Cystatins: unravelling the biological implications for neuroprotection.

Cystatins, a family of proteins known for their inhibitory role against cysteine proteases, have garnered significant attention in the field of neurodegeneration. Numerous genetic, experimental, and clinical studies concerning cystatin C suggest it plays an important role in the course of neurodegenerative diseases. Its beneficial effects are associated with cysteine protease inhibition, impact on ß-amyloid aggregation, as well as regulation of cell proliferation, autophagy, and apoptosis. Cystatin isolated from chicken egg white, called ovocystatin, has been widely used in medical and pharmaceutical research due to its structural and biological similarities to human cystatin C. This article focuses on the potential use of cystatins, with special emphasis on easily obtained ovocystatin, in the treatment of neurodegenerative diseases, such as dementia. The current evidence on cystatin use has shed light on its mechanisms of action and therapeutic implications for neuroprotection and maintenance of cognitive functions.

Coping of Chronically-Ill Patients during the COVID-19 Pandemic: Comparison between Four Groups.

In many countries, the COVID-19 pandemic led to healthcare reorganization limiting access to diagnostic or therapeutic procedures for chronically-ill patients. In this article, we describe the psychological consequences and coping strategies of several groups of chronically-ill patients. During the cross-sectional survey conducted in 2020, we enrolled 398 patients with four different chronic conditions (psoriasis, multiple sclerosis, and patients who have undergone a kidney transplant or received dialysis). The study sample was examined regarding the experienced stress levels (Perceived Stress Scale) and coping strategies (Brief-COPE). All four groups of patients most commonly declared using problem-focused coping strategies and least commonly reported the use of avoidant coping. Higher levels of perceived stress strongly correlated with self-blaming. The participants who declared previous psychiatric treatment or psychotherapy were more likely to use self-blaming, behavioral disengagement, substance use, and avoidant coping, while previous psychotherapy additionally correlated with emotion-focused coping. Group comparison identifies patients with a chronic neurological disease, such as multiple sclerosis, at higher risk of a less beneficial coping profile than kidney transplant recipients. Further focus on education and early interventions in at-risk individuals is needed, and widely targeted mental health programs are indicated in order to improve the mental health of patients suffering from chronic diseases.

Neuroinflammation in Dementia-Therapeutic Directions in a COVID-19 Pandemic Setting.

Although dementia is a heterogenous group of diseases, inflammation has been shown to play a central role in all of them and provides a common link in their pathology. This review aims to highlight the importance of immune response in the most common types of dementia. We describe molecular aspects of pro-inflammatory signaling and sources of inflammatory activation in the human organism, including a novel infectious agent, SARS-CoV-2. The role of glial cells in neuroinflammation, as well as potential therapeutic approaches, are then discussed. Peripheral immune response and increased cytokine production, including an early surge in TNF and IL-1ß concentrations activate glia, leading to aggravation of neuroinflammation and dysfunction of neurons during COVID-19. Lifestyle factors, such as diet, have a large impact on future cognitive outcomes and should be included as a crucial intervention in dementia prevention. While the use of NSAIDs is not recommended due to inconclusive results on their efficacy and risk of side effects, the studies focused on the use of TNF antagonists as the more specific target in neuroinflammation are still very limited. It is still unknown, to what degree neuroinflammation resulting from COVID-19 may affect neurodegenerative process and cognitive functioning in the long term with ongoing reports of chronic post-COVID complications.

What Do We Know about Social and Non-Social Factors Influencing the Pathway from Cognitive Health to Dementia? A Systematic Review of Reviews.

The heterogeneous and multi-factorial nature of dementia requires the consideration of all health aspects when predicting the risk of its development and planning strategies for its prevention. This systematic review of reviews provides a comprehensive synthesis of those factors associated with cognition in the context of dementia, identifying the role of social aspects and evidencing knowledge gaps in this area of research. Systematic reviews and meta-analyses from 2009-2021 were searched for within Medline, PsycINFO, CINAHL Complete, Cochrane, and Epistemonikos. Reviewers independently screened, reviewed, and assessed the records, following the PRISMA-2020 guidelines. From 314 included studies, 624 cognitive-related factors were identified, most of them risk factors (61.2%), mainly belonging to the group of 'somatic comorbidities' (cardiovascular disease and diabetes) and 'genetic predispositions'. The protective factors (20%) were mainly related to lifestyle, pointing to the Mediterranean diet, regular physical activity, and cognitively stimulating activities. Social factors constituted 9.6% of all identified factors. Research on biological and medical factors dominates the reviewed literature. Greater social support and frequent contact may confer some protection against cognitive decline and dementia by delaying its onset or reducing the overall risk; however, overall, our findings are inconsistent. Further research is needed in the fields of lifestyle, psychology, social health, and the protective factors against cognitive decline and dementia.

