Prevention, diagnosis and clinical management of hereditary breast cancer beyond BRCA1/2 genes.

The detection of germline pathogenic variants (gPVs) in BRCA1/2 and other breast cancer (BC) genes is rising exponentially thanks to the advent of multi-gene panel testing. This promising technology, coupled with the availability of specific therapies for BC BRCA-related, has increased the number of patients eligible for genetic testing. Implementing multi-gene panel testing for hereditary BC screening holds promise to maximise benefits for patients at hereditary risk of BC. These benefits range from prevention programs to antineoplastic-targeted therapies. However, the clinical management of these patients is complex and requires guidelines based on recent evidence. Furthermore, applying multi-gene panel testing into clinical practice increases the detection of variants of uncertain significance (VUSs). This augments the complexity of patients' clinical management, becoming an unmet need for medical oncologists. This review aims to collect updated evidence on the most common BC-related genes besides BRCA1/2, from their biological role in BC development to their potential impact in tailoring prevention and treatment strategies.

Cancer genetic counselling for hereditary breast cancer in the era of precision oncology.

A relevant percentage of breast cancers (BCs) are tied to pathogenetic (P)/likely pathogenetic (LP) variants in predisposing genes. The knowledge of P/LP variants is an essential element in the management of BC patients since the first diagnosis because it influences surgery and subsequent oncological treatments and follow-up. Moreover, patients with metastatic BCs can benefit from personalized treatment if carriers of P/LP in BRCA1/2 genes. Multigene panels allow the identification of other predisposing genes with an impact on management. Cascade genetic testing for healthy family members allows personalized preventive strategies. Here, we review the advances and the challenges of Cancer Genetic Counseling (CGC). We focus on the area of oncology directed to hereditary BC management describing the peculiar way to lead CGC and how CGC changes over time. The authors describe the impact of genetic testing by targeted approach or universal approach on the management of BC according to the stage at diagnosis. Moreover, they describe the burden of CGC and testing and future perspectives to widely offer testing. A new perspective is needed for models of service delivery of CGC and testing, beyond formal genetic counselling. A broader genetic test can be quickly usable in clinical practice for comprehensive BC management and personalized prevention in the era of precision oncology.

S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study.

OBJECTIVE: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC. DESIGN: This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy. METHODS: The S-GRAS score was calculated as a sum of the following points: tumour stage (1-2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0-9% = 0; 10-19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0-1, 2-3, 4-5, and 6-9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell's Concordance index (C-index) and Royston-Sauerbrei's R2D statistic. RESULTS: We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0-9) (C-index = 0.73, R2D = 0.30, and C-index = 0.79, R2D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4-5. CONCLUSION: The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

New perspectives for mitotane treatment of adrenocortical carcinoma.

Adrenocortical carcinoma (ACC) is an aggressive cancer characterized by poor survival. Apart from radical surgery, there is a limited range of therapeutic options and mitotane remains the cornerstone of medical treatment of ACC in either adjuvant or palliative settings. The aim of adjuvant mitotane therapy is to reduce the risk of ACC recurrence following surgical removal of the tumor. Use of mitotane in an adjuvant setting is off-label, but the recent guidelines endorsed by the European Society of Endocrinology (ESE) and the European Network for the Study of Adrenal Tumors (ENSAT) recommend it in ACC patients at high risk of recurrence. The palliative use of mitotane for treatment of advanced ACC aims at controlling tumor progression and, when present, hormone secretion. In this clinical setting, mitotane is used in association with chemotherapy to treat the more aggressive forms, while mitotane monotherapy is reserved for less progressive ACC. Many years after its introduction in clinical practice, there are still uncertainties surrounding the use of this old drug and the derived benefits. Moreover, physicians who use mitotane should recognize and manage the systemic effects of the drug that need a complex supporting therapy.

Adjuvant mitotane therapy is beneficial in non-metastatic adrenocortical carcinoma at high risk of recurrence.

