Academic literature on the topic 'Low-grade chronic syndromes'

Fibromyalgia syndrome is defined as chronic widespread pain and tenderness. It is associated with fatigue, sleep disorder, functional somatic syndromes, mental and physical disorders, as well as disability and diminished quality of life. We aimed to analyse the effects of an olive tree-based supplement and a gluten-free, FODMAP and low histamine diet (IGUBAC-Diet®), with antioxidant and anti-inflammatory characteristics, in women with fibromyalgia. A randomized, controlled, clinical trial, with 31 women (55.87±11.86 years) diagnosed with fibromyalgia was conducted in 2016. Chronic Pain Grade Scale, Pain Catastrophizing Scale, Fatigue Severity and Impact Scale were used. Anthropometric parameters and symptoms progression were measured before and after two months of treatment with olive tree-based supplement and IGUBAC-Diet®. Other secondary outcome measures include blood biochemical analysis. Patients improved Chronic Pain Grade Scale scores after intervention and all groups experienced a reduction in the perception of pain catastrophizing. Positive changes were found all groups for Fatigue Severity Scale, but not for Fatigue Impact Scale scores. Significant variations (p < 0.05) were observed in symptoms frequency. The olive tree-based food supplement and the gluten-free, FODMAP and low histamine diet had beneficial effects on the intensity of fibromyalgia symptoms. This short-time strategy may be used to improve fibromyalgia patient’s well-being.

Abstract According to the FAB and WHO classifications, the diagnosis of acute erythroid leukemia is based on the numbers of nucleated red blood cells and myeloid blasts in the bone marrow. The WHO classification recognizes two types of acute erythroid leukemia; M6A with 51–80% erythroid precursors and with 20% or more of the non-erythroid precursors being myeloid blasts; and M6B with more than 80% of the nucleated cells in the bone marrow consisting of erythroid precursors, regardless of the percentage of the myeloid blasts. Previous studies have shown that many cases of acute erythroid leukemia arise in patients with a history of myelodysplastic syndrome and in other cases acute erythroid leukemia is associated with significant dysplastic features. The significance of the number of erythroid precursors is not well known in the myelodysplastic syndromes. In the present study, we included 617 consecutive patients with low-grade myelodysplasia (482 patients with refractory anemia [RA] and 135 patients with refractory anemia with ringed sideroblasts [RARS]). Among this group, 82 patients with 50% or more of erythroid precursors had shorter survival compared with 535 patients with less than 50% erythroid precursors (P &lt; .01; Figure 1). The shorter survival in those with 50% or more of erythroid precursors may reflect the tendency of these patients to have worse International Prognostic Scoring System (IPSS) scores. Thus, among the patients with less than 50% erythroid precursors and primary MDS, 35% were IPSS low, 52% IPSS intermediate 1, and 13% IPSS intermediate 2. For the patients with 50% or more of erythroid precursors, the corresponding proportions were 14%, 57%, and 29%, respectively (P &lt; .001). As a result of the association between IPSS and the percentage of erythroid precursors, the percentage of erythroid precursors had no effect on survival within individual IPSS groups. Similarly, the percentage of erythroid precursors had no prognostic significance in patients with refractory anemia with excess blasts (RAEB) or chronic myelomonocytic leukemia (CMML). Our findings demonstrate that in low-grade dysplasia (RA and RARS) the number of erythroid precursors may represent an important prognostic marker. These findings implicate that the percentage of erythroid precursors should be considered in the classification of the low-grade myelodysplastic syndromes. A multivariate analysis will be performed to ascertain the relative effects of IPSS score and the percentage of erythroid precursors on prognosis in patients with low-grade myelodysplasia. Figure Figure

This narrative review provides a summary introduction to the relationship between stroke and physical and cognitive frailty syndromes and the neuro-inflammatory similarities (including inflammaging) between the two. The review argues the potential effects of Post COVID-19 Neurological Syndrome (PCNS, also known as Long COVID) with similar pathophysiology. Many patients who have suffered from acute stroke experience long-lasting symptoms affecting several organs including fatigue, brain fog, reduced physical activity, loss of energy, and loss of cognitive reserve, culminating in the loss of independence and poor quality of life. This is very similar to the emerging reports of PCNS from different parts of the world. Stroke, particularly in older adults with comorbidities appears to impact the health and welfare of patients by reducing central neuronal input and neuromuscular function, with muscular atrophy and neuropsychiatric complications. The cumulative effects can potentially lead to a range of physical and cognitive frailty syndromes, which, in many cases may be attributed to persistent, maladapted, low grade, chronic inflammation. Meanwhile, post-COVID-19 Neurological Syndrome (also known as Long COVID Syndrome) appears to share a similar trajectory, adding further urgency for investigations into the mechanisms underlying this constellation of symptoms.

Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.

Osteoarthritis (OA) is a musculoskeletal disease characterized by cartilage degeneration and stiffness, with chronic pain in the affected joint. It has been proposed that OA progression is associated with the development of low-grade inflammation (LGI) in the joint. In support of this principle, LGI is now recognized as the major contributor to the pathogenesis of obesity, aging, and metabolic syndromes, which have been documented as among the most significant risk factors for developing OA. These discoveries have led to a new definition of the disease, and OA has recently been recognized as a low-grade inflammatory disease of the joint. Damage-associated molecular patterns (DAMPs)/alarmin molecules, the major cellular components that facilitate the interplay between cells in the cartilage and synovium, activate various molecular pathways involved in the initiation and maintenance of LGI in the joint, which, in turn, drives OA progression. A better understanding of the pathological mechanisms initiated by LGI in the joint represents a decisive step toward discovering therapeutic strategies for the treatment of OA. Recent findings and discoveries regarding the involvement of LGI mediated by DAMPs in OA pathogenesis are discussed. Modulating communication between cells in the joint to decrease inflammation represents an attractive approach for the treatment of OA.

