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Aims: Diabetic peripheral neuropathy (DPN) often coexists with sudomotor dysfunction, resulting in an increased risk of diabetic foot. This study aimed to explore an efficient method for early diagnosis of DPN by establishing a quantitative Neuropad. Methods: We recruited 518 patients with type 2 diabetes. Neuropathy Symptoms Score (NSS) combined with Neuropathy Disability Score (NDS) was used to assess distal symmetrical peripheral neuropathy (DSPN). The area under the ROC curve (AUROC), sensitivity, and specificity were used to compare the diagnostic efficacy of quantitative Neuropad (the change rate of the chromatic aberration value per minute) and two types of visual Neuropad (visual Neuropad A: whether the time to complete colour change within 10 min, visual Neuropad B: the time to complete colour change) for DPN. Results: We did not observe very good diagnostic efficacy of Neuropad (visual Neuropad A and B: 0.59 and 0.64, quantitative Neuropad AUROC: 0.62–0.64) when using standard DSPN diagnostic criteria (NDS 6–12 or NDS 3–5 combined with NSS 5–9). When DPN was assessed by NSS + NDS ≥ 4, visual Neuropad B improved the specificity (AUROC 0.72, 67.00%, specificity 71.70%) by extending the detection time compared with visual Neuropad A (AUROC 0.62, sensitivity 81.80%, specificity 41.70%). Quantitative Neuropad significantly improved the diagnostic effect (AUROC 0.81, sensitivity 80.0%, specificity 76.3%) and reduced the detection time (4 min). Conclusions: This study provides a new quantitative Neuropad, which has great potential to be an extremely useful diagnostic tool for early screening of sudomotor dysfunction in the clinical practice. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to investigate the association of fasting C-peptide and glucagon with diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2DM). Methods A comprehensive evaluation was conducted on 797 patients with T2DM to assess the various risk factors affecting DPN. The subjects were categorized into short duration and long duration group according to the duration of diabetes with a threshold of 10 years. Logistic regression analysis was employed to examine the association between DPN and islet function, as well as other parameters. Receiver operating characteristic curve analysis was performed to evaluate the predictive capability of glucagon. Results The fasting C-peptide levels were significantly lower in the DPN patients with short duration of diabetes, but lost significance in the long duration group. Conversely, a decreased level of glucagon was only observed in DPN patients with long duration of diabetes. For the group with long duration of diabetes, glucagon was the sole risk factor associated with DPN. The receiver operating characteristic curve analysis revealed that glucagon in the long duration group exhibited a moderate area under the curve of 0.706. Conclusions The serum glucagon levels in T2DM patients with DPN exhibited bidirectional changes based on the duration of diabetes. Decreased glucagon was associated with DPN in T2DM patients with long duration of diabetes. What is already known on this topic Diabetic peripheral neuropathy (DPN), a common complication of diabetes, significantly impairs the quality of life. Although increased level of serum glucagon in T2DM patients has been well documented, the impact of glucagon on T2DM patients with DPN remains unclear. What this study adds The serum glucagon levels in T2DM patients with DPN exhibited bidirectional changes based on the duration of diabetes. Decreased glucagon was associated with DPN in T2DM patients with long duration of diabetes. How this study might affect research, practice, or policy In clinical practice, patients with T2DM with a long duration of disease should pay attention to the occurrence and progression of DPN when using antidiabetic drugs target glucagon. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) is considered one of the most common chronic complications of diabetes. Impairment of mitochondrial function is regarded as one of the causes. Iron–sulfur clusters are essential cofactors for numerous iron–sulfur (Fe-S)-containing proteins/enzymes, including mitochondrial electron transport chain complex I, II, and III and aconitase. Methods: To determine the impact of hyperglycemia on peripheral nerves, we used Schwann-like RSC96 cells and classical db/db mice to detect the expression of Fe-S-related proteins, mitochondrially enzymatic activities, and iron metabolism. Subsequently, we treated high-glucose-induced RSC96 cells and db/db mice with pioglitazone (PGZ), respectively, to evaluate the effects on Fe-S cluster biogenesis, mitochondrial function, and animal behavior. Results: We found that the core components of Fe-S biogenesis machinery, such as frataxin (Fxn) and scaffold protein IscU, significantly decreased in high-glucose-induced RSC96 cells and db/db mice, accompanied by compromised mitochondrial Fe-S-containing enzymatic activities, such as complex I and II and aconitase. Consequently, oxidative stress and inflammation increased. PGZ not only has antidiabetic effects but also increases the expression of Fxn and IscU to enhance mitochondrial function in RSC96 cells and db/db mice. Meanwhile, PGZ significantly alleviated sciatic nerve injury and improved peripheral neuronal behavior, accompanied by suppressed oxidative stress and inflammation in the sciatic nerve of the db/db mice. Conclusions: Iron–sulfur cluster deficiency may contribute to hyperglycemia-mediated DPN. [ABSTRACT FROM AUTHOR]

Background: Peripheral neuropathy (PN) is a prominent complication in persons with type 2 diabetes mellitus (T2DM) and has a major influence on morbidity. Emerging evidence suggests that elevated plasma fibrinogen (FIB) levels, which are indicative of inflammation and coagulation, may be linked to various diabetic complications. Nevertheless, there hasn't been much research done on the connection between PN and plasma fibrinogen levels in T2DM. Objective: This study aimed to investigate the correlation between plasma fibrinogen levels and the presence of PN in patients with T2DM. Patients and methods: A cross-sectional study that included 120 patients diagnosed with T2DM. They were divided into 2 equal groups: Group I contained 60 patients with diabetic peripheral neuropathy (DPN) and group II that involved 60 patients without DPN. Results: The study revealed a significant increase in serum fibrinogen levels in patients with diabetic neuropathy. Those with diabetic neuropathy had a mean fibrinogen level of 11.585 ± 4.256, compared to 1.798 ± 0.566 in patients without neuropathy (p-value < 0.001). Furthermore, the study indicated that plasma fibrinogen levels were significantly higher in patients with severe diabetic neuropathy, with a mean of 14.813 ± 3.713, followed by those with moderate neuropathy (mean 10.315 ± 2.562), and the lowest levels were observed in patients with mild neuropathy (mean 8.331 ± 3.558), with a p-value of 0.001. Conclusion: Increased plasma fibrinogen levels are substantially related with DPN in patients with T2DM. These results indicate that plasma fibrinogen could potentially act as a biomarker for identifying T2DM patients who are at increased risk of developing PN. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) occurs in >50% of diabetic patients and is a high risk‐factor of balance problems and risk of falls. Impaired balance can lead to reduced function, which has a detrimental effect on patients' quality of life. Structured strength and balance training can result in sustained improvements in muscle strength, coordination, balance, functional status and quality of life. Objective: To determine the combined effects of strength and balance training versus aerobic training on balance, severity of symptoms of DPN, and quality of life in patients with DPN. Methods: This double blinded, two arm parallel design Randomized Clinical Trial. The study was conducted from March to December 2020 in the AIMS diabetic center Peshawar, Pakistan. Participants were selected through convenience sampling technique and randomly allocated into strength plus balance and aerobic training groups. Type 2 diabetic patients of both sexes, aged 40 to 80 years, with a Toronto neuropathy score ≥6 recruited, while patients with ulceration/infection of feet, medical/Surgical conditions, and non‐ambulatory patients were excluded from this study. Intervention was applied 3 days a week for 8 weeks. The Toronto clinical neuropathy system was used to assess neuropathy severity, SF‐36 to assess quality of life and the Berg balance scale was used for assessment of balance. Assessment was done at the baseline and after 8 weeks of intervention using SPSS. Version 22 was used for analysis. Results: The mean age of the participants was 60.80 ± 9.73. Between group analysis, which showed were statistically insignificant for neuropathy severity, balance and all domains of quality of life (p‐value >0.05) except SF‐36 General Health Perception Score, with Mean ± SD of 62.50 ± 7.54 in group A versus Mean ± SD of in group B 60.00 ± 15.98 (p‐value = 0.05). Within group analysis showed statistically significant results for neuropathy severity, balance and all domains of quality of life (p‐value<0.05). Conclusion: This study concluded that there is a statistically significant effect of structured balance and strength training and aerobic training on severity of DPN, balance and quality of life. But there was no statistically significant difference in improvement between the two intervention groups. [ABSTRACT FROM AUTHOR]

