Molecular mechanisms for the antitumor activity of inositol hexakisphosphate (IP6).
Inositol hexakisphosphate (IP6), a naturally occurring polyphosphorylated carbohydrate, has been reported to have significant in vivo and in vitro anticancer activity against numerous tumors. However, the molecular mechanism of the anticancer effect of IP6 has not been fully elucidated. Using K-562 human leukemia cells we analysed the induction of the erythroid differentiation program, as well as modulation of the gene expression profile of K-562 leukemia cells treated with IP6. A single treatment with IP6 (0.75 or 5.0 mM) resulted in a time- and dose-dependent growth inhibition of K-562 cells and also activation of the erythroid differentiation program. K-562 cells expressed a concomitant differentiation after 12 hours of exposure. Possible molecular mechanisms and key signaling pathways, as well as gene expression behind this anticancer effect were examined using oligonucleotide microarrays and quantitative real-time PCR. Treatment with IP6 (750 microM, 5 mM) had a marked impact, resulting in early (60 min) and late (12 h) modulation of expression of about 1800 and 1200 transcripts (at p<0.05). Through microarray analysis, the anticancer effect of IP6 in K-562 was found to be associated with the modulation of multiple genes involved in immunity, Wnt and IGF pathways, PI3 kinase signaling and apoptosis. Using selected subsets of genes, the microarray hits could be validated by Q-PCR. A 2-fold upregulation of the apoptosis pathway, measured using the BAX/BCL-2 ratio was observed for 12 hours. IP6 (5 mM) induced up to 6-fold increases in differentiation measured by hemoglobin synthesis, yielding up to 70% of benzidine-positive cells at 120 hours. The results of this study show that IP6 is a strong inducer of differentiation (cytostatic effect) and a moderately strong inducer of apoptosis (cytotoxic effect). Evidence has been provided to show that the growth inhibitory effects of IP6 are mediated through the modulation of key signaling pathways.


[Congenital adrenal hyperplasia: clinical aspects and neonatal screening].
Congenital adrenal hyperplasia (CAH) is a disorder of adrenal steroid synthesis. In 95% of CAH cases, it is caused by 21-hydroxylase deficiency, leading to cortisol deficiency and (in most cases) aldosterone deficiency. The compensatory increase in ACTH secretion by the pituitary gland leads to stimulation of the adrenal glands and, consequently, overproduction of androgens. The classic form is well known due to the congenital virilisation seen in affected girls. However, the cortisol and aldosterone deficiency is at least equally important in both sexes as it can cause an Addisonian crisis within the first weeks of life. For these reasons, a neonatal CAH screening program has been introduced in the Netherlands. Screening results in earlier detection and treatment. The prevalence of the classic form of the disease is 1:12.000 in the Netherlands. Non-classic 21-hydroxylase deficiency is more frequent, presenting with signs of androgen excess from childhood through to adulthood. Treatment of CAH consists of hormonal replacement and surgical correction in case of congenital virilisation in girls. Long-term treatment results, including height at adulthood, have improved over the last decades. Nevertheless, fertility problems can occur in both sexes.


Food-dependent exercise-induced anaphylaxis occurred only in a warm but not in a cold environment.
Food-dependent exercise-induced anaphylaxis (FDEIA) is a type of exercise-induced anaphylaxis associated with postprandial exercise. We describe a 19-year-old man with FDEIA. Our patient complained of urticaria, angioedema, dizziness and hypotension associated with exercise after ingestion of walnut-containing foods in a warm environment. Skin prick test and prick to prick test were positive for walnut antigen. The attack didn't occur by free running outside for 10 min 2 h after taking walnuts, and the temperature was about -2℃. Food-exercise test was done again in a warm environment based on prior history. Anaphylaxis was developed after exercise for 10 min in a warm environment after taking walnuts. Some environmental factors such as high temperature and high humidity or cold temperature may influence exercise-induced anaphylaxis. In our case, the cofactor was a warm environment: the challenge test done in a cold environment was negative, but positive in a warm environment. Physicians should be aware that the challenge test of FDEIA can show different results depending on temperature.


Menopause and mental well-being: timing of symptoms and timing of hormone treatment.
In the aftermath of the Women's Health Initiative studies, both the clinical and basic science communities had to sort out divergent results among experimental findings, observational data and randomized controlled trials in order to establish a shared analysis. The scientific community formally debates the role of different HRT formulations, hormone doses, time of treatment initiation since the menopause and the age of treated women. Basic scientists demonstrated that the multiple neuroprotective effects of estrogen on brain cells may induce a differential biological response according to the time of treatment. Progesterone (but not all synthetic progestins) also has pivotal neuroactive functions in animal models of reproductive aging. Additionally, epidemiological surveys provide information regarding the detrimental role of hypogonadism on mental well-being. The present article briefly summarizes current evidence supporting the neuroactive role of estrogen, with reference to the clinical finding sustaining the intriguing hypothesis of the early female brain senescence as a highly responsive period to estrogen treatment.


Seed germination from lowland tapir (Tapirus terrestris) fecal samples collected during the dry season in the Northern Brazilian Amazon.
This study evaluated the potential of lowland tapirs as seed dispersers in the northern Brazilian Amazon. The study analyzed the viability of seeds after passage through the gut. Fecal samples were collected from 6 different vegetation physiognomies in Viruá National Park during the dry season. The samples were then kept in a greenhouse for 16 months to allow the seeds to germinate. The seedling species were identified and classified according to the type of fruit, plant habit, seed size and type of ingestion. Of the 111 fecal samples, 94 (84.7%) had viable seeds of 75 species. Melastomataceae was the most frequent family with viable seeds in the fecal samples (69.1% of samples, N= 18 species). The data suggest that the importance of the lowland tapirs as dispersers is not restricted to the species consumed actively by frugivory but also extends to species accidentally consumed during browsing. The occurrence of both large and small viable seeds in the fecal samples as well as a number of large drupes, which probably cannot be transported via endozoochory by any other animal species, provide evidence of the ecological importance of lowland tapirs to the dynamics of the forest-campinarana vegetation mosaic in the region.


Remote care for mental health: qualitative study with service users, carers and staff during the COVID-19 pandemic.
To explore the experiences of service users, carers and staff seeking or providing secondary mental health services during the COVID-19 pandemic. Qualitative interview study, codesigned with mental health service users and carers. We conducted semistructured, telephone or online interviews with a purposively constructed sample; a lived experience researcher conducted and analysed interviews with service users. Analysis was based on the constant comparison method. National Health Service (NHS) secondary mental health services in England between June and August 2020. Of 65 participants, 20 had either accessed or needed to access English secondary mental healthcare during the pandemic; 10 were carers of people with mental health difficulties; 35 were members of staff working in NHS secondary mental health services during the pandemic. Experiences of remote care were mixed. Some service users valued the convenience of remote methods in the context of maintaining contact with familiar clinicians. Most participants commented that a lack of non-verbal cues and the loss of a therapeutic 'safe space' challenged therapeutic relationship building, assessments and identification of deteriorating mental well-being. Some carers felt excluded from remote meetings and concerned that assessments were incomplete without their input. Like service users, remote methods posed challenges for clinicians who reported uncertainty about technical options and a lack of training. All groups expressed concern about intersectionality exacerbating inequalities and the exclusion of some service user groups if alternatives to remote care are lost. Though remote mental healthcare is likely to become increasingly widespread in secondary mental health services, our findings highlight the continued importance of a tailored, personal approach to decision making in this area. Further research should focus on which types of consultations best suit face-to-face interaction, and for whom and why, and which can be provided remotely and by which medium.


Oxygen tensiometry as a predictor of wound healing in total ankle arthroplasty.
Total ankle arthroplasty (TAA) typically involves an anterior approach to the ankle that has been shown to have a risk for wound healing problems. We explored the possibility of using oxygen tensiometry as a predictor of incision healing problems in patients undergoing TAA. The study included 25 patients who underwent TAA with the Scandinavian Total Ankle Replacement (STAR) system at our institution during a three-year period. Transcutaneous oxygen measurements of both ankles were obtained postoperatively to determine whether the results of transcutaneous oxygen tensiometry correlated with wound healing problems. Patients with wound healing problems were compared with those who had an uneventful incision healing. Seven patients (28%) had wound healing problems after TAA, and five patients (20%) had early wound erythema. Wound healing problems included delayed healing in five patients and dehiscence in two patients. Three patients had transcutaneous oxygen tension of less than 40 mmHg (a threshold for impaired skin oxygenation) on the operative side, of whom one had healing difficulty whereas two did not. When the threshold was extended to 50 mmHg, seven patients (28%) had low readings, two having wound healing problems. There was no significant difference with respect to oxygen measurements between patients with and without wound healing problems (p=0.3). Oxygen tensiometry is not thought to be useful for predicting patients at risk for postoperative wound healing complications after TAA, suggesting that, if adequate pulses are present before surgery, the trauma of using excessive superficial traction on the skin during surgery is more responsible for wound healing problems than the underlying blood supply.


Combining Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors to Target Multiple Organ Defects in Type 2 Diabetes.
Long-term risks of macro- and microvascular complications may be reduced in people with type 2 diabetes who achieve early and sustained glycemic control. Delays in attaining A1C goals are associated with poor long-term cardiovascular (CV) outcomes. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are glucose-lowering therapies that act through complementary mechanisms of action with regard to the pathophysiologic defects of type 2 diabetes. Trials of agents in both drug classes have demonstrated improvements in CV and renal outcomes. This review discusses the rationale for combination therapy with a GLP-1 receptor agonist and an SGLT2 inhibitor, including early initiation of this combination in newly diagnosed patients. This combination may lead to timely glycemic control and potentially additive CV and renal benefits. Clinical studies of the combination have shown partially additive effects on A1C reduction, additive effects on weight reduction, and potentially synergistic effects on blood pressure reduction. Long-term studies are needed to determine whether the combination provides an additional effect on CV and renal outcomes compared with agents from either drug class when used alone.


