Targeting PI3K/AKT and MEK/ERK pathways for synergic effects on improving features of peripheral diabetic neuropathy.

Diabetic neuropathy is one of the most serious and common complications of diabetes with a wide spectrum, affecting 30-50% of diabetic patients. However, the current treatments of this disorder, mainly based on controlling blood glucose level, show an inadequate clinical outcome. Better approaches are needed. In this fashion, it is noted that promoting nerve regeneration and preventing nerve degeneration should be focused on equally and appropriately. In this mini review, how more effective approaches are in targeting PI3K/AKT and MEK/ERK pathways in the treatment of peripheral diabetic neuropathy is discussed. Future treatment of peripheral diabetic neuropathy should consider these approaches.

Discovering child sexual abuse material creators' behaviors and preferences on the dark web.

BACKGROUND: Producing, distributing or discussing child sexual abuse materials (CSAM) is often committed through the dark web to stay hidden from search engines and to evade detection by law enforcement agencies. Additionally, on the dark web, the CSAM creators employ various techniques to avoid detection and conceal their activities. The large volume of CSAM on the dark web presents a global social problem and poses a significant challenge for helplines, hotlines and law enforcement agencies. OBJECTIVE: Identifying CSAM discussions on the dark web and uncovering associated metadata insights into characteristics, behaviors and motivation of CSAM creators. PARTICIPANTS AND SETTING: We have conducted an analysis of more than 353,000 posts generated by 35,400 distinct users and written in 118 different languages across eight dark web forums in 2022. Out of these, approximately 221,000 posts were written in English and contributed by around 29,500 unique users. METHOD: We propose a CSAM detection intelligence system. The system uses a manually labeled dataset to train, evaluate and select an efficient CSAM classification model. Once we identify CSAM creators and victims through CSAM posts on the dark web, we proceed to analyse, visualize and uncover information concerning the behaviors of CSAM creators and victims. RESULT: The CSAM classifier, based on Support Vector Machine model, exhibited good performance, achieving the highest precision of 92.3 % and accuracy of 87.6 %. While, the Naive Bayes combination is the best in term of recall, achieving 89 %. Across the eight forums in 2022, our Support Vector Machine model detected around 63,000 English CSAM posts and identified near 10,500 English CSAM creators. The analysis of metadata of CSAM posts revealed meaningful information about CSAM creators, their victims and social media platforms they used. This included: (1) The topics of interest and the preferred social media platforms for the 20 most active CSAM creators (For example, two top creators were interested in topics like video, webcam and general content in forums, and they frequently used platforms like Omegle and Skype); (2) Information about the ages and nationalities of the victims typically mentioned by CSAM creators, such as victims aged 12 and 13 with nationalities including British and Russian; (3) social media platforms preferred by CSAM creators for sharing or uploading CSAM, include Omegle, YouTube, Skype, Instagram and Telegram. CONCLUSION: Our CSAM detection system exhibits high performance in precision, recall, and accuracy in real-time when classifying CSAM and non-CSAM posts. Additionally, it can extract and visualize valuable and unique insights about CSAM creators and victims by employing advanced statistical methods. These insights prove beneficial to our partners, i.e. national hotlines and child agencies.

Combined PTEN Knockdown and Local Insulin in Chronic Experimental Diabetic Neuropathy.

Diabetic polyneuropathy (DPN) renders progressive sensory neurodegeneration linked to hyperglycemia and its associated metabolopathy. We hypothesized that there may be additive impacts of direct insulin signaling, independent of glycemia and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) knockdown on neuropathy. Our targets for combined interventions were neurons and Schwann cells (SCs) in vitro and chronic type 1 DPN in mice. Insulin receptor expression was not altered by high-glucose conditions in neurons or SCs, and insulin promoted survival of neurons and proliferation of SCs in vitro. There were additive impacts between insulin signaling and PTEN knockdown in sensory neuron outgrowth and in axon myelination by SCs. In a chronic mouse model of experimental DPN, unilateral intra-hind paw injections of a PTEN siRNA and local insulin had additive impacts on correcting key features of chronic experimental DPN independent of glycemia, including motor axon conduction and thermal and mechanical sensory loss. Moreover, combined interventions improved sural and tibial nerve myelin thickness, hind paw epidermal innervation, and pAkt expression in dorsal root ganglion sensory neurons. We conclude that local PTEN inhibition or knockdown and insulin provide additive trophic support for sensory neurons and SCs while reversing key abnormalities of experimental DPN but without requiring metabolic correction. ARTICLE HIGHLIGHTS: Impaired growth and plasticity of neurons may contribute to chronic diabetic polyneuropathy. Both direct insulin signaling of neurons and neuron knockdown of the protein phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a roadblock to neuronal regenerative growth, offer direct support of neurons. Direct insulin and PTEN knockdown using siRNA had additive impacts on neuron survival, Schwann cell proliferation, neuron outgrowth, and myelination in vitro. Combined local insulin and PTEN siRNA hind paw injections improved abnormalities in chronic experimental diabetic polyneuropathy, including sensory axon loss, independently of glycemia.

