Genetic Variants Influence the Development of Diabetic Neuropathy.

The exact mechanism by which diabetic neuropathy develops is still not fully known, despite our advances in medical knowledge. Progressing neuropathy may occur with a persistently favorable metabolic status in some patients with diabetes mellitus, while, in others, though seldom, a persistently unfavorable metabolic status is not associated with significant neuropathy. This might be significantly due to genetic differences. While recent years have brought compelling progress in the understanding of the pathogenetic background-in particular, accelerated progress is being made in understanding molecular biological mechanisms-some aspects are still not fully understood. A comparatively small amount of information is accessible on this matter; therefore, by summarizing the available data, in this review, we aim to provide a clearer picture of the current state of knowledge, identify gaps in the previous studies, and possibly suggest directions for future studies. This could help in developing more personalized approaches to the prevention and treatment of diabetic neuropathy, while also taking into account individual genetic profiles.

Genetic Factors Associated with the Development of Neuropathy in Type 2 Diabetes.

Neuropathy is a serious and frequent complication of type 2 diabetes (T2DM). This study was carried out to search for genetic factors associated with the development of diabetic neuropathy by whole exome sequencing. For this study, 24 patients with long-term type 2 diabetes with neuropathy and 24 without underwent detailed neurological assessment and whole exome sequencing. Cardiovascular autonomic function was evaluated by cardiovascular reflex tests. Heart rate variability was measured by the triangle index. Sensory nerve function was estimated by Neurometer and Medoc devices. Neuropathic symptoms were characterized by the neuropathy total symptom score (NTSS). Whole exome sequencing (WES) was performed on a Thermo Ion GeneStudio S5 system determining the coding sequences of approximately 32,000 genes comprising 50 million base pairs. Variants were detected by Ion Reporter software and annotated using ANNOVAR, integrating database information from dbSNP, ClinVar, gnomAD, and OMIM. Integrative genomics viewer (IGV) was used for visualization of the mapped reads. We have identified genetic variants that were significantly associated with increased (22-49-fold) risk of neuropathy (rs2032930 and rs2032931 of recQ-mediated genome instability protein 2 (RMI2) gene), rs604349 of myosin binding protein H like (MYBPHL) gene and with reduced (0.07-0.08-fold) risk (rs917778 of multivesicular body subunit 12B (MVB12B) and rs2234753 of retinoic acid X receptor alpha (RXRA) genes). The rs2032930 showed a significant correlation with current perception thresholds measured at 5 Hz and 250 Hz for n. medianus (p = 0.042 and p = 0.003, respectively) and at 5 Hz for n. peroneus (p = 0.037), as well as the deep breath test (p = 0.022) and the NTSS (p = 0.023). The rs2032931 was associated with current perception thresholds (p = 0.003 and p = 0.037, respectively), deep breath test (p = 0.022), and NTSS (p = 0.023). The rs604349 correlated with values measured at 2000 (p = 0.049), 250 (p = 0.018), and 5 Hz (p = 0.005) for n. medianus, as well as warm perception threshold measured by Medoc device (p = 0.042). The rs2234753 showed correlations with a current perception threshold measured at 2000 Hz for n. medianus (p = 0.020), deep breath test (p = 0.040), and NTSS (p = 0.003). There was a significant relationship between rs91778 and cold perception threshold (p = 0.013). In our study, genetic variants have been identified that may have an impact on the risk of neuropathy developing in type 2 diabetic patients. These results could open up new opportunities for early preventive measures and might provide targets for new drug developments in the future.

Thyroid Hormones, Glucocorticoids, Insulin, and Bone.

Several endocrine systems have important effects on bone tissue. Thyroid hormones are essential for normal growth and development. Excess of these hormones will result in clinically significant changes that may require intervention. Glucocorticoids also have a marked effect on bone metabolism by several pathways. Their endogenous or exogenous excess will induce pathological processes that might elevate the risk of fractures. Insulin and the carbohydrate metabolism elicit a physiological effect on bone; however, the lack of insulin (type 1 diabetes) or insulin resistance (type 2 diabetes) have deleterious influence on bone tissue.

[Brentuximab vedotin treatment in patients with relapsed or refractory Hodgkin lymphoma. A Hungarian retrospective study]. / Relabáló/refrakter Hodgkin-lymphoma brentuximab vedotin kezelése. Hazai tapasztalatok.

