortality rate ratio are underestimated and screening is considered more effective than it actually is. These effects may be sizeable, notably if non-attendance is common. Correcting for attendance status is important in the calculation of the excess mortality rate in prostate cancer patients that can be used in conjunction with a disease-specific mortality analysis in a randomized controlled cancer screening trial.


Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor.
Profound cellular immunodeficiency occurs as the result of mutations in proteins involved in both the differentiation and function of mature lymphoid cells. We describe here a novel human immune aberration arising from a truncation mutation of the interleukin-2 receptor alpha chain (CD25), a subunit of the tripartite high-affinity receptor for interleukin 2. This immunodeficiency is characterized by decreased numbers of peripheral T cells displaying abnormal proliferation but normal B cell development. Extensive lymphocytic infiltration of tissues, including lung, liver, gut, and bone, is observed, accompanied by tissue atrophy and inflammation. Although mature T cells are present, the absence of CD25 does affect the differentiation of thymocytes. While displaying normal development of CD2, CD3, CD4, and CD8 expression, CD25-deficient cortical thymocytes do not express CD1, and furthermore they fail to normally down-regulate levels of the anti-apoptotic protein bcl-2.


Structural evaluation of the prefrontal cortex in schizophrenia.
Altered prefrontal cortical function has been repeatedly implicated in the pathophysiology of schizophrenia. Attempts to determine whether this altered function is associated with structural changes in the prefrontal cortex have been hampered by the failure to examine more anatomically and functionally homogeneous regions. The authors have developed a reliable set of anatomical landmarks for subdividing the prefrontal cortex into superior, middle, inferior, and orbital regions, in order to determine whether patients with schizophrenia exhibit selective morphological abnormalities of the prefrontal cortex. Magnetic resonance imaging (MRI) studies were obtained in 24 normal control subjects (14 men and 10 women) and 18 patients with schizophrenia (12 men and six women) by using a high-resolution thin spoiled-gradient recall acquisition in the steady-state protocol. The MRI images were used to determine prefrontal gray matter volumes for the four prefrontal regions and prefrontal total gray and white volumes. Patients with schizophrenia exhibited selective gray matter volume reductions in the right and left inferior prefrontal cortex. There were no significant group differences in the other prefrontal regions. Patients with schizophrenia also exhibited decreased prefrontal total white matter and total volumes; there was no significant difference in prefrontal total gray matter volume. Patients with schizophrenia are characterized by relatively selective reductions in inferior prefrontal cortex gray matter volumes.


Effect of pH on the Early Development of the Biofouling Ascidian Ciona robusta.
Ocean acidification (OA) impacts the survival, fertilization, and community structure of marine organisms across the world. However, some populations or species are considered more resilient than others, such as those that are invasive, globally distributed, or biofouling. Here, we tested this assumption by investigating the effect of pH on the larval development of one such tunicate, Ciona robusta, which is currently exposed to a wide range of pH levels. Consistent with our hypothesis, C. robusta larvae developed and metamorphosed at a rate comparable to control (pH 8.0) at modest near-future conditions (pH 7.7) over a 58-hour period. However, development was stunted at the extreme low pH of 6.8 such that no embryo progressed beyond late cleavage after 58 hours. Interestingly, piecewise regression of the proportion of embryos at the most advanced stage at a given time point against pH identified a breakpoint with the highest pH (~pH 7.6) at around hatching. The variation in breakpoint pH throughout ontogeny highlighted that the sensitivity to decreasing pH differs significantly between developmental stages. More broadly, our results show that even a cosmopolitan, biofouling, invasive species could be negatively impacted by decreasing pH.


Pyoderma faciale. A review and report of 20 additional cases: is it rosacea?
Pyoderma faciale was originally described by O'Leary and Kierland in 1940. It is characterized by the sudden onset of monstrous coalescent nodules and confluent draining sinuses confined to the face of young women in their early 20s. This report summarizes our results in 20 cases. The women were 15 to 46 years old (mean, 25 years). All women were flushers and blushers. Histopathologic examination revealed a dense perivascular and periadnexial infiltrate, including granulocytes, eosinophils with epithelioid granulomas, and septal and lobular panniculitis. No consistent laboratory abnormalities were found. After much therapeutic experimentation, we developed an effective treatment plan, based on a combination of oral isotretinoin and corticosteroids. We regard it as an extreme form of rosacea and suggest it be renamed rosacea fulminans in analogy with its counterpart, acne fulminans.


The patient: a novel source of error in clinical temperature measurement using infrared aural thermometry.
The vital signs are an important component of patient assessment. With respect to body temperature; there has been a move away from mercury-in-glass thermometers toward the relatively inexpensive, safer to use infrared tympanic, auricular, or ear thermometer. Although already in widespread use, the reliability of these devices has increasingly been called into question. Few studies, however, have considered that the problem might reside outside the device itself. To investigate the correlation between left ear temperature and right ear temperature using an infrared tympanic thermometer (ITT). A prospective, single-blind trail with randomized assignment of the first ear to be assessed. Welsh Institute of Chiropractic (WIOC), University of Glamorgan. One hundred and thirty two (132) asymptomatic subjects who were opportunistically sampled on entry into the WIOC. None of the subjects had any neurologic deficit, or any known underlying pathologic problems. All were students at the University of Glamorgan (age range, 18-48 years). A smaller sample of the same cohort was used on a separate occasion to compare ITTs from 2 different manufacturers using the same protocol. Measurement of ear (ear canal/tympanic) temperature bilaterally using an ITT. Bilateral asymmetry in ear canal temperature. Analysis consisted of nonparametric statistical tests, using Spearman's correlation for comparison and the Wilcoxon matched pairs test for differences. In 132 subjects who completed the main study, although a degree of correlation was found, the relationship did not extrapolate through zero. At temperatures more than 0.4 degrees C above or below 36.7 degrees C, there was a significant difference in temperature in the left compared with the right ear. Additionally, the left ear tended to register a lower temperature than the right ear at temperatures below 36.7 degrees C, whereas the left ear tended to read a higher temperature than the right ear above 36.7 degrees C. The authors suggest that clinicians consider measuring both ears, and take the greater of the readings to be a more accurate reflection of the patient's core temperature. The difference may perhaps even be related to the person's health. This change in methodology should increase the reliability of the measurement and go some way toward restoring confidence in the use of ITT devices.


