Claudio Tana

Pain thresholds in women with chronic pelvic pain.

Purpose of review To update on the latest developments in sensory changes of female patients with chronic pelvic pain (CPP). CPP is very common, but its pathophysiology is still controversial. Evaluation of pain sensitivity in painful and nonpainful areas is key to understanding the underlying peripheral vs. central contributions to the symptom. This in turn is fundamental to improving the treatment strategies. Recent findings We reviewed the experimental studies published over the last year on pain thresholds to different stimuli measured at both the somatic and visceral level in women with different forms of recurrent or CPP. The majority of the studies indicate a pain threshold decrease to most stimuli in skin, subcutis and muscle in painful pelvic areas, the site of referred pain from pelvic viscera, as well as a decreased pain threshold in most viscera (colon and urinary bladder). A significant threshold decrease is also found in deep somatic tissues (subcutis and muscle) outside the painful zone in the most severe cases, indicating a state of central sensitization. Summary These findings have important implications for clinical practice: pain threshold measurement in both painful and nonpainful sites could have important predictive value of the clinical evolution and response to therapy of CPP.

New insights into the cardiovascular risk of migraine and the role of white matter hyperintensities: is gold all that glitters?

The role of migraine as an independent risk factor for cardiovascular events has been debated for several years, while it is more established for ischemic stroke. Recently, new studies have examined the likelihood of migraine to determine cardiovascular events, supporting the hypothesis of a predominant role in patients with migraine with aura, the risk including both sexes. In the literature, multiple pathophysiological mechanisms are described to explain this association, and are here discussed. Furthermore, the emerging evidence that a higher headache frequency and long-term migraine may worsen the cardio-metabolic profile in migraineurs (e.g. with a higher Framingham risk score and risk of developing atherosclerosis, insulin resistance and metabolic syndrome) makes it increasingly necessary to reduce the number and severity of attacks, not only to alleviate the painful symptoms, but also to improve the prognosis in these patients.

Sarcoidosis vs. Sarcoid-like reactions: The Two Sides of the same Coin?