INTRODUCTION: The treatment of relapsed or refractory Hodgkin lymphoma is still a major therapeutic challenge. The use of brentuximab vedotin, an anti-CD30 antibody-drug conjugate, represents a promising approach for these patients, however clinical outcomes have not yet been evaluated in Hungary. AIM: Our aim was to assess the efficacy, safety and outcome of brentuximab vedotin treatment in Hungarian Hodgkin lymphoma patients. METHOD: In this retrospective case note review we enrolled patients at 6 clinical sites countrywide who were diagnosed with Hodgkin lymphoma and received brentuximab vedotin between 1 January 2013 and 31 December 2016. RESULTS: A total of 86 patients were treated with brentuximab vedotin during the examined period. Before therapy initiation 66% of our patients had advanced-stage disease. Overall response rate to brentuximab vedotin, administered before autologous hematopoietic stem cell transplantation (n = 54) was 66.6%, complete remission rate was 42.6%. Thirty patients received brentuximab vedotin after AHSCT, 46.67% responded to treatment, 30% achieved complete remission. Thirty-six patients received the drug as a single-agent therapy, 50 patients were given brentuximab vedotin in combination, 39 of them with bendamustin. Toxicity was observed only in 13.95% of our patients, most common symptom was skin rash. Based on our analysis the estimated 5-year overall survival rate was 78.7%, the estimated progression free survival rate was 23.59 months (95% CI: 19.50-27.68). CONCLUSION: Brentuximab vedotin carries a substantial improvement in the treatment of relapsed or refractory Hodgkin lymphoma. Our results underline prior observations published in the literature. The use of brentuximab vedotin in combination can be beneficial, however further investigation is needed on the subject. Orv Hetil. 2017; 158(41): 1630-1634.

[Chemotherapy-induced peripheral neuropathy: characteristics, diagnosis and treatment]. / Kemoterápia okozta szenzoros neuropátiák jellegzetességei, diagnosztikája és kezelése.

Longer remissions and better overall survival rates can be achieved with the introduction of new, effective treatments and targeted therapies in the past 1-2 decades, however, the incidence of side effects is also increasing parallelly. Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially debilitating side effect due to peripheral somatic or autonomic nerve dysfunction. CIPN becomes increasingly important, as it affects patients' quality of life, and it is very often a dose limiting factor with the potential for reduced treatment efficacy. The pathomechanism, diagnosis, prevention and treatment possibilities are described in this review with special attention to the different groups of drugs.

Heart rate variability is severely impaired among type 2 diabetic patients with hypertension.

INTRODUCTION: The aim of our study was to evaluate the relative effect of diabetes and hypertension on heart rate variability. RESEARCH DESIGN AND METHODS: Four age-matched groups including type 2 diabetic patients with and without hypertension, non-diabetic patients with essential hypertension and healthy control subjects were studied. Autonomic function was evaluated by the standard cardiovascular reflex tests and 24-hour heart rate variability measurement. Heart rate variability was characterized by the triangular index value and by the spectral components of the frequency domain analysis. RESULTS: According to the two-way analysis of variance on ranks, all parameters were influenced negatively by diabetes (heart rate variability triangular index: p < 0.001; low-frequency component: p < 0.0001; high-frequency component: p < 0.001; and total power: p < 0.0001), whereas hypertension had a negative effect only on the low-frequency component (p < 0.05). The interaction between hypertension and diabetes was not significant, indicating that their effects on the heart rate variability parameters are additive. Beat-to-beat variation upon deep breathing, the most sensitive cardiovascular reflex test was also negatively influenced by both diabetes (p < 0.001) and hypertension, (p < 0.05), and their effects were additive. CONCLUSIONS: Diabetes appears to have a greater effect on autonomic dysfunction compared with hypertension. Patients suffering from both diabetes and hypertension are at the highest risk of reduced heart rate variability. Early assessment of the autonomic nerve function is suggested in diabetic patients with hypertension.

No clear evidence of neuropathy among patients with high risk for the development of prediabetes/diabetes-a pilot study.