Virgin coconut oil (VCO) is a processed form of coconut meat that is pure and free of free fatty acids. VCO is widely recognized as a cooking oil, cosmetic, antioxidant and beneficial for health, due to its high content of lauric acid. The method used in this research is a combination of qualitative and quantitative methods. The stages carried out in this research start from literature study, field research, laboratory analysis, data processing, and reporting. The purpose of this research is to produce VCO by utilizing CaO from oysters and Eco-enzyme to de-emulsify proteins to separate oil from water and measure the decrease in free fatty acid number and the decrease in peroxide number as quality parameters of the VCO produced. The application of CaO and Eco-enzyme fermentation is simple by mixing 0.2 g, 0.4 g, 0.6 g CaO and 0.2 mL, 0.4 mL, 0.6 mL Eco-enzyme respectively with 100 mL coconut milk. After treatments, it can be concluded that: separation of water from oil in the manufacture of VCO from coconut milk can occur using CaO and using Eco-enzyme It means that de-emulsification of protein in coconut milk is working well. To determine the quality of production VCO from CaO de-emulsification found 50.00 % the decreasing of Free Fatty Acid number and the decreasing of peroxide number is 28.57 %. From eco-enzyme de-emulsification the results are 55.55 %, the decrease of the acid number (DAN) and 57.14% the decrease of the peroxide number (DPN). [ABSTRACT FROM AUTHOR]

To investigate the effect of tanshinone IIA sulfonate sodium combined with α-Lipoic acid on fasting blood sugar (FPG), 2h postprandial blood glucose (2hPG), total cholesterol (TG), triacylglycerol (TC) and therapeutic effect in patients with diabetes peripheral neuropathy (DPN). The control group (n=52) was treated with tanshinone IIA sodium sulfonate alone. The study group was treated with α-Lipoic acid and tanshinone IIA sodium sulfonate. The changes in blood glucose, blood lipid levels, oxidative stress indicators and the improvement of nerve function conduction of both two groups were compared. After treatment, study group’s FPG, 2hPG, TG and TC were found to be lower than the control group (P<0.05). The levels of Super oxide dismutase (SOD) and nitric oxide (NO) in the study group were higher than those in the control group. The study group had lower Malondialdehyde (MDA) (P<0.05). The study group had higher nerve motor conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) (P<0.05). Tanshinone IIA sulfonate sodium combined with α-Lipoic acid can improve DPN patients’ blood glucose and lipid levels, alleviate the oxidative stress reaction of the body, promote the recovery of nerve conduction function and enhance the therapeutic effect. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) is the most frequent kind of neuropathy globally. DPN is one of the most prevalent and serious microvascular consequences of diabetes. Objective: To assess prevalence of DPN, its pattern, severity and associated risk factors in Benha City, Egypt. Patients and methods: This cross-sectional observational study was conducted on 500 diabetic patients (type 1 and type 2). All patients were subjected to complications of diabetes especially microvascular and macrovascular complications, diabetic foot and history of previous operations, physical examinations (general, neurological, sensory examination and Toronto clinical scoring system (TCSS)) and laboratory investigations (CBC, hemoglobin A1c (HbA1c), kidney function tests, liver function tests, serum thyroid-stimulating hormone and lipogram). Results: Body mass index (BMI), height, duration of diabetes, HbA1c, and thyroid-stimulating hormone (TSH) had a strong positive significant correlation with TCSS score (r=0.338, P< 0.001; r=0.335, P< 0.001; r=0.630, P< 0.001; r=0.806, P< 0.001; r=0.332, P< 0.001 respectively). Low-density lipoprotein-cholesterol (LDL-C) level and triglycerides level had no significant correlation with TCSS score (r= 0.015, P= 0.743; r= 0.074, P= 0.097 respectively). Conclusions: The primary risk factors include higher BMI, height, hard working, smoking, poor glycemic management, extended diabetes mellitus (DM), metformin use, chronic kidney disease (CKD), and an abnormal thyroid profile. After documenting these findings, a greater effort should be made to lower the frequency and severity of PDN in diabetic patients by education emphasising regular foot care, strict glucose control, and lifestyle adjustment. [ABSTRACT FROM AUTHOR]

Dip‐pen nanolithography (DPN) is a powerful and unique technique for precisely depositing tiny nano‐spherical cap shapes (nanoclusters) onto a desired surface. In this study, a meta‐chemical surface (MCS; a pattern with advanced features) is developed by DPN and applied to electrochemical lead sensing, yielding a calibration curve in the ppb range. An ink mixture of PMMA and NTPH (which binds to Pb (II), as supported by DFT calculations) is patterned over a Pt surface. The average height of the nanoclusters is ≈13 nm with a high surface area‐to‐volume ratio, which depends on the ink composition and the MCS surface. This ratio affected the sensitivity of the MCS as a detecting tool. The results indicate that the sensor's features can be controlled by the ability to control the size of the nanoclusters, attributed to the unique properties of the DPN production method. These results are significant for the water‐source purification industry. [ABSTRACT FROM AUTHOR]

Diabetic Peripheral Neuropathy (DPN) poses an escalating threat to public health, profoundly impacting well-being and quality of life. Despite its rising prevalence, the pathogenesis of DPN remains enigmatic, and existing clinical interventions fall short of achieving meaningful reversals of the condition. Notably, neurostimulation techniques have shown promising efficacy in alleviating DPN symptoms, underscoring the imperative to elucidate the neurobiochemical mechanisms underlying DPN. This study employs an integrated multi-omics approach to explore DPN and its response to neurostimulation therapy. Our investigation unveiled a distinctive pattern of vesicular glutamate transporter 2 (VGLUT2) expression in DPN, rigorously confirmed through qPCR and Western blot analyses in DPN C57 mouse model induced by intraperitoneal Streptozotocin (STZ) injection. Additionally, combining microarray and qPCR methodologies, we revealed and substantiated variations in the expression of the Amyloid Precursor Protein (APP) family in STZ-induced DPN mice. Analyzing the transcriptomic dataset generated from neurostimulation therapy for DPN, we intricately explored the differential expression patterns of VGLUT2 and APPs. Through correlation analysis, protein-protein interaction predictions, and functional enrichment analyses, we predicted the key biological processes involving VGLUT2 and the APP family in the pathogenesis of DPN and during neurostimulation therapy. This comprehensive study not only advances our understanding of the pathogenesis of DPN but also provides a theoretical foundation for innovative strategies in neurostimulation therapy for DPN. The integration of multi-omics data facilitates a holistic view of the molecular intricacies of DPN, paving the way for more targeted and effective therapeutic interventions. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) is considered one of the most common chronic complications of diabetes. Impairment of mitochondrial function is regarded as one of the causes. Iron–sulfur clusters are essential cofactors for numerous iron–sulfur (Fe-S)-containing proteins/enzymes, including mitochondrial electron transport chain complex I, II, and III and aconitase. Methods: To determine the impact of hyperglycemia on peripheral nerves, we used Schwann-like RSC96 cells and classical db/db mice to detect the expression of Fe-S-related proteins, mitochondrially enzymatic activities, and iron metabolism. Subsequently, we treated high-glucose-induced RSC96 cells and db/db mice with pioglitazone (PGZ), respectively, to evaluate the effects on Fe-S cluster biogenesis, mitochondrial function, and animal behavior. Results: We found that the core components of Fe-S biogenesis machinery, such as frataxin (Fxn) and scaffold protein IscU, significantly decreased in high-glucose-induced RSC96 cells and db/db mice, accompanied by compromised mitochondrial Fe-S-containing enzymatic activities, such as complex I and II and aconitase. Consequently, oxidative stress and inflammation increased. PGZ not only has antidiabetic effects but also increases the expression of Fxn and IscU to enhance mitochondrial function in RSC96 cells and db/db mice. Meanwhile, PGZ significantly alleviated sciatic nerve injury and improved peripheral neuronal behavior, accompanied by suppressed oxidative stress and inflammation in the sciatic nerve of the db/db mice. Conclusions: Iron–sulfur cluster deficiency may contribute to hyperglycemia-mediated DPN.