Objective. Description of clinical forms of chronic HCV infection in the observed patients, clarifications of options and causes of virological failures of primary interferon-free therapy (DAAT/1) and the results of repeated interferon-free treatment (DAAT/2).Materials and methods. 8 patients with chronic RNA HCV viremia (subtypes 1b+/–1a and 3а/3ab) were prospectively observed who suffered a virological failure of primary interferon-free therapy with original inhibitors in the form of relapse of RNA HCV viremia and aviremic low-level replication RNA HCV in PBMCs (peripheral mononuclears), but then achieved HCV eradication with a repeated course of interferon-free therapy.Results. Two variants of virological failures of primary interferon-free therapy were noted — relapse of RNA HCV viremia and aviremic low-level replication of RNA HCV in PBMCs. A number of unfavorable prognosis signs (individual clinical and laboratory syndromes and laboratory parameters) were revealed, which were observed in most patients who did not achieve HCV eradication using primary interferon-free therapy with antiviral drugs: HCV-associated syndromes of low-grade systemic inflammation (LGSI), benign lymphoproliferation and autoantibody production, a high level viral load of HCV RNA viral load in blood plasma, HBV-coinfection without HBsAg and cirrhosis of the liver in the outcome of chronic hepatitis C. The target result of repeated interferon-free therapy, confirmed by the sustainable virological response after 12 weeks after the end of the treatment (SVR12), was achieved in all «losers» of primary interferon-free therapy.Conclusion. The unfavorable prognostic signs identified in the majority of «losers» of primary interferon-free therapy in the form of individual clinical and laboratory syndromes and laboratory parameters may be associated with potential virological inefficiency of therapy. Based on logistic regression analysis, the value of each of the identified features for predicting different outcomes of primary interferon-free therapy in a large group of patients with HCV is shown. Pangenotypic combinations of GLE/PIB+SOF+/–RBV and VEL/SOF+RBV inhibitors have shown their high antiviral efficacy in the treatment of relapse of RNA HCV viremia and aviremic low-level replication of RNA HCV in peripheral mononuclears for all the patients for whom primary interferon-free therapy was unsuccessful.

Abstract Effective treatment options for patients with lower-risk myelodysplastic syndromes (MDS) are limited. However, around one-third of patients experience transformation to acute myeloid leukemia, and absent transformation, complications of chronic cytopenias (including infection), and iron-overload syndromes can be fatal. Although 5-azacitidine, decitabine, and lenalidomide have improved treatment options for patients with MDS, these are not routinely used in patients with lower-risk disease. Histone deacetylase (HDAC) enzymes are overexpressed in several tumor types including MDS, and regulate transcriptional and post-transcriptional processes. Vorinostat (Zolinza®) has been shown to inhibit class I and II HDAC enzymes, and has been approved by the FDA for the treatment of cutaneous manifestations of T-cell lymphoma in patients with persistent or recurrent disease, on or following 2 prior systemic therapies. Vorinostat induces cell-cycle arrest, apoptosis, or differentiation in a variety of cultured transformed cell lines, and has demonstrated activity against leukemias in in vivo non-clinical models and in phase I and II clinical trials. Efficacy data in these early phase trials prompted an investigation of vorinostat monotherapy in lower-risk MDS. The potency and tolerability of vorinostat suggest it may be effective in the treatment of MDS. Here, we report preliminary results of a randomized phase II study evaluating once-daily and three-times-daily (tid) intermittent dosing schedules of vorinostat in patients with low and intermediate-1 risk MDS. Primary objectives included assessment of the efficacy, safety, and tolerability of vorinostat. Eligible patients were aged ≥18 years, had either previously untreated disease, or were ≥4 weeks from any prior treatment regimen (including growth factors). Patients’ performance status was ≤2 on the ECOG performance scale, they had adequate organ function, and were either red blood cell transfusion dependent or had a hemoglobin level of ≤11g/dL at the time of screening, or had platelets ≤100 × 109/L at the time of screening. Eligible patients were assigned to 1 of 2 oral dosing regimens: vorinostat 400 mg daily or vorinostat 200 mg tid. Treatment was administered over a 21-day cycle (14 days’ therapy and 7 days’ rest), with patients receiving up to 8 cycles, or until the patient experienced unacceptable toxicity, disease progression, or withdrew consent. In total, 18 patients (12 male, 6 female; mean age 67.4 years) have been randomized, including 5 with low-risk MDS and 13 with intermediate-1 risk MDS, as defined by the International Prognostic Scoring System. Of the patients enrolled, 12 (3 low-risk and 9 intermediate-1 risk MDS) were evaluable for response and have received between 2 and 6 cycles of treatment. Stable disease has been reported in all 12 patients, with a reported duration of between 22–146 days (low-risk MDS) and 1–136 days (intermediate-1 risk MDS). A total of 11/18 (61%) patients have discontinued, 2 due to adverse events (1 event of grade 4 neutropenia [unrelated to study medication] and 1 event of grade 3 neuropathy [drug related]), 1 due to deviation from protocol, 4 due to lack of efficacy, 3 due to physician decision, 1 due to progressive disease, and 1 because of withdrawal of consent. Most adverse events were gastrointestinal disorders: diarrhea in 10 patients (7 grade 1, 3 grade 2), nausea in 9 patients (6 grade 1, 3 grade 2), and vomiting in 6 patients (5 grade 1, 1 grade 2). Grade 4 neutropenia, anemia, and thrombocytopenia were observed in 2, 1, and 1 patients, respectively; however these were unrelated to study medication. Data from this study indicate that vorinostat administered in a 21-day cycle has acceptable safety and tolerability.

