bluuebunny/crossref_metadata_2025 huggingface dataset:
Doses of chloroquine in the treatment of malaria by Plasmodium vivax in patients between 2 and 14 years of age from the Brazilian Amazon basin
Authors: de Sena Luann Wendel Pereira , Mello Amanda Gabryelle Nunes Cardoso , Ferreira Michelle Valéria Dias , de Ataide Marcieni Andrade , Dias Rosa Maria , Vieira José Luiz Fernandes
Published: December 2019

Background

A total dose of chloroquine of 25 mg/kg is recommended by the World Health Organization (WHO) to treat malaria by Plasmodium vivax. In several endemic areas, including the Brazilian Amazon basin, anti-malarial drugs are dispensed in small plastic bags at a dosing regimen based on age. This practice can lead to suboptimal dosing of the drug, which can impact treatment outcomes. The aim of the present study was to estimate the extent of sub-dosing of chloroquine in children and adolescents with vivax malaria using an age-based dose regimen, in addition to investigating the influence of age on the plasma concentrations of chloroquine and desethylchloroquine.

Methods

A study of cases was conducted with male patients with a confirmed infection by P. vivax, ages 2 to 14 years, using a combined regimen of chloroquine and primaquine. Height, weight and body surface area were determined at admission on the study. The total dose of chloroquine administered was estimated based on the weight and on the body surface area of the study patients. Chloroquine and desethylchloroquine were measured on Day 7 in each patient included in the study by a high-performance liquid chromatographic method with fluorescence detection.

Results

A total of 81 patients were enrolled and completed the study. The median age was 9 years (2–14 years). All patients presented negative blood smears at 42 days follow-up. The total dose of chloroquine ranged from 13.1 to 38.1 mg/kg. The percentage of patients with a total dose of the drug below 25 mg/kg ranged from 29.4 to 63.6%. The total dose of chloroquine administered based on BSA ranged from 387 to 1079 mg/m2, increasing with age. Plasma chloroquine concentrations ranged from 107 to 420 ng/ml, increasing with age. For desethylchloroquine, the plasma concentrations ranged from 167 to 390 ng/ml, with similar values among age-groups.

Conclusion

The data demonstrated the widespread exposure of children and adolescents to suboptimal doses of chloroquine in the endemic area investigated.
Understanding challenges to malaria elimination in Nepal: a qualitative study with an embedded capacity-building exercise
Authors: Adhikari Shiva Raj , Sapkota Vishnu P. , Thapa Arjun K. , Acharya Yubraj
Published: December 2019

Background

The Nepalese Government has made significant progress toward the elimination of malaria. However, given the surge in the prevalence of non-communicable diseases, such as diabetes and hypertension, and the localized nature of malaria prevalence, malaria elimination will remain a challenge. In the current study, the authors sought to understand local perceptions on threats to malaria elimination in three endemic districts.

Methods

The authors conducted a capacity-building exercise embedded within a qualitative study. The study component aimed to understand how local policymakers and actors perceive challenges in malaria elimination. For them to be able to articulate the challenges, however, an understanding of malaria elimination in the context of a broader health system in Nepal would be required. The capacity-building component, thus, involved providing that knowledge.

Results

Although the prevalence of malaria is high in the three districts where the study was conducted, there are significant gaps in human resources, diagnosis and treatment, and the provision of indoor residual spraying and long-lasting insecticide treated nets. More importantly, the authors’ experience suggests that it may be possible to capitalize on local expertise in order to identify gaps in malaria elimination at a sub-national level by building in a capacity-building exercise within a study.

Conclusions

Locals in three malaria-endemic districts of Nepal perceive that there are significant gaps in human resources, diagnosis and treatment, the provision of insecticide treated nets, and indoor residual spraying.
Extended versus non-extended lymphadenectomy during radical cystectomy for patients with bladder cancer: a meta-analysis of the effect on long-term and short-term outcomes
Authors: Wang Yu-Chen , Wu Jie , Dai Bo , Shen Yi-Jun , Ma Chun-Guang , Ye Ding-Wei , Zhu Yi-Ping
Published: December 2019

Background

Pelvic lymphadenectomy (PLND) is an integral part of curative surgery for high-risk non-muscle invasive and muscle-invasive bladder cancer. The therapeutic value of extended PLND is controversial.

Methods

We conducted a comprehensive online search in PubMed, EMBASE, and the Cochrane Library databases for relevant literature directly comparing extended PLND (e-PLND) with non-extended PLND (ne-PLND) from database inception to June 2019. We performed the meta-analysis to evaluate the impact of PLND templates on recurrence-free survival (RFS), disease-specific survival (DSS), overall survival (OS), rates of postoperative major complications, and mortality within 90 days of surgery.

Results

A total of 10 studies involving 3979 patients undergoing either e-PLND or ne-PLND were included. The results showed that e-PLND was significantly associated with better RFS (HR 0.74, 95% CI 0.62–0.90, p = 0.002) and DSS (HR 0.66, 95% CI 0.55–0.79, p < 0.001). However, no correlation was found between e-PLND template and a better OS (HR 0.93, 95% CI 0.55–1.58, p = 0.79). Postoperative major complications were similar between e-PLND group and ne-PLND group, as was mortality within 90 days of surgery.

