Systematic review and meta-analysis of automated methods for quantifying enlarged perivascular spaces in the brain.

Research into magnetic resonance imaging (MRI)-visible perivascular spaces (PVS) has recently increased, as results from studies in different diseases and populations are cementing their association with sleep, disease phenotypes, and overall health indicators. With the establishment of worldwide consortia and the availability of large databases, computational methods that allow to automatically process all this wealth of information are becoming increasingly relevant. Several computational approaches have been proposed to assess PVS from MRI, and efforts have been made to summarise and appraise the most widely applied ones. We systematically reviewed and meta-analysed all publications available up to September 2023 describing the development, improvement, or application of computational PVS quantification methods from MRI. We analysed 67 approaches and 60 applications of their implementation, from 112 publications. The two most widely applied were the use of a morphological filter to enhance PVS-like structures, with Frangi being the choice preferred by most, and the use of a U-Net configuration with or without residual connections. Older adults or population studies comprising adults from 18 years old onwards were, overall, more frequent than studies using clinical samples. PVS were mainly assessed from T2-weighted MRI acquired in 1.5T and/or 3T scanners, although combinations using it with T1-weighted and FLAIR images were also abundant. Common associations researched included age, sex, hypertension, diabetes, white matter hyperintensities, sleep and cognition, with occupation-related, ethnicity, and genetic/hereditable traits being also explored. Despite promising improvements to overcome barriers such as noise and differentiation from other confounds, a need for joined efforts for a wider testing and increasing availability of the most promising methods is now paramount.

Brain washing and neural health: role of age, sleep, and the cerebrospinal fluid melatonin rhythm.

The brain lacks a classic lymphatic drainage system. How it is cleansed of damaged proteins, cellular debris, and molecular by-products has remained a mystery for decades. Recent discoveries have identified a hybrid system that includes cerebrospinal fluid (CSF)-filled perivascular spaces and classic lymph vessels in the dural covering of the brain and spinal cord that functionally cooperate to remove toxic and non-functional trash from the brain. These two components functioning together are referred to as the glymphatic system. We propose that the high levels of melatonin secreted by the pineal gland directly into the CSF play a role in flushing pathological molecules such as amyloid-ß peptide (Aß) from the brain via this network. Melatonin is a sleep-promoting agent, with waste clearance from the CNS being highest especially during slow wave sleep. Melatonin is also a potent and versatile antioxidant that prevents neural accumulation of oxidatively-damaged molecules which contribute to neurological decline. Due to its feedback actions on the suprachiasmatic nucleus, CSF melatonin rhythm functions to maintain optimal circadian rhythmicity, which is also critical for preserving neurocognitive health. Melatonin levels drop dramatically in the frail aged, potentially contributing to neurological failure and dementia. Melatonin supplementation in animal models of Alzheimer's disease (AD) defers Aß accumulation, enhances its clearance from the CNS, and prolongs animal survival. In AD patients, preliminary data show that melatonin use reduces neurobehavioral signs such as sundowning. Finally, melatonin controls the mitotic activity of neural stem cells in the subventricular zone, suggesting its involvement in neuronal renewal.

Giant tumefactive mesencephalothalamic Virchow-Robin space with triventricular hydrocephalus: a case-based systematic literature review.

BACKGROUND: The perivascular spaces of the brain are also known as Virchow-Robin spaces (VRSs). Dilated Virchow-Robin spaces in the brainstem are rare and mainly cause symptoms due to obstructive hydrocephalus, less frequently because of their size, mass effect, and impact on eloquent structures. CASE ILLUSTRATION: We present a patient with giant tumefactive VRS with hydrocephalus and neurological symptoms who was treated with endoscopic third ventriculostomy (ETV) followed by microscopic cyst fenestration. On the basis of this observation, we performed a thorough review of the literature to evaluate different treatment options. RESULTS: An 11-year-old girl presented with a headache for 3 months. The patient had a giant tumefactive mesencephalothalamic VRS with triventricular hydrocephalus. She was initially treated with endoscopic third ventriculostomy and multiple cyst fenestration. Symptomatic cyst regrowth required multiple cyst fenestrations via transcallosal transchoroidal (N = 2) and subtemporal approaches (N = 1) at the 2- and 4-year follow-ups. A literature review of these conditions allowed the detection of 12 cases (including our index case), and only 25% (3/12) of the patients underwent cyst fenestration 16.7% (2/12) required endoscopic fenestration and 8.3% (1/12) required microscopic fenestration. CONCLUSION: Giant mesencephalothalamic dVRSs are rare in the pediatric population. These patients are usually symptomatic due to obstructive hydrocephalus. Surgical options are endoscopic third ventriculostomy, ventricular shunt procedures, or direct cyst fenestration (microscopic or endoscopic). Close follow-up is mandatory owing to the risk of progression of the disease. Cyst fenestration resolves symptoms immediately, as it addresses both hydrocephalus and mass effects due to the cystic lesion in the same setting.