Insulin enhances neurite extension and myelination of diabetic neuropathy neurons.

Background: The authors established an in vitro model of diabetic neuropathy based on the culture system of primary neurons and Schwann cells (SCs) to mimic similar symptoms observed in in vivo models of this complication, such as impaired neurite extension and impaired myelination. The model was then utilized to investigate the effects of insulin on enhancing neurite extension and myelination of diabetic neurons. Methods: SCs and primary neurons were cultured under conditions mimicking hyperglycemia prepared by adding glucose to the basal culture medium. In a single culture, the proliferation and maturation of SCs and the neurite extension of neurons were evaluated. In a co-culture, the percentage of myelination of diabetic neurons was investigated. Insulin at different concentrations was supplemented to culture media to examine its effects on neurite extension and myelination. Results: The cells showed similar symptoms observed in in vivo models of this complication. In a single culture, hyperglycemia attenuated the proliferation and maturation of SCs, induced apoptosis, and impaired neurite extension of both sensory and motor neurons. In a co-culture of SCs and neurons, the percentage of myelinated neurites in the hyperglycemia-treated group was significantly lower than that in the control group. This impaired neurite extension and myelination was reversed by the introduction of insulin to the hyperglycemic culture media. Conclusions: Insulin may be a potential candidate for improving diabetic neuropathy. Insulin can function as a neurotrophic factor to support both neurons and SCs. Further research is needed to discover the potential of insulin in improving diabetic neuropathy.

Structural textile pattern recognition and processing based on hypergraphs.

The humanities, like many other areas of society, are currently undergoing major changes in the wake of digital transformation. However, in order to make collection of digitised material in this area easily accessible, we often still lack adequate search functionality. For instance, digital archives for textiles offer keyword search, which is fairly well understood, and arrange their content following a certain taxonomy, but search functionality at the level of thread structure is still missing. To facilitate the clustering and search, we introduce an approach for recognising similar weaving patterns based on their structures for textile archives. We first represent textile structures using hypergraphs and extract multisets of k-neighbourhoods describing weaving patterns from these graphs. Then, the resulting multisets are clustered using various distance measures and various clustering algorithms (K-Means for simplicity and hierarchical agglomerative algorithms for precision). We evaluate the different variants of our approach experimentally, showing that this can be implemented efficiently (meaning it has linear complexity), and demonstrate its quality to query and cluster datasets containing large textile samples. As, to the best of our knowledge, this is the first practical approach for explicitly modelling complex and irregular weaving patterns usable for retrieval, we aim at establishing a solid baseline.

Diabetic neuropathy research: from mouse models to targets for treatment.

Diabetic neuropathy is one of the most serious complications of diabetes, and its increase shows no sign of stopping. Furthermore, current clinical treatments do not yet approach the best effectiveness. Thus, the development of better strategies for treating diabetic neuropathy is an urgent matter. In this review, we first discuss the advantages and disadvantages of some major mouse models of diabetic neuropathy and then address the targets for mechanism-based treatment that have been studied. We also introduce our studies on each part. Using stem cells as a source of neurotrophic factors to target extrinsic factors of diabetic neuropathy, we found that they present a promising treatment.

Effects of morning vs. evening combined strength and endurance training on physical performance, sleep and well-being.