Numerous studies have been done to advance the development of efficient, simple, and cheap sensors, especially for glucose, which are important in the pharmaceutical and food industries. The most common sensors and biosensors used today are based on electrochemistry. The novelty of this study is the use of dip‐pen nanolithography (DPN) in order to pattern a mixture of glucose oxidase with PMMA as nanoclusters and develop meta‐chemical surface (MCS), which leads to highly efficient working electrodes with increased detection sensitivity compared to the today‐known glucose sensors (∼1×10-9 ${\sim 1\times 1{0}^{-9}}$ M was detected in the current study). Our novel and important results support the feasibility of using DPN to develop sensors on various electrode surfaces patterned with different active species, especially in systems requiring target substance detection over large concentration ranges. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic distal symmetric polyneuropathy (DDSP) is the most prevalent form of diabetic peripheral neuropathy, and 25% of patients develop pain in their toes. DDSP is associated with increased cutaneous microvessel density (MVD), reduced skin blood flow, endothelial dysfunction, and impaired fluid filtration with vasodilation. The Piezo family of mechanosensitive channels is known to be involved in the control of vascular caliber by converting mechanical force into intracellular signals. Furthermore, Piezo2 is particularly involved in peripheral pain mechanisms of DDSP patients. To date, very little is known about the number, structure, and PIEZO expression in cutaneous blood vessels (BVs) of individuals with DDSP and their relation with pain and time span of diabetes. Methods and results: We studied microvessels using endothelial markers (CD34 and CD31) and smooth cell marker (a-SMA) by indirect immunohistochemical assay in sections of the glabrous skin of the toes from patients and controls. MVD was assessed through CD34 and CD31 immunoreaction. MVD determined by CD34 is higher in short-term DDSP patients (less than 15 years of evolution), regardless of pain. However, long-term DDSP patients only had increased BV density in the painful group for CD31. BVs of patients with DDSP showed structural disorganization and loss of shape. The BVs affected by painful DDSP underwent the most dramatic structural changes, showing rupture, leakage, and abundance of material that occluded the BV lumen. Moreover, BVs of DDSP patients displayed a Piezo1 slight immunoreaction, whereas painful DDSP patients showed an increase in Piezo2 immunoreaction. Discussion: These results suggest that alterations in the number, structure, and immunohistochemical profile of specific BVs can explain the vascular impairment associated with painful DDSP, as well as the temporal span of diabetes. Finally, this study points out a possible correlation between increased vascular Piezo2 immunostaining and pain and decreased vascular Piezo1 immunostaining and the development of vasodilation deficiency. [ABSTRACT FROM AUTHOR]

Abstract Numerous studies have been done to advance the development of efficient, simple, and cheap sensors, especially for glucose, which are important in the pharmaceutical and food industries. The most common sensors and biosensors used today are based on electrochemistry. The novelty of this study is the use of dip‐pen nanolithography (DPN) in order to pattern a mixture of glucose oxidase with PMMA as nanoclusters and develop meta‐chemical surface (MCS), which leads to highly efficient working electrodes with increased detection sensitivity compared to the today‐known glucose sensors ( ∼1×10-9 M was detected in the current study). Our novel and important results support the feasibility of using DPN to develop sensors on various electrode surfaces patterned with different active species, especially in systems requiring target substance detection over large concentration ranges.

Introduction: Diabetic distal symmetric polyneuropathy (DDSP) is the most prevalent form of diabetic peripheral neuropathy, and 25% of patients develop pain in their toes. DDSP is associated with increased cutaneous microvessel density (MVD), reduced skin blood flow, endothelial dysfunction, and impaired fluid filtration with vasodilation. The Piezo family of mechanosensitive channels is known to be involved in the control of vascular caliber by converting mechanical force into intracellular signals. Furthermore, Piezo2 is particularly involved in peripheral pain mechanisms of DDSP patients. To date, very little is known about the number, structure, and PIEZO expression in cutaneous blood vessels (BVs) of individuals with DDSP and their relation with pain and time span of diabetes.Methods and results: We studied microvessels using endothelial markers (CD34 and CD31) and smooth cell marker (α-SMA) by indirect immunohistochemical assay in sections of the glabrous skin of the toes from patients and controls. MVD was assessed through CD34 and CD31 immunoreaction. MVD determined by CD34 is higher in short-term DDSP patients (less than 15 years of evolution), regardless of pain. However, long-term DDSP patients only had increased BV density in the painful group for CD31. BVs of patients with DDSP showed structural disorganization and loss of shape. The BVs affected by painful DDSP underwent the most dramatic structural changes, showing rupture, leakage, and abundance of material that occluded the BV lumen. Moreover, BVs of DDSP patients displayed a Piezo1 slight immunoreaction, whereas painful DDSP patients showed an increase in Piezo2 immunoreaction.Discussion: These results suggest that alterations in the number, structure, and immunohistochemical profile of specific BVs can explain the vascular impairment associated with painful DDSP, as well as the temporal span of diabetes. Finally, this study points out a possible correlation between increased vascular Piezo2 immunostaining and pain and decreased vascular Piezo1 immunostaining and the development of vasodilation deficiency.

Abstract Background Increased serum carcinoembryonic antigen (CEA) levels are reported to be associated with various metabolic and inflammatory diseases. This study assessed whether high-normal serum CEA is related to diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D). Methods All subjects received DPN assessment based on neuropathic symptoms, neuropathic signs, and nerve conduction studies to calculate composite Z scores of nerve latency, amplitude and conduction velocity (NCV). DPN was confirmed by both at least a presentation of neuropathic symptoms/signs and an abnormal nerve conduction index. Serum CEA levels and other clinical indices were also synchronously detected. Multivariable linear regression analyses were used to determine the independent effects of serum CEA levels on nerve conduction indices, multivariable logistic regression analyses were used to determine the independent impact of CEA levels on the risk of DPN, and receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic capability of CEA levels to discriminate DPN. Results We ultimately recruited 402 eligible subjects with normal ranges of serum CEA for this study, and 25.4% (n = 102) were determined to have DPN. After adjusting for other clinical covariates, serum CEA levels were independently associated with the composite Z score for latency (β = 0.132, t = 2.330, p = 0.021), amplitude (β = − 0.164, t = − 2.838, p = 0.005) and NCV (β = − 0.210, t = − 3.662, p