Pathogenesis of Cerebral Small Vessel Disease: Role of the Glymphatic System Dysfunction.

Cerebral small vessel disease (CSVD) is a group of pathologies that affect the cerebral blood vessels. CSVD accounts for 25% of strokes and contributes to 45% of dementia. However, the pathogenesis of CSVD remains unclear, involving a variety of complex mechanisms. CSVD may result from dysfunction in the glymphatic system (GS). The GS contains aquaporin-4 (AQP-4), which is in the perivascular space, at the endfeet of the astrocyte. The GS contributes to the removal of waste products from the central nervous system, occupying perivascular spaces and regulating the exchange and movement of cerebrospinal fluid and interstitial fluid. The GS involves astrocytes and aquaporin channels, which are components of the blood-brain barrier, and problems with them may constitute the pathogenesis of CSVD. Vascular risk factors, including diabetes, dilate the perivascular space, disrupting the glymphatic system and the active regulation of AQP-4. CSVD exacerbation due to disorders of the GS is associated with multiple vasculopathies. Dysfunction of the glymphatic system and AQP-4 interferes with the functioning of the blood-brain barrier, which exacerbates CSVD. In a long-term follow-up of CSVD patients with microbleeds, lacunar infarcts, and white matter hyperintensity, several vascular risk factors, including hypertension, increased the risk of ischemic stroke. Dysfunction of the GS may be the cause of CSVD; however, the underlying treatment needs to be studied further.

Rudolph Virchow's Upper Silesia report: the starting point for his simultaneous engagement with public health and antisemitism.

In 2023 an important anniversary took place. It regards Virchow's report on the Upper Silesia epidemic typhus, which was associated with the death of numerous Polish peasants. It is also the starting point of Virchow's political career and fight against antisemitism, which has reached fearful levels in academia. Antisemitism is not new, but the recrudescence following the October 7th massacre of Jewish and not-Jewish people is appalling and recalls Virchow's vehemence of the past a few decades before the Nazi extermination of the Shoah during the World War II.

[History of the study of amyloidosis: from the Rokitansky's theory to the present day].

In the history of amyloidosis studying the concept of liquids dyscrasia has been predominated and finally it is resulted in accepting a serum protein-precursor as a leading amyloidogenic factor in the disease pathogenesis. Consequently basic diagnostic and treatment strategy was aimed to find and eliminate this protein from the blood and this approach evidenced high effectiveness in most frequent AA and AL-amyloidosis characterized with anomaly high levels of precursors in the blood. At the same time there are less frequent and slower progressing inheritant forms of systemic amyloidosis including transthyretin induced, which are less depending on amyloidogenecity of amyloid precursor and because of that, in example, the effectiveness of transthyretin stabilizers or blockers of its synthesis is limited comparing with the precursor elimination in AA or AL. Developed in the middle of XX century a theory of local synthesis by macrophages is more preferable to describe the pathogenesis of these forms. And modern proteome analysis using give rise to confirm the key meaning of macrophage in the amyloidogenesis and proves necessity to know deeply mechanisms of macrophagial autophagia - basic tool of maintaining intracellular protein homeostasis. That is why it is difficult to hope on high effectiveness of chemical amyloid solvents in vivo, which being under macrophages regulation never could realize its chemical activities.

Automated Methods for Detecting and Quantitation of Enlarged Perivascular spaces on MRI.

The brain's glymphatic system is a network of intracerebral vessels that function to remove "waste products" such as degraded proteins from the brain. It comprises of the vasculature, perivascular spaces (PVS), and astrocytes. Poor glymphatic function has been implicated in numerous diseases; however, its contribution is still unknown. Efforts have been made to image the glymphatic system to further assess its role in the pathogenesis of different diseases. Numerous imaging modalities have been utilized including two-photon microscopy and contrast-enhanced magnetic resonance imaging (MRI). However, these are associated with limitations for clinical use. PVS form a part of the glymphatic system and can be visualized on standard MRI sequences when enlarged. It is thought that PVS become enlarged secondary to poor glymphatic drainage of metabolites. Thus, quantitating PVS could be a good surrogate marker for glymphatic function. Numerous manual rating scales have been developed to measure the PVS number and size on MRI scans; however, these are associated with many limitations. Instead, automated methods have been created to measure PVS more accurately in different diseases. In this review, we discuss the imaging techniques currently available to visualize the glymphatic system as well as the automated methods currently available to measure PVS, and the strengths and limitations associated with each technique. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.