Objective Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment. Design and methods We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I-II vs stage III), hormone secretion (yes vs no) and Ki67 index. Results The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58-4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02). Conclusions Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.

Global Longitudinal Strain in master athletes and in hypertensive patients with the same degree of septal thickness.

Athletes may have electrocardiogram (ECG) repolarization abnormalities during stress test suggestive for ischemia in the absence of ischemic coronary artery disease, often in a setting of myocardial septum hypertrophy. Global longitudinal strain (GLS) might be altered in these athletes compared to hypertensive patients with the same degree of septal thickness. About 735 consecutive athletes were screened for mandatory assessment of fitness to participate in competitive sports. At the stress test, 23 (19 M, 4 F) were found to have ECG repolarization abnormalities suggestive for ischemia in the presence of normal coronary vessels. They were matched to a control group of 23 hypertensive patients with no ECG abnormalities during stress test and the same degree of septal thickness. A transthoracic echocardiography for evaluation of global longitudinal strain (GLS) was performed. Interventricular septum thickness (IST) and relative wall thickness (RWT) were also calculated. A preserved ventricular function was seen in both groups (64 ± 8% in cases vs 60 ± 6% in controls, P = 0.42). IST and RWT were not significantly different. GLS was significantly lower in athletes vs hypertensive patients (-18.7 ± 2.5 vs -21.67 ± 0.27, P = 0.001). In athletes with septal hypertrophy and a positive stress test not associated to coronary disease, GLS is lower with respect to a population of hypertensive patient with the same degree of septal hypertrophy. Further investigations in a larger population are required to better define the potentiality of GLS in differentiating pathological vs physiological septum hypertrophy.

Effects of periodontal therapy on glucose management in people with diabetes mellitus.

AIM: The primary aim of this study was to examine the effects of intensive periodontal therapy on HbA(1c) in a mixed diabetes mellitus (DM) (types 1 and 2) population with moderate periodontitis (PD). METHODS: A total of 93 subjects with PD and DM, recruited from referrals to the Department of Endocrinology at the Perugia Hospital, were included in a follow-up cohort clinical study comprising two parallel periodontal therapy groups-one receiving intensive periodontal therapy (IPT, n=44) and the other serving as controls (CPT, n=49)-with an 8-month follow-up. Clinical periodontal examinations and blood samples were collected 4 and 8 months after the completion of therapy. RESULTS: The IPT group presented with greater reductions of all periodontal indices compared with the CPT group at both follow-ups (P<0.001). Whereas, after 4 months, there were no major differences in HbA(1c) levels between groups, after 8 months, the IPT group presented with a 0.57% (95% CI: 0.12 to 1.09) greater reduction in HbA(1c) than the CPT group (P=0.03). This reduction was independent of age, gender, smoking and body mass index. However, the difference in HbA(1c) was greater in individuals with type 2 DM (0.95% reduction, 95% CI: 0.32 to 1.58; P=0.004) compared with those with type 1 DM. CONCLUSION: IPT resulted in greater improvement of gingival health in patients with DM. Improved oral health in those with type 2 DM may have an effect on medium-term glucose management and could possibly lead to long-term health benefits. (ISRCTN00559156).

Extrusion and infection incidence in scleral buckling surgery with the use of silicone sponge: to soak or not to soak? An 11-year retrospective analysis.

PURPOSE: To assess the incidence of extrusion and infections of encircling silicone sponges in scleral buckling surgery for retinal detachment with and without the use of an intraoperative antibiotic soaking procedure. METHODS: The authors performed a retrospective analysis reviewing the charts of 1127 patients who underwent episcleral buckling surgery operated by the same surgeon in three different institutions during a period of 11 years. The authors reviewed the charts of patients treated with a single episcleral silicone sponge (Labtician) indentation in three different models. The infection prophylaxis on the operating field was the same in all cases and only since February 1997 was the silicone sponge preoperatively treated with an antibiotic soaking procedure. RESULTS: No immediate postoperative infections were reported in the operated eyes. Three eyes had an implant extrusion and in all these cases silicone sponge removal was performed. All three extrusion cases developed when sponge soaking was not adopted. CONCLUSIONS: The data indicate that the soaking procedure does not decrease extrusion and infection incidence in scleral buckling surgery when both accurate surgical technique and disinfection prophylaxis are performed.