SummaryDifferentiating between sarcoidosis as an autonomous disease and sarcoid-like reactions requires considerable efforts. The epithelioid cell granuloma is not equivalent to sarcoidosis because it may be identified in a number of infectious and noninfectious disorders, including neoplastic diseases. At the current state of knowledge, accurate distinction between different causes of epithelioid cell granulomas is in many cases not possible. Despite being characteristic of sarcoidosis and sarcoid-like reactions, the epithelioid cell granuloma is not their synonym, as numerous other causes can give rise to such a type of granulomatous infiltrate. Its etiology should be sought through careful additional investigations, including the genetic signature of both conditions.Sarcoid-like reactions may be grouped generally into several subtypes. The differentiation between each one of them requires a certain combination of diagnostic tests. The major objective of these tests is to exclude or to prove the presence of an infectious, tumoral, or immunogenic antigen on the one hand, and to characterize the genetic profile of the affected patients (for example, sarcoidosis-specific genes) on the other. Only thus may one accurately differentiate between the two pathologic conditions described earlier in the abstract.The clear differentiation between sarcoidosis as a separate disease and sarcoid-like pathologies leads to the more precise clarification of the final diagnosis, which may in turn allow for a more appropriate therapy and improvement in the quality of life of the patients. Equating sarcoid granulomas with sarcoidosis can lead to serious consequences in a number of patients. Sadly enough, after scrutinizing the current available data in the world literature, one cannot find criteria to allow such distinction in a high percentage of the investigated cases.This critical review provides a completely new pathogenetic and diagnostic algorithm, helping in the differentiation between the disease sarcoidosis and the sarcoid-like pathologies with different etiology. An update on the inclusion criteria from the ATS/ERS/WASOG (American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders) statement (which at the current state of knowledge seems to be ineffective) for the diagnosis of sarcoidosis is also suggested.In conclusion, molecular mimicry may be seen as the main pathogenic generator not only of sarcoidosis but also of sarcoid-like reactions. A completely new and exact definition of the notion of or the sarcoidosis disease itself will be possible only after 1.defining the genetic risk for the development of sarcoidosis as an autonomous disease and supplementing the sarcoidosis consensus of ATS/ERS/WASOG from 1999 with this important information, and2.defining the notion of a sarcoid-like reaction and its subforms.ZusammenfassungDie Unterscheidung von Sarkoidose als eigenständiger Erkrankung und sarkoidaler Reaktion erfordert erhebliche Anstrengungen. Der Nachweis epitheloidzelliger Granulome ist nicht der Diagnose einer Sarkoidose gleichzusetzen, da diese bei einer Vielzahl von infektiösen und nicht infektiösen Erkrankungen, einschließlich der Tumore, auftreten können. Mit unserem derzeitigen Wissensstand ist die exakte Differenzierung bezüglich ihrer Ursachen aus nicht immer möglich. Obwohl die epitheloidzelligen Granulome charakteristisch für Sarkoidose und sarkoidale Reaktionen sind, können zahlreiche andere Ursachen für ihre Entstehung verantwortlich sein. Ihre Ätiologie sollte durch sorgfältige zusätzliche Untersuchungen einschließlich der genetischen Signatur beider Erkrankungen geklärt werden.Sarkoidale Reaktionen können in verschiedene Subtypen klassifiziert werden. Deren Unterscheidung bedarf einer gewissen Kombination der Untersuchungsverfahren. Hauptanliegen dieser Untersuchungen ist die Verifizierung bzw. der Ausschluß infektiöser, tumoraler oder immunogener Antigene einerseits und die Beschreibung des genetischen Profils des betroffenen Patienten (z.B. sarkoidose-spezifische Gene) andererseits. Nur hierdurch wird eine exakte Differenzierung beider Pathologien (Sarkoidose, sarkoidal) möglich.Die eindeutige Differenzierung von Sarkoidose und sarkoidaler Reaktion als verschiedene Erkrankungen erlaubt eine präzisere Diagnose, eine zielgerichtetere Behandlung und die Verbesserung der Lebensqualität der Patienten. Umgekehrt kann die Nichtbeachtung dieses Grundsatzes zu ernsten Konsequenzen für betroffene Patienten führen. Leider ist bietet die wissenschaftliche Weltliteratur bislang keine Kriterien, die eine klare Unterscheidung beider Pathologien bei einem hohen Prozentsatz der Patienten erlaubt.Diese kritische Übersicht entwickelt einen komplett neuen pathogenetischen und diagnostischen Algorithmus zur Differenzierung von Sarkoidose und sarkoidaler Reaktion verschiedener Ätiologien. Ein Update der Einschlußkriterien der ATS/ERS/WASOG (American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders) für die Sarkoidose-Diagnose wird ebenfalls vorgeschlagen.Schlußfolgerungen: Molekulare Mimikry kann als wesentlicher Motor nicht allein für die Sarkoidose, sondern auch die sarkoidale Reaktion angesehen werden. Eine komplett neue und exakte Definition der Diagnose Sarkoidose wird nur dann möglich werden, wenn: 1.Das genetische Risiko der Sarkoidoseentwicklung bestimmt und der Konsensus der ATS/ERS/WASOG von 1999 implementiert wird.2.Die sarkoidale Reaktion und ihre Subtypen bestimmt werden.

microRNA profiling in atherosclerosis, diabetes, and migraine

Abstract microRNAs (miRNAs) are a broad group of endogenous small non-coding molecules that reduce the transcription of mRNA and play a key role in post-transcriptional gene processes. miRNAs are involved in onset and progression of several human disorders such as infectious and immune non-infectious diseases, cancers, metabolic and cardiovascular disorders. They regulate the expression of gene targets (e.g. oncogenes and tumor suppressor genes) and act as gene repressors with mRNA binding and cleavage. The increasing evidence that miRNAs play a key role in the pathogenesis of cardiovascular conditions could radically change the future management approach to these disorders. This review focuses on current knowledge about the influence of miRNAs on cardiovascular disease, with particular regard to common conditions such as atherosclerosis, diabetes and migraine. Key messages miRNAs are a group of endogenous small non-coding RNA segments measuring 19–25 nucleotides that are involved in physiologic processes and onset and progression of disorders such as infectious and immune non-infectious diseases, cancers, metabolic and cardiovascular disorders. miRNAs expression guarantees vascular integrity, by regulating apoptosis, VEGF pathway and VCAM 1 expression (−126), and is involved in atherosclerotic plaque formation process and progression. Hyperglycemia, overt diabetes, and their complications are associated with overexpression of several miRNAs. An altered expression of miRNAs has also been postulated in migraine patients, although only a few preliminary studies have so far been performed with this respect.