Triple Negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2. TNBC accounts for 15-20% of all breast cancer cases but accounts for over 50% of mortality. We propose that Estrogen receptor-beta (ERβ) and IGF2 play a significant role in the pathogenesis of TNBCs, and could be important targets for future therapy. Tissue microarrays (TMAs) from over 250 TNBC patients' were analyzed for ERβ and IGF2 expression by immunohistochemistry. Expression was correlated with clinical outcomes. In addition, TNBC cell lines Caucasians (CA): MB-231/BT549 and African Americans (AAs): MB-468/HCC70/HCC1806 were used to investigate the effect of hormonal and growth factor regulation on cell proliferation. TMAs from AAs had higher expression of ERβ and IGF2 expression when compared to CA. ERβ and IGF2 were found to be upregulated in our TNBC cell lines when compared to other cell types. TNBC cells treated with ERβ agonist displayed significant increase in cell proliferation and migration when compared to controls. AA tissue samples from TNBC patients had higher expression of ERβ. African-American breast cancer TNBC tissue samples from TNBC patients have higher expression of ERβ. In addition, TNBC cell lines were also found to express high levels of ERβ. IGF2 increased transcription of ERβ in TNBC cells. Understanding the mechanisms of IGF2/ERβ axis in TNBC tumors could provide an opportunity to target this aggressive subtype of breast cancer.

Background: Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer. TNBC lacks targeted therapy receptors, rendering endocrine and HER2-targeted therapies ineffective. TNBC is typically treated with cytotoxic chemotherapy followed by surgery. Targeting epigenetic modifications could potentially be a new effective TNBC target therapy. The aim of this study is to examine the effects of epigenetic drugs, decitabine as DNA methyltransferase inhibitor (DNMTI) and vorinostat as histone deacetylase inhibitor (HDACI), and the ERβ agonist DPN on ERα and ERβ re-expressions in the MDA-MB-231 cells as a model of TNBC.Methods: Using MTT assay, the IC50 of decitabine, vorinostat, and DPN on MDA-MB-231 cells were determined. The effects of all drugs alone or in combinations on MDA-MB-231 cells were evaluated. qRT-PCR was used to determine ERα & ERβ gene expression. Caspase-3 activity and the protein expression levels of VEGF, Cyclin D1, and IGF-1 were assessed.Results: Both ERα and ERβ mRNA were re-expressed in different high levels in all treated groups, especially in the triple therapy group compared with control. Significantly, the triple drugs therapy showed the lowest levels of VEGF, Cyclin D1, and IGF-1 and the highest level of Caspase-3 activity, indicating a possible antitumor effect of ERβ activation through decreasing proliferation and angiogenesis and increasing apoptosis in MDA-MB-231 cells.Conclusions: The antiproliferative effect of ERβ could be retained when co-expressed with Erα using a powerful epigenetic combination of Decitabine and vorinostat with DPN. [ABSTRACT FROM AUTHOR]

Background: Increased serum carcinoembryonic antigen (CEA) levels are reported to be associated with various metabolic and inflammatory diseases. This study assessed whether high-normal serum CEA is related to diabetic peripheral neuropathy (DPN) in patients with type 2 diabetes (T2D). Methods: All subjects received DPN assessment based on neuropathic symptoms, neuropathic signs, and nerve conduction studies to calculate composite Z scores of nerve latency, amplitude and conduction velocity (NCV). DPN was confirmed by both at least a presentation of neuropathic symptoms/signs and an abnormal nerve conduction index. Serum CEA levels and other clinical indices were also synchronously detected. Multivariable linear regression analyses were used to determine the independent effects of serum CEA levels on nerve conduction indices, multivariable logistic regression analyses were used to determine the independent impact of CEA levels on the risk of DPN, and receiver operating characteristic (ROC) curve analysis was used to assess the diagnostic capability of CEA levels to discriminate DPN. Results: We ultimately recruited 402 eligible subjects with normal ranges of serum CEA for this study, and 25.4% (n = 102) were determined to have DPN. After adjusting for other clinical covariates, serum CEA levels were independently associated with the composite Z score for latency (β = 0.132, t = 2.330, p = 0.021), amplitude (β = − 0.164, t = − 2.838, p = 0.005) and NCV (β = − 0.210, t = − 3.662, p < 0.001). Moreover, the prevalence of DPN in the first, second, third and fourth quartiles of CEA level was 12.9%, 19.0%, 29.4% and 40.4%, respectively (p for trend < 0.001); the corresponding adjusted odds ratios and 95% CIs for DPN in CEA quartiles were 1, 1.47 (0.45–4.82), 1.72 (0.54–5.53) and 4.58 (1.39–15.06), respectively. Furthermore, the optimal cut-off value of high-normal serum CEA to discriminate DPN was ≥ 2.66 ng/mL, with a Youden index of 0.28, sensitivity of 66.67% and specificity of 61.00%. Conclusions: Increased serum CEA levels within the normal range are closely linked to dysfunction of peripheral nerve conduction and the risk of DPN, and high-normal serum CEA levels are a potential risk factor for DPN in T2D. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) is considered as one of the most important complications of diabetes mellitus. At present, effective treatments that might improve the damaged neurological function in DPN are sorely needed. As myricetin has been proved to possess excellent neuroprotective and antioxidant effects, it might have therapeutic potential for DPN. Therefore, the purpose of our study was to detect the potential beneficial effect of myricetin on DPN. A single dose of 50 mg/kg of streptozotocin was applied in rats for the establishment of diabeticmodels. Different doses of myricetin (0.5mg/kg/day, 1.0mg/kg/day, and 2.0 mg/kg/day) were intraperitoneally injected for 2 weeks from the 21st day after streptozotocin injection. After the final myricetin injection, behavioral, electrophysiological, biochemical, and protein analyses were performed. In the present study, myricetin significantly ameliorated diabetes-induced impairment in sensation, nerve conduction velocities, and nerve blood flow. In addition, myricetin significantly reduced the generation of advanced glycation end-products (AGEs) and reactive oxygen species (ROS), and elevated Na+, K+-ATPase activity and antioxidant activities in nerves in diabetic animals. Additional studies revealed that myricetin significantly raised the hydrogen sulfide (H2S) levels, and elevated the expression level of heme oxygenase-1 (HO-1) as well as nuclear factor-E2-related factor-2 (Nrf2) in diabetic rats. In addition, myricetin has the capability of decreasing plasma glucose under diabetic conditions. The findings in our present study collectively indicated that myricetin could restore the impaired motor and sensory functions under diabetic conditions. The Nrf2-dependent antioxidant action and the capability of decreasing plasma glucose might be the underlying mechanisms for the beneficial effect of myricetin on impaired neural functions. Our study showed the therapeutic potential of myricetin in the management of DPN. [ABSTRACT FROM AUTHOR]

Abstract Background Diabetes mellitus (DM) is a metabolic disease which is complicated by occurrence of diabetic peripheral neuropathy (DPN). Vitamin D deficiency contributes to the etiology and progression of type 2 DM and development of micro-vascular complications so in this study we assessed vitamin D level in diabetic patients to evaluate the association between vitamin D level and occurrence of diabetic neuropathy and to assess if there is relationship with certain subtypes of diabetic neuropathy. This case–control study was conducted on 80 type 2 diabetic patients divided into four groups equally. (A): Diabetic patients with painful diabetic neuropathy. (B): Diabetic patients with painless diabetic neuropathy. (C): Diabetic patients with painless neuropathy, but have neuropathic ulcer. (D): Diabetic patients without neuropathy. All patients underwent clinical, neurological examination and nerve conduction study. Then CBC and vitamin D were estimated in the studied groups. Results Vitamin D level among the studied painful diabetic neuropathy group (A) ranged from 5.3 to 40.5 ng/dl with mean 17.4 ± 10.9. 70% of them had deficient vitamin D level. In the painless diabetic neuropathy group (B), vitamin D level ranged from 6.5 to 35.5 ng/dl with mean 18.9 ± 8.49. 60% of them had deficient vitamin D level, while only 5% of the diabetic patients without neuropathy had deficient vitamin D level. There is significant negative correlation between vitamin D level and score of neuropathy where the lower vitamin D level the higher neuropathy score. Conclusion Lower vitamin D levels were found in diabetic patients with neuropathy especially those with painful neuropathy.