Abstract The outcome of severe aplastic anemia, refractory to immunosuppressive therapy or observed in case of Fanconi anemia (FA), is usually poor in the absence of Hematopoietic Stem Cell Transplantation (HSCT). Umbilical cord blood is an alternative stem cell source for patients without matched related or unrelated donors. However, single cord blood unit is associated with high transplant related mortality due to the low cell dose infused in previous highly transfused patients. We have driven the hypothesis that double cord blood transplantation (dCBT) could circumvent the cell dose problem. For the purpose of this study, we have studied 13 patients with bone marrow failure syndromes given 2 partially matched dCBT from 2004 to 2007. The diagnoses were FA (n=9), SAA (n=4) and PNH (n=1). Among those patients, 5 (39%) received a dCBT as a rescue of previous rejected transplants (2 SAA and 3 FA). All patients received a fludarabine-based regimen, with TBI (2 Gy) for 4 patients. Cord blood units were a 4/6 or 5/6 HLA A, B and DR match with the patient except one which was 3/6. Graft versus host disease (GVHD) prophylaxis consisted in CSA+MMF. Steroids were given from day 7 to day 14 and stopped in case of no GVHD. Five male (39%) and 8 female (61%) with a median age of 16 years (range 7–31) were treated. The cell doses infused were a median of 5.0 × 107 NC/Kg (4–9) and 5.3 × 105 CD34+ cells/Kg (2–8). Graft rejection was seen in 5 patients (2 previously allotransplanted). Among those patients, one displayed a temporary mixed chimerism before rejection and another presented an autologous reconstitution. Among the remaining 8 patients, the median time to an absolute neutrophils count &gt; 500 was 25 days (range 14–42) and the median time to a platelet count &gt; 20,000 was 39 days. In these last patients, we observed a complete donor chimerism with one cord blood unit during 100 days after dCBT. Acute GVHD grade II–III was scored in 9 patients (69%) (7 grade II, 2 grade III). No patients presented acute GVHD grade IV. Four patients out of 8 developed Chronic GVHD (3 limited and 1 extensive). Four patients died (1 GVHD, 2 fungal infection, 1 thrombotic microangiopathy). With a median follow-up of 13 months (range 1 to 19 months), the overall survival was 55% (±15%) for all patients. The median survival of patients who were transplanted twice was 50% (±25%). In conclusion, dCBT seems to be an option to treat patients with bone marrow failure syndromes and without a suitable compatible HLA donor. Those results need to be established on a large number of patients to warrant the inclusion of dCBT in the treatment strategy of diseases with high risk of rejection.

Abstract The value of prolonged administration of arsenic trioxide (ATO) was examined in patients (pts) with MDS and CMML. ATO (0.25 mg/kg) was given intravenously over 1 hour daily for five days followed by 0.25 mg/kg twice weekly for 11 weeks. Pts were assessed at 4 weeks, at the end of the first course, and then monthly. Pts with stable disease were eligible for further courses. The study included 14 RBC transfusion-dependent MDS pts (6 RA/RARS, 8 RAEB; 12 IPSS risk Low/Int1, 2 Int2/High), and 3 CMML pts. Median age was 67 years (range 46–84). Six pts had a history of previous treatment other than supportive care. 16 pts were evaluable for toxicity and response. One pt received 3 courses, 3 received 2 courses, and 13 received 1 course. Hematologic responses (IWG criteria) were observed in 4 pts (25%) and 9 (6 MDS,3 CMML) had stable disease: FAB Type of response Time to response Duration RA Minor erythroid 2 months 3 mo, RBC independence RAEB Major neutrophil and platelet 2 mo 3 mo RAEB BM blast decrease 18% to &lt;5% 1 mo 14 mo, stable pancytopenia RAEB Hematologic/cytogenetic CR 1 mo 6 mo Hematologic/cytogenetic CR was achieved in one pt: a 76 year old male, RAEB-2, Int 2, complex chromosomal abnormalities, who had previously failed thalidomide for 6 months and thalidomide + cyclosporin A for 3 months. Of the 3 CMML pts, one had transient reduction of absolute monocyte counts during each of 2 courses; all 3 had stable disease. In 24 courses there were 6 febrile episodes in 4 patients, requiring admission, all in pts with pre-existing neutropenia; 1 Grade 3 and 1 Grade 4 thrombocytopenia, 1 Grade 3 neutropenia, all requiring dose modification; 1 episode of accelerated functional cardiac rhythm; and 1 anemia-precipitated congestive heart failure, which was unlikely related to the drug. There were 22 episodes of Grade 1 or 2 drug-related toxicities. Four responses of 3–7+ mo. duration were observed, including 1 CR, suggesting activity in an as yet undefined subgroup of MDS pts. No benefit of prolonged treatment was documented. ATO was safe in this outpatient setting for elderly patients. Observed low toxicity and documented activity support future trials of ATO in combination with other agents in treatment of MDS.

