Hypericin, a potential new BH3 mimetic.
Many types of cancer such as prostate cancer, myeloid leukemia, breast cancer, glioblastoma display strong chemo resistance, which is supported by enhanced expression of multiple anti-apoptotic Bcl-2, Bcl-XL and Mcl-1 proteins. The viable anti-cancer strategies are based on developing anti-apoptotic Bcl-2 proteins inhibitors, BH3 mimetics. Our focus in past years has been on the investigating a new potential BH3 mimetic, Hypericin (Hyp). Hyp is a naturally occurring photosensitive compound used in photodynamic therapy and diagnosis. We have demonstrated that Hyp can cause substantial effects in cellular ultrastructure, mitochondria function and metabolism, and distribution of Bcl2 proteins in malignant and non-malignant cells. One of the possible mechanisms of Hyp action could be the direct interactions between Bcl-2 proteins and Hyp. We investigated this assumption by in silico computer modelling and in vitro fluorescent spectroscopy experiments with the small Bcl2 peptide segments designed to correspond to Bcl2 BH3 and BH1 domains. We show here that Hyp interacts with BH3 and BH1 peptides in concentration dependent manner, and shows the stronger interactions than known BH3 mimetics, Gossypol (Goss) and ABT-263. In addition, interactions of Hyp, Goss and ABT263, with whole purified proteins Bcl-2 and Mcl-1 by fluorescence spectroscopy show that Hyp interacts stronger with the Bcl-2 and less with Mcl-1 protein than Goss or ABT-263. This suggest that Hyp is comparable to other BH3 mimetics and could be explore as such. Hyp cytotoxicity was low in human U87 MG glioma, similar to that of ABT263, where Goss exerted sufficient cytotoxicity, suggesting that Hyp acts primarily on Bcl-2, but not on Mcl-1 protein. In combination therapy, low doses of Hyp with Goss effectively decreased U87 MG viability, suggesting a possible synergy effect. Overall, we can conclude that Hyp as BH3 mimetic acts primarily on Bcl-2 protein and can be explored to target cells with Bcl-2 over-expression, or in combination with other BH3 mimetics, that target Mcl-1 or Bcl-XL proteins, in dual therapy.


Evaluation of Associations of Alzheimer's Disease Risk Variants that Are Highly Expressed in Microglia with Neuropathological Outcome Measures.
A number of Alzheimer's disease (AD) susceptibility loci are expressed abundantly in microglia. We examined associations between AD risk variants in genes that are highly expressed in microglia and neuropathological outcomes, including cerebral amyloid angiopathy (CAA) and microglial activation, in 93 AD patients. We observed significant associations of CAA pathology with APOEɛ4 and PTK2B rs28834970. Nominally significant associations with measures of microglial activation in white matter were observed for variants in PTK2B, PICALM, and CR1. Our findings suggest that several AD risk variants may also function as disease modifiers through amyloid-β metabolism and white matter microglial activity.


Design of a local bump feedback system for a variably polarizing undulator.
A local bump feedback system is under construction to correct the orbit distortion caused by the magnetic field errors of a double-array undulator used to generate linear and circular polarization of light for a soft X-ray beamline. The local bump orbit is created by steering coils several turns long and four sets of steering magnets. The kick angle of the long steering coils and the steering magnets is determined according to the motion of the undulator and by detecting the beam position.


Karyometric marker features in fine needle aspirates of invasive follicular carcinoma of the thyroid.
Karyometric measurements were performed on fine needle aspirates of clearly identifiable tumor areas and adjacent normal-appearing areas in the surgical specimens from ten patients with invasive follicular carcinoma of the thyroid. Similar measurements were performed on aspirates from nine patients free of thyroid disease (controls). A total of 95 karyometric features were evaluated for each nucleus. Analysis of variance of optical density values indicated (1) a similarity between tumor and normal-appearing nuclei from carcinoma cases, (2) a significant difference between those nuclei and control nuclei and (3) that most of the differences were due to the differences of tissue origin. Stepwise linear discriminant analysis selected ten features that produced a statistically highly significant separation of tumor nuclei from control nuclei. A similar analysis selected six features that produced a statistically highly significant discrimination of normal-appearing nuclei from control nuclei; the validity of those karyometric features as markers of malignancy in normal-appearing nuclei from tissues adjacent to invasive follicular carcinomas of the thyroid was demonstrated by analysis in further training and control sets of nuclei. This analysis in thyroid aspirates identified more marker features than did a previous similar analysis using tissue sections.


Estrogenic Effects of the Extracts from the Chinese Yam (Dioscorea opposite Thunb.) and Its Effective Compounds in Vitro and in Vivo.
The aim of this study was to explore the estrogenic effects of the extracts from Chinese yam and its effective compounds. The activity of the yam was investigated by the uterine weight gain of mice and a proliferation assay of breast cancer cell lines (MCF-7 cell); the estrogenic activity was comprehensively evaluated by a serum pharmacology experiment. The levels of estradiol (E2), follicle stimulating hormone (FSH), and luteinizing hormone (LH) were also measured. Western blot analysis and antagonist assays with faslodex (ICI182,780), methylpiperidino-pyrazole (MPP), Delta (9) -tetrahydrocannabinol (THC), and G-15 were used to explore the mechanism of the effects of the yam. To find the effective compounds of the yam which play a role in its estrogen-like effects, we used the same methods to study the effects of adenosine and arbutin. The Chinese yam and two main compounds, adenosine and arbutin, have estrogen-like effects. The mechanism of the yam which plays a role in its estrogen-like effects was mainly mediated by the estrogen receptors ERα, ERβ, and GPR30; that of adenosine was mainly mediated by estrogen receptors ERα and ERβ, and that of arbutin was mainly mediated by estrogen receptors ERβ and GPR30. The Chinese yam has estrogen-like effects; adenosine and arbutin are two of the effective compounds in the yam which play a role in its estrogen-like effects.


Enhanced excitability compensates for high-pressure-induced depression of cortical inputs to the hippocampus.
High pressure (>1.0 MPa) induces the high-pressure neurological syndrome (HPNS) characterized by increased excitability of the CNS and cognitive impairments involving memory disorders. The perforant-path transfer of cortical information to the hippocampal formation is important for memory acquisition. High pressure may alter information transfer in this connection. We used rat corticohippocampal slices for studying the effect of pressure on the transfer function between synaptic inputs from the medial perforant path (MPP) and spike generation by granule cells (GC) of the dentate gyrus. High pressure (10.1 MPa) reduced single MPP field excitatory postsynaptic potential (fEPSP) amplitude and slope by nearly 50%. Field antidromic action potentials (AAPs) elicited by stimulation of GC axons, and population spike (PS) generation by the pressure-depressed MPP fEPSP were not significantly altered at hyperbaric conditions. Nevertheless the relationship PS/fEPSP increased at high pressure, indicating dendritic hyperexcitability in the GC. PSs elicited by paired-pulse MPP fEPSPs at 10- to 200-ms interstimulus intervals and PS generated by trains of five fEPSPs at 25 Hz were also not affected in spite of severe pressure-induced synaptic depression. Similarly, trains of AAPs at 25-50 Hz were not significantly changed. Trains of fEPSPs at higher frequency (50 Hz), however, induced additional spikes at high pressure, indicating pressure disruption of the regular low-pass filter properties of the DG. Such effect was closely mimicked by partial blockade of GABAA inhibition. High pressure depresses synaptic activity while increases excitability in the neuronal dendrites but not in the axons. This mechanism, allowing neuronal communication at low input signals, may partially cope with pressure effects at the low frequency range (<25 Hz) but losses reliability at higher frequencies (>50 Hz).


Treatment in idiopathic thrombocytopenic purpura in the elderly: about a retrospective study.
There are no specific recommendations on the care of elderly patients with ITP. A retrospective study over two academic centers (Reims and Strasbourg), focused on patients over 65 who have been diagnosed idiopathic thrombocytopenic purpura in two unit of internal medicine. 41 patients were enrolled, including 27 women (66%). The median age is 76.75 years. On admission, the average thrombocytopenia is 34.45 G/L; 24 patients (58.5%) showed severe bleeding mucosal and/or visceral signs; 37 patients (90%) had a first-line treatment. Corticosteroids established for 23 patients (56%). At 1 and 6 months, complete response was 9 patients (39%) and 2 patients (9%) respectively. Adverse events reported for 20 patients (87%). Polyvalent immunoglobulins were used for 6 (16%) with no response at 6 months. 5 patients were treated with danazol. At 6 months, partial response in 3 patients (60%) and failure in 2 patients (40%). Splenectomy was performed for 8 patients (21%). At 1 month, a complete response observed for 7 patients. At 6 months, a failure observed in 4 patients. After failure of first-line treatments, we noted the use of rituximab for 4 patients (9.7%) with a complete response for 1 patient, partial response in 2 patients and a failure for a patient for whom the "eltrombopag" was set up with a partially response. Monitoring of 41 patients, during 7 years, objectified 3 deaths. The clinical presentation of idiopathic thrombocytopenic purpura in the elderly seems more severe. Therapeutic responses are essentially identical to those observed in younger patients, but greater toxicity. Data on biologics is nonexistent in elderly outside small retrospective series. Studies are underway to better assess their effectiveness, long-term safety as well as their mechanism of action.


[Effect of a deficiency in the mononuclear phagocyte system and the administration of yeast polysaccharide on the development of a heterotopic source of hematopoiesis].
Mononuclear phagocyte system (MPS) deficiency was induced by repeated peritoneal lavage in (C57Bl x CBA) F1 mice. The animals were then used as donors or recipients in heterotopic bone marrow transplantation. Yeast polysaccharide (YP) produced by Cryptococcus luteolus strain 228 was injected weekly (25 mg/kg) during 30 days after bone marrow transplantation under the kidney capsule. Bone marrow transplantation from MPC-deficient mice to intact mice 30 days later resulted in no variations from the control in cellularity and ossicle weight. YP produced an increase in cellularity, but not in ossicle weight. In the opposite experimental scheme (transplantation from intact mice to MPS-deficient mice) an increase in both cellularity and weight was not noticed. YP injections in this case resulted in the reduction of heterotopic organ size to the control level. Possible mechanisms of this phenomenon are discussed.