Amyloid PET in clinical practice: Its place in the multidimensional space of Alzheimer's disease.
Amyloid imaging is currently introduced to the market for clinical use. We will review the evidence demonstrating that the different amyloid PET ligands that are currently available are valid biomarkers for Alzheimer-related β amyloidosis. Based on recent findings from cross-sectional and longitudinal imaging studies using different modalities, we will incorporate amyloid imaging into a multidimensional model of Alzheimer's disease. Aside from the critical role in improving clinical trial design for amyloid-lowering drugs, we will also propose a tentative algorithm for when it may be useful in a memory clinic environment. Gaps in our evidence-based knowledge of the added value of amyloid imaging in a clinical context will be identified and will need to be addressed by dedicated studies of clinical utility.


Screening membrane interactions of pesticides by cells decorated with chromatic polymer nanopatches.
Elucidating the factors contributing to the cell toxicity of pesticides and other environmentally sensitive small molecules is critical for evaluation of their health impacts and for understanding the biological processes that they affect. Disruption and permeation of the plasma membrane, which constitutes the critical interface between the cell and its environment, are recognized initiators of cytotoxicity. We present a new approach for predicting pesticide cytotoxicity through rapid screening of membrane interactions of pesticides using a recently developed live-cell chromatic sensor. The sensing platform comprises living mammalian cells labeled with polydiacetylene (PDA), a chromatic polymer that undergoes intense fluorescence transformations induced by structural perturbations of the membrane bilayer. Within a short time after the addition of membrane-interacting tested compounds to the labeled cells, the PDA patches emit high fluorescence, which can be monitored by conventional spectroscopy and microscopy apparatuses. The chromatic technology facilitates rapid evaluation of membrane activity of pesticide compounds and is capable of distinguishing between toxic effects associated with membrane interactions vs intracellular mechanisms.


Increase in the intensity of an optical signal with fluorescein during proton and carbon-ion irradiation.
Although the imaging of luminescence emitted in water during irradiation of protons and carbon ions is a useful method for range and dose estimations, the intensity of the images is relatively low due to the low photon production of the luminescence phenomenon. Therefore, a relatively long time is required for the imaging. Since a fluorescent dye, fluorescein, may increase the intensity of the optical signal, we measured the luminescence images of water with different concentrations of fluorescein during irradiation of protons and carbon ions and compared the results with those by measurements with water. A cooled charge-coupled device (CCD) camera was used for imaging a water phantom with different concentrations of fluorescein from 0.0063 to 0.025 mg/cm3 , in addition to a water phantom without fluorescein during irradiation of 150-MeV protons and 241.5-MeV/n carbon ions. For both protons and carbon ions, the intensity of the luminescence images increased as the concentration of fluorescein increased. With a fluorescein concentration of 0.025 mg/cm3 , the intensities increased to more than 10 times those of water for both protons and carbon ions. Although the shape of the depth profiles of luminescence images of water with fluorescein appeared similar to that of water for protons, those for carbon ions were different from those of water due to the increase in the Cherenkov light component at shallow depths by the decrease in the angular dependencies of the Cherenkov light. We confirmed the increase in intensity of the luminescence of water by adding fluorescein for particle ions. With a small amount of Cherenkov light contamination in the images, such as protons, the relative distributions of the luminescence images with fluorescein were similar to that of water and will be used for range or dose determination in a short time.


Safety and effectiveness of ceftaroline fosamil in children: a systematic review and meta-analysis.
Antibiotic resistance is an increasingly growing health problem worldwide, so it is imperative to look for new, more effective antibiotics. Ceftaroline has a broad spectrum of activity against clinically relevant Grampositive strains, including methicillin-resistant Staphylococcus aureus and resistant Streptococcus pneumoniae strains, as well as Gram-negative pathogens implicated in skin and soft tissue infections or community-acquired pneumonia; it is therefore a potential therapeutic option. We conducted a systematic review to assess whether ceftaroline was safer and more effective than comparators. A comprehensive bibliographic search was done to identify experimental clinical trials that compared the safety and effectiveness of ceftaroline to a comparator in the pediatric population. The rate of therapeutic failure was used to determine the effectiveness, while the presence of any adverse event was considered for safety. Three studies were identified: two in community-acquired pneumonia and one in skin and soft tissue infections. No study showed a difference in the risk for therapeutic failure, relative risk (RR): 0.97 (0.54-1.73), or safety criterion, RR: 0.79 (0.51-1.23). The available evidence suggests that ceftaroline may be a valid therapeutic option for the management of skin and soft tissue infections or community-acquired pneumonia in pediatric patients. No studies with a high-quality of evidence were observed in other types of infections or in patients admitted to the critical care unit.


Insights into the Genetic Evolution of Duck Hepatitis A Virus in Egypt.
Duck hepatitis virus (DHV) is one of the commercially important diseases of ducklings worldwide. It is an acute and highly infectious disease of ducklings caused by three different serotypes (1-3) of duck hepatitis A virus (DHAV), and serotype 1 is the most common in poultry. To date, little is known about the prevalence and genetic characterisation of DHAV-1 in Egypt. In the current study, isolation and complete genomic analyses of DHAVs circulating in commercial duck farms in different Egyptian governorates were conducted. A total of eighteen samples were collected from six Egyptian governorates of 3-11 days old ducklings (Pekin and Mullard) with a history of nervous signs and high mortality rates. Five out of eighteen (5/18) samples were screened positive for the DHAV-1 based on the VP1 gene. These samples were individually used for virus isolation in embryonated duck embryos (EDE), followed by complete genome sequencing. Phylogenomic analyses showed that DHAV serotype I; genotype I were diversified into four different groups (1-4). Most of the recent circulating Egyptian DHAV strains are clustered within group 4, while isolates characterised within this study were clustered within group 1. Recombination analyses revealed that the emergence of a new recombinant virus-DHAV-1 strain Egypt-10/2019-through recombination. Likewise, the selective pressure analyses showed the existence, inside or near areas of the viral attachment or related functions, of positive scores highlighting the importance of natural selection and viral evolution mechanism at different protein domains. The findings of this study provide updated information on the epidemiological and genetic features of DHAV-1 strains and underscore the importance of DHAV surveillance as well as re-evaluation for currently used vaccines.


Impact of traveling on transmission trends of human monkeypox disease: worldwide data based observational analysis.
Human monkeypox is an emerging viral zoonotic disease caused by a monkeypox virus (MPXV). This year since early May 2022, the virus swiftly spread involved 94 countries, and 41,358 people, and has developed a highly challenging and threatening situation worldwide. This study aimed to investigate the impact of traveling on the transmission of human monkeypox disease and comprehend the link between monkeypox exported cases in the context of the global outbreak. In this study, we identified data from two leading health organizations, the World Health Organization (WHO), and the Centers for Disease Control Prevention (CDC), as well as 40 documents that were identified through the search engines Web of Science, Pub-Med, Medline, EMBASE, Scopus, and Google Scholar using the keywords "monkeypox," "human monkeypox," "imported"', "exportation" "travelers," and "prevalence." Finally, two international organizations WHO, and CDC, and out of 40 documents, 10 (25.0%) were included in the analysis, and the remaining 30 (75.0%) documents were excluded. The studies originated from the United Kingdom, the United States of America, Singapore, Israel, the Republic of Korea, Taiwan, and India. The data on transmission trends and human monkeypox was recorded and analyzed. The epidemiological data for exported monkeypox cases were analyzed jointly for understanding the transmission trends of exportations and the geographic context of the monkeypox outbreak. Ten people had a travel history, six had a travel history from Nigeria to the United Kingdom (2), Nigeria to the United States of America (2), Nigeria to Singapore (1) and Nigeria to Israel (1). Moreover, from Germany to Taiwan (1), Germany to the Republic of Korea (1) and the United Arab Emirates to India (2). Among these 10 people, all travelers were male (100%), with age ranges of 20-38 years, seven people (70%) developed clinical symptoms before the start of travel, three people (30%) developed symptoms 2-6 days after the travel, and one person (10%) developed clinical symptoms in the flight during the journey. The study findings conclude that traveling can cause the spread of human monkeypox disease in various countries. The findings support the hypothesis that virus sources can travel and spread the disease from person to person and from region to region. The international health authorities must implement global preventive policies to control the burden of the disease both at regional and international levels.


The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer.
The Keap1-Nrf2 pathway is the major regulator of cytoprotective responses to oxidative and electrophilic stress. Although cell signaling pathways triggered by the transcription factor Nrf2 prevent cancer initiation and progression in normal and premalignant tissues, in fully malignant cells Nrf2 activity provides growth advantage by increasing cancer chemoresistance and enhancing tumor cell growth. In this graphical review, we provide an overview of the Keap1-Nrf2 pathway and its dysregulation in cancer cells. We also briefly summarize the consequences of constitutive Nrf2 activation in cancer cells and how this can be exploited in cancer gene therapy.