Introduction: Autonomic and sensory neuropathy have been observed in both prediabetes and manifest diabetes mellitus. However, there is a lack of available data regarding whether patients at a moderate or high risk of developing diabetes, yet without a current diagnosis of prediabetes or diabetes, exhibit an increased prevalence of neuropathy. Methods: FINDRISC (Finnish Diabetes Risk Score) was used to classify individuals at risk (≥12 points, n = 44; control <12 points, n = 28). HbA1c levels >5.6% served as exclusion criteria, and patients with known medical conditions predisposing to neuropathy were also excluded. Cardiac autonomic function (Ewing tests) and peripheral sensory neuropathy (Neurometer and Q-sense) were assessed by standardized protocols, and their potential association with increased FINDRISC points was analyzed using a regression model. Results: Mean age was 46.7 ± 14.3 years in the control and 55.7 ± 14.1 years in the increased risk group. Male/female ratio did not differ. Individuals with increased risk of diabetes were more obese (BMI: 29.9 ± 12.5 kg/m2 vs. 25.9 ± 8.9 kg/m2). Additionally, hypertension was more frequent among them (68.2% vs. 17.9%), and their lipid parameters were also less favorable. Parasympathetic neuropathy was present in both groups (56.8% vs. 32.1%, respectively). Sympathetic neuropathy was not found. Sensory nerve dysfunction was of low prevalence in the high-risk group and did not occur in healthy controls. In multiple logistic regression analysis, HbA1c exhibited an independent association with parasympathetic neuropathy (OR: 5.9; 95% CI: 1.08-32.68; p < 0.041). Discussion: An increased risk of developing prediabetes/diabetes does not appear to have a strong correlation with an increased likelihood of developing autonomic or sensory neuropathy. However, the etiology behind the occurrence of parasympathetic autonomic neuropathy in healthy individuals remains unknown.

A comprehensive analysis of diabetic patient data before and during the COVID-19 pandemic - Lessons from the MÉRY diabetes database (MDD).

AIMS: Our study examined changes in average blood glucose levels (ABG), measurement frequency (MF), and data uploading (DU) before and during the COVID-19 pandemic in 882-day spans, which were divided into further 20-week intervals to highlight the pandemic's impact. METHODS: T-Tests assessed the statistical significance of blood glucose data from 26,655/20,936 patients and 19.5/16.6 million records during pre-COVID/COVID. RESULTS: During COVID, patients had significantly lower ABG levels (9.1/8.9 mmol/L, p < 0.001). Weekly DU decreased (155,945/128,445, p < 0.05), while daily MF increased (0.83/0.87, p < 0.001). Comparing the last 20 weeks pre-COVID to the first 20 weeks during COVID, ABG levels were lower (9.0 /8.9, p < 0.01), MF increased (0.83 /0.99, p < 0.001), and DU decreased (153,133/145,381, p < 0.05). In the initial 20 weeks of COVID compared to the second 20 weeks of COVID, ABG increased (8.9/9.1, p < 0.01), MF decreased (0.99/0.95, p < 0.001), and DU decreased (145,381/140,166, p < 0.05). Our most striking observation was the temporary dramatic fall in glucose uploads during the first few weeks of COVID. The changes of ABG and MF values were statistically significant, but were not deemed clinically relevant. CONCLUSIONS: Despite COVID's prolonged impact, diabetic patients showed improved attitudes. A significant drop in data uploads occurred during the first 20 weeks of COVID; home office and lockdowns apparently disrupted patient routines.

The handgrip test - A historical test for diabetic autonomic neuropathy or a marker of something else?

Cardiovascular autonomic neuropathy (CAN) is a frequent complication of diabetes mellitus and is associated with increased morbidity and mortality in patients with diabetes. Hence, early and correct diagnosis of CAN is crucial. Standard cardiovascular reflex rests (CARTs) have been the gold standard of CAN assessment. Originally, CARTs consisted of five reflex tests, but measuring diastolic blood pressure response to sustained handgrip exercise has no longer been suggested as an established clinical test. Increasing body of evidence suggests that isometric handgrip test should no longer be used for the evaluation of sympathetic dysfunction during cardiovascular autonomic neuropathy assessment in diabetic patients. The associations of isometric handgrip test results with parameters of hypertension and markers of hypertension-related target-organ damage in diabetic and non-diabetic individuals point toward its potential role as a screening tool to identify patients with high cardiovascular risk. The current review summarizes historical view of standard cardiovascular reflex tests and latest data on isometric handgrip test.

Low-burden TP53 mutations represent frequent genetic events in CLL with an increased risk for treatment initiation.