ABSTRACT: This research generated a formal method for global ‘situation modelling’ of near-critical and critical phenomena. The new paradigms and the construction of mental reality or social spaces do not explain the damaged world we leave to our children and the degeneration of health. The ‘physical’ was explored experimentally through the reputed imperfection of the body in daily living and the ecology of its health. An ‘integral’ methodology allowed combining this with a study of general perspectives in many fields. This theoretical and empirical study was framed according to a third-order logic: (1) The variety and inconsistency of perspectives on the unclear notion of ‘health’ required a generalist (meta-)classification or organising principle applicable in particular to health. The method of ‘perspectival analysis’ is based on the field- and domain-specific vocabularies, number of categories, and image types used in formulating explanation/ experience in each framework, in both scientific and human domains. This theoretical study was (2) grounded in a ‘radical empirical’ study of the effects of nutrition and healing techniques on a low-grade chronic syndrome (not life threatening but connected to stress, inflammation, swelling, tissues wasting). A ‘local-case’ experimental research design (representative of an aspect of health), and new topographic ‘gauging’ techniques were devised to observe small spatial changes (positioning, distortion, distribution). The results and concrete/ practice models led to the same conclusion as the abstract study: all our perspectives on health, body and space, have some underlying systemic form, and have in common two unifying frames – duality and polarisation –, characteristic also of point-set theory derived frameworks. Using them allows ‘circumnavigating’ the essential of all possible perspectives, without becoming lost in their details. However, they leave non-local effects, anomalies (or ’bad behaviour’) and periodical instability unexplained. (3) These were investigated by studying behaviour (irrespective of whether internal or external), and ‘not well understood’ induced health manifestations, and by mapping their topologic properties of small deformation through (a) a ‘local’ cognitive consideration of experience construction, the research process itself, and the intellectual skill of model-making, (b) etymologic studies to track forward semantic developments and perspectival shifts and inversions, (c) a graphic study of the universal symbolic forms in models, traditions, and dreams, tracing them back to ‘world-origin’ models (appearance/occurrence), and shape-icons (mental, cultural), such as tree, ladder, mountain or vortex-vertex spiral. This thesis examines health disturbance, physical distortions and cultural deformations, their usual descriptions as timed changes, and shows how two fundamental parameters of direction and motion (or movement, energy, 'Wind') define geometries of binding, or directional activation (or active projection). These culturo-mental geometries produce generic images of locally induced phenomena, and represent boundary phenomena globally as 'natural' in the spatial-physical world, and as 'hidden' or latent in the human world. Their downside is to introduce systematic instability in our expressions, models of culture/civilisation, as well as in health manifestations. All these are found to be rooted in modelling styles derived from the 'local' geometry of observing – framing – a field in 'perspective', mostly based on vision, audition, and skin surface (touch). These geo-Metries are used to explain and justify in particular the instability and recurrent crises of health in chronic syndromes and ageing, and the ‘badly behaved’ health of childhood and adult females (eg consequences of pregnancy). The conclusion imposed itself that the ‘physical world of humans’ is shaped through critical response and boundaries, and it appears that physical integrity, including sound health, sanity and even safety, cannot be preserved but by conscious alert attention or voluntary practice or effort (eg ‘workout’). Some experiences recounted in this work (some from the literature) led to an opposite presupposition. Three possible logics rule deployments of perspective into flat, spherical, and hyperbolic geometries (a known basis of mathematics). Which is used depends on the ‘local’ state of criticality (sense of urgency, emergency, pressure) of the observing body-brain-‘system’. It correlates with this universally assumed vertical axis, with the exclusive use [instruments too] of the senses of the head and of ‘skin-encapsulated’ derived systemic definitions of ‘the world’ and ‘the observer’ (self or body). These allow localising and attributing properties to one or the other or their combination. However, they can also be considered as undifferentiated properties, ‘non-local’ but governing, of the ‘physical world of humans’ as it is apprehended in daily living, manifesting in a surface-related sense of swelling and gravity. A simple form of geometric topology ‘without hole’ (without discontinuity), here introduced through two cognitive experiments, animations, and images, can describe this. The method of ‘nexial-topology’ produces an ‘animated imaging’ that can be used to model (but not ‘represent’ in word, number, or realistic/ naturalistic images) the situation reaching ‘critical boundary’. It then shows auto-reinforcing self-organisation and auto-destruction in ‘passing’ it. Yet, it can also be used as a ‘native gauging’ expressed in gesture or body posture, related to intuition, instinct, and the rare ‘thinking in image’. As such, it describes approaching ‘critical boundary’ (versus ‘reaching’) as auto-limiting. A crucial finding is that ‘spontaneous’ behaviours (non-induced, non-intended) can ensure the integrity of health under operation in most conditions, and stop extremes. Yet, they are usually deemed meaningless, random or useless, and are systematically suppressed by enculturation and prevented by civilised lifestyles. ‘Nexial-topology’ gives a clear meaning to them, and can model the ‘ease’ of health and of daily living. It gives access to more basic options, with wider effects, more immediate than all our solutions, often ignored because too obvious. For example, ‘global warming’ could be addressed as a non-local property and a deployment into crises to ‘stop’, rather than separate problems of water, resources, heated behaviour, inflammatory and ‘water diseases’. KEYWORDS: Interdisciplinary research, cross-disciplinary methodologies, modal logic, fundamental problem, general relativity, localisation, physicalism, geometric quantization, occurrence, appearance, extension, projection, attribution, distributed, anthropic principle, anthropomorphism, unified, unbounded, left, right, spiral, viral, genetic drift, natural, life, human nature, human pressure, limit, extreme, threshold, validity, value, critical decision making, apperception, child cognition, sense, semantic drift, Four Elements, symbolic inversion. THIS IS A MULTI-MEDIA THESIS. FOR A SITE MAP OF THE NAMES AND DISPLAY ONLINE OF THE 52 FILES OF THIS THESIS, PLEASE CONSULT THE SECTION: ORGANISATION OF THE MULTI-MEDIA MATERIALS IN THIS THESIS, IN THE FRONT PAGES FILE (SOURCE 2), BEFORE THE TABLE OF CONTENTS.