Conclusion

e-PLND template is correlated with favorable RFS and DSS outcomes for patients with bladder cancer. e-PLND did not have more postoperative major complications than did ne-PLND.
How and why do win–win strategies work in engaging policy-makers to implement Health in All Policies? A multiple-case study of six state- and national-level governments
Authors: Kokkinen Lauri , Freiler Alix , Muntaner Carles , Shankardass Ketan
Published: December 2019

Background

Much of the research about Health in All Policies (HiAP) implementation is descriptive, and there have been calls for more evaluative evidence to explain how and why successes and failures have occurred. In this cross-case study of six state- and national-level governments (California, Ecuador, Finland, Norway, Scotland and Thailand), we tested hypotheses about win–win strategies for engaging policy-makers in HiAP implementation drawing on components identified in our previous systems framework.

Methods

We used two sources of data — key informant interviews and peer-reviewed and grey literature. Using a protocol, we created context–mechanism–outcome pattern configurations to articulate mechanisms that explain how win–win strategies work and fail in different contexts. We then applied our evidence for all cases to the systems framework. We assessed the quality of evidence within and across cases in terms of triangulation of sources and strength of evidence. We also strengthened hypothesis testing using replication logic.

Results

We found robust evidence for two mechanisms about how and why win–win strategies build partnerships for HiAP implementation — the use of shared language and the value of multiple outcomes. Within our cases, the triangulation was strong, both hypotheses were supported by literal and contrast replications, and there was no support against them. For the third mechanism studied, using the public-health arguments win–win strategy, we only found evidence from Finland. Based on our systems framework, we expected that the most important system components to using win–win strategies are sectoral objectives, and we found empirical support for this prediction.

Conclusions

We conclude that two mechanisms about how and why win–win strategies build partnerships for HiAP implementation — the use of shared language and the value of multiple outcomes — were found as relevant to the six settings. Both of these mechanisms trigger a process of developing synergies and releasing potentialities among different government sectors and these interactions between sectors often work through sectoral objectives. These mechanisms should be considered when designing future HiAP initiatives and their implementation to enhance the emergence of non-health sector policy-makers’ engagement.
Is fibrodysplasia ossificans progressiva an interleukin-1 driven auto-inflammatory syndrome?
Authors: Haviv Ruby , Moshe Veronica , De Benedetti Fabrizio , Prencipe Giusi , Rabinowicz Noa , Uziel Yosef
Published: December 2019

Background

Fibrodysplasia ossificans progressiva (FOP) is the most catastrophic form of heterotopic ossification, due to ongoing intracellular signaling through the bone morphogenic protein pathway. The paroxysmal appearance of inflammatory lumps and elevated inflammatory markers during flares, suggest that FOP is an auto-inflammatory disease. Based on evidence, demonstrating a role for interleukin-1β (IL-1β) in other forms of heterotopic ossification, we hypothesized that treating FOP patients with anti-IL-1 agents could help lower the rate of FOP paroxysms and/or limit the symptoms and residual lesions.

Case presentation

A 13.5-year-old Arab boy was diagnosed with FOP. Treatment with anti-inflammatory drugs did not change the disease course. New lumps appeared in a rate of approximately one every 8 days. Treatment with the anti-IL-1 agents anakinra and canakinumab resulted in significantly lower rate of paroxysms (every 22–25 days, of which almost all involved only 2 existing lumps), as well as shorter duration. High levels of IL-1β were found in the patient’s plasma samples, collected during a paroxysm that appeared 8 weeks after the last canakinumab dose. In contrast, IL-1β plasma levels were undetectable in the previous three plasma samples, obtained while he was treated with anti-IL-1 agents.

Conclusions

Our data demonstrate the efficacy of anti-IL-1 agents in the treatment of a patient with FOP. Results showing the marked increase in IL-1β plasma levels during a paroxysm support a role for IL-1β in the pathogenesis of FOP and further provide the rationale for the use of anti-IL-1 agents in FOP treatment.
“I feel myself incomplete, and I am inferior to people”: experiences of Sudanese women living with obstetric fistula in Khartoum, Sudan
Authors: Ahmed Salma A. E. , Thorsen Viva C.
Published: December 2019

Background

Obstetric fistula is among the most devastating maternal morbidities that occur as a result of prolonged, obstructed labor. Usually, the child dies in a large number of the cases. Moreover, some of the women become infertile while the majority suffer physical, psychosocial and economic challenges. Approximately 5000 new cases of obstetric fistula occur in Sudan each year. However, their experiences are under documented. Therefore, this study aimed to shed light on their daily lives living with obstetric fistula and how they cope.

Methods

Using a qualitative study design, 19 women living with obstetric fistula were interviewed. The study took place in the fistula ward located in Khartoum hospital and the fistula re-integration center in Khartoum, Sudan. Thematic analysis approach was employed. Stigma and coping theories guided the data collection, analysis, and discussion of the findings.