Prospective Registry of Embolization of Intracranial Aneurysms Using HydroSoft Coils: Results of the Japanese HydroSoft Registry.
The effect of HydroSoft coils on the prevention of recanalization and thrombosis after embolization is unclear. We herein report the results of the single-armed prospective Japanese HydroSoft Registry. Aneurysms with a diameter of <10 mm that were treated with a ≥50% length of HydroSoft coils were registered. We evaluated the safety and recanalization rate and analyzed the factors related to their recanalization and thrombosis 1 year later. In total, 122 aneurysms were registered. Their mean maximum diameter and neck length were 6.4 and 3.9 mm, respectively. The mean length of the HydroSoft coils was 84.3%. No intracranial hemorrhage occurred, but 2 patients developed minor ischemic strokes. Angiographic examination immediately after the procedure showed complete obliteration, neck remnant (NR), and body filling (BF) in 20 (16.4%), 32 (26.2%), and 67 (54.9%) cases, respectively. One-year follow-up angiography showed complete obliteration, NR, and BF in 68 (55.7%), 15 (12.3%), and 15 (12.3%) cases, respectively, and 5 aneurysms (4.1%) were recanalized (4 and 1 with BF and NR as their initial angiographic result, respectively). Another 11 aneurysms still showed BF, although their thrombosis was promoted. No significant factors related to recanalization were identified. A high volume embolization ratio and small neck were significantly associated with thrombosis 1 year after embolization with HydroSoft coils. The safety and prevention of recanalization 1 year after the treatment appeared acceptable. The high volume embolization ratio associated with HydroSoft coils could induce progression of thrombosis for aneurysms characterized by NR and BF during the follow-up period.


Quality of Life Improvements in Patients with Lymphedema After Surgical or Nonsurgical Interventions with 1-Year Follow-Up.
Background: Lymphedema may impact patients' health-related quality of life (HRQoL). The purpose of this study was to evaluate HRQoL after two different treatments to the 12-month follow-up point. Methods and Results: Study participants were patients with moderate lymphedema in the upper or lower limb who attended a Swedish rehabilitation program (RP) undergoing conservative treatment, or those with severe, chronic lymphedema dominated by excess adipose tissue, who underwent liposuction (LS) combined with controlled compression therapy (CCT) in Australia, Scotland, or Sweden. The patients completed the Lymphedema Quality of Life Inventory (LyQLI) before intervention and after 1, 3, 6, and 12 months. Mean values and standard deviations were calculated for total limb volume and excess limb volume. Mean values were also calculated for the three LyQLI domains (physical, psychosocial, and practical). To detect and analyze differences in LyQLI responses in the three domains, the Wilcoxon signed rank test was performed. In the RP, 18 eligible patients completed the LyQLI. The results show improvements in HRQoL in physical (p = 0.003) and psychosocial domains (p = 0.002) at 1 month after the RP, with results remaining steady for 12 months for the physical domain (p = 0.024). Fifty-seven eligible LS patients completed the LyQLI. The results show improvements in HRQoL in all three domains (p < 0.001), with results remaining steady up to the 12-month follow-up (p < 0.001). The total volume in affected limb and the excess volume decreased significantly in both patient groups 1 month after intervention (p < 0.001). Conclusions: Treatment with a conservative RP in moderate lymphedema or with LS combined with CCT in severe lymphedema improves HRQoL.


Update on patient privacy legislation.
The administrative simplification provisions of HIPAA will establish the first national standards for the electronic transmission of health care transactions with which all federal programs (DOD, Medicare, and Medicaid) and all private health plans must comply. Individuals and organizations should prepare themselves, their systems, and their processes to meet these new administrative and financial data standards and requirements. The benefits of standardized electronic transactions on achieving a single paper-free claims submission to be used by all providers and payers is of obvious benefit. Not so obvious are consequences associated with limiting the access and use of existing data repositories on a variety of clinical, administrative, and research functions. It is critically important in this age of increased accountability for fiscal restraint and improving the outcomes of entire patient populations that clinicians, managers, organizations, and researchers to use data for a variety of clinical, quality improvement/evaluation, and research purposes. Administrative simplification and protecting individual privacy should not be achieved by overly bureaucratic and restrictive responses that impede epidemiologic and health services research, quality improvement activities, and optimization strategies for improving the health of populations. While the health system understands the need for some increased regulation to ensure the privacy of individual patient privacy in the "wired" world solutions must be found and overly restrictive consequences associated with prohibiting access to data must be resolved. More than ever, the entire system requires data to inform every level and type of decision made. Legislation and bureaucratic processes that do not understand and support responsible data-driven decision-making will serve to roll-back, not advance health system improvement. As we prepare ourselves for HIPAA compliance and the expectations of the benefits it will achieve, we must wait to see what impact it will have on clinical, administrative, and research functions concerned with improvement.


Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity.
To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures. Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture. Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-alpha of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07). Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-alpha and in vitro sensitivity in a small number of patients.


Use of the Italian version of the Pediatric Asthma Quality of Life Questionnaire in the daily practice: results of a prospective study.
Asthma is a serious global health problem and its prevalence is increasing, especially among children. It represents a significant social and economic burden, and it can severely affect the health-related quality of life (HRQL) of patients. Among the numerous questionnaires aiming at evaluating asthma HRQL in children, the Pediatric Asthma Quality of Life Questionnaire (PAQLQ) has proved to have good measurement properties.The present study was aimed at investigating the possible role of the Italian, self-administered version of the PAQLQ in the routine clinical evaluation of children affected by bronchial asthma. 52 Italian children and adolescents (40 males and 12 females), aged 6 to 17 years, affected by allergic asthma, were enrolled. Each patient was evaluated twice, and at each visit asthma control and severity were assessed, spirometry was performed and the patients completed the self-administered version of the PAQLQ. The questionnaire was well-accepted and understood by the children. Children showed an overall good quality of life, with mild impairment in the activity and emotional function domains. The PAQLQ showed an overall good correlation with the clinical and functional indexes that are normally evaluated in follow-up visits of asthmatic patients. The PAQLQ appeared to be strongly related to asthma control, both at the first (p < 0.01) and second (p < 0.001) time of the study. The PAQLQ was also seen to decrease with increasing asthma severity. The results suggest a better compliance of the children towards completion of the questionnaire at t1. Finally, the PAQLQ does not appear to discriminate HRQL in patients with good lung function. The Italian version of the PAQLQ is a quick-to-administer aid to clinical activity and can add valuable information to symptom reports, objective measurements and clinical assessment of asthma control and severity in daily clinical practice. Re-administration at each follow-up visit allows HRQL to be monitored over time.


The impact of MLC transmitted radiation on EPID dosimetry for dynamic MLC beams.
The purpose of this study was to experimentally quantify the change in response of an amorphous silicon (a-Si) electronic portal imaging device (EPID) to dynamic multileaf collimator (dMLC) beams with varying MLC-transmitted dose components and incorporate the response into a commercial treatment planning system (TPS) EPID prediction model. A combination of uniform intensity dMLC beams and static beams were designed to quantify the effect of MLC transmission on EPID response at the central axis of 10 x 10 cm2 beams, at off-axis positions using wide dMLC beam profiles, and at different field sizes. The EPID response to MLC transmitted radiation was 0.79 +/- 0.02 of the response to open beam radiation at the central axis of a 10 x 10 cm2 field. The EPID response to MLC transmitted radiation was further reduced relative to the open beam response with off-axis distance. The EPID response was more sensitive to field size changes for MLC transmitted radiation compared to open beam radiation by a factor of up to 1.17 at large field sizes. The results were used to create EPID response correction factors as a function of the fraction of MLC transmitted radiation, off-axis distance, and field size. Software was developed to apply the correction factors to each pixel in the TPS predicted EPID image. The corrected images agreed more closely with the measured EPID images in areas of intensity modulated fields with a large fraction of MLC transmission and, as a result the accuracy of portal dosimetry with a-Si EPIDs can be improved. Further investigation into the detector response function and the radiation source model are required to achieve improvements in accuracy for the general case.


Characterization and localization of adenosine 3':5'-monophosphate-binding proteins in the nervous system of Aplysia.
Earlier work in Aplysia californica has indicated that sensitization of the gill reflex, a simple form of learning, is produced by cAMP-dependent protein phosphorylation which regulates the flux of ions in sensory neurons of the abdominal ganglion. These changes in ion flux result in the enhanced release of neurotransmitter from synapses of the sensory neurons which, in turn, mediate the behavior. Because it can be presumed that protein phosphorylation regulates the functioning of ion channel proteins, we have characterized cAMP-binding proteins photoaffinity labeled with 8-N3-cAMP and have found that, unlike other tissues, the nervous system contains a great variety of binding species. Also unlike other tissues, several of the binding proteins in neurons are associated with membrane, and these components are concentrated in fractions enriched in nerve endings. Selectivity of phosphorylation, not only between substrates in cytosol and membrane but also between different regions of the cell, is thus possible because of the variety of cAMP-binding proteins in neurons. We think that these membrane-associated binding proteins are the most likely candidates for the regulatory subunits of the cAMP-dependent kinases that control the functioning of ion channel proteins at the synapse.


Oxidation and reduction control of the inactivation gating of Torpedo ClC-0 chloride channels.
Oxidation and reduction (redox) are known to modulate the function of a variety of ion channels. Here, we report a redox regulation of the function of ClC-0, a chloride (Cl(-)) channel from the Torpedo electric organ. The study was motivated by the occasional observation of oocytes with hyperpolarization-activated Cl(-) current when these oocytes expressed ClC-0. We find that these atypical recording traces can be turned into typical ClC-0 current by incubating the oocyte in millimolar concentrations of reducing agents, suggesting that the channel function is regulated by oxidation and reduction. The redox control apparently results from an effect of oxidation on the slow (inactivation) gating: oxidation renders it more difficult for the channel to recover from the inactivated states. Introducing the point mutation C212S in ClC-0 suppresses the inactivation state, and this inactivation-suppressed mutant is no longer sensitive to the inhibition by oxidizing reagents. However, C212 is probably not the target for the redox reaction because the regulation of the inactivation gating by oxidation is still present in a pore mutant (K165C/K165 heterodimer) in which the C212S mutation is present. Taking advantage of the K165C/K165 heterodimer, we further explore the oxidation effect in ClC-0 by methane thiosulfonate (MTS) modifications. We found that trimethylethylammonium MTS modification of the introduced cysteine can induce current in the K165C/K165 heterodimer, an effect attributed to the recovery of the channel from the inactivation state. The current induction by MTS reagents is subjected to redox controls, and thus the extent of this current induction can serve as an indicator to report the oxidation state of the channel. These results together suggest that the inactivation gating of ClC-0 is affected by redox regulation. The finding also provides a convenient method to "cure" those atypical recording traces of ClC-0 expressed in Xenopus oocytes.