Laparoscopic repair of incisional hernia. Risk factors for the conversion.
Some factors may affect the conversion to open of the laparoscopic treatment of incisional hernia. Their presence can help to choose the most appropriate technique identifying patients at high risk conversion. A retrospective study has been performed on a cohort of 306 patients, selected among those undergone to elective laparoscopic surgery for post incisional hernia between 2005 and 2015. Only symptomatic patients with single site wall defect, diameter between 5 and 10 cm, ASA ≤3, have been included. Patients were divided in 2 groups, Laparoscopic (L) and Converted (C) and preoperatory data were evaluated and statistically analyzed. The L group accounted for 228 patients and C group for 78 patients. The univariate analysis showed that risk factor for conversion included BMI ≥ 30, Smoking, Diabetes mellitus, Prior emergency surgery. Age > 60 years was associate with lower risk of conversion. The result of this retrospective study allows us to say that the choice of the technique, in the presence of multiple risk factors, should be carefully assessed and discussed with the patient. A prospective study with a larger number of patients would allow a better definition of the risk determined by individual factors and the development of a score that could be used in practice to simplify the risk assessment KEY WORDS: Conversion to open surgery, Incisional hernia, Laparoscopy, Risk factors.


Modeling supravalvular aortic stenosis syndrome with human induced pluripotent stem cells.
Supravalvular aortic stenosis (SVAS) is caused by mutations in the elastin (ELN) gene and is characterized by abnormal proliferation of vascular smooth muscle cells (SMCs) that can lead to narrowing or blockage of the ascending aorta and other arterial vessels. Having patient-specific SMCs available may facilitate the study of disease mechanisms and development of novel therapeutic interventions. Here, we report the development of a human induced pluripotent stem cell (iPSC) line from a patient with SVAS caused by the premature termination in exon 10 of the ELN gene resulting from an exon 9 four-nucleotide insertion. We showed that SVAS iPSC-derived SMCs (iPSC-SMCs) had significantly fewer organized networks of smooth muscle α-actin filament bundles, a hallmark of mature contractile SMCs, compared with control iPSC-SMCs. The addition of elastin recombinant protein or enhancement of small GTPase RhoA signaling was able to rescue the formation of smooth muscle α-actin filament bundles in SVAS iPSC-SMCs. Cell counts and BrdU analysis revealed a significantly higher proliferation rate in SVAS iPSC-SMCs than control iPSC-SMCs. Furthermore, SVAS iPSC-SMCs migrated at a markedly higher rate to the chemotactic agent platelet-derived growth factor compared with the control iPSC-SMCs. We also provided evidence that elevated activity of extracellular signal-regulated kinase 1/2 is required for hyperproliferation of SVAS iPSC-SMCs. The phenotype was confirmed in iPSC-SMCs generated from a patient with deletion of elastin owing to Williams-Beuren syndrome. SVAS iPSC-SMCs recapitulate key pathological features of patients with SVAS and may provide a promising strategy to study disease mechanisms and to develop novel therapies.


Quartz Crystal Microbalance Electronic Interfacing Systems: A Review.
Quartz Crystal Microbalance (QCM) sensors are actively being implemented in various fields due to their compatibility with different operating conditions in gaseous/liquid mediums for a wide range of measurements. This trend has been matched by the parallel advancement in tailored electronic interfacing systems for QCM sensors. That is, selecting the appropriate electronic circuit is vital for accurate sensor measurements. Many techniques were developed over time to cover the expanding measurement requirements (e.g., accommodating highly-damping environments). This paper presents a comprehensive review of the various existing QCM electronic interfacing systems. Namely, impedance-based analysis, oscillators (conventional and lock-in based techniques), exponential decay methods and the emerging phase-mass based characterization. The aforementioned methods are discussed in detail and qualitatively compared in terms of their performance for various applications. In addition, some theoretical improvements and recommendations are introduced for adequate systems implementation. Finally, specific design considerations of high-temperature microbalance systems (e.g., GaPO₄ crystals (GCM) and Langasite crystals (LCM)) are introduced, while assessing their overall system performance, stability and quality compared to conventional low-temperature applications.


The ocular manifestations of congenital infections produced by toxoplasma and cytomegalovirus.
Chorioretinitis is the most common ocular manifestation of congenital toxoplasmosis occurring in both symptomatic and the more freqeunt subclinical form of the disease. Chorioretinitis also occurs in symptomatic congenital cytomegalovirus (CMV) but not in the subclinical form of this congenital congenital infection. Diagnosis cannot be made from ocular signs alone. Knowledge of the epidemiology of both congenital infections along with information about the postnatal history will assist in the differentiation.


Intraepithelial and lamina propria leucocyte subsets in inflammatory bowel disease: an immunohistochemical study of colon and rectal biopsy specimens.
To gain new insights into the pathogenesis and differential diagnosis of ulcerative colitis and colonic Crohn's disease. Immunohistochemistry for different leucocyte subsets was performed in biopsy specimens of the sigmoid colon and rectum from 55 patients with inflammatory bowel disease and 11 healthy controls. Colonic biopsy specimens from patients with active ulcerative colitis had significantly higher numbers of CD45+ and CD3+ leucocytes compared with those from patients with inactive disease, and higher numbers of total leucocytes and macrophages than those from patients with Crohn's disease. Rectal biopsy specimens from patients with Crohn's disease had greater numbers of intraepithelial leucocytes (CD45, CD3 and CD8 cells) than specimens from patients with active or inactive ulcerative colitis, or from healthy controls. Because of the phenotypic differences in the inflammatory infiltrate in the mucosa from the sigmoid colon and the rectum, the segment of the intestine to be biopsied should be specified. Assessment of the leucocytic component of the intraepithelial infiltrate in rectal biopsy specimens was more useful than examination of colonic biopsy specimens in the differential diagnosis of ulcerative colitis and Crohn's disease.


Increase in chloride permeability of snail neurons during high potassium-induced hyperpolarization.
High K+-induced hyperpolarization was recorded intracellularly from the snail neurons, Euhadra subnimbosa, and the ionic mechanism underlying this hyperpolarization was analyzed in comparison with the ACh-induced hyperpolarization of the same cell, the latter known to be Cl(-)-dependent. The membrane resistance always decreased during both hyperpolarizing responses to high K+ (24mM) and ACh (0.1 mM). Both hyperpolarizing responses to high K+ and ACh were reversed in Cl(-)-free Ringer to the depolarizing responses. Both hyperpolarizing responses to high K+ and ACh were markedly augmented immediately after returning to normal Cl- from Cl(-)-free Ringer perfusion. Increase in intracellular Cl(-)-concentration by a leak from KCl-electrode reversed both hyperpolarizing responses to high K+ and ACh. Reversal potential of high K+-response was always 10-20 mV more positive than that of ACh-response, when measured in normal Ringer perfusion. Intracellular Cl(-)-concentration of the cells which were hyperpolarized by high K+ was estimated to be one half of that of the cells which were depolarized by high K+. Above results indicated that the high K+-induced hyperpolarization is due to the permeability increase of the postsynaptic membrane toward Cl-, masking the depolarizing effect of high K+ on the same membrane.