Brain volume measurements in patients with human T-cell lymphotropic virus-1-associated tropical spastic paraparesis.

Human T-cell lymphotropic virus (HTLV)-1 is associated with a chronic progressive neurologic disease known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) that affects 0.2% to 3% of HTLV-1-infected people. The authors aimed at exploring, in vivo, whether brain volume reduction occurs in patients with HAM/TSP through the use of magnetic resonance imaging (MRI). T1 pre/postcontrast spin echo-weighted images (WIs) and T2WIs of the brain were obtained in 19 HAM/TSP patients and 14 age-and sex-matched healthy volunteers. Both patients and healthy individuals were imaged at a 1.5-Tesla magnet by employing a conventional head coil. Focal T1 and T2 abnormalities were calculated and two measurements of brain parenchyma fraction (BPF) were obtained by using SIENAx (Structural Image Evaluation,using Normalisation, of Atrophy; University of Oxford, Oxford, UK) and MIPAV (Medical Image Processing, Analysis, and Visualization; National Institutes of Health, Bethesda, USA) from T1WIs. No significant differences in BPF were found between patients and healthy subjects when using either SIENAx or MIPAV. Analysis of individual patients detected that BPF was lower by 1 standard deviation (SD) relative to patients' average BPF in one patient. The authors conclude that reductions in BPF do not occur frequently in patients with HAM/TSP. However, the authors believe that one individual case of significant brain atrophy raises the question as to whether atrophy selectively targets the spinal cord of HAM/TSP patients or may involve the brain as well. A larger patient population analyzing regional brain volume changes could be helpful in determining whether brain atrophy is a marker of disease in patients with HAM/TSP.

Sarcoma del estroma endometrial de bajo grado. Caso clínico de presentación polipoide / Low Grade Endometrial Stromal Sarcoma. Polypoid Form Case Presentation

Se expone en este artículo el caso de una paciente de 44 años con episodios esporádicos de sangrados genitales. la ecografía informó útero aumentado de tamaño con múltiples miomas y un pólipo endometrial. La citología histerectomía total simple en febrero de 2004. Se efectuó el diagnóstico microscópico del pólipo SEEBG polipoide con infiltración miometrial incipiente

Pyrolysis process for the treatment of scrap tyres: preliminary experimental results.

The aim of this work is the evaluation, on a pilot scale, of scrap tyre pyrolysis process performance and the characteristics of the products under different process parameters, such as temperature, residence time, pressure, etc. In this frame, a series of tests were carried out at varying process temperatures between 550 and 680 degrees C, other parameters being equal. Pyrolysis plant process data are collected by an acquisition system; scrap tyre samples used for the treatment, solid and liquid by-products and produced syngas were analysed through both on-line monitoring (for gas) and laboratory analyses. Results show that process temperature, in the explored range, does not seem to seriously influence the volatilisation reaction yield, at least from a quantitative point of view, while it observably influences the distribution of the volatile fraction (liquid and gas) and by-products characteristics.

Beta-cell crosstalk: a further dimension in the stimulus-secretion coupling of glucose-induced insulin release.