ABSTRACT: This research generated a formal method for global ‘situation modelling’ of near-critical and critical phenomena. The new paradigms and the construction of mental reality or social spaces do not explain the damaged world we leave to our children and the degeneration of health. The ‘physical’ was explored experimentally through the reputed imperfection of the body in daily living and the ecology of its health. An ‘integral’ methodology allowed combining this with a study of general perspectives in many fields. This theoretical and empirical study was framed according to a third-order logic: (1) The variety and inconsistency of perspectives on the unclear notion of ‘health’ required a generalist (meta-)classification or organising principle applicable in particular to health. The method of ‘perspectival analysis’ is based on the field- and domain-specific vocabularies, number of categories, and image types used in formulating explanation/ experience in each framework, in both scientific and human domains. This theoretical study was (2) grounded in a ‘radical empirical’ study of the effects of nutrition and healing techniques on a low-grade chronic syndrome (not life threatening but connected to stress, inflammation, swelling, tissues wasting). A ‘local-case’ experimental research design (representative of an aspect of health), and new topographic ‘gauging’ techniques were devised to observe small spatial changes (positioning, distortion, distribution). The results and concrete/ practice models led to the same conclusion as the abstract study: all our perspectives on health, body and space, have some underlying systemic form, and have in common two unifying frames – duality and polarisation –, characteristic also of point-set theory derived frameworks. Using them allows ‘circumnavigating’ the essential of all possible perspectives, without becoming lost in their details. However, they leave non-local effects, anomalies (or ’bad behaviour’) and periodical instability unexplained. (3) These were investigated by studying behaviour (irrespective of whether internal or external), and ‘not well understood’ induced health manifestations, and by mapping their topologic properties of small deformation through (a) a ‘local’ cognitive consideration of experience construction, the research process itself, and the intellectual skill of model-making, (b) etymologic studies to track forward semantic developments and perspectival shifts and inversions, (c) a graphic study of the universal symbolic forms in models, traditions, and dreams, tracing them back to ‘world-origin’ models (appearance/occurrence), and shape-icons (mental, cultural), such as tree, ladder, mountain or vortex-vertex spiral. This thesis examines health disturbance, physical distortions and cultural deformations, their usual descriptions as timed changes, and shows how two fundamental parameters of direction and motion (or movement, energy, 'Wind') define geometries of binding, or directional activation (or active projection). These culturo-mental geometries produce generic images of locally induced phenomena, and represent boundary phenomena globally as 'natural' in the spatial-physical world, and as 'hidden' or latent in the human world. Their downside is to introduce systematic instability in our expressions, models of culture/civilisation, as well as in health manifestations. All these are found to be rooted in modelling styles derived from the 'local' geometry of observing – framing – a field in 'perspective', mostly based on vision, audition, and skin surface (touch). These geo-Metries are used to explain and justify in particular the instability and recurrent crises of health in chronic syndromes and ageing, and the ‘badly behaved’ health of childhood and adult females (eg consequences of pregnancy). The conclusion imposed itself that the ‘physical world of humans’ is shaped through critical response and boundaries, and it appears that physical integrity, including sound health, sanity and even safety, cannot be preserved but by conscious alert attention or voluntary practice or effort (eg ‘workout’). Some experiences recounted in this work (some from the literature) led to an opposite presupposition. Three possible logics rule deployments of perspective into flat, spherical, and hyperbolic geometries (a known basis of mathematics). Which is used depends on the ‘local’ state of criticality (sense of urgency, emergency, pressure) of the observing body-brain-‘system’. It correlates with this universally assumed vertical axis, with the exclusive use [instruments too] of the senses of the head and of ‘skin-encapsulated’ derived systemic definitions of ‘the world’ and ‘the observer’ (self or body). These allow localising and attributing properties to one or the other or their combination. However, they can also be considered as undifferentiated properties, ‘non-local’ but governing, of the ‘physical world of humans’ as it is apprehended in daily living, manifesting in a surface-related sense of swelling and gravity. A simple form of geometric topology ‘without hole’ (without discontinuity), here introduced through two cognitive experiments, animations, and images, can describe this. The method of ‘nexial-topology’ produces an ‘animated imaging’ that can be used to model (but not ‘represent’ in word, number, or realistic/ naturalistic images) the situation reaching ‘critical boundary’. It then shows auto-reinforcing self-organisation and auto-destruction in ‘passing’ it. Yet, it can also be used as a ‘native gauging’ expressed in gesture or body posture, related to intuition, instinct, and the rare ‘thinking in image’. As such, it describes approaching ‘critical boundary’ (versus ‘reaching’) as auto-limiting. A crucial finding is that ‘spontaneous’ behaviours (non-induced, non-intended) can ensure the integrity of health under operation in most conditions, and stop extremes. Yet, they are usually deemed meaningless, random or useless, and are systematically suppressed by enculturation and prevented by civilised lifestyles. ‘Nexial-topology’ gives a clear meaning to them, and can model the ‘ease’ of health and of daily living. It gives access to more basic options, with wider effects, more immediate than all our solutions, often ignored because too obvious. For example, ‘global warming’ could be addressed as a non-local property and a deployment into crises to ‘stop’, rather than separate problems of water, resources, heated behaviour, inflammatory and ‘water diseases’. KEYWORDS: Interdisciplinary research, cross-disciplinary methodologies, modal logic, fundamental problem, general relativity, localisation, physicalism, geometric quantization, occurrence, appearance, extension, projection, attribution, distributed, anthropic principle, anthropomorphism, unified, unbounded, left, right, spiral, viral, genetic drift, natural, life, human nature, human pressure, limit, extreme, threshold, validity, value, critical decision making, apperception, child cognition, sense, semantic drift, Four Elements, symbolic inversion. THIS IS A MULTI-MEDIA THESIS. FOR A SITE MAP OF THE NAMES AND DISPLAY ONLINE OF THE 52 FILES OF THIS THESIS, PLEASE CONSULT THE SECTION: ORGANISATION OF THE MULTI-MEDIA MATERIALS IN THIS THESIS, IN THE FRONT PAGES FILE (SOURCE 2), BEFORE THE TABLE OF CONTENTS.
Doctor of Philosophy (PhD)