Age-associated deficits in pattern separation functions of the perirhinal cortex: a cross-species consensus.
Normal aging causes a decline in object recognition. Importantly, lesions of the perirhinal cortex produce similar deficits and also lead to object discrimination impairments when the test objects share common features, suggesting that the perirhinal cortex participates in perceptual discrimination. The current experiments investigated the ability of young and aged animals to distinguish between objects that shared features with tasks with limited mnemonic demands. In the first experiment, young and old rats performed a variant of the spontaneous object recognition task in which there was a minimal delay between the sample and the test phase. When the test objects did not share any features ("Easy" perceptual discrimination) both young and aged rats correctly identified the novel object. When the test objects contained overlapping features, however, only the young rats showed an exploratory preference for the novel object. In Experiment 2, young and aged monkeys were tested on an object discrimination task. When the object pairs were dissimilar, both the young and aged monkeys learned to select the rewarded object quickly. In contrast, when LEGOs® were used to create object pairs with overlapping features, the aged monkeys took significantly longer than did the young animals to learn to discriminate between the rewarded and the unrewarded object. Together, these data indicate that behaviors requiring the perirhinal cortex are disrupted in advanced age, and suggest that at least some of these impairments may be explained by changes in high-level perceptual processing in advanced age.


HIV prevention needs among street-based male sex workers in Providence, Rhode Island.
We examined data derived from a needs assessment of the personal and social characteristics and HIV risk behavior of street-based male sex workers, in Providence, Rhode Island, who engage in transactional sexual intercourse with other men. Substance use, injected drugs, needle sharing, and psychosocial distress were highly prevalent among the sample. History of physical, sexual, and emotional abuse was associated with increased risk of condomless anal sexual intercourse with paying male clients.


Inadequate prophylactic effect of low-molecular weight heparin in critically ill COVID-19 patients.
The aim of this study was to investigate potential markers of coagulopathy and the effects of thromboprophylaxis with low-molecular-weight heparin (LMWH) on thromboelastography (TEG) and anti-factor Xa in critically ill COVID-19 patients. We conducted a prospective study in 31 consecutive adult intensive care unit (ICU) patients. TEG with and without heparinase and anti-factor Xa analysis were performed. Standard thromboprophylaxis was given with dalteparin (75-100 IU/kg subcutaneously). Five patients (16%) had symptomatic thromboembolic events. All patients had a maximum amplitude (MA) > 65 mm and 13 (42%) had MA > 72 mm at some point during ICU stay. Anti-factor Xa activity were below the target range in 23% of the patients and above target range in 46% of patients. There was no significant correlation between dalteparin dose and anti-factor Xa activity. Patients with COVID-19 have hypercoagulability with high MA on TEG. The effect of LMWH on thromboembolic disease, anti-factor Xa activity and TEG was variable and could not be reliably predicted. This indicates that standard prophylactic doses of LMWH may be insufficient. Monitoring coagulation and the LMWH effect is important in patients with COVID-19 but interpreting the results in relation to risk of thromboembolic disease poses difficulties.


Saddle block analgesia for high-dose-rate brachytherapy: A prospective study.
To determine effective spinal anesthetic dosing of hyperbaric bupivacaine for patients undergoing high-dose-rate (HDR) brachytherapy for prostate cancer. A total of 199 HDR prostate brachytherapy sessions (n=115 patients) under spinal anesthesia with five doses of hyperbaric bupivacaine were prospectively analyzed. Patients received either 11.25mg (n=40 sessions), 15mg (n=63 sessions), 18mg (n=25 sessions), 18.75mg (n=17 sessions), or 20.25mg (n=54 sessions) of 0.75% of bupivacaine with 20microg of fentanyl in 8.25% of dextrose (Hospira, Healthcare Corporation, Montréal, Canada). Sensory block level, intraoperative hypotension, incidence of nausea and vomiting, time to ambulation, and time to discharge were recorded. We assessed for the presence of any transient neurologic symptoms post discharge. The 11.25-mg group had a mean peak sensory block height of L1 at 90min, which was significantly lower than the other groups. Block heights were also decreased at the 5, 60, 120, 150, 180, and 300min time points (p<0.05). The mean time to ambulation was 403+/-92min and to discharge was 427+/-70min; no difference among groups was found. Hypotension was not observed in the 11.25-mg group, whereas the incidence of operative hypotension was 8% in each of the other groups. No transient neurologic symptoms were reported postoperatively. The 11.25-mg dose of hyperbaric bupivacaine was sufficient to provide intraoperative anesthesia for catheter placement and sufficient postoperative residual analgesia for the duration that the catheters were left in situ and subsequently removed.


Software platform for rapidly creating computational tools for mass spectrometry-based proteomics.
We describe and demonstrate the proteomics computational toolkit provided in the open-source msInspect software distribution. The toolkit includes modules written in Java and in the R statistical programming language to aid the rapid development of proteomics software applications. It contains tools for processing and manipulating standard MS data files, including signal processing of LC-MS data and parsing of MS/MS search results, as well as for modeling proteomics data structures, creating charts, and other common tasks. We present this toolkit's capability to rapidly develop new computational tools by presenting an example application, Qurate, a graphical tool for manually curating isotopically labeled peptide quantitative events.


Genetic susceptibility to refractive error: association of vasoactive intestinal peptide receptor 2 (VIPR2) with high myopia in Chinese.
Myopia is the most common ocular disease worldwide. We investigated the association of high myopia with the common single nucleotide polymorphisms (SNPs) of five candidate genes - early growth response 1 (EGR1), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS), jun oncogene (JUN), vasoactive intestinal peptide (VIP), and vasoactive intestinal peptide receptor 2 (VIPR2). We recruited 1200 unrelated Chinese subjects with 600 cases (spherical equivalent ≤-8.00 diopters) and 600 controls (spherical equivalent within ±1.00 diopter). A discovery sample set was formed from 300 cases and 300 controls, and a replication sample set from the remaining samples. Tag SNPs were genotyped for the discovery sample set, and the most significant haplotypes and their constituent SNPs were followed up with the replication sample set. The allele and haplotype frequencies in cases and controls were compared by logistic regression adjusted for sex and age to give P a values, and multiple comparisons were corrected by permutation test to give P aemp values. Odd ratios (OR) were calculated accordingly. In the discovery phase, EGR1, JUN and VIP did not show any significant association while FOS and VIPR2 demonstrated significant haplotype association with high myopia. In the replication phase, the haplotype association for VIPR2 was successfully replicated, but not FOS. In analysis combining both sample sets, the most significant association signals of VIPR2 were the single marker rs2071625 (P a = 0.0008, P aemp = 0.0046 and OR = 0.75) and the 4-SNP haplotype window rs2071623-rs2071625-rs2730220-rs885863 (omnibus test, P a = 9.10e-10 and P aemp = 0.0001) with one protective haplotype (GGGG: P aemp = 0.0002 and OR = 0.52) and one high-risk haplotype (GAGA: P aemp = 0.0027 and OR = 4.68). This 4-SNP haplotype window was the most significant in all sample sets examined. This is the first study to suggest a role of VIPR2 in the genetic susceptibility to high myopia. EGR1, JUN, FOS and VIP are unlikely to be important in predisposing humans to high myopia.


Changing relationship with voices: new therapeutic perspectives for treating hallucinations.
A growing body of research on verbal hallucinations shows the importance of beliefs about and relationships with the voices for their pathological course. In particular, beliefs about the omnipotence of the voices and the need to control them, and relationships with them that involve efforts to resist or fight them, have shown themselves to be more pathogenic than effective. Likewise, treatments aimed at eliminating the voices, be they based on medication or 'traditional' cognitive-behavioural therapy, have not always been successful. A series of strategies focused on changing relationships with the voices instead of trying to eliminate them-including mindfulness, acceptance, experiential role plays and re-authoring lives-is emerging as a new perspective for the treatment of hallucinations. All of these strategies are based on the person, not on the syndrome, which also represents a new conception of the problem, in a phenomenological-social perspective, alternative to the predominant medical conception.


Correlation analysis of feeding intolerance and defecation after primary anastomosis for neonatal intestinal atresia.
To investigate the correlation between postoperative feeding intolerance and defecation, with a view to carrying out prognostic assessment and timely intervention for the recovery of postoperative gastrointestinal function. The 114 neonates with congenital intestinal atresia who underwent primary anastomosis admitted to Shenzhen Children's Hospital from January 2014 to December 2022 were studied, and the patients' basic information, intraoperative conditions, postoperative feeding and defecation, and hospitalization time were retrospectively analyzed. The risk factors for feeding intolerance after primary anastomosis for intestinal atresia are the gestational days, the time of the first postoperative defecations, the number of defecations on the previous day and the average number of defecations before feeding. The incidence of postoperative feeding intolerance is higher in preterm infants, and pediatricians can decide the timing of breastfeeding on the basis of the patients' defecation. The focus on accurate defecation may be more meaningful in determining and predicting postoperative feeding intolerance in the infants.


Abortion without free and informed consent? An Austrian case of first impression.
Notwithstanding the question of whether abortion is generally or exceptionally a legitimate means of family planning, it is basically agreed that abortion is not justifiable without free and informed consent of the pregnant woman. However, if abortion is held by the legislature to be a "ground of justification" (i.e., a far-reaching exception to criminal liability), is it true that abortion may also be carried out for the benefit of a pregnant woman who is not able to give free and informed consent? Should a substituted-judgment approach be applied in cases where the woman is incompetent to decide? Or should the pregnant woman's relatives' interests be taken into account exclusively? The author tries to answer these questions, which were tackled by the Austrian Supreme Court in a recent case.