Objective: To investigate the relationship between diabetic peripheral neuropathy (DPN) and gait abnormality in diabetic patients. Methods: Related research concerning the gait of diabetic patients with and without DPN was collected and analyzed by searching PubMed, Embase, and Web of Science. Statistical analysis was performed by using RevMan 5.3 software. Results: Twenty-one studies were included in this meta-analysis, consisting of 499 diabetic neuropathy patients and 467 diabetes controls without neuropathy. Meta-analysis results showed lower gait velocity, shorter stride length, longer stride time, longer stance time, and higher maximum knee extension moment in the DPN group, compared with their counterparts. Conclusion: Among diabetic patients, those complicated with DPN possess lower gait velocity, shorter stride length, longer stride time, longer stance time, and higher maximum knee extension moment. [ABSTRACT FROM AUTHOR]

Aiming at many problems caused by manual acceptance in decoration projects, this paper proposes an improved SSD algorithm and applies it to supervision work to replace manual acceptance and promote the realization of intelligent supervision. Since the SSD algorithm has problems such as re-examination of the same target and poor detection of small targets, the DPN network is used to replace the basic feature extraction network VGG16 in this paper. DPN combines the advantages of Resnet and Densenet and has better feature extraction ability. The feature maps are fused by weighted FPN to highlight the contributions of feature maps of different layers and enrich the semantics of feature maps for prediction. The use of depthwise separable convolution reduces the number of parameters of the model and improves the inference speed of the algorithm. The experimental comparison shows that the average accuracy of the improved model is increased by 3.47%, and the average accuracy of small number detection is improved by up to 15%, which proves that the new model has a good effect in the task of supervision target detection. [ABSTRACT FROM AUTHOR]

ObjectiveTo investigate the relationship between diabetic peripheral neuropathy (DPN) and gait abnormality in diabetic patients.MethodsRelated research concerning the gait of diabetic patients with and without DPN was collected and analyzed by searching PubMed, Embase, and Web of Science. Statistical analysis was performed by using RevMan 5.3 software.ResultsTwenty-one studies were included in this meta-analysis, consisting of 499 diabetic neuropathy patients and 467 diabetes controls without neuropathy. Meta-analysis results showed lower gait velocity, shorter stride length, longer stride time, longer stance time, and higher maximum knee extension moment in the DPN group, compared with their counterparts.ConclusionAmong diabetic patients, those complicated with DPN possess lower gait velocity, shorter stride length, longer stride time, longer stance time, and higher maximum knee extension moment.

Most diabetes patients eventually suffer from peripheral nerve degeneration. Unfortunately, there is no treatment for the condition and its mechanisms are not well understood. There is, however, an emerging consensus that the inability of peripheral nerves to regenerate normally after injury contributes to the pathophysiology. We have previously shown that regeneration of peripheral axons requires local axonal translation of a pool of axonal mRNAs and that the levels and members of this axonal mRNA pool are altered in response to injury. Here, we show that following sciatic nerve injury in a streptozotocin rodent model of type I diabetes, this mobilization of RNAs into the injured axons is attenuated and correlates with decreased axonal regeneration. This failure of axonal RNA localization results from decreased levels of the RNA binding protein ZBP1. Over-expression of ZBP1 rescues the in vitro growth defect in injured dorsal root ganglion neurons from diabetic rodents. These results provide evidence that decreased neuronal responsiveness to injury in diabetes is due to a decreased ability to alter the pool of axonal mRNAs available for local translation, and may open new therapeutic opportunities for diabetic peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. It often causes symmetrical paresthesia, loss of sensation, and hyperalgesia. Without early intervention, it might lead to diabetic foot ulceration, gangrene, and subsequent amputation in people with diabetes. DPN is an insidious disease and often underdiagnosed. This paper reviews the current national and international prevalence of DPN, screening methods for early DPN, including quantitative sensory measurement, neurological function scoring system, confocal microscopy, and high-frequency ultrasound, and summarizes the related research progress, clinical application, and development prospects of these methods in recent years. [ABSTRACT FROM AUTHOR]

Over the past half-century, the nursing profession has made great strides in terms of professionalization, status, and compensation. The pervasive focus on coordination and quality of health care in recent health care reform continues to stress effective partnerships between nurses and physicians. However, implicit and often gendered notions of professional authority continue to create barriers to effective communication between nurses and physicians. Relying on interviews and extended observations, this brief reports findings of an in-depth study of nurse-physician interactions in a California hospital. The research has direct implications for the job satisfaction and retention of nurses. The findings also highlight how subtle power dynamics limit the potential of promising organizational change initiatives in the wake of healthcare reform.

Most diabetes patients eventually suffer from peripheral nerve degeneration. Unfortunately, there is no treatment for the condition and its mechanisms are not well understood. There is, however, an emerging consensus that the inability of peripheral nerves to regenerate normally after injury contributes to the pathophysiology. We have previously shown that regeneration of peripheral axons requires local axonal translation of a pool of axonal mRNAs and that the levels and members of this axonal mRNA pool are altered in response to injury. Here, we show that following sciatic nerve injury in a streptozotocin rodent model of type I diabetes, this mobilization of RNAs into the injured axons is attenuated and correlates with decreased axonal regeneration. This failure of axonal RNA localization results from decreased levels of the RNA binding protein ZBP1. Over-expression of ZBP1 rescues the in vitro growth defect in injured dorsal root ganglion neurons from diabetic rodents. These results provide evidence that decreased neuronal responsiveness to injury in diabetes is due to a decreased ability to alter the pool of axonal mRNAs available for local translation, and may open new therapeutic opportunities for diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus. It often causes symmetrical paresthesia, loss of sensation, and hyperalgesia. Without early intervention, it might lead to diabetic foot ulceration, gangrene, and subsequent amputation in people with diabetes. DPN is an insidious disease and often underdiagnosed. This paper reviews the current national and international prevalence of DPN, screening methods for early DPN, including quantitative sensory measurement, neurological function scoring system, confocal microscopy, and high-frequency ultrasound, and summarizes the related research progress, clinical application, and development prospects of these methods in recent years.