TP53 aberrations predict chemoresistance and represent a contraindication for the use of standard chemoimmunotherapy in chronic lymphocytic leukaemia (CLL). Recent next-generation sequencing (NGS)-based studies have identified frequent low-burden TP53 mutations with variant allele frequencies below 10%, but the clinical impact of these low-burden TP53 mutations is still a matter of debate. In this study, we aimed to scrutinise the subclonal architecture and clinical impact of TP53 mutations using a sensitive, NGS-based mutation analysis in a 'real-world' cohort of 901 patients with CLL. In total, 225 TP53 mutations were identified in 17.5% (158/901) of the patients; 48% of these alterations represented high-burden mutations, while 52% were low-burden TP53 mutations. Low-burden mutations as sole alterations were identified in 39% (62/158) of all mutated cases with 82% (51/62) of these being represented by a single low-burden TP53 mutation. Patients harbouring low-burden TP53 mutations had significantly lower time to first treatment compared to patients with wild-type TP53. Our study has expanded the knowledge on the frequency, clonal architecture, and clinical impact of low-burden TP53 mutations. By demonstrating that patients with sole low-burden TP53 variants represent more than one-third of patients with TP53 mutations and have an increased risk for treatment initiation, our findings strengthen the need to redefine the threshold of TP53 variant reporting to below 10% in the routine diagnostic setting.

Long term follow-up of refractory/relapsed hairy cell leukaemia patients treated with low-dose vemurafenib between 2013 and 2022 at the Department of Internal Medicine and Oncology, Semmelweis University.

Introduction: Hairy cell leukemia (HCL) is an indolent B-cell lymphoproliferative disease. BRAF V600E mutation is detected in nearly all classical HCL cases which offers the possibility of targeted therapy. Objective: The aim of our study was to assess the efficacy of low-dose vemurafenib as well as to assess the long term outcome of HCL patients treated with this drug at the Department of Internal Medicine and Oncology at Semmelweis University. Methods: We report on 10 patients with classical HCL treated with low-dose vemurafenib at our Department between 2013 and 2022. Results: As a result of fixed time low-dose vemurafenib treatment, 5 of 10 patients (5/10) achieved partial remission, 4 (4/10) had stable disease, and 1 (1/10) had MRD positivity. No patients achieved complete remission. The median progression-free survival was 28.5 months while the overall survival was 82 months. Conclusion: We confirm that low dose of vemurafenib is effective and safe in the vast majority of patients with HCL. This small-molecule oral treatment allows to gain valuable time-months or even years-before further, usually parenteral treatment options have to be given or before previous treatment has to be repeated. There are also promising data supporting the combination of vemurafenib with other drugs for the treatment of HCL patients which could provide even further possibility to bridge treatment.

How to evaluate over 60 million blood glucose data - The design of the MÉRY Diabetes Database.

AIMS: The aim of the article is to describe the method for creating a close to ideal diabetes database. The MÉRY Diabetes Database (MDD) consists of a large quantity of reliable, well-maintained, precise and up-to-date data suited for clinical research with the intention to improve diabetes care in terms of maintaining targeted blood glucose levels, avoiding hypoglycemic episodes and complications and improving patient compliance and quality of life. METHODS: Based on the analysis of the databases found in the literature and the experience of our research team, nine important characteristics were identified as critical to an ideal diabetes database. The data for our database is collected using MÉRYkék glucometers, a device that meets all requirements of international regulations and measures blood glucose levels within the normal range with appropriate precision (10 %). RESULTS: Using the key characteristics defined, we were able to create a database suitable for the analysis of a large amount of data regarding diabetes care and outcomes. CONCLUSIONS: The MDD is a reliable and ever growing database which provides stable and expansive foundation for extensive clinical investigations that hold the potential to significantly influence the trajectory of diabetes care and enhance patient outcomes.

Case Report: Development of Diffuse Large B Cell Lymphoma a Long Time After Hairy Cell Leukemia.

Hairy cell leukaemia (HCL) is a rare B cell malignancy with an indolent course leading to pancytopaenia due to bone marrow infiltration. It has been proposed that HCL patients are at risk of developing a secondary malignancy, with a marked likelihood of the development of other hematologic malignancies including Hodgkin lymphoma and high-grade non-Hodgkin lymphomas. Here, we present the case of two patients who developed diffuse large B cell lymphoma after a long course of hairy cell leukaemia. In the case of the female patient, we report on the occurrence of a third malignant disease, which is very uncommon. With our case descriptions we contribute to the very small number of similar cases reported.

