The tetraspanin transmembrane protein CD53 mediates dyslipidemia and integrates inflammatory and metabolic signaling in hepatocytes.

Tetraspanins are transmembrane signaling and proinflammatory proteins. Prior work demonstrates that the tetraspanin, CD53/TSPAN25/MOX44, mediates B-cell development and lymphocyte migration to lymph nodes and is implicated in various inflammatory diseases. However, CD53 is also expressed in highly metabolic tissues, including adipose and liver; yet its function outside the lymphoid compartment is not defined. Here, we show that CD53 demarcates the nutritional and inflammatory status of hepatocytes. High-fat exposure and inflammatory stimuli induced CD53 in vivo in liver and isolated primary hepatocytes. In contrast, restricting hepatocyte glucose flux through hepatocyte glucose transporter 8 deletion or through trehalose treatment blocked CD53 induction in fat- and fructose-exposed contexts. Furthermore, germline CD53 deletion in vivo blocked Western diet-induced dyslipidemia and hepatic inflammatory transcriptomic activation. Surprisingly, metabolic protection in CD53 KO mice was more pronounced in the presence of an inciting inflammatory event. CD53 deletion attenuated tumor necrosis factor alpha-induced and fatty acid + lipopolysaccharide-induced cytokine gene expression and hepatocyte triglyceride accumulation in isolated murine hepatocytes. In vivo, CD53 deletion in nonalcoholic steatohepatitis diet-fed mice blocked peripheral adipose accumulation and adipose inflammation, insulin tolerance, and liver lipid accumulation. We then defined a stabilized and trehalase-resistant trehalose polymer that blocks hepatocyte CD53 expression in basal and over-fed contexts. The data suggest that CD53 integrates inflammatory and metabolic signals in response to hepatocyte nutritional status and that CD53 blockade may provide a means by which to attenuate pathophysiology in diseases that integrate overnutrition and inflammation, such as nonalcoholic steatohepatitis and type 2 diabetes.

CTCF shapes chromatin structure and gene expression in health and disease.

CCCTC-binding factor (CTCF) is an eleven zinc finger (ZF), multivalent transcriptional regulator, that recognizes numerous motifs thanks to the deployment of distinct combinations of its ZFs. The great majority of the ~50,000 genomic locations bound by the CTCF protein in a given cell type is intergenic, and a fraction of these sites overlaps with transcriptional enhancers. Furthermore, a proportion of the regions bound by CTCF intersect genes and promoters. This suggests multiple ways in which CTCF may impact gene expression. At promoters, CTCF can directly affect transcription. At more distal sites, CTCF may orchestrate interactions between regulatory elements and help separate eu- and heterochromatic areas in the genome, exerting a chromatin barrier function. In this review, we outline how CTCF contributes to the regulation of the three-dimensional structure of chromatin and the formation of chromatin domains. We discuss how CTCF binding and architectural functions are regulated. We examine the literature implicating CTCF in controlling gene expression in development and disease both by acting as an insulator and a factor facilitating regulatory elements to efficiently interact with each other in the nuclear space.

Nanogels with covalently bound and releasable trehalose for autophagy stimulation in atherosclerosis.

Atherosclerosis, cholesterol-driven plaque formation in arteries, is a complex multicellular disease which is a leading cause of vascular diseases. During the progression of atherosclerosis, the autophagic function is impaired, resulting in lipid accumulation-mediated foam cell formation. The stimulation of autophagy is crucial for the recovery of cellular recycling process. One of the potential autophagy inducers is trehalose, a naturally occurring non-reducing disaccharide. However, trehalose has poor bioavailability due to its hydrophilic nature which results in poor penetration through cell membranes. To enhance its bioavailability, we developed trehalose-releasing nanogels (TNG) for the treatment of atherosclerosis. The nanogels were fabricated through copolymerization of 6-O-acryloyl-trehalose with the selected acrylamide-type monomers affording a high trehalose conjugation (~ 58%, w/w). TNG showed a relatively small hydrodynamic diameter (dH, 67 nm) and a uniform spherical shape and were characterized by negative ζ potential (-18 mV). Thanks to the trehalose-rich content, TNG demonstrated excellent colloidal stability in biological media containing serum and were non-hemolytic to red blood cells. In vitro study confirmed that TNG could stimulate autophagy in foam cells and enhance lipid efflux and in vivo study in ApoE-/- mice indicated a significant reduction in atherosclerotic plaques, while increasing autophagic markers. In conclusion, TNG hold great promise as a trehalose delivery system to restore impaired autophagy-mediated lipid efflux in atherosclerosis and subsequently reduce atherosclerotic plaques.

