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Clinical Neuroscience

NOVEMBER 30, 2020

Positive airway pressure normalizes glucose metabolism in obstructive sleep apnea independent of diabetes and obesity

KABELOĞLU Vasfiye, SENEL Benbir Gulçin, KARADENIZ Derya

The relationship among obstructive sleep apnea syndrome (OSAS), type 2 diabetes mellitus (DM2) and obesity is very complex and multi-directional. Obesity and increased visceral fat are important perpetuating factors for DM2 in patients with OSAS. On the other hand, OSAS itself leads to obesity by causing both leptin and insulin resistance as a consequence of activation of the sympathetic nervous system. Risk for developing DM2 further increases in patients with OSAS and obesity. Data regarding effects of positive airway pressure (PAP) therapy, gold standard treatment for OSAS, on glycemic control were inconsistent due to variability in duration of and adherence to PAP therapy. In our cohort study we investigated effects of PAP treatment on glucose metabolism in normal-weighted non-diabetic OSAS patients, in obese non-diabetic OSAS patients, and in OSAS patients with DM2. We prospectively analyzed 67 patients diagnosed with OSAS and documented to be effectively treated with PAP therapy for three months. Apnea-hypopnea index was highest in the diabetic group, being significantly higher than in the normal-weighted group (p=0.021). Mean HOMA values were significantly higher in obese (p=0.002) and diabetic group (p=0.001) than normal-weighted group; the differences were still significant after PAP therapy. HbA1c levels were significantly higher in diabetic group compared to those in normal-weighted (p=0.012) and obese (p=0.001) groups. After PAP treatment, decrease in HbA1c levels were significant in normal-weighted (p=0.008), obese (p=0.034), and diabetic (p=0.011) groups. There was no correlation with the change in HbA1c levels and age (p=0.212), BMI (p=0.322), AHI (p=0.098) or oxygen levels (p=0.122). Our study showed that treatment of OSAS by PAP therapy offers beneficial effect on glucose metabolism, not only in diabetic patients, but also in obese and normal-weighted OSAS patients. Although data regarding overall effects of PAP therapy on glycemic control present contradictory results in the literature, it should be emphasized that duration and adherence to PAP therapy were main determinants for beneficial outcome of treatment.

Hypertension and nephrology

SEPTEMBER 30, 2020

[Post-career development of cardiometabolic changes and hypertension in competitive athletes]

LELBACH Ádám, KÁNTOR Márk, KOLLER Ákos

[Regular physical activity is essential in delaying the aging processes (e.g. arterial remodelling – stiffening, metabolism, bodyweight), the beneficial effects of competitive sports – especially strength sports – according to the recent data of the literature are questionable. The beneficial effects of physical activity on the cardiovascular (CV) system are well known, however less is known regarding the delayed impacts of high intensity competitive sports on the CV system, especially after the sport career is over. This review summarizes the effects of active competitive sport and the post-career period on the cardiometabolic system with special attention to the systemic blood pressure and the development of metabolic syndrome. After sport career, the welldeveloped high performance cardiovascular- and metabolic system suddenly is much less used, but still supported by sport-level diet. It is well known that hypertension is a significant pathogenic factor in the development of cardiovascular diseases, characterized – among others – by reduced elasticity of large- and medium- sized vessels thereby importantly contributing to the development of systolic hypertension. Inflammation and thrombus formation both play an important role in the development of vascular injury and atherosclerosis. The increased tone of microvessels can impair the blood supply of certain organs, including the coronary circulation. It has been ample shown, that regular non-competitive, aerobic exercise activities are important factors in preventing hypertension. Such pathological changes become more evident after the development of post-career obesity, as well as the development of hypertension due to the activation of the renin-angiotensin system through sodium retention and other metabolic changes (increased glucose tolerance, insulin resistance, type II diabetes mellitus). It has been ample shown, that regular non-competitive, dynamic aerobic exercise activities are important factors in preventing hypertension. The frequency, intensity, type, and time (FITT) principle of exercise prescription is the first and common therapeutic approach, which represents the translation of cardiovascular basic science research results into hypertension treatment, thus can provide a personalized physical activity program/therapy according to medical needs not just for the post-career sportspersons, but the wide range of patients.]

Lege Artis Medicinae

JULY 01, 2020

[Sarcopenia – muscle loss – pathomechanism, clinical presentation and metabolic comorbidities]