Tumor necrosis-initiated complement activation stimulates proliferation of medulloblastoma cells.
We sought to determine the effect of necrosis-induced activation of the complement protein C3 in medulloblastoma. Twelve medulloblastoma surgical specimens were evaluated for complement activation using immunohistochemistry, with H&E stains performed on adjacent tissue sections to determine the relationship of complement activation to necrotic tissue. Flow cytometry and Western blot were performed on three established medulloblastoma lines and one surgically-procured cell culture to determine expression of C3a receptor (C3aR) in medulloblastoma. In vitro proliferation of siRNA C3aR knockdown cells was compared to that of control siRNA cells with cell line Daoy. Three surgical specimens were found to have necrosis on H&E sections. In each case, iC3b staining was identified on adjacent sections, limited to the necrotic region. In no case did necrosis occur without iC3b staining on adjacent sections. C3aR protein was demonstrated on both the three established cell lines and on the surgical culture. Proliferation assays of Daoy cells with siRNA knockdown vs. control siRNA revealed significantly reduced proliferation at 72 h (p = 0.001). Necrosis is associated with complement activation in medulloblastoma. Medulloblastoma cells express C3aR, and siRNA-mediated knockdown of C3aR inhibits proliferation of these cells in vitro.


Aerosol keratopathy: a revised MacLean classification.
Case report. Chemical keratopathy has been linked to many household aerosols. We present a dramatic case of aerosol keratopathy. The finding of an unexplained epithelial or superficial stromal keratopathy must alert the physician to inquire about the use of household aerosols near the patient's face. We also propose a revised classification system based on the work of MacLean.


Intranasal Oxytocin Affects Amygdala Functional Connectivity after Trauma Script-Driven Imagery in Distressed Recently Trauma-Exposed Individuals.
Approximately 10% of trauma-exposed individuals go on to develop post-traumatic stress disorder (PTSD). Neural emotion regulation may be etiologically involved in PTSD development. Oxytocin administration early post-trauma may be a promising avenue for PTSD prevention, as intranasal oxytocin has previously been found to affect emotion regulation networks in healthy individuals and psychiatric patients. In a randomized double-blind placebo-controlled between-subjects functional magnetic resonance (fMRI) study, we assessed the effects of a single intranasal oxytocin administration (40 IU) on seed-based amygdala resting-state FC with emotion regulation areas (ventromedial prefrontal cortex (vmPFC), ventrolateral prefrontal cortex (vlPFC)), and salience processing areas (insula, dorsal anterior cingulate cortex (dACC)) in 37 individuals within 11 days post trauma. Two resting-state scans were acquired; one after neutral- and one after trauma-script-driven imagery. We found that oxytocin administration reduced amygdala-left vlPFC FC after trauma script-driven imagery, compared with neutral script-driven imagery, whereas in PL-treated participants enhanced amygdala-left vlPFC FC was observed following trauma script-driven imagery. Irrespective of script condition, oxytocin increased amygdala-insula FC and decreased amygdala-vmPFC FC. These neural effects were accompanied by lower levels of sleepiness and higher flashback intensity in the oxytocin group after the trauma script. Together, our findings show that oxytocin administration may impede emotion regulation network functioning in response to trauma reminders in recently trauma-exposed individuals. Therefore, caution may be warranted in administering oxytocin to prevent PTSD in distressed, recently trauma-exposed individuals.


Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum.
The metabolism of pentose-phosphate was investigated in Plasmodium falciparum-infected normal and glucose-6-phosphate dehydrogenase (G6PD)-deficient human red blood cells in vitro. 5'-Phosphoribosyl-1-pyrophosphate (PRPP) content of infected normal red blood cells was increased 50-60-fold at the parasite trophozoite growth stage over that of uninfected cells. The PRPP increment in infected G6PD-deficient cells at comparable stage and parasitemia was only 40% of the value in normal infected cells. Red blood cell PRPP synthetase activity did not change during the growth cycle of the parasite and was similar in both normal and G6PD-deficient cells. Reduced glutathione (GSH) content of G6PD-deficient cells under conditions of culture fell to low or undetectable levels. These low levels of GSH were shown to inhibit the function of red blood cell PRPP synthetase, which requires GSH for full activity. Measurements of the incorporation of 1-14C or 6-14C selectively labeled glucose into parasite nucleic acids revealed that in normal infected red cells, approximately 20% of the pentose was produced via the oxidation of glucose-6-phosphate, whereas in infected G6PD-deficient cells (Mediterranean type), none of the pentose was produced via the oxidative pathway. It is concluded that the low level of reduced GSH found in G6PD deficiency and the resultant partial inhibition of PRPP synthetase together with the missing oxidative pathway for ribose phosphate production can account fully for the reduced parasite growth rate in G6PD-deficient red blood cells described previously. Of these two mechanisms, the predominant one is the impaired PRPP synthetase activity due to low GSH levels in enzyme-deficient red blood cells. The contribution to the ribose-phosphate pool by the hexose monophosphate shunt is relatively minor. A co-existing oxidative stress (which is often hypothesized to mediate the destruction of parasitized red blood cells) is not required to explain growth inhibition in this scheme and does not represent the most straight-forward explanation of the data described in this report.


Circulating Tregs Accumulate in Omental Tumors and Acquire Adipose-Resident Features.
Tumors that metastasize in the peritoneal cavity typically end up in the omental adipose tissue, a particularly immune-suppressive environment that includes specialized adipose-resident regulatory T cells (Treg). Tregs rapidly accumulate in the omentum after tumor implantation and potently suppress antitumor immunity. However, it is unclear whether these Tregs are recruited from the circulation or derived from preexisting adipose-resident Tregs by clonal expansion. Here we show that Tregs in tumor-bearing omenta predominantly have thymus-derived characteristics. Moreover, naïve tumor antigen-specific CD4+ T cells fail to differentiate into Tregs in tumor-bearing omenta. In fact, Tregs derived from the pretumor repertoire are sufficient to suppress antitumor immunity and promote tumor growth. However, tumor implantation in the omentum does not promote Treg clonal expansion, but instead leads to increased clonal diversity. Parabiosis experiments show that despite tissue-resident (noncirculating) characteristics of omental Tregs in naïve mice, tumor implantation promotes a rapid influx of circulating Tregs, many of which come from the spleen. Finally, we show that newly recruited Tregs rapidly acquire characteristics of adipose-resident Tregs in tumor-bearing omenta. These data demonstrate that most Tregs in omental tumors are recruited from the circulation and adapt to their environment by altering their homing, transcriptional, and metabolic properties.