A Simple Synthesis of Reduction-Responsive Acrylamide-Type Nanogels for miRNA Delivery.

MicroRNAs (miRNAs) have great therapeutic potential; however, their delivery still faces huge challenges, especially given the short half-life of naked miRNAs due to rapid hydrolysis or inactivation by abundant nucleases in the systemic circulation. Therefore, the search for reliable miRNA delivery systems is crucial. Nanogels are one of the more effective nanocarriers because they are biocompatible and have a high drug-loading capacity. In this study, acrylamide-based nanogels containing cationic groups and redox-sensitive crosslinkers were developed for cellular delivery of anti-miR21 (a-miR21). To achieve this, post-polymerization loading of a-miR21 oligonucleotides into nanogels was performed by utilizing the electrostatic interaction between positively charged nanogels and negatively charged oligonucleotides. Different molar ratios of the amine groups (N) on the cationic nanogel and phosphate groups (P) on the miRNA were investigated. An N/P ratio of 2 allowed high miRNA loading capacity (MLC, 6.7% w/w) and miRNA loading efficiency (MLE, 99.7% w/w). Successful miRNA loading was confirmed by dynamic light scattering (DLS) and electrophoretic light scattering (ELS) measurements. miRNA-loaded nanogels (NG/miRNA) formed stable dispersions in biological media and showed an enhanced miRNA release profile in the presence of glutathione (GSH). Moreover, the addition of heparin to dissociate the miRNA from the cationic nanogels resulted in the complete release of miRNA. Lastly, a cell uptake study indicated that NG/miRNA could be easily taken up by cancer cells.

pH and Reduction Dual-Responsive Nanogels as Smart Nanocarriers to Resist Doxorubicin Aggregation.

The use of smart nanocarriers that can modulate therapeutic release aided by biological cues can prevent undesirable cytotoxicity caused by the premature release of cytotoxic drugs during nanocarrier circulation. In this report, degradable nanocarriers based on pH/reduction dual-responsive nanogels were synthesized to encapsulate doxorubicin hydrochloride (DOX) and specifically boost the release of DOX in conditions characteristic of the cancer microenvironment. Nanogels containing anionic monomer 2-carboxyethyl acrylate (CEA) and N,N'-bis(acryloyl)cystamine (CBA) as a degradable crosslinker have been successfully synthesized via photoinitiated free radical polymerization. The loading process was conducted after polymerization by taking advantage of the electrostatic interaction between the negatively charged nanogels and the positively charged DOX. In this case, a high drug loading capacity (DLC) of up to 27.89% was achieved. The entrapment of DOX into a nanogel network could prevent DOX from aggregating in biological media at DOX concentrations up to ~160 µg/mL. Anionic nanogels had an average hydrodynamic diameter (dH) of around 90 nm with a negative zeta (ζ) potential of around -25 mV, making them suitable for targeting cancer tissue via the enhanced permeation effect. DOX-loaded nanogels formed a stable dispersion in different biological media, including serum-enriched cell media. In the presence of glutathione (GSH) and reduced pH, drug release was enhanced, which proves dual responsivity. An in vitro study using the HCT 116 colon cancer cell line demonstrated the enhanced cytotoxic effect of the NG-CBA/DOX-1 nanogel compared to free DOX. Taken together, pH/reduction dual-responsive nanogels show promise as drug delivery systems for anticancer therapy.

The Core-Shell Structure, Not Sugar, Drives the Thermal Stabilization of Single-Enzyme Nanoparticles.

Trehalose is widely assumed to be the most effective sugar for protein stabilization, but exactly how unique the structure is and the mechanism by which it works are still debated. Herein, we use a polyion complex micelle approach to control the position of trehalose relative to the surface of glucose oxidase within cross-linked and non-cross-linked single-enzyme nanoparticles (SENs). The distribution and density of trehalose molecules in the shell can be tuned by changing the structure of the underlying polymer, poly(N-[3-(dimethylamino)propyl] acrylamide (PDMAPA). SENs in which the trehalose is replaced with sucrose and acrylamide are prepared as well for comparison. Isothermal titration calorimetry, dynamic light scattering, and asymmetric flow field-flow fraction in combination with multiangle light scattering reveal that two to six polymers bind to the enzyme. Binding either trehalose or sucrose close to the enzyme surface has very little effect on the thermal stability of the enzyme. By contrast, encapsulation of the enzyme within a cross-linked polymer shell significantly enhances its thermal stability and increases the unfolding temperature from 70.3 °C to 84.8 °C. Further improvements (up to 92.8 °C) can be seen when trehalose is built into this shell. Our data indicate that the structural confinement of the enzyme is a far more important driver in its thermal stability than the location of any sugar.

