Current Problems of the Diagnostics and Treatment of Sepsis and Burn Injuries: The Modified Pathogenetic Concept

Background: The deep understanding of pathogenesis is a key moment in the formation of the modern strategy of modern medicine. We conducted the thorough analysis of the microscopic processes occurring in the bodies of patients with purulent-septic complications. The modified pathogenetic concept of the diagnostic and treatment model of diseases with septic complications is presented. The obtained information about the mechanisms of origin and development of these diseases is fundamentally important for finding the modern effective methods of treating patients. The aim of the research is to modify treatment tactics for patients with sepsis and burn injuries based on the modified pathogenetic concept using modern diagnostics, i.e. the method of fluorescence spectroscopy (MFS) and biomarkers. Materials and Methods: The proposed modified pathogenetic concept of the diagnostic and treatment model of diseases with purulent-septic complications along with standard methods was used successfully for effective treatment of 15 patients with sepsis and 25 with burn injuries. Results: 3 main scenarios of behaviour of spectral-fluorescence characteristics of patients with sepsis are illustrated. Spectral-fluorescence markers of sepsis were studied, which are informative 24 to 48 hours before the appearance of obvious clinical and laboratory signs of significant changes in the general somatic status of patients. Conclusions: The proposed diagnostic and therapeutic approach is new and fundamentally important for diagnostics and monitoring of the process of treatment of patients with purulent-septic diseases and burn injuries. An in-depth understanding of the dynamics of septic complications and the corresponding changes of the main markers of these diseases during treatment is especially relevant. The use of infusion therapy with solutions of donor albumin as an effective pathogenetic treatment is scientifically justified.

Infectious burden and atherosclerosis: A clinical issue

Atherosclerotic cardiovascular diseases, chronic inflam-matory diseases of multifactorial etiology, are the lead-ing cause of death worldwide. In the last decade, more infectious agents, labeled as "infectious burden", rather than any single pathogen, have been showed to con-tribute to the development of atherosclerosis through different mechanisms. Some microorganisms, such as Chlamydia pneumoniae(C. pneumoniae), human cytomegalovirus, etc. may act directly on the arterial wall contributing to endothelial dysfunction, foam cell formation, smooth muscle cell proliferation, platelet ag-gregation as well as cytokine, reactive oxygen specie, growth factor, and cellular adhesion molecule produc-tion. Others, such as Helicobacter pylori(H. pylori), in-fluenza virus, etc. may induce a systemic inflammation which in turn may damage the vascular wall(e.g., by cytokines and proteases). Moreover, another indirect mechanism by which some infectious agents(such as H. pylori, C. pneumoniae, periodontal pathogens, etc.) may play a role in the pathogenesis of atherosclero-sis is molecular mimicry. Given the complexity of the mechanisms by which each microorganism may con-tribute to atherosclerosis, defining the interplay of moreinfectious agents is far more difficult because the pro-atherogenic effect of each pathogen might be ampli-fied. Clearly, continued research and a greater aware-ness will be helpful to improve our knowledge on the complex interaction between the infectious burden and atherosclerosis.

Acute respiratory distress syndrome and lung injury: Pathogenetic mechanism and therapeutic implication

To review possible mechanisms and therapeutics for acute lung injury(ALI) and acute respiratory distress syndrome(ARDS). ALI/ARDS causes high mortality. The risk factors include head injury, intracranial disorders, sepsis, infections and others. Investigations have indicated the detrimental role of nitric oxide(NO) through the inducible NO synthase(i NOS). The possible therapeutic regimen includes extracorporeal membrane oxygenation, prone position, fluid and hemodynamic management and permissive hypercapnic acidosis etc. Other pharmacological treatments are anti-inflammatory and/or antimicrobial agents, inhalation of NO, glucocorticoids, surfactant therapy and agents facilitating lung water resolution and ion transports. β-adrenergic agonists are able to accelerate lung fluid and ion removal and to stimulate surfactant secretion. In con-scious rats, regular exercise training alleviates the endotoxin-induced ALI. Propofol and N-acetylcysteine exert protective effect on the ALI induced by endotoxin. Insulin possesses anti-inflammatory effect. Pentobarbital is capable of reducing the endotoxin-induced ALI. In addition, nicotinamide or niacinamide abrogates the ALI caused by ischemia/reperfusion or endotoxemia. This review includes historical retrospective of ALI/ARDS, the neurogenic pulmonary edema due to head injury, the detrimental role of NO, the risk factors, and the possible pathogenetic mechanisms as well as therapeutic regimen for ALI/ARDS.