Background: Diabetes mellitus (DM) is a metabolic disease which is complicated by occurrence of diabetic peripheral neuropathy (DPN). Vitamin D deficiency contributes to the etiology and progression of type 2 DM and development of micro-vascular complications so in this study we assessed vitamin D level in diabetic patients to evaluate the association between vitamin D level and occurrence of diabetic neuropathy and to assess if there is relationship with certain subtypes of diabetic neuropathy. This case–control study was conducted on 80 type 2 diabetic patients divided into four groups equally. (A): Diabetic patients with painful diabetic neuropathy. (B): Diabetic patients with painless diabetic neuropathy. (C): Diabetic patients with painless neuropathy, but have neuropathic ulcer. (D): Diabetic patients without neuropathy. All patients underwent clinical, neurological examination and nerve conduction study. Then CBC and vitamin D were estimated in the studied groups. Results: Vitamin D level among the studied painful diabetic neuropathy group (A) ranged from 5.3 to 40.5 ng/dl with mean 17.4 ± 10.9. 70% of them had deficient vitamin D level. In the painless diabetic neuropathy group (B), vitamin D level ranged from 6.5 to 35.5 ng/dl with mean 18.9 ± 8.49. 60% of them had deficient vitamin D level, while only 5% of the diabetic patients without neuropathy had deficient vitamin D level. There is significant negative correlation between vitamin D level and score of neuropathy where the lower vitamin D level the higher neuropathy score. Conclusion: Lower vitamin D levels were found in diabetic patients with neuropathy especially those with painful neuropathy. [ABSTRACT FROM AUTHOR]

Diabetic neuropathy is one of the most common microvascular complications associated with diabetes mellitus. Diabetic peripheral neuropathy (DPN) has been linked to hyperglycaemia and long duration of uncontrolled type 2 diabetes mellitus (T2DM) as measured by glycosylated haemoglobin (HbA1c). To our knowledge the estimated duration between diagnosis and developing DPN and the level of HbA1c have not yet been investigated in Sudanese patients with type 2 DM. Therefore, this study aims to investigate the relationship between the duration of diabetes and HbA1c with nerve conduction velocity (NCV) in patients with type 2 DM. This cross-sectional study recruited 63 male and female patients with T2DM who attended the diabetic outpatient clinic of Academy Charity Teaching Hospital (ACTH) and Alzaytouna Private Hospital for Nerve Conduction Velocity (NCV) and electromyography (EMG) tests. Nerve conduction was done by using ADInstruments PowerLab series 26. SPSS was used to analyse the data and p-value < 0.05 was considered significant. The mean duration of DM was 14.7 (± SD 9.24) years and the mean age of participants was 57.71 (± SD 12.2) years. The most common symptom was numbness (50%). Pearson's correlation test revealed a significant negative correlation between HbA1c and nerve conduction velocity (r = 0.4, p < 0.05) and negative significant correlation between the duration and the amplitude (r = 0.35, p < 0.05). There is a slowing of nerve conduction velocity in type 2 diabetic patients, which is accelerated by the poor glycaemic control (HbA1c). These findings support the need for tight glycaemic control to avoid drastic neuropathic complications of diabetes. [ABSTRACT FROM AUTHOR]

Background: Diabetic peripheral neuropathy (DPN) is one of the most common and complex chronic complications of diabetes, but it is clinically lacking effective means for early diagnosis and early treatment. MicroRNA, in the occurrence and development of the disease, has an important regulatory role. Its role in diabetes has been reported more. However, specific research on microRNA in DPN is rare. Methods: Based on the results of bioinformatics screening, miR-377 and miR-216a, their respective target molecules growth association protein 43 (GAP-43) and angiopoietin-like 4 protein (ANGPTL4), and related pathways peroxisome proliferator activated receptor gamma (PPARG) and chemerin were tested by RT-qPCR and ELISA in blood samples of DPN to analyze the correlation between these differentially expressed molecules and clinico-pathological factors of DPN. Results: In this study, we found that miR-377, miR-216a, GAP-43, ANGPTL4, and PPARG were significantly differentially expressed genes for DPN. The correlation analysis showed that they were closely related to the clinical indicators of DPN suggesting that they may be involved in the development of DPN. In addition, receiver operating characteristic (ROC) curves generated for miR216a, miR377, ANGPTL4, GAP43, PPARG revealed that they can be used as new molecular diagnostic markers of DPN. Conclusions: miR-216a, miR-377, ANGPTL4, GAP-43, and PPARG could potentially be biomarkers of DPN. [ABSTRACT FROM AUTHOR]

Cluster headache (CH) refers to the most painful primary headache that sometimes leads to poor quality of life and associated disability. So far, no treatment has been found to cure CHs. In this study, we introduce a novel and effective surgery for CH. We studied 6 patients with CH diagnosed according to the criteria of the Headache Classification Committee of the IHS, third edition, who were eligible for surgical treatment on the basis of strong requirements. All of them underwent temporal craniectomy and transection of the greater superficial petrosal nerve and deep petrosal nerve pathway to the sphenopalatine ganglion. All 6 patients had the surgery for CH and follow-up per 3 months. We significantly cured their pain and autonomic dysfunction. In the follow-up process none of the patients had reoccurring alacrimia. All of them had reduction of secretion of nasal, oral mucosa, and parotid and were satisfied with the surgery. All 6 patients with CH received surgery by transection greater superficial petrosal nerve and deep petrosal nerve pathway to the sphenopalatine ganglion and were completely cured, and adverse events and serious complications did not occur. [ABSTRACT FROM AUTHOR]

Patients with diabetes mellitus may experience painful and nonpainful diabetic peripheral neuropathy (DPN). This article offers an overview of DPN and the clinical assessment and management of patients with DPN, as well as the nurse's role in supporting these patients. [ABSTRACT FROM AUTHOR]

Diabetic peripheral neuropathy (DPN) is one of the major diabetes associated microvascular complications. The current study was designed to elucidate the association of angiotensin-converting enzyme (ACE) gene polymorphism with diabetic peripheral neuropathy in Khyber Pakhtunkhwa, Pakistani population. The study was comprised of 320 DPN patients, 202 diabetic patients without complication and 240 unrelated healthy individuals as control subjects. Blood samples were collected and phenol chloroform method was applied for the extraction of genomic DNA. Polymerase chain reaction (PCR) was used to determine ACE gene I/D polymorphism. In order to visualize the DNA polymorphic fragments, the amplicons were further subjected to gel electrophoresis. The results for I/D polymorphism of ACE gene rs 179975 revealed that the homozygous "DD" genotype was found significantly greater in patients with DPN in comparison to controls (OR: 1.5818; 95% CI 1.1053-2.2638, p=0.012). In the same way, the allele frequency was also analyzed and D allele was declared as vulnerability/ susceptibility/ risk factor for DPN (p=<0.05). ACE gene I/D polymorphism in diabetic patients is associated with DPN and significant steps should be taken to avoid DPN in Pakistani population. [ABSTRACT FROM AUTHOR]

Deep penetrating nevi (DPN) are rare melanocytic nevi, which can exhibit atypical histological features hampering the differentiation from malignant melanoma. DPN are considered benign melanocytic lesions, but rare spread to lymph nodes and unfavorable clinical outcomes associated with borderline/atypical DPN (B-DPN) has been reported. Since no guidelines are available for DPN and B-DPN, we aimed to review the literature on DPN and B-DPN to assess the management and prognosis. We screened 3,513 references from EMBASE, Scopus and Medline databases, and included 15 studies with a total of 355 DPN patients and 48 B-DPN patients. Therapeutic interventions ranged from simple excision to wide excisions and sentinel lymph node biopsy (SLNB), with block lymph node dissection in some positive SLNB cases. Follow-up periods ranged from 3 months to 23 years during which a total of five recurrences, two in DPN and three in B-DPN group, and three metastases, in B-DPN group, were reported. While some of the included studies comprised clinical and histopathological correlation, few included genetic assessment. The present review highlights the need for prospective cohort studies applying composite measures to identify effective regimens of diagnostic workup and treatment in DPN and B-DPN.