Psychometric validation of the Polish version of the Central Sensitization Inventory in subjects with chronic spinal pain.

BACKGROUND: Central sensitization is an amplification of neuronal signaling within the central nervous system. The Central Sensitization Inventory was introduced in 2012. A Polish version of the CSI (CSI-Pol) was developed in 2019, but it was not psychometrically validated. The aim of this study was to validate the CSI-Pol in a sample of Polish-speaking patients with chronic spinal pain and compare them with a group of healthy control subjects. METHODS: The CSI-Pol was administered to 151 patients with chronic spinal pain recruited from two centers. It was re-administered 7 days later. The psychometric properties were then evaluated, including test-retest reliability, construct validity, factor structure and internal consistency. We correlated the CSI-Pol with functional scales, depression and social support scales and compared CSI-Pol scores in the clinical subjects with 30 healthy control subjects recruited from medical staff and their families. RESULTS: The CSI-Pol demonstrated excellent internal consistency (Cronbach's α =0,933) and test-retest reliability (Intraclass Correlation Coefficients - ICC =0.96), as well as significant positive associations with other patient-reported scales, including the Neck Disability Index (r = 0.593), Revised Oswestry Low Back Pain Disability Questionnaire (r = 0.422), and other measures of functional and depressive states. An exploratory factor analysis resulted in a 4-factor model. CSI-Pol scores in the clinical sample (35.27 ± 17.25) were significantly higher than the control sample (23.3 ± 8.9). CONCLUSION: The results of this study suggest that the CSI-Pol may be a useful clinical tool for assessing central sensitization related symptoms and guiding appropriate treatment in Polish-speaking patients with spinal pain.

Noninvasive celiac plexus radiosurgery in palliative treatment for patients with symptomatic pancreatic cancer.

Advanced pancreatic cancer is commonly associated with significant visceral pain, radiating in a belt-like distribution to the upper abdomen, referring to the lower back, and significantly affecting patients' quality of life (QoL). The pain is often poorly controlled by pharmacotherapy, or the doses necessary to control the pain produce substantial adverse effects. Other available pain management options include invasive celiac plexus block or neurolysis, palliative radiotherapy, and systemic chemotherapy, all with limited efficacy. In this case report, we present the first non-invasive celiac plexus radiosurgery performed in Europe in a patient with pancreatic cancer, demonstrating that significant pain relief can be achieved through a non-invasive procedure performed within 2 outpatient visits.

Risk factors for shivering during caesarean section under spinal anaesthesia. A prospective observational study.

BACKGROUND: Shivering during caesarean section (CS) under spinal anaesthesia is a common phenomenon. It could not only alter patient's physiology by increasing oxygen consumption but also affect the parturient's experience of childbirth. Shivering is thought to be associated with intraoperative hypothermia, but the risk factors and exact mechanism remain unclear. METHODS: We conducted a prospective, observational study to examine the potential risk factors for intraoperative shivering, including anxiety levels. Two hundred patients undergoing elective CS under spinal anaesthesia were recruited. Parturient anxiety levels were evaluated using the State-Trait Anxiety Inventory (STAI) questionnaire. Age, weight, height, BMI, anxiety level, number of previous deliveries, sensory block level, level of education, temperature difference during surgery and American Society of Anesthesiologists score were investigated as potential risk factors. Stepwise logistic regression was used to assess the predictors for shivering. RESULTS: Data from 155 parturients were analysed. Shivering incidence was 21.9% (34 parturients). The statistical model predicted 8.5% of a shivering incidence variability (R-square Nagelkerke = 0.085). Out of all measured variables, only the number of previous deliveries [(W) = 4.295 Exp(B) = 0.562 P < .05] and STAI-X1 [(W) = 4.127 Exp(B) = 1.052 P < .05] were significant. In our model, the risk of shivering decreased by 44% with every previous delivery and increased by 5.2% with each 1-point increase in STAI-X1. CONCLUSION: We failed to prove a strong correlation between the measured variables and shivering. Our findings, however, support the hypothesis, that to a limited extent, anxiety promotes shivering during CS.