Correlation between Migraine Severity and Cholesterol Levels

Several studies have documented increased cardiovascular risk factors, particularly hypercholesterolemia, in the migraine population with respect to controls. However, no studies have investigated the possible relationship between headache severity parameters and lipid serum levels.

Immunopathogenesis of sarcoidosis and risk of malignancy: a lost truth?

The hypothesis of a relationship between sarcoidosis and malignancy was firstly formulated in 1972 by Brincker. He documented an association of sarcoid reactions or sarcoidosis with 19 lymphomas and associated malignancies. Based on various epidemiological studies, for more than 20 years sarcoidosis has been considered as a condition at increased risk for cancer, particularly lymphoproliferative disorders. The existence of a sarcoidosis-lymphoma syndrome was therefore proposed, highlighting, as a potential mechanism, the uncontrolled lymphocyte proliferation and mitotic activity. A reduced ability to eliminate an antigen and chronic inflammation have been suggested as triggering events. Leading to a reduced tumor immune surveillance, a diminished myeloid dendritic cells (mDC) function, despite up-regulated co-stimulatory and maturation markers, was also raised as potential mechanism. However, some subsequent studies have questioned the presence of a close association between the two entities and have explained those previously published as the result of selection bias and misclassification. Recently, a Swedish population-based cohort study documented a significant overall excess incidence of cancer among sarcoidosis patients, especially those with multiple hospitalizations or admission in older age, emphasizing again a potential neoplastic risk. Therefore, currently, whether these patients have an increased risk of developing malignant lesions is still debated. Larger and unbiased studies are needed before drawing definite conclusions.

Advantages and Limitations of Focal Liver Lesion Assessment with Ultrasound Contrast Agents: Comments on the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) Guidelines

Contrast-enhanced ultrasound (CEUS) represents a significant breakthrough in sonography. Due to US contrast agents (UCAs) and contrast-specific techniques, sonography offers the potential to show enhancement of liver lesions in a similar way as contrast-enhanced cross-sectional imaging techniques. The real-time assessment of liver perfusion throughout the vascular phases, without any risk of nephrotoxicity, represents one of the major advantages that this technique offers. CEUS has led to a dramatic improvement in the diagnostic accuracy of US and subsequently has been included in current guidelines as an important step in the diagnostic workup of focal liver lesions (FLLs), resulting in a better patient management and cost-effective therapy. The purpose of this review was to provide a detailed description of contrast agents used in different cross-sectional imaging procedures for the study of FLLs, focusing on characteristics, indications and advantages of UCAs in clinical practice.

Aging Gut Microbiota at the Cross-Road between Nutrition, Physical Frailty, and Sarcopenia: Is There a Gut–Muscle Axis?

Inadequate nutrition and physical inactivity are the mainstays of primary sarcopenia–physiopathology in older individuals. Gut microbiota composition is strongly dependent on both of these elements, and conversely, can also influence the host physiology by modulating systemic inflammation, anabolism, insulin sensitivity, and energy production. The bacterial metabolism of nutrients theoretically influences skeletal muscle cell functionality through producing mediators that drive all of these systemic effects. In this study, we review the scientific literature supporting the concept of the involvement of gut microbiota in primary sarcopenia physiopathology. First, we examine studies associating fecal microbiota alterations with physical frailty, i.e., the loss of muscle performance and normal muscle mass. Then, we consider studies exploring the effects of exercise on gut microbiota composition. Finally, we examine studies demonstrating the possible effects of mediators produced by gut microbiota on skeletal muscle, and intervention studies considering the effects of prebiotic or probiotic administration on muscle function. Even if there is no evidence of a distinct gut microbiota composition in older sarcopenic patients, we conclude that the literature supports the possible presence of a “gut–muscle axis”, whereby gut microbiota may act as the mediator of the effects of nutrition on muscle cells.

Pitfalls of contrast-enhanced ultrasound (CEUS) in the diagnosis of splenic sarcoidosis.