Findings

Women in our study suffered a challenging physical life due to leakage of urine. In addition, they encountered all forms of stigmatization. Women used both emotion-focused and problem-focused coping techniques to mitigate the consequences of obstetric fistula.

Conclusion

The study findings underscore the importance of obstetric fistula prevention programs and the urgency of repair surgeries to alleviate women’s suffering. Community sensitization, rehabilitation and re-integration of women back to their communities are also important strategies on their journey to wholeness.
NAD-linked mechanisms of gene de-repression and a novel role for CtBP in persistent adenovirus infection of lymphocytes
Authors: Dickherber Megan L. , Garnett-Benson Charlie
Published: December 2019

Background

Adenovirus (AdV) infection is ubiquitous in the human population and causes acute infection in the respiratory and gastrointestinal tracts. In addition to lytic infections in epithelial cells, AdV can persist in a latent form in mucosal lymphocytes, and nearly 80% of children contain viral DNA in the lymphocytes of their tonsils and adenoids. Reactivation of latent AdV is thought to be the source of deadly viremia in pediatric transplant patients. Adenovirus latency and reactivation in lymphocytes is not well studied, though immune cell activation has been reported to promote productive infection from latency. Lymphocyte activation induces global changes in cellular gene expression along with robust changes in metabolic state. The ratio of free cytosolic NAD+/NADH can impact gene expression via modulation of transcriptional repressor complexes. The NAD-dependent transcriptional co-repressor C-terminal Binding Protein (CtBP) was discovered 25 years ago due to its high affinity binding to AdV E1A proteins, however, the role of this interaction in the viral life cycle remains unclear.

Methods

The dynamics of persistently- and lytically-infected cells are evaluated. RT-qPCR is used to evaluate AdV gene expression following lymphocyte activation, treatment with nicotinamide, or disruption of CtBP-E1A binding.

Results

PMA and ionomycin stimulation shifts the NAD+/NADH ratio in lymphocytic cell lines and upregulates viral gene expression. Direct modulation of NAD+/NADH by nicotinamide treatment also upregulates early and late viral transcripts in persistently-infected cells. We found differential expression of the NAD-dependent CtBP protein homologs between lymphocytes and epithelial cells, and inhibition of CtBP complexes upregulates AdV E1A expression in T lymphocyte cell lines but not in lytically-infected epithelial cells.

Conclusions

Our data provide novel insight into factors that can regulate AdV infections in activated human lymphocytes and reveal that modulation of cellular NAD+/NADH can de-repress adenovirus gene expression in persistently-infected lymphocytes. In contrast, disrupting the NAD-dependent CtBP repressor complex interaction with PxDLS-containing binding partners paradoxically alters AdV gene expression. Our findings also indicate that CtBP activities on viral gene expression may be distinct from those occurring upon metabolic alterations in cellular NAD+/NADH ratios or those occurring after lymphocyte activation.
Peer involvement and cross-sector efforts in establishing integrated treatment of hepatitis C virus infection for people with substance use disorders: experiences from Norway
Authors:   for the INTRO-HCV Study Group, Lygren Ole Jørgen , Bjørnestad Ronny , Løberg Else-Marie , Bonnier Martine Lepsøy , Buljovcic Vibeke Bråthen , Johansson Kjell Arne , Fadnes Lars T.
Published: December 2019

Background

For people with opioid dependence in Norway, chronic hepatitis C virus (HCV) infections contribute to high mortality and high morbidity. Around 50% of patients in medically assisted rehabilitation (MAR) have been shown to have HCV, and the current prevention and control efforts have been mostly unsuccessful. Thus, there is a need for new strategies for people-centred service delivery and innovative methods to improve health outcomes.

Methods

Over the last few years, the city of Bergen, Norway, has developed a cross-sector collaboration with substantial peer involvement in research and health provision related to substance use. User group representatives for people receiving MAR, addiction medicine health personnel, infectious disease specialists, policy makers in the municipality, low-threshold health care centres for people with substance use disorders in Bergen Municipality and researchers in the INTRO-HCV project have made concerted efforts in this regard. We will present here some of the strategies and steps we have taken.

Results

We have established an integrated HCV treatment scheme for people who inject drugs or who have opioid dependence. More than 800 persons have been tested for HCV within these frames, and more than 250 persons have been given treatment for HCV within the project. The integrated treatment of HCV is offered both in MAR outpatient clinics, municipal low-threshold healthcare centres, and local and regional prisons. The preliminary results indicate an increase in HCV treatment uptake among those receiving integrated treatment (96% initiating treatment compared to 75%). The user group organisation ProLAR Nett has established an outreach service to screen for HCV, increase awareness and reduce the proportion of people unknowingly living with HCV while informing and motivating people to receive treatment. Together with the other stake holders, peer user group, health care, research planning, concert events, and policy panels have been held.