碩士
嘉南藥理科技大學
生物科技系暨研究所
95
Polycystic ovary syndrome (PCOS) is a common endocrinologic disease in women. It will increase the risks of cardiovascular disease, insulin resistance and diabetes. The symptoms are including hyperinsulinemia, ovulatory dysfunction, hyperandrogenism, infertility and abortion. At present, the first line treatment for PCOS is the use of insulin sensitizer or combined with clomiphene. The studies about the use of metformin in PCOS are well-documented, recently. In addition, metformin will improve the severity of metabolic syndrome and decrease the complication. In genetic study, there are gene polymorphism in insulin receptor that will result in the occurrence of this disease, especially in the change of insulin receptor substrate-1 (IRS-1). The polymorphism in IRS-1 (Gly972Arg) will lead to the occurrence of insulin resistance, and type II diabetes and reflect low-grade chronic inflammation. The laboratory data in women with PCOS demonstrated several significant changes: (1)(Gly/Arg) group of Body weight : pre-tx 63.70 ± 14.00 kg, post-tx 62.12 ± 13.76 kg; (2)(Gly/Arg) group of the HOMA-IR: pre-tx 10.21±10.72,post-tx 4.44±2.86，(3)(Gly/Gly) group of the soluble vascular adhesion molecule-1 (sVCAM-1), the marker of low-grade chromic inflammation, decreased significantly from pre-tx421.81±133.68 decrease to post-tx 331.32±118.31(ng/ml). Elevated serum levels of sVCAM-1 has been associated with the severity of insulin-resistant states, and the higher level of sVCAM-1 might increase the risk of diabetes and potentially changes those may lead to cardiovascular disease. Herein, in this study we have distinguished these different phenotypes on the basis of their endocrine and metabolic features and their circulating markers of CV risk, and correlate to IRS-1 polymorphism. The results showed the benefits of using metformin to PCOS patients. It still needs more cases to clarify the relationship between IRS gene polymorphism after metformin use in PCO women.

Haematological malignancies examines the epidemiology, genetics, clinical presentation and classification of these diseases, and presents current treatment approaches for each. First are the acute leukaemias, and the management of acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Chronic myeloid leukaemia, its genetics and sensitivity to tyrosine kinase inhibitors, is described. Myelodysplastic syndromes and their management, are followed by chronic lymphoid leukaemias, a large heterogeneous group of diseases, and their treatment. Hodgkin lymphoma, its pathology and presentation, staging and role of PET scanning, is described along with current treatment with chemotherapy and limited radiotherapy. Non-Hodgkin lymphoma is another heterogeneous group of diseases, divided into low-grade and high-grade pathology, and varying in their genetics, presentation, and management. Rituximab is a key component of chemotherapy regimens against B-cell lymphoma. Myeloma and other plasma cell dyscrasias are described, and treatment options reviewed. Myeloma remains incurable, but with appropriate management consistent with prolonged good quality life. Treatment includes chemotherapy, bisphosphonate therapy, analgesics and radiotherapy, Throughout this chapter is emphasised the importance of clinical trials in driving the rapid improvements in treatment of these diseases.

Chronic tubulointerstitial nephropathies (CTINs) are a group of renal diseases, characterized by variable interstitial inflammation and fibrosis and tubular atrophy, and a slow course towards end-stage renal disease (ESRD). The causes of CTIN are numerous, including nephrotoxic drugs and chemicals, infections, autoimmune diseases, obstructive uropathies, and metabolic disorders. Taken together, CTIN are responsible for less than 10% of all ESRD cases requiring renal replacement therapy. The clinical manifestations of CTIN typically comprise low-grade proteinuria, leucocyturia, and variably reduced glomerular filtration rate (GFR), whereas the blood pressure is usually normal or moderately increased. Tubular abnormalities are common, including type 2 (proximal) renal tubular acidosis, Fanconi syndrome, nephrogenic diabetes insipidus, and type 1 (distal) renal tubular acidosis, with hypokalaemia and nephrolithiasis. Radiology exams reveal shrunken kidneys, sometimes with irregular outlines. A renal biopsy is often required for the diagnosis of CTIN and its aetiology. The treatment of CTIN mainly involves discontinuation of exposure to nephrotoxins and specific therapy of renal infections, urinary tract obstruction, or underlying systemic diseases. Agents like ACE inhibitors and pirfenidone, which might reduce interstitial inflammation and fibrosis, are still under clinical evaluation.

