Pathophysiological Body Reactivity and Interactions in Comorbidities. Synergism Versus Antagonism of Disease Pathways and Etiopathogenetic Clusters in Comorbidity Conditions.

Complexity, variability, nonlinearity and adaptive alterations in human health and disease are considered within the integral body physiology. Sokolic's principles and Koshland's pillars of life are referred as a conceptual frameworks for the whole-body performance. Disease pathways and etiopathogenetic clusters (EPCs) form networks. Due to EPCs, pathways and networks body reactivity gets reduced, and may lead to latent insufficiencies, a decompensation and death. Networking can be triggered by various etiologies. Overlapping of one disease network with the other simultaneous ones may lead to interferences of a disease development and manifestations. Comorbidity effects may be synergistic, and thus it leads to a more severe disease state. On the other side, antagonistic interaction of the two disease may lead to improvement and/or prevention. 20 comorbidities of each type are outlined in this paper.

Graphic Mapping of Clinical Disease Pathways Reveals a Complex Networking and Clustering Due to Natural Etiopathogenetic Interconnectivity.

Human physiology is a complex, nonlinear, self-regulated system, in which multiple functional subsystems act within the whole body reactivity. Understanding of physiology and pathophysiology requires integration of both clinical and basic factual knowledge and regulatory homeodynamic concepts. Two integrative methods have been developed to improve understanding of disease processes and natural development. Their features are here shortly presented. Matrix led algorhythmic analysis and re-synthesis puts together patients' clinical data along with a broad academic knowledge which may be relevant to it. Graphic representation enables outlining a multiple interconnections among etiopathogenetic components within the human body. The etiopathogenetic clusters (EPCs) are crossing points, the integrative hubs of disease pathways. Multiple diseases of triggered by independent etiologies often converge to a common EPC, and thus contributing to natural networking of physiological processes in health and diseases. Contemporary biomedical sciences have been daily producing copious amounts of data whose participation in integrative physiology is yet to be explored within the whole body reactivity. Graphic representation and active composition of pathophysiological processes stimulates a synthetic reasoning as a subroutine intellectual habit, critically relevant to both physicians and biomedical researchers. Integrative pathophysiology facilitates anchoring of a whole body and local etiopathogenetic mechanisms. This may be of special importance in contemporary trends of the intensive compartmentalization in medicine.

The Physician Versus the Scientist. An essay on differences between the medical practitioner and the biomedical researcher in their professional aims, methods, conceptual reasoning and mission.

The physician is the central figure in practical medicine. The biomedical researcher is the central figure in scientific investigation of biomedical phenomena. Both sides contribute to understanding of physiology of health and disease. In this paper, several epistemological, value-related attitudes, ethical and pragmatic differences between the two sides are outlined. Distinguished professional features stem out of differences in respective missions, education, methodology, ethical concerns and ways of reasoning. Clinical expertise is driven by benefits of the patient, whereas researcher expertise is driven by scientific curiosity towards more reliable knowledge. The eight operational and four cognitive/epistemological differences of scientific versus clinical expertise are shortly discussed. Those pairs of differences are not necessarily reducible to each other. Better understanding of these standpoints may be important for closer communications of two sides and their contributions to applicative and cognitive advancements of human physiology.

95th Anniversary of Pathophysiology in Croatia.