Mg and its alloys are highly prone to corrosion, which is an important consideration in many industries and applications. However, most available methods for studying the buildup of Mg corrosion layers as a function of time—an indirect measure of corrosion rate—are not sufficiently sensitive to monitor the early stages of the process. In this letter, a simple and innovative method is reported for monitoring changes in Mg corrosion layer thickness in various solutions, under close-to-natural conditions and starting from the first minutes of the process. Dip-pen nanolithography (DPN) was first used to pattern poly(methyl methacrylate) (PMMA) reference lines on the surface of the Mg alloy AE53, so as to indicate the initial conditions. Then, AFM was used—for the first time to the best of our knowledge—to measure the thickness of corrosion layers forming on three adjacent 100 µm × 100 µm surface areas at several time points (5–30 min) after immersion in solution. Test solutions included either saline or phosphate-buffered saline (PBS), in each case either with or without the addition of Fenton reagents, which are known to accelerate corrosion and are highly relevant for biological implants that employ Mg alloys as degradable substrates. In all tested solutions, the buildup of corrosion layers showed the expected dynamics—namely, an increase followed by a decrease and again an increase in layer thickness; however, the layers were considerably thicker in PBS than in saline, and in solutions with Fenton reagents than in those without them. These results demonstrate the unique advantage of the AFM instrument, as compared with other methods (such as SEM and potentiodynamic polarization), for measuring corrosion buildup, as the layer growth process can be accurately measured under natural conditions, in the presence of solutions, and from its very early stages. We report a simple and an innovative method for monitoring changes in corrosion layer thickness in various solutions, under close-to-natural conditions, starting from the first minutes of the process. We used dip-pen nanolithography by the NLP2000 to pattern reference lines on the surface of the Mg alloy AE53, which allowed us to accurately monitor the buildup of the corrosion layers using AFM at various time points after immersion in saline and PBS with or without the addition of Fenton reagents. [ABSTRACT FROM AUTHOR]

Background: Diabetic polyneuropathy (DPN) is the major microvascular complication of type 2 diabetes mellitus (T2DM). Painful-DPN is a major cause of mortality as well as morbidity. Long non-coding RNAs (IncRNAs) and microRNAs (miRNA) have emerged as critical regulators of many diseases, however, little is known about their expression patterns and functions in T2DM and its complications. Objective: To investigate the expression profile levels of IncRNA MALAT-1 and miRNA-9 in Egyptian patients with T2DM and to explore their associations with clinical and electrophysiological tests of both painful and painless DPN. Patients and Methods: This cross-sectional controlled study enrolled 55 patients with DPN and 40 controls. All participants were subjected to a complete neurological examination and electrophysiological tests involving nerve conduction studies. The expression levels of IncRNA MALAT-1 and miRNA-9 were measured by quantitative real-time polymerase chain reaction (qRT-PCR). Results: The relative expression levels of MALAT-1 and miRNA-9 were significantly upregulated in patients with DPN (0.219±0.061, 0.006454±0.0018, respectively) compared to controls (0.111±0.013, 0.0033±0.004, respectively). Interestingly, the relative expression levels of MALAT-1 and miRNA-9 were significantly upregulated in patients with painful DPN (0.206±0.037, 0.0045±0.0008, respectively) compared to patients with painless DPN 0.219±0.083, 0.0058±0.0017, respectively). Patients with DPN had sensory-motor axonal polyneuropathy which was affecting both lower limbs more than upper limbs. P<0.001*. Conclusions: The relative expression levels of MALAT-1 and miRNA-9 were significantly upregulated in patients with DPN more specifically in patients with painful DPN groups, hence, MALAT-1 and miRNA-9 could be used as useful and reliable diagnostic biomarkers of DPN. [ABSTRACT FROM AUTHOR]

Deep penetrating nevi (DPN) are rare melanocytic nevi, which can exhibit atypical histological features hampering the differentiation from malignant melanoma. DPN are considered benign melanocytic lesions, but rare spread to lymph nodes and unfavorable clinical outcomes associated with borderline/atypical DPN (B-DPN) has been reported. Since no guidelines are available for DPN and B-DPN, we aimed to review the literature on DPN and B-DPN to assess the management and prognosis. We screened 3,513 references from EMBASE, Scopus and Medline databases, and included 15 studies with a total of 355 DPN patients and 48 B-DPN patients. Therapeutic interventions ranged from simple excision to wide excisions and sentinel lymph node biopsy (SLNB), with block lymph node dissection in some positive SLNB cases. Follow-up periods ranged from 3 months to 23 years during which a total of five recurrences, two in DPN and three in B-DPN group, and three metastases, in B-DPN group, were reported. While some of the included studies comprised clinical and histopathological correlation, few included genetic assessment. The present review highlights the need for prospective cohort studies applying composite measures to identify effective regimens of diagnostic workup and treatment in DPN and B-DPN. [ABSTRACT FROM AUTHOR]

[Display omitted] • Binding free energy studies showed that MMGBSA approach reproduced better the experimental binding free energy tendency. • Per-residue decomposition analysis allowed identification of the key residues contributing the most to the binding. • Differences in affinity between ERβ and ligands result from the number and energy of the total per-residue contribution. Estrogen receptors (ERs) are nuclear factors that exist as two subtypes: ERα and ERβ. Among the different selective ERβ agonist ligands, the widely used ERβ-selective agonist DPN (diarylpropionitrile) is highlighted. Recent experimental and thermodynamic information between R-DPN and S-DPN enantiomers with ERβ is important for evaluating further the ability of MD simulations combined with end-point methods to reproduce experimental binding affinity and generate structural insight not provided through crystallographic data. In this research, starting from crystallographic data and experimental binding affinities, we explored the structural and thermodynamic basis of the molecular recognition of ERβ with DPN and derivatives through triplicate MD simulations combined with end-point methods. Conformational analysis showed some regions with the highest mobility linked to ligand association that, at the time, impacted the total protein fluctuation. Binding free energy (ΔG) analysis revealed that the Molecular Mechanics Generalized-Born Surface Area (MMGBSA) approach was able to reproduce the experimental tendency with a strong correlation (R = 0.778), whereas per-residue decomposition analysis revealed that all the systems interacted strongly with eight residues (L298, E305, L339, M340, L343, F356, H475, and L476). The comparison between theoretical studies using the MMGBSA approach with experimental results provides new insights for drug designing of new DPN derivatives. [ABSTRACT FROM AUTHOR]

Diabetic Peripheral Neuropathy (DPN) poses an escalating threat to public health, profoundly impacting well-being and quality of life. Despite its rising prevalence, the pathogenesis of DPN remains enigmatic, and existing clinical interventions fall short of achieving meaningful reversals of the condition. Notably, neurostimulation techniques have shown promising efficacy in alleviating DPN symptoms, underscoring the imperative to elucidate the neurobiochemical mechanisms underlying DPN. This study employs an integrated multi-omics approach to explore DPN and its response to neurostimulation therapy. Our investigation unveiled a distinctive pattern of vesicular glutamate transporter 2 (VGLUT2) expression in DPN, rigorously confirmed through qPCR and Western blot analyses in DPN C57 mouse model induced by intraperitoneal Streptozotocin (STZ) injection. Additionally, combining microarray and qPCR methodologies, we revealed and substantiated variations in the expression of the Amyloid Precursor Protein (APP) family in STZ-induced DPN mice. Analyzing the transcriptomic dataset generated from neurostimulation therapy for DPN, we intricately explored the differential expression patterns of VGLUT2 and APPs. Through correlation analysis, protein-protein interaction predictions, and functional enrichment analyses, we predicted the key biological processes involving VGLUT2 and the APP family in the pathogenesis of DPN and during neurostimulation therapy. This comprehensive study not only advances our understanding of the pathogenesis of DPN but also provides a theoretical foundation for innovative strategies in neurostimulation therapy for DPN. The integration of multi-omics data facilitates a holistic view of the molecular intricacies of DPN, paving the way for more targeted and effective therapeutic interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Wu, Jiang, Cao and Chen.)