Hepatitis C virus-related mixed cryoglobulinemia: Is genetics to blame?

Mixed cryoglobulinemia(MC)is the extrahepatic manifestation most strictly correlated with hepatitis C virus(HCV)infection;it is a benign autoimmune and lymphoproliferative disorder that evolves to lymphoma in5%-10%of cases.MC is reputed to be a multistep and multifactorial process whose pathogenicity is still poorly understood.It is still unknown why only some chronically infected HCV patients develop MC and only some of these exhibit systemic symptoms(MC syndrome).Several studies have investigated the pathogenetic basis of MC and the most recent ones suggest that the virus is able to trigger such a disorder only in the presence of genetic factors that are still unknown.Here,we try to clarify the complex relationship between HCVrelated MC and the host’s genetic background.The data that we report are heterogeneous and sometimes even conflicting.Therefore,large,multicenter studies are clearly needed.The identification of a characteristic genetic signature of cryoglobulinemic patients would be an important step toward a personalized approach in their clinical care.The new wide-ranging genomics technologies will hopefully help to resolve these complex issues.

Discussion on the TCM Treatment of Hypertension from Pathogenetic Viewpoints of Modern Medicine

The ideal hypotensive agent should possess three essentials, i.e. to depress the blood pressure surely and steadily, and to block the renin-angio-tensin system (RAS)(1). Currently, Western medical treatment could depress the blood pressure rapidly and surely through reducing blood volume and dilating blood vessels, while traditional Chinese medicine (TCM) shows its superiorities in al-

THERAPY FOR CANCER—METHODS AND SUGGESTIONS

On the basis of the theory of Traditional Chinese Medicine,authors put forwathe etiopathogenesis and pathogenetic mechanism of solid tumors,and formulated a scheme for tre^ment of cancer with acupuncture therapy.

Symptomatic and pathogenetic treatment of diabetic neuropathy Role of alpha-lipoic acid

Diabetic neuropathy, the most common form of peripheral neuropathy, presents as different forms of focal or diffuse neuropathy, including the disabling, or potentially life-threatening clinical entities of painful diabetic neuropathy, autonomic neuropathy, and diabetic foot. The pathogenesis of diabetic neuropathy results from the concurrent action of various intersecting factors of nerve damage, such as oxidative stress and mitochondrial dysfunction, inflammation, microangiopathy and ischemia, triggered by hyperglycemia and related biochemical changes. Symptomatic treatment of diabetic neuropathy mainly concerns therapies for neuropathic pain, interventions targeted at the organ systems involved in autonomic neuropathy, and management of diabetic foot. Therapeutic approaches to the pathogenesis of diabetic neuropathy have focused on the different components of the causes of nerve damage, particularly oxidative stress, which has been demonstrated to play a central role. Alpha-lipoic acid, a potent lipophilic free radical scavenger, has been used in treatment of patients with diabetic neuropathy, displaying efficacy on the chief symptoms, including neuropathic pain, and showing that neuropathic deficits may be improved by treatment. Current evidence suggests a possible efficacy of alpha-lipoic acid not only for neuropathic symptoms, but also for reducing the risk factors for diabetic neuropathy.