Effectiveness and potential mechanism of Jiawei-Xiaoyao-San for hyperthyroidism: a systematic review.
To evaluate the effectiveness and potential mechanism of traditional Chinese medicine Jiawei-Xiaoyao-San (JWXYS) as an adjunct or mono- therapy for antithyroid drugs (ATDs) in the treatment of hyperthyroidism. Eight databases and three trial registries were searched from inception until May 2023. Randomized controlled trials (RCTs) were included and meta-analysis was conducted using RevMan 5.4 and Stata 14.0. The Cochrane risk of bias (ROB) tool 1.0 and GRADE tool was used for quality appraisal. The findings from case reports using mono-JWXYS and pharmacological studies were summarized in tables. Thirteen RCTs with 979 participants were included. The majority of the included studies were assessed as high risk of bias in one ROB domain. Compared with ATDs, JWXYS plus ATDs resulted in lower free triiodothyronine (FT3) (MD = -1.31 pmol/L, 95% CI [-1.85, -0.76]; low-certainty), lower free thyroxine (MD = -3.24 pmol/L, 95% CI [-5.06, -1.42]; low-certainty), higher thyroid stimulating hormone (MD = 0.42 mIU/L, 95% CI [0.26, 0.59]; low-certainty), higher effectiveness rate of traditional Chinese medicine syndrome (RR = 1.28, 95% CI [1.08, 1.52]; low-certainty), lower goiter score (MD = -0.66, 95% CI [-1.04, -0.29]; very low-certainty), lower thyrotrophin receptor antibody (SMD = -0.44, 95% CI [-0.73, -0.16]; low-certainty) and fewer adverse events (AEs) (RR = 0.34, 95% CI [0.18, 0.67]; moderate-certainty). Compared with regular dosage of ATDs, JWXYS plus half-dose ATDs resulted in fewer AEs (RR = 0.24, 95% CI [0.10, 0.59]; low-certainty). Compared with ATDs in 1 trial, JWXYS resulted in higher FT3, lower goiter score and fewer AEs. Three case reports showed that the reasons patients sought TCM-only treatment include severe AEs and multiple relapses. Three pharmacological studies demonstrated that JWXYS restored Th17/Treg balance, lowered deiodinases activity, regulated thyroid cell proliferation and apoptosis, and alleviated liver oxidative stress in mouse or rat models. JWXYS may enhance the effectiveness of ATDs for hyperthyroidism, particularly in relieving symptoms and reducing AEs. Mono-JWXYS is not recommended except in patients intolerant to ATDs. The findings should be interpreted with caution due to overall high risk of bias. Further pharmacological studies with more reliable models are needed. https://www.crd.york.ac.uk/prospero/, identifier CRD42023394923.


OBSERVER-BASED CONTROL OF A DUAL-STAGE PIEZOELECTRIC SCANNER.
Despite its proven success in a wide variety of applications, the atomic force microscope (AFM) remains limited by its slow imaging rate. One approach to overcome this challenge is to rely on algorithmic approaches that reduce the imaging time not by scanning faster but by scanning less. Such schemes are particularly useful on older instruments as they can provide significant gains despite the existing (slow) hardware. At the same time, algorithms for sub-sampling can yield even greater improvements in imaging rate when combined with advanced scanners that can be retrofitted into the system. In this work, we focus on the use of a dual-stage piezoelectric scanner coupled with a particular scanning algorithm known as Local Circular Scan (LCS). LCS drives the tip of the AFM along a circular trajectory while using feedback to center that circle on a sample edge and to move the circle along the feature, thus reducing imaging time by concentrating the samples to the region of interest. Dual-stage systems are well-suited to LCS as the algorithm is naturally described in terms of a high-frequency, short range path (the scanning circle) and a slower, long range path (the track along the sample). However, control of the scanner is not straightforward as the system is multi-input, single-output. Here we establish controllability and observability of the scanning stage, allowing us to develop individual controllers for the long-range and short-range actuators through the principle of separation. We then use an internal model controller for the short range actuator to track a sinusoidal input (to generate the circular motion) and a state-space set-point tracking controller for the long range actuator. The results are demonstrated through simulation.


[Caesarean section after severe trauma and cardiac arrest - a case report].
A 40 year-old woman with a prominent abdomen was hit by a car on the motorway. The emergency call was "cardiac arrest after multiple trauma in a woman in the late stages of pregnancy". The patient was asystole as indicated by the electrocardiogram 6 minutes after the primary emergency call. Cardiopulmonary resuscitation and endotracheal intubation was performed and a total dose of 3 mg epinephrine was given intravenously. The patient remained asystole. In this preclinical situation the suspected pregnancy could neither be excluded nor confirmed. At least 30 minutes would have been necessary to transfer the patient to the next hospital to perform a caesarean section under controlled conditions. A second physician - trained in obstetrics - was called to perform caesarean section preclinically. In addition, a special ambulance was called to provide sufficient postdelivery care of the neonate. However, the second physician who arrived 18 minutes later was not an obstetrician but also an anaesthesiologist who was trained in neonatal intensive care. At this time - 33 minutes after the first emergency call - the emergency physicians decided to perform a caesarean section immediately. However, the patient was not pregnant. Obviously, the primary emergency call was misleading. The skills of the emergency physicians and the conditions at the site of the emergency have to be weighed carefully against the expected time that is needed to reach the next hospital where a caesarean section can be performed under controlled conditions. In this case, both emergency physicians were anaesthesiologists and they had no doubt that the patient was in the late stages of pregnancy. Due to the prolonged cardiac arrest that did not respond to cardiopulmonary resuscitation both physicians were convinced that immediate preclinical caesarean section represented the only therapeutical option for the unborn patient.