The aim of the present study was to examine how combined strength and endurance training in the morning and evening influences the adaptations in strength and endurance performance, perception of time management, psychological well-being and sleep. The combined training period lasted for 24 weeks and the participants were divided into the morning training (MG, n = 18), evening training (EG, n = 24) and control groups (CG, n = 10). Isometric leg press force (iLP), maximal oxygen consumption (VO2max), sleep behavior, fatigue, time management, motivation, self-esteem and health-related quality of life (HRQoL) were assessed. Morning to evening difference in iLP was observed in both MG and EG at Pre and Post, with higher force values in the evening, but not for VO2max. iLP force increased significantly in EG in the morning (p < 0.001) and evening (p = 0.010). VO2max increased in MG and EG both in the morning (both p < 0.001) and in the evening (MG: p < 0.001; EG: p = 0.003). Participants of the present study slept 7-8 h per night and the self-reported sleep duration, get-up time and the average time to go to bed were similar between the groups and did not change from Pre to Post. From HRQoL dimensions, the score for bodily pain decreased in MG (p = 0.029) and significant between-group differences were observed for Pre-Post changes in MG and EG (p = 0.001) as well as between MG and CG (p < 0.001). In vitality, a significant between-group difference was observed for Pre to Post changes in MG and EG (p = 0.014). Perception of time management decreased in EG (p = 0.042) but stayed unchanged for MG and CG. For the intrinsic motivation to participate, significant between-group differences were observed for MG and EG (p = 0.033) and between MG and CG (p = 0.032) for Pre to Post changes. Self-esteem improved in MG (p = 0.029) and EG (p = 0.024). The present combined strength and endurance training program performed in the morning and in the evening led to similar improvements in strength and endurance performance. Training in the morning or in the evening did not disrupt the already good sleep behavior and it was able to further increase the self-esteem. Although training in the morning hours may leave more time for free time activities or social life (i.e. family and friends) compared to the evening training, it might be more challenging to stay motivated to participate in prolonged training programs in the morning hours.

Impaired peripheral nerve regeneration in type-2 diabetic mouse model.

Peripheral neuropathy is one of the most common and serious complications of type-2 diabetes. Diabetic neuropathy is characterized by a distal symmetrical sensorimotor polyneuropathy, and its incidence increases in patients 40 years of age or older. In spite of extensive research over decades, there are few effective treatments for diabetic neuropathy besides glucose control and improved lifestyle. The earliest changes in diabetic neuropathy occur in sensory nerve fibers, with initial degeneration and regeneration resulting in pain. To seek its effective treatment, here we prepared a type-2 diabetic mouse model by giving mice 2 injections of streptozotocin and nicotinamide and examining the ability for nerve regeneration by using a sciatic nerve transection-regeneration model previously established by us. Seventeen weeks after the last injection, the mice exhibited symptoms of type-2 diabetes, that is, impaired glucose tolerance, decreased insulin level, mechanical hyperalgesia, and impaired sensory nerve fibers in the plantar skin. These mice showed delayed functional recovery and nerve regeneration by 2 weeks compared with young healthy mice and by 1 week compared with age-matched non-diabetic mice after axotomy. Furthermore, type-2 diabetic mice displayed increased expression of PTEN in their DRG neurons. Administration of a PTEN inhibitor at the cutting site of the nerve for 4 weeks promoted the axonal transport and functional recovery remarkably. This study demonstrates that peripheral nerve regeneration was impaired in type-2 diabetic model and that its combination with sciatic nerve transection is suitable for the study of the pathogenesis and treatment of early diabetic neuropathy.

Does small-dose fentanyl improve perioperative outcomes in the ambulatory setting? A randomized, double-blind, placebo-controlled study.

BACKGROUND: Despite its widespread use, the beneficial effect of low-dose fentanyl administered at induction of anesthesia on perioperative outcomes has not been studied in the ambulatory setting. Therefore, this study was designed to test the hypothesis that administration of small-dose fentanyl vs. saline during induction reduces coughing and movements without adversely affecting recovery after day-surgery. METHODS: One hundred consenting outpatients scheduled to undergo superficial surgical procedures under general anesthesia with a laryngeal mask airway (LMA) device for airway management were randomly assigned to one of two treatment groups: control (n = 50) or fentanyl (n = 50). After administration of 2 ml of the unlabelled study medication containing either fentanyl (100 µg) or saline, anesthesia was induced with lidocaine 30-50 mg and propofol 2 mg/kg IV followed by the insertion of an LMA device. General anesthesia was maintained using a propofol infusion, 75 µg/kg/min, and desflurane (2-5% end-tidal) in 100% oxygen. RESULTS: Coughing was observed in six (12%) and ten (20%) in the fentanyl and control group, respectively (P = 0.41). The incidence of movements during surgery was lower in the fentanyl group (18% vs. 31%, P < 0001). There were no significant differences in early and late recovery times or pain scores between the two groups. CONCLUSION: Administration of a small-dose of fentanyl at induction of anesthesia significantly reduced purposeful movements during day-surgery under propofol-desflurane anesthesia. No significant difference was found in coughing or recovery times.

Targeting gene expression to the female larval fat body of transgenic Aedes aegypti mosquitoes.