The versatile roles of CARDs in regulating apoptosis, inflammation, and NF-κB signaling.
CARD subfamily is the second largest subfamily in the DD superfamily that plays important roles in regulating various signaling pathways, including but not limited to NF-kB activation signaling, apoptosis signaling and inflammatory signaling. The CARD subfamily contains 33 human CARD-containing proteins, regulating the assembly of many signaling complexes, including apoptosome, inflammsome, nodosome, the CBM complex, PIDDosome, the TRAF2 complex, and the MAVS signalosome, by homotypic CARD-CARD interactions. The mechanism of how CARDs find the right binding partner to form a specific complex remains unclear. This review uses different classification schemes to update the classification of CARD-containing proteins. Combining the classification based on domain structures, functions, associated signaling complexes, and roles would help better understand the structural and function diversity of CARD-containing proteins. This review also summarizes recent structural studies on CARDs. Especially, the CARD-containing complexes can be divided into the homodimeric, heterodimeric, oligomeric, filamentous CARD complexes and the CARD-ubiquitin complex. This review will give an overview of the versatile roles of CARDs in regulating signaling transduction, as well as the therapeutic drugs targeting CARD-containing proteins.


The Effects of Group Play Therapy on Self-Concept Among 7 to 11 Year-Old Children Suffering From Thalassemia Major.
Children suffering from thalassemia have higher levels of depression and lower levels of self-concept. The aim of this study was to determine if group play therapy could significantly increase self-concept among children with thalassemia major ages 7 to 11 years old in teaching hospitals of Golestan province, Iran, in 2012. In this randomized, controlled clinical trial, 60 children with thalassemia major were randomly assigned to intervention (30 children) and control (30 children) groups. The intervention included eight 45 to 60 minute sessions during four weeks, during which the intervention group received group play therapy. The control group received no interventions. Self-concept was measured three times using the Piers-Harris children's self-concept scale: before, immediately after, and a month after the intervention. For the intervention group, results showed that the mean self-concept score was significantly higher at the second point in time compared to the baseline (P < 0.001), going from 60.539 to 69.908. Likewise, comparing the first and third time points, the mean score significantly increased and reached 70.611 (P < 0.001). Furthermore, changes in the mean score from the second to the third time point, though non-significant (P = 0.509), followed the trend, going from 69.908 to 70.611. For the control group, comparing the first, second, and third time points did not result in any significant change in the mean score (P > 0.05). The results showed that group play therapy improves self-concept in children suffering from thalassemia major.


Design and preclinical testing of an anti-CD41 CAR T cell for the treatment of acute megakaryoblastic leukaemia.
Acute megakaryoblastic leukaemia (AMkL) is a rare subtype of acute myeloid leukaemia (AML) representing 5% of all reported cases, and frequently diagnosed in children with Down syndrome. Patients diagnosed with AMkL have low overall survival and have poor outcome to treatment, thus novel therapies such as CAR T cell therapy could represent an alternative in treating AMkL. We investigated the effect of a new CAR T cell which targets CD41, a specific surface antigen for M7-AMkL, against an in vitro model for AMkL, DAMI Luc2 cell line. The performed flow cytometry evaluation highlighted a percentage of 93.8% CAR T cells eGFP-positive and a limited acute effect on lowering the target cell population. However, the interaction between effector and target (E:T) cells, at a low ratio, lowered the cell membrane integrity, and reduced the M7-AMkL cell population after 24 h of co-culture, while the cytotoxic effect was not significant in groups with higher E:T ratio. Our findings suggest that the anti-CD41 CAR T cells are efficient for a limited time spawn and the cytotoxic effect is visible in all experimental groups with low E:T ratio.


Isoprostane measurement in plasma and urine by liquid chromatography-mass spectrometry with one-step sample preparation.
Isoprostane F(2alpha) (iPF(2alpha)-III) concentration in plasma and urine is widely accepted as a measure of oxidative stress. Gas chromatography-mass spectrometry (GC/MS) methods for measuring iPF(2alpha)-III involve several steps of sample preparation and are labor-intensive, and ELISA methods, although easier to use, are less reliable. Therefore we developed a simple and sensitive method involving 1-step sample cleanup and HPLC/MS quantification. Samples of plasma or urine were enriched with a deuterated (iPF(2alpha)-III-D4) standard, treated with KOH to liberate the bound isoprostanes, then loaded onto an immunoaffinity column, and the bound isoprostane was eluted with 95% ethanol. The concentrated sample was injected onto a C-18 HPLC column, and the isoprostane was eluted with a gradient of acetonitrile in water and analyzed by electrospray negative ionization, selectively monitoring the ions 353.2 (iPF(2alpha)-III) and 357.2 (iPF(2alpha)-III-D4). The amount of isoprostane in the sample was calculated from the ratio of the intensities of the 2 ions. The described method has a detection limit of 0.5 ng/L, with a linear dynamic range of 1-5000 ng/L. The intra- and interassay imprecisions were 4.68% and 3.88%, respectively. The values obtained correlated strongly with the GC/MS procedure (r = 0.80), but the absolute values were approximately 4- to 5-fold lower, because the present method measures specifically 1 isomer of isoprostane, whereas the GC/MS method measures 4 isomers together. Because of its simplicity and lower limit of quantification, the present method provides a useful noninvasive tool for determining oxidative stress in patients.


Integrative dynamic therapy for bulimia nervosa: An evidence-based case study.
Both cognitive-behavioral therapy (CBT) and psychodynamic psychotherapy are commonly used to treat eating disorders. To further investigate the effectiveness of integrative dynamic therapy (IDT) for bulimia nervosa (BN), our research group undertook a randomized, controlled pilot study comparing IDT with CBT for BN. The case described here was selected from a sample of N = 38 female patients with the symptoms of BN who enrolled in the study. IDT incorporated aspects of the first 4-week stage of CBT, including psychoeducation, self-monitoring, and regular eating. Subsequently, the treatment focused on emotional expression, emotion regulation (defenses), intrapsychic conflict, and interpersonal relationships. The objectives of the report are to demonstrate the effectiveness of an integrative approach to the treatment of eating disorders to address the symptoms of BN and personality issues using pre-, mid-, and posttreatment data, and to illustrate the patient and clinician reactions to each approach to treatment using excerpts from session transcripts and alliance data. (PsycINFO Database Record


Construct validity of a Physical Work Environment Satisfaction Questionnaire.
Many theories of behavior at work fail to consider the effects of the physical environment on employees' behavior and attitudes. The purpose of this research was to gather evidence of the construct validity of the Physical Work Environment Satisfaction Questionnaire (PWESQ) and of the validity of the physical work environment satisfaction construct. Evidence of the construct validity of the PWESQ was sought through its administration, along with a number of established measures of work attitudes, to 641 employees in 8 organizations. The data provided evidence of the validity of both the physical work environment satisfaction construct and the PWESQ as a valid measure of that construct. Practical and theoretical implications, as well as implications for future research, are discussed.


The practice of emergency medicine in Fukuoka City Hospital, a secondary emergency facility in Japan.
The transition of emergency departments and the current situation of emergency medicine (EM) in Fukuoka City Hospital (FCH) were reviewed. The data concerning emergency medicine, such as the transition of intra-hospital emergency systems, were obtained from annual reports published in our hospital. Additionally, the data regarding educational programs for emergency room staff, the number of patients taken to the emergency room by ambulances, the activities regarding the Fukuoka Medical Rally (FMR) and the disaster relief team (DRT) were also reviewed and analyzed. Departments of neurology, neurosurgery, emergency, and cardiology were opened sequentially, starting in 2003, with an establishment of facilities of an emergency room (ER), intensive care unit (ICU), stroke care unit (SCU), and coronary care unit (CCU). Regarding educational programs, lectures and demonstrations on basic and advanced life support techniques were given to all staff annually starting in 2004, and resident doctors completed rotations in the ER and the ICU for three months. FCH staff consistently obtained excellent results at the FMR. Ambulance crews attended lectures and received training on EM and intra-tracheal intubation. The numbers of patients taken by ambulance to FCH increased from 129 in 2002 to 2,316 in 2011. The DRT was dispatched to respond to disasters that occurred in Japan. As a secondary emergency hospital, FCH has developed a system to accept emergency patients. This project will contribute to the improvement of the EM system in the area.


Implementing a residency program for the acute care nurse practitioner.
A clinical residency program for acute care nurse practitioners (ACNPs) was developed to facilitate the strengthening of practice competencies and role performance. Strengthening collaboration between physicians and ACNPs and supporting the growth of ACNPs through supportive and individualized learning opportunities were key components to a highly successful initiative.


Scaling hypothesis leading to generalized extended self-similarity in turbulence.
A scaling hypothesis leading to generalized extended self-similarity (GESS) for velocity structure functions, valid for intermediate scales in isotropic, homogeneous turbulence, is proposed. By introducing an effective scale ŕ, monotonically depending on the physical scale r, with the use of the large deviation theory, the asymptotic forms of the probability densities for the velocity differences u(r) and for the coarse-grained energy-dissipation rate fluctuations epsilon(r), compatible with this GESS, are proposed. The probability density for epsilon(r) is shown to have the form P(r)(epsilon) approximately equal to epsilon(-1)(ŕ/L)(S(ŕ)[z(ŕ)](epsilon))) with z(ŕ)(epsilon)=ln(epsilon/epsilon(L))/ln(L/ŕ), where L and epsilon(L) are the stirring scale and the coarse-grained energy-dissipation rate over the scale L. The concave function S(ŕ)(z), the spectrum, plays the central role of the present approach. Comparing the results with numerical and experimental data, we explicitly obtain the fluctuation spectra S(ŕ)(z).


Evaluation of sorafenib in Chinese unresectable hepatocellular carcinoma patients with prior surgery and portal vein tumor thrombosis: A subset analysis of GIDEON study data.
The purpose of this study was to examine the safety and efficacy of sorafenib in Chinese patients with unresectable hepatocellular carcinoma. Data of 338 Chinese patients from the Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib study database were included. Patients were divided into those who received and did not receive sorafenib prior to surgical resection and those with and without portal vein tumor thrombosis. In the non-surgery group, the median survival was 302 days (95% confidence interval: 244-371), and the median time from diagnosis to death was 428 days (95% confidence interval: 352-556); in the surgery group, half of the patients survived for 345 days and the median time from diagnosis to death was 1000 days (95% confidence interval: 750-2816). Median progression-free survival and median time to progression were not different between the two groups. Median overall survival was 360 days (95% confidence interval: 309-435) in the non-portal vein tumor thrombosis group and 240 days (95% confidence interval: 181-296) in the portal vein tumor thrombosis group; median time between hepatocellular carcinoma diagnosis and death was 750 days (95% confidence interval: 472-1000) and 420 days (95% confidence interval: 252-567), respectively, in the two groups. Median progression-free survival was 209 days (95% confidence interval: 166-264) for patients without portal vein tumor thrombosis and 154 days (95% confidence interval: 112-202) for patients with portal vein tumor thrombosis; median time to progression was 295 days (95% confidence interval: 209-463) and 221 days, respectively. Adverse events were generally comparable regardless of prior surgery and portal vein tumor thrombosis status. We thus conclude that earlier administration of sorafenib may result in improved outcomes in patients with unresectable hepatocellular carcinoma and portal vein tumor thrombosis.