Androgen Receptor and Beyond, Targeting Androgen Signaling in Castration-Resistant Prostate Cancer.
The development of metastatic castration-resistant prostate cancer (mCRPC) signals the terminal disease phase. The preceding hormone-dependent disease setting is effectively managed with androgen deprivation therapy. This foundation of treatment has a high rate of biochemical and clinical response and meaningful clinical benefit but is finite in duration as most cancers will progress to castration resistance. Historically, treatment for mCRPC entailed androgen receptor (AR) inhibitors (nilutamide, flutamide, bicalutamide), nonspecific steroidal biosynthesis inhibitors (ketoconazole, itraconazole), steroids (prednisone, diethylstilbesterol, dexamethasone), or palliative chemotherapy (mitoxantrone, estramustine), but none of these strategies impacted survival. Docetaxel was the first agent to demonstrate a survival improvement in this population, and other therapies followed (cabazitaxel, sipuleucel-T and radium-223). Understanding how prostate cancer cells grow in a systemic androgen-deprived environment further changed this clinical landscape. Deciphering what steroidogenic enzymes are overactive and required for testosterone/dihydrotestosterone synthesis has yielded therapies directed toward both adrenal and tumor-derived androgens. All androgens normally act through AR, and this fact remains true in mCRPC. The cancer accomplishes this by overexpressing the receptor (by genomic copy-number gains or RNA amplification), mutating it directly to lose its selectivity for testosterone/dihydrotestosterone, or selecting for splice variants that do not require ligand at all. These resistance mechanisms result in persistent AR-mediated signaling. Through this understanding, drugs targeting non-ligand-binding aspects of AR functioning (e.g., nuclear translocation, cofactor recruitment) have been developed. Finally, how AR interacts with other signaling pathway is being explored, and new combinations of targets to test are being proposed. Multiple compounds remain in various stages of clinical development based on targeting these resistance pathways, and hopefully, they will further the armamentarium for mCRPC. This review visits these mechanisms of resistance, how they are targeted, and remaining challenges in implementing these therapies into clinical practice among the other approved treatments.


[Cholecystectomy during pregnancy].
Cholecystectomy during pregnancy happens to be the second most common cause of laparotomy. The reported incidence of the procedure is I of every 1250 to 12,500 pregnancies. We have done a retrospective study from january 1989 to december 1994, at Instituto Nacional de Perinatología, having 35,080 deliveries registered, four of them with reported cholecystectomy during pregnancy. The average of maternal age resulted in 20.2 years, varying from 16 to 23 years. Three patients were multigravidas, and just one primigravida. Gestational age at the time of diagnosis and surgery was reported in 17 to 23.4 weeks. We found one twin pregnancy, and that two patients had history of chronic colecistitis. In the 100% of cases laparotomy and cholecystectomy was done, with preterm labor as the most frequent complication. There were 3 fetal loss in study and only 2 pregnancies were delivered at term. In this review the estimated frequency of cholecystectomy was 1 of 8780 deliveries, being the second cause of quirurgical treatment during pregnancy, after appendicectomy. There were reported 50% fetal deaths, and no severe maternal complications.


The risk factors of postoperative infarction after surgical clipping of unruptured anterior communicating artery aneurysms: anatomical consideration and infarction territory.
An anterior communicating artery is a common location for both ruptured and unruptured intracranial aneurysms, and microsurgery is sometimes necessary for their successful treatment. However, postoperative infarction should be considered during clipping due to the complex surrounding structures of anterior communicating artery aneurysms. This study aimed to evaluate the risk factors of postoperative infarction after surgical clipping of unruptured anterior communicating artery aneurysms and its clinical outcomes. The data of patients who underwent microsurgical clipping of an unruptured anterior communicating artery aneurysm in our hospital between January 2008 and December 2020 were retrospectively analyzed. The patients' demographic data, anatomical features of the anterior communicating artery complex and aneurysm, surgical technique, characteristics of postoperative infarction, and its clinical course were evaluated. Notably, among 848 patients, 66 (7.8%) and 34 (4%) patients had radiologic and symptomatic infarctions, respectively. Univariate and multivariate logistic regression analyses showed that hypertension (odds ratio (OR), 1.99; [Formula: see text]), previous stroke (OR, 3.89; [Formula: see text]), posterior projection (OR, 5.58; [Formula: see text]), aneurysm size (OR, 1.17; optimal cut-off value, 6.14 mm; [Formula: see text]), and skull base-to-aneurysm distance (OR, 1.15; optimal cut-off value, 11.09 mm; [Formula: see text]) were associated with postoperative infarction. In the pterional approach, a closed A2 plane was an additional risk factor (OR, 1.88; [Formula: see text]). Infarction of the subcallosal and hypothalamic branches was significantly associated with symptomatic infarction ([Formula: see text]). Hypertension, previous stroke, posteriorly projecting aneurysms, aneurysm size, and highly positioned aneurysms are independent risk factors for postoperative infarction during surgical clipping of an unruptured anterior communicating artery aneurysm. Additionally, a closed A2 plane is an additional risk factor of postoperative infarction in patients undergoing clipping via the pterional approach.


Identification of a small molecule activator of SIRT1 gene expression.
Increased SIRT1 expression exerts beneficial effects in transgenic animal models, ameliorating the onset and progression of aging-related disease phenotypes in various organs including the heart. The potential beneficial effects of SIRT1 have made SIRT1 a prime therapeutic target for age-related diseases and considerable efforts led to the identification of small molecule activator of SIRT1 protein. Thus far, however, a small molecule activator of SIRT1 gene expression has not been reported. Here, we report that syringaresinol, isolated from Panax ginseng berry pulp, is an activator of SIRT1 gene expression. Using human umbilical endothelial cells (HUVECs), we show that syringaresinol treatment induced binding of FOXO3 to the SIRT1 promoter in a sequence-specific manner, leading to induction of SIRT1 expression. Increased SIRT1 expression in HUVECs by syringaresinol treatment delayed cellular senescence and improved various markers of endothelial functions in a FOXO3 dependent manner. Collectively, these findings bring to light a new transcription activator of SIRT1 that may have therapeutic potential.


Necessary and sufficient conditions for evolutionary suicide.
Evolutionary suicide is an evolutionary process where a viable population adapts in such a way that it can no longer persist. It has already been found that a discontinuous transition to extinction is a necessary condition for suicide. Here we present necessary and sufficient conditions, concerning the bifurcation point, for suicide to occur. Evolutionary suicide has been found in structured metapopulation models. Here we show that suicide can occur also in unstructured population models. Moreover, a structured model does not guarantee the possibility of suicide: we show that suicide cannot occur in age-structured population models of the Gurtin-MacCamy type. The point is that the mutant's fitness must explicitly depend not only on the environmental interaction variable, but also on the resident strategy.