Mapping the complexity of dementia: factors influencing cognitive function at the onset of dementia.

BACKGROUND: Dementia is a multi-factorial condition rather than a natural and inevitable consequence of ageing. Some factors related to dementia have been studied much more extensively than others. To gain an overview of known or suspected influential factors is a prerequisite to design studies that aim to identify causal relationships and interactions between factors. This article aims to develop a visual model that a) identifies factors related to cognitive decline that signal the onset of dementia, b) structures them by different domains and c) reflects on and visualizes the possible causal links and interactions between these factors based on expert input using a causal loop diagram. METHOD: We used a mixed-method, step-wise approach: 1. A systematic literature review on factors related to cognitive decline; 2. A group model building (GMB) workshop with experts from different disciplines; 3. Structured discussions within the group of researchers. The results were continuously synthesized and graphically transformed into a causal loop diagram. RESULTS: The causal loop diagram comprises 73 factors that were structured into six domains: physical (medical) factors (23), social health factors (21), psychological factors (14), environmental factors (5), demographic factors (5) and lifestyle factors (3). 57 factors were identified in the systematic literature review, additionally 16 factors, mostly of the social health cluster, were identified during the GMB session and the feedback rounds. CONCLUSION: The causal loop diagram offers a comprehensive visualisation of factors related to cognitive decline and their interactions. It supports the generation of hypotheses on causal relationships and interactions of factors within and between domains.

Novel psychopathological picture during the COVID-19 pandemic based on a first episode of psychotic depression. / Nowy obraz objawów psychopatologicznych w dobie pandemii COVID-19 na podstawie pierwszego epizodu depresji psychotycznej.

The emerging SARS-CoV-2 pandemic is known to take a toll on both physical and mental health. We present a case of a patient with a first episode of severe depression with COVID-19-related psychotic features. A patient with no history of mental disorders was admitted to the Psychiatric Unit due to the symptoms of severe depressive episode with psychotic features. Progressive deterioration of his mental health, behavior and activity was observed in March of 2020. He was not infected nor exposed to infectious agents but presented delusions about being infected with SARS-CoV-2 and being a source of transmission to other people. He suffered from Hashimoto disease and recently diagnosed lymphoma which further diagnosis was postponed. He was administrated venlafaxine 150 mg and mirtazapine 45 mg with addition of olanzapine up to 20 mg and risperidone up to 6 mg per day. No side effects were reported. The patient reached a full recovery with the exception of slightly blunted ability to feel pleasure, minor problems with concentration and occasional pessimistic thoughts. Discussion: The social distancing recommendations put a psychological strain related to alienation and negative emotions which can favor development of depressive symptoms. Analysis of psychological mechanisms related to the pandemic and restrictions is significant for limiting negative influence of global crisis on individual mental well-being. Conclusions: In this case the impact of global anxiety and its integration into the developing psychopathological symptoms is especially significant. The circumstances surrounding an episode of affective disorder may shape its course and thought content.

The Effectiveness of Computerized Cognitive Training Combined With Whole Body Cryotherapy in Improving Cognitive Functions in Older Adults. A Case Control Study.