The chronic form of drug-induced tubulointerstitial nephritis (CTIN) is an insidious disease and most probably represents the common final response pattern of the kidney to a variety of agents (including analgesics, lithium, antineoplastic chemotherapeutic agents, like cisplatin and nitrosoureas, and immunosuppressive drugs, such as ciclosporin and tacrolimus). Drug-induced CTIN is usually asymptomatic, presenting with slowly progressive renal impairment. Because of its insidious nature, CTIN is often diagnosed incidentally on routine laboratory screening or evaluation of CKD. The diagnosis of drug-induced CTIN largely depends on the history of exposure to a nephrotoxic drug. Clinical investigations may show modest elevation in serum creatinine, evidence of tubular dysfunction (e.g. renal tubular acidosis), or Fanconi syndrome (i.e. aminoaciduria, glycosuria, hypophosphataemia, and hypouricaemia). Urinalysis may be normal or show low-grade proteinuria (< 1.5 g/day) and/or pyuria. Diagnosis depends on renal biopsy, which reveals variable cellular infiltration of the interstitium, tubular atrophy, and fibrosis. Analgesic nephropathy is possibly still the most common category of CTIN worldwide. The amount of phenacetin-acetaminophen combination required to cause CTIN has been estimated to be at least 2–3 kg over many years. Lithium-induced CTIN occurs in a small subset of patients receiving long-term lithium therapy, who have had repeated episodes of lithium toxicity, with high serum drug levels. CTIN induced by ciclosporin or tacrolimus is common among patients receiving kidney, heart, liver, and pancreas transplants. The mechanism appears to be dependent largely on the potent vasoconstrictive effects of these drugs. The recognition of a potential association between a patient’s renal disease and exposure to a drug is crucial, because, unlike many other forms of renal disease, drug-induced CTIN can be prevented and even reversed, by avoiding additional drug exposure.

AbstractAlthough chronic lymphocytic leukaemia (CLL) was one of the first two entities in which CAR-T cells were evaluated, it has not yet arrived in the clinical routine. Since the landmark study by Porter et al. (2011), only six CLL-specific clinical trials have been published, altogether comprising no more than 155 patients (Porter et al. 2015; Gill et al. 2018; Turtle et al. 2017; Gauthier et al. 2020; Siddiqi et al. 2020; Wierda et al. 2020; Frey et al. 2020). All six of these studies investigated CD19-directed CAR-T constructs in heavily pretreated patients, mostly having failed BTKi+/− venetoclax therapy. Despite overall response rates of 60–95%, including MRD clearance in a large proportion of patients, the CR rates appear to be relatively low, and only a few durable responses have been reported in patients achieving a CR (Porter et al. 2015; Frey et al. 2020; Cappell et al. 2020). While toxicity includes 5–20% grade 3 cytokine release syndrome and 5–25% grade 3 neurotoxicity and appears manageable, long-term efficacy remains an unresolved issue. CLL-specific efficacy barriers for CD19 CAR-T cells could include a reduced capacity for sustained T cell expansion in extensively pretreated elderly CLL patients (Lemal and Tournilhac 2019), along with impaired T cell motility, impaired T cell mitochondrial fitness, and T cell exhaustion (Bair and Porter 2019). Concurrent use of ibrutinib might reduce the CRS rate and severity (Gauthier et al. 2020; Gill et al. 2018; Wierda et al. 2020) without impairing CAR-T cell expansion.

The term thrombocytosis refers to a platelet count elevated above 450 × 10⁹/litre, which can be (1) primary—including essential thrombocythaemia, chronic myeloid leukaemia, polycythaemia vera, and myelodysplastic syndromes; or (2) secondary—including iron deficiency, infection, blood loss, and malignancy. Essential thrombocythaemia: aetiology—the JAK2 V617F missense mutation typical of polycythaemia vera is found in about 50% of cases. In addition, 10% of patients have a mutation in the thrombopoietin receptor gene, MPL, and 30% have a mutation in calreticulin (CALR). Approximately 10% of patients have none of these mutations and are referred to as ‘triple negative’ essential thrombocythaemia. Diagnosis requires all of the following four major criteria: (1) platelet count greater than 450 × 10⁹/litre; (2) bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei without a significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibres; (3) failure to meet the criteria for other myeloproliferative neoplasms; and (4) presence of JAK2, CALR, or MPL mutations. Alternatively, diagnosis can be met when the first three major criteria are present and the one minor criterion, namely the presence of another clonal marker or absence of evidence for reactive thrombocytosis. Treatment requires risk stratification based on the age of the patient and any prior history of thrombosis, with treatment being reserved for those at a high risk of developing complications and not introduced simply on the basis of platelet counts alone unless there is extreme thrombocytosis (>1500 × 10⁹/litre). Therapies include low-dose aspirin and cytoreduction.