Translation and cross-cultural adaptation of the Polish Central Sensitization Inventory.

OBJECTIVES: The Central Sensitization Inventory (CSI) is a new, simple clinimetric instrument intended to help doctors who deal with pain of unclear origin. It may be particularly useful when there is a large component of neuropathic pain and to assess non-specific symptoms associated with the phenomenon of central sensitization known under the common name of the central sensitization syndrome. The aim of this study is to perform translation of the CSI into Polish, its cultural adaptation and its preparation for further validation. The proposed adaptation of the scale may be applied both at the clinical level and at the level of primary care. MATERIAL AND METHODS: The CSI translation process took place in several stages. Firstly, the text of the questionnaire was translated from English to Polish by five independent translators. Secondly, the optimal version of the text was determined and, at the third stage, it was submitted to a linguist in order to assess it in the context of the idiomatic and semantic clarity. Thirdly, the translation was passed on to a native speaker who verified the congruence of the Polish translation with its original version. At a later stage, the effect of translating the scale and its usefulness were discussed by a group of experts in order to adapt a cultural tool. The final step was to provide it to be completed and evaluated by twenty anonymous patients with the aim of pre-assessing the level of its understanding. RESULTS: The final result of the undertaken activities is the Polish version of the CSI ready for validation. CONCLUSIONS: After the multistage preparation and thorough verification of the Polish questionnaire at conceptual, empirical, semantic and idiomatic levels, necessary due to numerous cultural and linguistic differences, the Polish translation of the CSI seems to be a product ready for further validation and introduction to clinical practice.

Transdermal and Topical Drug Administration in the Treatment of Pain.

The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients' age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review is aimed at presenting current knowledge on analgesics administered by transdermal and topical routes for physicians, nurses, pharmacists, and other health care professionals dealing with patients suffering from pain. Analgesics administered transdermally or topically act through different mechanisms. Opioids administered transdermally are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central and peripheral nervous system. Non-steroidal anti-inflammatory drugs (NSAIDs) applied topically render analgesia mainly through a high concentration in the structures of the joint and a provision of local anti-inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants (i.e., doxepin, amitriptyline) act mainly locally in tissues through receptors and/or ion channels. Transdermal and topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects. The transdermal route apart from the above-mentioned advantages and provision of long period of analgesia may be more convenient, especially for patients who are unable to take drugs orally. Topically and transdermally administered opioids are characterised by a lower risk of addiction compared to oral and parenteral routes.

Impact of somatic PI3K pathway and ERBB family mutations on pathological complete response (pCR) in HER2-positive breast cancer patients who received neoadjuvant HER2-targeted therapies.

BACKGROUND: The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies. METHODS: Baseline tumour biopsies were available from 74 patients with HER2-positive breast cancer who were enrolled in the phase II TCHL neoadjuvant study (ICORG 10-05) assessing TCH (docetaxel, carboplatin, trastuzumab) (n = 38) versus TCL (docetaxel, carboplatin, lapatinib) (n = 10) versus TCHL (docetaxel, carboplatin, trastuzumab, lapatinib) (n = 40), each for six cycles. Activating mutations in PIK3CA and ERBB family genes were identified using mass spectrometry-based genotyping. Phosphatase and tensin homolog (PTEN) expression was assessed by immunohistochemistry. RESULTS: PIK3CA and/or ERBB family mutations were detected in 23 (31.1%) tumour samples tested, whereas PTEN expression was low in 31.1% of cases tested. Mutation frequency was similar in each treatment arm (31.3% in TCH arm, 30% in TCL arm and 31.3% in TCHL arm) and was not influenced by oestrogen receptor (ER) status (27.6% in ER-negative patients, 33.3% in ER-positive patients) or progesterone receptor (PR) status (32.6% in PR-negative patients, 29% in PR-positive patients). There was no significant difference in pathological complete response (pCR) rates between 47 patients with wild-type (WT) tumours and 22 patients whose tumours carried mutations (in either PIK3CA or ERBB family genes) (42.5% vs. 54.5%; p = 0.439). Similarly, there was no significant difference in pCR rates between patients with PIK3CA/ERBB family mutated/PTEN-low (i.e., PI3K-activated) tumours and patients without PI3K activation (50% vs. 44%; p = 0.769). However, in the TCHL (but not the TCH) group, the pCR rate was higher for 9 patients with PIK3CA/ERBB family mutated tumours than for 20 patients with PIK3CA/ERBB family WT tumours (77.8% vs. 35%; p = 0.05). CONCLUSIONS: Our results indicate that patients who receive neoadjuvant TCHL and have PIK3CA/ERBB family mutated tumours may be more likely to have a pCR than patients with WT tumours. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01485926 . Registered on 2 December 2011.