University level of Pathophysiology research and teaching in Croatia had started with the third year of Medical School of Zagreb in academic year 1919./20. Ever since, despite historical changes of the main university stake holder, the state of Croatia, Department of Pathophysiology development progressed and has made visible academic achievements, with a broader effect in medical community. The first 95 years of academic tradition and major achievements are shortly described in this paper. Professor Miroslav Mikulicic envisioned Pathophysiology in close relations with Pharmacology and made the pioneering steps of establishing the "double" department at Salata. His group was academically very pro-active, with strong international scientific participation and recruitment of professionals. The group published the first voluminous textbook of Pharmacology and Pathophysiology, in Croatian. In fifties, professor Pavao Sokolic established clinical pathophysiology within the Hospital Centre at Rebro. Out of "double" department two new departments were founded, the Pathophysiology one was completed with the clinical ward. That institutional move from Salata hill to the Rebro hill was a necessary gigantic step and a prerequisite for the proper further development. It was in accordance with the concept of the Mikulicic's program of Pathophysiology from 1917. Pavao Sokolic has been remembered for his visions, deep insights into etiopathogenesis, ability to transfer knowledge and friendly relations to students. Sharp intellectual power, emanating charisma, academic erudition and unique clinical competencies made the legendary image of the "Teacher" - as students used to refer to him with admiration. He was second to no one when complex patient issues were to be resolved. Clinical Hospital Centre Zagreb and his Department at Rebro have become a referral point to whom to go to despair. Students recognized in their Teacher the landmark of Croatian medicine, which made a lasting legacy on generations to come. Professor Stjepan Gamulin made molecular medicine the working reality at Rebro. Both in clinical research, and in health system as diagnostic service and tool for all centers in Croatia, molecular measurement in tissue samples came into usage in daily physicians reasoning and therapy prescriptions. Macromolecular aspects of disease have come of age and became clinimetric signs of patients' condition. Professor Gamulin with his group and associated authors wrote the textbook of pathophysiology, which in upcoming 30 years had 7 editions, has become the bestseller in medicine. The textbook was translated and published in English and Albanian. In the most recent book professor Gamulin turned the focus of medical community to clinical epidemiology and a need for retrospective insights into medical efficiency. Medical performance can be improved with the improvement of understanding of underlying etiopathogenetic relations as the foundation of therapy-is the main message. Following the academic legacy and spirit of three charismatic authorities we established two methods of teaching/learning in medicine. The two methods opened up a new avenue, so important for the era of postgenomic plethora of information and demands of precision/personalized medicine. Methodology has been introduced timely. It is student-friendly and usable for advanced types of education. Problem based algorhytmic matrices stimulate analysis and resynthesis of etiopathogenetic pathways. Graphic presentation of the solution integrates horizontal, vertical and longitudinal aspects of the problem. The companion textbook in the form of problem solver has been published in 3 editions, and contains 128 study solved cases. It was published in English, as well. Out of algorhythmic analysis the etiopathogenetic clusters (EPCs) are composed of etiopathogenetic pathway analysis. EPCs are natural units of disease development, the crossing points of processes. They are integrative hubs which tend to make networks of EPCs. Four volume textbook has been published, which elaborates 91 EPCs with 1165 study cases. Unique approach in the first 95 years was defined as Zagreb School of Pathophysiology. It made visible effect outside academia and recognizable image at the international level, in scientific, educational and practical aspects of activities.

Rho-kinase inhibitors protect against neonatal hyperoxia-induced airway hyperreactivity in a rat pup model: Role of prostaglandin F2α.

BACKGROUND: Oxygen therapy in preterm neonates is associated with airway hyperreactivity. The role of Rho/Rho-kinase smooth muscle signaling in hyperoxia-induced airway hyperreactivity remains understudied. We hypothesized that inhibition of Rho-kinase will attenuate airway hyperreactivity induced by neonatal hyperoxia. METHODS: Newborn rats were raised in hyperoxia (>95% O2 ) or ambient air (AA) for 7 days. Subgroups were injected with a Rho-kinase inhibitor: Y-27632 (10 mg·kg-1 ·day-1 ) or fasudil (10 mg·kg-1 ·day-1 ), or a FP receptor antagonist - AS604872 (30 mg·kg-1 ·day-1 ). After exposures, tracheal cylinders were prepared for in vitro wire myography. Contraction to methacholine or PGF2α was measured in the presence or absence of tissue-bath Y-27632, fasudil, or AS604872. Lung PGF2α levels, Rho-kinase protein level and Rho-kinase 1 activity were measured by ELISA. RESULTS: Tracheal smooth muscle contraction was significantly greater in hyperoxic compared to AA groups. Both, Y-27632 and fasudil significantly decreased contractility to MCh or PGF2α in hyperoxic groups versus hyperoxic controls (p < 0.001), but did not alter AA group responses. Inhibition of FP receptors attenuated responses to PGF2α . Hyperoxia significantly increased lung PGF2α compared to AA (p < 0.01), but Rho-kinase inhibition did not influence PGF2α level. Rho-kinase protein level (p < 0.001) and activity (p < 0.01), were increased by hyperoxia, but blockade of FP receptor reduced the Rho-kinase 1 activity (p < 0.05) under hyperoxic condition. CONCLUSIONS: This study demonstrates an active role of Rho/Rho-kinase signaling on hyperoxia-induced airway hyperreactivity. These findings suggest that Rho-kinase inhibitors might serve as an effective therapy for hyperoxia-induced airway hyperreactivity.

[Clinical and etiopathogenetic role of plasminogen and metaloproteinase systems in the tumor growth. Pericellular proteolysis of extracellular matrix and tumor growth]. / Klinicka i etiopatogenetska uloga plazminogenskoga i metaloproteinaznoga sustava u tumorskome rastu. Pericelularna razgradnja medustanicnoga matriksa i tumorski rast.