Estrogen favors the differentiation of ovarian tissues in the ambisexual gonads of anemonefish Amphiprion clarkii.
All undifferentiated gonads of anemonefish first differentiate into ovaries, and then testicular tissue appear among ovarian tissue, and finally form ambisexual gonads with both ovarian and testicular tissues. The role of estradiol-17beta (E2) in differentiation of ovarian cells is well conserved across phyla; however, its role in development of ambisexual gonads is poorly understood. Here we demonstrate that the E2 produced during the differentiation of ovarian cells does not allow testicular cells to differentiate in the prospective ambisexual gonad. We examined the immunolocalization of the steroidogenic enzyme cytochrome aromatase (P450(arom)), which is involved in E2 production. In the gonads, numbers of the P450(arom) -positive cells increased during ovarian differentiation. However, immunopositive cells with weak signal intensity were seen in the interstitial areas among oocytes and between oocytes and testicular tissue undergoing testicular differentiation. In contrast, P450(arom) -positive cells were not found in any testicular tissues of the ambisexual gonads. We also examined changes in E2 production in vitro in the gonads during testicular differentiation. E2 was high in the ovaries before the appearance all of testicular tissue, and decreased accompanying the differentiation of testicular tissue. These results suggest a balance of estrogen/androgen seems to be important during sex differentiation, and then a shift from estrogen to androgen production may induce testicular differentiation in the ovary. Further, exogenous E2 treatment suppressed naturally occurring differentiation of testicular cells forming exclusively ovarian tissues in the gonad in vivo, suggesting the increase of estrogen blocks the differentiation of testicular tissue and the formation of ambisexual gonad.


Phenotypic effects of targeted mutations in the small subunit rRNA gene of Tetrahymena thermophila.
Tetrahymena thermophila is an ideal organism with which to study functional aspects of the rRNAs in vivo since the somatic rRNA genes of T. thermophila can be totally replaced by cloned copies introduced via microinjection. In this study, we made small insertions into seven sites within the small subunit rRNA gene and observed their phenotypic effects on transformed cells. Two mutated genes coding for rRNA (rDNAs), both of which bear insertions in highly conserved sequences, failed to transform and are therefore believed to produce nonfunctional rRNAs. Three other altered rDNAs produce functional rRNAs that can substitute for most or all of the cellular rRNA. Two of these bear insertions in highly variable regions, and, surprisingly, the other has an insertion in a region that is well conserved for both sequence and secondary structure among eucaryotes. In addition, two other insertions appear to destabilize rRNAs that contain them. Our findings make predictions concerning the positions of some of these sites within the tertiary structure of the small ribosomal subunit and thus serve as an in vivo test of the existing tertiary structure models for the small subunit rRNA. Our results are in good agreement with expectations based on sequence comparison and in vitro work.


Microsatellite instability analysis in typical and progressed mantle cell lymphoma and B-cell chronic lymphocytic leukemia.
Microsatellite instability (MSI) is characterized by tumor-associated alterations in the germline size of microsatellite repeats caused by a reduced efficacy of the DNA mismatch repair machinery. The aim of this study was to investigate the presence of MSI in a number of cases of indolent and aggressive mantle cell lymphoma (MCL) and B-cell chronic lymphocytic leukemia (B-CLL) to determine its possible role in the initial development and progression of these disorders. We examined the presence of MSI in 28 B-CLL, 24 typical and 4 transformed B-CLL (Richter's syndrome) and 29 MCL, 19 typical and 10 blastoid variants by using a panel of 10 microsatellite markers and analyzed them using an AbiPrism 310 DNA sequencer. Fisher's exact test was used to compare categorical variables and Mann-Whitney's U-test for continuous variables. MSI alterations were not observed in any case of MCL or Richter's syndrome and in only three (13%) patients with typical B-CLL. Two of these patients also had loss of heterozygosity in one of the 10 sites examined. These patients presented with a more advanced stage, diffuse bone marrow involvement, and poorer performance status than patients without these alterations. These findings indicate that MSI is not involved in the pathogenesis or progression of B-CLL and MCL but may appear in a small subset of patients with advanced B-CLL.


Frequency of blood pressure and estimated glomerular filtration rate monitoring in patients affected by hypertension: a retrospective study with 176 565 patients in Germany.
The aim of this study was to analyze the frequency of blood pressure (BP) and estimated glomerular filtration rate (eGFR) monitoring in hypertension patients followed in primary care practices in Germany. This study included patients who had received at least two hypertension diagnoses (ICD-10: I10) in 2016. The primary outcome of this study was the frequency of BP and eGFR monitoring in patients with hypertension in the year 2016. The impact of the different demographic and clinical variables on the likelihood of receiving at least two BP and at least one eGFR tests was analyzed using multivariate logistic regression models. These two cutoff values were selected on the basis of the recommendations of the European Society of Hypertension and the European Society of Cardiology. This study included 176 565 patients, 53.0% of whom were women. The mean age was 68.2 years (SD=13.3 years). The mean number of BP tests was 1.9 (SD=3.1), whereas the mean number of eGFR tests was 0.2 (SD=0.8) in 2016. Only 33.7 and 9.1% of the population received at least two BP tests and one eGFR test, respectively. Older age (>60 years), comorbidities (particularly diabetes, hyperlipidemia, and renal insufficiency), and the number of antihypertensive treatments were associated with higher odds of receiving at least two BP and at least one eGFR tests, whereas the duration of hypertension was associated negatively with these odds. The frequency of BP and eGFR monitoring was low in Germany in 2016. Several demographic and clinical variables had a significant impact on this frequency.


Diffusion imaging of the congenitally thickened corpus callosum.
This report presents 4 subjects with congenital segmental callosal thickening, an uncommon malformation studied with MR imaging and DTI. Medical records were reviewed for genetic testing and neurodevelopmental status. Three subjects had profound developmental delay; 3 had seizures. MR imaging showed segmental thickening of the rostral and/or midcallosal body. Associated anomalies included polymicrogyria in 1 patient and optic hypoplasia in 1. DTI showed that the segmental thickening was due to anomalous longitudinal supracallosal fibers visually separable from the paired cingulum in 3 patients; in 1 patient, the cingulum was poorly formed. Genetic testing was negative for Fragile X syndrome. Microarray DNA analysis showed 3 copy losses (2q27.3, 3p21.31, 7q21.11) and 1 copy gain (8p11.23) in 1 patient, while testing in the other subject was negative for losses or gains. Potential explanations for the anomalous fibers include heterotopic cingulum, an enlarged indusium griseum, and aberrant callosal fibers.


Toxic ocular effects of ethambutol.
Ethambutol hydrochloride has been used in the treatment of tuberculosis for 25 years. Its only important adverse effect, retrobulbar neuritis, is thought to be a minor concern with conventional dosages. The author presents four cases of serious visual impairment due to ethambutol therapy. Three of the patients were receiving a maintenance dosage of 15 mg/kg per day. The fourth patient was inadvertently given 25 mg/kg per day for 4 months. After therapy with the drug was stopped, improvement was slow, with complete recovery in two cases and only minor residual changes in a third. The patient who received the higher dosage of ethambutol suffered permanent, marked impairment. Ethambutol appears to contribute little to modern short-course antituberculous regimens that include more potent agents such as isoniazid and rifampin. In view of this and the potential for serious visual impairment, alternative antituberculous agents should be considered.


Measuring research impact: a large cancer research funding programme in Australia.
Measuring research impact is of critical interest to philanthropic and government funding agencies interested in ensuring that the research they fund is both scientifically excellent and has meaningful impact into health and other outcomes. The Beat Cancer Project (BCP) is a AUD $34 m cancer research funding scheme that commenced in 2011. It was initiated by an Australian charity (Cancer Council SA), and supported by the South Australian Government and the state's major universities. This study applied Buxton and Hanney's Payback Framework to assess research impact generated from the BCP after 3 years of funding. Data sources were an audit of peer-reviewed publications from January 2011 to September 2014 from Web of Knowledge and a self-report survey of investigators awarded BCP research funding during its first 3 years of implementation (2011-2013). Of the 104 surveys, 92 (88%) were completed. The BCP performed well across all five categories of the Payback Framework. In terms of knowledge production, 1257 peer-reviewed publications were generated and the mean impact factor of publishing journals increased annually. There were many benefits to future research with 21 respondents (23%) reporting career advancement, and 110 higher degrees obtained or expected (including 84 PhDs). Overall, 52% of funded projects generated tools for future research. The funded research attracted substantial further income yielding a very high rate of leverage. For every AUD $1 that the cancer charity invested, the BCP gained an additional AUD $6.06. Five projects (5%) had informed policy and 5 (5%) informed product development, with an additional 31 (34%) and 35 (38%) projects, respectively, anticipating doing so. In terms of health and sector and broader economic benefits, 8 (9%) projects had influenced practice or behaviour of health staff and 32 (34%) would reportedly to do so in the future. Research impact was a priority of charity and government funders and led to a deliberate funding strategy. Emphasising research impact while maintaining rigorous, competitive processes can achieve the joint objectives of excellence in research, yielding good research impact and a high rate of leverage for philanthropic and public investment, as indicated by these early results.