Conclusions

Peer involvement seems to have increased testing rates for HCV and acknowledgment of its importance. This seems to have improved health care for people with opioid dependence in Bergen over the last few years, particularly relating to the treatment of HCV. These experiences might be helpful in the planning of integrated policies in other settings that seek to eliminate the HCV endemic.
Risk factors for refracture after plate removal for midshaft clavicle fracture after bone union
Authors: Tsai Shang-Wen , Ma Hsuan-Hsiao , Hsu Fang-Wei , Chou Te-Feng Arthur , Chen Kun-Hui , Chiang Chao-Ching , Chen Wei-Ming
Published: December 2019

Background

Open reduction and internal fixation (ORIF) with plates and screws is one of the treatment options for clavicle fractures. However, an additional operation for implant removal after union of the fracture is commonly performed due to a high incidence of hardware irritation. Despite union of the fracture, a subsequent refracture might occur after removal of the implant which requires additional surgeries for fixation. This study aims to determine the risk factors associated with refracture of the clavicle after hardware removal.

Methods

We retrospectively reviewed the medical records of 278 patients that were diagnosed with a midshaft clavicle fracture (male 190; female 88) that had (1) undergone ORIF of the clavicle with plates and (2) received a second operation for removal of hardware after solid union of the fracture between 2010 and 2017. Their mean age was 40.1 ± 15.1 years, and mean interval from fixation to plate removal was 12.5 ± 7.5 months. The patients were then divided into two groups based on the presence of refracture (n = 20) or without refracture (n = 258). We analyzed patient demographics, interval between fixation and implant removal, fracture classification (AO/OTA, Robinson), fixation device, whether wires or interfragmentary screws were used, clavicular length, and bone diameter at the fracture site.

Results

The overall refracture rate was 7.2%, and the mean interval between plate removal and refracture was 23.9 days. A multivariate analysis showed that female (adjusted odds ratio [aOR] 4.74; 95% CI 1.6–14.1) and body mass index [BMI] (for every 1-unit decrease, aOR 1.25; 95% CI 1.06–1.48) were risk factors for refracture. In women, BMI was the only risk factor. The optimal BMI cutoff value was 22.73. In a female patient with a lower BMI, the refracture rate was 29.8%.

Conclusions

There are no significant radiographic parameters associated with refracture. Routine plate removal in a female patient with a low BMI after bony union of a midshaft clavicle fracture is not recommended because of a high refracture rate.
LRRK2 Biology from structure to dysfunction: research progresses, but the themes remain the same
Authors: Berwick Daniel C. , Heaton George R. , Azeggagh Sonia , Harvey Kirsten
Published: December 2019

Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson’s disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at thetrans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places.
Global burden of breast cancer and attributable risk factors in 195 countries and territories, from 1990 to 2017: results from the Global Burden of Disease Study 2017
Authors: Li Na , Deng Yujiao , Zhou Linghui , Tian Tian , Yang Si , Wu Ying , Zheng Yi , Zhai Zhen , Hao Qian , Song Dingli , Zhang Dai , Kang Huafeng , Dai Zhijun
Published: December 2019

Background

Statistical data on the incidence, mortality, and burden of breast cancer and the relevant risk factors are valuable for policy-making. We aimed to estimate breast cancer incidence, deaths, and disability-adjusted life years (DALYs) by country, gender, age group, and social-demographic status between 1990 and 2017.

Methods

We extracted breast cancer data from the 2017 Global Burden of Disease (GBD) study from 1990 through 2017 in 195 countries and territories. Data about the number of breast cancer incident cases, deaths, DALYs, and the age-standardized rates were collected. We also estimated the risk factors attributable to breast cancer deaths and DALYs using the comparative risk assessment framework of the GBD study.

Results

In 2017, the global incidence of breast cancer increased to 1,960,681 cases. The high social-development index (SDI) quintile included the highest number of breast cancer death cases. Between 2007 and 2017, the ASDR of breast cancer declined globally, especially in high SDI and high middle SDI countries. The related DALYs were 17,708,600 in 2017 with high middle SDI quintile as the highest contributor. Of the deaths and DALYs, alcohol use was the greatest contributor in most GBD regions and other contributors included high body mass index (BMI) and high fasting plasma glucose.

Conclusion

The increasing global breast cancer burden is mainly observed in lower SDI countries; in higher SDI countries, the breast cancer burden tends to be relieving. Therefore, steps against attributable risk factors should be taken to reduce breast cancer burden in lower SDI countries.
Early onset retinal dystrophies: clinical clues to diagnosis for pediatricians
Authors: Suppiej Agnese , Marino Silvia , Reffo Maria Eleonora , Maritan Veronica , Vitaliti Giovanna , Mailo Janette , Falsaperla Raffaele
Published: December 2019

Introduction

Inherited retinal dystrophies are major cause of severe progressive vision loss in children. Early recognition and diagnosis are essential for timely visual rehabilitation during the appropriate stages of the visual development, as well as for genetic diagnosis and possible gene therapy. The aim of this study is to characterize a pattern of the initial visual symptoms, which could help the pediatricians and the primary care providers to suspect an inherited retinal disorder in its early stage.

Methods

We analyzed the initial clinical symptoms, based on parental report during the first visit to specialist, in 50 children diagnosed with retinal dystrophy confirmed by full-field electroretinography. The analysis included the age of symptoms onset and the type of visual symptoms, both in the total population and in the following diagnostic subgroups: rod-cone dystrophy (n.17), cone-rod dystrophy (n.12), achromatopsia (n.13), congenital stationary night blindness (n.6) and Leber’s congenital amaurosis (n.2).