Band shape heterogeneity of the low-energy chlorophylls of CP29: absence of mixed binding sites and excitonic interactions.
A number of spectroscopic characteristics of three almost isoenergetic, red-shifted chlorophylls (chls) in the PS II antenna complex CP29 are investigated with the aim of (i) determining whether their band shapes are substantially identical or not, (ii) addressing the topical problem of whether they are involved in excitonic interactions with other chls, and (iii) establishing whether their binding sites may be defined as "mixed" with respect to their capacity to bind chls a and b. The three chls A2-CHL612, A3-CHL613, and B3-CHL614 were analyzed after in vitro apoprotein-pigment reconstitution using the CP29 coding sequence from Arabidopsis thaliana for both the wild-type and mutant complexes. Difference spectra thermal broadening analyses indicated that the half-bandwidths varied between 12 and 15 nm (at room temperature), due mainly to differences in the optical reorganization energy (25-40 cm(-1)). Moreover, only the A2 chl displayed an intense vibrational band in the 300-600 cm(-1) interval from the 0-0 transition. We conclude that within the red absorbing (approximately 680 nm) antenna chls of a single chl-protein complex a marked spectral band shape heterogeneity exists. By analysis of the absorption and circular dichroism spectra no evidence was found of significantly strong excitonic interactions. The single gene mutation of the A3 and B3 binding sites causes absorption changes in both the long wavelength chl a absorbing region and in the chl b spectral region. This has previously been observed and was attributed to "mixed" chl a/b binding sites [Bassi, R., Croce, R., Cugini, D., and Sandona, D. (1999) Proc. Natl. Acad. Sci. U.S.A. 96,10056-10061]. This interpretation, while in principle not being unreasonable, is shown to be incorrect for these two chls.


Evolutionary advantage of small populations on complex fitness landscapes.
Recent experimental and theoretical studies have shown that small asexual populations evolving on complex fitness landscapes may achieve a higher fitness than large ones due to the increased heterogeneity of adaptive trajectories. Here, we introduce a class of haploid three-locus fitness landscapes that allow the investigation of this scenario in a precise and quantitative way. Our main result derived analytically shows how the probability of choosing the path of the largest initial fitness increase grows with the population size. This makes large populations more likely to get trapped at local fitness peaks and implies an advantage of small populations at intermediate time scales. The range of population sizes where this effect is operative coincides with the onset of clonal interference. Additional studies using ensembles of random fitness landscapes show that the results achieved for a particular choice of three-locus landscape parameters are robust and also persist as the number of loci increases. Our study indicates that an advantage for small populations is likely whenever the fitness landscape contains local maxima. The advantage appears at intermediate time scales, which are long enough for trapping at local fitness maxima to have occurred but too short for peak escape by the creation of multiple mutants.


Democracy and power in alcohol premises licensing: A qualitative interview study of the Scottish public health objective.
There is international interest in how the availability of alcohol can be controlled to reduce harms. An objective of 'protecting and improving public health' was introduced to alcohol premises licensing in Scotland in 2005, resulting in public health actors engaging with licensing in new ways. We aimed to explore their experiences, including perceptions of the distribution of power, and constraints on their influence and that of the general public within the licensing system. In-depth, semi-structured interviews were conducted with 13 public health actors who had recent and extensive experience of involvement in local licensing in 20 Scottish licensing jurisdictions. Interviews were audio-recorded and analysed using an inductive framework approach. Public health actors reported experiencing the licensing process as inherently unfair, with structures and traditions that were largely unhelpful to their efforts to support the public health objective. These included influence exerted by local officials, the formal and quasi-judicial conduct of licensing meetings, and the disparity in resources available to public health actors versus licence applicants-with many larger applicants engaging specialist lawyers to represent their interests. The influence of public opinion-through, for instance, elected representatives' perceptions of public attitudes, consultation exercises and local 'licensing forums'-was seen as having a limited effect on decision-making. Changes to Scottish alcohol licensing ostensibly designed to enhance democratic engagement and promote public health, were as yet insufficient to change the system, or empower stakeholders, to fully achieve those goals.


Sacituzumab Govitecan as a Second-Line Treatment in Relapsed/Refractory Metastatic Triple-Negative Breast Cancer Patients: A Systematic Review and Meta-analysis.
Chemotherapy, the only treatment option for metastatic triple-negative breast cancer (mTNBC), showed decreased survival rates. Trophoblast cell surface antigen-2 (Trop-2) could be a possible target for antibody-drug conjugates (ADCs). Sacituzumab govitecan (SG), an anti-Trop-2 ADC for pretreating relapsed/refractory mTNBC patients, was studied to know the efficacy and safety profile of the drug in mTNBC. The present review searched MEDLINE (via PubMed), WHO Clinical Trial Registry, Clinical Trials.gov, and Cochrane Central Register of Controlled Trials until December 25, 2022. The studies searched comprised randomized trials and observational studies (retrospective [case-control, cross-sectional] and prospective [cohort designs]). Efficacy assessment was performed in terms of complete response (CR), partial response (PR), objective response rate (ORR), stable disease (SD), progressive disease (PD), and clinical benefit rate (CBR), and safety in terms of adverse events. The overall random-effects pooled prevalence of CR was 4.9 (95% CI: 3.2-7.1), PR was 35.6 (95% CI: 31.5-39.9), ORR was 6.8 (95% CI: 5.9-7.8), SD was 8.0 (95% CI: 6.7-9.4), PD was 5.1 (95% CI: 4.1-6.3), and CBR was 13.4 (95% CI: 11.8-15.1). Adverse events associated with the drug were neutropenia, fatigue, anemia, nausea, and others. This is the first meta-analysis conducted in relapsed/refractory mTNBC patients and found that SG is efficacious but associated with some adverse effects that are related to exposure to the drug. The application of these results will allow clinicians to use SG in the management of patients with mTNBC.


Intraspecific polymorphism of ribosomal DNA loci number and morphology in Brachypodium pinnatum and Brachypodium sylvaticum.
The genus Brachypodium has become the target of extensive cytomolecular studies since one of its representatives, B. distachyon, has been accepted as a model plant for temperate cereals and forage grasses. Recent preliminary studies suggested that intraspecific rDNA polymorphism can occur in at least two members of the genus, B. sylvaticum and B. pinnatum, so the aim of this study was to further analyse this phenomenon. FISH with 25S rDNA and 5S rDNA probes was performed on somatic metaphase chromosomes, supplemented by the silver staining technique which distinguishes transcriptionally active from inactive 18S-5.8S-25S rDNA loci. The number, size and chromosomal distribution of 5S rDNA loci were very constant: two loci were invariably observed in all studied diploid accessions of both species, while four 5S rDNA loci were present in the tetraploid B. pinnatum. In contrast to 5S rDNA loci, those of the 35S rDNA were more variable. Two or three loci were observed in the diploid B. pinnatum and four in tetraploid accessions. In chromosome complements of B. sylvaticum accessions from two to six 35S rDNA sites were detected. Regardless of total rDNA locus number, only two were transcriptionally active in diploid accessions of both species, while two or four were active in the tetraploid B. pinnatum. Additionally, the fluorescent CMA/DAPI banding method was used to identify the relation between rDNA sites and CMA+ bands. It was revealed that the number and chromosomal distribution of CMA+ bands are in congruence only with 35S rDNA loci which gave strong FISH signals.