By observing the real-time behavior of focal liver lesions at three vascular phases (arterial, portal-venous, and late), contrast-enhanced ultrasound (CEUS) has been successfully applied to differentiate benign from malignant hepatic nodules. In recent years, numerous studies highlighted the usefulness of CEUS also for other applications such as abdominal trauma, renal, pancreatic, thyroid, and inflammatory bowel diseases, supporting its role even in differentiating benign from malignant splenic nodules. Therefore, the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) recently updated the guidelines for the use of ultrasound contrast agents in clinical practice, pointing out the indication to characterize splenic parenchymal inhomogeneity or suspected lesions found on conventional ultrasound (BUS). We describe the case of a patient with a history of colon cancer and finding, at BUS and CEUS, of hypoechoic lesions with a highly suggestive pattern for metastases, subsequently histologically proved to be splenic localizations of a benign and multisystemic granulomatous disease such as sarcoidosis. We therefore reviewed the current literature focusing on the role of CEUS in differentiating benign from malignant splenic lesions, emphasizing on the lack of data and numerical shortage of sarcoidosis derived-lesions in the available studies. We conclude that sarcoidosis remains a diagnosis of exclusion and new studies are needed before defining precise indications of CEUS in these patients.RiassuntoL’ecografia con mezzo di contrasto (CEUS) è una metodica diagnostica minimamente invasiva ed ampiamente utilizzata, negli ultimi decenni, per differenziare le lesioni epatiche benigne dalle maligne, valutandone l’aspetto contrastografico nelle tre fasi vascolari (arteriosa, portale-venosa e tardiva). Negli ultimi anni, numerosi studi hanno messo in evidenza ulteriori indicazioni della CEUS, tra cui il trauma addominale, le lesioni focali renali, pancreatiche, tiroidee e le malattie infiammatorie intestinali, supportandone un ruolo anche nella differenziazione tra lesioni spleniche benigne e maligne. Pertanto, la Federazione Europea delle Società di Ultrasonologia in Medicina e Biologia (EFSUMB), ha recentemente aggiornato le linee guida per l’utilizzo dell’ecografia con mezzo di contrasto nella pratica clinica, sottolineando, tra le varie indicazioni, quella di caratterizzare le lesioni spleniche o disomogeneità parenchimali sospette, riscontrate incidentalmente all’esame ecografico convenzionale. Nel seguente articolo descriviamo il caso di una paziente con anamnesi per carcinoma del colon e riscontro, all’esame ecografico convenzionale, di lesioni ipoecogene di non univoca interpetazione e caratterizzate, alla CEUS, da un pattern contrastografico altamente suggestivo per metastasi. Tali lesioni si sono poi rivelate essere, all’esame istologico, localizzazioni di una malattia benigna, multisistemica e granulomatosa quale la sarcoidosi. Abbiamo pertanto effettuato una revisione approfondita della letteratura focalizzando sul ruolo della CEUS nel differenziare le lesioni spleniche benigne dalle maligne, enfatizzando sulla carenza di studi riguardanti la caratterizzazione, attraverso la CEUS, delle lesioni derivate dalla sarcoidosi. Tale malattia rimane, pertanto, una diagnosi di esclusione e sono necessari ulteriori studi prima di definire precise indicazioni della CEUS nei pazienti affetti.

The "mystery" of cutaneous sarcoidosis: facts and controversies.

The reason why the cutaneous form of sarcoidosis is well known in the literature is because of its spectrum of manifestations granting it the fame of a Great Imitator. The mystery shrouding the pathogenesis of this rare cutaneous disease is still there (in spite of the fundamental progress of the various diagnostic methods in current day medicine). The production of the morphological substrate – the epithelioid cell granuloma – which is considered to be characteristic of skin sarcoidosis, could, however, also be the end result of a reaction to i) various specific infectious agents such as Leishmaniasis cutis, coccidioidomycosis, etc., ii) certain residual bacterial or other mycobacterial antigens which, at the moment of setting the diagnosis are - by definition - non-infectious but still immunogenic, as well as iii) different tumor antigens in lesional tissue or other location. Often, differentiating between sarcodiosis and a sarcoid-like reaction, based on the updated criteria for cutaneous sarcoidosis, is problematic to downright impossible. A future characterization of the genetic signature of the two conditions, as well as the implementation of additional mandatory panels for i) the identification of certain infectious or ii) non-infectious but immunogenic and iii) tumor antigens in the epithelioid cell granuloma (or in another location in the organism), could be a considerable contribution to the process of differentiating between the two above-mentioned conditions. This will create conditions for greater accuracy when setting the subsequent therapeutic approaches.