Pancreatic beta-cells are connected by gap junction channels made of a connexin protein, referred to as Cx36. Through these channels, beta-cells are coupled to each other, i.e. exchange cytoplasmic ions and small metabolites. Previous experiments have indicated that these exchanges are important for coordinating the function of individual cells within pancreatic islets, particularly with regard to glucose-induced insulin secretion. Advances in molecular biology, genetics and mouse transgenic approaches allow now for a direct experimental testing of this mechanism in vitro as well as in vivo. Recent experiments in rodent and culture models suggest that connexin-dependent cell-to-cell crosstalk is a significant player in the multifactorial regulation of insulin secretion and, possibly, of other beta-cell functions, such as growth. Elucidating the still obscure mechanism whereby connexin signalling exerts this influence will provide insights on the contribution of direct cell-to-cell interactions in the physiological regulation of beta-cell life. The presence of Cx36 within human pancreatic islets, raises the further challenge to determine whether a dysfunction of connexin signaling may contribute to the pathophysiology of beta-cell dysfunctions in type I and/or type II diabetes. Efforts to understand the functions of beta-cell connexins are also a prerequisite for the engineering of surrogate cells and their proper tridimensional packaging, which are instrumental for the future implementation of a replacement cell therapy in diabetic patients.

Medication administration errors in adult patients in the ICU.

OBJECTIVE: To quantify the incidence and specify the types of medication administration errors from a list of error-prone medications and to determine if patient harm resulted from these errors. DESIGN: An observational evaluation. SETTING: Five intensive care units (ICUs) in the United States. PATIENTS AND PARTICIPANTS: Eight hundred fifty-one patients who were at least 18 years of age and admitted to surgical, medical or mixed ICUs during a 3 month period were included. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: A list of error-prone medications was adapted from the literature and evaluated for medication errors and patient harm. Of 5,744 observations in 851 patients, 187 (3.3%) medication administration errors were detected. the therapeutic classes most commonly associated with errors were vasoactive drugs 61 (32.6%) and sedative/analgesics 48 (25.7%). The most common type of error was wrong infusion rate with 71 (40.1%) errors. Twenty-one errors did not reach the patient and 159 reached the patient but did not result in harm, increased monitoring or intervention. Five errors required increased patient monitoring and two required intervention. None of the errors resulted in patient death. CONCLUSIONS: This multicenter evaluation found fewer medication administration errors than the published literature, possibly due to the varying observational techniques and pharmacist involvement. Lorazepam and wrong infusion rates are associated with errors that occurred frequently, resulted in the greatest potential for harm and were common oversights in the system. These errors should be considered potential areas for betterment in the medication use process to improve patient safety.

Cx36 and the function of endocrine pancreas.

The secretory, duct, connective and vascular cells of pancreas are connected by gap junctions, made of different connexins. The insulin-producing beta-cells, which form the bulk of endocrine pancreatic islets, express predominantly Cx36. To assess the function of this connexin, we have first studied its expression in rats, during sequential changes of pancreatic function which were induced by the implantation of a secreting insulinoma. We observed that changes in beta-cell function were paralleled by changes in Cx36 expression. We have also begun to investigate mutant mice lacking Cx36. The absence of this protein did not affect the development and differentiation of beta-cells but appeared to alter their secretion. We have studied this effect in MIN6 cells which spontaneously express Cx36. After stable transfection of a construct that markedly reduced the expression of this connexin, we observed that MIN6 cells were no more able to secrete insulin, in contrast to wild type controls, and differentially displayed a series of still unknown genes. The data provide evidence that Cx36-dependent signaling contributes to regulate the function of native and tumoral insulin-producing cells.

Junctional communication of pancreatic beta cells contributes to the control of insulin secretion and glucose tolerance.

Proper insulin secretion requires the coordinated functioning of the numerous beta cells that form pancreatic islets. This coordination depends on a network of communication mechanisms whereby beta cells interact with extracellular signals and adjacent cells via connexin channels. To assess whether connexin-dependent communication plays a role in vivo, we have developed transgenic mice in which connexin 32 (Cx32), one of the vertebrate connexins found in the pancreas, is expressed in beta cells. We show that the altered beta-cell coupling that results from this expression causes reduced insulin secretion in response to physiologically relevant concentrations of glucose and abnormal tolerance to the sugar. These alterations were observed in spite of normal numbers of islets, increased insulin content, and preserved secretory response to glucose by individual beta cells. Moreover, glucose-stimulated islets showed improved electrical synchronization of these cells and increased cytosolic levels of Ca(2+). The results show that connexins contribute to the control of beta cells in vivo and that their excess is detrimental for insulin secretion.