Unilateral subcortical extensive dilated perivascular spaces associated with superior sagittal sinus perivenous dilated spaces.

We present the MRI of a 70-year-old patient showing unilateral subcortical extensive dilated perivascular spaces with surrounding fluid-attenuated inversion recovery hyperintensities associated with the presence of small cysts and tubular hypointensities in and near the superior sagittal sinus co-locating with draining cortical veins on gadolinium-enhanced T1-weighted imaging representing probably (dilated) spaces between pial sheath and cortical vein walls. These (peri)venous superior sagittal sinus cysts seem to represent either hydrops cause (by blocking interstitial fluid flow in perivenous subpial space, via meningeal lymphatics) or consequence (where cysts might have been formed due to subpial fluid flow obstruction by unknown cause).

Dilated Virchow Robin spaces in brainstem.

Virchow Robin spaces are normally found pial-lined perivascular spaces traversing from subarachnoid space to the brain parenchyma. Giant dilated Virchow robin spaces (dVRS) are rare. They do not require any surgical intervention unless they are causing symptoms. Here we report a young boy with an incidentally detected giant dVRS in brainstem which was referred for surgery with an initial impression of glioma. Knowledge about such an entity is important to prevent mismanagement.

Melatonin in ventricular and subarachnoid cerebrospinal fluid: Its function in the neural glymphatic network and biological significance for neurocognitive health.

The central nervous system (CNS) is endowed with a specialized cerebrospinal fluid (CSF)/lymph network which removes toxic molecules and metabolic by-products from the neural parenchyma; collectively, this has been named the glymphatic system. It allows CSF located in the subarachnoid space which surrounds the CNS to enter the depths of the brain and spinal cord by means of Virchow-Robin perivascular and perivenous spaces. CSF in the periarterial spaces is transferred across the astrocytic end feet which line these spaces aided by AQ4 channels; in the interstitium, the fluid moves via convection through the parenchyma to be eventually discharged into the perivenous spaces. As it passes through the neural tissue, the interstitial fluid flushes metabolic by-products and extracellular toxins and debris into the CSF of the perivenous spaces. The fluid then moves to the surface of the CNS where the contaminants are absorbed into true lymphatic vessels in the dura mater from where it is shunted out of the cranial vault to the cervical lymph nodes. Pineal melatonin released directly into the CSF causes the concentration of this molecule to be much higher in the CSF of the third ventricle than in the blood. After the ventricular melatonin enters the subarachnoid and Virchow-Robin spaces it is taken into the neural tissue where it functions as a potent antioxidant and anti-inflammatory agent. Experimental evidence indicates that it removes pathogenic toxins, e.g., amyloid-ß and others, from the brain to protect against neurocognitive decline. Melatonin levels drop markedly during aging, coincident with the development of several neurodegenerative diseases and the accumulation of the associated neurotoxins.

The blood-CSF-brain route of neurological disease: The indirect pathway into the brain.

The brain is protected by the endothelial blood-brain barrier (BBB) that limits the access of micro-organisms, tumour cells, immune cells and autoantibodies to the parenchyma. However, the classic model of disease spread across a disrupted BBB does not explain the focal distribution of lesions seen in a variety of neurological diseases and why lesions are frequently adjacent to the cerebrospinal fluid (CSF) spaces. We have critically reviewed the possible role of a blood-CSF-brain route as a disease entry pathway into the brain parenchyma. The initial step of this pathway is the transfer of pathogens or immune components from the blood into the CSF at the choroid plexuses, where the blood-CSF barrier (BCSFB) is located. The flow of CSF results in disease dissemination throughout the CSF spaces. Access to the brain parenchyma from the CSF can then occur across the ependymal layer at the ventricular surface or across the pial-glial barrier of the subarachnoid space and the Virchow-Robin spaces. We have reviewed the anatomy and physiology of the blood-CSF-brain pathway and the brain barriers controlling this process. We then summarised the evidence supporting this brain entry route in a cross-section of neurological diseases including neuromyelitis optica, multiple sclerosis, neurosarcoidosis, neuropsychiatric lupus, cryptococcal infection and both solid and haematological tumours. This summary highlights the conditions that share the blood-CSF-brain pathway as a pathogenetic mechanism. These include the characteristic proximity of lesions to CSF, evidence of disruption of the brain barriers and the identification of significant pathology within the CSF. An improved understanding of pathological transfer through the CSF and across all brain barriers will inform on more effective and targeted treatments of primary and secondary diseases of the central nervous system.