Low Ankle Sprains: A Current Review of Diagnosis and Treatment.
LLow ankle sprains are common injuries in young athletes. Hence, it is imperative that low ankle sprains are diagnosed and treated quickly and effectively. We reviewed the: (1) anatomy; (2) imaging; (3) physical exam findings; and (4) treatment modalities regarding these injuries. Plain radiographs are standard of care and routine MRI is not recommended for suspected sprains. However, physical exam findings often may guide management decisions. The majority of patients diagnosed with low ankle sprains are treated with a one- to two-week immobilization period with physical therapy focused on peroneal proprioception and strength. If a prolonged non-operative course fails, or there is gross instability upon physical exam (grade III sprain), surgical reconstruction may be considered and may lead to excellent outcomes. When low ankle sprains do occur, the great majority may be treated non-operatively. In the event that conservative modalities fail, surgical reconstruction may be considered with an open modified Brostrom reconstruction as the current standard of care.


Modal processing of Hartmann and Shack-Hartmann patterns by means of a least squares fitting of the transverse aberrations.
Instead of measuring the wavefront deformations, Hartmann and Shack-Hartmann tests measure wavefront slopes, which are equivalent to ray transverse aberrations. Numerous integration methods have been described in the literature to obtain the wavefront deformations from these measurements. Basically, they can be classified in two different categories, i.e., modal and zonal. Frequently, a least squares fit of the transverse aberrations in the x direction and a least squares fit of the transverse aberrations in the y direction is performed to obtain the wavefront. In this work, we briefly describe a modal method to integrate Hartmann and Shack-Hartmann patterns by means of a single least squares fit of the transverse aberrations simultaneously instead of the traditional x-y separate method. The proposed method uses monomial calculation instead of using Zernike polynomials, to simplify numerical calculations. Later, a method is proposed to convert from monomials to Zernike polynomials. An important obtained result is that if polar coordinates are used, angular transverse aberrations are not actually needed to obtain all wavefront coefficients.


Gene polymorphism of xenobiotic detoxification in children with bronchial asthma.
Children are the most susceptible to harmful external factors due to the incomplete development of all functional body systems. The ecological situation the problem of influence of genetic and environmental factors on the pathogenesis of chronic respiratory diseases in children and its investigation is very impotent today. Among it the bronchial asthma is a leader among bronchial and pulmonary diseases caused by the influence of pneumotropic pollutants. The aim of our research was to study the phenotypic characteristics of asthma in Pre-Carpathian children with different types of allelic gene polymorphism of the first phase of xenobiotic detoxification of microsomal epoxide hydrolases (mEPHX1). The phenotypic peculiarities of bronchial asthma in 94 children from Ivano-Frankivsk region with different types of allelic gene polymorphism of the first phase of xenobiotic detoxification - mEPXH1 have been investigated. The material of genetic investigations was DNA isolated from leukocytes of patients' peripheral blood. Isolation and purification of DNA was carried out using commercial kits DIAtom TM DNA Prep200, GenePak DNA PCR test (LLC "Laboratory IzoGen") according to the manufacturer's recommendations. The association between polymorphism of gene mEPXH1 and susceptibility to occurrence and severity of BA in children have been described. It has been established that the manifestation of asthma as eco-determined pathology is affected by individual types of metabolic activity of genes of xenobiotic detoxification. It has been proved that patients with uncontrolled asthma have genotypes CC and GG (p <0.05) much more often. Children with asthma often have high enzymatic activity of a gene mEPHX1 (polymorphic variants of AG and AA-TT-TT). A "slow" functional state of gene mEPHX1 corresponding to homo- and hetero-zygotes for the mutant alleles: СС-АА and ТС-АА is also a frequent phenomenon. It has been established that bronchial asthma as eco-determined pathology is affected by individual variants of metabolic activity of genes of xenobiotic detoxification.


Biologically effective doses in radiotherapy of cervical carcinoma*.
Presented study evaluates biologically effective dose (BED) in patients receiving low-medium dose-rate (LDR/MDR) brachytherapy (BRT) plus external beam radiotherapy (XRT) based on tumor cell proliferation values in cancer of the cervix patients. This study includes 229 patients treated entirely by radiotherapy at the Centre Oncology in Krakow. Doses to Point A were estimated for total treatment for each brachytherapy insertion. BED3 were calculated for reference points in the rectum. The linear quadratic equation was used to calculate BED, which is proportional to log cell kill, and the normalized total dose (NTD), that is, equivalent to a 2 Gy fraction schedule. In BEDs 10 calculation overall treatment time for each patient. Tumor proliferation rate was based on Bromodeoxyuridine labeling index (BrdUrdLI) assessed on biopsy material before beginning the radiotherapy. Total BED at those points was summed for each patient. The medium overall treatment time was 90 days (range 30--210). The mean calculated total BED for point A for tumour and "early reactions" was equal to 104.0 Gy10 and 229.0 Gy3 for the rectum, equivalent to NTD=86.6 Gy and 137.4 Gy in 2 Gy fractions, respectively. Kaplan-Meier analysis revealed that age >50 years, higher than mean BRBEDs and totBEDs doses, gaps in treatments shorter than 40 days and disease free survival (DFS) was significant prognostic factor for overall survival. In the multivariate Cox anaysis age >50 years, BRBED10 >77 Gy and gaps ?40 days appeared to be significant for overall survival. None of the examined parameters was significant for tumor control. However, patientś age and shorter gaps in the treatment were predictive for DFS.


Survival rates indicate that correlations between community-weighted mean traits and environments can be unreliable estimates of the adaptive value of traits.
Correlations between community-weighted mean (CWM) traits and environmental gradients are often assumed to quantify the adaptive value of traits. We tested this assumption by comparing these correlations with models of survival probability using 46 perennial species from long-term permanent plots in pine forests of Arizona. Survival was modelled as a function of trait × environment interactions, plant size, climatic variation and neighbourhood competition. The effect of traits on survival depended on the environmental conditions, but the two statistical approaches were inconsistent. For example, CWM-specific leaf area (SLA) and soil fertility were uncorrelated. However, survival was highest for species with low SLA in infertile soil, a result which agreed with expectations derived from the physiological trade-off underpinning leaf economic theory. CWM trait-environment relationships were unreliable estimates of how traits affected survival, and should only be used in predictive models when there is empirical support for an evolutionary trade-off that affects vital rates.


HIV-2 infection in hospitalized patients in Bissau, Guinea-Bissau.
During 11 months in 1989-1990, 1009 consecutive hospitalized adult patients admitted to the medical wards of the National Hospital in Bissau were interviewed, examined clinically, and tested for antibodies to HIV-1 and HIV-2. The prevalence of HIV-2 infection was 20.4% (206 out of 1009) and of HIV-2-associated AIDS 4.4% (44 out of 1009). HIV-2 infection was more frequent in women (25%, 110 out of 440) than in men (16.9%, 96 out of 569). HIV-1 infection was diagnosed in one patient only, and one patient (with AIDS) had reactivity to both HIV-1 and HIV-2. Among HIV-2-seropositive patients, AIDS was demonstrated in 21.3% and AIDS-related symptoms (not fulfilling the AIDS criteria) in 19.4%. The frequency of AIDS-associated symptoms was significantly higher in HIV-2-seropositive patients than in seronegative patients. The clinical profile of the HIV-2-associated AIDS cases was very similar to that described in HIV-1-associated AIDS cases in Africa. Seven out of 51 patients fulfilling the clinical criteria for AIDS were HIV-seronegative. The World Health Organization (WHO) clinical case definition for AIDS in Africa had a specificity of 99% and a positive predictive value of 86%. Tuberculosis was more common in HIV-2-seropositive patients (6.3%) than in HIV-2-seronegative patients (2.2%). A history of blood transfusion was a significant risk factor for HIV-2 infection. HIV-2 infection and AIDS are public health problems in Guinea-Bissau.


Risk factors of long term symptoms and outcomes among patients discharged after covid-19: prospective, multicentre observational study.
To investigate risk factors and subphenotypes associated with long term symptoms and outcomes after hospital admission for covid-19. Prospective, multicentre observational study. 93 hospitals in France. Data from 2187 adults admitted to hospital with covid-19 in France between 1 February 2020 and 30 June 2021. Primary endpoint was the total number of persistent symptoms at six months after hospital admission that were not present before admission. Outcomes examined at six months were persistent symptoms, Hospital Anxiety and Depression Scale, six minute walk test distances, 36-Item Short Form Health Survey scores, and ability to resume previous professional activities and self-care. Secondary endpoints included vital status at six months, and results of standardised quality-of-life scores. Additionally, an unsupervised consensus clustering algorithm was used to identify subphenotypes based on the severity of hospital course received by patients. 1109 (50.7%) of 2187 participants had at least one persistent symptom. Factors associated with an increased number of persistent symptoms were in-hospital supplemental oxygen (odds ratio 1.12, 95% confidence interval 1 to 1.24), no intensive care unit admission (1.15, 1.01 to 1.32), female sex (1.33, 1.22 to 1.45), gastrointestinal haemorrhage (1.51, 1.02 to 2.23), a thromboembolic event (1.66, 1.17 to 2.34), and congestive heart failure (1.76, 1.27 to 2.43). Three subphenotypes were identified: including patients with the least severe hospital course (based on ventilatory support requirements). Although Hospital Anxiety and Depression Scale scores were within normal values for all groups, patients of intermediate severity and more comorbidities had a higher median Hospital Anxiety and Depression Scale score than did the other subphenotypes. Patients in the subphenotype with most severe hospital course had worse short form-36 scores and were less able to resume their professional activity or care for themselves as before compared with other subphenotypes. Persistent symptoms after hospital admission were frequent, regardless of acute covid-19 severity. However, patients in more severe subphenotypes had a significantly worse functional status and were less likely to resume their professional activity or able to take care of themselves as before. NCT04262921.


Interaction of spatially separated protein-DNA complexes for control of gene expression: operator conversions.
Two operators, spatially separated from each other and from the promoters, repress the gal operon when bound to Gal repressor. Conversion of either gal operator to a lac operator results in derepression, although both Gal and Lac repressors are present, suggesting that mere occupation of operator sites is not sufficient to cause repression. Conversion of both operators to lac operators restores normal repression in the presence of Lac repressor protein. We propose that normal repression requires interaction between operator-bound like repressor molecules; this generates a DNA loop, which is part of a higher order structure. RNA polymerase and cyclic AMP receptor protein are present in this complex but unable to initiate transcription because of the higher order structure. Such higher order DNA-multiprotein complexes could occur in a variety of genetic regulatory systems that are controlled from distal sites by regulatory proteins.