Clinical, clinicopathologic, and parasitologic observations of trypanosomiasis in dogs infected with North American Trypanosoma cruzi isolates.
Nineteen purebred Beagles of various ages (4, 5, 13, and 47 weeks) were inoculated with North American Trypanosoma cruzi isolates obtained from an opossum (Tc-O), an armadillo (Tc-A), or a dog (Tc-D). Dogs were grouped on the basis of clinical outcome of infection. During the acute stage of disease, dogs of group 1 (n = 7 inoculated with Tc-O or Tc-A) died or were euthanatized because of the severity of disease. Dogs of group 2 (n = 5 inoculated with Tc-O or Tc-A) developed acute disease, but survived to develop chronic disease. Dogs of group 3 (n = 7 Tc-D-inoculated dogs) developed neither acute nor chronic disease. Dogs of group 4 (n = 4--2 dogs 13 weeks old and 2 dogs 47 weeks old) served as noninoculated controls. Clinical signs associated with severe acute myocarditis developed in dogs of groups 1 and 2 between postinoculation day (PID) 15 and 28. Generalized lymphadenopathy and lymphocytosis were observed in all dogs of groups 1, 2, and 3 between PID 14 and 17. Serum alanine transaminase and aspartate transaminase activities and urea nitrogen concentration were high, and glucose concentration was low prior to death of dogs in group 1. Serum activities of isoenzymes of creatine kinase were significantly (P less than 0.05) high in only 1 dog (group 1), whereas serum lactate dehydrogenase isoenzyme activities were not significantly high in any dog.(ABSTRACT TRUNCATED AT 250 WORDS)


Toxic polyneuropathies in Italy due to leather cement poisoning in shoe industries. A light- and electron-microscopic study.
The peripheral nerve biopsy specimens of 4 cases of toxic polyneruopathies induced by exposure to leather cement in shoe industries were studied. Analysis of the cements used in the manufacturing process proved them to contain n-hexane as a volatile substance. Light- and electron-microscopic examination of nerve biopsies showed segmental swelling of axons due to the accumulation of packed filaments and thinning of the overlying myelin sheath. Neither active nerve fibre degeneration nor regeneration were frequently seen. It has been suggested that features of so-called giant axonal neuropathy are the most common pattern of peripheral nerve degeneration in chronic n-hexane intoxication.


Nuclear factor erythroid 2 (NF-E2) p45-related factor 2 interferes with homeodomain-interacting protein kinase 2/p53 activity to impair solid tumors chemosensitivity.
Resistance to chemotherapy represents a major hurdle to successful cancer treatment. A key role for efficient response to anticancer therapies is played by TP53 oncosuppressor gene that indeed is mutated in 50% of human cancers or inactivated at protein level in the remaining 50%. Homeodomain-interacting protein kinase 2 (HIPK2) is the wild-type p53 (wtp53) apoptotic activator, and its inhibition by hypoxia or hyperglycemia may contribute to tumor chemoresistance mainly by impairing p53 apoptotic activity. Another important molecule able to induce chemoresistance is nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) transcription factor, whose activation by oxidative and/or electrophilic stress regulates a transcriptional antioxidant program allowing cancer cells to adapt and survive to stresses. NRF2 may shift from cytoprotective to tumor-promoting function, according to tumor phases. NRF2 may crosstalk with both wtp53 and mutant p53 (mutp53), inhibiting the wtp53 apoptotic function and strengthening the mutp53 oncogenic function. NRF2 has also been shown to induce HIPK2 mRNA expression cooperating in inducing cytoprotection. Although HIPK2, p53, and NRF2 have been individually extensively studied, their interplay has not been clearly addressed yet. On the basis of the background and our results, we aim at hypothesizing the unexpected pro-survival activity played by the NRF2/HIPK2/p53 interplay that can be hijacked by cancer cells to bypass drugs cytotoxicity.


[The terminal patient and psychotherapeutic approach].
The end stage situation, namely AIDS and malignant diseases, patients are analysed by the authors from the psychiatric and psychologic standpoint. A multidisciplinary clinical approach is pointed out and psychotherapeutic attitude and action parameters are referred to achieve both the understanding of persons in those situations, and the correct clinical praxis towards them.


Secukinumab Self-Administration by Prefilled Syringe Maintains Reduction of Plaque Psoriasis Severity Over 52 Weeks: Results of the FEATURE Trial.
Secukinumab, a human monoclonal antibody that selectively targets interleukin-17A, is highly efficacious in the treatment of moderate-to-severe psoriasis, starting at early time points, with a sustained effect and a favorable safety profile. Patients with moderate-to-severe plaque psoriasis were randomized to secukinumab 300 mg, secukinumab 150 mg, or placebo self-administered by prefilled syringe at baseline, weeks 1, 2, and 3, and then every four weeks from week 4 to 48. Efficacy responses (≥ 75/90/100% improvement in Psoriasis Area and Severity Index [PASI 75/90/100] and clear/almost clear skin by Investigator's Global Assessment 2011 modified version [IGA mod 2011 0/1]) were measured to week 52. Patient-reported usability of the prefilled syringe was evaluated by the Self-Injection Assessment Questionnaire to week 48. The efficacy of secukinumab increased to week 16 and was maintained to week 52. With secukinumab 300 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 83.5%/68.0%/47.5% and 71.5% of patients when analyzed by multiple imputation, respectively, and by 75.9%/62.1%/43.1% and 63.8% of patients when analyzed by nonresponder imputation, respectively. With secukinumab 150 mg at week 52, PASI 75/90/100 and IGA mod 2011 0/1 responses were achieved by 63.5%/50.3%/31.1% and 43.6% of patients when analyzed by multiple imputation, respectively, and by 61.0%/49.2%/30.5% and 42.4% of patients when analyzed by nonresponder imputation, respectively. Self-reported acceptability of the prefilled syringe was high throughout the study. The incidence of adverse events (AE) was well balanced between groups, with AEs reported in 74.4% of patients receiving secukinumab 300 mg and 77.3% of patients receiving secukinumab 150 mg. Nasopharyngitis was the most common AE across both secukinumab groups. Self-administration of secukinumab by prefilled syringe was associated with robust and sustained efficacy and a favorable safety profile up to week 52.

 J Drugs Dermatol. 2016;15(10):1226-1234.


[Emergency treatment of stroke patients--what does the primary health care do?].
Has new evidence concerning acute care for stroke patients changed medical practice in primary health care in Norway? What type of wards are currently used when stroke patients are admitted to hospital? These questions are discussed on the basis of data from telephone interviews with chief medical officers in a representative sample of 77 Norwegian local administrative areas (municipalities). 60% of the medical officers state that admission practices are more liberal now than five years ago. Less severe cases are admitted to hospital more often. 34% claim that there has been no change, and 1% report that the practice is stricter now than before. According to our informants, routines for transport, managing TIA and managing nursing home patients with acute stroke vary. 26% of all stroke patients have access to stroke units. In most cases (59%) an ordinary medical ward is the only option.


RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer.
BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.


Safety of a feed additive consisting of lignosulphonate for all animal species (Borregaard AS).
Following a request from the European Commission, the EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety of lignosulphonate, when used as a technological additive (functional group: binders) in feed for all animal species. In two previous assessments, the FEEDAP Panel concluded that the maximum level proposed of 10,000 mg lignosulphonate/kg complete feed is safe for weaned piglets, pigs for fattening, chickens for fattening, laying hens and cattle for fattening, but a margin of safety could not be identified. Consequently, these conclusions could not be extrapolated to other animal species/categories. In the current application, the applicant proposed to reduce the maximum content of lignosulphonate in feed for all animal species to 8,000 mg/kg complete feed. The results of two newly submitted tolerance studies allowed the Panel to conclude that 8,000 mg lignosulphonate/kg complete feed is also safe for dairy cows and salmonids, with a margin of safety of at least 1.25. Considering the results of the studies previously assessed and those of the two new tolerance studies, the FEEDAP Panel concluded that lignosulphonate is safe for all animal species when used at a maximum content of 8,000 mg/kg complete feed.


Contractility and Myofibrillar Content in Skeletal Muscle are Decreased During Post-Sepsis Recovery, But Not During the Acute Phase of Sepsis.
Convalescence in humans after severe sepsis occurs over weeks to months and is associated with prolonged functional disabilities and impaired quality-adjusted survival. While much is known regarding the acute early phase of sepsis, there is a knowledge gap pertaining to restoration of muscle mass and function after elimination of the septic nidus. We used a sepsis-recovery model-where cecal-ligation-puncture (CLP) was performed in adult male mice followed 24 h later by removal of the cecum and antibiotic treatment-to assess changes in the abundance of muscle contractile proteins and function during the acute phase of sepsis (24 h post-CLP) and during the recovery phase (day 10 post-CLP). Although body weight and food consumption decreased acutely with sepsis, both had normalized by day 10; however, extensor digitorum longus mass remained decreased 10%. During acute sepsis, there were few contractile defects or significant changes in contractile proteins. In contrast, during sepsis recovery, specific maximum isometric twitch and specific maximum tetanic force were decreased ≈50%, compared with time-matched pair-fed controls, and defects were independent of the concomitant reduction in muscle mass. Force generation in sepsis-recovery mice was decreased 30% with increasing stimulus frequency. Contractile defects during sepsis-recovery were associated with 50% to 90% reductions in thin filament (troponin T, troponin I, tropomyosin, α-sarcomeric actin), thick filament (myosin heavy and myosin light chains), Z-disc (α-actinin 3), and M-band (myomesin-2) proteins, but no change in the intermediate filaments desmin and vimentin. During sepsis recovery, myofibrillar protein synthesis did not differ from control, but synthesis of sarcoplasmic proteins was increased 60%. These data suggest intrinsic defects in muscle contractile function exist during the recovery phase of sepsis and may negatively impact convalescence.