Intercellular Ca2+ waves in mechanically stimulated articular chondrocytes.

Articular cartilage is a tissue designed to withstand compression during joint movement and, in vivo, is subjected to a wide range of mechanical loading forces. Mechanosensitivity has been demonstrated to influence chondrocyte metabolism and cartilage homeostasis, but the mechanisms underlying mechanotransduction in these cells are poorly understood. In many cell types mechanical stimulation induces increases of the cytosolic Ca2+ concentration that propagates from cell to cell as an intercellular Ca2+ wave. Cell-to-cell communication through gap junctions underlies tissue co-ordination of metabolism and sensitivity to extracellular stimuli: gap junctional permeability to intracellular second messengers allows signal transduction pathways to be shared among several cells, ultimately resulting in co-ordinated tissue responses. Mechanically-induced Ca2+ signalling was investigated with digital fluorescence video imaging in primary cultures of rabbit articular chondrocytes. Mechanical stimulation of a single cell, obtained by briefly distorting the plasmamembrane with a micropipette, induced a wave of increased Ca2+ that was communicated to surrounding cells. Intercellular Ca2+ spreading was inhibited by 18 alpha-glycyrrhetinic acid, suggesting the involvement of gap junctions in signal propagation. The functional expression of gap junctions was assessed, in confluent chondrocyte cultures, by the intercellular transfer of Lucifer yellow dye in microinjection experiments while the expression of connexin 43 could be detected in Western blots. A series of pharmacological tools known to interfere with the cell calcium handling capacity were employed to investigate the mechanism of mechanically-induced Ca2+ signalling. In the absence of extracellular Ca2+ mechanical stimulation induced communicated Ca2+ waves similar to controls. Mechanical stress induced Ca2+ influx both in the stimulated chondrocyte but not in the adjacent cells, as assessed by the Mn2+ quenching technique. Cells treatment with thapsigargin and with the phospholipase C inhibitor U73122 blocked mechanically-induced signal propagation. These results provide evidence that in chondrocytes mechanical stimulation activates phospholipase C, thus leading to an increase of intracellular inositol 1,4,5-trisphosphate. The second messenger, by permeating gap junctions, stimulates intracellular Ca2+ release in neighbouring cells. Intercellular Ca2+ waves may provide a mechanism to co-ordinate tissue responses in cartilage physiology.

Estuarine and habitat-related differences in growth rates of young-of-the-year winter flounder (Pseudopleuronectes americanus) and tautog (Tautoga onitis) in three northeastern US estuaries.

Instantaneous growth rates of young-of-the-year winter flounder Pseudopleuronectes americanus (Walbaum) (12.0-60.4 mm standard length, SL) and tautog Tautoga onitis (Linnaeus) (21.4-73.8 mm total length, TL) from three estuarine systems in New Jersey (Great Bay-Little Egg Harbor and Navesink River) and Connecticut (Hammonasset River) were used in an attempt to assess the relative quality of selected nominal habitats. A series of short-term field caging experiments were conducted during 1994 and 1995 in: macroalgae (primarily, Ulva lactuca), eelgrass (Zostera marina), unvegetated areas adjacent to macroalgae and eelgrass and tidal creeks in Spartina dominated marsh. Growth rates varied with habitat, estuary and year. Comparisons across nominal habitats within and among estuaries did not show any one habitat with consistently higher growth, and growth was relatively independent of whether a habitat was vegetated or adjacent to vegetation. The growth rates of winter flounder and tautog from the Hammonasset River were not different among habitats in either year of the study. In the Great Bay-Little Egg Harbor, both winter flounder and tautog had higher growth rates in macroalgae with growth in eelgrass varying significantly between years. Conversely, in the Navesink River both species had higher growth rates in eelgrass. Environmental changes associated with temperature and dissolved oxygen appeared to influence growth rates. Winter flounder growth rate and survival was depressed in tidal marsh creeks in the three estuaries and in vegetated macroalgae habitats in the Navesink River where dissolved oxygen levels were often very low (<2 mgl(-1)) for extended periods. In summary, the growth rates of the young-of-the-year of these two species varied temporally and were dependent on the interaction of both the specific estuary and habitat in which the experiments took place. Further, habitat quality, as defined by relative growth rate, was difficult to evaluate because it can be variable and nominal habitat designations are often not sufficient to define the boundaries of a species habitat requirements.