Screening for micro-albuminuria with Micro-Bumintest tablets and albumin/creatinine ratio.
The value of Micro-Bumintest tablets and the albumin/creatinine ratio in first morning (FM) urine samples to screen for micro-albuminuria in diabetic patients was evaluated. The A/C ratio in FM urine was highly correlated with the urinary albumin excretion (UAE) rate in micrograms/min in timed overnight (0) urine (R = 0.95, p < 0.001). The sensitivity, specificity and positive and negative predictive values of an A/C ratio > 3.0 to predict micro-albuminuria defined as an UAE > 20 micrograms/min were 94, 92, 92 and 94% respectively. The day-to-day fluctuation of albumin excretion varied between 10 and 105%. The sensitivity, specificity and positive and negative predictive values of micro-bumintest tablet reactions on FM urine samples to predict an A/C ratio > 3.0 were 93, 59, 63 and 91% respectively. It is concluded that for screening of micro-albuminuria the A/C ratio in FM urine is as precise as timed 0 urine collection, but with more comfort for the patient. Micro-Bumintest tablets are useful as an initial screening test and will decrease the number of quantitative albumin measurements in the screening programme by about 30% if only urine samples with positive tablet test are selected for a further investigation. Because of considerable day-to-day fluctuation of urinary albumin excretion several urine samples should be investigated before presence of incipient diabetic nephropathy is assumed.


A self-coupling multi-port microcoil resonator.
A new type of self-coupling multi-port microcoil resonator using a microfiber coupler is presented. The microresonators, a simple combination of a microfiber coupler and microcoil resonator, were fabricated by coiling a four port microfiber coupler around a low index support rod to induce optical resonance via coupling between adjacent turns. Light propagates along the coil whilst the beating between the supermodes of the coupler is still present, giving an increased extinction ratio and an output spectrum strongly dependent on the microfiber coupler diameter. The multiport microcoil resonator was embedded in a low refractive index polymer to improve its robustness and the polarization dependence was further analyzed.


CD49b Targeting Inhibits Tumor Growth and Boosts Anti-tumor Immunity.
The suppressive function of T-regulatory cells (Tregs) can have a detrimental effect on immune responses against tumor cells. Within the Treg cells subset, a new non-classical population has been reported, which expresses high levels of CD49b molecule and, depending on their activation status, can also express the canonical Tregs transcription factor Foxp3. In this report, we sought to characterize Tregs subsets in a murine melanoma model and disrupt the CD49b/CD29 axis by administering an anti-CD29 antibody in tumor-bearing mice. Our data shows that whereas in the draining lymph nodes, the Tr1 cells subset composes <5% of CD4+ T cells, in the tumor, they reach ∼30% of CD4+ T cells. Furthermore, Tr1 cells share the expression of suppressive molecules, such as Nrp-1, PD-1, and CD73, which are highly expressed on Tr1 cells found in tumor-infiltrating leukocytes (TILs). Regardless of the phenotypic similarities with cTreg cells, Tr1 cells display a low proliferative activity, as shown in the kinetics and the incorporation of 5-bromodeoxyuridine (BrdU) experiments. With the intent to impact on Tr1 cells, we administered anti-CD29 antibody into tumor mice, observing that the treatment effectively inhibits tumor growth. This effect is at least mediated by the enrichment of pro-inflammatory T cells, including IFN-γ+ cTreg and IFN-γ+ Tr1 cells (with reduced expression of IL-10), plus Th1 and Tc cells. In this study, we present Tr1 cell characterization in tumor-bearing animals and introduce CD29 as a target for tumor therapy, supported by a meta-analysis indicating that CD29 is present in human biopsies.


Caffeic acid attenuates lipopolysaccharide-induced sickness behaviour and neuroinflammation in mice.
Accumulating data links inflammation, oxidative stress and immune system in the pathophysiology of major depressive disorders. Sickness behaviour is a set of behavioural changes that develop during infection, eventually leading to decrease in mobility and depressed behaviour. Lipopolysaccharide (LPS) induces a depression-like state in animals that mimics sickness behaviour. Caffeic acid, a naturally occurring polyphenol, possesses antioxidant and anti-inflammatory properties. The present study was designed to explore the potential of caffeic acid against LPS-induced sickness behaviour in mice. Caffeic acid (30mg/kg) and imipramine (15mg/kg) were administered orally one hour prior to LPS (1.5mg/kg) challenge. Behavioural assessment was carried out between 1 and 2h and blood samples were collected at 3h post-LPS injection. Additionally, cytokines (brain and serum) and brain oxidative stress markers were estimated. LPS increased the systemic and brain cytokine levels, altered the anti-oxidant defence and produced key signs of sickness behaviour in animals. Caffeic acid treatment significantly reduced the LPS-induced changes, including reduced expression of inflammatory markers in serum and whole brain. Caffeic acid also exerted an anti-oxidant effect, which was evident from the decreased levels of oxidative stress markers in whole brain. Our data suggests that caffeic acid can prevent the neuroinflammation-induced acute and probably the long term neurodegenerative changes.