Results

The majority of children (80%) had the onset of clinical symptoms before one year of age. The most frequent visual complaints reported by parents were nystagmus (76%), visual loss (28%) and photophobia (8%). Nystagmus was the first symptom reported by parents if the disease onset was before the age of six months, while the onset after the six months of age was more likely associated with the complain of vision loss.

Conclusions

Low vision and nystagmus observed by parents, particularly in the first year of life, may represent a red flag, prompting an appropriate ophthalmological workup for inherited retinal dystrophy.
Parasitological, serological and molecular survey of camel trypanosomiasis in Somalia
Authors: Hassan-Kadle Ahmed A. , Ibrahim Abdalla M. , Nyingilili Hamisi S. , Yusuf Abdulkarim A. , Vieira Thállitha S. W. J. , Vieira Rafael F. C.
Published: December 2019

Background

Camel trypanosomiasis or surra is of great concern in Somalia, since the country possesses the largest one-humped camel (Camelus dromedarius) population in the world. Civil war in Somalia has resulted in the destruction of educational, research, economic and social structures, making the country scores very low for most humanitarian indicators. Previous studies on detection of Trypanosoma species in Somali camels have only been performed during the 1990s using standard trypanosome detection methods (STDM). Considering the lack of state-of-the-art knowledge on camel trypanosomiasis in Somalia, the present study aimed to assess the prevalence of Trypanosoma spp. in three districts of Somalia.

Methods

A total of 182 blood samples from C. dromedarius from nomadic and dairy farms were evaluated using STDM, serological (CATT/T. evansi) and molecular (ITS1-PCR) methods.

Results

All samples were negative for Trypanosoma spp. by STDM. A total of 125/182 (68.7%, 95% CI: 61.4–75.3%) camels were seropositive for T. evansi by CATT/T. evansi. Camels reared in nomadic system were more likely to be seropositive for T. evansi than those under dairy production system (OR: 5.6, 95% CI: 2.1–15.2, P = 0.0001). Five out of 182 (2.7%, 95% CI: 0.9–6.3%) camels tested positive for Trypanosoma sp. by ITS1-PCR. Sequencing of the ITS1 region of the Trypanosoma species detected herein revealed that camels were infected with T. evansi and T. simiae.

Conclusions

Trypanosoma evansi is highly prevalent in camels from the Banadir region of Somalia, particularly in nomadic herds. To our knowledge, this is the first study to confirm infections with T. evansi and T. simiae in Somali camels through DNA sequencing. Our data highlight the need for implementation of adequate control measures aiming to reduce the impact on camel production in the country.
Pregnancy after mumps: a case report
Authors: Shahabi Parviz , Asadzadeh Shiva , Bannazadeh Baghi Hossein , Sadeghzadeh Oskouei Behnaz
Published: December 2019

Introduction

Oophoritis, a complication of mumps, is said to affect only 5% of all postpubertal women. In this report, we present a case of a 31-year-old Iranian woman with amenorrhea and infertility due to an infantile uterus and atrophic ovaries associated with contracting mumps at a young age. She later successfully carried a healthy baby to term.

Case presentation

The patient was diagnosed with oophoritis when she was 8 years of age. She had no menses before treatment. The patient underwent a low-dose contraceptive treatment from age 19 until she was 31 years of age. During this period, the size of her uterus was constantly monitored, which revealed constant yet slow uterine growth. At age 31, Drospil (containing 3 mg of drospirenone and 0.03 mg ethinyl estradiol) treatment was initiated and administered for 3 months, which led to substantial uterine growth and menses. After her uterus had reached a mature size, the patient was referred to an assisted reproductive technology clinic. There she received a donor oocyte that was fertilized with the sperm of her husband. She had a successful low-risk pregnancy after the second embryo transfer.

Conclusion

Low-dose contraceptive treatment containing progesterone, followed by Drospil, which includes both estradiol and progesterone, had a synergistic effect that led to the growth of the patient’s uterus.
Electromagnetic field treatment increases purinergic receptor P2X7 expression and activates its downstream Akt/GSK3β/β-catenin axis in mesenchymal stem cells under osteogenic induction
Authors: Zhang Yingchi , Li Wenkai , Liu Chaoxu , Yan Jiyuan , Yuan Xuefeng , Wang Wei , Wang Huaixi , Wu Hua , Yang Yong
Published: December 2019

Background

Imbalance in bone formation and resorption is a crucial component of the pathological process leading to osteoporosis. Electromagnetic fields (EMFs) have been reported to be beneficial to osteogenesis, although the exact mechanism has not been fully clarified. Purinergic receptor P2X7 is expressed in osteoblasts and is reported to participate in the regulation of bone metabolism.

Objectives

To elucidate the link between EMFs and P2X7 expression and investigate its potential as a novel therapeutic target in osteoporosis.

Method

We investigated the effect of EMFs on P2X7 expression and downstream signaling in human bone marrow mesenchymal stem cells (h-MSCs). We also established an ovariectomized (OVX) osteoporosis rat model to evaluate the therapeutic efficacy of combining EMFs with P2X7 agonists.