Hidden Area and Mechanical Nonlinearities in Freestanding Graphene.
We investigated the effect of out-of-plane crumpling on the mechanical response of graphene membranes. In our experiments, stress was applied to graphene membranes using pressurized gas while the strain state was monitored through two complementary techniques: interferometric profilometry and Raman spectroscopy. By comparing the data obtained through these two techniques, we determined the geometric hidden area which quantifies the crumpling strength. While the devices with hidden area ∼0% obeyed linear mechanics with biaxial stiffness 428±10 N/m, specimens with hidden area in the range 0.5%-1.0% were found to obey an anomalous nonlinear Hooke's law with an exponent ∼0.1.


Stabilization of Hydrogen Production via Methanol Steam Reforming in Microreactor by Al2O3 Nano-Film Enhanced Catalyst Adhesion.
In hydrogen production by methanol steam reforming reaction with microchannel reactor, Al2O3 thin film formed by atomic layer deposition (ALD) was introduced on the surface of microchannel reactor prior to the coating of catalyst particles. Methanol conversion rate and hydrogen production rate, increased in the presence of Al2O3 thin film. Over-view and cross-sectional scanning electron microscopy study showed that the adhesion between catalyst particles and the surface of microchannel reactor enhanced due to the presence of Al2O3 thin film. The improvement of hydrogen production rate inside the channels of microreactor mainly came from the stable fixation of catalyst particles on the surface of microchannels.


Multiple Acquisitions of Pathogen-Derived Francisella Endosymbionts in Soft Ticks.
Bacterial endosymbionts of ticks are of interest due to their close evolutionary relationships with tick-vectored pathogens. For instance, whereas many ticks contain Francisella-like endosymbionts (FLEs), others transmit the mammalian pathogen Francisella tularensis. We recently sequenced the genome of an FLE present in the hard tick Amblyomma maculatum (FLE-Am) and showed that it likely evolved from a pathogenic ancestor. In order to expand our understanding of FLEs, in the current study we sequenced the genome of an FLE in the soft tick Ornithodoros moubata and compared it to the genomes of FLE-Am, Francisella persica-an FLE in the soft tick Argus (Persicargas) arboreus, Francisella sp. MA067296-a clinical isolate responsible for an opportunistic human infection, and F. tularensis, the established human pathogen. We determined that FLEs and MA067296 belonged to a sister taxon of mammalian pathogens, and contained inactivated versions of virulence genes present in F. tularensis, indicating that the most recent common ancestor shared by FLEs and F. tularensis was a potential mammalian pathogen. Our analyses also revealed that the two soft ticks (O. moubata and A. arboreus) probably acquired their FLEs separately, suggesting that the virulence attenuation observed in FLEs are not the consequence of a single acquisition event followed by speciation, but probably due to independent transitions of pathogenic francisellae into nonpathogenic FLEs within separate tick lineages. Additionally, we show that FLEs encode intact pathways for the production of several B vitamins and cofactors, denoting that they could function as nutrient-provisioning endosymbionts in ticks.


Cardiac rhythm after the Mustard operation for complete transposition of the great arteries.
The Mustard operation corrects the effects of congenital transposition of the great arteries by creating an intraarterial baffle to direct pulmonary venous blood to the tricuspid orifice and systemic venous blood to the mitral orifice. To identify the long-term effects of this procedure, we followed 372 patients with complete transposition of the great arteries who survived the Mustard operation for at least three months. The mean follow-up period was 4.5 years (range, 0.4 to 15.9); the mean age at operation was 2.0 years. Mean resting heart rates were consistently lower than those for age-matched normal children. Seventy-six per cent of the patients had sinus rhythm during the year of operation--a figure that decreased to 57 per cent by the end of the eighth postoperative year. Twenty-five patients died during the follow-up period, nine suddenly. Life-table analysis revealed a cumulative survival rate of 91 per cent for 11 years and 71 per cent for 15 years after the operation. No strong risk factor for sudden unexpected death identified. This study demonstrates that extended survival among patients with transposition can be expected after the Mustard operation. However, over time there is a decreasing prevalence of normal sinus rhythm in survivors, as well as a small risk of sudden death.


Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4.
The human cytochromes P450 (CYPs) mediating amitriptyline N-demethylation have been identified using a combination of enzyme kinetic and chemical inhibition studies. Amitriptyline was N-demethylated to nortriptyline by microsomes from cDNA transfected human lymphoblastoid cells expressing human CYPs 1A2, 2C9, 2C19, 2D6, and 3A4. CYP 2E1 showed no detectable activity. While CYP 2C19 and CYP 2D6 showed high affinity, CYP 3A4 showed low affinity; CYP 2C9 and 1A2 showed intermediate affinities. Based on these kinetic parameters and estimated relative abundance of the different CYPs in human liver, CYP 2C19 was identified as the major amitriptyline N-demethylase at low (therapeutically relevant) amitriptyline concentrations, whereas CYP 3A4 may be more important at higher amitriptyline concentrations. Chemical inhibition studies with ketoconazole and omeprazole indicate that CYP 3A4 is the major amitriptyline N-demethylase at 100 mumol/L amitriptyline, while CYP 2C19 is equally important at a substrate concentration of 5 mumol/L. The CYP 1A2 inhibitor alpha-naphthoflavone and the CYP 2C9 inhibitor sulfaphenazole produced much less inhibition of amitriptyline N-demethylation at both substrate concentrations. Quinidine produced no detectable inhibition. The kinetics of amitriptyline N-demethylation by human liver microsomes were consistent with a two enzyme model, with the high affinity component exhibiting Michaelis Menten kinetics and the low affinity component exhibiting Hill enzyme kinetics. No difference was apparent in the kinetics of amitriptyline N-demethylation in two liver samples with low levels of CYP 2C19 activity compared with two other samples with relatively normal 2C19 activity. This may reflect the importance of higher substrate concentration values in estimation of kinetic parameters in vitro.


Changes in TRPV1-Mediated Physiological Function in Rats Systemically Treated With Capsaicin on the Neonate.
Capsaicin is the active component of chili peppers and is a hydrophobic, colorless, odorless, and crystalline to waxy compound. The transient receptor potential vanilloid 1 (TRPV1) is the capsaicin receptor channels that are involved in a variety of functions like transduction and transmission of the physiological stimulus. Subcutaneous injection of capsaicin to a newborn rat leads to involuntary lifelong TRPV1 desensitization. Various physiological changes including sensory and homeostatic actions in the body associated with neonatal capsaicin treatment are induced by direct TRPV1 channel targeting. Interesting changes include unique phenomena such as the reduction in pain perception, abnormal body temperature, increase in infection, infectious or neuropathological itching, and irregular circadian core body temperature rhythm. These symptoms are associated with relatively higher fever or loss of sensory c-fiber related to TRPV1 desensitization. The aforementioned outcomes not only provide a warning about the risk of capsaicin exposure in newborns but also indicate the possible occurrence of relatively rare diseases that are difficult to diagnose. Therefore, Therefore, the present review aims to summarize the unique phenomena caused by systemic capsaicin administration in neonatal rats.


Using the human CYP26A1 gene promoter as a suitable tool for the determination of RAR-mediated retinoid activity.
We have used a shortened construct form of the CYP26A1 gene promoter, in a promoter-less vector with either luciferase (known as E4) or a red fluorescent protein, RFP (known as E4.2) as the reporter gene and examined their responses to retinoids in transfected HepG2 and HEK293T cells. The promoter responded linearly to a wide concentration range of at-RA in cells cotransfected with retinoic acid receptors (RAR). The promoter also responded quantitatively to retinol and various other retinoids. An isolated clonal line of HEK293T cells that was permanently transfected with the promoter driving the expression of RFP responded to both at-RA and retinol, and the responses could be measured by fluorescence microscopy and flow cytometry. The promoter was also used to assess the retinoid activity of 3 novel synthetic retinoid analogues. Among them, EC23 was shown to be more potent than at-RA at lower concentrations and also more stable than at-RA. The promoter was also used to estimate the retinoid activities of intact rat serum samples as well as extracts of rat liver and lung, using retinol and at-RA as the reference standards. The retinoid activities could be measured in control rat serum samples and were increased in the serum of at-RA-treated rats. The total retinol and at-RA levels in the rat liver and lung samples determined by this promoter-based assay were compared with total retinol levels determined by the UPLC as the conventional methods. This system should offer a biologically-based alternative to mass-based retinoid analysis.


Chronic thyroiditis as a favorable prognostic factor in papillary thyroid carcinoma.
A subgroup of patients with papillary thyroid carcinoma (PTC) also has chronic thyroiditis (CT) as an associated disease of the thyroid. To assess the prognostic value of CT in patients with PTC, we reviewed the histological slides of 2225 patients with PTC who had undergone surgery between 1971 and 1992. Of the 2225 patients, 692 were excluded from the analysis because regional lymph nodes and/or nonneoplastic thyroid tissues were unavailable for histological assessment. The series included 281 patients with CT in nonneoplastic thyroid tissue and 1252 without CT. We performed statistical analyzes by the log-rank test and Cox's proportional-hazard method. Sixty-two (5.0%) of the 1252 patients without CT died of metastatic disease during the follow-up period and the relapse-free 10-year survival rate was 85%. By contrast, only 2 (<1.0%) of the 281 patients with CT died, and their relapse-free 10-year survival rate was 95%. The difference between patients with CT and those without CT in terms of relapse-free and overall survival was statistically significant (p < 0.0001). Risk factors for unfavorable outcome were age 45 years or more, absence of psammoma bodies, and absence of CT (p < 0.0001), followed by vascular invasion (p = 0.0007), male sex (p = 0.0013), and metastasis to regional lymph nodes (p = 0.047). Multivariate analysis indicated that all of these factors with the exception of gender were independent factors in the final model for overall survival. Chronic thyroiditis in the nonneoplastic thyroid of patients with PTC is a powerful prognostic factor for both relapse-free and overall survival.