Small and Large Magnetic Resonance Imaging-Visible Perivascular Spaces in the Basal Ganglia of Parkinson's Disease Patients.

BACKGROUND: Although previously thought to be asymptomatic, recent studies have suggested that magnetic resonance imaging-visible perivascular spaces (PVS) in the basal ganglia (BG-PVS) of patients with Parkinson's disease (PD) may be markers of motor disability and cognitive decline. In addition, a pathogenic and risk profile difference between small (≤3-mm diameter) and large (>3-mm diameter) PVS has been suggested. OBJECTIVE: The aim of this study was to examine associations between quantitative measures of large and small BG-PVS, global cognition, and motor/nonmotor features in a multicenter cohort of patients with PD. METHODS: We performed a cross-sectional study examining the association between large and small BG-PVS with Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Parts I-IV and cognition (Montreal Cognitive Assessment) in 133 patients with PD enrolled in the Ontario Neurodegenerative Disease Research Initiative study. RESULTS: Patients with PD with small BG-PVS demonstrated an association with MDS-UPDRS Parts I (P = 0.008) and II (both P = 0.02), whereas patients with large BG-PVS demonstrated an association with MDS-UPDRS Parts III (P < 0.0001) and IV (P < 0.001). BG-PVS were not correlated with cognition. CONCLUSIONS: Small BG-PVS are associated with motor and nonmotor aspects of experiences in daily living, while large BG-PVS are associated with the motor symptoms and motor complications. © 2022 International Parkinson and Movement Disorder Society.

Sleep and perivascular spaces in the middle-aged and elderly population.

Sleep has been hypothesised to facilitate waste clearance from the brain. We aimed to determine whether sleep is associated with perivascular spaces on brain magnetic resonance imaging (MRI), a potential marker of impaired brain waste clearance, in a population-based cohort of middle-aged and elderly people. In 559 participants (mean [SD] age 62 [6] years, 52% women) from the population-based Rotterdam Study, we measured total sleep time, sleep onset latency, wake after sleep onset and sleep efficiency with actigraphy and polysomnography. Perivascular space load was determined with brain MRI in four regions (centrum semiovale, basal ganglia, hippocampus, and midbrain) via a validated machine learning algorithm using T2-weighted MR images. Associations between sleep characteristics and perivascular space load were analysed with zero-inflated negative binomial regression models adjusted for various confounders. We found that higher actigraphy-estimated sleep efficiency was associated with a higher perivascular space load in the centrum semiovale (odds ratio 1.10, 95% confidence interval 1.04-1.16, p = 0.0008). No other actigraphic or polysomnographic sleep characteristics were associated with perivascular space load in other brain regions. We conclude that, contrary to our hypothesis, associations of sleep with perivascular space load in this middle-aged and elderly population remained limited to an association of a high actigraphy-estimated sleep efficiency with a higher perivascular space load in the centrum semiovale.

[Morphological characteristics of the brain nervous tissue during aging]. / Morfologicheskaya kharakteristika nervnoi tkani golovnogo mozga pri starenii.

OBJECTIVE: Identification of morphological manifestations and evaluation of morphometric parameters of the nervous tissue in various structures of the human brain during aging. MATERIAL AND METHODS: Autopsy material was obtained from patients whose causes of death were not associated with neurological diseases. Three age groups were studied: young (35-45 years old) (n=10); eldery (75-89 years old) (n=20); centenarians (over 90 years old) (n=10). Quantitative analysis of large neurons in the compact part of the substantia nigra, basal ganglia, layer V of the cortex, and the pyramidal layer of the hippocampus was carried out. In addition, the brain mass, the thickness of the cortex of the precentral gyrus were measured, the glial index was calculated, and the morphological signs of age-related involution of the brain tissue and intracerebral vessels were assessed. RESULTS: In senile and centenarians, compared with young people, there was a progressive reduction in large neurons of layer V of the cortex, basal ganglia, the pyramidal layer of the hippocampus and substantia nigra, a decrease in brain mass and thickness of the cortex of the precentral gyrus, as well as an increase in the glial index. Changes in blood vessels characteristic of aging are described. Also, during aging, signs characteristic of neurodegeneration were found. CONCLUSION: The results of the study confirm that such brain structures as the cortex of the precentral gyrus, the hippocampus, the basal ganglia, and the substantia nigra lose large neurons with age, followed by the development of gliosis. The identified morphological changes characteristic of aging are phenomenologically similar to a certain set of morphological changes in neurodegenerative diseases of late age.