Results

EMF treatment increased P2X7 expression in h-MSCs under conditions of osteogenic induction but not under regular culture conditions. P2X7 or PI3K/Akt inhibition partially inhibited the pro-osteogenic effect of EMF and lowered the EMF-stimulated activity of the Akt/GSK3β/β-catenin axis. No additive effect of this suppression was observed following simultaneous inhibition of P2X7 and PI3K/Akt. EMF treatment in the presence of a P2X7 agonist had a greater effect in increasing osteogenic marker expression than that of EMF treatment alone. In the OVX osteoporosis model, the therapeutic efficacy of combining EMFs with P2X7 agonists was superior to that of EMF treatment alone.

Conclusions

EMF treatment increases P2X7 expression by h-MSCs during osteogenic differentiation, leading to activation of the Akt/GSK3β/β-catenin axis, which promotes the osteogenesis. Our findings also indicate that combined EMF and P2X7 agonist treatment may be an effective novel strategy for osteoporosis therapy.
Global stability analysis for a generalized delayed SIR model with vaccination and treatment
Authors: Elazzouzi A. , Lamrani Alaoui A. , Tilioua M. , Tridane A.
Published: December 2019

In this work, we investigate the stability of an SIR epidemic model with a generalized nonlinear incidence rate and distributed delay. The model also includes vaccination term and general treatment function, which are the two principal control measurements to reduce the disease burden. Using the Lyapunov functions, we show that the disease-free equilibrium state is globally asymptotically stable if $\mathcal{R}_{0} \leq 1 $R0≤1, where $\mathcal{R}_{0} $R0 is the basic reproduction number. On the other hand, the disease-endemic equilibrium is globally asymptotically stable when $\mathcal{R}_{0} > 1 $R0>1. For a specific type of treatment and incidence functions, our analysis shows the success of the vaccination strategy, as well as the treatment depends on the initial size of the susceptible population. Moreover, we discuss, numerically, the behavior of the basic reproduction number with respect to vaccination and treatment parameters.
Cost-effectiveness analysis comparing ceftazidime/avibactam (CAZ-AVI) as empirical treatment comparing to ceftolozane/tazobactam and to meropenem for complicated intra-abdominal infection (cIAI)
Authors: Kongnakorn Thitima , Eckmann Christian , Bassetti Matteo , Tichy Eszter , Di Virgilio Roberto , Baillon-Plot Nathalie , Charbonneau Claudie
Published: December 2019

Background

The rising incidence of resistance to currently available antibiotics among pathogens, particularly Gram-negative pathogens, in complicated intra-abdominal infections (cIAIs) has become a challenge for clinicians. Ceftazidime/avibactam (CAZ-AVI) is a fixed-dose antibiotic approved in Europe and the United States for treating (in combination with metronidazole) cIAI in adult hospitalised patients who have limited or no alternative treatment options. The approval was based on the results of RECLAIM, a Phase III, parallel-group, comparative study (RECLAIM 1 [NCT01499290] and RECLAIM 2 [NCT01500239]). The objective of our study was to assess the cost-effectiveness of CAZ-AVI plus metronidazole compared with 1) ceftolozane/tazobactam plus metronidazole and 2) meropenem, as an empiric treatment for the management of cIAI in Italy.

Methods

A sequential, patient-level simulation model, with a 5-year time horizon and 3% annual discount rate (applied to both costs and health benefits), was developed using Microsoft Excel® to demonstrate the clinical course of the disease. The impact of resistant pathogens was included as an additional factor.

Results

In the base-case analysis, the CAZ-AVI sequence (CAZ-AVI plus metronidazole followed by a colistin + tigecycline + high-dose meropenem combination after treatment failure), when compared to sequences for ceftolozane/tazobactam (ceftolozane/tazobactam plus metronidazole followed by colistin + tigecycline + high-dose meropenem after treatment failure) and meropenem (meropenem followed by colistin + tigecycline + high-dose meropenem after treatment failure), had better clinical outcomes with higher cure rates (93.04% vs. 91.52%; 92.98% vs. 90.24%, respectively), shorter hospital stays (∆ = − 0.38 and ∆ = − 1.24 days per patient, respectively), and higher quality-adjusted life years (QALYs) gained per patient (4.021 vs. 3.982; 4.019 vs. 3.960, respectively). The incremental cost effectiveness ratio in the CAZ-AVI sequence was €4099 and €15,574 per QALY gained versus each comparator sequence, respectively, well below the willingness-to-pay threshold of €30,000 per QALY accepted in Italy.

Conclusions

The model results demonstrated that CAZ-AVI plus metronidazole could be a cost-effective alternative when compared with other antibiotic treatment options, as it is expected to provide better clinical benefits in hospitalised patients with cIAI in Italy.
Daily rhythms in food intake and locomotor activity in a colony of domestic cats
Authors: Parker Marine , Lamoureux Sarah , Challet Etienne , Deputte Bertrand , Biourge Vincent , Serra Jessica
Published: December 2019

Background

Daily rhythms have been widely investigated in various mammals but, surprisingly, literature is scarce and conflicting regarding the domestic cat, Felis catus. This may come from the difficulty to analyse rhythms in a species showing high interindividual variability and from the common idea that the rhythms of the cat are rather random. To elucidate the subject, two groups of indoor cats (14 in total) living in a cattery room, were followed on a 24 h/7 day basis, using advanced telemetry technologies, i.e. passive RFID, automated weighing of electronic scales and UWB technology with accuracy ensuring a good reliability of the results.