Different expression levels of spartin cause broad spectrum of cellular consequences in human neuroblastoma cells.

Hereditary spastic paraplegia describes a diverse group of neurodegenerative conditions characterised by progressive spasticity and weakness of the lower limbs. Mutations in the SPG20 gene encoding spartin cause an autosomal recessive hereditary spastic paraplegia known as Troyer syndrome. To evaluate the cellular consequences of sustained spartin depletion in neuronal cells, we established several clonal SH-SY5Y cell lines with different level of spartin knockdown. Here, we report that cells with modest spartin downregulation show signs of neuronal differentiation such as increased neuritogenesis and cytoskeleton rearrangement. Interestingly, we also indicate that permanent high level spartin depletion results in impaired cell growth and multiple mitochondrial aberrations, which we speculate, arise as a result of chronic oxidative stress. Our studies demonstrate that the scale of spartin downregulation is the major factor that determines the severity of cellular consequences observed and suggest that there is a critical level of spartin expression which must be maintained for proper cellular functions.

The effectiveness of neurolytic block of sphenopalatine ganglion using zygomatic approach for the management of trigeminal neuropathy.

This study was performed to present the outcomes of trigeminal neuropathy management with the application of neurolytic block of sphenopalatine ganglion. This type of procedure is used in cases where pain is not well controlled with medical treatment. Twenty patients were treated with sphenopalatine ganglion neurolysis after their response to pharmacological management was not satisfactory. Significant pain relief was experienced by all but one patient and they were able to reduce or stop their pain medication. The time of pain relief was between a few months and 9 years during the study period. Number of procedures implemented varied as some of the patients have been under the care of our Pain Clinic for as long as 18 years, satisfied with this type of management and willing to have the procedure repeated if necessary. It appears that neurolytic block of sphenopalatine ganglion is effective enough and may be an option worth further consideration in battling the pain associated with trigeminal neuropathy.

5% lidocaine medicated plasters vs. sympathetic nerve blocks as a part of multimodal treatment strategy for the management of postherpetic neuralgia: a retrospective, consecutive, case-series study.

INTRODUCTION: 5% lidocaine medicated plasters (5% LMP) have been appointed as a first-line treatment for post-herpetic neuralgia (PHN), while formerly used sympathetic nerve blocks (SNBs) were recently denied their clinical efficacy. The aim of this study was to compare the results of PHN management with the use of SNBs and 5% LMP as a first-line treatment. MATERIAL AND METHODS: This study was designed as a retrospective, consecutive, case-series study. Data of 60 consecutive PHN patients with allodynia treated with the use of SNBs and 60 subsequent patients managed with 5% LMP were analyzed. Pain severity after 8 weeks was assessed to recognize the results of the implemented therapy, with numeric rating scale (NRS) score <3 or =3 considered a success. Additionally, the number of pain-free patients (NRS=0) after 8 weeks were identified in both groups and compared. RESULTS: The rate of failures in SNBs and 5% LMP group was similar (18.9% vs. 27.1% of poor treatment results, respectively), with the average change in NRS of 5.88 ± 2.41 in nerve blocks and 5.01 ± 1.67 in lidocaine group (p=0.02). Significant difference was also noted in the rates of pain-free patients: 20 patients (34.4%) treated with SNBs and 8 (13.5%) using 5% LMP were pain-free after 8 weeks of treatment. CONCLUSION: It may be concluded that SNBs may still be considered useful in PHN management, as it appears that in some cases this mode of treatment may offer some advantages over 5% LMP.

Diagnosis and management of neuropathic pain: review of literature and recommendations of the Polish Association for the study of pain and the Polish Neurological Society - part one.