Perivascular spaces and brain waste clearance systems: relevance for neurodegenerative and cerebrovascular pathology.

Perivascular spaces (PVS) of the brain, often called Virchow-Robin spaces, comprise fluid, cells and connective tissue, and are externally limited by astrocytic endfeet. PVS are involved in clearing brain waste and belong to the "glymphatic" system and/or the "intramural periarterial drainage" pathway through the basement membranes of the arteries. Related brain waste clearance systems include the blood-brain barrier, scavenger cells, cerebrospinal fluid, perineural lymphatic drainage pathways and the newly characterised meningeal lymphatic vessels. Any functional abnormality of PVS or related clearance systems might lead to accumulation of brain waste. It has been postulated that PVS enlargement can be secondary to accumulation of ß-amyloid. Lack of integrity of the vascular wall, microbleeds, cerebral amyloid angiopathy (CAA) and enlarged PVS often occur in the preclinical stages of Alzheimer's disease, preceding substantial brain atrophy. PVS enlargement in the form of état criblé at the basal ganglia has also been considered to reflect focal atrophy, most probably secondary to ischaemic injury, based upon both pathological and imaging arguments. In addition, distinct topographic patterns of enlarged PVS are related to different types of microangiopathy: CAA is linked to enlarged juxtacortical PVS, whereas subjects with vascular risk factors tend to have enlarged PVS in the basal ganglia. Therefore, enlarged PVS are progressively being regarded as a marker of neurodegenerative and cerebrovascular pathology. The present review addresses the evolving concept of PVS and brain waste clearance systems, the potential relevance of their dysfunction to neurodegenerative and cerebrovascular pathology, and potential therapeutic approaches of interest.

Subependymal hyperintense layer on CISS sequence: An MRI study.

PURPOSE: The present study aimed to explore the subependymal layers overlying the cerebral ventricles using magnetic resonance imaging. METHODS: A total of 69 outpatients underwent constructive interference in steady-state (CISS) sequence in thin-sliced, coronal, and sagittal sections. RESULTS: The subependymal layers were delineated as linear hyperintensities, coursing along the outer margins of the ventricular walls. On coronal images, the hyperintensities surrounding the anterior horn of the lateral ventricle were identified in 97% of patients, while those of the third ventricle were identified in 96% of patients. In the trigone and posterior horn of the lateral ventricle, the hyperintensities were delineated in all patients. On sagittal images, subependymal hyperintensities were identified in all. At the level of the anterior horn and third ventricle, the subependymal hyperintensities were found to communicate with the Virchow-Robin spaces (VRSs) in 68% and 65% of patients, respectively. At the level of the trigone and posterior horn of the lateral ventricle, the VRSs communicated with the subependymal hyperintensities in 83% of patients. CONCLUSIONS: Subependymal hyperintensity may represent an inflow passage of the VRSs that jointly contribute to efficient transependymal migration of the interstitial fluid into the ventricular cerebrospinal fluid.

Hypomelanosis of Ito presenting with unilateral dilation of Virchow-Robin spaces: a case report.

Hypomelanosis of Ito is a rare heterogeneous neurocutaneous disorder often associated with central nervous and musculoskeletal system involvement. Herein, we report the first case of hypomelanosis of Ito in the literature presenting with unilateral dilation of Virchow-Robin spaces (VRS). A girl aged 16 years old presented with a 1-year history of headache. Her physical and neurological examinations were normal, except for the presence of unilateral cutaneous macular hypopigmented whorls and streaks on lower side of the right trunk and lower limb, termed as Blaschko's lines. She had mild deficits in cognitive and adaptive functioning. Hearing, renal, dental, ophthalmologic, metabolic, and cardiac assessments were normal. Brain magnetic resonance imaging (MRI) showed markedly unilateral hemispheric enlarged VRS without contrast enhancement and diffusion restriction. To the best of our knowledge, our case is the first report describing the unilateral hemispheric enlarged VRS in a patient with hypomelanosis of Ito. Our report suggested that hypomelanosis of Ito may have unilateral dilation of VRS in brain MRI.

Chronic kidney disease correlates with MRI findings of cerebral small vessel disease.