Comparative analysis of the five major Erwinia chrysanthemi pectate lyases: enzyme characteristics and potential inhibitors.
In Erwinia chrysanthemi 3937, pectate lyase activity mainly results from the cumulative action of five major isoenzymes, PelA to PelE. Comparison of their amino acid sequences revealed two families, PelB-C and PelA-D-E. Molecular cloning permitted expression of the different pel genes in Escherichia coli and the isolation of each Pel independently from the other isoenzymes. We used similar experimental conditions to overproduce and purify the five Pels in a one-step chromatography method. We analyzed some of the basic enzymatic properties of these five isoenzymes. PelA has a low specific activity compared to the other four enzymes. PelB and PelC have a high affinity for their substrate: about 10-fold higher than the enzymes of the PelA-D-E group. The optimum pH is more alkaline for PelB and PelC (about 9.2) than for PelA, PelD, and PelE (from 8 to 8.8). Below pH 7, activity was negligible for PelB and PelC, while PelA, PelD, and PelE retained 25 to 30% of their activities. The temperature optima were determined to be 50 degrees C for PelD and PelE, 55 degrees C for PelA, and 60 degrees C for PelB and PelC. Enzymes of the PelB-C group are more stable than those of the PelA-D-E group. Use of substrates presenting various degrees of methylation revealed that PelA, PelD, and PelE are active only for very low levels of methylation, while PelB and PelC are more active on partially methylated pectins (up to 22% for PelC and up to 45% for PelB). Pectate lyases have an absolute requirement for Ca2+ ions. For the five isoenzymes, maximal activity was obtained at a Ca2+ concentration of 0.1 mM. None of the tested cations (Ba2+, Co2+, Cu2+, Mg2+, Mn2+, Sr2+, Zn2+) can substitute for Ca2+. At a high concentration (1 mM), most of the divalent cations inhibited pectate lyase activity. In addition, we demonstrated that two compounds present in plant tissues, epicatechin and salicylic acid, inhibit the pectate lyases at a concentration of 0.2 mM.


Lost in Translation? Finding Our Way To Effective Alzheimer's Disease Therapies.
Efforts over the past two decades to develop effective disease-modifying treatments for Alzheimer's disease have been disappointing, while parallel efforts in another chronic neurologic disease, multiple sclerosis, have been remarkably productive. In an effort to advance development of therapeutics for Alzheimer's disease, these two fields are contrasted in terms of the utility of animal models, definition of study populations, and utility of biomarkers. Possible solutions are suggested, and the review concludes with description of some active peer-reviewed, publicly funded clinical studies which address some of the identified weaknesses in past clinical trials for age-related dementia.


Scanning Kelvin nanoprobe detection in materials science and biochemical analysis.
The Kelvin nanoprobe is an extremely sensitive instrument capable of discerning subtle molecular interactions using vibrating electromagnetic and acoustic fields. It is based on the measurement of a fundamental material property, the work function. Modulation of this substrate parameter is caused by the adsorption or desorption of molecules, oxidation, corrosion, contamination, mechanical stress, illumination, temperature changes, electrostatic charging, surface treatment, attached dipolar structures and/or the immobilization of biomolecules. The present article explains the general principles of the method and offers an indication of the wide range of possible applications, with an emphasis on potential use in the biotechnological arena.


Quantum dynamics of light-driven chiral molecular motors.
The results of theoretical studies on quantum dynamics of light-driven molecular motors with internal rotation are presented. Characteristic features of chiral motors driven by a non-helical, linearly polarized electric field of light are explained on the basis of symmetry argument. The rotational potential of the chiral motor is characterized by a ratchet form. The asymmetric potential determines the directional motion: the rotational direction is toward the gentle slope of the asymmetric potential. This direction is called the intuitive direction. To confirm the unidirectional rotational motion, results of quantum dynamical calculations of randomly-oriented molecular motors are presented. A theoretical design of the smallest light-driven molecular machine is presented. The smallest chiral molecular machine has an optically driven engine and a running propeller on its body. The mechanisms of transmission of driving forces from the engine to the propeller are elucidated by using a quantum dynamical treatment. The results provide a principle for control of optically-driven molecular bevel gears. Temperature effects are discussed using the density operator formalism. An effective method for ultrafast control of rotational motions in any desired direction is presented with the help of a quantum control theory. In this method, visible or UV light pulses are applied to drive the motor via an electronic excited state. A method for driving a large molecular motor consisting of an aromatic hydrocarbon is presented. The molecular motor is operated by interactions between the induced dipole of the molecular motor and the electric field of light pulses.


Evaluation of Anthelmintic Activity and Composition of Pumpkin (Cucurbita pepo L.) Seed Extracts-In Vitro and in Vivo Studies.
A significant number of studies report growing resistance in nematodes thriving in both humans and livestock. This study was conducted to evaluate the in vitro and in vivo anthelmintic efficiency of Curcubita pepo (C. pepo) L. hot water extract (HWE), cold water extract (CWE) or ethanol extract (ETE) on two model nematodes: Caenorhabditis elegans (C. elegans) and Heligmosoides bakeri (H. bakeri). Raman, IR and LC-MS spectroscopy analyses were performed on the studied plant material to deliver qualitative and quantitative data on the composition of the obtained extracts: ETE, HWE and CWE. The in vitro activity evaluation showed an impact of C. pepo extracts on C. elegans and different developmental stages of H. bakeri. The following in vivo experiments on mice infected with H. bakeri confirmed inhibitory properties of the most active pumpkin extract selected by the in vitro study. All of the extracts were found to contain cucurbitine, aminoacids, fatty acids, and-for the first time-berberine and palmatine were identified. All C. pepo seed extracts exhibited a nematidicidal potential in vitro, affecting the survival of L1 and L2 H. bakeri larvae. The ETE was the strongest and demonstrated a positive effect on H. bakeri eggs hatching and marked inhibitory properties against worm motility, compared to a PBS control. No significant effects of pumpkin seed extracts on C. elegans integrity or motility were found. The EtOH extract in the in vivo studies showed anthelmintic properties against both H. bakeri fecal egg counts and adult worm burdens. The highest egg counts reduction was observed for the 8 g/kg dose (IC50 against H. bakeri = 2.43; 95% Cl = 2.01-2.94). A decrease in faecal egg counts (FEC) was accompanied by a significant reduction in worm burden of the treated mice compared to the control group. Pumpkin seed extracts may be used to control of Gastrointestinal (G.I.) nematode infections. This relatively inexpensive alternative to the currently available chemotherapeutic should be considered as a novel drug candidate in the nearest future.


Dynamics of spinning particle pairs in a single-layer complex plasma crystal.
Spontaneous formation of spinning pairs of particles, or torsions, is studied in a single-layer complex plasma crystal by reducing the discharge power at constant neutral gas pressure. At higher gas pressures, torsions spontaneously form below a certain power threshold. Further reduction of the discharge power leads to the formation of multiple torsions. However, at lower gas pressures the torsion formation is preceded by mode-coupling instability (MCI). The crystal dynamics are studied with the help of the fluctuation spectra of crystal particles' in-plane velocities. Surprisingly, the spectra of the crystal with torsions and MCI are rather similar and contain hot spots at similar locations on the (k,ω) plane, despite very different appearances of the respective particle trajectories. The torsion rotation speed is close (slightly below) to the maximum frequency of the in-plane compressional mode. When multiple torsions form, their rotation speeds are distributed in a narrow range slightly below the maximum frequency.