Malignant solid tumor associated with hypereosinophilic syndrome / Malignus solid tumorhoz társuló hypereosinophil szindróma

Hypereosinophilic syndrome is characterized by chronic eosinophil overproduction, resulting in multiple organ damages due to eosinophil infiltration and mediator release. According to the etiology, we distinguish between myeloproliferative disorders, parasitic infections, solid tumors, T-cell lymphomas and idiopathic forms. In our case report, the 49-year-old man was hospitalized with weight loss, leg edema and tachycardia. In his laboratory tests increased biliary obstructive parameters as well as extreme leukocytosis and eosinophilia had been highlighted. We started our evaluation with a strong suspicion of hematologic malignancy. The CT scan of the thorax, abdomen and pelvis described hepatosplenomegaly, multiple intrahepatic lesions and an uncertain solitary cystic lesion in the tail of the pancreas with abnormal lymph nodes and pleural fluid. The described CT image and the other clinical parameters were primarily consistent with the manifestation of chronic myeloid leukemia. However, the diagnosis was not confirmed by peripheral blood smear, flow cytometry, bone marrow biopsy or genetic tests. After these results, we continued the assessment towards solid tumor associated leukemoid reaction, core biopsy was performed to verify the liver lesions. The biopsy confirmed the infiltration of a poorly differentiated epithelial tumor as a metastasis of pancreatobiliary carcinoma. To the best of our knowledge, this is the first case report on hypereosinophilic syndrome associated with gastrointestinal solid tumors in the Hungarian medical literature. It draws attention to the differential diagnosis of extreme leukocytosis and eosinophil ratios and by the absence of confirmed hematological disease the importance of early biopsy sampling of solid lesions.

Vitamin D in the Prevention and Treatment of Diabetic Neuropathy.

PURPOSE: Neuropathy is one of the most important complications of diabetes. According to recent advances, vitamin D deficiency might play a role in the development and progression of diabetic neuropathy. Moreover, therapeutic vitamin D supplementation has the potential to improve this condition. The aim of the present review was to summarize new data available in this area. METHODS: The PubMed database was searched for articles written in English and published through September 2021, using combinations of the following key words: vitamin D, diabetes, diabetes mellitus, diabetic neuropathy, polyneuropathy, peripheral neuropathy, cardiac autonomic neuropathy, supplementation, and therapy. FINDINGS: A number of studies have suggested that vitamin D deficiency can play a significant role in the development of peripheral neuropathy, diabetic foot ulcers, as well as cardiovascular autonomic neuropathy in patients with type 2 diabetes. Vitamin D supplementation might serve as an effective adjuvant therapy for neuropathic pain and may slow or stop the progression of neural damage. IMPLICATIONS: Vitamin D therapy for diabetic complications could be a reliable option; however, further studies are needed to confirm this notion.

The Role of Biofactors in Diabetic Microvascular Complications.

Microvascular complications are responsible for a major proportion of the burden associated with diabetes contributing to substantial morbidity, mortality, and healthcare burden in people with diabetes. Retinopathy, nephropathy, and neuropathy constitute the leading causes of blindness, end-stage renal disease, and lower-extremity amputations, respectively. Since the efficacy of causal therapies of diabetic microvascular complications is limited, especially in type 2 diabetes, there is an unmet need for adjunct treatments which should be effective despite ongoing hyperglycemia. Experimental studies have indicated that diabetic microvascular complications can be prevented or ameliorated by various biofactors in animal models by interfering with the pathophysiology of the underlying condition. Some of the findings related to biofactors, like α-lipoic acid and benfotiamine, could be translated into the clinical arena and confirmed in clinical trials, especially in those focusing on diabetic polyneuropathy. Given the micronutrient nature of these compounds, their safety profile is excellent. Thus, they have the potential to favorably modify the natural history of the underlying complication, but long-term clinical trials are required to confirm this notion. Ultimately, biofactors should expand our therapeutic armamentarium against these common, debilitating, and even life-threatening sequelae of diabetes.

Management of antiplatelet therapy in acute coronary syndrome patients with thrombocytopenia / Akut coronaria szindrómán átesett thrombocytopeniás betegek thrombocytaaggregáció-gátló gyógyszeres kezelése.