Objective: Cerebral small vessel disease (CSVD) and chronic kidney disease (CKD) may be part of a multisystem small-vessel disorder. Since the kidney and brain share unique susceptibilities to vascular injury, kidney impairment may be predictive of the presence and severity of CSVD. This study explored the relationship between CSVD and CKD. Methods: Between December 2015 and December 2017 (follow-up 10-20 months) 52 patients with chronic nephritis and CKD were classified into a progressive group (n = 17) and stable group (n = 35). Age, gender, hypertension, diabetes and smoking were matched between groups. CSVD features of both groups, including enlarged Virchow-Robin spaces (VRS), white matter lesions (WML), lacunar infarcts (LI), and cerebral microbleeds (CMB) were evaluated by magnetic resonance (MR) imaging. Results: WML and CMB in the progressive group were exacerbated at follow-up compared to initial exam (p = 0.004 and 0.041, respectively). There was no significant change in VRS, WML, LI, or CMB in the stable group at follow-up compared to initial exam. CMB were significantly different between the progressive group and stable group at follow-up.etimtaed Glomerular filtration rate (eGFR) was significantly correlated with VRS, WML, and CMB at follow-up (p = 0.037, 0.041, and 0.009, respectively). Conclusions: Patients with progressive CKD have a higher prevalence and severity of CSVD, which correlates with deterioration of renal function as assessed by decreased eGFR. Thus EGFR may also be of value in the prediction of cerebral small vessel disease.

Classification and Treatment of Diseases in the Age of Genome Medicine Based on Pathway Pathology.

The focus of pathology as a biomedical discipline is the identification of the pathomechanisms of diseases and the integration of this knowledge into routine diagnosis and classification. Standard tools are macroscopic and microscopic analysis complemented by immunohistochemistry and molecular pathology. So far, classification has been based on the paradigm of cellular pathology established by Rudolf Virchow and others more than 150 years ago, stating that diseases originate from diseased cells. This dogma is meanwhile challenged by the fact that cells can be fully reprogrammed. Many diseases are nowadays considered to originate from undifferentiated stem cells, induced into a diseased state by genetic or epigenetic alterations. In addition, the completion of the Human Genome Project, with the identification of more than 20.000 genes and a much higher number of gene variants and mutations, led to the concept that diseases are dominated by genetics/epigenetics rather than cells of origin. The axiom of cellular pathology, however, still holds true, as cells are the smallest animate units from which diseases originate. Medical doctors and researchers nowadays have to deal with a tremendous amount of data. The International Classification of Diseases will expand from 14.400 entities/codes in ICD-10 to more than 55.000 in ICD-11. In addition, large datasets generated by "genomics", e.g., whole-genome sequencing, expression profiling or methylome analysis, are meanwhile not only applied in research but also introduced into clinical settings. It constitutes a major task to incorporate all the data into routine medical work. Pathway pathology may help solve this problem. It is based on the realization that diseases are characterized by three essential components: (i) cells of origin/cellular context and (ii) the alteration of cellular as well as (iii) molecular/signal transduction pathways. The concept is illustrated by elaborating on two key cellular pathways, i.e., the cellular senescence of normal cells and the immortality of cancer cells, and by contrasting single cell/single pathway diseases, such as mycoplasma and coughing pneumonia, with complex diseases such as cancer, with multiple cell types as well as multiple affected cellular and signaling pathways. Importantly, the concept of pathway pathology is not just intended to classify disease, but also to conceive new treatment modalities. This article is dedicated to Dr. Leonard Hayflick, who made basic discoveries in pathway pathology not only by identifying cells causing disease (Mycoplasma pneumoniae) and establishing cell strains for treating disease (WI-38 for viral vaccines), but also by first describing cellular senescence and immortality.

[Rudolf Virchow's life path of as a reflection of the development of medicine in the 19th century (on the occasion of 200th birth anniversary)]. / Zhiznennyi put' Rudol'fa Virkhova kak otrazhenie razvitiya meditsiny XIX veka (k 200-letiyu so dnya rozhdeniya).

The article describes the life path of Rudolf Virchow (1821-1902), an outstanding German pathologist, one of the founders of scientific medicine, the creator of the scientific system known as cellular pathology, the author of numerous works on general biology, anthropology, ethnography, and archaeology. It assesses the contribution of the scientist to the development of science and culture in the nineteenth century. A relationship is shown between the formation of a modern scientific approach in medical sciences and the multifaceted activities of Rudolf Virchow.