Objectives: Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) are common in elderly population, and constitute a high-risk group for progression to dementia. Innovative, complex, and engaging non-pharmacological methods of cognitive stimulation, implementable at this stage, are needed. The aim of the study was to determine the effect of Computerized Cognitive Training (CCT) combined with Whole Body Stimulation (WBC) on cognitive functions of older adults with SCD and MCI. Methods: A 9-week single-blind pre/post case control trial was conducted. The study enrolled 84 adults aged 60 or older, allocated to one of two intervention groups: EG; CCT with psychoeducation, EG2; CCT with psychoeducation and 10 WBC sessions, or the control group (CG), which comprised patients receiving usual care. The primary outcome measures were cognitive functions evaluated with MoCA scale and several other neuropsychological tools. Depressive symptoms assessed with the GDS scale constituted the secondary outcome measures. Results: The results show evidence for increased performance in the assessment of general cognitive functioning in both EGs (p ≤ 0.05). Significant improvement was also visible in several cognitive domains, such as verbal fluency (EG1 & EG2), learning ability and immediate memory (EG1 & EG2), delayed memory (EG2), attentional control (EG1), and information processing (EG2) (p ≤ 0.05). However, only in the group with combined interventions (CCT + WBC) the participants presented significantly less depressive symptoms (p ≤ 0.05). Conclusions: The results of the study suggest that CCT, especially in combination with WBC, might be a practical and effective method of improving cognitive performance. Moreover, this combination leads to a reduction of depressive symptoms.

Diffuse axonal injury - an interdisciplinary problem. Current knowledge and two case reports. / Rozlany uraz aksonalny ­ problem interdyscyplinarny. Stan wiedzy i opis dwóch przypadków klinicznych.

Diffuse axonal injury (DAI) is a microscopic damage of axons in the brain. Its occurrence results from head trauma with acceleration or deceleration. This article presents current knowledge about DAI and two cases of patients who experienced DAI as a consequence of a traffic accident. A26 years old man was brought to hospital after traffic accident during which his vehicle had overturned. Computed tomography (CT) showed features of brain edema and disseminated small petechiae. Psychiatric consultation on ninth day of hospitalization showed memory deficits presenting as retrograde and anterograde amnesia, attention deficits and lack of criticism in regard to his condition. A 38 years old woman who was hit by a car while cycling was admitted to hospital. CT scan showed features of brain edema, subarachnoid hemorrhage and multiple fractures. On the tenth day of hospitalization the patient was confused, did not remember new information, her psychomotor drive was increased and she presented lack of criticism in regard to her condition. While suspecting DAI we should be vigilant, particularly in cases of patients hospitalized due to traffic accidents with behavioral problems, features of amnestic syndrome and without significant focal neurological symptoms.

Gut microbiota in dementia. Critical review of novel findings and their potential application.

There is a great deal of impetus for the comprehensive understanding of the complete pathological function, genetic information, and functional diversity of the gut microbiota that favors the development of dementia. It has been reported that patients with mild cognitive impairment and Alzheimer's disease present with several metabolic and immune-inflammatory alterations. The recently highlighted aspects of human health linked to cognitive decline include insulin-resistance, obesity, and chronic low-grade inflammation. Gut microbiota is known to produce neurotransmitters, such as GABA, acetylcholine, dopamine or serotonin, vitamins, intestinal toxins, and modulate nerve signaling - with emphasis on the vagus nerve. Additionally, gut dysbiosis results in impaired synthesis of signaling proteins affecting metabolic processes relevant to the development of Alzheimer's disease. Due to numerous links of gut microbiota to crucial metabolic and inflammatory pathways, attempts aimed at correcting the gut microflora composition may affect dementia pathology in a pleiotropic manner. Taking advantage of the metabolic effects of cold exposure on organisms by the introduction of whole-body cryostimulation in dementia patients could lead to alterations in gut microbiota and, therefore, decrease of an inflammatory response and insulin resistance, which remain one of the critical metabolic features of dementia. Further studies are needed in order to explore the potential application of recent findings and ways of achieving the desired goals.

SARS-CoV-2 pandemic and the population with dementia. Recommendations under the auspices of the Polish Psychiatric Association. / Pandemia SARS-CoV-2 a populacja osób z otepieniem. Rekomendacje pod patronatem Polskiego Towarzystwa Psychiatrycznego.