Összefoglaló. Az akut coronaria szindrómán (ACS) átesett betegek kezelésének alappillére a kettos (aszpirin + klopidogrél ) thrombocytaaggregáció-gátló kezelés. Az immunthrombocytopeniás purpurás (ITP-s) betegek - és különösen azok, akik refrakter ITP miatt thrombopoetinanalóg kezelésben részesülnek - külön elbírálást igényelnek. 50-100 G/l thrombocytaszám közötti és vérzéses szövodménnyel nem rendelkezo ACS-s betegeken a gyógyszerkibocsátó stent beültetését követoen kettos thrombocytaaggregáció-gátló kezelést csak 1 hónapig kell alkalmazni (ez az idotartam átlagos vérzéses rizikójú betegeken 1 év), majd klopidogrél-monoterápia javasolt. Munkánk során a 2015. január 1. és 2020. október 1. között a Semmelweis Egyetem I. Belgyógyászati Klinikáján kezelt ITP-s betegek körében vizsgáltuk az ACS elofordulását és lefolyását. Klinikánkon az elmúlt 5 évben gondozott, 168 ITP-s beteg közül 3 beteg esetében alakult ki ACS. A refrakter ITP kezelésének részeként mind a 3 beteg thrombopoetinanalóg - (2 beteg romiplosztim-, 1 beteg eltrombopág-) kezelésben részesült. A 3 ITP-s betegünk egyikénél sem alakult ki vérzéses szövodmény a thrombopoetinanalóg-kezelés és a thrombocytaaggregáció-gátlás mellett. Elso betegünk esetében 5 év alatt három alkalommal alakult ki ACS (egy ízben fémstentet és két alkalommal gyógyszerkibocsátó stentet kapott). A második betegnél két alkalommal (1 év különbséggel), a harmadik betegnél egy esetben történt gyógyszerkibocsátó stent beültetése. ITP és ACS együttes fennállása esetén az akut és a hosszú távú gyógyszeres kezelés egyéni mérlegelést igényel. Ezen speciális betegcsoport számára a kezelési irányelv kidolgozása megfontolandó. Orv Hetil. 2021; 162(33): 1335-1340. Summary. Dual antiplatelet therapy (DAPT) consisting of aspirin and clopidogrel is essential in the treatment of acute coronary syndrome (ACS). Immune thrombocytopenic purpura (ITP) patients - and especially those receiving thrombopoietin analog (TPO) treatment - deserve special attention. In ACS patients with platelet counts between 50 G/L and 100 G/L and no bleeding symptoms, DAPT is indicated for 1 month after the placement of new generation drug-eluting stents (the length of treatment is 1 year in the case of patients with average bleeding risk) followed by clopidogrel monotherapy. In patients with average bleeding risk, DAPT is recommended for 1 year after the ACS. Our aim was to investigate the incidence and outcome of ACS in ITP patients, who were treated in our clinic between 1st January 2015 and 1st October 2020. Out of 168 patients treated for ITP, 3 patients suffered from ACS in the last 5 years. These patients received TPO treatment (2 patients subcutan romiplostim, 1 patient oral eltrombopag). None of these ITP patients treated with DAPT and with TPO analog suffered from bleeding complications. 1 patient developed ACS three times within the last 5 years (he received bare-metal stent once and drug-eluting stent twice). Drug-eluting stent was placed once in the third, and twice (with 1 year difference) in the second patient. Acute and long-term medication of patients suffering from both ITP and ACS is a challenging task and needs individual evaluation. Establishment of treatment guidelines for this special group is warranted. Orv Hetil. 2021; 162(33): 1335-1340.

Association of Cardiovascular Autonomic Neuropathy and Distal Symmetric Polyneuropathy with All-Cause Mortality: A Retrospective Cohort Study.

BACKGROUND: People with diabetic cardiovascular autonomic neuropathy (CAN) have increased cardiovascular mortality. However, the association between distal symmetric polyneuropathy (DSPN) or CAN with all-cause mortality is much less investigated. Thus, we set out to examine the effect of CAN and DSPN on all-cause mortality in a well-phenotyped cohort. METHODS: All diabetes cases (n = 1,347) from the catchment area of a secondary diabetes care centre who had medical examination including neuropathy assessment between 1997 and 2016 were followed up for all-cause mortality in the NHS Hungary reimbursement database until 2018. We investigated the association of CAN (Ewing tests) and DSPN (Neurometer) with all-cause mortality using Cox models stratified by diabetes type. RESULTS: Altogether, n = 131/1,011 persons with type 1/type 2 diabetes were included. Of the participants, 53%/43% were male, mean age was 46 ± 12/64 ± 10 years, diabetes duration was 13 ± 10/7 ± 8 years, 42%/29% had CAN, and 39%/37% had DSPN. During the 9 ± 5/8 ± 5-year follow-up, n = 28/494 participants died. In fully adjusted models, participants with type 1 diabetes patients with versus without DSPN had an increased mortality (HR 2.99, 95% CI 1.4-8.63), while no association with CAN was observed. In type 2 diabetes, both DSPN and CAN independently increased mortality (HR 1.32, 95% CI: 1.07-1.64, and HR 1.44, 95% CI: 1.17-1.76). CONCLUSIONS: Our results are compatible with an increased risk of mortality in people with type 1 diabetes and DSPN. Furthermore, we report a similarly strong association between DSPN and CAN and all-cause mortality in type 2 diabetes mellitus.