VERECKEI Edit, HODINKA László

[Sarcopenia, or the age-related involution of muscle strength and muscle mass, is a serious public health concern, due to the growing number of elderly population caused by nowadays demographic changes i.e. prolonged life expectancy. By ageing, the muscle tissue is shrinking gradually, leading to the loss of muscle strength and masses. This condition is called sarcopenia. Sar­co­penia is the simultaneous decrease of muscle mass, muscle strength and functional independence. In parallel the physical performance deteriorates (weakness, slowness and poor physical balancing). Fatigue, el­derly behaviour and weight loss are the consequences of these accumulating deficits, which associate with cognitive decline and result in increasing social isolation. The primary form of sarcopenia is the decrease of the energy production of muscle cells and then the death of muscle cells. Se­con­dary, endocrine dysfunctions, diseases of the nervous system, decreased physical activity, malnutrition or malabsorption, chronic infection accelerate the process and aggravate the patient’s condition. Complex genetic, biochemical and endocrine mechanisms take part in the development of sarcopenia. This involution is due to the impaired balance of restoring and depleting processes of muscles. A questionnaire and algorithm have been developed to recognize, screen and diagnose the risks of sarcopenic condition; these separate the sarcopenic and non-sarcopenic patients with specific cut-off values. Sar­co­penia can be diagnosed based on walking speed, decreased handgrip strength and measured or calculated muscle mass in persons over 65. Sarcopenia can be considered as a phenomenon of “physiological” aging, however, it becomes a disease when diagnostic cut-offs are exceeded and the patient experiences functional disability and declining quality of life. Prevention and treatment of sarcopenia and reducing the risk of falling are based on regular active resistance and coordination exercises. Options for pharmaceutical treatments are limited since despite of identified molecular targets there are no convincingly effective innovative therapy on the horizon. Nevertheless, there are some weak evidence for efficacy of the application of amino acids stimulating muscle cell differentiation, such as leucine or the analogue of beta-hydoxy-methylbutyrate beside exercise therapy.]

Clinical Oncology

APRIL 10, 2019

[CDK 4/6 Inhibitors in Breast Cancer: Current Controversies and Future Directions]

SPRING M. Laura, WANDER A. Seth, ZANGARDI Mark, BARDIA Aditya

[Purpose of review: To describe the clinical role of CDK 4/6 inhibitors in hormone receptor-positive (HR+) metastatic breast cancer (HR+MBC) as well as current controversies and evolving areas of research. Recent fi ndings: Palbociclib, ribociclib, and abemaciclib are each approved in combination with an aromatase inhibitor or fulvestrant for HR+MBC. Abemaciclib is also approved as monotherapy for pre-treated patients. Key questions in the fi eld include whether all patients with HR+MBC should receive a CDK 4/6 inhibitor up front versus later line, impact on overall survival, role of continued CDK 4/6 blockade, mechanism of clinical resistance, and treatment sequencing. Summary: The development of CDK 4/6 inhibitors has changed the therapeutic management of HR+MBC. Additional research is needed to determine optimal treatment sequencing, understand mechanisms governing resistance, and develop novel therapeutic strategies to circumvent or overcome clinical resistance and further improve the outcomes of patients with MBC.]

Clinical Oncology

FEBRUARY 20, 2019

[Molecular subtypes and the evolution of treatment decisions in metastatic colorectal cancer]

RODRIGO Dienstmann, RAMON Salazar, JOSEP Tabernero

[Colorectal cancer (CRC) has clinically-relevant molecular heterogeneity at multiple levels: genomics, epigenomics, transcriptomics and microenvironment features. Genomic events acquired during carcinogenesis remain drivers of cancer progression in the metastatic setting. For example, KRAS and NRAS mutations defi ne a population refractory to EGFR monoclonal antibodies, BRAFV600E mutations associate with poor outcome under standard therapies and response to targeted inhibitors in combinations, while HER2 amplifi cations confer unique sensitivity to double HER2 blockade. Multiple rare gene alterations driving resistance to EGFR monoclonal antibodies have been described with signifi cant overlap in primary and acquired mechanisms, in line with a clonal selection process. In this context, sequential analysis of circulating tumor DNA has the potential to guide drug development in a treatment refractory setting. Rare kinase fusion events and complex alterations in genes involved in DNA damage repair have been described, with emerging evidence for targetability. On the other hand, transcriptomic subtypes and pathway activation signatures have also shown prognostic and potential predictive value in metastatic CRC. These markers refl ect stromal and immune microenvironment interactions with cancer cells. For example, the microsatellite instable (MSI) or POLE ultramutant CRC population is particularly sensitive to immune checkpoint inhibitors, while tumors with a mesenchymal phenotype are characterized by activation of immunosuppressive molecules that mandate stratifi ed development of novel immunotherapy combinations. In this manuscript we review the expanding landscape of targetable oncogenic alterations and signatures in metastatic CRC and discuss the clinical implementation of novel molecular diagnostic tests.]

Clinical Oncology

DECEMBER 10, 2018

[Advancing therapies in metastatic castration-resistant prostate cancer]

GIULIA Baciarello, MARCO Gicci, KARIM Fizazi

[Introduction: Prostate cancer is the second most common cause of cancer world wide and is the most frequently detected cancer in the European Union in men over 50 years of age. Androgen deprivation therapy remains the corner stone of treatment for recurrent or metastatic disease. Unfortunately, nearly all patients will develop resistance to androgen blockade leading to castration-resistant prostate cancer (CRPC). Over the last 10 years, new treatment shaved ramatically improved overall survival of men with mCRPC. Current therapies are basedon AR-axis inhibitors and taxane-based chemotherapies, aswell as radiopharmaceuticals and Sipuleucel T. Areas covered: The authors provide a review of the current fi eld of systemic therapy in metastatic CRPC. This is followed by an in-depth analysis of recent developments in treatment, and the biological rationale behind these therapies. Expert opinion: Since several trials with docetaxel or novel hormonal agents showed improvement in overall survival in metastatic castration-sensitive prostate cancer, aswell as in non-metastatic castrationresistant patients, it is expected that a growing subgroup of patients will be expose dearlierto chemotherapy and to AR targeted agents. It becomes then fundamental to fi nd novel strategies to over come drug resistance and further improve survival.]