SARS-CoV-2 poses a particular risk to the elderly and people with many comorbidities. In the case of people with dementia, the compliance with sanitary recommendations and the necessary physical isolation can have far-reaching negative consequences in terms of limiting the continuation of tailored care, support and treatment. The recommendations related to the SARS-CoV-2 pandemic must take into account not only the medical consequences of lack of access to medical care, but also their long-term effects and the disease progression in accordance with the concept of social health. A plan of action for the psychoeducation of informal carers, adapted to the elderly group (including people with dementia), is also necessary. Prepared under the auspices of the Polish Psychiatric Association, the recommendations for people living alone, with their family and in long-term care facilities are intended to draw attention to key epidemiological issues that can be planned by medical staff within the organization of patient care. However, mental and social needs of patients, whose fulfilment is particularly significant in times of restrictions related to everyday activities, are of equal importance. Further monitoring of the epidemiological situation and scientific reports related to the SARS-CoV-2 pandemic are necessary to verify and update the guidelines.

Quality of life, depression and anxiety in living donor kidney transplantation.

Due to its numerous advantages, transplantation from a living kidney donor is the best method of renal replacement therapy. However, the characteristics of the procedure require to consider well-being of not only the recipient, but also the donor - a person who suddenly becomes a patient despite former good health. The living donation is a selfless act, but also a decision that may endanger one's own health. The aim of this article was to review the current knowledge concerning the quality of life, symptoms of anxiety and depression occurring among living kidney donors and recipients. In order to do that, we performed a systematic research in the PubMed, Google Scholar and CINAHL databases for the years 2000-2019 with the use of key words. The inclusion and exclusion criteria were met by only 15 articles. This study shows that the mental state of donors is generally better than that of recipients. Additionally, reduction of anxiety and depression as well as increase in the quality of life occurs in both donors and recipients in the post-transplant period compared to the time before surgery. Further research is needed on this topic in order to improve psychological aspects of care of live kidney donors and recipients.

Insulin enhancement of the antitumor activity of chemotherapeutic agents in colorectal cancer is linked with downregulating PIK3CA and GRB2.

The present state of cancer chemotherapy is unsatisfactory. New anticancer drugs that marginally improve the survival of patients continue to be developed at an unsustainably high cost. The study aimed to elucidate the effects of insulin (INS), an inexpensive drug with a convincing safety profile, on the susceptibility of colon cancer to chemotherapeutic agents: 5-fluorouracil (FU), oxaliplatin (OXA), irinotecan (IRI), cyclophosphamide (CPA) and docetaxel (DOC). To examine the effects of insulin on cell viability and apoptosis, we performed an in vitro analysis on colon cancer cell lines Caco-2 and SW480. To verify the results, we performed in vivo analysis on mice bearing MC38 colon tumors. To assess the underlying mechanism of the therapy, we examined the mRNA expression of pathways related to the signaling downstream of insulin receptors (INSR). Moreover, we performed Western blotting to confirm expression patterns derived from the genetic analysis. For the quantification of circulating tumor cells in the peripheral blood, we used the maintrac method. The results of our study show that insulin-pretreated colon cancer cells are significantly more susceptible to commonly used chemotherapeutics. The apoptosis ratio was also enhanced when INS was administered complementary to the examined drugs. The in vivo study showed that the combination of INS and FU resulted in significant inhibition of tumor growth and reduction of the number of circulating tumor cells. This combination caused a significant downregulation of the key signaling substrates downstream of INSR. The results indicate that the downregulation of PIK3CA (phosphatidylinositol 3-kinase catalytic subunit alpha), which plays a critical role in cell signaling and GRB2 (growth factor receptor-bound protein 2), a regulator of cell proliferation and differentiation may be responsible for the sensitizing effect of INS. These findings were confirmed at protein levels by Western blotting. In conclusion, these results suggest that INS might be potentially applied to clinical use to enhance the therapeutic effectiveness of chemotherapeutic drugs. The findings may become a platform for the future development of new and inexpensive strategies for the clinical chemotherapy of tumors.

Tackling Alzheimer's disease: Hypothetical synergism between anti-inflammatory and anti-diabetic agents.