[Rudolph Tegner: The blind from Marrakech (1949-1950)].
The Danish sculptor and painter Rudolph Tegner (1873-1950) has built his own Museum in Dronningmolle, where his sculptures enrich the unique landscape. His last and incomplete plaster on a simple, raw wooden scaffold sculpture The Blind from Marrakech (Fig. 1) show five persons moan about, carrying a dead body. All persons are missing their arms. Tegner had a number of years earlier been in Marrakech and had watched a funeral procession, where blind beggars had carried a dead old woman raised high above the bearers on a kind of pall. In a small version of the statue cast, later in bronze from 1963, showed 15 bearers, on both sides of the bier (Fig. 2 & 3). Nine and 15 bearers are looking up, two right in front, and the rest are looking down. Totally blind people can not see the light but can see up to the divine Heaven. Some blind have kept the gleam. The confusion with the eye direction shows that they really are blind. However 10 of the 15 blind people had hollow in the eye (excenteratio orbitae) in contrast to the dead woman. The dead woman had been the blinds' mistress. The last work The Blind in Marrakech may also be the despair of the artist.


Astragaloside IV Prevents Obesity-Associated Hypertension by Improving Pro-Inflammatory Reaction and Leptin Resistance.
Low-grade pro-inflammatory state and leptin resistance are important underlying mechanisms that contribute to obesity-associated hypertension. We tested the hypothesis that Astragaloside IV (As IV), known to counteract obesity and hypertension, could prevent obesity-associated hypertension by inhibiting pro-inflammatory reaction and leptin resistance. High-fat diet (HFD) induced obese rats were randomly assigned to three groups: the HFD control group (HF con group), As IV group, and the As IV + α-bungaratoxin (α-BGT) group (As IV+α-BGT group). As IV (20 mg·Kg-1·d-1) was administrated to rats for 6 weeks via daily oral gavage. Body weight and blood pressure were continuously measured, and NE levels in the plasma and renal cortex was evaluated to reflect the sympathetic activity. The expressions of leptin receptor (LepRb) mRNA, phosphorylated signal transducer and activator of transcription-3 (p-STAT3), phosphorylated phosphatidylinositol 3-kinase (p-PI3K), suppressor of cytokine signaling 3 (SOCS3) mRNA, and protein-tyrosine phosphatase 1B (PTP1B) mRNA, pro-opiomelanocortin (POMC) mRNA and neuropeptide Y (NPY) mRNA were measured by Western blot or qRT-PCR to evaluate the hypothalamic leptin sensitivity. Additionally, we measured the protein or mRNA levels of α7nAChR, inhibitor of nuclear factor κB kinase subunit β/ nuclear factor κB (IKKβ/NF-KB) and pro-inflammatory cytokines (IL-1β and TNF-α) in hypothalamus and adipose tissue to reflect the anti-inflammatory effects of As IV through upregulating expression of α7nAChR. We found that As IV prevented body weight gain and adipose accumulation, and also improved metabolic disorders in HFD rats. Furthermore, As IV decreased BP and HR, as well as NE levels in blood and renal tissue. In the hypothalamus, As IV alleviated leptin resistance as evidenced by the increased p-STAT3, LepRb mRNA and POMC mRNA, and decreased p-PI3K, SOCS3 mRNA, and PTP1B mRNA. The effects of As IV on leptin sensitivity were related in part to the up-regulated α7nAchR and suppressed IKKβ/NF-KB signaling and pro-inflammatory cytokines in the hypothalamus and adipose tissue, since co-administration of α7nAChR selective antagonist α-BGT could weaken the improved effect of As IV on central leptin resistance. Our study suggested that As IV could efficiently prevent obesity-associated hypertension through inhibiting inflammatory reaction and improving leptin resistance; furthermore, these effects of As IV was partly related to the increased α7nAchR expression.


IgG4 and IgE co-positive group found in idiopathic orbital inflammatory disease.
To reveal the cytokines involved in idiopathic orbital inflammatory disease (IOID) and the relationship between Th17 cells, IgE and IOID pathogenesis. Whole blood samples were processed immediately after collection and serological IgG4, IgG, and IgE antibodies were tested using ELISA. IOID and orbital cavernous hemangioma (CH) tissue samples underwent Bio-Plex multiplex cytokine detection. Hematoxylin-Eosin (HE) staining of all paraffin samples suggested the histological features of IOIDs, and expressions of IgG4 and IL-17A in affected tissues were detected by immunohistochemistry. Among 40 IOID plasma samples, 52.5% (21/40) were positive for IgG4 and 25% (10/40) were positive for IgE. Overlapped IgG4 or IgE positive samples accounted for 22.5% (9/40). Therefore, IOID samples were separated into three groups. The IgE+/IgG4+ group had a relevantly lower level of pro-inflammatory cytokine expression. IL-4 (Th2 cell related), IL-10 and TGF-β1 (Treg cell immunity related) were elevated in all three groups. Some of the Th17 cell related cytokines (i.e. IL-17A/F, IL-25, IL-23, and IL-33) displayed higher expression levels in the IgE-/IgG4- group compared to the other two groups. We discovered an IgG4-IgE co-positive group as well as Th17 cell immune involvement in IgG4-IgE co-negative subgtroup in IOID for the first time. The pathogenesis of IOID could differ from different subgroups according to the IgG4 and IgE detection. Therefore, we recommend that, Treatment stratagy should be made according to the clinical assessment of IgG4-IgE and Th17 profile detection.


Quantitative analysis of retinal microvascular changes in macular telangiectasia type 2 using optical coherence tomography angiography.
To evaluate retinal vascular changes on optical coherence tomography angiography (OCTA) in patients with macular telangiectasia type 2 (MacTel 2) and to assess their correlation with visual acuity. Twenty-six patients (52 eyes) with MacTel 2 and 20 age-matched controls (40 eyes) were included. Fundus examinations, including fundus autofluorescence, swept-source optical coherence tomography, and OCTA, were performed. Differences in the vascular density in the fovea and parafovea, the area of the foveal avascular zone, and the diameter of the ellipsoid zone defect of the two groups were analyzed. The foveal vascular density of the superficial capillary plexus was significantly lower in the MacTel 2 group than in the control group (p = 0.027). The vascular density in the entire deep capillary plexus was also significantly less in the MacTel 2 group than in the control group (all p < 0.05). The mean diameter of ellipsoid-zone disruption on OCT in the MacTel 2 group was 634.6 ± 104.3 𝜇m. The foveal avascular zone areas of the superficial and deep capillary plexuses were significantly enlarged in the MacTel 2 group compared to those in the control group (0.45 ± 0.12 mm2 vs. 0.27 ± 0.08 mm2, p < 0.001; 0.56 ± 0.15 mm2 vs. 0.40 ± 0.14 mm2, p = 0.001). In addition, the enlarged foveal avascular zone of the superficial and deep plexus was negatively correlated with best corrected visual acuity (logMAR) in MacTel 2 patients (p = 0.013, r = -0.642 and p = 0.042, and r = -0.511, respectively). Retinal vascular density changes occur in the superficial fovea and in the entire deep capillary plexus of patients with MacTel 2. The enlarged foveal avascular zone areas of the superficial and deep plexuses were prominent in the MacTel 2 group, and this enlargement correlates with worsened visual acuity.


Modifiable life style factors and risk for incident endometriosis.
Caffeine, alcohol, smoking and physical activity are known to alter sex steroid synthesis, which may affect hormone-dependent gynaecologic disease risk, such as endometriosis; however, few studies have assessed life style factors prior to endometriosis diagnosis. Four hundred and seventy three women, ages 18-44 years, underwent laparoscopy or laparotomy, regardless of clinical indication, at 14 clinic sites, 2007-2009. Women with prior surgically confirmed endometriosis were excluded. Life style factors were assessed prior to surgery. Adjusted risk ratios (RR) of endometriosis by caffeine, alcohol, smoking (serum cotinine), and physical activity were estimated, adjusting for age, marital status, education, race/ethnicity, age at menarche, gravidity, BMI, study site, and other life style factors. There were no associations between women with endometriosis and alcohol consumption (RR 0.9, 95% CI 0.7, 1.3), caffeine consumption (RR 1.1, 95% CI 0.8, 1.5), or smoking (serum cotinine <10 vs ≥10 ng/mL; RR 1.0, 95% CI 0.7, 1.6). Similar null findings were found between endometriosis and weekly occurrences of physical activity and total walking, moderate, and vigorous activity; a modest trend was found between total daily sitting time and increased endometriosis risk. This study, which is unique in its capture of life style exposures prior to incident endometriosis diagnosis, largely found no association between alcohol, caffeine, smoking, and physical activity and risk of endometriosis.


Relationships between mesolimbic dopamine function and eating behavior.
These experiments are the first to correlate a specific stimulus of eating--the orosensory stimulation by sucrose--to mesolimbic dopaminergic activity. The pharmacological results and the increase in hypothalamic DOPAC/DA are convergent evidence for this relationship. The meaning of the relationship is not clear. The possibility that the decreased intake after dopaminergic receptor antagonist treatment and the increase in hypothalamic DOPAC/DA is related to the ingestive movements necessary for sham feeding seems unlikely for the following reasons: first, at least one dose of the antagonist had a preferential inhibition on sucrose intake compared to water intake; second, the D1 and D2 selective receptor antagonists decreased the initial rate of sucrose intake, but did not affect the rate of decay of sucrose intake over a 30-min test; third, in the second neurochemical experiment (Table 1), the volume ingested during 9 min of sham feeding 10% sucrose was not significantly different from the volume ingested from sham feeding 40% sucrose, but there was a significantly larger increase in the hypothalamic DOPAC/DA after 40% sucrose. Of course, a finer measurement of movements, such as lick rate, may reveal a significant difference that would correlate with the metabolic change. Fourth, striatal DOPAC/DA did not change during sham feeding of sucrose. Fifth, Bailey et al. demonstrated that a response-frequency summation analysis of the inhibitory effect of pimozide on sucrose intake did not reveal a motoric deficit. Thus, we interpret the increase of hypothalamic DOPAC/DA during the sham feeding of sucrose as evidence that activation of mesolimbic dopaminergic terminals in the hypothalamus is necessary for the normal processing of the central sensory and/or positive-reinforcing information produced by oral sucrose stimulation. Experiments are in progress to test this hypothesis and to attempt to distinguish between the sensory and positive-reinforcing effects of sucrose during sham feeding. In addition to generating this specific hypothesis concerning sucrose and hypothalamic DA activity, the results of these experiments suggest that the sham feeding preparation will be useful for the analysis of the important problem of the natural reinforcing properties of sweet taste. And finally, since sham feeding of sucrose is a form of oral self-stimulation, it provides a new experimental tool for comparing the role of central DA mechanisms in the positive-reinforcing effects of food, psychostimulant self-administration, and intracranial electrical self-stimulation.