Pericellular proteolysis is a cascade process involved in degradation of extracellular matrix. This process is included in various physiological and pathological processes. Pericellullar proteolysis has major functions like degradation of tissue stroma and weakening of intercellular connections but it also has a function in the synthesis of bioactive molecules (cytokines, growth factors and inhibitory factors). Plasminogen system is involved in fibrinolysis and starts metalloproteinase activation. Activity of proteolytic molecules is controlled by the rate of zymogenic activation, half-life of molecules, and action of inhibitory molecules. Inhibition is achieved through direct binding of inhibitor and enzyme and takes a few steps. Pericellular proteolysis is involved in tumor invasion and metastasis, inflammatory reaction, degenerative diseases and other diseases. Pathophysiological regulation of pericellular proteolysis in mentioned diseases contributes to clinical properties of diseases and has diagnostic and therapeutic importance.

Prognostic value of circulating Bcl-2 and anti-p53 antibodies in patients with breast cancer: A long term follow-up (17.5 years).

BACKGROUND: Apoptosis inhibition is a major tumorigenic factor. Bcl-2 dysregulation and TP53 mutation status, which may correlate with autoantibody generation, contribute to impaired apoptosis. OBJECTIVE: This study aimed to investigate the prognostic value of circulating Bcl-2 and anti-p53 antibodies (p53Abs) in a 17.5-year follow-up of breast cancer patients. We also analyzed the correlations of Bcl-2 and p53Abs with various clinicopathological parameters in order to assess their impact on tumor aggressiveness. METHODS: Serum Bcl-2 and p53Abs levels were analyzed by the enzyme-linked immunosorbent assay (ELISA) in 82 patients with invasive breast cancer and twenty individuals without malignancy. RESULTS: Serum Bcl-2 and p53Abs levels in breast cancer patients were significantly higher than those in controls. Patients with high levels of Bcl-2 (cut-off 200 U/ml) had a poorer prognosis (17.5-year survival) than those with lower Bcl-2 values. In combined analysis the subgroup of patients with elevated p53Abs (cut-off 15 U/ml) and elevated Bcl-2 (cut-offs 124 U/ml and 200 U/ml) had the worse prognosis in 17.5-year survival. In correlation analysis p53Abs and Bcl-2 were associated with unfavorable clinicopathological parameters. CONCLUSIONS: Our results suggest that breast cancer patients with high serum levels of p53Abs and Bcl-2 present an especially unfavorable group in a long follow-up.

Non-linear actions of physiological agents: Finite disarrangements elicit fitness benefits.

Finite disarrangements of important (vital) physiological agents and nutrients can induce plethora of beneficial effects, exceeding mere attenuation of the specific stress. Such response to disrupted homeostasis appears to be universally conserved among species. The underlying mechanism of improved fitness and longevity, when physiological agents act outside their normal range is similar to hormesis, a phenomenon whereby toxins elicit beneficial effects at low doses. Due to similarity with such non-linear response to toxins described with J-shaped curve, we have coined a new term "mirror J-shaped curves" for non-linear response to finite disarrangement of physiological agents. Examples from the clinical trials and basic research are provided, along with the unifying mechanisms that tie classical non-linear response to toxins with the non-linear response to physiological agents (glucose, oxygen, osmolarity, thermal energy, calcium, body mass, calorie intake and exercise). Reactive oxygen species and cytosolic calcium seem to be common triggers of signaling pathways that result in these beneficial effects. Awareness of such phenomena and exploring underlying mechanisms can help physicians in their everyday practice. It can also benefit researchers when designing studies and interpreting growing number of scientific data showing non-linear responses to physiological agents.

[Pathophysiology of ischaemia-reperfusion injury]. / Patofiziologija ishemijsko-reperfuzijske ozljede.

Reperfusion of ischaemic tissue provides oxygen and substrates that are necessary for tissue recovery and concurrently removes toxic metabolites. However, reperfusion may induce various detrimental processes that may cause further tissue damage. Such deterioration of tissue function after reperfusion is defined as ischaemia-reperfusion injury. The consequences of ischemia-reperfusion injury vary from reversible cell dysfunction to local and remote tissue destruction, multiple organ failure and death. The pathogenesis of ischaemia-reperfusion injury is complex and includes excessive production of reactive oxygen species, activation of neutrophils, activation of complement, involvement of cytokines and other inflammatory mediators, vasoactive substances NO and endothelin. This review discusses the pathophysiology of ischaemia-reperfusion injury, the mechanisms of reactive oxygen species production, and the role of other factors in the pathogenesis of such injury. Several approaches and procedures used in pre-clinical and clinical studies in order to limit ischaemia-reperfusion injury are also presented.

Circulating cytokine levels in acute pancreatitis-model of SIRS/CARS can help in the clinical assessment of disease severity.