Results

While covering on average 1.74 ± 0.4 km and eating 46.4 ± 3.6 g (≈ 179 kcal) of dry food per day, findings indicate 24 h periodicity in the locomotor and feeding rhythms of the cats. Systematically, their locomotor behaviour was more rhythmic than their eating behaviour (p < 0.01), possibly reflecting the flexibility of the eating patterns of the cat initially enabling it to adapt to daily rhythms of its prey. In their daily patterns, the indoor individuals showed two main troughs of activity and food intake—in the middle of the day and in the middle of the night—and two main peaks: one in the morning (especially before sunrise and food renewal), the other in the evening (following the end of the work day of the animal staff and before sunset), supporting previous work demonstrating peaks at dusk and dawn and confirming the crepuscular nature of the species. No general pattern emerged according to a more nocturnal versus diurnal organisation.

Conclusions

Bimodality, more than chronotypes, seems therefore to best characterise the activity and feeding rhythms of the species as it was demonstrated in the individuals among the different categorisations. By validating the use of new tracking technologies as well as of adapted chronobiological parameters to assess the daily rhythm of cats living indoors, this study opens the way for more adequate analyses of cat behaviour through time under various conditions.
Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer’s disease and aged brains: increased levels correlate with neuropathology
Authors: Mendsaikhan Anarmaa , Tooyama Ikuo , Bellier Jean-Pierre , Serrano Geidy E. , Sue Lucia I. , Lue Lih-Fen , Beach Thomas G. , Walker Douglas G.
Published: December 2019

Progranulin (PGRN) is a protein encoded by the GRN gene with multiple identified functions including as a neurotrophic factor, tumorigenic growth factor, anti-inflammatory cytokine and regulator of lysosomal function. A single mutation in the human GRN gene resulting in reduced PGRN expression causes types of frontotemporal lobar degeneration resulting in frontotemporal dementia. Prosaposin (PSAP) is also a multifunctional neuroprotective secreted protein and regulator of lysosomal function. Interactions of PGRN and PSAP affect their functional properties. Their roles in Alzheimer’s disease (AD), the leading cause of dementia, have not been defined. In this report, we examined in detail the cellular expression of PGRN in middle temporal gyrus samples of a series of human brain cases (n = 45) staged for increasing plaque pathology. Immunohistochemistry showed PGRN expression in cortical neurons, microglia, cerebral vessels and amyloid beta (Aβ) plaques, while PSAP expression was mainly detected in neurons and Aβ plaques, and to a limited extent in astrocytes. We showed that there were increased levels of PGRN protein in AD cases and corresponding increased levels of PSAP. Levels of PGRN and PSAP protein positively correlated with amyloid beta (Aβ), with PGRN levels correlating with phosphorylated tau (serine 205) levels in these samples. Although PGRN colocalized with lysosomal-associated membrane protein-1 in neurons, most PGRN associated with Aβ plaques did not. Aβ plaques with PGRN and PSAP deposits were identified in the low plaque non-demented cases suggesting this was an early event in plaque formation. We did not observe PGRN-positive neurofibrillary tangles. Co-immunoprecipitation studies of PGRN from brain samples identified only PSAP associated with PGRN, not sortilin or other known PGRN-binding proteins, under conditions used. Most PGRN associated with Aβ plaques were immunoreactive for PSAP showing a high degree of colocalization of these proteins that did not change between disease groups. As PGRN supplementation has been considered as a therapeutic approach for AD, the possible involvement of PGRN and PSAP interactions in AD pathology needs to be further considered.
Triiodothyronine modulates neuronal plasticity mechanisms to enhance functional outcome after stroke
Authors: Talhada Daniela , Feiteiro Joana , Costa Ana Raquel , Talhada Tiago , Cairrão Elisa , Wieloch Tadeusz , Englund Elisabet , Santos Cecília Reis , Gonçalves Isabel , Ruscher Karsten
Published: December 2019

The development of new therapeutic approaches for stroke patients requires a detailed understanding of the mechanisms that enhance recovery of lost neurological functions. The efficacy to enhance homeostatic mechanisms during the first weeks after stroke will influence functional outcome. Thyroid hormones (TH) are essential regulators of neuronal plasticity, however, their role in recovery related mechanisms of neuronal plasticity after stroke remains unknown. This study addresses important findings of 3,5,3′-triiodo-L-thyronine (T3) in the regulation of homeostatic mechanisms that adjust excitability – inhibition ratio in the post-ischemic brain. This is valid during the first 2 weeks after experimental stroke induced by photothrombosis (PT) and in cultured neurons subjected to an in vitro model of acute cerebral ischemia. In the human post-stroke brain, we assessed the expression pattern of TH receptors (TR) protein levels, important for mediating T3 actions.