Pediatric Oxygen Therapy: A Clinical Update.
Oxygen therapy is a life-saving, medical intervention in the management of hospitalized children. The goal of oxygen therapy is to prevent or treat tissue hypoxia. Oxygen should be prescribed according to the principles of drug prescription, however, use of oxygen in clinical practice is often inappropriate without knowledge of its potential risks and benefits. This article summarizes practical aspects of clinical use of oxygen in terms of indication, administration, and monitoring, weaning, discontinuation and oxygen toxicity to rationalize therapy and achieve maximum benefits.


Tracking Antibody Distribution with Near-Infrared Fluorescent Dyes: Impact of Dye Structure and Degree of Labeling on Plasma Clearance.
Monoclonal antibodies labeled with near-infrared (NIR) fluorophores have potential use in disease detection, intraoperative imaging, and pharmacokinetic characterization of therapeutic antibodies in both the preclinical and clinical setting. Recent work has shown conjugation of NIR fluorophores to antibodies can potentially alter antibody disposition at a sufficiently high degree of labeling (DoL); however, other reports show minimal impact after labeling with NIR fluorophores. In this work, we label two clinically approved antibodies, Herceptin (trastuzumab) and Avastin (bevacizumab), with NIR dyes IRDye 800CW (800CW) or Alexa Fluor 680 (AF680), at 1.2 and 0.3 dyes/antibody and examine the impact of fluorophore conjugation on antibody plasma clearance and tissue distribution. At 0.3 DoL, AF680 conjugates exhibited similar clearance to unlabeled antibody over 17 days while 800CW conjugates diverged after 4 days, suggesting AF680 is a more suitable choice for long-term pharmacokinetic studies. At the 1.2 DoL, 800CW conjugates cleared faster than unlabeled antibodies after several hours, in agreement with other published reports. The tissue biodistribution for bevacizumab-800CW and -AF680 conjugates agreed well with literature reported biodistributions using radiolabels. However, the greater tissue autofluorescence at 680 nm resulted in limited detection above background at low (∼2 mg/kg) doses and 0.3 DoL for AF680, indicating that 800CW is more appropriate for short-term biodistribution measurements and intraoperative imaging. Overall, our work shows a DoL of 0.3 or less for non-site-specifically labeled antibodies (with a Poisson distribution) is ideal for limiting the impact of NIR fluorophores on antibody pharmacokinetics.


Functional human antigen-specific T cells produced in vitro using retroviral T cell receptor transfer into hematopoietic progenitors.
In vitro production of human T cells with known Ag specificity is of major clinical interest for immunotherapy against tumors and infections. We have performed TCRalphabeta gene transfer into human hemopoietic progenitors from postnatal thymus or umbilical cord blood, and subsequently cultured these precursors on OP9 stromal cells expressing the Notch human ligand Delta-like1. We report here that fully mature, functional T cells with controlled Ag specificity are obtained from such cultures. Using vectors encoding TCRalphabeta-chains directed against melanoma (MART-1), viral (CMV), and minor histocompatibility (HA-2) Ags, we show that the obtained Ag-specific T cells exert cytolytic activity against their cognate Ag and expand in vitro upon specific TCR stimulation. Therapeutic applications may arise from these results because they provide a way to produce large numbers of autologous mature Ag-specific T cells in vitro from undifferentiated hemopoietic progenitors.


Compensation for chronic oxidative stress in ALADIN null mice.
Mutations in the AAAS gene coding for the nuclear pore complex protein ALADIN lead to the autosomal recessive disorder triple A syndrome. Triple A patients present with a characteristic phenotype including alacrima, achalasia and adrenal insufficiency. Patient fibroblasts show increased levels of oxidative stress, and several in vitro studies have demonstrated that the nucleoporin ALADIN is involved in both the cellular oxidative stress response and adrenal steroidogenesis. It is known that ALADIN knock-out mice lack a phenotype resembling human triple A syndrome. The objective of this study was to determine whether the application of chronic oxidative stress by ingestion of paraquat would generate a triple A-like phenotype in ALADIN null mice. Adult male mice were fed either a paraquat (0.25 g/kg diet) or control diet for 11 days. After application of chronic oxidative stress, ALADIN knock-out mice presented with an unexpected compensated glutathione metabolism, but lacked a phenotype resembling human triple A syndrome. We did not observe increased levels of oxidative stress and alterations in adrenal steroidogenesis in mice depleted for ALADIN. This study stresses the species-specific role of the nucleoporin ALADIN, which in mice involves a novel compensatory mechanism for regulating the cellular glutathione redox response.


Extracts of Dracocephalum tanguticum Maxim Ameliorate Acute Alcoholic Liver Disease via Regulating Transcription Factors in Mice.
Alcoholic liver disease (ALD) caused by excessive drinking is a health and economic concern worldwide. Given the high morbidity, mortality, and the progressive nature of ALD, finding effective interventions is essential. Previous studies have confirmed that edible food plants and their bioactive compounds exert a protective effect against ALD. Dracocephalum tanguticum Maxim (DTM) is one of the important traditional Tibetan medicines in China with the effect of clearing away liver heat, used for the treatment of hepatitis. In this study, the DTM chloroform extract (DtM-C), ethyl acetate extract (DtM-E), and n-butanol extract (DtM-B) were obtained by ethanol extraction combined with fractional extraction. Acute ALD was induced in mice given intragastric ethanol. Serum and liver biochemical markers were detected by ELISA. Liver histological observation, Oil Red O, and Masson's trichrome staining were performed. Liver injury cells were induced by ethanol. The cell vitality was detected by using MTT colorimetry. The expressions of Nrf2, NF-κB, STAT3, AP-1, CREB, HIF-1α, HO-1, NQO-1, GSTA1, IKB2, and Keap1 were detected by real-time polymerase chain reaction (PCR) to elucidate the mechanism of hepatoprotective effect, and the results were verified by using Western blot. The results of serum liver function indicators (ALT, AST, and ADH), serum hepatic lipid indicators (TC, TG, HDL-C, and LDL-C), and lipid peroxidation indicators (ADH, MDA, SOD, CAT, and GSH-Px) in liver tissue and liver histological observation showed that DtM-E could improve liver function, alleviate fatty degeneration, edema, cell necrosis, and liver fibrosis caused by alcohol. DtM-E also increased the vitality of EtOH-induced liver injury cells, upregulated the mRNA expression of Nrf2, HO-1, NQO-1, and GSTA1, while downregulated the expression of Keap-1, p65, and NF-κB. Western blot results were consistent with PCR. The results suggest that DtM-E has a protective effect against ALD in vitro and in vivo, and its mechanism of action may be related to the activation of Nrf2/Keap-1 and inhibition of the P65/NF-κB signaling pathways.


The phosphatase system in Saccharomyces cerevisiae.
The yeast Saccharomyces cerevisiae has at least six species of acid and alkaline phosphatases with different cellular localizations, as well as inorganic phosphate (Pi) transporters. Most of the genes encoding these enzymes are coordinately repressed and derepressed depending on the Pi concentration in the growth medium. The Pi signals are conveyed to these genes through a regulatory circuit consisting of a set of positive and negative regulatory proteins. This phosphatase system is interested as one of the best systems for studying gene regulation in S. cerevisiae due to the simplicity of phenotype determination in genetic analysis. With this methodological advantage, considerable amounts of genetic and molecular evidence in phosphatase regulation have been accumulated in the past twenty-five years. This article summarizes the current progress of research into this subject.


PRG: A Distance Measurement Algorithm Based on Phase Regeneration.
With the booming development of the Internet of things (IoT) industry, the demand of positioning technology in various IoT application scenarios is also greatly increased. To meet the positioning requirements of the IoT application, we propose a distance measurement method based on phase regeneration that can provide positioning capability for IoT applications in indoor and outdoor environments. The PRG algorithm consists of two phases: coarse ranging phase and fine ranging phase. Fingerprint positioning algorithm based on Gradient Boost Decision Tree (GBDT) is used to determine coarse distance. The host machine measures the difference between the transmitted carrier phase and the received regenerative carrier phase to fix the fine distance and then the coarse distance is used to determine the carrier phase integer ambiguity. Finally, high precision ranging is realized. Simulation results show that the PRG method can achieve range finding with decimeter level precision under the 10 MHz subcarrier frequency.


Stability, correlates, and time-covarying associations of peer victimization from grade 4 to 12.
The purpose of the study was to examine stability, correlates, and time-covarying associations of peer victimization. The total sample size was 1,206 adolescents (M(age) at initial time point = 9.74 years, SD = .60; 59.5% White, 21.6% African American, 12.9% Hispanic American, 6% Other/Unknown) followed across 9 yearly waves of data collection from elementary school through middle and high school (Grades 4-12). In each year, peer victimization was assessed with peer nominations; externalizing behavior, peer sociability, and school competence were assessed with teacher ratings; and internalizing behavior was assessed with self-reports. High stability of peer victimization was found across the 9 years of the study. Victimization correlated positively with externalizing and internalizing behaviors and negatively with peer sociability and school competence in the elementary school years, whereas only the association with peer sociability remained significant throughout the middle and high school years. Growth curve modeling showed that victimization, as a time-varying predictor across Grades 4 to 12, significantly predicted the level of each outcome measure at the end of the trajectory, and the rate of change leading up to this end point. Gender differences were found for each of the main results. The results of the current study highlight the importance of developing a long-term dynamic view and understanding of the emergence of peer victimization and its related consequences across childhood and adolescence. Although peer victimization is strongly linked to a variety of adjustment problems in elementary school, these associations seem to become weaker in middle and high school.


Dietary Vitamin B6 Intake Associated with a Decreased Risk of Cardiovascular Disease: A Prospective Cohort Study.
Although the biological mechanisms underlying the beneficial effects of vitamin B6 on cardiovascular disease (CVD) have been reported on, epidemiological studies have yielded controversial results, and data on the Korean population are limited. This study examined the association between dietary vitamin B6 intake and CVD incidence in Koreans. A total of 9142 participants of the Korean Genome and Epidemiology Study, aged 40-69 years, who did not have CVD or cancer at the baseline were included in the analysis. Dietary data were assessed using a validated semi-quantitative food frequency questionnaire. CVD incidence was assessed using biennial questionnaires and confirmed through repeated personal interviews. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard regression models. After multivariate adjustment, a higher vitamin B6 intake was significantly associated with a decreased CVD risk in men (HR: 0.44; 95% CI: 0.25-0.78); no such association was observed in women. Dose-response analysis confirmed the presence of inverse linearity between vitamin B6 intake and CVD incidence in men (p for nonlinearity = 0.3). A higher dietary intake level of vitamin B6 was associated with a reduced CVD risk in Korean men. These observations require further verification in other populations.