This chapter covers tumours of the haemopoietic system. Hodgkin lymphoma: clinical features, diagnosis, and staging, treatment of early and advanced stages, management of recurrence, and long-term toxicities and fertility issues are discussed. It outlines current treatment strategies that aim to maintain the high cure rates reached for all stages of the disease with chemotherapy and radiotherapy while further improving outcome and minimizing or preventing therapy-induced complications, such as infertility, cardiopulmonary toxicity, and second malignancies. For non-Hodgkin lymphoma, the clinical features, treatment of low-grade disease, diffuse large B-cell lymphoma, mantle cell lymphoma, cutaneous non-Hodgkin lymphomas, and extranodal involvement are discussed. Diagnosis with molecular profiling is used to define and stratify approaches to treatment for adult acute lymphoblastic leukaemia; adult acute myeloid leukaemia; chronic myeloid leukaemia; chronic lymphocytic leukaemia; hairy cell leukaemia; myelodysplastic syndrome; multiple myeloma; solitary plasmacytoma; monoclonal gammopathy of undetermined significance; smouldering myeloma; Waldenstrom’s macroglobulinaemia; amyloidosis and POEM syndrome; heavy chain disease; and histiocyte disorders.

Adipocyte expansion, which involves adipose tissue-derived mesenchymal stem cells (ASCs), is a critical process with implications in the pathogenesis of metabolic syndrome and insulin resistance associated with obesity. Impaired subcutaneous adipogenesis leads to dysfunctional, hypertrophic adipocytes, chronic low-grade inflammation, and peripheric insulin resistance. Alternatively, it has also been proposed that the preservation of the functionality of subcutaneous adipocyte precursors could contribute to some obese individuals remaining metabolically healthy. Very few studies evaluated the changes in the adipogenic differentiation for human subcutaneous ASCs following bariatric surgery. Weight loss after bariatric surgery involves extensive remodeling of adipose tissue, comprising the hyperplasia-hypertrophy balance. Subcutaneous ASCs may be implicated in the variations of bariatric outcomes, through a different restoration in their proliferative and adipogenic potential. Weight loss induced by bariatric surgery correlates to the subcutaneous ASC functions and could explain the variability of metabolic improvement. Limited research data are available to the present and these data support the importance of diagnosis of subcutaneous ASCs functions as predictors of metabolic improvement after bariatric surgery.

Brachycephalic obstructive airway syndrome (BOAS) is a conformation-related respiratory disorder of dog breeds with congenitally flattened facial and skull anatomy. BOAS is characterized by chronic shortness of breath and subsequent difficulty in exercising, a tendency to overheat, increased and abnormal respiratory noise, and low oxygen levels. The aim of our retrospective study was to inves-tigate the level of red blood cell distribution width (RDW), a biomarker of chronic hypoxemia, in groups of BOAS patients with different degrees of BOAS and a group of healthy non-brachycephalic dogs. Red blood cell distribution width provides information on the variability in the red blood cell volume. It is a simple and inexpensive variable included in the complete blood count report. Seventy-two BOAS patients and 24 non-brachycephalic dogs were included in this retrospective study. Pa-tients with BOAS were classified into grade 1 (13 dogs), grade 2 (27 dogs), and grade 3 (32 dogs) according to the severity of the disease. In our study, a significantly (p < 0.05) higher RDW was found in all groups of BOAS patients compared to the non-brachycephalic dog group. However, we found no significant difference in RDW between the groups of BOAS patients. Thus, we may conclude that BOAS patients have increased variability in the size of red blood cells compared with healthy non-brachycephalic dogs. Our results warrant further studies to determine the potential utility of RDW in BOAS and to clarify the role of RDW in BOAS patients in relation to the severity of BOAS and cardiovascular risk. Keywords: Brachycephaly; Brachycephalic obstructive airway syndrome; Dogs; Haematology; Erythrocytes; Red blood cell distribution width

Review question / Objective: The aim of this study was to conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) in order to properly examine the evidence on the effects of walnut consumption on chosen indicators of inflammation and metabolic syndrome in mature adults. Condition being studied: Metabolic syndrome (MetS), chronic, low-grade inflammation, and oxidative stress are all important risk factors for morbidity and death, with a higher frequency in the elderly population. Information sources: We conducted a comprehensive search in five databases: Pubmed, EMBASE, Scopus, Cochrane, ClinicalTrials, from inception.

Review question / Objective: To provide the essential findings in the field of overlap syndrome of chronic obstructive pulmonary disease and obstructive sleep apnea, including prevalence, possible predictors, association with clinical outcomes, and severity compared to both chronic obstructive pulmonary disease and obstructive sleep apnea patients. Condition being studied: OSA is characterized by complete cessation (apnea) or significant decrease (hy-popnea) in airflow during sleep and recurrent episodes of upper airway collapse cause it during sleep leading to nocturnal oxyhemoglobin desaturations and arousals from rest. The recurrent arousals which occur in OSA lead to neurocognitive consequences, daytime sleepiness, and reduced quality of life. Because of apneas and hypopneas, patients are experiencing hypoxemia and hypercapnia, which result in increasing levels of catecholamine, oxidative stress, and low-grade inflammation that lead to the appearance of cardio-metabolic consequences of OSA. COPD is a chronic inflammatory lung disease defined by persistent, usually pro-gressive AFL (airflow limitation). Changes in lung mechanics lead to the main clini-cal manifestations of dyspnea, cough, and chronic expectoration. Furthermore, patients with COPD often suffer from anxiety and depression also, the risk of OSA and insomnia is higher than those hospitalized for other reasons. Although COPD is twice as rare as asthma but is the cause of death eight times more often.