Alpha-lipoic acid alters the antitumor effect of bortezomib in melanoma cells in vitro.

Bortezomib (BOZ) is a proteasome inhibitor chemotherapeutic agent utilized to treat multiple myeloma and recently offered to cure melanoma. Bortezomib-induced neuropathy is one of the dose-limiting side-effects, which can be treated with antioxidants (e.g. alpha-lipoic acid-ALA and Vitamin B1-vit B1). We hypothesized that these antioxidants may counteract the antitumor activity by disrupting the BOZ-induced pathways (e.g. proteasome inhibition or reactive oxygen species generation). The objectives were: (i) to verify the anti-proliferative effect of BOZ; (ii) to compare the influence of the antioxidants on the antitumor effect of BOZ in melanoma (A2058) and myeloma (U266) cells. At first, the reduction in the anti-proliferative effect of BOZ by ALA was proved in melanoma cells. Analysis of p53 phosphorylation and the cell cycle progression revealed that ALA failed to counteract these effects of BOZ. Nevertheless, a good correlation was found between the inhibition of the anti-proliferative effect, the anti-proteasome activity and the oxidative stress level after the co-treatment with 20 ng/mL BOZ + 100 µg/mL ALA. Downregulation of apoptotic proteins such as HO-1 and Claspin along with the inhibition of the cleavage of Caspase-3 indicated the proteomic background of the altered responsiveness of the melanoma cells exposed to BOZ + ALA. This phenomenon draws attention to the proper application of cancer supportive care to avoid possible interactions.

Diabetic Cardiovascular Autonomic Neuropathy, the Handgrip Test and Ambulatory Blood Pressure Monitoring Parameters: Are There Any Diagnostic Implications?

Cardiovascular autonomic neuropathy (CAN) is a common complication of diabetes mellitus. Cardiovascular reflex tests (CARTs) are the gold standard in the diagnosis of CAN, but the handgrip test is no longer recommended to be performed. Previously, the inverse association between the presence of hypertension and handgrip test abnormality was demonstrated and hypertension as major cause for excessive diastolic blood pressure rise during handgrip testing in diabetic individuals proposed. The aim of the present study is to describe more precisely the association between handgrip test and hypertension by performing ambulatory blood pressure monitoring (ABPM) among diabetic patients. A more comprehensive evaluation of the relationship between cardiovascular autonomic function, hypertension and the handgrip test was targeted using heart rate variability (HRV) analysis. Our study involved 163 patients with diabetes. Cardiovascular autonomic neuropathy was assessed by the CARTs and sustained handgrip test was performed. All patients underwent ABPM and HRV analysis well. CAN was diagnosed in 69 patients. Significant associations were found between the diastolic blood pressure increase in response to handgrip exercise and the 24-h (rho = 0.245, p = 0.003), daytime (rho = 0.230, p = 0.005) and night-time (rho = 0.230, p = 0.006) mean systolic and 24-h diastolic (rho = 0.176, p = 0.034) blood pressure values, systolic blood pressure load (rho = 0.252, p = 0.003) and systolic (rho = 0.236, p = 0.005) and diastolic (rho = 0.165, p = 0.047) hyperbaric impacts. Higher values of ambulatory blood pressure monitoring parameters are associated with greater increases in diastolic blood pressure during isometric handgrip exercise. Diastolic blood pressure elevations during the handgrip test are also correlated, in order to diminished heart rate variability parameters attributable to parasympathetic dysfunction highlighting the pivotal role of sympathetic overactivity in evolving handgrip test results. Our study provides further evidence on the inverse association between handgrip test abnormality and hypertension in diabetic patients.