Our results show that T3 modulates several plasticity mechanisms that may operate on different temporal and spatial scales as compensatory mechanisms to assure appropriate synaptic neurotransmission. We have shown in vivo that long-term administration of T3 after PT significantly (1) enhances lost sensorimotor function; (2) increases levels of synaptotagmin 1&2 and levels of the post-synaptic GluR2 subunit in AMPA receptors in the peri-infarct area; (3) increases dendritic spine density in the peri-infarct and contralateral region and (4) decreases tonic GABAergic signaling in the peri-infarct area by a reduced number of parvalbumin+ / c-fos+ neurons and glutamic acid decarboxylase 65/67 levels. In addition, we have shown that T3 modulates in vitro neuron membrane properties with the balance of inward glutamate ligand-gated channels currents and decreases synaptotagmin levels in conditions of deprived oxygen and glucose. Interestingly, we found increased levels of TRβ1 in the infarct core of post-mortem human stroke patients, which mediate T3 actions. Summarizing, our data identify T3 as a potential key therapeutic agent to enhance recovery of lost neurological functions after ischemic stroke.
Inventory and new records of benthic amphipods from macrophytes and fine sand communities of the Bizerte lagoon (Tunisia, SW Mediterranean Sea)
Authors: Khammassi Marwa , Jourde Jérôme , Zaabar Wahiba , Laabidi Sarra , Sauriau Pierre-Guy , Achouri Mohamed Sghaier
Published: December 2019

Shallow water benthic communities from the Bizerte lagoon (northern Tunisia) were investigated at 33 stations sampled in April and July of 2016 and 2017. A total of 18 amphipod species were recorded among which two new species were recorded: one for Tunisian coasts (Jassa marmorata) and a second one for the Mediterranean Sea (Serejohyale spinidactylus). In addition, and compared to previous studies, nine amphipod species were collected for the first time in this lagoon. Amphipod assemblages were numerically dominated by the families Melitidae (28%), Caprellidae (14.5%) and Ampithoidae (11.7%). Three species: Cymadusa filosa, Dexamine spinosa and Elasmopus rapax were numerically dominant. According to their biogeography, most of the recorded amphipod species (11–18) showed an Atlantic–Mediterranean distribution, whereas four were cosmopolitan and three lessepsian Indo-Pacific migrants, but no species were Mediterranean endemic. Specimens of both Jassa marmorata and Serejohyale spinidactylus are illustrated and described.
Adenosine as cardioprotective in off-pump coronary artery bypass grafting
Authors: Aziz Mai Mohsen Abdel , Hamid Ahmad Mostafa Abdel , Hamid Hadil Magdy Abdel
Published: December 2019

Objective

To assess the effect of adenosine as a cardioprotective drug and its role in attenuating ischemia-reperfusion injury during off-pump coronary artery bypass surgery.

Background

Cardioprotective drugs have long been investigated for use during off-pump coronary artery bypass surgery to attenuate ischemia-reperfusion injury and limit hemodynamic instability. Adenosine has been investigated due to its cardioprotective effect that is mediated through A1 and A3 adenosine receptors. Stimulation of these receptors reproduces the infarct-limiting effect of ischemic preconditioning.

Methods

After approval of the local ethics committee and informed written consent, fifty patients undergoing elective off-pump coronary artery bypass grafting were prospectively studied. The adenosine group received an infusion of Adenoscan at a rate of 50 μg/kg/min for 15 min. The control group received normal saline at the same rate and volume calculated. Pulmonary artery catheter was introduced through the right internal jugular vein. Cardiac output measurements were obtained. Cardiac index, stroke volume, systemic vascular resistance, pulmonary vascular resistance, right ventricular stroke work index, and left ventricular stroke work index were derived. Hemodynamic measurements were recorded together with blood levels of troponin I and CK-MB fraction to detect perioperative myocardial necrosis. Postoperative duration of mechanical ventilation, ICU stay together with inotropic support quantification using inotropic score were recorded.

Results

Fifty patients were included in the study. In the adenosine group, the infusion of adenosine resulted in a significant reduction in mean pulmonary artery pressure after stopping drug infusion (18 ± 2.2 mmHg versus 31 ± 4.1 mmHg). There was a recorded increase in cardiac index in the adenosine group that started 15 min after adenosine infusion and lasted for 12 h postoperatively (p < 0.001). Also, adenosine infusion resulted in a reduction in pulmonary vascular resistance that exceeded the reduction in systemic vascular resistance which resulted in a decrease in pulmonary vascular resistance/systemic vascular resistance ratio (0.14 in adenosine group 15 min after injection versus 0.28 in control group) and (0.11 in adenosine group 12 h postoperatively versus 0.26 in control group). The cTroponin I measured 6 h postoperatively was less in the adenosine group compared with the control group (5.8 ± 2.8 ng/ml versus 16.5 ± 3.9 ng/ml).

Conclusion

Adenosine infusion during off-pump coronary artery surgery may improve cardiac index, reduce the need for inotropes, and have cardioprotective effect.