Alzheimer's disease (AD) remains one of the greatest global concerns. Current treatment of AD - the acetylcholinesterase inhibitors - provides temporary improvement of cognitive functions, but does not affect the core of the underlying pathological process. There is still the need for alternative approaches, preferably ones based on the upstream events in the AD pathogenesis. The nature of AD pathogenesis remains complicated and not entirely explained. It is assumed to comprise of many interrelated events which can sequentially lead to further pathologies - as a kind of vicious cycle. The solution in this case could be to interact with these processes on multiple levels at the same time. The proposed approach hopes to achieve the state of equilibrium between two pathological pathways via reducing their dynamics on appropriate levels. The first step is to inhibit Tumor Necrosis Factor signaling related to inflammatory response. The second is to take advantage of the influence of insulin signaling on amyloid-ß processing to restore its proper clearance. Employing two only partially-beneficial approaches into a novel approach aims at breaking the "vicious cycle" and eliciting synergistic effect via working on different levels simultaneously. The effect of such therapy could allow physicians to completely inhibit neural damage. The proposed strategy may prove easily introducible as an efficacious clinical approach employing novel anti-TNF agents in combination with anti-diabetic agents. Data is needed on its influence on cognitive functions, any occurrence of adverse effects, and the development of models of optimal doses and their temporal location.

Predictors of mortality in older patients admitted to a geriatric hospital.

AIM: The identification of older patients at risk of mortality is important to provide properly tailored care and effectively manage healthcare resources. The present study aimed to identify predictors of all-cause mortality related to geriatric patients' clinical, functional and sociodemographic status at admission. METHODS: A retrospective study was carried out of patients admitted to a geriatric hospital from January to May 2013. A total of 208 patients were enrolled in the study. The outcome measure was 4-year mortality. RESULTS: The mortality rate was 26%. We found that age, red blood cells count and white blood cells count, as well as C-reactive protein level, albumin level and high-density lipoprotein cholesterol level significantly correlated with mortality. Furthermore, the presence of clinical symptoms, such as pressure ulcers and depressed level of consciousness, was predictive of poor outcome. Multidimensional aspects of aging that are assessed in the Comprehensive Geriatric Assessment - activities of daily living, instrumental activities of daily living, Barthel scale, Mini-Mental State Examination and The Clock Drawing Test - appeared to be strong predictors of 4-year mortality. The expression to estimate the probability of mortality based on the examined variables correctly classified nearly 85% of the analyzed cases. CONCLUSIONS: Early detection of high-risk patients is of particular significance to reach a better survival rate among older adults. Clinicians should put more stress on the comprehensive surveillance of geriatric patients, rather than focusing solely on the treatment of chronic diseases. Geriatr Gerontol Int 2019; 19: 70-75.

Insulin-induced enhancement of MCF-7 breast cancer cell response to 5-fluorouracil and cyclophosphamide.

The study was designed to evaluate the potential use of insulin for cancer-specific treatment. Insulin-induced sensitivity of MCF-7 breast cancer cells to chemotherapeutic agents 5-fluorouracil and cyclophosphamide was evaluated. To investigate and establish the possible mechanisms of this phenomenon, we assessed cell proliferation, induction of apoptosis, activation of apoptotic and autophagic pathways, expression of glucose transporters 1 and 3, formation of reactive oxygen species, and wound-healing assay. Additionally, we reviewed the literature regarding theuse of insulin in cancer-specific treatment. We found that insulin increases the cytotoxic effect of 5-fluorouracil and cyclophosphamide in vitro up to two-fold. The effect was linked to enhancement of apoptosis, activation of apoptotic and autophagic pathways, and overexpression of glucose transporters 1 and 3 as well as inhibition of cell proliferation and motility. We propose a model for insulin-induced sensitization process. Insulin acts as a sensitizer of cancer cells to cytotoxic therapy through various mechanisms opening a possibility for metronomic insulin-based treatments.

Insulin and novel thioglycosides exert suppressive effect on human breast and colon carcinoma cells.

The rationale for the implementation of novel therapies should be based on hallmarks of cancer. Two novel compounds labelled as thioglycoside A and B were designed and evaluated on breast and colon cancer cell lines. We assessed their cytotoxic effect after sensitizing cancer cells with insulin. In order to explore the underlying mechanisms, we performed tests to assess cell migration and motility, apoptosis, expression of glucose transporter 1 and proapoptotic proteins. Both compounds proved to have an antitumor effect which was significantly enhanced in combination with insulin. Linking glucose and anticancer agent presents an approach that exploits the Warburg effect. Targeting dysfunctional glycometabolism and increased glucose absorption is emerging as a promising anticancer strategy.