The prognostic impact of SYT-SSX fusion type and histological grade in pediatric patients with synovial sarcoma treated according to the CWS (Cooperative Weichteilsarkom Studie) trials.
The aim of our analysis was the evaluation of the prognostic impact of SYT-SSX fusion status and histological grading in synovial sarcoma (SS) of children and adolescents in the context of the consistent multimodal treatment strategy of the CWS (Cooperative Weichteilsarkom Studie; Cooperative Soft Tissue Sarcoma Study Group) and in comparison with other risk factors. Between 1986 and 2006, out of 243 patients with SS, tumor samples from 84 patients with localized disease were available for RT-PCR analysis. Outcome depending on fusion status in the context with known clinical risk factors was analyzed. No prognostic significance was shown for SYT-SSX fusion status and for histological grade. Highest significance of negative prognostic impact was found for large tumor size in uni- and multivariate analysis (P < 0.01). Furthermore, male gender was shown to be an adverse prognostic factor in multivariate analysis (P = 0.01). Based on our results, neither histological grading nor SYT-SSX fusion status seems to be suitable for outcome prediction and risk stratification in localized SS treated according to the CWS. This is in contrast to several other publications concerning more heterogeneous age groups including children and adults, and this indicates that prognostic factors should not be interpreted apart from the particular study population and the therapeutic context.


Dynamics of Gene Expression Responses for Ion Transport Proteins and Aquaporins in the Gill of a Euryhaline Pupfish during Freshwater and High-Salinity Acclimation.
Pupfishes (genus Cyprinodon) evolved some of the broadest salinity tolerances of teleost fishes, with some taxa surviving in conditions from freshwater to nearly 160 ppt. In this study, we examined transcriptional dynamics of ion transporters and aquaporins in the gill of the desert Amargosa pupfish (Cyprinodon nevadensis amargosae) during rapid salinity change. Pupfish acclimated to 7.5 ppt were exposed to freshwater (0.3 ppt), seawater (35 ppt), or hypersaline (55 ppt) conditions over 4 h and sampled at these salinities over 14 d. Plasma osmolality and Cl- concentration became elevated 8 h after the start of exposure to 35 or 55 ppt but returned to baseline levels after 14 d. Osmolality recovery was paralleled by increased gill Na+/K+-ATPase activity and higher relative levels of messenger RNAs (mRNAs) encoding cystic fibrosis transmembrane conductance regulator (cftr) and Na+/K+/2Cl- cotransporter-1 (nkcc1). Transcripts encoding one Na+-HCO3- cotransporter-1 isoform (nbce1.1) also increased in the gills at higher salinities, while a second isoform (nbce1.2) increased expression in freshwater. Pupfish in freshwater also had lower osmolality and elevated gill mRNAs for Na+/H+ exchanger isoform-2a (nhe2a) and V-type H+-ATPase within 8 h, followed by increases in Na+/H+ exchanger-3 (nhe3), carbonic anhydrase 2 (ca2), and aquaporin-3 (aqp3) within 1 d. Gill mRNAs for Na+/Cl- cotransporter-2 (ncc2) also were elevated 14 d after exposure to 0.3 ppt. These results offer insights into how coordinated transcriptional responses for ion transporters in the gill facilitate reestablishment of osmotic homeostasis after changes in environmental salinity and provide evidence that the teleost gill expresses two Na+-HCO3- cotransporter-1 isoforms with different roles in freshwater and seawater acclimation.


Effects of minute doses of ethylenebisdithiocarbamate disodium salt (nabam) and its degradative products on connective tissue envelopes of the notochord in Xenopus: an ultrastructural study.
The fungicide ethylenebisdithiocarbamate disodium salt (nabam) at 40 or 100 micrograms/l has deleterious effects on the survival of Xenopus laevis embryos. The tissues of the notochordal enveloping layer show definite alterations at the ultrastructural level. There is a significant reduction or absence of the collagen fibres of the outer connective tissue cells. Embryos treated with 100 micrograms/l nabam stored for 3 weeks developed more severe malformations of the enveloping connective tissue layers of the notochord similar to the embryos immersed in combinations of ethylene thiourea and methyl isothiocyanate. In these animals the arrangement of collagen fibres of the notochordal sheath showed complete disarray. Furthermore, the elastica externa was reduced and fragmented. These fine structural observations clearly demonstrate the deleterious effects of this pesticide on cells and tissues of developing systems.


[The role of substance P and somatostatin in acupuncture and moxibustion-induced postsynaptic inhibition].
Our previous work indicated that acupuncture and moxibustion (heating acupoints with a special lamp) could produce inhibitory effects on the tail flick reflex and the nociceptive response of dorsal horn neurons. In the present study the role of somatostatin (SS) and substance P (SP) in acupuncture and moxibustion-induced postsynaptic inhibition was further investigated. The experiments were performed on male adult Wistar rats. The antidromic action potential (AAP) induced by cervical cord stimulation was extracellulary recorded at lumbar cord (L3-4). The latency of AAP was used to represent the excitability of postsynaptic projecting neurons. The effects of acupuncture (0.5 ms, 3.3 Hz, 2 mA) for five minutes or moxibustion (the temperature up to 45-46 degrees C) for six minutes at Huantiao points on the latency of AAP were observed. And then the effects of topical administration of SS or SP antiserum on either acupuncture or moxibustion-induced postsynaptic inhibition were observed. The latency of AAP was markedly prolonged by acupuncture and moxibustion. The maximal prolongation was 0.196 +/- 0.071 ms (n = 12, P < 0.02) and 0.176 +/- 0.062 ms (n = 11, P < 0.02) respectively. After topical administration of SS antiserum (1:40, 10 microliters), the latency of AAP was slightly prolonged by either acupuncture or moxibustion. The maximal prolongation (0.041 +/- 0.029 ms and 0.016 +/- 0.020 ms) was significantly reduced by SS antiserum (P < 0.05). While pretreated with SP antiserum, the latency was still prolonged by moxibustion (0.142 +/- 0.067 ms), but not by acupuncture (-0.003 +/- 0.046 ms). It is referred that postsynaptic inhibition may be involved in both acupuncture analgesia and moxibustion analgesia. The former is predominately mediated by SP and partially by SS, while the latter mainly by SS but not by SP.


How Are Indeterminate Pulmonary Nodules at Diagnosis Associated with Survival in Patients with High-Grade Osteosarcoma?
Pulmonary metastases are a poor prognostic factor in patients with osteosarcoma; however, the clinical significance of subcentimeter lung nodules and whether they represent a tumor is not fully known. Because the clinician is faced with decisions regarding biopsy, resection, or observation of lung nodules and the potential impact they have on decisions about resection of the primary tumor, this remains an area of uncertainty in patient treatment. Surgical management of the primary tumor is tailored to prognosis, and it is unclear how aggressively patients with indeterminate pulmonary nodules (IPNs), defined as nodules smaller than 1 cm at presentation, should be treated. There is a clear need to better understand the clinical importance of these nodules. (1) What percentage of patients with high-grade osteosarcoma and spindle cell sarcoma of bone have IPNs at diagnosis? (2) Are IPNs at diagnosis associated with worse metastasis-free and overall survival? (3) Are there any clinical or radiologic factors associated with worse overall survival in patients with IPN? Between 2008 and 2016, 484 patients with a first presentation of osteosarcoma or spindle cell sarcoma of bone were retrospectively identified from an institutional database. Patients with the following were excluded: treatment at another institution (6%, 27 of 484), death related to complications of neoadjuvant chemotherapy (1%, 3 of 484), Grade 1 or 2 on final pathology (4%, 21 of 484) and lack of staging chest CT available for review (0.4%, 2 of 484). All patients with abnormalities on their staging chest CT underwent imaging re-review by a senior radiology consultant and were divided into three groups for comparison: no metastases (70%, 302 of 431), IPN (16%, 68 of 431), and metastases (14%, 61 of 431) at the time of diagnosis. A random subset of CT scans was reviewed by a senior radiology registrar and there was very good agreement between the two reviewers (κ = 0.88). Demographic and oncologic variables as well as treatment details and clinical course were gleaned from a longitudinally maintained institutional database. The three groups did not differ with regard to age, gender, subtype, presence of pathological fracture, tumor site, or chemotherapy-induced necrosis. They differed according to local control strategy and tumor size, with a larger proportion of patients in the metastases group presenting with larger tumor size and undergoing nonoperative treatment. There was no differential loss to follow-up among the three groups. Two percent (6 of 302) of patients with no metastases, no patients with IPN, and 2% (1 of 61) of patients with metastases were lost to follow-up at 1 year postdiagnosis but were not known to have died. Individual treatment decisions were determined as part of a multidisciplinary conference, but in general, patients without obvious metastases received (neo)adjuvant chemotherapy and surgical resection for local control. Patients in the no metastases and IPN groups did not differ in local control strategy. For patients in the IPN group, staging CT images were inspected for IPN characteristics including number, distribution, size, location, presence of mineralization, and shape. Subsequent chest CT images were examined by the same radiologist to reevaluate known nodules for interval change in size and to identify the presence of new nodules. A random subset of chest CT scans were re-reviewed by a senior radiology resident (κ = 0.62). The association of demographic and oncologic variables with metastasis-free and overall survival was first explored using the Kaplan-Meier method (log-rank test) in univariable analyses. All variables that were statistically significant (p < 0.05) in univariable analyses were entered into Cox regression multivariable analyses. Following re-review of staging chest CTs, IPNs were found in 16% (68 of 431) of patients, while an additional 14% (61 of 431) of patients had lung metastases (parenchymal nodules 10 mm or larger). After controlling for potential confounding variables like local control strategy, tumor size, and chemotherapy-induced necrosis, we found that the presence of an IPN was associated with worse overall survival and a higher incidence of metastases (hazard ratio 1.9 [95% CI 1.3 to 2.8]; p = 0.001 and HR 3.6 [95% CI 2.5 to 5.2]; p < 0.001, respectively). Two-year overall survival for patients with no metastases, IPN, or metastases was 83% [95% CI 78 to 87], 65% [95% CI 52 to 75] and 45% [95% CI 32 to 57], respectively (p = 0.001). In 74% (50 of 68) of patients with IPNs, it became apparent that they were true metastatic lesions at a median of 5.3 months. Eighty-six percent (43 of 50) of these patients had disease progression by 2 years after diagnosis. In multivariable analysis, local control strategy and tumor subtype correlated with overall survival for patients with IPNs. Patients who were treated nonoperatively and who had a secondary sarcoma had worse outcomes (HR 3.6 [95% CI 1.5 to 8.3]; p = 0.003 and HR 3.4 [95% CI 1.1 to 10.0]; p = 0.03). The presence of nodule mineralization was associated with improved overall survival in the univariable analysis (87% [95% CI 39 to 98] versus 57% [95% CI 43 to 69]; p = 0.008), however, because we could not control for other factors in a multivariable analysis, the relationship between mineralization and survival could not be determined. We were unable to detect an association between any other nodule radiologic features and survival. The findings show that the presence of IPNs at diagnosis is associated with poorer survival of affected patients compared with those with normal staging chest CTs. IPNs noted at presentation in patients with high-grade osteosarcoma and spindle cell sarcoma of bone should be discussed with the patient and be considered when making treatment decisions. Further work is required to elucidate how the nodules should be managed. Level III, prognostic study.