As the fat body is a critical tissue for mosquito development, metamorphosis, immune and reproductive system function, the characterization of regulatory modules targeting gene expression to the female mosquito fat body at distinct life stages is much needed for multiple, varied strategies for controlling vector-borne diseases such as dengue and malaria. The hexameric storage protein, Hexamerin-1.2, of the mosquito Aedes atropalpus is female-specific and uniquely expressed in the fat body of fourth instar larvae and young adults. We have identified in the Hex-1.2 gene, a short regulatory module that directs female-, tissue-, and stage-specific lacZ reporter gene expression using a heterologous promoter in transgenic lines of the dengue vector Aedes aegypti. Male transgenic larvae and pupae of one line expressed no Escherichia coli ß-galactosidase or transgene product; in two other lines reporter gene activity was highly female-biased. All transgenic lines expressed the reporter only in the fat body; however, lacZ mRNA levels were no different in males and females at any stage examined, suggesting that the gene regulatory module drives female-specific expression by post-transcriptional regulation in the heterologous mosquito. This regulatory element from the Hex-1.2 gene thus provides a new molecular tool for transgenic mosquito control as well as functional genetic analysis in aedine mosquitoes.

Financial burden of health care for HIV/AIDS patients in Vietnam.

OBJECTIVE: To assess the out-of-pocket (OOP) payments for health-care services of HIV/AIDS patients, and identify associated factors in Vietnam. METHODS: Cross-sectional multisite survey of 1016 HIV/AIDS patients attending 7 hospitals and health centres in Ha Noi, Hai Phong and Ho Chi Minh City in 2012. RESULTS: HIV/AIDS patients used inpatient and outpatient care on average 5.1 times (95% CI = 4.7-5.4) besides ART services. Inpatient care cost US$ 461 on average and outpatient care US$ 50. Mean annual health-care expenditure for HIV/AIDS patients was US$ 188 (95% CI = 148-229). 35.1% of households (95% CI = 32.2-38.1) experienced catastrophic health expenditure; 73.3% (95% CI = 70.6-76.1) of households would be affected if ART were not subsidised. Being a patient at a provincial clinic, male sex, unstable employment, being in the poorest income quintile, a CD4 count of <200 cells/mL and not yet receiving ART increased the likelihood of catastrophic medical expense. CONCLUSIONS: HIV/AIDS patients in Vietnam frequently use medical services and incur OOP payments for health care. Scaling up free-of-charge ART services, earlier access to and initiation of ART, and decentralisation and integration of HIV/AIDS-related services could reduce their financial burden.

Dynamic topology representing networks.

In the present paper, we propose a new algorithm, namely the Dynamic Topology Representing Networks (DTRN) for learning both topology and clustering information from input data. In contrast to other models with adaptive architecture of this kind, the DTRN algorithm adaptively grows the number of output nodes by applying a vigilance test. The clustering procedure is based on a winner-take-quota learning strategy in conjunction with an annealing process in order to minimize the associated mean square error. A competitive Hebbian rule is applied to learn the global topology information concurrently with the clustering process. The topology information learned is also utilized for dynamically deleting the nodes and for the annealing process. Properties of the DTRN algorithm will be discussed. Extensive simulations will be provided to characterize the effectiveness of the new algorithm in topology preserving, learning speed, and classification tasks as compared to other algorithms of the same nature.

Neutron beam radiotherapy for recurrent prostate cancer following radical prostatectomy.

PURPOSE: To evaluate the effectiveness of neutron beam radiotherapy (NXRT) to treat recurrent prostate cancer following radical prostatectomy (RP). METHODS AND MATERIALS: Twenty-five patients who failed RP received NXRT at our institution. The pathological stages ranged from T2c-T3c, with 16 patients having either seminal vesicle involvement and/or nodal metastases. Sixteen patients also received neoadjuvant hormones. Freedom from relapse (FFR) was defined by an undetectable PSA (PSA < or =0.2). Median follow-up was 27 months, with no patients lost to follow-up. RESULTS: Postneutron PSA became initially undetectable in 84% of patients. The actuarial FFR is 36% at 3 years. Nine patients remain NED, 12 patients have an elevated PSA only, 2 patients have clinical recurrence, and 2 patients are dead of prostate cancer. Pre-NXRT PSA levels of < or =1.0 vs. >1.0 predicted for outcome, with a FFR at 3 years of 76 vs. 14% (p = 0.003). Patients with a persistently elevated PSA following RP were not effectively salvaged by NXRT, with a 12% FFR at 3 years compared to a 62% FFR for patients whose PSA initially normalized following RP (p = 0.03). There was no difference in treatment outcomes based on fields encompassing pelvic nodes vs. fields directed to the prostatic fossa only. There were no severe (RTOG Grade 3) late complications. CONCLUSION: NXRT is an effective salvage treatment for carefully selected patients. This group includes patients whose PSA initially normalized following RP, and whose pre-NXRT PSA < or =1.0.