The aim of our study was to evaluate the pro- and anti-inflammatory cytokine response during acute pancreatitis and its predictive value on severity of disease. A hospital-based prospective clinical study was conducted. Twenty patients with acute pancreatitis were enrolled during a 12-month period. Plasma concentrations of TNF-α, IL-1ß, IL-6, and IL-10 were determined at days 1, 2, 3, 6, and 9. The patient population was analyzed by type of acute pancreatitis. Severity was defined according to the Atlanta criteria for assessing severity of acute pancreatitis. Clinical variables were recorded to patients classified in one of two groups: severe acute pancreatitis (SAP group) and mild acute pancreatitis (MILD group). Patients with SAP had significantly higher average levels of IL-6 compared to the MILD group patients (539.2 pg/L vs. 23.4 pg/L, p < 0.0001). Also, the values of IL-10 were significantly higher in patients with SAP (242.4 pg/L vs. 8.1 pg/L, p = 0.003). The values of TNF-α were not significantly different in both groups. The value of IL-6 and IL-10 showed a positive correlation (r = 0.7964, p < 0.0001). Although a relatively small sample of patients was used, we can conclude that the determination of the value of IL-6 and IL-10 can help in the clinical assessment of disease severity.

Prognostic significance of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) in patients with primary invasive ductal breast carcinoma - a 7.5-year follow-up study.

AIMS AND BACKGROUND: Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor (PAI-1) are key molecules in pericellular proteolysis, a process that plays an important role in tumor invasion and metastasis. In the current study we investigated the prognostic significance of uPA and PAI-1 in primary invasive breast cancer. METHODS AND STUDY DESIGN: uPA and PAI-1 antigen levels were determined by enzyme-linked immunosorbent assay in cytosols of 177 invasive ductal carcinoma specimens. The prognostic significance of uPA and PAI-1 was assessed for overall survival. The median follow-up time was 90 months. RESULTS: In univariate analysis, both uPA (third versus first tertile range of values; P = 0.02; HR = 2.08) and PAI-1 (third versus first tertile; P = 0.0007; HR = 3.1) were significant prognostic markers for overall survival. In multivariate analysis only nodal status (N2 vs N0; P = 0.0001; HR = 3.94) and PAI-1 (third versus first tertile; P = 0.004; HR = 3.05) remained significant independent prognostic factors. Both uPA and PAI-1 were correlated with established prognostic markers including histological grade, tumor size and Nottingham index. CONCLUSION: Our study with a 7.5-year follow-up confirmed the relation between elevated uPA and PAI-1 values and an aggressive course of invasive breast cancer. The prognostic significance of PAI-1 as an independent marker was proved for the overall group of breast cancer patients and the subgroup of node-positive patients.

Vitamin D status, dependence on age, and seasonal variations in the concentration of vitamin D in Croatian postmenopausal women initially screened for osteoporosis.

Vitamin D deficiency is associated with secondary hyperparathyroidism, increased bone turnover, and bone loss, leading to increased risk for osteoporotic fractures. The objective of this study was to investigate the prevalence of inadequate (insufficient or deficient) serum vitamin D levels in Croatian postmenopausal women initially screened for osteoporosis. Assessment of 25-hydroxyvitamin D (25(OH)D) was performed in 120 Croatian postmenopausal women aged > or =50 years. Three cut-off levels of vitamin D inadequacy were investigated: <75, <50, and <30 nmol/L. Among the included patients, only 14.2% of women complied with diagnostic criteria for osteoporosis. A total of nine (7.5%) had vitamin D levels greater than 75 nmol/L, suggesting that 92.5% of postmenopausal women had inadequate vitamin D status. The prevalence of two different cut-off point groups was 63.3% (<50 nmol/L) and 14.2% (<30 nmol/L). Mean (+/-SD) serum level of 25(OH)D was 46.94 (16.77) nmol/L. Vitamin D was exhibiting declining values with increasing age (r = -0.28; P = 0.002). The prevalence of vitamin D levels below 30 nmol/L was high in patient aged > or =65 years (23.8%). The highest mean level of vitamin D was detected in summer, with significant differences from spring and winter (P = 0.015 and P = 0.022, respectively). The results of this study indicate a high prevalence of vitamin D inadequacy in Croatian postmenopausal women initially screened for osteoporosis. High prevalence coupled with the rising recognition of potential clinical significance of the vitamin D inadequacy makes this highly interesting intervention target, suggesting that the attempts to increase the awareness on this issue are needed.

Macromolecular oxidation in anisotonic suspensions of mouse spleen cells.

Macromolecular oxidative alterations have been analysed in vitro in anisotonic suspensions of mouse splenocytes. Both hypertonicity and hypotonicity induced the generation of thiobarbituric acid reactive species (TBARS) and carbonylation of the proteins, which took place along with cell death. Addition of antioxidants partially inhibited oxidative changes in isotonic and hypotonic suspensions. Anisotonic shock of mouse splenocytes proved to be an inducer of oxidative stress. The oxidative macromolecular alterations might contribute to pathogenesis of cell death caused by osmotic stress.