Roles of Serum Amyloid A 1 Protein Isoforms in Rheumatoid Arthritis

Secondary amyloid A amyloidosis,a lethal complication,is induced when acute or chronic infection coexists with over-secretion of the serum amyloid A 1(SAA1)protein and deposition in key internal organs.Previously,using the whole-exome sequencing method,we identified a novel deleterious mutation SAA1.2 in rheumatoid arthritis(RA)patients.However,the role of SAA1 in RA pathogenesis and its complications remains unknown.The purpose of this study was to determine the pathogenetic roles of SAA1 protein isoforms in RA progression.We modified an experimental adenovirus infection protocol to introduce SAA1.2 gene alleles into the knee joints of mice and used SAA1.3 and SAA1.5 as controls.Microcomputed tomography analysis was applied to determine changes in bone morphology and density.Immunohistochemical(IHC)analysis,flow cytometry,enzyme-linked immunosorbent assay(ELISA),and real-time polymerase chain reaction(RT-PCR)were used to investigate disease progression and cytokine alterations in the course of adenoviral SAA-induced knee joint inflammation and bone destruction.We found that the arthritis-inducing effect of SAA1.2 transcription in the knee joints and mutant SAA1 protein secretion in blood resulted in the stimulation of immune responses,leading to CD8^(+)T cell and pro-inflammatory cytokine elevation,such as interleukin(IL)-6,IL-22,matrix metalloproteinase(MMP)-3,MMP-9,with subsequent synovial inflammation and bone destruction.These findings indicate that SAA1 protein isoforms,particularly SAA1.2,play a significant role in the induction and progression of RA and may have potential value in the early diagnosis and severity prediction of RA.

Association of neuroelectrophysiology and analysis of cerebrospinal fluid immunoglobulin with pathogenetic conditions of patients with Guillain-Barre syndrome

BACKGROUND： Guillain-Barre syndrome （GBS） is an autoimmune disease which is characterized by demyelination of peripheral nerve and nerve root, and inflammatory reaction of lymphocyte and macrophage. Neuroelectrophysiological examination and cerebrospinal fluid （CSF） analysis are of significance for its diagnosis. OBJECTIVE： To study the association of neuroelectrophysiology and cerebrospinal fluid immunoglobulin （CSF-lg） with pathogenetic conditions of patients with GBS. DESIGN： Case control study SETTING： Department of Neurology, Shenzhen Municipal Shekou Group Hospital; Department of Neuroelectrophysiology, People＇s Hospital of Guangdong Province. PARTICIPANTS： A total of 32 GBS patients including 18 males and 14 females who aged from 17 to 72 years were selected as experimental group from the Department of Neurology, People＇s Hospital of Guang- dong Province from January 2004 to December 2005. All cases conformed with GBS diagnostic criteria established by Asbury in 1990 and they were divided into three types according to neurological criteria established by Chinese Neurology and Psychology Journal in 1993： mild, moderate and severe types. Another 30 patients with vascular headache were selected as control group from the same hospital including 14 males and 16 females who aged from 17 to 79 years. METHODS： ① Neuroelectrophysiological examination： Multiple-functional electromyography device provided by Nicolet Company, USA was used to measure nerve conduction velocity （NCV）, including motor nerve conduction velocity （MCV） and sensory nerve conduction velocity （SCV）; meanwhile, electromyologram （EMG）, somatosensory evoked potential （SEP） and electroencephalogram （EEG） were also measured. ② Detection of CSF-lg： Concentrations of IgG, IgA and IgM were measured with immunofixation electrophoresis. ③Follow-up： Among 32 GBS patients, 14 cases received follow-up after treatment and the longest fol- low-up time was 1 year after onset. Among them, 8 cases were reexaminined with neuroelectrophysiological and CSF examinations. MAIN OUTCOME MEASURES： Results of NCV, EMG, SEP and EEG; comparison of CSF-lg content; results of follow-up examinations. RESULTS： All 32 GBS cases and 30 patients with vascular headache were involved in the final analysis. ① Abnormal rate of neuroelectrophysiological test： 75% of NCV, 88% of F-wave, 53% of MCV, 25% of SEP, 47% of EMG and 31% of EEG. There were no significant differences among various types （P 〉 0.05）. ② Results of CSF-lg test： There were no significant differences among various types （P 〉 0.05）; however, abnormalities in experimental group was higher than those in control group （P 〈 0.01）. CONCLUSION ： Results of follow-up study suggest that improvement of clinical symptom is earlier than neuroelectrophysiological recovery; MCV and EMG recoveries are faster than that of NCV; the earlier the abnormality of EMG, the poorer the recovery. CSF4g recovers normally along improvement of clinical symptoms. It is of significance for neuroelectrophysiology and abnormality of CSF-Ig to determine degree of peripheral nerve demyelination and prognosis.