Hypertension and nephrology

DECEMBER 12, 2019

[Hypertension and brain function. Correlation of high blood pressure and demencia in aging. Hypertension in young-middle adults - demencia in elderly]

SZÉKÁCS Béla, KÉKES Ede

[The cerebral vascular damage caused by hypertension is manifested primarily in cognitive dysfunction, which is caused by hypoperfusion of brain tissue, ischemic, or bleeding stroke, or white matte injury. Hypertension may not only result in cerebral damage to the vascular background - dementia -, but may also contribute to the development and progression of classical gene-related Alzheimer’s disease. Blood pressure gradually increases in the elderly and in the very elderly, and the frequency of hypertension-mostly as isolated systolic hypertension - is 50% to 70%. High blood pressure predominately, or in full, means not only an increase in the circulatory resistance of the small children, but also, as part of the aging of the body, the rigidity (stiffness) of the arteries. At the same time, the incidence of dementia, along with age, rises sharply - up to 20% in those over 65 years of age, and over 40% in 80-90 years of age. The relationship between high blood pressure and dementia from the young age to the very old age may change as a function of current age. In the very old age of life, the varying influence of other pathological factors other than hypertension is becoming more and more important in the deterioration of both the vascular structure and the brain function. In this late stage of life, the very advanced rate of aging and nutritive blood flow often require higher perfusion pressure, and the not enough thought-out blood pressure reduction can be more damaging than a protective effect on brain condition or function. SPRINT MIND - the Intense Blood Pressure Reduction - hasn’t resolved the question, and we can legally assume that the 130-140 Hgmm SBP. Is the most favorable for dementia. The value of DBP 70 Hgmm is definitely unfavorable.]

Hypertension and nephrology

MAY 10, 2019

[Diabetology in dialysis]

MÁCSAI Emília, HALMAI Richárd, NEMERE Éva, BRASNYÓ Pál, KISS István

[According to epidemiological data, the number of diabetic patients requiring dialysis is increasing. Burnt-out diabetes, new onset diabetes during chronic dialysis treatment and new onset diabetes after transplantation diabetes are new types of diabetes compared to the traditional division forms. It is utmost important to evaluate education ability and acceptance the core values of lifestyle changes. Clear guidelines for oral anti-diabetic and insulin therapy have not yet been developed since this group of patients did not participate in previous major surveys. In order to formulate individualized therapeutic recommendations, it is imperative to perform regular glucose self-monitoring, which is also the cornerstone of solving unexpected situations. Both in hemodialysis and peritoneal dialysis, special considerations should be applied to the diabetic patient group, this review focuses on the current understanding of available relevant knowledge and summarizes presumably extrarenal diabetic complications as well.]

Clinical Oncology

MAY 10, 2018

[Fusions in solid tumors]

KOPPER László

[Genetic fusions are the cosequence of genomic rearrangement including chromosomal inversion, interstitial deletion, duplication, amplifi cation, translocation. Fusions can influence tumor development and progression. Fusions fi rst discovered in hematological malignances (e.g. BCR-ABL), butlater more and more were identified dueto the higly sensitive NGS. It has been found that the oncogenic fusions are in minority in a given tumor. Today, some fusions were apprevedas targets (ALK, ROS1, PDGFB) by FDA. Asino ther targeted therapy resistance is in evitable, which is a very important challenge for newly designed drugs.]

Hypertension and nephrology

FEBRUARY 20, 2019

[The importance of statin therapy in hypertension]

PARAGH György, PÁLL Dénes

[Hypertension and hypercholesterolaemia often co-occur and promote early cardiovascular disease. Previous studies have shown that antihypertensive treatment may be more effective if LDL cholesterol is also reduced. This may be due to the increased expression of angiotensin-1 receptor in hypercholesterolaemia, which increases peripheral vascular resistance through angiotensin-2, and adversely affects endothelial and smooth muscle cells. Other authors indicate that high cholesterol levels increase the production of angiotensin-2 through the activation of the chymase system. High cholesterol levels increase the amount of circulating oxidized LDL which binds to the transmembrane oxidized LDL receptor (LOX- 1) also activates the angiotensin-1 receptor. In addition, angiotensin-2 has an effect on intracellular cholesterol synthesis by enhancing the key enzyme of the synthesis of intracellular cholesterol, HMG-CoA reductase. The authors present the studies that support cholesterol lowering can contribute to lowering blood pressure and other major meta-analyses in which the beneficial effects of cholesterol lowering and lipid lowering on blood pressure reductions were not proven. In the background, it may well be that these studies are not designed to evaluate the effect of cholesterol-lowering drugs on hypertension in patients with hypercholesterolaemia, and non-statin-treated patients are not randomized.]