Acrocallosal syndrome in a young hypertensive male.
Acrocallosal syndrome is an extremely rare genetic disorder with autosomal recessive inheritance. It is characterised by moderate to severe mental retardation, hypotonia, agenesis of the corpus callosum and preaxial polydactyly involving both feet and the facial features like broad forehead and hypertelorism. The authors report a case of a young hypertensive male who presented with unprovoked seizures for the first time who had multiple craniofacial, digital dysmorphic features with moderate mental retardation. The diagnosis of acrocallosal syndrome was arrived at after neuroimaging showed agenesis of corpus callosum with interhemispheric cysts.


[Relationship between bleomycin-induced pulmonary fibrosis and vascular endothelial cell injury].
To explore the relationship between the injury of vascular endothelial cells and formation of lung fibrosis by bleomycin (BLM) in rats. The rats of experimental groups were treated with bleomycin intratracheally to induce pulmonary fibrosis. The expression of vascular endothelial growth factor (VEGF) in pulmonary tissues were analyzed qualitatively and quantitatively by immunohistochemistry and image analysis system. (1) HISTOLOGY: Edema in rat alveoli and alveolar septum, inflammatory cells exudation, degeneration and necrosis of type I and type II alveolar epithelial cells (AETI and AETII), ruptured alveolar basement membrane, as well as swollen vascular endothelial cells and karyopyknosis were observed in 3 d and 7 d after treatment with BLM. AETII proliferation, with more fibroblasts in alveolar septum, and new capillary vessel formation in 7, 14 d, as well as thickened alveolar septum, damaged alveolar structure, and obvious pulmonary tissue fibrosis in 28 d after treatment with BLM were observed. (2) Immunohistochemistry: in normal control, VEGF expressed weakly in pulmonary tissue distributing mainly in AETII, bronchial epithelial cells, alveolar macrophages and leydig's cells. While in bleomycin treated groups, the expression of VEGF increased markedly. The expression in AETII, and pulmonary macrophage were significantly higher than that in control in 3 d to 28 d (P < 0.05, P < 0.01). The rat leydig's cells also had higher expression of VEGF in 7, 14, 28 d (P < 0.05, P < 0.01). The high expression of VEGF is related to vascular endothelial cells injury which may be one of important factors in the formation of bleomycin-induced pulmonary fibrosis.


The burden of disabilities in Sidama National Regional State, Ethiopia: A cross-sectional, descriptive study.
Assessing the burden and describing the status of people with disabilities is very essential. The previous studies conducted about the prevalence, causes, and types of disability in Ethiopia were inconsistent and disagreeable. To determine the prevalence, causes, and types of disabilities in Sidama National Regional State, Ethiopia. A house-to-house census was carried out on a total of 39,842 households in 30 randomly selected kebeles of the Dale and Wonsho districts and Yirgalem city administration, Sidama National Regional State. The data were collected using structured and pretested questionnaires via the Kobo Collect application from May 01 to 30, 2022. The analysis was performed by STATA version 16 software. After cleaning and organizing, descriptive statistics were employed to characterize the study findings. In this study, people with disabilities aged one to 80 years old were included. The mean Standard Deviation (SD) age of people with disabilities in years was 31.95 (15.33). Of 228,814 people, 1,694 were people with disabilities in Dale and Wonsho districts and Yirgalem city administration, with a prevalence of 0.74% (95% CI: 0.72, 0.76). Of the causes of disability, 61% of the disabilities were due to illness, injury, and accidents. Extremity paralysis (35.4%), vision disability (20.13%), hearing disability (19.7%), walking disability (14.7%), and cognitive disabilities (7.7%) were the identified types of disabilities. This study revealed that the burden of disability is considerable in Dale and Wonsho districts and Yirgalem city administration. The vast majority of disability causes could have been avoidable. As a result, developing and implementing various strategies to raise community awareness about the causes and preventive measures is critical.


Sagnac interferometry based on ultraslow polaritons in cold atomic vapors.
The advantages of light and matter-wave Sagnac interferometers--large area on one hand and high rotational sensitivity per unit area on the other--can be combined utilizing ultraslow light in cold atomic gases. While a group-velocity reduction alone does not affect the Sagnac phase shift, the associated momentum transfer from light to atoms generates a coherent matter-wave component which gives rise to a substantially enhanced rotational signal. It is shown that matter-wave sensitivity in a large-area interferometer can be achieved if an optically dense vapor at subrecoil temperatures is used. Already a noticeable enhancement of the Sagnac phase shift is possible, however, with far fewer cooling requirements.


Maxillary Arch Dimensions in Children with Unilateral Cleft Lip and Palate Receiving Alveolar Bone Grafting.
To analyse the maxillary arch dimensions of children aged 9 and 12 with unilateral cleft lip and palate (UCLP) who received orthodontic treatment and secondary alveolar bone grafting. This retrospective cohort study was performed on 30 patients with UCLP. All patients were treated at the Cleft Lip and Palate Centre, which is part of the University Medical Centre Amsterdam and Academic Centre for Dentistry Amsterdam, the Netherlands. Children with non-syndromic UCLP who received pre- and postsurgical orthodontics combined with secondary alveolar bone grafting between the ages of 9 and 12 years were included. Maxillary arch dimensions were assessed on 60 digitised dental casts with measurements of the intermolar widths, interpremolar widths, arch perimeters, arch lengths, arch widths, and palatal depths. The results of a paired-samples t-test revealed a statistically significant increase (P < .05) in intermolar width 1, intermolar width 3, interpremolar width 1, arch perimeter, and arch width between the ages of 9 (T0) and 12 (T1). Intermolar width 2 and the palatal depth decreased statistically significantly between T0 and T1. Analysis of maxillary arch dimensions of children with UCLP indicates significant changes between 9 and 12 years of age. This suggests that orthodontic treatment and secondary alveolar bone grafting can be effective in improving maxillary arch dimensions. However, there is a need for collaborative research and data collection in order to provide sensible and evidence-based care to patients with cleft lip and palate.


A case of neurotoxicity following 5-fluorouracil-based chemotherapy.
5-Fluorouracil (5-FU) is a commonly used chemotherapeutic agent. However, its neurotoxicity is rare and not well recognized. We report a case of 5-FU neurotoxicity with organic brain syndrome and progression to multifocal leukoencephalopathy in a 44-year-old male patient having malignant gastrointestinal stromal tumor. 5-FU-induced neurotoxicity should, therefore, be considered as an important differential diagnosis in cancer patients with neurological abnormality and history of chemotherapy.


Reaction Pathway Dependence in Plasmonic Catalysis: Hydrogenation as a Model Molecular Transformation.
The localized surface plasmon resonance (LSPR) excitation in plasmonic nanoparticles can enhance or mediate chemical transformations. Increased reaction rates for several reactions have been reported due to this phenomenon; however, the fundamental understanding of mechanisms and factors that affect activities remains limited. Here, by investigating hydrogenation reactions as a model transformation and employing different reducing agents, H2 and NaBH4 , which led to different hydrogenation reaction pathways, we observed that plasmonic excitation of Au nanoparticle catalysts can lead to negative effects over the activities. The underlying physical reason was explored using density functional theory calculations. We observed that positive versus negative effects on the plasmonic catalytic activity is reaction-pathway dependent. These results shed important insights on our current understanding of plasmonic catalysis, demonstrating reaction pathways must be taken into account for the design of plasmonic nanocatalysts.


Generation of inner ear organoids from human pluripotent stem cells.
The sensory epithelia of the inner ear contain mechanosensitive hair cells that transmit sound, gravity and head motion signals. This protocol describes an in vitro 3D differentiation method, by which the inner ear sensory epithelium harboring hair cells are derived from human pluripotent stem cells (hPSCs). To begin the differentiation, hPSCs are aggregated in low-binding 96-well plates and treated with extracellular matrix proteins to promote epithelialization. By recapitulating signaling pathway activation and attenuation during in vivo inner ear development, the aggregates are treated with small molecules and recombinant proteins that modulate signaling pathways such as BMP, FGF and WNT in a stepwise manner. These treatments induce sequential formation of non-neural ectoderm (NNE), otic-epibranchial progenitor domain (OEPD), and otic placodes. The otic placodes subsequently undergo self-guided morphogenesis to form otic vesicles, which eventually give rise to sensory epithelia containing inner ear hair cells and supporting cells, as well as neurons forming synapses with the hair cells. These hPSC-derived inner ear sensory structures are designated human inner ear organoids. As human inner ear biopsies are nearly impossible to obtain without causing severe injuries to the auditory system of the patients, the human inner ear organoid system provides a powerful in vitro platform for studying human inner ear disease and development.


Serotonin-norepinephrine receptor interactions in the brain: implications for the pharmacology and pathophysiology of affective disorders.
When chronically administered, most clinically effective antidepressant treatments (pharmacotherapy and ECT) reduce the sensitivity of the norepinephrine-sensitive adenylate cyclase in brain which, in turn, is associated with a down-regulation of the beta-adrenoceptor subpopulation. Because this norepinephrine receptor system is linked to an amplifier system, small changes in the number of receptors or in the accumulation of the second messenger cyclic AMP will be amplified. Results of the studies discussed in this paper demonstrate that an intact serotonergic neuronal input is required for the proper functioning of beta-adrenoceptors and for the down-regulation of the density of these receptors by antidepressant treatments. Under conditions of impaired serotonergic activity, beta-adrenoceptors display profound decreases in agonist but not in antagonist affinity. The changes are reminiscent of "uncoupled" receptors. While beta-adrenoceptors are coupled in a stimulatory fashion to adenylate cyclase, resulting in the formation of the second messenger cyclic AMP, serotonin (5-HT) receptors are linked to phosphatidylinositol hydrolysis (5-HT2 receptors in cortex, 5-HT1C receptors in choroid plexus) generating two second messengers, diacylglycerol and inositol-1,4,5-trisphosphate. The final common pathway of aminergic receptor activation seems to be protein-kinase-mediated protein phosphorylation leading to changes in cellular activity. Evidence is presented suggesting that the delayed down-regulation of the linked 5-HT/norepinephrine beta-adrenoceptor system by antidepressant treatment reflects a therapeutically relevant biochemical action and prompts the generation of the "5-HT/norepinephrine link hypothesis" of affective disorders.


Intercollicular commissural connections refine the representation of sound frequency and level in the auditory midbrain.
Connections unifying hemispheric sensory representations of vision and touch occur in cortex, but for hearing, commissural connections earlier in the pathway may be important. The brainstem auditory pathways course bilaterally to the inferior colliculi (ICs). Each IC represents one side of auditory space but they are interconnected by a commissure. By deactivating one IC in guinea pig with cooling or microdialysis of procaine, and recording neural activity to sound in the other, we found that commissural input influences fundamental aspects of auditory processing. The areas of nonV frequency response areas (FRAs) were modulated, but the areas of almost all V-shaped FRAs were not. The supra-threshold sensitivity of rate level functions decreased during deactivation and the ability to signal changes in sound level was decremented. This commissural enhancement suggests the ICs should be viewed as a single entity in which the representation of sound in each is governed by the other.