Neuropathic pain still present a major diagnostic and therapeutic challenge despite considerable progress in understanding of its mechanisms and publication of number of studies which assessed the efficacy and safety of drugs used in the symptomatic treatment. In practice, it is diagnosed less frequently than recognised in the epidemiological studies, and many patients do not achieve satisfactory outcomes of treatment. A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on neuropathic pain, with special focus on the published international recommendations, and formulated recommendations on neuropathic pain diagnosis and treatment, in accordance with the principles of evidence-based medicine. The paper presents also background information on the neuropathic pain definition, epidemiology, pathomechanism and method of assessment. The diagnosis of neuropathic pain may be established based on medical history and physical examination including special assessment of the somatosensory system. First-line drugs used in pharmacological management of neuropathic pain are: tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, gabapentin, pregabalin, opioids and lidocaine patches.

Diagnosis and management of neuropathic pain: review of literature and recommendations of the Polish Association for the Study of Pain and the Polish Neurological Society - Part Two.

Neuropathic pain may be caused by a variety of lesions or diseases of both the peripheral and central nervous system. The most common and best known syndromes of peripheral neuropathic pain are painful diabetic neuropathy, trigeminal and post-herpetic neuralgia, persistent post-operative and post-traumatic pain, complex regional pain syndrome, cancer-related neuropathic pain, HIV-related neuropathic pain and pain after amputation. The less common central pain comprises primarily central post-stroke pain, pain after spinal cord injury, central pain in Parkinson disease or in other neurodegenerative diseases, pain in syringomyelia and in multiple sclerosis. A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on various types of neuropathic pain, with special focus on the available international guidelines, and has formulated recommendations on their diagnosis and treatment, in accordance with the principles of evidence-based medicine (EBM). High quality studies on the efficacy of various medicines and medical procedures in many neuropathic pain syndromes are scarce, which makes the recommendations less robust.

Prospective evaluation of pain control and quality of life in patients with chronic pancreatitis following bilateral thoracoscopic splanchnicectomy.

BACKGROUND: Abdominal pain in chronic pancreatitis (CP) is the most common symptom with a highly unfavorable impact on the quality of life. It has been shown that bilateral thoracoscopic splanchnicectomy (BTS) may produce marked pain relief for the majority of patients. The aim of this study was to evaluate the effectiveness of BTS in pain control and quality-of-life improvement in patients with a severe form of CP. METHODS: Between April 2000 and April 2009, a total of 30 patients qualified for BTS due to CP-related pain. Their age ranged from 28 to 60 years. A 12-month follow-up period was planned for all the patients enrolled. To evaluate effectiveness of BTS, an 11-point Numeric Rating Scale (NRS) and the Quality of Life Questionnaire C-30 (QLQ-C30) in its basic form, developed by European Organization for Research and Treatment of Cancer, were used. An NRS value between 0 and 3 was considered a positive postoperative pain control result. RESULTS: The bilateral splanchnicectomy procedure was performed successfully in 27 of 30 qualified patients. A positive effect based on decreased pain (p < 0.05) at 12 months was achieved in 24 patients (80 %). The initial change in quality of life was not significant but it gradually improved with time (preop vs. 12 months QLQ-C30 score, p < 0.001). CONCLUSIONS: This study showed that BTS is safe and efficacious for pain alleviation in patients with severe CP. It may significantly increase the chances of a long-lasting, life-changing improvement in the quality of life.

Trehalose-Bearing Carriers to Target Impaired Autophagy and Protein Aggregation Diseases.

In recent years, trehalose, a natural disaccharide, has attracted growing attention because of the discovery of its potential to induce autophagy. Trehalose has also been demonstrated to preserve the protein's structural integrity and to limit the aggregation of pathologically misfolded proteins. Both of these properties have made trehalose a promising therapeutic candidate to target autophagy-related disorders and protein aggregation diseases. Unfortunately, trehalose has poor bioavailability due to its hydrophilic nature and susceptibility to enzymatic degradation. Recently, trehalose-bearing carriers, in which trehalose is incorporated either by chemical conjugation or physical entrapment, have emerged as an alternative option to free trehalose to improve its efficacy, particularly for the treatment of neurodegenerative diseases, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and cancers. In the current Perspective, we discuss all existing literature in this emerging field and try to identify key challenges for researchers intending to develop trehalose-bearing carriers to stimulate autophagy or inhibit protein aggregation.