Exploring Cancer Therapeutics with Natural Products from African Medicinal Plants, Part II: Alkaloids, Terpenoids and Flavonoids.
Cancer stands as second most common cause of disease-related deaths in humans. Resistance of cancer to chemotherapy remains challenging to both scientists and physicians. Medicinal plants are known to contribute significantly to a large population of Africa, which is to a very large extent linked to folkloric claims which is part of their livelihood. In this review paper, the potential of naturally occurring anti-cancer agents from African flora has been explored, with suggested modes of action, where such data is available. Literature search revealed plant-derived compounds from African flora showing anti-cancer and/or cytotoxic activities, which have been tested in vitro and in vivo. This corresponds to 400 compounds (from mildly active to very active) covering various compound classes. However, in this part II, we only discussed the three major compound classes which are: flavonoids, alkaloids and terpenoids.


Evaluation of the on-line electrical conductivity of milk in mastitic dairy cows.
Mastitis is a persistent, inflammatory reaction of the udder tissue, which entails a decline in potassium, and is also responsible for a higher somatic cell count (SCC) and electrical conductivity (EC) of milk. The measurement of EC is an indirect, rapid method to detect subclinical mastitis from milk. The aim of this study was to analyse the EC of milk throughout the lactation, around the day of mastitis detection, and also to estimate its heritability based on data from a large-scale dairy farm. Shortly after calving the EC value generally decreases; however, it was discovered that from the thirteenth week onwards, substantial differences arise between the mastitic and healthy groups of cows. The authors observed a significant (P < 0.001) increase in EC before the detection of clinical mastitis. This higher value (around 11 mS) persisted for 4 days, then it gradually returned to the normal level. The EC of milk from daughters sired by different bulls responded differently in case of mastitis. The heritability of EC seems to be high (h2 = 0.56). Therefore, the EC trait can be a beneficial indicator in detecting mastitis and should be considered in sire selection.


Hybrid surgery with PEEK rods for lumbar degenerative diseases: a 2-year follow-up study.
Finite element analyses and biomechanical tests have shown that PEEK rods promote fusion and prevent adjacent segment degeneration. The purpose of this study was to evaluate the effects and complications of hybrid surgery with PEEK rods in lumbar degenerative diseases. From January 2015-December 2017, 28 patients who underwent lumbar posterior hybrid surgery with PEEK rods were included in the study. The patients were diagnosed with lumbar disc herniation, lumbar spinal stenosis, or degenerative grade I spondylolisthesis. Before the operation and at the last follow-up, the patients completed lumbar anteroposterior and lateral X-ray, dynamic X-ray, MRI examinations. In addition, at the last follow-up the patients also completed lumbar CT examinations. The radiographic parameters, clinical visual analog scale (VAS) score and Oswestry disability index (ODI) score were compared. The average age of the patients was 44.8 ± 12.6 years, and the average follow-up duration was 26.4 ± 3.6 months. The VAS score improved from 6.3 ± 1.6 to 1.0 ± 0.9, and the ODI score decreased from 38.4 ± 10.8 to 6.8 ± 4.6. The fusion rate of the fused segment was 100%. There were no significant changes in the modified Pfirrmann classifications or disc height index for the nonfused segments and the upper adjacent segments from pre- to postoperatively. No cases of screw loosening, broken screws, broken rods or other mechanical complications were found. Hybrid surgery with PEEK rods for lumbar degenerative diseases can yield good clinical results and effectively reduce the incidence of complications such as adjacent segment diseases.


Severe morbidity after antiretroviral (ART) initiation: active surveillance in HIV care programs, the IeDEA West Africa collaboration.
The causes of severe morbidity in health facilities implementing Antiretroviral Treatment (ART) programmes are poorly documented in sub-Saharan Africa. We aimed to describe severe morbidity among HIV-infected patients after ART initiation, based on data from an active surveillance system established within a network of specialized care facilities in West African cities. Within the International epidemiological Database to Evaluate AIDS (IeDEA)--West Africa collaboration, we conducted a prospective, multicenter data collection that involved two facilities in Abidjan, Côte d'Ivoire and one in Cotonou, Benin. Among HIV-infected adults receiving ART, events were recorded using a standardized form. A simple case-definition of severe morbidity (death, hospitalization, fever>38°5C, Karnofsky index<70%) was used at any patient contact point. Then a physician confirmed and classified the event as WHO stage 3 or 4 according to the WHO clinical classification or as degree 3 or 4 of the ANRS scale. From December 2009 to December 2011, 978 adults (71% women, median age 39 years) presented with 1449 severe events. The main diagnoses were: non-AIDS-defining infections (33%), AIDS-defining illnesses (33%), suspected adverse drug reactions (7%), other illnesses (4%) and syndromic diagnoses (16%). The most common specific diagnoses were: malaria (25%), pneumonia (13%) and tuberculosis (8%). The diagnoses were reported as syndromic in one out of five events recorded during this study. This study highlights the ongoing importance of conventional infectious diseases among severe morbid events occurring in patients on ART in ambulatory HIV care facilities in West Africa. Meanwhile, additional studies are needed due to the undiagnosed aspect of severe morbidity in substantial proportion.


Safety and feasibility of convection-enhanced delivery of nimustine hydrochloride co-infused with free gadolinium for real-time monitoring in the primate brain.
Convection-enhanced delivery (CED) has been developed as an effective drug-delivery strategy for brain tumors. Ideally, direct visualization of the tissue distribution of drugs infused by CED would assure successful delivery of therapeutic agents to the brain tumor while minimizing exposure of the normal brain tissue. We previously showed the anti-tumor efficacy of nimustine hydrochloride (ACNU) delivered via CED against a rodent intracranial xenografted tumor model. Here, we developed a method to monitor the drug distribution using a non-human primate brain. CED of a mixture of ACNU with gadodiamide was performed using three non-human primates under real-time magnetic resonance imaging monitoring. Animals were clinically observed for any toxicity after infusion. Two months later, their brains were subjected to histological examination for the evaluation of local toxicity. Another one animal was euthanized immediately after CED of a mixture of ACNU, gadodiamide, and Evans blue dye to evaluate the concordance between ACNU and gadodiamide distributions. The harvested brain was cut into blocks and the ACNU content was measured. Real-time magnetic resonance imaging monitoring of co-infused gadodiamide confirmed the success of the infusion maneuver. In the monkey that also received Evans blue, the distribution of Evans blue was similar to that of gadodiamide and paralleled the measured ACNU content, suggesting concordance between ACNU and gadodiamide distributions. Histological examination revealed minimum tissue damage with the infusion of ACNU at 1 mg/ml, determined as a safe dose in our previous rodent study. CED of ACNU can be co-administered with gadodiamide to ensure successful infusion and monitor the distribution volume.


[Characteristics of the genus Glugea (Protozoa, Microsporidia) based on the example of the type species Glugea anomala (Moniez, 1887) Gurley 1893 and its varieties].
A study of the life cycles of some varieties of Glugea anomala has shown that the genus Glugea is a distinct genus having the following diagnosis. Sporoblasts and spores are formed as a result of step by step decay of the multinuclear plasmodium situated inside the sporogonal vacuole (sporont). Ripe spores either remain connected together in groups with irregular (6 to 32) often uneven number of spores of lie singly, seldom in pairs. Microsporidia are able to cause extremely strong hypertrophy of the host's infected cell which is transformed into a round white cyst filled with the parasite's spores.


Identification and haplotype analysis of apolipoprotein B-100 Arg3500-->Trp mutation in hyperlipidemic Chinese.
DNA screening for apolipoprotein (apo) B-100 mutations was performed in hyperlipidemic Chinese. The apo B-100 gene segment surrounding previously identified familial defective apo B-100 (FDB) mutations was amplified by PCR and subjected to single-strand conformation polymorphism (SSCP) analysis. One subject's aberrant SSCP band was cloned and sequenced to study the molecular lesions. A recurrent ArgCGG-to-TrpTGG mutation (R3500W) in the codon 3500 of the apo B-100 gene was identified. The C-to-T transition creates a NlaIII site and permits rapid restriction analysis of the mutation. A total of 373 hyperlipidemic patients and 309 controls were screened for R3500W. Nine unrelated subjects were shown to be heterozygous for the mutation, and no R3500W carriers were found in the control group (P = 0.004). Six polymorphic markers, including five restriction fragment length polymorphisms and one hypervariable repeat region, were used for haplotype analysis on the mutant allele. In two families, the R3500W mutation could be unambiguously assigned to a unique haplotype XbaI-/MaeI+/MspI+/EcoRI+/ Eco57I+/34 3'HVR repeats; in the other seven unrelated heterozygotes, this finding was consistent when an unequivocal haplotype was deduced. The results suggest that all R3500W alleles are identical by descent in our population. The fact that the same mutant allele was identified in other Asians with FDB indicates a common Asian origin for the R3500W mutations.