• MScanFit MUNE yields detailed information on motor unit loss. • Motor involvement in diabetic neuropathy may be present as early as sensory involvement. • MScanFit MUNE provides sensitive detection of motor involvement in diabetic polyneuropathy. Detection of motor involvement in diabetic polyneuropathy (DPN) by nerve conduction studies (NCS) does not occur until there is substantial loss of motor units, because collateral reinnervation maintains compound muscle action potential (CMAP) amplitude. Motor unit number estimation (MUNE) methods may therefore be more sensitive. This study was undertaken to test whether the novel method, MScanFit MUNE (MScan) can detect motor involvement in DPN despite normal NCS. Fifty-two type-2 diabetic patients and 38 healthy controls were included. The median nerve was examined in all participants using standard NCS and a detailed CMAP scan, used for MScan. Additional lower extremity NCS in patients were used for DPN diagnosis. Of 52 diabetic patients, 21 had NCS-defined DPN while lower extremity NCS were normal in 31 patients. MScan motor unit number and size showed higher sensitivity and incidence of abnormality than motor NCS parameters, and a similar sensitivity to sensory NCS. MScan is able to detect motor axonal damage at times when collateral reinnervation limits NCS changes. MScan is a sensitive method to detect motor involvement in DPN, which our data suggests is present as early as sensory. [ABSTRACT FROM AUTHOR]

The Center for Disease Control (CDC) estimates that 29 million Americans have diabetes, and 70% of diabetic patients develop diabetic peripheral neuropathy [1,2]. Up to 27% of the direct medical cost of diabetes may be attributed to DPN [3]. A 2013 article from the American Diabetes Association reported a $176 billion direct medical cost of diabetes in 2012 [4]. DPN patients often suffer from shooting and burning pain in their distal limbs and a severe loss of sensation. Diabetic foot ulcers, infections, and amputations may follow. Currently available treatments: tricyclic antidepressants, anticonvulsants such as gabapentin and pregabalin, serotonin and norepinephrine reuptake inhibitor, duloxetine, topical 5% lidocaine (applied to the most painful area) can manage painful symptoms but do not address the underlying pathologies of DPN and diabetic wound ulcers. A combination of pain-reducing medications can provide relief when individual medications fail, and opioids such as tramadol and oxycodone may be administered with these medications to reduce pain [5]. Due to the prevalence of diabetes, DPN, and diabetic foot ulcers, and because of the lack of available effective treatments to directly address the pathology contributing to these conditions, novel treatments are being sought. Our hypothesis is that a deficiency of nitric oxide synthase in diabetic patients leads to a lack of vascularization of the peripheral nerves, which causes DPN; and this could be treated with vasodilators such as nitric oxide. In this paper, the mechanisms of DPN are reviewed and analyzed to elucidate the potential of a transdermal nitric oxide application for the treatment of DPN and diabetic wound ulcers by increasing vasodilation. • Currently available treatments can manage painful symptoms of Diabetic Peripheral Neuropathy (DPN) but do not address the underlying pathologies of DPN and diabetic wound ulcers. • A deficiency of nitric oxide synthase in diabetic patients may lead to a lack of vascularization of the peripheral nerves, which causes DPN. • A transdermal nitric oxide application is envisioned for the treatment of DPN and diabetic wound ulcers by increasing vasodilation. [ABSTRACT FROM AUTHOR]

Diabetic-induced peripheral neuropathy (DPN) is a highly complex and frequent diabetic late complication, which is manifested by prolonged hyperglycemia. However, the molecular mechanisms underlying the pathophysiology of nerve damage and sensory loss remain largely unclear. Recently, alteration in metabolic flux has gained attention as a basis for organ damage in diabetes; however, peripheral sensory neurons have not been adequately analyzed with respect to metabolic dysfunction. In the present study, we attempted to delineate the sequence of event occurring in alteration of metabolic pathways in relation to nerve damage and sensory loss. C57Bl6/j wild-type mice were analyzed longitudinally up to 22 weeks in the streptozotocin (STZ) model of type 1 diabetes. The progression of DPN was investigated by behavioral measurements of sensitivity to thermal and mechanical stimuli and quantitative morphological assessment of intraepidermal nerve fiber density. We employed a mass spectrometry-based screen to address alterations in levels of metabolites in peripheral sciatic nerve and amino acids in serum over several months post-STZ administration to elucidate metabolic dysfunction longitudinally in relation to sensory dysfunction. Although hyperglycemia and body weight changes occurred early, sensory loss and reduced intraepithelial branching of nociceptive nerves were only evident at 22 weeks post-STZ. The longitudinal metabolites screen in peripheral nerves demonstrated that compared with buffer-injected age-matched control mice, mice at 12 and 22 weeks post-STZ showed an early impairment the tricaoboxylic acid (TCA cycle), which is the main pathway of carbohydrate metabolism leading to energy generation. We found that levels of citric acid, ketoglutaric acid (2 KG), succinic acid, fumaric acid, and malic acid were observed to be significantly reduced in sciatic nerve at 22 weeks post-STZ. In addition, we also found the increase in levels of sorbitol and L-lactate in peripheral nerve from 12 weeks post-STZ injection. Amino acid screen in serum showed that the amino acids valine (Val), isoleucine (Ile), and leucine (Leu), grouped together as BCAA, increased more than twofold from 12 weeks post-STZ. Similarly, the levels of tyrosine (Tyr), asparagine (Asn), serine (Ser), histidine (His), alanine (Ala), and proline (Pro) showed progressive increase with progression of diabetes. Our results indicate that the impaired TCA cycle metabolites in peripheral nerve are the primary cause of shunting metabolic substrate to compensatory pathways, which leads to sensory nerve fiber loss in skin and contribute to onset and progression of peripheral neuropathy. [ABSTRACT FROM AUTHOR]

Highlights • Acute estradiol administration decrease the number of AVP immunoreactive neurons in SON and PVN. • ERβ and GPER mediate the acute effects of estradiol decreasing the AVP-ir in the PVN. • GPER mediates the acute effects of estradiol decreasing the AVP-ir in the SON. Abstract The ovarian hormone 17β-estradiol is known to regulate the release, expression and immunoreactivity of arginine-vasopressin (AVP) in the supraoptic and paraventricular hypothalamic nuclei of rodents. Previous studies have shown that estrogen receptor α is involved in the effects of chronic estradiol administration on arginine-vasopressin immunoreactivity in the female rat hypothalamus. In this study we have examined the effect of an acute administration of estradiol or specific agonists for estrogen receptors α, β and G protein-coupled estrogen receptor 1 on the immunoreactivity of arginine-vasopressin in the hypothalamus of adult ovariectomized female rats. Acute estradiol administration resulted in a significant decrease in the number of arginine-vasopressin immunoreactive neurons in the supraoptic and paraventricular nuclei after 24 h. The effects of the specific estrogen receptors agonists suggest that the action of estradiol on arginine-vasopressin immunoreactivity is mediated in the supraoptic nucleus by G protein-coupled estrogen receptor 1 and in the paraventricular nucleus by both estrogen receptor β and G protein-coupled estrogen receptor 1. Thus, in contrast to previous studies on the effect of chronic estrogenic treatments, the present findings suggest that estrogen receptor β and G protein-coupled estrogen receptor 1 mediate the acute effects of estradiol on arginine-vasopressin immunoreactivity in the hypothalamus of ovariectomized rats. [ABSTRACT FROM AUTHOR]