Syllabic constraints in the phonological errors of an aphasic patient.

The Sonority Dispersion Principle (Clements, 1990) states that the sharper the rise in sonority between the beginning of the syllable and the nucleus, the better the syllable. So far evidence in favour of this principle has been derived mainly from the distributional properties of syllable types and, to a lesser extent, from language acquisition. The case of DB, presented in this study, provides strong evidence that the Sonority Dispersion Principle also applies to an explanation of aphasic errors and revives Jakobson's idea that the same principles of complexity can explain the distribution of syllables, language acquisition, and language loss (Jakobson, 1941, 1968). Although some evidence that sonority constraints aphasic errors has been presented before, this is the first study reporting systematic effects of sonority-based complexity in aphasia.

Mechanism of mechanically induced intercellular calcium waves in rabbit articular chondrocytes and in HIG-82 synovial cells.

Intercellular communication through gap junctions allows tissue coordination of cell metabolism and sensitivity to extracellular stimuli. Intercellular Ca2+ signaling was investigated with digital fluorescence video imaging in primary cultures of articular chondrocytes and in HIG-82 synovial cells. In both cell types, mechanical stimulation of a single cell induced a wave of increased Ca2+ that was communicated to surrounding cells. Intercellular Ca2+ spreading was inhibited by 18alpha-glycyrrhetinic acid, demonstrating the involvement of gap junctions in signal propagation. In the absence of extracellular Ca2+, mechanical stimulation induced communicated Ca2+ waves similar to controls; however, the number of HIG-82 cells recruited decreased significantly. Mechanical stress induced Ca2+ influx both in the stimulated chondrocyte and HIG-82 cell, but not in the adjacent cells, as assessed by the Mn2+ quenching technique. Treatment of cells with thapsigargin and with the phospholipase C (PLC) inhibitor U73122 blocked mechanically induced signal propagation. These results provide evidence that in chondrocytes and in HIG-82 synovial cells, mechanical stimulation activates PLC, thus leading to an increase of intracellular inositol 1,4,5-trisphosphate. The second messenger, by permeating gap junctions, stimulates intracellular Ca2+ release in neighboring cells. It is concluded that intercellular Ca2+ waves may provide a mechanism to coordinate tissue responses in joint physiology.

Intercellular calcium signalling between chondrocytes and synovial cells in co-culture.

Intercellular communication allows the co-ordination of cell metabolism between tissues as well as sensitivity to extracellular stimuli. Paracrine stimulation and cell-to-cell coupling through gap junctions induce the formation of complex cellular networks that favour the intercellular exchange of nutrients and second messengers. Heterologous intercellular communication was studied in co-cultures of articular chondrocytes and HIG-82 synovial cells by measuring mechanically induced cytosolic changes in Ca2+ ion levels by digital fluorescence video imaging. In confluent co-cultures, mechanical stimulation induced intercellular Ca2+ waves that propagated to both cell types with similar kinetics. Intercellular wave spreading was inhibited by 18alpha-glycyrrhetinic acid and by treatments inhibiting the activation of purinoreceptors, suggesting that intercellular signalling between these two cell types occurs both through gap junctions and ATP-mediated paracrine stimulation. In rheumatoid arthritis the formation of the synovial pannus induces structural changes at the chondrosynovial junction, where chondrocyte and synovial cells come into close apposition: these results provide the first evidence for direct intercellular communication between these two cell types.