[Prehospital phase of myocardial infarct].
After admission to the Coronary Care Unit 101 patients suffering from proved myocardial infarction were inquired about their prehospital phase. In the near future of the acute infarction the patients consulted their doctors more frequently. 73% had prodromi. The longest section of the prehospital phase was caused by the patient's decision time and the time between the call for help and the arrival at the hospital. However the transportation time was only 5% of the prehospital phase. Smoker's decision time was half that of non-smokers. Patients younger than 50 years had a longer decision time than patients of other agegroups. There was no differences in the prehospital phase for different days of the week, but the prehospital phase was longer at night than by day. To shorten the prehospital phase probably the best way is to cut down the decision time by medical advice and public information. In the case of the community of Hannover the advantages of a mobile coronary care unit are questionable.


CSF GABA is reduced in first-episode psychosis and associates to symptom severity.
Schizophrenia is characterized by a multiplicity of symptoms arising from almost all domains of mental function. γ-Aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the brain and is increasingly recognized to have a significant role in the pathophysiology of the disorder. In the present study, cerebrospinal fluid (CSF) concentrations of GABA were analyzed in 41 first-episode psychosis (FEP) patients and 21 age- and sex-matched healthy volunteers by high-performance liquid chromatography. We found lower CSF GABA concentration in FEP patients compared with that in the healthy volunteers, a condition that was unrelated to antipsychotic and/or anxiolytic medication. Moreover, lower CSF GABA levels were associated with total and general score of Positive and Negative Syndrome Scale, illness severity and probably with a poor performance in a test of attention. This study offers clinical in vivo evidence for a potential role of GABA in early-stage schizophrenia.


Dietary Patterns and Physical Activity Levels Among People With Type 2 Diabetes.
The aim of our study was to assess the association of eating habits with the dietary patterns of people with diabetes. This cross-sectional study was conducted at National Institute of Diabetes and Endocrinology (NIDE), Dow University Hospital in Karachi, Pakistan. A total 301 patients aged >18 with type 2 diabetes came to Outpatient department were recruited. Structured questionnaire was used to assess general characteristics, Anthropometric measurements, biochemical markers, and dietary intake. A total of 301 patients with type 2 diabetes mellitus were included in this study. The average age of patients was 51.6 (SD ± 11.1) years which ranged from 21 to 80 years whereas the average BMI was 27.2 kg / m2 (SD ± 5.6). Overall, 42% of patients were found to often have less than 1 serving of fruit, and 45% had less than 3 servings of vegetables daily. Of all, 77 (26%) patients often distributed carbohydrates all over the day. Results revealed that HbA1c was higher in those patients who took more than 3 roti (approximately each roti weight 60-80 g) (P-value < .001) and full plate rice approximately 300 to 355 g cooked weight in a whole day (P-value < .001) as compared to those patients whose intake of roti was 3 or less than 3 and rice was a half plate. Moreover, out of 301 patients, 102 were found physically active (52% females and 48% males), while 199 were not active. Pain in legs and lack of motivation were common barrier to physical activity. Our study revealed that patients' fruits and vegetable intake was not optimum, diet was not balanced and the quantity of starchy carbohydrates was not controlled which may affect their HBA1C levels. Proper counseling and awareness about the importance of a balanced diet and portion control in diabetes are needed.


Primary Amine Tethered Small Molecules Promote the Degradation of X-Linked Inhibitor of Apoptosis Protein.
We hypothesized that the proximity-driven ubiquitylation of E3-interacting small molecules could affect the degradation of E3 ubiquitin ligases. A series of XIAP BIR2 domain-binding small molecules was modified to append a nucleophilic primary amine. This modification transforms XIAP binders into inducers of XIAP degradation. The degradation of XIAP is E1- and proteasome-dependent, dependent on the ligase function of XIAP, and is rescued by subtle modifications of the small molecule that would obviate ubiquitylation. We demonstrate in vitro ubiquitylation of the small molecule that is dependent on its interaction with XIAP. Taken together, these results demonstrate the designed ubiquitylation of an engineered small molecule and a novel approach for the degradation of E3 ubiquitin ligases.


Colony-morphology screening uncovers a role for the Pseudomonas aeruginosa nitrogen-related phosphotransferase system in biofilm formation.
Pseudomonas aeruginosa is an opportunistic human pathogen whose survival is aided by forming communities known as biofilms, in which cells are encased in a self-produced matrix. We devised a mutant screen based on colony morphology to identify additional genes with previously unappreciated roles in biofilm formation. Our screen, which identified most known biofilm-related genes, also uncovered PA14_16550 and PA14_69700, deletions of which abrogated and augmented biofilm formation respectively. We also identified ptsP, which encodes enzyme I of the nitrogen-regulated phosphotransferase (PTS(Ntr)) system, as being important for cyclic-di-GMP production and for biofilm formation. Further experiments showed that biofilm formation is hindered in the absence of phosphotransfer through the PTS(Ntr), but only in the presence of enzyme II (PtsN), the putative regulatory module of the PTS(Ntr). These results implicate unphosphorylated PtsN as a negative regulator of biofilm formation and establish one of the first known roles of the PTS(Ntr) in P. aeruginosa.


Macrophages and intravascular OCT bright spots: a quantitative study.
This study hypothesized that bright spots in intravascular optical coherence tomography (IVOCT) images may originate by colocalization of plaque materials of differing indexes of refraction. To quantitatively identify bright spots, we developed an algorithm that accounts for factors including tissue depth, distance from light source, and signal-to-noise ratio. We used this algorithm to perform a bright spot analysis of IVOCT images and compared these results with histological examination of matching tissue sections. Bright spots are thought to represent macrophages in IVOCT images, and studies of alternative etiologies have not been reported. Fresh human coronary arteries (n = 14 from 10 hearts) were imaged with IVOCT in a mock catheterization laboratory and then processed for histological analysis. The quantitative bright spot algorithm was applied to all images. Results are reported for 1,599 IVOCT images co-registered with histology. Macrophages alone were responsible for only 23% of the bright spot-positive regions, although they were present in 57% of bright spot-positive regions (as determined by histology). Additional etiologies for bright spots included cellular fibrous tissue (8%), interfaces between calcium and fibrous tissue (10%), calcium and lipids (5%), and fibrous cap and lipid pool (3%). Additionally, we showed that large pools of macrophages in CD68(+) histology sections corresponded to dark regions in comparative IVOCT images; this is due to the fact that a pool of lipid-rich macrophages will have the same index of refraction as a pool of lipid and thus will not cause bright spots. Bright spots in IVOCT images were correlated with a variety of plaque components that cause sharp changes in the index of refraction. Algorithms that incorporate these correlations may be developed to improve the identification of some types of vulnerable plaque and allow standardization of IVOCT image interpretation.


Abdominal operations for intraabdominal metastases from extraabdominal primary tumors.
Forty consecutive patients with an extraabdominal primary tumor, later treated surgically for intraabdominal problems, were investigated. The most common causes of abdominal operations were intestinal obstruction (N = 17), intraabdominal tumor mass (N = 8), and intraabdominal hemorrhage (N = 5). The overall postoperative mortality was 25%, morbidity 48%, median survival 3 months, and cumulative 5 year survival 3%. The mortality after emergency procedures, 67%, was significantly higher (P less than 0.01) than after elective operations, 18%. Conditions requiring enterostomy (N = 14) were associated with a mortality of 36%, whereas the figures in resected (N = 13) and bypassed (N = 7) patients were 14% and 17%, respectively. Wound infection (N = 5) and pulmonary infection (N = 5) were the most common complications, and pulmonary infection was fatal in three of the five cases. Of the patients, 22 (55%) were discharged from hospital to their home; ten (25%) of them had postoperatively a 3 month relief of cancer symptoms and four (10%) a 6 month relief. Nine patients (25%) have survived for over 1 year and one (3%) for over 5 years. It is concluded that abdominal procedures seldom prevent further cancer growth within these patients and that symptoms are relieved only in one in every four patients. According to strict criteria, these operations are useful and can add to patient comfort.


Traditional Chinese Medicine for Coronary Artery Disease Treatment: Clinical Evidence From Randomized Controlled Trials.
Traditional Chinese medicine has a history of more than 2,000 years and has been widely used in clinical practice. However, due to the lack of a reliable scientific basis, the role of traditional Chinese medicine in the prevention and treatment of coronary artery disease is not clear. At present, the existing randomized controlled trials about traditional Chinese medicine for coronary artery disease have defects, small sample sizes, and different results, so it is difficult to make a clear conclusion on the actual advantages and disadvantages of traditional Chinese medicine. In this review, the efficacy and safety of traditional Chinese medicine in the prevention and treatment of coronary artery disease were systematically evaluated through randomized controlled trials, most of which were double-blind trials. We reviewed 17 randomized controlled trials that included a total of 11,726 coronary artery disease patients. The methodological quality of the trials was generally high, with nine (52.94%) having a modified Jadad score of 7 and only three (17.65%) having a modified Jadad score of <3. There are 16 trials (94.12%) reporting safety; the safety of traditional Chinese medicine seems not to be inferior to that of mimetic, placebo, or western medications. Moreover, the results from 17 randomized controlled trials (100.00%) showed that traditional Chinese medicine can be applied as a complementary and alternative method to the primary and secondary prevention of coronary artery disease, and only six trials (35.29%) described adverse cardiovascular events specifically. However, it is necessary to assess the safety and efficacy of traditional Chinese medicine in treating coronary artery disease with long-term hard endpoints.


Accuracy of the diagnosis in suspected intraepithelial neoplasia of the cervix.
520 patients with a preoperative diagnosis of cervical intraepithelial neoplasia (CIN) were operated. The diagnoses obtained by colposcopically directed biopsy and endocervical curettage were compared with those obtained by cone biopsy or/and hysterectomy. Underdiagnosis occurred in 18.9% of the cases, if severe dysplasia and carcinoma in situ were considered to be separate conditions. When these two diagnoses were combined as CIN 3 the underdiagnosis rate declined to 11.0%. CIN 3 changed to invasive carcinoma in 1.5% and to microinvasive carcinoma in 4.4% of the cases. The preoperative diagnosis of CIN seems not to be accurate enough to make cone biopsy totally unnecessary as a complementary diagnostic step.