Pandemic and modern medicine:Time to recognize and correct previous misconceptions

A sudden increase in the number of viral pneumonias with the onset of the COVID-19 pandemic revealed defects in the provision of medical care for acute pneumonia in the lungs.Localization of the inflammatory process and its functional consequences indicate the identity of all forms of acute pneumonia,regardless of the etiology,and the need to develop treatment principles based on the pathogenesis of the disease.

Genetics and pathophysiology of mammalian sulfate biology

Nutrient sulfate is essential for numerous physiological functions in mammalian growth and development. Accordingly, disruptions to any of the molecular processes that maintain the required biological ratio of sulfonated and unconjugated substrates are likely to have detrimental consequences for mammalian physiology. Molecular processes of sulfate biology can be broadly grouped into four categories： firstly, intracellular sulfate levels are maintained by intermediary metabolism and sulfate transporters that mediate the transfer of sulfate across the plasma membrane; secondly, sulfate is converted to 3＇-phosphoadenosine 5＇-phosphosulfate （PAPS）, which is the universal sulfonate donor for all sulfonation reactions; thirdly, sulfotransferases mediate the intracellular sulfonation of endogenous and exogenous substrates; fourthly, sulfate is removed from substrates via sulfatases. From the literature, we curated 91 human genes that encode all known sulfate transporters, enzymes in pathways of sulfate generation, PAPS synthetases and transporters, sulfotransferases and sulfatases, with a focus on genes that are linked to human and animal pathophysiology. The predominant clinical features linked to these genes include neurological dysfunction, skeletal dysplasias, reduced fecundity and reproduction, and cardiovascular pathologies. Collectively, this review provides reference information for genetic investigations of perturbed mammalian sulfate biology.

Pathogenetic mechanism of senile calcific aortic stenosis:the role of apoptosis

Abstract Objective To investigate the pathogenetic mechanisms leading to the development of calcific degeneration of the aortic valve in the elderly patients with particular reference to the relationship between apoptosis and calcification in the aortic valve tissue. Methods High resolution scanning and transmission electron microscopic observations of the calcified aortic valves obtained during aortic valve replacement were carried out in 10 patients with senile calcific aortic stenosis. Results Various degrees of endothelial alterations from focal disruption of individual endothelial cells to extensive denudation of entire endothelium were observed particularly on the aortic side of the valve tissues. The apoptotic changes occurring in the nuclei of endothelial cells and fibroblasts were common findings in the calcified valve tissues. It was noteworthy that the severity of endothelial damage was closely related to apoptotic changes of the fibroblasts. Calcific deposits were frequently observed in association with the cellular fragments mainly derived from the apoptotic fibroblasts. Conclusions Our results strongly indicate that apoptosis may play an important role in the alterations of endothelial integrity leading to the increased filtration of calcium into the deeper layer of the valve tissues. Then, the cellular degradation products and organelles extruded from the dead cells, mainly resulted from apoptosis provided the substrates for calcium binding with progressive development of calcification in the valve tissue. Although the role of apoptosis in contribution to the pathogenesis of senile calcific aortic stenosis is evident, further studies using modern molecular biotechnology are mandatory in order to clarify the mechanism for the initiation of apoptotic process in the endothelial cells and fibroblasts.